Abstract 12609: Impaired Mitochondrial Respiration Precedes Clinical Heart Failure in Right Ventricular Pressure Overload

Abstract

Introduction: Congenital heart disease patients with right-sided obstruction have increased stress on the right ventricle (RV) leading to right ventricular hypertrophy (RVH) and failure (RVF). The critical role of mitochondrial energetics in the development of RVH and RVF is not known. We hypothesize that mitochondrial dysfunction contributes to the chronic energy deficit and mechanical dysfunction in heart failure. Methods: Adult, male FVB mice underwent pulmonary artery banding (PAB) to induce RVH (n=9) and RVF (n=4) and were compared to sham-operated controls (n=9). We used a high-resolution Oxygraph2K respirometer to measure oxygen consumption in tissue and in isolated mitochondria from the RV free wall. We evaluated leak respiration during substrate utilization by complex 1-NADH dehydrogenase and complex 2-succinate dehydrogenase and during maximal ATP generation by complex 5-ATP synthase. Groups were compared using ANOVA. Data is presented as mean ± SEM (*p<0.05). Results: All mice had a PAB gradient of 30-40 mmHg by echocardiography. RVH mice had preserved systolic function while RVF mice had heart failure (ascites, tachypnea, hepatomegaly) and decreased function (Table). RVH showed preserved complex 1 mediated respiration but lower complex 2 and 5 respiration and lower respiratory control ratios (RCR) while in RVF, all complexes showed impaired respiration (Table). However, isolated mitochondria from RVF demonstrated preserved respiratory capacity when supplied with exogenous substrates and no change in complex levels. Conclusion: Mitochondrial respiration is impaired even in stable RVH and progressively worsens in RVF in vivo. Interestingly, isolated mitochondria show normal respiration in RVF when supplied with substrates ex vivo suggesting a defect with substrate delivery rather than intrinsic mitochondrial function. Strategies to enhance substrate delivery may improve ATP generation and thereby preserve function in heart failure.