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. 2018 Apr 6;7(8):e007546.
doi: 10.1161/JAHA.117.007546.

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

Matthias Kohlhauer  1   2 , Sam Dawkins  3 , Ana S H Costa  4 , Regent Lee  3 , Timothy Young  1 , Victoria R Pell  1 , Robin P Choudhury  3 , Adrian P Banning  5 , Rajesh K Kharbanda  3   5 ; Oxford Acute Myocardial Infarction (OxAMI) Study; Kourosh Saeb-Parsy  6 , Michael P Murphy  7 , Christian Frezza  4 , Thomas Krieg  8 , Keith M Channon  9   5
Affiliations

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

Matthias Kohlhauer et al. J Am Heart Assoc. .

Abstract

Background: Ischemia-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 results: Blood 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.

Conclusion: Succinate release by the myocardium correlates with the extent of ischemia.

Keywords: ischemia–reperfusion injury; mitochondria; myocardial ischemia; myocardial metabolism.

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Figures

Figure 1
Figure 1
Specific release of metabolites from the heart in ST‐segment–elevation myocardial infarction. Metabolites were quantified by liquid chromatography and mass spectrometry in paired samples of coronary artery (CA) and coronary sinus (CS) blood. The cardiac release ratio was calculated from the difference between CA and CS concentration, divided by the CA concentration. Each bar represents the median and interquartile range of the cardiac release ratio. Positive values represent a release of the metabolite into the blood by the heart, whereas negative values represent consumption of the metabolite from the blood by the heart. For each metabolite, cardiac release ratio has been compared with systemic release ratio (presented in Figure S1). *P<0.05 for cardiac vs systemic release ratio.
Figure 2
Figure 2
Blood succinate concentrations in patients with Angina, NSTEMI or STEMI. Absolute succinate concentrations in coronary artery, coronary sinus, and peripheral vein blood were compared for patients with angina, NSTEMI, or STEMI (A) and for patients undergoing coronary angiography without PCI, PCI for angina or NSTEMI, or PPCI for STEMI (B). A, *P<0.05 vs patients with angina; † P<0.05 vs NSTEMI patients for the corresponding sampling site. B, *P<0.05 vs patients with PCI patients; † P<0.05 vs no‐PCI patients for the corresponding sampling site. NSTEMI indicates non–ST‐segment–elevation myocardial infarction; PCI, percutaneous coronary intervention; PPCI, primary percutaneous coronary intervention; STEMI, ST‐segment–elevation myocardial infarction.
Figure 3
Figure 3
Correlation between coronary sinus succinate concentration and acute myocardial edema. Acute ischemia–reperfusion injury was quantified by T2 magnetic resonance imaging of edema within 2 days after primary percutaneous coronary intervention in patients with ST‐segment–elevation myocardial infarction due to left anterior descending or circumflex coronary artery occlusions. The extent of left ventricular (LV) myocardial edema, expressed as a percentage of LV mass, was correlated with coronary sinus succinate concentration.
See this image and copyright information in PMC

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