The impact of CYP2C9 and VKORC1 genetic polymorphism and patient characteristics upon warfarin dose requirements in an adult Turkish population.

In this study, we investigated the contribution of vitamin K epoxide reductase (VKORC1) and cytochrome P450 2C9 (CYP2C9) genotypes, age, and body surface area (BSA) on warfarin dose requirements and in an adult Turkish population. Blood samples were collected from 100 Turkish patients with stable warfarin dose requirements and an international normalized ratio (INR) of the prothrombin time within the therapeutic range. Genetic analyses for CYP2C9 genotypes (*2 and *3 alleles) and VKORC1 -1639 G>A polymorphism were performed and venous INR determined. The mean warfarin daily dose requirement was higher in CYP2C9 homozygous wild-type patients, compared to those with the variant *3 allele (P < 0.05), similar to those with the variant *2 allele (P > 0.05) and highest in patients with the VKORC1 -1639 GG genotype compared to those with the GA genotype and the AA genotype (P < 0.01). The time to therapeutic INR was longer in CYP2C9 homozygous wild-type patients compared with those with the variant *2 and *3 alleles (P < 0.01), and longer in patients with the VKORC1 (position -1639) GG genotype compared with those with the GA genotype and the AA genotype (P < 0.01). The multivariate regression model including the variables of age (R (2) = 4.4%), BSA (R (2) = 27.4%), CYP2C9 (R (2) = 8.1%), and VKORC1 genotype (R (2) = 34.1%) produced the best model for estimating warfarin dose (R (2) = 60.4%). VKORC1 genotype and CYP2C9 polymorphism affect daily dose requirements and time to therapeutic INR in Turkish patients receiving warfarin for anticoagulation.

[A rare coronary anomaly detected during primary percutaneous coronary angioplasty: totally occluded left main coronary artery originating from the right coronary artery]. / Primer perkütan koroner anjiyoplasti sirasinda karsilasilan nadir bir koroner anomali: Sag koroner arterden ayrilan sol ana koroner arterin tam tikanikligi.

Left main coronary artery originating from the right coronary artery (RCA) is a rare anomaly. A 52-year-old male patient was submitted to catheterization laboratory for primary percutaneous coronary angioplasty with a diagnosis of acute anterior myocardial infarction. He had several risk factors including smoking, hypertension, and type 2 diabetes mellitus. Selective right coronary angiography showed an eccentric 85% stenosis at the mid-segment of the RCA, and the left main coronary artery originating from the right aortic sinus. The proximal segment of the left main coronary artery was completely occluded with thrombus and there was severe stenosis (95%) at the bifurcation of the left anterior descending artery with the circumflex artery. A metal stent was implanted in the stenotic segment of the left main coronary artery. The patient was discharged on the seventh day of stent implantation without any complications. Coronary artery bypass grafting was planned for stenotic lesions in the RCA and at the bifurcation of the left anterior descending artery with the circumflex artery.

The role of clopidogrel and acetylsalicylic acid in the prevention of early-phase graft occlusion due to reactive thrombocytosis after coronary artery bypass operation.

BACKGROUND: Reactive thrombocytosis has been reported in 20% of patients after coronary artery bypass grafting (CABG), a frequency that might be related to the high incidence of thrombotic complications. The present study was planned to investigate the effect of combined treatment with clopidogrel and acetylsalicylic acid (ASA) on post-CABG reactive thrombocytosis. METHODS: Included in this prospective, randomized study were 60 patients who underwent CABG operation with a 6-month follow-up. Three study groups were defined: group 1 (n = 20), a control group of patients who have not developed reactive thrombocytosis after CABG surgery; group 2 (n = 20), patients who have developed reactive thrombocytosis and continue taking ASA (300 mg/day); and group 3 (n = 20), patients who have developed reactive thrombocytosis and continue taking ASA (300 mg/day) with the addition of clopidogrel (75 mg/day). RESULTS: The mean ages and sex distributions of the patient groups were similar. There were no significant differences between the groups regarding cardiovascular risk factors, baseline laboratory findings, or intraoperative characteristics. Thrombocytosis disappeared within the first month after the operation in both treatment groups. An evaluation of graft patency in the sixth postoperative month revealed that group 2 had significantly more patients with a "positive" result in the exercise test than group 3 and that group 3 had a lower incidence of graft occlusion than group 2 (P < .01). CONCLUSIONS: Combination antiplatelet therapy with ASA and clopidogrel seems to be more effective than ASA alone for maintaining graft patency in patients with reactive thrombocytosis.

