Objective-Observational studies have reported enhanced response to clopidogrel in smokers (the smokers' paradox). We examined whether genetic variations in the cytochrome and drug transporter system are associated with the effect of smoking on clopidogrel response. Methods and Results-Clopidogrel on-treatment platelet reactivity (OPR) was measured in 1431 consecutive patients who underwent coronary angiography. Gene samples were available and genotyping was successful in 1123 patients. Nine candidate single-nucleotide polymorphisms in 5 cytochrome genes and 1 drug transporter gene were assessed. Key Words: thienopyridines Ⅲ CYP1A2 Ⅲ cigarette smoking Ⅲ genetic polymorphism Ⅲ on-treatment platelet reactivity C lopidogrel is a prodrug that needs to be converted into an active metabolite via the hepatic cytochrome P450 enzyme system before it irreversibly binds to P2Y 12 adenosine diphosphate receptors. Only 15% of clopidogrel is converted into active metabolites; the remaining 85% is inactivated by plasma esterases. 1,2 High on-treatment platelet reactivity (HOPR) to clopidogrel is associated with increased occurrence ischemic events. [3][4][5] An increase in activation of the hepatic cytochrome pathway would result in enhancement of clopidogrel responsiveness. Cigarette smoking has been shown to be associated with improved responsiveness to clopidogrel, resulting in decreased clopidogrel on-treatment platelet reactivity (OPR), 6 -8 and enhanced benefit among chronic clopidogrel users. 9 Moreover, a recent analysis of the CHARISMA data showed that the effect of clopidogrel in reducing cardiovascular mortality is greatest among current smokers and is significantly decreased in nonsmokers. 10 The mechanism of this so-called smokers' paradox is unknown. The cytochrome P450 1A2 enzyme, which is also involved in clopidogrel activation, has been postulated to be associated with smoking. 11,12 Therefore, we sought to investigate the effect of cigarette smoking on OPR to clopidogrel and whether the genetic status of major cytochrome enzymes involved in clopidogrel metabolism may be involved in increased clopidogrel response in smokers. Methods Study PopulationThe CROSS-VERIFY cohort (measuring clopidogrel resistance to assure safety after percutaneous coronary intervention using VerifyNow) is a prospective cohort including all patients undergoing coronary angiography or percutaneous coronary intervention (PCI) who agreed to measurement of clopidogrel OPR with the VerifyNow P2Y 12 assay after clopidogrel therapy at Seoul National University Hospital (Seoul, Korea).

Objective: Imaging modalities such as intravascular ultrasonography or computed tomography or angiography have shown limitations in assessing coronary calcification. In this study, we investigated whether quantitative indices of optical coherence tomography (OCT) in calcified lesions are correlated with the late outcome of a coronary stent.Methods: We consecutively enrolled patients who had more than grade 2 coronary calcification on fluoroscopy. OCT was performed at baseline, immediately after stenting, and at 9 months after stenting. We analyzed qualitative and quantitative characteristics of plaque, calcification, and stent-related indices.Results: All images of 3-time points were available in a total of 10 patients. Calcified lesions were frequently associated with thin cap fibroatheroma (100%), plaque erosion (20%), or rupture (20%) before the procedure. Thrombus was found in 100% of cases in the OCT immediately after stenting. Maximal calcium area before stenting was strongly correlated with late luminal loss assessed by 9-month follow-up OCT (r= 0.766, P= 0.01).Conclusion: Preprocedural OCT assessment on calcified coronary lesion may predict high-risk procedure and late stent outcome. Further studies are warranted to confirm these findings.