Sodium-glucose cotransporter 2 inhibitors are associated with reduced circulating activin A and modulation of BMP/activin signaling in ischemic cardiomyopathy with high echocardiographic probability of pulmonary hypertension.

Pulmonary hypertension (PH) frequently complicates heart failure with reduced ejection fraction (HFrEF), worsening prognosis despite limited therapeutic options. Whether sodium-glucose cotransporter 2 inhibitors (SGLT2i) improve PH beyond their established hemodynamic effects remains unclear. Seventy-four patients with ischemic HFrEF after acute myocardial infarction and a high echocardiographic probability of PH were prospectively enrolled in a single-center, non-randomized study. Patients received either an SGLT2i (dapagliflozin or empagliflozin, 10 mg/day; n = 42) plus guideline-directed medical therapy or guideline-directed medical therapy alone (n = 32). Untargeted plasma proteomics (pooled samples), microRNA profiling, and selected biomarkers of senescence and oxidative stress were performed. Candidate findings were validated by ELISA and qRT-PCR. Complementary in vivo and in vitro experiments evaluated empagliflozin in ischemia/reperfusion injury and hypoxic human pulmonary artery endothelial cells and cardiomyocytes. SGLT2i therapy was associated with lower circulating activin A and miR-1306-5p levels, improved World Health Organization functional class, fewer signs of right-heart failure, reduced echocardiographic probability of PH, and enhanced right ventricle-pulmonary artery coupling. In experimental models, empagliflozin reduced activin A, increased BMPR2 expression, and improved post-ischemic ventricular function. Similar molecular changes were observed in hypoxic endothelial cells and cardiomyocytes. Chloroquine partially attenuated these effects, suggesting a possible involvement of autophagy. Across complementary clinical and experimental models, SGLT2i treatment was consistently associated with reduced activin A signaling. Modulation of the BMP/activin/TGFβ pathway represents a biologically plausible mechanism associated with SGLT2 inhibitor therapy that may contribute to the observed phenotype in ischemic HFrEF with a high echocardiographic probability of PH.