atherogenic dyslipidemia

Circulation

Introduction: The 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. Hypothesis: Considering 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 Methods: Human 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 analysis: cell viability, apoptosis and necrosis, lipid peroxidation and intracellular Ca 2+ 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. Results: Evolocumab co-incubated with anticancer drugs increased significantly the cell viability from 38 to 58 % compared to doxorubicin, trasuzumab and nivolumab groups (p&lt;0,01 for all). Evolocumab downregulates MyD88, mTORC-1 and nuclear NF-kB with a significant reduction in IL-1α, IL-1β, IL17-α, G-CSF and GM-CSF (p&lt;0.05 vs doxorubicin, trasuzumab and nivolumab groups). Conclusions: The PCSK9 inhibitor evolocumab exerts cytoprotective effects on cardiomyocytes during exposure to doxorubicin, trastuzumab and anti PD-1 antibody nivolumab. This study open to new preclinical trials aimed to decrease cardiotoxicity during anticancer th...

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