Safety and Tolerability of the Nutritional Supplement, Nicotinamide Riboside, in Systolic Heart Failure

营养补充剂烟酰胺核苷治疗收缩性心力衰竭的安全性和耐受性

• 批准号: 9113264
• 负责人: Kevin D. O'Brien
• 金额: $ 11.59万
• 依托单位: UNIVERSITY OF WASHINGTON
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-06-01 至 2018-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9113264
• 关键词: ATP Synthesis Pathway; Activities of Daily Living; Affect; Animal Model; Bioavailable; Biology; Blood; Cardiac; Caring; Chronic; Chronic stress; Clinic Visits; Data; Development; Diet and Nutrition; Dietary Supplementation; Disease; Dose; Echocardiography; Electrolytes; Ensure; Etiology; Exploratory/Developmental Grant; Flushing; Glucose; Goals; Health; Heart; Heart failure; Human; Image; Impairment; Innovative Therapy; Insulin; Insulin Resistance; Intervention; Laboratory Finding; Left Ventricular Ejection Fraction; Leukocytes; Link; Lipids; Maximum Tolerated Dose; Medical; Mitochondria; Mitochondrial Proteins; Modeling; Monitor; Mus; Muscle; Myocardial; Myocardial dysfunction; NADH; NIH Program Announcements; NMR Spectroscopy; Niacinamide; Nicotinamide Mononucleotide; Nicotinic Acids; Oral; Oxidative Phosphorylation; Oxidative Stress; Participant; Patients; Pilot Projects; Placebos; Prevention; Production; Protein Acetylation; Pruritus; Randomized; Relative (related person); Research Project Grants; Rodent Model; Safety; Serum; Starvation; Supplementation; Surrogate Endpoint; Symptoms; Systolic heart failure; Testing; Therapeutic Uses; Three-Dimensional Echocardiography; Time; Tissues; Translating; Uric Acid; Ventricular Function; Visit; Walking; Wit; base; dietary supplements; improved; innovation; mitochondrial dysfunction; mouse model; new therapeutic target; nicotinamide-beta-riboside; peripheral blood; pressure; prevent; response; screening; therapy development

DESCRIPTION (provided by applicant): Medical care of heart failure (HF) has been stagnant for the past 20 years; innovative therapy is urgently needed. A novel therapeutic target, mitochondrial dysfunction, has been implicated in multiple diseases, including heart failure. However, there currently is no specific treatment for mitochondrial dysfunction in human heart failure or any other disease. Mitochondria-based therapy development has been hampered both by limited understanding of how mitochondrial impairment causes cardiac dysfunction, and by a lack of interventions shown to improve mitochondrial function. Recently, we demonstrated in a murine model, that impaired mitochondrial oxidative phosphorylation led to an increased myocardial NADH/NAD+ ratio and increased mitochondrial protein acetylation, without affecting mitochondrial ROS production or ATP synthesis. These changes rendered the heart susceptible to chronic stresses, which accelerated the development of heart failure. We observed a similar increase of NADH/NAD+ ratio and increase in protein acetylation in animal models of heart failure due to chronic pressure overload with no prior mitochondrial dysfunction. Supplying the NAD+ precursor, nicotinamide mononucleotide (NMN), to these mice normalized the NADH/NAD+ ratio, prevented increased mitochondrial protein acetylation and improved cardiac function. Though NMN is not orally bioavailable, we and others have shown that oral supplementation with nicotinamide riboside (NR), the precursor from which NMN is produced, also decreases (normalizes) tissue NADH/NAD+ ratio and improves mitochondrial function in mouse models. These animal model results suggest a conceptually innovative mechanism linking mitochondrial dysfunction to the development and progression of heart failure that is distinct from the existing hypotheses of oxidative stress and energy starvation. Thus, we hypothesize that oral supplementation with NR will improve the NADH/NAD+ ratio caused by mitochondrial dysfunction during chronic stresses, and improve functional capacity and ventricular function in systolic heart failure. We therefore propose a first-in-human, safety and tolerability trial of the nutritional supplement, nicotinamide riboside (NR) in 30 participants wit clinically-stable, systolic heart failure. NR is a relative of niacin, but a closer relative of nicotinamide which, unlike niacin, does not induce flushing or pruritis and has no effect on lipid levels. NR does not induce insulin resistance or dysglycemia in mouse models. Thus, NR would potentially be cheap, safe, well-tolerated and readily available. The application is in response to the program announcement of "Nutrition and Diet in the Causation, Prevention, and Management of Heart Failure" as NR has recently been approved for human use as a health supplement. As NR has not been used therapeutically in heart failure patients, we will utilize the R21 mechanism to support a pilot study with the following aims: 1) to determine the safety and tolerability of NR in patients with clinically-stable, systolic heart failure (LVEF <40%); 2) to determine whether, at the doses employed, NR has measureable effects on leukocyte NAD+ level and NADH/NAD+ ratio; and 3) to explore the potential range of effects of NR supplementation on heart failure surrogate endpoints.

