Canadian Journal of Cardiology
Review| Volume 31, ISSUE 11, P1338-1350, November 2015

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The Genetic Challenges and Opportunities in Advanced Heart Failure

  • Fady Hannah-Shmouni
    Advanced Heart Failure and Cardiomyopathy Program, Division of Cardiovascular Medicine, Yale-New Haven Hospital, Yale School of Medicine, New Haven, Connecticut, USA

    Department of Internal Medicine, Yale-New Haven Hospital, Yale School of Medicine, New Haven, Connecticut, USA

    Cardiovascular Genetics Program, Yale-New Haven Hospital, Yale School of Medicine, New Haven, Connecticut, USA
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  • Sara B. Seidelmann
    Advanced Heart Failure and Cardiomyopathy Program, Division of Cardiovascular Medicine, Yale-New Haven Hospital, Yale School of Medicine, New Haven, Connecticut, USA

    Department of Internal Medicine, Yale-New Haven Hospital, Yale School of Medicine, New Haven, Connecticut, USA

    Cardiovascular Genetics Program, Yale-New Haven Hospital, Yale School of Medicine, New Haven, Connecticut, USA
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  • Sandra Sirrs
    Adult Metabolic Diseases Clinic, Division of Endocrinology, Vancouver General Hospital, University of British Columbia, Vancouver, British Columbia, Canada
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  • Arya Mani
    Department of Internal Medicine, Yale-New Haven Hospital, Yale School of Medicine, New Haven, Connecticut, USA

    Cardiovascular Genetics Program, Yale-New Haven Hospital, Yale School of Medicine, New Haven, Connecticut, USA

    Department of Genetics, Yale-New Haven Hospital, Yale School of Medicine, New Haven, Connecticut, USA
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  • Daniel Jacoby
    Corresponding author: Dr Daniel Jacoby, 333 Cedar Street, PO Box 208017, New Haven, Connecticut 06520-8017, USA. Tel.: +1-203-785-7191; fax: +1-203-785-2917.
    Advanced Heart Failure and Cardiomyopathy Program, Division of Cardiovascular Medicine, Yale-New Haven Hospital, Yale School of Medicine, New Haven, Connecticut, USA

    Department of Internal Medicine, Yale-New Haven Hospital, Yale School of Medicine, New Haven, Connecticut, USA
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Published:August 21, 2015DOI:


      The causes of heart failure are diverse. Inherited causes represent an important clinical entity and can be divided into 2 major categories: familial and metabolic cardiomyopathies. The distinct features that might be present in early disease states can become broadly overlapping with other diseases, such as in the case of inherited cardiomyopathies (ie, familial hypertrophic cardiomyopathy or mitochondrial diseases). In this review article, we focus on genetic issues related to advanced heart failure. Because of the emerging importance of this topic and its breadth, we sought to focus our discussion on the known genetic forms of heart failure syndromes, genetic testing, and newer data on pharmacogenetics and therapeutics in the treatment of heart failure, to primarily encourage clinicians to place a priority on the diagnosis and treatment of these potentially treatable conditions.


      L’étiologie de l’insuffisance cardiaque est variée. Les causes génétiques représentent une entité clinique importante et peuvent être divisées en deux grandes catégories : les myocardiopathies familiales et métaboliques. Les caractéristiques distinctives pouvant se manifester aux stades précoces de la maladie s’apparentent souvent aux caractéristiques d’autres maladies, comme dans le cas des myocardiopathies génétiques (c.-à-d. myocardiopathie familiale hypertrophique ou maladie mitochondriale). Dans le cadre de cet article de synthèse, l’accent sera mis sur les troubles génétiques associés à l’insuffisance cardiaque de stade avancé. En raison de l’importance émergente de ce sujet et de son ampleur, nous désirons concentrer la discussion sur les formes génétiques connues des syndromes d’insuffisance cardiaque, le dépistage génétique, et les nouvelles données sur la pharmacogénétique et les agents thérapeutiques utilisés dans le traitement de l’insuffisance cardiaque, principalement pour encourager les cliniciens à prioriser le diagnostic et le traitement de ces affections pouvant être traitées.
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        • Go A.S.
        • Mozaffarian D.
        • Roger V.L.
        • et al.
        Heart disease and stroke statistics–2013 update: a report from the American Heart Association.
        Circulation. 2013; 127: e6-245
        • Dunlay S.M.
        • Shah N.D.
        • Shi Q.
        • et al.
        Lifetime costs of medical care after heart failure diagnosis.
        Circ Cardiovasc Qual Outcomes. 2011; 4: 68-75
        • Braunwald E.
        Heart failure.
        JACC Heart Fail. 2013; 1: 1-20
        • Bui A.L.
        • Horwich T.B.
        • Fonarow G.C.
        Epidemiology and risk profile of heart failure.
        Nat Rev Cardiol. 2011; 8: 30-41
        • McMurray J.J.
        • Petrie M.C.
        • Murdoch D.R.
