Editorial introductions
Current Opinion in Cardiology was launched in 1985. It is part of a successful series of review journals whose unique format is designed to provide a systematic and critical assessment of the literature as presented in the many primary journals. The field of cardiology is divided into 14 sections that are reviewed once a year. Each section is assigned a Section Editor, a leading authority in the area, who identifies the most important topics at that time. Here we are pleased to introduce the Section Editors for this issue.
Section Editors William J. McKenna
Dr William McKenna is Professor of Cardiology, at University College London, UK and Clinical Director of The Heart Hospital, University College London Hospitals Trust. He was born in Montreal, Canada and completed a Bachelor of Arts Degree at Yale University before graduating from McGill University Medical School. He completed Internal Medicine Training in at the Royal Victoria Hospital in Montreal and in 1976 moved to the Hammersmith Hospital Royal Postgraduate Medical School in London to train in cardiology. In 1988 he took up a post as Sugden Senior Lecturer in the Division of Cardiological Sciences at St George’s Hospital Medical School and in 1993 was made professor of cardiac medicine. In October 2000 he was appointed British Heart Foundation (BHF) Professor of Molecular Cardiology and in July 2003 moved to University College London (UCL) as Professor of Cardiology and was appointed Clinical Director of The Heart Hospital, University College London Hospital (UCLH) NHS Trust from September 2004. In August 2008 he was appointed Acting Director (West) of the Institute of Cardiovascular Science, UCL/UCLH Trust. His main interests have been in clinical and basic research of the cardiomyopathies. His recent work has contributed to the identification of disease-causing genes in hypertrophic, dilated and arrhythmogenic right ventricular cardiomyopathy, to
the establishment of new diagnostic criteria within the context of familial disease, and to the establishment of algorithms to identify patients at high risk of sudden death. William T. Abraham
William T. Abraham, M.D., F.A.C.P., F.A.C.C. is Professor of Internal Medicine and Chief of the Division of Cardiovascular Medicine at The Ohio State University College of Medicine, USA. He also serves as Deputy Director of the Dorothy M. Davis Heart and Lung Research Institute. Dr Abraham earned his medical degree from Harvard Medical School in Boston, Massachusetts, following which he completed his residency in internal medicine and fellowships in cardiology and heart failure/cardiac transplantation at the University of Colorado Health Sciences Center. He previously held faculty appointments at the University of Colorado, the University of Cincinnati, and the University of Kentucky. He is board certified in Internal Medicine and in Cardiovascular Diseases. Dr Abraham’s research interests include the role of the kidney in heart failure, neurohormonal mechanisms in heart failure, sleep disordered breathing in heart failure, and clinical drug and device trials in heart failure and cardiac transplantation. Dr Abraham has received grants from the National Institutes of Health, the American College of Cardiology, and the Aetna Quality Care Foundation and has participated as Principal Investigator in more than 100 multicenter clinical drug and device trials. In addition to authoring more than 600 original papers, abstracts, book chapters, and review articles, Dr Abraham has co-edited a leading textbook on heart failure entitled Heart Failure: A Practical Approach to Treatment. Dr Abraham serves on the editorial boards of several major journals including Congestive Heart Failure and Journal Watch Cardiology. He is also a scientific reviewer for such publications as Circulation, the European Heart Journal, and the Journal of the American College of Cardiology. Dr Abraham has been recognized as one of the ‘‘Best Doctors in America’’ for six consecutive years.
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Editorial introductions
David Feldman
Dr Feldman MD, PhD, FACC, FAHA is the Director of Heart Failure and Cardiac Transplant at The Ohio State University (OSU), USA. Dr Feldman is also the director of the heart failure fellowship program at OSU. He has appointments in the Departments of Cardiovascular Medicine, Physiology and Cell Biology as well as in the school of Pharmacy.
Dr Feldman’s research interests include the study of Gprotein coupled receptors, mechanisms of heart failure, genomic-mediated developmental changes and cardiac transplantation. He is currently funded by multiple National Institute of Health grants and the Heart failure Society of America. His research endeavors have included both basic and clinical research as he has extensive publications in both clinical and basic science. Despite his research, Dr Feldman continues to have a busy clinical practice. His clinical focus is cardiac transplant, end-stage disease management, and critical care.
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Lamin A/C deficiency as a cause of familial dilated cardiomyopathy Rohit Malhotra and Pamela K. Mason University of Virginia Health System, Charlottesville, Virginia, USA Correspondence to Pamela K. Mason, Assistant Professor of Medicine, PO Box 800158, University of Virginia Health System, Charlottesville, VA 22908-0158, USA Tel: +1 434 924 2465; fax: +1 434 924 2581; e-mail:
[email protected] Current Opinion in Cardiology 2009, 24:203–208
Purpose of review Familial dilated cardiomyopathy is an underrecognized form of dilated cardiomyopathy. Lamin A/C deficiency is probably the most common cause of familial dilated cardiomyopathy. This review will focus on the emerging knowledge of epidemiology, diagnosis, and treatment of patients with lamin A/C deficiency, as well as possible disease mechanisms. Recent findings Screening of patients with dilated cardiomyopathy continues to indicate that lamin A/C deficiency is a significant cause. Multiple novel mutations have been found, suggesting that many mutations are limited to individuals or families. It is unknown how mutations cause the syndrome, although an animal model has shown that lamin A/C insufficiency causes apoptosis, particularly in the conduction system. Inheritance is predominantly autosomal dominant, but penetrance is variable. For symptomatic patients, the course is malignant, with conduction system disease, atrial fibrillation, heart failure, and sudden cardiac death. The data are contradictory, and currently, there is no clear marker for when a lamin A/C-deficient patient is at risk for sudden death. Summary Lamin A/C deficiency is an important cause of dilated cardiomyopathy, and diagnosis requires that clinicians have a high index of suspicion. Our knowledge of the mechanisms, diagnosis, and treatment of lamin A/C deficiency is incomplete. It is clear that patients with this condition have a malignant course and need to be followed aggressively. Keywords familial dilated cardiomyopathy, lamin A/C deficiency, sudden cardiac death Curr Opin Cardiol 24:203–208 ß 2009 Wolters Kluwer Health | Lippincott Williams & Wilkins 0268-4705
Introduction Dilated cardiomyopathy (DCM) accounts for approximately 60% of all cardiomyopathies [1]. DCM is a major source of morbidity and mortality, causing congestive heart failure (CHF) and sudden cardiac death (SCD). This is a clinically heterogeneous disease and can be caused by ischemia, valvular disease, virus exposure, toxin exposure, or infiltrative disease. When no overt cause of DCM is found, it is termed idiopathic dilated cardiomyopathy (IDC). Over the last several decades, it has become increasingly clear that the cause of many ‘idiopathic’ dilated cardiomyopathies is genetic. Familial dilated cardiomyopathy (FDC) is now thought to account for up to 50% of IDC patients, whereas in the early 1980s the reported incidence of FDC was 2–6.5% [2–5]. Most of these cases (>90%) are thought to show autosomal dominant inheritance, although X-linked and autosomal recessive forms have been identified [6]. There are many factors that 0268-4705 ß 2009 Wolters Kluwer Health | Lippincott Williams & Wilkins
have hindered the diagnosis of FDC. Identifying patients with possible FDC requires there be sufficient family history to find that there are at least two first-degree family members with IDC. Many patients do not know their family histories or have small families. In addition, this disease has variable and age-dependent penetrance even within families [5,7,8,9,10]. Patients who have FDC may have other causes of DCM, such as coronary artery disease or valvular heart disease, which confound the true diagnosis. The challenges in recognizing FDC families clinically have made identifying culprit genes difficult. Even when FDC families are identified, only a small number of patients are available. Most research has evaluated candidate genes. More than 20 different genes have been identified in patients with FDC (Table 1). These include genes that affect sarcomeric proteins, cytoskeletal proteins, nuclear proteins, ion channel proteins, and mitochondria [1,11,12,13]. Many of these mutations have been found in few patients, and, indeed, may only DOI:10.1097/HCO.0b013e32832a11c6
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204 Molecular genetics
Table 1 Genes that have been implicated in the development of dilated cardiomyopathy Locus
Gene
1p1-q21 1q32 1q42-q43 2q31 2q35 3p21 3p22-p25 5q33 6q22.1 10q22-q23 11p11 11p15 12p12 12q22 14q12 15q14 15q22 17q12 19q13
Lamin A/C Troponin T a-Actinin Titin Desmin Troponin C SCN5A d-Sarcoglycan Phospholamban Metavinculin Myosin-binding protein-C Cardiac muscle LIM protein SUR2A Thymopoietin b-Myosin heavy chain Cardiac actin a-Tropomyosin Telethonin Troponin I
Table adapted from [1,11,12].
account for FDC within single patients or families. Although up to 50% of patients with IDC may have FDC by history, a genetic test may identify the cause in only a small minority of patients. The exception to this is lamin A/C mutation. Lamin A/C mutations are thought to be the cause in up to 10% of FDC cases [14]. Multiple different mutations have been found in the lamin A/C gene (LMNA) and testing is available at several centers. The diagnosis of lamin A/C deficiency denotes important prognostic information [8,15–19]. These patients often have a particularly malignant course and the penetrance for some mutations approaches 100% as patients age. In this review, we will focus on the recent advances in the epidemiology, diagnosis, and treatment of lamin A/C deficiency as a cause of isolated cardiomyopathy. Many of the other mutations described above cause concomitant skeletal muscle disease or other forms of cardiomyopathy such as hypertrophic cardiomyopathy and will be covered in other sections.
Lamin A and C Lamin A and C are type V intermediate filament proteins found in the nuclear membrane or lamina [20,21]. LMNA is found on chromosome 1q21.2-q21.3. Lamin A and C are created by alternative splicing. They are expressed in terminally differentiated somatic cells and found in multiple different tissues, including skeletal and cardiac muscle. The protein is composed of a conserved rod domain with a globular head and tail region. The functions of lamin A and C are incompletely understood, but it is thought that they are important in maintaining nuclear architecture, DNA replication, RNA
transcription, cell cycle regulation, cell differentiation, and apoptosis. Recent in-vitro data suggest various mutations in the gene may each lead to different alterations in protein function [22]. This could lead to dramatically different physiologic consequences for distinct mutations.
Laminopathies There are over 200 mutations described in LMNA, which can cause over 20 different phenotypes. This constellation of syndromes is known as the laminopathies. It is unknown how the mutations cause the syndromes, and up to 25% of patients with LMNA mutation may remain asymptomatic [23]. Many laminopathies have a multisystem phenotype, and virtually all symptomatic patients have some form of cardiac involvement. Emery–Dreifuss muscular dystrophy causes muscular dystrophy and DCM. Hutchinson–Gilford progeria syndrome causes accelerated aging. Other phenotypes cause partial lipodystrophy or neuropathy. When patients have multisystem phenotypes, it is easier to recognize a probable familial cause for their cardiomyopathy. However, there are a significant number of patients with lamin A/C mutation who have only cardiac manifestations. These patients often remain undiagnosed.
Cardiac manifestations of lamin A/C deficiency The earliest cardiac finding in patients with lamin A/C deficiency is usually conduction system disease. In a meta-analysis of 299 carriers of a lamin A/C mutation, 18% of patients less than 10 years of age had evidence of delayed intracardiac conduction. In patients over 30 years of age, 92% had conduction system disease, with 44% requiring pacemaker placement [14]. In early stages, patients have a characteristic electrocardiogram with low amplitude P waves, prolonged PR interval, but a relatively normal QRS complex (Fig. 1). Patients subsequently develop atrial fibrillation and DCM. A high incidence of thromboembolic events has been noted in lamin A/C-deficient patients (30%), but whether this is related to undiagnosed atrial dysrhythmias or factors specific to lamin A/C deficiency is unknown [24]. By age 50, over 60% of patients have symptoms of CHF [14]. A recent animal model of lamin A/C haploinsufficiency has suggested a mechanism for the clinical cardiac findings [25]. The earliest finding in mice with one abnormal LMNA allele was programmed cell death of atrioventricular nodal myocytes. Subsequently, the mice developed worsening electrophysiologic disease. Ultimately, the nonconducting myocytes also experienced apoptosis, leading to DCM.
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Lamin A/C deficiency as a cause of FDC Malhotra and Mason 205 Figure 1 Characteristic electrocardiogram from an asymptomatic patient with lamin A/C deficiency
Conduction system disease is generally the earliest finding in patients with lamin A/C deficiency. Patients demonstrate low amplitude P waves, prolonged PR intervals, but narrow QRS complexes.
Lamin A/C-deficient patients are at high risk of SCD, probably at significantly higher risk than patients with other forms of DCM [26]. In one Dutch kindred, there was a precipitous decline in survival after age 40, and by age 65 no family members were alive [27]. Meune et al. [15] found that, in a small cohort of patients with known lamin A/C defects, 42% of patients experienced SCD. The approximate mean age and mean ejection fraction in this cohort were 42 years and 58%, indicating that this group experienced SCD at young age and with relatively preserved ejection fraction. Other recent studies have also found that risk of SCD precedes left ventricular dysfunction [28]. Further, in the meta-analysis described above, the need for a pacemaker or the presence of a pacemaker did not seem to be predictive of SCD [14]. A more recent study by Pasotti et al. [29] also found that patients with lamin A/C defects experienced a malignant course. By examining 94 patients derived from a genetic analysis of 27 families with DCM, they were able to identify risk factors for SCD. Univariate analysis indicated that New York Heart Association class III or IV, clinical manifestation of LMNA deficiency, conduction system disease, left ventricular ejection fraction (LVEF) less than 35%, left ventricular end-diastolic volume more than 180 ml, and history of competitive athleticism were predictive of death, CHF, heart transplant, or SCD. Multivariate analysis identified only function class III or IV and history of competitive sports as independent predictors of an event. SCD occurred in 6.3 per 100 person years among affected individuals. Both competi-
tive sports for greater than 10 years and genotype were predictive on multivariate analysis of risk of SCD. In contradiction to previous data, those who did not manifest disease did not have clinical events. However, by age 60, all patients with a mutation manifested disease, indicating 100% penetrance over time.
Genetic screening Several mutations in LMNA were identified in five families with DCM with conduction system disease by Fatkin et al. in 1999 [19]. The location of the mutation within the gene altered the phenotype. Since then, multiple familial studies [23,30,31,32] have identified a number of other novel mutations in exons as well as splicing sites. These mutations generate missense, splice site, nonsense, and deletion mutations. The recent genetic study by Parks et al. [30] of 324 unrelated DCM patients identified 11 novel LMNA mutations. This study identified a prevalence of LMNA mutations of 5.9% in the FDC and DCM patients evaluated. Several family members of the probands enrolled in this study carried pathogenic LMNA mutations without disease manifestations, demonstrating a variable penetrance of the disease process. In contrast, there were kindreds in which only some of the family members who had DCM had LMNA mutations. This study demonstrates the difficulty in developing a screening examination that does not involve sequencing the entire genetic locus for LMNA, including introns. However, novel mutations may not alter protein structure or function, thus
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206 Molecular genetics
confounding results of these sequencing tests. No repository to maintain a correlation between identified genetic mutations and clinical manifestations exists. Genetic screening is most useful in identified FDC families. The probands have usually already developed clinical disease, although some known mutations do have a more malignant course, which can help with prognosis and therapy. Unfortunately, many newly diagnosed lamin A/C-deficient families are found to have novel mutations. However, identifying a specific genetic mutation within a family can be important for family planning and directing follow-up for the family members. Family members of probands should undergo genetic counseling. Although up to 10% of the IDC patients may have lamin A/C defects, generalized screening of the DCM population is not performed. There are too many unidentified mutations and comprehensive screening is insensitive [33]. There are also substantial resource and financial barriers to this kind of testing. We are likely many years from being able to comprehensively screen patients genetically for FDC.
Clinical screening Identifying new lamin A/C-deficient families requires a high index of suspicion. Patients with IDC and at least one other first-degree relative with IDC should be considered for genetic screening. Most patients with lamin A/C deficiency do have conduction system disease as one of the first features, and up to 30% of patients with DCM and conduction system disease are thought to have lamin A/C deficiency [2–5]. Finally, while lamin A/C deficiency causes isolated cardiomyopathies, it often causes DCM in conjunction with other clinical findings, particularly skeletal muscle abnormalities. Careful history, physical examination, and laboratory testing in patients can often identify evidence of mild limb-girdle muscular dystrophies or neuropathies in them or their family members. At this time, there is no consensus on the frequency or type of screening that patients with known mutations and no clinical phenotype should undergo. Recommendations have been made to screen family members of affected patients every 3–5 years with physical examination, electrocardiogram, and echocardiogram, but it is unknown whether the frequency of screening should increase as patients get older, given that penetrance increases as patients age [12]. In addition, the particular genotype alters the rate of disease progression and it is unknown how this should affect the screening process. Several studies have suggested that left ventricular enlargement may be one of the earliest findings in asymptomatic patients who go on to develop symptomatic FDC [4,34]. Left bundle branch block (LBBB) has also been
implicated as an early warning sign [12]. These findings warrant more frequent and aggressive follow-up. Of particular concern in the lamin A/C-deficient population is the accelerated risk of SCD. The data are conflicting, but there is evidence that these patients are at risk prior to the development of the usual markers for SCD that are used for other forms of DCM, particularly left ventricular dysfunction and CHF symptoms. There is currently no clear marker that can be identified by physical examination, laboratory work, or imaging study that indicates that a patient with lamin A/C deficiency is now at risk for SCD. MRI has been evaluated as a modality to diagnose subclinical disease in asymptomatic patients with lamin A/C deficiency [35,36,37]. One recent study [35] evaluated the use of MRI to diagnose cardiac involvement in 12 patients with one mutated allele and no disease manifestations. MRI studies demonstrated differences in these patients when compared with 14 control patients. There was no single parameter that identified patients at risk, but an amalgam of parameters calculated from MRI measurements was different in carriers when compared with normals, suggesting that MRI may identify patients who are predisposed to disease. These patients will need to be followed up to determine whether they will manifest symptoms in order to determine the true predictive capacity of MRI in these patients. Should all of these patients develop conduction system disease or CHF, a cardiac MRI may predict who will require more aggressive therapy.
Therapy There is little data to guide therapy for patients with lamin A/C deficiency. Standard medical therapies for CHF are employed when patients develop left ventricular dysfunction [33]. It is unknown whether these patients benefit from being started on angiotensin-converting enzyme inhibitors or b-blockers prior to the development of CHF. It is also unknown whether the use of b-blockers will exacerbate or reveal underlying conduction system disease. Patients do often progress to end-stage CHF, and transplantation has been described for this population [17]. There is a substantial role for device therapy in this population. Many of these patients will require pacemakers due to severe conduction system disease. The optimal timing of implantable cardioverter defibrillator (ICD) placement remains undefined. Meune et al. [15] placed ICDs in 19 patients who had lamin A/C mutations and indications for pacemakers, but had no traditional indications for ICDs. Eight of these patients (42%) received appropriate shocks. It has been suggested that
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Lamin A/C deficiency as a cause of FDC Malhotra and Mason 207
the development of conduction system disease may be a marker of fibrosis, which also puts the patient at risk for SCD. The use of electrophysiology studies has also been recommended as a screening tool. However, other data indicate that the need for or presence of a pacemaker does not affect SCD risk [14]. A recent study [29] did not find that asymptomatic patients were at risk of SCD. In the absence of conclusive data, there should be a low threshold to place ICDs in these patients. It is clear that lamin A/C-deficient patients have a malignant course and are at high risk for SCD. Knowledge of the patient’s family history of SCD can help guide timing as well. The fact that competitive sports may be a risk marker for poor prognosis in patients with lamin A/C deficiency suggests that these patients may not fit into a standard cardiac paradigm [29]. Earlier screening may be necessary if athleticism is detrimental in order to prevent asymptomatic individuals from being too athletic. However, data are limited and we would refrain at this time from limiting activity based upon a potential risk rather than confirmed causality.
Conclusion FDC accounts for a larger proportion of IDC than has been recognized by the clinical cardiology community. There are multiple different genes that have been identified as causes of FDC in a limited number of patients, but lamin A/C deficiency is one of the most prevalent of the genetic causes of IDC. Our knowledge of appropriate diagnosis and treatment of patients with lamin A/C deficiency is incomplete. However, symptomatic patients can have a very malignant course with severe CHF and ventricular dysrhythmias. Clinicians should have high index of suspicion for the diagnosis of FDC and particularly lamin A/C deficiency. Further, they should have a low threshold to treat patients for left ventricular dysfunction and ventricular dysrhythmias.
References and recommended reading Papers of particular interest, published within the annual period of review, have been highlighted as: of special interest of outstanding interest Additional references related to this topic can also be found in the Current World Literature section in this issue (p. 260). 1 Karkkainen S, Peuhkurinen K. Genetics of dilated cardiomyopathy. Ann Med 2007; 39:91–107. A comprehensive review of the known genetic mutations that have been shown to cause FDC.
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Hershberger RE, Hanson E, Jakobs PM, et al. Novel lamin A/C mutation in a family with dilated cardiomyopathy, prominent conduction system disease, and need for permanent pacemaker implantation. Am Heart J 2002; 144:1081–1086.
van Spaendonck-Zwarts KY, van den Berg MP, van Tintelen JP. DNA analysis in inherited cardiomyopathies: current status and clinical relevance. Pacing Clin Electrophysiol 2008; 31:S46–S49. A review of the use of genetic testing in the evaluation, diagnosis, and treatment of patients with forms of inherited cardiomyopathy.
9
10 Rankin J, Auer-Grumbach M, Bagg W, et al. Extreme phenotypic diversity and nonpenetrance in families with LMNA gene mutation R644C. Am J Med Genet 2008; 146A:1530–1542. A series of patients with the same missense mutation. This study highlights the variability in penetrance and phenotype for lamin A/C deficiency. 11 Hershberger RE. Familial dilated cardiomyopathy. Prog Ped Cardiol 2005; 20:161–168. 12 Crispell KA, Hanson EL, Coates K, et al. Periodic rescreening is indicated for family members at risk of developing familial dilated cardiomyopathy. J Am Coll Cardiol 2002; 39:1503–1507. 13 Burkett EL, Hershberger RE. Clinical and genetic issues in familial dilated cardiomyopathy. J Am Coll Cardiol 2005; 45:969–981. 14 van Berlo JH, deVoogt WG, van der Kooi AJ, et al. Meta-analysis of clinical characteristics of 299 carriers of LMNA gene mutations: do lamin A/C mutations portend a high risk of sudden death? J Mol Med 2005; 83:79–83. 15 Meune C, van Berlo J, Anselme F, et al. Primary prevention of sudden death in patients with lamin A/C gene mutations. N Engl J Med 2006; 354:209–210. 16 Taylor MR, Fain PR, Sinagra G, et al. Natural history of dilated cardiomyopathy due to lamin A/C gene mutations. J Am Coll Cardiol 2003; 41:771–780. 17 Sylvius N, Bilinska ZT, Veinot JP, et al. In vivo and in vitro examination of the functional significances of novel lamin gene mutations in heart failure patients. J Med Genet 2005; 42:639–647. 18 Arbustini E, Pilotto A, Repetto A, et al. Autosomal dominant dilated cardiomyopathy with atrioventricular block: a lamin A/C defect-related disease. J Am Coll Cardiol 2002; 39:981–990. 19 Fatkin D, MacRae C, Sasaki T, et al. Missense mutations in the rod domain of the lamin A/C gene as causes of dilated cardiomyopathy and conductionsystem disease. N Engl J Med 1999; 341:1715–1724. 20 Gruenbaum Y, Goldman RD, Meyuhas R, et al. The nuclear lamina and its functions in the nucleus. Int Rev Cytol 2006; 226:1–62. 21 Shumaker DK, Kuczmarski ER, Goldman RD. The nucleoskeleton: lamins and actin are major players in essential nuclear functions. Curr Opin Cell Biol 2003; 15:358–366. 22 Sylvius N, Hathaway A, Boudreau E, et al. Specific contribution of lamin A and lamin C in the development of laminopathies. Exp Cell Res 2008; 314:2362– 2375. In-vitro study evaluating the effects of lamin A and C overexpression in COS7 cells. The results suggested that different mutations in lamin A and C may cause differential effects on cellular function. 23 Sylvius N, Tesson F. Lamin A/C and cardiac diseases. Curr Opin Cardiol 2006; 21:159–165. 24 van Tintelen JP, Hofstra RMW, Katerberg H, et al. High yield of LMNA mutations in patients with dilated cardiomyopathy and/or conduction disease referred to cardiogenetics outpatient clinics. Am Heart J 2007; 154:1130– 1139. A series of patients with FDC who were screened for lamin A/C deficiency. This study found several different mutations that resulted in different clinical courses.
