Severe obesity in human HFpEF alters contractile protein function and organization.

Summary

In human HFpEF with severe obesity, cardiomyocytes show markedly impaired contractile reserve with reduced calcium- and length-dependent tension, power, and myosin activation, correlating with BMI and exercise hemodynamics. A selective increase in troponin-I Thr181 phosphorylation appears specific to HF with obesity and may drive sarcomere dysfunction; deficits may be reversible with weight loss, suggesting therapeutic opportunities with weight reduction and sarcomere enhancers.

Key Findings

• Obese HFpEF cardiomyocytes exhibit markedly reduced calcium- and length-stimulated tension, power, and myosin activation.
• Defects correlate with BMI and exercise hemodynamics in HFpEF, not in non-failing controls, and appear reversible with weight loss.
• Troponin-I Thr181 phosphorylation increases only in HF with obesity, implicating it in sarcomere dysfunction.
• Findings suggest benefits of weight reduction and sarcomere enhancers in obesity-related HFpEF.

Clinical Implications

For obese HFpEF, structured weight reduction may restore myocyte function, and sarcomere-targeted therapies (e.g., myosin modulators or phosphorylation-state modulators) warrant clinical testing, especially in obesity-driven phenotypes.

Limitations

• Sample size and detailed cohort composition are not specified in the abstract, limiting generalizability.
• Causality and therapeutic efficacy of sarcomere enhancers were not tested in interventional human studies.

Future Directions

Prospective interventional trials of weight loss strategies and sarcomere-targeted modulators in obesity-driven HFpEF; phospho-switch targeting of troponin-I Thr181 to test causal reversibility.