Effects of drug-eluting stents on systemic inflammatory response in patients with unstable angina pectoris undergoing percutaneous coronary intervention.

Inflammatory markers are elevated in acute coronary syndromes, and are also known to play a crucial role in the pathogenesis of neointimal proliferation and stent restenosis. Drug-eluting stents (DESs) have been shown to decrease stent restenosis in different studies. In this study, we aimed to investigate the effect of treatment with DESs on systemic inflammatory response in patients with unstable angina pectoris who underwent percutaneous coronary intervention (PCI). We compared plasma high-sensitivity C-reactive protein (hsCRP), human tumor necrosis factor alpha (Hu TNF-alpha), and interleukin 6 (IL-6) levels after DES (dexamethasone-eluting stent [DEXES], and sirolimuseluting stent [SES]) implantation with levels after bare metal stent (BMS) implantation. We performed PCI with a single stent in 90 patients (62 men; 59 +/- 9 years of age; n = 30 in the BMS group, n = 30 in the DEXES group, n = 30 in the SES group) who had acute coronary syndrome. Plasma hsCRP, Hu TNF-alpha, and IL-6 levels were determined before intervention and at 24 h, 48 h, and 1 week after PCI. The results were as follows. Plasma hsCRP levels at 48 h (11.19 +/- 4.54, 6.43 +/- 1.63 vs 6.23 +/- 2.69 mg/l, P = 0.001) after stent implantation were significantly higher in the BMS group than in the DES group; this effect persisted for 7 days (P = 0.001). Plasma Hu TNF-alpha levels at each time point were higher in the SES group than in the BMS and DEXES groups (P < 0.05). The time course of Hu TNF-alpha values was similar in all groups. Although IL-6 levels at baseline and at 24 and 48 h showed no statistically significant difference between the study groups, postprocedural values at 7 days were slightly statistically significant in the SES group (P = 0.045). Drug-eluting stents showed significantly lower plasma hsCRP levels after PCI compared with BMSs. This may reflect the potent effects of DESs on acute inflammatory reactions induced by PCI.

Endothelial nitric oxide synthase gene (T-786C) polymorphism in patients with slow coronary flow.

OBJECTIVES: In this study, we aimed to investigate the relationship between T-786C polymorphism of the endothelial nitric oxide synthase (eNOS) gene and slow coronary flow (SCF). STUDY DESIGN: A total of 56 patients with SCF but otherwise normal coronary arteries (mean age 48+/-9 years) and 37 controls with normal coronary angiograms (mean age 50+/-12 years) were enrolled in the study. Screening for the eNOS T-786C polymorphism was performed by restriction fragment length polymorphism methodology. RESULTS: In normal coronary artery and SCF groups, TT genotype frequency was 23 (62.2%) versus 22 (39.3%), TC heterozygote genotype frequency was 11 (29.7%) versus 30 (53.6%), and CC homozygote genotype frequency was 3 (8.1%) versus 4 (7.1%), respectively (P=0.07). In dominant model statistical analysis, total CC and CT genotype frequency in control and study groups was found to be 14 (37.3%) versus 34 (60.7%), respectively (P=0.025). A positive correlation was found between the mean thrombolysis in myocardial infarction frame count and C allele in patients with SCF (r=0.21, P=0.043). CONCLUSION: We concluded that the T-786C polymorphism of eNOS gene might be a risk factor for the SCF.

