Redefining heart failure: the utility of genomics.

In this era of genomics, new technologies and the information that they generate have a wide range of potential applications to heart failure. Though there has not been widespread practical use of genomic information in everyday practice, there are many examples of how this information is beginning to transform the way we look at disease states in terms of diagnosis, prognosis, and treatment. The experience of oncology and other fields helps inform the heart failure field of not only the use of this information in investigating diagnosis, prognosis, and treatment response, but the reciprocal nature of this information. This information can be clinically useful (for instance, predicting treatment response) as well as further drive laboratory investigation (teasing out the biological pathways in non-responders to treatment can be a focus of new drug discovery); this is the essence of translational medicine. We believe that this is a good time to review where new technologies and information they generate can be placed into our classic understanding of heart failure: that is how we might redefine cardiomyopathy given our new information. Here we will review genomic evidence to date and how it can and may be considered in the evaluation and management of cardiomyopathies.

[1]  P. Burch,et al.  Desmin mutation responsible for idiopathic dilated cardiomyopathy. , 1999, Circulation.

[2]  T. Klingler,et al.  Noninvasive Discrimination of Rejection in Cardiac Allograft Recipients Using Gene Expression Profiling , 2006, American journal of transplantation : official journal of the American Society of Transplantation and the American Society of Transplant Surgeons.

[3]  J. Seidman,et al.  The Genetic Basis for Cardiomyopathy from Mutation Identification to Mechanistic Paradigms , 2001, Cell.

[4]  G. MacGowan,et al.  Pharmacogenetic interactions between angiotensin-converting enzyme inhibitor therapy and the angiotensin-converting enzyme deletion polymorphism in patients with congestive heart failure. , 2004, Journal of the American College of Cardiology.

[5]  L. Mestroni,et al.  Clinical StudiesFamilial dilated cardiomyopathy: Evidence for genetic and phenotypic heterogeneity☆ , 1999 .

[6]  T. Rebbeck,et al.  Common variant in AMPD1 gene predicts improved clinical outcome in patients with heart failure. , 1999, Circulation.

[7]  R. Mobini,et al.  Ser49Gly of β1‐adrenergic receptor is associated with effective β‐blocker dose in dilated cardiomyopathy , 2005 .

[8]  B Maisch,et al.  Report of the 1995 World Health Organization/International Society and Federation of Cardiology Task Force on the Definition and Classification of cardiomyopathies. , 1996, Circulation.

[9]  L. Mestroni,et al.  SCN5A Mutation Associated With Dilated Cardiomyopathy, Conduction Disorder, and Arrhythmia , 2004, Circulation.

[10]  Paul D Allen,et al.  Global gene expression profiling of end-stage dilated cardiomyopathy using a human cardiovascular-based cDNA microarray. , 2002, The American journal of pathology.

[11]  L. Hawthorn,et al.  Decreased SLIM1 Expression and Increased Gelsolin Expression in Failing Human Hearts Measured by High-Density Oligonucleotide Arrays , 2000, Circulation.

[12]  G. Valle,et al.  Mutations in Cypher/ZASP in patients with dilated cardiomyopathy and left ventricular non-compaction. , 2003, Journal of the American College of Cardiology.

[13]  Hans Lehrach,et al.  Expression profiling of human idiopathic dilated cardiomyopathy. , 2003, Cardiovascular research.

[14]  M. Keating,et al.  Metavinculin Mutations Alter Actin Interaction in Dilated Cardiomyopathy , 2002, Circulation.

[15]  K. Adams,et al.  β‐adrenergic Receptor Polymorphisms and Responses during Titration of Metoprolol Controlled Release/extended Release in Heart Failure , 2005, Clinical pharmacology and therapeutics.

[16]  T. Thum,et al.  Gene expression in distinct regions of the heart , 2000, The Lancet.

[17]  Jeffrey T. Chang,et al.  Oncogenic pathway signatures in human cancers as a guide to targeted therapies , 2006, Nature.

[18]  L. Miller,et al.  Alterations of gene expression in failing myocardium following left ventricular assist device support. , 2003, Physiological genomics.

[19]  J. Mesirov,et al.  Molecular classification of cancer: class discovery and class prediction by gene expression monitoring. , 1999, Science.

[20]  George C Tseng,et al.  Microarray gene expression profiles in dilated and hypertrophic cardiomyopathic end-stage heart failure. , 2002, Physiological genomics.

[21]  Joseph A Izatt,et al.  Drosophila as a model for the identification of genes causing adult human heart disease , 2006, Proceedings of the National Academy of Sciences of the United States of America.

[22]  Pharmacogenetic Interactions Between β-Blocker Therapy and the Angiotensin-Converting Enzyme Deletion Polymorphism in Patients With Congestive Heart Failure , 2001 .

