BACKGROUND: Sex differences have been described in adults with hypertrophic cardiomyopathy (HCM), but it is unknown if similar differences exist in childhood-onset disease. OBJECTIVES: This study aimed to investigate the influence of biological sex on the clinical characteristics and outcomes of children with HCM. METHODS: An international retrospective cohort of patients diagnosed with nonsyndromic HCM ≤16 years was formed. Sex differences in baseline characteristics and clinical outcomes were investigated. Primary outcome was all-cause mortality or cardiac transplantation. Secondary outcomes include major arrhythmic cardiac event and heart failure event. RESULTS: Of 1,433 patients diagnosed at a median age of 11 years (IQR: 6-14), 471 (33.0%) were female. Although there were no sex differences in phenotype in preadolescent patients (<12 years), adolescent female patients were more likely to have heart failure symptoms (n = 53 [31.9%] vs n = 86 [22.5%]; P = 0.019). Adolescent female patients had larger left atrial size (1.4 z-score [±2.3] vs 2.1 z-score [±2.5]; P = 0.0056) but there was no difference in degree of hypertrophy or proportion with obstructive disease. Over a median follow-up of 5.3 years (IQR: 2.9, 8.0) annual incidence of all-cause mortality or cardiac transplantation, major arrhythmic cardiac event or heart failure events did not vary by sex. CONCLUSIONS: Young female patients with HCM are more likely to experience heart failure symptoms and have echocardiographic features of diastolic impairment. Despite differences in phenotype, outcomes during childhood and young adulthood are not different. Further studies are required to explore the underlying mechanisms for these observed differences.

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; Medical Science Department School of Medicine Universitat de Girona Girona Spain

Cardiology Unit Cardiac Thoracic and Vascular Department IRCCS Azienda Ospedaliero Universitaria di Bologna Bologna Italy

Cardiology Unit Cardiac Thoracic and Vascular Department IRCCS Azienda Ospedaliero Universitaria di Bologna Bologna Italy; European Reference Network for Rare Low Prevalence and Complex Diseases of the Heart ERN GUARD Heart Amsterdam the Netherlands

Centre for Inherited Cardiovascular Diseases Great Ormond Street Hospital London United Kingdom

Centre for Inherited Cardiovascular Diseases Great Ormond Street Hospital London United Kingdom; Department of Cardiology Institute of Cardiovascular Sciences University College London London United Kingdom

Centre for Inherited Cardiovascular Diseases Great Ormond Street Hospital London United Kingdom; Department of Cardiology University of Exeter Exeter United Kingdom

Complexo Hospitalario Universitario A Coruna INIBIC CIBERCV Coruna Spain

Department of Cardiology Aarhus University Hospital Aarhus Denmark

Department of Cardiology Alder Hey Children's Hospital Liverpool United Kingdom

Department of Cardiology Bambino Gesu Hospital Rome Italy; Department Clinical Molecular Genetics and Precision Medicine Mediclinic City Hospital Dubai UAE

Department of Cardiology Birmingham Children's Hospital Birmingham United Kingdom

Department of Cardiology Bristol Royal Hospital for Children Bristol United Kingdom

Department of Cardiology Evelina Children's Hospital London United Kingdom

Department of Cardiology Fondazione Toscana G Monasterio Massa Pisa Pisa Italy

Department of Cardiology Fundación Favaloro University Hospital Buenos Aires Argentina

Department of Cardiology Ghent University Hospital Ghent Belgium

Department of Cardiology Glenfield Hospital Leicester United Kingdom

Department of Cardiology Hospital Garrahan Buenos Aires Argentina

Department of Cardiology Hospital General Universitario Gregorio Marañón Madrid Spain; Heart Failure and Inherited Cardiac Diseases Unit Department of Cardiology Hospital Universitario Puerta de Hierro Majadahonda IDIPHISA CIBERCV Madrid Spain

Department of Cardiology Hospital Saint Joseph Marseille France

Department of Cardiology Hospital Universitario Virgen de las Nieves Granada Spain

Department of Cardiology Institute of Cardiovascular Sciences University College London London United Kingdom

Department of Cardiology John Radcliffe Hospital Oxford United Kingdom; Department of Pediatric Cardiology Deutsches Herzzentrum der Charité Berlin Germany; Experimental and Clinical Research Center Charite Universitatsmedizin Berlin Berlin Germany

Department of Cardiology Kochi Medical School Hospital Kochi Japan

Department of Cardiology Leeds General Infirmary Leeds United Kingdom

Department of Cardiology Leiden University Medical Center Leiden the Netherlands

Department of Cardiology Mater Dei Hospital Msida Malta

Department of Cardiology Meyer Children's Hospital IRCSS Florence Italy

Department of Cardiology Monaldi Hospital Naples Italy

Department of Cardiology Necker Enfants Malades Hospital Paris France

Department of Cardiology Odense University Hospital Odense Denmark

Department of Cardiology Onassis Cardiac Surgery Center Athens Greece

Department of Cardiology Ospedaliero Universitaria di Parma Parma Italy

Department of Cardiology Our Lady's Children's Hospital Dublin Ireland

Department of Cardiology Papa Giovanni XXIII Hospital Bergamo Italy

Department of Cardiology Rio Hortega University Hospital Valladolid Spain

Department of Cardiology Royal Brompton and Harefield NHS Trust London United Kingdom

