Abstract 9384: Evolocumab, a Proprotein Convertase Subtilisin-Kexin Type 9 Inhibitor, Reduces Doxorubicin, Trastuzumab and Nivolumab Induced Cardiotoxicity Through Mtorc1 and Myd88 Related Pathways

• Published in: Circulation (New York, N.Y.) N.Y.), 2021-11, Vol.144 (Suppl_1), p.A9384-A9384
• Main Authors: Maurea, Nicola, Iovine, Martina, Buccolo, Simona, Paccone, Andrea, Cerrone, Francesca, Quagliariello, Vincenzo
• Format: Article
• Language: English
• ISSN: 0009-7322; 1524-4539
• DOI: 10.1161/circ.144.suppl_1.9384

IntroductionThe PCSK9 inhibitor evolocumab reduced low-density lipoprotein cholesterol and cardiovascular events in the FOURIER randomized clinical trial. Recent studies indicates the crucial involvement of PCSK9 in regulation of cardiac cell metabolism and survival. Doxorubicin and trastuzumab-induced cardiotoxicity still remains a clinically relevant problem in cancer patients. Patients treated with nivolumab experienced myocarditis, arrhythmia and heart failure; therefore finding new cardioprotective strategies in this patient cohort is a very important clinical need. HypothesisConsidering the expression of PCSK9 in heart tissue and cardiomyocytes, we aimed to study the direct effects of evolocumab in cardiomyocytes during exposure to doxorubicin, trastuzumab and nivolumab MethodsHuman fetal cardiomyocytes were exposed to subclinical concentration of doxorubicin, trastuzumab (both at 100 nM), nivolumab (200 nM) alone or in combination with evolocumab (50 nM) for 48h. After the incubation period, we performed the following analysiscell viability, apoptosis and necrosis, lipid peroxidation and intracellular Ca2+ concentration. Through ELISA method, we studied the expression of NLRP3 inflammasome, MyD88, mTORC1, nuclear NF-κB. Intracellular concentration of IL-1α, IL-1β, IL-2, IL-4, IL-6, IL-10, IL-12, IL17-α, IL-18, IFN-γ, TNF-α, G-CSF, and GM-CSF were also performed. ResultsEvolocumab co-incubated with anticancer drugs increased significantly the cell viability from 38 to 58 % compared to doxorubicin, trasuzumab and nivolumab groups (p