BS3 Proteomics of human heart failure: effects of mutations, medications and comorbidities

BackgroundWe have previously published large-scale cardiac proteomic data from heart failure (HF) patients with ischaemic heart disease (IHD) (Circulation, 2021). No similar proteomics analyses are available on hearts from HF patients with dilated cardiomyopathy (DCM).PurposeTo compare the effect of comorbidities, medications, and genetic mutations on the cardiac proteome of DCM patients.MethodsUsing quantitative, multiplexed proteomics, we analyzed left ventricular samples from patients with IHD (n=65) and DCM (n=114), and non-failing controls (n=19). Genomic data were obtained by whole-exome sequencing.ResultsIn all HF patients, a reduction in myofilament-related proteins was accompanied by a marked increase in cardiac tissue concentrations of atrial natriuretic factor (ANF). Compared to patients with IHD, hearts from DCM patients showed higher levels of proteasome components. In contrast to patients with IHD, few protein changes were associated with medication in DCM patients. Instead, comorbidities such as hypertension and atrial fibrillation were key determinants of the cardiac proteome in DCM. Using principal component analysis, we identified 4 clusters of DCM patients: the main clinical characteristics defining each cluster were hypertension, atrial fibrillation, sex and body mass index. With regards to genetic predisposition, almost 1 out of 5 DCM patients were carriers of titin-truncating variants. DCM patients with titin-truncating variants were significantly enriched in two clusters and characterized by a downregulation of thick filament constituents compared to non-carriers. Finally, among all quantified proteins, ANF levels varied the most between DCM patients. Cardiac tissue levels of ANF were highly correlated to the fibroblast activation marker periostin and to extracellular matrix proteoglycans, in particular versican. In contrast, ANF levels did not correlate to the cardiac collagen content. In cultured mouse fibroblasts, ANF stimulation induced proteoglycan expression, suggesting that ANF secreted by cardiomyocytes exerts paracrine effects on neighboring fibroblasts.ConclusionIn this largest proteomics analysis of human HF to date, we discerned the effects of mutations, medications and comorbidities on the cardiac proteome. DCM-causing mutations are associated with distinct proteomics profiles even in explanted hearts. Moreover, we describe a novel paracrine effect of ANF on the synthesis of proteoglycans by cardiac fibroblasts. Thus, be