Sex Differences in Age-Associated Concentric Remodeling and Diastolic Dysfunction

Diastolic dysfunction is a fundamental substrate in heart failure with preserved ejection fraction, with its modulation by age, sex, and cardiovascular risk factors under active investigation.

The purpose of this study was to determine the age onset of sex-related disparities in diastolic function to establish intrinsic sex differences in cardiac aging.

We analyzed key echocardiographic parameters related to left ventricular geometric remodeling and diastolic function in a large cohort (N = 42,077; females/males: 18,476/23,601) using covariate-adjusted general linear models. A sensitivity analysis was performed on a subgroup (N = 14,250) free of comorbidities.

Significant age-by-sex interactions were found for all key parameters with covariate adjustment (P < 0.001), indicating that age-associated differences diverged significantly between sexes. Females demonstrated increased age-related interventricular septal thickening, left ventricular end-diastolic diameter decline, and a marked rise in relative wall thickness after age 60 (interaction F = 18.88) indicating a shift toward concentric remodeling. Diastolic functional decline also exhibited a sex-dependent age-associated pattern: e' velocity decreased significantly and E/e' ratio increased significantly in females from the sixth decade (F = 26.32). Older females also exhibited larger left atrial volume index and higher tricuspid regurgitation pressure gradients. A composite z-score of these parameters revealed significant sex-specific disparities, pinpointing the sixth decade as the age of marked divergence in diastolic function (F = 36.86). These patterns persisted in the subanalysis of individuals without comorbidities.

The age-associated cardiac remodeling and reduced diastolic function in older females were independent of comorbidities, supporting intrinsic sex-specific differences in cardiac aging emerging after the menopausal transition. These findings support the development of precise, sex-specific prevention strategies.