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.

中文翻译：

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糖尿病心肌转录组显示 Erbb3 和 Hspa2 是心力衰竭的新型生物标志物


目的 糖尿病 （DM） 会增加心力衰竭的发病率并恶化 预后，但其在人类中的分子基础尚不清楚。我们旨在定义糖尿病心肌转录组并验证其循环蛋白形式的命中，以定义疾病机制和生物标志物。方法和结果 来自基因型-组织表达 （GTEx） 项目的 RNA 测序数据用于定义 DM 患者与非 DM 患者 （1 型或 2 型） 右心房 （RA） 和左心室 （LV） 心肌中的差异表达基因 （DEG）。DEGs 在英国生物样本库队列中被验证为血浆蛋白，寻找方向一致的差异表达。使用心脏磁共振成像、发生心力衰竭和心血管死亡率，在英国生物样本库参与者中对经过验证的血浆蛋白进行表征，无论糖尿病状态如何。我们在 RA 和 LV 中分别发现了 32 个和 32 个与 DM 相关的 DEGs，它们之间没有重叠。12 的血浆蛋白质组学数据可用，其中 ERBB3 、 NRXN3 和 HSPA2 （所有 LV 命中） 表现出方向一致性。无论 DM 状态如何，较低的循环 ERBB3 和较高的 HSPA2 与 LV 收缩力受损和较高的 LV 质量相关。与所有其他四分位数相比，循环 ERBB3 最低四分位数或循环 HSPA2 最高四分位数的参与者心力衰竭和心血管死亡的发生率增加。结论 DM 的特征是心肌中 Erbb3 表达较低，Hspa2 表达较高，两者血浆蛋白浓度方向一致。这些与 LV 功能障碍、心力衰竭和心血管死亡率有关。