Pulmonary Vascular Disease

Cardiol Clin 22 (2004) 353–365 Acute pulmonary embolism Victor F. Tapson, MD Division of Pulmonary and Critical Care Me...

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Cardiol Clin 22 (2004) 353–365

Acute pulmonary embolism Victor F. Tapson, MD Division of Pulmonary and Critical Care Medicine, 353 Bell Building, Duke University Medical Center, Durham, NC 27710, USA

Background and incidence

Pathophysiology

Pulmonary embolism (PE) occurs when venous thrombosis, usually from the deep veins of the proximal legs, travels to the lungs causing a potential spectrum of consequences, including dyspnea, chest pain, hypoxemia, and sometimes death. Deep venous thrombosis (DVT) and PE represent a continuum of the disease entity known as venous thromboembolism (VTE). PE probably accounts for 100,000 to 200,000 deaths per year in the United States [1,2]. Although some patients dying from acute PE have an underlying terminal illness, this disease entity seems to be responsible for death in a considerable number of patients with an otherwise good prognosis. Autopsy studies have repeatedly documented the high frequency with which PE has gone unsuspected and thus undetected [3]. VTE occurs worldwide and is usually, but not always, associated with speciﬁc risk factors [1,4–6]. A crucial point is that DVT and, therefore, PE are often preventable. Although other substances such as malignant cells, fat droplets, air bubbles, and carbon dioxide can embolize to the lung, this article focuses on VTE. Because of the lack of speciﬁc symptoms and signs, DVT and PE are frequently clinically unsuspected, leading to substantial diagnostic and therapeutic delays and resulting in considerable morbidity and mortality [1,2]. Furthermore, prophylaxis continues to be dramatically underused [4,7]. The incidence of VTE is high in hospitalized patients, and both surgical as well as medical patients are at risk.

One or more components of Virchow’s triad (stasis, hypercoagulability, and intimal injury), described more than 150 years ago, are present in nearly all patients [8]. The risk increases with age. Idiopathic VTE is well described and probably involves an underlying prothrombotic state that is present but awaits characterization. Deep vein thrombi frequently originate in the calf veins and propagate proximally before embolizing. Although emboli may occasionally originate directly from calf vein thrombi, more than 95% of thrombi that embolize to the lungs detach from a proximal deep vein of the lower extremities (including and above the popliteal veins). Thrombosis developing in the axillary-subclavian veins caused by the presence of a central venous catheter, particularly in patients with malignant disease and also in those with eﬀort-induced upper extremity thrombosis, may result in PE as well. The impact of a particular embolic event depends on the extent of reduction of the crosssectional area of the pulmonary arterial bed and on the presence or absence of underlying cardiopulmonary disease [9,10]. Hypoxemia stimulates sympathetic tone with resulting systemic vasoconstriction, increased venous return, and a rise in stroke volume. With massive emboli, cardiac output is diminished but may be sustained as the mean right atrial pressure increases. The increase in pulmonary vascular resistance impedes right ventricular outﬂow and thus reduces left ventricular preload. In the absence of underlying cardiopulmonary disease, occlusion of 25% to 30% of the vascular bed by emboli is associated with a rise in pulmonary artery pressure [10]. With further vascular obstruction, hypoxemia worsens, stimulating

Division of Pulmonary and Critical Care Medicine, Box 31175, Duke University Medical Center, Durham, NC 27710. E-mail address: [email protected]

0733-8651/04/$ - see front matter Ó 2004 Elsevier Inc. All rights reserved. doi:10.1016/j.ccl.2004.04.002

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V.F. Tapson / Cardiol Clin 22 (2004) 353–365

vasoconstriction and a further rise in pulmonary artery pressure. More than 50% obstruction of the pulmonary arterial bed is usually present before there is substantial elevation of the mean pulmonary artery pressure. When the extent of obstruction of the pulmonary circulation approaches 75%, the right ventricle must generate a systolic pressure in excess of 50 mm Hg and a mean pulmonary artery pressure greater than 40 mm Hg to preserve pulmonary perfusion. A normal right ventricle is rarely able to meet this demand and, hence, fails. Patients with underlying cardiopulmonary disease often experience a more substantial deterioration in cardiac output than normal individuals in the setting of massive PE. Supportive measures may sustain a patient with massive PE, but additional increments in embolic burden may be fatal.

Clinical manifestations Unfortunately, history and physical examination are notoriously insensitive and nonspeciﬁc for both DVT and PE [11–13]. Patients with lower-extremity venous thrombosis often do not exhibit erythema, warmth, pain, swelling, or tenderness. When these signs are present, they are nonspeciﬁc but may still merit further evaluation. Pain with dorsiﬂexion of the foot (Homans’ sign) may be present in the setting of DVT, but this ﬁnding is neither sensitive nor speciﬁc. The most common symptom of acute PE is dyspnea that is often sudden in onset. Pleuritic chest pain and hemoptysis occur more commonly with pulmonary infarction caused by smaller, peripheral emboli. Palpitations, cough, anxiety, and lightheadedness are among the nonspeciﬁc symptoms of acute PE but may result from a number of other entities, contributing to the diﬃculty in making the diagnosis. Syncope or sudden death may occur with massive PE. Pulmonary embolism should always be considered whenever unexplained dyspnea, syncope, hypotension, or hypoxemia is present [11–13]. Tachypnea and tachycardia are the most common signs of pulmonary embolism but are also nonspeciﬁc. Other physical ﬁndings include fever, wheezing, rales, a pleural rub, a loud pulmonic component of the second heart sound, a right-sided fourth heart sound, and a right ventricular lift. Dyspnea, tachypnea, and hypoxemia in patients with concomitant cardiopulmonary disease (such as congestive heart failure, pneumonia, or chronic obstructive pulmonary disease) may be caused

by the underlying disease or by superimposed acute PE. Symptoms and signs consistent with PE (Tables 1 and 2) should be particularly heeded in patients with risk factors for VTE such as concomitant malignancy, immobility, or the postoperative state. Diagnosis The diﬀerential diagnosis for acute DVT and for PE depends on the clinical presentation and the presence of concomitant disease. For example, when patients present with calf pain or swelling in the setting of risk factors for VTE, a diagnostic study should be pursued unless there is a clear, alternative explanation. For dyspnea or chest pain, the diﬀerential diagnosis includes a ﬂare of asthma or chronic obstructive lung disease, pneumothorax, pneumonia, anxiety with hyperventilation, heart failure, angina or myocardial infarction, musculoskeletal pain, rib fracture, pericarditis, pleuritis from collagen vascular disease, herpes zoster, intrathoracic cancer, and, occasionally, intra-abdominal processes such as acute cholecystitis. The presence of obvious risk factors for VTE, such as prolonged immobility [14], trauma [15–17], recent surgery [18], medical illness with reduced mobility [19], cancer [20,21], pregnancy [22], myocardial infarction [23], recent prolonged travel [24– 26], or previous thromboembolism in the setting of compatible symptoms and signs should prompt consideration of this entity. Acute PE can be superimposed upon another underlying cardiopulmonary disease, on which new or worsening symptoms are sometimes blamed. Table 1 Symptoms of acute pulmonary embolism

Symptom Dyspnea Pleuritic chest pain Cough Leg pain Hemoptysis Palpitations Wheezing Angina like pain

All Patients (n = 383)

Patients without Previous Cardiopulmonary Disease (n = 117)

78%

73%

59% 43% 27% 16% 13% 14%

66% 37% 26% 13% 10% 9%

6%

4%

Data from Refs. [12,13] and Stein PD, editor. Pulmonary embolism. Baltimore (MD): Williams and Wilkins; 1996.

V.F. Tapson / Cardiol Clin 22 (2004) 353–365 Table 2 Signs of acute pulmonary embolism

Tachypnea (20/min) Crackles Tachycardia (>100/min) Leg swelling Loud P2 DVT Wheezes Diaphoresis Temperature ($38.5() Pleural rub Fourth heart sound Third heart sound Cyanosis Homans’ sign Right ventricular lift

All Patients (n = 383)

Patients without Previous Cardiopulmonary Disease (n = 117)

73%

70%

55% 30%

51% 30%

31% 23% 15% 11% 10% 7%

28% 23% 11% 5% 11% 7%

4% –

3% 24%

5%

3%

3% 3% –

1% 4% 4%

DVT, deep venous thrombosis; P2, pulmonic component of second heart sound. Data from Refs. [12,13] and Stein PD, editor. Pulmonary embolism. Baltimore (MD): Williams and Wilkins; 1996.

Blood tests Hypoxemia is common in acute PE. Some individuals, particularly young patients without underlying lung disease, may have a normal arterial oxygen tension (PaO2) and even, rarely, a normal alveolar-arterial diﬀerence [11,13]. A sudden decrease in the PaO2 or in the oxygen saturation in a patient unable to communicate an accurate history (eg, a demented or mechanically ventilated patient) suggests the possibility of acute PE. The diagnostic utility of plasma measurements of circulating D-dimer (a speciﬁc derivative of cross-linked ﬁbrin) in patients with acute PE has been extensively evaluated [27–30]. A normal ELISA seems to be sensitive in excluding PE, particularly when the clinical suspicion is relatively low. A number of D-dimer assays are available, and their sensitivity and speciﬁcity vary [30]. A positive D-dimer test means that DVT or PE is possible, but it is by no means proof. Similarly, although a negative D-dimer may strongly suggest that VTE is absent, a high clinical suspicion should not be ignored.

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Clinical probability scores based on simple clinical parameters have been used together with a negative D-dimer to help exclude PE. In a recent prospective clinical trial, the SimpliRed D-dimer (AGEN Biomedical Limited, Brisbane, Australia) test, a rapid red blood cell agglutination D-dimer assay, was used together with simple scoring parameters readily available in the emergency department [28]. Of the 437 patients with a negative D-dimer result and low clinical probability in this study, only one developed PE during followup (Table 3). Whether or not such scoring systems are used, D-dimer assays may prove increasingly useful in excluding acute DVT and PE, particularly when low clinical suspicion supports its absence. Both cardiac troponin T and troponin I levels have been found to be elevated in acute PE [32,33]. This enzyme is speciﬁc for cardiac myocyte damage. The right ventricle seems to be the source of the enzyme elevation in acute PE and, in particular, in more massive embolism in which myocyte injury caused by right ventricular strain might be expected. Troponin levels cannot, however, be used like D-dimer testing; that is, when clinical suspicion is relatively low, they are not sensitive enough to rule out PE without additional diagnostic testing. Electrocardiography Electrocardiographic ﬁndings, which are present in most patients with acute PE, are nonspeciﬁc, but these abnormalities, including ST-segment abnormalities, T-wave changes, and left or right axis deviation, are common. Only one third of patients with massive or submassive emboli have manifestations of acute cor pulmonale such as the S1 Q3 T3 pattern, right bundle branch block, P-wave pulmonale, or right axis deviation. The usefulness of electrocardiography in suspected acute PE lies in its ability to establish or exclude alternative diagnoses such as acute myocardial infarction [13]. Chest radiography The chest radiograph is often abnormal in patients with acute PE, but, as with electrocardiography, it is nearly always nonspeciﬁc. Common radiographic ﬁndings include atelectasis, pleural eﬀusion, pulmonary inﬁltrates, and mild elevation of a hemidiaphragm [13]. Classic ﬁndings of pulmonary infarction such as Hampton’s hump or decreased vascularity (Westermark’s sign) are

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Table 3 Determining pretest probability of acute pulmonary embolism using point system and D-dimer result Variable DVT symptoms/signs PE as or more likelya HR >100 beats/min Immobilization/surgeryb Previous DVT or PE Hemoptysis Malignancy Total score <2.0 2.0 to 6.0 >6.0

Points 3.0 3.0 1.5 1.5 1.5 1.0 1.0 Pretest Probabilityc Low Moderate High

DVT, deep venous thrombosis; HR, heart rate; PE, pulmonary embolism. a PE is as likely or more likely than an alternative diagnosis. Physicians were told to use clinical information along with chest radiography, electrocardiography, and laboratory tests. b If within previous 4 weeks. c Of the 437 patients with a negative D-dimer result and low clinical probability, only one developed PE during follow-up; thus, the negative predictive value for the combined strategy of using the clinical model with D-dimer testing in these patients was 99.5%. Data from Ref [28].

suggestive of the diagnosis but are infrequent. A normal chest radiograph in the setting of severe dyspnea and hypoxemia without evidence of bronchospasm or anatomic cardiac shunt is strongly suggestive of PE. Pulmonary embolism frequently coexists with underlying heart or lung disease. Symptoms, signs, radiographic ﬁndings, electrocardiography, and the plasma D-dimer measurement cannot be considered diagnostic of PE. Similarly, symptoms, signs, and blood studies cannot prove the presence of DVT. When these entities are suspected, further evaluation with noninvasive or invasive testing is necessary. Deep venous thrombosis: the radiographic approach Venography has been the time-honored standard for the diagnosis of acute DVT. With the advent of ultrasound, a diagnostic test that is more than 90% sensitive in the setting of symptomatic DVT, venography is rarely used [34]. Similarly, another sensitive test, impedance plethysmography, is almost never used. MRI has proven extremely sensitive for both acute and chronic DVT [34–36], although it is generally not necessary. It is reasonable to consider MRI in the setting of suspected DVT when ultrasound cannot

be eﬀectively used. A major limitation of ultrasound is its reduced sensitivity in the setting of asymptomatic DVT. Thus, ultrasound is not generally used as a screening test. Pulmonary embolism: the radiographic approach Ventilation-perfusion scanning Historically, the ventilation-perfusion (VQ) scan was the most commonly used diagnostic test when PE was suspected. During the past decade, spiral (helical) CT scanning has essentially replaced it at most centers. A normal perfusion scan rules out the diagnosis with a high enough degree of certainty that further diagnostic evaluation is almost never necessary [37]. Matching areas of decreased ventilation and perfusion in the presence of a normal chest radiograph generally represent a process other than PE. Nondiagnostic scans of low or intermediate probability are commonly found with PE, however, and in such situations further evaluation with pulmonary arteriography is often appropriate. In the Prospective Investigation of Pulmonary Embolism Diagnosis (PIOPED), when the clinical suspicion was considered very high PE was present in 96% of patients with high-probability scans, in 66% of patients with intermediate scans, and in 40% of patients with low-probability scans [12]. If the clinical setting suggests the diagnosis, the possibility of PE should be rigorously pursued even when the lung scan shows low or intermediate probability. Stable patients with suspected acute PE, nondiagnostic lung scans, and adequate cardiopulmonary reserve (absence of hypotension or severe hypoxemia) may undergo noninvasive lower extremity testing in an attempt to diagnose DVT [38]. A positive compression ultrasound may present the opportunity to treat without further testing. If the ultrasound is negative, pulmonary angiography is an appropriate option. Serial noninvasive lower extremity testing in the setting of suspected PE should be performed only in centers where followup is guaranteed and validated protocols are used. MRI of the lower extremities may also be useful after a nondiagnostic lung scan if the medical facility has experience with this technique. Pulmonary arteriography Pulmonary arteriography remains the accepted standard technique for the diagnosis of acute PE. It is an extremely sensitive, speciﬁc, and safe test [39]. Complications of pulmonary arteriography in 1111 patients suspected of having PE in the

V.F. Tapson / Cardiol Clin 22 (2004) 353–365

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PIOPED included death in 0.5% and major nonfatal complications in 1% [12]. Pulmonary arteriography is used when PE must be diagnosed or excluded and preliminary testing has been nondiagnostic. In some centers, pulmonary arteriography can be performed at the bedside using a pulmonary artery catheter and ﬂuoroscopic guidance. It is being used less frequently because CT has increasingly been employed.

MRI

Spiral (helical) CT

Echocardiography in acute pulmonary embolism

Spiral CT scanning can be used for diagnosing both acute and chronic PE and is replacing VQ at many centers. Some clinical trials have suggested good sensitivity and speciﬁcity, but others reports have been less favorable. Retrospective reconstructions can be performed. A contrast bolus is required for imaging of the pulmonary vasculature. In at least one clinical trial, spiral CT was associated with greater than 95% sensitivity and speciﬁcity [40]. More recent and larger trials have suggested a lower sensitivity [41–48]. A large, prospective Swiss study revealed a sensitivity of 70%, suggesting that a negative CT scan may not absolutely rule out smaller emboli [49]. Data from the large, multicenter PIOPED II trial in the United States and Canada comparing CT (of the chest and legs) and VQ scanning is currently being analyzed. Spiral CT has the greatest sensitivity for emboli in the main, lobar, or segmental pulmonary arteries. The speciﬁcity for clot in these vessels is excellent. For subsegmental emboli, spiral CT seems to be less accurate, although the importance of emboli of this size has been questioned. The outcome of selected patients with a negative CT scan in the setting of suspected PE seems to be good in trials published thus far [50]. The use of thinner sections and techniques such as multiplanar three-dimensional reformation may enhance the usefulness of spiral CT for diagnosing PE. An advantage of spiral CT over VQ scanning and arteriography is the ability to deﬁne nonvascular structures such as lymphadenopathy, lung tumors, emphysema, and other parenchymal abnormalities as well as pleural and pericardial disease [51]. Another advantage of spiral CT over other diagnostic methods is the rapidity with which a study can be performed. Potential disadvantages of CT are that it is not portable at present and, because intravenous contrast is necessary, patients with signiﬁcant renal insuﬃciency cannot be scanned without risk of renal failure.

Echocardiography, which can often be obtained more rapidly than either lung scanning or pulmonary arteriography, may reveal ﬁndings that strongly support hemodynamically signiﬁcant pulmonary embolism [53]. Imaging or Doppler abnormalities of right ventricular size or function may suggest the diagnosis. Unfortunately, because these patients often have underlying cardiopulmonary disease such as chronic obstructive lung disease, neither right ventricular dilation nor hypokinesis can be used reliably even as indirect evidence of PE. In patients with documented acute PE, echocardiographic evidence of right ventricular dysfunction has been suggested as a means by which to determine the need for thrombolytic therapy [54]. Such cases need to be considered individually, and severe right ventricular dysfunction should lower the threshold for thrombolytic therapy once contraindications have been considered. Transesophageal echocardiography has also been evaluated in the setting of acute PE, and although it is less convenient, it may prove to have advantages over the transthoracic approach. (The role of echocardiography in acute and chronic pulmonary embolism is further discussed by Daniels et al in this issue). Intravascular ultrasound imaging has been shown in both experimental and clinical settings to image large emboli adequately and may be performed at the bedside [55]. Published guidelines suggest that clinicians be aﬀorded a certain degree of ﬂexibility in the diagnostic approach to suspected acute PE [56].

MRI has been used to evaluate clinically suspected PE, but at present the main advantage of MRI in this disease process is the excellent sensitivity and speciﬁcity for the diagnosis of DVT [41,52]. Disadvantages include the potential diﬃculty in transporting and performing the technique in critically ill patients. Additional prospective investigations will determine the role of this modality in the evaluation of VTE.

Treatment Options for treatment of acute DVT and PE include anticoagulation with low-molecular-weight heparin (LMWH) (Box 1) or standard heparin, thrombolytic therapy, and inferior vena cava ﬁlter placement. Massive PE is occasionally treated

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Box 1. Initiation of LMWH for therapy of acute DVT or PE Determine appropriateness of outpatient therapya Begin subcutaneous administration of LMWHb. Determine whether monitoring is needed (in patients with extremes of weight, renal insufficiency, or pregnancy). Administer warfarin from day 1 at an initial dose of 5 to 10 mg, adjusted according to INR. Check platelet count between days 3 and 5 for heparin-induced thrombocytopenia. Stop LMWH after 5 or more days of combined therapy and when INR is 2.0 or more for 2 consecutive days. Anticoagulate with warfarin for 3 months or longer (goal, INR 2.0–3.0)c. DVT, deep venous thrombosis; LMWH, low-molecular-weight heparin; INR, international normalized ratio; PE, pulmonary embolism. a Potential outpatients should be medically stable without severely symptomatic DVT. They should be compliant, capable of self-administration (or have a family member or visiting nurse for administration), and at low risk of bleeding; reimbursement should be addressed. b Enoxaparin (Lovenox) and tinzaparin (Innohep) are the two LMWHs that are approved by the Food And Drug Administration (FDA) for treatment of VTE. Although LMWH preparations are sometimes used for patients presenting with PE in the United States, and although clinical trials support this use, the FDA approvals read ‘‘established DVT with or without PE.’’ c The duration of warfarin therapy should be at least 6 to 12 months in patients with idiopathic venous thromboembolism.

with surgical embolectomy. Each approach has speciﬁc indications as well as advantages and disadvantages. Heparin and low-molecular-weight heparin The primary anticoagulants used to treat acute DVT or PE are unfractionated heparin and LMWH. These substances exert a prompt antithrombotic eﬀect by accelerating the action of antithrombin III, thus preventing thrombus extension. Although they do not directly dissolve thrombus or emboli, they allow the ﬁbrinolytic system to proceed unopposed and more readily reduce the size of the thromboembolic burden. Although thrombus growth can be prevented, early recurrence can sometimes develop even in the setting of therapeutic anticoagulation. LMWH preparations have substantial advantages over unfractionated heparin [57,58]. Because of these advantages, use of unfractionated heparin is becoming less common. When DVT or PE is diagnosed or strongly suspected, anticoagulation should be immediately instituted unless contraindications are present. Conﬁrmatory diagnostic testing should be arranged as soon as possible. When treatment with standard, unfractionated, intravenous heparin is initiated, the activated partial thromboplastin time

(aPTT) should be followed at 6-hour intervals until it is consistently in the therapeutic range of 1.5 to 2.0 times control values. This range corresponds to a heparin level of 0.2 to 0.4 U/mL as measured by protamine sulfate titration. Achieving a therapeutic aPTT within 24 hours after the onset of treatment of PE has been shown to reduce the recurrence rate, and it has become evident that the traditional heparin regimen consisting of a 5000-U bolus and 1000 U/h is inadequate in many patients. Heparin is administered as an intravenous bolus of 5000 U followed by a maintenance dose of at least 30,000 to 40,000 U/24 hours by continuous infusion [59]. The lower dose is administered if the patient is considered at high risk for bleeding. This aggressive approach decreases the risk of subtherapeutic anticoagulation. It is possible that early initiation of warfarin without heparin or LMWH may intensify hypercoagulability and increase the clot burden because of the short-half life of anticoagulation factors (factors C and S) that are also inhibited by warfarin. Factor VII is the primary clotting factor aﬀecting the prothrombin time and has a half-life of about 6 hours. Deﬁnitive anticoagulation requires the depletion of factor II (thrombin), which takes approximately 5 days. Thus, treatment with intravenous heparin or LMWH for at least 5 days is generally recommended. Heparin should be main-

V.F. Tapson / Cardiol Clin 22 (2004) 353–365

tained at a therapeutic level until two consecutive therapeutic international normalized ratio (INR) values of 2.0 to 3.0 have been documented at least 24 hours apart. The LMWH preparations have numerous advantages over unfractionated heparin and have dramatically changed treatment of thromboembolic disease. Among the diﬀerences between these two substances are the greater bioavailability of the LMWHs and more predictable dosing [57,58]. LMWHs can be subcutaneously administered once or twice daily even at therapeutic doses and do not require monitoring of the aPTT. Intravenous LMWH is not required in VTE. In addition, LMWHs have a more profound eﬀect in inhibiting clotting factor Xa relative to thrombin. The reduced frequency of heparin-induced thrombocytopenia with LMWH relative to unfractionated heparin is a compelling reason to use LMWH instead of unfractionated heparin whenever possible. Because of their eﬃcacy, safety, and convenience compared with standard heparin, these drugs are replacing standard heparin in many settings. A number of clinical trials and meta-analyses have strongly suggested the eﬃcacy and safety of LMWH for treatment of established acute proximal DVT using recurrent symptomatic VTE as the primary outcome measure [60–65]. The incidence of DVT and recurrent bleeding in these trials indicates that LMWH preparations are at least as eﬀective and as safe as unfractionated heparin. Meta-analytic data suggest that in the treatment of established proximal DVT the use of LMWH reduces bleeding rates and mortality compared with unfractionated heparin [65]. Monitoring anti-factor Xa levels seems reasonable in certain settings such as in morbidly obese patients, very small patients (<40 kg), pregnant patients, and patients with renal insuﬃciency. Because these drugs are renally metabolized, monitoring is important, particularly when the creatinine clearance is less than 30 mL/min. With severe renal insuﬃciency, standard heparin should be considered. There is not clear agreement on a weight limit above which LMWH should not be used, but some believe that an upper limit of approximately 120 to 150 kg is reasonable, with intravenous standard heparin being used in larger patients. It is unnecessary to monitor anti-factor Xa levels in other patients. Two pivotal trials published in the same issue of The New England Journal of Medicine in 1996 emphasized that therapy with LMWH could be

359

safely initiated at home or continued at home after a brief hospitalization [66,67]. In the United States, at the present time, two LMWH preparations (enoxaparin and tinzaparin) are approved by the Food and Drug Administration (FDA) for treating patients presenting with DVT with or without acute PE. The most widely used LMWH, enoxaparin, is approved for both inpatient and outpatient use at a dose of 1 mg/kg subcutaneously every 12 hours or at 1.5 mg/kg once daily for inpatient use. These regimens were proven eﬀective in a large study of inpatients in which both doses proved as eﬀective and as safe as unfractionated heparin. There is also experience with LMWH for treatment of patients presenting with PE [61]. Finally, a novel synthetic pentasaccharide anticoagulant, fondaparinux, has been studied in patients with acute DVT and PE and has proven eﬀective for these indications [68]. Although this drug is approved for prophylaxis in speciﬁc orthopedic populations, it is not approved by the FDA for therapy of acute VTE in the United States at the present time. It should be noted that the prophylactic doses of these agents diﬀer from the doses used for treating active disease. The characteristics of LMWHs compared with standard unfractionated heparin are shown in Table 4. Documented proximal DVT or PE should be treated for 3 to 6 months. Treatment over a more extended interval is appropriate when signiﬁcant risk factors persist, when thromboembolism is idiopathic, or when previous episodes of VTE have been documented.

Direct thrombin inhibitors Newer antithrombotic agents are being investigated. Whereas heparin and LMWH work indirectly, requiring antithrombin III as a cofactor, hirudin is a direct thrombin inhibitor that has several advantages over heparin, including eﬃcacy against ﬁbrin clot-bound thrombin. This drug, derived from the saliva of the medicinal leach (Hirudo medicinalis), does not require cofactors and is not inactivated by platelet factor 4 or plasma proteins. As with heparin, these direct thrombin inhibitors have narrow therapeutic indices. Currently, ximelagatran, an oral direct thrombin inhibitor, is being studied extensively and can simplify the acute as well as chronic treatment of VTE. It has proven eﬀective for treatment of VTE compared with placebo after extended warfarin therapy [69].

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Table 4 A comparison of LMWH with unfractionated heparin Characteristic Mean molecular weight Protein binding Anti-Xa activity Anti-Ila activity Administration (treatment) Administration (prophylaxis) Monitoring during treatment Outpatient therapy Incidence of HIT Reversibility with protamine

UFH

LMWH

12,000–15,000 substantial substantial substantial

4,000–6,000 minimala substantial minimal

intravenous

subcutaneous

subcutaneous aPTT every 6 hours diﬃcult 3% to 5%

subcutaneous none in most settingsb simpliﬁed <1%

complete

partial

PTT, activated partial thromboplastin time; HIT, heparin-induced thrombocytopenia; LMWH, lowmolecular-weight heparin; UFH, unfractionated heparin. a This implies signiﬁcantly superior bioavailability of LMWH relative to UFH. b LMWH requires monitoring in renal insuﬃciency (creatinine clearance <30 mL/min), signiﬁcant obesity (>150 kg), very small patients (<40 kg), and pregnant patients. Anti-Xa levels are followed, not the activated partial thromboplastin time.

Studies have been completed and are pending publication regarding the successful use of this drug compared with LMWH and warfarin in acute VTE [70]. Although ximelagatran is associated with transient elevation in hepatic transaminases between approximately 8 and 12 weeks, this elevation is generally transient and reversible even with continued exposure to the drug. Monitoring of liver function will probably be recommended, however, at least temporarily. The oral delivery, rapid onset, lack of signiﬁcant drug and food interactions, and lack of need for INR monitoring are among the advantages over warfarin. Bleeding is the major complication of anticoagulation therapy. The rates of major bleeding in recent trials using heparin administered by continuous infusion or high-dose subcutaneous injection are less than 5%. Heparin-induced thrombocytopenia (deﬁned as a platelet count drops to less than 100,000 to 150,000 mm3) typically develops 5 or more days after the initiation of heparin therapy and occurs in about 5% of patients [71]. The syndrome is caused by heparin-dependent IgG antibodies that activate platelets through their Fc receptors. If a patient is treated with heparin, and the platelet count pro-

gressively decreases to 100,000/mm3 or less, heparin should be discontinued. The formation of heparin-dependent IgG antibodies and the risk of thrombocytopenia are lower with LMWH than with standard heparin [71]. Both argatroban and lepirudin have been approved by the FDA for use in the setting of VTE with heparin-induced thrombocytopenia. The halflife of argatroban is 45 minutes, but it is prolonged in patients with hepatic dysfunction. Lepirudin is excreted by the kidneys, so the dosage must be reduced in patients with renal insuﬃciency. This drug has a short circulating half-life of 1.3 hours in patients with normal renal function, but the half-life may be as long as 2 days in patients with advanced renal failure. Although there is no antidote for lepirudin at present, the short half-life in patients with normal renal function allows rapid correction of prolonged aPTTs. A detailed discussion of heparin-induced thrombocytopenia is beyond the scope of this article. Bleeding related to warfarin therapy increases with intensity and duration of therapy. Warfarininduced skin necrosis is a rare but serious complication mandating immediate cessation of the drug. It is related, at least in some patients, to protein C or S deﬁciency. Warfarin crosses the placenta and may cause fetal malformations if used during pregnancy. Vena cava interruption When anticoagulation is contraindicated, a ﬁlter can be placed in the inferior vena cava to prevent lower-extremity thrombi from embolizing to the lungs. The primary indications for ﬁlter placement are contraindications to anticoagulation, recurrent embolism while receiving adequate therapy, and signiﬁcant bleeding complications during anticoagulation [72]. Filters are sometimes placed in the setting of massive PE when it is believed that any further emboli might be lethal, particularly if thrombolytic therapy is contraindicated. A number of ﬁlter designs exist but the Greenﬁeld ﬁlter has been most widely used. Filters can be inserted through the jugular or femoral vein. These devices are eﬀective, and complications, including insertion-related problems and migration, are unusual. More recently, temporary ﬁlters have been placed in patients in whom the risk of bleeding seems short term. Most of these devices can be removed up to 2 weeks later, and some may remain in place even longer with subsequent removal.

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Thrombolytic therapy Thrombolytic agents activate plasminogen to form plasmin that then results in ﬁbrinolysis as well as ﬁbrinogenolysis. These agents can dramatically accelerate clot lysis in acute PE (and DVT), and such an approach was ﬁrst documented more than several decades ago. Clinical trials have culminated in the approval of streptokinase, urokinase, and recombinant tissue-type plasminogen activator for the treatment of massive PE [73,74]. Although tenecteplase has been studied extensively in acute myocardial infarction and would be expected to be eﬀective in VTE, far fewer data are available for this agent. The speciﬁc FDA-approved regimens are shown in Box 2. For the past several decades the clearly accepted recommendation for thrombolytic therapy has been PE with hemodynamic instability (hypotension). Thrombolytic therapy should also be considered in patients with severely compromised oxygenation. Although thrombolytic therapy may result in rapid improvement of right ventricular function in patients with acute PE, there has been controversy as to whether patients with echocardiographic right ventricular dysfunction but without hypotension should receive this treatment. Several large studies have suggested that thrombolytic therapy should be considered in such patients, and a recent clinical trial indicated a less-frequent need for escalation of treatment when thrombolytic therapy was used in the setting of PE with right ventricular dysfunction [75]. The method of delivery of thrombolytic agents has also been investigated. Although standard- or low-dose intrapulmonary arterial thrombolytic infusions have been used to deliver a high concentration of drug in close proximity to the clot, intravenous therapy seems to be adequate in most cases [76]. More direct techniques, such as catheter-directed administration of intraembolic

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thrombolytic therapy, have been used in small clinical studies, but the data are inadequate to formulate recommendations [77,78]. The use of thrombolytic therapy in patients with proximal occlusive DVT associated with signiﬁcant swelling and symptoms is increasing. Catheter-directed techniques are often employed [79]. In DVT, such aggressive therapy with thrombolytics may reduce the frequency of postphlebitic syndrome. Hemorrhage is the primary adverse eﬀect associated with thrombolytic therapy [80,81]. Both lysis of hemostatic ﬁbrin plugs and ﬁbrinogenolysis can lead to bleeding complications, which commonly occur at sites of invasive procedures such as pulmonary arteriography or arterial line placement. Invasive procedures should be minimized as much as possible. The most devastating complication associated with thrombolytic therapy is the development of intracranial hemorrhage, which occurs in less than 1% of patients. Retroperitoneal hemorrhage may result from a vascular puncture above the inguinal ligament and may be life threatening. The primary contraindications to thrombolytic therapy include active bleeding, surgery within the previous 1 to 2 weeks (depending on the speciﬁc procedure), intracranial pathology, or previous intracranial surgery. When patients seem to be at extraordinary risk of rapid death from PE, clinical judgment should be individualized with regard to contraindications. Management of unstable hemodynamics in massive pulmonary embolism Massive PE should always be suspected in the setting of the sudden onset of hypotension or extreme hypoxemia. The presence of electromechanical dissociation or sudden cardiac arrest should always make massive embolism a consideration. Once massive PE associated with

Box 2. Thrombolytic therapy for acute pulmonary embolism: approved regimens Streptokinase: 250,000 U intravenously (loading dose over 30 minutes); then 100,000 U/h for 24 hoursa Urokinase: 2000 U/lb intravenously (loading dose over 10 minutes); then 2000 U/pound/h for 12 to 24 hours Tissue-type plasminogen activator: 100 mg intravenously over 2 hours a Streptokinase administered over 24 to 72 hours at this loading dose and rate has also been approved for use in patients with extensive DVT.

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hypotension or severe hypoxemia is suspected, supportive vasoactive treatment is immediately initiated. Intravenous saline should be infused rapidly but cautiously, because right ventricular function is often markedly compromised. Dopamine or norepinephrine seem to be the favored choices of vasoactive therapy in massive PE and should be administered if the blood pressure is not rapidly restored [82]. Because death in this setting results from right ventricular failure, some have recommended dobutamine as a means to augment right ventricular output [83]. A vasopressor such as norepinephrine combined with dobutamine might oﬀer optimal results, and further exploration of such combined therapy would prove enlightening. Oxygen therapy is administered, and thrombolytic therapy is considered, as described previously. Pulmonary embolectomy may be appropriate in patients with massive embolism who cannot receive thrombolytic therapy. Prognosis The International Cooperative Pulmonary Embolism Registry included 2454 consecutive patients with a diagnosis of PE, and PE was the principal cause of death [84]. The 3-month mortality was 17.5%. In the PIOPED, the mortality rate was approximately 15%, but only 10% of deaths during the ﬁrst year of follow-up were attributed to PE [12]. Mean 1-month mortality rates of treated and untreated PE have been estimated at 8% and 30%, respectively. Although a small percentage of patients with acute PE ultimately develop chronic dyspnea and hypoxemia because of chronic thromboembolic pulmonary hypertension, most patients who survive the acute episode have no long-term pulmonary sequelae. Chronic leg pain and swelling from DVT (postphlebitic syndrome) may result in signiﬁcant morbidity, however. Prevention Measures to prevent VTE seem to be grossly underused [4,7]. A substantial reduction in the incidence of DVT can be achieved when patients at risk receive appropriate prophylaxis. For example, the risk of DVT after total hip or knee replacement is 50% or more without prophylaxis. The superiority of LMWH over unfractionated heparin has been demonstrated in these settings, and extending the duration of prophylaxis to approximately 1 month after surgery further re-

duces the DVT rate in total hip replacement [85,86]. Unfractionated heparin is not recommended in total joint replacement. In hospitalized general medical patients, anticoagulant prophylaxis should always be strongly considered because the rate of DVT, based upon a venographic endpoint, is as high as 15% in patients receiving placebo [31]. The rate of DVT, including proximal DVT, is statistically signiﬁcantly lower when enoxaparin is administered compared with placebo [31]. Either LMWH (enoxaparin, 40 mg, subcutaneously once daily) or subcutaneous heparin (5000 U every 8 hours) seems to be adequate for medical patient prophylaxis [87,88]. Although 5000 U of heparin every 12 hours has been commonly used, fewer data support this preventive regimen in medical patients. Intermittent pneumatic compression devices should be used when pharmacologic prophylaxis is contraindicated. Both methods combined are reasonable in patients deemed to be at exceptionally high risk, but an additional reduction in risk in such patients has not been well substantiated. Each hospitalized patient should be assessed for the need for such prophylactic measures, and all hospitals should strongly consider formulating written guidelines for each particular clinical setting, based upon the available medical literature [89]. References [1] Anderson FA, Wheeler HB. Venous thromboembolism: risk factors and prophylaxis. Clin Chest Med 1995;16:235–51. [2] Dalen JE, Alpert JS. Natural history of pulmonary embolism. Prog Cardiovasc Dis 1975;17:257–70. [3] Lindblad B, Eriksson A, Bergquist D. Autopsyveriﬁed pulmonary embolism in a surgical department: analysis of the period from 1951 to 1988. Br J Surg 1991;78:849–52. [4] Goldhaber SZ, Tapson VF. A prospective registry of 5,451 patients with ultrasound conﬁrmed deep vein thrombosis. Am J Cardiol 2004;93:259–62. [5] Coon WW. Risk factors in pulmonary embolism. Surg Gynecol Obstet 1976;143:385–90. [6] Kakkar VV, Howe CT, Nicolaides AN, et al. Deep vein thrombosis of the legs: is there a ‘‘high risk’’ group? Am J Surg 1970;120:527–30. [7] Bratzler DW, Raskob GE, Murray CK, et al. Underuse of venous thromboembolism prophylaxis for general surgery patients. Physician practices in the community hospital setting. Arch Intern Med 1998;158:1909–12. [8] von Virchow R. Weitere Untersuchungen ueber die Verstopfung der Lungenarterien und ihre Folge.

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Cardiol Clin 22 (2004) 401–415

Cardiac catheterization techniques in pulmonary hypertension Paulo Guillinta, MD, Kirk L. Peterson, MD, Ori Ben-Yehuda, MD* Division of Cardiology, Department of Medicine, University of California, San Diego, 200 West Arbor Drive, San Diego, CA 92110, USA

Once considered dangerous and potentially life threatening, cardiac catheterization of the patient with pulmonary hypertension can be performed safely and provides essential information in the diagnosis and management of pulmonary hypertension. This article summarizes the modern techniques used for right-heart catheterization, selective pulmonary angiography, and pulmonary angioscopy in the evaluation of the patient with pulmonary hypertension or with suspected chronic thromboembolic disease. Cardiac catheterization of the patient with suspected pulmonary hypertension is essential to determine accurately the cause and extent of disease. In patients with suspected chronic thromboembolic pulmonary hypertension (CTEPH), pulmonary angiography remains an essential part of the diagnostic evaluation and selection of appropriate patients for surgical pulmonary thrombendarterectomy. Although historically pulmonary angiography has been considered contraindicated in the presence of severe pulmonary hypertension, advances in cardiac and pulmonary angiographic techniques allow this procedure to be performed in a safe manner with acceptable risk. In reviewing the technique of right-heart catheterization, pulmonary angiography, and angioscopy in the patient with pulmonary hypertension, the authors draw on the experience of more than 20 years of catheterization of patients with severe pulmonary hypertension at the University of California, San Diego (UCSD) Medical Center,

* Corresponding author. E-mail address: [email protected] (O. Ben-Yehuda).

where more than 2500 such procedures have been performed.

Indications and considerations for catheterization of the patient with pulmonary hypertension Catheterization plays an integral part in the evaluation of the patient with pulmonary hypertension. The primary goals of catheterization are to determine right ventricular and pulmonary artery hemodynamics, to exclude left-to-right cardiac shunts and any signiﬁcant left-sided cardiac disorder, to assist in the determination of the cause of pulmonary hypertension, and to test the response of therapeutic agents. In patients with suspected CTEPH, pulmonary angiography and angioscopy are used to assess clot location, extent, and size to determine candidacy for pulmonary thrombendarterectomy.

Safety considerations Early case reports [1–4] of fatalities associated with pulmonary angiography in patients with pulmonary hypertension have led to a lingering perception that the procedure is associated with considerable risk, primarily because of acute right ventricular failure and arrhythmias. Even rightheart catheterization alone [5] was reported to be potentially dangerous. Larger series have since been published, both in acute and chronic pulmonary embolism and in mild as well as severe pulmonary hypertension. Mills et al [6] described three deaths in 1350 patients (incidence of 0.2%), all of whom had right ventricular end diastolic pressure of 20 mm Hg or higher. Nicod et al [7]

0733-8651/04/$ - see front matter Ó 2004 Elsevier Inc. All rights reserved. doi:10.1016/j.ccl.2004.04.011

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reported on the original series of 67 patients from UCSD undergoing CTEPH evaluation. Mean pulmonary arterial pressures (PAPs) were 47 13 mm Hg, with a right ventricular end diastolic pressure of 13 6 mm Hg and a cardiac index of 2.2 0.7 L/min. There were no deaths attributable to CTEPH. By 1991 this series had expanded to include more than 300 patients, without a death. Since then right-heart catheterization and pulmonary angiography have been performed in approximately 200 patients with severe pulmonary hypertension annually at UCSD, without a death related to the procedure (more than 2500 patients to date). There thus are no absolute contraindications to pulmonary angiography, and the procedure can be performed safely, provided certain precautions and advances in technique are employed. Nonfatal adverse reactions include transient hypotension and general catheterization-related adverse events such as inadvertent arterial puncture, oversedation, pneumothorax, and contrast agent–related nephropathy [8]. To minimize these risks, the authors use the following procedures at UCSD [9]: 1. Before the procedure echocardiography is performed, detecting potential clots in the right atrium or right ventricle or the presence of an atrial septal defect/patent foramen ovale. 2. Heart rate, rhythm, oxygen saturation, and systemic and PAP should be continuously monitored. Supplemental oxygen is provided to maintain oxygen saturation over 90%. 3. Access to the pulmonary vessels through the neck is preferred to avoid potential dislodgement of unsuspected venous thrombi involving the femoral vein, iliac vein, or inferior vena cava and to facilitate angioscopy. The authors prefer the internal jugular vein to the subclavian vein to reduce the risk of pneumothorax, which is likely to be poorly tolerated in these patients who are often hypoxemic. 4. Hemodynamics are assessed using a balloon ﬂotation catheter (Swan-Ganz catheter), at times stiffened with a 0.025-cm guide wire. This stiffening greatly facilitates the catheterization in these patients, who frequently have enlarged right ventricles, signiﬁcant tricuspid regurgitation, severely elevated PAPs, and low cardiac output. CO2 is used for balloon inﬂation to minimize the possi-

5.

6.

7.

8.

bility of paradoxical embolism in case of balloon rupture. A stiff, side-hole catheter such as a 7-F or 8-F NIH or Berman catheter is most commonly used to inject the pulmonary arteries. The injection through the side holes allows good opaciﬁcation with reduced injection velocity and pressure. Catheter retraction and whipping during injection are also minimized. Unilateral, sequential injection of the contrast agent in to each main pulmonary artery is preferred. Injection into the right atrium or right ventricle is avoided, thereby eliminating the possibility of intramyocardial injection. The catheter is positioned near the origin of the lower lobe vessels, and the contrast agent is allowed to ﬁll the upper lobes in retrograde fashion. Non-ionic contrast is preferred because fewer adverse reactions and minimal hemodynamic compromise are experienced [10,11]. Cardiac output and speed of run-off during small hand injection are used to determine the amount of contrast agent needed for assessment of the pulmonary vasculature anatomy. A smaller amount of contrast material is needed in patients with slow run-off or low cardiac output. At UCSD, the total amount of contrast medium used ranges from 20 to 65 mL. The usual injection is of 55 mL at a rate of 22 mL/second, with adjustments based on the patient’s cardiac output, assessment of the pulmonary vasculature during the hand injection, and pulmonary pressures. For example, the total occlusion of the main descending pulmonary artery after the takeoff of the upper lobe branch would necessitate a reduction of the total contrast to approximately 20 mL. Conversely, the presence of a brisk runoff during the hand injection coupled with a high cardiac output would lead to injection of more than the standard 55 mL.

Right-heart catheterization Evaluation of hemodynamics by right-heart catheterization plays an integral part of the evaluation of patients with pulmonary hypertension. The goals of right-sided catheterization are (1) to measure PAP directly and estimate pulmonary vascular resistance, (2) to evaluate for left-toright shunts, and (3) to test the response to therapeutic agents.

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During right-heart catheterization by balloon ﬂotation catheter, rapid determination and continuous monitoring of pressures in the right ventricle, right atrium, and pulmonary artery and of postcapillary wedge pressure are possible. Understanding of normal and pathologic pressure waveforms is important to recognize certain cardiac disorders such as valvular and pericardial disease. In patients with primary pulmonary hypertension (PPH), particular attention should be paid to the right atrial pressure and right ventricle end-diastolic pressure. In the National Heart Lung and Blood Institute registry, mean right atrial pressure and decreased cardiac index were the most important predictive variables for survival in patients with PPH [12]. The patient with PPH commonly has elevated right atrial pressure, elevated mean PAP, reduced cardiac index, and low or normal postcapillary wedge pressure [8]. A postcapillary wedge pressure is obtained with an end-hole catheter positioned in a side branch of the pulmonary artery facing a pulmonary capillary bed. One pitfall to avoid is wedging the balloon too proximally, creating a hybrid tracing of pressures between actual PAP and postcapillary wedge pressure, resulting in an overestimation of the postcapillary wedge pressure (Fig. 1). Deﬂating the balloon to decrease its size will allow the catheter to be wedged in a smaller, more distal branch of the pulmonary artery. Caution should be taken to avoid overwedging and possible pulmonary artery rupture, a potentially lethal event. Fortunately in pulmonary hypertension the thickened, hypertrophied arterial wall provides some protection against rupture. When it is not clear whether a wedge tracing has been obtained, a blood sample is obtained through the distal port. In the wedge position arterial saturation should be present as blood from the capillary bed is aspirated. The authors have also found that typically the more narrow, tapering anatomy of the left pulmonary artery allows more reliable wedge determinations. The use of a J-tipped 0.25 wire to guide the Swan-Ganz catheter to the left pulmonary artery is essential. Typically patients with either PPH or CTEPH have low to normal wedge pressures. In the presence of substantially elevated postcapillary wedge pressure, left-heart catheterization should be performed to exclude pulmonary venoocclusive disease, mitral stenosis, or left ventricular dysfunction. Cardiac output is best determined by the Fick method in the setting of low cardiac output states or when there is signiﬁcant tricuspid regurgita-

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tion. This method requires measuring oxygen consumption directly, because estimations of oxygen consumption may not apply to seriously ill patients with pulmonary hypertension and may introduce signiﬁcant calculation errors. In experienced hands, however, determination of cardiac output by thermodilution techniques is usually satisfactory for the adjustment of therapy in these patients [13].

