Clin Res Cardiol (2023). https://doi.org/10.1007/s00392-023-02180-w

Molecular phenotyping of human diabetic cardiomyopathy

J. Gollmer1, H. Horstmann2, L. Potter3, I. Vosko1, T. Tomin4, D. von Lewinski1, S. Sedej5, D. Scherr1, A. Wende3, P. Rainer1, A. Zirlik1, D. Wolf2, H. Bugger1

1Klinische Abteilung für Kardiologie, LKH-Univ. Klinikum Graz - Universitätsklinik für Innere Medizin, Graz, AT; 2Klinik für Kardiologie und Angiologie I, Universitäts-Herzzentrum Freiburg - Bad Krozingen, Freiburg im Breisgau; 3Department of Pathology, Univertsity of Alabama at Birmingham, Birmingham, US; 4Institute of Chemical Technologies and Analytics TU Wien, TU Vienna, Wien, AT; 5Experimentelle Kardiologie, LKH-Univ. Klinikum Graz - Universitätsklinik für Innere Medizin, Graz, AT;

Type 2 diabetes (T2D) increases the risk for heart failure (HF) even in the absence of coronary artery disease and other known etiologies of HF, a condition referred to as diabetic cardiomyopathy. Numerous mechanisms have been proposed to underlie diabetic cardiomyopathy based on rodent studies, however these mechanisms remain largely unexplored in humans. Here, we performed transcriptional and proteomic profiling of left ventricular samples of 8 subjects with T2D, preserved ejection fraction (EF; 63,5%) and no history of ischemic heart disease (= Db-pEF), thus closely matching the definition of diabetic cardiomyopathy, and of 15 non-diabetic individuals with normal EF (64,7%) and no history of ischemic heart disease serving as controls. Using whole heart RNA sequencing, 738 differentially expressed genes (DEGs) were identified in Db-pEF hearts compared to controls. Pathway analysis revealed that upregulated genes enriched in the extracellular matrix receptor interaction pathway, suggesting structural remodeling in Db-pEF hearts. However, no other pathways proposed to underlie diabetic cardiomyopathy showed a significant enrichtment of DEGs in Db-pEF hearts. A whole heart proteomics analysis using label-free LC-MS/MS resulted in detection of 1169 proteins, 66 of which were significantly regulated. Again, none of the suspected pathways of diabetic cardiomyopathy were altered. In contrast, cardiomyocyte-selective analysis of gene expression using single nuclei RNA sequencing revealed significant enrichments of DEGs in many pathways proposed to underlie rodent diabetic cardiomyopathy, including mitochondrial dysfunction, oxidative stress, PPAR signaling, fatty acid oxidation, advanced glycation endproduct signaling, or insulin resistance, among others. In particular, all detected genes encoding for proteins related to fatty acid uptake and oxidation were upregulated, and differential regulation of ROS-producing and ROS-detoxifying enzymes was observed. Thus, diabetes induces gene expression changes in human cardiomyocytes consistent with mechanisms proposed to induce cardiac dysfunction in animal models of diabetes. Cell-type specific analysis of the transcriptome by single nuclei RNA sequencing provided superior resolution of transcriptomic changes and more detailed insights into pathology compared to conventional whole heart transcriptomics.

https://dgk.org/kongress_programme/jt2023/aP964.html