        • Davie A.P.
        Clinical epidemiology of heart failure: public and private health burden.
        Eur Heart J. 1998; 19: P9-16
        • Monserrat L.
        • Hermida M.
        • Bouzas B.
        • et al.
        Familial dilated cardiomyopathy in patients transplanted for idiopathic dilated cardiomyopathy.
        Rev Esp Cardiol. 2002; 55 ([in Spanish]): 725-732
        • Rowin E.J.
        • Maron B.J.
        • Kiernan M.S.
        • et al.
        Advanced heart failure with preserved systolic function in nonobstructive hypertrophic cardiomyopathy: under-recognized subset of candidates for heart transplant.
        Circ Heart Fail. 2014; 7: 967-975
        • Maron B.J.
        • Towbin J.A.
        • Thiene G.
        • et al.
        Contemporary definitions and classification of the cardiomyopathies: an American Heart Association Scientific Statement from the Council on Clinical Cardiology, Heart Failure and Transplantation Committee; Quality of Care and Outcomes Research and Functional Genomics and Translational Biology Interdisciplinary Working Groups; and Council on Epidemiology and Prevention.
        Circulation. 2006; 113: 1807-1816
        • Maron B.J.
        • Gardin J.M.
        • Flack J.M.
        • et al.
        Prevalence of hypertrophic cardiomyopathy in a general population of young adults. Echocardiographic analysis of 4111 subjects in the CARDIA Study. Coronary Artery Risk Development in (Young) Adults.
        Circulation. 1995; 92: 785-789
        • Richard P.
        • Charron P.
        • Carrier L.
        • et al.
        Hypertrophic cardiomyopathy: distribution of disease genes, spectrum of mutations, and implications for a molecular diagnosis strategy.
        Circulation. 2003; 107: 2227-2232
        • Klues H.G.
        • Schiffers A.
        • Maron B.J.
        Phenotypic spectrum and patterns of left ventricular hypertrophy in hypertrophic cardiomyopathy: morphologic observations and significance as assessed by two-dimensional echocardiography in 600 patients.
        J Am Coll Cardiol. 1995; 26: 1699-1708
        • Basso C.
        • Corrado D.
        • Bauce B.
        • Thiene G.
        Arrhythmogenic right ventricular cardiomyopathy.
        Circ Arrhythm Electrophysiol. 2012; 5: 1233-1246
        • Coonar A.S.
        • Protonotarios N.
        • Tsatsopoulou A.
        • et al.
        Gene for arrhythmogenic right ventricular cardiomyopathy with diffuse nonepidermolytic palmoplantar keratoderma and woolly hair (Naxos disease) maps to 17q21.
        Circulation. 1998; 97: 2049-2058
        • Kushwaha S.S.
        • Fallon J.T.
        • Fuster V.
        Restrictive cardiomyopathy.
        N Engl J Med. 1997; 336: 267-276
        • Sen-Chowdhry S.
        • Syrris P.
        • McKenna W.J.
        Genetics of restrictive cardiomyopathy.
        Heart Fail Clin. 2010; 6: 179-186
        • McNally E.M.
        • Golbus J.R.
        • Puckelwartz M.J.
        Genetic mutations and mechanisms in dilated cardiomyopathy.
        J Clin Invest. 2013; 123: 19-26
        • Pantazis A.A.
        • Elliott P.M.
        Left ventricular noncompaction.
        Curr Opin Cardiol. 2009; 24: 209-213
        • Kohli S.K.
        • Pantazis A.A.
        • Shah J.S.
        • et al.
        Diagnosis of left-ventricular non-compaction in patients with left-ventricular systolic dysfunction: time for a reappraisal of diagnostic criteria?.
        Eur Heart J. 2008; 29: 89-95
        • Arbustini E.
        • Weidemann F.
        • Hall J.L.
        Left ventricular noncompaction: a distinct cardiomyopathy or a trait shared by different cardiac diseases?.
        J Am Coll Cardiol. 2014; 64: 1840-1850
        • Lang T.F.
        Adult presentations of medium-chain acyl-CoA dehydrogenase deficiency (MCADD).
        J Inherit Metab Dis. 2009; 32: 675-683
        • Tein I.
        Disorders of fatty acid oxidation.
        Handb Clin Neurol. 2013; 113: 1675-1688
        • Spiekerkoetter U.
        Mitochondrial fatty acid oxidation disorders: clinical presentation of long-chain fatty acid oxidation defects before and after newborn screening.
        J Inherit Metab Dis. 2010; 33: 527-532
        • Schaefer A.M.
        • McFarland R.
        • Blakely E.L.
        • et al.
        Prevalence of mitochondrial DNA disease in adults.
        Ann Neurol. 2008; 63: 35-39
        • Koopman W.J.
        • Willems P.H.
        • Smeitink J.A.
        Monogenic mitochondrial disorders.
        N Engl J Med. 2012; 366: 1132-1141
      1. De Castro M, Johnston J, Biesecker L. Determining the prevalence of McArdle disease from gene frequency by analysis of next-generation sequencing data [e-pub ahead of print]. Genet Med, accessed March 5, 2015.