Response of vasodilator challenge in the cardiac catheterization laboratory Vasoconstriction of the pulmonary vessels is one of the prominent pathologic features seen in patients with pulmonary hypertension of any cause, particularly in those with PPH [14]. Unfortunately, no hemodynamic or demographic characteristics exist to predict which patients are likely to beneﬁt from long-term vasodilator therapy [15,16]. In more recent studies, Groves et al [17] illustrated that the initial response to vasodilatory therapy accurately predicts the patient with PPH who is likely to beneﬁt from long-term oral therapy. In addition, patients who demonstrate a reduction in total pulmonary resistance index of more than 50% in response to short-term epoprostenol (prostacyclin, PGI2) challenge at the time of diagnosis had longer disease evolutions and better prognoses than patients with a lower vasodilator response [18,19]. For these reasons [3], it is important to assess the response to vasodilator therapy in patients with PPH in the cardiac catheterization laboratory. Nitric oxide and PGI2 are useful drugs to test pulmonary vasoreactivity because they are potent, short acting, and can be titrated. The acute eﬀects of inhaled nitric oxide and PGI2 on pulmonary artery pressure are similar [20,21]. Inhaled nitric oxide more consistently reﬂects the changes in pulmonary vascular tone and seems to be the better predictor of the long-term response to oral vasodilator treatment, making it the preferred agent for assessing pulmonary vasoreactivity [22]. Nitroprusside has fallen out of favor for assessing pulmonary vasoreactivity in patients with chronic pulmonary hypertension because this drug causes systemic hypotension compared with nitric oxide, at doses that cause similar degrees of pulmonary vasodilation [23]. Pulmonary arterial pressures, right ventricular pressures, cardiac output, and postcapillary wedge pressure are recorded during infusions of inhaled

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Fig. 1. (A) Hybrid tracing of pulmonary artery pressure and wedge tracing overestimating wedge pressure. (B) Actual pulmonary capillary wedge pressure tracing once the balloon is deﬂated and allowed to wedge in a smaller, more distal branch of the pulmonary artery.

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nitric oxide. Administration of inhaled nitric oxide with oxygen seems to be safe and provides additional pulmonary vasodilation in this patient population [24]. Pulmonary pressure are recorded during administration of 100% oxygen and inhaled nitric oxide dosed at 20 to 80 parts per million. The authors typically administer nitric oxide for 10 minutes, with repeat recordings obtained during the ﬁnal 5 minutes of the inhalation. Although a mild reduction in pulmonary vascular resistance (<20%) can be seen in most patients, even those with CTEPH, signiﬁcant reductions of more than 20% are seen in only one fourth of patients [25]. Pulmonary angiography: anatomy Accurate evaluation of the pulmonary angiogram requires knowledge of the pulmonary vas-

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culature anatomy (Figs. 2 and 3). The main pulmonary artery arises from the pulmonary conus of the right ventricle, anterior and to the left of the aorta. It takes a posteromedial direction until its bifurcation into the right and left pulmonary arteries. The right pulmonary artery courses anterior to the right mainstem bronchus. It gives rise to the right upper lobe branch within the mediastinum. The left pulmonary artery passes over the left mainstem bronchus and descends posterior to the bronchus before the origin of the left upper lobe branch. The vessels then branch and are closely related to bronchial branching within the lung. Angiographic ﬁlms are taken using anteroposterior and lateral projections. The lateral projection is particularly helpful in separating the overlapping tributaries of the right middle and right lower lobe and left lingual and left lower lobe. It also allows a clear separation

Fig. 2. (A) Anteroposterior view of the anatomy of the right pulmonary artery. (B) Lateral view. (Reproduced from Peterson KL, Nicod P. Catheterization and angiography in pulmonary hypertension. In: Shure D, Auger W, Moser K, et al, editors. Cardiac catheterization: methods, diagnosis, and therapy. Philadelphia: W.B. Saunders; 1977. p. 404; with permission.)

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Fig. 3. Anatomy of the left pulmonary artery in (A) anteroposterior and (B) lateral views. (Reproduced from Peterson KL, Nicod P. Catheterization and angiography in pulmonary hypertension. In: Shure D, Auger W, Moser K, et al, editors. Cardiac catheterization: methods, diagnosis, and therapy. Philadelphia: W.B. Saunders; 1977. p. 405; with permission).

between the superior segmental artery and the artery to the middle lobe.

Pulmonary angiography: interpretation in the patient with pulmonary hypertension Pulmonary angiography of the patient with pulmonary hypertension plays a central role in delineating the precapillary cause of elevated pulmonary pressures. Distinguishing major-vessel from small-vessel disease allows the correct therapeutic approach to be determined. Auger et al [26] described the angiographic patterns seen in patients with chronic thromboembolic disease. These patterns include pouching abnormalities, vascular webs or bandlike constrictions, intimal irregularities, abrupt narrowing of

major pulmonary vessels, and obstruction of major pulmonary vessels, most commonly at points of origin (Figs. 4–8). Although pulmonary arterial webs are typically seen in patients with chronic thromboemboli, they are also seen in congenital stenotic lesions of the pulmonary vessels and with vasculitides such as Takayasu’s arteritis [27,28]. Patients with congenital stenotic lesions of the pulmonary vasculature present at an early age and typically have coexisting cardiac abnormalities. Most Takayasu patients with pulmonary vessel involvement demonstrate systemic manifestations. Total obstruction or abrupt narrowing of the pulmonary vessel, typically seen in chronic thromboemboli, can also be seen in extrinsic compression from extensive mediastinal or hilar lymphadenopathy, ﬁbrosing mediastinitis, and pulmonary

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Fig. 4. (A) The anteroposterior view of the right pulmonary artery in a patient with CTEPH. Note the marked hypovascularity, irregularity of the main descending pulmonary artery, and complete occlusion of most segmental branches. (B) The lateral view of the artery shown in 4A. Note the separation of the right middle lobe branches from the right lower lobe segments. In this view the middle lobe is perfused, as is the superior segment.

vascular or primary lung malignancies [29–32]. Chest CT aids in making the distinguishing these entities from chronic thromboembolic disease. Occasionally, several vascular abnormalities occur in the same patient. In this scenario, the pulmonary angiogram may aid in identifying the

Fig. 5. Right pulmonary angiogram shows central pulmonary artery enlargement and pouching abnormality in the right lower lobe vessel seen in chronic thromboembolic disease.

patient with acute on chronic thromboembolic disease (Fig. 9). Sharply deﬁned luminal defects are seen in small, acute emboli. Proximal pulmonary artery enlargement and bandlike abnormalities are typically seen in chronic thromboembolic disease but not in acute embolic disease. The hemodynamic data can also assist in distinguishing chronic from acute embolism. Pulmonary hypertension with mean PAPs above 35 mm Hg suggest chronicity, because the right ventricle in acute pulmonary embolism without previous pulmonary hypertension is incapable of generating such high pulmonary pressures [33]. The classic angiographic ﬁndings in patients with PPH include normal or dilated central arteries with pruning of the small, more distal, nonelastic arteries [8]. Pruning of the pulmonary vessels may also be seen with chronic thromboembolic disease, but in this scenario pruning is regional and more proximal [34]. A key question that the pulmonary angiogram addresses in patients with suspected CTEPH is the extent and surgical accessibility of chronic clot. The presence of bilateral disease and proximal involvement (main pulmonary trunks, lobar arteries, and segmental arteries) predicts surgical accessibility. Correlation with ﬁndings on the perfusion scan is essential, because the presence

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Fig. 6. (A) Anteroposterior view of the right pulmonary artery demonstrating hypoperfusion of the lower lobe. (B) Only on the lateral ﬁlm does the extent of occlusion of the posterior basal segment and narrowing of the middle lobe branch become evident. The superior segment is also subtotally occluded.

of segmental defects is predictive of surgical success (see articles in this issue by Auger et al and Thistlethwaite et al).

When there is signiﬁcant proximal disease (eg, complete occlusions of lobar vessels), the inter-

pretation of pulmonary angiograms is straightforward. In the UCSD experience the pulmonary angiogram is suggestive but not deﬁnitive in about 20% to 25% of cases. The recanalization of chronic clot allows contrast to permeate through the lesions, and the pulmonary angiogram can underestimate disease just as the perfusion scan can. In addition, the presence of defects at the

Fig. 7. Abrupt narrowing of the pulmonary vessel seen in chronic thromboembolic disease.

Fig. 8. Anteroposterior projection shows complete obstruction of the right main pulmonary artery.

Pulmonary angioscopy

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Fig. 9. Anteroposterior view demonstrates acute on chronic thromboemboli. Note the distinct numerous luminal ﬁlling defects (solid arrow) in a bandlike or web abnormality.

transition between segmental and subsegmental vessels may raise doubt regarding the surgical accessibility. In the patient with markedly elevated pulmonary hypertension (pulmonary vascular resistance >800 dynes/second/cm5) surgical risks rise signiﬁcantly if insigniﬁcant clot is removed during surgery, leaving the patient with severe pulmonary hypertension. Fiberoptic angioscopy, developed to allow direct visualization of the interior of the central pulmonary vessels up to the segmental and sub-

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segmental levels, is used to deﬁne surgical accessibility better in borderline cases [35,36]. The challenges entailed in performing pulmonary angioscopy include the need to maneuver through an often hypertrophied right ventricle, the wide variation in pulmonary vessel size with varying anatomic branching, the large number of branches that require visualization, and the robust collateral circulation from the bronchial circulation. At UCSD pulmonary angioscopy has progressed through several stages of development over the past 20 years. The approach has been to use a balloon system to occlude blood ﬂow completely in the vessel that is being visualized, rather than a ﬂushing (hemodilution) approach as has been used in the coronary circulation. Hemodilution is not practicable in the large pulmonary arteries and would entail dangerous ﬂuid overload in these patients with right-heart failure. The angioscope presently used is a 120-cm ﬁberoptic device, 3 mm in diameter (Figs. 10 and 11). It can be ﬂexed 90( at the tip allowing navigation through the pulmonary tree. The occluding balloon is attached at a modiﬁed spool-like stainless steel lip, which allows secure tying of the disposable balloons. The balloon at the distal end is inﬂated with carbon dioxide to protect from air embolism in case of balloon rupture, a precaution of particular importance given the elevated rightsided pressures with potential for right- to-left embolism in patients with patent foramen ovale. The balloon is connected to a syringe by a tube in the angioscope, allowing deﬂation during the advancement of the catheter and inﬂation to occlude the vessel as well as allow ﬂotation further downstream.

Fig. 10. The pulmonary angioscope. (Courtesy of Olympus Corporation, Lake Success, NY.)

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Fig. 11. Inﬂated balloon attached to the distal tip of the angioscope.

Because of the size of the angioscope (3 mm) an 11-F sheath is used. Although angioscopy can be accomplished from the femoral approach, it is much easier to navigate the instrument through the right ventricle using the internal jugular vein approach, particularly from the right. Two operators are needed to guide the angioscope, with one advancing and torquing the instrument and the other ﬂexing and extending it using the built-in deﬂectors. Angioscopy is most helpful in deﬁning the starting point of chronic thrombi and establishing whether they are within surgical reach. This procedure enables the examiner to determine operability of patients with chronic pulmonary thromboemboli in approximately 75% of the cases when the ﬁndings on the pulmonary angiogram are questionable [34]. A detailed map of the major pulmonary vessels can be performed safely within 20 minutes, without signiﬁcant morbidity, in this patient population. The main complications encountered have been transient ventricular ectopy during transit in the ventricle and minor local bleeding from the 11-F sheath site in the neck. During the procedure the ﬂuoroscopy images are recorded to localize the lesions seen on angioscopy and are correlated with the anatomy as deﬁned in the pulmonary angiogram. Normal pulmonary ﬁndings are of smooth, pale white, glistening intima (Fig. 12). Bifurcations are typically round and regular in appearance. In patients with pulmonary hypertension, either primary arterial hypertension or secondary to CTEPH, the arterial walls may demonstrate small, yellowish atheroscleroticlike plaques as well as more diﬀuse yellowish colorations (Figs. 13 and 14). Patients with chronic thrombi have irregular pulmonary arterial walls with transluminal bands

Fig. 12. Normal bifurcation of a pulmonary artery.

and obstructive lesions and irregular vessel ostia. Thin membranes can also be visualized. At times reddish-purplish subacute thrombi can be seen, which are distinct from the white ﬁbrotic lesions of chronic organized and recanalized clot. Small-vessel arteriopathy in patients with chronic thromboembolic pulmonary hypertension Although the main site of vasculopathy and increased resistance in CTEPH is in the large, elastic pulmonary arteries, a signiﬁcant number of patients have concomitant small-vessel arteriopathy that may persist despite the removal of proximal clot. These patients are at increased risk of persistent pulmonary hypertension after pulmonary thrombendarterectomy. Severe persistent pulmonary hypertension after surgery accounts for more than one third of perioperative mortality and up to 50% of long-term deaths. Recently the pulmonary artery occlusion technique [37] has been used to attempt to partition the pulmonary resistance into an upstream component (Rup) and downstream (small arterial plus venous) component. Using a standard Swan-Ganz catheter (Edwards Lifesciences Corporation, Irvine, CA) the pulmonary pressure signal is ﬁltered using a twopole digital low-pass ﬁlter with a cutoﬀ at 18 Hz. A biexponential ﬁtting of the pressure decay curve is then performed, which allows estimation of the derived occlusion pressure (Poccl). Rup is then calculated as follows: Rup mean pulmonary artery pressure Poccl ¼ ð%Þ mean pulmonary artery pressure Ppao where Ppao is the ﬁnal pulmonary artery occluded pressure (wedge pressure). In patients with

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Fig. 13. Angioscopic ﬁndings in CTEPH. Note the ﬁbrotic white material with membranes, webs, and pitting.

Fig. 14. Angioscopic ﬁndings in CTEPH. Note the yellow plaque prominent in B, G, and K. Membranes, webs, and masslike ﬁbrotic tissue can be seen.

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Fig. 15. Pulmonary artery pressure occlusion waveforms from two patients with (A) mainly upstream resistance and (B) mainly downstream resistance. In A the pressure drops more rapidly with balloon occlusion, resulting in lower Poccl and higher Rup%.

small-vessel arteriopathy the Poccl pressure is higher (a longer time is required for the pressure to reach Ppao), and therefore the Rup % is lower (Fig. 15). In a study [37] of 26 patients with suspected CTEPH, there was an excellent correlation between Rup % before pulmonary thrombendarterectomy and hemodynamic response to surgery. Moreover, all four patients with Rup % below 60 did not survive surgery (Fig. 16). Coronary arteriography Before pulmonary thrombendarterectomy the authors routinely perform coronary arteriography on all male patients above the age of 40 and female patients above the age of 45 and do so for

younger patients if ﬁndings are suggestive of coronary disease. In the presence of markedly enlarged proximal pulmonary arteries, the left main pulmonary artery may become compressed and give the appearance of ostial left main stenosis [38]. Best visualized in the let anterior oblique cranial view (Fig. 17), this ﬁnding is usually devoid of other evidence of atherosclerosis and is not in itself an indication for bypass surgery, especially if the patient’s pulmonary pressures decrease after surgery. Summary Cardiac catheterization of the patient with pulmonary hypertension plays an integral part in

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Fig. 16. Correlation between preoperative Rup % and postoperative outcomes. (A) Postoperative pulmonary resistance (B) Mean postoperative pulmonary pressure. (Reproduced from Kim NH, Fesler P, Channick RN, et al. Preoperative pulmonary partitioning of pulmonary vascular resistance correlates with early outcome after thromboendarterectomy for chronic thromboembolic pulmonary hypertension circulation. 2004;109:19; with permission.)

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Fig. 17. Left main ostial compression from an enlarged pulmonary artery. (Reproduced from Bonderman D, Fleischmann D, Prokop M, et al. Imges in cardiovascular medicine. Left main coronary artery compression by the pulmonary trunk in pulmonary hypertension. Circulation 2002;105:265; with permission.)

the diagnostic evaluation. Right-heart hemodynamics, pulmonary angiography, and pulmonary angioscopy oﬀer a way to determine the cause of disease safely and accurately and to oﬀer potentially life-saving therapies.

References [1] Dotter CT, Jackson FS. Death following angiocardiography. Radiology 1950;54:527–33. [2] Diamond EG, Gonlubol F. Death following angiocardiography: report of two cases after administration of diodrast and neo-iopax, respectively. N Engl J Med 1953;249:1029–31. [3] Alexander JK, Gonzales DA, Fred HL. Angiographic studies in cardiorespiratory diseases: special reference to thromboembolism. JAMA 1966;198: 575–8. [4] Snider GL, Ferris E, Gaensler EA, et al. Primary pulmonary hypertension: a fatality during pulmonary angiography. Chest 1973;64:628–35. [5] Caldini P, Gensini GG, Hoﬀman MS. Primary pulmonary hypertension with death during right heart catheterization. Am J Cardiol 1959;519–27. [6] Mills SR, Jackson DC, Older RA, et al. The incidence, etiologies, and avoidance of complications of pulmonary angiography in a large series. Radiology 1980;136:295–9. [7] Nicod P, Peterson KL, Levine M, et al. Pulmonary angiography in severe chronic pulmonary hypertension. Ann Intern Med 1987;107:565–8. [8] Rich S, Dantzker DR, Ayres SM, et al. Primary pulmonary hypertension: a national prospective study. Ann Intern Med 1987;107:216–23.

[9] Peterson KL, Nicod P. Catheterization and angiography in pulmonary hypertension. In: Shure D, Auger W, Moser K, et al, editors. Cardiac catheterization: methods, diagnosis, and therapy. Philadelphia: W.B. Saunders; 1977. p. 401–14. [10] Kumazaki T. Ioxaglate versus diatrizoate in selective pulmonary angiography. Part II: cardiovascular responses. Acta Radiol 1985;26:635. [11] Smith DC, Lois JF, Gomes AS, et al. Pulmonary angiography: comparison of cough stimulation eﬀects of diatrizoate and ioxaglate. Radiology 1987; 162:617–8. [12] D’Alonzo GE, Barst RJ, Ayres SM, et al. Survival in patients with primary pulmonary hypertension: result from a national prospective registry. Ann Intern Med 1991;115:343–9. [13] Rubin LW, Rich S. Primary pulmonary hypertension. In: Georgiou D, Cao T, Shapiro S, et al, editors. Hemodynamic evaluation in primary pulmonary hypertension. New York: Marcel Dekker; 1997. p. 253–86. [14] Wagenvoort CA. Vasoconstriction and medial hypertrophy in pulmonary hypertension. Circulation 1960;22:535–46. [15] Weir EK, Rubin LJ, Ayres SM, et al. The acute administration of vasodilator therapy in primary pulmonary hypertension: experience from the National Institute of Health Registry on Primary Pulmonary Hypertension. Am Rev Resp Dis 1989; 140:1623–40. [16] Weir EK. Acute vasodilator testing and pharmacological treatment of primary pulmonary hypertension. In: Fishman AP, editor. The pulmonary circulation: normal and abnormal: mechanisms, management and the national registry. Philadelphia: University of Pennsylvania Press; 1990. p. 485–99. [17] Groves BM, Badesch DB, Turkevich D, et al. Correlation of acute prostacyclin response in primary (unexplained) pulmonary hypertension with eﬃcacy of treatment with calcium channel blockers and survival. In: Hummes JR, Reeves JT, Weir EK, editors. Ion ﬂux in pulmonary vascular control. New York: Plenum Press; 1993. p. 317–30. [18] Rich S, Brundage BH. High-dose calcium channelblocking therapy for primary pulmonary hypertension: evidence of long-term reduction in pulmonary arterial hypertension and regression of right ventricular hypertrophy. Circulation 1987;76:135–41. [19] Olivier R, Re´za A, Franc¸ois B, et al. Clinical signiﬁcance of the pulmonary vasodilator response during short-term infusion of prostacyclin in primary pulmonary hypertension. Circulation 1996; 93:484–8. [20] Rich S, Kaufmann E, Levy PS. The eﬀects of high doses of calcium-channel blocker on survival in primary pulmonary hypertension. N Engl J Med 1992;327:76–81.

P. Guillinta et al / Cardiol Clin 22 (2004) 401–415 [21] Sitbon O, Brenot F, Denjean A, et al. Inhaled nitric oxide as a screening vasodilator agent in primary pulmonary hypertension. Am J Respir Crit Care Med 1995;151:384–9. [22] Morales-Blanhir J, Santos S, de Jover L, et al. Clinical value of vasodilator test with inhaled nitric oxide for predicting long-term response to oral vasodilators in pulmonary hypertension. Respir Med 2004;98:225–34. [23] Cockrill BA, Kacmarek RM, Fifer MA, et al. Comparison of eﬀects of nitric oxide, nitroprusside, and nifedipine on hemodynamics and right ventricular contractility in patient with chronic pulmonary hypertension. Chest 2001;119: 128–36. [24] Atz AM, Adatia I, Lock JE, et al. Combined eﬀects of nitric oxide and oxygen during acute pulmonary vasodilator testing. J Am Coll Cardiol 1999;33: 813–9. [25] Rich S, Kaufmann E, Levy PS. The eﬀect of high doses of calcium-channel blockers on survival in primary pulmonary hypertension. N Engl J Med 1992;327:76. [26] Auger WR, Fedullo PF, Moser KM, et al. Chronic major-vessel thromboembolic pulmonary artery obstruction: appearance at angiography. Radiology 1992;182:393–8. [27] Peterson KL, Fred HL, Alexander JK. Pulmonary arterial webs: a new angiographic sign of previous thromboembolism. N Engl J Med 1967;277:33. [28] Haas A, Stiehm R. Takayasu’s arteritis presenting as pulmonary hypertension. Am J Dis Child 1986; 140:372–4. [29] Cho SR, Tisnado J, Cockrell CH, et al. Angiographic evaluation of patients with unilateral massive perfusion defects in the lung scan. Radiographics 1987;7:729–45.

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[30] Arnett EN, Bacos JM, Macher AM, et al. Fibrosing mediastinitis causing pulmonary arterial hypertension without pulmonary venous hypertension. Am J Med 1977;63:634–43. [31] Carlin BW, Moser KM. Pulmonary artery obstruction due to malignant ﬁbrous histiocytoma. Chest 1987;92:173–5. [32] Schermoly M, Overman J, Pingleton SK. Pulmonary artery sarcoma—unusual pulmonary angiographic ﬁndings—a case report. Angiology 1987;38: 617–21. [33] Dalen JE, Banas JS, Brooks HL, et al. Resolution rate of acute pulmonary embolism in man. N Engl J Med 1969;280:1194–9. [34] Peterson KL, Nicod P. Cardiac catheterization: methods, diagnosis, and therapy. In: Shure D, Auger W, Moser K, et al, editors. Pulmonary angioscopy. Philadelphia: W.B. Saunders; 1997. p. 257–65. [35] Shure D, Gregoratos G, Moser KM. Fiberoptic angioscopy: role in the diagnosis of chronic pulmonary arterial obstruction. Ann Intern Med 1985;103:844–50. [36] Ricou F, Nicod PH, Moser KM, et al. Catheterbased intravascular ultrasound imaging of chronic thromboembolic pulmonary disease. Am J Cardiol 1991;67:749–52. [37] Kim NHS, Fesler P, Channick RN, et al. Preoperative partitioning of pulmonary vascular resistance correlates with early outcome after thromboendarterectomy for chronic thromboembolic pulmonary hypertension. Circulation 2004; 109:18–22. [38] Bonderman D, Fleischmann D, Mathias P, et al. Left main coronary artery compression by the pulmonary trunk in pulmonary hypertension. Circulation 2002;105:265.

Cardiol Clin 22 (2004) 453–466

Chronic thromboembolic pulmonary hypertension William R. Auger, MDa,*, Kim M. Kerr, MDa, Nick H.S. Kim, MDa, Ori Ben-Yehuda, MDb, Kirk U. Knowlton, MDb, Peter F. Fedullo, MDa a

Division of Pulmonary and Critical Care Medicine, University of California, San Diego, 9300 Campus Point Drive, La Jolla, CA 92037, USA b Division of Cardiology, University of California, San Diego, 200 West Arbor Drive, San Diego, CA 92103, USA

Throughout the late nineteenth and early twentieth century, several published autopsy reports described massive thrombosis of the major pulmonary vessels. These reports typically described organized thrombus in the pulmonary arteries in association with other diseases, such as tuberculosis, lung cancer, and congenital heart disease. Only rarely was organized thrombus in the pulmonary arteries appreciated in the absence of another pathologic condition [1]. Ante-mortem diagnosis and the description of the syndrome of chronic thrombotic obstruction of the major pulmonary arteries ﬁrst received attention in the 1950s [1–4]. Carroll and colleagues [4] were the ﬁrst to use ﬁrst cardiac catheterization and pulmonary angiography in the characterization of this unusual disease. In 1958, Hurwitt [5] reported the ﬁrst surgical attempt to remove the adherent thrombus from the vessel wall. Although the patient died, this operation provided the conceptual foundation for the distinction between acute and chronic thromboembolic disease of the pulmonary vascular bed and established that an endarterectomy, not an embolectomy, is necessary for a successful surgical remedy for this disease. The ﬁrst bilateral pulmonary thromboendarterectomy through a transverse sternotomy using cardiopulmonary bypass is credited to Houk and colleagues [6] in 1963. Reports describing the natural history and clinical characteristics of

* Corresponding author. E-mail address: [email protected] (W.R. Auger).

chronic thromboembolic disease and small, anecdotal series reporting surgical successes in the treatment of this disorder appeared with increasing frequency over the ensuing 2 decades [7–14]. A review of the world’s experience with pulmonary thromboendarterectomy up to 1985, however, showed an overall perioperative mortality rate of 22% in the 85 operated patients [15]. Consequently, although chronic thromboembolic pulmonary hypertension (CTEPH) was acknowledged as a potentially curable form of pulmonary hypertension, the operative risks, the limited availability of specialty diagnosticians and surgeons capable of evaluating and treating this disorder, and underrecognition of the disease by the worldwide medical community continued to relegate CTEPH to the realm of a medical oddity with a poor prognosis until the late 1980s. With improved diagnostic capabilities, surgical techniques, endarterectomy instrumentation, and postoperative management, Daily and Moser [16–19] at the University of California, San Diego (UCSD) subsequently published several reports heralding the advancements in managing CTEPH. In 1987, Moser and colleagues [17] reported the largest series of operated CTEPH patients at a single medical center to date (42 patients); in-hospital mortality was 16.6%. In addition, this publication documented the considerable postoperative improvements in pulmonary hemodynamics and functional capacity experienced by these patients, clinical gains that were sustained a year or more beyond surgery. During the past 2 decades, there has been a steady rise in the number of CTEPH patients

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undergoing surgery and in the number of programs worldwide dedicated to the diagnosis and management of this patient population. At UCSD, more than 1600 patients from national and international referral sources have undergone pulmonary thromboendarterectomy between 1989 and 2003 [20]. Programs in North America, Europe, Japan, and Australia have evolved to manage an increasing medical need [21–30]. Although the growing number of CTEPH patients might seem to reﬂect an increasing prevalence of disease, the most likely explanation is greater physician recognition of this disorder. The rise in worldwide interest is further fueled by the understanding that medical management of CTEPH is ineﬀective in altering prognosis, that perioperative mortality rates are declining, and that pulmonary thromboendarterectomy can dramatically improve pulmonary hemodynamic status, functional outcome, and long-term survival.

Natural history The pathophysiologic events leading to CTEPH are not entirely understood. Contributing to the gaps in the understanding of this process has been the typical presentation of patients late in the course of the disease, often without a history of a venous thromboembolic event or events. Consequently, a retrospective piecing together of historical and clinical clues, along with a knowledge of the natural history of acute thromboembolic events, has by necessity become the foundation of the understanding of the evolution of CTEPH. The development of CTEPH seems to be an extension of the natural history of acute pulmonary embolism, although it occurs in only a minority of patients. Although estimates vary, chronic thromboembolic disease of suﬃcient severity to require surgical intervention results in approximately 0.1% to 0.3% of patients surviving an acute embolic event [30,31]. Thrombus resolution with restoration of normal gas exchange and exercise tolerance occurs in most patients who experience an acute thromboembolic event. Recent data, however, suggest that incomplete anatomic and hemodynamic recovery occur more often than previously realized in patients who have been diagnosed with acute thromboembolic disease and who have received appropriate therapy, placing some of these patients at risk for developing CTEPH [32–34]. It is also apparent

that apparently acute pulmonary embolic events may be asymptomatic or may be misdiagnosed symptomatic embolic events [35,36], adding further to the pool of potential CTEPH candidates. In either scenario, inadequate thrombus resolution following one or more embolic events seems to be the inciting condition in most patients who eventually develop chronic thromboembolic disease of the major pulmonary vessels [37–39]. Deﬁning an underlying predisposition that might account for the aberrant pathway following a thromboembolic event or events has been elusive in most CTEPH patients. In a small number of patients with established disease, abnormal ﬁbrinolysis can be identiﬁed [40,41] or a prothrombotic risk factor can be detected. The presence of a lupus anticoagulant or anticardiolipin antibodies can be established in 10% to 24% of patients with chronic thromboembolic disease [42,43]. Hereditary thrombophilias such as protein C, protein S, and antithrombin III deﬁciencies cumulatively appear in less than 5% of patients [30]; factor VLeiden can be detected in 4% to 6.5% of CTEPH patients [43,44]. The incidence of other thrombophilic tendencies, such as the prothrombin gene mutation 20,210 G/A, elevated factor VII levels, and hyperhomocystinemia, have not been adequately established in this patient population [44]. A retrospective review of the clinical course of most CTEPH patients reveals that there is invariably an intervening period of months to years before cardiopulmonary complaints ﬁrst appear if the initial, suspected thromboembolic event was asymptomatic. For patients left with a modest degree of exercise intolerance after a pulmonary embolic event, a slow progression of symptoms is typically observed. During this period pulmonary hypertension and compensatory right ventricular changes slowly occur. Numerous factors probably aﬀect the progression of these changes and, therefore, the timing of patient presentation. For example, the patient’s age, previous physical health and state of conditioning, residence at altitude, and comorbid medical conditions (eg, chronic obstructive pulmonary disease [COPD], or coexisting coronary artery disease) seem to inﬂuence the clinical impact of chronic thromboembolic disease on any individual patient. What remains unclear is the pathophysiologic basis for the progression of pulmonary hypertension during this period. In certain patients, hemodynamic progression may involve thromboembolic recurrence or in situ pulmonary artery thrombosis. Small-vessel hypertensive arteriopathy, similar to

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that seen in other forms of pulmonary hypertension, seems to develop in most CTEPH patients [45,46]. This supposition is supported by several observations in this patient population: (1) pulmonary hemodynamic progression typically occurs in the absence of recurrent pulmonary embolic events or in situ pulmonary artery thrombosis; (2) there is a poor correlation between the extent of central vessel occlusion and the degree of pulmonary hypertension, suggesting that a component of the increased pulmonary vascular resistance is from the unobstructed, distal vascular bed; and (3) histopathology demonstrates hypertensive arteriopathic changes in the resistance of vessels of lung regions both involved and uninvolved in proximal vessel–organized thromboembolic disease [45]. If CTEPH is left untreated, or should a patient’s cardiopulmonary symptoms go undiagnosed (or be misdiagnosed), progressive pulmonary hypertension, right ventricular failure, and ultimately death are the expected outcomes. Long-term survival of untreated CTEPH patients is poor and correlates with the degree of pulmonary hypertension at the time of presentation. Riedel and colleagues [37] demonstrated that the 10-year survival probability in thromboembolic patients with mean pulmonary pressure between 31 mm Hg and 40 mm Hg at the time of presentation is 50%. If the initial mean pulmonary artery pressure is 41 mm Hg to 50 mm Hg, survival probability declines to 20% over 10 years, and when the initial mean pulmonary pressure is above 50 mm Hg, 10-year survivorship is only 5%. A recent report from Poland reached similar conclusions [47]. In this study, 49 CTEPH patients deemed unsuitable for surgery were treated with anticoagulants only. Prognosis was adversely aﬀected by the presence of signiﬁcant pulmonary hypertension (mean pulmonary artery pressure > 30 mm Hg), coexisting chronic obstructive pulmonary disease, and poor exercise tolerance. Clinical presentation and patient evaluation At initial presentation, CTEPH patients most commonly complain of exertional dyspnea and an unexpected decline in exercise capabilities. Although individual tolerances vary, the physiologic basis for these complaints relates to limitations in cardiac performance caused by an elevated pulmonary vascular resistance and increased minute ventilatory needs from an elevated alveolar dead space. Patients can experience a nonproductive

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cough, especially with exertion. Hemoptysis occurs rarely and is generally from a bronchial arterial source. Atypical chest pains are often pleuritic in nature, presumably because of peripherally infarcted lung. Exertion-related chest discomfort also occurs, however, and can often focus the initial patient evaluation on the status of the coronary vessels. This complaint typically occurs late in the course of CTEPH, as does exertionrelated presyncope, syncope, and resting dyspnea. At this point right ventricular function is unable to accommodate normal metabolic demands. The nonspeciﬁcity of these complaints contributes to the diagnostic delay experienced by most patients with chronic thromboembolic disease. Reports indicate that the delay from the onset of cardiopulmonary symptoms to the correct diagnosis can often range between 2 to 3 years [22,30]. The patient’s age, the presence or absence of coexisting cardiopulmonary disease, and prior level of physical conditioning (sedentary versus athletic) further complicate the timing and severity of symptoms at initial presentation. It is uncommon for a patient to present with a history and array of symptoms that immediately focus the diagnostician’s attention on the possibility of chronic thromboembolic disease. Consequently, during the course of their illness many CTEPH patients have been improperly labeled with alternative diagnoses, such as physical deconditioning, mild COPD, new-onset asthma, valvular heart disease, or, on occasion, psychogenic dyspnea. Findings on physical examination are generally most remarkable during the more advanced stages of disease. Even in the setting of severe pulmonary hypertension, patients can appear relatively well. The ﬁndings of pulmonary hypertension—a right ventricular lift, an accentuated pulmonic component of the second heart sound, a right ventricular S4 gallop, and tricuspid regurgitation—need to be carefully discerned. Only when signiﬁcant right ventricular dysfunction intervenes do severe tricuspid regurgitation, jugular venous distension, a right ventricular S3 gallop, hepatomegaly, ascites, peripheral edema, and cyanosis become evident. Lower-extremity examination may also disclose superﬁcial varicosities and venous stasis skin discoloration in patients with prior, symptomatic venous thrombosis. Unless there is coexisting parenchymal lung disease or airﬂow obstruction, auscultation of the lungs is typically normal. In approximately 30% of patients, a pulmonary ﬂow murmur can be auscultated over the lung ﬁelds [48]. Distinct from murmurs of

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a cardiac origin, these vascular bruits arise from turbulent ﬂow across large, narrowed pulmonary vessels. Therefore they would not be present in a small-vessel pulmonary vascular disease such as idiopathic (primary) pulmonary arterial hypertension. These bruits, however, are not speciﬁc for CTEPH. They can be found in any disease state that is characterized by focal narrowing of major pulmonary vessels and have been described in congenital branch stenoses of the pulmonary arteries and large-vessel pulmonary vasculitis. Routine hematologic and blood chemistry tests can detect secondary organ dysfunction in the case of signiﬁcant right ventricular impairment. Longstanding hypoxemia may result in polycythemia; blood urea nitrogen, serum creatinine, and uric acid levels can be elevated as a result of a poor cardiac output and reduction in renal blood ﬂow; and hepatic congestion may result in signiﬁcantly abnormal liver function studies. Thrombocytopenia and a prolonged activated partial thromboplastin time in the absence of heparin anticoagulation should alert the clinician to the possible presence of a lupus anticoagulant. Pulmonary function testing, typically performed during an evaluation of a patient’s dyspnea, is most useful in deﬁning coexisting parenchymal lung disease or airﬂow obstruction. For patients with CTEPH alone, spirometry is generally unremarkable, although lung-volume measurements may disclose mild to moderate restrictive impairment caused by parenchymal scarring from prior lung infarction [49]. A mild to moderate reduction in single-breath diﬀusing capacity for carbon monoxide (DLCO) can be present in CTEPH. A normal value, however, does not exclude consideration of this diagnosis, and a severe reduction in DLCO suggests an alternative diagnosis that signiﬁcantly aﬀects the small pulmonary vascular bed [50–52]. Resting arterial blood gas analysis generally reveals a relatively normal oxygen level (PaO2), although, when measured, dead-space ventilation can be elevated. With exercise, CTEPH patients often exhibit a decline in PaO2 levels and an inappropriate increase in dead-space ventilation. These ﬁndings reﬂect ventilation-perfusion (V/Q) inequalities and an inappropriate cardiac output response to exercise; the latter manifests in a low mixed venous oxygen saturation [53]. Hypoxemia at rest suggests severe right ventricular dysfunction or the presence of a right-to-left shunt through a patent foramen ovale. Chest radiography can be deceptively normal in the early stages of CTEPH. With the develop-

ment of signiﬁcant pulmonary hypertension, enlargement of the right ventricle and pulmonary outﬂow tract can be observed. Dilatation of the central pulmonary vessels, which is occasionally mistaken for hilar adenopathy, is also a radiographic feature at this stage. Although symmetric dilatation is seen in patients with small-vessel pulmonary hypertension, CTEPH patients often demonstrate irregularly shaped and asymmetrically enlarged proximal vessels [54,55]. In the absence of coexisting parenchymal lung disease, inﬁltrates are not typical features of CTEPH, although hypo- and hyperperfused lung regions may be present. In poorly perfused lung, peripheral alveolar opacities and linear scarlike lesions from prior infarctions are commonly observed. Pleural eﬀusions, however, are uncommon unless right ventricular dysfunction, high right atrial pressure, volume overload, and ascites are clinically evident. The clinical presentation and results of the routine studies are occasionally suﬃcient to raise suspicions of a cardiac or pulmonary vascular cause for a patient’s complaints. These possibilities should also be entertained when a pulmonary diagnosis cannot be readily established as the basis for an individual’s exertional dyspnea. Transthoracic echocardiography then becomes a valuable study to suggest or conﬁrm elevated pulmonary pressures and to exclude primary pathology of the left ventricle, valvular disease, or intracardiac shunting as the cause for the pulmonary hypertension. Current technology allows an estimate of pulmonary artery systolic pressures with Doppler analysis of the degree of tricuspid regurgitation and an estimate of cardiac output. Right-heart chamber enlargement, abnormal right ventricular systolic function, paradoxical interventricular septal motion, and the impact of an enlarged right ventricle on left ventricular ﬁlling are additional echocardiographic ﬁndings in the setting of significant pulmonary hypertension [56]. The venous injection of contrast medium or agitated saline during echocardiography is of additional value in detecting a patent foramen ovale or a previously unsuspected septal defect. In symptomatic patients with echocardiographic evidence of only minimal pulmonary hypertension or modest right ventricular compromise at rest, a study obtained during exercise may document a substantial rise in pulmonary artery pressures along with an increase in right-heart size. This ﬁnding depicts the physiologic basis for a patient’s exertional dyspnea and underscores the observation that with chronic

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thromboembolic obstruction of suﬃcient extent, the normal pulmonary vasodilatory response to exercise is abolished, and augmentation of cardiac output is accompanied by a nearly linear increase in pulmonary artery pressures [57]. Once the diagnosis of pulmonary hypertension has been established, radioisotopic V/Q scanning plays a pivotal role in distinguishing between large-vessel occlusive disease and small-vessel pulmonary vascular disease [55,58]. Patients with CTEPH invariably demonstrate one or more segmental or larger perfusion defects in lung regions with normal ventilation (Fig. 1). This ﬁnding is in contrast to the normal or mottled subsegmental perfusion pattern observed in idiopathic pulmonary arterial hypertension or in other forms of small-vessel pulmonary vascular disease [59,60]. The magnitude of perfusion defects in chronic thromboembolic disease often understates the actual degree of vascular obstruction as determined by angiography or at surgery [61]. During the process of organization proximal vessel thromboemboli may recanalize or narrow

Fig. 1. Lung perfusion study in a patient with chronic thromboembolic pulmonary hypertension. Ventilation scan was normal.

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the vessel so that, to a limited degree, radiolabeled macroaggregated albumin may pass beyond the region of partial obstruction, thereby creating gray zones or areas of relative hypoperfusion on V/Q scan. Furthermore, mismatched segmental defects in patients with pulmonary hypertension are not speciﬁc for chronic thromboembolic disease. Extrinsic compression of proximal vessels (as seen with mediastinal adenopathy or ﬁbrosis, primary pulmonary vascular tumors, pulmonary veno-occlusive disease, and large-vessel pulmonary arteritis) may result in a V/Q appearance indistinguishable from CTEPH [62–64]. Consequently, additional imaging studies are typically necessary to establish diagnosis. Despite the increasing reliance on CT of the chest in the evaluation of the pulmonary vascular bed and thromboembolic disease, its role in patients with suspected CTEPH remains incompletely deﬁned. CT ﬁndings in chronic thromboembolic disease include mosaic perfusion of the lung parenchyma, central pulmonary vessel enlargement accompanied by variation in the size of segmental-level vessels (often diminutive in lung regions most involved with chronic thrombi), peripheral, scarlike densities in hypoattenuated lung regions, and the presence of mediastinal collateral vessels [65–68]. With contrast enhancement, organized thrombus often seems to line the larger pulmonary vessels in either a concentric or eccentric manner (Fig. 2). This appearance is to be distinguished from the intraluminal ﬁlling defects seen in acute thromboembolic disease. CT imaging is also valuable in providing information about the status of the lung parenchyma in patients with coexisting emphysematous or restrictive lung disease and in detecting mediastinal pathology that might account for occlusion of the central pulmonary arteries [69], particularly in patients with unilateral occlusion of a main pulmonary artery [70,71]. Thromboemboli may organize and become endothelialized in such a manner that their presence on CT angiography may not be apparent, however. Consequently, the absence of lining thrombus within the central pulmonary vessels does not exclude the diagnosis of chronic thromboembolic disease or the possibility of surgical intervention. Conversely, the demonstration of central thrombus has been described in primary pulmonary hypertension and other end-stage lung disorders [72,73]. Surgical endarterectomy in these cases involves a substantial perioperative mortality risk and is unlikely to mitigate the existing pulmonary hypertension. As

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Fig. 2. Contrast chest CT scan in the patient shown in Fig. 1. Features of CTEPH include variable parenchymal perfusion (mosaic perfusion), web defects involving the right main pulmonary artery, irregularity and abrupt narrowing of the right descending pulmonary artery, intimal thickening of the left descending pulmonary artery, and bronchial collaterals.

a result, CT of the chest in the evaluation of the pulmonary hypertensive patient, although valuable in many respects, should not be the sole determinant in deciding whether or not a patient with suspected CTEPH is a candidate for surgical intervention. For patients with suspected chronic thromboembolic disease, right-heart catheterization and pulmonary angiography should be pursued. Pulmonary angiography, in most cases, is the most reliable means of deﬁning the extent and proximal location of organized thromboemboli. Several angiographic patterns have been found to correlate with the presence of chronic thromboembolic material at the time of surgery [74]. These patterns include vascular webs or bandlike narrowings, intimal irregularities, pouch defects, abrupt and often angular narrowing of major pulmonary arteries, and obstruction of pulmonary vessels, frequently at their point of origin. These ﬁndings are distinct from the intraluminal ﬁlling defects observed in acute pulmonary embolic disease, and in most patients with CTEPH two or more of these angiographic ﬁndings are present (Fig. 3), usually with bilateral involvement. Despite the value of pulmonary angiography, in a subgroup of patients the diagnosis of chronic thromboembolic disease and the surgical accessibility of the suspicious lesions by angiography

Fig. 3. Right pulmonary arteriogram of a patient with CTEPH in the anteroposterior and lateral projections. The anteroposterior projection demonstrates extensive areas of hypoperfusion with complete occlusion of a branch to the upper lobe and marked irregularity of the main descending pulmonary artery. The lateral projection shows a pouch occlusion of the descending pulmonary artery after the middle lobe of the right lung with absence of ﬂow to the entire right lower lobe. Because of overlap in the anteroposterior projection, the degree of chronic thromboembolic disease and its exact anatomic location are more clearly delineated in the lateral projection.

remain a question. Visualization of the vascular intima with a pulmonary angioscope has proven to be a useful in addressing this issue [75]. The angioscope, a ﬁberoptic device 120 cm in length and 3.0 mm in external diameter with 180( ﬂexion and extension capabilities at its tip, is introduced through an internal jugular vascular sheath and passed into the pulmonary arteries using ﬂuoroscopic guidance. Inﬂation of a balloon tied to the tip of the angioscope obstructs pulmonary artery blood ﬂow and allows visualization of the vessel lumen. Organized thromboemboli appear as irregularities or pitting of the intimal surface, as bands traversing the vascular lumen, as irregularly shaped vessel ostia, and as recanalization or multiple vascular channels where a single lumen should be present. At the University of California, San Diego (UCSD) Medical Center, angioscopy is performed in approximately 20% to 25% of patients undergoing an evaluation to determine their candidacy for pulmonary thromboendarterectomy. The procedure has proven most useful in predicting a beneﬁcial hemodynamic outcome in patients with relatively modest pulmonary hypertension in whom angiographic ﬁndings did not precisely deﬁne the proximal extent of the chronic

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thromboembolic disease and in conﬁrming operability in patients with severe pulmonary hypertension who would not have been deemed surgical candidates based on angiographic ﬁndings alone [76]. The techniques of pulmonary angiography and angioscopy are described in greater detail in the article by Guillinta et al in this issue.

