HFpEF women exhibited greater cardiomyocyte dysfunction due to higher inflammation and oxidative stress compared to HFpEF men, with increased passive stiffness (Fpassive).
Are there sex-specific differences in functional and molecular remodeling driven by inflammation, oxidative stress, and stress signaling pathways in cardiomyocytes of HFpEF patients?
Women with HFpEF demonstrate greater cardiomyocyte stiffness and dysfunction than men, mediated by heightened inflammation, oxidative stress, and impaired stress signaling pathways.
Abstract Background Heart failure with preserved ejection fraction (HFpEF) predominantly affects women than men. HFpEF is characterized by cardiac dysfunction associated with metabolic, inflammatory, oxidative stress and stress signaling pathways. However, the molecular interplay of these pathways in male vs. female HFpEF remains inadequately elucidated. Purpose Our study aimed to investigate the effects of inflammation, oxidative stress and stress signaling pathways on diastolic dysfunction in male vs. female HFpEF patients. Methods Left ventricular myocardial biopsies were procured transvascularly in HFpEF patients. HFpEF patients (34) were subdivided based on gender: 16 women vs. 18 men. The passive stiffness (Fpassive) was measured in demembranated cardiomyocytes by force measurements. Inflammatory and oxidative stress markers, stress signaling, and autophagy pathways were evaluated using western blotting, immunofluorescence, and ELISA techniques. Results Pro-inflammatory cytokines and oxidative stress markers were increased more in HFpEF female compared to HFpEF male. Although HFpEF women exhibited more inflammation and oxidative stress, coronary artery dilations to acetylcholine (ACh) and sodium nitroprusside (SNP, the direct nitric oxide donor) were similar in both genders but reduced compared to the control group. Cardiomyocyte passive force (Fpassive) was higher in HFpEF women compared to HFpEF men due to a more significant reduction of titin phosphorylation in HFpEF women. Elevated mitochondrial oxidative stress in cardiomyocytes in HFpEF women was associated with more impairment of the NO-sGC-PKG pathway, thereby increasing Fpassive. Moreover, deranged regulation of heat shock proteins HSP27 and α-B-crystallin was observed in HFpEF women compared to HFpEF men. Addition of HSP27 shifted the Fpassive-sarcomere length relation downward, making the cardiomyocyte more compliant in both genders but more in HFpEF men than in HFpEF women suggesting aggregation of titin in both genders but perhaps more in HFpEF women. HSP27 failed to fully shift the Fpassive-sarcomere length relation downward to donor baselines in HFpEF women, which was further corrected by subsequent PKG treatment. Protease enzymes including caspase 1, caspase 3, caspase 9 and caspase 12 were significantly increased in women HFpEF. Additionally, significant differences were also noted in autophagy proteins beclin-1, light chain 3 (LC3A/B), autophagy related gene (ATG5), lysosome-associated membrane protein 2 (LAMP2), between male vs. female HFpEF. Conclusion Our findings suggest HFpEF women had higher cardiomyocyte dysfunction due to deranged stress pathways driven by higher inflammation and oxidative stress in the cardiomyocyte. Therapeutic strategies that target these pathways, including anti-inflammatory, mitochondrial antioxidants, and chaperone-mediated protection, may enhance myocardial function in female and male HFpEF patients.
Sultana et al. (2026) studied this question. HFpEF women exhibited greater cardiomyocyte dysfunction due to higher inflammation and oxidative stress compared to HFpEF men, with increased passive stiffness (Fpassive).