Therapeutic Strategies Targeting Inherited Cardiomyopathies
- 735 Downloads
Purpose of Review
Cardiomyopathies due to genetic mutations are a heterogeneous group of disorders that comprise diseases of contractility, myocardial relaxation, and arrhythmias. Our goal here is to discuss a limited list of genetically inherited cardiomyopathies and the specific therapeutic strategies used to treat them.
Research into the molecular pathophysiology of the development of these cardiomyopathies is leading to the development of novel treatment approaches. Therapies targeting these specific mutations with gene therapy vectors are on the horizon, while other therapies which indirectly affect the physiologic derangements of the mutations are currently being studied and used clinically. Many of these therapies are older medications being given new roles such as mexiletine for Brugada syndrome and diflunisal for transthyretin amyloid cardiomyopathy. A newer targeted therapy, the inhibitor of myosin ATPase MYK-461, has been shown to suppress the development of ventricular hypertrophy, fibrosis, and myocyte disarray and is being studied as a potential therapy in patients with hypertrophic cardiomyopathy.
While this field is too large to be completely contained in a single review, we present a large cross section of recent developments in the field of therapeutics for inherited cardiomyopathies. New therapies are on the horizon, and their development will likely result in improved outcomes for patients inflicted by these conditions.
KeywordsHypertrophic cardiomyopathy Arrhythmogenic cardiomyopathy Amyloidosis Lamin mutations Hemochromatosis Fabry’s disease SCN5A mutation Catecholaminergic polymorphic ventricular tachycardia
Compliance with Ethical Standards
Conflict of Interest
Kenneth Varian declares no conflict of interest.
W. H. Wilson Tang is supported by grants from the National Institutes of Health (NIH) and the Office of Dietary Supplements (R01HL103866, P20HL113452, R01DK106000, R01HL126827).
Human and Animal Rights and Informed Consent
This article does not contain any studies with human or animal subjects performed by any of the authors.
Papers of particular interest, published recently, have been highlighted as: • Of importance
- 12.• Mazzanti A, Maragna R, Faragli A, Monteforte N, Bloise R, Memmi M, et al. Gene-specific therapy with mexiletine reduces arrhythmic events in patients with long qt syndrome type 3. J Am Coll Cardiol. 2016;67:1053–8. In this retrospective cohort study, patients with LQT3 syndrome treated with mexiletine had shortening of their QTc interval and a reduction in arrhythmic events. PubMedPubMedCentralCrossRefGoogle Scholar
- 13.Priori SG, Blomstrom-Lundqvist C, Mazzanti A, Blom N, Borggrefe M, Camm J, et al. 2015 esc guidelines for the management of patients with ventricular arrhythmias and the prevention of sudden cardiac death: the task force for the management of patients with ventricular arrhythmias and the prevention of sudden cardiac death of the european society of cardiology (esc). Endorsed by: Association for european paediatric and congenital cardiology (aepc). Eur Heart J. 2015;36:2793–867.PubMedCrossRefGoogle Scholar
- 27.Leren IS, Saberniak J, Majid E, Haland TF, Edvardsen T, Haugaa KH. Nadolol decreases the incidence and severity of ventricular arrhythmias during exercise stress testing compared with beta1-selective beta-blockers in patients with catecholaminergic polymorphic ventricular tachycardia. Heart Rhythm. 2016;13:433–40.PubMedCrossRefGoogle Scholar