Surgical selection and preoperative management Patients with suspected chronic thromboembolic pulmonary hypertension undergo evaluation with the goals of establishing the need for surgical intervention, determining the surgical accessibility of the chronic thromboemboli, and estimating the risk of surgery and anticipated hemodynamic outcome for the individual patient. Most patients who ultimately go on to surgery exhibit a pulmonary vascular resistance greater than 300 dynes/ second/cmÿ5. At centers reporting their experience with pulmonary thromboendarterectomy, preoperative pulmonary vascular resistance is typically in the range of 700 to 1100 dynes/second/cmÿ5 [22–30]. At this level of pulmonary hypertension, patients can experience considerable impairment at rest and with exercise, and, in the absence of surgical intervention, prognosis is poor [37,47]. For patients with less severe pulmonary hypertension, surgery is considered based on individual circumstances. Included in this category are patients with chronic thromboemboli involving one main pulmonary artery, those with particularly vigorous lifestyle expectations (eg, professional athletes), and patients who live at altitude. Surgery would be performed to alleviate the exercise impairment associated with high dead space and minute ventilatory demands. Surgery is also occasionally oﬀered to patients with normal pulmonary hemodynamics or mild pulmonary hypertension at rest who have documented elevation of their pulmonary pressures with exertion. This group of patients has received increasing attention during the past several years because of growing concerns that their pulmonary hypertension is likely to progress in the absence of surgical intervention. An absolute criterion for surgery is the presence of accessible chronic thrombi as assessed by pulmonary angiography or angioscopy. The experience of the surgical team dictates what can be considered accessible. Current surgical techniques allow removal of organized thrombi in the main and lobar levels, extending to the proximal seg-

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mental vessels. Dissection of segmental-level thrombus requires greater surgical skill and experience. In either situation, an accurate determination of accessible disease and a prediction that the removal of these lesions will reduce right ventricular afterload and pulmonary pressures are essential for a successful surgical outcome. In this assessment, the proximal location of the chronic thromboemboli is important, and a consideration of the extent of accessible disease in relation to the degree of pulmonary hypertension is critical. With experience, it has become apparent that the increase in pulmonary vascular resistance associated with chronic thromboembolic disease arises not only from the central, surgically accessible lesions but also from the distal, surgically inaccessible thromboemboli and the secondary, small-vessel arteriopathy. Pulmonary thromboendarterectomy relieves only the portion of the pulmonary vascular resistance arising from the accessible component of the chronic thromboembolic disease. Therefore, a focus of the preoperative evaluation is attempting to partition the proximal component of vascular resistance from that caused by distal disease. In patients with a signiﬁcant amount of coexisting distal disease, an endarterectomy of the proximal lesions theoretically will fail to mitigate pulmonary vascular resistance substantially. In patients with severe pulmonary hypertension and right ventricular dysfunction, this surgical outcome is associated with high risk of hemodynamic instability and death in the early postoperative period. Several techniques for evaluating the partitioning of the upstream and downstream components of pulmonary vascular resistance in the CTEPH patient are currently under investigation [77,78]. Kim and colleagues [79], using a pulmonary artery occlusion technique, have demonstrated that a preoperative upstream resistance of less than 60% correlated strongly with signiﬁcant pulmonary hypertension postoperatively and a higher incidence of postoperative death. The third consideration in assessing surgical candidacy is the presence of comorbid conditions that may adversely aﬀect perioperative mortality or morbidity. Coexisting coronary artery disease, parenchymal lung disease, renal insuﬃciency, hepatic dysfunction, or the presence of a hypercoagulable state may complicate patient management during the postoperative period. The reversal of pulmonary hypertension and right ventricular dysfunction with pulmonary thromboendarterectomy often improves hepatic and renal function postoperatively, however, and for

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patients with coronary artery or valvular heart disease, coronary artery bypass grafting or valve replacement can be performed at the time of the pulmonary thromboendarterectomy without increasing surgical risk [80]. Consequently, advanced age or the presence of collateral disease is not an absolute contraindication to pulmonary thromboendarterectomy, although they do aﬀect risk assessment and postoperative management strategies. One exception seems to be the presence of severe parenchymal or obstructive lung disease. The postoperative course in these patients frequently is complicated by prolonged ventilatory support, and the cardiopulmonary beneﬁts of pulmonary thromboendarterectomy often result in minimal symptomatic improvement. Recent reports have suggested that the degree of pulmonary hypertension preoperatively correlates with a higher postendarterectomy mortality rate. Hartz et al [24] found that a preoperative pulmonary vascular resistance above1100 dynes/ second/cmÿ5 and a mean pulmonary artery pressure above 50 mm Hg predicted a higher operative mortality. Tscholl and colleagues [81] also showed that a pulmonary vascular resistance above 1136 dynes/second/cmÿ5 adversely inﬂuenced postoperative survivorship [81], and in a recent report of 500 operated patients by Jamieson et al [20], a preoperative pulmonary vascular above 1000 dynes/second/cmÿ5 was associated with a postoperative mortality rate of 10.1%, compared with 1.3% in patients with a preoperative pulmonary vascular resistance below 1000 dynes/second/ cmÿ5. Although these observations have not been substantiated by others [29], they have stimulated interest in the use of pulmonary vasodilator therapy in CTEPH patients before endarterectomy. It is hypothesized that with pulmonary vasodilator therapy the improved pulmonary hemodynamic proﬁle in patients with the severest form of CTEPH would lessen their perioperative mortality risk. Using intravenous prostacyclin for a period of 46 12 days before surgery, Nagaya and colleagues [82] demonstrated a 28% decrease in pulmonary vascular resistance (1510 53 to 1088 58 dynes/second/cmÿ5) and a reduction in brain natriuretic peptide levels in 12 CTEPH patients who ultimately went on to pulmonary thromboendarterectomy. Perioperative mortality in this patient group was 8.3%, compared with no deaths in the group of 21 CTEPH patients with a preoperative pulmonary vascular resistance of 1200 dynes/second/cmÿ5 or less. Postoperative hemodynamic improvement was comparable

between groups. This study, however, failed to determine whether the group with greater pulmonary hypertension would have achieved a similar outcome in the absence of pretreatment.

Pulmonary thromboendarterectomy Because the details of pulmonary thromboendarterectomy are reviewed by Thistlethwaite and Jamieson in an accompanying article in this issue and in other publications [20,83,84], only selected features of the operation are highlighted here. Surgical success requires a true endarterectomy to remove the organized thrombi, not an embolectomy. The chronic thromboembolic material is ﬁbrotic and is incorporated into the native vascular wall. An endarterectomy involves identiﬁcation of the pseudointima and creation of a dissection plane, often down to the media of the vessel, to free the thrombotic residua adequately from the central vascular bed. The removal of nonadherent, partially organized thrombus within the lumen of the central pulmonary arteries is ineﬀective in reducing right ventricular afterload. Creation of too deep a plane poses the risk of pulmonary artery perforation. The operation is performed through a median sternotomy, which allows access to the central pulmonary vessels of both lungs. Because patients with signiﬁcant CTEPH have bilateral disease, the advantages to this approach are evident. A sternotomy also avoids the pleural space and the potential to disrupt pleural adhesions and the extensive collateral bronchial circulation that develops as a result of chronically obstructed pulmonary arteries. Furthermore, this approach achieves adequate exposure if other cardiac procedures, such as coronary artery or valve surgery, are required. In a recent review of 1190 patients undergoing pulmonary thromboendarterectomy at UCSD Medical Center, 90 patients (7.6%) required a combined procedure (excluding closure of a patent foramen ovale, which occurs in approximately 30% of thromboendarterectomies). Eighty-three patients underwent coronary bypass graft surgery, three underwent tricuspid valve repair, two had mitral valve repair, and two required aortic valve replacement [80]. Cardiopulmonary bypass with periods of circulatory arrest is essential to ensure optimal exposure of the pulmonary vascular intima in a bloodless ﬁeld. The signiﬁcant back bleeding created by bronchial arterial blood ﬂow is mitigated by

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interrupting the cardiopulmonary bypass. The periods of circulatory arrest are limited to 20 minutes, with resumption of blood ﬂow and restoration of mixed venous O2 saturation between each period of circulatory arrest. With experience, endarterectomy of either the right or left pulmonary vessel usually can be completed within one arrest period. This exposure allows the circumferential dissection of thromboembolic residua from the involved lobar, segmental, and subsegmental vessels. Over the past few years, modiﬁcations of the surgical approach have been suggested in an eﬀort to decrease risk and improve hemodynamic outcome. Dartevelle and colleagues [85] have suggested the use of intraoperative video-assisted angioscopy to increase visibility in the distal pulmonary arteries, allowing surgical intervention in patients with previously inaccessible disease. Zund et al [21] have advocated division rather than retraction of the superior vena cava to improve exposure of the right pulmonary artery. Selective antegrade cerebral perfusion during circulatory arrest has been proposed to decrease the risk of neurologic sequelae [86]. Outcome following pulmonary thromboendarterectomy Meticulous management of patients following pulmonary thromboendarterectomy and an understanding of the physiologic changes that occur postoperatively are essential to achieving successful outcomes [87]. In addition to complications seen in other forms of cardiac surgery involving cardiopulmonary bypass, such as arrhythmias, coagulation disorders, wound infections, delirium, and nosocomial pneumonia, postendarterectomy patients often experience two unique problems that adversely eﬀect oxygenation during the postoperative period: reperfusion lung injury and pulmonary artery steal. Reperfusion lung injury, clinically and biochemically, seems to be a form of high permeability, neutrophil-mediated lung damage. Leading to the need for prolonged mechanical ventilation (> 2 days) in up to one third of operated patients, severe reperfusion lung injury contributes to perioperative mortality in approximately half of the patients who die following pulmonary thromboendarterectomy. Although the exact pathophysiologic basis for this lung injury remains uncertain, its clinical behavior has been adequately described [88]. The onset of injury typically

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occurs within the ﬁrst 24 hours postoperatively, although it may appear anytime up to 72 hours following surgery. Its severity is highly variable, ranging from mild to moderate hypoxemia in most aﬀected patients, to an acute, hemorrhagic and fatal form. Unique to this type of lung injury is that it is typically limited to endarterectomized lung regions. In these same lung regions, pulmonary arterial blood ﬂow is preferentially distributed, contributing to a greater degree of transpulmonary shunting and hypoxemia. The management of reperfusion lung edema is, to a large extent, supportive until resolution occurs. High-dose corticosteroids have been used to modulate the inﬂammatory component of the process, although their eﬀectiveness is unpredictable. Positional changes occasionally improve V/Q mismatch, although, again, these measures are not uniformly eﬀective. The use of inverseratio ventilation, a low-volume ventilatory strategy to minimize ongoing alveolar damage, and incremental levels of positive end-expiratory pressure have variably proved useful in improving ventilation–perfusion relationships and gas exchange. In a recent study of 47 patients undergoing pulmonary thromboendarterectomy, postoperative avoidance of inotropic catecholamines and vasodilators, along with a strategy of low-volume ventilation (<8 mL/kg), resulted in a lower incidence of reperfusion injury [89]. Inhaled nitric oxide has been reported to improve gas exchange, although experience has suggested that this eﬀect is transient and does not alter disease progression [90,91]. In extreme situations, extracorporeal support has been used successfully when aggressive conventional measures have been inadequate to maintain oxygenation. Further contributing to V/Q mismatching after endarterectomy is the occurrence of pulmonary artery steal, a postoperative redistribution of pulmonary blood ﬂow away from previously well-perfused lung segments and into newly endarterectomized lung regions. Although the basis for the shift in blood ﬂow is uncertain, clinical observations suggest that it occurs in most patients following pulmonary thromboendarterectomy, that it does not result from thrombosis of the nonoperated pulmonary segments, and that the distribution of pulmonary blood ﬂow improves over time in most patients [92,93]. In most CTEPH patients undergoing pulmonary thromboendarterectomy, both the shortterm and long-term hemodynamic outcomes have been favorable. With restoration of blood ﬂow to

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previously occluded lung segments, an immediate reduction in right ventricular afterload occurs, resulting in a decline in pulmonary artery pressures and an augmentation in cardiac output. Since 1997, several groups have reported such improvements in pulmonary hemodynamics following surgery [20,25–29,81,85,89,94,95]. In 500 consecutive operated patients at the UCSD Medical Center between 1998 and 2002, the pre- and postoperative hemodynamic values were mean pulmonary artery pressures, 46 11.0 mm Hg to 28 10.1 mm Hg (P < 0.0001); cardiac output, 3.8 1.3 L/min to 5.5 1.5 L/min (P < 0.0001); and pulmonary vascular resistance, 893 443.5 dynes/second/cmÿ5 to 285 214.7 dynes/second/ cmÿ5 (P < 0.0001) [20]. Furthermore, this hemodynamic improvement has been sustained for months to years after endarterectomy, accompanied by substantial gains in functional status, gas exchange, and quality of life [23,96–101]. Not all CTEPH patients experience normalization or near-normalization of pulmonary hemodynamics after endarterectomy. Approximately 10% to 15% of postoperative patients are left with a residual pulmonary vascular resistance above 500 dynes/second/cmÿ5. Although in two thirds of these patients the postoperative hemodynamic improvement is signiﬁcant, approximately 3% to 5% of operated patients experience minimal to no hemodynamic beneﬁt from surgery. The basis for this lack of improvement relates to the presence of a distal vasculopathy in which the pulmonary pressures and cardiac function are unaﬀected by the removal of chronic thromboembolic material from the proximal vessel. These patients are particularly diﬃcult to manage during the postoperative period. Depending on the level of residual pulmonary hypertension, postsurgical hemodynamic instability may result from the persistently elevated right ventricular afterload and also from the physiologic consequences of cardiopulmonary bypass, deep hypothermia, residual metabolic acidosis, and hypoxemia. Management goals include minimizing systemic oxygen consumption, optimizing right ventricular preload, and providing inotropic support while avoiding systemic hypotension and a drop in coronary perfusion pressure. Pharmacologic attempts at reducing right ventricular afterload in these patients are often ineﬀectual, because pulmonary vascular resistance is ﬁxed, and there is a risk of provoking a decrease in systemic vascular resistance. Inhaled nitric oxide oﬀers a theoretic advantage with its pulmonary vasodilatory

properties and negligible systemic vascular eﬀects. Anecdotal experience with this approach in the setting of persistent postoperative pulmonary hypertension has been disappointing, however. If the patient survives the immediate postoperative period, long-term pulmonary vasodilator therapy, such as the use of intravenous epoprostenol or an endothelin antagonist, should be considered [102]. It has been estimated that more than 2500 pulmonary thromboendarterectomies have been performed worldwide since 1970 [30], approximately 1700 of them at UCSD Medical Center. In patient series reported since 1996, operative mortality rates have ranged between 4.4% and 24% [20,24–29,81,85,89,94,95]. Factors that contribute to perioperative mortality risks have not been completely elucidated, although New York Heart Association class IV functional status, age older than 70 years, the severity of preoperative pulmonary vascular resistance, the presence of right ventricular failure (correlated with high right atrial pressures), morbid obesity, and the duration of pulmonary hypertension have been to reported to aﬀect postoperative survival [20,24,81,103,104]. Attributable causes of death following pulmonary thromboendarterectomy are variable. Cardiac arrest, multiorgan failure, uncontrollable mediastinal bleeding, sepsis syndrome, and massive pulmonary hemorrhage are among the causes of death cited [24,26–29,81]. Severe reperfusion lung injury and residual pulmonary hypertension and right ventricular dysfunction are the leading contributors to perioperative mortality in larger patient series [20]. Since the inception of the pulmonary thromboendarterectomy program at UCSD in 1970, there has been a steady decline in operative mortality rates. For the ﬁrst 200 operated patients between 1970 and 1990, the in-hospital mortality rate was 17.0%. For the 500 patients undergoing pulmonary thromboendarterectomy between 1994 and 1998, the operative mortality rate was 8.8%, declining further to 4.4% for the 500 patients operated on between 1998 and 2002 [20]. Results from this same group have also shown that longterm survivorship following hospital discharge is dramatically improved relative to these patients’ expected longevity without surgical intervention. In a cohort of 532 patients followed postoperatively for up to 19 years, Archibald et al [100] demonstrated a 75% probability of survivorship beyond 6 years. These encouraging results bear testimony to the eﬀectiveness of pulmonary thromboendarterectomy for the treatment of

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appropriately selected CTEPH patients. The declining perioperative mortality rates also possibly result from increasing physician awareness of the disease, prompting referrals to experienced surgical centers before the onset of the severe secondary peripheral arteriopathy and right-heart failure that can be so compromising to patient care. In pulmonary thromboendarterectomy, consistency of patient evaluation, surgical experience, and the knowledgeable delivery of postoperative care are of utmost importance in achieving sustained, positive outcomes.

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Classiﬁcation and epidemiology of pulmonary hypertension Vallerie V. McLaughlin, MD Pulmonary Hypertension Program, Division of Cardiovascular Medicine, University of Michigan, Woman’s RM. L3119, 1500 E. Medical Center Drive, Ann Arbor, MI 48109-0273, USA

In 1951, Dresdale et al [1], having collected data on 39 patients with unexplained pulmonary hypertension, coined the term primary pulmonary hypertension (PPH). Eight years later, Wood [2] described the clinical features of this disease in a series of 17 patients, and by 1971 more than 600 cases had been reported. Meanwhile, in 1967, cardiac catheterization laboratories in Switzerland noted an abrupt increase in the incidence of pulmonary hypertension for which neither a cardiac nor pulmonary cause could be found, and such patients were ultimately diagnosed as having PPH [3]. Shortly thereafter, similar reports from Germany and Austria implicated the popular overthe-counter appetite suppressant, aminorex, as the causative agent. Withdrawal of aminorex from the market was followed by a subsidence of the epidemic. Prompted by this outbreak and the many questions it raised, the World Health Organization (WHO) convened a meeting in 1973 in Geneva, Switzerland, and invited a small group of clinical cardiologists, clinical investigators, and pathologists to assess the understanding of PPH [4]. This meeting marked the beginning of attempts to classify this complex disease. With the widespread acceptance of PPH as a unique disease entity, all other forms of pulmonary hypertension were collectively referred to as secondary pulmonary hypertension. The remarkable advances in knowledge about pulmonary hypertension during the ensuing 25 years led to the second WHO cosponsored symposium on pulmonary hypertension in Evian, France,

E-mail address: [email protected]

in 1998. Larger and more diverse than the 1973 meeting, the Evian meeting addressed a broad array of topics including the nomenclature and classiﬁcation of all pulmonary hypertensive diseases. Fueled by the frustration that had arisen from the categorizing of a vast array of diﬀerent diseases as secondary pulmonary hypertension and the realization that pulmonary hypertension related to certain speciﬁc diseases is clinically and pathologically similar to PPH, new nomenclature, known as the Evian classiﬁcation, was proposed (Box 1). This classiﬁcation focused on the biologic expression of the disease and etiologic factors in an attempt to group these illnesses on the basis of clinical similarities. It served as a useful guide to the clinician both in terms of the diagnostic evaluation and the treatment algorithm. Category I, pulmonary arterial hypertension (PAH) included PPH, and also pulmonary hypertension associated with other disease entities that clinically appears similar to PPH in presentation and response to treatment. In addition, a functional classiﬁcation patterned after the New York Heart Association functional classiﬁcation for heart disease was developed to allow comparisons of patients with respect to the clinical severity of the disease process (Box 2). The main diﬀerence between the WHO functional classiﬁcation of pulmonary hypertension and the New York Heart Association functional classiﬁcation is the inclusion of patients with syncope as functional class IV in the former. The Evian classiﬁcation became well accepted by clinicians and has even been adapted by regulatory authorities for the purposes of drug registration, with both bosentan and treprostinil approved by the Food

0733-8651/04/$ - see front matter Ó 2004 Elsevier Inc. All rights reserved. doi:10.1016/j.ccl.2004.04.001

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Box 1. The Evian clinical classification of pulmonary arterial hypertension Pulmonary arterial hypertension (PAH) 1. Primary pulmonary hypertension Familial pulmonary hypertension 2. Primary pulmonary hypertension associated with Connective tissue disease Congenital heart disease Portal hypertension HIV infection Drugs /toxins (a) Anorexigens (b) Other agents

3. Persistent pulmonary hypertension of the newborn 4. Pulmonary veno-occlusive disease 5. Pulmonary capillary hemangiomatosis Pulmonary venous hypertension 1. Left-sided atrial or ventricular heart disease 2. Left-sided valvular heart disease 3. Extrinsic compression of central pulmonary veins Fibrosing mediastinitis Adenopathy/tumors 4. Other Pulmonary hypertension associated with disorders of the respiratory system or hypoxemia 1. Chronic obstructive pulmonary disease 2. Interstitial lung disease 3. Sleep-disordered breathing 4. Alveolar hypoventilation disorders 5. Chronic exposure to high altitude 6. Neonatal lung disease 7. Alveolar-capillary dysplasia 8. Other Pulmonary hypertension caused by chronic thrombotic or embolic disease 1. Thromboembolic obstruction of proximal pulmonary arteries 2. Thromboembolic obstruction of the distal pulmonary arteries 3. Pulmonary embolism (tumor, ova parasites, foreign material) Pulmonary hypertension due to disorders directly affecting the pulmonary vasculature 1. Inflammatory Schistosomiasis Sarcoidosis Histocytosis X Other Modified from Rich S, editor. Primary pulmonary hypertension: executive summary from the World Symposium – Primary Pulmonary Hypertension 1998. Available at: http://www.who.int/ncd/cvd/pph.html

and Drug Administration for the treatment of PAH. Although the Evian classiﬁcation has served the pulmonary hypertension community well, minor

modiﬁcations were proposed at the Third World Symposium on Pulmonary Arterial Hypertension, held in Venice, Italy, in 2003. Perhaps the most signiﬁcant change was to the nomenclature of PPH.

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Pulmonary arterial hypertension Box 2. WHO functional classification of pulmonary hypertension Class I – Patients with pulmonary hypertension but without resulting limitation of physical activity. Ordinary physical activity does not cause undue dyspnea or fatigue, chest pain, or syncope. Class II – Patients with pulmonary hypertension resulting in slight limitation of physical activity who are comfortable at rest. Ordinary physical activity causes undue dyspnea or fatigue, chest pain, or near syncope. Class III – Patients with pulmonary hypertension resulting in marked limitation of physical activity. They are comfortable at rest. Less than ordinary activity causes undue dyspnea or fatigue, chest pain, or near syncope. Class IV – patients with pulmonary hypertension with inability to carry out any physical activity without symptoms. These patients manifest signs of right heart failure. Dyspnea and/or fatigue may even be present at rest. Discomfort is increased by any physical activity. Modified from Rich S, editor. Primary pulmonary hypertension: executive summary from the world symposium – Primary Pulmonary Hypertension 1998. Available at: http://www.who.int/ncd/cvd/pph.html)

The term primary pulmonary hypertension has been abandon in favor of sporadic or idiopathic PAH, so category I consists of sporadic PAH (IPAH), familial PAH (FPAH), and PAH related to connective tissue disease, congenital heart disease, portal hypertension, HIV infection, drugs and toxins, and other causes (Box 3). Additionally, pulmonary veno-occlusive disease (PVOD) and pulmonary capillary hemangiomatosis (PCH) have been categorized as a subgroup of PAH, because the clinical presentation of and risk factors for these entities are similar. This article focuses on class I, PAH.

Sporadic pulmonary arterial hypertension Although IPAH (formerly referred to as PPH) is the best studied entity in this category, validated indices commonly used to quantify the occurrence of the disease in the population, such as incidence, prevalence, and mortality, are not available in the literature. Nevertheless, the incidence (number of new cases per year in a welldeﬁned population) has been estimated to vary from approximately one to two per 1 million inhabitants in countries such as the United States, France, and Israel [5,6]. Considering the rarity, subtle presentation, and diagnostic dilemma commonly posed by this disease, underdiagnosis and underreporting are probably widespread, making a true calculation of incidence diﬃcult. Lilienfeld and Rubin [7] examined the annual age-adjusted mortality rates for blacks and whites in the United States from 1979 to 1996. The highest mortality rates were noted among infants, whereas children in general experienced the lowest death rates. After childhood, death rates increased with age and were greater among women than men and among blacks than whites. The average annual age-adjusted mortality per 1 million persons from 1979 to 1996 was two for white men, ﬁve for black men, three for white women, and nine for black women. These authors also noted a temporal rise in mortality, which may indicate either better diagnosis of cases with no change in the underlying incidence or a real increase in the incidence of the disease. The largest natural history study of IPAH was the National Institutes of Health (NIH) Registry on PPH, which recruited 187 patients from 32 centers from 1981 to 1987 [8]. In this registry, IPAH was deﬁned as a mean pulmonary artery pressure (mPAP) of greater than 25 mm Hg at rest or 30 mm Hg with exercise, in the absence of another cause for the pulmonary hypertension. The mean age of patients enrolled was 36.4 years, with the highest frequency being in the third decade for female patients and in the fourth decade for male patients. Nine percent of patients were more than 60 years of age. The female-to-male ratio was 1.7:1 and was relatively constant throughout age groups. The distribution of patients by race was similar to that of the general population: 12.3% were black, and 2.3% were Hispanic. There was a greater female-to-male preponderance in the black population, at 4.3:1.

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Box 3. Revised* clinical and classification of pulmonary hypertension (Venice 2003) Pulmonary arterial hypertension (PAH) 1. *Idiopathic (IPAH) 2. Familial (FPAH) 3. PAH associated with Collagen vascular disease Congenital systemic to pulmonary shunts Portal hypertension HIV infection Drugs and toxins *Other (thyroid disorders, glycogen storage disease, Gaucher’s disease, hereditary hemorrhagic telangiectasia, hemoglobinopathies, myeloproliferative disorders, splenectomy) 4. Associated with significant venous or capillary involvement Pulmonary veno-occlusive disease (PVOD) Pulmonary capillary hemangiomatosis (PCH) 5. Persistent pulmonary hypertension of the Newborn *Pulmonary venous hypertension 1. Left-sided atrial or ventricular heart disease 2. Left-sided valvular heart disease *Pulmonary hypertension associated with hypoxemia 1. Chronic obstructive pulmonary disease 2. Interstitial lung disease 3. Sleep-disordered breathing 4. Alveolar hypoventilation disorders 5. Chronic exposure to high altitude 6. Developmental abnormalities *Pulmonary hypertension caused by chronic thrombotic or embolic disease 1. Thromboembolic obstruction of proximal pulmonary arteries 2. Thromboembolic obstruction of distal pulmonary arteries 3. Pulmonary embolism (tumor, parasites, foreign material) Miscellaneous: sarcoidosis, histiocytosis x, lymphangiomatosis, compression of pulmonary vessels (adenopathy, tumor, fibrosing mediastinitis) *Modifications from the Evian classification.

The most common presenting symptom was dyspnea (60%), with fatigue (19%), chest pain (7%), syncope (8%), near syncope (5%), palpitations (5%), and leg edema (3%) occurring less commonly at presentation. The mean time from the onset of symptoms to diagnosis was 2.03 4.9 years with a median time of 1.27 years. The mean right atrial pressure (mRAP) at diagnosis was 9.7 6 mm Hg, mPAP was 60 18 mm Hg, and the cardiac index was 2.3 0.9 L/min/m2. A subsequent survival analysis of 194 patients from the NIH registry documented a median survival of 2.8 years [9]. Survival rates at 1, 3,

and 5 years were 68%, 48%, and 34%, respectively. Advanced New York Heart Association functional class was associated with a poor survival, as were three hemodynamic variables: elevated mRAP, decreased cardiac index, and elevated mPAP. An equation to predict survival based on these three hemodynamic factors was formulated and was subsequently validated in an independent group of 61 patients [10]. Age and gender were not predictive of survival. Other retrospective series have documented similar demographics. The mean age of 44 patients diagnosed with IPAH in Israel from 1988 to 1997

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was 43 13 years, and the female-to-male ratio was 3.4:1 [5]. The mean and median time from onset of symptoms to diagnosis was 2.9 and 2 years, respectively. In a retrospective series of 61 IPAH patients in India, the mean age was 22.3 years with a female-to-male ratio of 1:1. The mean duration of symptoms before diagnosis was 2.5 years [11]. The mean age of 223 IPAH patients diagnosed in Japan between 1980 and 1990 was 28.4 17.0 years, and the female-to-male ration was 1.82:1. The mean time from the onset of symptoms until the diagnosis was 2.27 3.05 years [12].

Familial pulmonary arterial hypertension Within 3 years of Dresdale’s original description of IPAH in 1951, he recorded the occurrence of the disease in several members of one family [13]. It became apparent that this familial condition was more common than initially believed but had been unrecognized, in part because of patient and physician unawareness and in part because of the markedly reduced penetrance of the genetic defects. A pioneering report by Loyd et al [14] in 1984 indicated that some of the cases of IPAH had been mislabeled as a result of incomplete family histories. Although the true incidence of FPAH is unknown, initial series suggested that the incidence was rather low. In the NIH registry, there were 12 cases (6%) of familial pulmonary hypertension, deﬁned as disease aﬀecting a ﬁrstorder blood relative, 7 in men and 5 in women [8]. It was noted that patients who had a positive family history were usually diagnosed sooner after the onset of symptoms than were other registry patients (0.68 years compared with 2.56 years; P = 0.0002). Heightened patient and physician awareness in these cases may have led to earlier diagnosis. Notably, there were no diﬀerences in age, hemodynamic data, or symptoms among the familial and sporadic patients in the NIH registry. In a large series of IPAH patients treated with intravenous epoprostenol reported many years later, in 2002, 22 of 162 patients (13.6%) were reported as having familial disease [15]. It is more likely that this ﬁnding represents better recognition of FPAH rather than an increase in the incidence of the disease. FPAH segregates as an autosomal dominant trait but with markedly reduced penetrance [14]. The gene for FPAH has been localized using linkage analysis to chromosome 2q31-33 and has been designated as PPH1 [16]. The bone morphogenetic

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protein receptor type II (BMPR-II) gene (BMPR2), coding for a receptor member of the transforming growth factor beta family (TGF-b), has been identiﬁed as causative of FPAH [17,18]. BMPR-II is a ubiquitously expressed receptor for a family of secreted growth factors named for the bone morphogenetic proteins (BMPs) [19]. Part of the TGFb superfamily, BMPs were originally identiﬁed as proteins regulating growth and diﬀerentiation of bone and cartilage. More recently studies have demonstrated that these multifunctional cytokines regulate growth, diﬀerentiation, and apoptosis of various cell types. Based on analyses of multiple FPAH pedigrees, the FPAH gene seems to be transmitted as an autosomal dominant trait with incomplete penetrance [14,20]. Although vertical transmission, suggestive of a single dominant gene, is evident, the disease may skip generations or aﬀect only a few individuals among several members at risk. It has been estimated that the overall penetrance of the gene is approximately 10% to 20%. The reduced penetrance points to the likely requirement for additional factors, either environmental or genetic, in the pathogenesis of the disease. The worsening of familial disease in subsequent generations is known as genetic anticipation. This phenomenon has been well described in fragile X syndrome and in several dominantly inherited neurologic diseases such as myotonic dystrophy and Huntington’s disease. Genetic anticipation in FPAH was conﬁrmed by Loyd et al [21], who showed that the age at death was 45.6 14.4, 36.3 12.6, and 24.2 11 years in successive generations. Two recent studies have suggested that some cases of so-called IPAH may represent unidentiﬁed familial cases. Having evaluated several American families, Newman et al [22] uncovered a kindred aﬀected by FPAH that spans seven generations and involves ﬁve subfamilies initially not known to be related. This kindred included 12 aﬀected members who were initially thought to have IPAH and seven aﬀected members whose conditions were ﬁrst misdiagnosed as other cardiopulmonary diseases. Mutational analysis of the BMPR2 gene in six aﬀected members revealed the same missense mutation in exon 6. Detailed genealogic investigations revealed that these families were indeed related with common ancestors born in the nineteenth century. This ﬁnding supports the hypothesis that the incidence of FPAH is underestimated, with FPAH patients being categorized as having

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IPAH, particularly when detailed and accurate family histories are not available. Because resolution of this issue has important implications, Thomson et al [23] investigated the BMPR2 gene in a cohort of 50 unrelated patients with a clinical diagnosis of IPAH and no identiﬁable family history of the disease. Eleven diﬀerent heterozygous germline mutations of the BMPR2 gene were identiﬁed in 13 of the 50 patients studied. This ﬁnding suggests that molecular description of IPAH patients, based upon the presence or absence of BMPR2 mutations, may have important implications and further supports the theory that the true incidence of FPAH is higher than previously described. Now that the PPH1 gene has been identiﬁed, screening patients with IPAH or FPAH and family members of patients with FPAH is scientiﬁcally possible, but the appropriate use of this technique remains controversial. A commercially available, sensitive assay to detect mutations in the BMPR2 gene will undoubtedly be expensive and technically diﬃcult because of the size of the gene and the wide variety of sequence variants that have been shown to cause disease. Although families of FPAH patients may request genetic analysis, those carrying the mutation will not necessarily develop the disease, because the penetrance is low. The psychologic and ﬁnancial impact of this knowledge must be considered before testing, and appropriate genetic counseling must be provided. At this point, the role of genetic testing for this disease remains to be deﬁned.

Pulmonary arterial hypertension related to connective tissue disease PAH is a well-known complication of connective tissue diseases such as systemic sclerosis, systemic lupus erythematosus, mixed connective tissue disease, and, to a lesser extent, rheumatoid arthritis, dermatopolymyositis, and primary Sjo¨gren’s syndrome [24–30]. PAH occurs most commonly in association with the scleroderma spectrum of diseases and is the leading cause of scleroderma-related deaths in such patients [31]. Histopathologic changes in PAH associated with connective tissue disease are generally indistinguishable from those of classic IPAH [32]. Evaluating dyspnea in scleroderma patients and distinguishing PAH from pulmonary ﬁbrosis can sometimes present a diagnostic dilemma. Pioneering work by Steen and colleagues [33,34] has

demonstrated that patients with a decreasing or very low (<55%) diﬀusing capacity of carbon monoxide have a high likelihood of developing PAH. A reduction in diﬀusing capacity of carbon monoxide out of proportion to the reduction in vital capacity over time should prompt an evaluation for PAH in a scleroderma patient. Also, when evaluating dyspnea in this patient population, it is also important to exclude other potential confounding factors such as left ventricular dysfunction (both systolic and diastolic) and thromboembolic disease. Although the incidence of PAH in association with the scleroderma spectrum of disease has been estimated to be in the range of 30% to 50% based on echocardiographic studies, a more recent study using right heart catheterization as the basis of diagnosis has demonstrated an incidence of approximately 12%. Mukerjee et al [35] prospectively studied 722 patients with systemic sclerosis and conﬁrmed PAH by right-heart catheterization in 89 patients (12%). The mean age in the patients with PAH was 66 7 years, and there was a 4:1 preponderance of women, a ﬁnding consistent with previous data suggesting that patients with scleroderma-associated PAH tend to be older and that the female-to-male ratio is higher than in patients with IPAH. These investigators also noted an increased incidence of anticentromere antibody positivity in scleroderma patients with PAH. The mean time between the diagnosis of scleroderma and the diagnosis of PAH was 14 5 years. This landmark series also evaluated survival and prognostic factors in scleroderma-associated PAH. The 1-, 2-, and 3-year survival Rates were 81%, 63%, and 56%, respectively. Patients were enrolled in this registry between March 1998 and September 2002, and many received state-ofthe-art medical therapies. Of all the hemodynamic predictors of survival, the only one with independent predictive value was mRAP, for which the hazard ratio was 20.7 (P = 0.0001). In PAH associated with connective tissue disease, unlike IPAH, response to acute vasodilators did not inﬂuence survival. Patients with PAH associated with connective tissue disease may have a poorer prognosis than IPAH patients despite medical therapies. Although similar hemodynamic and exercise endurance beneﬁts were noted in the 12-week, randomized, openlabel trials with epoprostenol in both populations, a survival beneﬁt was noted only in the IPAH group [36,37]. In a large series of PAH patients treated with epoprostenol, Kuhn et al [38] demonstrated

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a higher mortality among patients with an underlying diagnosis of scleroderma than in patients with IPAH, congenital heart disease (CHD), or other PAH etiologies [38]. Kawut et al [39] compared outcomes of a cohort of 22 patients with scleroderma-related PAH with 33 patients with either IPAH, FPAH, or anorexigen-related PAH. Despite similar hemodynamics and treatment strategies, mortality was higher in the group with scleroderma-related PAH. The unadjusted hazard ratio was 2.9 (95% conﬁdence interval [CI], 1.1–7.8; P = 0.03), and the risk seemed to persist after adjustment for a variety of demographic, hemodynamic, and treatment variables.

Pulmonary arterial hypertension related to congenital heart disease Eisenmenger [40] ﬁrst described a patient with cyanosis and dyspnea since infancy who died of massive hemoptysis at the age of 32 years. Postmortem examination demonstrated a ventricular septal defect and severe pulmonary vascular disease. Subsequently, Wood [41] coined the term Eisenmenger syndrome to include all systemic-topulmonary arterial connections leading to pulmonary hypertension and resulting in a right-to-left or bidirectional shunt. The pulmonary vascular involvement from CHD generally follows a period of reduced pulmonary vascular resistance and high pulmonary blood ﬂow that occurs as the result of a large left-to-right shunt. Morphologic changes of the pulmonary vasculature over time include medial hypertrophy of the pulmonary arterioles, intimal proliferation and ﬁbrosis, occlusion of small arterioles, and, eventually, plexiform lesions, all of which are indistinguishable from the morphologic changes found in IPAH. As the pulmonary vascular resistance approaches or exceeds the systemic vascular resistance, the shunt is reversed, and blood ﬂows from right to left. The development of PAH in CHD seems to be related to the size of the defect. Although only 3% of patients with small to moderate-sized ventricular septal defects develop PAH, approximately 50% of those with ventricular septal defects greater than 1.5 cm in diameter develop PAH [42,43]. The type of defect is also important. About twice as many patients with any size ventricular septal defects than with atrial septal defects develop PAH [44,45]. Among those with large defects, almost all patients with truncus arteriosus, 50%

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of those with ventricular septal defects, and 10% of those with atrial septal defects develop PAH [46]. Among those with atrial septal defects, the incidence of PAH is greater in patients with sinus venosus defects (16%) than in patients with ostium secundum defects (4%) [47]. In fact, the debate continues as to whether a patient with a small atrial septal defect and PAH truly has PAH related to CHD or in fact has IPAH. Some patients are diagnosed with severe PAH years after ‘‘successful’’ correction of the congenital defect. In most instances, it remains unclear whether irreversible pulmonary vascular disease was present before the surgical intervention or the pulmonary vascular disease progressed despite the correction. Although the clinical manifestations of PAH associated with CHD include dyspnea and chest pain and in many respects are similar to IPAH, there are some important diﬀerences. Cyanosis may be present as a result of the right-to-left shunt. Although some patients may not appear cyanotic at rest, substantial exercise desaturation suggests a right-to-left shunt. Hemoptysis may occur because of rupture of dilated bronchial arteries. Blood dyscrasias including polycythemia, abnormal hemostasis, and a tendency toward thrombosis are common. Paradoxical embolization across the defect may result in cerebrovascular accidents. Perhaps because of the longstanding nature of the disease, these patients tend to be well compensated, and heart failure is uncommon. Survival in patients with PAH associated with CHD is better than in patients with IPAH. Hopkins and coworkers evaluated 100 patients with either IPAH or PAH related to CHD who underwent evaluation for lung transplantation but did not undergo the procedure [48]. The 1-, 2- and 3-year survival rates were 97%, 89%, and 77%, respectively, in the group with CHD-associated PAH and were 77%, 69%, and 35%, respectively in the IPAH group. Similarly, in a cohort of patients with PAH treated with epoprostenol, survival was greater for those with CHD than for those with IPAH [38].

Pulmonary arterial hypertension related to portal hypertension The recognition of the association of portal and pulmonary hypertension dates back to 1951 [49]. Since then, a number of case series have validated this observation [50–53]. Portal hypertension rather than the hepatic disorder itself seems to be the

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main determining risk factor for developing pulmonary hypertension, leading to the term portopulmonary hypertension [50,54]. Although liver disease is by far the most common cause of portal hypertension complicated by pulmonary hypertension, a minority of patients have portal hypertension secondary to nonhepatic causes such as biliary atresia, extraheptic portal vein obstruction, noncirrhotic portal ﬁbrosis, and idiopathic portal hypertension. The mechanism by which portal hypertension facilitates the development of pulmonary hypertension remains unknown. The presence of a porto-systemic shunt might allow vasoconstrictive and vasoproliferative substances, including serotonin, normally cleared by the liver, to reach the pulmonary circulation. Again, histologically, the disease is indistinguishable from IPAH. Pulmonary arterial hypertension is an uncommon complication of portal hypertension. In a large autopsy series, ﬁndings consistent with PAH were present in 0.73% of patients with cirrhosis compared with 0.13% in unselected autopsied patients [55]. Later studies based on right-heart catheterization data have suggested prevalence between 2% and 5% [52,56,57]. In patients with portal hypertension undergoing evaluation for liver transplantation, the prevalence of PAH has ranged from 3.5% to 8.5% [58– 60]. On average, the diagnosis of PAH is made 4 to 7 years after the diagnosis of portal hypertension, and the risk of developing PAH increases with the duration of portal hypertension [52,61]. Whether the severity of portal hypertension inﬂuences the development of PAH is controversial. The mean age at presentation, in the ﬁfth decade, tends to be slightly greater than that of IPAH patients, and the gender distribution is equal [52–54,62]. Although often the presenting symptoms are similar to IPAH, with dyspnea, chest pain, fatigue, and syncope, some patients are diagnosed serendipitously as they undergo evaluation for liver transplantation. Hemodynamically, compared with IPAH patients, patients with portopulmonary hypertension tend to have a higher cardiac output and lower systemic and pulmonary vascular resistance. When the PAH is untreated, the prognosis is poor, with a mean survival of 15 months after diagnosis [53]. Although patients with portopulmonary hypertension have been excluded from every clinical drug trial to date, some evidence suggests that epoprostenol may be an eﬀective treatment for such patients [63]. Although portopulmonary hypertension is a contraindication to liver transplantation in most instances, in highly

selected individuals the procedure has been shown to reverse the pulmonary vascular disease [64].

Pulmonary arterial hypertension related to HIV infection During the initial years of the HIV epidemic, noninfectious complications of the disease remained undetectable because they were overshadowed by the opportunistic infections and malignancies. With the advent of highly active antiretroviral therapy and the improved prognosis, noninfectious complications have emerged and are now well described in the literature. The ﬁrst case of PAH associated with HIV was reported in 1987 in a 40-year-old homosexual man with HIV and membranoproliferative glomerulonephritis [65]. One year later, Goldsmith et al [66] reported a series of ﬁve HIV-infected hemophiliacs with socalled PPH. Subsequently, two groups each reported series of six cases of PAH from cohorts of 1200 HIV-infected individuals; both groups estimated a cumulative incidence of 0.5% [67,68]. The Swiss HIV Cohort, a large case-control study involving 3349 HIV-infected patients over a period of 5.5 years, demonstrated a cumulative incidence of PAH of 0.57% (19 cases), resulting in an annual incidence of 0.1% [69]. Thus, compared with the annual incidence of IPAH in the general population, HIV infection carries a relative risk for the development of PAH of more than 600. Although every group at risk for HIV infection can be aﬀected, intravenous drug users seem to predominate in the published series. In two series of 86 and 82 patients, intravenous drug users accounted for 42% and 59% of the patients, respectively, whereas this risk factor is observed in approximately one third of the overall HIV population in developed countries [70,71]. Intravenous drug users may have additional risk factors for the development of PAH including foreign particle pulmonary emboli, portal hypertension, and substance abuse (eg, amphetamines and cocaine). The cause of the association remains unclear. The hypothesis of a direct infection of the pulmonary vascular wall has not been conﬁrmed [72,73]. This lack of understanding has led to as-yet-unproven speculation that HIV has an indirect eﬀect on the production of cytokines and growth factors by activated macrophages and lymphocytes. Interestingly, human herpes virus 8 has been implicated in HIV-related Kaposi sarcoma pathogenesis, and recently, an association between

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human herpes virus 8 and IPAH has been described [74]. Another report suggests that HIV-associated PAH may reﬂect a host response to HIV determined by one or more human leukocyte antigen-DR alleles located within the major histocompatibility complex [75]. The clinical and hemodynamic features of HIV-associated PAH are similar to those of IPAH. Survival in patients with HIV-associated PAH seems similar to that in the IPAH population. Opravil et al [69] performed a prospective, case-controlled, single-center study in 19 patients with HIV-associated PAH. The probability of surviving was signiﬁcantly decreased in patients with PAH compared with the control subjects (median survival, 1.3 versus 2.6 years). In a retrospective, uncontrolled, single-center study, Petitpretz and coworkers [76] identiﬁed 20 patients with HIV-associated PAH and compared their outcomes with those of 93 patients with IPAH identiﬁed between 1987 and 1992. Overall survival was poor and was not signiﬁcantly diﬀerent between the groups with HIV-associated PAH and IPAH (46% and 53% survival rates, respectively, at 2 years). Most of the deaths in the HIV group were related to PAH. More recently, Nunes and coworkers [71] reported overall 1-, 2-, and 3-year survival rates of 73%, 60%, and 47%, respectively, among 82 patients with HIV-associated PAH treated at a single center. Univariate analysis indicated that CD4 lymphocyte count of more than 212 cells/mm3, the use of combination antiretroviral therapy, and epoprostenol infusion were related to a better survival.

Pulmonary arterial hypertension related to drugs and toxins The epidemic that followed the introduction of aminorex fumarate has been well documented in the literature. The increase in incidence of pulmonary hypertension in the late 1960s was reported in Switzerland, Austria, and West Germany [3,77,78]. Although only 2% of the population that had taken aminorex developed pulmonary arterial hypertension, 61% of the 582 patients who were identiﬁed as new cases of PPH reported a history of aminorex intake. The relative risk for developing pulmonary hypertension in aminorex users was estimated to be 52:1 compared with patients without any exposure to the drug. Fenﬂuramine derivatives have been prescribed widely as anorectic agents since the early 1960s. Brenot

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and colleagues [79] studied a group of 73 patients with PPH and found that approximately 25% had been exposed to fenﬂuramine. Based on this observation, the International Primary Pulmonary Hypertension Study (IPPHS) was performed [80]. This study found a clear association between appetite suppressants and pulmonary hypertension (odds ratio, 6.3, 95% CI, 3–13.2). Ninety percent of the cases in which use of a speciﬁc product could be conﬁrmed had used a fenﬂuramine derivative. Observations in this trial also indicated that the risk of developing PAH increased markedly with the duration of use, with the relative risk being 23.1 for individuals who took the drug for more than 3 months. Although it is clear that there is a relationship between duration of use and relative risk, reports of individuals developing the disease after as little as 23 days of exposure have been documented [81]. The surveillance of North American Pulmonary Hypertension Study recently conﬁrmed this clear association between fenﬂuramine derivatives and pulmonary hypertension [82]. It also documented a high use of anorexigen among patients with PAH associated with other underlying conditions, such as connective tissue diseases. The withdrawal of these agents from the United States market in September 1997 may have well averted an incipient epidemic in the United States. The exact pathogenetic mechanism of PAH associated with fenﬂuramine derivatives remains unknown. One hypothesis is that alteration of the serotonin pathway might be the common denominator. Serotonin acts as a potent vasoconstrictor, can induce platelet aggregation, and is a potent factor stimulating pulmonary smooth muscle proliferation. The relationship between other amphetamine derivatives and PAH is less clear. The syndrome of pulmonary hypertension as a result of exposure to toxic rapeseed oil was ﬁrst suggested in Spain in early 1981 with the recognition of a multisystem disease that included pulmonary inﬁltrates [83]. Pulmonary hypertension was found in approximately 20% of hospitalized patients in the second through fourth month following the onset of the disease. Alonso-Ruiz et al [84] followed 332 cases of toxic oil syndrome for up to 8 years and found that 8.1% developed PAH. Although the condition regressed in most patients, some developed the more severe form of PAH. Microcystoscopic examination of the lungs of such patients demonstrated pulmonary hypertensive arteriopathy including medial hypertrophy, intimal ﬁbrosis, and plexiform lesions.