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Michels VV, Driscoll DJ, Miller FA. Familial aggregation of idiopathic dilated cardiomyopathy. Am J Cardiol 1985; 55:1232–1233.
25 Wolf CM, Wang L, Alcalai R, et al. Lamin A/C haploinsufficiency causes dilated cardiomyopathy and apoptosis-triggered cardiac conduction system disease. J Mol Cell Cardiol 2008; 44:293–303. This mouse model study demonstrated a possible mechanism for the clinical presentation of lamin A/C deficiency. Lamin A/C-deficient myocytes demonstrated apoptosis, particularly in conducting cells.
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26 Becane HM, Bonne G, Varnous S, et al. High incidence of sudden death with conduction system and myocardial disease due to lamins A and C gene mutation. Pacing Clin Electrophysiol 2000; 23:1661–1666.
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208 Molecular genetics 27 van Tintelen JP, Tio RA, Kerstjens-Frederikse WS, et al. Severe myocardial fibrosis caused by a deletion of the 50 end of the lamin A/C gene. J Am Coll Cardiol 2007; 49:2430–2439. A family study demonstrating the malignant course that many patients with lamin A/C deficiency experience. The patients were at high risk for CHF and sudden death. 28 de Backer J, van Beeumen K, Loeys B, Duytschaever M. Expanding the phenotype of sudden cardiac death – an unusual presentation of a family with a lamin A/C mutation. Int J Cardiol 2008. [Epub ahead of print] A family study that demonstrated that the risk of SCD preceded the development of left ventricular dysfunction. 29 Pasotti M, Klersy C, Pilotto A, et al. Long-term outcome and risk stratification in dilated cardiolaminopathies. J Am Coll Cardiol 2008; 52:1250–1260. A large series of 164 patients in 27 families with lamin A/C deficiency. These patients had a malignant course. The authors were able to identify several markers for risk of sudden death, including CHF, which is in contrast to previous studies. Athleticism was also a risk factor for sudden death. 30 Parks SB, Kushner JD, Nauman D, et al. Lamin A/C mutation analysis in a cohort of 324 unrelated patients with idiopathic or familial dilated cardiomyopathy. Am Heart J 2008; 156:161–169. A large series of patients who were found to have lamin A/C deficiency. Multiple different mutations were found with multiple different phenotypes. Not all affected family members were found to have the mutation, suggesting that not all lamin A/C defects cause disease. 31 Perrot A, Hussein S, Ruppert V, et al. Identification of mutational hot spots in LMNA encoding lamin A/C in patients with familial dilated cardiomyopathy. Basic Res Cardiol 2009; 104:90–99. A series of patients with FDC who were found to have lamin A/C deficiency. Two novel mutations were found and mutational hot spots were identified.
32 Rudenskaya GE, Polyakov AV, Tverskaya SM, et al. Laminopathies in Russian families. Clin Genet 2008; 74:127–133. A series of patients with lamin A/C deficiency who were genetically screened. Several novel mutations were discovered and mutational hot spots were identified. 33 Crispell K, Wray A, Ni H, et al. Clinical profiles of four large pedigrees with familial dilated cardiomyopathy: preliminary recommendations for clinical practice. J Am Coll Cardiol 1999; 34:837–847. 34 Michels VV, Moll PP, Miller FA, et al. The frequency of familial dilated cardiomyopathy in a series of patients with idiopathic dilated cardiomyopathy. N Engl J Med 1992; 326:77–82. 35 Koikkalainen JR, Antila M, Lotjonen JMP, et al. Early familial dilated cardiomyo pathy: identification with determination of disease state parameter from cine MR image data. Radiology 2008; 249:88–96. MRI was used to screen for preclinical findings in a series of patients with lamin A/C mutations who did not have clinical disease. 36 Jerosch-Herold M, Sheridan DC, Kushner JD, et al. Cardiac magnetic reso nance imaging of myocardial contrast uptake and blood flow in patients affected with idiopathic or familial dilated cardiomyopathy. Am J Physiol Heart Circ Physiol 2008; 295:H1234–H1242. MRI was used to evaluate alterations in blood flow in a series of patients with IDC or FDC. 37 Carboni N, Mura M, Marrosu G, et al. Muscle MRI findings in patients with an apparently exclusive cardiac phenotype due to a novel LMNA gene mutation. Neuromuscul Disord 2008; 18:291–298.
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Left ventricular noncompaction Antonios A. Pantazis and Perry M. Elliott The Heart Hospital, University College London/ University College London Hospital, London, UK Correspondence to Dr P. Elliott, The Heart Hospital, 16–18 Westmoreland Street, London W1G 8PH, UK Tel: +44 207 573 8888; fax: +44 207 573 8838; e-mail:
[email protected] Current Opinion in Cardiology 2009, 24:209–213
Purpose of review Isolated left ventricular noncompaction (LVNC) is a myocardial disorder characterized by excessive and prominent trabeculations of the left ventricle, associated with progressive systolic failure, stroke and arrhythmia. Until quite recently, LVNC was thought to be extremely rare, but, with greater awareness of the disease and improvements in echocardiographic technology, there has been a dramatic increase in the frequency of diagnosis. Recent studies suggest that the frequency of LVNC is determined in part by the diagnostic criteria used. Recent findings Up to 50% of adult patients with LVNC have mutations in genes encoding proteins of the cardiac sarcomere, suggesting that LVNC might represent a new disease paradigm in which mutations that more typically cause dilated and hypertrophic cardiomyopathies result in abnormal ventricular morphogenesis. Summary In this review, we briefly summarize current clinical literature on LVNC, with a particular focus on the limitations of current diagnostic criteria and emerging data on the genetics of the disorder. Keywords cardiomyopathies, left ventricular noncompaction, sarcomeric proteins Curr Opin Cardiol 24:209–213 ß 2009 Wolters Kluwer Health | Lippincott Williams & Wilkins 0268-4705
Introduction Left ventricular noncompaction (LVNC) is a myocardial disorder defined by the presence of prominent trabeculations on the luminal surface of the ventricle, associated with deep intertrabecular recesses that extend into the ventricular wall (Fig. 1). Histological findings are nonspecific, with areas of fibrosis interspersed with normal myocytes [1,2]. LVNC frequently occurs in association with other congenital heart abnormalities, including atrial and ventricular septal defects, congenital aortic stenosis and coarctation of the aorta [3–7]. LVNC in the absence of such lesions was, until quite recently, thought to be an extremely rare phenomenon with a prevalence between 0.05 and 0.24% [8,9], but, with improvements in diagnostic imaging, the frequency of diagnosis has dramatically increased in children and adults [10].
Pathogenesis Several hypotheses have been proposed to explain LVNC, but there is an emerging consensus that most cases of LVNC are the result of abnormal ventricular morphogenesis. Trabeculations in the embryonic murine heart are evident from day 10.5 (equivalent to the fourth 0268-4705 ß 2009 Wolters Kluwer Health | Lippincott Williams & Wilkins
gestational week in humans) when endocardium evaginates through the cardiac jelly to contact the adjacent myocardium [11]. Myocardial trabeculations at this early stage appear as projections of myocardium protruding into the ventricular lumen. Later, these undergo a process of compaction that results in a reduced inner layer of trabeculations, with the compacted layer forming the ventricular walls and conduction system; LVNC is thought to represent a failure of this process that results in an increase in the thickness of the trabecular layer relative to the compact layer of the ventricular walls.
Genetics of left ventricular noncompaction Some unconfirmed reports have suggested that the phenotype for isolated ventricular noncompaction may appear during adult life in patients with muscular dystrophy [12] or as a transient phenomenon during myocarditis [13]. At present, it would seem more appropriate to label such cases as ‘hypertrabeculation’ rather than noncompaction, although without serial echocardiographic data it may be impossible to distinguish the two. A number of studies suggest that many cases of LVNC are caused by inheritable genetic variants. The fact that DOI:10.1097/HCO.0b013e32832a11e7
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210 Molecular genetics Figure 1 Typical echocardiographic pictures of left ventricular noncompaction in apical four-chamber view (a) and short axis view (b)
Apical echocardiographic view of a noncompacted left ventricle with extended and prominent trabeculations in the apical region and in the lateral wall. Two-layered appearance of the myocardium in a short axis view of the left ventricle.
LVNC is compatible with survival into adulthood suggests that it is caused by defective maturation of the ventricle rather than its initial specification. Very few mutations of genes encoding the transcription factors and signaling molecules involved in left ventricular development are known disease alleles. One explanation might be that mutations in these genes are not compatible with survival. As inherited disease alleles, by definition, have to allow formation of the left ventricle (LV), it is more likely that the molecular defect in most cases of LVNC affects maturation of the ventricle. This distinction between ventricular maturation and ventricular specification is important as it questions the relevance of most published mouse ‘knock-out’ studies to human cardiac disease.
Several disease loci have been identified in humans: (1) G4.5 Mutations in G4.5 gene located at Xq28 are associated with Barth syndrome, an X-linked disorder that presents in infant males with dilated cardiomyopathy (DCM), LVNC, neutropenia, abnormal cholesterol metabolism, lactic acidosis, elevated 3-methylglutaconic acid and 2-ethylhydracrylic acid and cardiolipin abnormalities [14]. G4.5 encodes members of the tafazzin (TAZ) group of proteins, which are expressed primarily in heart and muscle cells and are thought to have acyltransferase functions within mitochondria. (2) ZASP ZASP is a cardiac and skeletal muscle Z-line protein that is expressed in the cytoplasm. The protein localizes together with actin and interacts with the C-terminus of a-actinin-2 via a PDZ domain. The PDZ domain-containing proteins interact with each other in the cytoskeletal structure and contribute to the assembly of membrane proteins. Thus, ZASP has an important role in the maintenance of the normal architecture of the myocytes. It is not surprising, therefore, that mutations in ZASP are responsible for DCM. The exact mechanism by which mutations result in LVNC is unclear [15]. (3) a-dystrobrevin a-dystrobrevin (DTNA) is a cytoskeletal protein component of the dystrophin-associated glycoprotein complex (DAPC), which is composed of three subcomplexes: the dystroglycan complex, the sarcoglycan complex and the cytoplasmic complex, which includes the syntrophins and dystrobrevins. These groups of proteins link the extracellular matrix to the dystrophin cytoskeleton of the muscle fibre. A mutation in the DTNA gene has been associated with LVNC [16], but, as in other genetic cardiomyopathies, there is significant variability in disease phenotype and severity. (4) Lamin A/C Lamins are major protein components of the nuclear lamina, the meshwork underlying the inner nuclear membrane. Mutations in the lamin A/C gene have been causally linked to different diseases [17] such as DCM with conduction system disease, limb girdle muscular dystrophy (LGMD), autosomal dominant variant of Emery–Dreifuss muscular dystrophy (EDMD) and partial lipodystrophy. The identification of isolated LVNC in a carrier of the lamin A/C mutation [18] does not explain the role of this protein in the pathogenesis of the disorder. (5) Sarcomeric protein genes Mutations in the genes encoding the thick and thin filaments of the cardiac sarcomere can cause hypertrophic cardiomyopathy (HCM) and DCM. Recent data from case reports and a large series of
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Left ventricular noncompaction Pantazis and Elliott 211
patients suggest that mutations in the same genes may be associated with an LVNC phenotype. Actin proteins are essential for the generation and maintenance of cell morphology and polarity. LVNC is described in association with an actin reported to cause apical hypertrophy. The same gene defect was also associated with an interatrial septal defect [19], an observation suggestive of the role of ACTC in cardiac morphogenesis. In a study of 63 patients [20] exhibiting features of LVNC, seven disease-causing mutations were found in b-myosin heavy chain (MYH7) and one in cardiac troponin T [troponin T type 2 (TNNT2)]. It is interesting, and may be of pathogenetic significance, that different phenotypes related to MYH7 mutations are caused by mutations clustering in specific areas of the gene, although some are more evenly spread. Although assessment of family members was limited, the penetrance of the mutations (defined by the presence of LVNC) was 100%.
Natural history Presentation with symptoms of heart failure and arrhythmia is described at all ages. Several studies [9,21,22] have suggested that afflicted patients have poor left ventricular function, with a high incidence of ventricular arrhythmias and systemic thromboembolism. Recent studies [10,23], nonetheless, report a much lower incidence of death, stroke or documented sustained ventricular arrhythmia, probably reflecting the identification of preclinical or mild cases.
Clinical diagnosis of left ventricular noncompaction Fine trabeculations are a feature of the normal LV, but it is only quite recently that technical advances such as harmonic imaging, contrast echocardiography and cardiac MRI have facilitated their visualization. A number of echocardiographic definitions for the diagnosis of LVNC have been proposed. Two are based on an analysis of fewer than 45 patients with a common phenotype [1,24]; the third is extrapolated from a postmortem study [25]. Although all definitions describe the morphology of the condition, they differ substantially in their approach. The method proposed originally by Chin et al. [24] compares the length of trabeculae with the thickness of the compacted wall in different echocardiographic views and at different levels of the LV in end diastole. Jenni et al. [1] have proposed a criterion that relies on the detection of two myocardial layers in short axis views of the LV in end systole. LVNC, in this instance, is defined by a ratio between the two layers. The third definition, proposed by Sto¨llberger et al. [25], determines the number of promi-
nent trabeculations visible in apical views of the LV in diastole. Cardiac magnetic resonance (CMR) imaging is also being used to detect LVNC. CMR has the advantage of good spatial resolution at the apex and lateral wall of the LV and, in a recent study [26], has been used to quantify the ratio of noncompacted and compacted layers in patients with LVNC and in normal controls. However, CMR studies have used an adapted version of existing echo criteria with all the same limitations. Moreover, direct comparison with echo is not always possible as the detection of the noncompact layer using CMR is performed in diastole, whereas the echocardiographic definition applies to systole (in the case of the criteria of Jenni et al. [1]).
Limitations of current diagnostic criteria Evidence from developmental studies, case reports and small clinical series supports the concept of LVNC as a genuine disease entity that may in some cases have an association with other cardiac and somatic abnormalities. However, a study from our own group [27] has recently shown that a high proportion of patients with systolic heart failure fulfill current diagnostic criteria for LVNC, at least when the criteria are applied retrospectively. This might be explained by a genuine congenital abnormality or an exaggeration of normal trabeculation patterns, but the fact that 8.3% of normal controls also fulfilled LVNC criteria suggests that prominent trabeculations in patients with heart failure could be no more than an incidental finding. This may be particularly true in black individuals, who have a higher incidence of trabeculation patterns fulfilling current diagnostic criteria, irrespective of the presence of left ventricular disease. Furthermore, the variable patterns of noncompacted hearts pose an additional difficulty in the characterization and quantification of the observed features (Figs. 1 and 2).
Clinical management Limited evidence is available about the management of LVNC. Specific treatment for the primary disorder is lacking, and the aim is to prevent the complications or manage the symptoms using treatment protocols extrapolated from the experience with other cardiomyopathies. The main clinical issues in this disease are thromboembolism, arrhythmia and heart failure [9]. Given that the risk of thromboembolism is probably lower than previously believed, anticoagulation is reserved for those patients who present with dilated LV and reduced systolic function with ejection fraction less than 40% or history of thromboembolism [23]. At earlier stages of the disease, aspirin can be used instead. The management of the systolic dysfunction is no different from that in DCM.
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212 Molecular genetics
Figure 2 The diagnostic criteria are not applicable in all cases
tion is a genuine clinical entity. The fact that it coexists with a range of abnormalities in left ventricular morphology and function suggests that it may be better to consider it as a marker of underlying myocardial disease rather than a discrete cardiomyopathy.
References and recommended reading Papers of particular interest, published within the annual period of review, have been highlighted as: of special interest of outstanding interest Additional references related to this topic can also be found in the Current World Literature section in this issue (p. 260).
Diffuse pattern of trabeculation at the apex of the left ventricle in an echocardiographic short axis of the left ventricle. This is a case in which the diagnostic criteria could not be applied.
In the case of symptomatic ventricular arrhythmia and in the context of impaired systolic function, prevention of a sustained and potentially lethal arrhythmic event is indicated using antiarrhythmic agents or implantable cardiac defibrillators in accordance with international guidelines.
Challenges for the future The emergence of LVNC as a new diagnosis in clinical cardiology presents clinicians with many diagnostic and therapeutic dilemmas. First, the limitations of current diagnostic criteria mean that it is important to consider family history, symptoms, left ventricular function and possibly ethnicity before making the diagnosis. Overdiagnosis of the condition may have social and financial and psychological ramifications for the individual and the family members. Once a diagnosis is made, the fact that isolated ventricular noncompaction is often a genetic disease means that it is important to counsel family members on their chance of having the same disease or an overlapping phenotype such as dilated or HCM. Finally, treatment should be patient-specific, focusing on the mechanism of symptoms and where appropriate the prevention of long-term complications. Clinical, genetic and basic research is ongoing, and it is anticipated that it will shed some light on the mechanisms of pathogenesis of noncompaction cardiomyopathy, the factors that can influence this and any disease-specific features that aid diagnosis and management.
Conclusion Although the diagnostic criteria for LVNC are imperfect, there is good evidence that pathological hypertrabecula-
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10 Pignatelli RH, McMahon CJ, Dreyer WJ, et al. Clinical characterization of left ventricular noncompaction in children: a relatively common form of cardiomyopathy. Circulation 2003; 108:2672–2678. 11 Sedmera D, Pexieder T, Vuillemin M, et al. Developmental patterning of the myocardium. Anat Rec 2000; 258:319–337. 12 Finsterer J, Sto¨llberger C, Gaismayer K, Janssen B. Acquired noncompaction in Duchenne muscular dystrophy. Int J Cardiol 2006; 106:420–421. 13 Pfammatter JP, Paul T, Flik J, et al. Q-fever associated myocarditis in a 14-yearold boy. Z Kardiol 1995; 84:947–950. 14 Ichida F, Tsubata S, Bowles KR, et al. Novel gene mutations in patients with left ventricular noncompaction or Barth syndrome. Circulation 2001; 103: 1256–1263. 15 Vatta M, Mohapatra B, Jimenez S, et al. Mutations in cypher/ZASP in patients with dilated cardiomyopathy and left ventricular noncompaction. J Am Coll Cardiol 2003; 42:2014–2027. 16 Kenton AB, Sanchez X, Coveler KJ, et al. Isolated left ventricular noncompaction is rarely caused by mutations in G4.5, a-dystrobrevin and FK binding protein-12. Mol Genet Metab 2004; 82:162–166. 17 Worman HJ, Bonne G. ‘Laminopathies’: a wide spectrum of human diseases. Exp Cell Res 2007; 313:2121–2133. 18 Hermida-Prieto M, Monserrat L, Castro-Beiras A, et al. Familial dilated cardiomyopathy and isolated left ventricular noncompaction associated with lamin A/C gene mutations. Am J Cardiol 2004; 94:50–54. 19 Monserrat L, Hermida-Prieto M, Fernandez X, et al. Mutation in the alphacardiac actin gene associated with apical hypertrophic cardiomyopathy, left ventricular noncompaction, and septal defects. Eur Heart J 2007; 28:1953– 1961. 20 Klaassen S, Probst S, Oechslin E, et al. Mutations in sarcomere protein genes in left ventricular noncompaction. Circulation 2008; 117:2893– 2901. A study that suggests that sarcomeric protein gene mutations are a common cause of LVNC.
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Left ventricular noncompaction Pantazis and Elliott 213 21 Ichida F, Hamamichi Y, Miyawaki T, et al. Clinical features of isolated noncompaction of the ventricular myocardium: long-term clinical course, hemodynamic properties, and genetic background. J Am Coll Cardiol 1999; 34:233–240. 22 Rigopoulos A, Rizos IK, Aggeli C, et al. Isolated left ventricular noncompaction: an unclassified cardiomyopathy with severe prognosis in adults. Cardiology 2002; 98:25–32. 23 Murphy RT, Thaman R, Blanes JG, et al. Natural history and familial characteristics of isolated left ventricular noncompaction. Eur Heart J 2005; 26:187–192. 24 Chin TK, Perloff JK, Williams RG, et al. Isolated noncompaction of left ventricular myocardium. A study of eight cases. Circulation 1990; 82:507–513.
25 Sto¨llberger C, Finsterer J, Blazek G. Left ventricular hypertrabeculation, noncompaction and association with additional cardiac abnormalities and neuromuscular disorders. Am J Cardiol 2002; 90:899–902. 26 Petersen SE, Selvanayagam JB, Wiesmann F, et al. Left ventricular noncompaction: insights from cardiovascular magnetic resonance imaging. J Am Coll Cardiol 2005; 46:101–105. 27 Kohli SK, Pantazis AA, Shah JS, et al. Diagnosis of left-ventricular noncompaction in patients with left-ventricular systolic dysfunction: time for a reappraisal of diagnostic criteria? Eur Heart J 2008; 29: 89–95. A study that compares the published diagnostic criteria for LVNC and reveals their limitations.
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Restrictive cardiomyopathy Jens Mogensena and Eloisa Arbustinib a Department of Cardiology, Skejby University Hospital, Brendstrupgaardsvej, Aarhus N, Denmark and b Academic Hospital, IRCCS Foundation Policlinico San Matteo, Pavia, Italy
Correspondence to Jens Mogensen, MD, PhD, Department of Cardiology, Skejby University Hospital, Brendstrupgaardsvej, 8200 Aarhus N, Denmark Tel: +45 89 49 61 99; fax: +45 89 49 60 02; e-mail:
[email protected] Current Opinion in Cardiology 2009, 24:214–220
Purpose of review Restrictive cardiomyopathy (RCM) is an uncommon myocardial disease characterized by impaired filling of the ventricles in the presence of normal wall thickness and systolic function. Most affected individuals have severe signs and symptoms of heart failure. A large number die shortly after diagnosis unless they receive a cardiac transplant. Controversy has existed about the exact definition of the condition and diagnostic criteria that will be discussed along with an update on recent findings. Recent findings Previously, RCM was believed to be of idiopathic origin unless otherwise associated with inflammatory, infiltrative or systemic disease. Recent investigations have shown that the condition may be caused by mutations in sarcomeric disease genes and even may coexist with hypertrophic cardiomyopathy in the same family. However, most sarcomeric RCM mutations appear to be de novo and associated with a severe disease expression and an early onset. Summary Recent reports suggest that mutations in sarcomeric contractile protein genes are not uncommon in RCM. These findings imply that RCM may be hereditary, and that clinical assessment of relatives should be considered in addition to genetic investigations when systemic disease has been excluded. Identification and risk stratification of affected relatives is important to avoid adverse disease complications and diminish the rate of sudden death. Keywords genetic investigations, inheritance, restrictive cardiomyopathy Curr Opin Cardiol 24:214–220 ß 2009 Wolters Kluwer Health | Lippincott Williams & Wilkins 0268-4705
Introduction Restrictive cardiomyopathy (RCM) is characterized by increased stiffness of the ventricles leading to compromised diastolic filling with preserved systolic function. These changes may develop in association with local inflammatory or systemic, infiltrative or storage disease (Fig. 1) [1]. Usually, patients develop severe symptoms of heart failure over a short period of time, and the majority die within a few years following diagnosis unless they receive a cardiac transplant [2]. The results of recent molecular genetic investigations have revealed that a substantial proportion of RCM without associated systemic disease is caused by mutations in sarcomeric disease genes that have been associated with hypertrophic cardiomyopathy (HCM), dilated cardiomyopathy (DCM) and noncompaction cardiomyopathy [3–5,6]. Controversy exists on how to define the condition because restrictive filling patterns of the ventricles occur in a wide range of different diseases [7–9]. It is the purpose of this review to demonstrate that a variety of 0268-4705 ß 2009 Wolters Kluwer Health | Lippincott Williams & Wilkins
myocardial and systemic diseases are associated with RCM. Therefore, the definition of RCM should be descriptive rather than categorical and reflect that many conditions may ultimately lead to RCM.
