Background: As Mendelian Randomization (MR) studies showed no effect of variants altering HDL-cholesterol (HDL-C) levels concerning Cardiovascular Disease (CVD) and novel therapeutic interventions aiming to raise HDL-C resulted to futility, the usefulness of HDL-C is unclear.

Objective: As the role of HDL-C is currently doubtful, it is suggested that the atheroprotective functions of HDLs can be attributed to the number of HDL particles, and their characteristics including their lipid and protein components. Scientific interest has focused on HDL function and on the causes of rendering HDL particles dysfunctional, whereas the relevance of HDL subclasses with CVD remains controversial.

Methods: The present review discusses changes in quality as much as in quantity of HDL in pathological conditions and the connection between HDL particle concentration and cardiovascular disease and mortality. Emphasis is given to the recently available data concerning the cholesterol efflux capacity and the parameters that determine HDL functionality, as well as to recent investigations concerning the associations of HDL subclasses with cardiovascular mortality.

Results: MR studies or pharmacological interventions targeting HDL-C are not in favor of the hypothesis of HDL-C levels and the relationship with CVD. The search of biomarkers that relate with HDL functionality is needed. Similarly, HDL particle size and number exhibit controversial data in the context of CVD and further studies are needed.

Conclusion: There is no room for the old concept of HDL as a silver bullet,as HDL-C cannot be considered a robust marker and does not reflect the importance of HDL particle size and number. Elucidation of the complex HDL system, as well as the finding of biomarkers, will allow the development of any HDL-targeted therapy.

背景：孟德尔随机化（MR）研究表明，改变心血管疾病（CVD）的高密度脂蛋白胆固醇（HDL-C）水平的变体没有作用，而旨在提高HDL-C的新型治疗措施却徒劳无功，HDL-C的有用性尚不清楚。

目的：由于目前对HDL-C的作用尚存疑问，因此建议将HDL的抗动脉粥样硬化功能归因于HDL颗粒的数量及其特征，包括其脂质和蛋白质成分。科学兴趣集中在HDL功能和导致HDL粒子功能失调的原因上，而HDL子类与CVD的相关性仍存在争议。

方法：本综述讨论了病理条件下HDL的质量变化和数量变化以及HDL颗粒物浓度与心血管疾病和死亡率之间的关系。重点是有关胆固醇流出能力和决定HDL功能的参数的最新可用数据，以及有关HDL亚类与心血管疾病死亡率相关性的最新研究。

结果：针对HDL-C的MR研究或药物干预措施不利于HDL-C水平的假设以及与CVD的关系。需要搜索与HDL功能相关的生物标记。同样，在CVD的背景下，HDL的粒径和数量也存在争议，需要进一步研究。

结论：HDL作为银弹的旧概念已经没有余地，因为HDL-C不能被视为可靠的标记，也不能反映HDL粒径和数量的重要性。对复杂的HDL系统的阐明以及生物标志物的发现，将允许开发任何以HDL为目标的疗法。