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The association of illicit substances with PAH is less clear. In the IPPHS study, use of intravenous drugs or cocaine was associated with an increased risk of the development of PAH (odds ratio, 2.9) but the numbers were small [80]. Interpretation of such data is also clouded by the known risk factors for PAH such as HIV infection and liver disease, which are prevalent in such a patient population. Use of oral contraceptives and antidepressants has not been associated with the development of PAH in well-designed epidemiologic studies. Pulmonary arterial hypertension related to other disease entities Type Ia glycogen storage disease is an autosomal or recessive disorder that is caused by a deﬁciency of glucose-6-phosphatase. It is a rare disease with an estimated incidence of 1 per 100,000; however, since 1980, seven cases of severe PAH have been described in patients with type I glycogen storage disease [85]. It has been suggested that this relationship might result from an abnormal production of vasoconstrictive amines such as serotonin. Again, the pulmonary histology was typical of PAH; however, the clinical course was that of rapidly worsening disease. PAH has been described in association with a variety of hematologic disorders. Primary pulmonary hypertension has been described in a patient with familial platelet storage pool disease [86]. Pulmonary hypertension has long been recognized as a complication of sickle cell hemoglobinopathy, although one must always consider left ventricular diastolic dysfunction in this particular patient population [87]. Other disorders of hemoglobin that have been associated with PPH include the beta-chain Hb Warsaw and Hb Washtenaw resulting in abnormally low oxygen aﬃnity [88,89]. A unifying mechanism for PAH in the hemoglobinopathies has not yet been identiﬁed. A clear association of PAH in the setting of hemorrhagic telangiectasia (Osler-Weber-Rendu syndrome) has been described. This syndrome is an autosomal dominant vascular dysplasia characterized by mucocutaneous telangiectasias aﬀecting primarily the nasal and gastrointestinal mucosa. Arterial venous malformations, particularly in the pulmonary, hepatic, and cerebral circulations, have been described. Although pulmonary arteriovenous malformations may produce clinically signiﬁcant right-to-left shunts and pulmonary hypertension related to a high ﬂow state, some patients develop PAH that is clinically

and histologically indistinguishable from IPAH. Genetic analysis has demonstrated that genes encoding TGF-b receptor proteins, including ALK-1, endoglin, and BMPR2, allow the demonstration of PAH in association with hereditary hemorrhagic telangiectasia [90]. Pulmonary veno-occlusive disease PVOD is a rare form of IPAH. The histopathologic diagnosis is based on the presence of obstructive eccentric ﬁbrous intimal pads within the pulmonary veins and venules. This obstruction may result in arterialization of the pulmonary veins and subsequent alveolar capillary congestion. Other histopathologic features of IPAH, such as medial hypertrophy and muscularization of the arterials with eccentric intimal ﬁbrosis, may also be seen. The pulmonary venous obstruction explains the increase in pulmonary capillary wedge pressure that may be observed in such patients. The disease tends to be patchy and may aﬀect some segments of the lungs and not others. The clinical ﬁndings, along with the ventilationperfusion scan showing diﬀuse, patchy, nonsegmental abnormalities, suggests the diagnosis on a clinical basis [91,92]. CT scans are commonly helpful and may demonstrate smooth interlobular septal thickening, ground-glass opacities, and a mosaic attenuation pattern. Unfortunately, the treatment of PVOD is diﬃcult. Anecdotal reports of the success of calcium-channel blockers in epoprostenol have been tempered by reports of these same treatments producing pulmonary edema. Early referral for lung transplantation should be strongly considered. Pulmonary capillary hemangiomatosis PCH was ﬁrst described in 1978 as a very rare cause of IPAH [93]. Unfortunately there are few reports in the medical literature, and it is diﬃcult to characterize the disease. The typical chest radiograph demonstrates a diﬀuse bilateral reticular nodular pattern associated with enlarged central pulmonary arteries [94]. Ventilation perfusion scans are often abnormal and may show both matched and unmatched defects. Characteristic high-resolution CT ﬁndings include diﬀuse bilateral thickening of the intralobular septae and small, centrilobular, poorly circumscribed, nodular opacities in addition to ground-glass opacities [95]. Histologically the disease consists of small irregular nodular foci of thin-walled, capillary-sized vessels that diﬀusely invade the lung parenchyma, the

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bronchiolar walls, and the adventitia of large vessels. These nodular lesions are commonly associated with alveolar hemorrhage. Changes of hypertensive arteriopathy, including intimal ﬁbrosis and medial smooth muscle cell hypertrophy, are also common. Many patients are young and present similarly to patients with IPAH, although hemoptysis may be more common. It is diﬃcult to distinguish PCH from IPAH clinically. Unfortunately the clinical course is usually one of progressive deterioration, leading to severe pulmonary hypertension, right-sided heart failure, and death. Again there are reports of intravenous epoprostenol being used; however, it may also be associated with the development of severe pulmonary edema [96]. Again, the only deﬁnitive therapy for these patients is bilateral lung transplantation. Persistent pulmonary hypertension of the newborn Persistent pulmonary hypertension of the newborn (PPHN) has been characterized as hypertrophic, hypoplastic, and reactive. In hypertrophic PPHN, the muscular tissue of the pulmonary arteries is hypertrophied and extends peripherally into the acini. PPHN is believed to result from sustained fetal hypertension from chronic vasoconstriction caused by chronic fetal distress. In hypoplastic PPHN, the lungs and pulmonary arteries are underdeveloped, usually as a result of congenital diaphragmatic hernia or prolonged leakage of the amniotic ﬂuid. In reactive PPHN, lung histology is presumably normal, but vasoconstriction causes pulmonary hypertension. High levels of vasoconstrictive mediators such as thromboxane, norepinephrine, and leukotrienes may be contributing factors. Although PPHN can vary in severity, severe cases are usually life threatening. PPHN is commonly associated with severe hypoxemia and the need for mechanical ventilation. Right-to-left shunting at the level of the ductus arteriosus or foramen ovale is common. Inhaled nitric oxide improves oxygenation and the disease course in such patients [97].

Pulmonary venous hypertension Pulmonary venous hypertension is deﬁned most commonly as pulmonary hypertension in the setting of elevated left-heart ﬁlling pressures. A wide variety of cardiac causes such as left ventricular systolic and diastolic dysfunction, mitral valve disease, aortic valve disease, restrictive myopathies,

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and constrictive pericarditis may result in pulmonary venous hypertension. At times patients may present with symptoms similar to PAH, including dyspnea on exertion, fatigue, chest pain, and lower extremity edema. Other cardinal symptoms of pulmonary venous hypertension include paroxysmal nocturnal dyspnea and orthopnea. Treatment of the underlying cardiac disorder is paramount to treating the pulmonary hypertension. Pulmonary hypertension associated with disorders of the respiratory system, or hypoxemia Numerous pulmonary disorders have been associated with pulmonary hypertension, and in such cases pulmonary hypertension tends to be modest, at much lower levels than seen in pulmonary arterial hypertension. Box 3 lists pulmonary disorders of the respiratory system that may be associated with pulmonary hypertension that are classiﬁed under this category. Again, treatment of the underlying disease is paramount to treatment of the pulmonary hypertension. Pulmonary hypertension caused by chronic thrombotic or embolic disease Pulmonary hypertension may be caused by chronic thrombotic or embolic obstruction of the pulmonary vasculature. This group of disorders is categorized as those caused by obstruction of the proximal pulmonary arteries, by obstruction of the distal pulmonary arteries, and by pulmonary embolism. The obstruction may be caused by tumor, parasites, or foreign material. This group of disorders is discussed extensively elsewhere in this issue and is not discussed further here. Miscellaneous causes of pulmonary hypertension Although sarcoidosis is considered a multisystem granulomatous disorder of unknown origin primarily aﬀecting the lung parenchyma, cardiac involvement may be present in up to a third of the cases. Pulmonary hypertension is most commonly the result of severe chronic ﬁbrocystic sarcoidosis and tends to be milder than in patients with pulmonary hypertension of other origins. A small subset of patients with sarcoidosis, however, may present with severe pulmonary hypertension believed to result from direct pulmonary vascular involvement. These patients, like those with

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pulmonary hypertension associated with other diseases, seem to be predisposed to the development of pulmonary vascular disease that is triggered in some way by the sarcoid disease process. Some patients with severe pulmonary hypertension have been treated with intravenous epoprostenol. Although this treatment may be eﬀective in treating right-sided heart failure and in improving pulmonary hemodynamics, it will have no eﬀect on underlying ﬁbrotic lung disease that may still render the patient symptomatic [98]. Other rare causes of pulmonary hypertension that are included in this miscellaneous category include histiocytosis x, ﬁbrosing mediastinitis, adenopathy, persistent pulmonary hypertension of the newborn, and tumors and lymphangiomatosis.

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Cardiol Clin 22 (2004) 367–373

Diagnosis and evaluation of the patient with pulmonary hypertension Nick H.S. Kim, MD a

Division of Pulmonary and Critical Care Medicine, University of California, San Diego, 9300 Campus Point Drive, La Jolla, CA 92037, USA

Deﬁnitions Pulmonary hypertension is deﬁned as mean pulmonary artery pressure greater than 25 mm Hg at rest or greater than 30 mm Hg with exercise [1]. The normal pulmonary circulation is a highcapacitance, low-resistance system; hence, the right ventricle is normally accustomed to relatively low after-load, even during exercise [2]. In pulmonary hypertension, persistent elevation of right ventricular after-load leads over time to right ventricular hypertrophy, enlargement, and ultimately failure. Early attempts at organizing the heterogeneous causes of pulmonary hypertension included anatomically and pathologically based classiﬁcation systems [3]. Although descriptive, these classiﬁcation systems lacked clinical practicality. Instead, clinicians often separated pulmonary hypertension simply into primary (idiopathic) and secondary causes. This division did not address the problem of diagnostic and treatment heterogeneity of the more common causes of pulmonary hypertension represented in the secondary group. The current classiﬁcation system for pulmonary hypertension categorizes pulmonary hypertension by shared clinical attributes [4]. The system oﬀers a more practical approach to diagnosis and classiﬁcation than earlier anatomically or pathologically based versions. Although the system was revised in 2003 at the Third World Symposium on PAH in Venice, Italy, it has maintained its structure and roots in clinical

E-mail address: [email protected]

utility. Pulmonary hypertension is now classiﬁed into ﬁve categories based largely on diagnostic and treatment implications: 1. Pulmonary arterial hypertension (PAH) 2. Pulmonary hypertension related to left-heart disease 3. Pulmonary hypertension related to lung disease or hypoxemia 4. Chronic thrombotic or embolic pulmonary hypertension 5. Miscellaneous McLaughlin’s review of pulmonary hypertension classiﬁcation in this issue gives a more detailed analysis.

Presentation Although presenting symptoms can vary depending on the cause of pulmonary hypertension, dyspnea and fatigue are the most common. In a National Institutes of Health (NIH) registry of 187 patients with PAH, dyspnea was present in 98% of patients and fatigue in 73% by the time of diagnosis [1]. Chest pain related to pulmonary hypertension was present in 47% of this cohort and can mimic angina pectoris. The cause of chest pain is likely from supply–demand mismatch of the right ventricle. Patients can also present with near syncope or syncope, edema, and ascites, all indicative of impaired cardiac output. Right upper quadrant pain can result from hepatic congestion. Hoarseness has been described from the enlarged left pulmonary artery impinging on the recurrent laryngeal nerve (Ortner’s sign).

0733-8651/04/$ - see front matter Ó 2004 Elsevier Inc. All rights reserved. doi:10.1016/j.ccl.2004.04.003

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Nonproductive cough and palpitations are also frequently reported. Productive cough, orthopnea, and wheezing are atypical and should alert the clinician to underlying respiratory disease or congestive heart failure. A careful history and physical examination can often direct the clinician to the cause of pulmonary hypertension. A thorough history should cover potential risk factors and associated conditions: 1. Family history of pulmonary hypertension 2. Current or remote use of anorexigens, amphetamines, or other illicit drugs 3. Connective tissue disease 4. Liver disease 5. HIV 6. Left-heart failure 7. Valvular disease 8. Chronic obstructive pulmonary disease (COPD), interstitial lung disease, or sleep apnea 9. Deep vein thrombosis or pulmonary embolism, thrombophilia There is a female preponderance in idiopathic PAH. Median age at presentation is in the 30s [1]. Familial PAH accounted for 6% of idiopathic PAH in a NIH registry of 187 cases; this number is probably an underestimation of actual prevalence. PAH is seen more frequently in patients who have used appetite suppressants and stimulants. The risk of developing PAH seems to be associated with duration of use [5]. Cocaine and methamphetamine use have also been associated with PAH [6]. PAH has been reported in 0.5% of HIVinfected patients [7]. Portopulmonary hypertension has been reported in 1% to 6% of patients with advanced liver disease [8–10]. PAH has also been seen in patients with liver disease without evidence of cirrhosis or portal hypertension [11]. Congenital heart diseases with systemic to pulmonary shunts can present with Eisenmenger’s complex with right-to-left shunting. These patients can have severely elevated pulmonary pressures (exceeding systemic pressures), often with compensated right-heart function. Connective tissue disease remains the most common cause of PAH. As many as 50% of patients with limited scleroderma (or CREST syndrome) have PAH [12]. Patients with diﬀuse scleroderma more frequently have pulmonary hypertension related to pulmonary ﬁbrosis [13]. An estimated 14% of patients with systemic lupus

erythematosus and 29% of patients with of mixed connective tissue disease have PAH [14,15]. Unlike PAH related to scleroderma, immunosuppression therapy has resulted in pulmonary hypertension improvement in select patients with PAH associated with systemic lupus erythematosus [16,17]. PAH also has been reported in patients with polymyositis, dermatomyositis, and rheumatoid arthritis [18,19]. Chronic thromboembolic pulmonary hypertension (CTEPH) is a potentially curable cause of severe pulmonary hypertension [20]. Representing an insidious sequela of pulmonary embolism, CTEPH has an estimated incidence ranging from 500 to 2500 new cases per year in the United States. Patients with CTEPH typically present with progressive dyspnea similar to patients with PAH. Evidence of prior deep venous thrombosis by duplex ultrasound is present in less than half of CTEPH patients. Unlike PAH, the primary treatment for CTEPH remains surgical (pulmonary thromboendarterectomy), often with rapid clinical improvement and recovery of normal right heart function. (See the discussions of CTEPH by Auger et al and of pulmonary thromboendarterectomy by Thisteltwaite et al in this issue.) At autopsy as many as 40% of patients with COPD have evidence of right-heart enlargement [21]. Pulmonary hypertension (deﬁned in these earlier reports as mean pulmonary arterial pressure >20 mm Hg) can be found in 40% and 70% of COPD patients with a forced expiratory volumes in 1 second of less than 1 L and less than 0.6L, respectively [22,23]. Pulmonary hypertension can be seen in patients with restrictive ventilatory diseases and is typically associated with severely reduced vital capacity and chronic respiratory acidosis on blood gas analysis. Rightheart dysfunction was found in 18% of patients with obstructive sleep apnea (OSA) [24]. Only half of these patients had pulmonary hypertension conﬁrmed by right-heart catheterization (RHC), suggesting the causes of right-heart dysfunction in OSA may be multifactorial. Elevated left atrial pressure and diastolic dysfunction may contribute to pulmonary hypertension seen in OSA [25,26]. Although the presence of pulmonary hypertension in OSA seems to correlate with severity of nocturnal desaturation and the presence of daytime hypoxia, the severity of apnea-hypopnea index does not seem to correlate with the presence of pulmonary hypertension [26–28]. With the exception of patients with severe interstitial lung diseases, the degree of pulmonary pressure

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elevation in patients with underlying lung or ventilatory disease tends to be mild or moderate. In pulmonary hypertension, ﬁndings on physical examination can be subtle. Vital signs may reveal resting tachycardia and reduced systemic pulse pressure. Central cyanosis is present in Eisenmenger’s complex and in pulmonary hypertension with shunting through a patent foramen ovale (PFO). Isolated peripheral cyanosis suggests low cardiac output. Lung examination in PAH and CTEPH is typically normal. Signiﬁcant crackles, evidence of mitral or aortic valve dysfunction, wheezing, or thoracic deformities should suggest underlying lung or left heart disease as the cause of pulmonary hypertension. Jugular venous distention, accentuated pulmonic component of the second heart sound, and tricuspid regurgitation louder with inspiration are characteristic cardiac examination ﬁndings in pulmonary hypertension. Additional signs of right ventricular dysfunction may include edema, ascites, hepatomegaly, and audible right-sided gallop. Diagnostic step 1: suspect pulmonary hypertension The ﬁrst and most important step in successfully making the diagnosis of pulmonary hypertension is considering it in the diﬀerential diagnosis. Pulmonary hypertension should be considered in any patient with persistent dyspnea, fatigue, or exercise intolerance without a readily attributable cause. Pulmonary hypertension should also be considered in any patient with symptoms of cardiopulmonary insuﬃciency who has not demonstrated improvement despite therapy for an initial working, but ultimately incorrect, diagnosis. Once pulmonary hypertension is considered, diagnostic investigation should begin by considering pulmonary hypertension related to left-heart or chronic lung disease. ECG and chest radiographs are two readily available, often valuable initial screening tests for chronic lung disease or left-heart disease. In PAH or CTEPH, ECG may reveal evidence of right ventricular hypertrophy, right atrial enlargement, rightward axis deviation, and right bundle branch block. Presence of P wave of 2.5 mm or greater in lead II and QR pattern in lead V1 were both associated with worsened survival in 51 PAH patients [29]. These ECG ﬁndings may not be present in early pulmonary hypertension [30]. In a cohort of 61 PAH patients, ECG was normal in 13% [31]. Chest radiographs are usually clear of parenchymal disease in PAH. Evidence of

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parenchymal infarct, scarring, or mosaic perfusion pattern may be seen in CTEPH [32]. On upright, posterior-anterior projection, a right descending pulmonary artery greater than 16 mm in width and a left main pulmonary artery greater than 18 mm in width suggest pulmonary hypertension [33]. Pruning of pulmonary arteries distal to the centrally enlarged vessels can be found in both PAH and CTEPH. The cardiac silhouette is often enlarged, particularly with prominence of right heart contour. Diagnostic step 2: echocardiogram and pulmonary function tests Transthoracic echocardiogram is the preferred test for screening for pulmonary hypertension and also for excluding signiﬁcant left-heart or valvular disease. The pulmonary artery systolic pressure (PASP) can be estimated in 59% to 72% of patients using Doppler interrogation of tricuspid regurgitation [34–36]. In patients with signiﬁcant lung disease, the PASP is often overestimated [37]. The presence of enlarged or hypertrophied right ventricle should also raise suspicion of pulmonary hypertension. Additional ﬁndings on echocardiography may include ﬂattening of the intraventricular septum, reduced respiratory variation of the vena cava, pericardial eﬀusion, and PFO [38]. The left ventricle systolic function is typically normal in PAH and CTEPH. Diastolic dysfunction in PAH and CTEPH is usually the result of impairment from an enlarged right heart. Evidence of signiﬁcant left atrial enlargement, leftsided valvular dysfunction or abnormality, or left ventricular systolic dysfunction warrants further investigation. (Daniels et al present a detailed review of echocardiography in pulmonary vascular disease elsewhere in this issue.) Complete pulmonary function testing (PFT) should be obtained in patients with persistent dyspnea and suspicion of pulmonary hypertension. The typical pattern on PFT of patients with PAH and CTEPH is mild restriction with reduced diﬀusion capacity for carbon monoxide (mean 60%) [39]. Normal PFT, however, does not rule out possible pulmonary hypertension. Analysis of arterial blood gases typically reveals chronic respiratory alkalosis and widened A-a gradient. Severe hypoxemia in the absence of pulmonary inﬁltrates suggests intracardiac shunting through a PFO (present in 24% of cases) [38]. Severely reduced diﬀusion abnormality on PFT should be investigated with a high-resolution CT scan

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Step 1. Suspect PH -persistent dyspnea, fatigue -risk factors or associated conditions -exam suggestive -obtain CXR, ECG

PH suspected Step 2. Echocardiogram and PFTs -estimate PA pressure -evaluate right heart size/function -screen for left heart/valvular diseaseA -screen for lung diseaseA -consider sleep test/high resolution CTA pulmonary vascular cause suspected

Step 3. Lung ventilation-perfusion scan -screen for CTEPHB -consider angiogram

PAH suspected

Step 4. Right heart catheterization -confirm PH -screen for left heart/valvular diseaseA -prognostic data -guide treatment decisions Fig. 1. Simpliﬁed four-step diagnostic algorithm for pulmonary hypertension. (A) Further investigate and treat left heart disease or lung-ventilatory disease causing PH. (B) Conﬁrm CTEPH with RHC-angiogram or refer to pulmonary thromboendarterectomy center.

screening for interstitial lung disease. Patients with history of excessive daytime somnolence or witnessed apneas should be tested with overnight oximetry or polysomnogram to rule out pulmonary hypertension related to sleep-disordered breathing. Although the severity of daytime hypoxia correlates with pulmonary hypertension, daytime hypoxia may not always be present. Although cardiopulmonary exercise testing has not been routinely obtained in patients with established pulmonary hypertension, it may be valuable in screening early-stage disease and pro-

vide additional prognostic data [40,41]. Reductions in Vo2max, anaerobic threshold, and ventilatory eﬃciency have been described and shown to correlate with pulmonary hypertension severity [42].

Diagnostic step 3: lung ventilation-perfusion scan Once an isolated vascular cause of pulmonary hypertension is suspected, a ventilation-perfusion scan should be obtained. Perfusion scan ﬁndings

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in PAH fall in three categories: (1) normal, (2) a heterogeneous or mottled pattern, with no defects larger than subsegment in size, or (3) preferential ﬂow to the posterior bases, which can be misinterpreted as CTEPH with upper-lobes involvement [32]. The second and third categories may warrant additional conﬁrmatory testing such as pulmonary angiogram or angioscopy. Although CT angiography has replaced the VQ scans in many centers as the diagnostic tool for detecting pulmonary embolism, the VQ scan remains the preferred screening test in CTEPH.

Diagnostic step 4: right-heart catheterization RHC provides the deﬁnitive diagnosis of pulmonary hypertension and should be obtained in all patients with PAH before treatment. RHC can also provide other diagnostic information and important prognostic data [43]. Obtaining a hepatic occlusion pressure with comparison to inferior vena cava pressure can screen for portal hypertension. In addition to estimating left atrial pressure, RHC can also detect mitral regurgitation and screen for intracardiac shunting. RHC is also required for acute vasodilator testing and, in select patients, for obtaining exercise hemodynamics and early response/titration of epoprostenol therapy. Lastly, RHC data are invaluable when considering treatment decisions from an ever-growing armament of pulmonary hypertension therapeutics (see the review of PAH by Williamson and Channick in this issue). Lung biopsy in pulmonary hypertension is risky and currently is not recommended for almost all cases of pulmonary hypertension. Screening serologic tests (antinuclear antibodies, HIV) and liver function tests should be obtained in patients suspected of having PAH. Although substantial progress has been made in recent years in the area of pulmonary hypertension–related genetics, a genetic screening test is currently not recommended or available for general diagnostic purposes [44,45].

Summary With a thorough history and a few tests, the nature and degree of pulmonary hypertension can be determined eﬃciently (Fig. 1). A high index of suspicion and a step-wise evaluation approach are necessary for accurate and timely diagnosis of pulmonary hypertension.

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Cardiol Clin 22 (2004) 441–452

Diagnosis and treatment of pulmonary arterial hypertension Richard Channick, MDa,*, Timothy L. Williamson, MDb a

Division of Pulmonary and Critical Care, University of California, San Diego, 9300 Campus Point Drive, La Jolla, CA 92037, USA b Division of Pulmonary and Critical Medicine Care Medicine, University of Kansas Hospital, 3901 Rainbow Boulevard, Kansas City, KS 66160, USA

Pulmonary arterial hypertension (PAH) is characterized by an elevated pulmonary vascular resistance (PVR) that, in the absence of intervention, progresses to right ventricular failure and death. When deﬁned clinically as a mean pulmonary artery pressure greater than or equal to 25 mm Hg at rest or 30 mm Hg with exercise, idiopathic PAH has been estimated to aﬀect at least 1 to 2 persons per million population [1], although secondary forms of the disease are much more common. The World Health Organization (WHO) classiﬁcation of pulmonary hypertension (PH) is reviewed in detail in the article by McLaughlin et al. This classiﬁcation is based on expert consensus opinion reached at the WHO Symposium on Pulmonary Hypertension in Evian, France in 1998. It divides PH into ﬁve categories, including PAH, pulmonary venous hypertension, PH associated with respiratory diseases, PH associated with embolic disease, and PH caused by diseases that directly aﬀect the pulmonary vasculature, such as sarcoidosis. Experts recently convened again in Venice, Italy in 2003 [1]. Among the modiﬁcations from the Venice meeting is that pulmonary hypertension without a known association or cause is no longer referred to as primary pulmonary hypertension (PPH), but instead as idiopathic (sporadic) PAH (IPAH) with a separate category for familial PAH (FPAH). Because of the body of literature * Corresponding author. E-mail address: [email protected] (R. Channick).

that has employed the term PPH, this article uses both terms interchangeably. In addition to IPAH, PAH can occur in association with other conditions such as connective tissue disease, congenital heart disease, portal hypertension, HIV, and prior ingestion of stimulant drugs such as fenﬂuramines, amphetamines, or cocaine. Of the various categories, only PAH is discussed in this article. The evaluation of pulmonary hypertension, however, should ascertain its proper cause and classiﬁcation, because many of the treatment options for PAH discussed here are not necessarily eﬃcacious and may be deleterious in patients with pulmonary hypertension secondary to other disorders. Although long considered a disease of pulmonary vasoconstriction, PAH should now more correctly be considered a disease of proliferation. Voelkel and Cool further review the pathology of this disorder elsewhere in this issue. Brieﬂy, PAH is characterized by increased pulmonary arterial thickness, dilated capillaries, and plexiform lesions that obstruct the vessel lumen [2]. Additionally, patients are at risk for in situ thrombosis secondary to increased platelet aggregation as a consequence of decreased nitric oxide and prostacyclin production [3]. Survival in PAH without intervention is dismal. A National Institutes of Health registry followed patients with PPH (idiopathic PAH) between 1985 and 1988, in an era that preceded currently available therapeutic agents [4]. Survival rates at 1, 3, and 5 years were 68%, 48% and 34%, respectively, with a median survival from diagnosis of 2.8 years.

0733-8651/04/$ - see front matter Ó 2004 Elsevier Inc. All rights reserved. doi:10.1016/j.ccl.2004.04.004

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Findings correlated with poorer prognosis included WHO functional class III or class IV (Box 1), presence of Raynaud’s phenomenon, increased right atrial pressure, increased pulmonary artery pressure, decreased cardiac index, and decreased diﬀusion [4]. In another study multivariate analysis suggested pericardial eﬀusion, enlarged right atrium, 6-minute walk distance, and mixed venous oxygen saturation as predictors of adverse outcomes [5]. Not all causes of PAH portend the same survival. Patients with PAH associated with the scleroderma spectrum of diseases, for example, have a worse prognosis than those with idiopathic PAH (PPH) [6]. Pulmonary veno-occlusive disease is associated with perhaps the worst survival, with 1-year mortality following diagnosis exceeding 70% [7]. Diagnosis The diagnosis of PAH requires a high index of suspicion, because presenting symptoms are often protean and common to a multitude of cardiopulmonary disorders. The goals of the PAH evaluation are severalfold: to establish the correct cause of dyspnea, to exclude treatable causes of PAH, to document the presence and severity of pulmonary hypertension and right ventricular dysfunction, to recognize the extent of functional impairment, and to use this information to help formulate a therapeutic regimen. The tools for accomplishing these tasks are largely those used daily by physicians to quantify and qualify other cardiopulmonary disorders, namely clinical ﬁndings, lung function testing, radiographic studies, echocardiograms, heart catheterization, and exercise testing. During the diagnostic process special

attention should be paid to excluding chronic thromboembolic disease, because a potentially corrective surgical procedure exists for this disorder [8,9]. The symptoms of PAH are nonspeciﬁc. Dyspnea is nearly universal as the disease progresses, but fatigue, chest pain, syncope, and near syncope are also common [10]. Given the vague nature of symptoms, it is not surprising that the time from symptom onset to deﬁnitive diagnosis averages 2 or more years [10]. The cardinal ﬁndings on physical examination in PAH are an accentuated second heart sound and a tricuspid regurgitation murmur, but both ﬁndings may be variably present. As pulmonary hypertension progresses, signs of right-heart failure may ensue as evidenced by jugular venous distention, a right ventricular heave, lower extremity edema, hepatomegaly, and ascites. During the physical examination particular attention should also be paid to ﬁndings suggestive of diseases known to be associated with PAH, such as collagen vascular disorders and chronic liver disease, because prognosis and treatment may vary by underlying cause. Additionally, the presence or absence of pulmonary ﬂow murmurs should be noted, because these murmurs are highly suggestive of chronic thromboembolic disease, pulmonary vasculitis, or pulmonic stenosis, and have not been reported in PAH from other causes [9]. Pulmonary function tests are often obtained during the course of an evaluation of dyspnea but have no ﬁndings speciﬁc for PAH. Diﬀusion is often only modestly decreased (69 25) [10]; more severe diﬀusion defects may indicate concurrent parenchymal disease. A pattern of mild

Box 1. World Health Organization functional class in pulmonary artery hypertension Class I: Patients in with pulmonary hypertension, but without resulting limitation of physical activity. Ordinary physical activity does not cause undue dyspnea or fatigue, chest pain, or near syncope. Class II: Patients with pulmonary hypertension resulting in slight limitation of physical activity. Patients are comfortable at rest, but ordinary physical activity causes undue dyspnea or fatigue, chest pain, or near syncope. Class III: Patients with pulmonary hypertension resulting in marked limitation of physical activity. Patients are comfortable at rest, but less than ordinary physical activity cause undue dyspnea or fatigue, chest pain, or near syncope. Class IV: Patients with pulmonary hypertension resulting in inability to perform any physical activity without symptoms. Patients manifest signs of right heart failure. Dyspnea and/or fatigue may be present at rest, and discomfort is increased by any physical activity.

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obstructive lung disease has been described in severe PAH [11]. Radiographic studies may be most useful to exclude competing explanations for dyspnea and, if PAH is present, to aid in excluding secondary causes. Chest radiographs may suggest interstitial or obstructive lung disease and demonstrate enlarged pulmonary arteries or cardiomegaly. CT scans may likewise exhibit enlarged pulmonary arteries and parenchymal lung disease but may also help detect chronic thromboembolic pulmonary hypertension, pulmonary veno-occlusive disease, pulmonary vascular tumors, or extrinsic compression of the pulmonary vessels. Lung perfusion scanning has a pivotal role in the evaluation of PAH, because it may reveal segmental and subsegmental defects consistent with chronic thromboembolic disease, prompting further evaluation by pulmonary angiography. High-probability perfusion scans, although highly suggestive of possible chronic thromboembolic disease, have also been reported in pulmonary veno-occlusive disease [12]. In contrast, lung perfusion scans in PAH are either normal or demonstrate a diﬀuse, mottled appearance. Echocardiography Echocardiography is a relatively inexpensive, noninvasive tool for estimating pulmonary artery pressures and detailing cardiovascular anatomy and function. In addition to providing an estimation of peak pulmonary artery pressure, echocardiography may provide useful assessments of chamber and valve morphology, presence of congenital heart disease, left ventricular systolic and diastolic function, and intracardiac or intrapulmonary shunting [13]. Pericardial eﬀusions are common (present in more than half of patients with severe PAH), and although they often are not hemodynamically signiﬁcant, they may carry prognostic signiﬁcance, with an association with right-heart failure, impaired exercise tolerance, and a poor 1-year survival [14]. Typical ﬁndings in severe PAH may include tricuspid regurgitation, right ventricular or atrial enlargement, and elevated pulmonary artery pressures. Several studies, however, have shown that the accuracy of echocardiography is limited when compared with direct measurement of pulmonary artery pressure by right-heart catheterization. Arcasoy and colleagues [15] examined 374 lung transplant candidates who underwent both procedures. Estimation of systolic pulmonary artery pressures by

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echocardiography was possible in only 44% of the patients, with a correlation coeﬃcient of 0.69. In 52% of patients studied, the diﬀerences between measurements on right-heart catheterization and echocardiography were greater than 10 mm Hg, and 48% of patients classiﬁed as having pulmonary hypertension on echocardiography were found to be misclassiﬁed after right-heart catheterization. Similarly, Cotton et al [16] looked at 78 liver transplant candidates. Systolic pulmonary artery pressures were signiﬁcantly higher when measured by echocardiography than when measured by right-heart catheterization, with a correlation coeﬃcient of only 0.46, and a positive predictive value of 37.5%. Negative predictive value, however, was nearly 92%. Daniels et al present a full discussion of echocardiography in pulmonary vascular disease elsewhere in this issue. Right-heart catheterization Given its limitations, echocardiography should not be used to diagnose PAH deﬁnitively. Rightheart catheterization remains the standard for determining pulmonary artery pressures and should always be performed before initiation of costly or invasive therapy. In addition to direct quantiﬁcation of pulmonary hemodynamics (which are correlated with prognosis [4]), rightheart catheterization may help exclude congenital heart disease, establish the presence and contribution of left-sided heart disease, and quantify vasodilator reserve (discussed further in the section on calcium-channel blockers). The details of the right-heart catheterization procedure are discussed elsewhere in this issue. Functional assessment Functional impairment in PAH may be identiﬁed subjectively or objectively. Subjectively, the WHO functional classiﬁcation detailed in Box 1 categorizes patients by reported exercise tolerance. Although this classiﬁcation system is not perfect, most PAH practitioners are familiar with its application, and it is widely used in research and therapeutic algorithms. Cardiopulmonary exercise testing provides an objective assessment of functional status correlates closely with mortality: a peak VO2max less than 10.4 mL/kg/min independently predicts decreased survival [17]. Cardiopulmonary exercise testing, however, is expensive, time consuming, diﬃcult to perform for many patients with advanced disease, and not universally available. For these reasons submaximal

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exercise testing to determine functional status is desirable. The 6-minute walk has been used as a reliable, well-validated examination in assessing exercise capacity. Simply, patients walk a premeasured course, at their own pace and without encouragement or direction from technicians, and the distance walked is measured. The 6-minute walk distance has been shown to be correlated with survival, with a distance less than 332 m associated with increased mortality [18]. The test is inexpensive, widely available, not overly burdensome to patients or providers, and reproducible. Six-minute walk testing has often served as the primary outcome endpoint in clinical trials of new therapies for PAH.

increase morbidity or mortality. This disease often aﬄicts women of childbearing age, and these patients should be strongly counseled to avoid pregnancy, because the mortality in patients with PAH who become pregnant has been reported to be as high as 30% to 56% [19,20]. Patients are often concerned about the level of activity that they are allowed to undertake. In general, patients should be encouraged to stay active to prevent deconditioning but cautioned to not overexert themselves to the point of severe dyspnea, chest pain, or syncope. Given the adverse eﬀect of altitude on the pulmonary vasculature, patients with PAH should avoid altitudes higher than approximately 4000 feet.

Treatment

Supportive therapies Despite limited evidence of their value, a number of nonspeciﬁc supportive therapies are frequently used in PAH, especially as right-heart failure ensues. The decision to initiate any of these treatments must be made on an individualized basis.

In the past 2 decades an exponential growth of interest and research in PAH has engendered several therapeutic options that were not available as recently as 5 years ago. The ideal goals of treatment are to improve symptoms and survival using the least invasive therapies possible. Given the expanding therapeutic options in PAH, it is important to understand which patients are appropriate for which therapy. Used inappropriately, many of the available PAH therapies have the potential for adversely aﬀecting patient outcome, so the dictum of primum non nocere must be paramount. For example, using PAH medications in patients with even modest degrees of left ventricular systolic or diastolic dysfunction can worsen clinical status. It is recommended that right-heart catheterization be performed before initiating therapy with most agents speciﬁc for the treatment of PAH, because right-heart catheterization is a powerful resource to determine contributions of left-sided heart disease and also provides indirect evidence of right ventricular compensation, knowledge that is useful in selecting the appropriate therapeutic regimen. Patients with WHO functional class III and class IV symptoms should be considered for referral to a center with speciﬁc focus and expertise in the management of pulmonary vascular disorders. General treatments Lifestyle modiﬁcation Treatment should be directed toward both pharmacologic interventions and lifestyle modiﬁcation, with avoidance of behaviors that might

Oxygen. Hypoxemia should be recognized and treated, both at rest and with exercise. When given acutely, 100% oxygen has been demonstrated to reduce mean pulmonary artery pressure and PVR modestly and to increase the cardiac index [21]. Few data exist regarding the long-term beneﬁts of oxygen in this disorder, but extrapolating the positive eﬀect of oxygen therapy on survival in patients with chronic obstructive pulmonary disorder [22], it seems reasonable that hypoxemia should be recognized and treated at rest and with exercise. Additionally, nocturnal oxygen desaturation is common in PAH [23], even in the absence of concurrent sleep-disordered breathing, and adequate oxygenation at night should be assured as well. Wafarin. Warfarin therapy is standard in patients with IPAH (PPH) and is often recommended in other forms of PAH based on two retrospective studies demonstrating a modest survival beneﬁt. PAH may be complicated by in situ thrombosis, and low-level anticoagulation with warfarin is often used in an eﬀort to help prevent this process. Two studies have established a beneﬁcial eﬀect on mortality [24,25]; one of these studies also exhibited improvement in quality-of-life indices [24]. Patients with chronic indwelling intravenous catheters and right-to-left intracardiac shunting may

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be especially strong candidates for chronic anticoagulation. Digoxin. Digoxin is often added to the regimen of patients with right-heart failure. In 17 patients examined in the catheterization laboratory, digoxin was shown to improve cardiac output somewhat and to decrease norepinephrine levels [26]. Long-term data on its eﬃcacy in PAH are lacking, however. Diuretics. Diuretics are also commonly used in PAH to decrease intravascular volume and to improve dyspnea. It is postulated that improvements in right ventricular geometry may decrease septal intrusion into the left ventricle, improving left-ventricular function as well.

Speciﬁc therapies In properly selected patients the therapies discussed here have been shown to modify the course of PAH signiﬁcantly and to improve symptoms, hemodynamics, and survival. Calcium-channel blockade Acute vasodilator challenge testing during right-heart catheterization may identify the small percentage of patients with PAH who have disease characterized primarily by vasoconstriction. Appropriate testing agents include inhaled nitric oxide, adenosine, and prostacyclin. The deﬁnition of a vasodilator responder has varied, but using a deﬁnition of a decrease in PVR of greater than 20%, Rich and colleagues [25] found 26% of patients to be responders. These patients were treated for up to 5 years with high doses of calcium-channel blockers (nifedipine with an average daily dose of 172 mg and diltiazem with an average daily dose of 720 mg). At 5 years 94% of responding patients were alive, compared with 55% of patients who were not responders. A recent retrospective study by Sitbon et al [27] suggests that only half of acute vasodilator responders will beneﬁt long term. In this study only 6% of all patients did well functionally when treated with calcium-channel blockers alone. These patients were those who achieved nearly normal pulmonary arterial pressures (mean, <37 mm Hg) and PVR (<5 Wood units) with adequate cardiac output during the vasodilator test. Similarly, Raﬀy et al [28] examined 91 consecutive patients undergoing vasodilator challenge with epoprostenol. Patients were classiﬁed by the magnitude of

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their response in depression of total pulmonary resistance: those with a depression of less than 20% were categorized as nonresponding, those with a depression of 20% to 50% as moderately responding, and those with a depression above 50% as highly responding. Two-year survival rates for these groups were 38%, 47%, and 62%, respectively (P < 0.05). Use of calcium-channel blockers for PAH should be reserved for the small subset of patients who exhibit near normalization of pulmonary artery pressures during vasodilator challenge with a preserved cardiac output. Long-term clinical response should be closely monitored, and treatment should be escalated if deterioration occurs. It thus seems that calcium-channel blockers are rarely beneﬁcial and should be used only in patients with a signiﬁcant acute vasodilator response and never in nonresponders. Calciumchannel blockers with signiﬁcant negative inotropic eﬀect, such as verapamil, should be avoided. Treatment with calcium-channel blockade should be avoided in patients who do not respond at vasodilator challenge, because serious adverse events have been reported in these patients [29]. Systemic hypotension in the setting of a ﬁxed right ventricular cardiac output may lead to decreased right coronary perfusion, with potential to cause syncope, chest pain, or even death. Treatment sequence Currently, the WHO functional class of patients largely guides therapy. Supportive therapy is used as indicated. In patients with functional class I and class II symptoms, speciﬁc therapy is not indicated, because the cost and risk of therapy in these patients has not been justiﬁed. Patients who are WHO functional class III should be considered for oral therapy, and patients whose disease progresses on oral therapy and patients with advanced class IV symptoms should be considered for intervention with prostacyclin. Unfortunately, cost and insurance coverage can also inﬂuence the selection of available agents: the cost of bosentan therapy can exceed US $25,000 per year, and the costs of epoprostenol and treprostinil therapy can each exceed US $100,000 per year. Although interest is growing in testing combination therapy, limited data are currently available. Endothelin receptor antagonists Endothelin is a smooth muscle mitogen and vasoconstrictive agent. Its production is increased in pulmonary hypertension [30] and is strongly

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correlated with pulmonary hemodynamics and 6-minute walk data [31]. Eﬀects are mediated through endothelin-A and endothelin-B receptors that are variably distributed throughout the lung. Both receptors may contribute to pulmonary artery smooth muscle cell proliferation and vascular remodeling [32]. Blockade of these receptors has generated signiﬁcant interest as a therapeutic target. Bosentan (Tracleer) is a nonselective endothelin receptor antagonist that has proven eﬃcacy in two double-blinded, multicenter, placebocontrolled trials. It is currently the only oral medication approved in the United States for PAH. In a pilot study, Channick and colleagues [33] randomly assigned 32 patients with idiopathic PAH or PAH associated with the scleroderma spectrum of disease to treatment with bosentan (62.5 mg twice daily for 1 month followed by 125 mg twice daily) or placebo in a study lasting 12 weeks. Six-minute walk distance improved by 70 m in the treatment group but declined by 6 m in the placebo group. Cardiac index improved, and PVR decreased, with associated improvements in Borg Dyspnea Index scores and functional class. Three patients in the placebo group withdrew from the study because of worsening clinical status. A larger follow-up study (BREATHE-1, the Bosentan Randomized Trial of Endothelin Antagonist Therapy) enrolled 213 WHO functional class III or class IV patients with idiopathic PAH or PAH associated with connective tissue disease and followed them for 16 weeks [34]. Six-minute walk distances again improved, as did Borg Dyspnea Index scores and WHO functional class. Although the preliminary study exhibited adverse events that did not diﬀer from placebo [33], BREATHE-1 found that some patients suﬀered a signiﬁcant elevation of hepatic transaminases [34]. These elevations resolved in all patients with dose reduction or discontinuation of bosentan, but the ﬁnding reﬂects the need for at least monthly monitoring of liver function tests in patients who receive this drug. When bosentan was introduced as a treatment for PAH, there was concern that delaying therapy with prostacyclin would adversely aﬀect survival. Recent survival data with bosentan oﬀer some reassurance that this is not the case. McLaughlin and colleagues [35] reported long-term follow-up of 169 patients with PPH who had been enrolled in the initial bosentan trials. Observed survival was compared with predicted survival using an equation based on initial NIH registry data

encompassing variables such as cardiac index, mean pulmonary artery pressure, and mean right atrial pressure. Actual survival in patients receiving bosentan at 1, 2, and 3 years was 96%, 89% and 86%, respectively, compared with predicted survivals of 69%, 57%, and 48%, respectively, at the same time intervals. Bosentan (Actelion Pharmaceuticals Ltd., Allschwil, Switzerland, 2003) is a class X drug in pregnancy, because animal studies have identiﬁed it as a teratogen. Female patients of childbearing age should be tested for pregnancy before starting treatment with bosentan and should use two forms of contraception, including a barrier method, because bosentan may aﬀect the eﬃcacy of oral contraceptive. Patients taking bosentan should not receive concurrent glyburide because an increased risk for elevations in transaminases has been associated with this combination, and they should not receive concurrent cyclosporine because markedly elevated bosentan levels have been reported with coadministration of both drugs. The Food and Drug Administration (FDA) approved bosentan for use in WHO functional class III or class IV patients. Eﬃcacy of this drug may not be seen for 2 to 3 months after initiation of therapy, and it should not be used as sole therapy for patients with advanced class IV disease who need a more immediate response. Bosetan is, however, the only currently approved oral therapy for PAH and should be considered ﬁrst-line therapy for patients with WHO functional class III symptoms. Prostacyclins Prostacyclin (PGI2) is produced by the vascular endothelium and has important vasodilatory, antiplatelet aggregation, and antiproliferative eﬀects. The production of prostacyclin synthase, the enzyme necessary for prostacyclin synthesis, is decreased in patients with PAH [3], as is the excretion of stable metabolites of PGI2 [36]. Replacement of prostacyclin, therefore, is a reasonable therapeutic option from a pathophysiologic standpoint. The agent with which there is the most experience is epoprostenol (Flolan). Epoprostenol is a synthetic salt of prostacyclin that has an extremely short half-life, 3 to 5 minuets, on average. Because of its short half-life, it must be given by continuous infusion through an indwelling venous catheter. In addition to the previously mentioned eﬀects of endogenous prostacyclin, chronic epoprostenol administration also improves right ventricular function and geometry

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[37] and improves the net balance between pulmonary endothelin-1 clearance and release [38]. Epoprostenol has been investigated in a variety of patient populations. In 81 patients with idiopathic PAH (PPH) and WHO functional class III and class IV symptoms followed for a 12-week period, epoprostenol improved 6-minute walk distances from 315 to 362 m, whereas patients in the control group deteriorated from 270 to 204 m over the study period [39]. Quality-of-life indices were improved, as were pulmonary hemodynamics, albeit modestly. There were eight deaths, all in the placebo group. The response to epoprostenol of patients with PAH associated with the scleroderma spectrum of disease has also been examined in a randomized, controlled fashion in 111 patients, also over a 12-week period [40]. Exercise capacity, dyspnea scores, and functional class improved in the treatment group. There was no demonstrated diﬀerence in survival, although the study was not powered to do so. A recent Cochrane review synthesized the results of seven randomized, controlled trials using intravenous prostacyclin or one of its analogues and found that over a 12-week period prostaglandins seem to improve exercise capacity, functional class, and several cardiopulmonary hemodynamic variables [41]. In addition to these beneﬁcial eﬀects, epoprostenol has been shown to aﬀect survival positively in studies involving both adults and children [42–44]. Epoprostenol, however, has a number of unfavorable characteristics that limit more widespread applicability. Its short half-life requires continuous intravenous administration, necessitating indwelling central venous access and the associated risks of catheter-related sepsis, cellulitis, thrombosis, pneumothorax, catheter dislodgement, and hemorrhage [39,40]. Additionally, adverse eﬀects related to the drug itself are common and include jaw pain, diarrhea, ﬂushing, headaches, nausea, vomiting, and anorexia [39,40]. Caution should be exercised when considering epoprostenol administration for subsets of PAH patients who have a signiﬁcant ﬁxed downstream obstruction such as pulmonary venoocclusive disease or pulmonary capillary hemangiomatosis. Case reports in both disorders report pulmonary edema that complicates epoprostenol delivery [45,46]. Despite its signiﬁcant drawbacks, epoprostenol is potentially life saving and is among the quickest acting of agents currently available. In the treat-

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ment algorithm described later, it is reserved for WHO functional class IV patients and (rarely) for WHO functional class III patients who are not candidates for less-invasive therapy. Because the instability of epoprostenol requires placement of an indwelling catheter for continuous infusion, with the subsequent risk of complications, there is much interest in providing prostacyclin therapy through alternate mechanisms of delivery. Treprostinil (Remodulin) is a prostaglandin analogue that is stable at room temperature (unlike epoprostenol, which must be kept cool) and has a much longer half-life than epoprostenol that permits subcutaneous administration of this drug. Treprostinil is delivered by continuous subcutaneous infusion in a manner similar to continuous insulin administration. The delivery pump is roughly the size of a pager and can be worn inconspicuously by the patient. Two studies have demonstrated the safety and eﬃcacy of treprostinil. Initial pilot studies compared intravenous treprostinil with intravenous epoprostenol, subcutaneous treprostinil with intravenous treprostinil, and subcutaneous treprostinil with placebo [47]. Intravenous treprostinil, subcutaneous treprostinil, and epoprostenol produced similar reductions in PVR (approximately 20%). When compared with placebo, subcutaneous treprostinil produced statistically signiﬁcant improvement in 6-minute walk distance (increase of 37 17 m versus a decline of 6 28 m in the placebo arm) and trends toward improved cardiac index and reduced PVR. A larger multicenter, randomized trial focused on 470 patients with idiopathic PAH, PAH associated with connective tissue disease, and PAH associated with congenital systemic to pulmonary shunts [48]. Patients with WHO class II, class III, or class IV symptoms were enrolled. After 12 weeks there was a 16-m diﬀerence in median 6-minute walk distances between treatment and placebo groups, and dyspnea indices improved in treated patients. Eighty-ﬁve percent of patients, however, reported signiﬁcant pain at the infusion site, and 8% of patients withdrew from the study because of pain. Other typical adverse eﬀects common to prostacyclin analogues, such as diarrhea, jaw pain, ﬂushing, and lower extremity pain, were also reported. In the United States, the FDA has approved treprostinil for patients with PAH characterized by WHO class II, class III, and class IV symptoms. Improvements in 6-minute walk distances, however, do not reach the magnitude demonstrated by

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epoprostenol, and to the authors’ knowledge, no signiﬁcant improvement in mortality has been demonstrated with treprostinil. Site pain is a signiﬁcant problem for patients receiving this drug and limits its utility in the management of PAH. Although approved for most classes of symptoms, treprostinil should primarily be reserved for patients with class IV symptoms who are not candidates for continuous intravenous infusion of epoprostenol and for patients with class III symptoms for whom treatment with currently available oral therapies is not appropriate. Two other prostacyclin analogues have been investigated and used outside the United States, but neither is currently available in the United States. Iloprost is a nebulized prostaglandin with demonstrated beneﬁcial eﬀects on functional class, 6-minute walk distance, and hemodynamics [49–51]. A mild cough, minor headache, jaw pain, and nausea were reported adverse eﬀects in these studies. Because of its short half-life, iloprost must be administered six to nine times per day. Beraprost is an oral prostacyclin analogue that is approved in Japan for PAH patients. The largest trial examined 130 WHO functional class II and class III patients and showed a diﬀerence in 6minute walk distance of 25.1 m between treatment and placebo groups, improved Borg dyspnea index, and no change in hemodynamics or functional class [52]. Adverse eﬀects included headache, ﬂushing, jaw pain, diarrhea, leg pain, and nausea. Table 1 summarizes the drugs used in treating PAH. Experimental therapies A number of therapies for PAH have shown promise in anecdotal case reports, small case

series, or preliminary studies but have not yet been examined in a large-scale randomized trial and have not received FDA approval. Two endothelin receptor antagonists fall into this category. Sitaxsentan is an endothelin-A receptor antagonist investigated by Barst and colleagues [53] in a pilot study involving patients with idiopathic PAH or PAH associated with collagen vascular disease or congenital systemic to pulmonary shunts. Six-minute walk distances improved from 466 132 m to 515 141 m (P = 0.006), and there were modest improvements in mean positive airway pressure and PVR. There were, however, two cases of acute hepatitis, one of which was fatal. A larger, randomized trial is ongoing at this time. Other experimental endothelin antagonists, such as ambrisentan, are also in the preliminary phases of investigation. Sildenaﬁl (Viagra) is a phosphodiesterase-5 inhibitor that is gaining increasing attention for the treatment of pulmonary vascular disease. Sildenaﬁl has potential vasodilatory properties mediated through cyclic GMP and cyclic AMP systems. Several small studies, short-term hemodynamic studies, and case reports have suggested beneﬁcial results in pulmonary hypertension of various origins, with improvement in hemodynamics, exercise capacity, functional class, and dyspnea indices [54–58]. Sildenaﬁl has also been used in combination with prostacyclins in small case series and in hemodynamic studies, also with encouraging results [59–61]. In a small open-label study, 16 patients with pulmonary ﬁbrosis and pulmonary hypertension were randomly assigned to intravenous epoprostenol or sildenaﬁl [62]. Both epoprostenol and sildenaﬁl were found to reduce PVR, but epoprostenol in this setting

Table 1 Drugs used in treating pulmonary arterial hypertension Drug

Route

Epoprostenol

Intravenous (continuous)

Treprostinil

Subcutaneous (continuous)

Iloprost Beraprost Bosentan Sitaxsentan Ambrisentan Sildenaﬁl

Inhaled (6–9 times/d) By mouth (4 times/d) By mouth (2 tunes/d) By mouth (1 time/d) By mouth (1 time/d) By mouth (3 times/d)

FDA Approval

Available in United States

Yes—WHO class III/IV Yes—WHO class II/III/IV No No Yes No No Not for PAH

Yes Yes No No Yes No No Yes

Notes Infection, catheter complications, rebound Infusion site pain Frequent inhalation Hepatic toxicity Experimental Experimental Oﬀ-label/experimental use

Abbreviations: FDA, Food and Drug Administration; PAH, pulmonary arterial hypertension.

