PI-043 - ATORVASTATIN AS A CARDIOPROTECTIVE AGENT AGAINST CARFILZOMIB-INDUCED CARDIOTOXICITY IN HUMAN INDUCED PLURIPOTENT STEM CELL-DERIVED CARDIOMYOCYTES.

M. Tantawy¹, F. Yu², Y. Zhang², D. Wang³, Y. Gong⁴; ¹University of Florida, University of Florida- Gainesville, FL, USA, ²University of Florida, University of Florida - Gainesville, FL, USA, ³University of Florida College of Pharmacy, University of Florida - Gainesville, FL, USA, ⁴University of Florida, GNV, United States.

Background: Proteasome inhibitors (PIs), such as carfilzomib (CFZ), have significantly advanced the treatment of newly diagnosed and relapsed Multiple Myeloma (MM). However, despite its therapeutic benefits, CFZ is linked to cardiovascular adverse events (CVAE), including heart failure (HF), which contribute to poorer outcomes in MM patients. This study explores the potential cardioprotective effects of atorvastatin in human-induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) treated with CFZ.

Methods: Human induced pluripotent stem cells (hiPSC-CMs) were treated with 1 µM CFZ for 24 hours. Experimental groups included those receiving CFZ alone, CFZ combined with atorvastatin, and untreated controls. Total RNA was extracted from biological triplicates for each group on Day 16 post-differentiation after 24-hour exposure to the treatments. RNA sequencing was performed using NovaSeq X, and differentially expressed gene analysis was conducted using DEseq2 in R.

Results: RNA sequencing revealed that CFZ treatment significantly reduced the expression of acetyl-CoA acetyltransferase 2 (ACAT2), a key enzyme in cholesterol metabolism that converts free cholesterol into cholesteryl esters. In CFZ-treated cells, ACAT2 expression was substantially lower (mean ± SD = 665 ± 103) compared to untreated controls (2548 ± 830), with a fold change (FC) of 0.22 (P = 2.3 x 10⁻¹⁵). However, co-treatment with atorvastatin restored ACAT2 expression to levels higher than those observed in CFZ alone (1947 ± 374, P= 3.8 x 10⁻¹⁸). This suggests that atorvastatin mitigates the effects of CFZ, normalizing gene expression. ACAT2's role in regulating cholesterol by converting free cholesterol into cholesteryl esters—a key factor in cardiovascular disease—these findings are significant.

Conclusion: These results suggest that atorvastatin may help counteract CFZ-induced cardiotoxicity by restoring ACAT2 expression levels, warranting further investigation into the mechanisms and potential clinical applications.