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.