Energy metabolism and NAD+/NADH in Right Ventricular Failure

右心室衰竭中的能量代谢和 NAD /NADH

• 批准号: 10629552
• 负责人: Kevin D. O'Brien
• 金额: $ 20.54万
• 依托单位: UNIVERSITY OF WASHINGTON
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-09-01 至 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10629552
• 关键词: Animal Model; Blood; Cardiac; Cardiac Myocytes; Cell Respiration; Cells; Cellular Metabolic Process; Chronic; Clinical Research; Complication; Disease; Early identification; Energy Metabolism; Epidemiology; Failure; Functional disorder; Gene Expression; Heart; Heart Transplantation; Heart failure; Homeostasis; Hydrogen; Inflammatory; Institution; Investigation; Left; Medical; Metabolic; Metabolism; Mononuclear; Nicotinamide adenine dinucleotide; Oral; Oral Administration; Outcome; Oxidation-Reduction; Oxidative Stress; Parents; Pathogenesis; Pathway interactions; Patient Care; Patients; Peripheral; Persons; Pharmacology; Quality of life; Regulation; Right ventricular structure; Role; Schedule; Signal Pathway; System; Ventricular; adjudication; cardioprotection; clinically relevant; human tissue; implantation; improved; left ventricular assist device; mitochondrial dysfunction; nicotinamide riboside supplementation; nicotinamide-beta-riboside; potential biomarker; randomized placebo-controlled clinical trial; right ventricular failure

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.

项目概要/摘要 在心力衰竭 (HF) 中观察到的线粒体功能障碍的机制之一是由于心脏功能下降 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+ 或其前体已被证明在心力衰竭动物模型中具有心脏保护作用。早期的 临床研究表明，口服 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，并降低 促炎基因表达。母体 R01 正在一项随机、安慰剂对照的临床试验中进行探索 试验 (NCT04528004) 短期口服 NR 补充剂是否会增加 HF 患者的 NAD+ 水平 计划进行 LVAD 植入的患者。而心肌细胞能量和 NAD+ 缺乏的作用以及 mi- 之前已经描述过心力衰竭的软骨功能障碍，其研究重点是病理生理学 左心室衰竭（LVF）。然而，尚不清楚是否在右侧观察到类似的代谢紊乱。 心室衰竭（RVF）。该补充申请建议检查 NAD+ 涉及的途径 长期接受 LVAD 支持的患者 RVF 的稳态和能量代谢。 RVF 发展向上 40% 的人长期接受 LVAD 支持，并且与更糟糕的结果相关。不幸的是，在 对于LVAD合并RVF的患者，心脏移植是唯一持久的选择。如果 NAD+ 体内平衡也是 per- 在衰竭的右心室中受到扰动，这一发现可能会扩展母版 R01 中探索的概念，介绍 NR 在治疗 RVF 中的潜在效用的机会。因为很多RVF患者 最终接受心脏移植，一项针对患有和不患有 LVAD 患者的移植心脏的研究 RVF 代表了研究心脏能量代谢信号通路作用的独特机会，特别是 在 RVF 的发病机制中，通常参与 NAD+ 代谢和氧化还原调节。此外，我们将描述—— 利用综合裁决系统对我们机构的 LVAD 患者中 RVF 的流行病学进行了解。 这些发现预计将产生重大影响，因为它们将为识别 确定潜在的生物标志物，以便及早识别这种并发症或药理学目标，以解决这一问题 无法治愈的疾病。