Circulating PCSK9 and Risk of Myocardial Infarction

Study Questions:

Circulating proprotein convertase subtilisin-kexin type 9 (PCSK9) binds to the low-density lipoprotein (LDL) receptor, leading to a decrease in number of receptors and a rise in serum LDL cholesterol (LDL-C), and has been shown to predict adverse outcomes in established cardiovascular disease (CVD). Is the level of PCSK9 a risk marker for myocardial infarction (MI) in the general population?

Methods:

A nested case-control study was conducted in Norway utilizing the second wave of the Hunt study, a population study conducted in 1995-1997 that included a self-administered questionnaire, clinic exam, and blood samples. Those with CVD were excluded, leaving a total of nearly 60,000 participants who were 97% ethnically homogenous. The primary endpoint for this study was a first MI by 2008. A minimum of two controls with available serum were selected per MI case, matched by age at risk and sex.

Results:

At baseline, mean age was 66.2 years, and 62.9% were men. Among MI cases, the median PCSK9 concentration was 128 ng/ml (interquartile range, 76-182 ng/ml) compared with 121 ng/ml (interquartile range, 69-174 ng/ml) among controls (p < 0.001). The median value was higher in women than in men; 136 ng/ml versus 116 ng/ml (p < 0.001). Participants in the higher quartiles of PCSK9 were more likely women; current smokers; to have higher levels of creatinine, high-sensitivity C-reactive protein (hsCRP), and body mass index (BMI); and a more unfavorable serum lipid profile than those in the lower quartiles, but had a higher high-density lipoprotein cholesterol. PCSK9 concentrations had a modest positive correlation with LDL-C, total cholesterol, BMI, and hsCRP. After adjustment for these and diabetes, blood pressure, and creatinine, the association of PCSK9 with MI risk was strongly attenuated, and there was no convincing trend across quartiles (p for linear trend = 0.53). Lipids, particularly LDL-C, were the most important factor to attenuate the predictive value of PCSK9.

Conclusions:

High levels of PCSK9 were positively, but modestly associated with risk of MI in age- and sex-adjusted analyses, but the association was largely attenuated after adjustment for LDL-C.

Perspective:

The results are consistent with the biological understanding of PCSK9 and that its effect on atherosclerosis is mainly mediated by decreasing LDL-receptor number, resulting in increased serum LDL particles.

Clinical Topics: Diabetes and Cardiometabolic Disease, Dyslipidemia, Prevention, Lipid Metabolism, Nonstatins, Novel Agents

Keywords: Atherosclerosis, Blood Pressure, Body Mass Index, C-Reactive Protein, Cholesterol, HDL, Cholesterol, LDL, Creatinine, Diabetes Mellitus, Dyslipidemias, Lipids, Myocardial Infarction, Primary Prevention, Proprotein Convertases, Receptors, LDL, Risk Factors, Subtilisins


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