Anna Kozieradzka

Coronary sinus concentrations of interleukin 6 and its soluble receptors are affected by reperfusion and may portend complications in patients with myocardial infarction

UNLABELLED Interleukin 6 (IL-6) is a pleiotropic cytokine involved in both inflammatory reaction and myocardial response to stress. Its effects largely depend on the concentration of the soluble receptors (sIL-6R and sgp130). We investigated the production of IL-6, sIL-6R and sgp130 by the heart during ischemia and reperfusion. METHODS The levels of IL-6 were determined in blood of 34 patients with first myocardial infarction (STEMI), left anterior descending (LAD) artery occlusion, otherwise normal coronaries, without significant co-morbidities and 16 comparable subjects with stable ischemic heart disease and lesion in LAD. Blood samples from coronary sinus (CS) and aorta (Ao) were drawn before percutaneous intervention (PCI), immediately after and at the end of the procedure. Venous blood from 30 healthy volunteers served as control. RESULTS STEMI patients presented high IL-6 concentrations that increased further after reperfusion when its levels in CS became significantly higher than in Ao. In both groups prior to the PCI there were significantly higher concentrations of sIL-6R in Ao than in CS. This difference disappeared immediately after reperfusion. STEMI patients who experienced cardiovascular complications had higher IL-6 concentration and higher transcardiac sIL-6R gradient than patients with event-free hospitalisation. This association was confirmed in multivariate logistic regression analysis. Myocardial infarction increases concentration of IL-6 that is further elevated by reperfusion. A transcardiac gradient of sIL-6R during ischemia may indicate that large amounts of soluble IL-6 receptors are bound to the infarcted heart and thus affect signal transduction. IL-6 and initial sIL-6R gradient may portend complications in STEMI patients.

Influence of atorvastatin on blood pressure control in treated hypertensive, normolipemic patients - An open, pilot study

Abstract Aims. The aim of the study was to determine whether a high dose of atorvastatin lowers blood pressure (BP) in normolipemic patients with well controlled primary arterial hypertension and if this effect is associated with alteration of biomarkers of endothelial function and oxidative stress. In this open-label study, normolipemic patients (n=56) were randomized in the proportion of 2:1 to receive atorvastatin 80 mg daily for 3 months (statin-treated, ST n=39), or to previous therapy (statin-free, SF). BP was measured using a 24-h ambulatory BP measurement device. Plasma levels of 6-keto-PGF1α (prostacyclin metabolite), serum nitric oxide (NO) and levels of autoantibodies immunoglobulin G against oxidatively modified low-density lipoprotein (ox-LDL) were measured. Major findings. The mean change in systolic BP and diastolic BP for ST was – 5.7 mmHg (95% CI –4.1 to –7.2 mmHg) and –3.9 mmHg (95% CI –2.7 to –5.0 mmHg), respectively. Hypotensive statin effect was independent of lipid lowering. No change of BP in SF patients was observed. In ST, prostacyclin metabolites and NO concentrations were not significantly increased and autoantibodies against ox-LDL concentrations did not change. In ST, the decrease in BP correlated with increase in NO and decrease in autoantibodies against ox-LDL. Principal conclusion. High-dose atorvastatin resulted in reduction of BP independently of lipid-lowering effect, changes in endothelial function and oxidative stress, but it was related to the increase in NO and decrease in autoantibodies against ox-LDL. However, because of the open design of the study, these results should be carefully debated.

High-sensitivity C-reactive protein and total antioxidant status in patients with essential arterial hypertension and dyslipidemia.

PURPOSE To assess low-grade, systemic inflammation and antioxidant status as additional factors contributing to pathophysiology of essential arterial hypertension (HTN) and compare them with traditional risk factors, like abnormal lipids profile, considering their potential diagnostic usefulness. MATERIAL AND METHODS Serum high-sensitivity C-reactive protein (hs-CRP) concentrations and total antioxidant status (TAS) were measured in 143 subjects - 71 patients with diagnosed HTN and in 72 healthy controls. RESULTS In hypertensive patients, as compared to healthy control group, the median hs-CRP concentration was higher (2.0 mg/L, 25%; 75% quartile range: 0.1; 27.1 vs 0.4 mg/L, 25%; 75% quartile range: 0.0; 4.6, respectively, p<0.001) and TAS concentration lower (1.4 mmol/L, 25%; 75% quartile range: 1.0; 2.1 vs 1.5 mmol/L, 25%; 75% quartile range: 0.5; 1.8, respectively, p=0.048). Hypertensives had higher low-density lipoprotein cholesterol concentration (LDL-C) as well as triglycerides concentration (TG) and lower high-density lipoprotein cholesterol concentration (HDL-C). Higher diagnostic sensitivity was found for hs-CRP (87%) and for TAS (89%). According to the global linear regression analysis, age, gender, hs-CRP, TAS and HDL-C were the only parameters influencing the occurrence of HTN. ROC analysis identified hs-CRP, HDL-C and TG as statistically significant to diagnose HTN (0.839; 0.816 and 0.855, respectively). Moreover, in ROC analysis there were no differences in hs-CRP and TAS in females and males. CONCLUSIONS These results indicate that low-grade, systemic inflammation measured by hs-CRP as well as antioxidant status assessed by TAS, in the presence of traditional risk factors, are significant factors contributing to pathophysiology and diagnosis of essential arterial hypertension.

