Lipoprotein(a) and Incident Atrial Fibrillation: Leveraging Nature's Randomization to Identify Novel Causal Associations.
Lipoprotein(a) and Incident Atrial Fibrillation: Leveraging Nature's Randomization to Identify Novel Causal Associations.
复制标题
脂蛋白（a）和心房颤动事件：利用自然的随机性来识别新的因果关系。
DOI：
10.1016/j.jacc.2022.02.026
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发表时间：
2022
影响因子：
24
通讯作者：
Khandelwal,Abha
中科院分区：
文献类型：
--
作者：
Kim,DanielSeung;Khandelwal,Abha
心房颤动 (AF) 是最常见的心律失常，与心力衰竭、中风和死亡风险增加相关。 1 年龄是 AF 的最强危险因素，但其他增加心房激惹或牵拉的疾病，如冠状动脉疾病 (CAD)、瓣膜性心脏病（包括主动脉瓣狭窄 [AS]）、心力衰竭、饮酒、甲状腺功能亢进、睡眠呼吸暂停和手术也会增加其风险。尽管流行病学与房颤发生有许多关联，但人们对这些危险因素影响房颤发病机制的具体分子机制知之甚少。脂蛋白 (a)(Lp [a]) 由连接到载脂蛋白 (a) 部分的低密度脂蛋白 (LDL) 样颗粒组成（图 1）。 Lp (a) 升高是一种普遍病症，已知在某些种族/族裔群体中更为常见，例如非裔美国人和南亚人。 Lp (a) 的血浆浓度由 LPA 基因变异决定。 2 Lp (a) 水平与心血管疾病和 AS 风险密切相关，与其他危险因素（包括 LDL 胆固醇升高）无关。尽管 Lp (a) 不会随时间或大多数环境因素（例如饮食、运动）而发生显着变化，但外源性他汀类药物的使用会轻微增加 Lp (a) 水平，而前蛋白转化酶枯草杆菌蛋白酶/kexin 9 型抑制剂和烟酸会适度降低 Lp (a) 水平。 3 鉴于 Lp (a) 在心血管疾病中的作用众所周知，并且缺乏直接降低其水平的疗法，药物干预已成为研究和开发的焦点。其中一种药物 pelacarsen 是一种反义寡核苷酸，可结合 LPA 信使 RNA 并降低 Lp (a) 水平，目前正在进行 3 期随机临床试验。 2 更多利用 RNA 沉默的药物目前正在进行 1 期和 2 期试验。 4
Atrial fibrillation (AF) is the most common cardiac arrhythmia and is associated with an increased risk of heart failure, stroke, and death. 1 Age is the strongest risk factor for AF, but other conditions that increase atrial irritability or stretch such as coronary artery disease (CAD), valvular heart disease (including aortic stenosis [AS]), heart failure, alcohol intake, hyperthyroidism, sleep apnea, and surgery also increase its risk. Despite these numerous epidemiologic associations with incident AF, little is known regarding the specific molecular mechanisms through which these risk factors affect pathogenesis of AF. Lipoprotein (a)(Lp [a]) is composed of a low-density lipoprotein (LDL)-like particle linked to an apolipoprotein (a) moiety (Figure 1). Elevated Lp (a) is a prevalent condition and known to be more common in some racial/ethnic groups such as African-American and South Asian individuals. Plasma concentrations of Lp (a) are genetically determined by LPA gene variation. 2 Lp (a) levels are strongly associated with cardiovascular disease and AS risk, independent of other risk factors, including elevated LDL cholesterol. Although Lp (a) does not vary significantly with time or most environmental factors (eg, diet, exercise), exogenous statin use mildly increases Lp (a) levels, whereas proprotein convertase subtilisin/kexin type 9 inhibitors and niacin modestly reduce Lp (a) levels. 3 Given the known role of Lp (a) in cardiovascular disease and the lack of a therapy to directly lower its levels, pharmacologic interventions have become a focus of research and development. One agent, pelacarsen, an antisense oligonucleotide that binds LPA messenger RNA and decreases Lp (a) levels, is presently in a phase 3 randomized clinical trial. 2 Several more agents leveraging silencing RNA are currently in phase 1 and 2 trials. 4