        • Arad M.
        • Maron B.J.
        • Gorham J.M.
        • et al.
        Glycogen storage diseases presenting as hypertrophic cardiomyopathy.
        N Engl J Med. 2005; 352: 362-372
        • Sachdev B.
        • Takenaka T.
        • Teraguchi H.
        • et al.
        Prevalence of Anderson-Fabry disease in male patients with late onset hypertrophic cardiomyopathy.
        Circulation. 2002; 105: 1407-1411
        • Weidemann F.
        • Niemann M.
        • Warnock D.G.
        • Ertl G.
        • Wanner C.
        The Fabry cardiomyopathy: models for the cardiologist.
        Annu Rev Med. 2011; 62: 59-67
        • Niemann M.
        • Herrmann S.
        • Hu K.
        • et al.
        Differences in Fabry cardiomyopathy between female and male patients: consequences for diagnostic assessment.
        JACC Cardiovasc Imaging. 2011; 4: 592-601
        • Jarcho J.A.
        • McKenna W.
        • Pare J.A.
        • et al.
        Mapping a gene for familial hypertrophic cardiomyopathy to chromosome 14q1.
        N Engl J Med. 1989; 321: 1372-1378
        • Alexander J.
        • Kowdley K.V.
        HFE-associated hereditary hemochromatosis.
        Genet Med. 2009; 11: 307-313
        • Herman D.S.
        • Lam L.
        • Taylor M.R.
        • et al.
        Truncations of titin causing dilated cardiomyopathy.
        N Engl J Med. 2012; 366: 619-628
        • Ackerman M.J.
        • Priori S.G.
        • Willems S.
        • et al.
        HRS/EHRA expert consensus statement on the state of genetic testing for the channelopathies and cardiomyopathies: this document was developed as a partnership between the Heart Rhythm Society (HRS) and the European Heart Rhythm Association (EHRA).
        Europace. 2011; 13: 1077-1109
        • Milting H.
        • Klauke B.
        Molecular genetics of arrhythmogenic right ventricular dysplasia/cardiomyopathy.
        Nat Clin Pract Cardiovasc Med. 2008; 5 ([author reply E2]): E1
        • Tester D.J.
        • Ackerman M.J.
        Genetic testing for potentially lethal, highly treatable inherited cardiomyopathies/channelopathies in clinical practice.
        Circulation. 2011; 123: 1021-1037
        • Niimura H.
        • Patton K.K.
        • McKenna W.J.
        • et al.
        Sarcomere protein gene mutations in hypertrophic cardiomyopathy of the elderly.
        Circulation. 2002; 105: 446-451
        • Cheng Z.
        • Fang Q.
        Danon disease: focusing on heart.
        J Hum Genet. 2012; 57: 407-410
        • Hagege A.A.
        • Caudron E.
        • Damy T.
        • et al.
        Screening patients with hypertrophic cardiomyopathy for Fabry disease using a filter-paper test: the FOCUS study.
        Heart. 2011; 97: 131-136
        • Palecek T.
        • Honzikova J.
        • Poupetova H.
        • et al.
        Prevalence of Fabry disease in male patients with unexplained left ventricular hypertrophy in primary cardiology practice: prospective Fabry cardiomyopathy screening study (FACSS).
        J Inherit Metab Dis. 2014; 37: 455-460
        • Havndrup O.
        • Christiansen M.
        • Stoevring B.
        • et al.
        Fabry disease mimicking hypertrophic cardiomyopathy: genetic screening needed for establishing the diagnosis in women.
        Eur J Heart Fail. 2010; 12: 535-540
        • Terryn W.
        • Deschoenmakere G.
        • De Keyser J.
        • et al.
        Prevalence of Fabry disease in a predominantly hypertensive population with left ventricular hypertrophy.
        Int J Cardiol. 2013; 167: 2555-2560
        • Hund E.
        • Linke R.P.
        • Willig F.
        • Grau A.
        Transthyretin-associated neuropathic amyloidosis. Pathogenesis and treatment.
        Neurology. 2001; 56: 431-435
        • Benson M.D.
        Inherited amyloidosis.
        J Med Genet. 1991; 28: 73-78
        • Jacobson D.R.
        • Pastore R.D.
        • Yaghoubian R.
        • et al.
        Variant-sequence transthyretin (isoleucine 122) in late-onset cardiac amyloidosis in black Americans.
        N Engl J Med. 1997; 336: 466-473
        • van Rijsingen I.A.
        • Arbustini E.
        • Elliott P.M.
        • et al.
        Risk factors for malignant ventricular arrhythmias in lamin a/c mutation carriers a European cohort study.
        J Am Coll Cardiol. 2012; 59: 493-500
        • Silvestri G.
        • Ciafaloni E.
        • Santorelli F.M.
        • et al.
        Clinical features associated with the A-->G transition at nucleotide 8344 of mtDNA (“MERRF mutation”).
