Elevated Levels of Lp(a) are Associated with Circulating Levels of PCSK9 and Coronary Atherosclerosis as Detected by Cardiac Computed Tomography Angiography

• Published in: Journal of clinical lipidology 2024-07, Vol.18 (4), p.e577-e578
• Main Authors: Brown, Bradley, Watson, David, Boatwright, Wess, Dayspring, Thomas, Barnes, Michael, Voros, Szilard
• Format: Article
• Language: English
• ISSN: 1933-2874; 1876-4789
• DOI: 10.1016/j.jacl.2024.04.117

Global Genomics Group, LLC is the sponsor of the GLOBAL clinical study. Editing support was provided by Susannah Thornhill, Ph.D. (BOLDSCIENCE Ltd.), and was funded by Novartis Pharmaceuticals Corporation, East Hanover, NJ, USA, in accordance with GPP 20. Lipoprotein(a) [Lp(a)] is the most prevalent genetic cause of atherosclerotic coronary artery disease, and proprotein convertase subtilisin/kexin type 9 (PCSK9) is a genetically and clinically validated target. Little is known about the relationship between Lp(a) isoform size, serum levels of PCSK9, and coronary atherosclerosis. We hypothesized that circulating PCSK9 levels are associated with circulating levels of small Lp(a) (≤24 Kringle IV type 2 repeats) and coronary atherosclerosis. The GLOBAL study (NCT01738828) enrolled patients referred for coronary computed tomography angiography (CCTA). Circulating PCSK9 was measured using ELISA (R&D Systems, MN). Circulating Lp(a) (nmol/L) was measured using isoform-independent ELISA. Kringle IV type 2 repeats and the percentage of each of the two Lp(a) isoforms were measured using a validated western blot technique (Northwest Lipid Metabolism and Diabetes Research Laboratories, WA). Circulating levels of small and large Lp(a) particles were calculated based on total Lp(a) and the percent contribution of each isoform. Coronary atherosclerosis was identified and quantified using CCTA in a core laboratory. First, we used linear regression to assess associations between PCSK9 and Lp(a) as continuous variables. Second, we compared serum levels of Lp(a) across PSCK9 quartiles using ANOVA. Third, the prevalence of coronary atherosclerosis was assessed based on serum PCSK9 and Lp(a) quartiles. We enrolled 340 patients: 53% female, mean age 55.6±9.8 years. Increasing levels of circulating PCSK9 were associated with increasing levels of Lp(a) when PCSK9 was assessed as a continuous variable (rho=0.11; p=0.038; Figure, Panel A) and when PCSK9 was assessed by quartiles (16±20.61, 24.05±29.5, 23.75±24.76, and 45±59.3 nmol/L, respectively; ANOVA p=0.043; Figure, Panel D). This association was seen for small Lp(a) particles (rho=0.122; p=0.026; Figure, Panels B and E) but was not seen for large Lp(a) particles (rho=0.055; p=0.32; Figure, Panels C and F). In patients in the highest Lp(a) quartile, the prevalence of coronary atherosclerosis across PCSK9 quartiles was 38.9%, 50.0%, 78.9%, and 77.8% (Figure, Panel G). Increasing levels of circulating PCSK9 are associated with hi