BACKGROUND: Although genetic variants in MYH7 are the most frequent cause of pediatric genetic dilated cardiomyopathy (DCM), there are no studies available describing this entity. We sought to describe clinical features, analyze variant location, and explore predictors of bad prognosis in pediatric MYH7-related DCM. METHODS AND RESULTS: We evaluated clinical records from 44 patients (24 men; median age at diagnosis, 0.54 [interquartile range, 0.01-10.8] years) with pathogenic/likely pathogenic variants in MYH7 diagnosed with DCM at pediatric age (<18 years) followed at 13 international centers. We also explored risk factors associated with a composite end point of end-stage heart failure defined as heart transplantation or heart failure-related death. Twenty-two patients (50%) were diagnosed at age <6 months, including 7 (16%) at birth. Left ventricular (LV) hypertrabeculation features were present in 15 (38%), particularly among patients with genetic variants in the head domain. After a median follow-up of 6.1 years (interquartile range, 1.9-13.4), 15 patients (36%) required a heart transplant (n=14) or died due to end-stage heart failure (n=1), 15 patients (36%) persisted with systolic dysfunction despite treatment, 12 (29%) had a significant increase in LV ejection fraction, and 2 were lost to follow-up. Overall, end-stage heart failure event rate was 25% at 5 years. New York Heart Association class III to IV (hazard ratio [HR], 7.67 [95% CI, 2.16-27.2]; P=0.002) and LV ejection fraction ≤35% (HR, 4.00 [95% CI, 1.11-14.4]; P=0.03) were the best predictors of bad prognosis. CONCLUSIONS: Pediatric MYH7-related DCM is characterized by early onset, frequent LV hypertrabeculation, and poor prognosis. Advanced New York Heart Association class and low LV ejection fraction emerged as predictors of end-stage heart failure.

Ann and Robert H Lurie Children's Hospital of Chicago Division of Cardiology Northwestern University Feinberg School of Medicine Chicago IL USA

Arrhythmia Inherited Cardiac Diseases and Sudden Death Unit Hospital Sant Joan de Déu Esplugues de Llobregat Barcelona Spain

Arrítmies pediàtriques cardiologia genètica i mort sobtada Malalties Cardiovasculars en el desenvolupament Institut de Recerca Sant Joan de Déu Esplugues de Llobregat Barcelona Spain

Cardiology Department AP HP Cochin Hospital Paris Cedex 14 France

Cardiology Unit Meyer Children's Hospital IRCCS Florence Italy

Centro Nacional de Investigaciones Cardiovasculares Madrid Spain

CIBER Cardiovascular Instituto de Salud Carlos 3 Madrid Spain

Complejo Hospitalario Universitario de Badajoz Spain

Department of Cardiology Aarhus University Hospital Aarhus Denmark

Department of Cardiology Boston Children's Hospital Harvard Medical School Boston MA USA

Department of Cardiology Institute for Clinical and Experimental Medicine Prague Czech Republic

Department of Cardiology University Medical Centre Utrecht Utrecht University Utrecht the Netherlands

Department of Genetics University Medical Centre Utrecht Utrecht University Utrecht the Netherlands

Department of Pediatric Cardiology University Medical Centre Utrecht Utrecht University Utrecht the Netherlands

Department of Pediatrics School of Medicine and Health Sciences Universitat de Barcelona Spain

European Reference Network for Rare and Low Prevalence Complex Diseases of the Heart ERN GUARD Heart Amsterdam the Netherlands

Facultad de Medicina Universidad Complutense Madrid Spain

Faculté de Médecine Paris Université Paris Cité Paris France

Heart Failure and Inherited Cardiac Diseases Unit Department of Cardiology Hospital Universitario Puerta de Hierro IDIPHISA Madrid Spain

Inheritance Cardiovascular Disease Unit Pediatric Cardiology Hospital Materno Infantil Gregorio Marañón Madrid Spain

Inherited Cardiac Diseases Unit Cardiology Department Vall Hebron Hospital Barcelona Spain

Instituto de Investigación Sanitaria Gregorio Marañón Madrid Spain

Laboratorio de Cardiogenética IMIB Arrixaca Universidad de Murcia Spain

Medical Science Department School of Medicine Universitat de Girona Spain

Unidad de Cardiopatías Familiares Complexo Hospitalario Universitario A Coruña INIBIC A Coruña Spain

