CYP2C19 基因多态性与冠心病危险因素对氯吡格雷抵抗的影响

目的:观察细胞色素P450系统药物代谢酶CYP2C19基因多态性以及相关临床因素对氯吡格雷抵抗的影响。方法:选择2010年11月至2011年5月我科拟行PCI术治疗的冠心病患者共145例,均给予氯吡格雷300mg负荷剂量,75mg维持剂量。①通过流式细胞仪检测血管舒张因子刺激酸磷蛋白血小板反应性指数VASP PRI(以VASP PRI≥50%,定义为氯吡格雷抵抗)分为氯吡格雷抵抗组和氯吡格雷反应组。②检测入选患者的药物代谢酶CYP2C19的基因型;根据不同等位基因功能缺失,分为快代谢基因型(*1/*1)、中间代谢基因型(*1/*2、*1/*3)和慢代谢基因型(*2/*2、*2/*3、*3/*3)。③观察CYP2C19基因型及相关临床危险因素对氯吡格雷反应性的影响,④观察氯吡格雷抵抗与临床不良终点事件主要临床不良终点事件[心源性死亡、再发心肌梗死、靶病变再次血运重建术(TLR)]和次要临床终点事件(支架内血栓形成、脑血管意外、大出血)之间的相关性。结果:检测出氯吡格雷抵抗的患者31例,其发生率为20.67%;检测出CYP2C19慢代谢基因型携带患者19例,所占比例为12.67%。慢代谢基因型患者与(快代谢基因型+中间代谢基因型患者)之间VASP PRI比为(49.20±8.45)%VS(44.17±5.41)%,P<0.05,氯吡格雷抵抗发生率之比为35.49%(n=11)VS16.81%(n=20),P<0.05。多元回归分析提示CYP2C19慢代谢基因型(OR:4.43;95%CI:3.28-8.37,P<0.05)和2型糖尿病(OR:2.76;95%CI:2.13-6.14;P<0.05)是氯吡格雷抵抗的两种危险因素。临床随访结果显示氯吡格雷抵抗组与氯吡格雷反应组主要临床不良终点事件的发生率比为6.45%(n=2)vs2.63%(n=3),P<0.05。结论:携带CPY2C19慢代谢基因型和患有2型糖尿病是导致氯吡格雷抵抗的两种重要的危险因素,氯吡格雷抵抗的发生增加了临床不良终点事件的风险。     

ABCB1 C3435T Polymorphism and Response to Clopidogrel Treatment in Coronary Artery Disease (CAD) Patients: A Meta-Analysis

Background

A number of investigators have evaluated the association between the ABCB1 polymorphism and clopidogrel responding, but the results have been inconclusive. To examine the risk of high platelet activity and poor clinical outcomes associated with the ABCB1 C3435T polymorphism in CAD patients on clopidogrel, all available studies were included in the present meta-analysis.

Methods

We performed a systematic search of PubMed, Scopus and the Cochrane library database for eligible studies. Articles meeting the inclusion criteria were comprehensively reviewed, and the available data were accumulated by the meta-analysis.

Results

It was demonstrated that the ABCB1 C3435T variation was associated with the risk of early major adverse cardiovascular events (MACE) (T vs. C OR, 1.34; 95% CI, 1.10 to 1.62; P = 0.003; TT vs. CC: OR, 1.77; 95% CI, 1.19 to 2.63; P = 0.005; CT + TT vs.CC: OR, 1.48; 95% CI, 1.06 to 2.06; P = 0.02) and the polymorphism was also associated with the risk of the long-term MACE in patients on clopidogrel LD 300 mg (T vs. C: OR, 1.28; 95% CI, 1.10 to 1.48; P = 0.001; TT vs. CC: OR, 1.59; 95% CI, 1.19 to 2.13; P = 0.002; CT + TT vs.CC: OR, 1.39; 95% CI, 1.08 to 1.79; P = 0.01). The comparison of TT vs. CC was associated with a reduction in the outcome of bleeding (TT vs. CC: OR, 0.51; 95% CI, 0.40 to 0.66; P<0.00001). However, the association between ABCB1 C3435T polymorphism and platelet activity and other risk of poor clinical outcomes was not significant.

Conclusions

The evidence from our meta-analysis indicated that the ABCB1 C3435T polymorphism might be a risk factor for the MACE in patients on clopidogrel LD 300 mg, and that TT homozygotes decreased the outcome of bleeding compared with CC homozygotes.     

