Cholesterol Crystals in Atherosclerosis and Other Related Diseases

George S. Abela, M.D., M.Sc., M.B.A. Michigan State University

Department of Medicine, CardiologyB208 Clinical Center, East Lansing, MI 48824Phone: 517-353-1754; Fax: 517-353-4978; email: abela@msu.edu

Stefan Mark Nidorf, M.B.B.S., F.R.A.C.P., M.D. Cardiologist Sir Charles Gairdner Hospital

The Heart and Vascular Research Institute 3/140 Mount Bay RdPerth, Western Australia 6000 (61+) 4803000 smnidorf@gmaiol.com

George S. Abela is a physician scientist and chief of cardiology at Michigan State University. He has conducted and authored the seminal research describing for the first time the critical role of cholesterol crystals in tissue injury. This was accomplished by demonstrating that cholesterol expands in volume when transformed from a liquid to solid state generating the hypothesis that this expansion in the confined environment of an atherosclerotic plaque can lead to rupture and erosion. Support data comes from demonstration of extensive crystals perforating ruptured plaques only in patients who died with myocardial infarction. Moreover, by modifying the tissue preparation process that avoids ethanol for scanning electron microscopy, he and lab co-workers were able to preserve the crystals from being dissolved by ethanol dehydration, a protocol that had been established centuries earlier. This unraveled the extent and severity of mechanical injury to the arterial wall by sharp tipped cholesterol crystals. He demonstrated that this process is not only present in coronary artery atherosclerotic plaques but also in cardiac valves, various solid cancers, brains from Alzheimer patients and most recently was found by other investigators in diabetic retinopathy. This universal process is a source of inflammation triggered by the transformation of cholesterol as a metastable molecule into a flat crystal. In a collaboration between Dr. Abela and immunologists, they demonstrated the role of cholesterol crystals in triggering inflammation via the NLRP3 inflammasome similar to the mechanism described for uric acid crystals. Overall, atherosclerosis as a crystalloid disease was recognized based on the discoveries made in Dr. Abela’s laboratory at Michigan State University.

Stefan Mark Nidorf   is a clinical cardiologist practicing in Perth Western Australia affiliated the Heart and Vascular Research Institute at the Perkins Research Institute. His clinical research interest in atherosclerosis led him to initiate the LoDoCo trials of low dose colchicine for the secondary prevention of chronic coronary disease, the rationale of which has been strengthened by an improved understanding of how cholesterol transitions from an essential molecule into a crystalline form that can act toinitiate and perpetuate the chronic and acute manifestations of atherosclerosis.