The relationship between circulating microRNAs and left ventricular mass in symptomatic heart failure patients with systolic dysfunction.

BACKGROUND: In recent years, many microRNAs (miRNAs) were shown to be dysregulated in specific tissues playing critical roles in the pathogenesis and progression of heart failure (HF). Left ventricular (LV) mass (LVM) has long been recognised as an important prognostic marker in systolic HF patients. AIM: We hypothesised that circulating miRNAs may be associated with LVM in systolic HF patients. The present study aimed to evaluate the relationship between previously reported and novel dysregulated circulating miRNAs and echocardiographically determined LVM in symptomatic HF patients with LV systolic dysfunction. METHODS: Forty-two consecutive patients diagnosed with NYHA II-IV symptomatic systolic HF and a control group consisting of 15 age- and sex-matched healthy volunteers were enrolled. After labelling extracted RNA, poly-A tails were added. RNAs were later hybridised on a GeneChip miRNA 2.0 array. After hybridisation and staining, arrays were scanned to determine miRNA expression levels, and differentially expressed miRNAs were identified. RESULTS: Eighteen miRNAs were found to be upregulated in serum of HF patients, while 11 were demonstrated to be downregulated. When the association between dysregulated miRNAs and echocardiographic findings was investigated, miR-182 (p = 0.04), miR-200a* (p = 0.019), and miR-568 (p = 0.023) were found to be inversely correlated with LVM index (LVMI), while miR-155 (p = 0.019) and miR-595 (p = 0.04) were determined to be positively correlated with LVMI. CONCLUSIONS: The results of our study revealed that dysregulated circulating miRNAs were correlated with anatomic changes in LV, in terms of LVMI, in symptomatic HF patients with systolic LV dysfunction.

The prognostic value of circulating microRNAs in heart failure: preliminary results from a genome-wide expression study.

INTRODUCTION: Recent studies have demonstrated the potential of microRNAs (miRNA) as biomarkers in various cardiovascular disorders. The aim of the present study was to quantitatively evaluate the expression levels of miRNAs in patients with chronic congestive heart failure (CHF) in order to identify differential expression profiles as biomarkers with prognostic values. MATERIALS AND METHOD: The study included 20 clinically stable [New York Heart Association (NYHA) II] and 22 decompensated (NYHA III and IV) CHF patients and 15 healthy controls. miRNA profiling was performed using a microarray method. Dysregulated miRNAs were evaluated for their biomarker potential. RESULTS: Microarray profiling revealed an increase in the expression of miR-21, miR-650, miR-744, miR-516-5p, miR-1292, miR-182, miR-1228, miR-595, miR-663b, miR-1296, miR-1825, miR-299-3p, miR-662 miR-122, miR-3148 and miR-518e and a decrease in the expression of miR-129-3p, miR-3155, miR-3175, miR-583, miR-568, miR-30d, miR-200a-star, miR-1979, miR-371-3p, miR-155-star and miR-502-5p in sera of CHF patients. The prognostic value of miR-182 [area under the curve (AUC) 0.695] was found to be superior to pro-brain type natriuretic peptide (NT-proBNP; AUC 0.350) and high-sensitivity C-reactive protein (hs-CRP) (AUC 0.475) by receiver operator characteristic (ROC) analysis. Cox regression analysis showed that miR-182 could predict cardiovascular mortality (P = 0.032). CONCLUSION: We demonstrated the increased expression levels of circulating miRNAs in CHF as compared with controls. Moreover, miR-182 was found to be a potential prognostic marker in CHF.

The assessment of the relationship between variations in the apelin gene and coronary artery disease in Turkish population.

OBJECTIVE: Apelin is a novel endogenous peptide with inotropic and vasodilatory properties and is the ligand for the angiotensin receptor-like 1 (APJ) receptor. The aim of the study was to investigate the association of 2 single-nucleotide polymorphisms (SNPs) in the apelin gene with susceptibility to coronary artery disease (CAD) in the Turkish population. METHODS: The present observational case-control study consisted of 244 subjects (134 angiographically proven CAD patients and 110 healthy controls) aged 30-65 years. The association of 2 SNPs (rs3115758 and rs3115759) in the apelin gene and CAD risk was investigated. Real-time polymerase chain reaction (RT-PCR) was used to analyze the 2 SNPs in both the CAD and the healthy subjects. Allele and genotype frequencies between patients and control groups were compared using the Chi-square (χ2) test. The relationships of the 2 polymorphisms with the presence of CAD were determined with multiple binary logistic regression analysis after adjustment for CAD risk factors. RESULTS: TT and AA risk genotypes of the rs3115758 and rs3115759 variants in the apelin gene were found to be significantly related with the risk of CAD with the same power (OR: 6.36, 95% CI: 1.41-28.6) (p=0.007). After adjustments for traditional CAD risk factors, the homozygous TT genotype for rs3115758 and AA genotype for rs3115759 increased the CAD risk, both with an OR of 5.91. CONCLUSION: Genetic variants in the apelin gene are significantly associated with the risk of CAD in the Turkish population.

