Empagliflozin attenuates pulmonary vascular hemodynamic progression and improves right ventricular adaptation in overcirculation-induced pulmonary hypertension

Background Right ventricular (RV) failure is the principal determinant of prognosis in pulmonary arterial hypertension (PAH). While current therapies primarily target pulmonary vasoconstriction and vascular remodeling, no treatment directly addresses RV maladaptation. Sodium–glucose cotransporter-2 (SGLT2) inhibitors exert cardioprotective effects beyond glycemic control and have shown favorable pulmonary hemodynamic and anti-remodeling effects in experimental small-animal PAH. However, their impact in hyperflow-associated PAH and on RV metabolic adaptation remains poorly defined. Purpose To evaluate the effects of empagliflozin on pulmonary vascular hemodynamics, RV adaptation, myocardial energetics, and histopathology in a large-animal model of hyperflow-induced PAH. Methods Twenty Large-White pigs with PAH induced by surgical aorto–pulmonary shunting were randomized to empagliflozin (10 mg/day) or placebo for 8 weeks. Multimodality assessment at baseline and last of follow-up included right heart catheterization, cardiac magnetic resonance (CMR) with tagging and spectroscopy. At study completion, myocardial tissue was analyzed using histology, high-resolution mitochondrial respirometry, and transmission electron microscopy. A group of 9 age-matched naïve pigs served as controls for mitochondrial analyses. Results Empagliflozin significantly attenuated the progression of indexed pulmonary vascular resistance compared with placebo (-0.59 ± 1.11 WU/m² vs 0.56 ± 1.27 WU/m², Figure 1A). This effect was driven by stabilization of mean pulmonary arterial pressure despite similar changes in left ventricular filling pressures. CMR demonstrated attenuation of RV myocardial strain impairment with empagliflozin (4.84±3.58 vs 0.22±2.74, p=0.003, Figure 1B), despite preserved RV ejection fraction and unchanged volumes. CMR spectroscopy revealed preservation of myocardial energetic status, with a smaller decline in the phosphocreatine-to-ATP ratio in empagliflozin-treated animals (p=0.05, Figure 1C). Histological analysis showed significantly reduced RV fibrosis and cardiomyocyte hypertrophy (Figure 1D). Mitochondrial functional parameters exhibited an intermediate phenotype between placebo-treated PAH animals and healthy controls. Conclusion In a large-animal model of hyperflow-associated PAH, empagliflozin attenuated pulmonary vascular hemodynamic progression and improved RV functional adaptation. These findings support the concept that modulation of RV energetics and ventriculo–arterial coupling may represent a complementary therapeutic axis in hyperflow-driven disease.