Elevated Circulating PCSK9 Concentrations Predict Subclinical Atherosclerotic Changes in Low Risk Obese and Non-Obese Patients

Abstract

IntroductionMany studies have highlighted the important role of PCSK9 in the development of cardiometabolic changes and its possible function as a biomarker of myocardial infarction or ischemic heart disease. This study aimed to determine the relationship between circulating PCSK9 levels and subclinical vascular changes in the group of low risk patients without manifest cardiovascular diseases.MethodsIn this study, 120 healthy patients, free of manifest cardiovascular diseases, diabetes mellitus, and without lipid-lowering therapy, were divided into three groups based on BMI: normal weight (N = 50), overweight (N = 30), and obese (N = 40). Biochemical parameters, including basic lipid and non-lipid ones, were analyzed. PCSK9 levels were measured by ELISA, vascular changes were quantified by carotid ultrasound (carotid artery intima-media thickness, cIMT), and arterial stiffness parameters (pulse wave velocity, PWV; augmentation index, AI; stiffness parameter, β) were measured by an echo-tracking method.ResultsPlasma levels of PCSK9 significantly increased in obese (172.78 ± 51.67 ng/mL) in comparison with overweight (120.14 ± 37.64, p < 0.001) and normal weight groups (114.92 ± 35.87, p < 0.001). Differences between the overweight and normal weight groups were not significant (p = 0.85). The level of PCSK9 significantly correlated with values of BMI (p < 0.001, r = 0.38). In addition to increase in laboratory parameters associated with moderate metabolic changes, significant increase in cIMT and parameters of vascular changes (β, AI, PWV) were detected in groups with elevated BMI. Significant positive linear correlation of PCSK9 concentrations and cIMT (p < 0.001, r = 0.39), PWV (p < 0.001, r = 0.31), and β (p < 0.001, r = 0.3) were found. In multivariable regression analysis after adjusting for gender, age, BMI, and LDL, the impact of PCSK9 on cIMT, β, and PWV remained significant (p = 0.006, 0.03, and 0.002, respectively).ConclusionPCSK9 plasma levels significantly correlated with subclinical vascular changes and their values were significantly elevated in obese subjects. We assume that PCSK9 could be used as a predictor of early vascular involvement, prior to the existence of manifest atherosclerosis. These results also highlight the role of anti-PCSK9 treatment in primary prevention.

Proteomic profiles before and during weight loss: Results from randomized trial of dietary intervention

“…One such example was our observation that circulating proprotein convertase subtilisin/kexin type 9 (PCSK9) levels were positively correlated with BMI, as well as tracked with weight loss. This extends prior smaller studies where PCSK9 has been positively associated with obesity cross-sectionally 27,28 , and is particularly notable in light of the known role of PCSK9 levels in LDL cholesterol metabolism and atherosclerosis development [29][30][31] . Another interesting observation is that elevated AXL Receptor Tyrosine Kinase (AXL) levels among obese individuals decreased upon weight loss.…”

PCSK9 is Expressed in Human Visceral Adipose Tissue and Regulated by Insulin and Cardiac Natriuretic Peptides

“…The concentrations of PCSK9 in adipose tissue positively correlated with BMI values, the most used clinical index of adiposity. Interestingly, PCSK9 plasma concentrations were also related to carotid artery intima-media thickness (cIMT) in overweight and obese individuals, in comparison with the normal weight group, suggesting that PCSK9 could be an indicator as well as a player of cardiometabolic and vascular changes induced by excessive adiposity [31].…”

PCSK9 concentrations in different stages of subclinical atherosclerosis and their relationship with inflammation

“…This study aimed to determine the serum PCSK9 concentrations at different degrees of subclinical atherosclerosis and then to compare them with the subclinical inflammation measured by the hsCRP. In our previous study [14], we found that there was a significant correlation between the PCSK9 concentrations and elevated BMI values. This study also indicated that the weight gain was related to elevated circulating levels of PCSK9.…”

“…From this study, we excluded those patients with one or more of the exclusion criteria: patients undergoing a lipidlowering therapy or patients not meeting the minimum period of three months of discontinuation of therapy, lipid profile outside the inclusion criteria and secondary cause of dyslipidaemia, manifested CV diseases (such as ischaemic heart diseases, etc. ), patients with diabetes mellitus, acute infection or chronic inflammatory diseases, significant dietary or lifestyle changes in the period shorter than six months based on the protocol of our parallel study [14].…”

“…• Normal cIMT (cIMT <75‰ ): patients with the cIMT values below 75‰ for the age and sex of the patients. Subclinical vascular changes were detected by an ultrasound measurement of the carotid artery intima-media thickness (cIMT) and by the Echo-tracking method, as described before [14]. Patients were further classified into the study groups according to the values of cIMT.…”