Department of Medicine, Division of Cardiology, Michigan State University, East Lansing, Michigan, USA.
Am J Cardiol. 2011 Jun 15;107(12):1710-7. doi: 10.1016/j.amjcard.2011.02.336. Epub 2011 Apr 18.
Pleiotropic effects of statins have not been fully elucidated. Recently we demonstrated that cholesterol expands when crystallizing and may trigger plaque rupture. The present study evaluated the potential direct effects of statins in altering cholesterol crystallization as a possible mechanism for plaque stabilization independent of cholesterol lowering. Cholesterol powder was dissolved in oil with and without pravastatin, simvastatin, or atorvastatin (10 to 90 mg) and then allowed to crystallize to measure peak volume expansion (ΔVE) in graduated cylinders. Effect of ΔVE on fibrous membrane damage was also evaluated. Human coronary, carotid, and peripheral arterial plaques (65 plaques from 55 patients) were incubated with statin or saline solution using matched plaque segments to evaluate direct effects of statins on preformed crystals. Also, the effect of in vivo use of oral statins on crystal structure was examined by scanning electron microscopy and crystal content in plaques scored from 0 to +3. For all statins, ΔVE decreased significantly in a dose-dependent fashion (0.76 ± 0.1 vs 0 ml at 60 mg, p <0.001). By scanning electron microscopy crystal structure with statins had loss of pointed tip geometries, averting fibrous membrane damage. Cholesterol crystal density was markedly decreased and appeared dissolved in human plaques incubated with statins (+2.1 ± 1.1 vs +1.3 ± 1.0, p = 0.0001). Also, plaques from patients taking oral statins compared to controls had significantly more dissolving crystals (p = 0.03). In conclusion, statins decreased ΔVE by altering cholesterol crystallization and blunting sharp-tipped crystal structure and dissolving cholesterol crystals in human arteries in vivo and in vitro, providing plaque stabilization.
他汀类药物的多效性尚未完全阐明。最近我们证明胆固醇在结晶时会膨胀，并可能引发斑块破裂。本研究评估了他汀类药物改变胆固醇结晶的潜在直接作用，作为一种独立于降胆固醇作用的斑块稳定的可能机制。胆固醇粉末溶解在油中，加入或不加入普伐他汀、辛伐他汀或阿托伐他汀（10 至 90 毫克），然后让其结晶，在刻度量筒中测量峰值体积膨胀（ΔVE）。还评估了ΔVE对纤维膜损伤的影响。用人冠状动脉、颈动脉和外周动脉斑块（来自 55 名患者的 65 个斑块）用他汀类药物或生理盐水孵育，使用匹配的斑块段来评估他汀类药物对预先形成的晶体的直接作用。此外，通过扫描电子显微镜检查体内使用口服他汀类药物对晶体结构的影响，并对斑块进行评分（0 至+3），以评估晶体含量。对于所有他汀类药物，ΔVE 均呈剂量依赖性显著降低（60mg 时为 0.76±0.1ml，p<0.001）。通过扫描电子显微镜观察，他汀类药物处理后的晶体结构失去了尖点几何形状，避免了纤维膜损伤。胆固醇晶体密度明显降低，在与他汀类药物孵育的人斑块中似乎溶解（+2.1±1.1 比+1.3±1.0，p=0.0001）。此外，与对照组相比，服用口服他汀类药物的患者的斑块中有更多溶解的晶体（p=0.03）。总之，他汀类药物通过改变胆固醇结晶、钝化尖锐晶体结构以及在体内和体外溶解人动脉中的胆固醇晶体，从而减少 ΔVE，提供斑块稳定。
