PCSK9 as a Biomarker of Cardiovascular Disease

Abstract

PCSK9 is a secreted protein which in circulation promotes lysosomal degradation of the low-density lipoprotein receptor (LDLR). Hence, it is informative to measure its concentration in blood. Circulating PCSK9 exists in several forms its parent form and a furin-cleaved form and a low-density lipoprotein (LDL)bound form and a free form. The furin-cleaved and LDL-bound forms are much less active. Most studies have not clearly distinguished among these forms. In a different context, in individuals receiving anti-PCSK9 monoclonal antibody (mAb) therapy, there is an Ab-bound form and a mAb-free form. Future measurements of circulating PCSK9 will need to account for the heterogeneity of PCSK9 in circulation. Circulating PCSK9 concentration shows a diurnal rhythm and it decreases beyond similar to 16 h of fasting. It has a wide 50- to 100-fold range within a population and is rightward skewed, higher in women than men, and higher after menopause. In male adolescents, it decreases with age, while in female adolescents, it increases with age. It is elevated in pregnancy at term, and umbilical cord blood has lower serum PCSK9 levels than maternal blood. Ideally, measurement of plasma PCSK9 should be standardized to time of day and feeding status. Plasma PCSK9 levels associate with LDL cholesterol (LDL-C) levels in most states of health and disease. The positive correlation between serum PCSK9 and LDL-C is relatively weak in contrast to the much greater effect of genetic variation in PCSK9 activity on serum LDL-C levels. GOF and LOF mutations and polymorphisms of PCSK9 are often reflected in higher and lower plasma PCSK9 levels, respectively, but this is not always the case. Plasma PCSK9 measurement in various states of health and disease has enhanced our knowledge of lipoprotein metabolism in general and in abnormal states associated with CVD. It is currently not seen as a clinical marker of CVD risk or disease progression. There are early reports indicating an association between plasma PCSK9 levels and vascular disease, independent of other traditional risk factors, but underlying pathophysiologic mechanisms are still unclear. Plasma PCSK9 may serve in the future as a biomarker for the selection of patients for anti-PCSK9 mAb therapy. It has also been measured in response to various forms of lipid-altering drug therapy. Statin therapy increases plasma PCSK9 levels. These data will need further development in order to serve as an aid to the establishment of the pharmacokinetic and pharmacodynamic properties of various forms of therapy. In clinical practice, it could be helpful in determining statin dosage, but its measurement is not essential as it is possible to simply titrate the dose of statin upward or downward as guided by LDL-C response. In clinical research, plasma PCSK9 levels provide hypothesis-generating information which could help the design of basic science experiments that explore mechanisms of regulation, metabolism, and role of PCSK9.