Lipoprotein(a) Particle Production as a Determinant of Plasma Lipoprotein(a) Concentration Across Varying Apolipoprotein(a) Isoform Sizes and Background Cholesterol-Lowering Therapy.

Background-Elevated lipoprotein(a) (Lp(a)), a low-density lipoprotein-like particle bound to the polymorphic apolipoprotein(a) (apo (a)), may be causal for cardiovascular disease. However, the metabolism of Lp(a) in humans is poorly understood. Methods and Results-We investigated the kinetics of Lp(a)-apo(a) and low-density lipoprotein-apoB-100 in 63 normolipidemic men. The fractional catabolic rate (FCR) and production rate PR) were studied. Plasma apo(a) concentration was significantly and inversely associated with apo(a) isoform size (r=- 0.536, P<0.001) and apo(a) FCR (r =- 0.363, P<0.01), and positively with apo(a) PR (r=0.877, P<0.001). There were no significant associations between the FCRs of apo(a) and low-density lipoprotein-apoB-100. Subjects with smaller apo(a) isoform sizes (<= 22 kringle IV repeats) had significantly higher apo(a) PR (P<0.05) and lower apo(a) FCR (P<0.01) than those with larger sizes. Plasma apo(a) concentration was significantly associated with apo(a) PR (r=0.930, P<0.001), but not with FCR (r=-0.012, P>0.05) in subjects with smaller apo(a) isoform size. In contrast, both apo(a) PR and FCR were significantly associated with plasma apo(a) concentrations (r=0.744 and -0.389, respectively, P<0.05) in subjects with larger isoforms. In multiple regression analysis, apo(a) PR and apo(a) isoform size were significant predictors of plasma apo(a) concentration independent of low-density lipoprotein-apoB-100 FCR and background therapy with atorvastatin and evolocumab. Conclusions-In normolipidemic men, the plasma Lp(a) concentration is predominantly determined by the rate of production of Lp (a) particles, irrespective of apo(a) isoform size and background therapy with a statin and a proprotein convertase subtilisin-kexin type 9 inhibitor. Our findings underscore the importance of therapeutic targeting of the hepatic synthesis and secretion of Lp(a) particles. Lp(a) particle catabolism may only play a modest role in determining Lp(a) concentration in subjects with larger apo(a) isoform size.