Department of Cardiology Royal Hospital for Children Glasgow United Kingdom

Department of Cardiology Southampton General Hospital Southampton United Kingdom

Department of Cardiology The Children's Memorial Health Institute Warsaw Poland

Department of Cardiology The Freeman Hospital Newcastle United Kingdom

Department of Cardiology The Royal Children's Hospital Melbourne Australia; Department of Cardiology University of Melbourne Melbourne Australia; Department of Cardiology Murdoch Children's Research Institute Parkville Australia

Department of Cardiology UMPCD Bucharest Bucharest Romania

Department of Cardiology University Hospital La Paz Madrid Spain

Department of Cardiology University Hospital Motol Prague Czech Republic

Department of Cardiology University Hospital of Wales Cardiff United Kingdom

Department of Cardiology University Hospital Virgen de la Arrixaca Murcia Spain

Department of Cardiology Val D'Hebron University Hospital Barcelona Spain

Department of Pediatric Cardiology and General Pediatrics Medical University of Warsaw Warsaw Poland

Department of Pediatric Cardiology New Children's Hospital University of Helsinki Helsinki Finland

Department of Pediatrics Faculty of Medicine and Graduate School of Medicine Hokkaido University Hospital Sapporo Japan

Department of Pediatrics Hospital Universitario Puerta de Hierro Majadahonda Madrid Spain

DZHK Partner Site Berlin Berlin Germany

European Reference Network for Rare Low Prevalence and Complex Diseases of the Heart ERN GUARD Heart Amsterdam the Netherlands; 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; Medical Science Department School of Medicine Universitat de Girona Girona Spain; Pediatrics Department School of Medicine Universitat de Barcelona Barcelona Spain

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

Heart Muscle Disease Registry Trieste University of Trieste Trieste Italy

University of Medicine and Pharmacy Victor Babes Timisoara Department of Pediatrics Children's Hospital 'Louis Turcanu' Timisoara Romania

Zobrazit více v PubMed

Regitz-Zagrosek V., Gebhard C. Gender medicine: effects of sex and gender on cardiovascular disease manifestation and outcomes. Nature Reviews Cardiology. 2023;20(4):236–247. PubMed PMC

Lakdawala N.K., Olivotto I., Day S.M., et al. Associations between female sex, sarcomere variants, and clinical outcomes in hypertrophic cardiomyopathy. Circ Genom Precis Med. 2021;14(1) doi: 10.1161/circgen.120.003062. PubMed DOI

Olivotto I., Maron M.S., Adabag A.S., et al. Gender-related differences in the clinical presentation and outcome of hypertrophic cardiomyopathy. J Am Coll Cardiol. 2005;46(3):480–487. doi: 10.1016/j.jacc.2005.04.043. PubMed DOI

Dimitrow P.P., Czarnecka D., Jaszcz K.K., Dubiel J.S. Sex differences in age at onset of symptoms in patients with hypertrophic cardiomyopathy. J Cardiovasc Risk. 1997;4(1):33–35. doi: 10.1177/174182679700400106. PubMed DOI

Kubo T., Kitaoka H., Okawa M., et al. Gender-specific differences in the clinical features of hypertrophic cardiomyopathy in a community-based Japanese population: results from Kochi RYOMA study. J Cardiol. 2010;56(3):314–319. doi: 10.1016/j.jjcc.2010.07.004. PubMed DOI

Geske J.B., Ong K.C., Siontis K.C., et al. Women with hypertrophic cardiomyopathy have worse survival. Eur Heart J. 2017;38(46):3434–3440. doi: 10.1093/eurheartj/ehx527. PubMed DOI PMC

Rowin E.J., Maron M.S., Wells S., Patel P.P., Koethe B.C., Maron B.J. Impact of sex on clinical course and survival in the contemporary treatment era for hypertrophic cardiomyopathy. J Am Heart Assoc. 2019;8(21) doi: 10.1161/jaha.119.012041. PubMed DOI PMC

Kim M., Kim B., Choi Y.J., et al. Sex differences in the prognosis of patients with hypertrophic cardiomyopathy. Sci Rep. 2021;11(1):4854. doi: 10.1038/s41598-021-84335-1. PubMed DOI PMC

Ingles J., Burns C., Bagnall R.D., et al. Nonfamilial hypertrophic cardiomyopathy: prevalence, natural history, and clinical implications. Circ Cardiovasc Genet. 2017;10(2) doi: 10.1161/circgenetics.116.001620. PubMed DOI

