Ridvan Yalcin

Lack of Association Between Matrix Metalloproteinase-9 and Endothelial Nitric Oxide Synthase Gene Polymorphisms and Coronary Artery Disease in Turkish Population

Polymorphic variants of genes encoding proteins involved in vascular remodeling may genetically diverge among different populations and play a role in the susceptibility to the coronary artery disease (CAD). MMP-9-1562 C/T (rs3918242), eNOS T-786C (rs2070744), and Glu298Asp (rs1799983) are among the most studied of these polymorphisms. The aim of this study was to determine the relationship between CAD and these polymorphisms in the Turkish population. The analysis included 146 CAD+ and 122 CAD- individuals. Genomic DNA was isolated from whole blood and genotyping was performed by the PCR-RFLP method. No significant associations were found between -1562 C/T (p = 0.557), Glu298Asp (p = 0.432), and -786 T/C (p = 0.055) polymorphisms and CAD. The distribution of each haplotype also did not differ between CAD+ and the CAD- samples (p > 0.05). The present investigation is the first to study an association between -1562 C/T polymorphism and CAD in the Turkish population. In conclusion, no appreciable differences between CAD+ and CAD- samples were found in terms of polymorphisms mentioned above.

Carotid intima–media thickness in patients with cardiac syndrome X and its association with high circulating levels of asymmetric dimethylarginine

BACKGROUND The cause of myocardial ischemia and chest pain in patients with cardiac syndrome X (CSX) has been explained by mechanisms including endothelial dysfunction. CSX patients have higher levels of asymmetric dimethylarginine (ADMA) and increased mean common carotid intima-media thickness (C-IMT). Accordingly, this study was designed to examine C-IMT with its association serum endothelial function parameters in patients with CSX. METHODS The study population consisted of 30 enrolled consecutive patients with diagnosis of CSX. As a control group, 30 individuals with the complaint of anginal chest pain without any ischemia on myocardial perfusion scintigraphy and with normal coronary angiographies were selected. C-IMT was measured by recording ultrasonographic images of both the left and the right common carotid artery. Plasma levels of L-arginine, ADMA, and nitrate/nitrite (NO(x)) were measured from blood samples. RESULTS Both C-IMT (mm) and carotid atherosclerotic plaques were significantly higher in patients with CSX than in control group. Also, the plasma level of NO(x), L-arginine, and L-arginine/ADMA ratio were lower in patients with CSX than they were in the control group subjects. Plasma ADMA level increased in the CSX patients group. Correlation analysis showed significant positive correlation with C-IMT and plasma ADMA levels and showed significant negative correlation with plasma NO(x) and L-arginine levels. L-arginine/ADMA ratio and C-IMT was also showed significant negative correlation with the same analysis. CONCLUSIONS CSX patients had higher plasma ADMA levels and C-IMT values than the controls, reflecting the presence of subclinical atherosclerosis. These findings suggest that, besides endothelial dysfunction, presence of atherosclerosis may also contribute to the etiopathogenesis of the CSX phenomenon.

Renal dysfunction is the most important predictor of the extent and severity of coronary artery disease in patients with diabetes mellitus.

ObjectivesDiabetic patients tend to have more extensive and diffuse coronary artery disease (CAD) that may contribute to the less favorable outcomes in them. The aim of this study was to elucidate the predictors of the angiographic severity and extent of CAD in patients with diabetes. MethodsA total of 203 diabetic patients (116 men; mean age, 61.9±10.8) who were referred for a first coronary angiogram were included. The extent and severity of CAD was assessed in several ways. The first was a simple classification in one-vessel, two-vessel, and three-vessel disease scoring system. The total numbers of segments with ≥20 and ≥50% stenosis were calculated as CASS 20 and CASS 50 scores, respectively. Hamsten and Gensini scores were also calculated. ResultsOf the 203 patients included in the study, 175 (86.2%) had CAD. Multivariate ordinal logistic regression analysis showed that age (Wald 5.741, P=0.017), glomerular filtration rate (Wald 5.032, P=0.025), previous myocardial infarction (Wald 10.955, P=0.001), and family history of CAD (Wald 7.236, P=0.007) were independent predictors of the severity of CAD, as assessed by the clinical zero-vessel to three-vessel disease scoring system. On stepwise multiple linear regression analysis, glomerular filtration rate was an independent predictor of the CASS 20 (r=−0.221, P=0.004), CASS 50 (r=−0.239, P=0.005), Gensini (r=−0.328, P<0.001), and Hamsten (r=−0.320, P<0.001) scores. Previous myocardial infarction was an independent predictor of the CASS 50 (r=0.355, P<0.001), Gensini (r=0.350, P<0.001), and Hamsten (0.256, P<0.001) scores. Age and sex were independent predictors for the CASS 50 (r=0.174, P=0.039; r=0.172, P=0.016, respectively) and Hamsten (r=0.212, P=0.011; r=0.244, P=0.001, respectively) scores. ConclusionRenal function is one of the most important factors associated with the extent and severity of coronary atherosclerosis, whereas classical coronary risk factors and the degree of metabolic control were not associated with the severity of coronary atherosclerosis in diabetic patients.