中国苗族人群中细胞色素P450 2C19基因多态性的研究

为研究细胞色素P45 0 2C19在中国苗族人群中的基因型 ,采用聚合酶链式反应与限制性内切核酸酶片段长度多态性技术分析了 98例无血缘关系苗族人群的基因型。结果显示 5 0人为CYP2C19野生型纯合子 (wt/wt) ;39人为CYP2C19m1杂合子 (wt/m1) ;9人为CYP2C19m1突变型纯合子 (m1/m1)。与国内外相关报道比较 ,本实验得出的CYP2C19m1突变频率与文献报道相符     

Determinants of Reduced Antiplatelet Effect of Aspirin in Patients with Stable Coronary Artery Disease

BackgroundAspirin is a cornerstone in management of coronary artery disease (CAD). However, considerable variability in the antiplatelet effect of aspirin has been reported.AimTo investigate independent determinants of reduced antiplatelet effect of aspirin in stable CAD patients.MethodsWe performed a cross-sectional study including 900 stable, high-risk CAD patients. Among these, 795 (88%) had prior myocardial infarction, 250 (28%) had type 2 diabetes, and 170 (19%) had both. All patients received 75 mg aspirin daily as mono antiplatelet therapy. The antiplatelet effect of aspirin was assessed by measurement of platelet aggregation employing 1) multiple electrode aggregometry (MEA, Multiplate Analyzer) in whole blood anticoagulated with citrate or hirudin using arachidonic acid (AA) or collagen as agonists, and 2) VerifyNow Aspirin Assay. Compliance was assessed by measurement of serum thromboxane B₂.ResultsPlatelet count, prior myocardial infarction, type 2 diabetes and body mass index were independent determinants of increased AA-induced MEA platelet aggregation in citrate and hirudin anticoagulated blood (p-values ≤ 0.045). Similar results were found with VerifyNow. Prior coronary artery bypass grafting, age, smoking (MEA, AA/citrate) and female gender (MEA, AA/hirudin) were also independent determinants of increased platelet aggregation (p-values ≤ 0.038). Compliance was confirmed by low serum thromboxane B₂ levels in all patients (median [25%;75%]: 0.97 [0.52;1.97], range 0.02-26.44 ng/ml).ConclusionPlatelet count, prior myocardial infarction, type 2 diabetes and body mass index were independent determinants of increased platelet aggregation, indicating that these characteristics may be key factors in reduced antiplatelet effect of aspirin in stable CAD patients.     

The Role of Paraoxonase 1 (PON1) Gene Polymorphisms in Coronary Artery Disease: A Systematic Review and Meta-Analysis

Although many studies have investigated the association of paraoxonase 1 (PON1) polymorphisms with coronary artery disease (CAD). However, the outcomes were not consistent and remain uncertain. Therefore, it is the need of the hour to analyze the available literature and evaluate the association of PON1 polymorphisms with the CAD. All the relevant studies published in the English language from January 1, 2000, up to September 20, 2020, were identified by searching through various electronic databases. The two researchers independently extracted the information. The data were analyzed by using the MetaGenyo program. The pooled odds ratio was used to find the associations between CAD and PON1 polymorphisms. In the final analysis, we include 10 studies regarding the association of PON1 polymorphisms (rs662 and rs854560) with CAD. Overall, the Q192R polymorphism increased the risk of CAD in the tested genetic models including the homozygote model: OR 1.35, CI 1.02–1.79; allelic model: OR 1.16, CI 1.00–1.33; dominant model: OR 1.25, CI 1.03–1.52. The L55M polymorphism does not significantly associated with CAD in all the tested genetic models including the homozygote model: OR 1.00 CI, 0.64–1.56; allelic model: OR 1.02, 95% CI 0.84–1.23; dominant model: OR 1.08, CI 0.89–1.31. Further analysis showed no publication bias exists in meta-analysis. Our findings suggested that rs662 in the coding region was significantly associated with the CAD however, rs854560 has no significant association with the disease. Nevertheless, in future, there is a need for more studies with a larger sample size which may provide a more definite conclusion.