描述(申请人提供)：心力衰竭(HF)的医疗护理在过去的20年里一直停滞不前；迫切需要创新的治疗方法。线粒体功能障碍是一种新的治疗靶点，它与包括心力衰竭在内的多种疾病有关。然而，目前还没有针对人类心力衰竭或任何其他疾病的线粒体功能障碍的特效药。由于对线粒体损伤如何导致心脏功能障碍的了解有限，以及缺乏改善线粒体功能的干预措施，基于线粒体的治疗发展一直受到阻碍。最近，我们在一个小鼠模型中证明，线粒体氧化磷酸化受损导致心肌NADH/NAD+比值增加，线粒体蛋白乙酰化增加，而不影响线粒体ROS的产生或ATP的合成。这些变化使心脏容易受到慢性压力的影响，从而加速了心力衰竭的发展。我们观察到，在没有线粒体功能障碍的慢性压力超负荷所致的心力衰竭动物模型中，NADH/NAD+比率和蛋白乙酰化水平也有类似的增加。向这些小鼠提供NAD+前体烟酰胺单核苷酸(NMN)可使NADH/NAD+比值正常化，防止线粒体蛋白乙酰化增加，并改善心功能。虽然NMN没有口服生物利用度，但我们和其他人已经表明，口服补充NMN的前体烟酰胺核苷(NR)也可以降低(正常化)组织NADH/NAD+比率，并改善小鼠模型的线粒体功能。这些动物模型结果表明，一种概念上的创新机制将线粒体功能障碍与心力衰竭的发展和进展联系起来，这与现有的氧化应激和能量饥饿假说不同。因此，我们假设口服NR可以改善慢性应激时线粒体功能障碍引起的NADH/NAD+比值，并改善收缩期心衰患者的心功能和心功能。因此，我们建议对30名临床稳定的收缩性心力衰竭患者进行首次人体安全性和耐受性试验，试验对象为营养补充剂烟酰胺核苷(NR)。NR是烟酸的近亲，但也是烟酰胺的近亲，与烟酸不同，它不会引起潮红和瘙痒，也不会对血脂水平产生影响。NR不会在小鼠模型中引起胰岛素抵抗或血糖紊乱。因此，天然橡胶有可能是廉价、安全、耐受性好和容易获得的。该应用程序响应于 “心力衰竭的起因、预防和管理中的营养和饮食”作为NR的计划公告最近已被批准作为健康补充剂用于人类。由于NR尚未用于心力衰竭患者的治疗，我们将利用R21机制支持一项先导性研究，目的如下：1)确定NR在临床稳定的收缩性心力衰竭(LVEF&lt；40%)患者中的安全性和耐受性；2)确定在所使用的剂量下，NR是否对白细胞NAD+水平和NADH/NAD+比率有可测量的影响；以及3)探索补充NR对心力衰竭替代终点的潜在影响范围。