Expression of HMG-CoA reductase in human coronary atherosclerotic plaques and relationship to plaque destabilisation Cheol Whan Lee, 1 Chan-Sik Park, 2 Ilseon Hwang, 3 Youngji Kim, 4 Duk-Woo Park, 1 Soo-Jin Kang, 1 Seung-Hwan Lee, 1 Young-Hak Kim, 1 Seong-Wook Park, 1 Seung-Jung Park 1 ABSTRACT Background Little is known about hydroxy-3- methylglutaryl coenzyme A (HMG-CoA) reductase expression in human coronary atherosclerotic plaques. Objective To investigate the expression of HMG-CoA reductase in coronary atherectomy tissues obtained from patients with unstable and stable angina and examine the relationship of HMG-CoA with plaque instability. Methods Atherectomy specimens were obtained from 43 patients with unstable (n¼22) or stable (n¼21) angina who underwent directional coronary atherectomy for de novo coronary artery lesions. The specimens were stained with haematoxylineeosin and incubated with antibodies specific to HMG-CoA reductase, macrophages, smooth muscle cells and endothelial cells. Histology and immunohistochemistry data were morphometrically evaluated using an image-analysing system. Results Baseline characteristics were similar between the two groups. Immunopositive areas of HMG-CoA reductase, macrophages, endothelial cells and thrombi were significantly greater in patients with unstable angina than those in patients with stable angina. However, the immunopositive area of smooth muscle cells was not different between the two groups. Macrophage-positive areas correlated well with areas of HMG-CoA reductase in patients with unstable angina (r¼0.72, p<0.001), but not in patients with stable angina (r¼0.02, p¼0.937). Conclusion HMG-CoA reductase was present in coronary atherosclerotic plaques and was more commonly expressed in unstable plaques than in stable plaques. Local HMG-CoA reductase in coronary artery lesions may contribute to plaque instability. Hydroxy-3-methylglutaryl coenzyme A (HMG- CoA) reductase is a rate-limiting enzyme of the mevalonate pathway that produces cholesterol and other isoprenoids. 1 Inhibitors of HMG-CoA reduc- tase (statins) limit cholesterol biosynthesis and also the generation of the isoprenoids involved in inflammatory processes. The benefits of statin therapy in patients with acute coronary syndrome (ACS) appear extremely rapidly. 2e4 The potential mechanisms of these early benefits are not fully understood but are probably not attributable to altered lipid profiles, which require a longer dura- tion of treatment. 15e7 HMG-CoA reductase is a ubiquitous enzyme present in vascular and inflammatory cells, as well as hepatocytes. 18 In the vessel wall, HMG-CoA reductase may produce isoprenoids and induce inflammatory responses with plaque destabilisa- tion. 8 Statins are likely to penetrate the vessel wall and rapidly stabilise vulnerable plaques by directly inhibiting the HMG-CoA reductase in lesions. 89 Little is known, however, about the expression of HMG-CoA reductase in human coronary athero- sclerotic plaques and its relation to ACS. In this study, we investigated the expression of HMG-CoA reductase in coronary atherectomy tissues retrieved from patients with unstable and stable angina and examined the relationship of HMG-CoA reductase to plaque instability. METHODS Study population A total of 43 native coronary plaques were obtained from 43 patients undergoing directional coronary atherectomy. Clinical and procedural information were prospectively obtained. Patients were classi- fied as having unstable (n¼22) or stable angina (n¼21) and each specimen corresponded to a single patient’s de novo lesion that was responsible for the clinical presentation. Stable angina was defined as typical exertional angina without symptom change within 1 month before the procedure, and unstable angina as acute rest angina (within the previous 48 h, Braunwald class 3B) or subacute rest angina (2e30 days previously, Braunwald class 2B). A culprit lesion was identified based on angio- graphic lesion morphology, functional studies and intravascular ultrasound findings. The atherectomy procedures of the culprit lesion were carefully performed with intravascular ultrasound guidance. Atherectomy specimens were immediately removed from the cutter housing and immersed in 2-methybutane solution, then stored in a nitrogen tank. The study protocol was approved by the institutional review committee and all patients provided informed consent. Tissue preparation and immunohistochemical staining were carried out using standard methods. 10 Tissue preparation Tissue specimens were entirely embedded in OCT compound (Miles, Diagnostics Division, Elkhart, Indiana, USA), snap-frozen in liquid-nitrogen- cooled isopentane (Sigma-Aldrich, St Louis, Missouri, USA) and stored at À708C until used. The samples were cryosectioned (4 mm thick) onto 1 Department of Medicine, University of Ulsan, Seoul, Korea 2 Department of Pathology, University of Ulsan, Seoul, Korea 3 Department of Pathology, School of Medicine, Keimyung University, 194 Dongsan-Dong, Choong-Ku, Daegu, Korea 4 Asan Insitute of Life Science, University of Ulsan, Seoul, Korea Correspondence to Dr Seung-Jung Park, Division of Cardiology, Asan Medical Center, University of Ulsan, 388-1 Pungnap-dong, Songpa-gu, Seoul, 138-736, Korea; sjpark@amc.seoul.kr CWL and CSP contributed equally to this paper. Accepted 3 June 2010 Published Online First 19 July 2010 Heart 2011;97:715e720. doi:10.1136/hrt.2009.190934 715 Coronary artery disease group.bmj.com on December 24, 2014 - Published by http://heart.bmj.com/ Downloaded from