Clinical characteristics Adult RCM patients present with dyspnea, fatigue and limited exercise capacity. They may experience palpitation accompanied by dizziness due to supraventricular arrhythmia (SVT). Thromboembolic complications are common and may be the initial presentation of the condition. In children, RCM may present with failure to thrive, fatigue and even syncope [8,9]. In advanced cases, patients develop raised jugular venous pressures, peripheral edema, liver enlargement and ascites. Chest radiograph usually shows a normal-sized heart with enlarged atria and variable degrees of pulmonary congestion. The ECG exhibits large P waves indicating biatrial enlargement accompanied by various ST segment and T wave abnormalities (Fig. 2b). Echocardiography typically reveals biatrial enlargement, a normal or slightly DOI:10.1097/HCO.0b013e32832a1d2e
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Restrictive cardiomyopathy Mogensen and Arbustini 215 Figure 1 Restrictive cardiomyopathy
Restrictive cardiomyopathy
Inflammatory
Infiltrative
Storage
Idiopathic
Endomyocardial fibrosis
Amyloidosis
Hemochromatosis
Loeffler cardiomyopathy
Sarcoidosis
Glycogen storage disease
Postirradiation therapy
Fabry disease
Patients need to be assessed in relation to familial involvement and the potential genetic basis. Adapted from [1].
impaired systolic function and mitral inflow Doppler velocities indicative of severe diastolic dysfunction (Fig. 2a). These include increased ratio of early diastolic filling to atrial filling, decreased E-deceleration time and decreased isovolumic relaxation time (IVRT) (Fig. 3). Invasive pressure measurements within the ventricles during cardiac catheterization are characterized by an early diastolic dip quickly followed by a plateau, also called the ‘square-root sign’. Usually, the diastolic pressure of both ventricles is elevated with the highest plateau being in the left ventricle [2]. However, when diagnosing RCM, it is important to realize that pressure measurements obtained during cardiac catheterization as well as Doppler velocities vary according to preload, which in turn is highly dependent on the current medication of individual patients. For instance, aggressive diuretic therapy will tend to normalize filling pressures and diastolic volumes. Furthermore, pressures and velocities also vary in response to heart rate and rhythm [7].
Diagnosis
RCM in patients with mild systolic dysfunction or mild left ventricular hypertrophy or both, the specific values for Doppler velocities and diastolic volumes and whether systemic diseases such as amyloidosis and glycogen storage diseases should be classified as RCM [7,10]. Recently, a working group of the European Society of Cardiology (ESC) proposed revised classification of cardiomyopathies reflecting the clinical disease expression of the conditions focusing on ventricular morphology and function and the familial/genetic background [11]. Specifically, the classification characterizes cardiomyopathies in relation to the familial background. In this context, RCM is defined as a condition presenting with restrictive ventricular physiology in the presence of normal or reduced diastolic volumes and normal ventricular wall thickness in the absence of ischemic heart disease, hypertension, valvular heart disease and congenital heart disease. This broad definition should help physicians to identify the condition and consider further diagnostic investigations to reveal the cause that may include cardiac biopsies, family screening and genetic investigations.
It has been difficult to obtain consensus about uniform diagnostic criteria of RCM. From a historical perspective, there has been general agreement that RCM should be considered in patients presenting with heart failure in the presence of a nondilated, nonhypertrophic left ventricle with preserved contractility but abnormal diastolic function. There is uncertainty regarding the diagnosis of
Differentiation of RCM from constrictive pericarditis is important, as patients suffering from the latter condition may recover completely following surgical removal of the fibrotic pericardium. However, the distinction between the two conditions may be difficult. Noninvasive realtime imaging with echo Doppler and respirometry provides
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216 Molecular genetics Figure 2 Restrictive cardiomyopathy
Clinical characteristics of restrictive cardiomyopathy in a 19-year-old male who was diagnosed at the age of 16 years following a stroke as previously reported [7]. (a) Apical four-chamber echocardiogram in systole with marked biatrial dilatation, normal-sized ventricles and normal wall thickness. (b) Twelve-lead ECG in sinus rhythm with prominent P waves, T wave inversion and incomplete right bundle branch block. (c) Microscopy of heart tissue obtained postmortem with myocyte hypertrophy, abundant fibrosis and myofibrillar disarray characteristic of the histological findings in HCM (hematoxylin–eosin staining, x40). aVF, augmented vector foot; aVL, augmented vector left; aVR, augmented vector right; HCM, hypertrophic cardiomyopathy. Part (a) adapted from [3]. Parts (b) and (c) reproduced from [3].
the mainstay of diagnosis. Patients with restriction will not have sufficient respiratory variation. Cardiac magnetic resonance and computed tomography (CT) may be useful to assess pericardial thickness, whereas MRI with late enhancement may facilitate diagnosis of infiltrative myocardial disease, for example, amyloidosis. During invasive investigation, it is possible to obtain simultaneous pressure measurements in the ventricles, and both conditions are characterized by rapid early diastolic filling with diastolic dip and plateau waveform. There may be a pressure difference between left ventricular end-diastolic pressure (LVEDP) and right ventricular end-diastolic pressure (RVEDP) in RCM, which is considered significant if diastolic pressure is
more than 5–7 mmHg, in contrast to constrictive pericarditis, in which the pressures tend to be equal in both ventricles. Nonetheless, no technique is totally reliable, and in some patients it is necessary to perform a diagnostic pericardiectomy [2,7,12,13].
Outcome RCM carries a poor prognosis, particularly in children, despite optimal medical treatment. Several studies [14,15] have reported that 66–100% die or receive a cardiac transplant within a few years of diagnosis. In one study of 18 RCM children, five died suddenly without signs of heart failure. However, they had severe angina
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Restrictive cardiomyopathy Mogensen and Arbustini 217 Figure 3 Doppler velocities in restrictive cardiomyopathy
Typical restrictive Doppler findings including increased E to A ratio (2.1), decreased E-deceleration time (90 ms) and decreased isovolumetric relaxation time (40 ms). A, atrial filling; E, early diastolic filling.
and ECG evidence of ischemia. Four hearts of children who died suddenly were available for autopsy and revealed acute myocardial infarcts, subendocardial ischemic necrosis or chronic ischemic scarring, despite normal appearance of their coronary arteries. These findings led the authors to suggest that pediatric patients with RCM represent a population of children who are at high risk for ischemiarelated complications and death in addition to heart failure. In adults, two studies [16,17] have reported that 32–44% suffered a cardiovascular-related death within 5 years following diagnosis. The outcome is highly correlated to symptoms and signs of heart failure. Embolic stroke is a common complication as a consequence of large atria and SVT. Therefore, prophylactic anticoagulant therapy should be considered in all RCM patients with enlarged atria even before SVT has developed.
Familial restrictive cardiomyopathy associated with sarcomeric gene mutations In 1992, Feld and Caspi [18] reported a family with a mixed appearance of RCM and HCM. The cardiac morphology of a deceased individual with RCM showed typical features of HCM with myocyte disarray. Angelini et al. [19] reported similar histomorphological features of seven patients with a clinical diagnosis of RCM and suggested that RCM and HCM may represent two different phenotypes of the same basic sarcomeric disease, although no genetic investigations were performed. We investigated a large family in which the proband and two additional individuals were diagnosed with RCM,
nine individuals had clinical features of HCM and 12 individuals died suddenly. Linkage analysis for selected sarcomeric contractile protein genes identified troponin I [troponin I (TNNI3)] as the likely disease gene [3]. Subsequent mutation analysis revealed a missense mutation, which segregated with the disease in the family (lod score: 4.8). To elucidate whether TNNI3 mutations were common in RCM, mutation analysis was performed in nine unrelated RCM patients with unexplained restrictive filling patterns, gross atrial dilatation, normal systolic function and normal wall thickness. Histology of heart tissue from several individuals showed myofibril disarray characteristic of HCM (Fig. 2c). TNNI3 mutations were identified in seven of 10 patients including the index family of the study. Two of the mutations identified in young individuals were de-novo mutations. All mutations were novel missense mutations and appeared in conserved and functionally important domains of the gene. We concluded that mutations in cardiac troponin I were responsible for the development of RCM in a significant proportion of patients diagnosed with RCM. Additional TNNI3 mutations have been reported in RCM, as well as mutations in other sarcomeric genes including troponin T (TNNT2), b-myosin heavy chain (MYH7) and a-cardiac actin (ACTC) [15,20–22]. Most of the mutations reported appeared de novo with a severe disease expression and onset of symptoms in childhood leading to premature death or cardiac transplantation shortly after diagnosis. These findings imply that RCM is part of the clinical expression of hereditary sarcomeric contractile protein disease, and familial evaluation should be
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218 Molecular genetics Figure 4 Cardiac amyloidosis
considered whenever an individual has been diagnosed with RCM.
Familial restrictive cardiomyopathy, atrioventricular block and desmin accumulation Desmin-related myopathies are very rare disorders characterized by intracytoplasmatic accumulation of desmin caused by mutations in the gene for either desmin (DES) or a-B-crystallin (CRYAB). Diagnosis requires ultrastructural investigation and immunohistochemistry of cardiac or skeletal muscle biopsy to reveal desmin deposits [23]. The disease expression may involve skeletal muscle only, affect both cardiac and skeletal muscle simultaneously or have an isolated impact on the heart [24–27]. Very few families have been reported with isolated RCM and cardiac-specific accumulation of desmin. In one large four-generation family, no disease gene was identified, whereas another report identified four independent individuals with RCM, atrioventricular block and mutations of the DES gene [23,28]. Genetic investigations and clinical assessment of relatives revealed one de-novo mutation, one mutation with recessive inheritance and two dominant mutations with a total number of three affected relatives. Penetrance was 100%, and all but one had advanced atrioventricular block. Recognizing that this disease expression is extremely rare, the authors suggested that desmin accumulation might be considered in patients presenting with RCM and atrioventricular block.
Cardiac amyloidosis By tradition, cardiac amyloidosis has been classified as a RCM, as deposits of amyloid within the heart typically result in restrictive filling patterns [10,11]. However, this condition is also characterized by increased ventricular wall thickness and impaired systolic function. Echocardiography often reveals a remarkable homogeneous granular sparkling of the myocardium, and valves are often thickened due to amyloid infiltration. In addition, the ECG of patients with cardiac amyloidosis often shows low voltage in standard leads. Cardiac biopsies show typical features of amyloid deposits (Fig. 4a–c). A variety of diseases are associated with sporadic occurrence of Figure 4 (continued)
Clinical characteristics of a 46-year-old male who was diagnosed with cardiac amyloidosis at the age of 42 years because of heart failure symptoms. (a) Apical four-chamber view in systole with biatrial dilatation, normal-sized ventricles and significant thickening of ventricular walls that
appears bright and sparkling. (b) Twelve-lead ECG in sinus rhythm with low voltage in standard leads. (c) Microscopy of cardiac biopsies stained with hematoxylin–eosin showing extensive infiltration of amyloid between myocytes (x40). The small picture inserted shows cardiac tissue from the same patient stained with Congo red, which defines amyloid deposits by its green refringence under polarized light. aVF, augmented vector foot; aVL, augmented vector left; aVR, augmented vector right.
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Restrictive cardiomyopathy Mogensen and Arbustini 219
cardiac amyloidosis, whereas hereditary appearances most often are caused by mutations in the genes for transthyretin and apolipoprotein A1 [29,30].
Other rare familial diseases associated with restrictive cardiomyopathy Hemochromatosis is an autosomal recessive disorder leading to iron deposition in multiple organs resulting in widespread damage. Although clinical disease expression in many cases is unpredictable, most patients present with a variety of symptoms from different organ systems, whereas only few patients have isolated cardiac manifestations and very rarely RCM [29]. Anderson–Fabry’s disease is an X-linked lysosomal storage disorder caused by mutations in the gene for a-galactosidase A (GLA). Glycosphingolipids accumulate in multiple organs and cause substantial morbidity and mortality, especially in men. In women, isolated affection of the heart is more frequent than in men, and affected women most often present with symptoms late in life. Typical echocardiographic findings include left ventricular hypertrophy, modest diastolic filling abnormalities and thickening of the valves [31–33]. RCM in the context of Fabry’s disease with normal ventricular wall thickness is extremely rare [34]. The same seems to be the case with a variety of rare hereditary glycogen storage diseases exhibiting different modes of transmission.
Nonfamilial restrictive cardiomyopathy Sporadic RCM may be diagnosed in patients affected by systemic diseases including scleroderma and sarcoidosis [29]. Patients who previously have undergone radiotherapy of the chest, as in Hodgkin’s disease, have an increased risk of developing myocardial and endocardial fibrosis many years later leading to RCM. Restrictive ventricular physiology can also be caused by endocardial fibrosis in association with hypereosinophilic syndromes or induced by exposure to various drugs and parasitic infections [30].
Conclusion RCM is an uncommon condition with a poor outcome unless patients receive a cardiac transplant. RCM is generally seen in association with local inflammatory or systemic diseases. The finding of TNNI3 mutations in a substantial proportion of patients fulfilling diagnostic criteria of idiopathic RCM suggested a causal relationship between gene abnormality and disease. This has prompted genetic investigations of other RCM patients and confirmed that RCM in many instances is part of the clinical expression of sarcomeric contractile protein disease. De-novo mutations appear to be prevalent findings especially in children and young adults, suggesting that they are associated with a more severe disease expression
and early onset in comparison with mutations that have been inherited through many generations. As RCM, HCM, DCM and even noncompaction cardiomyopathy may be caused by mutations in the same genes, previous perceptions of cardiomyopathies as separate and distinct clinical and pathophysiological entities are difficult to sustain. It is important to realize that transitional forms of the conditions frequently appear even within the same family affected by the same mutation. Therefore, the diagnosis of any condition likely to be a cardiomyopathy should lead to family screening for a potential hereditary disorder. Identification and risk stratification of affected relatives is important to avoid adverse disease complications and diminish the rate of sudden death.
References and recommended reading Papers of particular interest, published within the annual period of review, have been highlighted as: of special interest of outstanding interest Additional references related to this topic can also be found in the Current World Literature section in this issue (pp. 260–261). 1
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10 Richardson P, McKenna W, Bristow M, et al. Report of the 1995 World Health Organization/International Society and Federation of Cardiology Task Force on the definition and classification of cardiomyopathies. Circulation 1996; 93:841–842. 11 Elliott P, Andersson B, Arbustini E, et al. Classification of the cardiomyopa thies: a position statement from the European Society Of Cardiology Working Group on myocardial and pericardial diseases. Eur Heart J 2008; 29:270– 276. An important study discussing and proposing a novel definition of cardiomyopathies. 12 Reuss CS, Wilansky SM, Lester SJ, et al. Using mitral ‘annulus reversus’ to diagnose constrictive pericarditis. Eur J Echocardiogr 2008. [Epub ahead of print] 13 Sengupta PP, Krishnamoorthy VK, Abhayaratna WP, et al. Comparison of usefulness of tissue Doppler imaging versus brain natriuretic peptide for differentiation of constrictive pericardial disease from restrictive cardiomyopathy. Am J Cardiol 2008; 102:357–362. 14 Rivenes SM, Kearney DL, Smith EO, et al. Sudden death and cardiovascular collapse in children with restrictive cardiomyopathy. Circulation 2000; 102:876–882.
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220 Molecular genetics 15 Kaski JP, Syrris P, Burch M, et al. Idiopathic restrictive cardiomyopathy in children is caused by mutations in cardiac sarcomere protein genes. Heart 2008; 94:1478–1484. The first genetic study of children with RCM revealing that sarcomeric gene mutations are not an uncommon cause. 16 Kubo T, Gimeno JR, Bahl A, et al. Prevalence, clinical significance, and genetic basis of hypertrophic cardiomyopathy with restrictive phenotype. J Am Coll Cardiol 2007; 49:2419–2426. 17 Ammash NM, Seward JB, Bailey KR, et al. Clinical profile and outcome of idiopathic restrictive cardiomyopathy. Circulation 2000; 101:2490–2496. 18 Feld S, Caspi A. Familial cardiomyopathy with variable hypertrophic and restrictive features and common HLA haplotype. Isr J Med Sci 1992; 28:277–280. 19 Angelini A, Calzolari V, Thiene G, et al. Morphologic spectrum of primary restrictive cardiomyopathy. Am J Cardiol 1997; 80:1046–1050. 20 Karam S, Raboisson MJ, Ducreux C, et al. A de novo mutation of the beta cardiac myosin heavy chain gene in an infantile restrictive cardiomyopathy. Congenit Heart Dis 2008; 3:138–143. 21 Peddy SB, Vricella LA, Crosson JE, et al. Infantile restrictive cardiomyopathy resulting from a mutation in the cardiac troponin T gene. Pediatrics 2006; 117:1830–1833. 22 Gambarin FI, Tagliani M, Arbustini E. Pure restrictive cardiomyopathy associated with cardiac troponin I gene mutation: mismatch between the lack of hypertrophy and the presence of disarray. Heart 2008; 94:1257. 23 Arbustini E, Pasotti M, Pilotto A, et al. Desmin accumulation restrictive cardiomyopathy and atrioventricular block associated with desmin gene defects. Eur J Heart Fail 2006; 8:477–483.
24 Arbustini E, Morbini P, Grasso M, et al. Restrictive cardiomyopathy, atrioventricular block and mild to subclinical myopathy in patients with desminimmunoreactive material deposits. J Am Coll Cardiol 1998; 31:645–653. 25 Bergman JE, Veenstra-Knol HE, van Essen AJ, et al. Two related Dutch families with a clinically variable presentation of cardioskeletal myopathy caused by a novel S13F mutation in the desmin gene. Eur J Med Genet 2007; 50:355–366. 26 Kaminska A, Strelkov SV, Goudeau B, et al. Small deletions disturb desmin architecture leading to breakdown of muscle cells and development of skeletal or cardioskeletal myopathy. Hum Genet 2004; 114:306–313. 27 Li D, Tapscoft T, Gonzalez O, et al. Desmin mutation responsible for idiopathic dilated cardiomyopathy. Circulation 1997; 100:461–464. 28 Zhang J, Kumar A, Stalker HJ, et al. Clinical and molecular studies of a large family with desmin-associated restrictive cardiomyopathy. Clin Genet 2001; 59:248–256. 29 Lubitz SA, Goldbarg SH, Mehta D. Sudden cardiac death in infiltrative cardiomyopathies: sarcoidosis, scleroderma, amyloidosis, hemachromatosis. Prog Cardiovasc Dis 2008; 51:58–73. 30 Kushwaha SS, Fallon JT, Fuster V. Restrictive cardiomyopathy. N Engl J Med 1997; 336:267–276. 31 Zarate YA, Hopkin RJ. Fabry’s disease. Lancet 2008; 372:1427–1435. 32 Clarke JT. Narrative review: Fabry disease. Ann Intern Med 2007; 146:425– 433. 33 Linhart A, Lubanda JC, Palecek T, et al. Cardiac manifestations in Fabry disease. J Inherit Metab Dis 2001; 24 (Suppl 2):75–83. 34 Cantor WJ, Butany J, Iwanochko M, Liu P. Restrictive cardiomyopathy secondary to Fabry’s disease. Circulation 1998; 98:1457–1459.
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EDITORIAL COMMENT
Beyond the guidelines: where evidence ends and the frontier begins David S. Feldman The Ohio State University Suite, 200 Davis Heart and Lung Research Institute, Columbus, Ohio, USA Correspondence to David S. Feldman, MD, PhD, The Ohio State University Suite, 200 Davis Heart and Lung Research Institute, 473 West 12th Avenue, Columbus, OH 43210-1252, USA Tel: +1 614 293 4967; fax: +1 614 293 5614; e-mail:
[email protected] Current Opinion in Cardiology 2009, 24:221–222
Heart failure continues to be one of the leading causes of death in the western world. Although we have a significant amount of data and multiple sets of guidelines for the management of chronic systolic heart failure, there are many nuances in these management schemes that fall beyond the limits of the guidelines because of a scarcity of data. This group of articles is devoted to areas that are predominantly beyond the boundaries of the current guidelines, purview, leaving the clinicians to rely on best practice methodologies. The first article, by Eapen and Rogers, addresses the relevance of reverse remodeling in systolic heart failure as a surrogate endpoint. These authors make the case that an improvement in ventricular geometry is strongly correlated with improvement in heart failure outcomes observed in large clinical trials. With the current multimodality approach to heart failure therapy (i.e. drugs and devices), discerning the relevance of a new therapy is becoming more difficult and costly. Future clinical trials should consider direct and indirect measures of reverse remodeling as endpoints. This methodology may decrease the ‘n’ value required to achieve relevance by incorporating these metrics into an endpoint strategy, thereby making new drugs trials realistic. This strategy of incorporating changes of reverse remodeling should include functional measures of recovery as well as molecular signaling to increase the granularity of a new therapeutic intervention. Traditionally, the 6-min walk test and echocardiography have been used despite all the misgivings that researchers and the US Food and Drug Administration (FDA) have had regarding these modalities. Less commonly used are cardiac magnetic resonance and VO2 studies. Future studies should also include biomarkers that focus on myocyte and fibroblast signaling as well as global changes in RNA fingerprinting that are consistent with cellular as well as ventricular reverse remodeling. The authors suggest that reverse remodeling may be more than a surrogate marker and perhaps a relevant milestone in the cessation of a progressive disease. 0268-4705 ß 2009 Wolters Kluwer Health | Lippincott Williams & Wilkins
The evaluation of clinical trials and patient outcomes becomes even more difficult when investigators are targeting patients with diastolic dysfunction or patients with heart failure and preserved left ventricular function. The seven diastolic heart failure trials evaluated in this second review article highlight the importance of understanding the underlying pathophysiology and relevance of careful inclusion and exclusion criteria, as any therapeutic intervention intended to modify heart failure outcomes must first identify a target population. This has been more difficult than one may anticipate, as there is a paucity of acceptable animal models to reproduce diastolic disorder. This gap in our current knowledge has slowed the development of effective treatment options for diastolic heart failure, as clinicians and trialists have been left in an interesting position of predominately relying on human data to design the current trials and presumed relevant endpoints. This theme of a limited data set is further continued in the next review on right ventricular heart failure (RVHF). In this section, Drs McDonald and Ross purport that RVHF is becoming a more common entity in clinical practice and is associated with increasingly inferior outcomes. As with diastolic heart failure patients, many of these individuals are followed with an imaging modality; however, the therapy and the ‘point-of-no-return’ for RVHF are predominately based on best clinical practice and a search for underlying reversible causes. With persistently elevated right-sided filling pressures, patients insidiously develop a low cardiac output related, in part, to right ventricle–left ventricle (RV–LV) transport issues leading to end-organ hypoperfusion (e.g. the cardio-renal syndrome). The patient’s clinical status may be further impaired as LV diastolic filling becomes impaired through mechanical ventricular interdependence. With a deficient dataset, clinicians have sought to apply therapies utilized in the past for chronic left-sided systolic heart failure, primary pulmonary hypertension therapies, and more recently the utilization of mechanical therapies. As an emerging therapy modality, ventricular assist devices (VADs) may help treat elevated intracardiac and pulmonary pressures in patients who are recalcitrant to conventional medical therapy. Many of these issues regarding patient selection are addressed in the review by Lietz and Miller. In this article, the authors help clinicians decide how to choose appropriate patients for VAD therapy, as success of this DOI:10.1097/HCO.0b013e32832ad871
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222 Cardiac failure
therapy is often determined by the selection of patients and the timing of their operation. In the past, both physicians and patients have underestimated the mortality of a given patient. This review provides some objective criteria and a consensus of expert opinions to optimize the opportunity that these very infirm patients will have the best chance of operative success and returning home. They base their evaluation on clinical severity of heart failure, cardiac and anatomic considerations, other concordant disease pathology or life-limiting illnesses, psychosocial and age-related considerations, and assessment of operative risk. Subsequent to VAD implantation, Drs Mountis and Starling address many of the relevant management considerations, including nutrition, drive-line care, anticoagulation, and others. These authors advocate a multidisciplinary team approach with standardization of care to optimize patient results. Our goal in compiling these studies from different authors and their provocative subjects was to facilitate an exchange of information and to help remind us that we still have a lot of work to do to develop evidence-based algorithms for the treatment of acute decompensated heart failure, rightsided heart failure, diastolic heart failure, and the management and selection of VAD patients. As our field evolves, we believe we must think about all of these patients as part of an overriding heart failure disease management strategy.
These articles are also a call for the medical community to embrace translational science. If we are to adequately address the needs of these patients, it will be done in a piecemeal way by investigating mechanisms of disease and not just endpoints. When we are looking for future therapies, we should not expect to go from ‘nearly terminal’ to running on a treadmill with a single intervention. As we expect to use multiple therapies for stage C and D patients, we should expect different interventions for recovering facets of that disease process. Similarly to cancer, in heart failure we must first slow the disease process that is contributing to the patient’s demise (treat symptoms and relieve suffering). Second, we must arrest the process, similarly to how oncologists comment on neoplasias being in ‘remission’. Third, we must address the root of the disease to ultimately alter mortality. With each patient who presents with new challenges, many do not fit neatly into the guidelines; however, if we focus on three questions, we will provide the best possible care with the data available. These are: why did a given patient get sick? what are we going to do to make them feel better? and how are we going to stop the patient from getting sick again? Although this simple approach is far from ideal, it will be the best we can do until we have more data and perhaps more wisdom.
