Energy metabolism and NAD+/NADH in Right Ventricular Failure

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PROJECT SUMMARY/ABSTRACT One mechanism of mitochondrial dysfunction observed in heart failure (HF) is due to a decrease in the cardiac nicotinamide adenine dinucleotide (NAD+)/nicotinamide adenine dinucleotide hydrogen (NADH) ratio. NAD+ is a crucial regulator of cell metabolism and oxidative stress. Importantly, increasing NAD+ through administra- tion of NAD+ or its precursors has been shown to have cardioprotective effects in animal models of HF. Early clinical studies have demonstrated that oral administration of the NAD+ precursor, nicotinamide riboside (NR), increases blood NAD+ levels, improves oxidative metabolism in peripheral mononuclear cells, and decreases pro-inflammatory gene expression. The parent R01 is exploring in a randomized, placebo-controlled clinical trial (NCT04528004) whether short-term oral NR supplementation increases NAD+ levels in HF pa- tients scheduled for LVAD implantation. While the role of cardiomyocyte energy and NAD+ deficiency, and mi- tochondrial dysfunction in HF has been described previously, its study has focused on the pathophysiology of left ventricular failure (LVF). However, it is unknown if similar metabolic disarrangements are observed in right ventricular failure (RVF). This Supplemental application proposes examining the pathways involved in NAD+ homeostasis and energy metabolism in RVF of patients chronically supported with LVAD. RVF develops in up to 40% of people chronically supported with an LVAD and is associated with worse outcomes. Unfortunately, in LVAD patients with RVF, heart transplantation is the only durable option. If NAD+ homeostasis is also per- turbed in the failing right ventricle, this finding might expand the concept explored in the parent R01, introduc- ing the opportunity of the potential utility of NR in the treatment of RVF. Because many patients with RVF eventually receive heart transplantation, a study of the explanted hearts of LVAD patients with and without RVF represents a unique opportunity to study the roles of cardiac energy metabolic signaling pathways, partic- ularly for NAD+ metabolism and redox regulation, in the pathogenesis of RVF. Additionally, we will character- ize the epidemiology of RVF in LVAD patients at our institution utilizing a comprehensive adjudication system. These findings are expected to have a significant impact because they will provide crucial information to iden- tify potential biomarkers for early identification of this complication or pharmacological targets to tackle this cur- rently untreatable disease.