Metabolomic Profiling in Acute ST‐Segment–Elevation Myocardial Infarction Identifies Succinate as an Early Marker of Human Ischemia–Reperfusion Injury

Abstract

BackgroundIschemia–reperfusion injury following ST‐segment–elevation myocardial infarction (STEMI) is a leading determinant of clinical outcome. In experimental models of myocardial ischemia, succinate accumulation leading to mitochondrial dysfunction is a major cause of ischemia–reperfusion injury; however, the potential importance and specificity of myocardial succinate accumulation in human STEMI is unknown. We sought to identify the metabolites released from the heart in patients undergoing primary percutaneous coronary intervention for emergency treatment of STEMI.Methods and ResultsBlood samples were obtained from the coronary artery, coronary sinus, and peripheral vein in patients undergoing primary percutaneous coronary intervention for acute STEMI and in control patients undergoing nonemergency coronary angiography or percutaneous coronary intervention for stable angina or non‐STEMI. Plasma metabolites were analyzed by targeted liquid chromatography and mass spectrometry. Metabolite levels for coronary artery, coronary sinus, and peripheral vein were compared to derive cardiac and systemic release ratios. In STEMI patients, cardiac magnetic resonance imaging was performed 2 days and 6 months after primary percutaneous coronary intervention to quantify acute myocardial edema and final infarct size, respectively. In total, 115 patients undergoing acute STEMI and 26 control patients were included. Succinate was the only metabolite significantly increased in coronary sinus blood compared with venous blood in STEMI patients, indicating cardiac release of succinate. STEMI patients had higher succinate concentrations in arterial, coronary sinus, and peripheral venous blood than patients with non‐STEMI or stable angina. Furthermore, cardiac succinate release in STEMI correlated with the extent of acute myocardial injury, quantified by cardiac magnetic resonance imaging.ConclusionSuccinate release by the myocardium correlates with the extent of ischemia.

Succinate induces skeletal muscle fiber remodeling via SUCNR1 signaling

“…Regular exercise and chronic hypoxia are natural stimuli that produce sustainable cardioprotection against ischemia reperfusion . Consistent with the important role of succinate in muscle metabolism and fiber remodeling we showed, succinate is elevated in the blood in response to exercise and accumulated rapidly in hypoxic/ischemic tissues , suggesting a potential role of succinate in exercise/hypoxia‐mediated cardioprotection. Succinate may act as a paracrine or endocrine signaling molecules via SUCNR1 to regulate local cellular metabolism , or increase tissue blood supply through the renin‐angiotensin system, thereby alleviating tissue hypoxia and hypoxia adaptation of metabolism in the environment .…”

Accumulation of Succinate in Cardiac Ischemia Primarily Occurs via Canonical Krebs Cycle Activity

“…Plasma succinate may participate in a similar cycle, perhaps with glutamine/glutamate as metabolites returning to hypoxic tissue. In agreement with this, a recent study on plasma metabolites in the coronary sinus of ischemic human myocardium identified elevated succinate and lower glutamate ( Kohlhauer et al, 2018 ).…”

Mitochondria as a therapeutic target for common pathologies

“…Furthermore addition of malonate upon reperfusion is also protective 130,131 . In addition, some succinate is released from the ischemic tissue into the circulation upon reperfusion 132 and can activate the pro-inflammatory succinate receptor (SUNCR1) which is expressed in immune cells, thereby stimulating inflammatory damage [133][134][135] . These findings suggest that inhibitors of succinate accumulation during ischemia, and its oxidation and release during reperfusion are promising therapeutic agents 136 .…”