Cardiomyopathy in muscular dystrophies

Cardiomyopathy in muscular dystrophies

Important muscular dystrophies due to mutations in structural cytoskeletal dystrophin gene are known as dystrophinopathies. They include Duchenne muscular dystrophy, Becker muscular dystrophy and X-linked dilated cardiomyopathy. Primary presentation of most dystrophinopathies is skeletal muscle weakness. Duchenne muscular dystrophy is caused by mutations leading to absence of functional dystrophin. Becker muscular dystrophy is due to mutations resulting in reduced amounts of shortened dystrophin protein.

Cardiac muscle being a striated muscle, is affected in many types of muscular dystrophies. Cardiomyopathy would contribute significantly to the morbidity and mortality of dystrophinopathies. Those with dystrophinopathies would benefit from annual cardiovascular imaging studies and cardiovascular therapies if needed [1].

Important causes of mortality in dystrophinopathies with cardiomyopathy are heart failure, heart block and ventricular arrhythmias. Early detection and initiation of heart failure treatment may delay progression of cardiomyopathy in muscular dystrophy. Important ECG finding in cardiomyopathy due to muscular dystrophy is a dominant R wave in lead V1. Cardiac magnetic resonance (CMR) imaging can show late gadolinium enhancement typically in the epicardial lateral wall [2].

The effect of early angiotensin-converting enzyme (ACE) inhibitor therapy in patients with normal left ventricular function on the progression of myocardial fibrosis in Duchenne and Becker muscular dystrophies have been studied in a randomized clinical trial [3]. It was a two center trial including 76 male patients undergoing two CMR studies with a two year interval for assessment of ventricular function and myocardial fibrosis. 42 patients with myocardial fibrosis with and normal left ventricular ejection fraction (LVEF) were randomized to receive or not receive ACE inhibitor therapy.

70 of the patients in the study had Duchenne muscular dystrophy while 6 had Becker muscular dystrophy and the mean age at baseline was 13.1 years. 55 patients had myocardial fibrosis and 13 had left ventricular systolic dysfunction. Myocardial fibrosis at baseline was found to be an independent predictor of lower LVEF at follow up. Patients with myocardial fibrosis on CMR had a higher probability of cardiovascular events. Those randomized to ACE inhibitor therapy showed a slower progression of myocardial fibrosis compared to the untreated group. ACE inhibitor therapy was an independent indicator of decreased progression of myocardial fibrosis on multivariate analysis [3].

An earlier study had evaluated the effect of perindopril in 57 children with Duchenne muscular dystrophy and radionuclide LVEF more than 55% [4]. Phase I of the study was a three year multicenter, randomized double blind trial while in phase II all patients received perindopril for 24 more months.  LVEF was measured at 0, 36, and 60 months in that study. At the end of 60 months, there was only a single patient with LVEF <45% in those on perindopril while there were 8 patients in the control group (p – 0.02).

Addition of eplerenone to background ACE inhibitor or angiotensin receptor blocker (ARB) therapy has been shown to attenuate the progressive decline in left ventricular systolic function in another study [5]. It was a randomised, double blind, placebo controlled trial in 42 boys aged 7 years or older with Duchenne muscular dystrophy from 3 centers.

They had myocardial damage demonstrated by late gadolinium enhancement on CMR with preserved LVEF at baseline. Patients were already on background clinician-directed therapy with either ACE inhibitor or ARB. Primary outcome assessed was change in left ventricular circumferential strain at 12 months, as a measure of contractile dysfunction. Decline in left ventricular circumferential strain at 12 months was less in those who received eplerenone compared to placebo (p = 0.02) [5].

A retrospective analysis has shown that a combination of ACE inhibitor and beta blocker has a beneficial effect on long term survival of Duchenne muscular dystrophy patients with heart failure. The effect was more in patients with asymptomatic left ventricular dysfunction [6].

