title: Patients with both CYP2C19 loss-of-function allele and peripheral endothelial dysfunction are significantly correlated with adverse cardiovascular events following coronary stent implantation.
abstract: BACKGROUND
  There is some controversy regarding the effect of CYP2C19 polymorphism on clinical outcome in patients receiving dual antiplatelet therapy (DAPT). Peripheral endothelial dysfunction has recently been reported to predict adverse cardiovascular events. We hypothesized that CYP2C19 loss-of-function (LOF) allele carriers with peripheral endothelial dysfunction had worse prognosis. The aim of this study was to evaluate an additive effect of peripheral endothelial dysfunction on clinical outcome following percutaneous coronary intervention (PCI) in patients with a CYP2C19 variant.
  
  
  METHODS
  We enrolled 434 patients on DAPT following PCI. CYP2C19 genotype was examined, and we divided patients into two groups: carriers, who had at least one CYP2C19 LOF allele, and non-carriers. Peripheral endothelial dysfunction was examined using reactive hyperemia-peripheral arterial tonometry index (RHI), and we divided patients into low and high RHI. Thus, subjects were divided into four groups, and clinical events were followed up.
  
  
  RESULTS
  A total of 55 patients had a cardiovascular event. Kaplan-Meier analysis demonstrated a significantly higher probability of cardiovascular events in carriers with low RHI (log-rank test: p=0.007). Multivariate Cox proportional hazards analysis identified both CYP2C19 LOF allele possession (hazard ratio (HR): 1.94; 95% confidence interval (CI): 1.1-3.69; p=0.045) and low RHI (HR: 2.15; 95% CI: 1.22-3.78; p=0.008) as independent and significant predictors of future cardiovascular events.
  
  
  CONCLUSIONS
  CYP2C19 LOF allele carriers with peripheral endothelial dysfunction were significantly correlated with cardiovascular events. The additional evaluation of peripheral endothelial function along with CYP2C19 polymorphism might improve risk stratification after coronary stent implantation.
authors: Department of Cardiovascular Medicine, Graduate School of Medical Sciences, Kumamoto University, Kumamoto City, Japan.
authors: Noriaki
authors: N
authors: Tabata
authors: Department of Cardiovascular Medicine, Graduate School of Medical Sciences, Kumamoto University, Kumamoto City, Japan. Electronic address: shokimot@kumamoto-u.ac.jp.
authors: Seiji
authors: S
authors: Hokimoto
authors: Department of Cardiovascular Medicine, Graduate School of Medical Sciences, Kumamoto University, Kumamoto City, Japan.
authors: Tomonori
authors: T
authors: Akasaka
authors: Department of Cardiovascular Medicine, Graduate School of Medical Sciences, Kumamoto University, Kumamoto City, Japan.
authors: Yuichiro
authors: Y
authors: Arima
authors: Department of Cardiovascular Medicine, Graduate School of Medical Sciences, Kumamoto University, Kumamoto City, Japan.
authors: Kenji
authors: K
authors: Sakamoto
authors: Department of Cardiovascular Medicine, Graduate School of Medical Sciences, Kumamoto University, Kumamoto City, Japan.
authors: Eiichiro
authors: E
authors: Yamamoto
authors: Department of Cardiovascular Medicine, Graduate School of Medical Sciences, Kumamoto University, Kumamoto City, Japan.
authors: Kenichi
authors: K
authors: Tsujita
authors: Department of Cardiovascular Medicine, Graduate School of Medical Sciences, Kumamoto University, Kumamoto City, Japan.
authors: Yasuhiro
authors: Y
authors: Izumiya
authors: Department of Cardiovascular Medicine, Graduate School of Medical Sciences, Kumamoto University, Kumamoto City, Japan.
authors: Megumi
authors: M
authors: Yamamuro
authors: Department of Cardiovascular Medicine, Graduate School of Medical Sciences, Kumamoto University, Kumamoto City, Japan.
authors: Sunao
authors: S
authors: Kojima
authors: Department of Cardiovascular Medicine, Graduate School of Medical Sciences, Kumamoto University, Kumamoto City, Japan.
authors: Koichi
authors: K
authors: Kaikita
authors: Division of Pharmacology and Therapeutics, Graduate School of Medical and Pharmaceutical Sciences, Kumamoto University, Kumamoto City, Japan.
authors: Naoki
authors: N
authors: Kumagae
authors: Division of Pharmacology and Therapeutics, Graduate School of Medical and Pharmaceutical Sciences, Kumamoto University, Kumamoto City, Japan.
authors: Kazunori
authors: K
authors: Morita
authors: Division of Pharmacology and Therapeutics, Graduate School of Medical and Pharmaceutical Sciences, Kumamoto University, Kumamoto City, Japan.
authors: Kentaro
authors: K
authors: Oniki
authors: Division of Pharmacology and Therapeutics, Graduate School of Medical and Pharmaceutical Sciences, Kumamoto University, Kumamoto City, Japan.
authors: Kazuko
authors: K
authors: Nakagawa
authors: Department of Community Medicine, Kumamoto University Hospital, Kumamoto City, Japan.
authors: Kunihiko
authors: K
authors: Matsui
authors: Department of Cardiovascular Medicine, Graduate School of Medical Sciences, Kumamoto University, Kumamoto City, Japan.
authors: Hisao
authors: H
authors: Ogawa
mesh_terms: D000368:Aged; D000789:Angina, Unstable / Q000453:epidemiology; D065731:Cytochrome P-450 CYP2C19 / Q000235:genetics*; D004730:Endothelium, Vascular / Q000503:physiopathology*; D005260:Female; D005500:Follow-Up Studies; D005838:Genotype; D006333:Heart Failure / Q000453:epidemiology; D006579:Heterozygote; D006801:Humans; D007564:Japan / Q000453:epidemiology; D008297:Male; D008875:Middle Aged; D009203:Myocardial Infarction / Q000453:epidemiology; D009204:Myocardial Revascularization / Q000706:statistics & numerical data; D062645:Percutaneous Coronary Intervention / Q000009:adverse effects*; D011110:Polymorphism, Genetic; D016016:Proportional Hazards Models; D011446:Prospective Studies; D015607:Stents; D020521:Stroke / Q000453:epidemiology
chemical_list: D065731:Cytochrome P-450 CYP2C19
keywords: CYP2C19; Clopidogrel; Endothelial dysfunction; Stent