Study Registration: PROSPERO registration number CRD42020202278

     

104名藏族志愿者中细胞色素P450 2C19m1的基因多态性

细胞色素P450 2C19（CYP2C19）参与临床上许多重要药物的代谢。根据其代谢S－美芬妥英或其他CYP2C19底物的能力不同,有强代谢者（EMs）和弱代谢者（PMs）之分。PMs表型的频发率存在明显的种族差异。在本文中,我们主要报道了细胞色素P450 2C19 m1在中国藏族人群中的多态性分布。在104例无血缘关系藏族人群中,49人（47.1%）为CYP2C19野生型纯合子（wt/wt）,46人（44.2%）为CYP2C19m1杂合子（wt/m1）,9人（8.7%）为CYP2C19m1突变型纯合子（m1/m1）。CYP2C19野生型等位基因频率为0.692,CYP2C19m1等位基因频率为0.308。该结果与国内外报道的中国其余民族的CYP2C19m1等位基因频率相比具有一定可比性。 关键词：细胞色素P450 2C19;基因型;藏族;聚合酶链反应;限制性内切核酸酶片段长度多态（RFLP）Abstract: Cytochrome P 450 2C19（CYP2C19） is involved in the metabolism of a number of clinically used drugs. Individuals can be characterized as extensive metabolizers （EMs）or poor metabolizers（PMs）, according to the drugs-metabolized ability of CYP2C19 in population studies. The incidence of poor metabolizer phenotype shows marked interracial differences. In this article we report the gene polymorphism of CYP2C19 in Zang population. There were 49 wild-type homozygotes（wt/wt）, 46 were heterozygotes（wt/m1） and 9 were homozygotes（m1/m1） among 104 unrelated Zang subjects. The frequency of CYP2C19m1 allele was 0.308, which was in agreement with that in other published data.     

中国苗族人群中细胞色素P450 2C19基因多态性的研究

为研究细胞色素P4502C19在中国苗族人群中的基因型,采用聚合酶链式反应与限制性内切核酸酶片段长度多态性技术分析了98例无血缘关系苗族人群的基因型。结果显示50人为CYP2C19野生型纯合子（wt/wt）;39人为CYP2C19m1杂合子（wt/m1）;9人为CYP2C19m1突变型纯合子（m1/m1）。与国内外相关报道比较,本实验得出的CYP2C19m1突变频率与文献报道相符。 Abstract：In order to study the cytochrome P450 2C19 gene polymorphism in Miao population, the genotypes of ninety-eight unrelated Miao subjects were studied by polymera se chain reaction and restricted fragment length polymorphism (RFLP). The result s showed that fifty were homozygous for wild-type (wt/wt); thirty-nine wer e heterozygous for the CYP2C19m1 (wt/m1);nine were homozygou s for CYP2C19m1(m1/m1).The frequency of CYP2C19m1 was in agreement with that of other published data.     

Genetic Polymorphisms of Cytochrome P450 and Matrix Metalloproteinase in Chronic Obstructive Pulmonary Disease

We investigated whether polymorphisms of cytochrome P450 (CYP) and matrix metalloproteinase (MMP) are associated with the development and severity of chronic obstructive pulmonary disease (COPD). Genotypes of 184 patients with COPD and 212 controls were determined by polymerase chain reaction, followed by restriction fragment length polymorphism. The homozygous T allele of MMP-9 was significantly higher in patients with COPD than in controls (14.7% vs. 7.5%). The odds ratio was 2.4 (95% CI 1.1–5.9). No differences were observed in the frequency of polymorphic genotypes in CYP1A1, 1A2, MMP-1 and -3. During combined analysis of these candidate genes, we found strong indicators for susceptibility to COPD (combined with homozygotes *2A for CYP1A1 and T alleles of MMP-9 versus others = 3.3, 95% CI 1.2–8.6). The frequency of the homozygous *2A allele of CYP1A1 was significantly higher in very severe COPD (P < 0.01). Combinations of genetic variants including *2A homozygotes of CYP1A1 and T alleles in MMP-9 are significant indicators for susceptibility to COPD. The homozygous *2A allele of CYP1A1 is an independent risk factor for very severe COPD.     

Structural Characterization of Human Cytochrome P450 2C19: ACTIVE SITE DIFFERENCES BETWEEN P450s 2C8, 2C9, AND 2C19*?

