Right Ventricle Dysfunction Correlates With Reduced Mitochondrial Respiratory Supercomplex Assembly In Human Hearts With Group II Pulmonary Hypertension

Introduction: RV dysfunction and failure is a common consequence of pressure overload associated with all types of pulmonary hypertension. Metabolic and mitochondrial structure and function alterations are further associated with RV dysfunction and failure. Mitochondrial respiratory supercomplexes (mSC) are physically associated assemblies of electron transport chain (ETC) complexes I, III, and IV which are thought to promote improved bioenergetic capacity and efficiency. We previously found reductions in mSC in animal models of PH. It is currently unknown if mSC are reduced in human right ventricle with PH and RV dysfunction. Methods: Failing hearts were harvested from patients at the time of transplant (n=20). Sample from the RV were frozen and later mitochondrial isolated and solubilized for Clear-native PAGE (CN-PAGE) to determine complex IV activity. Gels were normalized to Coomassie stained protein via far-red imaging. mSC activity was determined as amount of active CIV in the SC region (>1mD). Only patients with a recent right heart catheterization prior to transplant were used for correlation analysis. Pulmonary artery pulsatility index (PA systolic pressure-PA diastolic pressure/ right atrial pressure (PAPi)) and right atrial pressure to pulmonary capillary wedge pressure (RAP:PCWP) were used as indicators of pulmonary right ventricular dysfunction. Results: The majority of patients displayed high mPAP, however PH with RV dysfunction is associated with high mPAP and RAP:PSWP and low PAPi while high mPAP, low RAP:PSWP, and high PAPi indicate PH with normal or preserved RV dysfunction. SC activity as measured as CIV activity in SC region positively correlated with PAPI, (r=.6, P=.004) and negatively with RAP/PCWP (r= - .57, P=.009). There was no correlation with non-SC CIV activity as measured by CN-PAGE. Conclusion: The severity of RV dysfunction in humans with Group II PH is correlated with reduction in activity of mSC in RV mitochondria