Human Atherogenesis with Underlying Dysfunctional HDL-Free Cholesterol

动脉粥样硬化性心血管疾病（ASCVD）和血浆高密度脂蛋白胆固醇（HDL-C）是 负相关。一个模型将这种相关性归因于HDL作为游离胆固醇受体的作用 (FC)从动脉壁巨噬细胞转移（FC流出），在一些研究中，FC流出更好地预测 ASCVD高于HDL-C浓度。然而，增加血浆HDL的干预措施未能降低ASCVD， 矛盾的是，几项研究显示高密度脂蛋白血症患者的ASCVD死亡率较高。的 这种矛盾的来源是未知的，适当的治疗方法还没有制定，在这种情况下， 反向过程HDL-FC内流的作用（可能由过量HDL-FC支持）尚不清楚。小鼠 缺乏HDL受体的Scarb 1-/-小鼠是人高HDL表型的稳健模型。 与野生型小鼠相比，Scarb 1-/-小鼠更易患动脉粥样硬化，血浆HDL水平更高 更富FC。这产生了高HDL-FC生物利用度的状态，我们将其表示为一个指数： FCBI = HDL颗粒数（HDL-P）x mol% HDL-FC。这一概念上的新指标首次由本 该研究小组报告说，HDL-FCBI随着野生型小鼠<人<<Scarb 1-/-小鼠而增加， 与野生型小鼠相比，Scarb 1-/-小鼠从HDL转移到巨噬细胞的FC更多。因此，我们假设， 在血浆HDL-C非常高的人群中，ASCVD的机制相似。我们的目标是比较 冠状动脉钙化评分分别为阳性（CACS>0）和阴性（CACS=0）的患者 作为ASCVD和非ASCVD的三个亚组-高（HH）、中等（IH）或最佳（OH） 血浆HDL-C浓度-并检测ASCVD是否与高HDL-FCBI相关。根据 我们假设，a）HH患者的HDL-FCBI高于OH患者，ASCVD患者的HDL-FCBI高于非ASCVD患者 患者，尤其是具有高血浆HDL-C的那些，和B）从HDL转移的FC的幅度， ASCVD患者对巨噬细胞的作用将大于非ASCVD患者对HDL的作用， 尤其是在具有高血浆HDL-C的ASCVD患者中。这一假设得到了以下研究的支持： Scarb 1-/-小鼠，其中HDL-FCBI的一种组分降低，并且伴随其，ASCVD降低HDL-P， 普罗布考或mol% HDL-FC通过增加FC酯化抑制ASCVD。CACS与HDL的比较- 所有三个组的FCBI将揭示非线性函数关系。 传统上，医生测量HDL和LDL的总胆固醇含量。这些 这些指标具有良好但不完美的预测价值，主要是因为TC、FC和 胆固醇酯具有不同的代谢路线，可能差异性地导致ASCVD。验证 在人体中的研究假设将为测量血浆脂蛋白FC提供令人信服的基本原理， 用于ASCVD诊断和用于降低血浆-尤其是HDL-FC的疗法的制剂。

Atherosclerotic cardiovascular disease (ASCVD) and plasma high-density lipoprotein cholesterol (HDL-C) are negatively correlated. One model assigns this correlation to the role of HDL as an acceptor of free cholesterol (FC) transfer from arterial-wall macrophages (FC efflux), and in some studies, FC efflux better predicted ASCVD than HDL-C concentration. However, interventions that increase plasma HDL failed to reduce ASCVD, and, paradoxically, several studies revealed higher ASCVD mortality among patients with very high HDL. The source of this paradox is unknown, appropriate therapies have not been formulated, and in this context, the role of the reverse process, HDL-FC influx, which may be supported by excess HDL-FC, is unknown. Mice deficient in the HDL-receptor, Scarb1-/- mice, are a robust model of the human high-HDL phenotype. Compared to wild-type mice, Scarb1-/- mice are more athero-susceptible and have higher plasma levels of HDL that is more FC-rich. This produces a state of high HDL-FC bioavailability, which we express as an index: HDL- FCBI = HDL particle number (HDL-P) x mol% HDL-FC. This conceptually new metric was first reported by this study team, which reported that HDL-FCBI increases as wild-type mice < human << Scarb1-/- mice and that more FC transfers from HDL from Scarb1-/- vs. wild-type mice to macrophages. Thus, we hypothesize that similar mechanisms underlie ASCVD among humans with very high plasma HDL-C. Our goal is to compare patients with positive (CACS>0) and negative (CACS=0) coronary artery calcium scores respectively assigned as ASCVD and non-ASCVD in three subgroups—those with high (HH), intermediate (IH), or optimal (OH) plasma HDL-C concentrations—and test whether ASCVD is associated with a high HDL-FCBI. According to our hypothesis, a) HDL-FCBI will be higher among HH vs. OH patients and among ASCVD vs. non-ASCVD patients, especially those with high plasma HDL-C, and b) the magnitude of FC transfer from HDL from ASCVD patients to macrophages will be greater than that from HDL from non-ASCVD patients, again especially among ASCVD patients with high plasma HDL-C. This hypothesis is supported by studies of Scarb1-/- mice in which a component of HDL-FCBI is reduced and with it, ASCVD—reducing HDL-P with probucol or mol% HDL-FC by increased FC esterification suppressed ASCVD. Comparison of CACS vs. HDL- FCBI of all three groups will reveal a non-linear functional relationship. Traditionally, physicians have measured HDL and LDL in terms of their total cholesterol content. These measures have had good but imperfect predictive value, mainly because the two components of TC, FC and cholesteryl esters, have distinct metabolic itineraries that may differentially contribute to ASCVD. Validation of the study-hypotheses in humans would provide a compelling rationale for measuring plasma lipoprotein FC as an ASCVD diagnostic and for the formulation of therapies that reduce plasma- and especially HDL-FC.