A Shift in the Balance of Regulatory T and T Helper 17 Cells in Rheumatic Heart Disease

Background Autoimmunity plays an essential role in the pathogenesis of rheumatic heart disease (RHD); however, cellular mechanisms of autoimmune response are unclear. Whereas T helper 17 (TH17) and regulatory T cells (Treg) cells share a common differentiation pathway, they play opposite roles in the immune tolerance and autoimmune diseases. Although high TH17/Treg ratio has been shown in several autoimmune diseases, no data are available in RHD. This study investigated the balance between TH17 and Treg in rheumatic mitral valve disease (MVD). Methods Forty patients with rheumatic MVD and 23 control subjects were enrolled into the study. All subjects underwent clinical, electrocardiographic, and echocardiographic evaluation. The percentages of circulating TH17 and Treg cells were analyzed by flow cytometry. Serum levels of high-sensitivity C-reactive protein (hs-CRP) and cytokines were assessed by enzyme-linked immunosorbent assay. Results As compared with control subjects, rheumatic MVD patients showed significant increase in peripheral TH17 percentage, high serum levels of TH17-related cytokine interleukin 17A, and an obvious decrease in the percentage of Treg cells. T helper 17/Treg ratio was significantly high in rheumatic MVD patients compared with control subjects (P = 0.0001). Serum concentrations of hs-CRP in rheumatic MVD group were higher than those of the control subjects, and hs-CRP levels correlated with the TH17/Treg ratio (r = 0.71, P = 0.0001). Serum levels of transforming growth factor β1 were increased in rheumatic MVD group compared with those of the control subjects. Conclusions The results indicated that high TH17/Treg ratio exists inrheumatic MVD. This imbalance may play a role in the pathogenesis, and TH17/Treg balance may be a promising therapeutic approach in RHD.

The Role of Matrix Metalloproteinase-2 Promoter Polymorphisms in Coronary Artery Disease and Myocardial Infarction

The matrix metalloproteinase (MMP) family are key enzymes involved in the breakdown of the extracellular matrix in normal physiological processes, including tissue remodeling, and disease processes, such as arthritis and metastasis. The promoter polymorphism in the MMP2 gene may be responsible for multiple diseases related to extracellular matrix degradation. Therefore, we aimed to investigate the relationship between genotypes or haplotypes of -1575 G/A, -1306 C/T, -790 T/G, and -735 C/T promoter polymorphisms and coronary artery disease (CAD) with or without myocardial infarction (MI) history. This study included 298 patients with angiographically confirmed CAD and 299 age matched controls. Genomic DNA was isolated from whole blood and genotyping was performed by the polymerase chain reaction-restriction fragment length polymorphism method. No significant associations were found between -1575 G/A, -1306 C/T, and -790 T/G polymorphisms and CAD with or without MI history. However, the frequency of the -735 TT genotype was significantly lower in the controls than in the patients with MI alone when compared with the CC genotype (p=0.021). Only the distribution of the ACGC haplotype in CAD patients exhibited a significant difference than that in controls (p<0.05). The distribution of other haplotypes did not differ between CAD patients and controls. The present investigation is the first report to detect an association between MMP2 promoter polymorphisms and CAD with or without MI history in the Turkish population. Further case-control studies in CAD development might be contributed to clarify the role of these polymorphisms.

