Department of Biochemistry, Schulich School of Medicine & Dentistry, University of Western Ontario, London, Ontario, Canada.
Robarts Research Institute, Schulich School of Medicine & Dentistry, University of Western Ontario, London, Ontario, Canada.
Nat Rev Cardiol. 2019 May;16(5):305-318. doi: 10.1038/s41569-018-0153-2.
Epidemiological and clinical studies over the past decade have firmly established that elevated plasma concentrations of lipoprotein(a) (Lp(a)) are an important, independent and probably causal risk factor for the development of cardiovascular diseases. Whereas a link between Lp(a) levels and atherosclerotic cardiovascular disease (ASCVD) has been appreciated for decades, the role of Lp(a) in calcific aortic valve disease (CAVD) and aortic stenosis has come into focus only in the past 5 years. ASCVD and CAVD are aetiologically distinct but have several risk factors in common and similar pathological processes at the cellular and molecular levels. Oxidized phospholipids, which modify Lp(a) primarily by covalent binding to its unique apolipoprotein(a) (apo(a)) component, might hold the key to Lp(a) pathogenicity and provide a mechanistic link between ASCVD and CAVD. Oxidized phospholipids colocalize with apo(a)-Lp(a) in arterial and aortic valve lesions and directly participate in the pathogenesis of these disorders by promoting endothelial dysfunction, lipid deposition, inflammation and osteogenic differentiation, leading to calcification. The advent of potent Lp(a)-lowering therapies provides the opportunity to address directly the causality of Lp(a) in ASCVD and CAVD and, more importantly, to provide both a novel approach to reduce the residual risk of ASCVD and a long-sought medical treatment for CAVD.
在过去的十年中,流行病学和临床研究已经明确证实,脂蛋白(a)(Lp(a))的血浆浓度升高是心血管疾病发展的一个重要的、独立的、可能是因果关系的危险因素。虽然 Lp(a)水平与动脉粥样硬化性心血管疾病(ASCVD)之间的联系已经被人们认识了几十年,但 Lp(a)在心脏瓣膜钙化性疾病(CAVD)和主动脉瓣狭窄中的作用仅在过去 5 年才引起关注。ASCVD 和 CAVD 在病因上是不同的,但有几个共同的危险因素,在细胞和分子水平上也有相似的病理过程。氧化磷脂主要通过共价结合到其独特的载脂蛋白(a)(apo(a))成分上修饰 Lp(a),这可能是 Lp(a)致病机制的关键,也为 ASCVD 和 CAVD 之间提供了一个机制联系。氧化磷脂与 apo(a)-Lp(a)在动脉和主动脉瓣病变中共同定位,并通过促进内皮功能障碍、脂质沉积、炎症和成骨分化,导致钙化,直接参与这些疾病的发病机制。强效的 Lp(a)降低疗法的出现为直接解决 Lp(a)在 ASCVD 和 CAVD 中的因果关系提供了机会,更重要的是,为降低 ASCVD 的残余风险提供了一种新的方法,也为 CAVD 提供了一种长期寻求的治疗方法。
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