[23]  E. Lakatta,et al.  Sex- and age-dependent human transcriptome variability: Implications for chronic heart failure , 2003, Proceedings of the National Academy of Sciences of the United States of America.

[24]  Jianbo Li,et al.  The gene expression fingerprint of human heart failure , 2002, Proceedings of the National Academy of Sciences of the United States of America.

[25]  M. Kamisago Mutations in Sarcomere Protein Genes as a Cause of Dilated Cardiomyopathy , 2000 .

[26]  A J Belanger,et al.  Epidemiology of heart failure. , 1991, American heart journal.

[27]  Ronald W. Davis,et al.  Quantitative Monitoring of Gene Expression Patterns with a Complementary DNA Microarray , 1995, Science.

[28]  G. Jennings,et al.  Beta-adrenoceptor genotype influences the response to carvedilol in patients with congestive heart failure. , 2003, Pharmacogenetics.

[29]  F. Ruddle,et al.  Toward a complete map of the human genome. , 1987, Genomics.

[30]  R. Hershberger,et al.  Clinical and genetic issues in familial dilated cardiomyopathy. , 2005, Journal of the American College of Cardiology.

[31]  J. Mogensen,et al.  Novel mutation in cardiac troponin I in recessive idiopathic dilated cardiomyopathy , 2004, The Lancet.

[32]  G. Dorn,et al.  β1-adrenergic receptor polymorphisms confer differential function and predisposition to heart failure , 2003, Nature Medicine.

[33]  John Atherton,et al.  Mutations of TTN, encoding the giant muscle filament titin, cause familial dilated cardiomyopathy , 2002, Nature Genetics.

[34]  L. Staudt,et al.  The use of molecular profiling to predict survival after chemotherapy for diffuse large-B-cell lymphoma. , 2002, The New England journal of medicine.

[35]  Ralph D'Agostino,et al.  Combination of isosorbide dinitrate and hydralazine in blacks with heart failure. , 2004, The New England journal of medicine.

[36]  Ulrike Mende,et al.  Dilated Cardiomyopathy and Heart Failure Caused by a Mutation in Phospholamban , 2003, Science.

[37]  Mutations in the human δ-sarcoglycan gene in familial and sporadic dilated cardiomyopathy , 2000 .

[38]  H. Katus,et al.  Frequency and phenotypes of familial dilated cardiomyopathy. , 1998, Journal of the American College of Cardiology.

[39]  Yudong D. He,et al.  A Gene-Expression Signature as a Predictor of Survival in Breast Cancer , 2002 .

[40]  M. Rich,et al.  CONGESTIVE HEART FAILURE IN OLDER ADULTS * : Epidemiology, Pathophysiology, and Etiology of Congestive Heart Failure in Older Adults , 1997, Journal of the American Geriatrics Society.

[41]  L. Mestroni,et al.  Natural history of dilated cardiomyopathy due to lamin A/C gene mutations. , 2003, Journal of the American College of Cardiology.

[42]  R Horn,et al.  Primary structure and functional expression of the human cardiac tetrodotoxin-insensitive voltage-dependent sodium channel. , 1992, Proceedings of the National Academy of Sciences of the United States of America.

[43]  M. Bristow,et al.  Economic impact of heart failure in the United States: time for a different approach. , 1994, The Journal of heart and lung transplantation : the official publication of the International Society for Heart Transplantation.

[44]  F. Whitby,et al.  Mutations that alter the surface charge of alpha-tropomyosin are associated with dilated cardiomyopathy. , 2001, Journal of molecular and cellular cardiology.

[45]  Raimond L Winslow,et al.  Gene expression profiles in end-stage human idiopathic dilated cardiomyopathy: altered expression of apoptotic and cytoskeletal genes. , 2004, Genomics.

[46]  Masahiko Hoshijima,et al.  Tcap gene mutations in hypertrophic cardiomyopathy and dilated cardiomyopathy. , 2004, Journal of the American College of Cardiology.

[47]  J. Cohn,et al.  Definition, classification, and staging of the adult cardiomyopathies: a proposal for revision. , 2004, Journal of cardiac failure.

[48]  S. Kardia,et al.  Synergistic Polymorphisms of β1- and α2C-Adrenergic Receptors and the Risk of Congestive Heart Failure , 2002 .

[49]  S. Solomon,et al.  Mutations in sarcomere protein genes as a cause of dilated cardiomyopathy. , 2001, The New England journal of medicine.

[50]  D. Marchuk,et al.  QTL mapping in a mouse model of cardiomyopathy reveals an ancestral modifier allele affecting heart function and survival , 2005, Mammalian Genome.

[51]  D. Marchuk,et al.  Multiple quantitative trait loci modify the heart failure phenotype in murine cardiomyopathy. , 2003, Human molecular genetics.

