Prophylactic dapagliflozin attenuates pulmonary vascular remodelling, preserves right ventricular function, and maintains exercise capacity in a monocrotaline-induced pulmonary hypertension rat model
S Asal, S Kilic, S Yavuz, M Babaoglu, C Demirtas, M Yildirim, U Aykin, A G Sade, A Oz, T Cinar, M UzunAbstract
Background
Pulmonary arterial hypertension (PAH) is a progressive disorder characterised by vascular remodelling, elevated pulmonary vascular resistance, and right ventricular (RV) failure. Preventive strategies for at-risk populations remain absent. SGLT2 inhibitors confer pleiotropic cardioprotective benefits, yet their prophylactic potential in PAH is unexplored. We investigated whether dapagliflozin pretreatment attenuates MCT-induced pulmonary hypertension.
Methods
Twenty-four male Sprague-Dawley rats were randomised to Control, MCT (60 mg/kg s.c., day 30), or MCT+DAPA (oral dapagliflozin 1.5 mg/kg/day × 30 days prior to MCT; n=8/group). Serial echocardiography (days 1, 30, 60), forced swimming (15 sessions), electrocardiography, terminal right atrial pressure (RAP), and histopathological quantification of pulmonary arteriolar medial wall thickness (MWT) were performed.
Results
MCT induced profound RV dysfunction (TAPSE: 1.5±0.3 mm), pulmonary arterial dilatation (4.7±0.3 mm), abbreviated acceleration time (PAAT: 17.8±2.1 ms), RV dilatation (RVD 7.3±0.8 mm), elevated RAP (11.00±2.13 mmHg), and severe arteriolar MWT (59.2±6.9%), all p<0.001 vs. Control. Dapagliflozin pretreatment significantly attenuated each parameter: TAPSE 2.4±0.3 mm; PAAT 32.8±4.0 ms; PA diameter 3.4±0.3 mm; RAP 6.61±1.49 mmHg; MWT 32.1±3.4% (~46% reduction; all p<0.001 vs. MCT) (Figure 1). LV systolic function was preserved across all groups (LVEF p=0.328). Exercise capacity diverged markedly from session 10: MCT median 214 s vs. MCT+DAPA 1187 s vs. Control 2250 s at session 15 (p<0.001). MCT-induced ECG abnormalities (tachycardia, PR prolongation, QRS widening, QTc prolongation) were partially normalised by dapagliflozin. Representative Doppler images demonstrating preserved PAAT are shown in Figure 2.
Conclusions
Prophylactic dapagliflozin comprehensively attenuated MCT-induced pulmonary hypertension, preserving RV function, reducing vascular remodelling, normalising electrophysiology, and maintaining exercise capacity. These findings support investigation of SGLT2 inhibitors as preventive agents in PAH.Figure-1For image description, please refer to the figure legend and surrounding text.Figure-2For image description, please refer to the figure legend and surrounding text.