Associations Between Female Sex, Sarcomere Variants, and Clinical Outcomes in Hypertrophic Cardiomyopathy

Neal K. Lakdawala*, Iacopo Olivotto, Sharlene M. Day, Larry Han, Euan A. Ashley, Michelle Michels, Jodie Ingles, Christopher Semsarian, Daniel Jacoby, John L. Jefferies, Steven D. Colan, Alexandre C. Pereira, Joseph W. Rossano, Sam Wittekind, James S. Ware, Sara Saberi, Adam S. Helms, Allison L. Cirino, Leslie A. Leinwand, Christine E. SeidmanCarolyn Y. Ho

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

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Abstract

Background: The impact of sex on phenotypic expression in hypertrophic cardiomyopathy (HCM) has not been well characterized in genotyped cohorts. Methods: Retrospective cohort study from an international registry of patients receiving care at experienced HCM centers. Sex-based differences in baseline characteristics and clinical outcomes were assessed. Results: Of 5873 patients (3788 genotyped), 2226 (37.9%) were women. At baseline, women were older (49.0±19.9 versus 42.9±18.4 years, P<0.001) and more likely to have pathogenic/likely pathogenic sarcomeric variants (HCM patients with a sarcomere mutation; 51% versus 43%, P<0.001) despite equivalent utilization of genetic testing. Age at diagnosis varied by sex and genotype despite similar distribution of causal genes. Women were 3.6 to 7.1 years older at diagnosis (P<0.02) except for patients with MYH7 variants where age at diagnosis was comparable for women and men (n=492; 34.8±19.2 versus 33.3±16.8 years, P=0.39). Over 7.7 median years of follow-up, New York Heart Association III-IV heart failure was more common in women (hazard ratio, 1.87 [CI, 1.48-2.36], P<0.001), after controlling for their higher burden of symptoms and outflow tract obstruction at baseline, reduced ejection fraction, HCM patients with a sarcomere mutation, age, and hypertension. All-cause mortality was increased in women (hazard ratio, 1.50 [CI, 1.13-1.99], P<0.01) but neither implantable cardioverter-defibrillator utilization nor ventricular arrhythmia varied by sex. Conclusions: In HCM, women are older at diagnosis, partly modified by genetic substrate. Regardless of genotype, women were at higher risk of mortality and developing severe heart failure symptoms. This points to a sex-effect on long-term myocardial performance in HCM, which should be investigated further.

Original languageEnglish
Pages (from-to)E003062
JournalCirculation: Genomic and Precision Medicine
Volume14
Issue number1
DOIs
Publication statusPublished - 1 Feb 2021

Bibliographical note

Funding Information:
The Sarcomeric Human Cardiomyopathy Registry (SHaRe) is supported by an unrestricted research grant from MyoKardia, including funds to individual sites for database support. Dr Lakdawala is supported by an unrestricted grant from the Linda Joy Pollin Center for Women's Cardiovascular Health. Dr Semsarian is supported by a National Health and Medical Research Council, Australia Practitioner Fellowship (no. 1154992). No sponsor played a role in the design or conduct of this study nor participated in the preparation, review, or approval of the article

Funding Information:
The Sarcomeric Human Cardiomyopathy Registry (SHaRe) is supported by an unrestricted research grant from MyoKardia, including funds to individual sites for database support. Dr Lakdawala is supported by an unrestricted grant from the Linda Joy Pollin Center for Women’s Cardiovascular Health. Dr Semsarian is supported by a National Health and Medical Research Council, Australia Practitioner Fellowship (no. 1154992). No sponsor played a role in the design or conduct of this study nor participated in the preparation, review, or approval of the article.

Publisher Copyright:
© 2021 Lippincott Williams and Wilkins. All rights reserved.

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