PANORAMA-HF study, the largest prospective pediatric heart failure trial till date has been completed in January 2022 and had patients with Duchenne muscular dystrophy and heart failure [7,8]. Initial 12 week analysis of PANORMA-HF trial showed that sacubitril/valsartan reduced NT-proBNP in children with heart failure from systemic LV systolic dysfunction. Based on this United States Food and Drug Administration (US FDA) Center for Drug Evaluation and Research approved sacubitril/valsartan for the treatment of certain patients aged one year and older with heart failure in 2019 [9].

References

1. Kamdar F, Garry DJ. Dystrophin-Deficient Cardiomyopathy. J Am Coll Cardiol. 2016 May 31;67(21):2533-46. doi: 10.1016/j.jacc.2016.02.081. PMID: 27230049.
2. Indorkar R, Al-Yafi M, Romano S, Levin BR, Farzaneh-Far A. Cardiomyopathy in muscular dystrophy. QJM. 2018 Apr 1;111(4):267-268. doi: 10.1093/qjmed/hcx220. PMID: 29149277.
3. Silva MC, Magalhães TA, Meira ZM, Rassi CH, Andrade AC, Gutierrez PS, Azevedo CF, Gurgel-Giannetti J, Vainzof M, Zatz M, Kalil-Filho R, Rochitte CE. Myocardial Fibrosis Progression in Duchenne and Becker Muscular Dystrophy: A Randomized Clinical Trial. JAMA Cardiol. 2017 Feb 1;2(2):190-199. doi: 10.1001/jamacardio.2016.4801. PMID: 27926769.
4. Duboc D, Meune C, Lerebours G, Devaux JY, Vaksmann G, Bécane HM. Effect of perindopril on the onset and progression of left ventricular dysfunction in Duchenne muscular dystrophy. J Am Coll Cardiol. 2005 Mar 15;45(6):855-7. doi: 10.1016/j.jacc.2004.09.078. PMID: 15766818.
5. Raman SV, Hor KN, Mazur W, Halnon NJ, Kissel JT, He X, Tran T, Smart S, McCarthy B, Taylor MD, Jefferies JL, Rafael-Fortney JA, Lowe J, Roble SL, Cripe LH. Eplerenone for early cardiomyopathy in Duchenne muscular dystrophy: a randomised, double-blind, placebo-controlled trial. Lancet Neurol. 2015 Feb;14(2):153-61. doi: 10.1016/S1474-4422(14)70318-7. Epub 2014 Dec 30. Erratum in: Lancet Neurol. 2015 Feb;14(2):135. PMID: 25554404; PMCID: PMC4361281.
6. Ogata H, Ishikawa Y, Ishikawa Y, Minami R. Beneficial effects of beta-blockers and angiotensin-converting enzyme inhibitors in Duchenne muscular dystrophy. J Cardiol. 2009 Feb;53(1):72-8. doi: 10.1016/j.jjcc.2008.08.013. Epub 2008 Oct 23. Erratum in: J Cardiol. 2009 Apr;53(2):316. PMID: 19167641.
7. Shaddy R, Canter C, Halnon N, Kochilas L, Rossano J, Bonnet D, Bush C, Zhao Z, Kantor P, Burch M, Chen F. Design for the sacubitril/valsartan (LCZ696) compared with enalapril study of pediatric patients with heart failure due to systemic left ventricle systolic dysfunction (PANORAMA-HF study). Am Heart J. 2017 Nov;193:23-34. doi: 10.1016/j.ahj.2017.07.006. Epub 2017 Jul 17. PMID: 29129252.
8. Adorisio R, Mencarelli E, Cantarutti N, Calvieri C, Amato L, Cicenia M, Silvetti M, D’Amico A, Grandinetti M, Drago F, Amodeo A. Duchenne Dilated Cardiomyopathy: Cardiac Management from Prevention to Advanced Cardiovascular Therapies. J Clin Med. 2020 Oct 1;9(10):3186. doi: 10.3390/jcm9103186. PMID: 33019553; PMCID: PMC7600130.
9. New Drug Therapy Approvals 2019. US FDA website. Available at: https://www.fda.gov/drugs/new-drugs-fda-cders-new-molecular-entities-and-new-therapeutic-biological-products/new-drug-therapy-approvals-2019. Accessed on 30 August 2022.