Background

Elevated plasma lipoprotein (a) [Lp(a)] and coronary artery calcification (CAC) are established cardiovascular risk factors that correlate with each other. We hypothesized that other cardiovascular risk factors could affect their relationship.

Methods

We tested for interactions of 24 study variables related to dyslipidemia, diabetes, insulin resistance, hypertension, inflammation and coagulation with baseline Lp(a) on change in CAC volume and density over 9.5 years in 5975 Multi-Ethnic Study of Atherosclerosis (MESA) participants, free of apparent cardiovascular disease at baseline.

Results

Elevated Lp(a) was associated with larger absolute increase in CAC volume (3.21 and 4.45 mm³/year higher for Lp(a) ≥30 versus <30 mg/dL, and Lp(a) ≥50 versus <50 mg/dL, respectively), but not relative change in CAC volume. No association was found with change in CAC density when assessing continuous ln-transformed Lp(a). The association between elevated Lp(a) (≥30 mg/dL) and absolute change in CAC volume was greater in participants with higher circulating levels of interleukin-2 soluble receptor α, soluble tumor necrosis factor alpha receptor 1 and fibrinogen (15.33, 11.81 and 7.02 mm³/year in quartile 4, compared to -3.44, -0.59 and 1.91 mm³/year in quartile 1, respectively). No significant interaction was found for other study variables. Similar interactions were seen when assessing Lp(a) levels ≥50 mg/dL.

Conclusions

Elevated Lp(a) was associated with an absolute increase in CAC volume, especially in participants with higher levels of selected markers of inflammation and coagulation. These results suggest Lp(a) as a potential biomarker for CAC volume progression.

Background

Proprotein subtilisin kexin type 9 (PCSK9) and lipoprotein (a) [Lp(a)] levels are causative risk factors for coronary heart disease.

Objectives

The objective of the study was to determine the impact of lipid-lowering treatments on circulating PCSK9 and Lp(a).

Methods

We measured PCSK9 and Lp(a) levels in plasma samples from Investigation of Lipid Level Management to Understand its Impact in Atherosclerotic Events trial patients with coronary heart disease and/or type II diabetes (T2D) mellitus. Patients received atorvastatin, which was titrated (10, 20, 40, or 80 mg/d) to achieve low-density lipoprotein cholesterol levels <100 mg/dL (baseline) and were subsequently randomized either to atorvastatin + torcetrapib, a cholesterol ester transfer protein inhibitor, or to atorvastatin + placebo.

Results

At baseline, both plasma PCSK9 and Lp(a) were dose-dependently increased with increasing atorvastatin doses. Compared with patients without T2D, those with T2D had higher PCSK9 (357 ± 123 vs 338 ± 115 ng/mL, P = .0012) and lower Lp(a) levels (28 ± 32 vs 32 ± 33 mg/dL, P = .0005). Plasma PCSK9 levels significantly increased in patients treated with torcetrapib (+13.1 ± 125.3 ng/mL [+3.7%], P = .005), but not in patients treated with placebo (+2.6 ± 127.9 ng/mL [+0.7%], P = .39). Plasma Lp(a) levels significantly decreased in patients treated with torcetrapib (-3.4 ± 10.7 mg/dL [-11.1%], P < .0001), but not in patients treated with placebo (+0.3 ± 9.4 mg/dL [+0.1%], P = .92).

Conclusion

In patients at high cardiovascular disease risk, PCSK9 and Lp(a) are positively and dose-dependently correlated with atorvastatin dosage, whereas the presence of T2D is associated with higher PCSK9 but lower Lp(a) levels. Cholesterol ester transfer protein inhibition with torcetrapib slightly increases PCSK9 levels and decreases Lp(a) levels.