Evaluation of association between common genetic variants on chromosome 9p21 and coronary artery disease in Turkish population.

OBJECTIVE: Coronary artery disease (CAD), which develops from complex interactions between genetic and enviromental factors, is a leading cause of death worldwide. Based on genome-wide association studies (GWAS), the chromosomal region 9p21 has been identified as the most relevant locus presenting a strong association with CAD in different populations. The aim of the present study was to investigate the association of two SNPs on chromosome 9p21 on susceptibility to CAD and the effect of these SNPs along with cardiovascular risk factors on the severity of CAD in the Turkish population. METHODS: This study had an observational case-control design. We genotyped 460 subjects, aged 30-65 years, to investigate the association of 2 SNPs (rs1333049, rs2383207) on chromosome 9p21 and CAD risk in Turkish population. Real-time polymerase chain reaction (RT-PCR) was used to analyze the 2 SNPs in CAD patients and healthy controls. The genotype and allelic variations of these SNPs with the severity of CAD was also assessed using semi-quantitative methods such as the Gensini score. Student's t test and multiple regression analysis were used for statistical analysis. RESULTS: The SNPs rs1333049 and rs2383207 were found to be associated with CAD with an adjusted OR of 1.81 (95% Cl 1.05-3.12) and 2.12 (95% CI 1.19-4.10) respectively. After adjustment of CAD risk factors such as smoking, family history of CAD and diabetes, the homozygous AA genotype for rs2383207 increased the CAD risk with an OR 3.69. Also a very strong association was found between rs1333049 and rs2383207 and Gensini scores representing the severity of CAD (p<0.001). CONCLUSION: The rs2383207 and rs1333049 SNPs on 9p21 chromosome were significantly associated with the risk and severity of CAD in the Turkish population.

Chromosome 9p21 rs10757278 polymorphism is associated with the risk of metabolic syndrome.

Metabolic syndrome (MetS) is a common multifactorial disorder that involves abdominal obesity, dyslipidemia, hypertension, and hyperglycemia. Genome-wide association studies have identified a major risk locus for coronary artery disease and myocardial infarction on chromosome 9p21. Here, we examined the frequency of single nucleotide polymorphisms (SNPs) on chromosome 9p21 in a sample of Turkish patients with MetS and further investigated the correlation between regional SNPs, haplotypes, and MetS. The real-time polymerase chain reaction (RT-PCR) was used to analyze 4 SNPs (rs10757274 A/G, rs2383207 A/G, rs10757278 A/G, rs1333049 C/G) in 291 MetS patients and 247 controls. Analysis of 4 SNPs revealed a significant difference in the genotype distribution for rs2383207, rs10757278, and rs1333049 between MetS patients and controls (p = 0.041, p = 0.005, p = 0.023, respectively) but not for rs10757274 (p = 0.211). MetS and control allelic frequencies for rs2383207, rs10757278, and rs1333049 were statistically different (p < 0.05). The rs2383207 AG variant, was identified as a MetS risk factor (p = 0.012, OR = 33.271; 95 % CI: 2.193-504.805) and the AA haplotype in block 1 and the GC, AG haplotypes in block 2 were associated with MetS (χ(2) = 3.875, p = 0.049; χ(2) = 9.334, p = 0.0022; χ (2) = 9.134, p = 0.0025, respectively). In this study, we found that chromosome 9p21 SNP rs10757278 and related haplotypes correlate with MetS risk. This is the first report showing an association between a 9p21 variant and MetS and suggests that rs10757278 polymorphism may confer increased risk for disease.

Circulating p53 and cytochrome c levels in acute myocardial infarction patients.

BACKGROUND: Apoptosis causes myocardiocyte loss during and after myocardial infarction. Therapeutic approaches designed to arrest apoptosis would be a significant new development in the recovery of acute myocardial infarction (AMI). In order to examine apoptotic markers in the circulation, serum levels of p53 and cytochrome c were assessed in patients with AMI. METHODS: Blood samples were taken on admission (before initiation of therapy) and on the 3rd and 7th days of hospitalization. Serum levels of p53 and cytochrome c were measured by enzyme-linked immunassay. RESULTS: The serum level of p53 was higher in AMI patients on admission compared to the control group. A time-dependent decrease was observed in the serum level of p53, but there was no significant change in the serum level of cytochrome c during therapy. CONCLUSIONS: p53, but not cytochrome c, appears to have potential as a biomarker for reporting on apoptosis following myocardial infarction.