- 30.• van der Werf C, Kannankeril PJ, Sacher F, Krahn AD, Viskin S, Leenhardt A, et al. Flecainide therapy reduces exercise-induced ventricular arrhythmias in patients with catecholaminergic polymorphic ventricular tachycardia. J Am Coll Cardiol. 2011;57:2244–54. In this retrospective analysis, patients with genotype positive CPVT previously uncontrolled by conventional drug therapy started on flexainide had a reduction in exercise-induced ventricular arrhymias. PubMedPubMedCentralCrossRefGoogle Scholar
- 31.Watanabe H, van der Werf C, Roses-Noguer F, Adler A, Sumitomo N, Veltmann C, et al. Effects of flecainide on exercise-induced ventricular arrhythmias and recurrences in genotype-negative patients with catecholaminergic polymorphic ventricular tachycardia. Heart Rhythm. 2013;10:542–7.PubMedCrossRefGoogle Scholar
- 34.Hwang HS, Hasdemir C, Laver D, Mehra D, Turhan K, Faggioni M, et al. Inhibition of cardiac ca2+ release channels (ryr2) determines efficacy of class i antiarrhythmic drugs in catecholaminergic polymorphic ventricular tachycardia. Circ Arrhythm Electrophysiol. 2011;4:128–35.PubMedPubMedCentralCrossRefGoogle Scholar
- 36.Liu N, Denegri M, Ruan Y, Avelino-Cruz JE, Perissi A, Negri S, et al. Short communication: flecainide exerts an antiarrhythmic effect in a mouse model of catecholaminergic polymorphic ventricular tachycardia by increasing the threshold for triggered activity. Circ Res. 2011;109:291–5.PubMedCrossRefGoogle Scholar
- 40.Schneider HE, Steinmetz M, Krause U, Kriebel T, Ruschewski W, Paul T. Left cardiac sympathetic denervation for the management of life-threatening ventricular tachyarrhythmias in young patients with catecholaminergic polymorphic ventricular tachycardia and long qt syndrome. Clin Res Cardiol. 2013;102:33–42.PubMedCrossRefGoogle Scholar
- 42.McNamara C, Cullen P, Rackauskas M, Kelly R, O'Sullivan KE, Galvin J, et al. Left cardiac sympathetic denervation: case series and technical report. Ir J Med Sci. 2017;Google Scholar
- 43.Costello JP, Wilson JK, Louis C, Peer SM, Zurakowski D, Nadler EP, et al. Surgical cardiac denervation therapy for treatment of congenital ion channelopathies in pediatric patients: a contemporary, single institutional experience. World J Pediatr Congenit Heart Surg. 2015;6:33–8.PubMedCrossRefGoogle Scholar
- 51.Ruberg FL, Maurer MS, Judge DP, Zeldenrust S, Skinner M, Kim AY, et al. Prospective evaluation of the morbidity and mortality of wild-type and v122i mutant transthyretin amyloid cardiomyopathy: The Transthyretin Amyloidosis Cardiac Study (TRACS). Am Heart J. 2012;164:222–8. e221 PubMedCrossRefGoogle Scholar
- 55.Damy T, Judge DP, Kristen AV, Berthet K, Li H, Aarts J. Cardiac findings and events observed in an open-label clinical trial of tafamidis in patients with non-val30met and non-val122ile hereditary transthyretin amyloidosis. J Cardiovasc Transl Res. 2015;8:117–27.PubMedPubMedCentralCrossRefGoogle Scholar
- 61.• Coelho T, Adams D, Silva A, Lozeron P, Hawkins PN, Mant T, et al. Safety and efficacy of RNAi therapy for transthyretin amyloidosis. N Engl J Med. 2013;369:819–29. In this non-randomised heathy volunteer controlled study, patients with transthyreting amyloidosis were treated with RNA interference which suppressed the production of transthyretin. This proved the concept that targeting messenger RNA was feasible in reducing the disease-causing mutant protein. PubMedCrossRefGoogle Scholar