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Strategies to attenuate pathological remodeling in heart failure Zubin Eapena and Joseph G. Rogersa,b a
Division of Cardiology, Department of Medicine and Duke Clinical Research Institute, Duke University, Durham, North Carolina, USA b
Correspondence to Joseph G. Rogers, MD, Associate Professor of Medicine, Duke University Medical Center, Box 3034 DUMC, Durham, NC 27710, USA Tel: +1 919 681 3398; fax: +1 919 681 7755; e-mail:
[email protected] Current Opinion in Cardiology 2009, 24:223–229
Purpose of review The incidence of heart failure is increasing due to an aging population and improved management of diseases that are precursors to ventricular dysfunction. The success of therapeutic advances has created a challenge for the next generation of investigational heart failure treatments because the mortality rate has decreased to such a degree that larger trials will be needed to demonstrate mortality advantage. Prior work has linked favorable changes in ventricular geometry to improved survival, suggesting that remodeling may be a suitable surrogate endpoint. Recent findings In addition to the established benefits of neurohormonal blockade, new mechanical and electrical therapies are proving beneficial in heart failure. Passive cardiac support devices and cardiac resynchronization therapy have been recently demonstrated to induce reverse remodeling of the left ventricle and may improve outcomes, including quality of life, functional status, and mortality. Summary Ventricular remodeling is strongly correlated with improvement in other heart failure outcomes. Early phase trials of novel therapeutics should carefully examine remodeling to obtain an efficacy signal. Larger clinical investigations should include remodeling metrics as endpoints and consider their use in a composite primary endpoint to reduce trial size. Keywords cardiac resynchronization therapy, cardiac support device, heart failure, ventricular remodeling Curr Opin Cardiol 24:223–229 ß 2009 Wolters Kluwer Health | Lippincott Williams & Wilkins 0268-4705
Introduction Myocardial injury elicits a prototypical response that is central to progressive, chronic heart failure. The cardiac phenotype that accompanies ventricular systolic dysfunction is characterized by variable degrees of dilation of the affected chamber and hypertrophy of the viable segments of myocardium. Fundamental to our understanding of these alterations in cardiac structure and function are pathologic alterations in loading conditions and activation of neurohormonal pathways, both of which serve as targets for therapies demonstrated to improve quality of life and reduce heart failure mortality. The impact of myocardial infarction (MI) on ventricular geometry and function in an animal model of coronary artery ligation was described in 1985 by Pfeffer et al. [1], who demonstrated a strong relationship between the size of the myocardial injury and the degree of left ventricular (LV) remodeling and mortality. The same investigators showed a beneficial reduction in LV end-diastolic volume index in rats treated with the angiotensin-converting 0268-4705 ß 2009 Wolters Kluwer Health | Lippincott Williams & Wilkins
enzyme inhibitor (ACEi) captopril (Fig. 1). Others have confirmed the relationship between myocardial injury, activation of neurohormonal pathways, and the pathologic cardiac phenotype associated with heart failure [2–5]. Further, it has been demonstrated that treatment strategies resulting in reversal of pathologic remodeling typically also reduce heart failure mortality, whereas therapies with adverse impact on survival have minimal or no effect on ventricular remodeling [6–10]. In this review, we will discuss the evidence supporting the beneficial impact of medical therapy targeting neurohormonal inhibition as well as mechanical and electrical therapies that have linked remodeling and mortality in systolic heart failure. Inhibition of angiotensin-converting enzyme and angiotensin receptor blockade
Remodeling and functional impairment of myocardial contractility have been associated with high intramyocardial levels of angiotensin, norepinephrine, and aldosterone [11]. Furthermore, neurohormonal activation DOI:10.1097/HCO.0b013e32832a11ff
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224 Cardiac failure Figure 1 Captopril administered to rats for 3 months following myocardial infarction induced by coronary artery ligation
Figure 2 Least squares mean changes (WSEM) from baseline in left ventricular internal diastolic diameter/body surface area (cm/m2)
ml/kg 3.5 Months 4
12
24
3
Last observation
0.05 LSM changes 0 + SEM
2.5 2
--0.05
1.5
--0.1
1
--0.15
0.5
--0.2
(n = 323) P = 0.252
(n = 275) P = 0.311 (n = 138) P = 0.061
(n = 327) P < 0.001
0 Non-MI
Small
Moderate
Large
Extensive
Infarct size Left ventricular end-diastolic volume indices of captopril-treated rats (solid bars) were significantly less than those of untreated rats (open bars). Captopril reduces left ventricular volumes following myocardial infarction. Data from [1].
appears to be integral in the development of myocardial hypertrophy. Thus, it follows that pharmacologic inhibition of dysregulated neurohormonal pathways might play an important role in stabilization or reversal of pathological remodeling and improve clinical outcomes. As noted above, early animal experiments demonstrated that addition of an ACEi following MI attenuated the remodeling process and reduced mortality [12]. These early findings provided the groundwork for human trials focused on renin–angiotensin pathway inhibition. The Studies of Left Ventricular Dysfunction (SOLVD) Treatment trial examined the effects of enalapril on survival in patients with diminished LV function. Patients with clinical heart failure [primarily New York Heart Association (NYHA) class II–III] and an ejection fraction of 0.35 or less were randomized to receive enalapril or placebo in a double-blind fashion [13]. During an average follow-up of 41.4 months, enalapril-treated patients experienced significantly fewer deaths, primarily as a result of reduction in progressive heart failure, and fewer hospitalizations. An echocardiography substudy examining the impact of enalapril on LV function and geometry revealed that patients in the placebo arm had progressive LV dilation, whereas those treated with enalapril had sustained reductions in LV dimensions [14,15]. Similar outcomes have been demonstrated with captopril [16] and ramipril [17], suggesting a causative relationship between ACEi, reverse ventricular remodeling, and mortality reduction. Blockade of the effects of the renin–angiotensin system utilizing angiotensin receptor blockers (ARBs) also
The P values refer to the LSM comparison between the valsartan (solid bars) and placebo (open bars) groups by analysis of covariance. n ¼ total number of patients in the valsartan and placebo treatment groups. Valsartan favorably reduces left ventricular size in patients with chronic heart failure. LSM, Least squares mean. Data from [18].
appears to be linked to reverse ventricular remodeling and mortality benefit. Patients intolerant of ACEi treated with valsartan in the Valsartan-Heart Failure trial (ValHeFT) benefited from reduction in both all-cause mortality and combined mortality and morbidity (17.3 vs. 27.1%, P ¼ 0.017 and 24.9 vs. 42.5%, P < 0.001, respectively) compared with those treated with placebo [18]. Furthermore, patients in the valsartan group demonstrated improvement in remodeling indices with a significantly smaller mean LV internal diastolic dimension index than patients randomized to placebo (Fig. 2) [18]. Similar reductions in morbidity and mortality were seen in the Candesartan in Heart failure - Assessment of Reduction in Mortality and morbidity (CHARM)alternative trial, a study that assessed the benefits of candesartan vs. placebo in patients intolerant of ACEi [19]. b-Adrenergic antagonism
Ventricular remodeling and progression of the heart failure syndrome also result from activation of the sympathetic nervous system, and b-adrenergic antagonists have well characterized beneficial effects on cardiac remodeling and heart failure mortality. The mechanism of these benefits is likely multifactorial and related to negative chronotropy, which reduces myocardial oxygen consumption, reduction of the impact of high intramyocardial norepinephrine levels, and decreased myocardial ischemia and infarction [20]. The effects of b-blockade appear to be independent of ACE inhibition, despite coregulation of these pathways [21]. Post-MI patients with LV dysfunction treated with an ACEi who were subsequently randomized to carvedilol experienced significant reduction in all-cause mortality, cardiovascular
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Strategies to attenuate pathological remodelling in heart failure Eapen and Rogers 225
mortality, and nonfatal recurrent MI [22]. Doughty et al. [23] demonstrated the incremental beneficial effects of carvedilol on LV volumes, function, and wall motion score in patients treated with ACEis. Similarly, the Australia–New Zealand Heart Failure Research Collaborative group showed that the addition of carvedilol in the treatment regimen of patients treated with optimal doses of ACEi resulted in a further reduction in LV volumes at 6 and 12 months compared with those treated with placebo [24]. Other measures of LV remodeling, such as LV mass, cardiac sphericity, and mitral regurgitation, decrease as early as 4 months after the initiation of carvedilol [25]. Similar findings have been shown with metoprolol in patients with mild-to-moderate heart failure and chronic LV dysfunction. The Metoprolol CR/XL Randomized Intervention Trial in Congestive Heart Failure (MERIT-HF) trial demonstrated the benefits of sustained-release metoprolol in patients with NYHA II–IV heart failure, including a 34% relative risk reduction in all-cause mortality at 12 months, reduction in hospitalization for cardiovascular causes, and improvement in NYHA functional class and quality of life measures [26,27]. The magnetic resonance imaging substudy showed that, compared with placebo, metoprololtreated patients had significant reductions in LV enddiastolic volume, LV end-systolic volume, and LV mass as well as improvement in ejection fraction. The Carvedilol and ACE-Inhibitor Remodeling Mild Heart Failure Evaluation (CARMEN) trial randomized 572 patients with chronic heart failure to receive carvedilol, enalapril, or the combination of these two agents. Over an 18-month follow-up period, the LV end-systolic volume index decreased by 5.4 ml/m2 (P ¼ 0.0015) using combination therapy compared with enalapril alone [21]. CARMEN emphasized the importance of simultaneous inhibition of multiple neurohormonal pathways to optimize remodeling outcomes in chronic systolic heart failure and reinforced the recommendations to utilize a multidrug regimen in the care of these patients.
systolic heart failure in the Randomized Aldactone Evaluation Study (RALES) [29]. Patients randomized to spironolactone derived a 30% relative risk reduction in mortality over 36 months compared with placebotreated patients. Some of the benefits of aldosterone antagonism in patients with ischemic heart disease and chronic heart failure appear to be related to remodeling of the cardiac extracellular matrix. The failing heart is histologically characterized by increased interstitial fibrosis, which is postulated to contribute to the diastolic filling abnormalities commonly seen in systolic heart failure. Brilla et al. [30] showed that aldosterone stimulated collagen synthesis in cultured adult rat cardiac fibroblasts. Thus, the impact of aldosterone on myocardial fibrosis may be attenuated by inhibiting the neurohormonal influences of aldosterone. Revascularization
Acute MI results in a well characterized series of molecular and cellular events that result in the ventricular remodeling and contractile dysfunction that accompany diminished survival. Ischemia-induced myocyte necrosis, consequent ventricular stiffness, and diminished contractility lead to adverse loading conditions characterized by elevated cardiac filling pressures [31]. An inflammatory response ensues with migration of monocytes and neutrophils into the infarct zone resulting in additional myocardial injury. Early remodeling occurs as a result of degradation of the myocardial extracellular matrix by matrix metalloproteinases and serine proteases [32]. Remodeling continues resulting from myocyte hypertrophy and the development of collagenous scar. Infarct artery patency favorably influences both early and late ventricular remodeling by salvaging stunned myocardium and limiting the extension of an infarct zone [33]. Patency of infarct-related arteries has independent, long-term prognostic value following thrombolysis for acute MI and correlates with improvement in LV volumes and function [34–36].
Aldosterone antagonism
Aldosterone receptor antagonists represent the third class of agents shown to reduce mortality in systolic heart failure. Two pivotal trials form the basis for the addition of these agents to ACEi/ARB and b-blockers. The Eplerenone Post-AMI Heart Failure Efficacy and Survival Study (EPHESUS) trial randomized patients with a recent MI, depressed LV ejection fraction, mild heart failure symptoms and treatment with ACEi and b-blockers to receive either placebo or eplerenone. Patients treated with eplerenone experienced a 17% risk reduction in cardiovascular mortality (P ¼ 0.005) and a 21% reduction in risk of sudden cardiac death (P ¼ 0.035) [28]. Another aldosterone receptor antagonist, spironolactone, was studied in patients with more symptomatic
Correction of mitral regurgitation
Mitral valve regurgitation commonly accompanies LV remodeling and is caused by a variety of mechanisms, including annular dilatation, papillary muscle displacement, and abnormalities of myocardial contractility that result in ventricular dyssynchrony. Functional mitral regurgitation begets further LV dysfunction and remodeling through chronic volume loading, increased ventricular transmural pressure, and increased wall stress. Moderate-to-severe mitral regurgitation is seen in up to 50% of patients with dilated cardiomyopathy and is an independent prognostic factor for adverse heart failure outcomes [37,38]. Correction of functional mitral regurgitation has been targeted as a means of preventing
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226 Cardiac failure Figure 3 Reduction in left ventricular volumes in the Acorn trial
Figure 4 Examples of passive cardiac support devices
(a) Reduction in LV end-diastolic volume - MV surgery stratum Change from 0 baseline (ml) --10 --20 --30 --40 --50 --60 --70
n = 144 P = 0.0001
3
n = 127 P = 0.0001
n = 124 P = 0.0001
6
12
n = 81 P = 0.0001
18
n = 46 P <0.0001
24
Months since randomization
(b) Reduction in LV end-systolic volume - MV surgery stratum
(a) The Acorn graphic on the left is from [42]. (b) The Paracor Heart Net photo is from http://www.theheart.org/displayItem.do?primaryKey= 741347&type=img.
Change from 0 baseline (ml) --10 --20 --30 --40 --50 --60
n = 144 P = 0.0025
n = 127 P = 0.002
3
6
n = 124 P = 0.0001
n = 81 P = 0.0001
n = 46 P <0.0007
12
18
24
Months since randomization
Data from [40].
progressive ventricular remodeling [39]. Mitral valve repair with an undersized annuloplasty ring was evaluated in a cohort of 48 patients with advanced symptomatic heart failure and severe mitral regurgitation. The NYHA functional class improved at 22 months (3.9 0.3 to 2.0 0.6) and there was a reduction in recurrent hospitalizations. Importantly, the investigators demonstrated improvements in LV end-diastolic volume, sphericity, and ejection fraction 24 months following the procedure [41]. The Acorn trial (discussed below) randomized a cohort of patients with nonischemic cardiomyopathy, NYHA class III–IV symptoms treated with optimal medical therapy to mitral valve repair with or without a cardiac support device (CSD). After a median follow-up of 22.9 months, mitral repair patients had progressive and significant reduction in LV volumes in addition to improvements in quality of life and functional class (Fig. 3) [40]. Passive cardiac support devices
Several implantable devices have been developed to prevent or reverse cardiac remodeling in heart failure. The conceptual benefit of passive CSDs arose from insights into dynamic cardiomyoplasty, the procedure in which the latissimus dorsi muscle was mobilized, wrapped around the heart, and trained to contract in synchrony with the heart. Kass et al. [40] performed serial pressure–volume studies, which suggested that the benefit from dynamic cardiomyoplasty was less from
active support during systole than it was from passive constraint, which reversed remodeling. To date, the largest clinical experience with CSD examined the Acorn CorCap device (Acorn Cardiovascular, St Paul, Minnesota, USA), a preformed mesh of polyethylene terephthalate fibers that is surgically placed around the ventricles (Fig. 4) [42]. The CorCap CSD was designed to minimize wall stress by providing support during diastolic filling. While the device preserves and improves LV geometry, it has also been shown to attenuate interstitial fibrosis and increase capillary density [43]. The Acorn trial assessed the efficacy of the CorCap CSD and its impact on heart failure progression defined by symptomatic change and the necessity for subsequent procedures. Patients treated with the CorCap CSD had a significant reduction in the need for major cardiac procedures, including heart transplantation, LV-assisted device placement, repeat mitral valve and tricuspid valve surgeries, and biventricular pacemakers [44]. Further, those treated with the CorCap CSDs exhibited significant decreases in LV end-diastolic volume (average difference 18.8 ml; P ¼ 0.005) and LV end-systolic volume (average difference 15.6 ml; P ¼ 0.013) compared with the control [45]. The Paracor Cardiac HeartNet Ventricular Support System (Paracor Medical Inc, Sunnyvale, California, USA) is a second CSD (Fig. 4). In early testing, treated patients have demonstrated improved NYHA functional class, quality of life, and 6-min walk distances [46]. Additionally, 6-month echocardiographic follow-up in humans has revealed significant reductions in LV end-diastolic and end-systolic volumes as well as LV mass [45]. The HeartNet is undergoing further evaluation in the Prospective Evaluation of Elastic Restraint to Lessen the Effects of Heart Failure (PEERLESS-HF) trial to determine whether the device provides symptomatic and mortality benefits in heart failure patients on optimal medical therapy [47].
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Strategies to attenuate pathological remodelling in heart failure Eapen and Rogers 227
Cardiac resynchronization therapy
Patients with NYHA class III–IV heart failure have derived benefit from cardiac resynchronization therapy (CRT) as a means of correcting mechanical dyssynchrony that accompanies a prolonged QRS duration [48]. In addition to improving contractile function and hemodynamic parameters, CRT has been shown to reverse ventricular remodeling, both in the short-term as well as chronically. Statistically significant reductions in LV end-systolic volume have been demonstrated as early as 1 week after initiation of CRT, and termination of CRT results in rapid reversal of the improvements in ventricular remodeling [49]. Randomized clinical trials have demonstrated favorable long-term impact on reverse remodeling, including a 15% absolute reduction in LV end-diastolic diameter at 6 months [50]. In the Cardiac Resynchronization in Heart Failure (CARE-HF) study, which randomized 813 patients to medical therapy alone or medical therapy with CRT, a statistically significant reduction in the end-systolic volume index was observed in patients receiving CRT [51]. LV end-systolic volumes progressively improved with a mean reduction of 18.2 and 26% at 3 and 18 months, respectively [51]. Similarly, the Multicenter InSync Randomized Clinical Evaluation (MIRACLE) study evaluated the impact of CRT in a cohort of 323 heart failure patients with moderate-tosevere symptoms. Doppler echocardiograms performed 3 and 6 months after device implantation revealed that CRT was associated with symptomatic benefit, decreased LV end-systolic and end-diastolic volumes, reduced LV mass, increased ejection fraction, and diminished mitral regurgitation [52]. A follow-up study [53] confirmed the persistence of these findings at 12 months. Although symptomatic benefit following CRT does not correlate with long-term survival, Yu et al. [54] demonstrated that reverse LV remodeling was an independent predictor of Figure 5 Kaplan–Meier curve for all-cause mortality dichotomized by the status of left ventricular reverse remodeling
All-cause mortality Survival
1.0 0.9 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0.0
+ ++ +++ ++++ ++++++ ++ ++ +++ ++
+ +++++++ ++
+++ +++
++
++ +++
+
∆ LVVs > 10%
+
∆ LVVs < 10%
survival in a cohort of 114 patients with advanced heart failure. In this analysis, clinically relevant reverse remodeling, defined as a 10% reduction in LV end-systolic volume, was the most potent predictor of all-cause and cardiovascular mortality (Fig. 5).
Conclusion Therapies that attenuate the pathological remodeling seen following cardiac injury are strongly associated with reductions in morbidity and mortality. The armamentarium of proven therapies for patients with systolic heart failure, including drugs that inhibit the renin–angiotensin system, the sympathetic nervous system, and aldosterone; revascularization; passive cardiac restraint devices; and cardiac resynchronization have had dramatic impacts on heart failure morbidity and mortality. As heart failure mortality continues to decrease, it will become increasingly difficult to demonstrate the mortality benefit of future therapies without very large patient populations and prolonged follow-up. Ventricular remodeling has proven to be a strong surrogate endpoint in established therapies and may find further use as a primary endpoint in future heart failure trials. In fact, it has been argued that ventricular remodeling may not be just a surrogate measure in heart failure but rather a representation of the disease process itself [55]. Whether a surrogate or direct measure of heart failure, pathological remodeling appears to be a critical target for heart failure therapies that are linked to more patient-centric outcomes such as mortality.
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The challenges associated with current clinical trials for diastolic heart failure Vinay Thohan and Shomeet Patel Department of Cardiology, Wake Forest University School of Medicine, Winston-Salem, North Carolina, USA Correspondence to Vinay Thohan, MD, FACC, Department of Cardiology, Wake Forest University School of Medicine, Medical Center Boulevard, Watlington One, Winston-Salem, NC 27157, USA Tel: +1 336 716 3095; e-mail:
[email protected] Current Opinion in Cardiology 2009, 24:230–238
Purpose of review Diastolic heart failure (DHF) is the culmination of various cardiovascular insults, producing a proportionally greater alteration of diastolic performance, subtle reductions of systolic function and the clinical syndrome of heart failure. Over half of heart failure patients aged 65 years or older have DHF, which carries similar morbidity and mortality to systolic heart failure (SHF). The aging population and increased prevalence of hypertension, diabetes mellitus and obesity will result in disproportionately higher incidence of DHF. Recent findings To date, seven large placebo-controlled trials have been conducted in DHF and none have convincingly demonstrated substantial morbidity or mortality reductions. This review will highlight DHF clinical trial efforts and provide explanations for the discordance between clinical trial patients and clinical practice patients. Summary Greater parity between clinical trial and clinical practice can be achieved by selecting DHF patients in the context of a few general principles: trials should enrol patients on the basis of the diagnostic criteria set forth by the European Study Group on Diastolic Heart Failure. A history of (<6 months) or current hospitalization for heart failure along with prespecified higher grades of diastolic dysfunction insures that a sufficiently at-risk population is studied. Patients with DHF are older, with multiple noncardiovascular comorbidities, and longer trial duration (>3 years) may be plagued with competing risks. Keywords clinical trials, diastolic heart failure, heart failure with preserved ejection fraction Curr Opin Cardiol 24:230–238 ß 2009 Wolters Kluwer Health | Lippincott Williams & Wilkins 0268-4705
Introduction Improved screening, diagnostic and therapeutic options for patients with a wide range of cardiovascular conditions have resulted in earlier detection and treatment of chronic cardiovascular diseases, which has undoubtedly contributed to improvements in survival [1,2]. However, the combination of sustained or inadequately controlled chronic cardiovascular insults (such as hypertension, coronary heart disease, atrial fibrillation, diabetes mellitus and obesity) and individual susceptibility, compounded by time, is sufficient to produce the clinical syndrome of heart failure. This concept helps to explain both the dramatic rise in patients who suffer with chronic heart failure (CHF) [2] despite decreasing overall mortality from cardiovascular diseases [1] and, specifically, the lack of effective treatment for diastolic heart failure (DHF). 0268-4705 ß 2009 Wolters Kluwer Health | Lippincott Williams & Wilkins
Heart failure contributes to over one million hospitalizations annually and, among patients over the age of 65 years, is the most common cause of repeat hospitalizations within 60 days [3]. Over half of these patients have been designated to have a normal ejection fraction and they have inpatient, 90-day and 1-year mortalities of 2.9, 29 and 65%, respectively [4–6,7]. Compounding the staggering $34.8 billion annual cost is that the incidence of heart failure continues to climb, with current annual estimates of 600 000 new cases [3]. Although patients with chronic systolic heart failure (SHF) have evidence-based treatments that reduce both morbidity and mortality [2,8], those with DHF do not. The aging population and rise in the prevalence of hypertension, diabetes mellitus and obesity may result in disproportionately higher numbers of people who suffer with DHF in the coming years. These facts underscore the need to DOI:10.1097/HCO.0b013e328329f8fd
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Challenges with diastolic heart failure trials Thohan and Patel 231
develop appropriate treatment paradigms for DHF. This study will focus on the treatment challenges associated with DHF, review recent clinical trials and provide a framework for novel therapeutic interventions.