To identify the structural features underlying the distinct substrate and inhibitor profiles of P450 2C19 relative to the closely related human enzymes, P450s 2C8 and 2C9, the atomic structure (Protein Data Bank code 4GQS) of cytochrome P450 2C19 complexed with the inhibitor (2-methyl-1-benzofuran-3-yl)-(4-hydroxy-3,5-dimethylphenyl)methanone (Protein Data Bank chemical component 0XV) was determined to 2.87 Å resolution by x-ray crystallography. The conformation of the peptide backbone of P450 2C19 is most similar to that of P450 2C8, but the substrate-binding cavity of P450 2C8 is much larger than that of P450 2C19 due to differences in the amino acid residues that form the substrate-binding cavities of the two enzymes. In contrast, the substrate-binding cavity of P450 2C19 is much more similar in size to that of the structure of the P450 2C9 flurbiprofen complex than to that of a modified P450 2C9 or that of P450 2C8. The cavities of the P450 2C19 0XV complex and the P450 2C9 flurbiprofen complex differ, however, because the helix B-C loops of the two enzymes are dissimilar. These conformational differences reflect the effects of adjacent structural elements that interact with the B-C loops and that differ between the two enzymes. The availability of a structure for 2C19 will facilitate computational approaches for predictions of substrate and inhibitor binding to this enzyme.     

Polymorphisms in cytochrome P450 2C19 enzyme and cessation of leflunomide in patients with rheumatoid arthritis

Introduction

Rational selection of disease modifying anti-rheumatic drugs in the treatment of rheumatoid arthritis (RA) has many potential advantages, including rapid disease control, reduced long-term disability and reduced overall cost to the healthcare system. Inter-individual genetic differences are particularly attractive as markers to predict efficacy and toxicity, as they can be determined rapidly prior to drug selection. The aims of this study, therefore, were to investigate the association between differences in genes associated with the metabolism, clearance and efficacy of leflunomide with its cessation in a group of rheumatoid arthritis patients who were treated with an intensive contemporary, treat-to-target approach.

Methods

This retrospective cohort study identified all individuals who received leflunomide and were enrolled in the Early Arthritis inception cohort at the Royal Adelaide Hospital between 2001 and July 2011. Inclusion criteria were age (>18) and a diagnosis of rheumatoid arthritis. Patients were excluded if a DNA sample was not available, if they withdrew from the cohort or if clinical data were insufficient. Subjects were followed for 12 months or until either another disease modifying antirheumatic drug was added or leflunomide was ceased. The following single nucleotide polymorphisms (SNPs) were determined: CYP2C19*2 (rs4244285), CYP2C19*17 (rs12248560), ABCG2 421C>A (rs2231142), CYP1A2*1F (rs762551) and DHODH 19C>A (rs3213422). The effects of variables on cessation were assessed with Cox Proportional Hazard models.

Results

Thirty-three of 78 (42.3%) patients ceased leflunomide due to side effects. A linear trend between cytochrome P450 2C19 (CYP2C19) phenotype and leflunomide cessation was observed, with poor and intermediate metabolizers ceasing more frequently (adjusted Hazard Ratio = 0.432 for each incremental change in phenotype, 95% CI 0.237 to 0.790, P = 0.006). Previously observed associations between cytochrome P450 1A2 (CYP1A2) and dihydro-orotate dehydrogenase (DHODH) genotype and toxicity were not apparent, but there was a trend for ATP-binding cassette sub-family G member 2 (ABCG2) genotype to be associated with cessation due to diarrhea.

Conclusions

CYP2C19 phenotype was associated with cessation due to toxicity, and since CYP2C19 intermediate and poor metabolizers have lower teriflunomide concentrations, it is likely that they have a particularly poor risk:benefit ratio when using this drug.     

Cytochrome P450 2E1 Gene Polymorphisms/Haplotypes and Anti-Tuberculosis Drug-Induced Hepatitis in a Chinese Cohort

Objective

The pathogenic mechanism of anti-tuberculosis (anti-TB) drug-induced hepatitis is associated with drug metabolizing enzymes. No tagging single-nucleotide polymorphisms (tSNPs) of cytochrome P450 2E1(CYP2E1) in the risk of anti-TB drug-induced hepatitis have been reported. The present study was aimed at exploring the role of tSNPs in CYP2E1 gene in a population-based anti-TB treatment cohort.

Methods and Design

A nested case-control study was designed. Each hepatitis case was 14 matched with controls by age, gender, treatment history, disease severity and drug dosage. The tSNPs were selected by using Haploview 4.2 based on the HapMap database of Han Chinese in Beijing, and detected by using TaqMan allelic discrimination technology.

