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

Abstract

<p><b><i>Background—</i></b>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.</p><p> <b><i>Methods and Results—</i></b>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 (<i>r</i>=−0.536, <i>P</i><0.001) and apo(a) FCR (<i>r</i>=−0.363, <i>P</i><0.01), and positively with apo(a) PR (<i>r</i>=0.877, <i>P</i><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 (<i>P</i><0.05) and lower apo(a) FCR (<i>P</i><0.01) than those with larger sizes. Plasma apo(a) concentration was significantly associated with apo(a) PR (<i>r</i>=0.930, <i>P</i><0.001), but not with FCR (<i>r</i>=−0.012, <i>P</i>>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 (<i>r</i>=0.744 and −0.389, respectively, <i>P</i><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.</p><p> <b><i>Conclusions—</i></b>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.</p>