The inverse relationship between low plasma high-density lipoprotein cholesterol (HDL-C) concentrations and increased risk of Atherosclerotic Cardiovascular Disease (ASCVD) is well-known. However, plasma HDL-C concentrations are highly variable in subjects with ASCVD. In clinical outcome trials, pharmacotherapies that increase HDL-C concentrations are not associated with a reduction in ASCVD events. A causal relationship between HDL-C and ASCVD has also been questioned by Mendelian randomization studies and genome-wide association studies of genetic variants associated with plasma HDL-C concentrations. The U-shaped association between plasma HDL-C concentrations and mortality observed in several epidemiological studies implicates both low and very high plasma HDL-C concentrations in the etiology of ASCVD and non- ASCVD mortality. These data do not collectively support a causal association between HDL-C and ASCVD risk. Therefore, the hypothesis concerning the association between HDL and ASCVD has shifted from focus on plasma concentrations to the concept of functionality, in particular cellular cholesterol efflux and HDL holoparticle transport. In this review, we focus on these new concepts and provide a new framework for understanding and testing the role of HDL in ASCVD.

低血浆高密度脂蛋白胆固醇 (HDL-C) 浓度与动脉粥样硬化心血管疾病 (ASCVD) 风险增加之间的反比关系是众所周知的。然而，ASCVD 受试者的血浆 HDL-C 浓度变化很大。在临床结果试验中，增加 HDL-C 浓度的药物疗法与减少 ASCVD 事件无关。HDL-C 和 ASCVD 之间的因果关系也受到孟德尔随机化研究和与血浆 HDL-C 浓度相关的遗传变异的全基因组关联研究的质疑。在几项流行病学研究中观察到的血浆 HDL-C 浓度与死亡率之间的 U 形关联表明低和非常高的血浆 HDL-C 浓度与 ASCVD 和非 ASCVD 死亡率的病因有关。这些数据并不共同支持 HDL-C 和 ASCVD 风险之间的因果关系。因此，关于 HDL 和 ASCVD 之间关联的假设已经从关注血浆浓度转移到功能性概念，特别是细胞胆固醇流出和 HDL 全颗粒转运。在这篇综述中，我们关注这些新概念，并为理解和测试 HDL 在 ASCVD 中的作用提供了一个新框架。