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increased ventilation/perfusion mismatch and adversely aﬀected arterial oxygenation. Sildenaﬁl, in contrast, maintained ventilation/perfusion matching and raised arterial oxygenation. In original studies in patients with erectile dysfunction, the drug has been shown to be relatively safe, with headache, ﬂushing, and dyspepsia the most commonly reported adverse eﬀects [63]. Visual disturbances were also reported in this same series. Phase III trials are currently ongoing with sildenaﬁl in the setting of PAH. For the time being, its use should be considered investigational. A myriad of pathophysiologic defects in PAH are potential therapeutic targets, and it is conceivable that combination therapy acting on two or more targets could improve outcomes in this disease. Ongoing studies are scrutinizing this hypothesis. A number of novel therapies have been suggested in PAH in animal models or small case reports. They include aerosolized adrenomedullin [64], oral dehydroepiandrosterone (DHEA) [65], simvastatin [66], and vasoactive intestinal peptide [67]. All are in the most preliminary stages of investigation and warrant further study before widespread clinical application. Surgical options in pulmonary hypertension Chronic thromboembolic pulmonary hypertension should be diﬀerentiated from pulmonary hypertension of other causes, because a potentially curative operative procedure exists for this entity. Chronic thromboembolic pulmonary hypertension and the surgery to treat it, namely pulmonary thromboendarterectomy, are beyond the scope of this article and are reviewed elsewhere in this issue. Atrial septostomy was ﬁrst described in 1983 [68] and is an option in patients with severe PAH who do not respond to maximal medical therapies. Sandoval and colleagues [69] reported their experiences with the procedure in a series of 15 such patients who underwent graded balloon dilation atrial septostomy. In the 14 patients who survived the procedure, right ventricular end diastolic procedure was immediately decreased, and cardiac output was improved, although at the expense of systemic oxygen desaturation secondary to the increased right to left shunting. Functional class and exercise capacity were improved as well. Atrial septostomy should be considered in patients with severe PAH and recurrent syncope or progressive right

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ventricular failure despite maximal medical therapy, as a bridge to transplantation if maximal medical therapy has failed, and as a palliative procedure when no other option exists [1]. It should be attempted only in institutions with experience in its use. Contraindications include patients with impending death, receiving maximal cardiopulmonary support, or with preprocedure systemic oxygen saturations of less than 90% [1]. PAH is a declining indication for lung and heart-lung transplantation compared with other indications for transplantation (constituting 4.5% of procedures over a 7-year period [70]), probably because of advances in the medical management of the disease. In the United States, most transplant centers perform bilateral single-lung transplantations for PAH, although a small percentage of centers perform single-lung transplantation for this disorder. Heart-lung transplantation is reserved for patients with PAH secondary to congenital systemic-to-pulmonary shunts that cannot be surgically corrected by isolated lung transplantation. Heart-lung transplantation in PAH is more frequently employed in Europe [70]. Early mortality is higher in patients with PAH than that in patients with other indications for transplantation, but overall survival approximates 83%, 73%, 57%, 45%, and 23% at 3 months, 1 year, 3 years, 5 years, and 10 years, respectively [70]. Timing of lung transplantation is problematic. There is currently, in the United States, no priority for severity of patient illness, and priority is strictly related to time accrued while waiting for transplantation. Wait times average approximately 17 months but can be 36 months or longer [71]. Heart-lung transplant lists may have even longer wait times. Therefore, if a physician waits to refer a patient with severe PAH until the patient is in extremis, it is unlikely that the patient will survive to transplantation. Although the decision to refer for lung transplantation must be individualized to each patient, in general consideration for referral should be given to the patient who has ‘‘symptomatic, progressive disease which, despite medical or surgical treatment, leaves the patient in NYHA III or NYHA IV’’ [72]. From a practical standpoint, because the clinical course of patients with PAH can be quite variable, the authors refer patients for lung transplant evaluation if medical management necessitates the initiation of intravenous or subcutaneous prostaglandin administration.

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Summary The diagnosis of pulmonary hypertension requires a high index of suspicion and careful attention to assessing the severity and classiﬁcation of disease. Proper evaluation and understanding of determinants of severity in PAH are necessary to guide appropriate therapy. There are now highly eﬀective therapies for PAH that have meaningfully improved the outcome for patients, and it likely that that the future is even brighter, with development of combination regimens and additional therapies that attack speciﬁc targets within the pulmonary vasculature and right ventricle. Despite the increasing availability of oral therapies for PAH, consideration should be given to referral of patients with functional class III and IV symptoms to specialized PAH centers that may have additional experience in the timing and nature of escalation of therapy when needed. Referral also may help concentrate a fairly rare population of patients to facilitate research that, one hopes, may lead to continued advances in the management of this disease. Although survival remains limited, the authors are encouraged by the interest and commitment to this disease that has engendered continued progress in the development of an armamentarium to ﬁght it. References [1] Simonneau G, Galie` N, Rubin L, Langleben D, Seeger W, Domenighetti G, et al. Clinical classiﬁcation of pulmonary hypertension. J Am Coll Cardiol 2004;43:55–125. [2] Meyrick B. The pathology of pulmonary artery hypertension. Clin Chest Med 2001;22:393. [3] Tuder RM, Cool CD, Geraci MW, et al. Prostacyclin synthase expression is decreased in lungs from patients with severe pulmonary hypertension. Am J Respir Crit Care Med 1999;159:1925. [4] D’Alonzo GE, Barst RJ, Ayres SM, et al. Survival in patients with primary pulmonary hypertension. Results from a national prospective registry. Ann Intern Med 1991;115:343. [5] Raymond RJ, Hinderliter AL, Willis PW, et al. Echocardiographic predictors of adverse outcomes in primary pulmonary hypertension. J Am Coll Cardiol 2002;39:1214. [6] Kawut SM, Taichman DB, Archer-Chicko CL, et al. Hemodynamics and survival in patients with pulmonary arterial hypertension related to systemic sclerosis. Chest 2003;123:344. [7] Holcomb BW Jr, Loyd JE, Ely EW, et al. Pulmonary veno-occlusive disease: a case series and new observations. Chest 2000;118:1671.

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Echocardiography in pulmonary vascular disease Lori B. Daniels, MDa,b, David E. Krummen, MDa,b, Daniel G. Blanchard, MD, FACCa,b,* a

Division of Cardiology, Department of Medicine, University of California, San Diego School of Medicine, University of California, San Diego, 200 West Arbor Drive, San Diego, CA 92103, USA b University of California, San Diego Medical Center, 200 West Arbor Drive San Diego, CA 92103, USA

The assessment of pulmonary artery pressure, right ventricular function, right ventricular ﬁlling pressure, and tricuspid regurgitation provides invaluable information in the care of patients with pulmonary vascular disease. Echocardiography provides a rapid, noninvasive, portable, and accurate method to evaluate these parameters and also provides information on left ventricular and valvular function. Echocardiography has therefore become one of the most commonly performed diagnostic studies in patients with pulmonary vascular disease, and the technique’s applications in this area are likely to grow. This article presents an overview of the current uses of echocardiography in pulmonary vascular disease and pulmonary hypertension.

Echocardiographic measurements in pulmonary hypertension Measurement of right ventricular volume and function Measurement of right ventricular volume and function is important in making the diagnosis of pulmonary hypertension, but, because of the complex three-dimensional shape of the right ventricle, accurate measurement of right ventricular size and ejection fraction is diﬃcult. In the apical four-chamber view, enlargement of the right ventricle can be determined qualitatively * Corresponding author. UCSD Medical Center, 200 W. Arbor Drive, #8411, San Diego, CA 92103. E-mail address: [email protected] (D.G. Blanchard).

when its chamber cross-sectional area exceeds that of the left ventricle (Fig. 1). In addition, right ventricular enlargement is present when the distal portion of the right ventricle shares space with the left ventricle at the cardiac apex in the apical four-chamber view. Normally, the cardiac apex is exclusively composed of left ventricular myocardium. Quantitative measurements of right ventricle size, thickness, and cross-sectional area can also be obtained [1]. Right ventricular systolic function can be expressed as the percent of change in right ventricular area during the cardiac cycle: ð½EDA ESA EDAÞ 100% EDA is the right ventricular area from the apical four-chamber view at end-diastole, and ESA is the right ventricular area at end-systole. Normal right ventricular fractional area change is 40% to 45% [2]. Because right ventricular functional measurement is highly dependent upon afterload and transseptal pressure gradients, the percent of change in cross-sectional area is not routinely quantiﬁed [3]. Tricuspid regurgitation Tricuspid regurgitation is often present in the setting of pulmonary hypertension and ranges from mild to severe. Tricuspid regurgitation may be caused by dilatation of the tricuspid annulus and morphologic alteration of right ventricular geometry [4] as well as by chordal traction of the valve leaﬂets [5]. Although the severity of tricuspid regurgitation does not necessarily correlate with the degree of pulmonary hypertension, reversal of pulmonary hypertension leads to

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artery systolic pressure is ﬁrst to record the maximum tricuspid regurgitant jet velocity (VTR). This velocity can then be translated into the pressure gradient between the right ventricle and right atrium using the modiﬁed Bernoulli equation. The accuracy of this method depends on obtaining the true maximum VTR. The interrogating Doppler ultrasound beam must be parallel (or nearly so) to the direction of blood ﬂow in the jet of TR (Fig. 2). The apical or right ventricular inﬂow views are most commonly used for this analysis. The peak right ventricular and pulmonary artery systolic pressure can then be calculated (in the absence of pulmonic stenosis) as Fig. 1. Apical four-chamber view in severe pulmonary hypertension. The right atrium (RA) and ventricle are markedly enlarged, and the right ventricle (RV) is hypertrophied. The interventricular septum is shifted leftward, and the left-heart chambers appear compressed.

signiﬁcantly decreased tricuspid regurgitation in many cases, especially when the tricuspid regurgitation is caused by annular dilatation [6]. Estimation of pulmonary arterial pressure by the Bernoulli equation Transthoracic echocardiography (TTE) provides a readily available, noninvasive assessment of right-sided intracardiac pressures. The most reliable approach for approximating pulmonary

Pulmonary artery pressure ¼ 4VTR2 þ right atrial pressure ½7: Right atrial pressure can be estimated from the size and variation in the inferior vena cava (IVC) during quiet respiration. Best visualized from a subcostal window, the IVC normally has a diameter of 1.2 to 2.3 cm (Fig. 3) and should collapse by at least 50% during inspiration [8]. IVC dilation (or lack of collapse during inspiration) correlates with a higher right atrial pressure (eg, 10–15 mm Hg) [7]. In the setting of a dilated IVC, a complete lack of variation in IVC diameter with quick inspiration (a sniﬀ) suggests a right atrial pressure of at least 20 mm Hg. Pulmonary artery diastolic pressure also can be estimated from the velocities of the pulmonic

Fig. 2. Continuous-wave spectral Doppler tracing of tricuspid regurgitation (TR) recorded in a modiﬁed apical fourchamber plane. The peak velocity of the TR jet is 5.2 m/s, suggesting a gradient of 108 mm Hg.

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nary hypertension include a decrease in the velocity-time integral of ﬂow through the pulmonic valve and a shortening of the acceleration time (measured from beginning of ﬂow through the pulmonic valve to peak velocity.) The acceleration time (AT, in milliseconds) can be used to estimate the mean pulmonary artery pressure in mm Hg [11,12] according to the equation Mean pulmonary artery pressure ¼ 80 ðAT=2Þ:

Acute pulmonary embolus Fig. 3. Subcostal view of the inferior vena cava (IVC) emptying into the right atrium (RA). A hepatic vein is also visible (arrow).

regurgitant Doppler tracing [9,10] (Fig. 4). Again, using the modiﬁed Bernoulli equation, the enddiastolic velocity of the pulmonic regurgitation jet can be used to calculate the instantaneous gradient between the pulmonary artery and the right ventricle. The pulmonary artery diastolic pressure is obtained by adding this calculated gradient to the estimated right atrial pressure. Other ﬁndings in right ventricular dysfunction and pulmonary hypertension Other characteristic Doppler abnormalities seen in right ventricular dysfunction and pulmo-

Typical ﬁndings on transthoracic echocardiography Depending on the size of the thromboembolus, patients with acute pulmonary embolism may have a number of abnormalities on TTE. Rarely, a large thrombus may be directly visualized in a proximal pulmonary artery or in transit in the right-heart chambers (Fig. 5A–C) [13]. The most common echocardiographic ﬁndings, however, are caused by acute right-sided pressure overload. With acute massive pulmonary embolism, the right ventricle dilates and becomes markedly hypokinetic. Abnormal motion of the interventricular septum with ﬂattening or bulging toward the left ventricle in diastole may be seen (Fig. 6). Such paradoxical septal motion can result in left ventricular diastolic impairment, with decreased early diastolic ﬁlling

Fig. 4. Spectral Continuous-Wave Doppler tracing of pulmonic insuﬃciency (measured in the parasternal short-axis view at the base of the heart). The end-diastolic velocity is 2.2 m/s, suggesting a gradient between the pulmonary artery and right ventricle of 19 mm Hg at end-diastole.

Fig. 5. (A) Parasternal short-axis transthoracic echo image of a large thrombus (T) lodged in the bifurcation of the right and left main pulmonary arteries. Ao, ascending aorta; PA, main pulmonary artery. (B) Subcostal four-chamber view of a serpentine right atrial thrombus (**). On real-time imaging, the thrombus was very mobile. LV, left ventricle; RV, right ventricle. (C) Transesophageal image of a thrombus in transit. A venous thromboembolus has traveled to the right atrium (RA) and is lodged in a patent foramen ovale. A portion of the thrombus extends into the left atrium (LA).

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and increased reliance on the atrial kick (this process has been called the reverse Bernheim phenomenon) [14,15]. On Doppler examination of transmitral diastolic blood ﬂow, this phenomenon is seen as a decrease in the early rapid ﬁlling velocity (E wave) and an increase in the atrial contraction velocity (A wave). This septal impairment of left ventricular diastolic ﬁlling may further contribute to the low cardiac output seen in cases of massive pulmonary embolism. A ratio of right ventricle–to–left ventricle enddiastolic diameter (measured in the parasternal or subcostal view) greater than the upper normal limit of 0.6 helps indicate right ventricular dysfunction and may distinguish between massive and nonmassive pulmonary embolism [16,17]. In addition, tricuspid regurgitation is common in acute pulmonary embolism (Fig. 7) and provides a useful way to assess pulmonary artery pressure. The right atrium and the IVC often dilate in acute massive pulmonary embolism, reﬂecting elevated right-sided pressures, and the IVC fails to collapse normally during inspiration. Interatrial shunting can occur if a patent foramen ovale is present and right ventricular pressure is signiﬁcantly elevated. Unfortunately, the Doppler and two-dimensional echocardiographic ﬁndings of right ventricular dysfunction and right-sided pressure overload are not speciﬁc for pulmonary embolism: other diseases, including primary pulmonary hypertension, right ventricular myocardial infarction, cardiomyopathy, or right ventricular dysplasia, or acute exacerbations of obstructive pulmonary dis-

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ease may produce similar ﬁndings. Hypokinesis of the right ventricle free wall with sparing of apical function (McConnell’s sign) has been proposed as a relatively speciﬁc sign of right ventricular dysfunction caused by acute pulmonary embolism rather than other causes, but the overall clinical utility of this observation is debatable [18]. The degree of pulmonary hypertension seen with acute pulmonary embolism is usually mild to moderate, but right ventricular dysfunction is not universally present in acute pulmonary embolism [19]. Approximately 20% of patients with acute pulmonary embolism conﬁrmed by ventilationperfusion (V/Q) scan or angiography may have normal ﬁndings on TTE [20,21]. Visualization of the right and left pulmonary arteries is sometimes diﬃcult, and detection of pulmonary thromboemboli is unusual in most cases of pulmonary embolism. Furthermore, echocardiographic images may be of limited usefulness in patients who are obese, have hyperinﬂated lungs, or are immobile (including those on mechanical ventilators). Because of these limitations, TTE is not recommended as a primary diagnostic tool in acute pulmonary embolism. Nonetheless, it may be helpful in diagnosing or excluding alternative causes of sudden hemodynamic instability, including cardiac tamponade, aortic dissection, and acute valvular insuﬃciency [22]. Typical ﬁndings on transesophageal echocardiography Transesophageal echocardiography (TEE) can detect all the ﬁndings detected by TTE but is much more eﬀective in the direct visualization of thrombi in the central pulmonary arteries. TEE visualizes the main pulmonary artery and the right pulmonary artery well, although the intervening left main bronchus may obscure the left pulmonary artery In the appropriate clinical setting, the ﬁnding of an intraluminal pulmonary artery mass is reasonably speciﬁc for the diagnosis of acute pulmonary embolism [7–9,23,24]. The sensitivity of TEE in acute pulmonary embolism varies among studies and depends on operator expertise and patient selection. False-positive results, however, are distinctly unusual [7–9,24]. Uses of echocardiography in acute pulmonary embolism

Fig. 6. Short-axis view in right ventricular overload. The interventricular septum is ﬂattened and pushed toward the left ventricle. LV, left ventricle; RV, right ventricle.

Although TTE is not the recommended diagnostic test for pulmonary embolism, it nonetheless can play a major role in the assessment of

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Fig. 7. Short-axis view through the base of the heart showing signiﬁcant tricuspid regurgitation. A multicolored jet of tricuspid regurgitation is seen in the right atrium (RA) during systole. LV, left ventricle; RV, right ventricle.

prognosis and management of this condition. Echocardiographic analysis of right ventricular function has proven useful in the risk stratiﬁcation of patients with pulmonary embolism. In a recent study of 209 consecutive patients with pulmonary embolism, the 65 who were hemodynamically stable but had right ventricular dysfunction on TTE had an in-hospital mortality rate of 5% versus 0% in those without right ventricular dysfunction [25]. In another study of 126 consecutive pulmonary embolism patients, echocardiography emerged as the strongest predictor of in-hospital mortality, because the risk of in-hospital death was six times greater for the patients with right ventricular dysfunction than for those with normal right ventricular function [21]. At 1-year follow-up, there was still a 2.4 relative risk of mortality associated with right ventricular dysfunction. In patients without an underlying malignancy, the pulmonary embolism mortality rate was 7.7% in patients with right ventricular hypokinesis but 0% in those without right ventricular dysfunction. Right ventricular hypokinesis on baseline echocardiography was also an important predictor of increased mortality in the International Cooperative Pulmonary Embolism Registry. Right ventricular hypokinesis was associated with a twofold increase in mortality and was as important a predictor of poor outcome as advanced age, cancer, congestive heart failure, and renal insuﬃciency [26]. Finally, in the Manage-

ment, Strategy and Prognosis of Pulmonary Embolism Registry (MAPPET) study of 1001 patients, right ventricular dysfunction was an independent and signiﬁcant marker of increased mortality [27]. Whether right ventricular dysfunction should be used to determine which patients receive thrombolytic therapy remains controversial. There is a general consensus that thrombolysis is the treatment of choice in patients with massive pulmonary embolism accompanied by hemodynamic collapse, and in these patients echocardiography is useful for monitoring changes in cardiac function with treatment [28]. There is, however, a signiﬁcant subset of patients with acute pulmonary embolism (as high as 40%) who do not have signiﬁcant hemodynamic compromise but still exhibit right ventricular dysfunction on TTE [25,26]. These patients may beneﬁt from thrombolytic therapy. In a randomized trial of thrombolysis plus anticoagulation versus anticoagulation alone, Goldhaber et al [28] found that 5 of 23 patients with right ventricular hypokinesis and dilatation had recurrent pulmonary embolism after receiving intravenous heparin alone, whereas pulmonary embolism did not recur in any of the 23 patients with right ventricular dysfunction who received thrombolytics. Patients given thrombolytics also had greater recovery of right ventricular function at 24 hours, improved absolute pulmonary perfusion, and decreased right ventricular end-diastolic

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area, though overall mortality was unchanged [28]. In the MAPPET registry, Konstantinides et al [27,29] found a lower 30-day mortality in subgroup of 719 normotensive patients with pulmonary embolism and right ventricular overload who were treated with thrombolytics than in those treated with intravenous heparin alone (4.7% mortality in the 169 patients initially treated with thrombolytics versus 11.1% in the 550 patients who initially received anticoagulation alone, P = 0.016). Other studies, however, have had conﬂicting results. A recent study by Hamel et al [30] assessed 128 patients with massive pulmonary embolism, stable hemodynamics, and right ventricular dysfunction. In their analysis, treatment with low-molecular-weight heparin resulted in a trend toward decreased mortality compared with treatment with thrombolytics (0% versus 6.3%, P = 0.12), with fewer major bleeding events. Overall, it seems that patients with acute pulmonary embolism and right ventricular dysfunction detected on echocardiography represent a group at higher risk [31]. These patients merit aggressive therapy, but it is not completely clear whether the addition of thrombolytics decreases the risk of early death. Another subgroup of patients who may beneﬁt from echocardiography is those presenting with acute pulmonary embolism and signiﬁcant pulmonary hypertension (pulmonary artery systolic pressure >50 mm Hg). In a 5-year study of 78 patients with pulmonary embolism, Ribeiro et al [32] found that this degree of initial pulmonary hypertension conferred an odds ratio of 3.3 for persistent pulmonary hypertension or right ventricular dysfunction. They reported an early exponential rate of decline in pulmonary artery pressures, followed by a stable period after 6 weeks. In this study, 5% of patients with acute pulmonary embolism developed persistent cardiopulmonary disability and chronic right-heart dysfunction, a percentage higher than previously estimated [33–35]. Thus, follow-up echocardiography at 6 weeks can identify the high-risk subgroup of patients with persistent pulmonary hypertension and right ventricular dysfunction who are potential candidates for pulmonary thromboendarterectomy [36]. Recommendations for transthoracic echocardiography in acute pulmonary embolism As discussed previously, many patients with acute pulmonary embolism have normal echocar-

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diograms, and the routine use of TTE for diagnosis of pulmonary embolism is not recommended. Echocardiography may be appropriate, however, when the diagnosis is in question. In such cases, pulmonary embolism may be conﬁrmed or another cause of the patient’s symptoms may be detected. Additionally, TTE is indicated in patients with conﬁrmed pulmonary embolism, because the ﬁnding of right atrial or right ventricular thrombi often mandates the use of thrombolytics to prevent recurrent and potentially fatal pulmonary embolism. In hemodynamically unstable patients with suspected pulmonary embolism, TTE can be used as a rapid initial test. If signiﬁcant right ventricular dysfunction is present, pulmonary embolism is likely. Finally, echocardiography can help monitor treatment response in patients with documented acute pulmonary embolism. Serial echocardiography can predict the development of CTEPH and canassesssuitabilityforfuturepulmonarythromboendarterectomy. Use of transesophageal echocardiography Only a few studies have examined the role of TEE in acute pulmonary embolism. In patients with suspected acute pulmonary embolism who present with shock or recent cardiopulmonary resuscitation, completion of standard diagnostic tests such as V/Q scanning, CT, and pulmonary angiography can be diﬃcult. In these critically ill patients, bedside TEE may be useful. For example, a study of TEE in 25 patients presenting with pulseless electrical activity found that 14 had isolated right ventricular enlargement. Of these, 9 had acute pulmonary emboli [37]. One recent report by Krivec et al [38] examined 24 critically ill patients with unexplained shock and jugular venous distention. They found that 17 patients (70%) had right ventricular dilatation with global hypokinesis. TEE examination detected proximal pulmonary emboli in 12 of these patients and reduced right pulmonary artery ﬂow in one additional patient. Of these 13 patients, 12 eventually had documentation of massive pulmonary embolism (either by V/Q scan or post mortem study). The few studies available suggest that TEE can provide direct visualization of proximal pulmonary arterial thrombi and so can be useful for determining surgical accessibility in patients with massive pulmonary embolism and refractory circulatory collapse.

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Echocardiography in chronic right ventricular overload and pulmonary hypertension The nonspeciﬁc nature of symptoms from chronic pulmonary hypertension often impedes the early diagnosis of the condition. For example, Rubin et al [39] reported a mean time from presentation to diagnosis of approximately 2 years in patients with pulmonary hypertension. In general, pulmonary vascular disease should be suspected when symptoms of dyspnea cannot be easily explained. When pulmonary hypertension is suspected from physical examination or screening tests (such as electrocardiography or chest radiographs), Doppler echocardiography is the best subsequent test to evaluate right-heart function and pressure. In many cases, TTE is the ﬁrst test to detect an elevation of right ventricular pressure [40]. TTE also provides important information about prognosis and response to treatment in these patients [3,41]. Echocardiographic features of chronic pulmonary hypertension Tricuspid valve As noted previously, tricuspid regurgitation is common in the setting of pulmonary hypertension but may regress with reversal of the pressure overload. A recent study by Sadeghi et al [42] evaluated patients with CTEPH and severe tricuspid regurgitation who subsequently underwent pulmonary thromboendarterectomy. Seventy per-

cent of the patients had resolution of tricuspid regurgitation after pulmonary thromboendarterectomy, often despite persistent tricuspid annular dilation. The 30% of patients with persistent severe tricuspid regurgitation had less postoperative decrease in pulmonary artery pressure. Thistlethwaite et al [43] reported that intraoperative classiﬁcation of pulmonary thromboembolic disease helps predict successful decreases in pulmonary artery pressure and tricuspid regurgitation severity in patients with CTEPH: those with thrombus in the main lobar pulmonary arteries had the greatest improvement in these parameters following pulmonary thromboendarterectomy. Inferior vena cava and right-heart chambers As described previously, the right atrium and IVC are commonly dilated in patients with pulmonary hypertension (Fig. 8). This dilation is generally a manifestation of signiﬁcant tricuspid regurgitation, elevated right ventricular diastolic pressure, or both. Additionally, elevation of right atrial pressure may cause the interatrial septum to bulge toward the left atrium. Right atrial pressure in chronic pulmonary hypertension can be estimated by means similar to the method described for acute pulmonary embolism. The pulmonary artery is often dilated in the setting of chronic pulmonary hypertension and right ventricular hypertrophy. Pulmonic valvular regurgitation frequently occurs as well, and, as noted previously, the regurgitant ﬂow velocity can

Fig. 8. Subcostal view demonstrating a dilated inferior vena cava (IVC). Diameter of the IVC is more than 2.5 cm. LA, left atrium; RA, right atrium.

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be used to estimate the pulmonary artery diastolic pressure [9,10]. M-mode examination of the pulmonic valve in pulmonary hypertension may show a characteristic W-shaped motion of the valve leaﬂet during systole [44–46]. This midsystolic closure of the valve and partial reopening in late systole, sometimes called the ﬂying-W sign (Fig. 9), is probably caused by elevated pulmonary vascular resistance and early reﬂection of the systolic pressure wave within the proximal pulmonary arteries [47]. There also may be a loss of the normal presystolic opening of the pulmonic valve with atrial contraction (the ‘‘a’’ dip). Because of the large diﬀerence between right ventricular pressure and pulmonary artery pressure throughout diastole, the pressure generated by the atrial kick is insuﬃcient to open the pulmonic valve even partially. Chronic pulmonary hypertension ultimately leads to right ventricular hypertrophy, enlargement, and depressed systolic function. Echocardiographic measurements of right ventricle wall thickness can be performed from the parasternal and subcostal views, and a value of more than 5 mm is diagnostic for right ventricular hypertrophy [48]. In the setting of right ventricular hypertrophy, the moderator band is often hypertrophied and thickened as well [3]. Left-heart chambers and interventricular septum The left ventricle size is normal to small in severe pulmonary hypertension and right ventric-

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ular hypertrophy [49]. Left ventricular diastolic dysfunction often occurs in right ventricular hypertrophy and reﬂects the degree of right ventricular overload and septal distortion seen with pulmonary hypertension. This diastolic left ventricular dysfunction may be caused by abnormal relaxation of the interventricular septum, which, in cases of severe pulmonary hypertension, functions as part of the right ventricle rather than as part of the left ventricle. More recent studies, however, suggest that the abnormal diastolic transmitral Doppler ﬂow patterns may stem from relative underﬁlling of the left ventricle in the setting of low right ventricular cardiac output [50]. In addition, the transmitral Doppler diastolic E to A ratio seems to correlate directly with cardiac output and inversely with pulmonary artery pressure (Fig. 10A, B) [50]. As with pulmonary embolism, in right ventricular overload with CTEPH the interventricular septum is often ﬂattened in the parasternal shortaxis TTE view and may actually bulge into the left ventricle. The timing of this septal distortion helps distinguish between pressure and volume right ventricular overload. In pure right ventricular volume overload, the right ventricular diastolic pressure may equal or exceed that within the left ventricle, whereas the systolic pressure of the left ventricle greatly exceeds that of the right ventricle. Therefore, the interventricular septum ﬂattens during diastole but returns to its normal curvature

Fig. 9. M-mode echocardiogram of the pulmonic valve in severe pulmonary hypertension. A characteristic W-shaped motion of the valve (the ﬂying-W sign) is present during systole.

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Fig. 10. (A) Inverse correlation between transmitral E/A ratio and mean pulmonary artery (PA) pressure in patients before and after pulmonary thromboendarterectomy. (B) Direct correlation between transmitral E/A ratio and cardiac output (CO) in patients before and after pulmonary thromboendarterectomy. (From Mahmud E, Raisinghani A, Hassankhani A, Sadeghi SM, Strachen GM, Auger A, et al. Correlation of left ventricular diastolic ﬁlling characteristics with right ventricular overload and pulmonary artery pressure in chronic thromboembolic pulmonary hypertension. J Am Coll Cardiol 2002;40:318–24; with permission).

during systole (Fig. 11A, B). With right ventricular pressure overload, however, the abnormally high right ventricular pressures persist through the entire cardiac cycle, and the interventricular septum remains deformed during both systole and diastole (Fig. 12A, B) [51]. This septal distortion can be quantiﬁed using the eccentricity index, a ratio of the two minor axes of the left ventricle measured in the parasternal short-axis plane. Normally, the left ventricle eccentricity index is 1.0 during both systole and diastole (ie, the left ventricle is circular in cross-section throughout

the cardiac cycle). In cases of right ventricular volume overload, the eccentricity index is abnormal during diastole (when the interventricular septum bulges toward the left ventricle) but returns to normal during systole. In right ventricular pressure overload, the eccentricity index is abnormal throughout the cardiac cycle, reﬂecting persistent septal deformation. The left atrium may appear compressed in the transverse plane because of leftward bulging of the interatrial septum. The mitral valve annulus may also be distorted by enlargement of the right

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Fig. 11. (A) Parasternal short-axis diastolic image in right ventricular volume overload. The interventricular septum is ﬂattened and bulges toward the left. LV, left ventricle; RV, right ventricle. (B) Parasternal short-axis systolic image in right ventricular volume overload. The interventricular septum appears normal and is rounded toward the right, reﬂecting the much higher pressure in the left ventricle (LV) compared with the right ventricle (RV).

ventricle, and the mitral valve may sometimes prolapse into the left atrium during systole (even though the mitral valve is morphologically normal). Relief of pulmonary hypertension often eliminates this ﬁnding of pseudoprolapse [52].

coronary sinus dilation frequently accompanies pulmonary hypertension, correlating with right atrial pressure and size [54].

Diﬀerential diagnosis of chronic pulmonary hypertension Pericardium A signiﬁcant proportion of patients with chronic pulmonary hypertension have pericardial eﬀusions. Eﬀusion size has been linked with right atrial pressure and is probably cause by impaired lymphatic and venous drainage [53]. Similarly,

Echocardiography can reliably diﬀerentiate various causes of pulmonary hypertension secondary to elevated left atrial pressure, including mitral and aortic valvular disease, cardiomyopathy, constrictive pericarditis, and cor triatriatum. In addition, contrast echocardiography using

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Fig. 12. (A) Parasternal short-axis diastolic image in right ventricular pressure overload. The interventricular septum is ﬂattened and bulges toward the left. LV, left ventricle; RV, right ventricle. (B) Parasternal short-axis systolic image in right ventricular pressure overload. The interventricular septum remains ﬂattened and continues to bulge toward the left, reﬂecting the abnormally elevated pressure in the right ventricle (RV) during systole. LV, left ventricle.

intravenous agitated saline can detect intracardiac shunts leading to pulmonary hypertension. In the absence of left-heart disease or intracardiac shunts, chronic pulmonary hypertension is most often caused by either idiopathic pulmonary arterial hypertension (sporadic/familial or associated with diseases such as HIV or collagen vascular disease) or CTEPH. Echocardiographic diﬀerentiation between these two entities is problematic.

Several studies have shown diﬀerent characteristics in these two patient groups using echocardiographic variables [55,56] and high-ﬁdelity pulmonary artery pressure waveforms [57–59], but in a prospective evaluation of 142 consecutive admissions for undiﬀerentiated symptomatic pulmonary hypertension, echocardiography was unable to distinguish one group from the other reliably [60]. Therefore, other diagnostic tests such as V/Q

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scanning, spiral CT, and pulmonary angiography are recommended for deﬁnitive diagnosis of CTEPH versus pulmonary arterial hypertension. Utility of echocardiography for prognosis and treatment of chronic pulmonary hypertension Echocardiography plays an important role in predicting the prognosis of patients with pulmonary hypertension. For example, Raymond et al [2] found that pericardial eﬀusion, right atrial enlargement and interventricular septal distortion predicted adverse outcomes in primary pulmonary hypertension. Similarly, D’Alonzo et al [61] reported a worsened survival in patients with pulmonary arterial hypertension, with elevated pulmonary artery pressure, right atrial pressure, and decreased cardiac output found on echocardiographic examination. Eysmann [62] added a shortened pulmonary artery Doppler acceleration time to the list of echocardiographic parameters associated with poor survival in pulmonary arterial hypertension. Pulmonary arterial hypertension: use of echocardiography in diagnosis and management Pulmonary arterial hypertension remains a difﬁcult disease to manage despite recent advances in drug therapy including intravenous epoprostenol [63] and, more recently, inhaled iloprost [64] and oral bosentan [65]. Preliminary studies also suggest an adjunctive role for oral sildenaﬁl [66]. Prognosis remains poor, but echocardiography has proven useful in assessing response to therapy. In a study by Hinderliter et al [67] the echocardiographic characteristics of 81 patients with severe pulmonary arterial hypertension were followed prospectively for 12 weeks. Baseline echocardiographic measures of right ventricular end-diastolic area, eccentricity index, pericardial eﬀusion size, and tricuspid regurgitation jet area were inversely correlated with baseline exercise capacity. After 12 weeks of intravenous prostacyclin infusion, right ventricular end-diastolic area, systolic and diastolic eccentricity index, and maximal VTR were improved. Quality of life was not signiﬁcantly associated with echocardiographic ﬁndings, however, and Doppler echocardiography was unable to quantify accurately small changes in pulmonary artery pressure associated with prostacyclin therapy in individual patients. Despite these limitations, it seems reasonable that patients with primary pulmonary hypertension should undergo echocardiography at regular

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intervals to detect markers of poor prognosis. More aggressive therapy and lung transplant evaluation would then be indicated for these patients [2]. Chronic thromboembolic pulmonary hypertension In contrast to idiopathic pulmonary arterial hypertension (primary pulmonary hypertension), CTEPH is often markedly improved by pulmonary thromboendarterectomy. Several studies have demonstrated that the changes in the anatomic and physiologic abnormalities of pulmonary hypertension can be monitored by echocardiography. As mentioned previously, Sadeghi et al [42] found that the severity of tricuspid regurgitation generally lessened after pulmonary thromboendarterectomy, most notably in patients with marked decreases in pulmonary artery pressure. Additionally, measurements of right ventricular area and systolic function (eg, fractional area change) improve when right ventricular afterload is decreased by pulmonary thromboendarterectomy [4]. Some of these anatomic changes occur immediately after pulmonary thromboendarterectomy, but additional improvements are seen over time as the right ventricle remodels [3]. Right atrial size decreases signiﬁcantly after pulmonary thromboendarterectomy [68], and both IVC diameter and pulmonary artery size return to nearly normal within 2 weeks after successful surgery [65,68]. The left ventricular eccentricity index returns to approximately 1.0 after pulmonary thromboendarterectomy, and both the E/A ratio and isovolumetric relaxation time normalize. Cardiac output increases signiﬁcantly after surgery [4,50,69]. Mahmud et al [50] found that the transmitral E/A ratio can be used as a noninvasive marker of successful pulmonary thromboendarterectomy, because a postoperative E/A ratio of more than 1.5 correlates with both normal cardiac output and pulmonary artery pressure. Mild pulmonary hypertension The long-term prognosis of mild pulmonary hypertension is diﬃcult to predict and varies with the causative factor. Therefore, a complete evaluation is recommended to exclude correctable causes in asymptomatic patients who are serendipitously diagnosed with mild pulmonary hypertension. In patients with unexplained mild pulmonary hypertension, serial echocardiographic examinations at 6- to 12-month intervals seem

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prudent; earlier evaluation is warranted if symptoms develop [41]. [3]

Transesophageal echocardiography in pulmonary hypertension TEE can be clinically useful in some cases of pulmonary hypertension. For example, Dittrich et al [3] reported modest success using TEE in the identiﬁcation of pulmonary artery thrombus. TEE has also been used to assess the inﬂuence of pericardial constraint and adaptation in CTEPH [70]. Gorcsan et al [71] found that TEE revealed therapy-altering data in 25% of patients with severe pulmonary hypertension. Other techniques such as TTE, CT angiography, V/Q scintigraphy, and pulmonary angiography seem to be more useful in the diagnosis and management of pulmonary hypertension, however. Therefore, current guidelines do not recommend the routine use of TEE in pulmonary hypertension but reserve it for the subset of cases in which other diagnostic studies are equivocal.

[4]

[5]

[6]

[7]

[8]

Summary Pulmonary vascular disease is an entity of diverse causes and varied morphologic and physiologic derangements. Echocardiography has evolved into a primary clinical tool for the diagnosis and management of pulmonary vascular disease and pulmonary hypertension. Echocardiography can help quantify right-heart function, right atrial and ventricular pressures, left ventricular function, and responses to treatment. The role of echocardiography in this area continues to evolve. Areas of active investigation include threedimensional echocardiographic assessment of right ventricular function, noninvasive analysis of right ventricular myocardial strain, and characterization of right ventricular function using tissue Doppler imaging [72].

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Cardiol Clin 22 (2004) 417–429

Molecular biology of primary pulmonary hypertension Mehran Mandegar, MDa, Patricia A. Thistlethwaite, MD, PhDb, Jason X.-J. Yuan, MD, PhDa,* a

Division of Pulmonary and Critical Care Medicine, Department of Medicine, University of California, San Diego, 9500 Gilman Drive, LaJolla, CA 92093-0725, USA b Division of Cardiothoracic Surgery, Department of Surgery; University of California at San Diego Medical Center, 200 West Arbor Drive, San Diego, CA 92103, USA

Basic molecular and pathologic derangements Clinically, severe pulmonary hypertension presents in primary forms (PPH), both sporadic and familial, and in association with other illnesses (formerly referred as secondary pulmonary hypertension). As detailed in the article by McLaughlin in this issue, in the Venice classiﬁcation PPH is now classiﬁed as idiopathic pulmonary arterial hypertension (IPAH) or familial pulmonary arterial hypertension (FPAH), with both entities included in the category of pulmonary arterial hypertension (PAH). Because much of the literature has referred to both entities as PPH, and because molecular mechanisms are commonly shared in IPAH and FPAH, this article uses the traditional term PPH, encompassing both IPAH and FPAH. Regardless of etiology, pulmonary hypertension has histologic features manifested by vascular remodeling, complex lumen-occluding vascular lesions (plexiform lesions), and in situ thrombosis [1]. The plexiform lesions generally occur in small arteries and arterioles. These lesions are composed of tufts of cellular capillary formations resembling a vascular plexus within the lumen of dilated aneurysmal thin-walled arteries. Because plexiThis work was supported by grants from the National Heart, Lung, and Blood Institute of the National Institutes of Health (HL 54043, HL 64945, HL 69758, HL66012 and HL 66941). * Corresponding author. E-mail address: [email protected] (J.X.-J. Yuan).

form lesions occur in patients with PPH as well as those with secondary pulmonary hypertension, they are not pathognomonic for PPH [2]. The origin of plexiform lesions seems to be somewhat diﬀerent in the primary and secondary forms of pulmonary hypertension. Although signiﬁcant uncertainty remains, some investigators believe proliferation of smooth muscle and its transformation into myoﬁbroblasts are responsible for the formation of these lesions [2–4]. Others propose that in PPH endothelial cells are responsible for the formation of these lesions in response to cytokines, growth factors, or vascular injury [1,2,4]. This hypothesis is supported by studies that indicate that the endothelial cells of the plexiform lesions isolated from the lungs of patients with PPH proliferate in a monoclonal fashion, whereas the lesions from patients with secondary pulmonary hypertension have polyclonal cell populations [5]. Recent studies have revealed much at the genetic, cellular, and molecular levels about the determinants and derangements leading to the development of PPH. The histologic ﬁndings in this disease are generally characterized by obliteration of the lumen of precapillary small pulmonary arteries in association with medial hypertrophy, concentric laminar intimal ﬁbrosis, and ﬁbrinoid degeneration, and with the formation of plexiform lesions and in situ thrombosis [6]. These changes in the structural integrity of the arterial vessels, called vascular remodeling, are now generally accepted as the main histologic abnormality in PPH.

