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Systems characterization of differential plasma metabolome perturbations following thrombotic and non-thrombotic myocardial infarction.

ABSTRACT: Myocardial infarction (MI) is an acute event characterized by myocardial necrosis. Thrombotic MI is caused by spontaneous atherosclerotic plaque disruption that results in a coronary thrombus; non-thrombotic MI occurs secondary to oxygen supply-demand mismatch. We sought to characterize the differential metabolic perturbations associated with these subtypes utilizing a systems approach. Subjects presenting with thrombotic MI, non-thrombotic MI and stable coronary artery disease (CAD) were included. Whole blood was collected at two acute time-points and at a time-point representing the quiescent stable disease state. Plasma metabolites were analyzed by untargeted UPLC-MS/MS and GC-MS. A weighted network was constructed, and modules were determined from the resulting topology. To determine perturbed modules, an enrichment analysis for metabolites that demonstrated between-group differences in temporal change across the disease state transition was then conducted. BIOLOGICAL SIGNIFICANCE:We report evidence of metabolic perturbations of acute MI and determine perturbations specific to thrombotic MI. Specifically, a module characterized by elevated glucocorticoid steroid metabolites following acute MI showed greatest perturbation following thrombotic MI. Modules characterized by elevated pregnenolone metabolites, monoacylglycerols, and acylcarnitines were perturbed following acute MI. A module characterized by a decrease in plasma amino acids following thrombotic MI was differentially perturbed between MI subtypes.

SUBMITTER: Trainor PJ

PROVIDER: S-EPMC5496773 | biostudies-literature | 2017 May

REPOSITORIES: biostudies-literature

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Systems characterization of differential plasma metabolome perturbations following thrombotic and non-thrombotic myocardial infarction.

Trainor Patrick J PJ Hill Bradford G BG Carlisle Samantha M SM Rouchka Eric C EC Rai Shesh N SN Bhatnagar Aruni A DeFilippis Andrew P AP

Journal of proteomics 20170322

Myocardial infarction (MI) is an acute event characterized by myocardial necrosis. Thrombotic MI is caused by spontaneous atherosclerotic plaque disruption that results in a coronary thrombus; non-thrombotic MI occurs secondary to oxygen supply-demand mismatch. We sought to characterize the differential metabolic perturbations associated with these subtypes utilizing a systems approach. Subjects presenting with thrombotic MI, non-thrombotic MI and stable coronary artery disease (CAD) were includ ...[more]

PMID: 28341595

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Project description:BackgroundPreclinical data suggest that an acute inflammatory response following myocardial infarction (MI) accelerates systemic atherosclerosis. Using combined positron emission and computed tomography, we investigated whether this phenomenon occurs in humans.Methods and resultsOverall, 40 patients with MI and 40 with stable angina underwent thoracic 18F-fluorodeoxyglucose combined positron emission and computed tomography scan. Radiotracer uptake was measured in aortic atheroma and nonvascular tissue (paraspinal muscle). In 1003 patients enrolled in the Global Registry of Acute Coronary Events, we assessed whether infarct size predicted early (≤30 days) and late (>30 days) recurrent coronary events. Compared with patients with stable angina, patients with MI had higher aortic 18F-fluorodeoxyglucose uptake (tissue-to-background ratio 2.15±0.30 versus 1.84±0.18, P<0.0001) and plasma C-reactive protein concentrations (6.50 [2.00 to 12.75] versus 2.00 [0.50 to 4.00] mg/dL, P=0.0005) despite having similar aortic (P=0.12) and less coronary (P=0.006) atherosclerotic burden and similar paraspinal muscular 18F-fluorodeoxyglucose uptake (P=0.52). Patients with ST-segment elevation MI had larger infarcts (peak plasma troponin 32 300 [10 200 to >50 000] versus 3800 [1000 to 9200] ng/L, P<0.0001) and greater aortic 18F-fluorodeoxyglucose uptake (2.24±0.32 versus 2.02±0.21, P=0.03) than those with non-ST-segment elevation MI. Peak plasma troponin concentrations correlated with aortic 18F-fluorodeoxyglucose uptake (r=0.43, P=0.01) and, on multivariate analysis, independently predicted early (tertile 3 versus tertile 1: relative risk 4.40 [95% CI 1.90 to 10.19], P=0.001), but not late, recurrent MI.ConclusionsThe presence and extent of MI is associated with increased aortic atherosclerotic inflammation and early recurrent MI. This finding supports the hypothesis that acute MI exacerbates systemic atherosclerotic inflammation and remote plaque destabilization: MI begets MI.Clinical trial registrationURL: https://www.clinicaltrials.gov. Unique identifier: NCT01749254.

Project description:Following acute myocardial infarction, clinical studies show alterations in the blood levels of corin, a cardiac-selective activator of the natriuretic peptides pro-atrial natriuretic peptide (pro-ANP) and pro-B-type natriuretic peptide (pro-BNP). However, the temporal changes in circulating and cardiac corin levels and their relationships to the severity of myocardial infarction have not been studied. The main objective of this study was to examine the relationship between cardiac and circulating corin levels and their association with cardiac systolic function and infarct size during the early phase of acute myocardial infarction (<72 h) in a translationally relevant induced coronary ligation mouse model. This acute phase timeline was chosen to correlate with the clinical practice within which blood samples are collected from myocardial infarction patients. Heart and plasma samples were examined at 3, 24, and 72 hours post acute myocardial infarction. Plasma corin levels were examined by enzyme-linked immunosorbent assay, transcripts of cardiac corin, pro-ANP and pro-BNP by quantitative real-time polymerase chain reaction, cardiac corin expression by immunohistology, infarct size by histology and heart function by echocardiography. Plasma corin levels were significantly increased at 3 (P<0.05), 24 (P<0.001), and 72 hours (P<0.01) post-acute myocardial infarction. In contrast, cardiac corin transcript levels dropped by 5% (P>0.05), 69% (P<0.001) and 65% (P<0.001) and immunoreactive cardiac corin protein levels dropped by 30% (P<0.05), 76% (P<0.001) and 75% (P<0.001), while cardiac pro-ANP and pro-BNP transcript levels showed an opposite pattern. Plasma corin levels were negatively correlated with immunoreactive cardiac corin (P<0.01), ejection fraction (P<0.05) and fractional shortening (P<0.05), but positively correlated with infarct size (P<0.01). In conclusion, acute myocardial infarction induces rapid increases in plasma corin and decreases in cardiac corin levels. In the early phase of acute myocardial infarction, plasma corin levels are inversely correlated with heart function and may reflect the severity of myocardial damage.

Dataset Information

Systems characterization of differential plasma metabolome perturbations following thrombotic and non-thrombotic myocardial infarction.

Publications

Systems characterization of differential plasma metabolome perturbations following thrombotic and non-thrombotic myocardial infarction.

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