Diabetic ischaemic cardiomyopathy: Characterising the left ventricular myocardial molecular profile in advanced human heart failure

Ischaemic cardiomyopathy (ICM) is the most common cause of heart failure (HF) and often coexists with diabetes mellitus (DM). Yet, their combined effects are seldom investigated and are poorly understood. Herein, we performed multi-omic analyses of end-stage ICM with DM (ICM-DM) against ICM-No DM, non-ischaemic (dilated) cardiomyopathy with DM (NICM-DM), NICM-No DM, and healthy age-matched donors (AMD). Tissue was sourced from pre-mortem human left ventricular myocardium. Though fatty acid oxidation (FAO) proteins were down-regulated in ICM-DM relative to AMD and other HF, the unique ICM-DM down-regulation of acylcarnitines, perilipin, and ketone body, amino acid, and glucose metabolising proteins indicated FAO may not be entirely impaired. Oxidative phosphorylation appeared reduced in HF but exacerbated in ICM-DM, consistent with purportedly increased oxidative stress. Extracellular matrix proteins including collagens were up-regulated principally in ICM-DM despite the absence of macroscopic scar tissue. These findings were supported histologically and in metabolomic and RNA sequencing analyses. The aim of this study was to perform multi-omics analyses on cryopreserved pre-mortem human left ventricular myocardium to uncover the influence of DM in end-stage HF, and the molecular characteristics of ICM with DM (ICM-DM), thereby creating a comprehensive molecular resource of diabetes related heart failure.