0733-8651/04/$ - see front matter Ó 2004 Elsevier Inc. All rights reserved. doi:10.1016/j.ccl.2004.04.005

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Pulmonary vascular remodeling involves a heterogeneous constellation of multiple genetic, cellular, molecular, and humoral abnormalities that share a common end result. The cellular factors include the ion-channel dysfunction that ultimately disturbs intercellular Ca2þ homeostasis. Other factors include the circulating mediators and molecular signaling mechanisms that are involved in stimulation of gene transcription, promotion of the cell cycle (mitosis), and factors involved in creating a proliferative and vasoconstrictive milieu in the pulmonary arterial bed. Multiple studies point to mutations in the bone morphogenetic protein (BMP) receptor type II gene (BMPR2) as the prime suspect in this condition, although BMPR2 mutations are present only in 40% to 50% of patients with familial PPH and in 15% to 25% of patients with sporadic or idiopathic PPH. Mutations in the BMPR2 gene seem somehow ultimately to aﬀect pulmonary vascular remodeling with increased proliferation and decreased apoptosis of pulmonary artery smooth muscle cells (PASMCs), giving them a growth advantage, and increased vascular tone and vasoconstriction. Evidence suggests that medial hypertrophy, which is the most consistent pathologic ﬁnding in PPH, is mainly caused by intrinsic abnormalities in PASMCs. Sustained vasoconstriction also promotes smooth muscle cell hypertrophy and hyperplasia. Vasoconstriction and cellular proliferation may both involve signaling processes that result in parallel intracellular events in vascular remodeling and in the development of pulmonary hypertension. The involvement of human herpes virus 8 (HHV-8) infection in lung tissue from some patients with PPH has been demonstrated, whereas cells of the same type from patients with secondary pulmonary hypertension lack any evidence of this infection [7]. The histologic and immunohistochemical resemblance of the plexiform lesions in patients with PPH to cutaneous Kaposi’s sarcoma lesions further supports the possible involvement of HHV-8, because HHV-8 is a vasculotropic virus that is thought to be the cause of all clinical types of Kaposi’s sarcoma [8]. Only one of three patients with HIV-1–associated severe pulmonary hypertension was positive for HHV-8 infection, however, suggesting that HIV1–associated pulmonary hypertension can occur independently of HHV-8 infection [7]. In situ thrombosis is another major characteristic pathophysiologic abnormality in severe pulmonary hypertension. Interaction of growth

factors and platelets with dysfunctional endothelial cells that creates a procoagulant environment within the pulmonary vascular bed is believed to be responsible in part for this pathologic ﬁnding. Elevated levels of plasma ﬁbrinopeptide-A and prolonged half-life of ﬁbrinogen have been demonstrated in patients with PPH and may contribute to enhanced procoagulant activity and thrombosis. Additionally, diminished ﬁbrinolytic activity and elevated levels of plasminogen activator inhibitor have been demonstrated in more than 70% of patients with PPH [9]. Furthermore, both patients with PPH and patients with secondary pulmonary hypertension have been shown to have elevated levels of urinary metabolites of thromboxane, an indicator of platelet activation [10]. The release of vasoconstrictors, such as serotonin (5-hydroxytryptamine, 5-HT) and thromboxane-A2 (TXA2), and the stimulation of cell proliferation by platelet-derived growth factor (PDGF) and vascular endothelial growth factor (VEGF) are associated with platelet activation and thrombosis. Abnormal functioning of a von Willenbrand’s factor has also been reported in patients with PPH [11]. There is a signiﬁcant increase in von Willenbrand’s antigen immunostaining in the pulmonary vascular endothelium of the patients with pulmonary hypertension secondary to congenital heart disease, indicating a ﬂowinduced change in the functional activity of these cells [12]. Elevated levels of von Willenbrand’s factor may, therefore, stimulate aggregation and adhesion of platelets to pulmonary vessel walls that are already damaged and stressed by pulmonary hypertension or intrinsic endothelial cell abnormalities. Thrombus formation follows aggregation and activation of platelets and may play a signiﬁcant role in stimulating vasoconstriction and cellular proliferation by releasing vasoactive substances and mitogens. Defects in ﬁbrinolysis pathways, on the other hand, may further encourage this process and exacerbate its obliterative results. Although it is clear that platelets, ﬁbroblasts, endothelial cells, and in situ thrombosis are all involved in pulmonary vascular remodeling, pulmonary vasoconstriction and PASMC proliferation are the fundamental derangements underlying vascular remodeling and the subsequent development of severe pulmonary hypertension. The focus in this article is largely on the molecular determinants that unite these two fundamental derangements and their role in the development and maintenance of severe pulmonary hypertension.

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Pulmonary vasoconstriction in primary pulmonary hypertension Vasoconstriction in human pulmonary arteries generally refers of tensile reduction in the crosssectional area of the lumen of the vessel, eﬀectively decreasing its diameter. This decrease in the crosssectional diameter of the arteries is a main factor contributing to elevation of pulmonary vascular resistance (PVR), which is ultimately manifested as elevated pulmonary arterial pressure (PAP). Vasoconstriction, by itself, also promotes smooth muscle cell hypertrophy and hyperplasia [13]. Changes in [Ca2þ]cyt in PASMC play a critical role in pulmonary vasoconstriction and vascular remodeling because an increase in [Ca2þ]cyt is a major trigger for smooth muscle contraction and an important stimulus for smooth muscle cell growth. [Ca2þ]cyt in PASMC is increased by the trans-sarcolemmal inﬂux of Ca2þ through Ca2þ channels and the release of Ca2þ from the intercellular stores. Ca2þ inﬂux through plasmalemma involves multiple Ca2þ-permeable channels that are expressed in the plasma membrane [14]. The sarcolemmal Ca2þ channels are functionally classiﬁed into three families: (1) voltage-dependent Ca2þ channels (VDCCs) that are regulated by changes in membrane potential (Em), (2) receptor-operated Ca2þ channels (ROCs) that are regulated by interactions of agonists with respective receptors, and (3) store-operated Ca2þ channels (SOCs) that are regulated by the concentration (or capacity) of Ca2þ in the sarcoplasmic reticulum [14–16]. The excitation-contraction coupling processes in pulmonary vascular smooth muscle depend on the function of all these channels. A change in Em, for example, is required for the electromechanical coupling that alters vascular tone, and the activity of VDCC is central to this excitation-contraction coupling mechanism. Em in PASMCs governs the activity of VDCCs, which are opened by membrane depolarization and closed by membrane hyperpolarization [15,17]. Resting Em in PASMCs, normally between 70 and 50 mV, is primarily determined by the activity of Kþ permeability across the plasma membrane [18]. At rest, the PASMC membrane is more permeable to Kþ than to any other ions, therefore the resting Em is close to the equilibrium potential for Kþ (EK). Kþ currents through Kþ channels thus play a predominant role in modulating the Em. Currents through voltage-gated Kþ (KV) channels (IK(V)), in particular, have been demonstrated to be predominately responsible for

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the maintenance of the Em in PASMCs under resting conditions [18]. Altered activity of Kþ channels (eg, Kv channels) thus alters Em, inﬂuencing the extent of Ca2þ inﬂux through the VDCCs. Decreased expression or functioning of Kþ channels leads to sustained membrane depolarization and contributes to sustained elevation of [Ca2þ]cyt by (1) activating VDCC, (2) facilitating the production of inositol 1,4,5-trisphosphate (IP3), which stimulates the release of SR Ca2þ into the cytoplasm, and (3) promoting Ca2þ entry through the reverse mode of Naþ/Ca2þ exchange [19]. Indeed, decreased Kþ channel expression and inhibition of Kþ-channel function in PASMCs have been identiﬁed in patients with PPH. The resultant membrane depolarization increases [Ca2þ]cyt by opening VDCCs in PASMCs, causes pulmonary vasoconstriction, and enhances vascular medial hypertrophy [20,21]. Pulmonary arterial wall remodeling: role of intracellular Ca2+ Under normal conditions there is a ﬁne balance between the cellular proliferation and apoptosis in the cells that comprise the walls of pulmonary arteries. This balance is responsible for maintaining the thickness and tissue mass of the arterial walls at an optimal level. If this balance is disturbed so that there is more proliferation and less apoptosis, the arterial wall thickens, narrowing the lumen and ultimately obliterating the blood vessel. This process causes an overall decrease in the cross-sectional area through which the cardiac output from the right ventricle can ﬂow, in eﬀect increasing the PVR. This process also decreases the vascular compliance, which is necessary to accommodate an increase in cardiac output (as during a progressively heavy exercise) by vasodilation (arterial distention) and recruitment of previously unperfused vessels. The structural changes that lead to this pathologic abnormality are referred to as vascular remodeling. Loss of vascular compliance and increased PVR caused by vascular remodeling lead to progressively pronounced pulmonary hypertension and have indeed been found to be the predominate pathologic ﬁnding in PPH. Elevated [Ca2þ]cyt stimulates mitosis Pulmonary vasoconstriction and vascular remodeling may share a common pathway involving signaling processes that result in parallel intracellular events that ultimately lead to the structural

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changes that are the hallmark of PPH. Disturbances in [Ca2þ]cyt homeostasis in PASMCs is at least partly responsible for both of these processes. PASMC proliferation and growth have been shown to be regulated by [Ca2þ]cyt. Nuclear Ca2þ concentration ([Ca2þ]n) is rapidly raised because of an elevated [Ca2þ]cyt [22]. Nuclear Ca2þ is an essential component of cell mitosis and proliferation. Elevated [Ca2þ]cyt, therefore, propels the quiescent cells into the cell cycle and through mitosis, promoting cellular proliferation [23]. When [Ca2þ]cyt rises, Ca2þ binds calmodulin to form an activated complex. The Ca2þ/calmodulin complex is known to regulate the cell cycle as well as certain Ca2þ-dependent cytoplasmic signal transduction proteins that are involved in cellular proliferation. For example, mitogen-activated protein II kinase (MAP-KII), an enzyme involved in the phosphorylation cascade, is activated by a rise in [Ca2þ]cyt [24]. Furthermore, elevated [Ca2þ]cyt is involved in stimulating the expression of the early responsive gene, c-fos. This gene contains two Ca2þ-sensitive elements in its promoter: the serum response element (which binds with serum response factor [SRF] and ternary complex factor [TCF]), and the cAMP response element that binds to cAMP response element binding protein (CREB). A rise in [Ca2þ]cyt activates SRF and TCF, and a rise in [Ca2þ]n activates CREB, hence promoting activation and expression of c-fos [23]. Ca2þ stored within SR plays an important role in cell proliferation. Depletion of Ca2þ from the IP3-sensitive Ca2þ stores has been shown to arrest cell growth, whereas its repletion allows continued sarcoplasmic/endoplasmic reticular function (such as lipid synthesis and protein sorting and processing) and the resumption of the S phase of cell cycle leading to mitosis and cellular proliferation. Therefore, increased [Ca2þ]cyt and [Ca2þ]SR are both required for PASMC mitosis and proliferation. Resting [Ca2þ]cyt has been shown to be significantly elevated in proliferating PASMCs as compared with that in growth-arrested cells, suggesting that enhanced Ca2þ inﬂux is required for smooth muscle contraction and for cell growth and proliferation [25]. Elevated [Ca2þ]cyt in endothelial cells increases activating protein-1 binding activity and growth factor synthesis Activating protein-1 (AP-1) is a family of transcription factors that controls gene expression

directly by regulating genes that contain the AP-1 binding site (50 -TGACTCA-30 [TRE] or 50 TGACGTCA-30 [CRE]) in their promoters, or indirectly by forming heterodimers with other types of transcription factors such as signal transducer and activator of transcription [26]. This family of proteins is composed of Jun (v-Jun, c-Jun, JunB, and JunD), Fos (v-Fos, c-Fos, FosB, Fra1, and Fra2), or activating transcription factor (ATF2, ATF3/LRF1, B-ATF) subunits [27]. AP-1 genes, often referred to as oncogenes, are usually involved in the regulation of cell proliferation, migration, and apoptosis by encoding vasoactive agonists, such as endothelin-1 (ET-1), and mitogens, such as VEGF and PDGF. Cellular proliferation and growth are greatly accelerated in tumor cells that overexpress AP-1 [28]. Genes encoding AP-1 are Ca2þ sensitive [29]. Elevated [Ca2þ]cyt or [Ca2þ]n increases the transcription of AP-1 and augments AP-1 DNA binding activity in pulmonary arterial endothelial cells (PAECs) [30]. Furthermore, the expression of c-fos and cjun proto-oncogenes is increased as a result of the sustained elevation of [Ca2þ]cyt caused by Ca2þ inﬂux [29,31–34]. It has recently been shown that chronic hypoxia in human PAECs increases the mRNA and protein expression of TRPC4, a cation-channel subunit involved in forming heterotetrameric SOC. This process leads to an enhanced amplitude and current density of SOC currents (ISOC) [30]. The resultant increase in the Ca2þ entry through SOC, referred as capacitative Ca2þ entry, along with elevated [Ca2þ]cyt, augments AP-1 binding activity leading to an increased expression of AP-1–responsive genes (eg, ET-1, PDGF, VEGF). Chronic hypoxia-induced pulmonary hypertension is associated with increased synthesis and release of ET-1 and PDGF [35]. This association suggests that a rise in PAEC [Ca2þ]cyt during chronic hypoxia may be partly responsible for pulmonary vascular remodeling. Pulmonary vascular remodeling: role of inhibited apoptosis in pulmonary artery smooth muscle cells As mentioned previously, a ﬁne balance between PASMC proliferation and apoptosis is required to maintain the normal structural and functional integrity of the pulmonary vasculature, whereas vascular remodeling in PPH involves a disturbance of this balance. Both increased proliferation and decreased apoptosis in PASMC would lead to vessel wall thickening. Inhibited

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apoptosis has been implicated in the development and maintenance of severe pulmonary hypertension. Decreased Kþ-channel activity is associated with decreased apoptosis in pulmonary artery smooth muscle cells One of the hallmarks of the apoptotic process is apoptotic volume decrease (AVD) and subsequent cell shrinkage. Maintenance of a high concentration of intercellular Kþ ([Kþ]i) is required to maintain a normal cell volume. Loss of [Kþ]i has been shown to be responsible in part for the AVD. Activation of Kþ channels in the plasma membrane induces or accelerates AVD and apoptosis by enhancing Kþ eﬄux or loss. On the other hand, inhibition or decreased activity of Kþ channels has been shown to cause accumulation of Kþ in the cells, allowing the maintenance of a suﬃciently high [Kþ]i, to decelerate AVD and inhibit apoptosis [36]. In addition to its role in controlling cell volume, a high [Kþ]i is required for suppression of caspases and nucleases, which are believed to be the ﬁnal mediators of apoptosis [37]. Decreased expression of functional KV channels in PASMC, as witnessed in PPH, attenuates programmed cell death by decelerating AVD and inhibiting the activity of cellular caspases, thereby disrupting the balance between PASMC proliferation and apoptosis and promoting pulmonary vascular medial hypertrophy. Several types of Kþ channels are expressed in human PASMC. Role of Bcl-2–mediated inhibition on Kþ-channel activity in enhancing cell survival Bcl-2 is an antiapoptotic membrane protein whose function is to attenuate apoptosis by four mechanisms: (1) by inhibiting cytochrome c and apoptogenic protease release from the mitochondrial intermembrane space into the cytosol, thereby enhancing cell survival, (2) by inhibiting function of Kþ channels, (3) by regulating inﬂux of protons into the mitochondria, and (4) by maintaining [Ca2þ]ER and [Ca2þ]SR. Studies of rat PASMCs overexpressing Bcl-2 have shown decreased expression of KV channel a subunits. This decrease leads to a decrease in whole-cell Kþ currents through the KV channels, leading to elevated [Kþ]i and inhibition of AVD and apoptosis [38,39]. Lung tissues from patients with sporadic and familial PPH have been demonstrated to have an

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increased expression of Bcl-2 mRNA in addition to mutations in BMP-R2 gene. In PASMCs from PPH patients, BMP-mediated apoptosis is significantly inhibited in comparison with normal PASMCs [40]. It is, therefore, reasonable to hypothesize that the increased Bcl-2 gene transcription in PASMCs may be involved in the development of pulmonary vascular medial hypertrophy in PPH patients who have a mutated BMPR2 gene or dysfunctional BMP signaling pathways. Bone morphogenetic protein receptor type II gene mutations in primary pulmonary hypertension Study of families aﬄicted by PPH have shown that mutations in the BMPR2 gene (located in chromosome 2q33) are strongly associated with familial PPH and occur in 15% to 25% of patients with sporadic PPH. Frameshifts, partial deletions, and splice-site, non-sense, and mis-sense mutations, most of which lead to premature termination of protein synthesis, have all been implicated. BMPs are signaling molecules that belong to the transforming growth factor-b (TGF-b) superfamily and play an important role in regulating cell proliferation, diﬀerentiation, and apoptosis [41– 43]. In humans, a variety of cell types, including PASMCs and PAECs, synthesize and secrete BMPs. Similar to TGF-b, the signal transduction of BMP-mediated pathways involves two types of transmembrane serine-threonin kinase receptor proteins: BMP receptor type I (BMP-R1a and BMP-R1b) and type II (BMP-R2) [41]. These receptor proteins reside on the surface of cytoplasmic membrane of cells and in their free form consist of both homomeric and heterogeneous proteins (BMP-R1a, -R1b, and BMP-R2). Binding of BMP ligand (eg, BMP-2 and -7) to either of the receptors (BMP-R1 or -R2) leads to heterooligomerization of BMP-R1 and -R2 and formation of ligand-receptor complex, which in turn activates the downstream signaling elements such as the receptor-activated ‘‘mothers against decapentaplegic’’ (Smad) proteins (Smad-1, -5, and -8). The activated BMP-R1 phosphorylates the RSmad proteins (eg, Smad-3, -5, and -8), which are then dimerized with co-Smad (eg, Smad-4) forming a complex signaling protein that can translocate into the nucleus. The R-Smad and co-Smad complex is involved in regulation of transcription of certain Smad-responsive genes that contain the Smad binding sequence (50 -CAGAC-30 and

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50 -GTCTG-30 ) in their promoter [41,43–45]. Many of the Smad-responsive genes encode proteins that are required for apoptosis and inhibition of cellular proliferation [41–44]. In addition to R-Smad and co-Smads, humans also express antagonistic Smads such as Smad-6 and -7, which mediate negative feedback within TGF-b/BMP signaling pathways and regulatory inputs from other pathways. The antagonistic Smads compete with R-Smad for the activated tyrosine kinase and therefore inhibit activation of R-Smads [41]. Smad-6 inhibits BMP signaling by blocking activation of Smad-1, -5, or -8 [46]. Increased Smad in the nucleus can have three eﬀects: (1) activation of gene transcription by binding onto the Smad-binding sequence in the promoter, (2) formation of heterogeneous polymers with other transcription factors to mediate apoptosis, and (3) formation of heterogeneous polymers with corepressors such as the homeodomain protein transforming growth-interacting factor and two related proteins c-Ski and SnoN to induce repression of target gene transcription [41,47,48]. In mammalian cells, another inhibitor of Smads is the Smad-interacting protein-1, and zinc-ﬁnger/homeodomain protein that interacts with Smad-1 and -5, inhibiting BMP-mediated eﬀects [41]. Furthermore, activation of Smad proteins is inhibited by overexpression of calmodulin, a Ca2þ-sensitive cytosolic protein. Calmodulin attenuates the response of TGF-b/BMP signaling transduction. This eﬀect suggests that elevated levels of [Ca2þ]cyt can lead to activation of calmodulin, which inhibits Smad proteins, having an inhibitory eﬀect on TGF-b/BMP signaling pathway and on TGF-b/BMP -mediated apoptosis in human PASMCs. Mutations in the BMPR2 gene can negatively inﬂuence the binding of BMP ligand to either of the receptors either by lack of expression of these receptors at protein level or by production of structurally dysfunctional proteins. Attenuation of activated BMP-R proteins leads to decreased formation of Smad complexes that are necessary for continued apoptosis and inhibition of proliferation. Numerous studies have elucidated multiple cellular and molecular pathologic abnormalities that are often associated with the development of PPH. The exact pathologic mechanisms by which mutations in the BMPR2 gene relate to each of these derangements in mediate vascular remodeling in patients with PPH is not yet clearly understood. The authors’ previous study [40] has suggested that, in normal PASMCs, BMPs

induce apoptosis by decreasing the expression of Bcl-2. In PASMCs from PPH patients, the BMPmediated inhibition of Bcl-2 and apoptosis are markedly attenuated because of dysfunctional BMP signaling. The interaction of BMPs with Bcl-2 proteins through BMP receptors provides a potential mechanism by which mutations of BMP-R2 may cause pulmonary vascular medial hypertrophy: increased expression of Bcl-2 inhibits the release of cytochrome c from mitochondria, thereby attenuating PASMC apoptosis [40].

Other molecular mechanisms involved in the development of pulmonary hypertension In addition to the derangements of ion channels and intercellular ion concentrations, mutations of BMPR2 gene, and dysfunction of BMP signaling, substantial and convincing evidence now indicates that multiple derangements in complex intracellular signaling pathways might contribute to the manifestation of PPH. Recent studies have shown that PPH involves a heterogeneous constellation of multiple cellular, genetic, molecular, and humoral abnormalities that all lead, in one way or another, to pulmonary vascular remodeling, which is the hallmark of PPH. Ion-channel dysfunction and disturbance of intercellular Ca2þ homeostasis, as discussed earlier, are examples of the cellular and genetic factors involved. Other factors include the circulating mediators and molecular signaling mechanisms involved in stimulation of gene transcription and promotion of the cell cycle (mitosis) and factors involved in creating a proliferative and vasoconstrictive milieu in pulmonary arterial bed. Role of 5-HTT and 5-HTR and the second-hit theory The prolonged use of certain appetite suppressants (ie, aminorex, fenﬂuramine, and dexfenﬂuramine) increases the risk for the development of PPH by 30-fold when compared with the general population. These drugs interact with monoamine system in the brain, potently inhibiting neuronal serotonin (5-HT) reuptake by inhibiting 5-HT transport proteins (5-HTT) and by triggering indolamine release and consequently, an increase in the amount of extracellular 5-HT [49]. The adverse eﬀects of these anorexigenic drugs in the development of plexogenic pulmonary arteriopathy, mostly conﬁned to the small muscular arteries and arterioles in the lungs, suggest that

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they have a molecular target that is selectively present in the pulmonary arteries. Initial data suggested that elevated levels of circulating 5-HT could lead to pulmonary vasoconstriction and PASMC proliferation. This possibility was consistent with reports of elevated plasma 5-HT levels under several conditions leading to the development of pulmonary hypertension [50]. Concentration of serum 5-HT level does not necessarily reﬂect the 5-HT concentration in the local microenvironments surrounding PAECs and PASMCs. 5-HT is also released from a variety of pulmonary neuroendocrine cells and neuroepithelial bodies that are present throughout the airways and possibly may be released from PASMCs [51]. This process increases the availability of free 5-HT in the local pulmonary microenvironment, making 5-HT more likely to aﬀect pulmonary vasculature than systemic vessels. Vasoconstriction occurs when 5-HT binds to 5-HT2 and 5-HT1B/1D receptors (5-HTR). The 5HT is then transported inside the cells by 5-HTT. The 5-HTR and 5-HTT are abundantly expressed in the lung, where they are predominantly located in the PASMCs [52]. Once internalized, the 5-HT can exert its mitogenic and comitogenic eﬀects on PASMCs [49]. The precise relationship between 5-HTR and 5-HTT is yet to be clearly deﬁned. Nevertheless, it seems that activation of either the 5-HTT or the 5-HTR by 5-HT, depending on cell type, can initiate a signaling process that activates cell proliferation and hyperplasia. The fact that pulmonary hypertension develops in only a minority of the individuals who ingest appetite suppressants suggests that these patients may have a genetic predisposition that makes them vulnerable to the disease after a second ÔhitÕ occurs, namely the eﬀect of these drugs. These medications might elevate the 5-HT levels in the local milieu. Alternatively, they might directly stimulate the overexpression of 5-HTT in PASMCs in genetically predisposed patients, thereby causing pulmonary vasoconstriction, PASMC growth, and development of PPH. Aminorex and fenﬂuramine derivatives interact with 5-HTT in a speciﬁc manner, further suggesting that the 5-HTT may be a critical target by which appetite suppressants initiate the development of pulmonary hypertension. Recent studies have shown that there is increased expression of 5-HTT in the lung tissues and pulmonary arteries isolated from patients with PPH, and there is marked enhancement of the proliferative growth response of cultured PASMCs to 5-HT but not to

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other growth factors [53]. Additionally, the increased expression of 5-HTT in patients with PPH has been associated with polymorphism of the 5-HTT gene promoter. Also, targeted 5-HTT gene disruption in a study of the mice showed that these mice were less prone to develop severe hypoxic pulmonary hypertension than the wildtype controls [54] and that selective 5-HTT inhibitors attenuate hypoxic pulmonary hypertension, further supporting this hypothesis. Conversely, increased 5-HTT expression has been shown to be associated with increased severity of hypoxic pulmonary hypertension [53]. Therefore, the expression or function of 5-HTT in PASMCs seems to play a critical role in the extent of hypoxia-induced pulmonary vascular remodeling. It has been well established that a polymorphism in the promoter region of the human 5-HTT gene alters its transcriptional activity. Thus the level of its expression is genetically predetermined based on its genotype. The polymorphism involves two alleles: the L allele (‘‘long 5-HTT gene promoter’’) is a 44–base pair insertion that has a twofold to threefold higher level of 5-HTT gene transcription than the S allele, which consists of the 44–base pair deletion. It is believed that 60% to 70% of patients with PPH have the L/L genotype, whereas the L/L genotype is present only in 20% to 30% of the control population of white subjects, suggesting that L/L genotype may confer genetic susceptibility to PPH [49]. As mentioned previously, mutations in the BMPR2 gene as well as mutations associated with impaired signaling through other members of the TGF-b receptor family have been strongly associated with familial and sporadic PPH. It is not yet well established how the 5-HTT pathway is aﬀected by a common BMPR2 mutation. PPH does not occur in all persons with BMPR2 mutations, however, suggesting that other environmental or associated genetic factors may play a critical role. Because normal signaling from BMP-R2 is associated with suppression of PASMC proliferation and induction of PASMC apoptosis, it is plausible that BMP-R2 may antagonize the eﬀects of 5-HT [40,42]. The BMPR2 mutation could therefore allow a stronger response to the eﬀects of 5-HT in the cells, particularly in patients with L/L genotype, allowing heightened expression of the 5-HTT. It remains to be determined if patients carrying both BMPR2 mutation and the 5-HTT polymorphism have heightened proliferative response to 5-HT in their PASMCs. Whether aberrant BMP-R2 signal transduction and gene

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expression are complementary to increased 5-HTT signaling and gene expression is still under study. Elevated angiopoietin-1 activity contributes to pulmonary vascular remodeling During the early stages of life, angiopoietin-1, a 70-kD protein that is secreted by PASMCs, acts as an angiogenic factor and is essential for lung vascular development and stabilization. The receptor for angiopoietin-1 is tyrosine kinase with immunoglobulin and epidermal growth factor homology domain 2 (TIE2), which is present only on vascular endothelium [55]. During blood vessel formation, the interaction between the ligand, angiotensin-1, and the receptor, TIE2, on the endothelial cells induces the recruitment, migration, and proliferation of smooth muscle cells around the endothelial vascular network. Angiopoietin-1 is minimally expressed in adult human lung once development is complete [56,57]. Aberrant overexpression and high steady-state levels of angiopoietin-1 have been observed in PASMCs from patients with acquired and primary nonfamilial pulmonary hypertension. The tyrosine phosphorylation of the TIE2 receptor in pulmonary vascular endothelium directly correlates with the severity of the disease [56,57]. Additionally, elevated levels of angiopoietin-1 seem to shut oﬀ the expression of BMP-R1a, a transmembrane protein required for BMP-R2 signaling in PAECs [56,57]. These observations suggest that the development of pulmonary hypertension may involve a molecular cascade in which the steady-state levels of BMP-R1a in PAECs are decreased by angiopoietin-1. Furthermore, the expression of angiopoietin-1 in the adult human lung seems to be the cause of pulmonary hypertension rather than being secondary to it [56]. BMP ligands exert their eﬀects through activation and heterodimerization of BMP-R1 and BMP-R2 on the cell surface, leading to Smad intracellular signaling [58]. The activation of BMP-R1a and BMP-R2 can aﬀect diﬀerent cell types diﬀerently, causing either promotion or inhibition of transcription [59,60]. PAECs in the lung tissue from patients with pulmonary hypertension have a markedly diminished expression of BMP-R1a mRNA. It is thus proposed that the nonfamilial forms of pulmonary hypertension may occur through angiopoietin-1–mediated inhibition of BMP-R1 expression, which attenuates BMP-R2 signaling. Therefore, the BMP-R2 signaling pathway is attenuated either by mutations

in the BMPR2 gene in familial PPH or by the angiopoietin-1–dependent reduction of steadystate levels of BMP-R1a in sporadic pulmonary hypertension, leading to stimulation of cellular proliferation and attenuation of apoptosis. Endothelium-derived factors and growth factors in pulmonary hypertension Under normal conditions, vasodilation and recruitment of previously underperfused vessels allows pulmonary vasculature to accommodate up to a sixfold rise in cardiac output without any signiﬁcant rise in the PAP. This mechanism for vascular compliance is maintained by a variety of active mediators produced by the PAECs. These mediators include endothelium-derived relaxing factors such as nitric oxide (NO) and prostacyclin, which usually act in coordination with endothelium-derived constricting factors such as ET-1, thromboxane, and 5-HT to accommodate changes in the cardiac output and keep the PAP relatively constant. Derangements in the activity or function of these endothelium-derived factors can lead to an elevated vasomotor tone and endothelial and smooth muscle cell proliferation, causing vascular remodeling and inciting thrombosis. The role of NO in inhibiting smooth muscle cell growth and constriction and inhibiting platelet aggregation is well established [61]. NO generated by nitric oxide synthase (NOS)-I (nNOS) and -III (eNOS) are responsible for maintaining normal vascular tone and neuronal signal transduction. NOS-II, which is expressed in a variety of cells within the body, is a calcium-independent isoform that is able to generate NO in great quantities over longer periods of time and is the predominant isoform during inﬂammatory processes [62]. The expression of NOS-III is diminished in the pulmonary arteries of patients with pulmonary hypertension who have severe morphologic abnormalities [63]. Furthermore, NOSIII may play an important role in maintaining normal vascular tone as evidenced by the study of mice mutant to the NOS-III, which exhibit increased PAP and impaired relaxation to acetylcholine [64]. On the other hand, NOS-I knockout mice have not been shown to develop pulmonary hypertension or structural remodeling, an observation that suggests that NOS-I may not be involved in pulmonary hypertension [18]. ET-1 is a potent vasoconstrictor and a mitogen promoting smooth muscle cell proliferation. ET-1 is initially produced as a 38–amino acid active

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peptide, which is then converted into a 21–amino acid peptide by the action of endothelin converting enzyme (ECE) [65]. Expression of ECE-1 has been demonstrated in the airway epithelium, smooth muscle cells, macrophages, and vascular endothelial cells of normal lungs and of diseased lungs in patients with pulmonary hypertension. ECE-1 is particularly abundant in the vascular endothelium of the pulmonary arteries in patients with mild to severe pulmonary hypertension [66]. The vasoconstrictor eﬀect of ET-1 is mediated thorough ETA, a receptor that is present on the surface membrane of PASMCs. Endothelial cells also express ETB on their cell membranes. ETB mediates the vasodilatory eﬀects of ET-1, modulates the synthesis of ET-1, and is responsible for clearance of circulating ET-1 [67]. Bosentan, an orally active nonpeptide that is a highly speciﬁc competitive antagonist of both ETA and ETB, has been demonstrated to inhibit pulmonary vascular remodeling associated with pulmonary hypertension [68]. Human trials of this drug have been promising in reversal of PPH and regression of histologic changes associated with this disease [69]. Several studies have demonstrated interaction between ET-1 and NO. In patients with pulmonary hypertension, there is increased ET-1 production and decreased NO production [63]. In fact, ETB has been demonstrated to mediate vasorelaxation through the release of NO [65], and hypoxia inhibits ETB receptor–mediated NOS [70]. Impaired NOS and vasodilatation in chronic hypoxia have been shown to be associated with impaired cGMP-dependent mechanisms [71]. Phosphodiesterase inhibitors increase the intracellular concentration of cGMP and cAMP and have been shown to have vasodilatory properties on pulmonary circulation. Because inhibition of phosphodiesterases is inﬂuenced by natriuretic peptide activity [72], drugs that induce activity of natriuretic peptides have a protective eﬀect against the structural changes associated with chronic hypoxia. The beneﬁcial eﬀects of sildenaﬁl in this regard have been reported in published case reports [73]. Derangement in the function and activity of angiogenic factors has also been implicated in the development of PPH. Angiogenic factors are generally involved in lung development and exert a protective eﬀect by modulating adaptation to various abnormal conditions. TGF-b and VEGF, an angiogenic factor, have been implicated in the pathophysiology of pulmonary hypertension. Expression of VEGF-A, which is abundantly ex-

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pressed in adult lung [74], seems to be, in part, regulated by hypoxia. Chronic hypoxia has been shown to increase the expression of VEGF-A and its receptors VEGFR-1 and -2 in rat lung [75]. Adenovirus-mediated overexpression of VEGF-A in the lung has a protective eﬀect by attenuating the development of pulmonary hypertension, in part through an improvement in endotheliumdependent function [76]. In mice, targeted knockout of a single VEGF-A gene allele causes lethal impairment of angiogenesis [77]. The expression of VEGF-B, a more recently discovered member of VEGF family which is also expressed in lower levels in the walls of pulmonary arteries, does not seem to be regulated by hypoxia or cytokines [78]. VEGF-B is also active on VEGFR-1 but not on VEGFR-2. The role of VEGF-B in pulmonary hypertension is still unclear because VEGF-B knockout mice are healthy and fertile, except for having an abnormally small heart, coronary artery dysfunction, and impairment of recovery from cardiac ischemia [79]. The endogenous VEGF-B does not signiﬁcantly counteract the development of chronic hypoxic pulmonary hypertension, although its overexpression in the lung has been shown to be as potent as VEGF-A in attenuating the development of pulmonary hypertension and vascular remodeling [80]. Additionally, VEGF-A, but not VEGF-B, has been shown to stimulate eNOS expression and NO production. In mice overexpressing VEGF-A, the protective eﬀect seems to be related to induction of NOS, and in NOS-deﬁcient mice alveolar and associated vascular growth is impaired in hypoxia [81]. The arachidonic acid metabolite TXA2, which is an endothelium-derived vasoconstrictor, a mitogen for smooth muscle cell growth, and an agonist for platelet aggregation, has been found to contribute to vascular remodeling and histopathologic changes associated with PPH. Patients with PPH have been shown to have elevated levels of urinary 11-dehydro-TXB2, a major urinary metabolite of TXA2 [10], as well as elevated total body synthesis of TXA2, suggesting that TXA2 may play a role in pathogenesis of PPH [82]. It has not been determined precisely where TXA2 is produced in patients with PPH, but activated alveolar macrophages and platelets are one possibility [82]. Summary It is clear now that the etiology of PPH involves a heterogeneous constellation of multiple genetic,

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molecular, and humoral abnormalities. Studies have implicated derangements in multiple levels of genetic, molecular, cellular, hormonal, and humoral activity and function. For example, ionchannel synthetic, structural, and functional derangements (eg, decreased expression of functional KV channels) and multiple derangements in complex intracellular signaling pathways (eg, BMP and 5-HT signaling pathways) have been identiﬁed, all of which can contribute in diﬀerent ways to the manifestation of this disease in diﬀerent individuals. Although each abnormality seems important, none seems to be suﬃcient to cause the disease by itself. A complex web of interrelated events is often involved in the development of this process, which aﬀects the pulmonary vasculature in a selective fashion. Some of the derangements, such as the BMPR2 gene mutations, occur in cells throughout the body, but disease manifests only in the pulmonary vascular bed. Therefore, inheritance of BMPR2 gene mutation by itself should not be suﬃcient for the development of PPH, and experts have proposed the multiple-hit theory in which some of the hits confer pulmonary speciﬁcity. For instance, inheritance of BMPR2 gene mutation followed by acquired mutations in KV channels can trigger the development of severe PPH. Taking all these factors into consideration, one can classify the abnormalities that are responsible for the development and maintenance of PPH into three broad categories: (1) cellular factors that create a proliferative, antiapoptotic, and vasoconstrictive physiologic milieu, (2) circulating factors that promote a proliferative, antiapoptotic, and vasoconstrictive physiologic milieu, and (3) genetic molecular signaling factors that promote gene transcription and the cellular synthetic cycle, thereby promoting a proliferative, antiapoptotic, and vasoconstrictive physiologic milieu. The ﬁnal manifestation of all of these diverse abnormalities seems to be vascular remodeling that results from a disturbance in the ﬁne balance between the proliferation and apoptosis of PASMCs and derangements in the vascular tone in which chronic and sustained vasoconstriction leads to medial hypertrophy of the small to medium-sized pulmonary arteries. Vascular remodeling consists of narrowing of the lumen of pulmonary arteries and arterioles, thereby increasing PVR, and ensuing pulmonary hypertension. As research aimed at discovering eﬀective therapies for PPH continues, one should remember that the many diverse and often clinically occult abnormalities that have been implicated in

the development of PPH seem to share one ﬁnal pathway: vascular remodeling. Targeting vascular remodeling for therapeutic means would obviously be much more practical and eﬀective than developing numerous therapeutic modalities to reverse each of the unique pathogenic derangements in any individual. The authors suggest that any eﬀective future therapeutic modality should strive to prevent or reverse vascular remodeling by inhibiting proliferation and promoting apoptosis in PASMCs and possibly by attenuating the vascular tone and preventing vasoconstriction at a cellular level. A combined modality directed at these three fronts may provide synergistic eﬀects and ultimately improve the prognosis for PPH.

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Cardiol Clin 22 (2004) 343–351

Pathology of pulmonary hypertension Norbert F. Voelkel, MDa,b,*, Carlyne Cool, MDa,b a

Division of Pulmonary Sciences and Critical Care Medicine, Department of Pathology, University of Colorado Health Sciences Center, 4200 East Ninth Avenue, Denver, CO 80262, USA b Pulmonary Hypertension Center, 4200 East Nineth Avenue, Denver, CO 80262, USA

The pathology of pulmonary hypertension involves what is diseased, abnormal, or wrong in pulmonary hypertension. The pathophysiology of severe pulmonary hypertension largely has been worked out in the golden age of physiology. In more recent years investigators have been more concerned with the cellular and molecular abnormalities that characterize the lung circulation and the pressure- and volume-overloaded right ventricle. There are, therefore, two battlegrounds to consider: the lung vessels and the myocardium of the right ventricle. Although eﬀective treatments have been established that result in improved survival [1,2], no cure exists, and because the pathobiologic concepts have changed, further intense investigations are necessary. This article brieﬂy discusses the traditional concepts of severe pulmonary hypertension and then details how the concept of severe pulmonary hypertension has moved from a vasoconstrictive to an angioproliferative disorder. The seminal studies by the Wagenvoorts [3,4] and by Heath and Edwards [5] were based on standard histologic techniques and hematoxylineosin staining of tissues. Wagenvoort showed that primary pulmonary hypertension (PPH) is not a thromboembolic disease [3] and cleared the way for other pathogenetic concepts. Because some of the pulmonary arteries in PPH showed striking muscularization and a crenated internal elastic

* Corresponding author. Division of Pulmonary Sciences and Critical Care Medicine, 4200 East Nineth Avenue, C272, Denver, CO 80262. E-mail address: [email protected] (N.F. Voelkel).

lamina [4], vaso-constriction and ‘‘work hypertrophy’’ of the pulmonary arteries were considered as causative factors, especially because the models of pulmonary hypertension were rat chronic hypoxia and the monocrotaline model [6–8].

Hemodynamics in severe pulmonary hypertension The hemodynamic signature of severe pulmonary hypertension is the combination of an elevated pulmonary artery pressure and a decreased cardiac output [9]. As the disease progresses, the cardiac output becomes progressively lower and cannot be signiﬁcantly raised during exercise. Symptoms that ultimately lead a patient to seek medical evaluation include syncope, dyspnea on exertion, and fatigue. The pulmonary arterial wedge pressure is usually normal if the disease is caused by precapillary arterial remodeling, whereas the postcapillary forms of severe pulmonary hypertension are associated with left ventricular dysfunction or elevated wedge pressure. Based on the concept of precapillary arterial vasoconstriction that eventually results in morphologic changes of the vessels (a process somewhat glibly called remodeling), investigators believed that the earlier stages of severe pulmonary hypertension were characterized by a measure of vascular reactivity (ie, a signiﬁcant decrease in the mean pulmonary artery pressure and an increase in cardiac output after vasodilator drug challenge). Cardiologists in the 1960s—Paul Wood [10] among them—used the infusion of acetylcholine to test for pulmonary vasoreactivity. A modern interpretation of these historical data is that the acetylcholine-induced drop in pulmonary

0733-8651/04/$ - see front matter Ó 2004 Elsevier Inc. All rights reserved. doi:10.1016/j.ccl.2004.04.010

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Severe Pulmonary Hypertension

“reactive” vasodilator responder

“non–reactive”, no response to vasodilators

early RV failure compensated RV Fig. 1. Diagnostic paradigm for severe pulmonary hypertension.

GENETIC FACTORS

related to lung vasomotor tone control

related to lung vascular cell growth and differentiation

K+- channels

BMPRII

serotonin transporters

ALK-I

other genes

H1F-1α? estrogen receptor?

Shear stress

VSMC growth

endothelial cell growth

TSH

Anorexigen drugs

Hypertension-Diabetes

Hypothyroidism Co morbidities

estrogens viral infections Environmental factors

Fig. 2. Genetic factors in pulmonary hypertension. (thyroid stimulating hormone [TSH])

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artery pressure is caused by endothelial cell nitric oxide, and the lack of this response is now explained as a manifestation of pulmonary endothelial cell dysfunction [11]. A relatively small number of patients with severe pulmonary hypertension had a signiﬁcant reactive pulmonary vascular component when assessed at the time of their ﬁrst diagnostic right-heart catheterization [12]; this ﬁnding has recently been conﬁrmed in studies involving a large number of patients [13]. The growing recognition of this ﬁnding raises the question whether the socalled responders are patients with an altogether diﬀerent disease. This question is also raised by the observation that younger children are likely to show a robust vasodilator response, and that this response is observed less frequently as children get older [14]. A histologic assessment of the lung vessels at the time of the pulmonary vascular reactivity test would be required to ﬁnd out whether muscularized, but not lumen-obliterated, precapillary arterioles are associated with a strong vasodilator response and whether endothelial cell proliferation and lumen obliteration are associated with the absence of such a response. More work is required to clarify whether the responders represent an early manifestation of the same disease or a categorically diﬀerent disease. In practical, therapeutic terms, one form can be treated with Caþþ entry blockers [15] and another form (seen in most patients) does not respond to Caþþ channel blockers and must be treated diﬀerently. Thus the distinction between responders and nonresponders (Fig. 1) remains an important diagnostic task. A second distinction, also of prognostic importance, is the myocontractile reserve of the right ventricle. With the same degree of afterload, some patients develop early signs of right ventricular failure, whereas others remain relatively functional and compensated for quite sometime. The authors suggest that these varying coping mechanisms of the right ventricle may be genetically determined [9,16]. Genetic susceptibility and disease associations For decades, risk factors for the development of severe pulmonary hypertension have been known [17], and a familial form of PPH has been recognized [18]. In addition, HIV infection and hypothyroidism have been associated with PPH [19,20]. Although the recent discovery of the familial PPH gene, bone morphogenic protein receptor II

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(BMPR2) [21], a member of the transforming growth factor-beta (TGFb) superfamily, now provides one concrete gene target for detailed investigation, it is also clear that there are other genetic factors and conditions that facilitate, cooperate with, or trigger the development of secondary pulmonary hypertension. It is now known that only 50% of patients with familial PPH carry BMPR2 mutations and that about 10% of the

Fig. 3. (A) Plexiform lesions (P) located distal to the bifurcation of a small pulmonary artery (PA). The plexiform lesions are characterized by abnormal proliferations of endothelial cells that form multiple, irregular lumens. The plexiform lesions almost totally obliterate the lumens of the two branch vessels. Just distal to the plexiform lesion on the right is a dilated, ectatic channel ﬁlled with blood (arrow). (Hematoxylineosin, original magniﬁcation 200. (B) High-power magniﬁcation of plexiform lesion (P) occluding a small pulmonary artery. The endothelial cells are no longer normal ﬂattened cells lining a vessel lumen; they are disorganized, and their nuclei are somewhat enlarged and plump. (Hematoxylin-eosin, original magniﬁcation 400.)

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sporadic cases of PPH carry BMPR2 mutations [22]. The authors hypothesize that a wide spectrum of genetic and environmental disturbances [23,24] and a host of modiﬁer genes interact in a permissive fashion. Only when it is understood how these multiple inﬂuences come together in the lung circulation will there be a uniﬁed theory of secondary pulmonary hypertension [24]. For example, a relatively small number of HIV-infected patients develop severe pulmonary hypertension, approximately 30% of patients with the calcinosis, Raynaud’s phenomenon, esophageal dysfunction, sclerodactyly, and telangiectasia (CREST) variant of scleroderma develop severe pulmonary hypertension, and perhaps 10% of PPH patients have a thyroid problem. Millions of people have taken appetite-suppressant drugs; fortunately only a relatively small number of them developed severe pulmonary hypertension [25–27]. At the present state of knowledge one might attempt to work backwards from the pathobiology of the lesions, which are strategically located at sites of precapillary and arteriolar bifurcations [28] (in the lung, the lesions are found only in these locations). These vascular lesions have never reoccurred in a transplanted lung. This line of investigation places the target of these multiple genetic abnormalities in the lung, in a highly sitespeciﬁc fashion. What are the conditions that allow the development of pulmonary vascular abnormalities? Are there genetic determinants of pulmonary vasomotor tone control? For example, is there a genetic abnormality coding for a channelopathy [29] resulting in an impairment of opening of ion channels, as suggested for a certain class of Kþ channel [29] or serotonin transporters [30]? Such genetic abnormalities, if unopposed, could cause pulmonary vasoconstriction, impair-

ment of vascular cell apoptosis, and vascular smooth muscle growth [31]. Other genetic abnormalities could permit exuberant endothelial cell growth. For example, polymorphisms or mutations of genes that control the expression, function, and metabolism of growth factor–regulating proteins such as hypoxia-induced factor-a1(HIFla), estrogen [32], and leptin receptors may play a role. Fig. 2 shows possible interactions of genetic and pathobiologically important environmental factors.

