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: 10449138
• 负责人: Ali Poyan Mehr
• 金额: $ 75.76万
• 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/10449138
• 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.

项目总结/摘要 尽管手术技术和围手术期管理方法不断改进， 心脏手术后不良后果的发生率在全国仍然很高。不幸的是，到目前为止，没有 事实证明，干预措施在改变这些结果方面具有系统的效力。在最近的两项研究（自然 2016年，自然医学2018年），我们已经确定了内源性途径，通过这些途径，个体可以抵抗或 承受器官损伤我们已经暗示了一个新的行动的经典线粒体生物合成调节 PGC 1 α（过氧化物酶体增殖物激活受体γ共激活因子-1-α）保护肾脏NAD+水平 （烟酰胺腺嘌呤二核苷酸）通过增加其生物合成。我们成功地翻译了这些 将研究结果转化为早期的“概念验证”人体临床试验。我们已经证明， 通过口服给予NAD+前体烟酰胺（Nam）来增加NAD+不仅安全， 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 以及心脏手术患者的急性肾损伤。在本建议中， 心脏手术相关心肌损伤（NACAM）试验，我们将进行一项更大的2期随机试验， 一项双盲、安慰剂对照试验，旨在评价口服Nam预防糖尿病的有效性和安全性- 手术心肌损伤304例。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。我们的次要 终点包括急性肾损伤的发生率和尿喹啉酸/色氨酸（uQ：T）的变化 比率作为从头NAD+生物合成的机制标记，以帮助进一步推进我们对NAD+生物合成的理解。 缺血再灌注损伤（IRI）的病理机制。此外，研究 基线uQ：T比值作为NAD+生物合成受损的标志物可以帮助识别未来的高风险亚组。 临床试验丰富和有针对性的干预措施，以减轻心脏手术相关的IRI。额外 探索性结局将包括主要不良心脏和脑血管事件、主要 不利的肾脏结果和肾损伤的生物标志物。不良事件和其他信息 特别关注的医学事件，如住院时间和围手术期正性肌力药物， 还将确定血管加压药的使用。总体而言，拟议的研究将更明确地确定， NAD+/Nam代谢紊乱可能是器官损伤和风险分层的关键效应子， 外源性增强可以减少应激介导的器官损伤。这个项目的成功实施将揭开 一种安全、廉价的干预方法，以防止心脏手术引起的心肌和肾功能损害。 目前缺乏有效的预防措施。