Correlation of the myocardial performance index with plasma B-type natriuretic peptide levels in patients with mitral regurgitation.

OBJECTIVE: The Myocardial performance index (MPI) is an echocardiographic index of combined systolic and diastolic function, calculated as isovolumetric relaxation time plus isovolumetric contraction time divided by ejection time. The aim of this study was to define the correlation of the MPI with plasma B-type natriuretic peptide (BNP) levels and echocardiographic parameters in patients with chronic mitral regurgitation (MR). METHODS: About 33 patients with at least moderate MR of organic etiology were enrolled to the study. All patients undergone complete 2D and Doppler echocardiography. Plasma BNP levels were studied. RESULTS: BNP levels in NYHA classes I-III were 9.3 +/- 2.2 pg/ml, 61.3 +/- 12.2 pg/ml, and 199.6 +/- 55.2 pg/ml, respectively (I vs. II P < 0.001, I vs. III P < 0.001 and II vs. III P = 0.004). Myocardial performance index were 0.42 +/- 0.02, 0.49 +/- 0.02, and 0.52 +/- 0.03 in MR patients with NYHA I-III, respectively. MPI was significantly higher in patients with NYHA class III compared to NYHA I (P = 0.001) and NYHA II (P = 0.005). There were no correlations between MPI and left atrial diameter, MR jet area, MR index and systolic pulmonary artery pressure whereas left ventricle (LV) end-systolic volume (r = 0.38), LV end-diastolic volume (LVDV) (r = 0.40), LV ejection fraction (r = -0.59), NYHA class (r = 0.51) and plasma BNP levels (r = 0.67) were strongly correlated. Only independent variable affecting MPI was plasma BNP level (odds ratio [CI]: 2.18[0.002-0.098], P = 0.041). CONCLUSIONS: MPI is a powerful index in assessing the severity of left ventricular function and symptom severity in patients with MR. Plasma BNP is an independent predictor of MPI where both parameters assess combined systolic and diastolic LV function, effectively.

[Coronary artery ectasia: clinical and angiographical evaluation]. / Koroner arter ektazisi: klinik ve anjiyografik degerlendirme.

OBJECTIVES: We investigated the prevalence, distribution, risk factors, and prognosis of coronary artery ectasia (CAE) in patients undergoing coronary angiography for suspected coronary artery disease (CAD). STUDY DESIGN: Of 4,119 patients undergoing elective coronary angiography between 2003 and 2005, 173 patients (139 males, 34 females; mean age 61+/-11 years) had CAE, with a prevalence of 4.2%. Distribution of CAE was made according to the classification of Markis et al. The results were compared with those of 145 control patients (115 males, 30 males; mean age 61+/-10 years) who had CAD but not CAE. Following coronary angiography, treatment was designed as aortocoronary bypass (n=3), percutaneous coronary intervention (n=36), and medical therapy (n=98). The mean follow-up was 34.2+/-2.5 months. RESULTS: Among CAE patients, there was a marked male preponderance with 80.3%. Coronary ectasia was isolated in 46 patients (26.6%) and was associated with significant coronary artery stenoses in 127 patients (73.4%). The only significant difference with the control group with respect to baseline features was the higher frequency of hypertension in the CAE group (p=0.002). Coronary ectasia involved a single vessel in 67.1%, two vessels in 24.9%, and three vessels in 8.1%, with the right coronary artery being the most common localization (50.9%). The diameters of ectatic coronary arteries ranged from 3.2 mm to 9.7 mm (mean 5.6 mm). According to the classification of Markis et al., the majority of patients (64.2%) had type IV ectasia. In multiple regression analysis, hypertension was independently associated with CAE (OR: 0.378; 95% CI: 0.211-0.678; p=0.001). Mortality occurred in nine patients (5.2%). The annual mortality rates were 1.5%, 2.1%, and 2.9% with medical therapy, percutaneous coronary intervention, and aortocoronary bypass, respectively. CONCLUSION: Our findings suggest that further prospective studies focus on the dependent relationship between hypertension and CAE, and on marked coexistence of CAD and CAE.

