DOI: 10.1161/circ.148.suppl_1.12080 ISSN: 0009-7322

Abstract 12080: Comprehensive Proteomics Profiling of Human Myocardium Reveals Signaling Pathways Dysregulated in Severe Forms of Hypertrophic Cardiomyopathy

Heidi Hartman, Mark Sherrid, Kohei Hasegawa, Elizabeth Adlestein, Daniel Swistel, Albree Tower-Rader, Michael A Fifer, Veli K Topkara, mathew S Maurer, Muredach P Reilly, Yuichi Shimada
  • Physiology (medical)
  • Cardiology and Cardiovascular Medicine

Introduction: Hypertrophic cardiomyopathy (HCM) is the most common genetic cardiovascular disease, affecting 1 in 200-500 people. There is significant heterogeneity in disease severity. The signaling pathways that link gene mutations to severe HCM disease remain unknown. Analysis of the myocardial proteome is a novel approach to understanding severe forms of HCM.

Hypothesis: Comprehensive proteomics profiling of myocardium identifies signaling pathways that are differentially regulated in severe forms of HCM.

Methods: Proteomics profiling of 7289 proteins from myocardium was performed on patients with HCM. Univariable analysis with the Wilcoxon rank sum test or Spearman’s rank correlation test was used to determine the association between protein concentration and 5 clinical indicators of severe HCM: 1) left ventricular ejection fraction (LVEF), 2) atrial fibrillation (AF), 3) ventricular arrhythmias, 4) maximum septal thickness, and 5) late gadolinium enhancement (LGE) by cardiac magnetic resonance (CMR). Pathway analysis of proteins with significantly different concentrations (i.e., nominal p<0.05) in association with each clinical indicator was executed.

Results: There were 106 patients with HCM included in the study. Pathway analysis of proteins associated with each indicator of severe HCM revealed dysregulation of inflammatory pathways and Ras-MAPK-related pathways ( Figure ). Metabolic pathways and adhesion pathways were dysregulated in association with LVEF and AF. Dysregulation of angiogenesis pathways (e.g., HIF-1, VEGF) was associated with LGE (FDR<0.05).

Conclusions: Comprehensive proteomics profiling of human HCM myocardium was used to identify dysregulated signaling pathways associated with clinical features of severe HCM. Findings from this study support the role of both known (e.g., inflammation, metabolism, adhesion, and angiogenesis) and novel (e.g., Ras-MAPK) pathways in the development of severe forms of HCM.

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