Effect of serum YKL-40 on coronary collateral development and SYNTAX score in stable coronary artery disease

OBJECTIVE Many studies have revealed a role of YKL-40 as a new inflammatory biomarker in angiogenesis, inflammation, atherosclerosis and cardiovascular events. Thus, the aim of this study was to investigate the association of serum YKL-40 level with coronary collateral development and SYNTAX score in patients with stable coronary artery disease. METHODS A total of 165 patients who had ≥90% stenosis in at least one major coronary artery were prospectively enrolled in the study. Collateral degree was graded according to Rentrop-Cohen classification. Patients with grade 2 or 3 collateral degree were included in good collateral group and patients with grade 0 or 1 collateral degree were included in poor collateral group. The patients were also classified according to SYNTAX criteria, those with low (≤22) and those with high (>22) SYNTAX score. RESULTS Serum YKL-40 and hs-CRP levels were significantly lower in good collateral group. Furthermore, YKL-40 level showed significant positive correlations with SYNTAX score (r=0.486, p<0.001) and hs-CRP level (r=0.340, p<0.001). In multivariate regression analysis, serum YKL-40 (odds ratio: 0.928; 95% confidence interval: 0.917-0.940; p<0.001), duration of ischemic symptom and total occlusion were independent predictors of good collateral development. In ROC curve analysis, a YKL-40 value cut-off point of ≥168.5 predicted the high SYNTAX score with a sensitivity of 81.0% and specificity of 72.4%. CONCLUSIONS Increased serum YKL-40 level was related with poor collateral development and high SYNTAX score. According to these findings YKL-40 can be used as a predictor of good collateral development and high SYNTAX score.

Effects of left ventricular systolic dysfunction on left atrial appendage and left atrial functions in patients with chronic nonvalvular atrial fibrillation.

Objective — It has been claimed that left ventricular (LV) systolic dysfunction impairs left atrial (LA) and left atrial appendage (LAA) functions. In this study, we compared the LA and LAA function parameters in patients with chronic nonvalvular atrial fibrillation (AF) with and without LV systolic dysfunction. Methods and results — The study population consisted of 28 patients with chronic nonvalvular AF. Group I consisted of 12 patients with LV systolic dysfunction (mean age: 61 ± 14 years; LV ejection fraction: 44 ± 6%), group II of 16 patients with normal LV systolic function (mean age: 52 ± 15 years; LV ejection fraction: 65 ± 3%). LV ejection fraction (EF) was measured by echocardiography utilizing bi-plane area length method.The following LA and LAA transoesophageal echocardiography parameters were obtained: 1) LA diameter, 2) LAA ejection velocity, 3) LAA filling velocity, 4) LAA ejection fraction, 5) pulmonary venous (PV) systolic velocity, 6) PV diastolic velocity, 7) PV systolic velocity/diastolic velocity ratio.The left atrium diameter was significantly larger in group I than in group II (4.7 ± 0.7 cm vs. 3.8 ± 0.6 cm, p < 0.05). The LAA ejection velocity and LAA ejection fraction were significantly lower in group I than in group II (22.6 ± 15.5 cm/s vs 37.5 ± 11.3 cm/s and 26.9 ± 20.8% vs. 41.3 ± 10.9%, p < 0.05 for both comparisons). The PV systolic velocity and PV systolic velocity/diastolic velocity ratio were significantly smaller in group I than in group II (26.2 ± 14.8 cm/s vs. 51.5 ± 22 cm/s and 0.7 ± 0.6 vs. 1.2 ± 0.5, p < 0.05 for both comparisons). Although decreased LAA filling and PV diastolic velocities were determined in group I, no significant difference existed between groups I and II.Thrombus and/or spontaneous echo contrast (SEC) in the LA and/or LAA were more frequent in group I (75% vs. 18%, p < 0.05). Conclusion — These results indicate that LV systolic dysfunction impairs various LA and LA function parameters and is associated with an increased frequency of SEC and/or LA thrombus in patients with chronic nonvalvular AF.

Plasma osteopontin levels in prediction of prognosis in acute myocardial infarction.