- 67.Anderson LJ, Westwood MA, Holden S, Davis B, Prescott E, Wonke B, et al. Myocardial iron clearance during reversal of siderotic cardiomyopathy with intravenous desferrioxamine: a prospective study using t2* cardiovascular magnetic resonance. Br J Haematol. 2004;127:348–55.PubMedCrossRefGoogle Scholar
- 76.• Mehta A, Beck M, Elliott P, Giugliani R, Linhart A, Sunder-Plassmann G, et al. Enzyme replacement therapy with agalsidase alfa in patients with Fabry’s disease: an analysis of registry data. Lancet. 2009;374:1986–96. In this registry study of the 5-year outcomes of enzyme replacement therapy for patients with Fabry’s disease, quality of life improved significantly. A reduction in left ventricular mass for those with baseline left ventricular hypertrophy was also observed. PubMedCrossRefGoogle Scholar
- 86.Axelsson A, Iversen K, Vejlstrup N, Ho C, Norsk J, Langhoff L, et al. Efficacy and safety of the angiotensin ii receptor blocker losartan for hypertrophic cardiomyopathy: the inherit randomised, double-blind, placebo-controlled trial. Lancet Diabetes Endocrinol. 2015;3:123–31.PubMedCrossRefGoogle Scholar
- 88.Tsybouleva N, Zhang L, Chen S, Patel R, Lutucuta S, Nemoto S, et al. Aldosterone, through novel signaling proteins, is a fundamental molecular bridge between the genetic defect and the cardiac phenotype of hypertrophic cardiomyopathy. Circulation. 2004;109:1284–91.PubMedPubMedCentralCrossRefGoogle Scholar
- 90.Gaffin RD, Pena JR, Alves MS, Dias FA, Chowdhury SA, Heinrich LS, et al. Long-term rescue of a familial hypertrophic cardiomyopathy caused by a mutation in the thin filament protein, tropomyosin, via modulation of a calcium cycling protein. J Mol Cell Cardiol. 2011;51:812–20.PubMedPubMedCentralCrossRefGoogle Scholar
- 98.Rodriguez HM, Whitman-Cox S, Kawas R, Song Y, Sran A, Oslob J. Modulation of the cardiac sarcomere by a small molecule agent myk0000461: a potential therapeutic for the treatment of genetic hypertrophic cardiomyopathies. Biophys J. 2015;106Google Scholar
- 99.• Green EM, Wakimoto H, Anderson RL, Evanchik MJ, Gorham JM, Harrison BC, et al. A small-molecule inhibitor of sarcomere contractility suppresses hypertrophic cardiomyopathy in mice. Science. 2016;351:617–21. In this study, the small molecule MYK-461, which reduces contractility by inhibiting myosin ATPase, suppressed the development of the typical phenotypic markers of hypertrophic cardiomyopathy in mice carrying human mutations in the myosin heavy chain. PubMedPubMedCentralCrossRefGoogle Scholar
- 102.Flenner F, Friedrich FW, Ungeheuer N, Christ T, Geertz B, Reischmann S, Wagner S, Stathopoulou K, Sohren KD, Weinberger F, Schwedhelm E, Cuello F, Maier LS, Eschenhagen T, Carrier L. Ranolazine antagonizes catecholamine-induced dysfunction in isolated cardiomyocytes, but lacks long-term therapeutic effects in vivo in a mouse model of hypertrophic cardiomyopathy. Cardiovasc Res 2016;109(1):90–102.Google Scholar
- 104.Olivotto I, Hellawell JL, Farzaneh-Far R, Blair C, Coppini R, Myers J, et al. Novel approach targeting the complex pathophysiology of hypertrophic cardiomyopathy: the impact of late sodium current inhibition on exercise capacity in subjects with symptomatic hypertrophic cardiomyopathy (LIBERTY-HCM) trial. Circ Heart Fail. 2016;9:e002764.PubMedCrossRefGoogle Scholar
- 106.Lombardi R, Rodriguez G, Chen SN, Ripplinger CM, Li W, Chen J, et al. Resolution of established cardiac hypertrophy and fibrosis and prevention of systolic dysfunction in a transgenic rabbit model of human cardiomyopathy through thiol-sensitive mechanisms. Circulation. 2009;119:1398–407.PubMedPubMedCentralCrossRefGoogle Scholar