Cardiotoxicity Beyond Cardiomyocytes: Focus on the Role of Cardiac Fibroblasts and Endothelial Cells

Introduction: Anti-cancer treatments frequently have serious adverse effects on the cardiovascular system. Understanding the mechanisms underlying these cancer therapy-related cardiovascular toxicities is essential for their prevention and potential treatment. While research often centres on cardiomyocyte damage as the primary cause of cardiac injury, the roles of cardiac fibroblasts and endothelial cells are often neglected. In this study, we aimed to investigate the direct toxicity in cardiac fibroblast and endothelial cells of 35 FDA-approved anti-cancer drugs, of which the effects previously only had been explored in cardiomyocytes. Methods and Results: Metabolic cell viability in cardiac fibroblasts and endothelial cells was first determined using the CellTiter-Glo luminescence assay. If metabolic cell viability was reduced, lactate dehydrogenase was measured in the supernatant to assess cytotoxicity. Interestingly, certain anti-cancer treatments were able to increase metabolic cell viability. For these drugs, gene expression analysis assessing for myofibroblast differentiation and endothelial-to-mesenchymal transition was performed. Conclusion: Our study demonstrates that anti-cancer therapies indeed exhibited different toxicity profiles in cardiac fibroblasts and endothelial cells compared to cardiomyocytes and triggers specific pathophysiological transformations in response to anti-cancer drug exposure.