Mechanisms of T-lymphocyte Dysfunction in Dilated Cardiomyopathy Patients

In rodents, T-cells infiltrate the myocardium during heart failure (HF), promoting left-ventricular remodeling. However, it remains unclear whether T-cells also contribute to the HF pathogenicity in human dilated cardiomyopathy (DCM) patients. Thus, we analyzed published single-cell (n = 10) and single-nuclei (n = 38) RNA sequencing data from DCM patients. By using canonical correlation analysis (CCA) integration we were able to control for variation between data sources. Our analysis focused on characterizing the gene expression changes in cardiac T-cells to uncover potential mechanisms underlying their role in human HF. Patients with DCM had significantly more cardiac T-cells (% total cells, p<0.01), with gene signatures suggesting their heightened antigenic activation and proliferation. Of the eight distinct subtypes of cardiac T-cells which we identified, DCM patients were found to have a higher proportion of activated CD4+ T-cells (p < 0.01) and a lower proportion of resting CD4+ T-cells (p = 0.02) without any changes in CD8+ T-cells. Importantly, cardiac CD4+ T-cells in DCM patients were significantly enriched in genes involved in T-cell differentiation (Normalized enrichment score (NES) = -1.8, padj < 0.01), and downregulation of mitochondrial respiration (NES = 2.2, padj < 0.01). An upregulation of pathways involved in inflammation, T-cell exhaustion, and estrogen signaling further underscore an activated phenotype of cardiac CD4+ T-cells in DCM patients. This comprehensive analysis highlights a clear connection between T-cells and DCM, providing novel insights and potential avenues for targeted CD4+ T-cell specific immunotherapies. This work is supported by NIH grants HL153164 and HL167912. This abstract was presented at the American Physiology Summit 2025 and is only available in HTML format. There is no downloadable file or PDF version. The Physiology editorial board was not involved in the peer review process.