        Neurology. 1993; 43: 1200-1206
        • Yaplito-Lee J.
        • Weintraub R.
        • Jamsen K.
        • et al.
        Cardiac manifestations in oxidative phosphorylation disorders of childhood.
        J Pediatr. 2007; 150: 407-411
        • Nakagawa H.
        • Okayama S.
        • Kamon D.
        • et al.
        Refractory high output heart failure in a patient with primary mitochondrial respiratory chain disease.
        Intern Med. 2014; 53: 315-319
        • Pfeffer G.
        • Sirrs S.
        • Wade N.K.
        • Mezei M.M.
        Multisystem disorder in late-onset chronic progressive external ophthalmoplegia.
        Can J Neurol Sci. 2011; 38: 119-123
        • Talente G.M.
        • Coleman R.A.
        • Alter C.
        • et al.
        Glycogen storage disease in adults.
        Ann Intern Med. 1994; 120: 218-226
        • Wilde A.A.
        • Behr E.R.
        Genetic testing for inherited cardiac disease.
        Nat Rev Cardiol. 2013; 10: 571-583
        • Melacini P.
        • Basso C.
        • Angelini A.
        • et al.
        Clinicopathological profiles of progressive heart failure in hypertrophic cardiomyopathy.
        Eur Heart J. 2010; 31: 2111-2123
        • Gersh B.J.
        • Maron B.J.
        • Bonow R.O.
        • et al.
        2011 ACCF/AHA Guideline for the Diagnosis and Treatment of Hypertrophic Cardiomyopathy: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines. Developed in collaboration with the American Association for Thoracic Surgery, American Society of Echocardiography, American Society of Nuclear Cardiology, Heart Failure Society of America, Heart Rhythm Society, Society for Cardiovascular Angiography and Interventions, and Society of Thoracic Surgeons.
        J Am Coll Cardiol. 2011; 58: e212-e260
        • Teekakirikul P.
        • Kelly M.A.
        • Rehm H.L.
        • Lakdawala N.K.
        • Funke B.H.
        Inherited cardiomyopathies: molecular genetics and clinical genetic testing in the postgenomic era.
        J Mol Diagn. 2013; 15: 158-170
        • Ando Y.
        • Coelho T.
        • Berk J.L.
        • et al.
        Guideline of transthyretin-related hereditary amyloidosis for clinicians.
        Orphanet J Rare Dis. 2013; 8: 31
        • Casazza F.
        • Morpurgo M.
        The varying evolution of Friedreich’s ataxia cardiomyopathy.
        Am J Cardiol. 1996; 77: 895-898
        • Bos J.M.
        • Will M.L.
        • Gersh B.J.
        • et al.
        Characterization of a phenotype-based genetic test prediction score for unrelated patients with hypertrophic cardiomyopathy.
        Mayo Clin Proc. 2014; 89: 727-737
        • Van Driest S.L.
        • Ommen S.R.
        • Tajik A.J.
        • Gersh B.J.
        • Ackerman M.J.
        Yield of genetic testing in hypertrophic cardiomyopathy.
        Mayo Clin Proc. 2005; 80: 739-744
        • Andersen P.S.
        • Havndrup O.
        • Hougs L.
        • et al.
        Diagnostic yield, interpretation, and clinical utility of mutation screening of sarcomere encoding genes in Danish hypertrophic cardiomyopathy patients and relatives.
        Hum Mutat. 2009; 30: 363-370
        • Spirito P.
        • Seidman C.E.
        • McKenna W.J.
        • Maron B.J.
        The management of hypertrophic cardiomyopathy.
        N Engl J Med. 1997; 336: 775-785
        • Nagueh S.F.
        • Lombardi R.
        • Tan Y.
        • et al.
        Atorvastatin and cardiac hypertrophy and function in hypertrophic cardiomyopathy: a pilot study.
        Eur J Clin Invest. 2010; 40: 976-983
        • Maron M.S.
        • Kalsmith B.M.
        • Udelson J.E.
        • Li W.
        • DeNofrio D.
        Survival after cardiac transplantation in patients with hypertrophic cardiomyopathy.
        Circ Heart Fail. 2010; 3: 574-579
        • Riley M.P.
        • Zado E.
        • Bala R.
        • et al.
        Lack of uniform progression of endocardial scar in patients with arrhythmogenic right ventricular dysplasia/cardiomyopathy and ventricular tachycardia.
        Circ Arrhythm Electrophysiol. 2010; 3: 332-338
        • Philips B.
        • Madhavan S.
        • James C.
        • et al.
        Outcomes of catheter ablation of ventricular tachycardia in arrhythmogenic right ventricular dysplasia/cardiomyopathy.
        Circ Arrhythm Electrophysiol. 2012; 5: 499-505
        • Kirchhof P.
        • Fabritz L.
        • Zwiener M.
        • et al.
        Age- and training-dependent development of arrhythmogenic right ventricular cardiomyopathy in heterozygous plakoglobin-deficient mice.