Lorenzini M., Anastasiou Z., O'Mahony C., et al. Mortality among referral patients with hypertrophic cardiomyopathy vs the general European population. JAMA Cardiol. 2020;5(1):73–80. doi: 10.1001/jamacardio.2019.4534. PubMed DOI PMC

Farhat M.Y., Lavigne M.C., Ramwell P.W. The vascular protective effects of estrogen. FASEB J. 1996;10(5):615–624. PubMed

Hyun K.K., Redfern J., Patel A., et al. Gender inequalities in cardiovascular risk factor assessment and management in primary healthcare. Heart. 2017;103(7):492–498. PubMed

Kaski J.P., Syrris P., Esteban M.T.T., et al. Prevalence of sarcomere protein gene mutations in preadolescent children with hypertrophic cardiomyopathy. Circ Cardiovasc Genet. 2009;2(5):436–441. PubMed

Marston N.A., Han L., Olivotto I., et al. Clinical characteristics and outcomes in childhood-onset hypertrophic cardiomyopathy. Eur Heart J. 2021;42(20):1988–1996. PubMed PMC

Norrish G., Field E., Mcleod K., et al. Clinical presentation and survival of childhood hypertrophic cardiomyopathy: a retrospective study in United Kingdom. Eur Heart J. 2019;40(12):986–993. PubMed PMC

Arbelo E., Protonotarios A., Gimeno J.R., et al. 2023 ESC Guidelines for the management of cardiomyopathies: developed by the task force on the management of cardiomyopathies of the European society of cardiology (ESC) Eur Heart J. 2023;44(37):3503–3626. doi: 10.1093/eurheartj/ehad194. PubMed DOI

Lopez L., Colan S., Stylianou M., et al. Relationship of echocardiographic Z scores adjusted for body surface area to age, sex, race, and ethnicity: the pediatric heart network normal echocardiogram database. Circ Cardiovasc Imaging. 2017;10(11) PubMed PMC

Ross R.D. The Ross classification for heart failure in children after 25 years: a review and an age-stratified revision. Pediatr Cardiol. 2012;33:1295–1300. PubMed

Richards S., Aziz N., Bale S., et al. Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American college of medical genetics and genomics and the association for molecular pathology. Genet Med. 2015;17(5):405–424. doi: 10.1038/gim.2015.30. PubMed DOI PMC

Norrish G., Ding T., Field E., et al. Development of a novel risk prediction model for sudden cardiac death in childhood hypertrophic cardiomyopathy (HCM Risk-Kids) JAMA Cardiol. 2019;4(9):918–927. PubMed PMC

Sandstede J., Lipke C., Beer M., et al. Age-and gender-specific differences in left and right ventricular cardiac function and mass determined by cine magnetic resonance imaging. Eur Radiol. 2000;10:438–442. PubMed

Garmany R., Dasari S., Bos J.M., et al. A multi-omics atlas of sex-specific differences in obstructive hypertrophic cardiomyopathy. J Mol Cell Cardiol. 2024;196:26–34. doi: 10.1016/j.yjmcc.2024.09.005. PubMed DOI

Mendelsohn M.E., Karas R.H. The protective effects of estrogen on the cardiovascular system. N Engl J Med. 1999;340(23):1801–1811. PubMed

Olivotto I., Maron B.J., Tomberli B., et al. Obesity and its association to phenotype and clinical course in hypertrophic cardiomyopathy. J Am Coll Cardiol. 2013;62(5):449–457. PubMed

Balaji S., DiLorenzo M.P., Fish F.A., et al. Impact of obesity on left ventricular thickness in children with hypertrophic cardiomyopathy. Pediatr Cardiol. 2019;40:1253–1257. PubMed

Lorenzini M., Norrish G., Field E., et al. Penetrance of hypertrophic cardiomyopathy in sarcomere protein mutation carriers. J Am Coll Cardiol. 2020;76(5):550–559. doi: 10.1016/j.jacc.2020.06.011. PubMed DOI PMC

Norrish G., Cleary A., Field E., et al. Clinical features and natural history of preadolescent nonsyndromic hypertrophic cardiomyopathy. J Am Coll Cardiol. 2022;79(20):1986–1997. PubMed PMC

Ho C.Y., Day S.M., Ashley E.A., et al. Genotype and lifetime burden of disease in hypertrophic cardiomyopathy: insights from the Sarcomeric Human Cardiomyopathy Registry (SHaRe) Circulation. 2018;138(14):1387–1398. PubMed PMC

Akinrinade O., Lesurf R., Lougheed J., et al. Age and sex differences in the genetics of cardiomyopathy. J Cardiovasc Transl Res. 2023;16(6):1287–1302. doi: 10.1007/s12265-023-10411-8. PubMed DOI PMC

Miron A., Lafreniere-Roula M., Steve Fan C.-P., et al. A validated model for sudden cardiac death risk prediction in pediatric hypertrophic cardiomyopathy. Circulation. 2020;142(3):217–229. PubMed PMC