Exercise-induced increase in lipid peroxidation in patients with chronic heart failure: relation to exercise intolerance.

BACKGROUND: Little is known about the relationship between exercise intolerance and lipid peroxidation in chronic heart failure (CHF) patients. This study was designed to investigate the relationship between exercise-induced plasma malondialdehyde (MDA) changes in CHF patients and to determine whether there is any association between plasma MDA levels and exercise capacity assessed by cardiopulmonary exercise testing. METHODS: Cardiopulmonary exercise testing was applied to 31 CHF patients (16 ischemic, 15 idiopathic) and controls. Rest and peak exercise blood samples were analyzed for MDA. RESULTS: Patients with CHF had elevation of plasma MDA levels during exercise compared with controls (p < 0.001 vs. p = 0.588). MDA change remained significant both in ischemic and idiopathic cardiomyopathy groups (p < 0.05 and p < 0.01, respectively). Delta MDA (peak exercise MDA - rest MDA) showed significant inverse correlation with peak oxygen consumption in patients with CHF. CONCLUSION: Lipid peroxidation is increased in patients with CHF during exercise regardless of etiology, and this increase is inversely related to oxygen consumption.

Plasma homocysteine concentration in patients with poor or good coronary collaterals.

BACKGROUND: Elevated plasma homocysteine (Hcy) concentrations are associated with an increased risk of vascular disease. Hcy is known to inhibit endothelial cell proliferation in vitro. The purpose of the present study was to investigate the role of plasma Hcy concentrations on development of collateral circulation in single-vessel chronic total occlusion. METHODS AND RESULTS: Collateral status was determined by Rentrop's classification. Of 817 patients, 56 cases of pure single-vessel chronic total occlusion were studied. Plasma Hcy concentrations in patients with single-vessel total coronary occlusion were higher compared with controls (17.3 +/-12.6 micromol/L vs 10.9+/-4.9 micromol/L, p=0.015). There was no significant difference in plasma Hcy concentrations of the good and poor collateral groups (17.2+/-13.7 micromol/L vs 15.3+/-9.3 micromol/L, p=0.834). Plasma Hcy concentrations in individual Rentrop subclasses 0, 1, 2 and 3 were as follows: 15.9 +/-9.1, 16.3+/-12.4, 17.1+/-14.1 and 20.1+/-13.5 micromol/L (p=0.893). There was a positive linear correlation between Rentrop subclass and angina pectoris duration (r=0.41, p=0.003). Angina pectoris duration was the only independent variable affecting the development of coronary collaterals in the present study (odds ratio [confidence interval]: 1.85 [1.12-2.91], p=0.014). CONCLUSION: Patients with single-vessel chronic total occlusion had higher plasma Hcy concentrations than controls, but similar Hcy concentrations when compared according to the presence of poor or good coronary collaterals. There is a lack of association between plasma Hcy concentration and coronary collateral status in the current study.

Effects of folic acid and N-acetylcysteine on plasma homocysteine levels and endothelial function in patients with coronary artery disease.