        Circulation. 2006; 114: 1799-1806
        • James C.A.
        • Bhonsale A.
        • Tichnell C.
        • et al.
        Exercise increases age-related penetrance and arrhythmic risk in arrhythmogenic right ventricular dysplasia/cardiomyopathy-associated desmosomal mutation carriers.
        J Am Coll Cardiol. 2013; 62: 1290-1297
        • Maron B.J.
        • Chaitman B.R.
        • Ackerman M.J.
        • et al.
        Recommendations for physical activity and recreational sports participation for young patients with genetic cardiovascular diseases.
        Circulation. 2004; 109: 2807-2816
        • Xu T.
        • Yang Z.
        • Vatta M.
        • et al.
        Compound and digenic heterozygosity contributes to arrhythmogenic right ventricular cardiomyopathy.
        J Am Coll Cardiol. 2010; 55: 587-597
        • Tedford R.J.
        • James C.
        • Judge D.P.
        • et al.
        Cardiac transplantation in arrhythmogenic right ventricular dysplasia/cardiomyopathy.
        J Am Coll Cardiol. 2012; 59: 289-290
        • DePasquale E.C.
        • Nasir K.
        • Jacoby D.L.
        Outcomes of adults with restrictive cardiomyopathy after heart transplantation.
        J Heart Lung Transplant. 2012; 31: 1269-1275
        • Coelho T.
        • Adams D.
        • Silva A.
        • et al.
        Safety and efficacy of RNAi therapy for transthyretin amyloidosis.
        N Engl J Med. 2013; 369: 819-829
        • Megalla S.
        • Holtzman D.
        • Aronow W.S.
        • et al.
        Predictors of cardiac hepatopathy in patients with right heart failure.
        Med Sci Monit. 2011; 17: CR537-CR541
        • Hillege H.L.
        • Nitsch D.
        • Pfeffer M.A.
        • et al.
        Renal function as a predictor of outcome in a broad spectrum of patients with heart failure.
        Circulation. 2006; 113: 671-678
        • Topilsky Y.
        • Pereira N.L.
        • Shah D.K.
        • et al.
        Left ventricular assist device therapy in patients with restrictive and hypertrophic cardiomyopathy.
        Circ Heart Fail. 2011; 4: 266-275
        • Molina K.M.
        • Shrader P.
        • Colan S.D.
        • et al.
        Predictors of disease progression in pediatric dilated cardiomyopathy.
        Circ Heart Fail. 2013; 6: 1214-1222
        • Mahon N.G.
        • Murphy R.T.
        • MacRae C.A.
        • et al.
        Echocardiographic evaluation in asymptomatic relatives of patients with dilated cardiomyopathy reveals preclinical disease.
        Ann Intern Med. 2005; 143: 108-115
        • Regitz-Zagrosek V.
        • Petrov G.
        • Lehmkuhl E.
        • et al.
        Heart transplantation in women with dilated cardiomyopathy.
        Transplantation. 2010; 89: 236-244
        • Niemann M.
        • Stork S.
        • Weidemann F.
        Left ventricular noncompaction cardiomyopathy: an overdiagnosed disease.
        Circulation. 2012; 126: e240-e243
        • Brunetti-Pierri N.
        • Lamance K.M.
        • Lewis R.A.
        • Craigen W.J.
        30-year follow-up of a patient with classic citrullinemia.
        Mol Genet Metab. 2012; 106: 248-250
        • Hannah-Shmouni F.
        • McLeod K.
        • Sirrs S.
        Recurrent exercise-induced rhabdomyolysis.
        CMAJ. 2012; 184: 426-430
        • Weidemann F.
        • Niemann M.
        • Breunig F.
        • et al.
        Long-term effects of enzyme replacement therapy on fabry cardiomyopathy: evidence for a better outcome with early treatment.
        Circulation. 2009; 119: 524-529
        • Antunes A.P.
        • Nogueira C.
        • Rocha H.
        • Vilarinho L.
        • Evangelista T.
        Intermittent rhabdomyolysis with adult onset associated with a mutation in the ACADVL gene.
        J Clin Neuromusc Dis. 2013; 15: 69-72
        • Xiong D.
        • He H.
        • James J.
        • et al.
        Cardiac-specific VLCAD deficiency induces dilated cardiomyopathy and cold intolerance.
        Am J Physiol Heart Circ Physiol. 2014; 306: H326-H338
        • Behrend A.M.
        • Harding C.O.
        • Shoemaker J.D.
        • et al.
        Substrate oxidation and cardiac performance during exercise in disorders of long chain fatty acid oxidation.
        Mol Genet Metab. 2012; 105: 110-115
        • Baruteau J.
        • Sachs P.
        • Broue P.
        • et al.
        Clinical and biological features at diagnosis in mitochondrial fatty acid beta-oxidation defects: a French pediatric study from 187 patients. Complementary data.
        J Inherit Metab Dis. 2014; 37: 137-139
        • Arbustini E.
        • Diegoli M.
        • Fasani R.