Results

Eighty-nine anti-TB drug-induced hepatitis cases and 356 controls were included in this study. 6 tSNPs (rs2031920, rs2070672, rs915908, rs8192775, rs2515641, rs2515644) were genotyped and minor allele frequencies of these tSNPs were 21.9%, 23.0%, 19.1%, 23.6%, 20.8% and 44.4% in the cases and 20.9%, 22.7%, 18.9%, 23.2%, 18.2% and 43.2% in the controls, respectively. No significant difference was observed in genotypes or allele frequencies of the 6 tSNPs between case group and control group, and neither of haplotypes in block 1 nor in block 2 was significantly associated with the development of hepatitis.

Conclusion

Based on the Chinese anti-TB treatment cohort, we did not find a statistically significant association between genetic polymorphisms of CYP2E1 and the risk of anti-TB drug-induced hepatitis. None of the haplotypes showed a significant association with the development of hepatitis in Chinese TB population.     

Non-Invasive Detection of Coronary Endothelial Response to Sequential Handgrip Exercise in Coronary Artery Disease Patients and Healthy Adults

Objectives

Our objective is to test the hypothesis that coronary endothelial function (CorEndoFx) does not change with repeated isometric handgrip (IHG) stress in CAD patients or healthy subjects.

Background

Coronary responses to endothelial-dependent stressors are important measures of vascular risk that can change in response to environmental stimuli or pharmacologic interventions. The evaluation of the effect of an acute intervention on endothelial response is only valid if the measurement does not change significantly in the short term under normal conditions. Using 3.0 Tesla (T) MRI, we non-invasively compared two coronary artery endothelial function measurements separated by a ten minute interval in healthy subjects and patients with coronary artery disease (CAD).

Methods

Twenty healthy adult subjects and 12 CAD patients were studied on a commercial 3.0 T whole-body MR imaging system. Coronary cross-sectional area (CSA), peak diastolic coronary flow velocity (PDFV) and blood-flow were quantified before and during continuous IHG stress, an endothelial-dependent stressor. The IHG exercise with imaging was repeated after a 10 minute recovery period.

Results

In healthy adults, coronary artery CSA changes and blood-flow increases did not differ between the first and second stresses (mean % change ±SEM, first vs. second stress CSA: 14.8%±3.3% vs. 17.8%±3.6%, p = 0.24; PDFV: 27.5%±4.9% vs. 24.2%±4.5%, p = 0.54; blood-flow: 44.3%±8.3 vs. 44.8%±8.1, p = 0.84). The coronary vasoreactive responses in the CAD patients also did not differ between the first and second stresses (mean % change ±SEM, first stress vs. second stress: CSA: −6.4%±2.0% vs. −5.0%±2.4%, p = 0.22; PDFV: −4.0%±4.6% vs. −4.2%±5.3%, p = 0.83; blood-flow: −9.7%±5.1% vs. −8.7%±6.3%, p = 0.38).

Conclusion

MRI measures of CorEndoFx are unchanged during repeated isometric handgrip exercise tests in CAD patients and healthy adults. These findings demonstrate the repeatability of noninvasive 3T MRI assessment of CorEndoFx and support its use in future studies designed to determine the effects of acute interventions on coronary vasoreactivity.     

Toll-Like Receptor Induced CD11b and L-Selectin Response in Patients with Coronary Artery Disease

Toll-Like Receptor (TLR) -2 and -4 expression and TLR-induced cytokine response of inflammatory cells are related to atherogenesis and atherosclerotic plaque progression. We examined whether immediate TLR induced changes in CD11b and L-selectin (CD62L) expression are able to discriminate the presence and severity of atherosclerotic disease by exploring single dose whole blood TLR stimulation and detailed dose-response curves. Blood samples were obtained from 125 coronary artery disease (CAD) patients and 28 controls. CD11b and L-selectin expression on CD14+ monocytes was measured after whole blood stimulation with multiple concentrations of the TLR4 ligand LPS (0.01–10 ng/ml) and the TLR2 ligand P3C (0.5–500 ng/ml). Subsequently, dose-response curves were created and the following parameters were calculated: hillslope, EC50, area under the curve (AUC) and delta. These parameters provide information about the maximum response following activation, as well as the minimum trigger required to induce activation and the intensity of the response. CAD patients showed a significantly higher L-selectin, but not CD11b response to TLR ligation than controls after single dose stimulations as well as significant differences in the hillslope and EC50 of the dose-response curves. Within the CAD patient group, dose-response curves of L-selectin showed significant differences in the presence of hypertension, dyslipidemia, coronary occlusion and degree of stenosis, whereas CD11b expression had the strongest discriminating power after single dose stimulation. In conclusion, single dose stimulations and dose-response curves of CD11b and L-selectin expression after TLR stimulation provide diverse but limited information about atherosclerotic disease severity in stable angina patients. However, both single dose stimulation and dose-response curves of LPS-induced L-selectin expression can discriminate between controls and CAD patients.     

