Atherosclerotic plaques associated with acute coronary syndromes (ACS), i.e. culprit lesions, frequently feature a ruptured fibrous cap with thrombotic complications. On imaging, these plaques exhibit a low attenuation, lipid-rich, necrotic core containing cholesterol crystals and are inherently unstable. Indeed, cholesterol crystals are causally associated with plaque vulnerability in vivo; their formation results from spontaneous self-assembly of cholesterol molecules. Cholesterol homeostasis is a central determinant of the physicochemical conditions leading to crystal formation, which are favored by elevated membrane free cholesterol content in plaque endothelial cells, smooth muscle cells, monocyte-derived macrophages, and foam cells, and equally by lipid oxidation.

Emerging evidence from imaging trials in patients with coronary heart disease has highlighted the impact of intervention involving the omega-3 fatty acid, eicosapentaenoic acid (EPA), on vulnerable, low attenuation atherosclerotic plaques. Thus, EPA decreased features associated with unstable plaque by increasing fibrous cap thickness in statin-treated patients, by reducing lipid volume and equally attenuating intraplaque inflammation. Importantly, atherosclerotic plaques rapidly incorporate EPA; indeed, a high content of EPA in plaque tissue is associated with decreased plaque inflammation and increased stability. These findings are entirely consistent with the major reduction seen in cardiovascular events in the REDUCE-IT trial, in which high dose EPA was administered as its esterified precursor, icosapent ethyl (IPE); moreover, clinical benefit was proportional to circulating EPA levels.

Eicosapentaenoic acid is efficiently incorporated into phospholipids, where it modulates cholesterol-enriched domains in cell membranes through physicochemical lipid interactions and changes in rates of lipid oxidation. Indeed, biophysical analyses indicate that EPA exists in an extended conformation in membranes, thereby enhancing normal cholesterol distribution while reducing propagation of free radicals. Such effects mitigate cholesterol aggregation and crystal formation. In addition to its favorable effect on cholesterol domain structure, EPA/IPE exerts pleiotropic actions, including antithrombotic, antiplatelet, anti-inflammatory, and proresolving effects, whose plaque-stabilizing potential cannot be excluded.

Docosahexaenoic acid is distinguished from EPA by a higher degree of unsaturation and longer carbon chain length; DHA is thus predisposed to changes in its conformation with ensuing increase in membrane lipid fluidity and promotion of cholesterol aggregation into discrete domains. Such distinct molecular effects between EPA and DHA are pronounced under conditions of high cellular cholesterol content and oxidative stress.

This review will focus on the formation and role of cholesterol monohydrate crystals in destabilizing atherosclerotic plaques, and on the potential of EPA as a therapeutic agent to attenuate the formation of deleterious cholesterol membrane domains and of cholesterol crystals. Such a therapeutic approach may translate to enhanced plaque stability and ultimately to reduction in cardiovascular risk.

与急性冠状动脉综合征（ACS）相关的动脉粥样硬化斑块，即罪魁祸首病变，通常具有破裂的纤维帽和血栓并发症。在成像上，这些斑块显示出低衰减、富含脂质、含有胆固醇晶体的坏死核心，并且本质上是不稳定的。事实上，胆固醇结晶与体内斑块易损性有因果关系；它们的形成是胆固醇分子自发自组装的结果。胆固醇稳态是导致晶体形成的物理化学条件的主要决定因素，斑块内皮细胞、平滑肌细胞、单核细胞衍生的巨噬细胞和泡沫细胞中膜游离胆固醇含量升高以及脂质氧化同样有利于晶体形成。

来自冠心病患者影像学试验的新证据强调了涉及 omega-3 脂肪酸、二十碳五烯酸 (EPA) 的干预对脆弱的低衰减动脉粥样硬化斑块的影响。因此，EPA 通过增加他汀类药物治疗患者的纤维帽厚度、减少脂质体积和同样减弱斑块内炎症来减少与不稳定斑块相关的特征。重要的是，动脉粥样硬化斑块会迅速吸收 EPA；事实上，斑块组织中高含量的 EPA 与斑块炎症减少和稳定性增加有关。这些发现与 REDUCE-IT 试验中心血管事件的显着减少完全一致，在该试验中，高剂量 EPA 作为其酯化前体 icosapent ethyl (IPE) 给药；而且，

二十碳五烯酸被有效地掺入磷脂中，通过物理化学脂质相互作用和脂质氧化速率的变化调节细胞膜中富含胆固醇的区域。事实上，生物物理分析表明 EPA 以扩展构象存在于膜中，从而增强正常的胆固醇分布，同时减少自由基的传播。这种作用减轻了胆固醇聚集和晶体形成。除了对胆固醇结构域结构的有利影响外，EPA/IPE 还发挥多效性作用，包括抗血栓形成、抗血小板、抗炎和促分解作用，不能排除其稳定斑块的潜力。

二十二碳六烯酸与 EPA 的区别在于更高的不饱和度和更长的碳链长度；因此，DHA 倾向于改变其构象，随之而来的是膜脂质流动性的增加和胆固醇聚集到离散区域的促进作用。EPA 和 DHA 之间的这种截然不同的分子效应在高细胞胆固醇含量和氧化应激的条件下很明显。

本综述将重点关注胆固醇一水合物晶体在破坏动脉粥样硬化斑块稳定性方面的形成和作用，以及 EPA 作为治疗剂减弱有害胆固醇膜结构域和胆固醇晶体形成的潜力。这种治疗方法可以转化为增强斑块稳定性并最终降低心血管风险。