Extraordinary cause of ischemic chest pain in a young man: congenital ostial atresia of the right coronary artery.

Chest pain in a young person without cardiovascular risk factors is usually attributed to noncoronary causes; however, if the history suggests ischemic pain, the potential presence of unusual cardiovascular abnormalities should not be disregarded. The present case describes a young man with solitary congenital ostial atresia of right coronary artery, who to our knowledge is only the second case in the medical literature. Manifestation of ischemic symptoms in a relatively advanced age in patients with coronary artery atresia may mislead clinicians to interpret them as signs of atherosclerotic coronary artery disease. Therefore congenital coronary artery atresia should be a part of the differential diagnosis particularly in young patients with ischemic symptoms and no cardiovascular risk factors.

Relationship between two estrogen receptor-alpha gene polymorphisms and angiographic coronary artery disease.

OBJECTIVE: To investigate the association of estrogen receptor-alpha PvuII and BtgI polymorphisms with angiographic presence and severity of coronary artery disease (CAD). METHODS: Our cross-sectional study included 140 patients with >or=50% coronary stenoses (CAD group) and 47 patients with normal angiograms (CAD-free group) (total n=187, age 59.6+/- 13.2 years; 66 women). PvuII and BtgI genotype and allele distributions were determined by standard method of polymerase chain reaction and restriction fragment length polymorphism. The CAD subgroups by the number of diseased vessels were also defined. Variable associations and group differences were analyzed by independent t test, one-way ANOVA, Pearson's Chi-square, Spearman's correlation tests and logistic regression analyses. RESULTS: While there was no association between PvuII polymorphism and angiographic CAD (p=0.384), BtgI polymorphism was more prevalent in CAD-free group (23.4% vs. 10% (CAD group), OR=2.75, 95% CI=1.150 to 6.579, p=0.019). This difference was more pronounced in women (28.6% vs. 4.4%; OR=8.6; 95% CI=1.564 to 47.303; p=0.005) compared to men (p=0.391). Logistic regression analysis confirmed BtgI polymorphism as the most important predictor for a normal coronary angiogram among parameters such as body mass index, diabetes and age (OR 8.13, 95% CI 1.257 to 52.627, p=0.028). However, no significant association between BtgI polymorphism and the number of stenotic arteries was detected. CONCLUSION: ESR1 PvuII polymorphism is not associated with angiographically significant CAD. ESR1 BtgI polymorphism is strongly associated with the presence of normal coronary angiograms in women, which suggests protective effect. Further confirmation of these findings is required.

Serum myeloperoxidase level predicts reperfusion in patients with myocardial infarction receiving thrombolytic therapy.

Polymorphonuclear leukocytes play a central role in all stages of the atherothrombotic inflammatory process. The atherothrombotic activity of polymorphonuclear leukocytes is exerted by mediators such as myeloperoxidase (MPO). Although the role of MPO has been studied with respect to the development of adverse cardiac events in acute coronary syndromes (ACS), the association of this molecule with effectiveness of reperfusion in patients receiving thrombolysis is not yet known. The study population consisted of a total of 158 patients with acute coronary syndromes. Final diagnosis was ST-segment elevation myocardial infarction in 86 patients, 80 of whom received thrombolysis. Blood samples were drawn at presentation of the patients and serum myeloperoxidase levels were measured. Reperfusion was defined in terms of electrocardiographic ST-segment resolution. The serum levels of MPO were found to be correlated with rates of in-hospital adverse events including death (P < 0.001), reinfarction (P < 0.001), recurrent ischemia (P < 0.001), arrhythmias (P < 0.001), clinical heart failure (P < 0.001), and cardiogenic shock (P < 0.001). There was a significant difference in serum MPO levels between subjects with three-vessel disease and two- or one-vessel disease (P < 0.001). Pre-lytic serum high-sensitivity C-reactive protein levels in patients with successful reperfusion were lower than in patients with failed reperfusion (P < 0.001). Analysis of patients with ST segment elevation myocardial infarction receiving thrombolytic therapy revealed that pre-lytic serum MPO levels in patients with successful reperfusion were significantly lower than those of patients with failed reperfusion (P < 0.001). In the present study, serum MPO levels were found to be a strong predictor of response to thrombolytic treatment in patients with ST-segment elevation myocardial infarction. Therefore the level of inflammatory activity in acute coronary syndromes seems to influence the effectiveness of fibrinolysis.

Effects of serum homocysteine and adiponectin levels on platelet aggregation in untreated patients with essential hypertension.

