Evaluating sex as a modifier of cardiomyocyte relaxation in heart failure with preserved ejection fraction: calcium handling, titin, and bioenergetics

Abstract Background Women are disproportionately affected by heart failure with preserved ejection fraction (HFpEF), particularly at older ages, but this epidemiological pattern does not establish sex-modified cardiomyocyte mechanisms. We evaluated whether current evidence supports reproducible sex modification of the cellular processes governing diastolic function. Main body We separated cardiomyocyte diastolic dysfunction into calcium- and myofilament-dependent active relaxation and titin-dependent passive stiffness, with mitochondrial bioenergetics and redox state linking these processes. We assessed formal sex×disease or sex×target interactions, direct mechanical evidence, replication, and human translation. Findings varied with model, strain, age, reproductive state, disease driver, stage, and assay. Among the included studies, late sodium current was the only active-relaxation-related cellular endpoint with a reported formal sex×disease interaction, and this interaction was electrophysiological rather than mechanical. Titin- and NAD⁺-related interventions modified diastolic phenotypes in several HFpEF-like models, but none established a replicated sex-modified mechanical response. Human ventricular studies documented active-relaxation abnormalities, passive stiffness, and metabolic remodeling in separate cohorts, but the role of sex in these findings remains unresolved. Conclusion Current evidence does not justify using sex alone to define calcium- or titin-dominant HFpEF endotypes or select treatments. Reported differences are limited and vary with the model, endpoint, and clinical context. Prespecified sex comparisons linked to a relevant functional endpoint could help clarify the biological significance of these differences.