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.
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