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

Circ Genom Precis Med. 2021 Feb;14(1):e003062. doi: 10.1161/CIRCGEN.120.003062. Epub 2020 Dec 7.


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.

Keywords: cardiomyopathy, hypertrophic; genetics; heart failure; sarcomeres; women.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Aged
  • Cardiac Myosins / genetics
  • Cardiomyopathy, Hypertrophic / complications
  • Cardiomyopathy, Hypertrophic / diagnosis*
  • Cardiomyopathy, Hypertrophic / genetics
  • Carrier Proteins / genetics
  • Female
  • Genotype
  • Heart Failure / etiology
  • Heart Failure / mortality
  • Humans
  • Male
  • Middle Aged
  • Myosin Heavy Chains / genetics
  • Polymorphism, Genetic
  • Proportional Hazards Models
  • Registries
  • Retrospective Studies
  • Sarcomeres / genetics*
  • Sex Characteristics
  • Survival Rate
  • Ventricular Function, Left


  • Carrier Proteins
  • MYH7 protein, human
  • myosin-binding protein C
  • Cardiac Myosins
  • Myosin Heavy Chains