Experimental therapies for the hypertrophied right ventricle

The right ventricle (RV) of the heart is clearly an extremely important component of cardiovascular function and physiology. The RV is affected in many cardiovascular disease processes, including pulmonary arterial hypertension (PAH), congenital heart disease, and left ventricular failure. In PAH, the performance of the RV is the strongest predictor of morbidity and mortality. Several advances in PAH therapies have occurred over the past decade, including the use of phosphodiesterase-5 (PDE5) inhibitors, endothelin receptor antagonists (ETRAs), and experimental metabolic modulators (Dichloroacetate-DCA). Most therapies for PAH are focused on decreasing RV afterload by vasodilation of the pulmonary vasculature, though there is a surprising lack of focus on direct effects of therapies on the RV. In PAH, the RV compensates to the increase in afterload by hypertrophy, this hypertrophic defense mechanism eventual falls short and the RV progresses to failure and patient death.;The experiments and data gathered in this thesis represent the insight into the importance of the RV in PAH therapies and how these therapies directly mediate the state of inotropy of the RV. A conclusion of greater importance is the better understanding of RV-specific changes in gene expression when the RV undergoes hypertrophy. By demonstrating the up-regulation of protein expression in RVH we are able to potentially tailor therapies to only improve performance of the diseased RV, while sparing the LV if it is otherwise normal. This is a true shift in paradigm as all current cardiac therapeutics effect both right and left ventricle.;The specific aims of our investigations are to assess the effects of PAH therapies on RV in normal and hypertrophied states, as seen in PAH. We utilize human RV samples attained from cardiac surgical procedures to perform in-vitro analysis of protein and mRNA expression of the targets of PAH therapies. We also use a rat model of PAH and subsequent RV hypertrophy to verify human data and to also perform applied physiology experiments to isolate ex-vivo effects of PAH therapies on the RV. In the case of metabolic modulation by altering mitochondrial membrane potential (Δψm) with DCA, human samples were acutely analyzed for Δψm, which was then translated into correlations with the animal PAH model. In the case of PDE5 inhibitors, we found that target, PDE5, was highly expressed in patients and rats with RV hypertrophy (RVH), a novel finding as PDE5 was thought not to exist in the myocardium based on previous human and animal studies on normal RVs. This increased expression of PDE5 in RVH led to PDE5 inhibition causing a significant increase in contractility, while having no effect in the normal RV. A novel and unexpected finding, though it correlated with previously unexplained human data. The experiments with ETRAs showed human and rat expression of ET Receptor-A and Endothelin-1 (ET-1) was significantly increased in RVH. Since ET-1 is a positive inotrope in normal and hypertrophied myocardium, it was verified that ETRAs led to a decrease in contractility in both normal and to a greater magnitude in RVH ex-vivo hearts. The results of PDE5 inhibitors and ETRAs provide the grounds for a much more comprehensive assessment of RV function in PAH clinical trials, as the RVH myocardium is directly effected beyond mere reduction in afterload by decreased PVR. In the studies using metabolic modulation by DCA, we observed that in human and rat RVH there was a significant hyperpolarization of the Δψm compared to the normal RV. We were able to return Δψm toward baseline levels by treatment with DCA in-vitro, and ex-vivo contractility experiments revealed that DCA caused improved contractility in RVH, which was associated with a decrease in lactate production. The mechanism for DCA improving contractility results from improved coupling of glycolysis to glucose oxidation by DCA promoting entry of pyruvate into the mitochondria to cause aerobic oxidative phosphorylation.