Both transcriptomics and metabolomics hold promise for identifying acute coronary syndrome (ACS) but they have not been used in combination, nor have dynamic changes in levels been assessed as a diagnostic tool. We assessed integrated analysis of peripheral blood miRNA and metabolite analytes to distinguish patients with myocardial ischemia on cardiac stress testing. We isolated and quantified miRNA and metabolites before and after stress testing from seven patients with myocardial ischemia and 1:1 matched controls. The combined miRNA and metabolomic data were analyzed jointly in a supervised, dimension-reducing discriminant analysis. We implemented a baseline model (T0) and a stress-delta model. This novel integrative analysis of the baseline levels of metabolites and miRNA expression showed modest performance for distinguishing cases from controls. The stress-delta model showed worse performance. This pilot study shows potential for an integrated precision medicine approach to cardiac stress testing.

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40 Background: Acute coronary syndrome (ACS) is a growing global health problem, and 41 precision medicine techniques hold promise for the development of diagnostic indicators of 42 ACS. In this pilot, we sought to assess the utility of an integrated analysis of metabolomic and 43 microRNA data in peripheral blood to distinguish patients with abnormal cardiac stress testing 44 from matched controls.45 Methods: We used prospectively collected samples from emergency department (ED) 46 patients placed in an ED-based observation unit who underwent stress testing for ACS. We 47 isolated microRNA and quantified metabolites from plasma collected before and after stress 48 testing in patients with myocardial ischemia on stress testing versus those with normal stress 49 tests. The combined metabolomic and microRNA data were analyzed jointly for case (ischemia) 50 and 1:1 matched control patients in a supervised, dimension-reducing discriminant analysis.51 Two integrative models were implemented: a baseline model utilizing data collected prior to 52 stress-testing (T0) and a stress-delta model, which included the difference between post-stress 53 test (T1) and pre-stress test (T0).54 Results: Seven case patients with myocardial ischemia on ED cardiac stress testing (6 55 females, 85% Caucasian, mean Thrombolysis In Myocardial Infarction Score=3, 4 patients 56 ultimately received percutaneous coronary intervention) were 1:1 age and sex-matched to 57 controls. Several metabolites and microRNAs were differentially expressed between cases and 58 controls. Integrative analysis of the baseline levels of metabolites and microRNA expression 59 showed modest performance for distinguishing cases from controls with an overall error rate of 60 0.143. The stress-delta model showed worse performance for distinguishing cases from 61 controls, with an overall error rate of 0.500. 3 62 Conclusions: Given our small sample size, results are hypothesis-generating. However, 63 this pilot study shows a potential method for a precision medicine approach to cardiac stress 64 testing in patients undergoing workup for ACS. 65 66