The vascular lesions in severe pulmonary hypertension There are only a handful of pulmonary vascular abnormalities, which, for convenience, can be divided into abnormalities involving remodeling of the vascular wall and lumen-obliterating angioproliferative changes. Plexiform lesions, the prototypic angioproliferative lesions, are the hallmark of idiopathic and familial pulmonary arterial hypertension (PAH) and are characterized by abnormal proliferation of endothelial cells, forming multiple irregular lumens. Pure muscularization of precapillary arterioles without endothelial cell proliferation and lumen obliteration may exist in children but probably is rare in adults. These morphologic lesions are not pathognomonic for PAH but can occur in any severe case of pulmonary hypertension. Although all three layers of the small precapillary arteries can be involved, a plexiform lesion can arise from a nonmuscularized, thinwalled vessel. Muscularized vessels with a patent lumen can coexist with vessels occluded by concentric intima ﬁbrosis, and plexiform lesions and concentric intima ﬁbrosis seem to be topographim

Fig. 4. (A) Co-immunoﬂuorescence staining for Factor VIII–related antigen (green) and a-smooth muscle antigen (red) demonstrates smooth muscle hypertrophy of a small pulmonary artery in a patient with severe pulmonary hypertension. Nuclei are blue. The elastic laminae are light blue. (Original magniﬁcation 400.) (B) Vascular endothelial growth factor (VEGF) immunostaining of the smooth muscle layer in a pulmonary artery from a patient with severe pulmonary hypertension. VEGF is present in both the endothelial cells (arrow) and smooth muscle cells (arrowheads). The vessel lumen is at the upper left (L). (Original magniﬁcation 1000.) (C) Immunoﬂuorescent stain of a plexiform lesion: Factor VIII–related antigen (green), a-smooth muscle actin (red), nuclei (blue). Transitional cells are deﬁned by their coexpression of Factor VIII–related antigen and a-smooth muscle actin (yellow to orange, arrows). (Original magniﬁcation 1000.) (D) Plexiform lesion immunostained with antibodies to nitrotyrosine (brown). There is prominent nitrotyrosine staining in the plexiform lesion, consistent with a role for oxidative stress in the pathobiology of severe pulmonary hypertension. (Original magniﬁcation 400.) (E) Plexiform lesion immunostained with antibodies for aquaporin IV. (Original magniﬁcation 400.) (Courtesy of Dr. Michael Kasper, Institute of Anatomy, University of Dresden, Germany.) (F) Plexiform lesion immunostained with antibodies for podocalyxin. Podocalyxin is a podocytic protein that is highly speciﬁcally expressed in endothelium of blood vessels. (Original magniﬁcation 400.) (Courtesy of Dr. Michael Kasper, Institute of Anatomy, University of Dresden, Germany.)

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cally related, as shown by three-dimensional vascular reconstruction [28]. In addition, severe pulmonary hypertension associated with collagen vascular disorders frequently is characterized by a much greater degree of vessel adventitia thickening; this ﬁnding in association with a plexogenic

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arteriopathy suggests secondary pulmonary hypertension rather than PPH (C. Cool, unpublished data). Thromboembolic lesions are rarely seen today in lungs from patients with secondary pulmonary hypertension, because these patients are now eﬀectively treated with anticoagulants.

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Immunohistochemistry and in situ hybridization have been important tools in characterizing the vascular lesions in patients with secondary pulmonary hypertension [33–38]. The immunohistology of plexiform lesions, in the aggregate, indicates that the cells that form these lesions are phenotypically altered; in particular, there is a loss of tumor suppressor proteins [28,37] and overexpression of proapoptotic proteins [39] (Figs. 3 and 4). This ﬁnding is important, because new treatment strategies must be designed with the phenotypically altered smooth muscle and endothelial cells in mind [40–42]. One important diﬀerence between animal models of chronic hypoxia-induced pulmonary hypertension and human SVP is that the remodeling is not reversible in human SVP; pulmonary arterial muscularization may be the appropriate adaptive response to vascular wall stress [40,42], whereas endothelial cell proliferation constitutes the abnormal, obliterative response [42] that only occurs in genetically susceptible individuals. Based on animal experiments [43], the authors propose that the initiating event ultimately leading to plexogenic severe pulmonary hypertension is endothelial cell apoptosis at the sites of bifurcations that also are exposed to high shear stress. They further propose that the genetic susceptibility is likely to reside in the control of the appropriate replacement of apoptosed endothelial cells. What is called for in normal vascular biology is the maintenance of the endothelial monolayer; what probably happens in severe pulmonary hypertension is the evolution of apoptosis-resistant, proliferative cell phenotypes [37,43,44]. Inﬂammation is either primarily or secondarily involved in severe pulmonary hypertension [45– 47]. B and T lymphocytes [45] and mast cells [48] are found in the vascular lesions, and there are clusters of macrophages in close proximity to the plexiform lesions [35]. These cells may represent part of a local immune response. One also, however, must consider generalized immunologic problems, because patients with PPH have been shown to have elevated plasma levels of interleukin (IL)-1 and IL-6 [49]. IL- 6 protects endothelial cells against apoptosis [50], and IL-1b increases the expression of HIF-1a [51]. The interactions between the immune system and the lung circulation may be complicated, because patients with autoimmune disorders as well as patients with immune insuﬃciency may develop plexogenic pulmonary arteriopathy [19,52]. HIV infection has been associated with severe pulmonary hypertension, and

recently the authors [53] reported a high prevalence of human herpes virus 8 infection in patients with PPH but not in patients with secondary forms of severe pulmonary hypertension [53]. Plexiform lesions are similar to the lesions of Kaposi’s sarcoma lesions in several ways [53–56]. As already mentioned, endothelial cell apoptosis, as has been described in scleroderma [57], may be a primary event in severe pulmonary hypertension, and a viral infection could trigger both endothelial cell death (lytic phase of viral infection) and endothelial cell proliferation, the latter largely inﬂuenced by vascular endothelial growth factor (VEGF) [55,56,58]. Overexpression of HIF-1a, the VEGF receptor II (KDR) of angiopoietin I, and endothelin receptors [39,40,59] in the complex PPH vascular lesions can all be integrated into the concept of misguided angiogenesis [60] and neoplasic cell growth [61]; overexpression of 5-lipoxygenase and 5-lipoxygenase activating protein in pulmonary vascular endothelial cells in PPH [35] is also a feature consistent with neoplasia [62]. Microarray gene expression analysis of lung tissue samples from patients with PPH provided valuable information for subsequent focused studies demonstrating loss of expression of the tumor suppressor proteins caveolin-1 [63] and PPAR-c [37] in plexiform lesion cells. Serotonin [40] and endothelin may contribute to pulmonary artery smooth muscle cell growth [59] in some patients with severe pulmonary hypertension, and TGFb may cause transdiﬀerentiation of endothelial cells into myoﬁbroblasts [64]. Peripheral blood cells in severe pulmonary hypertension There is also evidence for an increase in circulating endothelial cells in severe pulmonary hypertension [65]; whether these cells are shed from the vascular lesions or are derived from bone marrow is not clear, but bone marrow–derived endothelial cell precursor cells (hemangioblasts) could gain access to the lung circulation and participate in the pathobiology of severe angioproliferative pulmonary hypertension [65]. In such a model of severe pulmonary hypertension, bone marrow–derived precursor cells (much like tumor emboli) would populate precapillary pulmonary arterioles, implant, proliferate, diﬀerentiate, and ultimately obliterate the vascular lumen. There is an increase in circulating endothelial cells in severe pulmonary hypertension [65], and

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peripheral blood monocytes (PBMCs) also carry disease-speciﬁc information. The rationale for the investigating PBMCs in severe pulmonary hypertension is straightforward. PBMCs are enriched in circulating endothelial cells, they are bathed in cytokines (eg, IL-1 and IL-6) and growth factors (eg, serotonin, endothelin, and VEGF), and they may be infected by viruses [66]. One would predict that the gene expression pattern of the PBMCs in severe pulmonary hypertension is characteristic, and indeed, it has recently been shown that microarray gene expression studies of PBMCs can diﬀerentiate between patients who have PPH and those who have secondary pulmonary hypertension (Bull TM, et al. Gene microarray analysis of peripheral blood cells in pulmonary arterial hypertension. Submitted for publication, 2004). In the near future a combination of gene expression analysis of PBMCs and plasma proteomics [67] may be the noninvasive tools used to characterize diﬀerent forms of secondary pulmonary hypertension and to discriminate, for example, between severe pulmonary hypertension associated with portal hypertension and severe pulmonary hypertension associated with the CREST variant of systemic sclerosis and provide clues for diﬀerential therapy and for prognosis.

Summary The group of diseases that present with severe pulmonary hypertension, whether related to congenital cardiac abnormalities, familial PAH, or even in association with HIV infection, can to a large extent be characterized histologically as angioproliferative disorders, possibly related to defects in apoptosis. Future therapeutic strategies will probably transcend the present vasodilator/ anticoagulation treatment paradigm and address the underlying molecular pathogenesis of these disorders.

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Pulmonary thromboendarterectomy surgery Patricia A. Thistlethwaite, MD, PhD*, Michael Madani, MD, Stuart W. Jamieson, MB, FRCS Division of Cardiothoracic Surgery, University of California, San Diego, 200 West Arbor Drive, San Diego, CA 92103-8892, USA

Considerable progress has been made over the past decade in understanding the etiology, prevalence, natural history, and therapeutic approach to chronic thromboembolic pulmonary hypertension. Pulmonary endarterectomy is now widely recognized as the deﬁnitive treatment for chronic pulmonary hypertension resulting from thromboembolic disease. Acute pulmonary thromboembolism and chronic thromboembolic pulmonary hypertension are signiﬁcant causes of morbidity and mortality in the United States and the world. The estimated incidence of acute pulmonary embolism is approximately 630,000 per year in the United States, based on clinical data [1,2], and is related to approximately 235,000 deaths per year, based on autopsy data. In 70% to 80% of patients for whom the primary cause of death was pulmonary embolism, the diagnosis was unsuspected ante mortem [3,4]. Of patients who survive an acute pulmonary embolic event, 0.5% to 2% will go on to develop chronic pulmonary hypertension [5,6]. Once pulmonary hypertension develops, the prognosis is poor, and this prognosis worsens in the absence of intracardiac shunt. Patients with pulmonary hypertension caused by pulmonary emboli fall into a higher risk category than those with Eisenmenger’s syndrome and encounter a higher mortality rate. In fact, once the mean pulmonary pressure in patients with thromboembolic disease exceeds 50 mm Hg, the 5-year mortality approaches 90% [7]. Therefore, despite an improved understanding of

* Corresponding author. E-mail address: [email protected] (P.A. Thistlethwaite).

pathogenesis, diagnosis, and management, pulmonary emboli and their long-term sequelae remain frequent and often fatal disorders. This article focuses on the surgical treatment of chronic thromboembolic pulmonary hypertension (CTEPH). A detailed review of the clinical manifestations and evaluation of the disease is provided in the article by Auger et al in this issue. Therefore only a brief overview of nonsurgical issues is provided here. Incidence and natural history of chronic thromboembolic pulmonary hypertension The natural history of pulmonary embolism is generally total embolic resolution or resolution leaving minimal residua with restoration of a normal hemodynamic status [8]. For unknown reasons, however, embolic resolution is incomplete in a small subset of patients. If the acute emboli are not lysed in 1 to 2 weeks, the embolic material becomes attached to the pulmonary arterial wall at the main pulmonary artery, lobar, segmental, or subsegmental levels [9]. With time, the initial embolic material progressively becomes converted into connective and elastic tissue. Often visualization of the pulmonary arteries by angioscopy a few weeks after unresolved pulmonary embolism reveals vessel narrowing at the site of embolic incorporation. In some patients, recanalization of some of the pulmonary arterial branches occurs, with the formation of ﬁbrous tissue in the form of bands and webs [10]. By a mechanism that is poorly understood, this chronic obstructive disease may also lead to a small-vessel arteriolar vasculopathy characterized by excessive smooth muscle cell proliferation

0733-8651/04/$ - see front matter Ó 2004 Elsevier Inc. All rights reserved. doi:10.1016/j.ccl.2004.04.009

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around small arterioles in the pulmonary circulation [11]. This small-vessel vasculopathy is seen in the remaining open vessels, which are subjected to long exposure at high ﬂow. Pulmonary hypertension results when the capacitance of the remaining open bed cannot absorb the cardiac output, either because of the degree of primary obstruction by embolus or because of the combination of a ﬁxed obstructive lesion and secondary small vessel vasculopathy. The incidence of pulmonary hypertension caused by chronic pulmonary embolism is even more diﬃcult to determine than that of acute pulmonary embolism. There are more than 500,000 survivors per year of acute symptomatic episodes of acute pulmonary embolization [6,12]. The incidence of chronic thrombotic occlusion or stenosis in the population depends on the percentage of patients that fails to resolve acute embolic material. One estimate is that chronic thromboembolic disease develops in only 0.5% of patients with a clinically recognized acute pulmonary embolism [6]; another [5] is that chronic thromboembolic disease occurs in 2%. If these ﬁgures are correct, and counting only patients with symptomatic acute pulmonary emboli, approximately 2500 to 10,000 individuals progress to chronic thromboembolic pulmonary hypertension in the United States each year. Because many (if not most) patients diagnosed with chronic thromboembolic disease have no antecedent history of acute embolism [13], the true incidence of this disorder may be higher. It is unclear why acute emboli fail to resolve in a subset of patients who subsequently develop pulmonary hypertension. An identiﬁable hypercoagulable state is found in only a minority of patients. A lupus anticoagulant is present in 10% to 20% of patients with chronic thromboembolic pulmonary hypertension [14,15]. Inherited deﬁciencies of protein C, protein S, and antithrombin III, as a group, can be identiﬁed in up to 5% of this population [16]. Studies to identify abnormalities in the ﬁbrinolytic pathway or within the pulmonary endothelium that would account for the incomplete thrombus dissolution have been unrevealing [17–19]. Without surgical intervention, the survival of patients with chronic thromboembolic pulmonary hypertension is poor and is inversely related to the degree of pulmonary hypertension at the time of diagnosis. Riedel et al [6] found 5-year survival rates of 30% among patients with a mean pulmonary artery pressure greater than 40 mm Hg at the

time of diagnosis and 10% in those whose pressure exceeded 50 mm Hg. In another study, a mean pulmonary artery pressure as low as 30 mm Hg was identiﬁed as a threshold for poor prognosis [20].

Clinical manifestations Patients with CTEPH usually present with subtle or nonspeciﬁc symptoms such as exertional dyspnea and exercise intolerance. As the disease progresses, additional symptoms such as edema, chest pain, light-headedness, and syncope may develop. Nonspeciﬁc chest pains occur in approximately 50% of patients with more severe pulmonary hypertension. Hemoptysis can occur, as in all forms of pulmonary hypertension. Peripheral edema, early satiety, and epigastric or right upper quadrant fullness or pain may develop as the right heart fails and cor pulmonale develops. Physical signs of pulmonary hypertension include a jugular venous pulse that is characterized by a large A-wave. As the right heart fails, the V-wave becomes predominant, and tricuspid insuﬃciency develops. Because of the large pressure gradient across the tricuspid valve in pulmonary hypertension, the murmur is high-pitched and may not exhibit respiratory variation. A speciﬁc ausculatory ﬁnding is a ﬂow murmur at the back that is thought to be from stenosed pulmonary vessels [21].

Diagnostic evaluation of chronic thromboembolic pulmonary hypertension Pulmonary vascular disease should be considered in the diﬀerential diagnosis of unexplained dyspnea. The diagnostic evaluation serves three purposes: to establish the presence and severity of pulmonary hypertension, to determine its cause, and, if thromboembolic disease is present, to determine to what degree it will be surgically correctible. Chest radiography is often unrevealing in the early stages of chronic thromboembolic pulmonary hypertension. As the disease progresses, several radiographic abnormalities may be found, including peripheral lung opacities suggestive of scarring from previous infarction, cardiomegaly with dilation and hypertrophy of the right-sided chambers, and dilation of the central pulmonary arteries. Pulmonary function tests are often obtained in the evaluation of dyspnea and serve to

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exclude the presence of obstructive airways or parenchymal lung disease. Twenty percent of patients have a mild to moderate restrictive defect that is caused by parenchymal scarring [22]. Arterial blood oxygen levels may be normal even in the setting of signiﬁcant pulmonary hypertension. Most patients, however, will experience a decline in PO2 with exertion [23]. Transthoracic echocardiography provides objective evidence of the presence of pulmonary hypertension. An estimate of pulmonary artery pressure can be provided by Doppler evaluation of the tricuspid regurgitant envelope. The myriad echocardiographic ﬁndings in CTEPH are detailed by Daniels et al elsewhere in this issue. Brieﬂy, these ﬁndings include right-heart enlargement, leftward displacement of the interventricular septum, and encroachment of the enlarged right ventricle on the left ventricular cavity with abnormal diastolic function of the left ventricle [24]. Contrast echocardiography may demonstrate a persistent foramen ovale, the result of high right atrial pressures opening a previously closed intraatrial communication. Once the diagnosis of pulmonary hypertension has been established, distinguishing between major-vessel obstruction and small-vessel pulmonary vascular disease is the next critical step. Radioisotope ventilation-perfusion (V/Q) lung scanning is the essential test for establishing the diagnosis of unresolved pulmonary thromboembolism. The V/ Q scan typically demonstrates one or more mismatched segmental defects caused by obstructive thromboembolism. This ﬁnding is in contrast to the normal or mottled perfusion scan seen in patients with primary pulmonary hypertension or other small-vessel forms of pulmonary hypertension [25]. During the process of reorganization, thromboemboli may recanalize or narrow the vessel lumen. A consequence of this partial recanalization is that the magnitude of the perfusion defects with CTEPH frequently underestimates the actual degree of pulmonary vascular obstruction as determined by angiography or surgery [26,27]. Cardiac catheterization provides essential information for the evaluation of patients with suspected thromboembolic pulmonary hypertension. Right-heart catheterization allows quantiﬁcation of the severity of pulmonary hypertension and assessment of cardiac function. Measurement of oxygen saturations in the vena cava, right-heart chambers, and the pulmonary artery may document previously undetected left-to-right shunting. Coronary angiography and left-heart catheteriza-

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tion provide additional information in those at risk for coronary artery or valvular disease and establish baseline measurements for cardiac output and left-heart function. This information is crucial in the preoperative risk assessment of patients deemed candidates for pulmonary endarterectomy. Pulmonary angiography is the criterion for deﬁning pulmonary vascular anatomy and is performed to identify whether chronic thromboembolic obstruction is present, to determine its location and relative surgical accessibility, and to rule out other diagnostic possibilities. Despite concerns regarding the safety of performing pulmonary angiography in patients with pulmonary hypertension, with careful monitoring, pulmonary angiography can be performed safely even in patients with severe pulmonary hypertension [28]. Biplane imaging is preferred, oﬀering lateral views that provide greater anatomic detail than the overlapped and obscured vessel images often seen with the anterior-posterior view. Maturation, organization, and recanalization of clot produces angiographic patterns of (1) pouch defects, (2) webs or bands, (3) intimal irregularities, (4) abrupt narrowing of major vessels, and (5) obstruction of main, lobar, or segmental pulmonary vessels [29]. In approximately 20% of cases, the diﬀerential diagnosis between primary pulmonary hypertension and distal small-vessel pulmonary thromboembolic disease is hard to establish. In these patients, pulmonary angioscopy may be often helpful [30]. More recently, helical computed tomography (CT) scanning has been used to screen patients with suspected thromboembolic disease [31,32]. CT features of chronic thromboembolic pulmonary hypertension include evidence of organized thrombus lining the pulmonary vessels in an eccentric fashion, enlargement of the right ventricle and central pulmonary arteries, variation in size of segmental arteries (relatively smaller in the aﬀected segments than in uninvolved areas), and parenchymal changes compatible with pulmonary infarction. Surgical selection Although there were previous attempts, Allison et al [33] performed the ﬁrst successful pulmonary thromboendarterectomy through a sternotomy using surface hypothermia in a patient with a 12-day history of pulmonary

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dynes/second/cmÿ5, typically in the range of 800 to 1200 dynes/second/cmÿ5 [35]. Although most patients have a pulmonary artery pressure less than systemic pressure, the hypertrophy of the right ventricle that occurs over time makes suprasystemic pulmonary hypertension possible. Therefore, many patients have a PVR level in excess of 1000 dynes/second/cmÿ5 and suprasystemic pulmonary artery pressures. There is no upper limit of PVR level, pulmonary artery pressure, or degree of right ventricular dysfunction that excludes patients from operation. For patients with milder pulmonary hypertension, the decision to operate is based on individual circumstances. Some patients elect to undergo surgery at this early stage of disease because of dissatisfaction with exercise limitations or because of concerns about clinical deterioration in the future. Those who choose not to pursue surgical intervention at early stages of the disease require close monitoring for progression of pulmonary hypertension. Because of the changes that can occur in the remaining patent (unaﬀected by clot or obstruction) pulmonary vascular bed subjected to the higher pressures and ﬂow, pulmonary endarterectomy is usually oﬀered to both symptomatic and asymptomatic patients whenever

embolism, but only fresh clots were removed, and an endarterectomy was not performed. Since then, there have been many reports of the surgical treatment of chronic pulmonary thromboembolism (Table 1), but by far the greatest surgical experience in pulmonary endarterectomy has been at the University of California, San Diego (UCSD) [34], where more than 1600 operations have been performed. The three major reasons for considering a patient for pulmonary endarterectomy are hemodynamic, respiratory, and prophylactic. The hemodynamic goal is to prevent or ameliorate right ventricular compromise caused by pulmonary hypertension. The respiratory objective is to improve function by removing a large ventilated but unperfused physiologic dead space. The prophylactic goals are to prevent progressive right ventricular dysfunction, retrograde extension of the clot, and the development of secondary vasculopathic changes in the remaining patent vessels. Pulmonary endarterectomy is considered in patients who are symptomatic and have evidence of hemodynamic or ventilatory impairment at rest or with exercise. Patients undergoing surgery typically exhibit a preoperative pulmonary vascular resistance (PVR) more than 300

Table 1 Midsized pulmonary endarterectomy series: 1988–2003

Author

Dates of Study

Hagl et al Nagaya et al Nagaya et al Mahmud et al Zoia et al Menzel et al Menzel et al Menzel et al Masuda et al Iwase et al Tscholl et al Tanabe et al D’Armini et al Menzel et al Ando et al Rubens et al Mares et al Dartevelle et al Kramm et al Gilbert et al

2000–2002 1998–2001 1996–2000 NR 1994–1999 NR 1996–1998 NR 1986–2001 1996–1999 1995–2001 1985–1998 1996–1999 1996–1998 1995–1999 1995–1999 NR 1996–1998 1989–1992 1994–1998

# Patients

Perioperative Deaths

Preoperative Mean PA Pressure

Postoperative Mean PA Pressure

Preoperative Mean PVR

Postoperative Mean PVR

30 21 34 39 38 11 24 39 50 21 69 26 33 39 24 21 47 68 54 17

3 0 0 0 3 0 0 0 NR 1 7 6 3 0 6 1 NR 4 12 4

56 NR 46 50 28 47 46 48 46 44 50 46 50 48 44 NR 48 53 49 NR

26 NR 19 28 18 26 25 25 29 19 28 28 16 27 16 NR 38 30 28 NR

873 893 1248 731 903 NR 839 NR 815 916 988 815 1056 895 1066 765 1478 1174 800 700

290 320 352 232 596 NR 281 NR 377 212 322 377 182 282 268 208 975 519 180 200

Abbreviations: NR, not recorded; PA, pulmonary artery; PVR, pulmonary vascular resistance.

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their angiograms demonstrate signiﬁcant thromboembolic disease [26].

Guiding principles of the operation There are several guiding principles for the operation. The operation must be bilateral because, for pulmonary hypertension to be a major factor, both pulmonary arteries are usually substantially involved. The only reasonable approach to both pulmonary arteries is through a median sternotomy. Historically, there were reports of unilateral operation, and occasionally this procedure is still performed through a thoracotomy [36]. The unilateral approach, however, ignores disease on the contralateral side, subjects the patient to hemodynamic jeopardy during the clamping of the pulmonary artery, and does not allow good visibility because of the continued presence of bronchial blood ﬂow. In addition, in CTEPH collateral channels develop through the bronchial arteries and also from diaphragmatic, intercostal, and pleural vessels. The dissection of the lung in the pleural space through a median sternotomy, apart from providing bilateral access, avoids entry into the pleural cavities and allows the ready institution of cardiopulmonary bypass. Cardiopulmonary bypass is essential to ensure cardiovascular stability when the operation is performed and to cool the patient to allow circulatory arrest. Very good visibility is required in a bloodless ﬁeld to deﬁne an adequate endarterectomy plane and to then follow the pulmonary endarterectomy specimen deep into the subsegmental vessels. Because of the copious bronchial blood ﬂow usually present in these cases, periods of circulatory arrest are necessary to ensure perfect visibility [37]. There have been sporadic reports of this operation performed without circulatory arrest [38]. Although endarterectomy is possible without circulatory arrest, a complete endarterectomy is not. The circulatory arrest is limited to the most distal portion of the endarterectomy process, deep in the subsegmental vasculature, and is usually limited to 20 minutes for each side, with restoration of ﬂow in between periods of arrest. A true endarterectomy in the plane of the media must be accomplished. The removal of visible thrombus is largely incidental to this operation. Indeed, in most patients, no free thrombus is present, and on initial direct examination the pulmonary vascular bed may appear

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normal. The early literature on this procedure indicates that thrombectomy was often performed without endarterectomy, and in these cases the pulmonary artery pressures did not improve, often resulting in death. An inferior vena cava ﬁlter is always placed before surgery unless an obvious upper extremity or cardiac source (eg, intraventricular pacing wire, ventriculo-atrial shunt) is present. In the latter case, any foreign material is removed, and alternative sites are used (eg, intravascular pacing leads are replaced with epicardial electrodes). Patients are treated with warfarin until the time of surgery, and warfarin therapy is continued lifelong after surgery.

Pulmonary endarterectomy: surgical technique After a median sternotomy incision is made, the pericardium is incised longitudinally and attached to the wound edges. Typically the right heart is enlarged, with a tense right atrium and a variable degree of tricuspid regurgitation. There is usually severe right ventricular hypertrophy, and with critical degrees of obstruction the patient’s condition may become unstable with manipulation of the heart. Anticoagulation is achieved with the use of beef-lung heparin sodium (400 units/kg, intravenously) administered to prolong the activated clotting time beyond 400 seconds. Full cardiopulmonary bypass is instituted with high ascending aortic cannulation and two caval cannulae. These cannulae must be inserted into the superior and inferior vena cavae suﬃciently to enable subsequent opening of the right atrium. The heart is emptied on bypass, and a temporary pulmonary artery vent is placed in the midline of the main pulmonary artery, 1 cm distal to the pulmonary valve. This placement marks the beginning of the left pulmonary arteriotomy. After cardiopulmonary bypass is initiated, surface cooling is begun using both a head jacket and a cooling blanket on the operating room table. The blood is cooled with the pump-oxygenator. During cooling, a 10(C gradient between arterial blood and bladder or rectal temperature is maintained [39]. Cooling generally takes 45 minutes to an hour. When ventricular ﬁbrillation occurs, an additional vent is placed in the left atrium through the right superior pulmonary vein. This vent prevents atrial and ventricular distension from the large amount of bronchial arterial

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blood ﬂow that is common in these patients. It is most convenient for the primary surgeon to stand initially on the patient’s left side. During the cooling period, some preliminary dissection can be performed, with full mobilization of the right pulmonary artery from the ascending aorta. All dissection of the pulmonary arteries takes place intrapericardially, and neither pleural cavity is entered. An incision is then made in the right pulmonary artery from beneath the ascending aorta out under the superior vena cava and entering the lower lobe branch of the pulmonary artery just after the take-oﬀ of the middle lobe artery. Any loose thrombus, if present, is removed. The endarterectomy cannot be performed in the presence of thrombus because it obscures the plane and prevents collapse of the endarterectomized specimen, hindering distal exposure. An embolectomy without subsequent endarterectomy is ineﬀective, but in most patients with CTEPH direct examination of the pulmonary vascular bed at operation generally shows no obvious embolic material. Therefore, to the inexperienced or cursory glance, the pulmonary vascular bed may well appear normal even in patients with severe CTEPH. If the bronchial circulation is not excessive, the endarterectomy plane can be found during this early dissection. Although a small amount of dissection can be performed before the initiation of circulatory arrest, it is unwise to proceed unless perfect visibility is obtained, because the development of a correct plane is essential. When the patient’s temperature reaches 20(C, the aorta is cross-clamped, and a single dose of cold cardioplegic solution is administered. Additional myocardial protection is obtained by wrapping a cooling jacket around the heart. The entire procedure is now performed with a single aortic cross-clamp period with no further administration of cardioplegic solution. A modiﬁed cerebellar retractor is placed between the aorta and superior vena cava. When back bleeding from bronchial collaterals obscures direct vision of the pulmonary vascular bed, thiopental (500 mg–1 g) is administered until the electroencephalogram becomes isoelectric. Circulatory arrest is then initiated, and the patient undergoes exsanguination. It is rare that more than one 20-minute period for each side is needed. Although retrograde cerebral perfusion has been advocated for total circulatory arrest in other procedures, it is not helpful in this operation because it does not allow a completely

bloodless ﬁeld, and, with the short arrest times required, it is not necessary. Any loose thrombotic debris encountered is removed. Then, a microtome knife is used to develop the endarterectomy plane posteriorly within the media of the vessel. Dissection in the correct plane is critical, because if the plane is too deep, the pulmonary artery may perforate, with fatal results, and if the dissection plane is not deep enough, inadequate amounts of the partially resorbed thromboembolic material will be removed. Once the plane is correctly developed, a full-thickness layer is left in the region of the incision to ease subsequent repair. For the endarterectomy, gentle traction with forceps while sweeping away the outer vessel wall layer will result in the progressive withdrawal of the endarterectomy specimen. The procedure is primarily performed with a long miniature sucker with a rounded tip [26]. As each lobar branch appears, it is grasped individually, and the specimen is withdrawn until each segmental vessel branches again. Each of these subsegmental specimens is then extracted. Removal of each lobar and then segmental branch makes subsequent distal dissection easier. If a large mass of endarterectomized tissue begins to obscure visibility, it is excised. The entire specimen can thus be removed for a length of approximately 20 cm. The distal-most portion endarterectomy is performed with an eversion technique. Perforation at the level of the subsegmental vessels will become completely inaccessible later, so care must be taken to remain in the plane of the media for endarterectomy. Clear visualization in a completely bloodless ﬁeld provided by circulatory arrest is therefore essential during development of the distal surgical plane, and this operation cannot be done properly without circulatory arrest. Each subsegmental branch must be followed and freed individually until it ends in a tail, beyond which there is no further obstruction. Residual material should never be cut free; the entire specimen should tail oﬀ and come free spontaneously. Once the right-sided endarterectomy is completed, circulation is restarted, and the arteriotomy is repaired with a continuous 6-0 polypropylene suture. The hemostatic nature of this closure is aided by the nature of the initial dissection, with the full thickness of the pulmonary artery being preserved immediately adjacent to the incision. After completing the repair of the right arteriotomy, the surgeon moves to the patient’s right side. The pulmonary vent catheter is withdrawn,

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and an arteriotomy is made from the site of the pulmonary vent hole laterally to the pericardial reﬂection, again avoiding entry into the left pleural space. Additional lateral dissection does not enhance intraluminal visibility, may endanger the left phrenic nerve, and makes subsequent repair of the left pulmonary artery more diﬃcult. The left-sided dissection is virtually analogous in all respects to that accomplished on the right. The duration of circulatory arrest intervals during the left-sided dissection is also subject to the same restriction as on the right. After the completion of the endarterectomy, cardiopulmonary bypass is re-instituted, and warming is commenced. Methylprednisolone (500 mg, intravenously) and mannitol (12.5 g intravenously) are administered, and during warming a 10(C temperature gradient is maintained between the perfusate and body temperature. If the systemic vascular resistance level is high, nitroprusside is administered to promote vasodilatation and warming. The rewarming period generally takes approximately 90 minutes but varies according to the body mass of the patient. When the pulmonary arteriotomy has been repaired, the pulmonary artery vent is replaced at the top of the incision. The right atrium is then opened and examined unless, before cardiopulmonary bypass, a negative bubble test revealed no persistent foramen ovale on transesophageal echocardiography. Otherwise, any intra-atrial communication (present in about 20% of patients) is closed at this point. Although tricuspid valve regurgitation is invariable in these patients and is often severe, tricuspid valve repair is not performed. Right ventricular remodeling occurs within a few days, with the return of tricuspid competence. If other cardiac procedures are required, such as coronary artery or mitral or aortic valve surgery, these are conveniently performed during the systemic rewarming period. Myocardial cooling is discontinued once all cardiac procedures have been concluded. The left atrial vent is removed, and the vent site is repaired. Air is evacuated from the heart, and the aortic crossclamp is removed. When the patient has rewarmed, cardiopulmonary bypass is discontinued. Dopamine hydrochloride is routinely administered at renal doses, and other inotropic agents and vasodilators are titrated as necessary to sustain acceptable hemodynamics. The cardiac output is generally high, with a low systemic vascular resistance. Temporary atrial and ventricular epicardial pacing wires are placed. Despite the duration of extracorporeal

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circulation, hemostasis is readily achieved, and the administration of platelets or coagulation factors is generally unnecessary. Wound closure is routine. A vigorous diuresis, the result of the previous systemic hypothermia, is usual for the next few hours. All patients are subjected to a maintained diuresis with the goal of reaching the patient’s preoperative weight within 24 hours. Extubation is usually performed on the ﬁrst postoperative day.

Thromboembolic disease classiﬁcation and prediction of surgical outcome Recently, four major types of pulmonary occlusive disease, based on anatomy and location of thrombus and vessel wall pathology, have been described [26]. This intraoperative classiﬁcation of disease allows the prediction of patient outcome after pulmonary endarterectomy [34,40]. 1. Type 1 disease (approximately 30% of cases of thromboembolic pulmonary hypertension) (Fig. 1)–fresh thrombus in the main or lobar pulmonary arteries. In this situation, major vessel clot is present and visible on the opening of the pulmonary arteries. This clot usually reﬂects main or lobar pulmonary vessel wall disease, with stasis, and fresh propagation of clot into the major pulmonary vessels. 2. Type 2 disease (approximately 60% of cases) (Fig. 2)–intimal thickening and ﬁbrosis with

Fig 1. Surgical specimen removed from right and left pulmonary arteries. Evidence of fresh thrombus indicates type 1 disease. Note that removal of only the fresh material leaves a large amount of disease behind. The ruler measures 15 cm.

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Fig. 2. Surgical specimen removed from right and left pulmonary arteries indicating type 2 disease. Note the extent of dissection down to the tail of end of each branch. The ruler measures 15 cm.

or without organized thrombus proximal to segmental arteries. In these cases only thickened intima can be seen, occasionally with webs in the main or lobar arteries. 3. Type 3 disease (approximately 10% of cases) (Fig. 3) –ﬁbrosis, intimal webbing, and thickening with or without organized thrombus within distal segmental and subsegmental arteries only. This type of disease presents the

most challenging surgical situation. No occlusion of vessels can be seen initially. The endarterectomy plane must be raised individually in each segmental and subsegmental branch. Type 3 disease is most often associated with presumed repetitive thrombi from indwelling catheters or ventriculo-atrial shunts, and sometimes represents burnedout disease, where most of the embolic material has been reabsorbed. 4. Type 4 disease–microscopic distal arteriolar vasculopathy without visible thromboembolic disease. Type 4 disease does not represent classic CTEPH and is inoperable. In this entity there is intrinsic small-vessel disease, although secondary thrombus may occur as a result of stasis. Small-vessel disease may be unrelated to thromboembolic events (primary pulmonary hypertension) or occur in relation to thromboembolic hypertension as a result of a high-ﬂow or high-pressure state in previously unaffected vessels similar to the generation of Eisenmenger’s syndrome. It has been shown that patients with type 3 and type 4 disease have more residual postoperative tricuspid regurgitation, higher postoperative pulmonary artery systolic pressures, and a higher postoperative PVR than those with type 1 or type 2 disease [41], as would be expected. Patients with distal thromboembolic disease (types 3 and 4) also had higher perioperative mortality, required longer inotropic support, and had longer hospital stays than patients with type 1 or type 2 thromboembolic disease. Thus the degree of improvement in pulmonary hypertension and tricuspid regurgitation after pulmonary endarterectomy is determined by the type and location of pulmonary thromboembolic disease.

Results of pulmonary endarterectomy

Fig. 3. Surgical specimen from right and left pulmonary arteries in type 3 disease. In this patient the dissection plane was raised at each segmental level. The ruler measures 15 cm.

Although pulmonary endarterectomy is now performed at several major cardiovascular centers throughout the world, the greatest experience with this operation has been at the UCSD, where the technique was pioneered and reﬁned. More than 1600 pulmonary endarterectomies have been performed at the UCSD since 1970 [34], whereas the entire reported world’s literature on this operation (exclusive of UCSD) is approximately 500 cases. Since 1990, when the surgical procedure was modiﬁed as described in this text, 1600 cases have been completed at UCSD. The mean patient age

475

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in the last 1300 patients at this center was 52 years, with a range of 8 to 85 years. There was a slight male predominance, reﬂecting disease predilection, surgical referral bias, or both. In nearly one third of cases, at least one additional cardiac procedure was performed at the time of operation. Most commonly, the adjunct procedure was closure of a persistent foramen ovale or atrial septal defect (26%) or coronary artery bypass grafting (8%). With this operation, a reduction in pulmonary pressures and resistance to normal levels and corresponding improvement in pulmonary blood ﬂow and cardiac output are generally immediate and sustained [41]. In general, these changes can be assumed to be permanent [42,43]. Table 2 lists the four largest published series of pulmonary endarterectomy results (all from UCSD) with respect to hemodynamic improvement [34,40, 44,45]. Before the operation, more than 50% of the patients in these studies were in New York Heart Association (NYHA) functional class III or IV; at 1 year after operation, 90% of patients were re-classiﬁed as NYHA functional class I or II. In addition, echocardiographic studies have demonstrated that, with the elimination of chronic pressure overload, right ventricular geometry rapidly reverts toward normal [46]. Right atrial and right ventricular hypertrophy and dilatation regresses. Tricuspid valve function returns to normal within a few days as a result of restoration of tricuspid annular geometry after the remodeling of the right ventricle; therefore tricuspid valve repair is not performed with this operation [47]. In addition to the UCSD experience, centers from around the world are now presenting results of mid-sized surgical series of pulmonary endarterectomy. Table 1 summarizes the survival and

hemodynamic outcomes after pulmonary endarterectomy from this growing body of surgical experience [9,24,38,42,47–61]. Severe reperfusion injury is the single most frequent complication after pulmonary endarterectomy, occurring in up to 10% of patients [62]. In most patients with reperfusion injury, the problem resolves with a short period of ventilatory support and aggressive diuresis. A minority of patients with severe lung reperfusion injury requires long periods of ventilatory support, and extreme cases require veno-venous extracorporeal support for oxygenation and blood carbon dioxide removal. Neurologic complications from circulatory arrest largely have been eliminated by shorter circulatory arrest periods and the use of a direct cooling jacket placed around the head. The head-wrap cooling jacket has been used in more than 1000 cases of pulmonary endarterectomy at UCSD without complication [34] and provides even cooling to the surface of the cranium, particularly the posterior. Rates of perioperative confusion and stroke for pulmonary endarterectomy are similar to those seen with conventional open-heart surgery. In the UCSD series, re-exploration for bleeding was necessary in 2.5% of patients, and 50% of patients required intraoperative or postoperative blood transfusion. Despite the length of this operation, wound infection occurred only in 1.8% of patients. The largest risk factor for operation remains the severity of PVR and the ability to lower it to a normal range at operation. Patients with high PVR with minimal vascular obstruction on angiogram (type 4 small-vessel vasculopathy) have the worst prognosis, and surgery did not alleviate pulmonary hypertension in this population. Type 4 pulmonary hypertensive disease represents

Table 2 Postoperative hemodynamic parameters: four largest series

Variable (mean) Decrease in PAS (mm Hg) Decrease in PAD (mm Hg) Decrease in PVR (dynes/s/cmÿ5) Increase in CO (l/min) Decrease in tricuspid regurgitant velocity (m/s)

Jamieson et al 2003 N = 500

Thistlethwaite et al 2002 N = 202

Thistlethwaite et al 2001 N = 90

Jamieson et al 1993 N = 150

29.0 20.4 10.8 10.5 597.0 404.2

31.9 18.9 13.1 9.20 547.2 387.7

34.7 19.1 11.5 8.70 520.6 285.7

31.8 ND 637.5

1.68 1.64 ND

1.62 0.61 1.37 0.75

2.36 1.68 1.27 0.87

1.8 ND

Abbreviations: CO, cardiac output; ND, not done; PAD, pulmonary artery diastolic pressure; PAS, pulmonary artery systolic pressure; PVR, pulmonary vascular resistance.

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vascular obstruction at the arteriolar/capillary level (primary pulmonary hypertension). This small-vessel vasculopathy is not inﬂuenced by blind endarterectomy of the proximal pulmonary arterial tree. Most early deaths after pulmonary endarterectomy are in this subgroup, and future eﬀorts are directed at identifying these patients more precisely in the preoperative setting to avoid unnecessary operation. In the UCSD experience, overall perioperative mortality was 9% for the entire cohort of patients, which encompasses a time span of 30 years. Most recently, surgical mortality for pulmonary endarterectomy approaches 4% [34]. This reduction reﬂects the learning curve for safely performing this operation and the reﬁnements in surgical technique that enhance patient outcome. A survey of surviving patients who underwent pulmonary endarterectomy between 1970 and 1995 in the UCSD series has formally evaluated long-term outcome from this operation [63]. Questionnaires were mailed to 420 patients more than 1 year after operation, and responses were obtained from 308 patients. Survival, functional status, quality of life, and the subsequent use of medical assistance were assessed. Survival after pulmonary endarterectomy was found to be 75% at 6 years or more. This survival exceeds single or double lung transplant survival for thromboembolic pulmonary hypertension. Ninety-three percent of the patients were found to be in NYHA class I or class II, whereas about 95% of the patients were in NYHA class III or class IV before surgery. Of the working population, 62% of patients who were unemployed before operation returned to work. Patients who had undergone pulmonary endarterectomy scored slightly lower than normal individuals in several quality-of-life components but signiﬁcantly higher than the patients before pulmonary endarterectomy. Only 10% of patients used oxygen after surgery. In response to the question, ‘‘How do you feel about the quality of your life since your surgery?’’ 77% replied much improved, and 20% replied improved. These data seem to conﬁrm that pulmonary endarterectomy oﬀers substantial improvement in survival, function, and quality of life. Summary Pulmonary hypertension caused by chronic pulmonary embolism is underrecognized and carries a poor prognosis. Medical therapy for this condition is ineﬀective and only transiently im-

proves symptoms. The only therapeutic alternative to pulmonary endarterectomy is lung transplantation. The advantages of pulmonary endarterectomy include a lower operative mortality, better long-term results with respect to survival and quality of life, and the avoidance of chronic immunosuppressive treatment and allograft rejection. Currently mortality rates for pulmonary endarterectomy are 4.4%, and the operation can provide sustained clinical beneﬁt. These results make it the treatment of choice over transplantation for thromboembolic disease to the lung both in the short and long term. Although pulmonary endarterectomy is technically demanding for the surgeon, requiring careful dissection of the pulmonary artery planes and the use of circulatory arrest, excellent results can be achieved. Improvements in operative technique developed over the last 4 decades allow pulmonary endarterectomy to be oﬀered to patients with an acceptable mortality rate and anticipation of clinical improvement. With the increasing recognition of patients presenting with thromboembolic pulmonary hypertension and the realization that pulmonary endarterectomy is a safe and eﬀective operation for this condition, it is anticipated that the use of pulmonary endarterectomy will grow in the future.

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[39] Winkler MH, Rohrer CH, Ratty SC, et al. Perfusion techniques of profound hypothermia and circulatory arrest for pulmonary thromboendarterectomy. J Extracorporeal Technology 1990;22:57–60. [40] Thistlethwaite PA, Mo M, Madani MM, et al. Operative classiﬁcation of thromboembolic disease determines outcome after pulmonary endarterectomy. J Thorac Cardiovasc Surg 2002;124:1203–11. [41] Menzel T, Kramm T, Mohr-Kahaly S, et al. Assessment of cardiac performance using Tei indices in patients undergoing pulmonary thromboendarterectomy. Ann Thorac Surg 2002;73:762–6. [42] Mayer E, Dahm M, Hake U, et al. Mid-term results of pulmonary thromboendarterectomy for chronic thromboembolic pulmonary hypertension. Ann Thorac Surg 1996;61:1788–92. [43] Kramm T, Mayer E, Dahm M, et al. Long-term results after thromboendarterectomy for chronic pulmonary embolism. Eur J Cardiothorac Surg 1999;15:579–84. [44] Jamieson SW, Auger WR, Fedullo PF, et al. Experience and results with 150 pulmonary thromboendarterectomy operations over a 29-month period. J Thorac Cardiovasc Surg 1993;106:116–27. [45] Thistlethwaite PA, Auger WR, Madani MM, et al. Pulmonary thromboendarterectomy combined with other cardiac operations: indications, surgical approach, and outcome. Ann Thorac Surg 2001;72: 13–9. [46] Thistlethwaite PA, Jamieson SW. Tricuspid valvular disease in the patient with chronic pulmonary thromboembolic disease. Curr Opin Cardiol 2003; 18:111–6. [47] Menzel T, Kramm T, Wagner S, et al. Improvement of tricuspid regurgitation after pulmonary thromboendarterectomy. Ann Thorac Surg 2002;73: 756–61. [48] Nagaya N, Sasaki N, Ando M, et al. Prostacyclin therapy before pulmonary thromboendarterectomy in patients with chronic thromboembolic pulmonary hypertension. Chest 2003;123:338–43. [49] Nagaya N, Ando M, Oya H, et al. Plasma brain natriuretic peptide as a noninvasive marker for eﬃcacy of pulmonary thromboendarterectomy. Ann Thorac Surg 2002;74:180–4. [50] Mahmud E, Rasinghani A, Hassankhani A, et al. Correlation of left ventricular diastolic ﬁlling characteristics with right ventricular overload and pulmonary artery pressure in chronic thromboembolic pulmonary hypertension. J Am Coll Cardiol 2002;40:318–24. [51] Zoia MC, D’Armini AM, Beccaria M, et al. Mid term eﬀects of pulmonary thromboendarterectomy

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Radiology of pulmonary vascular disease David L. Levin, MD, PhD*, Eric T. Goodman, MD Department of Radiology, University of California, San Diego Medical Center, 200 West Arbor Drive, San Diego, CA 92103, USA

The evaluation of suspected pulmonary vascular disease remains a diﬃcult task. The clinical work-up may include a variety of radiologic studies, and the clinician is presented with multiple options. It is important that the ordering physician be familiar with the indications and the speciﬁc advantages and disadvantages of each test. This article discusses the various modalities available to the clinician for the evaluation of suspected pulmonary vascular disease and the evaluation of several speciﬁc vascular diseases.

