Abstract Fri123: Identification of Candidate Coronary Metabolic Vasodilators Through Direct Interstitial Sampling

Introduction/Background: The workload of the heart in generating sufficient pressure to maintain systemic perfusion and facilitate hydrostatic exchange necessitates some of the highest metabolic demands of any organ. To meet these demands, the myocardium relies on aerobic metabolism, which is enabled by a continually changing coronary blood flow that matches changes in myocardial oxygen consumption-a process deemed coronary metabolic dilation (CMD). While various mechanisms for CMD have been proposed, specific metabolic signals coupling myocardial demand to coronary vasodilation remain undefined. Hypothesis/Aims: We hypothesize that CMD is mediated by a metabolic dilator produced during increased myocardial demand, resulting in increased interstitial concentration. Any candidate must be present in the interstitial fluid at effective concentrations; therefore, we aimed to collect and analyze myocardial interstitial fluid at varying levels of demand to generate a dataset for identifying potential metabolic dilators. Methods: A large animal model (swine) was used to explore metabolic-coronary mechanisms. Under general anesthesia, thoracotomies were performed to place biocompatible catheters into the left ventricular free wall to collect interstitial fluids. Myocardial oxygen demand was manipulated through alterations in cardiac electrical activity using a pacemaker attached to the epicardium. Interstitial fluid was collected at each level of pacing. Mass spectrometry-based global metabolomics was applied to measure metabolite levels in interstitial fluid. Results/Conclusion: We aimed to increase heart rate by increments of 5 bpm above baseline. This was achieved within 1.3 + 3.4% error. Analysis of interstitial fluid obtained during pacing identified 243 unique metabolites; 29 of these metabolites demonstrated increased concentrations from lowest to highest pacing level; of those, 14 went up in a rate-dependent manner. Several of those 14 metabolites are putative ligands for olfactory receptors of unknown function, identified in previous work by our research team. These receptors, when activated, have reported dilator capacity. This suggests a potential mechanistic link between metabolic demand and coronary vascular tone.