Objective We sought to explain the clinical importance of the osteopontin (OPN) in the setting of acute ST-elevation myocardial infarction (STEMI). Methods Eighty consecutive patients (55 ± 11 years, 12 women and 68 men) and sixty healthy control subjects were included in the study. In all patients, plasma OPN levels were assessed on admission and on the third day (peak value). Creatinine kinase (CK)/CK-myocardial band (MB), troponin I and N-terminal pro-brain natriuretic factor levels and echocardiographic fi ndings were also recorded. Patients were classifi ed into high and low OPN groups according to the median OPN value, and monitored for the occurrence of major adverse cardiovascular events (MACE). Results Patients with STEMI had higher OPN levels (23.8 [16.7-41.3] ng/ml) on admission than the control subjects (18.0 [11.3-31.5] ng/ml, P= 0.004). The third day value of OPN was signifi cantly higher (39.2 [27.2-56.0] ng/ml) than the OPN level on admission (23.8 [16.7-41.3] ng/ml, P < 0.001). Admission and peak OPN levels were not correlated with CK/CK-MB, white blood cell counts, troponin I and the N-terminal pro-brain natriuretic factor. The plasma OPN levels were not correlated with left ventricular wall motion score index either. In the subgroups of infarct localization and reperfusion strategy, plasma OPN levels were similar. When the patients were compared according to the median OPN values, there were no diff erences in the occurrence of MACE between the high and low OPN groups. Conclusion This study suggests, for the fi rst time, that the plasma OPN level increases in the fi rst hours of the acute STEMI; however, it could not be used as a prognostic biomarker of STEMI.

The Relationship of Serum Erythropoietin Level With Coronary Collateral Grade

BACKGROUND Erythropoietin has been shown to induce neovascularization and protect against ischemic vascular injury. We investigated whether a higher serum erythropoietin (EPO) level is related to better coronary collateral vessel grade. METHODS Ninety-nine patients with stable angina pectoris who have at least 1 coronary stenosis of equal to or greater than 70% at coronary angiography were prospectively enrolled. Serum EPO and vascular endothelial growth factor (VEGF) levels were studied. Coronary collateral degree was graded according to the Rentrop method. Patients with grade 2-3 collateral degree were included in the good collateral group and formed Group I. The patients with grade 0-1 collateral degree were included in the poor collateral group and formed Group II. RESULTS The serum EPO level was significantly higher in the good collateral group (17.3 ± 9.3 mU/mL vs 11.7 ± 5.0 mU/mL; P < 0.001). There was also a positive correlation between serum EPO level and Rentrop score (r = 0.39; P < 0.001). In multivariate analysis, serum EPO level (odds ratio [OR] 1.336; 95% confidence interval [CI], 1.120-1.593; P = 0.001), oxygen saturation (OR 0.638; 95% CI, 0.422-0.963; P = 0.033) and presence of chronic total occlusion (CTO) (OR 26.7; 95% CI, 3.874-184.6; P = 0.001) were independently related to well-developed coronary collaterals. CONCLUSIONS Higher serum EPO level is related to better coronary collateral development. Erythropoietin may have a positive effect on the development of collaterals and may provide a new agent for the treatment strategies to enhance coronary collateral vessel development.

Medium-term follow-up of intermediate coronary stenoses left unrevascularized based on myocardial fractional flow reserve findings.

Objective — Coronary stenoses of intermediate severity create difficulties in decision making when revascularization is concerned. Myocardial fractional flow reserve (mFFR), an accurate tool to identify physiological significance of individual coronary stenoses, may help solve this problem. Methods and results — Fifty-eight intermediate (30-70%) coronary stenoses in 51 patients (mean age 54.4 ± 8.9 years, 9 women) were left unrevascularized because of normal (≥ 0.75) mFFR findings and the patients were prospectively followed with regard to the occurrence of death, myocardial infarction and target vessel revascularization.The mean reference vessel diameter, percent stenosis and mFFR of the intermediate lesions were 3.3 ± 0.3 mm, 46.8 ± 9.2% and 0.86 ± 0.05, respectively. Of the 58 intermediate lesions, 20 (34%) were associated with perfusion defects on thallium scan. Significant (> 70%) disease in addition to the one with the intermediate stenosis was present in 1 coronary artery in 24 (47%), and 2 coronary arteries in 6 (12%) patients and angioplasty of at least one significant stenosis was performed at the initial evaluation in 18 (35%) patients. Follow-up for a mean of 16.6 ± 6.6 months disclosed no death or myocardial infarction.Target vessel revascularization was performed in 3 (6%) patients at a mean of 4 ± 2.6 months. A control angiogram, which was performed in 12 of 18 patients who had undergone angioplasty at the initial evaluation revealed restenosis in 3 (25%) patients with no significant angiographic changes in the target intermediate stenoses. Anginal status was found to be significantly improved at follow-up. Conclusions — In this study, we found that intermediate coronary stenoses with an mFFR ≥ 0.75 have a favourable medium-term clinical outcome with respect to major cardiac adverse events when left unrevascularized based on mFFR findings.