CONGRESS ABSTRACT

Background: Patients treated with 5-FU are exposed to high risk of acute chest pain, myocardial infarction, heart failure, arrhythmias, and sudden cardiac death. These patients need new cardioprotective strategies to reduce cardiovascular mortality. Vericiguat is a soluble guanylate cyclase (sGC) stimulator. It is used for the treatment of heart failure characterized by reduced ejection fraction. GLP-1 receptor agonists, like semaglutide, have shown cardiorenal benefits in patients with/without diabetes, proposing themselves as a new cardioprotective strategy in a broad patient setting. Purpose: We report for the first time the results of the use of combination therapy with a glucagon-like peptide-1 receptor agonist and sGCa for the treatment of 5-FU cardiotoxicity through NLRP3 pathways Methods:  Human cardiomyocytes (HFC cell line) were exposed to subclinical concentration of 5-FU (75 µM) alone or in combination with vericiguat (10 μM) and/or semaglutide (100 nM) for 48h. After the incubation period, we performed the following tests: determination of cell viability, through analysis of mitochondrial dehydrogenase activity, study of lipid peroxidation (quantifying cellular Malondialdehyde and 4-hydroxynonenal), cyclooxygenase-2 (COX-2) levels intracellular Ca2+ homeostasis. Moreover, pro-inflammatory studied were also performed (activation of NLRP3; expression of TLR4/MyD88; mTORC1 Fox01/3a; transcriptional activation of p65/NF-κB and expression of cytokines involved in cardiotoxicity (IL-1α, IL-1β, IL-2, IL-4, IL-6, IL-10, IL-12, IL17-α, IFN-γ, TNF-α, G-CSF, GM-CSF). Results: Vericiguat and semaglutide co-incubated with 5-FU exerts additive cardioprotective effects, compared to monotherapy regimens, enhancing cell viability of 57.2-66.8 % compared to only 5-FU treated cells (p<0,001 for all). A consistent reduction in COX-2 levels in cardiomyocytes were seen (-68.8% vs only 5-FU group); significant reductions of MDA, ferroptosis and intracellular levels of NLRP-3, MyD88, p65NF-KB, IL-1α, IL-1β, IL-6, IL-12, IL17-α, TNF-α, G-CSF were seen in semaglutide/vericiguat group vs only 5-FU group (p<0.001). Conclusion: For the first time, combination therapy with semaglutide and vericiguat was effective and superior, compared to monotherapy, to reduce 5-FU mediated cardiotoxicity through inflammasome and COX-2 pathways.