        • et al.
        Mitochondrial DNA mutations and mitochondrial abnormalities in dilated cardiomyopathy.
        Am J Pathol. 1998; 153: 1501-1510
        • Thorburn D.R.
        Mitochondrial disorders: prevalence, myths and advances.
        J Inherit Metab Dis. 2004; 27: 349-362
        • Parikh S.
        • Goldstein A.
        • Koenig M.K.
        • et al.
        Diagnosis and management of mitochondrial disease: a consensus statement from the Mitochondrial Medicine Society.
        Genet Med. 2015; 17: 689-701
        • Moses S.W.
        • Parvari R.
        The variable presentations of glycogen storage disease type IV: a review of clinical, enzymatic and molecular studies.
        Curr Mol Med. 2002; 2: 177-188
        • Crushell E.
        • Treacy E.P.
        • Dawe J.
        • Durkie M.
        • Beauchamp N.J.
        Glycogen storage disease type III in the Irish population.
        J Inherit Metab Dis. 2010; 33: S215-S218
        • Haller R.G.
        • Vissing J.
        Spontaneous “second wind” and glucose-induced second “second wind” in McArdle disease: oxidative mechanisms.
        Arch Neurol. 2002; 59: 1395-1402
        • Ben-Ami R.
        • Puglisi J.
        • Haider T.
        • Mehta D.
        The Mount Sinai Hospital clinicalpathological conference: a 45-year-old man with Pompe’s disease and dilated cardiomyopathy.
        Mount Sinai J Med. 2001; 68: 205-212
        • Herzog A.
        • Hartung R.
        • Reuser A.J.
        • et al.
        A cross-sectional single-centre study on the spectrum of Pompe disease, German patients: molecular analysis of the GAA gene, manifestation and genotype-phenotype correlations.
        Orphanet J Rare Dis. 2012; 7: 35
        • Gollob M.H.
        • Green M.S.
        • Tang A.S.
        • et al.
        Identification of a gene responsible for familial Wolff-Parkinson-White syndrome.
        N Engl J Med. 2001; 344: 1823-1831
        • Kelly B.P.
        • Russell M.W.
        • Hennessy J.R.
        • Ensing G.J.
        Severe hypertrophic cardiomyopathy in an infant with a novel PRKAG2 gene mutation: potential differences between infantile and adult onset presentation.
        Pediatr Cardiol. 2009; 30: 1176-1179
        • Wolf C.M.
        • Arad M.
        • Ahmad F.
        • et al.
        Reversibility of PRKAG2 glycogen-storage cardiomyopathy and electrophysiological manifestations.
        Circulation. 2008; 117: 144-154
        • Waldek S.
        • Patel M.R.
        • Banikazemi M.
        • Lemay R.
        • Lee P.
        Life expectancy and cause of death in males and females with Fabry disease: findings from the Fabry Registry.
        Genet Med. 2009; 11: 790-796
        • Meikle P.J.
        • Hopwood J.J.
        • Clague A.E.
        • Carey W.F.
        Prevalence of lysosomal storage disorders.
        JAMA. 1999; 281: 249-254
        • Lin H.Y.
        • Chong K.W.
        • Hsu J.H.
        • et al.
        High incidence of the cardiac variant of Fabry disease revealed by newborn screening in the Taiwan Chinese population.
        Circ Cardiovasc Genet. 2009; 2: 450-456
        • Creemers E.E.
        • Pinto Y.M.
        Molecular mechanisms that control interstitial fibrosis in the pressure-overloaded heart.
        Cardiovasc Res. 2011; 89: 265-272
        • Smith N.L.
        • Felix J.F.
        • Morrison A.C.
        • et al.
        Association of genome-wide variation with the risk of incident heart failure in adults of European and African ancestry: a prospective meta-analysis from the cohorts for heart and aging research in genomic epidemiology (CHARGE) consortium.
        Circ Cardiovasc Genet. 2010; 3: 256-266
        • Cappola T.P.
        • Matkovich S.J.
        • Wang W.
        • et al.
        Loss-of-function DNA sequence variant in the CLCNKA chloride channel implicates the cardio-renal axis in interindividual heart failure risk variation.
        Proc Natl Acad Sci U S A. 2011; 108: 2456-2461
        • Creemers E.E.
        • Wilde A.A.
        • Pinto Y.M.
        Heart failure: advances through genomics.
        Nat Rev Genet. 2011; 12: 357-362
        • International Human Genome Sequencing Consortium
        Finishing the euchromatic sequence of the human genome.
        Nature. 2004; 431: 931-945
        • Johansen Taber K.A.
        • Dickinson B.D.
        • Wilson M.
        The promise and challenges of next-generation genome sequencing for clinical care.
        JAMA Intern Med. 2014; 174: 275-280
        • Bamshad M.J.
        • Ng S.B.
        • Bigham A.W.
        • et al.
        Exome sequencing as a tool for Mendelian disease gene discovery.
        Nat Rev Genet. 2011; 12: 745-755
        • Talameh J.A.
