NAD+ Augmentation in Cardiac Surgery Associated Myocardial Injury

NAD 增强治疗心脏手术相关心肌损伤

• 批准号: 10206265
• 负责人: Ali Poyan Mehr
• 金额: $ 77.54万
• 依托单位: KAISER FOUNDATION RESEARCH INSTITUTE
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-07-01 至 2025-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10206265
• 关键词: Acute; Acute Renal Failure with Renal Papillary Necrosis; Adult; Adverse event; Affect; Anabolism; Area Under Curve; Attenuated; Biogenesis; Biological Markers; Blood Circulation; Cardiac; Cardiac Surgery procedures; Cardiovascular system; Cell Respiration; Cessation of life; Characteristics; Clinical; Clinical Trials; Clinical assessments; Closure by clamp; Comprehensive Health Care; Double-Blind Method; Drug Kinetics; Elderly; Enrollment; Event; Future; Heart; Homeostasis; Hospitalization; Hour; Human; Impairment; Incidence; Individual; Infrastructure; Injury to Kidney; Integrated Delivery of Health Care; Intervention; Investigation; Kidney; Knowledge; Length; Link; Measurement; Mediating; Medical; Medicine; Metabolic; Metabolism; Mitochondria; Mus; Nature; Niacinamide; Nicotinamide adenine dinucleotide; Operative Surgical Procedures; Oral; Oral Administration; Organ; Outcome; PPAR gamma; Pathway interactions; Patients; Perioperative; Phase; Pilot Projects; Population Heterogeneity; Postoperative Period; Predisposition; Prevalence; Prevention; Preventive therapy; Procedures; Production; Protocols documentation; Pump; Randomized; Reperfusion Injury; Risk; Safety; Serum; Special Event; Stress; Subgroup; Supplementation; System; Techniques; Testing; Thoracic Surgical Procedures; Tissues; Translating; Troponin T; Tryptophan; Vasoconstrictor Agents; adverse outcome; aortic valve replacement; base; cardioprotection; cerebrovascular; clinical effect; clinical efficacy; design; double-blind placebo controlled trial; efficacy evaluation; experience; follow-up; genetic manipulation; high risk; high risk population; hospital readmission; improved; improved outcome; insight; interest; multidisciplinary; myocardial injury; novel; organ injury; patient population; perioperative morbidity; perioperative mortality; phase 3 study; phase I trial; pre-clinical; preclinical study; prevent; primary endpoint; protective effect; quinolinate; randomized placebo-controlled clinical trial; renal ischemia; risk stratification; safety study; secondary endpoint; secondary outcome; sociodemographics; stressor; tissue biomarkers; tissue injury; urinary; vitamin analog

