Sunday, October 6, 2024
10/6/2024
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.
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