Abstract 3942: Serum Metabolomics Identifies Novel Signature Metabolites in Very Early Cardiac Ischaemia: First in Human Study
Early changes in cardiac metabolism during the initial stages of cardiac ischemia are thought to play a major role in pathophysiological processes underlying ischemic preconditioning and sudden cardiac death. To date mechanistic studies have been limited to targeted analysis of a very small number of metabolites compared to the overall size of the metabolome (<1%). Using Metabolomics, a powerful tool to detect widespread and rapid metabolic changes associated with human diseases, we aim to identify metabolite changes occurring early during cardiac ischemia in humans as a first step towards gaining insight into these key pathophysiological processes. Peripheral and coronary sinus venous samples from 25 pts in whom cardiac ischemia was induced by transient coronary artery occlusion during PCI at baseline, 1 & 5 min post occlusion were analyzed in an untargeted fashion using Ultra Performance Liquid Chromatography coupled to a LTQ-Orbitrap hybrid mass spectrometer. Data were validated in a second cohort of 20 patients undergoing PCI with this protocol. In the primary cohort, 3844 metabolite peaks were detected, of which 297 peaks (7.7%) showed significant difference between baseline & 5 min post coronary occlusion (P<0.01). 44 peaks remained statistically significant (P<0.01) following validation in the second cohort. Predominantly metabolic pathways involving lipids were perturbed early during cardiac ischaemia with changes in Lysophophatidylcholines, Glycerophospholipids and Diacylglycerols and Free Fatty acids (FFA) including Docosahexaenoic acid (DHA; 40% increase) and Arachidonic acid (AA; 60% increase) observed. These results show that only a minor fraction of the metabolome is altered during early cardiac ischaemia suggesting highly specific changes particularly involving lipid metabolism. Our unbiased approach identified metabolites previously shown to be detrimental to cardiac function such as AA and for the first time in humans increased cardio-protective n-3 FFA such as DHA. This provides novel insights into early cardiac ischaemia suggesting release of both protective and detrimental metabolites thus opening the possibility of developing pharmacological therapies that tip this balance towards a more favorable equilibrium.