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: 10671652
• 负责人: Ali Poyan Mehr
• 金额: $ 71.52万
• 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/10671652
• 关键词: Acute; Acute Renal Failure with Renal Papillary Necrosis; Adult; Adverse event; Affect; Anabolism; Aorta; Area Under Curve; Attenuated; Biogenesis; Biological Markers; Cardiac; Cardiac Surgery procedures; Cardiovascular system; Cell Respiration; Cessation of life; Characteristics; Circulation; 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; Ischemia; 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 alpha; 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; biomarker validation; 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; receptor; renal ischemia; safety study; secondary endpoint; secondary outcome; sociodemographics; stress reduction; 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正在逐步改进，但 在全国范围内，心脏手术后不良后果的发生率仍然很高。不幸的是，到目前为止，没有 事实证明，在改变这些结果方面，干预措施是系统有效的。在最近的两项研究中(《自然》 2016，自然医学2018)，我们已经确定了个体可能通过哪些内源性途径来抵抗或 经得起末梢器官损伤。我们已经暗示了典型的线粒体生物发生调节的一个新的作用 前列腺素C_1α(过氧化物酶体增殖物激活受体-1-α)保护肾脏NAD+水平的研究 (烟酰胺腺嘌呤二核苷酸)通过增加其生物合成。我们已经成功地翻译了这些 一项早期的“概念验证”人体临床试验的结果。我们已经证明了外生的 通过口服其前体烟酰胺(NAM)来增强NAD+不仅安全且 耐受性良好，但对减少术后心肌损伤可能有良好的临床效果 和心脏手术患者的急性肾损伤。在此建议的NAD+增强中 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， 评价口服NAM预防围绝经期高血压的疗效和安全性的双盲安慰剂对照试验 304例外科心肌损伤的临床分析。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/色氨酸(uq：t)的变化。 比率作为NAD+生物合成的机制标志，有助于进一步加深我们对NAD+生物合成的理解 心脏手术相关缺血再灌注损伤(IRI)的发病机制此外，还研究了 基线UQ：T比值作为NAD+生物合成受损的标志有助于识别未来的高危亚群 临床试验的充实和针对性干预以减轻心脏手术相关的IRI。其他内容 探索性结果将包括主要不良心脑血管事件、主要 不利的肾脏结局，以及肾脏损伤的生物标志物。不良事件和更多关于 特殊关注的医疗事件，如住院时间、围手术期肌力抑制和 血管升压药的使用也将得到确认。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危险分层的关键影响因素，以及 外源性增强可以减轻应激介导的器官损伤。对这个项目的成功追求可能会揭开 预防心脏手术引起的心肌和肾脏的安全和廉价干预的途径 伤害，目前缺乏任何有效的战略。

项目成果

Moving beyond COVID-19 Surge-Caring for Patients with Kidney Disease throughout the Pandemic.

超越 COVID-19 在整个大流行期间对肾病患者的激增护理。

• DOI: 10.34067/kid.0005452020
• 发表时间: 2020
• 期刊: Kidney360
• 作者: Belani,Sharina;Pravoverov,Leonid;Goes,NelsonB;Zheng,Sijie;Asovskaya,AnnaV;Kroupa,Paul;PoyanMehr,Ali
• 通讯作者: PoyanMehr,Ali