OBJECTIVE: Hyperhomocysteinaemia is related with premature coronary artery disease and adverse cardiac events in patients with coronary artery disease (CAD). It is assumed that hyper-homocysteinaemia causes endothelial dysfunction. In this study, the effect of folic acid and oral N-acetylcysteine (NAC) therapies on plasma homocysteine levels and endothelial function were evaluated in hyperhomocysteinaemic patients with CAD. METHODS AND RESULTS: 60 patients were randomized to either folic acid 5 mg or NAC 600 mg or placebo daily for eight weeks. Brachial artery endothelial functions were studied by using high-resolution ultrasound and assessed by measuring endothelium-dependent dilation (EDD) and endothelium-independent dilation (NEDD). Folic acid and NAC therapies decreased plasma homocysteine (from 21.7 +/- 8.7 micromol/l to 12.5 +/- 2.5 micromol/l, P < 0.001; from 20.9 +/- 7.6 micromol/l to 15.6 +/- 4.3 micromol/l, P = 0.03, respectively), and increased EDD (6.7 +/- 6.1% P = 0.002, 4.4 +/- 2.6% P < 0.001, respectively) compared with placebo. There was no significant difference in improving EDD between the folic acid and the NAC group (6.7 +/- 6.1%, 4.4 +/- 2.6%, P = 0. 168). In the univariate analyses there was an inverse correlation between the post-treatment homocysteine level and the percent change in EDD with folic acid therapy (r= -0.490, P = 0.028), but there was no correlation with the NAC therapy (r = 0.259, P = 0.333) CONCLUSION: In patients with hyperhomocysteinaemic CAD, folic acid and NAC lowered plasma homocysteine levels and improved endothelial function. The effects of both treatments in improvement of EDD were similar.

The relationship between endothelial nitric oxide synthase gene polymorphism (T-786 C) and coronary artery disease in the Turkish population.

Previous studies revealed that there were various mutations on endothelial nitric oxide synthase (eNOS) gene and these mutations might be a risk factor for coronary artery disease (CAD), myocardial infarction (MI), and hypertension (HT). In this study, we aimed to investigate the relationship between eNOS gene polymorphism (T-786 C) and coronary artery disease in the Turkish population. Two hundred and eleven unrelated individuals (152 male, 59 female, mean age 59 years, range 27-85) whose angiographic examinations were performed in our hospital were enrolled into the study; 159 of these had angiographically determined coronary artery lesions (>or=50% stenosis at least in one vessel). Fifty-two individuals were free of coronary artery disease on their coronary angiography. The Gensini scoring system was used to determine the severity of the CAD. The polymerase chain reaction (PCR) method was used for genotyping the individuals. To determine the independent risk factors for coronary artery disease, multivariate logistic regression analysis was used. The variant distribution of the T-786 C polymorphism was as follows. For all individuals: TT 94 (44.5%), TC 88 (41.7%), CC 29 (13.8%); in CAD patients: TT 63 (39.6%), TC 73 (45.9%), CC 23 (14.5%); and in normal individuals: TT 31 (59.6%), TC 15 (28.8%), CC 6 (11.5%). There was a statistically significant difference in the variant distribution between CAD and normal individuals (P<0.05). On the other hand, when we compared the frequency of the at-least-one-C-allele carriers (CC+TC, dominant model) and TT homozygous, those with at least one C allele were more prevalent in CAD patients. The results were as follows. In coronary artery disease patients: CC+TC 96 (60.4%), TT 63 (39.6%); in normals: TC+CC 21 (40.4%), TT 31 (59.6%) (P<0.01). When we compared the allele distribution (T vs C, additive model) between CAD patients and normal controls, the results were as follows: T 0.625 vs 0.740, C 0.375 vs 0.260; there was also a statistically significant association between CAD and C allele (P<0.05). When we compared the means of the Gensini scores between each genotype of the T-786 C mutation, there was a statistically significant difference. The results were TT (48.6+/-37.3, median 43.0), TC (55.4+/-41.2, median 41.0), CC (77+/-43.6, median 80.0) (P<0.05). Multivariate logistic regression analysis revealed that C-dominant (CC+TC) individuals had 2.9-fold more likelihood to suffer from CAD (odds ratio: 2.902; confidence interval: 1.272-6.622) (P<0.05). We conclude that the T-786 C polymorphism of eNOS gene might be a risk factor for coronary artery disease in the Turkish population.

Plasma soluble adhesion molecule levels in coronary artery ectasia.

