Abstract 13844: Comprehensive Proteomics Profiling of Myocardium Identifies Dysregulated Signaling Pathways in Hypertrophic Cardiomyopathy

Background:Hypertrophic cardiomyopathy (HCM) is the most common genetic cardiovascular disease. The signaling pathways that link gene mutations to the manifestation of clinically-overt HCM remain unknown.Hypothesis:Comprehensive proteomics profiling of myocardium identifies signaling pathways that are differentially regulated in HCM.Methods:We conducted a multicenter case-control study. Cases were patients with HCM who underwent septal myectomy. Controls were donors without cardiac disease whose heart was excised but could not be transplanted due to size mismatch. We performed proteomics profiling of 7289 proteins from myocardium and excluded 1222 proteins significantly correlated with age. We performed a univariable analysis of the remaining 6067 proteins to determine the association between protein concentration and disease status using the Wilcoxon rank sum test. We executed pathway analysis of proteins significantly dysregulated (i.e., univariable p <0.05) in cases with HCM compared to controls. Pathways with false discovery rate [FDR] <0.01 were considered to be dysregulated.Results:There were 121 patients included in the study, with 106 HCM cases and 15 controls. Among the 6067 proteins analyzed, 986 were differentially regulated between HCM cases and controls. Pathway analysis of these proteins revealed dysregulation of the Ras-MAPK pathway (FDR < 0.0001) and multiple metabolic pathways, mainly related to amino acid metabolism (Figure). Pathways that are known to be dysregulated in HCM, such as the TNF pathway and those related with inflammation, were also dysregulated.Conclusions:The present study represents the largest-scale (n >100) and most comprehensive proteomics profiling (>7000 proteins) of human HCM myocardium to date, elucidating dysregulation of both novel (e.g., Ras-MAPK, amino acid metabolism) and known (e.g., TNF, inflammation) pathways in patients with HCM.