Circulating angiopoietin-like protein 3 levels and subsequent cardiovascular outcomes in patients with coronary artery disease

Background Angiopoietin-like protein 3 (ANGPTL3) is a secretory glycoprotein mainly expressed in the liver, which regulates metabolism of triglyceride-rich lipoproteins. Pathophysiologically, ANGPTL3 inhibits lipoprotein lipase activity and endothelial lipase activity, which diminishes the clearance of triglyceride-rich lipoproteins. Furthermore, inhibition of endothelial lipase with ANGPTL3 increases low-density lipoprotein cholesterol (LDL-C) levels in circulation. These observations suggest ANGPTL3 as a potential driver associated with atherosclerotic cardiovascular disease. However, the association between circulating ANGPTL3 levels and atherosclerotic cardiovascular disease remains to be fully determined. Purpose To investigate the association of circulating ANGPTL3 concentrations with subsequent cardiovascular outcomes in patients with coronary artery disease (CAD). Methods This is a single-center study which enrolled a total of 231 patients with CAD. Serum ANGPTL3 concentrations were measured using a commercially available human ANGPTL3 enzyme-linked immunosorbent assay kit [#27750 Human ANGPTL3 (highly sensitive) Assay Kit]. Primary outcome was defined as a composite of all-cause death, non-fatal MI, stroke. Secondary outcome included a composite of all-cause death, stroke. Clinical characteristics, and primary and secondary outcomes were compared in those stratified into the two groups according to the median level of ANGPTL3 levels (≤ and > 363.4 ng/mL). Results In entire subjects, ANGPTL3 level was 363.4 (276.0–473.4) ng/mL, and it was non-normally distributed (Figure 1). Patients with ANGPTL3> 363.4 ng/mL were older and more likely to be female (p=<0.001) and have a greater frequency of CKD (p=0.024), whereas a lower proportion of dyslipidemia was observed in those with ANGPTL3> 363.4 ng/mL (Table) (p=0.020). There were no significant differences in the prevalence of ACS and CCS between the two groups (p=0.813). During the 5-year observational period, 20 primary and 14 secondary outcomes occurred in study population. There was a trend toward more frequent occurrence of primary outcomes in patients with ANGPTL3> 363.4 ng/mL, but this comparison did not meet statistical significance (Figure 2) (adjusted HR=2.88, 95%CI=0.84–9.89, p=0.093; adjusted by Age, Female, CKD, ACS presentation). With regard to secondary outcomes, ANGPTL3> 363.4 ng/mL was associated with a greater likelihood of experiencing secondary outcomes (Figure 3) (adjusted HR=5.32, 95%CI=1.25–22.71, p=0.024; adjusted by Age, Female, CKD, ACS presentation). Conclusion An increased risk of cardiovascular events, especially a composite of all-cause death and stroke, was observed in patients with CAD who exhibited ANGPTL3> 363.4 ng/mL. These findings suggest circulating ANGPTL3 as a potential therapeutic target to further mitigate subsequent cardiovascular events’ risks in patients with CAD.