Aim: To determine clinically significant factors which may alter the effect of dual antiplatelet therapy with aspirin and ticagrelor or clopidogrel in patients who had undergone percutaneous coronary intervention and stent implantation. Materials & methods: The study included 378 patients. All the patients had undergone percutaneous coronary intervention and stent implantation. Platelet aggregation and genotyping for CYP2C19 *2 (rs4244285) and CYP4F2 (rs2108622, rs1558139, rs3093135 and rs2074902) was performed. Results: Significantly lower platelet aggregation values (% agr ) were detected in ticagrelor users who carried CYP4F2 rs3093135 TT variant (14.67 ± 5.07% agr ) versus AA (22.88 ± 6.30% agr ), p = 0.0004, or AT (20.56 ± 6.51% agr ), p = 0.0126. Conclusion: Results of the current study showed that CYP4F2 rs3093135 TT variant carriers had a higher antiplatelet effect of ticagrelor, and more frequently had nonprocedural bleeding during ticagrelor therapy, as compared with AA and AT variant carriers. Dual antiplatelet therapy (DAPT) with aspirin and ADP receptor blocker (ticagrelor, prasugrel or clopidogrel) is recommended for the secondary prevention of ischemic complications in patients with acute coronary syndromes, following percutaneous coronary intervention (PCI) and stent implantation. In large trials, prasugrel and ticagrelor have showed superior therapeutic effect compared with clopidogrel. Prasugrel reduced primary end point (cardiovascular death, nonfatal myocardial infarction (MI) or stroke) in the Trial to Assess Improvement in Therapeutic Outcomes by Optimizing Platelet InhibitionThrombolysis In Myocardial Infarction 38 [1]. Ticagrelor was shown to reduce primary end point in the Platelet Inhibition and Patient Outcomes (PLATO) trial [2]. Thus, the European Society of Cardiology issued guidelines for the diagnosis and treatment of ST-elevation myocardial infarction (STEMI) [3], non-STEMI (NSTEMI) [4] and myocardial revascularization [5]. According to these guidelines, ticagrelor or prasugrel is now preferred over clopidogrel due to their increased antiplatelet activity and lower risk of vascular thrombotic events. However, ticagrelor or prasugrel may cause higher incidence of nonprocedural noncoronary artery bypass grafting bleeding [1,2,6].Clopidogrel, a key antagonist of platelet ADP receptors, has been in use over the past two decades. This prodrug is metabolized by two main competing pathways. The major one is via human hepatic carboxylesterase 1, which hydrolyze clopidogrel into inactive clopidogrel acid metabolite. The minor one consists of two CYP450-dependent steps [7,8]. During the first step, clopidogrel is metabolized into a thiolactone (2-oxo-clopidogrel) by CYP1A2, CYP2B6 and CYP2C19. The second step involves CYP2B6, CYP2C9, CYP2C19 and CYP3A4, which forms active thiol-containing metabolite [7]. In total,
Aim: The aim of this study was to determine the impact of genetic and nongenetic factors on treatment outcomes in patients receiving dual antiplatelet therapy after percutaneous coronary intervention and stent implantation. Materials & methods: Patients (n = 628) used clopidogrel or ticagrelor for at least 1 week before platelet aggregation test. Results: Multivariate binary regression analysis demonstrated that aspirin use and CYP4F2 T allele significantly increased odds for bleeding in clopidogrel users (OR: 2.488, 95% CI: 1.452–4.265; p = 0.001 and OR: 1.573, 95% CI: 1.066–2.320; respectively; p = 0.022). CYP4F2 T allele significantly increased odds for bleeding in ticagrelor users (OR: 8.270, 95% CI: 3.917–17.462; p < 0.001). Conclusion: Aspirin use and CYP4F2 T allele were significantly associated with bleeding during dual antiplatelet therapy.
