Sorbonne Université, ACTION Study Group, INSERM UMRS 1166, ICAN, Département de Cardiologie, Institut de Cardiologie, Hôpital de la Pitié-Salpêtrière (APHP).
INSERM UMRS1166, ICAN, Institute of CardioMetabolism and Nutrition, Hôpital Pitié-Salpêtrière (AP-HP), Sorbonne Université, Paris, France.
Curr Opin Cardiol. 2019 Nov;34(6):714-720. doi: 10.1097/HCO.0000000000000677.
Epidemiologic studies consistently demonstrated that patients with coronary artery disease (CAD) and low HDL cholesterol (HDL-C) are more likely to develop major adverse cardiovascular events as compared with those with normal or high HDL. However, several large randomized trials failed to demonstrate that a substantial, pharmacological-based, increase of HDL-C concentrations results in a clinically significant reduction of ischemic outcomes. This has been largely attributed to the fact that, although these drugs are able to raise the HDL-C concentration, they have no effect on HDL-C atheroprotective function. Subsequently, the 'HDL hypothesis' evolved, and the focus shifted from raising the concentration of HDL-C to raising the reverse cholesterol transport (RCT) function by increasing patients cholesterol efflux capacity (CEC) instead. Indeed, new data suggest that HDL-C metabolism and the ability of the HDL molecule to transport cholesterol from the atherosclerotic plaque to the liver, measured by the CEC, is more important than steady-state HDL-C levels. Modulation of the CEC has become, therefore, a promising therapeutic target in CAD patients. This article reviews the current data on the 'cholesterol efflux hypothesis' and discuss its ability to be modulated has a potential therapeutic target.
Recent data have demonstrated that impaired serum CEC was associated with increased mortality after a myocardial infarction (MI). Thus, therapeutic intervention aiming to improve CEC and RCT may reduce the risk of recurrent events. Early phase clinical studies targeting CEC showed promising results and a megatrial is ongoing testing the hypothesis that an improved RCT trough a modulation of the CEC can modify patient's prognosis after an acute MI.
The 'cholesterol efflux hypothesis' is now supported by several clinical studies and is being tested with a therapeutic candidate in a megatrial enrolling high-risk patient with MI.
流行病学研究一致表明，与正常或高 HDL 相比，患有冠状动脉疾病（CAD）和低 HDL 胆固醇（HDL-C）的患者更有可能发生主要不良心血管事件。然而，几项大型随机试验未能表明，通过药物治疗实质性地增加 HDL-C 浓度会导致缺血性结局的临床显著减少。这在很大程度上归因于这样一个事实，即尽管这些药物能够提高 HDL-C 浓度，但它们对 HDL-C 的抗动脉粥样硬化功能没有影响。随后，“HDL 假说”演变，关注点从提高 HDL-C 浓度转移到通过增加患者胆固醇流出能力（CEC）来提高逆向胆固醇转运（RCT）功能。事实上，新数据表明，HDL-C 代谢和 HDL 分子从动脉粥样硬化斑块向肝脏转运胆固醇的能力，通过 CEC 来衡量，比稳态 HDL-C 水平更重要。因此，调节 CEC 已成为 CAD 患者有前途的治疗靶点。本文综述了有关“胆固醇流出假说”的最新数据，并讨论了其作为潜在治疗靶点的调节能力。
最近的数据表明，血清 CEC 受损与心肌梗死后死亡率增加有关。因此，旨在改善 CEC 和 RCT 的治疗干预可能会降低复发事件的风险。针对 CEC 的早期临床研究显示出有希望的结果，一项大型试验正在测试假设，即通过调节 CEC 改善 RCT 可以改变急性 MI 后患者的预后。
“胆固醇流出假说”现在得到了几项临床研究的支持，并正在通过一项大型试验中的治疗候选药物进行测试，该试验招募了有 MI 高危的患者。