Modalities available for evaluation of pulmonary vascular disease A variety of radiographic methods are available for the evaluation of suspected pulmonary vascular disease. These methods include conventional radiographs and angiography, computed tomography (CT), nuclear medicine studies, and magnetic resonance imaging (MRI). Conventional radiographs Conventional radiographs are typically the initial studies obtained in the evaluation of suspected pulmonary disease. Although they have the advantage of being relatively inexpensive and readily available, they are comparatively insensitive and nonspeciﬁc, especially in the evaluation of pulmonary vascular disease. Conventional angiography Conventional angiography provides direct visualization of the pulmonary vasculature. It * Corresponding author. E-mail address: [email protected] (D.L. Levin).

requires the placement of a catheter into the vessel of interest. For the evaluation of pulmonary vascular disease, a catheter is typically advanced into the pulmonary artery through the systemic venous system. A large volume of contrast is injected at a high rate to opacify the pulmonary arterial system completely. A routine injection for a pulmonary arteriogram may require 40 mL of iodinated contrast material given at a rate of 20 mL/second. This rate is typically reduced in the presence of pulmonary hypertension. Although the technique is still used in the evaluation of suspected acute pulmonary embolism, it has been largely replaced by CT angiography. The continued important role of angiography in the evaluation of patients with suspected chronic pulmonary embolism (chronic thromboembolic pulmonary hypertension [CTEPH]) is discussed in detail in the article by Guillinta et al in this issue. Computed tomography CT is an extremely versatile technique that provides excellent evaluation of the pulmonary vasculature, mediastinal structures, and the lung parenchyma. CT uses an X-ray source that revolves around the patient, acquiring data from multiple angles. Conventional CT (third- and fourth-generation scanners) alternated the movement of the X-ray source and the movement of the patient. This process required relatively long scan times, and several consecutive breathholds were needed to image the chest completely. The technology has rapidly evolved with the development of helical and multidetector helical CT. With this technology, simultaneous movement of the X-ray source and the patient allows more rapid imaging with improved spatial resolution. The entire chest can now be imaged easily at high spatial resolution

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during a single breathhold, and after the intravenous injection of contrast material imaging can be timed to the peak enhancement of the pulmonary vessels. As a result, CT has become a primary modality for the evaluation of the pulmonary vascular disease. Nuclear medicine Scintigraphic techniques are also commonly used to evaluate pulmonary blood ﬂow. The most frequent method uses the intravenous injection of microaggregated albumin that has been labeled with technetium-99m. These particles lodge within the precapillary arterioles. Their distribution, measured with a gamma camera, is directly proportional to blood ﬂow. The images obtained are most frequently interpreted in a qualitative fashion, but quantiﬁcation of pulmonary blood ﬂow is possible. Scintigraphic ventilation/perfusion (V/Q) scans were the ﬁrst speciﬁc test ordered in the evaluation of suspected pulmonary embolism before the use of CT angiography. Magnetic resonance imaging MRI has limited utility in the evaluation of pulmonary disease, but various MR techniques, such as MR angiography, perfusion imaging, and ventilation imaging have been used in select centers to evaluate the pulmonary vasculature and cardiac structures (Fig. 1). Stein and colleagues have recently reviewed the use of MR angiography in the detection of pulmonary embolism [1]. Evaluation of speciﬁc pulmonary vascular diseases Pulmonary venous hypertension Pulmonary venous hypertension (PVH) is related to increased resistance to ﬂow within the pulmonary veins. The more common causes are left ventricular failure and mitral valve disease. Radiologically, PVH can be divided into three grades of severity. Grade I PVH is characterized by redistribution of pulmonary blood ﬂow and pulmonary vascular dilation. The latter ﬁnding, however, is far more common with chronic PVH [2]. Normally, there is preferential blood ﬂow to the lower lobes because of gravitational eﬀects. Pulmonary vascular dilation is identiﬁed primarily by vascular redistribution, with the upper lobe vessels becoming equal (balanced ﬂow) or greater (inverted ﬂow) in caliber compared with the lower lobe vessels [3]. Vascular redistribution should be

Fig. 1. (A) Coronal maximum intensity projection image from an MR angiogram. The arrow identiﬁes a region of absent arterial ﬂow within the right lung. (B) An embolus within the right interlobar pulmonary artery is identiﬁed on source images (arrow).

judged only with the patient in the fully upright position [2]. Grade II PVH is characterized by evidence of interstitial edema, with or without accompanying pleural eﬀusions (Fig. 2). Features of interstitial edema on conventional radiographs include Kerley B lines. Kerley B lines are horizontally oriented, thin, linear densities that are typically around 1 cm in length and are usually best identiﬁed at the lung periphery extending to the pleural surface. With pulmonary edema, Kerley B lines represent ﬂuid within the interlobular septa. The diﬀerential diagnosis for Kerley B lines, however, includes lymphangitic carcinomatosis, lymphatic obstruction, and pulmonary vein occlusion. Other evidence of interstitial edema includes indistinctness of the vessel margins, subpleural thickening along the ﬁssures, and peribronchial cuﬃng. Loss of vascular deﬁnition is subjective and is more easily

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Fig. 2. Frontal chest radiograph obtained from a patient with an acute pulmonary embolism. The left pulmonary artery is enlarged (small arrow), and a wedge-shaped peripheral opacity is present at the left costophrenic angle (large arrow).

identiﬁed with serial radiographs. Some authors consider subpleural thickening of the interlobar ﬁssures to be the most reliable ﬁnding of early interstitial edema [3]. Peribronchial thickening is best appreciated by identifying ring shadows of bronchi traveling end-on. Grade III PVH is characterized by the ﬂooding of edema ﬂuid into the alveoli. Radiographically, alveolar edema is characterized by diﬀuse opaciﬁcation of the lungs with obscuration of the pulmonary vessels, often with air-bronchograms (Fig. 3). This ﬁnding is most pronounced in the perihilar regions and is frequently described as having a batwing appearance. The diﬀerential diagnosis of diﬀuse alveolar ﬁlling includes both cardiogenic and noncardiogenic edema, pulmo-

Fig. 3. Single image from a conventional angiogram. Intravascular contrast is present streaming around a ﬁlling defect caused by a pulmonary embolism (arrow).

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nary hemorrhage, and infection, especially with atypical organisms (eg, pneumocystis carinii pneumonia, cytomegalovirus). Several investigators have correlated the radiographic grading of PVH and pulmonary artery wedge pressures [4,5]. Grade I PVH correlates to a wedge pressure of 12 to 19 mm Hg in acute PVH and 15 to 25 mm Hg in the setting of chronic mitral valvular disease. Grade II PVH correlates with a wedge pressure of 20 to 25 mm Hg in acute PVH or 25 to 30 mm Hg with chronic failure. Grade III correlates to a wedge pressure greater than 25 mm Hg in acute PVH or greater than 30 mm Hg in chronic PVH. This correlation is rough, at best, and is of limited practical value. This correlation is also aﬀected by a time lag, because the radiographs primarily identify intravascularto-interstitial ﬂuid shifts within the lung and concomitant disease. Pulmonary embolism The evaluation of suspected pulmonary embolism remains a signiﬁcant clinical challenge. Both the symptoms and clinical signs are nonspeciﬁc and fail to distinguish between patients with and without pulmonary embolism. The yearly incidence of pulmonary embolism is estimated to be between 300,000 and 500,000. Although the overall mortality from pulmonary embolism has decreased during the past 30 years, the case fatality rate for untreated pulmonary embolism may be as high as 15% at 3 months [6]. Chest radiography The major value of conventional radiographs is to exclude alternate diagnoses, such as pneumothorax, pneumonia, and pulmonary edema. An abnormal radiograph is seen in 84% patients with pulmonary embolism and in 66% of patients without pulmonary embolism [7]. The most frequent ﬁndings, however, are nonspeciﬁc and include atelectasis (seen in 68% of patients with pulmonary embolism), pleural eﬀusion (in 48%), and focal parenchymal opacities (in 35%). These ﬁndings are also common in patients who do not have pulmonary embolism. Several classic plainﬁlm signs have been described. These include Hampton’s hump, a peripheral wedge-shaped opacity; Westermark’s sign, focal oligemia within the lung distal to the embolus; and Fleischner’s sign, unilateral enlargement of the central pulmonary artery (Fig. 4). None of these signs reliably

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Fig. 4. Axial image from CT angiogram. A saddle embolus (arrow) extends into both the left and right main pulmonary arteries.

identiﬁes patients with acute pulmonary embolism, however. Nuclear medicine Until recently, ventilation/perfusion (V/Q) scanning was the mainstay in the evaluation of suspected pulmonary embolism, but V/Q scans do not provide a conclusive diagnosis in up to 80% of patients [8]. In patients with a high clinical pretest probability, a high-probability V/Q scan has a 96% positive predictive value. A lowprobability V/Q scan with a low clinical suspicion has a negative predictive value of 94%. Unfortunately, only 25% of all studies fall into one of these two categories. Data from the Prospective Investigation of Pulmonary Embolism Diagnosis study found that 15% of all patients with pulmonary embolism had a high-probability V/Q scan, 40% had an intermediate scan, 30% a had lowprobability scan, and 15% a had normal or nearly normal scan [9]. V/Q scans remain an integral part of the evaluation of patients with suspected CTEPH, as discussed in the article by Auger et al in this issue. Conventional angiography Conventional angiography has generally been considered the criterion standard, but it is infrequently ordered for the evaluation of suspected pulmonary embolism [10]. The study is associated with a low overall morbidity (2%–5%) and mortality (<1%). The ﬁndings of acute pulmonary embolism include an intraluminal ﬁlling defect and the abrupt termination of the contrast within a vessel (Fig. 5). Although conventional

Fig. 5. (A) Frontal chest radiograph obtained from a patient with grade II pulmonary edema. The pulmonary vessels are poorly deﬁned. The cardiac silhouette is enlarged. (B) Close-up demonstrates several Kerley B lines (arrowheads).

angiography is frequently thought to provide a deﬁnitive answer, interobserver disagreement can be signiﬁcant, especially for subsegmental emboli [11]. Additionally, data from animal studies suggest that conventional angiography and CT angiography have similar sensitivity and speciﬁcity for the detection of pulmonary embolism when compared with an independent, anatomic standard. Computed tomography CT angiography is rapidly becoming the test of choice in many institutions for the evaluation of suspected pulmonary embolism. Images are obtained using a volumetric scanning protocol. As with conventional angiography, the two primary

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ﬁndings of pulmonary embolism with CT are the identiﬁcation of an intraluminal thrombus and the abrupt termination of contrast within a vessel (Fig. 6). As with conventional radiographs, ancillary ﬁndings may be identiﬁed using CT. Peripheral wedge-shaped opacities and linear bands are both frequently seen in association with pulmonary embolism. When pulmonary embolism is not identiﬁed, CT has been shown to ﬁnd an alternate diagnosis in more than 50% of cases [12]. The sensitivity and speciﬁcity for the detection of a pulmonary embolism vary substantially between studies. Remy-Jardin et al [13] reported a sensitivity of 91% with a speciﬁcity of 78%, whereas Drucker et al [14] reported a sensitivity of 53% with a speciﬁcity of 81%. In a review of 11 published studies, Harvey [15] found an overall sensitivity for the detection of segmental or larger emboli of 74% to 81% with a speciﬁcity of 89% to 91%. An alternate method to evaluate the performance of CT in the evaluation of pulmonary embolism would be to determine the outcome in patients with a negative study. Goodman et al [16] prospectively followed patients with suspected pulmonary embolism. Of 198 patients with negative CT angiography, 2 had a documented pulmonary embolism within a 3-month period. This rate was a slightly greater percentage than for a normal V/Q scan but less than that seen with a low-probability study. Ryu et al [17] observed similar ﬁndings in a 3-month retrospective follow

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up of 951 patients with a negative CT angiogram. In their study, a 1% incidence of nonfatal pulmonary embolism and a 0.2% incidence of fatal pulmonary embolism were found. Pulmonary arterial hypertension Pulmonary arterial hypertension (PAH) and other causes of pulmonary hypertension, such as pulmonary hypertension caused by venous hypertension from left-heart failure, have both overlapping and unique attributes that may assist in the diﬀerential diagnosis. Chest radiography The primary radiographic ﬁnding of PAH is enlargement of the central pulmonary arteries (Fig. 7). Most frequently, this determination is made on the basis of a subjective impression. On the frontal radiograph, the diameter of the right interlobar pulmonary artery can be measured where it travels just laterally to the bronchus intermedius. At this level, a diameter greater than 16 mm (15 mm in women) suggests PAH [18]. The peripheral pulmonary vessels are most frequently decreased in caliber with rapid tapering of the vessel distal to the proximal artery. The peripheral vessels, however, may be dilated with congenital left-to-right shunts. In the setting of left ventricular failure leading to pulmonary hypertension, enlargement of the cardiac silhouette and features of chronic pulmonary edema are typically present. Computed tomography As with conventional radiographs, the primary CT ﬁnding of PAH is enlargement of the central pulmonary arteries. A diameter of the main pulmonary artery greater than 29 mm suggests but is not diagnostic of PAH [19]. In the setting of CTEPH, thrombus may be within the pulmonary arteries. An additional ﬁnding of CTEPH is mosaic attenuation within the lung parenchyma, reﬂecting heterogeneous pulmonary perfusion [20]. Pulmonary veno-occlusive disease

Fig. 6. Frontal chest radiograph obtained from a patient with grade III pulmonary edema. Diﬀuse air-space opacities are present bilaterally with complete obscuration of vascular margins.

Pulmonary veno-occlusive disease is a rare disease leading to PAH as a result of destruction of pulmonary veins. Clinically, the disease is characterized by evidence of both PAH and pulmonary edema. Pulmonary veno-occlusive disease has been reported in associated with a number of other diseases but may occur as an idiopathic process [21,22].

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Fig. 7. (A) Frontal chest radiograph obtained from a patient with primary pulmonary hypertension. There is enlargement of the main pulmonary artery (arrowheads). (B) Close-up demonstrates rapid tapering of a left upper lobe pulmonary artery (arrow).

Radiographically, the key features of pulmonary veno-occlusive disease are those of PAH and pulmonary edema, which is present in approximately 75% of patients [22]. The left atrium is not enlarged as it is with chronic congestive failure or mitral stenosis progressing to PAH (Fig. 8). Pulmonary arteriovenous malformation Pulmonary arteriovenous malformations (AVMs) can range in size from microscopic to

Fig. 8. (A) Frontal chest radiograph obtained from a patient with pulmonary veno-occlusive disease. Signs of pulmonary arterial hypertension are present along with features of pulmonary edema. There is enlargement of the central pulmonary arteries and the pulmonary vessels have indistinct margins. (B) Close-up demonstrates faint Kerley B lines (arrowheads).

several centimeters in diameter. Radiographically, pulmonary AVMs are typically round or oval in shape and are sharply deﬁned. The key to the diagnosis is the identiﬁcation of the feeding artery and draining vein. The draining vein is more readily identiﬁed because it is typically half the diameter of the AVM. Pulmonary AVMs are more common in the lower lobes and are multiple in roughly one third of cases. Helical CT is the study of choice in the evaluation of suspected pulmonary AVM and is readily able to charac-

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Fig. 9. Coronal reconstruction from helical CT. An arteriovenous malformation is present at the left lung base (arrow). Two large draining veins are present.

terize the feeding artery and draining vein (Fig. 9). This identiﬁcation is important in planning therapy, especially when embolization is considered. Because the key CT features are morphologic, contrast administration is necessary. Conventional pulmonary angiography is routinely performed before therapy. Summary Several radiologic methods are available for the evaluation of suspected pulmonary vascular disease. Of these, the conventional chest radiograph and CT are the most useful. Although conventional radiographs suﬀer from poor sensitivity and speciﬁcity, they are readily available and relatively inexpensive. They can exclude other signiﬁcant diseases and may suggest a speciﬁc vascular process. CT is the primary modality for evaluation of pulmonary vascular disease. It provides an excellent evaluation of the lung parenchyma, mediastinum, and pulmonary vasculature, and helical CT has largely replaced conventional angiography except for selective indications such as CTEPH. References [1] Stein PD, Woodard PK, Hull RD, Kayali F, Weg JG, Olson RE, et al. Gadolinium-enhanced magnetic resonance angiography for the detection of acute pulmonary embolism: an in-depth review. Chest 2003;124(6):2324–8. [2] Morgan PW, Goodman LR. Pulmonary edema and adult respiratory distress syndrome. Radiol Clin North Am 1991;29:943–63. [3] Ketai LH, Goodwin JD. A new view of pulmonary edema and acute respiratory distress syndrome. J Thorac Imaging 1998;13(3):147–71.

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[4] Higgins CB. Radiography of acquired heart disease. In: Higgins CB, editor. Essentials of cardiac radiology and imaging. Philadelphia: J.B. Lippincott; 1992. p. 1–48. [5] Pistolesi M, Miniati M, Milne EN, Giuntini C. The chest roentgenogram in pulmonary edema. Clin Chest Med 1985;144:879–94. [6] Fraser RS, Pare´ JAP, Fraser RG, Pare´ PD. Embolic and thrombotic diseases of the lungs. In: Synopsis of diseases of the chest. Philadelphia: W.B. Saunders; 1994. p. 539–73. [7] Stein PD, Terrin ML, Hales CA, Palevsky HI, Saltzman HA, Thompson BT, et al. Clinical, laboratory, roentgenographic, and electrocardiographic ﬁndings in patients with acute pulmonary embolism and no pre-existing cardiac or pulmonary disease. Chest 1991;100(3):598–603. [8] Goodman LR, Lipchik RJ. Diagnosis of acute pulmonary embolism: time for a new approach. Radiology 1996;199(1):25–7. [9] Stein PD, Gottschalk A. Critical review of ventilation/perfusion lung scans in acute pulmonary embolism. Prog Cardiovasc Dis 1994;37(1):13–24. [10] Sostman HD, Ravin CE, Sullivan DC, Mills SR, Glickman MG, Dorfman GS. Use of pulmonary angiography for suspected pulmonary embolism: inﬂuence of scintigraphic diagnosis. AJR Am J Roentgenol 1982;17(4):673–7. [11] Diﬃn DC, Leyendecker JR, Johnson SP, Zucker RJ, Grebe PJ. Eﬀect of anatomic distribution of pulmonary emboli on interobserver agreement in the interpretation of pulmonary angiography. AJR Am J Roentgenol 1998;171(4):1085–9. [12] Garg K, Sieler H, Welsh CH, Johnston RJ, Russ PD. Clinical validity of helical CT being interpreted as negative for pulmonary embolism: implications for patient treatment. AJR Am J Roentgenol 1999; 172(6):1627–31. [13] Remy-Jardin M, Remy J, Deschildre F, Artaud D, Beregi JP, Hossein-Foucher C, et al. Diagnosis of pulmonary embolism with spiral CT: comparison with pulmonary angiography and scintigraphy. Radiology 1996;200:699–706. [14] Drucker EA, Rivitz SM, Shepard JA, Boiselle PM, Trotman-Dickenson B, Welch TJ, et al. Acute pulmonary embolism: assessment of helical CT for diagnosis. Radiology 1998;209:235–41. [15] Harvey RT, Gefter WB, Hrung JM, Langlotz CP. Accuracy of CT angiography versus pulmonary angiography in the diagnosis of acute pulmonary embolism: evaluation of the literature with summary ROC curve analysis. Acad Radiol 2000;7(10): 786–97. [16] Goodman LR, Lipchik RJ, Kuzo RS, Liu Y, McAuliﬀe TL, O’Brien DJ. Subsequent pulmonary embolism: risk after a negative helical CT pulmonary angiogram—prospective comparison with scintigraphy. Radiology 2000;215(2):535–42.

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[17] Ryu JH, Swensen SJ, Olson EJ, Pelikka PA. Diagnosis of pulmonary embolism with use of computed tomographic angiography. Mayo Clin Proc 2001;76(1):59–65. [18] Chang CH. The normal roentgenographic measurement of the right descending pulmonary artery in 1,085 cases. Am J Roentgenol Radium Ther Nucl Med 1962;87:929–35. [19] Kuriyama K, Gamsu G, Stern RG, Cann CE, Herfkens RJ, Brundage BH. CT-determined pulmonary artery diameters in predicting pulmonary hypertension. Invest Radiol 1984;19(1):16–22.

[20] King MA, Bergin CJ, Yeung DW, Belezzouli EE, Olson LK, Ashburn WL, et al. Chronic pulmonary thromboembolism: detection of regional hypoperfusion with CT. Radiology 1994;191(2):359–63. [21] Swensen SJ, Tashjian JH, Myers JL, Engeler CE, Patz EF, Edwards WD, et al. Pulmonary venoocclusive disease: CT ﬁndings in eight patients. AJR Am J Roentgenol 1996;167(4):937–40. [22] Fraser RS, Mu¨ller NL, Colman N, Pare´ PD. Pulmonary hypertension. In: Diagnosis of diseases of the chest. 4th edition. Philadelphia: WB Saunders; 1994. p. 1879–945.

Cardiol Clin 22 (2004) 431–440

Tumors of the pulmonary vasculature Eunhee S. Yi, MD Department of Clinical Pathology, University of California, San Diego School of Medicine, 200 West Arbor Drive, San Diego, CA 92103-8720, USA

The pulmonary vasculature is comprised of pulmonary arteries, veins, and capillaries. Most primary tumors of the pulmonary vasculature are poorly diﬀerentiated, highly fatal sarcomas of the large main pulmonary arteries and veins. Pulmonary arterial sarcoma (PAS) is far more prevalent than its venous counterpart, although both arterial and venous sarcomas are quite rare [1]. Secondary involvement of the pulmonary vasculature by other primary or metastatic pulmonary malignant neoplasm is not as rare, however [2]. Pulmonary capillary hemangiomatosis (PCH), a low-grade tumor or tumor-like lesion of pulmonary capillaries, shows only a locally inﬁltrative growth without extrathoracic metastasis but causes severe pulmonary hypertension that is often accompanied by fatal right heart failure [3]. In a clinicopathologic study on the sarcomas of the great vessels, Burke and Virmani [1] divided the sarcomas of the aorta, pulmonary arteries and veins, and inferior vena cava into two major categories: intimal sarcoma and mural sarcoma. They concluded that most aortic and pulmonary arterial sarcomas are intimal sarcomas and that most sarcomas of the pulmonary veins and inferior vena cava are mural leiomyosarcomas. Mural sarcomas of the inferior vena cava comprise the largest subgroup of the primary tumors arising in the great blood vessels [1]. A worldwide registry of 218 patients demonstrating sarcomas of the inferior vena cava indicate that the incidence of sarcomas in the inferior vena cava is greater than that of sarcomas in great arteries [4]. The incidence of pulmonary vein sarcoma (PVS) is far lower than that of PAS [1,5]. Most intimal sarcomas of the aorta and the pulmonary arteries E-mail address: [email protected]

in that study were poorly diﬀerentiated or undiﬀerentiated sarcomas with a prominent intraluminal growth pattern, immunohistochemical evidences of myoﬁbroblastic diﬀerentiation, and a poorer prognosis than the mural leiomyosarcomas in the inferior vena cava and the pulmonary veins [1]. This article reviews the current clinicopathologic concepts on the primary sarcomas of pulmonary arteries and veins and PCH. Manifestations of the secondary tumors mimicking a primary pulmonary vascular tumor or idiopathic pulmonary hypertension are also discussed brieﬂy.

Primary sarcomas of pulmonary arteries General characteristics PAS encompasses intimal sarcomas and mural sarcomas arising in the intima and wall of the large pulmonary artery, respectively. Intimal sarcomas show the characteristic intraluminal polypoid growth pattern and histologic evidence of ﬁbroblastic or myoﬁbroblastic diﬀerentiation in most cases. Intimal sarcomas of the pulmonary artery have been used interchangeably with PAS in many previous studies, because intimal sarcomas comprise the vast majority of PASs with exceedingly rare cases of mural sarcomas—only two cases have been reported in the literature speciﬁcally as mural sarcoma [1]. Accordingly, the clinical and pathologic features of PAS in the literature mostly represent those of intimal sarcomas. Mural sarcomas are considered distinct from intimal sarcomas clinically and histogenetically, thus they are classiﬁed separately according to the histologic subtype as used in the classiﬁcation of

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general soft tissue sarcomas. It may be diﬃcult to distinguish mural sarcomas of pulmonary arteries from sarcomas originating in the pulmonary parenchyma [1]. Epidemiology PAS is a rare tumor—only a few hundred cases have been reported in the literature. The true incidence of PAS is unknown and probably underestimated, because many PAS cases are misdiagnosed as pulmonary embolism on preoperative work-ups, and some may remain unrecognized without pathologic examination. A recent review of 138 primary sarcomas of the pulmonary artery reported that the average age at diagnosis was 49.3 years (range 13–81 years) with a roughly equal sex distribution [6], while other previous studies have shown a slight female predominance [7–9]. Clinical manifestations The most common presenting symptom is dyspnea (72%), followed by chest/back pain (45%), cough (42%), hemoptysis (24%), weight loss (21%), malaise (10%), syncope (9%), fever (8%), and sudden death in rare cases [6]. These clinical ﬁndings are often indistinguishable from those of chronic thromboembolic pulmonary hypertension (CTEPH), but progressive weight loss, anemia, and fever are unusual for benign pulmonary vascular diseases and should raise a suspicion for malignancy [10]. Common physical signs include systolic ejection murmur, cyanosis, extremity edema, jugular venous distension, hepatomegaly, and clubbing [10]. PAS primarily metastasizes to the lung and mediastinum (50%) [6]. Distant extrathoracic metastases were reported in 16% of PAS cases, which is lower than in its counterpart in the aorta [6].

neous soft tissue density (from areas of necrosis, hemorrhage, and ossiﬁcation), enhancement after gadopentetate dimeglumine, vascular distension, and smooth vascular tapering without abrupt narrowings and cut-oﬀs (Fig. 1) [11]. Unilateral central pulmonary embolus is uncommon and suggests PAS [6,11]. High-resolution CT may show a mosaic pattern of lung attenuation as seen in the cases of CTEPH [13]. Neovascularization in PAS may be seen with bronchial arteriography [6]. Pulmonary angiography shows intraluminal masses and lung perfusion abnormalities with a smooth tapering of pulmonary arteries and ‘‘to-and-fro’’ motion of pedunculated or lobulated lesions [6]. Recently, intravascular ultrasound study and ﬂuorine-18-2-ﬂuoro-2 deoxy-D-glucosepositron emission tomographic tumor imaging have been reported as helpful ancillary techniques to reach the preoperative diagnosis of PAS [14,15]. Pathologic ﬁndings Intimal sarcomas of the pulmonary artery grossly resemble mucoid or gelatinous clots ﬁlling the lumens (Fig. 2). The main tumor masses extend distally along the branches of the pulmonary artery with a smooth tapering pattern (see Fig. 2). The cut surface of a tumor may show ﬁrm ﬁbrotic areas as well as bony/gritty and chondromyxoid areas depending on the histologic composition of the sarcoma. Hemorrhage and necrosis are common in high-grade PAS. The tumors are usually conﬁned to the intima and lumen but sometimes inﬁltrate into the adventitia or pulmonary parenchyma in advanced cases. Most PAS cases have bilateral pulmonary artery involve-

Imaging studies Radiologic ﬁndings of PAS also overlap with those of CTEPH, but the rate of preoperative diagnosis has increased remarkably in the last decade with advances in imaging technology [6,11,12]. Although most chest radiographic ﬁndings of PAS are nonspeciﬁc, solid sarcomatous expansions of the proximal pulmonary artery branches are highly suggestive of PAS, especially in the presence of associated pulmonary nodules, cardiac enlargement, and decreased vascularity [1]. Features in CT and MRI that favor the diagnosis of PAS over CTEPH include: heteroge-

Fig. 1. Axial CT scan showing large tumor mass (arrow) outlined by contrast material straddling the bifurcation of the pulmonary artery and extending into the left lower lobe branches (arrowhead ).

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Fig. 2. Gross photograph of PAS resected by pulmonary thromboendarterectomy procedure.

ment, although one side is usually dominant. The reported sites of tumor include pulmonary trunk (85%), right pulmonary artery (71%), left pulmonary artery (65%), pulmonary valve (32%), and right ventricular outﬂow tract (10%) [6]. Histologically, intimal sarcomas typically show patchy areas of spindle cell proliferation in a myxoid background, alternating with hypocellular collagenous stroma (Fig. 3). The tumor may be intimately incorporated with recanalizing thrombi, especially toward distal branches of the pulmonary artery (Fig. 4). Most intimal sarcomas are poorly diﬀerentiated or undiﬀerentiated and generally show immunohistochemical or ultrastructural evidence of myoﬁbroblastic diﬀerentiation (Fig. 5) [1,8,9,16–19]. Foci of osteosarcoma, chondrosarcoma, or rhabdomyosarcoma are reported to be more common in PAS than in its aortic counterpart (Fig. 6). Intimal sarcomas with a speciﬁc component can be designated with an appropriate modiﬁer (eg, intimal sarcoma with

Fig. 4. PAS (arrow) intimately incorporated with recanalizing thrombi in the tumor extending to the distal pulmonary artery branches (hematoxylin-eosin stain, original magniﬁcation 100).

focal osteosarcoma, chondrosarcoma, or rhabdomyosarcoma, and so forth). Immunohistochemically, the undiﬀerentiated tumor cells of intimal sarcomas are usually positive for vimentin and osteopontin, an extracellular matrix protein binding to av integrins [20]. Variable positivity for smooth muscle actin and desmin has been observed [1,8,9,16–19]. In typical intimal sarcomas, endothelial markers (CD31, CD34, and Factor VIII) are negative [1,8,9,16–19]. The two cases of mural sarcoma reported in the literature were described as leiomyosarcoma and pleomorphic sarcoma [1]. One case of mural sarcoma encountered at the University of California–San Diego Medical Center showed features of pleomorphic sarcoma. There is no speciﬁc histologic grading system for PAS; the two widely used generic grading systems for soft tissue sarcomas (NCI and FNCLCC systems) can be applied with tumor diﬀerentiation, mitotic count, and tumor necrosis as the parameters for scoring. Diﬀerential diagnosis

Fig. 3. PAS showing spindle cell proliferation, alternating with hypocellular collagenous stroma (hematoxylineosin stain, original magniﬁcation 100).

Pathologic diagnosis of PAS is fairly straightforward in most cases, though some resected pulmonary thrombi have a highly cellular foci of remodeling that can mimic a low-grade intimal sarcoma (Fig. 7A–D). The possibility of metastasis from other sites should always be excluded. Mural sarcomas of the pulmonary artery are very diﬃcult to distinguish from sarcomas of the lung parenchyma. Clinical and radiologic diﬀerential diagnoses include CTEPH, primary lung or mediastinal tumors, congenital pulmonary stenosis,

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Fig. 5. PAS with myoﬁbroblastic diﬀerentiation as shown by a smooth muscle actin immunostain in inset (hematoxylineosin and anti-smooth muscle actin immunostain, original magniﬁcation 200).

ﬁbrosing mediastinal tumors, primary pulmonary hypertension, and pulmonary infections (usually tuberculosis). Treatment and prognostic factors Currently, surgical resection is the single most eﬀective modality for short-term palliation [6,21]. The types of surgery for PAS recorded in the literature included pneumonectomy, local excision of the mass from vascular bed with plastic reconstruction, and endarterectomy [6,21,22]. The role of adjuvant therapy is yet to be determined; however, according to a review of 136 reported

Fig. 6. PAS showing chondrosarcomotous area (hematoxylin-eosin stain, original magniﬁcation 200).

PAS cases, adjuvant radiotherapy or chemotherapy after surgery improved 1-year (58% with adjuvant therapy from 31% surgery alone; P = .11) and 2-year (39% from 24%; P = .4) survival rate but had no eﬀect on 5-year survival (0% with adjuvant therapy versus 6% surgery alone) [6]. The small number of patients treated with radiotherapy and chemotherapy alone allowed no conclusion as to the therapeutic efﬁcacy [6]. Improved survival can probably be achieved by early diagnosis and radical surgical resection, possibly with adjuvant chemotherapy and radiation.

Fig. 7. (A–D) Variable degree of cytologic atypia seen in otherwise typical cellular organizing thrombi in pulmonary thromboendarterectomy specimens (hematoxylineosin stain, original magniﬁcation 200).

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The overall prognosis of PAS is very poor regardless of therapy, with the mean survival ranging from 14 to 18 months [1,8,22]. Long-term survival at 5 years or more after surgery has been reported in two cases of mural sarcoma [1] and one case of low-grade intimal sarcoma [23], suggesting mural origin and low histologic grade as favorable prognostic factors. Postulated cell of origin and molecular pathogenesis Intimal sarcomas presumably arise from pluripotential mesenchymal cells of the intima [1,8]. Primitive cells of the bulbus cordi in the trunk of the pulmonary artery have also been proposed as the origin [16]. The cell of origin for mural sarcomas is not clear, but mural sarcomas showing a leiomyosarcoma component probably derive from medial smooth muscle cells [1]. A previous comparative genomic hybridization study demonstrated that six of eight intimal sarcomas had gains or ampliﬁcations of the chromosomal region 12q13–q15 by conventional technique [24]. In the same study, microarraybased comparative genomic hybridization was also applied to further investigate the ampliﬁcation of putative oncogenes located in the chromosomal regions of 12q13–q15 (SAS/CDK4, MDM2, and GLI) and 4q12 (platelet-derived growth factor receptor alpha [PDGFRA]). The data suggested that the ampliﬁcations of SAS/ CDK4, MDM2, GLI, and PDGFRA were strongly associated with the tumorigenesis of pulmonary artery intimal sarcomas [24]. An immunohistochemical study examined the expression of apoptosis-related proteins p53, Bax, Bcl-2, Fas (CD95), Fas-ligand, and perforin in seven PAS cases and concluded that the apoptosis occurs in PAS by way of an induction of Bax, mostly independent of p53 [25]. Host defense against the sarcoma could be mediated by perforinexpressing lymphocytes, but not through the Fas/Fas-ligand pathway [25]. Primary sarcomas of pulmonary veins General characteristics Primary sarcomas of the pulmonary veins are mostly leiomyosarcomas that arise from the medial smooth muscle cells [5,26]. Intimal sarcomas derived from the pluripotential intimal cells may occur in the pulmonary veins as in the pulmonary arteries, but are exceedingly rare [1]. Most reported PVS cases extended to the left

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atrium [5,26,27]. The venous sarcomas are typically larger than sarcomas of the arteries and may remain asymptomatic for a long period when they lack luminal growth [1]. Epidemiology PVS is extremely rare and is outnumbered in the literature by PAS by approximately 20:1 [5]. There have been only 17 reported PVS cases in the literature do date [26]. However, the incidence of sarcomas in the inferior vena cava has been known to be somewhat greater than that of sarcomas in great arteries [1]. In fact, the true incidence may be even higher, considering the potential origin of some retroperitoneal leiomyosarcomas from the inferior vena that was obscured by the large size. Similarly, the pulmonary venous origin would be diﬃcult to establish in advanced cases of PVS, which might have attributed to the low number of documented cases. According to the largest compiled series of PVS including 17 cases, the mean age was 50.0 15.6 years (median 48.0 years; range 23–74 years) at the time of pathologic diagnoses [26]. Six patients were men and 11 were women [26]. Compared with the marked female predominance in leiomyosarcomas of the inferior vena cava (1:4.8) and a slight female dominance or equivocal gender diﬀerence in PAS patients, the female dominance in PVS patients appeared moderate (1:1.8) [26]. Clinical manifestations The presenting symptoms of those 17 patients were as follows: dyspnea (8); hemoptysis or bloody sputa (5); cough (4); chest pain and weight loss (3 each); ipsilateral pleural eﬀusion (2); palpitation (2); and mental disturbance, dizziness, weakness, paroxysmal tachycardia, orthopnea, and sputa (1 each) [26]. In three cases, hemoptysis was the major symptom and necessitated blood transfusion or emergency surgery [26]. Primary sites of leiomyosarcomas of the pulmonary vein were reported in the right side in 9 cases and the left side in 6 cases; the primary site was unknown in 2 cases [26]. Right superior and left inferior pulmonary veins (6 and 4, respectively) were reported as the frequent origins for leiomyosarcomas [26]. The left PVSs tended to enter the left atrium, which was recognized in 9 of 17 cases [26]. Five of 17 cases developed local or mediastinal recurrence [26]. Three patients showed metastases to the liver, scalp, or axillary lymphnode [26].

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Imaging studies There have been no comprehensive reports regarding radiologic ﬁndings in PVS, and only sporadic descriptions are available in the literature. One case presented as an asymptomatic right hilar mass on a routine chest radiograph, and another case reported pleural eﬀusion detected by chest CT [5,26]. Right upper lobe density on chest radiograph or left atrial tumor on CT scan have been reported in one case each [5,27]. Pathologic ﬁndings Grossly, the tumors typically presented as ﬂeshy white masses that ranged from 2 to 8.3 cm in greatest dimension [5,26]. Some tumors partially or completely occluded the lumen of the involved vessels in addition to the mural involvement, while others had only mural components [5,26]. Extension of the tumor into the left atrial lumen was commonly seen, but invasion of the left atrial wall was seen in only one case [5,26,27]. Extension of the tumor into the pulmonary parenchyma was seen in some cases [5,26]. Microscopically, most tumors were classiﬁable as intermediate- to high-grade leiomyosarcomas [5,26]. Tumors showed either predominant spindle cells with cigar-shaped nuclei or epithelioid cells. Multifocal calciﬁcations were also observed in some tumors. Mitotic activity ranged from less than 1 to 25 mitotic ﬁgures per 10 high power ﬁelds. Necrosis was extensive in most reported tumors. The metastases, when present, had the same morphology as the primary lesions. Immunohistochemically, the tumor cells were reported positive for smooth muscle actin, muscle-speciﬁc actin (HHF-35), desmin, and vimentin, but were negative for epithelial membrane antigen, S-100 protein, and Factor VIII–related antigen. Focal positivity to keratin and dotlike cytoplasmic MIC-2 reactivity have been reported in some cases [5]. Treatment and prognosis Little is known regarding the optimal therapy for PVS because of the rarity of documented cases with adequate treatment history and follow-up. Surgical resection with wide margins probably oﬀers the only chance of cure as in other leiomyosarcomas [5,26]. Chemotherapy and radiation therapy have not been shown to be eﬀective [5,26]. Two cases in the literature expressed estrogen or progesterone receptor protein on immunohistochemical staining, suggesting a potential role for hormone ablation therapy [5].

According to a review of 17 PVS cases, local or mediastinal recurrence occurred in ﬁve cases and metastasis to the liver, scalp, or axillary lymph node was recorded in three cases [26]. Among 16 reported cases with available prognostic data, six patients were already dead of disease at the time of the report [26]. The length of follow-up ranged from 2 months to 21 years after the surgery in the remaining 10 patients who were alive [26]. The postoperative survival at the time of 6 months and 1, 2, 3, and 5 years were 75%, 73%, 50%, 33%, and 20%, respectively [26]. Age at the time of operation, gender, or presence of subjective symptoms at the time of the surgery did not seem to have any signiﬁcant inﬂuence on the postoperative survival up to 2 years [26]. The size of the tumor, presence of tumor growth in the left atrium, and mitotic count did not appear to be signiﬁcant prognostic factors in PVSs [26]. Pulmonary capillary hemangiomatosis General characteristics PCH usually presents as a bilateral pulmonary disease of unknown origin and shows a proliferation of capillaries within the alveolar septa and into other structures including bronchial and venous walls, pleura, and even regional lymph nodes, rendering the histopathology of a lowgrade capillary neoplasm [28]. However, it is not clear if PCH represents a reactive, neoplastic, or congenital hamartomatous process [28]. Extrathoracic spread or atypical nuclear features have not been described in PCH cases previously [3]. Clinical features PCH has been reported to occur in patients 6 to 71 years of age, with a peak at the third and fourth decades [3,29–31]. Both males and females appear to be equally aﬀected. A hereditary form of PCH with probable autosomal–recessive inheritance pattern has been reported by Langleben et al [32]. Clinical manifestations include progressive shortness of breath, pleuritic chest pain, and frequent hemoptysis, which often lead to clinical evaluation of chronic thromboembolic diseases. Digital clubbing is infrequently reported in PCH [3,29]. Patients with PCH later develop clinical signs of cor pulmonale [3,28–30]. Right heart catheterization invariably reveals highly elevated pulmonary arterial pressures but normal pulmonary capillary wedge pressures [3]. Recognition of early signs and symptoms of PCH is

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important to initiate the consideration for bilateral lung transplantation, which may prevent a fatal outcome. The time from symptom onset to death ranges from 2 to 12 years [3]. Imaging studies Chest radiographs typically show a diﬀuse, bilateral, reticulonodular pattern with enlarged central pulmonary arteries [3,28–31]. CT shows enlarged pulmonary arteries and multiple small, bilateral, poorly deﬁned nodular opacities [3]. HRCT shows a mosaic pattern of attenuation of pulmonary parenchyma, which likely represents variable pulmonary perfusion [3]. Ventilation perfusion scans may show match defects [3]. Radionuclide lung scan shows the combination of enhanced perfusion in the hemangiomatous tissue and decreased perfusion in the regions with occluded vessels. Inhomogeneous perfusion in radionuclide lung scan may be helpful to distinguish PCH from other types of pulmonary hypertension [3]. Angiographic study may also be helpful in distinguishing PCH from other forms of pulmonary hypertension. Pathologic ﬁndings and histopathologic diﬀerential diagnosis Deﬁnite diagnosis requires a histologic examination [3,28–32]. Histologically, the lung shows a multifocal, widespread, dense proliferation of capillary-like endothelial-lined vessels within the alveolar walls, interlobular septa, peribronchial and perivascular connective tissue, and pleura (Fig. 8). The alveolar septal capillaries appear engorged and may extend around and into both arteries and veins. Pulmonary veins and venules

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may show narrowing or obliteration of the lumen that are reminiscent of pulmonary veno-occlusive disease (PVOD). Hemosiderosis and interstitial ﬁbrosis may be seen. Muscular pulmonary arteries usually show mild to moderate medial hypertrophy and intimal thickening, but plexiform lesion is not seen in PCH [3,28–32]. Histopathologic diﬀerential diagnosis of PCH includes PVOD, acute congestion, and atelectasis artifact. In some cases of PVOD, one may see foci of increased capillaries in the alveolar septa that are indistinguishable from capillary hemangiomatosis. However, the inﬁltrative growth into bronchial and venous walls in PCH is not prominent in PVOD. The luminal occlusion of pulmonary veins in PCH is not as widespread as in PVOD and is typically caused by proliferative capillaries. In contrast, the venous lumens in PVOD are mostly occluded by recanalizing or ﬁbrotic thrombi. However, there is still a signiﬁcant overlapping in clinicopathologic features of PCH and PVOD, and the distinction between PVOD and PCH may be arbitrary. Passive congestion causing alveolar capillary engorgement and atelectasis may give the superﬁcial impression of PCH. However, there is no evidence of capillary proliferation, thus there is no increased density of capillaries. Marked alveolar hemosiderosis seen in some PCH cases may mimic Goodpasture’s disease or idiopathic pulmonary hemosiderosis in a limited tissue sample. In fact, the case of PCH ﬁrst described by Wagenvoort et al was initially diagnosed as primary pulmonary hemosiderosis on open lung biopsy, but autopsy revealed typical features of PCH [28]. Diﬀuse pulmonary hemangiomatosis occurring in pediatric patients is a form of vascular malformation with extrapulmonary as well as pulmonary involvement and consists of numerous large and dilated vascular channels resembling a cavernous hemangioma, which should be easily distinguishable from small-sized capillaries in PCH [28].

Treatment and prognosis

Fig. 8. Pulmonary capillary hemangiomatosis showing markedly thickened alveolar septa with capillary proliferation (HE, 200 original magniﬁcation).

Only bilateral lung or heart–lung transplantation currently oﬀers long-term survival, although no optimal therapy for PCH has been established because of its rarity. Prostacyclin therapy is generally contraindicated because it may cause pulmonary edema [33]. Other potential therapies include inhaled NO and angiogenesis inhibitors such as interferon [34].

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Secondary tumor involvement of pulmonary vasculature Tumor embolization to pulmonary vasculature is common and has been reported in 26% of autopsies on patients who had extrathoracic malignancy [2]. Direct extension of tumor thrombus into the proximal pulmonary artery may occur in renal cell carcinomas as a continuous column of tumor thrombus ﬁlling the renal vein, inferior vena cava, and right atrium [35]. Polypoid growth within the main pulmonary arterial lumen has been reported as a rare growth pattern in primary lung carcinomas [36]. However, microscopic foci of pulmonary arterial invasion are not uncommon in resected lung specimens from primary lung carcinoma cases [37]. Surgical excision of the centrally located tumor embolus or thrombus could oﬀer a markedly improved prognosis; however, the preoperative diagnosis is diﬃcult [35–37]. The most common primary carcinomas giving rise to tumor emboli in the large pulmonary arteries include choriocarcinomas and carcinomas of the stomach, breast, prostate, liver, and kidney [38]. Two distinct patterns of pulmonary arterial metastasis have been described: thrombotic microangiopathy and vascular intimal carcinomatosis [38–40]. Thrombotic microangiopathy, also known as carcinomatous arteriopathy, carcinomatous endarteritis, or embolic carcinomatosis, has been reported in 3.3% of cancer patients in autopsy series [38–39]. It is most frequently associated with adenocarcinomas from various primary sites including the stomach, breast, colon, pancreas, and liver [38]. On histologic examination, pulmonary arteries and arterioles are occluded by ﬁbrocellular intimal proliferation and ﬁbrin thrombosis that contain only minor component of malignant tumor cells. However, these malignant cells are postulated to initiate the thrombotic process by way of local activation of coagulation [39]. Clinical manifestations include progressive dyspnea, cough, hypoxia, and pulmonary hypertension [38,39]. Pulmonary hypertension associated with thrombotic microangiopathy should be considered in the diﬀerential diagnosis of primary pulmonary hypertension, particularly in patients who develop subacute cor pulmonale and have known history of malignancy [38,39]. Chest radiography may be unremarkable despite severe clinical symptoms and signs [39]. The socalled ‘‘tree-in-bud’’ pattern, a ﬁnding more typically seen in cases of infectious bronchiolitis, has

been reported as a helpful ﬁnding in chest CT [40]. Pulmonary vascular intimal carcinomatosis is histologically characterized by a diﬀuse replacement of the arterial intima by the tumor cells that does not invade the medial wall or occlude the arterial lumen. This pattern was described by Kobayashi et al [41] in a case of transitional cell carcinoma of the renal pelvis that had an isolated metastasis to the muscular pulmonary arteries greater than 300 lm in diameter. Metastatic or primary tumors may also involve the large pulmonary veins with or without extension to the left atrium of the heart. Pulmonary infarction due to pulmonary venous tumor thrombus from metastatic osteogenic sarcoma has been reported [42]. Metastatic chondrosarcoma to the lung has been reported to present as an embolic cerebral infarction that was caused by invasion of the pulmonary veins and subsequent extension into the left atrium [43].

Summary The rare primary tumors arising from the pulmonary vasculature are mostly sarcomas of the main pulmonary arteries and veins. Sarcomas arising in the pulmonary arterial intima are far more prevalent than those arising in the venous intima or those arising in the muscular media of pulmonary arteries and veins. Clinically, intimal sarcomas of pulmonary arteries are often indistinguishable from pulmonary chronic thromboembolic diseases, which causes delayed diagnosis and fatal outcome. Most sarcomas of the pulmonary veins are mural sarcomas, which tend to follow a somewhat less dismal clinical course than intimal sarcomas of the pulmonary artery. Pulmonary capillary hemangiomatosis is a rare disease of unknown etiology that shows the histopathologic features of a locally inﬁltrative, low-grade neoplasm despite the high mortality rate due to the accompanying severe pulmonary hypertension. Secondary tumors in the pulmonary vasculature may masquerade as primary vascular tumors or as primary/idiopathic pulmonary hypertension. Thrombotic microangiopathy and intimal carcinomatosis have been described as the distinct patterns seen in the secondary arterial involvement. Pulmonary venous tumor thrombosis may result in pulmonary infarctions or even systemic infarctions by way of left atrial involvement with subsequent systemic tumor embolism.

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