Energy metabolism and NAD+/NADH in Right Ventricular Failure

项目总结/摘要 在心力衰竭（HF）中观察到的线粒体功能障碍的一种机制是由于心脏线粒体功能的减少。 烟酰胺腺嘌呤二核苷酸（NAD+）/烟酰胺腺嘌呤二核苷酸氢（NADH）比率。NAD+是 细胞代谢和氧化应激的重要调节剂。重要的是，通过管理增加NAD+ NAD+或其前体的作用已显示在HF动物模型中具有心脏保护作用。早期 临床研究已经证明口服给予NAD+前体，烟酰胺核苷（NR）， 增加血液NAD+水平，改善外周单核细胞的氧化代谢， 促炎基因表达。母体R 01正在一项随机、安慰剂对照临床试验中进行探索 试验（NCT 04528004）短期口服NR补充是否会增加HF患者的NAD+水平， 计划植入LVAD的患者。虽然心肌细胞能量和NAD+缺乏的作用，以及心肌细胞的能量缺乏， HF中的拓扑结构功能障碍以前已经描述过，其研究集中在以下的病理生理学： 左心室衰竭（LVF）。然而，目前尚不清楚是否在右侧中观察到类似的代谢紊乱。 心室衰竭（RVF）。本补充申请建议检查NAD+参与的途径 LVAD长期支持患者RVF的稳态和能量代谢。裂谷热发展于 到40%的人长期使用LVAD，并与更差的结果相关。不幸的是在 LVAD合并RVF患者，心脏移植是唯一持久的选择。如果NAD+稳态也是每- 在衰竭的右心室中，这一发现可能扩展了在亲本R 01中探索的概念， 利用NR治疗裂谷热的潜在效用的机会。因为许多裂谷热患者 最终接受心脏移植，一项对LVAD患者的心脏移植的研究， RVF代表了研究心脏能量代谢信号通路的作用的独特机会，特别是 特别是NAD+代谢和氧化还原调节，在裂谷热的发病机制。另外，我们将以- 利用综合裁定系统确定本机构LVAD患者中裂谷热的流行病学。 这些发现预计将产生重大影响，因为它们将提供关键信息，以确定- 确定潜在的生物标志物，以早期识别这种并发症或药理学靶点，以解决这种疾病， 无法治愈的疾病。

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.