PCSK9 Inhibitors in Cancer Patients Treated with Immune-Checkpoint Inhibitors to Reduce Cardiovascular Events: New Frontiers in Cardioncology

Abstract

Cancer patients treated with immune checkpoint inhibitors (ICIs) are exposed to a high risk of atherosclerosis and cardiometabolic diseases due to systemic inflammatory conditions and immune-related atheroma destabilization. Proprotein convertase subtilisin/kexin type 9 (PCSK9) is a key protein involved in metabolism of low-density lipoprotein (LDL) cholesterol. PCSK9 blocking agents are clinically available and involve monoclonal antibodies, and SiRNA reduces LDL levels in high-risk patients and atherosclerotic cardiovascular disease events in multiple patient cohorts. Moreover, PCSK9 induces peripheral immune tolerance (inhibition of cancer cell- immune recognition), reduces cardiac mitochondrial metabolism, and enhances cancer cell survival. The present review summarizes the potential benefits of PCSK9 inhibition through selective blocking antibodies and siRNA in patients with cancer, especially in those treated with ICIs therapies, in order to reduce atherosclerotic cardiovascular events and potentially improve ICIs-related anticancer functions.

RETRACTED ARTICLE: Potential use of proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibition and prevention method in viral infection

“…An exceptional decrease in LDL-C levels was the therapeutic benefit shown in studies with PCSK9 inhibitors, suggesting that more aggressive goals for LDL-C should be sought [ 18 ]. Studies using PCSK9 inhibitors have shown a remarkable therapeutic benefit—a reduction in LDL-C levels—suggesting the need for more stringent LDL-C targets [ 19 ] (Fig. 2 ).…”

The sGCa Vericiguat Exhibit Cardioprotective and Anti-Sarcopenic Effects through NLRP-3 Pathways: Potential Benefits for Anthracycline-Treated Cancer Patients

“…Several drugs and nutraceuticals are currently studied as potential cardioprotective tools in cancer patients [55]. Liposomal doxorubicin regimens, Dexrazoxane hydrochloride, gliflozins (SGLT-2i) [56], and Proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors [57] exert significant improvements of cardiac functions in cancer patients treated with anthracyclines but more randomized trials are needed to confirm this point. Great attention is paid to SGLT2i in cancer patients with or without diabetes under anthracycline therapy due to their beneficial effects, including reduction of ferroptosis, reduction of lipid peroxidation, improvement of mitochondrial functions, activation of pAMPK, and reduction of the NLRP3-dependent pathway [58].…”

Assessment of Native Myocardial T1 Mapping for Early Detection of Anthracycline-Induced Cardiotoxicity in Patients with Cancer: a Systematic Review and Meta-analysis

“…Interestingly, several recent studies have shown that sodium-glucose cotransporter 2 (SGLT2) inhibitors such as empagliflozin or dapagliflozin can reduce cardiac inflammation and fibrosis as well as improve cardiac function by suppressing the activation of NLRP3 inflammasome and MyD88 myddosome [ 33 , 35 ]. In addition to SGLT2 inhibitors, proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors have also demonstrated a potential protective effect against chemotherapy-induced cardiotoxicity by downregulating NLRP3 inflammasome and MyD88 myddosome [ 36 ]. Thus, it is likely that strategies that target NLRP3 inflammasome and MyD88 myddosome, such as SGLT2 inhibitors and potentially PCSK9 inhibitors, may hold promise in mitigating anthracycline-induced cardiotoxicity.…”