Myo-inositol trispyrophosphate improves oxygen delivery and right ventricular function in rat pressure overload model

Objective Right ventricular (RV) failure is the principal determinant of mortality in pulmonary arterial hypertension (PAH); however, current therapies target the pulmonary vasculature and do not directly address RV dysfunction. Impaired myocardial oxygen delivery has been implicated in the pathogenesis of RV failure. We investigated whether myo-inositol trispyrophosphate (ITPP), an allosteric effector of hemoglobin that enhances tissue oxygen unloading, preserves RV function and prevents metabolic dysfunction in a pulmonary artery banding (PAB) rat model of isolated RV pressure overload. Methods and Results Male Wistar rats underwent PAB or sham surgery and received chronic ITPP or vehicle. Echocardiography, pressure–volume analysis, myocardial oxygen tension (pO2), energetic profiling, and molecular markers of hypoxia and remodeling were assessed. PAB induced significant RV hypertrophy, dilation, impaired RV–pulmonary artery coupling, reduced myocardial pO2, and decreased energetic efficiency compared with sham controls. ITPP restored RV myocardial pO2, preserved systolic, but not diastolic function, improved RV–pulmonary artery coupling, and enhanced mechanical and energetic efficiency without altering RV afterload. While ITPP did not affect RV capillary density or function, it increased RV fibrosis. RV tissue hypoxia was not associated with hypoxia-inducible factor-1α (HIF-1α) activation; accordingly, ITPP’s protection was independent of HIF-mediated angiogenic responses. Conclusions ITPP directly improves RV myocardial oxygenation and energetic efficiency, preserving RV function in pressure overload independently of pulmonary vascular effects. These findings implicate RV hypoxia as a modifiable target in RV failure and support ITPP as a first-in-class, RV-directed therapeutic strategy for PAH.