Diagnosis, pathophysiology and therapeutic challenges DHF has had various designations; it has aptly been termed heart failure with a preserved ejection fraction, and its definition has evolved over the past 20 years. Furthermore, the lack of an acceptable animal model to reproduce the clinical syndrome has marred the development of effective treatment options for DHF, thus leaving investigators to focus on mechanisms which lead to observed alterations of diastolic properties. Although it is beyond the scope of this study to completely explore all the pathologic states that affect diastole, it suffices to state that the myocardium of patients who suffer with DHF has demonstrable abnormalities contributing to impaired suction, relaxation and compliance [9,10]. Underlying, and likely contributing to alterations in diastolic performance, are molecular processes that lead to interstitial and cellular remodeling [11–15]. The content and constituency of interstitial fibrosis [16], impaired cellular energetics via altered calcium handling [17,18], diminished elastic recoil resulting from isomeric changes of sarcomere proteins [19] and a host of neurohormonal activation [20] are some of the clearest
participants involved in the pathophysiology of DHF [14,21]. The myocardial substrate generated along with age-related vascular stiffness [22] and uncontrolled cardiovascular stimuli render the heart unable to fill under physiologic low pressures either at rest or, more importantly, with activity [9,23]. When elevated left ventricle (LV) filling pressures are temporally sustained and transmitted to the pulmonary circuit, classic heart failure symptoms promptly ensue (Fig. 1). Therefore, DHF is the result of various cardiovascular insults, culminating to produce proportionally greater alterations of diastolic performance, subtle reductions of systolic function [24] and the clinical syndrome of heart failure. Several large clinical data sets demonstrate that DHF afflicts older women with multiple comorbidities (Table 1) [25]. The most recent consensus document produced by the European Study Group on Diastolic Heart Failure (EDHF) [26] incorporates three main concepts (Fig. 2). The EDHF guidelines require the presence of signs or symptoms of heart failure, demonstrable cardiac remodeling and either invasive or noninvasive measures of abnormal diastolic parameters. Supplementing these diagnostic requisites are serum biomarkers. The strict criteria outlined are required for two interrelated reasons. First, many chronic cardiovascular and noncardiovascular conditions overlap with regard to their clinical presentations and have widely disparate outcome. Second, any therapeutic intervention intended to modify
Figure 1 Current conceptual understanding of diastolic heart failure
Temporally sustained myocardial injuries elicit interstitial and myocyte remodeling, resulting in diastolic dysfunction. These changes, compounded by age-dependent vascular stiffness, provide the appropriate milieu for DHF. Either acute or poorly controlled stimuli lead to elevation of LAP. When elevations in LAP are sufficient to cause pulmonary congestion, symptomatic heart failure ensues (at rest or with exercise) leading to hospitalization and death. DHF, diastolic heart failure; LAP, left atrial pressure.
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232 Cardiac failure Table 1 Prevalence of clinical characteristics among 11 hospital or community-based data sets Clinical characteristics Age (year) Women (%) Hypertension (%) Diabetes (%) Atrial fibrillation (%) Obesity (BMI > 30 kg/m2, %) SBP (mmHg) DBP (mmHg)
would favor the ACE-I arm. The depressed ejection fraction is the arbitrator and distinguishes heart failurespecific risk. Similarly, and likely more challenging, selecting a true DHF population may demonstrate differences in therapeutic strategies beyond control of comorbidities. Therefore, it is important to recognize that acute control of chronic cardiovascular conditions may result in short-term reductions of heart failure endpoints and strategies to address underlying mechanisms of disease would achieve sustained benefits. Therapeutics should be designed to address comorbidities with treatments that preferentially target underlying mechanisms of disease. It is in the context of this background that clinically relevant data, especially any treatment paradigms pertaining to DHF, must be discussed.
Mean value 73 58 74 32 29 40 146 77
DBP, diastolic blood pressure; SBP, systolic blood pressure. Adapted from [25].
heart failure outcomes must first identify a target population that is at sufficient risk for heart failure endpoints. As an example, a hypertensive population treated with an angiotensin-converting enzyme inhibitor (ACE-I) or calcium channel blocker to the same target blood pressure would have similar outcomes with regard to heart failure, death or hospitalization. However, a hypertensive depressed ejection fraction population, similarly treated,
Lessons learned from current clinic trials Historically, the first trial addressing DHF was the ancillary Digoxin Investigation Group (DIG) [27], designed to determine the impact of chronic digitalis treatment for
Figure 2 European Study Group on Diastolic Heart Failure group paradigm for the diagnosis of diastolic heart failure
Symptoms or signs of heart failure
Normal or mildly reduced left ventricular systolic function LVEF > 50% and LVEDVI < 97 ml/m2
Evidence of abnormal LV relaxation, filling, diastolic distensibility, and diastolic stiffness
Invasive hemodynamic measurements mPCWP > 12 mmHg or > 16 mmHg or τ > 48 ms or b > 0.27
TD EIE’>15
15 > EIE’ >8
Biomarkers NT-proBNP > 220 pg/ml or BNP > 200 pg/ml
Biomarkers NT-proBNP > 220 pg/ml or BNP > 200 pg/ml
Echo -- bloodflow doppler EIE>50yr < 0.5 and DT>50yr < 280 ms or Ard-Ad > 30 ms or LAVI >40 ml/m2 or LVMI > 122 g/m2 (O+): > 149 g/m2 (O+) or Atrial fibrillation
TD EIE’>8
HFNEF
Ard Ad, time difference in atrial wave of pulmonary venous flow and mitral A; b, modulus for compliance; BNP, b-type natriuretic peptide; DT, mitral E-wave deceleration time; E0 , early mitral annular tissue Doppler velocity; E, early mitral inflow velocity; HFNEF, heart failure normal ejection fraction; LVEDVI, left ventricular end-diastolic volume index; LVMI, left ventricular mass index; LVEF, left ventricular ejection fraction; mPCWP, mean pulmonary capillary wedge pressure; NT-proBNP, N-terminal pro b-type natriuretic peptide; TD, tissue Doppler; t, time constant for relaxation. Data from Paulus et al. [26].
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Challenges with diastolic heart failure trials Thohan and Patel 233
patients with heart failure. Investigators enrolled patients with a spectrum of ejection fractions and a total of 988 patients with left ventricular ejection fraction (LVEF) of at least 45%. In keeping with contemporary DHF demographics, patients were older and more likely women, and 86% were taking ACE-I. The conclusions in this subpopulation were similar to the overall trial; treatment with digoxin conferred no observed impact on all or causespecific mortality, and a trend toward reduction in heart failure hospitalizations was balanced with an increase in hospitalizations for worsening ischemia. Readmission rates were high; a total of 662 (67%) patients were hospitalized. However, only 197 (19.9%) of these were for CHF and 131 (13.1%) for conventional cardiac causes (myocardial infarction, stroke or revascularization), leaving a full 67% of patients being readmitted for presumably noncardiac causes [27]. Among the 116 deaths, 70% were cardiovascular and 56% of these were not due to heart failure. This investigation conceptually defined heart failure as a clinical syndrome without including ejection fraction as the distinguishing criterion. It also underscores the challenge of identifying a population at sufficient risk for morbidity and mortality endpoints attributable to DHF and not comorbidities or ‘noncardiovascular causes’. Although digoxin may have a role in patients with atrial fibrillation and heart failure, it is not therapy advocated for DHF. Kitzman et al. [28] demonstrated that DHF, as compared with age-matched controls, is associated with upregulation of a variety of neurohormones with levels that are similar to disease-matched SHF cohorts. Similarly, elevations of neurohormones among patients with DHF are associated with disease severity, exercise intolerance and other measures of cardiovascular outcome [20,23,29]. Chronic upregulation of the sympathetic nervous system mediated through interactions of norepinephrine and various adrenergic receptors is well characterized in a number of cardiovascular disease states, including hypertension, left ventricular hypertrophy, ischemic heart disease, atrial fibrillation and SHF. In fact, beta-blockers are the cornerstone for the treatment of each of these comorbidities of DHF and are class I indication for patients with American College of Cardiology (ACC)/American Heart Association (AHA) stage B, C and D heart failure [2,8]. A true large-scale clinical investigation of beta-adrenergic receptor blocker therapy has not been conducted in DHF. The SENIORS trial [30] examined 2128 elderly patients with a prior hospitalization for heart failure (<12 months) or an ejection fraction of 35% or less (<6 months). Despite the enrolment of older patients (mean age 76 years) with a high prevalence of hypertension (61%), coronary artery disease (68%), diabetes (26%) and atrial fibrillation (34%), a full 65% of the total cohort
studied had a LVEF of 35% or less (overall mean LVEF ¼ 36%). Although a treatment effect favoring nebivolol was documented irrespective of ejection fraction, fewer than 250 patients with LVEF more than 50% appeared to have been enrolled in this study. This trial underscores the difficulties in studying a DHF population, despite the requisite of age and presence of comorbidities. It is likely the small cohort of patients with LVEF of at least 50% in SENIORS trial represented DHF, but would have insufficient power to detect a true treatment effect. The Swedish Doppler Echocardiographic Study (SWEDIC) [31] investigated the impact of carvedilol on diastolic function among patients with preserved systolic function. Demographics reflect a DHF population with a mean age of 67 years, 44% women and 65% hypertensive. Analysis of 97 patients with diastolic dysfunction treated randomly with carvedilol over a 6-month period of time conferred improvement in early (E) to late (A) mitral filling with no change in the primary endpoint of composite score for diastolic function [31]. Left atrial volume (LAV) increased by 1 ml in the carvedilol group with no observed differences in LV remodeling. Subjective clinical assessment paradoxically favored placebo and authors reconcile this observation with the greater proportion of patients classified as having no symptoms at baseline (40 vs. 26%, carvedilol vs. placebo). The study was conducted prior to the EDHF criteria and underscores a central challenge with understanding DHF. Diastolic dysfunction does not equate with DHF; 80% of patients in the SWEDIC trial demonstrated diastolic dysfunction, whereas fewer than 20% had greater than New York Heart Association (NYHA) class II symptoms. Among community datasets, proportionally few ambulatory patients with diastolic dysfunction have DHF [4,32,33]. Furthermore, conventional Doppler mitral inflow parameters, while sensitive, are not sufficient to assess diastolic function as they are highly dependent on hemodynamic changes [34]. Diagnostic strategies now incorporate more specific measures of diastolic performance, and recent EDHF [26] rely heavily on tissue Doppler techniques to assess diastolic function and use measures of remodeling [left atrial volume (LAV) > 40 ml/m2 or sexspecific LV mass] and serologic natriuretic peptide levels in cases of indeterminate Doppler criteria (Fig. 2). Abnormalities of ventricular filling are central features of both the definition and diagnosis of DHF. Physiologically, tachycardia preferentially shortens diastolic filling and, under conditions of impaired left ventricular relaxation and compliance (diastolic dysfunction), will cause a rise in left ventricular end-diastolic and mean left atrial pressure [9]. Treatment with a beta-blocker prevents tachycardia and thereby prolongs diastolic filling and reduces left atrial pressure [23,35]. Beta-blocker therapy
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234 Cardiac failure
benefit and annualized mortality was low irrespective of treatment (candesartan 8.1% and placebo 9.1%). A trend towards reductions for heart failure hospitalization was conferred only after adjusting for covariates (hazard ratio 0.85 and P value of 0.051). Further extrapolation of the data indicates that 30% of 481 deaths were noncardiovascular in nature and, although 1834 patients were hospitalized, only 509 of 5055 admissions were for congestive heart failure (16.8%), another 16% for any cardiovascular cause; the remaining two out of three of hospitalizations are assumed to be noncardiovascular. The low heart failure event rates may reflect inadequate patient selection. Cross-sectional community-based studies systematically analyzing diastolic dysfunction with Doppler techniques and measuring LAV found that disease-specific mortality, heart failure hospitalization and symptom-limited heart failure were directly related to worsening diastolic dysfunction and increased LAV [4,40]. An echocardiographic substudy (CHARMES) [41] of 312 patients in the CHARM-preserved study found that 33% of patients had normal diastolic function and 22% had mild diastolic dysfunction. Normal or mild diastolic dysfunction carries the lowest overall risk for cardiovascular death or hospitalization, approximately 5% for normal and 6% for mild diastolic dysfunction (Fig. 3). Perhaps selection of patients utilizing consensus diagnostic criteria and incorporating patients with higher degrees of diastolic dysfunction would result in selection of a population at higher risk for heart failure.
for the treatment of DHF has been challenged by recent exercise metabolic testing data indicating that impaired chronotropic response to exercise contributes to observed exercise intolerance [36]. Given their benefits for a number of comorbidities, beta-blocker therapy may be difficult to establish as a stand-alone treatment for DHF. Chronic upregulation of the renin–angiotensin system (RAS) is a feature ubiquitously associated with a wide range of cardiovascular diseases, including hypertension, ischemic heart disease, atrial fibrillation and diabetes mellitus. Furthermore, myocardial remodeling is both experimentally and clinically attenuated by RAS inhibition [37,38] and would seem a plausible target for DHF therapy. Several large-scale randomized control clinical trials have been conducted to test whether attenuation of the RAS is associated with a favorable impact on DHF. The Candesartan in Heart Failure – Assessment of Mortality and Morbidity (CHARM)-preserved trial studied the effects of candesartan, an angiotensin receptor blocker (ARB), on the composite cardiovascular endpoints of mortality and heart failure admission among 3023 patients with a preserved systolic function [39]. Baseline features reflect DHF: 64% hypertensive, 56% ischemic heart disease and 29% atrial fibrillation. Although the average age (67 years) was lower than conventional DHF populations, 25% of all patients were 75 years or older and 40% were women. The mean ejection fraction was 54%, and 69% of enrolled patients were documented as having a prior heart failure hospitalization. After 3 years of follow-up, candesartan treatment conferred no cause-specific or total mortality
The irbesartan in heart failure with preserved systolic function (I-Preserve) trial [42] is the most recent assessment of RAS inhibition in DHF and sought to determine the clinical implications of irbesartan treatment for 4028
Figure 3 Clinical implications
(a)
(b)
1 Proportion free from CV 0.9 death or HF hospitalization 0.8 0.7
Mortality, % 25 20
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(a) Doppler assessment of diastolic dysfunction on cardiovascular death or heart failure hospitalization [41]. (b) Doppler diastolic dysfunction grade on , Normal diastolic function; , relaxation abnormality; , pseudonormal diastolic mortality in a cross-sectional community-based population [4]. , restrictive diastolic dysfunction; , moderate or severe diastolic dysfunction; , mild diastolic dysfunction; , normal diastolic dysfunction; function.
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Challenges with diastolic heart failure trials Thohan and Patel 235
patients over 49.5 months. Baseline characteristics of the study population reflected conventional DHF: mean age of 72 years, 60% women, 80% hypertensive, 41% obese, and 40% of patients had been hospitalized within the previous 6 months. The annualized event rate was surprisingly low (mortality 3.5% per year). Readmission rates were high (56%, n ¼ 2278); however, only 29% (n ¼ 661) were readmitted for heart failure, another 17.4% (n ¼ 397) for non-heart failure cardiovascular causes, and the remaining 1220 admissions (53% of total admissions) are presumed noncardiovascular. Authors conclude the lack of efficacy was related to the higher utilization of conventional medical therapies (ACE-I, 25%; spironolactone, 15%; beta-adrenergic blockers, 57%) as well as a high study-drug discontinuation rate (33%). Seventy-five percent of patients were assessed to have NYHA class III symptoms, which is surprising in light of the low annual mortality and low heart failurespecific readmission rates (approximately 7% per year). The subjective nature of NYHA classification may not confer the same implications for DHF as for SHF. The mean LVEF in I-Preserve was 60%, and, although we do not have information on baseline diastolic function, extrapolating from CHARMES [41], patients enrolled in I-Preserve would be expected to have normal or mild diastolic dysfunction. Contrasting I-Preserve with the African–American heart failure trial (AHeFT) helps to shed light on the challenges associated with DHF trial design. Among African–Americans with SHF (predominantly NYHA III) treated with excellent background medical therapy (86% on ACE or ARB, 74% beta-blocker and 38% aldosterone antagonist), the combination of fixed-dose isosorbide dinitrate and hydralazine (BiDil; NitroMed, Inc., Lexington, Massachusetts, USA) conferred an early and sustained reduction in both mortality and hospitalization, 43 and 33% relative risk reduction, respectively [43,44]. Annual placebo mortality was 12% (7.4% treatment arm), considerably higher than the I-Preserve population; furthermore, unlike DHF trials, 82% of deaths (n ¼ 86) were attributed to a cardiovascular cause [43]. The populations studied in the I-Preserve and AHeFT trials are clearly different on the basis of systolic function. However, I-Preserve enrolled older patients, predominantly NYHA class III patients, and 40% with prior heart failure hospitalization who were less frequently on standard heart failure therapy; arguably a higher-risk demographic [45]. Enrolment based on depressed ejection fraction allowed disease-specific event reductions favoring BiDil treatment in AHeFT; perhaps, in addition to standard clinical criteria, the selection of cohorts with more severe grades of diastolic dysfunction would similarly assign disease-specific risk. Perindopril for Elderly People with Chronic Heart Failure (PEP-CHF) investigations incorporated both clinical and echocardiographic diagnostics into enrolment
criteria and evaluated the effect of perindopril (ACE-I) in 850 patients followed over 26.2 months [46]. All patients enrolled were required to have a heart failure hospitalization (<6 months) attributable to DHF based on the presence of clinical and echocardiographic Doppler criteria. Baseline variables were consistent with a DHF population and mean LV wall thickness was between 1.2 and 1.3 cm. Importantly, fewer than 25% of patients met study diastolic criteria for DHF. Two hundred and seven patients (24.4%) reached the primary endpoint of allcause mortality or first heart failure hospitalization. Annualized mortality was approximately 5.9%. Event rates were lower than anticipated; however, limiting the analysis to the first year after randomization conferred trends favoring perindopril use (15.3% placebo vs. 10.8% perindopril, hazard ratio ¼ 0.69, P value ¼ 0.055), results which were driven by a reduction in heart failure hospitalization (n ¼ 53 placebo vs. n ¼ 34 perindopril, hazard ratio ¼ 0.63, P value ¼ 0.033). Furthermore, clinical improvements in NYHA classification, lower hospitalization length of stay, greater 6 min walk distance and reductions of plasma N-terminal pro b-type natriuretic peptide (NT-proBNP) were observed among patients treated with perindopril [46]. The addition of 6 min walk distance provided objectivity to functional capacity beyond NYHA classification. In general, among SHF populations, walk distances less than 300 m are associated with a higher proportion of NYHA III, as opposed to IPreserve patients, who had mean 6 min walk distance of 295 m, and 75% were designated NYHA class I or II. This discordance may underscore noncardiac comorbidities that limit exercise capacity among older patients with DHF. Kaplan–Meier endpoint analysis over the duration of the entire trial appears to demonstrate a reduction of events in the placebo arm after 12–18 months, coincidental with the greater than 35% open-labeled use of ACE-I during this same time interval (Fig. 4).
Figure 4 Perindopril for Elderly People with Chronic Heart Failure Kaplan–Meier analysis for primary endpoint of death or unplanned first hospitalization
(HR 0.92; 95% Cl 0.70--1.21; P = 0.545)
Proportion 40 having an event (%) 30
Placebo
Perindopril
20 10 0 0
1
2
3 Time (y)
CI, confidence interval. Data from Cleland et al. [46].
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236 Cardiac failure
The lower than anticipated event rates are in keeping with baseline relatively normal diastolic parameters. Two interrelated observations are worthy of mention; first, diastolic data presented represents mean values of the population studied and second, Tissue Doppler analysis was not conducted. Mitral inflow variables used to assess diastolic filling parameters are load-dependent, and abnormal relaxation, a hallmark of DHF, results in delayed and diminished early filling characterized by a low mitral E-wave velocity relative to the A wave, prolonged E-wave deceleration and isovolumetric times [34]. Among patients with normal systolic function, intermediate or pseudonormal mitral inflow patterns may represent normal patients with true normal filling (low cardiac risk) or patients with abnormal relaxation and elevated left atrial pressure (higher risk). Among patients with true diastolic relaxation abnormalities, diastolic tissue Doppler analysis provides a relatively load-insensitive measure of relaxation and, as a result, is more specific than traditional mitral inflow parameters [47] and is advocated by the EDHF group [26]. When left atrial pressure increases sufficiently to shorten isovolumic relaxation time (IVRT) and deceleration time and increase mitral E-wave velocity in a population of patients with diastolic dysfunction, the early mitral annular tissue Doppler velocity (E0 ) will not change and its ratio to E wave (E/E0 ) correlates with higher risk [48]. Mean Doppler data may not account for the spectrum of risk observed in populations of patients with diastolic dysfunction, and differential treatment effects may be discovered by pre-specifying heart failure patients with higher E/E0 ratios. The last medium-sized trial is the Hong Kong DHF study [49], which compared irbesartan or ramipril with the background of diuretic therapy. One hundred and fifty patients, mean age 74 years, 75% hypertension, 20% diabetes mellitus and 40% female, were randomly assigned to three treatment groups with diuretic alone as the active control. Approximately two-thirds of patients were designated NYHA class II, 6 min walk distance of 325 m and mean serum NT-proBNP was 595 904 pg/ml. Most importantly, color tissue Doppler-derived myocardial velocities of mitral inflow were averaged over five basal segments and, in addition to LV mass, were distinctly abnormal. Although the trial was powered to detect quality of life endpoints, this highly selected cohort had a very low 12-month mortality (<4%) with only 11.5% of patients rehospitalized for heart failure. This well designed trial highlights that patients meeting the EDHF Group criteria can be enrolled in DHF studies and that symptomatic relief with diuretic (thiazide or furosemide) therapy should be considered part of the therapeutic regimen for patients with DHF. The low event rates described in the Hong Kong DHF study despite confirmation of elevated NT-BNP and
Doppler measures of elevated left ventricular filling pressures is difficult to reconcile unless patients enrolled represent a distinct subset of DHF patients responsive to diuretics. Patients in the present study were excluded if they were hospitalized with a background treatment of ACE-I, ARB, calcium channel blockers or beta-blockers. Perhaps the failure of conventional medical therapy identifies a higher-risk set of patients among the DHF population. Data from the Organized Program To Initiate life-saving treatment In hospitaliZEd patients with Heart Failure (OPTIMIZE-HF) registry confirm that preserved ejection fraction heart failure patients are hospitalized despite taking conventional medical therapy: ACE-I (35%), ARB (13%), beta-blockers (52%), diuretics (58%) or all. Despite medical treatment, patients had high 60–90-day mortality (9.3%) and rehospitalization (30.9%) rates [7].
Current therapeutic recommendations The two central goals of any treatments for DHF must involve the reduction of morbidity (symptoms, exercise intolerance, and hospitalization) and improvement in survival. The lack of evidence-based therapy to guide clinicians treating patients with DHF has assigned all therapies, aside from the treatment of hypertension, a ‘C’ level of evidence. Given that DHF is the confluence of a number of heterogeneous diseases that preferentially impact ventricular filling sufficiently to cause intermittent elevation in left atrial pressure and result in the clinical syndrome of heart failure, it is not surprising that established treatments targeting comorbidities are advocated [1,26]. Unfortunately, the extent to which patients are comprehensively evaluated for contributing factors and treated to target goals is not known; on the basis of clinical trial experience, once target goals are achieved, heart failure event rates diminish. Furthermore, contemporary estimates find fewer than one-third of communitybased populations with hypertension, chronic angina and diabetes are treated to evidence-based goals, and 60% of United States adults are overweight or obese [3]. Beyond evaluating and titrating goal-targeted treatment for risk factors, some therapies may address pathophysiologic processes. In this regard, select prospective and retrospective data sets have clearly demonstrated that the control of volume with diuretics and treatments directed at abrogating RAS should be considered initial therapy for DHF. Strong, mechanistic data are emerging for the use of agents that block the cardiovascular effects of aldosterone [16,50,51], and we are awaiting the results of clinical trials.
Conclusion A range of potential therapeutic targets from neurohormonal blockade to mechanical diastolic dyssynchrony
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Challenges with diastolic heart failure trials Thohan and Patel 237
[52,53] has been identified, and ongoing trials will help clarify the optimal treatments for DHF. Whether extension of approaches addressing comorbidities or novel drugs designed to target pathologic mechanisms [54] will prevail will in large part rely on trial design and patient selection. The clinical investigations reviewed highlight the challenges facing both trial design and application of potential therapies for the treatment of DHF. Although a variety of specific stimuli (afterload, preload, ischemia, tachycardia, etc.) alter conventional parameters used to measure diastole, neither these changes nor baseline diastolic abnormalities are sufficient to result in the clinical syndrome of DHF, underscoring the axiom ‘diastolic dysfunction is not DHF’. Ideally, DHF trials should enroll patients based on the diagnostic criteria set forth by the EDHF [26]. They must account for the heterogeneous cardiovascular conditions that contribute to DHF, the intrinsic risk of patients for cardiovascularspecific endpoints (i.e. heart failure hospitalization vs. total hospitalization) and the spectrum of mortality even among those with a diagnosis of DHF. A history of (<6 month) or current hospitalization for heart failure will define a higher-risk population of patients for recurrent hospitalization but may not define those who will be hospitalized for recurrent heart failure. The reliance on echocardiographic criteria along with biomarker data will specifically segregate heart failure-attributable risks, and, further, prespecification of diastolic grades at the time of enrollment may ensure that a sufficiently at-risk population is studied. Finally, patients with DHF are older, with multiple noncardiovascular comorbidities, and as such longer trial duration may be plagued with competing risks for morbidity and mortality.
