Clin Res Cardiol (2022). https://doi.org/10.1007/s00392-022-02002-5

Targeting Endothelial Dysfunction and Senescence in HFpEF – whole transcriptome analysis of HFpEF patients to identify new therapeutic targets

L. Wurmbrand1, K. Kalies2, K. Knöpp1, J. Dutzmann1, M. Rieckmann2, D. G. Sedding1

1Klinik und Poliklinik für Innere Medizin III, Universitätsklinikum Halle (Saale), Halle (Saale); 2Klinik und Poliklinik für Innere Medizin III - Forschungslabor, Universitätsklinikum Halle (Saale), Halle (Saale);

Heart failure with preserved ejection fraction (HFpEF) remains a disease with a poor prognosis and increasing incidence in all Western countries mainly affecting the aging population. The development of new therapeutic approaches requires a deeper understanding of the pathogenesis at the cellular level. A causal reason and promising therapeutic option lays in understanding the central role of endothelial dysfunction in the context of cellular senescence. Circulating endothelial cells as a marker for endothelial damage and dysfunction, have already been examined quantitatively in general HF patients, HFpEF patients and healthy subjects. Here, we aim to isolate circulating endothelial cells to target endothelial dysfunction and identify new therapeutic targets by whole transcriptome analysis. Methods included the isolation of circulating endothelial cells (CEC) from whole blood samples via a newly established FACS panel. HFpEF patients were included based on their HFA-PEFF score. Young and old subjects served as non-diseased controls and were matched as closely as possible for sex and age. CEC were further processed for a whole transcriptome analysis. In total, we collected samples from n=15 patients per group. Mean age was 82.3 for the HFpEF group, 64.5 for the non-diseased control ‘old’, and 25 years for the non-diseased control ‘young’, HFA-PEFF score was 5, 0, and 0 points (P<0.05), and the proportion of female patients was 66%, 78%, and 77%, respectively. Including additional patient data, our collective was shown to be comparable to large HFpEF studies and clinical registries. CEC cells were sorted based on CD45-, CD11b- CD34+, CD31+ and CD146+ marker expression. The CEC of the aged group revealed upregulated expression of senescence markers p16, p21 and CD44. In the following Gene Set Enrichment Analysis, mainly proliferation- and transcription-associated gene sets in HFpEF were found to be highly regulated. In summary, we achieved to isolate CEC from whole blood of HFpEF-patients and matched controls. The whole transcriptome analyses may provide new clues for therapeutic strategies, which is now the subject of further in vitro and in vivo studies. Our goal is to develop new therapeutic targets after successful evaluation and modulation of the target genes.

https://dgk.org/kongress_programme/jt2022/aV939.html