Abstract 27P
Background
Oxidized low-density lipoprotein (Ox-LDL) is oxidatively modified form of LDL and it contributes to atherosclerotic plaque formation and progression. Recent findings reported that cardiovascular events (myocarditis and atherosclerosis) were higher after initiation of immune check-point inhibitors (ICIs), potentially mediated by accelerated progression of atherosclerosis. Optimization of cardiovascular risk factors and increased awareness of cardiovascular risk, prior to, during and after treatment, should be considered among patients on an ICI. We evaluated whether ox-LDL-induced apoptosis depended in part on the activation of NF-κb signaling pathway and NLRP3 during exposure of cardiomyocytes to nivolumab.
Methods
Human fetal cardiomyocytes (HFC cell line) in co-culture with hPBMC, were exposed to a clinically relevant concentration of nivolumab (100 nM) alone or combined with Ox-LDL at 1, 10 and 50 μg/mL for 24h. 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), intracellular Ca2+ homeostasis and apoptosis. Moreover, pro-inflammatory studied were also performed (activation of NLRP3 inflammasome, expression of TLR4 and NF-kB). In order to evaluate the pathways involved in Ox-LDL damage, TLR4 and NLRP3 inhibitors (TAK-242 and dapansutrile, respectively) were added during cell viability and apoptosis studies.
Results
Nivolumab exerts cytotoxic and pro-apoptotic effects in co-culture of cardiomyocytes and hPBMC. Ox-LDL increases nivolumab-induced cardiotoxicity in a manner that is sensitive to TLR4 and NLRP3. Incubation of cardiomyocytes with Ox-LDL (10 and 50 μg/mL) for 24 hours increased TLR4 and NF-κB expression significantly. Ox-LDL had pro-apoptotic effects in a concentration-dependent manner with the involvement of lipid peroxidation but not of intracellular calcium.
Conclusions
Ox-LDL exacerbates apoptosis and inflammation in cardiomyocytes during exposure to nivolumab turning the light on their role in ICI-induced cardiotoxicity.
Clinical trial identification
Editorial acknowledgement
Legal entity responsible for the study
The authors.
Funding
Ricerca Corrente.
Disclosure
All authors have declared no conflicts of interest.