Universidad Francisco de Vitoria Pozuelo de Alarcón Spain

Vall Hebron Research Unit Barcelona Spain

Zobrazit více v PubMed

Merlo M, Cannatà A, Gobbo M, Stolfo D, Elliott PM, Sinagra G. Evolving concepts in dilated cardiomyopathy. Eur J Heart Fail. 2018;20:228–239. doi: 10.1002/ejhf.1103 PubMed DOI

Sinagra G, Elliott PM, Merlo M. Dilated cardiomyopathy: so many cardiomyopathies! Eur Heart J. 2020;41:3784–3786. doi: 10.1093/eurheartj/ehz908 PubMed DOI

Garcia‐Pavia P, Kim Y, Restrepo‐Cordoba MA, Lunde IG, Wakimoto H, Smith AM, Toepfer CN, Getz K, Gorham J, Patel P, et al. Genetic variants associated with cancer therapy‐induced cardiomyopathy. Circulation. 2019;140:31–41. doi: 10.1161/CIRCULATIONAHA.118.037934 PubMed DOI PMC

Towbin JA, McKenna WJ, Abrams DJ, Ackerman MJ, Calkins H, Darrieux FCC, Daubert JP, de Chillou C, DePasquale EC, Desai MY, et al. 2019 HRS expert consensus statement on evaluation, risk stratification, and management of arrhythmogenic cardiomyopathy. Heart Rhythm. 2019;16:e301–e372. doi: 10.1016/j.hrthm.2019.05.007 PubMed DOI

Escobar‐Lopez L, Ochoa JP, Mirelis JG, Espinosa MÁ, Navarro M, Gallego‐Delgado M, Barriales‐Villa R, Robles‐Mezcua A, Basurte‐Elorz MT, Gutiérrez García‐Moreno L, et al. Association of genetic variants with outcomes in patients with nonischemic dilated cardiomyopathy. J Am Coll Cardiol. 2021;78:1682–1699. doi: 10.1016/j.jacc.2021.08.039 PubMed DOI

Jammal Addin MB, Young D, McCarrison S, Hunter L. Dilated cardiomyopathy in a national paediatric population. Eur J Pediatr. 2019;178:1229–1235. doi: 10.1007/s00431-019-03404-w PubMed DOI

Puggia I, Merlo M, Barbati G, Rowland TJ, Stolfo D, Gigli M, Ramani F, Di Lenarda A, Mestroni L, Sinagra G. Natural history of dilated cardiomyopathy in children. J Am Heart Assoc. 2016;5:1–10. doi: 10.1161/JAHA.116.003450 PubMed DOI PMC

Singh RK, Canter CE, Shi L, Colan SD, Dodd DA, Everitt MD, Hsu DT, Jefferies JL, Kantor PF, Pahl E, et al. Survival without cardiac transplantation among children with dilated cardiomyopathy. J Am Coll Cardiol. 2017;70:2663–2673. doi: 10.1016/j.jacc.2017.09.1089 PubMed DOI PMC

Quiat D, Witkowski L, Zouk H, Daly KP, Roberts AE. Retrospective analysis of clinical genetic testing in pediatric primary dilated cardiomyopathy: testing outcomes and the effects of variant reclassification. J Am Heart Assoc. 2020;9:e016195. doi: 10.1161/JAHA.120.016195 PubMed DOI PMC

Khan RS, Pahl E, Dellefave‐Castillo L, Rychlik K, Ing A, Yap KL, Brew C, Johnston JR, McNally EM, Webster G. Genotype and cardiac outcomes in pediatric dilated cardiomyopathy. J Am Heart Assoc. 2022;11:11. doi: 10.1161/JAHA.121.022854 PubMed DOI PMC

van der Meulen MH, Herkert JC, den Boer SL, du Marchie Sarvaas GJ, Blom N, ten Harkel ADJ, Breur HMPJ, Rammeloo LAJ, Tanke R, Marcelis C, et al. Genetic evaluation of a nation‐wide Dutch pediatric DCM cohort: the use of genetic testing in risk stratification. Circ Genom Precis Med. 2022;15:e002981. doi: 10.1161/CIRCGEN.120.002981 PubMed DOI PMC

de Frutos F, Ochoa JP, Navarro‐Peñalver M, Baas A, Bjerre JV, Zorio E, Méndez I, Lorca R, Verdonschot JA, García‐Granja PE, et al. Natural history of MYH7‐related dilated cardiomyopathy. J Am Coll Cardiol. 2022;80:1447–1461. doi: 10.1016/j.jacc.2022.07.023 PubMed DOI