Matrix metalloproteinase-3 (MMP-3) degrades extracellular matrix and may lead to development of dilatative pathology of ascending thoracic aorta. Expression of MMP-3 depends upon the 5A/6A polymorphism in the promoter region. An increased number of 5A alleles leads to high expression of MMP-3. Thus, objective of the study was to determine whether the 5A/6A polymorphism in the promoter region of MMP-3 gene is associated with the development of dilatative pathology of ascending thoracic aorta. We studied 76 patients (age ranged from 31 to 81 years; median age, 64 years) who underwent aortic reconstruction surgery due to dilatative pathology of ascending thoracic aorta and a random sample of the population (n=604) aged 25–64 years, all from Lithuania. DNA was analyzed by using real-time polymerase chain reaction to genotype polymorphism 5A/6A at a position – 1171 of the MMP3 gene promoter. The prevalence of MMP-3 genotypes was similar in the group of dilatative pathology of ascending thoracic aorta and random sample of population. The frequency of 5A allele did not differ significantly between both groups and was 0.506 and 0.514, respectively. Male carriers of 5A/5A genotype were significantly younger compared with those with the 6A/6A genotype. In conclusion, the frequency of MMP-3 promoter 5A/6A genotypes did not differ between the group of patients with dilatative pathology of ascending thoracic aorta and the random sample of population, but the males with dilatative pathology of ascending thoracic aorta and 5A/5A genotype required aortic reconstruction surgery at the younger age than the males carrying 6A/ 6A genotype in the MMP-3 promoter region.
Objective. Data on the impact of PAI-1-675 4G/5G genotype for fibrinolysis during myocardial infarction are inconsistent. The aim of our study was to evaluate the association of clinical and genetic (PAI-1-675 4G/5G polymorphism) factors with coronary artery occlusion in patients with myocardial infarction. Materials and Methods. PAI-1-675 4G/5G detection was achieved by using Sanger sequencing in a sample of patients hospitalized for stent implantation due to myocardial infarction. We categorized the patients into two groups: patients with coronary artery occlusion and patients without coronary artery occlusion according to angiographic evaluation. Results. We identified n = 122 (32.4%) 4G/4G, n = 186 (49.5%) 4G/5G, and n = 68 (18.1%) 5G/5G PAI-1 genotype carriers. Univariate and multivariate analysis showed that only the 4G/5G genotype was associated with coronary artery occlusion (OR: 1.656 and 95% CI: 1.009–2.718, p = 0.046). Conclusions. Our results showed that carriers of PAI-1 4G/5G genotype with myocardial infarction have increased odds of coronary artery occlusion more than 1.6 times in comparison to the carriers of homozygous genotypes.
Dual antiplatelet therapy with aspirin and clopidogrel is used to lower the risk of arterial thrombosis. However, this strategy is not always successful owing to high interindividual variability in response to antiplatelet therapy. To evaluate an impact of CYP2C19 G681A and CYP4F2 G1347A polymorphisms and clinical factors on dual antiplatelet effect of clopidogrel and aspirin. Totally 89 patients who continued dual aspirin and clopidogrel antiplatelet therapy for at least of 14 days were included into the further study. Test for platelet aggregation was performed according to the classical Born method. Genotyping of CYP2C19*2 and CYP2C19*3 and CYP4F2*3 was done by using commercial probes from Applied Biosystems (UK). Patient age, weight and body weight index did not correlate significantly with platelet aggregation level both induced by ADP and epinephrine (P > 0.05). Serum concentration of creatinine, diabetes, angiotensin II receptor blockers, B-blockers, statin or omeprazole use had no significant effect on platelet aggregation. The users of angiotensin-converting enzyme inhibitors had lower platelet aggregation levels with epinephrine vs. nonusers: 28.80 ± 13.25 vs. 51.15 ± 23.50, P < 0.03, respectively. Platelet aggregation with ADP was higher in CYP2C19*1*2 genotype carriers than in CYP2C19*1*1 carriers (P = 0.01). Platelet aggregation with epinephrine was higher in CYP4F2 GA genotype carriers than in GG (P = 0.04) or AA (P = 0.01) carriers. Our study confirms that CYP2C19 G681A genotype has an impact on antiplatelet effect of clopidogrel. The novelty is that the platelet aggregation after induction with epinephrine is influenced by CYP4F2 G1347A genotype.
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