Sex-specific associations of physical frailty with cardiac structure and function: a cross-sectional study based on UK Biobank.

backgroundFrailty, characterized by diminished physiological reserves and heightened vulnerability to adverse health outcomes, is a robust predictor of cardiovascular morbidity and mortality that extends beyond chronological age. Preclinical studies in aging mouse models have demonstrated that frailty—rather than age alone—drives adverse cardiac remodeling with distinct sex-specific patterns: ventricular dysfunction increases with frailty in males only, whereas atrial dysfunction affects both sexes. Whether these sex-dimorphic patterns translate to humans remains unknown. Epidemiologic data further highlight sex-related heterogeneity: men with frailty exhibit higher all-cause mortality, whereas frailty shows stronger associations with cardiovascular mortality in women, and heart failure with preserved ejection fraction (HFpEF) is approximately twice as prevalent in women. These observations raise the hypothesis that frailty associates with distinct cardiac phenotypes in men versus women.

methodsThis cross-sectional study included 48,993 UK Biobank participants (24,946 women, 24047 men) who underwent Cardiac Magnetic Resonance (CMR). The Fried phenotype categorized physical frailty as Robust, Pre-frail, or Frail. Multivariate linear regression (adjusted for comorbidities and lifestyle) was used to evaluate the associations between frailty severity and CMR-derived parameters, stratified by sex.

resultsFrailty was negatively associated with biventricular and atrial volume indices, left ventricular mass index, and left ventricular wall thickness in both sexes (all p < 0.01). Sex-frailty interaction analyses revealed that men exhibited greater sensitivity of ventricular structure to frailty: significant interactions were observed for left ventricular mass index (β=−1.474, p = 0.002) and left ventricular end-diastolic volume index (β=−1.455, p < 0.001), indicating steeper declines in men compared with women; a similar pattern was observed for right ventricular end-diastolic volume index (interaction β=−1.661, p < 0.001). Among functional parameters, only left ventricular ejection fraction showed a significant interaction (β = -0.007, p = 0.015), reflecting a compensatory pattern in men of preserving ejection fraction at the cost of structural remodeling. Women exhibited functional impairment, characterized by smaller left atrial ejection fraction (β=−0.797, p = 0.002) and decreased left ventricular global longitudinal strain negativity (β = 0.179, p = 0.028), but there are no significant sex-frailty interactions (p > 0.05).

conclusionsPhysical frailty demonstrates sex differentiated associations with cardiac magnetic resonance phenotypes. Men exhibit predominant structural changes, with approximately 50% greater absolute reductions in cardiac volumes and mass per unit increase in frailty severity (e.g., LVMi reduction in frail men was 1.52 times that in frail women); women exhibit predominant functional changes, including left atrial dysfunction and reduced longitudinal strain. The sex differences in CMR parameters suggest that clinical monitoring strategies should consider both sexes. These findings highlight the importance of sex-specific approaches to assessing and managing cardiovascular risk in frail individuals.