1 School of Medicine University of Western Australia Perth Australia.
2 School of Biomedical Science University of Western Australia Perth Australia.
J Am Heart Assoc. 2019 Apr 2;8(7):e011781. doi: 10.1161/JAHA.118.011781.
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 FCR s 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. Clinical Trial Registration URL : http://www.clinicaltrials.gov . Unique identifier: NCT 02189837.
背景 载脂蛋白(a)[Lp(a)]是一种与多态载脂蛋白(a)[apo(a)]结合的低密度脂蛋白样颗粒，可能与心血管疾病有关。然而，人类 Lp(a)的代谢仍知之甚少。
方法和结果 我们研究了 63 名血脂正常男性的 Lp(a)-apo(a)和低密度脂蛋白-apoB-100 的动力学。研究了其分数代谢率（FCR）和产生率（PR）。血浆 apo(a)浓度与 apo(a)同工型大小（r=-0.536，P<0.001）和 apo(a)FCR（r=-0.363，P<0.01）呈显著负相关，与 apo(a)PR（r=0.877，P<0.001）呈显著正相关。apo(a)和低密度脂蛋白-apoB-100 的 FCR 之间无显著相关性。apo(a)同工型较小（≤22 个四聚体重复）的患者，其 apo(a)PR（P<0.05）显著升高，而 apo(a)FCR（P<0.01）显著降低。apo(a)同工型较小的患者，血浆 apo(a)浓度与 apo(a)PR（r=0.930，P<0.001）显著相关，与 FCR（r=-0.012，P>0.05）无关。相反，apo(a)同工型较大的患者，apo(a)PR 和 FCR 均与血浆 apo(a)浓度显著相关（r=0.744 和 -0.389，分别，P<0.05）。在多元回归分析中，apo(a)PR 和 apo(a)同工型大小是独立于低密度脂蛋白-apoB-100FCR 和阿托伐他汀和前蛋白转化酶枯草溶菌素 kexin9 抑制剂背景治疗后，血浆 apo(a)浓度的显著预测因子。
结论 在血脂正常的男性中，血浆 Lp(a)浓度主要由 Lp(a)颗粒的产生率决定，而与 apo(a)同工型大小以及他汀类药物和前蛋白转化酶枯草溶菌素 kexin9 抑制剂的背景治疗无关。我们的研究结果强调了靶向治疗肝脏合成和分泌 Lp(a)颗粒的重要性。apo(a)同工型较大的患者中，Lp(a)颗粒的代谢可能仅在决定 Lp(a)浓度方面发挥适度作用。
临床试验注册网址：http://www.clinicaltrials.gov。唯一标识符：NCT 02189837。
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