Small extracellular vesicle-mediated adipocyte-cardiomyocyte crosstalk exacerbates heart failure with preserved ejection fraction.

Summary

In HFpEF models, visceral adipose tissue promotes disease via secretion of small extracellular vesicles enriched with miR-295-3p that targets ULK1, suppressing cardiac autophagy and worsening diastolic dysfunction. Inhibiting sEV release, silencing Rab27b in VAT, antagonizing miR-295-3p, or restoring autophagy (rapamycin/ULK1 overexpression) ameliorated HFpEF; human hearts with HFpEF showed reduced ULK1 and autophagy.

Key Findings

• VAT resection attenuated and VAT transplantation exacerbated HFpEF phenotypes in mice.
• VAT from HFpEF mice secreted more sEVs; pharmacologic inhibition of sEV release or VAT-specific Rab27b knockdown protected against HFpEF.
• sEV miR-295-3p targeted Ulk1 mRNA, impairing cardiac autophagy; antagomir therapy mitigated HFpEF.
• Human HFpEF hearts exhibited reduced ULK1 and autophagy; rapamycin or AAV9-ULK1 restored autophagy and improved phenotypes in mice.

Clinical Implications

While preclinical, the data argue for therapeutic strategies targeting adipose-derived vesicle trafficking or miR-295-3p and for autophagy-enhancing approaches in HFpEF, particularly in obese phenotypes. It also supports biomarker development (plasma sEV miRNA, cardiac ULK1) for patient stratification.

Limitations

• Predominantly male mouse models may limit sex-specific generalizability.
• Clinical efficacy and safety of targeting sEV trafficking or miR-295-3p remain untested in humans.

Future Directions

Develop circulating sEV miRNA signatures for HFpEF stratification, test miR-295-3p and autophagy-enhancing interventions in obese HFpEF, and assess sex-specific responses and long-term safety.