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

描述（由申请人提供）：心力衰竭（HF）的医疗保健在过去20年中一直停滞不前；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，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异性治疗方法。由于对线粒体损伤如何导致心功能障碍的理解有限，以及缺乏表明可以改善线粒体功能的干预措施，线粒体治疗的发展受到了阻碍。最近，我们在小鼠模型中证明，线粒体氧化磷酸化受损导致心肌NADH/NAD+比例增加，线粒体蛋白乙酰化增加，但不影响线粒体ROS生成或ATP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负荷心力衰竭动物模型中，NADH/NAD+比值和蛋白质乙酰化也有类似的增加。向这些小鼠提供NAD+前体烟酰胺单核苷酸（NMN），使NADH/NAD+比例正常化，防止线粒体蛋白乙酰化增加，改善心功能。虽然NMN不是口服生物可利用的，但我们和其他人已经证明，在小鼠模型中，口服补充烟酰胺核苷（NR） （NMN产生的前体）也可以降低（正常化）组织NADH/NAD+比率并改善线粒体功能。这些动物模型的结果表明，线粒体功能障碍与心力衰竭的发展和进展之间的概念创新机制不同于现有的氧化应激和能量饥饿假说。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，改善收缩期心力衰竭时的功能容量和心室功能。因此，我们建议在30名临床稳定的收缩期心力衰竭患者中进行营养补充剂烟酰胺核苷（NR）的首次人体安全性和耐受性试验。NR是烟酸的近亲，但是烟酰胺的近亲，与烟酸不同，烟酰胺不会引起潮红或瘙痒，对脂质水平没有影响。在小鼠模型中NR不诱导胰岛素抵抗或血糖异常。因此，NR可能是便宜、安全、耐受性良好且容易获得的。应用程序响应于

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.