Sex Differences in Age-Associated Concentric Remodeling and Diastolic Dysfunction

BACKGROUND: 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. OBJECTIVES: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.