Cohort Study Shows That a New HDL Apolipoproteomic Score Correlates with Both Risk of Coronary Artery Disease and Risk of Cardiovascular Death

In a study led by Dr. Pradeep Natarajan showed that an HDL apolipoproteomic score is associated with coronary artery disease (CAD). Additionally, the study published in the Journal of the American College of Cardiology showed that among individuals with CAD, this score is independently associated with cardiovascular death.

While previous studies have shown that high-density lipoprotein cholesterol (HDL-C) concentrations do not significantly alter CAD risk, there is recent evidence that suggests that genetic variations influencing plasma triglyceride-rich lipoproteins do affect the risk of CAD. Plasma lipoproteins comprise of a variety of different molecules including apolipoproteins. Studies have shown that the ratio of apolipoprotein B to apolipoprotein A-1 is better at predicting CAD events than conventional plasma lipid measures. Apolipoprotein B is typically found in low-density lipoprotein (LDL) and apo-A1 is typically found in HDL. Additionally, there are other apolipoproteins that have been associated with an increased CAD risk including apoC-2, apoC-3, and apoE. HDL is an important circulating reservoir of the various apolipoproteins and works to transfer these molecules to and from the various lipoprotein molecules as well as the liver. The authors derived a composite HDL apolipoproteomic score based on the presence of 5 apolipoproteins within HDL (apoA-1, apoC-1, apoC-2, apoC-3, and apoC-4) and evaluated those features in patients with and without CAD, as well as those who experienced a cardiovascular death. The investigators also assessed for correlation between the various apolipoproteins as well as the correlation between the apolipoproteins and the various cholesterol and lipid molecules.

The CASABLANCA (Catheter Sampled Blood Archine in Cardiovascular Diseases) study included 1,251 patients referred for coronary or peripheral angiography between 2008 and 2011. Of the total population, the authors identified patients who did not have a myocardial infarction and who underwent angiography (943 patients). The patients with the higher pCAD score tended to be male, have a history of hypertension, had a history of myocardial infarction or cerebrovascular accident/transient ischemic streak, were more likely to have diabetes and were more likely to have an elevated high sensitivity C-reactive protein (hs-CRP) level. The authors found that plasma apoA-1 and HDL-associated apoA-1 were strongly correlated (r (correlation coefficient) = 0.86, p <0.001). The calculated pCAD score was also strongly correlated with HDL-C (r= -0.86, p <0.001), triglycerides (r = 0.39, p <0.001) and plasma apoA-1 (r = -0.61, p <0.001). pCAD was not correlated with LDL-C or non-HDL-C. Among the various HDL apolipoproteins, pCAD was correlated with HDL apoA-1 (r=-0.71, p <0.001), HDL apoC-1 (r=-0.52, p <0.001), and HDL apoC-4 (r=0.18, p <0.001).

Out of the 943 patients in the study, 587 patients (62.2%) had CAD. CAD defined as having a lesion with more than 70% stenosis in one or more vessels. In an unadjusted model, a higher HDL pCAD score was associated with an increased risk of CAD (OR 1.64, p <0.001). Even after adjusting for known risk factors for CAD (such as age, sex, diabetes, smoking status, statin use, systolic blood pressure, hypertension, apoA-1 and apoB-2), the association remained significant (OR 1.39, p = 0.001). A total of 101 cardiovascular deaths (10.7%) occurred in the study. In the total population, pCAD was associated with cardiovascular death (HR 1.33, p = 0.005). While this association was not significant in patients without obstructive CAD on angiography (HR 1.00, p = 1.0), it was significant in patients with obstructive CAD (HR 1.36, p =0.01).

When discussing the results of the study, Dr. Natarajan wrote, “Our study highlights that atherosclerosis is influenced by a complex interplay of apolipoproteins across lipoprotein species; quantification of these components can inform risk and prognosis.” However, considering the observational nature of this study, the findings here cannot be interpreted as causal. In an editorial published with the study, Dr. Arnold von Eckardstein highlighted a potentially new knowledge gap: Assessing the score in asymptomatic individuals. He wrote, “the paper by Natarajan et al. is the preliminary highlight of a very interesting approach toward a novel functional biomarker of HDL. The pCAD score deserves further clinical evaluation, perhaps in asymptomatic individuals rather than in symptomatic patients who are already intensively treated with lipid-lowering drugs. In fact, other HDL biomarkers, including HDL-C, perform less well in CAD patients than in healthy individuals”.