Department of Medicine, University of California San Diego, La Jolla, CA, USA.
J Am Coll Cardiol. 2012 Aug 21;60(8):716-21. doi: 10.1016/j.jacc.2012.04.038.
Recent published studies have provided increasing evidence that lipoprotein(a) [Lp(a)] may be a potential causal, genetic, independent risk factor for cardiovascular disease (CVD). Lp(a) levels >25 mg/dl are present in ∼30% of Caucasians and 60% to 70% of Blacks. Lp(a) is composed of apolipoprotein B-100 and apolipoprotein (a) [(apo(a)]. Circulating Lp(a) levels are primarily influenced by the LPA gene without significant dietary or environmental effects, mediating CVD risk throughout the patient's lifetime. Recent clinical outcomes studies, meta-analyses, and Mendelian randomization studies, in which randomization of Lp(a) levels is achieved through the random assortment of LPA gene variants thereby removing confounders, have shown that genetically determined Lp(a) levels are continuously and linearly related to risk of CVD. Currently, Lp(a) pathophysiology is not fully understood, and specifically targeted therapies to lower Lp(a) are not available. We provide a rationale for increased basic and clinical investigational efforts to further understand Lp(a) pathophysiology and assess whether reducing Lp(a) levels minimizes CVD risk. First, a detailed understanding of Lp(a) synthesis and clearance has not been realized. Second, several mechanisms of atherogenicity are known to varying extent, but the relative contributions of each are not known. Lp(a) may be atherothrombotic through its low-density lipoprotein moiety, but also through apo(a), including its ability to be retained in the vessel wall and mediate pro-inflammatory and proapoptotic effects including those potentiated by its content of oxidized phospholipids, and antifibrinolytic effects. Finally, development of specific Lp(a)-lowering agents to potently lower Lp(a) will allow testing of mechanistic hypotheses in animal models and the design of randomized clinical trials to assess reduction in CVD. A convergence of academic, scientific, pharmaceutical, and National Institutes of Health priorities and efforts can make this a reality in the next decade.
最近发表的研究提供了越来越多的证据表明，脂蛋白(a) [Lp(a)] 可能是心血管疾病 (CVD) 的一个潜在的因果遗传独立危险因素。在 30%的白种人和 60%到 70%的黑种人中，脂蛋白(a)水平> 25mg/dl。脂蛋白(a)由载脂蛋白 B-100 和载脂蛋白(a) [(apo(a)]组成。循环中的脂蛋白(a)水平主要受 LPA 基因的影响，不受饮食或环境的显著影响，在患者的一生中调节 CVD 风险。最近的临床结局研究、荟萃分析和孟德尔随机化研究表明，通过随机分配 LPA 基因变异来实现脂蛋白(a)水平的随机分配，从而消除混杂因素，可以证明遗传决定的脂蛋白(a)水平与 CVD 风险呈连续线性关系。目前，脂蛋白(a)的病理生理学尚未完全了解，也没有专门针对降低脂蛋白(a)的靶向治疗方法。我们提供了增加基础和临床研究努力的理由，以进一步了解脂蛋白(a)的病理生理学，并评估降低脂蛋白(a)水平是否能最大限度地降低 CVD 风险。首先，对脂蛋白(a)合成和清除的详细了解尚未实现。其次，已知几种动脉粥样硬化的机制，但每种机制的相对贡献尚不清楚。脂蛋白(a)可能通过其低密度脂蛋白部分引起动脉粥样血栓形成，但也可能通过 apo(a)引起，包括其在血管壁中被保留并介导促炎和促凋亡作用的能力，包括其氧化磷脂含量增强的作用，以及抗纤维蛋白溶解作用。最后，开发特异性降低脂蛋白(a)的药物以有效地降低脂蛋白(a)水平，将允许在动物模型中测试机制假说，并设计随机临床试验以评估 CVD 的减少。学术、科学、制药和美国国立卫生研究院的优先事项和努力的融合可以使这在未来十年成为现实。
