Circulating PCSK9 and cardiovascular events in FH patients with standard lipid-lowering therapy

Abstract

Background: Proprotein convertase subtilisin/kexin 9 (PCSK9) has been proposed as a novel target for coronary artery disease (CAD). Familial hypercholesterolemia (FH) is characterized by high prevalence of CAD and major cardiovascular events (MACEs). However, no data is available on the association between PCSK9 levels and MACEs in FH patients with standard lipid lowering therapy. Methods: A total of 338 consecutive heterozygous FH (Dutch Lipid Clinic Network score ≥ 6) was enrolled and followed up for the occurrence of MACEs. Multidetector CT and coronary angiography were performed to determine coronary artery calcification score (CACS) and Gensini score (GS). Multivariable Cox regression analyses were used to calculate hazard ratios (HRs) with 95% confidence intervals (CIs). Plasma PCSK9 concentrations were determined by enzyme immunoassay. Results: PCSK9 was independently and positively associated CACS and GS at baseline. During a mean follow-up of 3 years, 33 (9.8%) events occurred. Patients with MACEs had higher median PCSK9 compared with those without (332.47 vs. 311.89 ng/mL, p = 0.038). Kaplan-Meier analysis revealed that patients with higher PCSK9 presented lower event-free survival (p = 0.0017). PCSK9 was statistically correlated with MACEs after adjusting for confounding factors, with the HR per SD being 1.86 (1.31-2.65) and 3.70 (1.16-11.82) for the highest tertile compared with the lowest tertile. Adding PCSK9 to Cox prediction model led to a statistical improvement in net reclassification and integrated discrimination. Conclusion: Elevated levels of PCSK9 were positively associated with the development of CAD and future cardiovascular events, suggesting that measurement of PCSK9 concentration might be useful for cardiovascular risk stratification. Further studies are needed to confirm our results.