The aim of the present study is to determine and correlate adiponectin, homocysteine, nitric oxide, and ADP-induced platelet aggregation levels in untreated patients with essential hypertension and healthy individuals. A total of 36 individuals, 23 untreated patients with essential hypertension and 13 healthy individuals, were included in the scope of this study. Enzyme-linked immunosorbent assay (ELISA) was used to determine the serum adiponectin and TNF-alpha levels. The levels of serum homocysteine were measured by using competitive chemiluminescent enzyme immunoassay. Serum concentrations of hsCRP were measured by the Nephelometer. Plasma nitrite, nitrate, and total nitric oxide (NOx) levels were determined by colorimetric method. Homocysteine and hsCRP levels in patients with essential hypertension were found to be significantly higher than those in the control group (P = 0.02, P = 0.001, respectively). The average platelet aggregation levels in patient group were higher than control group, but there were no statistically significant differences between them (P > 0.05). In addition, in patients with essential hypertension adiponectin and nitrite levels are significantly lower than control group (P < 0.001, P = 0.045, respectively). We have also found significant correlations between nitrite-platelet aggregation amplitude, nitrite-platelet aggregation slope, nitrite-adiponectin, homocysteine-platelet aggregation amplitude, and sistolic blood pressure-platelet aggregation amplitude levels (r = -0.844; P < 0.001, r = -0.680; P = 0.011, r = 0.454; P = 0.05, r = 0.414; P = 0.05, r = 0.442; P = 0.035, respectively). Increased homocysteine and decreased adiponectin serum levels in patients with essential hypertension correlate well with changes in ADP-induced conventional platelet aggregation. This association may potentially contribute to future thrombus formation and higher risks for cardiovascular events in hypertensive patients.

Takayasu disease with prominent pulmonary artery involvement: confusion with pulmonary disease leading to delayed diagnosis.

Pulmonary artery involvement as the initial predominant clinical manifestation in Takayasu arteritis (TA) is rare. We describe a young adult female who presented with life-threatening complications of proximal pulmonary arterial involvement of Takayasu arteritis. In our case, atypical presentation of TA with pulmonary symptoms due to pulmonary artery involvement resulted in an erroneous initial diagnosis of sarcoidosis and then tuberculosis. The frequency of such a clinical form could be underestimated given the difficulties involved in its diagnosis and because its features are similar to those of pulmonary disease.

Homocysteine and nitric oxide in patients undergoing diagnostic coronary angiography.

We evaluated the plasma homocysteine (tHcy) and nitric oxide metabolites (nitrite plus nitrate; NOx) data of consecutive patients undergoing diagnostic coronary angiography (n=79) with respect to the presence and severity of coronary artery disease (CAD), the presence of acute coronary syndromes (ACS), and the risk status of patients. Hyperhomocysteinemia (>15 micromol/L) was detected in 11% of the controls (n=19) and 37% of CAD patients (n=60) (p=0.03). Plasma tHcy in CAD patients was not significantly different from controls, but those with 3-vessel disease had a significantly higher tHcy concentrations than did controls (p=0.049). The patients with 3-vessel disease and ACS had the highest concentrations of tHcy (16.9 +- 4.4 micromol/L), and the difference from the ACS patients with 1- and 2-vessel involvement was significant (p=0.03). In patients with 1-vessel involvement, tHcy was correlated with NOx (r=0.62, p=0.005); in patients with 2- and 3-vessel disease this correlation could not be observed. The high-risk patients (n=51) had a higher mean number of vessel involvement and tHcy (p<0.001, p<0.05, respectively) but lower NOx (p<0.05) when compared to the low-risk patients (n=28). It appears that in the early stages of atherosclerosis hyperhomocysteinemia causes an increase in NOx production, but with progression of the disease this compensatory increase disappears.

Looking for Our Ten Years Results for Coronary Heart Disease and Ischemic Stroke Group for the Standpoint of Haemostasis.

To evaluate the role the coagulation and fibrinolysis abnormalities in the pathogenesis of ischemic stroke of undetermined etiology, we assayed plasma concentration of fibrinopeptide-A and thrombin-antithrombin III complex, both sensitive markers for thrombin activation and fibrin formation, and D-dimer, a marker of plasmin activity and fibrinolysis. Hemostatic markers were measured in 32 patients with acute stroke and 20 patients with chronic stroke, and compared with 21 normal subjects. Fibrinopeptid-A and thrombin-antithrombin III complex levels were not elevated significantly, whereas the D-dimer level was markedly raised in acute (p<< 0.001) and chronic (p< 0.05) phases of ischemic stroke in comparison with the control group. Prolonged elevation of D-dimer concentration suggests that hemostatic abnormalities have a primary role in the pathogenesis of ischemic stroke. The measurement of D-dimer concentration may help to better decide the indications for therapy of the patients with ischemic stroke of undetermined etiology.