BACKGROUND: Coronary artery ectasia (CAE) is defined as localized or diffuse dilatation of the coronary arteries. There are scarce data about the role of inflammation in CAE. In the present study, the plasma soluble adhesion molecules intercellular adhesion molecule 1 (ICAM-1) and vascular cell adhesion molecule 1 (VCAM-1) levels in CAE were investigated. METHODS: The study population (n = 67) consisted of four groups. Group 1: patients with normal coronary artery (NCA); group 2: patients with isolated ectasia without stenotic lesion; group 3: patients with obstructive coronary artery disease (OCAD) without CAE; group 4: patients with both OCAD and CAE. RESULTS: Plasma concentrations of ICAM-1 and VCAM-1 were higher in patients with isolated ectasia than in cases with NCA (p < 0.001 and p < 0.001, respectively). Compared with OCAD patients, patients with CAE had significantly elevated concentrations of ICAM-1 and VCAM-1 (p < 0.001 and p < 0.05, respectively). The levels of ICAM-1 and VCAM-1 of the CAE and OCAD group were higher than in patients in the OCAD group (p < 0.05 and p < 0.05, respectively). We detected a positive correlation between the presence of CAE and the levels of ICAM-1 and VCAM-1. Multivariate logistic regression analyses revealed a significant independent relation between the presence of CAE and ICAM-1 and VCAM-1. CONCLUSION: We found elevated plasma levels of ICAM-1 and VCAM-1 in patients with CAE and OCAD + CAE compared with subjects with NCA and OCAD. These data strongly suggest that more severe vascular wall inflammation may play a role in the pathogenesis of CAE.

Value of left atrial function in predicting exercise capacity in heart failure with moderate to severe left ventricular systolic dysfunction.

Left atrial (LA) function is associated with left ventricular (LV) diastolic filling and cardiac output response to exercise. But the relation between LA function and exercise performance has not been adequately evaluated. The aim of this study was to investigate the relation between LA function and exercise capacity in dilated cardiomyopathy (DCM) with cardiopulmonary exercise testing. Forty-four patients with a left ventricular end-diastolic dimension (LVDd) > or = 60 mm and an ejection fraction (EF) < or = 40%, and in normal sinus rhythm were included in this study. Patients were divided into group 1 and group 2 according to their exercise peak oxygen uptake (VO2) (group 1: peak VO2 >14 mL/kg/min, group 2: peak VO2 < or = 14 mL/ kg/min). LA function indices were defined as follows: LA end-systolic diameter (LASd), end-diastolic diameter (LADd), LA systolic volume (LASV), LA diastolic volume (LADV), LA ejection volume (LAEV), and LA ejection fraction (LAEF). LASd, LADd, LASV, and LADV were significantly increased in group 2 (P < 0.001, P < 0.001, P < 0.05, P < 0.005). Group 1 had significantly higher LAEF (P < 0.001 ) and LVEF (P < 0.05). Group 2 had significantly shorter exercise duration, and decreased anaerobic threshold levels and minute ventilation volumes (P < 0.001, P < 0.001, P < 0.005 ). There was a positive correlation between peak VO2 and LVEF (r = 0.46, P = 0.002), and LAEF (r = 0.61, P < 0.001), peak A wave velocity (r = 0.39, P = 0.009), E wave deceleration time (r = 0.56, P < 0.001), and isovolumic relaxation time (IVRT) (r = 0.35, P = 0.04). There was a negative correlation between peak VO2 and LASd (r = -0.53, P < 0.001) LADd (r = -0.59, P < 0.001), LASVI (r = -0.34, P = 0.027), LADVI (r = -0.37, P = 0.001), and the E/A ratio (r = -0.41, P = 0.006), Decreased LAEF and increased LA sizes were associated with decreased peak VO2. The results clearly demonstrate that LA functions at rest are related to exercise performance in patients with heart failure.