The diabetic myocardial transcriptome reveals Erbb3 as a novel biomarker of incident heart failure

Aims Diabetes mellitus (DM) increases heart failure incidence and worsens prognosis, but the molecular basis of diabetic heart disease is poorly defined in humans. We aimed to define the diabetic myocardial transcriptome and validate hits in their circulating protein form to define disease mechanisms and biomarkers. Methods and Results RNA-sequencing data from the Genotype-Tissue Expression (GTEx) project was used to define differentially expressed genes (DEGs) in right atrial (RA) and left ventricular (LV) myocardium from people with versus without DM (type 1 or 2). DEGs were validated in their circulating protein form in the UK Biobank cohort, searching for directionally concordant differential expression. Validated plasma proteins were characterized in UK Biobank participants, irrespective of diabetes status, using cardiac magnetic resonance imaging, incident heart failure and cardiovascular mortality. We found 32 and 32 DEGs associated with DM in the RA and LV, respectively, with no overlap between these. Plasma proteomic data was available for 6 hits, with only ERBB3 (LV hit) exhibiting directional concordance, being lower in myocardium and blood of people with DM. Irrespective of DM status, lower circulating ERBB3 was associated with impaired left ventricular contractility and higher LV mass. Participants in the lowest quartile of circulating ERBB3 had increased incident heart failure and cardiovascular death vs. participants in all other quartiles. Similar associations were noted for ERBB2 and ERBB4. Conclusions DM is characterized by lower ERBB3 expression in the myocardium and lower plasma protein concentration. This is associated with left ventricular dysfunction, incident heart failure and cardiovascular mortality.