Increased Production Rate of Apolipoprotein(a) is the Primary Mechanism for Increased Lipoprotein(a) Concentration in Patients with Hypercholesterolaemia on Statin Therapy

Abstract

Background: Elevated plasma concentration of lipoprotein(a) [Lp(a)] are associated with cardiovascular disease (CVD). Understanding the mechanism for the elevation in Lp(a), may be of clinical significance, especially in individuals with elevated Lp(a) concentrations. Aim: To determine the kinetic parameters of Lp(a)–apo(a) in individuals with high and low plasma Lp(a) concentrations (HLPA and LLPA, respectively). Methods: In a cross-sectional study, we recruited 14 subjects with high Lp(a) and 14 subjects with low Lp(a). Deuterated leucine (5 mg/kg) was administered to the subject. Lp(a) was isolated using magnetic beads/antibody, apo(a) was isolated using gel electrophoresis and enrichment measured using gas chromatography mass spectrometry. Lp(a) concentration in plasma was determined by a monoclonal antibody based ELISA and apo(a) isoform sizes were determined by high resolution agarose gel electrophoresis followed by immunoblotting. Results: Lp(a) concentration was significantly higher in HLPA subjects compared with LLPA (319.13 ± 28.00 vs 24.62 ± 8.59 nmol/L, p < 0.001). Apo(a) production rate (PR) was also significantly greater in HLPA subjects (195.89 ± 33.00 vs 6.93 ± 2.27 nmol/kg/day, p < 0.001). Apo(a) isoform size, expressed as number of apo(a) kringle 4 domains, was significantly larger in LLPA, compared with HLPA subjects (23.00 ± 2.54 vs 17.00 ± 0.29, p < 0.02). A high correlation was found between Lp(a) concentration and apo(a) PR (r = 0.95, p < 0.001). Conclusion: Apo(a) PR is the primary determinant of Lp(a) concentration in subjects with hypercholesterolaemia. This observation is consistent with the concept that Lp(a) isoform, which is determined genetically, determines apo(a) PR and hence Lp(a) concentration.