In this study, we set out to find the relationship between circulating levels of PCSK9 and subclinical vascular changes and to find out the relation between overweight, obesity, and PCSK9. Selection of patients with low cardiovascular risk according to the SCORE system allowed us to eliminate the effect of various other risk factors and proves the role of PCSK9 as a marker of subclinical changes as well as a mediating factor of these changes. Many studies have assumed that for the formation of cardiovascular changes and its complications, the interplay of various risk factors such as obesity, dyslipidemia, hypertension, insulin resistance, etc. is needed. Those factors increase the progression of vascular changes and the cardiovascular risk as well . It was found that even fatty tissue overgrowth (especially visceral) on its own acts as an independent risk factor of cardiometabolic disorders, and obesity itself interferes with dyslipidemia pathogenesis, insulin resistance, and hepatic steatosis. The precise pathomechanisms and relationship between obesity and cardiovascular risk are still not fully understood .
An important finding in this study is that PCSK9 concentrations were significantly elevated in overweight and obese individuals in comparison with the normal weight group. It is well known that the progression of atherosclerotic vascular changes depends on the metabolism of lipids, mainly of LDL particles. When an imbalance in lipid serum levels persists together with other risk factors, endothelial dysfunction followed by subclinical and clinical atherosclerotic changes arise . PCSK9 protein plays a key regulatory role in the metabolism of lipoproteins, but nowadays many non-lipid effects are studied such as effect on inflammation, glycemia, liver regeneration, and steatosis. Many studies have shown that PCSK9 may accelerate atherosclerosis and CAD by mechanisms independent from increased hepatic LDLR degradation . In our study, concentrations of PCSK9 significantly correlated with increased values of BMI. Increased weight and further increase of BMI increased the circulating levels of PCSK9 as well. Moreover, in overweight and obese patients, significant increase of cIMT in comparison with the normal weight group was observed. Values of cIMT significantly correlated with PCSK9 concentrations. Significant correlation of PCSK9 with cIMT as well as BMI suggests that circulating levels of PCSK9 could be a mediator of obesity-induced cardiometabolic changes. Many studies have shown that increased cIMT is an important prognostic marker for subsequent cardiovascular events such as MI and stroke, and a predictive factor of cardiovascular morbidity and mortality [18–21]. Similar increase in cIMT values or of the degree of atherosclerosis in obese in comparison with normal weight population has been observed in other studies [22, 23]. Ranges of cIMT physiological values have side (left or right side of internal carotid artery), age, and sex specificity. They increase with age and have slightly higher values in male subjects. Therefore, multivariate analysis was performed to analyze the effect of PCSK9, age, sex, BMI, and LDL on the values of cIMT. Significant effects of age, LDL, and PCSK9 were proved, according to which we suggest that PCSK9 could act as a significant mediator of vascular changes alongside LDL cholesterol and could also be an early marker of these changes. In this analysis the effect of BMI was not significant. We assume that significant elevation of PCSK9 could be regulated by paracrine function of the adipose tissue and this could be the mediator of metabolic changes, not the obesity itself. Similar results were found in other studies which observed a significant increase of PCSK9 levels in patients with metabolic syndrome and type 2 diabetes. In those studies, levels of PCSK9 correlated with proatherogenic phenotype and degree of insulin resistance .
Increase of the arterial stiffness represents the precursor of subclinical and manifest atherosclerotic vascular changes, whose quantification allows us to easily detect early changes. Arterial stiffness is strongly associated with the prevalence of cardiovascular diseases and cardiovascular mortality . Results of previous studies have shown that the parameters β and Ep correlate with the PWV and the elevations of these parameters have been associated with increased arterial stiffness and increased cardiovascular risk. Nevertheless, use of Ep in clinical practice may be limited, since the value can be affected by the pulse pressure. In contrast, the parameter β is less affected and is relatively independent of blood pressure . In a clinical study, Hirai et al.  found that the value of β does not change significantly with repeated measurements before and after injection of sodium nitroprusside, confirming that the value of β is relatively independent of blood pressure. Therefore, in our study, only the PWV, β, and AI were included for the measurement of arterial stiffness. Significant increase in all the aforementioned parameters was observed in overweight and obese groups, which confirms the impact of obesity on the artery wall. Significant linear positive correlation of PCSK9 and PWV, β, and AI was detected. After consideration of previously mentioned factors such as sex, age, BMI, and LDL, the significant effect of PCSK9 in multivariable regression persisted for PWV and β. Several previous studies have shown a correlation of increased levels of PCSK9 with ongoing acute coronary syndrome and polytrauma. A recent study showed that measuring circulating levels of PCSK9 in elderly patients could help determine the increase in cardiovascular risk and future risk of cardiovascular events. It was found that increased levels of PCSK9 were linked to more frequent cardiovascular events during a subsequent period of 15 years of study. Even after adjusting the levels of LDL cholesterol and the risk factors such as the diabetes mellitus, obesity, and the use of statins, this elevated risk persisted . In pathological conditions such as acute coronary syndrome, massive atherosclerosis, and multiple trauma, significant elevations in PCSK9 levels are present. Our study has shown that PCSK9 quantification in low risk patients could help us to identify patients who could benefit from statin, anti-PCSK9, or other dyslipidemia treatment prior to the development of plaque or manifest atherosclerosis. Our results also suggest that the mediator of obesity-induced cardiovascular risk can be elevated PCSK9 levels on its own.