Jansen M, de Brouwer R, Hassanzada F, Schoemaker AE, Schmidt AF, Kooijman‐Reumerman MD, Bracun V, Slieker MG, Dooijes D, Vermeer AMC, et al. Penetrance and prognosis of MYH7 variant‐associated cardiomyopathies. JACC: Heart Fail. 2024;12:134–147. doi: 10.1016/j.jchf.2023.07.007 PubMed DOI

Kelly MA, Caleshu C, Morales A, Buchan J, Wolf Z, Harrison SM, Cook S, Dillon MW, Garcia J, Haverfield E, et al. Adaptation and validation of the ACMG/AMP variant classification framework for MYH7‐associated inherited cardiomyopathies: recommendations by ClinGen's Inherited Cardiomyopathy Expert Panel. Genet Med. 2018;20:351–359. doi: 10.1038/gim.2017.218 PubMed DOI PMC

Colegrave M, Peckham M. Structural implications of β‐cardiac myosin heavy chain mutations in human disease. Anat Rec. 2014;297:1670–1680. doi: 10.1002/ar.22973 PubMed DOI

Moore JR, Leinwand L, Warshaw DM. Understanding cardiomyopathy phenotypes based on the functional impact of mutations in the myosin motor. Circ Res. 2012;111:375–385. doi: 10.1161/CIRCRESAHA.110.223842 PubMed DOI PMC

Onis M. WHO Child Growth Standards based on length/height, weight and age. Acta Paediatr. 2007;95:76–85. PubMed

Jenni R. Echocardiographic and pathoanatomical characteristics of isolated left ventricular non‐compaction: a step towards classification as a distinct cardiomyopathy. Heart. 2001;86:666–671. doi: 10.1136/heart.86.6.666 PubMed DOI PMC

Verdonschot JAJ, Hazebroek MR, Derks KWJ, Barandiarán Aizpurua A, Merken JJ, Wang P, Bierau J, van den Wijngaard A, Schalla SM, Abdul Hamid MA, et al. Titin cardiomyopathy leads to altered mitochondrial energetics, increased fibrosis and long‐term life‐threatening arrhythmias. Eur Heart J. 2018;39:864–873. doi: 10.1093/eurheartj/ehx808 PubMed DOI

Anon. ClinVar: MYH7 p.Glu525Lys. https://www.ncbi.nlm.nih.gov/clinvar/variation/132925/

Woodhead JL, Craig R. The mesa trail and the interacting heads motif of myosin II. Arch Biochem Biophys. 2020;680:108228. doi: 10.1016/j.abb.2019.108228 PubMed DOI PMC

Kampourakis T, Zhang X, Sun Y‐B, Irving M. Omecamtiv mercabil and blebbistatin modulate cardiac contractility by perturbing the regulatory state of the myosin filament. J Physiol. 2018;596:31–46. doi: 10.1113/JP275050 PubMed DOI PMC

Bernier TD, Buckley LF. Cardiac myosin activation for the treatment of systolic heart failure. J Cardiovasc Pharmacol. 2021;77:4–10. doi: 10.1097/FJC.0000000000000929 PubMed DOI PMC

Voors AA, Tamby JF, Cleland JG, Koren M, Forgosh LB, Gupta D, Lund LH, Camacho A, Karra R, Swart HP, et al. Effects of danicamtiv, a novel cardiac myosin activator, in heart failure with reduced ejection fraction: experimental data and clinical results from a phase 2a trial. Eur J Heart Fail. 2020;22:1649–1658. doi: 10.1002/ejhf.1933 PubMed DOI PMC

Teerlink JR, Diaz R, Felker GM, McMurray JJV, Metra M, Solomon SD, Adams KF, Anand I, Arias‐Mendoza A, Biering‐Sørensen T, et al. Cardiac myosin activation with omecamtiv mecarbil in systolic heart failure. N Engl J Med. 2021;384:105–116. doi: 10.1056/NEJMoa2025797 PubMed DOI