A metabolomic analysis of cardiac metabolism in a human model of early myocardial ischaemia

Abstract

Introduction: Acute myocardial ischaemia and the transition from reversible to irreversible myocardial injury are associated with abnormal metabolic patterns. Advances in metabolomics have extended our capabilities to define these metabolic perturbations on a metabolome-wide scale.

Objectives: This study was designed to identify changes in cardiac metabolism during the first 5 minutes following early myocardial ischaemia in humans, using an untargeted metabolomics approach.

Methods: Peripheral venous samples were collected from 46 patients in a discovery study (DS; 25 patients) and a validation study (VS; 21 patients). Coronary sinus venous samples were collected from 7 patients (4 for DS, 3 for VS). Acute cardiac ischaemia was induced by transient coronary occlusion during percutaneous coronary intervention (PCI). Blood samples were collected at baseline (prior to PCI), and at 1 and 5 mins following coronary occlusion. Samples were analyzed using Ultra Performance Liquid Chromatography- Mass Spectrometry (UPLS-MS) in an untargeted metabolomics approach.

Results: The study observed changes in the circulating levels of metabolites at 1 and 5 minutes following transient coronary ischaemia. Both DS and VS identified 54 and 55 metabolites respectively as significantly changed when compared to baseline levels. These include a range of metabolites which have previously been shown to be detrimental to cardiac function such as arachidonic acid, lysophosphatidylcholine, carnitine, and tryptophan, as well as metabolites which are known to have a cardio-protective effect, like docosahexaenoic acid. A further multivariate analysis to UPLS-MS serum data was performed to explore the effects of co-morbidities that may also have an influence on the metabolite profile. Principal component analysis, projection to latent structures and orthogonal projection to latent structures, discriminative analysis was used to test the statistical significance of the variables. Lysophosphatidylcholine, and 2-hydroxybutyric acid were noted to be influential metabolites with statistically significant models obtained for diabetes, body mass index, coronary versus peripheral collection site, and antianginal medications. Analysis revealed that none of the comorbidities influenced the metabolite pattern induced by ischaemia, suggesting myocardial specific metabolite perturbation as a consequence of controlled reversible myocardial ischaemia.

Conclusion: The study provides novel insights into cellular changes occurring in a human model of controlled early myocardial ischaemia. Distinct classes of metabolites were shown to be involved in the rapid cardiac response to ischaemia opening new avenues of research into diagnostic and therapeutic targets in those suffering acute cardiovascular events.