Prophylactic ranolazine and trimetazidine attenuate right ventricular dysfunction and improve exercise capacity in experimental pulmonary hypertension

Background Metabolic modulators ranolazine and trimetazidine have demonstrated therapeutic benefit in established pulmonary arterial hypertension (PAH), yet their prophylactic efficacy remains uninvestigated. We evaluated whether prophylactic administration of these agents could prevent PAH development and preserve right ventricular (RV) function in a monocrotaline (MCT)-induced rat model. Methods Thirty-two male Sprague-Dawley rats were randomized into four groups (n=8 each): Control, MCT (60 mg/kg subcutaneous, day 30), MCT+Trimetazidine (TMZ, 10 mg/kg/day oral), and MCT+Ranolazine (RAN, 50 mg/kg/day oral). Drug treatment was initiated 30 days before and continued 30 days after MCT injection (total 60 days). Assessments included transthoracic echocardiography, surface ECG, direct right atrial pressure (RAP) measurement, pulmonary histopathology (medial wall thickness, MWT), rotarod testing, and forced swim testing. Results MCT induced severe PAH with profound RV dysfunction: TAPSE was markedly reduced (1.21±0.18 vs. 3.57±0.16 mm; p<0.001), RV diameter increased (7.51±0.48 vs. 3.40±0.56 mm; p<0.001), RAP was markedly elevated (11.63±0.67 vs. 3.12±0.22 mmHg; p<0.001), and characteristic mid-systolic notching of pulmonary artery Doppler flow was observed (Figure 1). MCT caused severe pulmonary arteriolar medial hypertrophy (MWT 47.5±5.1% vs. 22.7±1.9%; p<0.001) (Figure 2), significant QTc prolongation (185±17 vs. 146±10 ms; p<0.001), doubled Tp-Te interval (39±3 vs. 18±3 ms; p<0.001), and severely impaired exercise capacity at day 60 (forced swim: 466 vs. 1721 s; p<0.001). Prophylactic TMZ and RAN significantly attenuated all these changes: TAPSE was preserved at 70–76% of control values (2.52±0.24 and 2.71±0.28 mm, respectively; both p<0.001 vs. MCT), RAP was substantially reduced (7.33±0.35 and 7.03±0.32 mmHg; both p<0.001 vs. MCT), and MWT was significantly attenuated (29.1±4.1% and 28.5±2.3%; both p<0.001 vs. MCT). RAN demonstrated superior antiarrhythmic efficacy, normalizing QTc (158±4 ms) and Tp-Te (21±3 ms) to near-control values. Exercise capacity was markedly preserved in both treatment groups (TMZ: 1033 s; RAN: 1155 s; both p<0.001 vs. MCT). Conclusion Prophylactic ranolazine and trimetazidine significantly attenuate experimental PAH by preserving RV function, reducing pulmonary vascular remodeling, and maintaining exercise capacity. Ranolazine additionally prevented adverse electrical remodeling. These findings support early metabolic intervention as a potential therapeutic strategy in PAH and warrant further clinical investigation.