[52]  H. Watkins,et al.  Severe disease expression of cardiac troponin C and T mutations in patients with idiopathic dilated cardiomyopathy. , 2004, Journal of the American College of Cardiology.

[53]  T. McIntosh,et al.  The Ile164 beta2-adrenergic receptor polymorphism adversely affects the outcome of congestive heart failure. , 1998, The Journal of clinical investigation.

[54]  F. Cappuccio,et al.  Variant of SCN5A Sodium Channel Implicated in Risk of Cardiac Arrhythmia , 2002, Science.

[55]  D. Rice Beneficiary Profile: Yesterday, Today, and Tomorrow , 1996, Health care financing review.

[56]  J. Ornato,et al.  ACC/AHA 2005 Guideline Update for the Diagnosis and Management of Chronic Heart Failure in the Adult—Summary Article , 2005 .

[57]  J. Seidman,et al.  Missense mutations in the rod domain of the lamin A/C gene as causes of dilated cardiomyopathy and conduction-system disease. , 1999, The New England journal of medicine.

[58]  Xinqiang Han,et al.  Genomic profiling of the human heart before and after mechanical support with a ventricular assist device reveals alterations in vascular signaling networks. , 2004, Physiological genomics.

[59]  K. Chien,et al.  Complexity in simplicity: monogenic disorders and complex cardiomyopathies. , 1999, The Journal of clinical investigation.

[60]  G. Dorn,et al.  Polymorphisms of the beta1-adrenergic receptor predict exercise capacity in heart failure. , 2002, American heart journal.

[61]  Ash A. Alizadeh,et al.  Individuality and variation in gene expression patterns in human blood , 2003, Proceedings of the National Academy of Sciences of the United States of America.

[62]  H. Vosberg,et al.  Low‐density DNA microarrays are versatile tools to screen for known mutations in hypertrophic cardiomyopathy , 2002, Human mutation.

[63]  B. Massie,et al.  Evolving trends in the epidemiologic factors of heart failure: rationale for preventive strategies and comprehensive disease management. , 1997, American heart journal.

[64]  Masahiko Hoshijima,et al.  The Cardiac Mechanical Stretch Sensor Machinery Involves a Z Disc Complex that Is Defective in a Subset of Human Dilated Cardiomyopathy , 2002, Cell.

[65]  M. Sarwal,et al.  Molecular heterogeneity in acute renal allograft rejection identified by DNA microarray profiling. , 2003, The New England journal of medicine.

[66]  L. Mestroni,et al.  Familial dilated cardiomyopathy: evidence for genetic and phenotypic heterogeneity. Heart Muscle Disease Study Group. , 1999, Journal of the American College of Cardiology.

[67]  Jeffrey L. Anderson,et al.  Sodium channel mutations and susceptibility to heart failure and atrial fibrillation. , 2005, JAMA.

[68]  J. Croft,et al.  Hospitalization of patients with heart failure: National Hospital Discharge Survey, 1985 to 1995. , 1999, American heart journal.

[69]  D. Stamatiou,et al.  Construction of a human cardiovascular cDNA microarray: portrait of the failing heart. , 2001, Biochemical and biophysical research communications.

[70]  Julie A. Johnson,et al.  Beta1-adrenergic receptor polymorphisms and left ventricular remodeling changes in response to beta-blocker therapy. , 2005, Pharmacogenetics and genomics.

[71]  Ash A. Alizadeh,et al.  Distinct types of diffuse large B-cell lymphoma identified by gene expression profiling , 2000, Nature.

[72]  E. Antman,et al.  ACC/AHA PRACTICE GUIDELINES ACC/AHA Guidelines for the Evaluation and Management of Chronic Heart Failure in the Adult: Executive Summary , 2002 .

[73]  P. Bushel,et al.  Alterations in apoptotic signaling in human idiopathic cardiomyopathic hearts in failure. , 2003, American journal of physiology. Heart and circulatory physiology.

[74]  M. Le Cunff,et al.  Transcriptomal analysis of failing and nonfailing human hearts. , 2003, Physiological genomics.

[75]  D. Marchuk,et al.  Genetic Modifier Loci Affecting Survival and Cardiac Function in Murine Dilated Cardiomyopathy , 2002, Circulation.

[76]  W. Koch,et al.  Differential gene expression and genomic patient stratification following left ventricular assist device support. , 2003, Journal of the American College of Cardiology.

[77]  H. Kroemer,et al.  CYP2D6 genotype and induction of intestinal drug transporters by rifampin predict presystemic clearance of carvedilol in healthy subjects , 2004, Clinical pharmacology and therapeutics.

[78]  P Corvol,et al.  An insertion/deletion polymorphism in the angiotensin I-converting enzyme gene accounting for half the variance of serum enzyme levels. , 1990, The Journal of clinical investigation.