title: Long-term use of oral nicorandil stabilizes coronary plaque in patients with stable angina pectoris.
abstract: OBJECTIVE
  The Impact of Nicorandil in Angina (IONA) trial demonstrated that the use of nicorandil, an anti-anginal drug, reduced future cardiovascular events in patients with stable angina. We hypothesized that nicorandil has beneficial effects on coronary arterial plaque characteristics and atherosclerogenesis.
  
  
  RESULTS
  Preintervention intravascular ultrasound-virtual histology was performed prospectively in 65 consecutive patients with stable angina pectoris. There were no differences in coronary risk factors between the nicorandil (n = 16) and non-nicorandil (n = 49) groups. However, the nicorandil group demonstrated a larger %fibrous tissue (68 ± 10 vs. 62 ± 11%, P = 0.049) and a smaller %necrotic core tissue (11 ± 7 vs. 16 ± 10%, P = 0.049) compared with the non-nicorandil group. Multiple regression analysis showed that %necrotic core tissue (P = 0.045) was negatively and %fibrous tissue (P = 0.026) was positively associated with the use of nicorandil independent of statin use. We also analyzed the effect of nicorandil on atherosclerotic lesion formation in a mouse model of atherosclerosis. Lipid profiles were unaffected, but the area of atherosclerotic lesion and plaque necrosis were significantly reduced following 8-week nicorandil treatment in ApoE-deficient mice fed an atherogenic diet. Nicorandil significantly reduced the expression levels of endoplasmic reticulum stress markers, C/EBP homologous protein (CHOP) and glucose regulated protein/BiP (GRP78) in atherosclerotic lesions. Nicorandil significantly attenuated tunicamycin-induced CHOP upregulation in cultured THP-1 macrophages.
  
  
  CONCLUSIONS
  Nicorandil exerts its anti-atherogenic effect by mechanisms different from those of statins. Long-term nicorandil treatment is a potentially suitable second-line prevention therapy for patients with coronary artery disease.
authors.affiliation: Department of Cardiovascular Medicine, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan. izumiya@kumamoto-u.ac.jp
authors.forename: Yasuhiro
authors.initials: Y
authors.lastname: Izumiya
authors.forename: Sunao
authors.initials: S
authors.lastname: Kojima
authors.forename: Shinobu
authors.initials: S
authors.lastname: Kojima
authors.forename: Satoshi
authors.initials: S
authors.lastname: Araki
authors.forename: Hiroki
authors.initials: H
authors.lastname: Usuku
authors.forename: Junichi
authors.initials: J
authors.lastname: Matsubara
authors.forename: Kenji
authors.initials: K
authors.lastname: Sakamoto
authors.forename: Kenichi
authors.initials: K
authors.lastname: Tsujita
authors.forename: Yasuhiro
authors.initials: Y
authors.lastname: Nagayoshi
authors.forename: Koichi
authors.initials: K
authors.lastname: Kaikita
authors.forename: Seigo
authors.initials: S
authors.lastname: Sugiyama
authors.forename: Hisao
authors.initials: H
authors.lastname: Ogawa
mesh_terms: D000284:Administration, Oral; D000368:Aged; D000369:Aged, 80 and over; D000787:Angina Pectoris / Q000000981:diagnostic imaging / Q000188:drug therapy* / Q000209:etiology; D000818:Animals; D001018:Aortic Diseases / Q000235:genetics / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D001057:Apolipoproteins E / Q000172:deficiency / Q000235:genetics; D050197:Atherosclerosis / Q000235:genetics / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D002317:Cardiovascular Agents / Q000008:administration & dosage*; D002478:Cells, Cultured; D016009:Chi-Square Distribution; D003324:Coronary Artery Disease / Q000150:complications / Q000000981:diagnostic imaging / Q000188:drug therapy*; D016207:Cytokines / Q000378:metabolism; D004195:Disease Models, Animal; D004334:Drug Administration Schedule; D004721:Endoplasmic Reticulum / Q000187:drug effects / Q000378:metabolism; D000091342:Endoplasmic Reticulum Chaperone BiP; D042783:Endothelial Cells / Q000187:drug effects / Q000378:metabolism; D005355:Fibrosis; D006801:Humans; D018836:Inflammation Mediators / Q000378:metabolism; D007564:Japan; D008055:Lipids / Q000097:blood; D016015:Logistic Models; D008264:Macrophages / Q000187:drug effects / Q000378:metabolism; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D008875:Middle Aged; D018832:Molecular Chaperones / Q000378:metabolism; D009336:Necrosis; D020108:Nicorandil / Q000008:administration & dosage*; D016017:Odds Ratio; D012189:Retrospective Studies; D013997:Time Factors; D016896:Treatment Outcome; D018084:Ultrasonography, Interventional
chemical_list: D001057:Apolipoproteins E; D002317:Cardiovascular Agents; D016207:Cytokines; D000091342:Endoplasmic Reticulum Chaperone BiP; C000717247:HSPA5 protein, human; C000717248:Hspa5 protein, mouse; D018836:Inflammation Mediators; D008055:Lipids; D018832:Molecular Chaperones; D020108:Nicorandil