        • McLeod H.L.
        • Adams Jr., K.F.
        • Patterson J.H.
        Genetic tailoring of pharmacotherapy in heart failure: optimize the old, while we wait for something new.
        J Card Fail. 2012; 18: 338-349
        • Rau T.
        • Heide R.
        • Bergmann K.
        • et al.
        Effect of the CYP2D6 genotype on metoprolol metabolism persists during long-term treatment.
        Pharmacogenetics. 2002; 12: 465-472
        • Zineh I.
        • Beitelshees A.L.
        • Gaedigk A.
        • et al.
        Pharmacokinetics and CYP2D6 genotypes do not predict metoprolol adverse events or efficacy in hypertension.
        Clin Pharmacol Ther. 2004; 76: 536-544
        • Sehrt D.
        • Meineke I.
        • Tzvetkov M.
        • Gultepe S.
        • Brockmoller J.
        Carvedilol pharmacokinetics and pharmacodynamics in relation to CYP2D6 and ADRB pharmacogenetics.
        Pharmacogenomics. 2011; 12: 783-795
        • Bijl M.J.
        • Visser L.E.
        • van Schaik R.H.
        • et al.
        Genetic variation in the CYP2D6 gene is associated with a lower heart rate and blood pressure in beta-blocker users.
        Clin Pharmacol Ther. 2009; 85: 45-50
        • Hasking G.J.
        • Esler M.D.
        • Jennings G.L.
        • et al.
        Norepinephrine spillover to plasma in patients with congestive heart failure: evidence of increased overall and cardiorenal sympathetic nervous activity.
        Circulation. 1986; 73: 615-621
        • Thomas J.A.
        • Marks B.H.
        Plasma norepinephrine in congestive heart failure.
        Am J Cardiol. 1978; 41: 233-243
        • Eichhorn E.J.
        • Bristow M.R.
        The Carvedilol Prospective Randomized Cumulative Survival (COPERNICUS) trial.
        Curr Control Trials Cardiovasc Med. 2001; 2: 20-23
        • Yancy C.W.
        • Jessup M.
        • Bozkurt B.
        • et al.
        2013 ACCF/AHA guideline for the management of heart failure: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines.
        J Am Coll Cardiol. 2013; 62: e147-239
        • Kotecha D.
        • Manzano L.
        • Altman D.G.
        • et al.
        Individual patient data meta-analysis of beta-blockers in heart failure: rationale and design.
        Syst Rev. 2013; 2: 7
      2. Effect of metoprolol CR/XL in chronic heart failure: Metoprolol CR/XL Randomised Intervention Trial in Congestive Heart Failure (MERIT-HF).
        Lancet. 1999; 353: 2001-2007
        • Liggett S.B.
        • Mialet-Perez J.
        • Thaneemit-Chen S.
        • et al.
        A polymorphism within a conserved beta(1)-adrenergic receptor motif alters cardiac function and beta-blocker response in human heart failure.
        Proc Natl Acad Sci U S A. 2006; 103: 11288-11293
        • Mialet Perez J.
        • Rathz D.A.
        • Petrashevskaya N.N.
        • et al.
        Beta 1-adrenergic receptor polymorphisms confer differential function and predisposition to heart failure.
        Nat Med. 2003; 9: 1300-1305
        • Borjesson M.
        • Magnusson Y.
        • Hjalmarson A.
        • Andersson B.
        A novel polymorphism in the gene coding for the beta(1)-adrenergic receptor associated with survival in patients with heart failure.
        Eur Heart J. 2000; 21: 1853-1858
        • Magnusson Y.
        • Levin M.C.
        • Eggertsen R.
        • et al.
        Ser49Gly of beta1-adrenergic receptor is associated with effective beta-blocker dose in dilated cardiomyopathy.
        Clin Pharmacol Ther. 2005; 78: 221-231
        • Lanfear D.E.
        • Jones P.G.
        • Marsh S.
        • et al.
        Beta2-adrenergic receptor genotype and survival among patients receiving beta-blocker therapy after an acute coronary syndrome.
        JAMA. 2005; 294: 1526-1533
        • Kaye D.M.
        • Smirk B.
        • Williams C.
        • et al.
        Beta-adrenoceptor genotype influences the response to carvedilol in patients with congestive heart failure.
        Pharmacogenetics. 2003; 13: 379-382
        • Shin J.
        • Lobmeyer M.T.
        • Gong Y.
        • et al.
        Relation of beta(2)-adrenoceptor haplotype to risk of death and heart transplantation in patients with heart failure.
        Am J Cardiol. 2007; 99: 250-255
        • Lobmeyer M.T.
        • Gong Y.
        • Terra S.G.
        • et al.
        Synergistic polymorphisms of beta1 and alpha2C-adrenergic receptors and the influence on left ventricular ejection fraction response to beta-blocker therapy in heart failure.
        Pharmacogenet Genomics. 2007; 17: 277-282
        • Chen L.
        • Meyers D.
        • Javorsky G.
