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.

项目摘要 /摘要 尽管手术技术和围手术期管理方法逐渐改善，但 心脏手术后不良后果的患病率在全国范围内仍然很高。不幸的是，迄今为止，没有 事实证明，干预在改变这些结果方面具有系统上有效。在最近的两项研究中（自然 2016年，自然医学2018），我们已经确定了个人可以抵抗或 承受最终器官受伤。我们已经实施了规范线粒体生物发生调节剂的新作用 PGC1α（过氧化物组增殖剂激活受体伽马共振剂1-α）捍卫NAD+的肾脏水平 （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 调查结果成为早期“概念证明”人类临床试验。我们已经表明了外源 通过其前体的烟酰胺（NAM）的口服给予NAD+的增强，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有利的临床作用 接受心脏手术的患者的急性肾脏损伤。在此拟议的NAD+增强中 心脏手术相关的心肌损伤（NACAM）试验，我们将进行较大的2阶段，随机，随机， 双盲，安慰剂对照试验，以评估口服NAM的效率和安全性 304例患者手术心肌损伤。这项研究的主要终点是血清心脏肌钙蛋白T 曲线下的区域（AUC）作为围攻性心肌损伤的经过验证的标记。我们的次要 终点包括急性肾脏损伤的事件，以及尿喹位/色氨酸的变化（UQ：T） 比率是从头nad+生物合成的机械标记，以进一步促进我们对 心脏手术的病理机制相关的缺血再灌注损伤（IRI）。另外，研究 基线UQ：T比为NAD+生物合成受损的标记物可以帮助识别未来的高风险亚组 临床试验富集和针对性的干预措施，以减轻心脏手术相关的IRI。额外的 探索性结果将包括重大不良心脏和脑血管事件的组合，重大 不良肾脏结局和肾脏损伤的生物标志物。不利事件和其他信息 特殊感兴趣的医疗事件，例如住院时间和围手术期肌肉和 还将确定使用加压剂。总体而言，拟议的研究将更明确地确定是否是否 NAD+/NAM代谢的进化可能是器官损伤和风险分层的关键效应因子，以及是否是 外部增强可能会减少应力介导的器官损伤。成功追求这个项目可以揭露 通往安全且廉价干预的道路，以防止心脏手术诱导的心肌和肾脏 目前缺乏任何有效策略的伤害。