Treatment with PCSK9 Inhibitor Evolocumab Improves Vascular Oxidative Stress and Arterial Stiffness in Hypercholesterolemic Patients with High Cardiovascular Risk

Abstract

Atherosclerosis and atherosclerotic-related cardiovascular diseases (ASCVD) are characterized by high serum levels of low-density lipoprotein cholesterol (LDL-C) that can promote the generation of reactive oxygen species (ROS). To answer the need for better LDL-C control in individuals at high and very high risk for CVD, a new injectable innovative family of lipid-lowering (LL) monoclonal antibodies against the protein convertase subtilisin/kexin type 9 (PCSK9) has been approved. However, the effect of these drugs on vascular function, such as ROS generation and arterial stiffness, has not already been extensively described. In this report, we present data from 18 males with high to very high CV risk undergoing LL treatment (LLT) with either statin and ezetimibe or ezetimibe monotherapy, who experienced, after a 2-month treatment with Evolocumab, a significant improvement in blood pressure (BP)-adjusted carotid–femoral pulse wave velocity (cfPWV) (p-value = 0.0005 in the whole cohort, p-value = 0.0046 in the sub-cohort undergoing background LLT with statin and ezetimibe, p-value = 0.015 in the sub-cohort undergoing background LLT with ezetimibe monotherapy), which was significantly associated with a decrease in freshly isolated leukocytes (PBMCS)-derived H2O2 production (p-value = 0.004, p-value = 0.02 and p-value = 0.05, respectively, in the whole cohort, in the statin + ezetimibe sub-cohort, and the ezetimibe sub-cohort). Our observations support the role of systemic oxidative stress in atherosclerosis and give a further rationale for using Evolocumab also for its effect in vascular disorders linked to oxidative processes.

Arterial Stiffness: From Basic Primers to Integrative Physiology

“…Consistent with the finding that circulating PCSK9 levels are correlated with PWV (122), short-term or chronic treatment with monoclonal antibodies against PCSK9 to reduce low density lipoproteincholesterol (LDL-C) in patients with familial hypercholesterolemia or very high cardiovascular risk decreases PWV. These persistent beneficial effects of PCSK9 inhibition, which affect both the macro-and microcirculation (endothelial dysfunction, arterial stiffness, and microvascular perfusion), are either correlated with or independent of LDL-C reduction (123)(124)(125). The expression of PCSK9 by several cell types, including ECs and VSMCs, is closely related to proinflammatory stimuli and production of reactive oxygen species.…”

Unraveling the Crosstalk between Lipids and NADPH Oxidases in Diabetic Kidney Disease

“…However, the mechanism by which PCSK9 inhibition might exert its protective effect in kidney disease is not well elucidated [ 45 , 103 ]. A possible mechanism by which PCSK9 inhibition might exert its protective effect is by decreasing oxidative stress [ 104 ]. Ginkgolide B treatment has been shown to inhibit Nox4 expression and attenuate mitochondrial ROS generation [ 105 ].…”