The HDLs circulating in human plasma are extremely complex, and their relationship with atherosclerotic cardiovascular disease (ASCVD) is complicated. Human HDLs comprise multiple discrete subpopulations of particles that differ in size, shape, charge, and in composition of both lipids and proteins. The individual constituents of HDLs enter the plasma separately and are assembled into HDL particles within the plasma. HDLs are subject to continuous remodelling by multiple plasma factors, and the individual constituents are subsequently removed from plasma separately rather than as an uptake of the intact particle. HDLs have several functions that have the potential to protect against atherosclerosis, although how the different functions relate to different HDL subpopulations is not known. It is also uncertain whether any of the known HDL functions directly or indirectly protect against development of ASCVD and associated clinical events. Large human population studies have shown consistently that a low concentration of HDL cholesterol is an independent predictor of an increased risk of having an ASCVD event. Furthermore, increasing HDL cholesterol levels in animals, whether by intravenous infusions of HDLs or by increasing the synthesis of apoA-I (the major HDL apolipoprotein) by transgenic expression of the ApoA1 gene, markedly decreases susceptibility to the development of atherosclerosis in both mice and rabbits. However, interventions that increase the concentration of HDL cholesterol in humans have, to date, failed to translate into a decrease in the risk of having an ASCVD event. In addition, there is robust evidence that some gene variants that increase the plasma concentration of HDL cholesterol are not accompanied by a reduced risk of having an ASCVD event. Now, as reported in a paper published in this issue, there is compelling evidence that people with extreme high levels of HDL cholesterol have an increased rather than a decreased risk of death from cardiovascular disease, cancer and, other causes. Analysis of data from the Copenhagen City Heart Study and the Copenhagen General Population Study has shown that the presence of an extremely high concentration of HDL cholesterol is predictive of an increase in all-cause mortality in both men and women. This analysis included 52 268 men and 64 240 women and provided 745 452 person-years of follow-up with 5619 deaths. The relationship between HDL cholesterol concentration and mortality was U-shaped, with an increased risk observed at both low levels and extreme high levels of HDL cholesterol. The lowest mortality was observed with HDL cholesterol levels of 1.9 mmol/L in men and 2.4 mmol/L in women. The observed increase in mortality in those with low levels of HDL cholesterol is consistent with findings from previous studies of the relationship of HDL cholesterol level with ASCVD. An increased mortality in those with extreme high levels of HDL cholesterol has also been reported previously. This observation of an increased mortality associated with extreme high HDL cholesterol has clinical implications, and risk algorithms that include HDL should be revised accordingly. The observation also indicates that ratios, such as the ratio of total cholesterol to HDL cholesterol, should no longer be included in algorithms designed to calculate ASCVD risk. There is no obvious mechanism to explain an increased mortality associated with extreme high levels of HDL cholesterol. It is possible, however, that some factor or factors leading to an increase in mortality also increase the concentration of HDL cholesterol, in which case the extreme high HDL cholesterol level may be a (non-causal) biomarker of an increased risk of death. The results of human population studies showing that a low level of HDL cholesterol is an independent predictor of the risk of having an ASCVD event have led to a view that HDL cholesterol may be protective. It is highly unlikely, however, that the cholesterol contained in HDL plays any protective role. Rather, if HDLs do protect, it is most likely to be the consequence of their protective functions rather than a simple increase in the amount of cholesterol transported in this lipoprotein fraction. Several well-documented functions of HDLs have the potential to protect against ASCVD (Figure 1). The most extensively studied of

中文翻译：

---

高密度脂蛋白胆固醇浓度或高密度脂蛋白功能：哪个重要？

人体血浆中循环的 HDL 极其复杂，它们与动脉粥样硬化性心血管疾病 (ASCVD) 的关系也很复杂。人类 HDL 包含多个离散的粒子亚群，这些粒子的大小、形状、电荷以及脂质和蛋白质的组成都不同。HDLs 的各个成分分别进入等离子体，并在等离子体中组装成 HDL 粒子。HDLs 受到多种血浆因子的持续重塑，随后将单独的成分从血浆中分离出来，而不是作为完整颗粒的吸收。HDLs 具有多种功能，有可能预防动脉粥样硬化，尽管不同功能与不同 HDL 亚群的关系尚不清楚。也不确定是否有任何已知的 HDL 功能直接或间接地防止 ASCVD 的发展和相关的临床事件。大量人群研究一致表明，低浓度的 HDL 胆固醇是发生 ASCVD 事件风险增加的独立预测因素。此外，增加动物的 HDL 胆固醇水平，无论是通过静脉输注 HDL 还是通过 ApoA1 基因的转基因表达增加 apoA-I（主要的 HDL 载脂蛋白）的合成，显着降低了小鼠和小鼠动脉粥样硬化发展的易感性。兔子。然而，迄今为止，增加人类 HDL 胆固醇浓度的干预措施未能转化为降低发生 ASCVD 事件的风险。此外，有强有力的证据表明，一些增加血浆 HDL 胆固醇浓度的基因变异不会降低发生 ASCVD 事件的风险。现在，正如本期发表的一篇论文所报道的，有令人信服的证据表明，HDL 胆固醇水平极高的人死于心血管疾病、癌症和其他原因的风险增加而不是降低。哥本哈根市心脏研究和哥本哈根普通人群研究的数据分析表明，高密度脂蛋白胆固醇浓度极高，预示着男性和女性的全因死亡率都会增加。该分析包括 52268 名男性和 64240 名女性，并提供了 745452 人年的随访，其中 5619 人死亡。HDL 胆固醇浓度与死亡率之间的关系呈 U 型，在低水平和极高水平的 HDL 胆固醇下都观察到风险增加。男性 HDL 胆固醇水平为 1.9 mmol/L，女性为 2.4 mmol/L，死亡率最低。在高密度脂蛋白胆固醇水平低的人群中观察到的死亡率增加与先前关于高密度脂蛋白胆固醇水平与 ASCVD 关系的研究结果一致。先前也有报道称，高密度脂蛋白胆固醇水平极高的人死亡率增加。这种与极高 HDL 胆固醇相关的死亡率增加的观察结果具有临床意义，应相应地修改包括 HDL 在内的风险算法。观察结果还表明，比率，例如总胆固醇与 HDL 胆固醇的比率，不应再包含在旨在计算 ASCVD 风险的算法中。没有明显的机制来解释与极高水平的 HDL 胆固醇相关的死亡率增加。然而，有可能导致死亡率增加的一些因素也增加了 HDL 胆固醇的浓度，在这种情况下，极高的 HDL 胆固醇水平可能是死亡风险增加的（非因果）生物标志物。人群研究结果表明，低水平的 HDL 胆固醇是发生 ASCVD 事件风险的独立预测因素，这导致了一种观点，即 HDL 胆固醇可能具有保护作用。然而，HDL 中所含的胆固醇不太可能起到任何保护作用。相反，如果 HDL 确实保护，这很可能是它们的保护功能的结果，而不是简单地增加在这种脂蛋白部分中运输的胆固醇量。HDL 的几个有据可查的功能具有预防 ASCVD 的潜力（图 1）。研究最广泛的