Cardiac metabolite exchange measured in pigs during myocardial ischemia and reperfusion

Abstract

Myocardial ischemia and reperfusion (I/R) injury are the primary contributors to death in patients with cardiovascular disease. While decades of research have elucidated the molecular players and biochemical mechanisms underlying I/R injury, how these pathologies influence the metabolic activities of the heart remains incompletely understood. Such a knowledge gap hampers the development of therapies aimed at mitigating the metabolic stresses of the heart during injury. Using comprehensive arteriovenous metabolomics in a highly relevant porcine I/R model, we report the metabolic landscape of cardiac metabolic changes after ischemia and during the reperfusion time course. Paradoxically, ischemia increases the cardiac uptake of circulating fatty acids while reperfusion for 60 minutes reverses this activity. By 120 minutes of reperfusion, the hearts resume the uptake of fatty acids, suggesting restoration of their metabolism. On the other hand, we found a strong release of amino acids by the heart only after 60-minute reperfusion, but not after 120-minute reperfusion, implicating I/R-induced transient protein degradation. In addition to these findings, we identified several previously unrecognized changes in cardiac metabolic inputs and outputs during I/R, including nucleotides, TCA cycle intermediates and creatine/creatinine. These data highlight the dynamic alterations in cardiac metabolism in response to I/R, providing insights into how to mitigate myocardial I/R injury.