Coronary Collateral Circulation in Patients of Coronary Ectasia with Significant Coronary Artery Disease

Objectives

Patients with coronary ectasia (CE) usually have coexisting coronary stenosis resulting in myoischemia. Coronary collateral plays an important role in protecting myocardium from ischemia and reducing cardiovascular events. However, limited studies investigate the role of CE in coronary collaterals development.

Methods

We evaluated 1020 consecutive patients undergoing coronary angiography and 552 patients with significant coronary artery disease (SCAD), defined as diameter stenosis more than 70%, were finally analyzed. CE is defined as the ectatic diameter 1.5 times larger than adjacent reference segment. Rentrop collateral score was used to classify patients into poor (grades 0 and 1) or good (grades 2 and 3) collateral group.

Results

73 patients (13.2%) had CE lesions which were most located in the right coronary artery (53.4%). Patients with CE had a lower incidence of diabetes (43.8% vs 30.1%, p = 0.03), higher body mass index (25.4±3.5 vs 26.7±4.6, p = 0.027) and poorer coronary collateral (58.2% vs 71.2%, p = 0.040). Patients with poor collateral (n = 331) had a higher incidence of CE (15.7% vs 9.5%, p = 0.040) and fewer diseased vessels numbers (1.96±0.84 vs 2.48±0.69, p<0.001). Multivariate analysis showed diabetes (odd ratio (OR) 0.630, p = 0.026), CE (OR = 0.544, p = 0.048), and number of diseased vessels (OR = 2.488, p<0.001) were significant predictors of coronary collaterals development.

Conclusion

The presence of CE was associated with poorer coronary collateral development in patients with SCAD.     

冠心病合并2型糖尿病的冠脉病变特征及危险因素分析

目的:探讨冠心病合并2型糖尿病的冠状动脉病变特征及其相关危险因素.方法:选择2010年1月至2012年1月我院经冠状动脉造影确诊为冠心病合并2型糖尿病的患者227例(DM组)和同期不合并2型糖尿病的冠心病患者229例(NDM组)为研究对象,回顾性分析其血脂、血糖及冠状动脉造影结果,比较两组患者冠状动脉病变的特点,探讨血糖水平对糖尿病合并冠心病患者冠状动脉病变的影响.结果:DM组患者总胆固醇(TC)、甘油三酯(TG)、低密度脂蛋白胆固醇(LDL-C)显著高于NDM组(P＜0.05),高密度脂蛋白胆固醇(HDL-C)显著低于NDM组(P＜0.05);DM组患者三支血管病变、弥漫性病变以及狭窄程度大于75％的血管的病例数百分率显著高于NDM组(P＜0.05);在DM患者中,血糖水平控制理想组(A组)的冠状动脉血管狭窄程度大于75％以及发生弥漫性病变的病例数百分率均显著低于血糖控制较差组(B组,P＜0.05).结论:2型糖尿病合并冠心病患者冠状动脉多表现为弥漫和多支病变,狭窄程度严重;血糖和血脂水平异常是其冠脉病变的危险因素;控制患者的血糖水平于正常范围可改善其冠状动脉病变程度并减小其病变范围.     

