Abstract 12145: N ⁶ -methyladenosine and Adenosine-to-Inosine Modifications as Biomarkers for Ischemic Heart Disease

Introduction: Chemical modifications in RNA have unveiled as a layer of molecular regulation with notable effects to the flow of genetic information from DNA through RNA to proteins. These epitranscriptomic modifications guide and contribute to normal and pathological cellular responses. To date, more than 170 epitranscriptomic modifications have been identified. Most interest has been attracted by RNA adenosines, which are also the ones most often modified. Especially N-6-methylation or deamination resulting in N 6 -methyladenosine (m 6 A) and inosine (A-to-I), respectively, have been associated with cardiovascular diseases, including atherosclerosis and myocardial ischemia, the lead causes of mortality. Remarkably, m 6 A and A-to-I modifications have emerged as early drivers of atherosclerosis and promising druggable targets. Hypothesis: The I schemic H eart D isease Epitran scriptomics and Biomarkers (IHD-EPITRAN) study aims to determine those features of IHD that are mirrored in the circulating blood epitranscriptome. In particular, the study focuses on changes in m 6 A and A-to-I in blood RNA. Methods: Patients (initial subgoal n=200) are recruited from four cohorts: (1) patients with myocardial infarction undergoing angioplasty and revascularization; (2) patients with stable IHD undergoing coronary artery bypass surgery; (3) controls without coronary obstructions undergoing valve replacement surgery due to aortic stenosis and (4) controls with healthy coronaries verified by computed tomography. The profiles of m 6 A and A-to-I in blood RNA will be charted using a combinatory approach including mass spectrometry and DNA/RNA sequencing and referenced to other modified nucleosides and candidate biomarkers for IHD and heart failure. The study is registered (ClinicalTrials.gov NCT04533282), is seeking collaborators (www.ihd-epitran.com), and has recruited 40 patients at the time of abstract submission. Conclusion: Comparison of blood m 6 A and A-to-I profiles combined with meticulous clinical evaluations can be expected to unveil epitranscriptomic biomarker candidates and drug targets for IHD.