References and recommended reading Papers of particular interest, published within the annual period of review, have been highlighted as: of special interest of outstanding interest Additional references related to this topic can also be found in the Current World Literature section in this issue (pp. 263–264). 1
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Trying to succeed when the right ventricle fails Michael A. McDonald and Heather J. Ross Division of Cardiology, Peter Munk Cardiac Centre, Toronto General Hospital, Toronto, Ontario, Canada Correspondence to Heather Ross, MD, Toronto General Hospital, NCSB 11-1203, 585 University Avenue, Toronto, ON M5G 2N2, Canada Tel: +1 416 340 3482; fax: +1 416 340 4134; e-mail:
[email protected] Current Opinion in Cardiology 2009, 24:239–245
Purpose of review Compared with the left ventricle, studies of right ventricular failure as a distinct clinical entity have lagged behind. Evolving appreciation of the prognostic significance of right ventricular dysfunction in the heart failure population and advances in noninvasive imaging have provided the impetus for recent investigation into the assessment and management of right ventricular failure. Recent findings Pulmonary hypertension and attendant right ventricular dysfunction are prevalent in patients with systolic and diastolic heart failure and are associated with poor survival. Simple echocardiographic and MRI indices of right ventricular function relate to prognosis and may also be useful in following response to therapy. Management of acute and chronic right ventricular failure is largely empiric and is focused on treating the underlying cause along with judicious use of diuretics and inotropes. The use of left ventricular assist devices to help treat pulmonary hypertension in heart failure is an emerging strategy in transplant-eligible patients. Summary Right ventricular failure is clinically significant and merits further dedicated study. Parameters of right ventricular dysfunction can be assessed noninvasively. An approach to the management of acute and chronic right ventricular failure should take into consideration novel pharmacologic and device-based therapies. Keywords heart failure, pulmonary hypertension, right ventricle, ventricular assist devices Curr Opin Cardiol 24:239–245 ß 2009 Wolters Kluwer Health | Lippincott Williams & Wilkins 0268-4705
Introduction
Defining the issue
The importance of right ventricular (RV) function in pulmonary vascular disease, left-sided heart disease and congenital heart disease is gaining increasing appreciation. However, despite recent advances in imaging and assessment, the pathophysiology of RV failure is incompletely understood, and RV-specific therapies remain elusive or unexplored. In contrast to left ventricular failure, there has been a paucity of research on RV failure as a distinct and separate entity per se; historically, the guiding principles for assessing and managing RV dysfunction have been extrapolated from studies of the left ventricle (LV) [1–3]. However, further insight into the fundamental anatomical and functional differences between the two ventricles as well as their physiologic interdependence highlights the inadequacy of this approach. This review will discuss the importance of RV failure especially as it relates to LV failure and will outline the role of different empiric therapies and evolving treatment strategies.
Right heart failure may be broadly defined as the inability of the right ventricle to maintain adequate circulation through the pulmonary vascular bed at normal central venous pressures. This process is often insidious and chronic as the RV is subjected to unfavorable loading conditions over time [i.e. pulmonary arterial hypertension (PAH)], or can occur acutely with precipitous hemodynamic deterioration and end-organ injury [i.e. massive pulmonary embolus with acute cor pulmonale, RV infarction, postcardiac transplant RV failure and RV failure following left ventricular assist device (LVAD) implantation].
0268-4705 ß 2009 Wolters Kluwer Health | Lippincott Williams & Wilkins
Adverse changes in right-sided afterload, preload or right ventricular contractility can result in RV decompensation, first characterized in 1974 [4] as a state of low cardiac output with elevated right-sided (right atrial and central venous) filling pressures. In isolated RV failure, pulmonary capillary wedge pressure (PCWP) and left-sided DOI:10.1097/HCO.0b013e328329e9e8
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240 Cardiac failure Figure 1 Septal shift and exaggerated ventricular interdependence in right ventricular dysfunction
Figure 2 Effect of increased afterload on right ventricular versus left ventricular function
Stroke volume 110 (% of control 100 value) 90 80 70
Right ventricle
Left ventricle
60 50 0
Because the RV is constrained by the pericardium (not shown), pathologically increased right ventricular filling pressures are transmitted to the interventricular septum, which shifts towards the LV and distorts the normal geometric relationship between the ventricles. This may mechanically disadvantage the RV and adversely affect left ventricular diastolic filling. LV, left ventricle; RV, right ventricle. Adapted from [3].
filling pressures are low, and pulmonary edema is absent. Chronic RV failure, with longstanding elevation of central venous pressures, can lead to atrial arrhythmias, peripheral edema, ascites and congestive dysfunction of the liver, kidneys and gut. Persistent low cardiac output due to an underfilled LV can precipitate classic symptoms of exercise intolerance and end-organ hypoperfusion. The clinical situation may be further exacerbated as LV diastolic filling becomes compromised through the mechanism of ventricular interdependence in which the RV is ‘constrained’ by the pericardium, and increased right-sided pressures cause the interventricular septum to shift and impinge on the LV cavity and left ventricular filling (Fig. 1).
10
20
30 100
110
120
130
140
P vessel (mmHg) Increased pulmonary artery pressures and RV afterload cause a marked reduction in right-sided stroke volume and cardiac output. By comparison, LV performance is less sensitive to increased systemic arterial pressure and afterload. LV, left ventricular; RV, right ventricular. Adapted from [5].
the different types of pulmonary hypertension is beyond the scope of this review; however, a distinction is made between PAH characterized by resting mean pulmonary artery pressure of more than 25 mmHg, PVR of more than 3 Wood units and PCWP of less than 15 mmHg, and pulmonary hypertension due to left-sided heart disease characterized by elevated left atrial pressures. Irrespective of the cause, right ventricular failure often represents the final common pathway portending a poor prognosis and may be a potential target for therapeutic intervention.
Table 1 Classification of pulmonary hypertension
Considerations in pulmonary hypertension
As shown in Fig. 2, RV function is very sensitive to alterations in afterload [5,6], and RV failure is often seen in the setting of pulmonary hypertension in which increased pulmonary vascular resistance (PVR) is the primary hemodynamic problem [7]. Ultimately, progressive RV dysfunction in this setting may lead to diminishing right-sided cardiac output and a decline in pulmonary artery pressures; hence, the diagnosis of RV failure in the setting of chronic pulmonary hypertension does not require pulmonary artery pressures to remain elevated. It may, therefore, be useful to consider the RV and pulmonary arteries together as a single, functional, interrelated unit [2]. The most recent classification of pulmonary hypertension centers on the underlying pathophysiologic process and response to therapy [7,8]. Table 1 outlines this current classification scheme. A detailed description of
Category
Examples
PAH
Idiopathic Familial Congenital systemic pulmonary shunts, connective tissue disease HIV Toxins Left-sided atrial or ventricular disease (LV systolic or diastolic dysfunction) Left-sided valvular heart disease Chronic obstructive lung disease Interstitial lung disease Sleep-disordered breathing Thromboembolic obstruction of pulmonary arteries Nonthrombotic obstruction of pulmonary arteries Sarcoidosis Histiocytosis X
Pulmonary hypertension with left heart disease Pulmonary hypertension associated with lung disease/hypoxia Pulmonary hypertension due to chronic thrombotic or embolic disease or both Miscellaneous
LV, left ventricular; PAH, pulmonary arterial hypertension. Adapted from [8].
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Trying to succeed when the right ventricle fails McDonald and Ross 241
Acute and chronic right ventricular failure: impact of the problem in left heart disease The most common underlying cause of pulmonary hypertension and RV failure is concomitant left-sided heart disease [1]. Although the exact prevalence is poorly defined [9], pulmonary hypertension is common in heart failure patients and is associated with a poor prognosis in ischemic and nonischemic cardiomyopathy [9–11,12]. Pulmonary hypertension in left ventricular dysfunction
Although previous work has been limited to patients with poor left ventricular systolic function, Kjaergaard et al. [12] recently evaluated the prognostic significance of elevated pulmonary pressures in a broad spectrum of heart failure patients enrolled in the EchoCardiography and Heart Outcome Study (ECHOS) [13]. Approximately 25% of the 388 patients in this cohort had preserved left ventricular function. Pulmonary artery pressure was found to be an independent predictor of overall mortality. In both low ejection fraction and preserved ejection fraction subgroups, patients with pulmonary systolic pressure at least 39 mmHg had significantly worse survival [12]. Although others have observed pulmonary hypertension and RV failure in patients with preserved left ventricular ejection fraction (LVEF) [14], this is the first study to demonstrate the prognostic importance of elevated pulmonary artery pressures in a contemporary heart failure population that includes both systolic and diastolic heart failure patients. Concomitant right ventricular and left ventricular dysfunction
By extension, RV dysfunction itself is a powerful and independent predictor of short and long-term survival in chronic LV systolic failure [10,15–18]. In studies [10,16,18] of selected patients with ischemic or nonischemic cardiomyopathy, RV dysfunction, usually defined by right ventricular ejection fraction (RVEF) of less than 0.35, has been observed in more than 50%. Ghio et al. [10] demonstrated the independent and additive effects of RV dysfunction and pulmonary hypertension in a low LVEF heart failure cohort. They also observed an inverse relation between RVEF and mean pulmonary artery pressures, suggesting that persistent elevation of pulmonary pressures is pathophysiologically important, and that RV dysfunction is not simply an epiphenomenon of the left ventricular cardiomyopathic process [10]. Javaheri et al. [19] assessed the prognostic significance of sleep-disordered breathing in patients with systolic heart failure. In a multivariable analysis, central sleep apnea and RV dysfunction were independent predictors of longterm mortality, suggesting that sleep apnea is linked to right ventricular dysfunction through chronic elevation of pulmonary artery pressures [19].
Right ventricular failure after left ventricular assist device implantation
Acute RV dysfunction after LVAD implantation for endstage heart failure is an increasingly important issue. The incidence of significant RV failure, typically defined as inotrope support for more than 14 days, inhaled nitric oxide (iNO) for at least 48 h or need for right ventricular assist device (RVAD), is approximately 30–40% and is associated with a perioperative mortality of nearly 40% [20,21,22]. A recent preoperative risk score for RV failure post-LVAD implantation found that preoperative vasopressor requirements and elevated serum aspartate aminotransferase, bilirubin and creatinine were independent predictors of RV failure [20]. This study implies that the end-organ effects of RV dysfunction add prognostic value beyond hemodynamic measurements taken in isolation. Moreover, anticipation and aggressive measures to manage the RV in this situation are warranted given the impact of RV failure on perioperative mortality.
Towards better assessment of right ventricular structure and function Because management of RV failure is largely empiric, an understanding of the unique anatomy and physiology of the RV is essential. The RV is a thin-walled complex three-dimensional structure designed for circulating high volumes in a low-resistance system. Compared with the LV, the bellows-like action of RV contraction against the interventricular septum generates less stroke work, and measures of RV performance are more load-dependent [3,6]. Although RV function is greatly affected by changes in afterload [5], chronic volume overload conditions such as atrial septal defects and tricuspid and pulmonary regurgitation are well tolerated, as is the Fontan circuit in which the RV is noncontributory. The RV ultimately fails, however, when PVR and right ventricular afterload increase [3,23]. Noninvasive markers of right ventricular function
Given the relative complexity of RV structure and function, there has been great interest in imaging the RV and assessing various prognostically important parameters. The valsartan in acute myocardial infarction trial (VALIANT) echocardiographic (ECHO) study assessed right ventricular function in postmyocardial infarction (MI) heart failure patients using two-dimensional right ventricular fractional area change (RVFAC) [24]. Higher rates of RV dysfunction after MI were observed than had previously been reported, and this was associated with a significantly increased risk of death, heart failure and stroke, independent of LV function [24]. In chronic heart failure patients, blunted RV tissue Doppler systolic velocity emerged as a novel predictor of cardiac death or heart failure hospitalization, suggesting
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242 Cardiac failure
that this may be a more sensitive marker of RV dysfunction than conventional parameters, including RVEF or RVFAC [25]. MRI imaging, currently the gold standard for assessment of RV dimensions and volumes [2,26,27], offers tremendous potential for evaluating RV function and perfusion [2]. MRI assessment of RV isovolumic relaxation time, a marker of RV diastolic function, has correlated well with PVR, and improved following afterload reduction with sildenafil [28]. This suggests that RV diastolic function and response to therapy can be assessed quantitatively and noninvasively. RV volumes calculated from multislice computed tomography (CT) scan imaging have shown excellent correlation with MRI imaging, providing an alternative modality for evaluating RV anatomy and function [29].
Managing chronic right ventricular dysfunction Although no specific therapies exist for chronic RV failure, treatment is generally based on identifying and correcting the underlying physiologic derangements. Appropriate therapy for left-sided heart disease should theoretically ameliorate chronically elevated PCWP and RV dysfunction; however, data directly supporting this are lacking. Carvedilol has been shown to increase both RVEF and LVEF compared with placebo in small studies [30,31] of systolic heart failure patients. A randomized controlled trial of darbepoetin a, a recombinant erythropoietin analogue, in 32 patients with heart failure also demonstrated improvements in LVEF and RVEF compared with placebo over 3 months [32]. Diuretics are standard therapy for conditions of volume overload. Despite the lack of evidence supporting their use in RV failure, a combination of loop diuretics, spironolactone and thiazides may be used to manage peripheral edema, ascites and end-organ congestion. Appropriate diuresis may have salutary effects on RV loading conditions without negatively impacting left ventricular preload and cardiac output. A pilot study [33] comparing the hemodynamic effects of loop diuretics found that torsemide effectively lowered central venous pressure and PCWP, improved cardiac output and had less neurohormonal activation than furosemide. These novel findings need to be confirmed in large-scale studies, but underscore the need to include pulmonary vascular and RV functional parameters in physiologic studies of heart failure. Can therapies for pulmonary arterial hypertension be extrapolated to heart failure patients?
In addition to chronically elevated filling pressures in ‘postcapillary’ pulmonary hypertension due to left heart
disease, many heart failure patients have superimposed elevations in PVR with a relatively fixed component of pulmonary hypertension due to an abnormal pulmonary arterial vasoconstrictor response and structural remodeling [9,34,35]. Conceptually, then, therapies for idiopathic PAH may be effective for some patients with pulmonary hypertension due to LV dysfunction. There are a number of issues with this approach. For example, PAH trials of prostacyclin analogues, endothelin receptor antagonists and phosphodiesterase inhibitors have not looked at long-term morbidity and mortality outcomes germane to the heart failure population. As well, available literature on prostacyclins and endothelin receptor antagonists in patients with advanced heart failure suggests an adverse effect on short-term mortality and worsening heart failure [36–38]. In the endothelin antagonist bosentan for lowering cardiac events in heart failure (ENABLE) study [38], the endothelin receptor antagonist bosentan showed no effect on mortality, but was associated with an increased risk of hospitalization for heart failure in patients with LV systolic dysfunction. In contrast, sildenafil, the prototypical phosphodiesterase inhibitor approved for PAH, has generated appreciable interest with respect to its potential efficacy in other types of pulmonary hypertension. Emerging data indicate a possible hemodynamic, functional and quality of life benefit in patients with chronic thromboembolic pulmonary hypertension [39], idiopathic pulmonary fibrosis [40] and left-sided heart failure [41,42]. Early studies [43,44] of sildenafil in heart failure patients with pulmonary hypertension demonstrated an improvement in exercise capacity following a single dose. A randomized trial of 34 patients found that sildenafil use in this population increased RVEF, cardiac output and exercise tolerance and was associated with better quality of life [41]. Although improvements in RV function in this study were attributed to observed reductions in PVR, Nagendran et al. [45] have shown that phosphodiesterase inhibition with sildenafil may result in augmented RV contractility, providing evidence for a right ventricular-specific inotrope effect. Mechanical solutions for pulmonary hypertension due to left heart disease
In end-stage heart failure, irreversible pulmonary hypertension remains a contraindication to transplantation as it imposes an unacceptable risk of death from postoperative RV failure [46,47]; the only treatment option, historically, has been heart–lung transplantation. Although sildenafil and other selective pulmonary vasodilators offer some promise of improving hemodynamics sufficiently to allow transplantation [42], experience with LVADs as a bridge to transplant eligibility for patients with severe pulmonary hypertension is growing. Amelioration of ‘fixed’ pulmonary hypertension with
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Trying to succeed when the right ventricle fails McDonald and Ross 243
LVADs has been described in a number of cases [35], including 26 patients successfully bridged to transplantation with outcomes similar to those transplanted without antecedent pulmonary hypertension [48]. Patel et al. [49] also retrospectively assessed the incidence of RV dysfunction following implantation of the pulsatile HeartMate I LVADs (Thoratec Corp., Pleasanton, California, USA) versus the axial-flow HeartMate II devices. In this study, both yielded comparable reductions in pulmonary pressures, although postoperative RV failure was common, occurring in 35% of pulsatile and 41% of axial-flow devices. This suggests that different approaches for unloading the LV have similar potential to mechanically disadvantage the RV, despite favorable effects on pulmonary hypertension and RV afterload.
Optimal right ventricular afterload
Acute decompensated right ventricular failure
Conclusion
Management of patients with acute decompensated RV failure is largely empiric and targeted towards treating underlying precipitants while optimizing conditions of RV preload, afterload and contractility.
Compared with the LV, studies of RV per se have lagged behind, with a general paucity of data to inform clinical decision-making. With the evolution of noninvasive imaging and greater insight into the prognostic significance of RV dysfunction, there are new opportunities to enrich our assessment and treatment of patients across a spectrum of cardiovascular disease. An approach to the management of acute and chronic RV failure should take into consideration novel pharmacologic and device-based therapies.
Optimal preload
Irrespective of the cause of RV failure, adequate RV preload may help maintain cardiac output via the Frank–Starling mechanism. Excessive volume loading in this setting can be detrimental, however, as pericardial constraint may adversely affect left ventricular diastolic filling via ventricular interdependence. Congestive hepatopathy, renal venous hypertension and gut edema lead to progressive end-organ dysfunction, and elevated right atrial pressures can precipitate supraventricular arrhythmias that further exacerbate the problem. Pulmonary artery catheterization may help guide resuscitative efforts; if the syndrome of RV failure persists and right-sided filling pressures remain above 12–15 mmHg, diuresis, inotrope therapy and aggressive afterload reduction are usually required [50], and renal replacement therapy may become necessary. Improving right ventricular contractility
Optimizing myocardial oxygen supply–demand balance mandates aggressive treatment of underlying ischemia [23]. In the face of persistently low cardiac output, dual chamber (right atrium and RV) pacing may be helpful in maintaining adequate heart rate or restoring atrioventricular synchrony or both. Inotropes, including epinephrine, milrinone and dobutamine, are frequently needed to augment contractility; however, milrinone and dobutamine may worsen systemic hypotension, requiring the addition of vasopressors [23,50,51]. Newer inotropes such as levosimendan have demonstrated improvements in parameters of RV function in animal models and early human studies [52,53]; however, their routine use in decompensated RV failure requires further investigation.
Minimizing positive intrathoracic pressure in ventilated patients and managing concomitant left ventricular dysfunction may have beneficial effects on RV afterload. In addition to these general measures, administering pulmonary artery vasodilators may be useful in the management of RV failure. In patients with RV infarction and cardiogenic shock, iNO has been shown to improve hemodynamic measures [54]. Inhaled prostacyclin analogues, iNO and oral sildenafil have all been used to successfully manage pulmonary hypertension and RV failure following cardiac surgery [55,56]. It remains to be seen whether broader applicability of these therapies to other patients with RV dysfunction will yield improvements in physiologic and clinical outcomes.
References and recommended reading Papers of particular interest, published within the annual period of review, have been highlighted as: of special interest of outstanding interest Additional references related to this topic can also be found in the Current World Literature section in this issue (pp. 264–267). 1
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Patient selection for left-ventricular assist devices Katherine Lietza and Leslie W. Millerb a Cardiovascular Divisions, Columbia-University Medical Center, New York, New York and bGeorgetown University-Washington Hospital Center, Washington, District of Columbia
Correspondence to Katherine Lietz, MD, PhD, Center for Advanced Cardiac Care, Columbia-Presbyterian Medical Center, PH12 Stem Rm 134, 622nd West 168th Street, New York, NY 10032, USA Tel: +1 212 305 9264; fax: +1 212 305 7439; e-mail:
[email protected] Current Opinion in Cardiology 2009, 24:246–251
Purpose of review Selection of appropriate candidates is one of the most important determinants of successful outcomes of left-ventricular assist device (LVAD) implantation. The review describes a step-by-step approach to evaluation of patients with end-stage heart failure for LVAD implantation. Recent findings This article includes a summary of the recently published guidelines on candidate selection for long-term mechanical circulatory support, current understanding of the optimal timing of device placement in the disease course and the utility of preoperative screening scales to estimate the patient’s operative risk. Summary As technology continues to improve and new devices provide greater safety and durability, continued efforts are needed to better define the clinical determinants of successful LVAD outcomes. Keywords advanced heart failure, patient selection, ventricular assist devices Curr Opin Cardiol 24:246–251 ß 2009 Wolters Kluwer Health | Lippincott Williams & Wilkins 0268-4705
Introduction Left-ventricular assist devices (LVADs) are totally implantable pumps designed for long-term mechanical circulatory support (MCS) in end-stage heart failure. The success of LVAD is largely determined by the appropriate selection of candidates [1–4]. This manuscript provides a systematic approach to patient evaluation prior to LVAD implantation. Although most of these recommendations are derived from the experiences with the pulsatile, pusher-plate design pumps, these considerations are likely applicable also to the recipients of new generation devices.
General criteria for eligibility Since there are very few prospective trials in patients who undergo LVAD placement as bridge to transplantation (BTT) [5] and very little data on the longterm use of MCS as a permanent alternative to heart transplantation, or destination therapy [6,7], most of the patient selection criteria for LVAD therapy, including the criteria for destination therapy published by the United States Centers for Medicare and Medicaid Services (CMS) [8] are very broad and based on clinical experiences of single centers and data collected by large multi-institutional registries [9,10]. According to the CMS, the destination therapy VADs are covered for patient who have chronic end-stage heart failure (New York Heart Association Class IV end-stage 0268-4705 ß 2009 Wolters Kluwer Health | Lippincott Williams & Wilkins
left ventricular failure for at least 90 days with a life expectancy of less than 2 years), are not candidates for heart transplantation, and meet all of the following conditions: (1) The patient’s Class IV heart failure symptoms have failed to respond to optimal medical management, including dietary salt restriction, diuretics, digitalis, beta-blockers, and ACE inhibitors (if tolerated) for at least 60 of the last 90 days. (2) The patient has a left ventricular ejection fraction (LVEF) less than 25%. (3) The patient has demonstrated functional limitation with a peak oxygen consumption of less than 12 ml/ kg/min; or the patient has a continued need for intravenous inotropic therapy owing to symptomatic hypotension, decreasing renal function, or worsening pulmonary congestion. (4) The patient has the appropriate body size (1.5 m2) to support the VAD implantation. The first formal recommendations regarding candidate selection for LVAD were outlined in the consensus statement from the Conference on the Current Applications and Future Trial Design of the Mechanical Cardiac Support in the year 2000 [11]. In 2006, a more detailed set of proposals was described in the Guidelines for the Care of Cardiac Transplant Candidates by the International Society for Heart and Lung Transplantation [12]. DOI:10.1097/HCO.0b013e32832a0743
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Patient selection for LVAD Lietz and Miller 247
Indications for left-ventricular assist device implantation The most common indication for LVAD implantation is BTT in transplant candidates with profound circulatory failure. This indication accounts for 80% of all LVAD implants [9,10], whereas device placements as destination therapy, or bridge to recovery, are less frequent. The classification of chronic MCS based on the original intent, however, is largely artificial. Patients’ condition often changes while on LVAD support. As many as 17% of destination therapy recipients eventually underwent heart transplantation [7], and one-third of BTT patients became nontransplant candidates with outcomes parallel to those of destination therapy [10].
