FIRST DEMONSTRATION BY CARDIAC COMPUTED TOMOGRAPHY THAT ELEVATED LIPOPROTEIN(A) IS ASSOCIATED WITH HIGH-RISK PARTIALLY CALCIFIED PLAQUE, EXTENSIVE PLAQUE BURDEN, AND LUMINAL STENOSIS, INDEPENDENT OF APOLIPOPROTEIN B LEVELS

Therapeutic Area

ASCVD/CVD Risk Assessment

Background

Lipoprotein(a) [Lp(a)] is an inherited, causal and independent driver of cardiovascular risk (or atherosclerotic cardiovascular disease). The GLOBAL study utilized multi-omic analyses and deep phenotyping of coronary atherosclerosis by coronary computed tomography angiography (CCTA) to unravel the underlying pathology of atherosclerotic coronary artery disease (CAD). The study evaluated the association between Lp(a) and the plaque characteristics. The objective of the sub-analysis was to determine the prevalence of high-risk (partially calcified plaque [PCP]) versus lower-risk (non-calcified plaque [NCP] and calcified plaque [CAP]), coronary plaque burden, and risk of luminal stenosis (≥70%) assessed by CCTA in patients with elevated Lp(a).

Methods

We analyzed data from patients enrolled in the GLOBAL clinical study who were referred for CCTA for suspected CAD. Lp(a) mass, molar concentration, Lp(a)-cholesterol, Lp(a)-kringle IV-2 and percentage of apo(a) isoforms and apolipoprotein B (ApoB) were measured. Plaque type was evaluated in each segment and measure of plaque burden and computed tomography (CT)-Leaman score, were calculated for each patient. Statistical associations were determined by Pearson’s correlation and compared across patients by analysis of variance (ANOVA).

Results

Overall, 340 patients were included (53% female; mean age±SD 55.6±9.8 years), 62% had ‘normal’/non-obstructive plaque. In patients with predominantly PCP, versus NCP or CAP, Lp(a)-cholesterol and small apo(a) isoforms were significantly higher. Plaque burden was significantly correlated with Lp(a) molar concentration (rho 0.16, P=0.003), Lp(a) mass (rho 0.18, P=0.001), Lp(a)-cholesterol (rho 0.16, P=0.003), and small apo(a) isoforms (rho 0.14, P=0.009). CT-Leaman score was significantly correlated with Lp(a) mass (ANOVA P=0.03). Patients with ≥70% vs <70% luminal stenosis had significantly higher Lp(a) molar concentration (44.75 vs 22.1 nmol/L, respectively; ANOVA P=0.015). When modeled over the range of ApoB, the association between Lp(a) and coronary plaque was strongest for PCP (rho 0.248, P<0.001) versus NCP or CAP. Lp(a) mass was a significant predictor of CT-Leaman score (rho 0.75, P<0.001).

Conclusions

Premature cardiovascular events seen in patients with high-Lp(a) appears to be driven through its association with high-risk PCP phenotypes and the magnitude of effect of Lp(a) was independent of apoB levels. Lp(a)-driven CAD is characterized by more extensive plaque burden and represents a unique high-risk phenotype.