Mechanisms of right ventricular remodeling

Right ventricular remodeling results from functional and structural adaptations in response to chronic pressure and/or volume overload. The ability of the right ventricle (RV) to sustain stroke volume and cardiac output in the presence of increased load determines the severity of clinical symptoms and is one of the most important determinants of clinical presentation and survival in patients with pulmonary arterial hypertension (PAH). In fact, clinical symptoms correlate poorly with resting mean pulmonary artery pressure (PAP). It is increasingly recognized that early pulmonary vascular (PV) remodeling is met with an initial adaptive RV hypertrophy, but with progressive PV and RV remodeling regional myocardial ischemia develops that leads to increased production of reactive oxygen species (ROS) in mitochondria (Mt), accumulation of Mt DNA damage, progressive respiratory chain dysfunction and eventual RV failure. Whether abnormalities in Mt function are a cause of RV failure is unknown. We propose that the metabolic response of the RV to alterations in load and pulmonary vascular function is the central determinant of RV-PV axis coupling and adaptation. Using human and preclinical studies, this proposal will identify and validate key metabolic regulatory pathways that may be targeted for the preservation or recovery of RV function. Aim: Ascertain metabolic adaptation in 2 patient cohorts with RV dysfunction in the setting of increased pulmonary vascular resistance. Methods: We propose to measure invasive hemodynamics at rest and with exercise using a standardized CPET protocol. Right heart catheterization (RHC) with assessment of PVR is the gold standard for the clinical evaluation of patients with Pulmonary Hypertension (PH). Examine the responses of the RV to increased afterload with respect to modulation of glucose oxidation, fatty acid oxidation, and glycolysis, and in the presence of pharmacologic and genetic modification of mitochondrial function. Anticipated Results: Therapeutic intervention (e.g. Ranolazine) will reverse the observed shift in metabolites in Aim 1 that favors glycolysis. The correction of the abnormal metabolomic footprint of exercise will be associated with improved RV and pulmonary vascular compliance and efficiency at rest and in response to the exercise stimulus. The imaging with 11C-acetate (positron emission tomography) will also reflect the shift back to the more efficient oxidative phosphorylation, as indicated by a steeper slope of the 11C-acetate washout curve. The P-V assessment will show improved diastolic relaxation and increased lusitropy.