The diabetic myocardial transcriptome reveals Erbb3 and Hspa2 as a novel biomarkers of incident heart failure

Abstract

Aims: Diabetes mellitus (DM) increases heart failure incidence and worsens prognosis, but its molecular basis 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 vs. without DM (type 1 or 2). DEGs were validated as plasma proteins 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 were available for 12, with ERBB3, NRXN3, and HSPA2 (all LV hits) exhibiting directional concordance. Irrespective of DM status, lower circulating ERBB3 and higher HSPA2 were associated with impaired LV contractility and higher LV mass. Participants in the lowest quartile of circulating ERBB3 or highest quartile of circulating HSPA2 had increased incident heart failure and cardiovascular death vs. all other quartiles.

Conclusion: DM is characterized by lower Erbb3 and higher Hspa2 expression in the myocardium, with directionally concordant differences in their plasma protein concentration. These are associated with LV dysfunction, incident heart failure, and cardiovascular mortality.

Keywords: Diabetes; Erbb3; Heart failure; Hspa2; Myocardium; RNA-seq.

Graphical Abstract

Created with BioRender.com.

Figure 1

Differential gene expression associated with diabetes in the RA and LV. Volcano plots illustrating differential gene expression for DM vs. without DM for RA (A: n = 120 vs. 305 participants) and LV (B: n = 100 vs. 329 participants). Each dot represents a gene, with red colour denoting those that achieve Benjamini–Hochberg FDR-adjusted P < 0.05 and log₂ fold change > 0.32 or < −0.32 (corresponding to a 25% difference in gene expression). Raw data are presented in Supplementary material online, Tables S1 and S2. LV, left ventricle; RA, right atrium.

Figure 2

Incident HF and cardiovascular mortality in plasma ERBB3, HSPA2, and NRXN3 quartiles. Kaplan–Meier curves illustrating probability of freedom from HF (A–C) or cardiovascular mortality (D–F) during long-term follow-up of the UKB cohort stratified into quartiles of plasma ERBB3 (A and D), HSPA2 (B and E), and NRXN3 (C and F). Quartile 1 represents the lowest quartile of expression and quartile 4 the greatest; each quartile includes 12 833 participants for ERBB3, 11 114 participants for HSPA2, and 10 890 participants or NRXN3.