Left ventricle-specific molecular influences of prominent cardiomyopathies in middle-aged humans

Abstract

The most common forms of cardiomyopathy and causes for the development of heart failure are ischaemic cardiomyopathy and non-ischaemic dilated cardiomyopathy, wherein pathology and dysfunction predominantly affect the left ventricle. Type 2 diabetes mellitus is often a comorbidity to patients with ischaemic cardiomyopathy as they share multiple risk factors contributing to their pathogenesis. Diabetes confounds and exacerbates pre-existing heart failure phenotypes. To differentiate the pathogenesis of ischaemic cardiomyopathy, which is left ventricle-specific arising from acquired heterogeneous causes, from non-ischaemic dilated cardiomyopathy with a similar gross phenotype but arises from homogeneous causes which can affect both ventricles, we must first characterise the left ventricle in comparison to the right ventricle. Herein, using unbiased proteomic and metabolomic mass spectrometry on pre-mortem human myocardium, we found non-pathological metabolic differences in the healthy left ventricle relative to the right ventricle such as down-regulated constituents of glycolysis, lipolysis, and oxidative phosphorylation were not conserved in end-stage heart failure. However, increased enrichment of pathogenic pathways was found in the left ventricle of ischaemic cardiomyopathy, confirming a left ventricular bias. Following this, we investigated the influence of diabetes in end-stage heart failure in a larger study, with a focus on ischaemic cardiomyopathy, by also incorporating RNA sequencing and histochemistry. This study indicated that diabetes not only resulted in increased fibrosis, and impaired contractility, glycolysis, and aerobic respiration in ischaemic cardiomyopathy, but also reduced ketone body metabolism and showed signs of fatty acid oxidation dependence and lipotoxicity despite a reduced expression of fatty acid oxidation proteins. These latter findings could be paradigm changing in understanding how diabetes exaggerates the heart failure phenotype.