PROJECT SUMMARY / ABSTRACT Despite progressive improvements in surgical techniques and peri-operative management approaches, the prevalence of adverse outcomes after cardiac surgery remains high nationally. Unfortunately, to date, no intervention has proven to be systematically effective in changing these outcomes. In two recent studies (Nature 2016, Nature Medicine 2018), we have identified endogenous pathways through which individuals may resist or withstand end-organ injury. We have implicated a novel action of the canonical mitochondrial biogenesis regulator PGC1α (peroxisome proliferator activated receptor gamma coactivator-1-α) to defend renal levels of NAD+ (nicotinamide adenine dinucleotide) by increasing its biosynthesis. We have successfully translated these findings into an early-stage “proof-of-concept” human clinical trial. We have shown that exogenous augmentation of NAD+ through the oral administration of its precursor, nicotinamide (Nam), is not only safe and well tolerated, but may have favorable clinical effects toward the reduction of postoperative myocardial injury and acute kidney injury in patients undergoing cardiac surgery. In this proposed NAD+ Augmentation in Cardiac Surgery Associated Myocardial Injury (NACAM) trial, we will conduct a larger, Phase 2, randomized, double-blind, placebo-controlled trial to evaluate the efficacy and safety of oral Nam for the prevention of peri- operative myocardial injury in 304 patients. The primary endpoint in this study is the serum cardiac troponin T Area Under the Curve (AUC) as a validated marker of peri-operative myocardial injury. Our secondary endpoints include the incidence of acute kidney injury, and changes in urinary quinolinate/tryptophan (uQ:T) ratio as mechanistic marker of de novo NAD+ biosynthesis to help further advance our understanding about the pathomechanism of cardiac surgery associated ischemia reperfusion injury (IRI). In addition, the study of baseline uQ:T ratio as a marker of impaired NAD+ biosynthesis can help identify a high-risk subgroup for future clinical trial enrichments and targeted interventions to alleviate cardiac surgery associated IRI. Additional exploratory outcomes will include a composite of major adverse cardiac and cerebrovascular events, major adverse kidney outcomes, and biomarkers of renal injury. Adverse events and additional information on medical events of special interest, such as length of hospitalization, and peri-operative inotrope and vasopressor use will also be ascertained. Overall, the proposed study will more definitively determine if derangement of NAD+/Nam metabolism may be a pivotal effector of organ injury and risk stratifier, and whether extrinsic augmentation may reduce stress-mediated organ injury. Successful pursuit of this project could unveil a path toward a safe and inexpensive intervention to prevent cardiac surgery-induced myocardial and renal injury which currently lacks any effective strategies.

项目概要/摘要 尽管手术技术和围手术期管理方法不断改进，但 不幸的是，迄今为止，全国范围内心脏手术后不良后果的发生率仍然很高。 最近的两项研究证明干预对于改变这些结果是系统有效的。 2016，Nature Medicine 2018），我们已经确定了个体可能抵抗或抵抗的内源途径 我们发现了经典线粒体生物合成调节剂的一种新作用。 PGC1α（过氧化物酶体增殖物激活受体γ共激活剂-1-α）可保护肾脏的 NAD+ 水平 （烟酰胺腺嘌呤二核苷酸）通过增加其生物合成我们已经成功翻译了这些。 我们已经证明了早期“概念验证”人体临床试验的结果。 通过口服 NAD+ 前体烟酰胺 (Nam) 来增强 NAD+ 不仅安全，而且 耐受性良好，但可能对减少术后心肌损伤具有良好的临床效果 以及接受心脏手术的患者的急性肾损伤。 心脏手术相关心肌损伤 (NACAM) 试验，我们将进行更大规模的 2 期随机、 双盲、安慰剂对照试验，评估口服 Nam 预防围产期并发症的有效性和安全性 304 名患者的手术心肌损伤本研究的主要终点是血清心肌肌钙蛋白 T。 曲线下面积 (AUC) 作为围手术期心肌损伤的有效标志物。 终点包括急性肾损伤的发生率以及尿喹啉/色氨酸 (uQ:T) 的变化 比率作为NAD+从头生物合成的机制标记，有助于进一步加深我们对NAD+生物合成的理解 此外，还有心脏手术相关缺血再灌注损伤（IRI）的病理机制。 基线 uQ:T 比率作为 NAD+ 生物合成受损的标志可以帮助识别未来的高风险亚组 丰富临床试验和有针对性的干预措施，以减轻心脏手术相关的 IRI。 探索性结果将包括主要不良心脑血管事件、主要不良事件的综合结果 不良肾脏结局、肾损伤的生物标志物以及不良事件和其他信息。 特别关注的医疗事件，例如住院时间、围手术期正性肌力药物和 总体而言，拟议的研究将更明确地确定是否使用血管加压药。 NAD+/Nam 代谢紊乱可能是器官损伤和风险分层的关键效应器，以及是否 外在增强可能会减少压力介导的器官损伤。该项目的成功实施可能会揭示这一点。 一种安全且廉价的干预措施，以预防心脏手术引起的心肌和肾脏疾病 目前缺乏有效的应对策略。