Selection of candidates for left-ventricular assist device implantation It is recommended that all patients undergo comprehensive evaluation prior to LVAD placement, which includes the following areas: clinical assessment of severity of heart failure (clinical presentation, cardiopulmonary stress testing, hemodynamic studies), cardiac and anatomic considerations (right ventricular function, arrhythmia, anatomic and body size considerations), noncardiac considerations (coexisting life-limiting illnesses, psychosocial and age-related considerations), and assessment of LVAD operative risk.
Clinical assessment of severity of heart failure Patients with end-stage heart failure comprise a heterogenous population in terms of their clinical presentation and outcomes. Seven INTERMACS levels have been proposed to classify the different degrees of clinical severity of stage D heart failure, in patients with New York Heart Association class IV symptoms [13]. The INTERMACS levels and their corresponding survival and potential benefit from MCS are illustrated in Fig. 1 [10]. Of note, this classification does not account for the presence of arrhythmias, which can place a patient in a more advanced level. Also, the corresponding survival is an estimate based on clinical observations and not the actual data. Despite these limitations, the INTERMACS stratification is one of the most helpful clinical indices to stratify the severity of heart failure in patients who reach the end stages of pump failure.
Figure 1 Clinical severity of end-stage heart failure defined by the Interagency Registry for Mechanically Assisted Circulatory Support (INTERMACS) levels
% 1-year survival 100%
7
Class IIIB Walking wounded Housebound
6
50% 25% 10%
5
Frequent flyer
4
Stable dependent
3
Sliding fast
2 1
Crash & burn Dying/MOF
0%
Intermacs level 5--7 3--4 1--2 MOF
Survival Months to years Weeks to months Hours to weeks Hours to days
VAD benefit Not established Yes Yes Bridge to decision in selected cases
The figure illustrates seven INTERMACS levels of clinical severity of endstage heart failure with the corresponding survival. The time frame for consideration of mechanical circulatory support and evidence from clinical trials of 1-year survival benefit with LVAD implantation is shown in the table.
MCS implantations [10]. Although there are no strict hemodynamic criteria for LVAD implantation, most of these patients have abnormally poor hemodynamics (cardiac index <2.0, wedge >20). It is important to emphasize that the incremental increase of inotrope dose, use of pressors or signs of end-organ dysfunction may be a far more important indicator to consider urgent device placement. It is recommended that LVAD implantations in INTERMACS level 1 and 2 be primarily used to rescue potential heart transplantation candidates, whereas destination therapy should be reserved for only stable patients as an elective surgery. Stable inotrope-dependent patient
Cardiogenic shock and patients declining on inotropes
Inotrope dependence is assessed either clinically by demonstrating improvement of heart failure symptoms, vital signs and end-organ function with the use of intravenous inotropic agents and/or hemodynamically by demonstrating improvement of pulmonary artery saturation and/or cardiac output at time of drug infusion. A trial to withdraw inotrope infusion may be attempted in stable inotrope-dependent patients (INTERMACS level 3 – ‘stable dependent’) to define true ‘dependence’. If recurrence of symptoms or end-organ dysfunction ensues, however, repeat attempts should be discouraged [12].
The two most common indications for LVAD placement include: cardiogenic shock (INTERMACS level 1 – ‘crash and burn’) and worsening of symptoms in inotrope-dependent patients (INTERMACS level 2 – ‘sliding down on inotropes’), which account for 60% of all
Inotrope dependence is associated with less than 50% 6months survival and urgent cardiac replacement therapy should be sought for these patients [14]. Both, heart transplantation and LVAD implantation have been
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248 Cardiac failure
shown to provide the greatest survival benefit at this stage of heart failure [15,16]. Although some of these patients can be maintained on continuous infusion of inotropic agents at home, urgent LVAD implantation should be considered if patients’ condition worsens [17]. The criteria for elective LVAD implantation in heart transplantation candidates have not been established. Nevertheless, elective device placement should be considered in patients with anticipated long waiting time to heart transplantation, such as those with anti-HLA antibodies, large body size or ABO blood type ‘O’ [17]. In contrast to transplant candidates, consideration for LVAD implantation as destination therapy in nontransplant candidates who reached inotrope dependence should not be deferred in time, as these patients derive no benefit from prolonged inotropic support, unless it is used to optimize right ventricular (RV) and end-organ function shortly prior to LVAD surgery. Patients with class IIIb/IV heart failure symptoms, not inotrope-dependent
Although the quality of life of patients in INTERMACS levels 4 through 6 is severely compromised, the right timing of LVAD implantation remains an area of controversy. Post-hoc analyses of destination therapy recipients in the REMATCH trial [15] and the postREMATCH cohort [7] showed no survival benefit with LVAD implantation; and early heart transplantation in ambulatory candidates provided little improvement of 1-year survival (94% 1-year survival with heart transplantation versus 89% 1-year survival without heart transplantation) [16]. Consideration for cardiac replacement, however, should not be delayed in these patients, as they comprise a heterogeneous group and their mortality risk may vary significantly. As many as 40% of ambulatory heart transplantation candidates require upgrade to highurgency status or emergency MCS implantation [18]. In noninotrope-dependent patients with class IIIb/IV heart failure cardiopulmonary testing is considered to be the best prognostic of long-term outcomes [19,20]. However, in the current era of medical and device therapy, the cardiopulmonary test in isolation from other predictors of survival may not be sufficient and composite risk scores may be more helpful, such as the Heart Failure Survival Score (HFSS) [21] or the Seattle Heart Failure Risk Score [22].
Cardiac and anatomic considerations Candidates for permanent LVAD implantation should be evaluated for the cardiac and anatomic conditions which can influence successful LVAD support. This includes right ventricular dysfunction, arrhythmia, anatomic and body size considerations. Some of these patients may be
more appropriate candidates for biventricular support or total artificial heart. Right ventricular function
In some patients with advanced heart failure, increased cardiac output and venous return at time of LVAD placement may ‘unmask’ the severity of native RV dysfunction and lead to severe RV failure, resulting in congestive renal and hepatic dysfunction or even cardiogenic shock due to underfilling of the pump. It is estimated that 20–35% of patients who undergo LVAD implant develop RV failure, which significantly contributes to postoperative mortality [23]. The assessment of RV function prior to LVAD implantation, therefore, is of critical importance. Although there have been several clinical predictors of postoperative RV failure identified in single-center series [23,24–31], prospective identification of patients at risk of postoperative RV failure remains challenging. In general, elevated right atrial pressure more than 20 mmHg, low mean pulmonary artery pressure less than 25 mmHg, low right ventricular stroke work index, large and hypokinetic RV (>200 ml), severe tricuspid regurgitation and markers of renal and hepatic dysfunction are all poor prognostics for isolated LV support. Some patients, such as those of smaller body size, females and those with nonischemic cardiomypathy may be at higher risk [23,24–31]. There is some data suggesting that an attempt to optimize RV function with medical therapy and intra-aortic balloon pump can reduce the need for RV assist device insertion [32]. If these attempts fail to correct elevated right-sided pressures, such patients should be considered for or anticipated to require biventricular support. Arrhythmias
Ventricular arrhythmias often resolve after adequate unloading of the left ventricle with LVAD support, unless there is underlying proarrhythmic pathology, such as in giant cell myocarditis. In the presence of normal pulmonary vascular resistance, the Fontan-like circulation allows the RV to maintain filling of the pump and tolerate even malignant ventricular tachyarrythmias while on LVAD support [33]. Preexisting implantable pacemaker (PPM) and intracardiac defibrillators (ICD) have been clinically shown to help adequately control the arrhythmic problems. Of note, some of the St. Jude ICD/PPM models may not be able to establish telemetry and be reprogrammed due to electromagnetic interference with HeartMate II LVAD [34]. Exchange of the programmer should be considered at the time of device implantation. Anatomic considerations
The most important anatomic requirement prior to LVAD implantation is a competent aortic valve. Mildto-moderate aortic insufficiency may increase in the
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Patient selection for LVAD Lietz and Miller 249
presence of elevated aortic root pressure and total unloading of the left ventricle, and surgical correction may be required [2]. Other considerations include a repair of severe mitral or tricuspid regurgitation, correction of mitral stenosis and conversion of metallic prosthetic aortic or mitral valves to a bioprosthesis at the time of LVAD implant. Atrial septal defects and patent foramen ovale are usually closed at the time of surgery. Challenging heart anatomy, such as hypertrophic cardiomyopathies, large ventricular septal defects or congenital cardiac disease, may often preclude LVAD use. Body habitus
Because of the large size of the first generation pusherplate pumps, such as the HeartMate XVE or Novacor LVADs, their use has been limited to patients with a body surface area more than 1.5 m2. Smaller pumps, such as the new generation axial flow or rotary pumps, may be utilized in patients with smaller body areas. In general, both extremes of body weight are associated with increased risk of postoperative complications [35]. Morbid obesity increases the risk of wound infections and prolongs time to match donor heart, whereas cachexia is a marker of severe nutritional deficiencies, and when associated with hypoalbuminemia it is a powerful prognostic of poor outcomes [7].
including stroke with severe impairment of ambulation. Unless it is a metastatic cancer, the history of previous malignancy does not constitute absolute contraindication to LVAD. Occasionally, LVAD may be utilized in these patients to allow proper oncologic treatment and achievement of the target cancer-free period prior to heart transplantation [7]. Presence of heparin-induced antibodies is currently considered a significant risk to postoperative complications with device placement. Psychiatric considerations
It is imperative that the candidate for LVAD shows ability to operate the device (changing batteries, recognize alarms or hand pump) and does not have any major psychiatric disorders, mental retardation or substance addition, which may interfere with compliance with medical regimen and clinic visit follow-up. Social considerations
Social workers should be involved to ensure that the home environment would allow candidates to be able to receive adequate postoperative wound care and medications. Availability of a support network such as a spouse or committed family member who can be available in case of device dysfunction is important. Demonstrated noncompliance with medical recommendations or follow-up is a relative contraindication.
Noncardiac considerations
Special circumstances
Patients evaluated for LVAD implantation should be screened for major comorbid conditions and psychosocial factors, which may preclude successful MCS outcomes or safe device operation.
Although comprehensive evaluation for LVAD implantation should be performed in all candidates, it is not always possible due to the time and logistic constraints. The most challenging clinical situation is acute cardiogenic shock in patients who cannot consent or participate in any type of preoperative evaluation. Brief medical and social history can be gathered prior to emergent LVAD implantation with studies showing similar outcomes of these surgeries to elective cases [36]. Short-term support with percutaneous or implantable devices as bridge to decision can be utilized in uncertain cases or in the case of patients presenting with multiorgan failure or uncertain neurologic status, or both, when permanent pump placement is contraindicated [37]. This may allow time for recovery and better assessment of device/transplant candidacy. The practice of salvaging older patients who are not heart transplantation candidates with emergent implantations as destination therapy should be discouraged due to poor outcomes of such endeavor.
Advanced recipient age
Although age by itself should not be considered a contraindication for LVAD implantation and successful outcomes have been observed in patients in the late 60s and 70s, it is important to note that older patients often have more coexisting comorbidities and thus may be more vulnerable to complications [7]. Moreover, everyday living with the device may present much greater physical, psychological and emotional challenge than to younger patients who are bridged to heart transplantation. Life-limiting comorbidities
Any systemic illness that limits predicted survival to less than 2 years independently of heart disease should be considered a contraindication to LVAD implantation [12]. Examples of severe primary diseases include advanced or irreversible pulmonary disease [forced expiratory volume in 1 s (FEV1) < 1], advanced hepatic disease (cirrhosis and portal hypertension), significant renal dysfunction (chronic hemodialysis or SCr > 3 deemed irreversible), severe peripheral vascular disease, irreversible neurologic or neuromuscular disorders,
Assessment of left-ventricular assist device operative risk The assessment of operative risk in LVAD candidates is of tremendous importance. Experiences with chronic MCS have consistently demonstrated that the vast majority of deaths occurred prior to hospital discharge
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250 Cardiac failure Table 1 Risk screening scales to predict mortality after LVAD implantation (A–C)
Figure 2 Survival with destination therapy by the operative risk
(A) Columbia University: Cleveland Clinic Risk Scale Patient characteristics Urine output <30 ml/h Central venous pressure >16 mmHg Prothrombin time >16 s Mechanical ventilation Redo surgery
Survival 100 (%) 80
Weighted Risk Score 3 2 2 2 1
Mechanical ventilation Postcardiotomy Bridge-to-bridge Central venous pressure >16 mmHg Prothrombin time >16 s
40%
(C) Destination Therapy Risk Score Patient characteristics Platelet count 148 103/ml Serum albumin 3.3 g/dl International normalization ratio >1.1 Vasodilator therapy Mean pulmonary artery pressures 25 mmHg Aspartate aminotransferase >45 U/ml Hematocrit 34% Blood urea nitrogen >51 U/dl No intravenous inotropes
Weighted Risk Score 7 5 4 4 3 2 2 2 2
Adapted with permission from [7,38,39].
and were largely related to operative complications, such as sepsis, multiorgan failure, bleeding, right ventricular failure and stroke [1–4,7,11]. Several risk factors have been identified to correlate with increased operative risk of LVAD placement, including the markers of right ventricular dysfunction [23,24–31,40], abnormal renal [7,9,40–43], liver [7,12,42] and lung function and history of pulmonary infarct [7,9,42], coagulation and hematologic abnormalities [7,9,38], nutritional deficiency [7], previous cardiac surgeries [38], small body surface area [7], active infection [7,38]. As there is no one predictor that would correlate with LVAD operative outcomes, composite risk scores have been used to help predict the outcomes with device placement, such as the APACHE II score (Acute Physiology and Chronic Health Evaluation) [43] and the Heart Failure Survival Score [21]. In recent years, risk scales have been derived in BTT patients [38,39] and those who underwent destination therapy [7], as shown in Table 1. The Destination Therapy Risk Score used the largest cohort of 222 patients studied to date [7]. It was designed to help clinicians prospectively estimate candidate 90-day probability of in-hospital mortality after LVAD implantation. Patients who were considered to have a lower operative risk (cumulative Destination Therapy Risk Score 16),
Medical therapy 26%
40 20
Weighted Risk Score 4 2 2 1 1
Acceptable operative candidates
60
(B) Columbia University – Cleveland Clinic Revised Risk Scale Patient characteristics
69%
High-risk operative candidates
19% 8%
0 0
4
8
12
16
20
24
Months after LVAD implantation
The graph shows 2-year survival with destination therapy stratified by the operative risk estimated using the Destination Therapy Risk Score in the post-REMATCH population of patients who underwent LVAD implantation as destination therapy in the United States between years 2002 and 2005. High-risk candidates were defined as those with in-hospital mortality risk >50%, which is equivalent to the Destination Therapy Risk Score >16. Adopted with permission from [44].
were more likely to survive surgery and achieved a 1-year survival ranging between 71 and 80%, whereas high-risk operative candidates had poor outcomes (1-year survival <15%), inferior to even those of medical therapy in the REMATCH trial (1-year survival 28%), as illustrated in Fig. 2 [44]. Of note, the Destination Therapy Risk Score did not account for the presence of mechanical ventilation, intraaortic balloon pump and the recipient body surface area less than 1.7 m2 due to their small prevalence in the studied cohort. Also data on INTERMACS levels of clinical severity of heart failure was not available. Hopefully, in the future new more sophisticated models will be derived from the newly established INTERMACS Registry.
Conclusion Appropriate assessment of candidates for LVAD implantations is of paramount importance. As technology will continue to advance and new devices provide life-saving treatment, more research will be needed to better understand the key determinants of successful operative and long-term LVAD outcomes.
References and recommended reading Papers of particular interest, published within the annual period of review, have been highlighted as: of special interest of outstanding interest Additional references related to this topic can also be found in the Current World Literature section in this issue (p. 267). 1
Miller LW. Patient selection for use of ventricular assist devices as a bridge to transplantation. Ann Thorac Surg 2003; 75:S66–S71.
2
Aaronson KD, Patel H, Pagani FD. Patient selection for left ventricular assist device therapy. Ann Thorac Surg 2003; 75:S29–S35.
3
Looebe M, Koerner MM, Laufeuent J, Noon GP. Patient selection for assist devices: bridge to transplant. Curr Opinion in Cardiology 2003; 18:141–146.
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
Patient selection for LVAD Lietz and Miller 251 4
Miller LW, Lietz K. Candidate selection for long-term left ventricular assist device therapy for refractory heart failure. J Heart Lung Transplant 2006; 25:756–764.
5
Miller LW, Pagani FD, Russell SD, et al., for the HeartMate II Clinical Investigators. Use of continuous-flow device in patients awaiting heart transplantation. N Engl J Med 2007; 357:885–896.
6
Rose EA, Gelijns AC, Moskowitz AJ, et al. Randomized Evaluation of Mechanical Assistance for the Treatment of Congestive Heart Failure (REMATCH) Study Group. Long-term mechanical left ventricular assistance for end-stage heart failure. N Engl J Med 2001; 345:1435–1443.
Lietz K, Long JW, Kfoury AG, et al. Outcomes of left ventricular assist device implantation as destination therapy in the post-REMATCH era. Implications for patient selection. Circulation 2007; 116:497–505. This paper describes outcomes of destination therapy in the post-REMATCH era in the US. The studied patients comprised the derivation cohort to design Destination Therapy Risk Score, which would allow clinicians to prospectively identify patients at risk of 90-days in-hospital death after elective LVAD implantation as destination therapy.
7
Centers for Medicare and Medicaid Services (CMS). The National Coverage Determination for Artificial Hearts and Related Devices. Online Manual System, Section 20.9. http://www.cms.hhs.gov/manuals/downloads/ncd103c1_Part1. pdf. [Accessed 1 November 2008] In March 2007 the United States Centers for Medicare and Medicaid Services updated the Medicare coverage determination, in which they outlined, in addition to the criteria for selecting patients for destination therapy, also details of the mandatory requirements regarding standards of care for destination therapy recipients.
8
9
Deng MC, Edwards LB, Hertz MI, et al. International Society for Heart and Lung Transplantation. Mechanical circulatory support device database of the International Society for Heart and Lung Transplantation: third annual report: 2005. J Heart Lung Transplant 2005; 24:1182–1187.
10 Interagency Registry for Mechanically Assisted Circulatory Support (INTER MACS) Official Website. http://www.intermacs.org/membership.aspx. [Accessed 28 November 2008] The INTERMACS Registry website provides current outcomes of mechanical circulatory support in patients who underwent device placement after 2006 in the United States. 11 Stevenson LW, Kormos RL. Consensus Conference Report: Mechanical Cardiac Support 2000: Current Applications and Future Trial Design. JACC 2000; 37:334–370.
22 Levy WC, Mozaffarian D, Linker DT, et al. The Seattle Heart Failure Model: prediction of survival in heart failure. Circulation 2006; 113:1424–1433. 23 Matthews JC, Koelling TM, Pagani FD, Aaronson KD. The right ventricular failure risk score a preoperative tool for assessing the risk of right ventricular failure in left ventricular assist device candidates. J Am Coll Cardiol 2008; 51:2163–2172. In this article authors designed a Right Ventricular Failure Risk Score in order to help clinicians estimate the risk of right ventricular failure after LVAD implantation. 24 Nakatani S, Thomas JD, Savage RM, et al. Prediction of right ventricular dysfunction after left ventricular assist device implantation. Circulation 1996; 94:II216–II221. 25 Farrar DJ, Hill JD, Pennington DG, et al. Preoperative and postoperative comparison of patients with univentricular and biventricular support with the Thoratec ventricular assist device as a bridge to cardiac transplantation. J Thorac Cardiovsc Surg 1997; 113:202–209. 26 Fukamachi K, McCarthy PM, Smedira NG, et al. Preoperative risk factors for right ventricular failure after implantable left ventricular assist device insertion. Ann Thorac Surg 1999; 68:2181–2184. 27 Ochiai Y, McCarthy PM, Smedira NG, et al. Predictors of severe right ventricular failure after implantable left ventricular assist device insertion: Analysis of 245 patients. Circulation 2002; 106: I198–202. 28 Kavarana MN, Pessin-Minsley MS, Urtecho J, et al. Right ventricular dysfunction and organ failure in left ventricular assist device recipients: a continuing problem. Ann Thorac Surg 2002; 73:745–750. 29 Morgan JA, John R, Lee BJ, et al. Is severe right ventricular failure in left ventricular assist device recipients a risk factor for unsuccessful bridging to transplant and posttransplant mortality. Ann Thorac Surg 2004; 77:859– 863. 30 Dang NC, Topkara VK, Mercando M, et al. Right heart failure after left ventricular assist device implantation in patients with chronic congestive heart failure. J Heart Lung Transplant 2006; 25:1–6. 31 Santambrogio L, Bianchi T, Fuardo M, et al. Right ventricular failure after left ventricular assist device insertion: preoperative risk factors. Interact Cardiovasc Thorac Surg 2006; 5:379–382. 32 Marquez TT, D’Cuhna J, John R, et al. Mechanical support for acute right ventricular failure: evolving surgical paradigms. J Thorac Cardiovasc Surg 2009; 137:e39–40. 33 Oz MC, Rose EA, Slater J, et al. Malignant ventricular arrhythmias are well tolerated in patients receiving long-term left ventricular assist devices. J Am Coll Cardiol 1994; 24:1688–1691.
12 Gronda E, Bourge RC, Constanzo MR, et al. Heart rhythm considerations in heart transplant candidates and considerations for ventricular assist devices: International Society of Heart and Lung Transplantation Guidelines for the Care of Cardiac Transplant Candidates: 2006. J Heart Lung Transplant 2006; 25:1043–1056.
34 Thoratec Corporation Official Website. HeartMate II Clinical Outcomes. http://www.thoratec.com/vad-trials-outcomes/clinical-outcomes/heartmatell-lvad.aspx. [Accessed 1 November 2008]
13 Stevenson LW. The evolving role of mechanical circulatory support in advanced heart failure. International Society for Heart and Lung Transplantation Monograph Series. Mechanical Circulatory Support. 1st ed. Elsevier Inc.; 2006.
35 Musci M, Loforte A, Potapov EV, et al. Body mass index and outcome after ventricular assist device placement. Ann Thorac Surg 2008; 86: 1236–1242.
14 Stevenson LW. Clinical use of inotropic therapy for heart failure: looking backward or forward? Circulation 2003; 108:397–492. 15 Stevenson LW, Miller LW, Desvigne-Nickens P, et al., REMATCH Investigators. Left ventricular assist device as destination for patients undergoing intravenous inotropic therapy: a subset analysis from REMATCH (Randomized Evaluation of Mechanical Assistance in Treatment of Chronic Heart Failure). Circulation 2004; 110:975–981. 16 Lietz K, Miller LW. Improved survival of patients with end-stage heart failure listed for heart transplantation: analysis of organ procurement and transplantation network/U.S. United Network of Organ Sharing data, 1990 to 2005. J Am Coll Cardiol 2007; 50:1282–1290. 17 Lietz K, Deng MC, Morgan J, et al. Selection of UNOS Status 1A Candidates for Mechanical Circulatory Support as Bridge-to-Transplantation (BTT) – Analysis of UNOS/OPTN 2000–2005. J Heart Lung Transplant 2007; 27: S244 [Abstract]. 18 Mokadam NA, Ewald GA, Damiano RJ, Moazami N. Deterioration and mortality among patients with United Network for Organ Sharing status 2 heart disease: caution must be exercised in diverting organs. J Thorac Cardiovasc Surgery 2006; 131:925–926. 19 Mehra MR, Kobashigawa J, Starling R, et al. Listing criteria for heart transplantation: International Society for Heart and Lung Transplantation guidelines for the care of cardiac transplant candidates: 2006. J Heart Lung Transplant 2006; 25:1024–1042. 20 Mancini DM, Eisen H, Kussmaul W, et al. Value of peak exercise oxygen consumption for optimal timing of cardiac transplantation in ambulatory patients with heart failure. Circulation 1991; 83:778–786. 21 Aaronson KD, Schwartz JS, Chen TM, et al. Development and prospective validation of a clinical index to predict survival in ambulatory patients referred for cardiac transplant evaluation. Circulation 1997; 95:2660–2667.