        • et al.
        Arg389Gly-beta1-adrenergic receptors determine improvement in left ventricular systolic function in nonischemic cardiomyopathy patients with heart failure after chronic treatment with carvedilol.
        Pharmacogenet Genomics. 2007; 17: 941-949
        • Johnson A.D.
        • Newton-Cheh C.
        • Chasman D.I.
        • et al.
        Association of hypertension drug target genes with blood pressure and hypertension in 86,588 individuals.
        Hypertension. 2011; 57: 903-910
      3. Effects of enalapril on mortality in severe congestive heart failure. Results of the Cooperative North Scandinavian Enalapril Survival Study (CONSENSUS). The CONSENSUS Trial Study Group.
        N Engl J Med. 1987; 316: 1429-1435
      4. Effect of enalapril on survival in patients with reduced left ventricular ejection fractions and congestive heart failure. The SOLVD Investigators.
        N Engl J Med. 1991; 325: 293-302
        • Rigat B.
        • Hubert C.
        • Alhenc-Gelas F.
        • et al.
        An insertion/deletion polymorphism in the angiotensin I-converting enzyme gene accounting for half the variance of serum enzyme levels.
        J Clin Invest. 1990; 86: 1343-1346
        • Schut A.F.
        • Bleumink G.S.
        • Stricker B.H.
        • et al.
        Angiotensin converting enzyme insertion/deletion polymorphism and the risk of heart failure in hypertensive subjects.
        Eur Heart J. 2004; 25: 2143-2148
        • Fatini C.
        • Sticchi E.
        • Marcucci R.
        • et al.
        ACE insertion/deletion, but not -240A>T polymorphism, modulates the severity in heart failure.
        J Investig Med. 2008; 56: 1004-1010
        • Struthers A.D.
        Aldosterone escape during angiotensin-converting enzyme inhibitor therapy in chronic heart failure.
        J Card Fail. 1996; 2: 47-54
        • Andersson B.
        • Sylven C.
        The DD genotype of the angiotensin-converting enzyme gene is associated with increased mortality in idiopathic heart failure.
        J Am Coll Cardiol. 1996; 28: 162-167
        • Myerson S.G.
        • Montgomery H.E.
        • Whittingham M.
        • et al.
        Left ventricular hypertrophy with exercise and ACE gene insertion/deletion polymorphism: a randomized controlled trial with losartan.
        Circulation. 2001; 103: 226-230
        • Cicoira M.
        • Zanolla L.
        • Rossi A.
        • et al.
        Failure of aldosterone suppression despite angiotensin-converting enzyme (ACE) inhibitor administration in chronic heart failure is associated with ACE DD genotype.
        J Am Coll Cardiol. 2001; 37: 1808-1812
        • McNamara D.M.
        • Holubkov R.
        • Postava L.
        • et al.
        Pharmacogenetic interactions between angiotensin-converting enzyme inhibitor therapy and the angiotensin-converting enzyme deletion polymorphism in patients with congestive heart failure.
        J Am Coll Cardiol. 2004; 44: 2019-2026
        • Psaty B.M.
        • Smith N.L.
        • Heckbert S.R.
        • et al.
        Diuretic therapy, the alpha-adducin gene variant, and the risk of myocardial infarction or stroke in persons with treated hypertension.
        JAMA. 2002; 287: 1680-1689
        • Verstuyft C.
        • Schwab M.
        • Schaeffeler E.
        • et al.
        Digoxin pharmacokinetics and MDR1 genetic polymorphisms.
        Eur J Clin Pharmacol. 2003; 58: 809-812
        • Laffer C.L.
        • Elijovich F.
        • Eckert G.J.
        • et al.
        Genetic variation in CYP4A11 and blood pressure response to mineralocorticoid receptor antagonism or ENaC inhibition: an exploratory pilot study in African Americans.
        J Am Soc Hypertens. 2014; 8: 475-480
        • Relling M.V.
        • Klein T.E.
        CPIC: Clinical Pharmacogenetics Implementation Consortium of the Pharmacogenomics Research Network.
        Clin Pharmacol Ther. 2011; 89: 464-467
        • Niwano K.
        • Arai M.
        • Koitabashi N.
        • et al.
        Lentiviral vector-mediated SERCA2 gene transfer protects against heart failure and left ventricular remodeling after myocardial infarction in rats.
        Mol Ther. 2008; 16: 1026-1032
        • del Monte F.
        • Hajjar R.J.
        • Harding S.E.
        Overwhelming evidence of the beneficial effects of SERCA gene transfer in heart failure.
        Circ Res. 2001; 88: E66-E67
        • Carè A.
        • Catalucci D.
        • Felicetti F.
        • et al.
        MicroRNA-133 controls cardiac hypertrophy.
        Nat Med. 2007; 13: 613-618
        • Wahlquist C.
        • Jeong D.
        • Rojas-Munoz A.
        • et al.
        Inhibition of miR-25 improves cardiac contractility in the failing heart.
        Nature. 2014; 508: 531-535