Cytochrome P450 2C19 polymorphism is associated with poor clinical outcomes in coronary artery disease patients treated with clopidogrel

Patients with lesser degrees of platelet inhibition in response to clopidogrel appear to be at increased risk for recurrent ischemic events. Cytochrome P450 (CYP) polymorphisms have been proposed as possible mechanisms for nonresponsiveness to clopidogrel. Published data on the association between CYP2C19*2 polymorphism and atherothrombotic events are inconclusive. To derive a more precise estimation of the relationship, a meta-analysis was performed. A total of eight prospective cohort studies including 2,345 patients carrying CYP2C19*2 variant allele and 5,935 cases with the wild-type genotype were included in this meta-analysis. Overall, borderline statistically significantly elevated risk of adverse clinical events was associated with genotyping 681G>A polymorphism (for AA + GA vs. GG: OR, 1.46; 95% CI, 1.01 to 2.13; P = 0.05). The summary odds ratio showed a significant association between the CYP2C19*2 polymorphism and an increased risk of cardiac mortality in the follow-up period (OR, 2.07; 95% CI, 1.22 to 3.52; P = 0.007). When studies evaluating myocadial infarction, stent thrombosis, and ischemic stroke, the presence of the variant allele was associated with significantly increased risks of recurrent atherothrombotic events. In summary, this meta-analysis indicated that CYP2C19*2 carrier status is significantly associated with an increased risk of adverse cardiovascular events.     

早发冠心病患者的危险因素及冠脉病变特点研究

目的:探讨早发冠心病(PCAD)患者的危险因素及冠脉病变特点。方法:收集2014年8月至2015年2月北京安贞医院急诊科行冠状动脉造影的1000例患者为研究对象,根据冠状动脉造影结果和临床资料分为早发冠心病(PCAD)组(男55岁,女65岁,n=340)、晚发冠心病组(n=300)和对照组(非冠心病者,n=360)。对三组患者的临床资料进行统计学分析,采用logistic回归分析PCAD患者的危险因素,并比较PCAD组与晚发冠心病组的冠状动脉病变特点。结果:Logistic回归分析结果提示:吸烟、早发冠心病家族史、高血压病及2型糖尿病是PCAD的独立危险因素(P0.001)。PCAD组单支病变比例显著高于晚发冠心病组(P0.05);回旋支、右冠状动脉病变比例低于晚发冠心病组(P0.05)。结论:吸烟、早发冠心病家族史、高血压病及2型糖尿病是PCAD的独立危险因素。早发冠心病患者冠脉病变主要累及前降支,单支病变多于晚发冠心病患者。     

阿托伐他汀改善冠心病患者血管内皮功能的临床研究

目的:观察短期阿托伐他汀治疗对高胆固醇血症的冠心病患者血管内皮功能的影响。方法:78例高胆固醇血症患者每日口服阿托伐他汀共8周,服药前后测量患者血清的总胆固醇(TC)、甘油三酯(TG)、低密度脂蛋白胆固醇(LDL-C)、高密度脂蛋白胆固醇(HDL-C)和氧化低密度脂蛋白(ox-LDL)以及NO值,并用彩色多普勒超声测定反应性充血时肱动脉内径的变化。结果:高胆固醇血症患者经阿托伐他汀8周治疗后,血清的TC、TG、LDL-C和ox-LDL明显下降,血清的HDL-C以及NO值明显增加,反应性充血时肱动脉内径扩张程度明显增加,这些与治疗前相比有明显差异。结论:阿托伐他汀治疗能使高胆固醇血症的冠心病患者血脂改变,NO值增加,血管内皮功能改善。     

Inhibitory Effects of the Monoamine Oxidase Inhibitor Tranylcypromine on the Cytochrome P450 Enzymes CYP2C19, CYP2C9, and CYP2D6

1. The inhibitory effects of tranylcypromine, a nonselective irreversible inhibitor of monoamine oxidase (MAO), on three cytochrome P450 (CYP) enzymes, namely CYP2C9, CYP2C19, and CYP2D6, have been evaluated in vitro. 2. The studies were conducted using cDNA-expressed human CYP enzymes and probe substrates. 3. A range of substrate concentrations was coincubated with a range of tranylcypromine concentrations in the presence of each of the CYP enzymes at 37 degrees C for a predetermined period of time. Product concentrations were quantified by HPLC with UV detection. 4. The results demonstrated that tranylcypromine is a competitive inhibitor of CYP2C19 (Ki = 32 microM) and CYP2D6 (Ki = 367 microM) and a noncompetitive inhibitor of CYP2C9 (Ki = 56 microM). 5. None of these inhibitory effects are considered clinically significant at usual therapeutic doses. However, in certain situations such as high dose tranylcypromine therapy, or in poor metabolizers of CYP2C19 substrates, clinically significant interactions might occur, particularly when tranylcypromine is coadministered with drugs with a narrow therapeutic index.