36 Williams M, Casher J, Joshi N, et al. Insertion of a left ventricular assist device in patients without thorough transplant evaluations: a worthwhile risk? J Thorac Cardiovasc Surg 2003; 126:436–441. 37 John R, Liao K, Lietz K, et al. Experience with the Levitronix CentriMag circulatory support system as a bridge to decision in patients with refractory acute cardiogenic shock and multisystem organ failure. J Thorac Cardiovasc Surg 2007; 134:351–358. 38 Oz MC, Godstein DJ, Peino P, et al. Screening scale predicts patients successfully receiving long-term implantable left ventricular assist devices. Circulation 1995; 92 (Suppl):II-169–II-73. 39 Rao V, Oz MC, Flannery MA, et al. Revised screening scale to predict survival after insertion of a left ventricular assist device. J Thorac Cardiovasc Surg 2003; 125:855–862. 40 Farrar DJ. Preoperative predictors of survival in patients with Thoratec ventricular assist devices as a bridge to transplantation. J Heart Lung Transplant 1994; 13:93–100. 41 Reedy JE, Swartz MT, Miller LW, Pennington DG. Bridge to transplantation: importance of patient selection. J Heart Lung Transplant 1990; 9:473–480. 42 Butler J, Geisberg C, Howser R, et al. Relationship between renal function and left ventricular assist device use. Ann Thorac Surg 2006; 81:1745–1751. 43 Gracin N, Johnson MR, Spokas D, et al. The use of APACHE II scores to select candidates for left ventricular assist device placement. J Heart Lung Transplant 1998; 17:1017–1023. 44 Lietz K, Miller LW. Destination therapy: current results and future promise. Semin Thorac Cardiovasc Surg 2008; 20:225–233. Review article which describes current outcomes of LVAD implantation as destination therapy in the United States, selection of candidates and the future areas of development.
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Management of left ventricular assist devices after surgery: bridge, destination, and recovery Maria M. Mountis and Randall C. Starling Department of Medicine, Heart and Vascular Institute, Kaufman Center for Heart Failure, Cleveland Clinic Foundation, Cleveland, Ohio, USA Correspondence to Dr Maria M. Mountis, 9500 Euclid Avenue J3-4, Cleveland, OH 44195, USA Tel: +1 216 636 6101; fax: +1 216 445 6197; e-mail:
[email protected] Current Opinion in Cardiology 2009, 24:252–256
Purpose of review As the use and understanding of mechanical circulatory support (MCS) increases, the management of these devices has become more conventional. The purpose of this review is to discuss the perioperative and long-term management of MCS patients. Recent findings With the advent of axial flow pumps, both perioperative and long-term management are more standardized. The issues of nutrition, physical therapy, drive line care, and readiness to transition to home are becoming more mainstream and are readily accepted into the community. However, many factors remain that are not well defined in dealing with anticoagulation, weaning of MCS, achieving optimal device settings, and end-of-life care. Summary Care for the MCS patient provided in a multidisciplinary team approach is imperative to allow for a seamless transition from the hospital and into the community and successful long-term outcomes. Keywords bridge to transplant, destination therapy, mechanical circulatory support, ventricular assist device Curr Opin Cardiol 24:252–256 ß 2009 Wolters Kluwer Health | Lippincott Williams & Wilkins 0268-4705
Introduction With the expanded and increased use of mechanical circulatory support (MCS) for bridge to cardiac transplantation (BTT), destination therapy, and bridge to recovery (BTR), the management of these patients is becoming more routine, although many unanswered questions remain in terms of optimization of axial flow pumps and weaning of devices for recovery. It is evident that there is increased demand for MCS-related services provided by healthcare workers, family members, and the community. This review provides a synopsis of how MCS patients are currently being managed in both the perioperative and long-term periods. A brief review of anticoagulation management, drive line care, infection prevention, hypertension management, end-of-life management, and the difficulties that are still encountered, will also be addressed.
Bridge to transplant As the number of organ donors remains stable and the number of patients waiting on the transplant list grows, the earlier use of MCS as a BTT has become a favored therapy [1,2,3]. In our institution, the majority of MCS patients are classified as BTT. Healing from the MCS surgery, improvement from the de-conditioned state, 0268-4705 ß 2009 Wolters Kluwer Health | Lippincott Williams & Wilkins
stabilization of renal function, achieving optimal nutritional status, and maintaining goal levels of physical therapy are benchmarks prior to re-activating the transplant listing. Close follow-up with cardiology, cardiothoracic surgery, and the pretransplant coordinators is maintained to review blood work, immunization status, and sensitization status. Some patients require a right heart catheterization (RHC) to assess pulmonary artery pressures. All undergo computed tomography (CT) scan of the chest to review cardiac anatomy prior to transplant.
Destination therapy As the aging US population lives longer with chronic illnesses, more individuals are not candidates for cardiac transplantation due to co-morbidities and may be offered MCS as destination therapy. The HeartMate XVE left ventricular assist device (LVAD) is FDA approved for use as destination therapy for patients with NYHA class IV heart failure who have received optimal medical therapy (OMT) for at least 60 of the last 90 days, have a life expectancy of less than 2 years, and are ineligible for transplantation (http://www.cms.hhs.gov/Transmittals/ Downloads/R68NCD.pdf). Two ongoing trials are randomizing patients to receive either newer generation MCS devices as destination therapy to the approved HeartMate XVE LVAD. DOI:10.1097/HCO.0b013e32832c7c09
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Management of left ventricular assist devices Mountis and Starling 253
Improved quality of life and integration into the community are goals for patients referred for destination therapy. Referring cardiologists and primary care physicians seldom hesitate to help care for these patients who require ongoing management of underlying medical illnesses. Destination therapy patients become proficient in attending to the drive line, monitoring vital signs, and reporting any device alarms to the implant center. As MCS therapy alters the trajectory of advanced heart failure, the resulting uncertainty can be anxiety-provoking to patients. Early involvement of colleagues from social work, bioethics, palliative care, psychiatry, and psychology is important to help provide destination therapy patients a functional and fulfilling life [4,5].
Bridge to recovery BTR patients may also present many challenges. Despite the existing risk calculators available from the Interagency Registry for Mechanically Assisted Circulatory Support (INTERMACS), Leitz, and the Seattle Heart Failure Score, choosing appropriate patients is fraught with uncertainty [6,7,8]. It appears that potential BTR individuals assessed after implant with nonischemic cardiomyopathy of less than 6 months’ duration, with ejection fractions more than 45%, end-diastolic dimension (EDD) less than 55 cm, and who are on OMT have the highest probability of recovery [9]. Patients with ischemic heart disease require viability assessment and may benefit from complete revascularization [10]. Regardless of cause, all BTR patients are treated aggressively with neurohormonal antagonists [11]. Angiotensinconverting enzyme inhibitors, angiotensin receptor blockers, beta-blockers, and aldosterone antagonists are uptitrated to published evidence-based heart failure guidelines.
removal of LV support. This involves a team from echocardiography, cardiology, MCS nurse coordinators, and cardiothoracic surgery, and a patient that is fully anticoagulated for this procedure. If EDD, ejection fraction, and pulmonary artery pressures remain stable, valvular insufficiency does not worsen, and there is appropriate ejection across the aortic valve, then a patient may be considered for device explant.
Perioperative management The perioperative management of MCS patients begins with appropriate selection. Timing of implanting a device continues to face many uncertainties. Several models exist to aid in predicting patients’ morbidity and mortality. Numerous inpatient and fewer outpatient risk studies have shown that worsening renal function, escalating diuretic requirement, and inability to tolerate OMT predict mortality. INTERMACS developed seven profiles that can assist in patient selection. In any well established MCS program, a multidisciplinary team carefully assesses preoperative risk and helps formulate a management strategy. Cardiothoracic surgeons, heart failure cardiologists, MCS clinicians, surgical intensivists, nurses, nutritionists, physical therapists, social workers, pharmacists, and house-staff work tirelessly to manage these complex individuals [14]. Postoperatively, a survey of all organ systems is conducted. Periodic neurological assessments evaluate eye-opening, limb movement, and command following, having a low threshold to obtain a brain CT scan, should there be a change in neurological function. Routine prophylaxis measures are followed for gastritis, aspiration, and deep venous thrombosis.
Clenbuterol, a selective beta-2 agonist, has been studied as a myocardial atrophy preventive and is approved for clinical use in Canada and Europe, but not in the United States. The Harefield Recovery Protocol Study (HARPS) is an ongoing clinical trial to evaluate whether advanced heart failure patients requiring MCS can recover sufficient myocardial function to allow explantation. HARPS combines the HeartMate XVE with conventional oral heart failure medications, followed by the addition of Clenbuterol. The HARPS trial is ongoing and enrolling patients in the United States (www.clinicaltrial.gov) [12].
From the infectious perspective, preoperative recommendations include maintaining current vaccination status and screening for staphylococcal colonization via nasal swab. Patients who test positive are treated with Mupirocin. Prior to surgery, patients wash with Hibiclens and are administered antimicrobial prophylaxis with Vancomycin and Aztreonam. Drive lines are covered with sterile occlusive dressings, are immobilized with a binder, and are maintained for 24 h. Dressings are changed daily unless bleeding occurs, which necessitates more frequent bandage changes. Maintaining well controlled glucose levels with an insulin infusion is important.
Patients with steady improvement of ejection fraction and LVEDD, on target neurohormonal antagonist therapy, who are fully revascularized, with no significant valvular abnormalities, and are felt to be recoverable, will undergo a ‘turn down’ echo with concomitant RHC [13]. The goal is to assess native myocardial function and the response of the pulmonary vasculature with slow
Early extubation occurs once a patient is deemed to be hemodynamically stable, have appropriate neurological function, controlled arrhythmias, minimal bleeding, scant secretions, and maintained on low dose vasopressors. Pulmonary artery catheters remain in for the first 48– 72 h to manage hemodynamics which are altered with the unloading of the LV.
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254 Cardiac failure
Many patients are placed on inhaled nitric oxide to help manage elevated pulmonary artery pressures and unload the right ventricle (RV), which also improves with diuresis and weaning off pressor support. Patients with chronically elevated central venous pressure (CVP) may have associated decreased glomerular filtration rate, diuretic unresponsiveness, and acute renal failure [15]. In these instances, early ultra-filtration may be quite effective. Echoes are performed intra-operatively and postoperatively, to assess placement of the MCS inflow cannula, unloading of the LV, and function of the RV. It is also used to ensure maintaining midline position of the interventricular septum and opening of the aortic valve. Once vasoactive medications have been discontinued and optimal fluid management has been achieved, a predischarge echo will be completed to optimize the device settings by adjusting RPMs [16,17]. When assessing the RV, the concern of right ventricular dysfunction is always present [18]. Insults to the RV may be precipitated by pulmonary hypertension, elevated CVP, and large amounts of blood products received intra-operatively. Reported impact of pulsatile versus axial flow devices on the RV have varied, and the data are still being collected. It appears that the axial flow devices, when managed appropriately, have less effect on the RV as long as the septum is maintained in a mid-line position and not forced to bow to the left with high flows. Management of right ventricular failure may include inotropic support for the RV, temporary RVAD support, and therapy for pulmonary hypertension including oxygenation, nitric oxide, and oral vasodilator therapy such as sildenafil. The need for chronic inotropic support is associated with poor outcomes [19]. Every effort is made to maintain normal sinus rhythm, as arrhythmias may affect MCS flows and lead to implantable cardioverter defibrillator (ICD) shocks [20]. The most common postoperative arrhythmias may be ventricular arrhythmias or ventricular fibrillation from electrolyte imbalances, adrenergic agents, or suction events from the increased pump flows leading to the outflow cannula abutting the interventricular septum. Arrhythmia treatment includes medical therapy or electrical cardioversion. ICD shocks are interrogated immediately postoperatively to turn the device on and to verify preoperative settings. Currently, no guidelines exist for the management of cardiac resynchronization therapy with MCS. Many centers will disable this function as it may interfere with septal motion, which is directly affected when RPMs are adjusted. The surgical team monitors the drainage from mediastinal and chest tubes, and once stable and after consider-
ing the patients’ comorbidities and risks for thrombosis, patients are started on anticoagulation with heparin and warfarin. Some centers have eliminated the use of heparin and have only initiated warfarin after patients leave the ICU and are taking oral nutrition. For patients with heparin-induced thrombocytopenia, thrombin inhibitors are utilized at the discretion of the implanting surgeon. The management of anticoagulation continues to be a controversial subject, as this topic has not been standardized in the MCS population. Guidelines and recommendations from the specific device companies are followed, although with certain comorbidities and the propensity of some patients to bleed, anticoagulation becomes quite difficult. Thromboelastography (TEG) is used by some centers to manage and adjust anticoagulation [21]. Protocols vary, although many include daily TEG to assess antiplatelet needs until satisfactory. Weekly multidisciplinary meetings are held to review patients and their progress. Recommendations made by dieticians, physical therapists, and social workers are followed closely to help with discharge planning. Cardiac rehabilitation is started as an inpatient and maintained through the postoperative period, as all patients are discharged to a local rehabilitation facility prior to discharge into their community. Lastly, each patient and their family will undergo training on their specific device with the nurse educator and must achieve certain competencies prior to discharge [22].
Long-term management Outpatient management of MCS patients is time-intensive, yet the same multidisciplinary approach is used in their long-term care. Many patients are waiting for transplant, whereas others adopt this new lifestyle permanently. Occasionally, patients deemed to be destination therapy or bridge to decision at the time of implant may have circumstances evolve that make them acceptable transplant candidates. A minority of individuals will be bridged to recovery. Successful discharge planning begins preoperatively, with assessment of the cognitive abilities of the patient and their support system, their home environment, and certain financial considerations. Device education and self-care management are completed by the VAD team. Discharge criteria entail suitable recovery from the surgical procedure, proficiency in the management of the equipment, and understanding the medical regimen. Readiness of the home includes grounded outlets, availability of an emergency generator, notifying the electrical company of life support in use, and providing the patient with an emergency contact list for the implanting hospital [23].
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Management of left ventricular assist devices Mountis and Starling 255
Once discharged, patients are followed in a fashion similar to newly transplanted patients. A typical visit schedule may be weekly for 1 month, biweekly for 1 month, then monthly. If patients do not reside locally, the care is shared by the referring cardiologist. Typical visit concerns are those of anticoagulation, nutrition, physical therapy, management of heart failure, hypertension, and psychosocial status.
Hypertension With the axial flow devices, conventional measurement of blood pressure (BP) is difficult, thus it becomes common practice to use the mean BP by a Doppler reading. In the immediate postoperative period, an arterial line is used to follow BP. After the patient transitions to the floor and in the outpatient setting, Doppler measurement with a manual BP cuff is used by listening to the first Korotkoff sounds, assumed to represent the mean BP. There appears to be a predisposition for patients to develop hypertension post-MCS implant and its management is crucial. We strive to maintain mean BP between 70 and 90 mmHg by using evidence-based medications for hypertension and heart failure. It is imperative to maintain ideal BP to prevent end-organ damage and to lower possible risks of cerebral bleeds.
needed. The ASA/CLO resistance panel is done to measure the arachidonic acid and adenosine di-phosphate aggregation with optimal arachidonic acid aggregation being less than 20% and ADP aggregation less than 70%. Hemolysis is less common in the axial flow pumps. Measurement of LDH and plasma free hemoglobin is performed with each visit. Potential sources of hemolysis are inflow and outflow cannula occlusions, liver dysfunction, and blood product use. Imaging of the device by echo or fluoroscopy and temporarily reducing pump speed may be required.
Drive line care Sterile technique is required during drive line care and is maintained on a daily basis. We offer instructional DVDs to nurses, caregivers, and home health aides to provide the utmost care and decrease the incidence of infection. As the drive line starts to heal and forms appropriate ingrowth, the amount of drainage will decrease. If this does not occur, patients may require a course of antibiotics to prevent overt drive line infections.
End of life Anticoagulation Attempts are made to closely follow the manufacturer’s printed guidelines for anticoagulation, yet managing thromboembolic and bleeding risks is a challenge (Table 1). A thorough understanding of the device, medications, and laboratory testing is necessary. In the outpatient setting, typical blood testing includes a PT/ INR, PTT, CBC, aspirin, and clopidogrel (ASA/CLO) resistance panel to determine effectiveness of antiplatelet therapy. Each patient’s nutritional status, degree of hepatic congestion and response to antiplatelet or anticoagulation therapy varies, and adjustments may be
In our institution, we are fortunate to have involvement of social workers and bioethicists work closely with our VAD patients. The guiding principle is respect for the patients and their rights and planning future care, which should include completion of advanced directives [24,25]. We integrate palliative care resources throughout the treatment process, beginning with preimplantation informed consent [26]. There is a commitment to evidence-based standards of care that is both ethically and legally supportable. There is a commitment by a multidisciplinary group of individuals to clear and consistent communication that can improve patient and family care, experiences, and outcomes.
Table 1 Anticoagulation and platelet inhibition for mechanical circulatory support devices
Aspirin Heparin Coumadin Persantine Clopidogrel Pentoxifylline Bivalrudin PT/INR aPTT Aggregation
HeartMate XVE
HeartMate II
Thoratec VAD
Novacor N-100
CardioWest TAH
X
X O X X O
X X X O O O
X X X X O O
X O X X O X
1.7–2.5 45–50 s titrating to 55–65 s within 48 h (1.4–1.7 times control) AA <20%; ADP <50%
2.5–3.5 45–50 s titrating to 55–65 s within 48 h (1.5 times control)
2.0–3.0 45–60 s (1.5–2.0 times control)
2.0–3.0 Titrate to 50–55 s
O
WNL WNL
This table reflects the practice in our institution. O, optionally used; X, routinely used.
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256 Cardiac failure
Conclusion MCS has become a mainstay of therapy for advanced heart failure. The comfort level with management of these patients continues to grow. Many unanswered questions and dilemmas remain regarding the management of MCS devices. What is the utility of biventricular pacing in the setting of MCS? Is there presumed to be acquired von Willebrand Factor in certain patients and how should it be managed [27]? What is the role of erythropoietin therapy in these patients? What are the long-term effects of nonpulsatile flow? How do we manage preexisting mechanical valves with devices? Do ICD shocks improve long-term mortality in VADs? As MCS therapy becomes mainstream serving thousands of patients, evidence-based care algorithms will evolve to optimize outcomes [28].
Dandel M, Weng Y, Siniawski H, et al. Prediction of cardiac stability after weaning from left ventricular assist devices in patients with idiopathic dilated cardiomyopathy. Circulation 2008; 118 (Suppl 1):S94–S105. This article reviews criteria that allow identification of patients which predicts stability after VAD explantation.
9
10 Allen LA, Felker GM. Advances in the surgical treatment of heart failure. Curr Opin Cardiol 2008; 23:249–253. 11 Soppa GKR, Barton PJR, Terracciano CMN, et al. Left ventricular assist device-induced molecular changes in the failing myocardium. Curr Opin Cardiol 2008; 23:206–218. 12 Yacoub MH, Birks EJ, Tansley P, et al. Bridge to recovery: The Harefield Approach. J Congest Heart Fail Circulat Support 2001; 2:27–30. 13 Maybaum S, Mancini D, Xydas S, et al. Cardiac improvement during mechanical circulatory support: a prospective multicenter study of the LVAD working group. Circulation 2007; 115:2497–2505. 14 Osaki S, Edwards NM, Velez M, et al. Improved survival in patients with ventricular assist device therapy: the University of Wisconsin Experience. Eur J Cardiothorac Surg 2008; 34:281–288. 15 Ronco C, Haapio M, House AA, et al. Cardiorenal syndrome. J Am Coll Cardiol 2008; 52:1527–1539. 16 Horton SC, Khodaveradian R, Chatelain P, et al. Left ventricular assist device malfunction: an approach to diagnosis by echocardiography. J Am Coll Cardiol 2005; 45:1435–1440.
References and recommended reading
17 Chumnanvej S, Wood MJ, MacGillivray TE, et al. Perioperative echocardiographic examination for ventricular assist device implantation. Anesth Analg 2007; 105:583–601.
Papers of particular interest, published within the annual period of review, have been highlighted as: of special interest of outstanding interest Additional references related to this topic can also be found in the Current World Literature section in this issue (pp. 267–268).
18 Matthews JC, Koelling TM, Pagani FD, et al. The right ventricular failure risk score: a pre-operative tool for assessing the risk of right ventricular failure in left ventricular assist device candidates. J Am Coll Cardiol 2008; 51:2163– 2172. This article reviews the clinical data that aid in stratifying the risk of RV failure and death after LVAD implantation.
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McCalmont V, Ohler L. Cardiac transplantation: candidate identification, evaluation, and management. Crit Care Nursing 2008; 3:216–229.
Miller LW, Pagani FD, Russell SD, et al. Use of a continuous-flow device in patients awaiting heart transplantation. N Engl J Med 2007; 357:885– 896. This article establishes the viability of continuous axial flow devices for bridging patients to transplantation.
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Jeevanandam V, Eisen H. Intermediate and long-term mechanical cardiac support. UpToDate 2008; version 16.2.
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Bramstedt KA. Destination nowhere: a potential dilemma with ventricular assist devices. ASAIO J 2008; 54:1–2.
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19 Schenk S, McCarthy PM, Blackstone EH, et al. Duration of inotropic support after left ventricular assist device implantation: risk factors and impact on outcome. J Thorac Cardiovasc Surg 2006; 131:447–454. 20 Christensen DM. Extreme heart makeover: understanding mechanic circulatory support. Nursing 2008; 38:49–53. 21 Nielsen VG, Kirklin JK, Holman WL, et al. Mechanical circulatory device thrombosis: a new paradigm linking hypercoagulation and hyperfibrinolysis. ASAIO J 2008; 54:351–358. 22 Slaughter MS, Sobieski MA, Martin M, et al. Home discharge experience with the thoratec TLC-II portable driver. ASAIO J 2007; 53:132–135. 23 Semuth SC, Richenbacher WE. Education of the ventricular assist device patient’s community services. ASAIO J 2001; 47:596–601. 24 Kirkpatrick JN, Fedson SE, Verdino R. Ethical dilemmas in device treatment for advanced heart failure. Curr Opin Support Palliat Care 2007; 1:267–273.
Lietz K, Long JW, Kfoury AG, et al. Outcomes of left ventricular assist device implantation as destination therapy in the post-REMATCH era: implications for patient selection. Circulation 2007; 116:497–505. This article reviews appropriate selection criteria of candidates and timing of LVAD implantation for improved outcomes of destination therapy.
25 Wiegand DLM, Kalowes PG. Withdrawal of cardiac medications and devices. AACN Adv Crit Care 2007; 4:415–425.
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27 Geisen U, Heilmann C, Beyersdorf F, et al. Nonsurgical bleeding in patients with ventricular assist devices could be explained by acquired von Willebrand disease. Eur J Cardiothorac Surg 2008; 33:679–684.
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26 Rizzieri AG, Verheijde JL, Rady MY, et al. Ethical challenges with the left ventricular assist device as a destination therapy. Philosophy Ethics Human Med 2008; 3:20–35.
28 Struber M, Sander K, Lahpor J, et al. HeartMate II left ventricular assist device: early European experience. Eur J Cardiothorac Surg 2008; 34:289–294.
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Bibliography Current World Literature This bibliography is compiled by clinicians from the journals listed at the end of this publication. It is based on literature entered into our database between 1 January 2008 and 31 December 2008 (articles are generally added to the database about two and a half months after publication). In addition, the bibliography contains every paper annotated by reviewers; these references were obtained from a variety of bibliographic databases and published between the beginning of the review period and the time of going to press. The bibliography has been grouped into topics that relate to the reviews in this issue.
Papers considered by the reviewers to be of special interest Papers considered by the reviewers to be of outstanding interest The number in square brackets following a selected paper, e.g. [7], refers to its number in the annotated references of the corresponding review. Current Opinion in Cardiology 2009, 24:257–271
Contents Molecular genetics 257 Hypertrophic cardiomyopathy 259 Arrhythmogenic right ventricular cardiomyopathy 260 Lamin A/C deficiency as a cause of familial dilated cardiomyopathy 260 Left ventricular noncompaction 260 Restrictive cardiomyopathy
Vol 24 No 3 May 2009
267 Management of HF patients when percutanous interventions are required: special considerations 267 Patient selection for left-ventricular assist devices 267 Management of left ventricular assist devices after surgery: bridge, destination, and recovery 268 Role of imaging in diagnosis of heart failure
261 Coexistent skeletal and cardiomyopathy
269 Cardiac resynchronisation and improvement in end style heart failure
261 Miscellaneous
270 Biomarkers
Cardiac failure
270 Miscellaneous
261 Hemodynamic of heart failure meets cell biology: the new paradigm 262 Mechanisms of chronic heart failure: therapeutic strategies that attenuate pathological remodeling in systolic heart failure 263 The challenges associated with current clinical trials for diastolic heart failure 264 Trying to succeed when the right ventricle fails
# 2009 Wolters Kluwer Health | Lippincott Williams & Wilkins 0268-4705
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