Hypotensive effect of atorvastatin is not related to changes in inflammation and oxidative stress

We sought to determine if atorvastatin lowers blood pressure in patients with previously diagnosed and well-controlled essential arterial hypertension and if this effect could be related to anti-inflammatory and anti-oxidative effects. Among 92 patients with essential arterial hypertension, we studied 56 non-smoking and normolipemic: 39 were randomized to receive 80 mg atorvastatin daily for 3 months (statin-treated patients, ST), and the rest continued a previous hypotensive therapy (statin-free patients, SF). Blood pressure was measured using a 24-h ambulatory blood pressure measurement device. Serum levels of high-sensitivity C-reactive protein (hs-CRP), total antioxidant status (TAS) and plasma peroxides (assessed by Oxystat) were measured in both groups. The mean change in systolic BP (SBP) for atorvastatin was -5.7 mmHg (95% confidence interval CI, -4.1 to -7.2 mmHg), and the mean change in diastolic BP (DBP) was -3.9 mmHg (95% CI, -2.7 to -5.0 mmHg). No change in BP in SF patients was observed. In the ST group, hs-CRP and peroxides did not significantly decrease. In the SF group, concentrations of hs-CRP proceeded to decrease while peroxides increased. In the ST group, changes in hs-CRP correlated with changes in total cholesterol and low-density lipoprotein cholesterol (r = 0.41, p = 0.013 and r = 0.35, p = 0.04, respectively) but did not correlate with changes in BP. The hypotensive statin effect was independent of the hypolipemic effect. During three months of observation, TAS concentrations in both groups remained stable. In this randomized study, additionally administered atorvastatin to non-smoking and normolipemic patients with well-controlled essential arterial hypertension resulted in reduction of BP. This effect was not followed by significant changes in hs-CRP, TAS or Oxystat concentrations. The hypotensive effect of atorvastatin did not depend on anti-inflammatory, anti-oxidative or hypolipemic actions.

Circadian variations of interleukin 6 in coronary circulations of patients with myocardial infarction.

UNLABELLED We hypothesize that higher morbidity of patients with ST-segment elevation myocardial infarction (STEMI) in the out-of-office hours differences in outcome after myocardial infarction may depend on the concentrations of inflammatory cytokines. The aim of the study was to determine the relation between the time of percutaneous coronary intervention (PCI) and local concentration of interleukin 6 (IL-6) and its soluble receptors (sIL-6R and sgp130) in patients with STEMI. METHODS AND RESULTS The study included 32 patients with invasively treated left anterior descending artery occlusion and no significant co-morbidities. Blood samples were drawn from coronary sinus and aorta before and after intervention. Patients admitted in the afternoon (13-20) presented significantly higher mean IL-6 levels in all samples than patients admitted in the morning. There was a positive correlation between time of intervention and concentrations of IL-6 in all samplings, but also with transcardiac IL-6 gradient at the end of procedure and IL-6 increase during PCI. We did not find any significant association between time of PCI and concentrations of sIL-6R and sgp130, time from pain to balloon, angiographic parameters or medical history. CONCLUSIONS Coronary concentration of IL-6 in patients with STEMI is significantly higher in the afternoon than in the morning. This might be involved in increased morbidity of those patients.

The association between type 2 diabetes mellitus and A1/A2 polymorphism of glycoprotein IIIa gene.

Glycoprotein IIIa (GpIIIa) is a membrane receptor, found in various tissues, that has two alleles: A1 and A2. Signalling cascade of GpIIIa is modulated by enzymes called calpains, proteases that may also influence glucose metabolism. There is one small study that shows a high association of A1/A2 polymorphism with type 2 diabetes mellitus. In our research we planned to evaluate the association of A1/A2 polymorphism with type 2 diabetes in a population of patients with ST elevation acute myocardial infarction (STEMI). The study comprised 352 individuals. From the cohort of patients hospitalised for STEMI we chose 113 patients with diagnosed diabetes (diabetic group) and 118 patients with STEMI and normal glucose metabolism (non-diabetic group). The population group consisted of 121 persons. Genotyping was performed by the restriction fragments length polymorphism (RFLP) method. The frequency of alleles in all groups was in Hardy-Weinberg equilibrium. The percentage of A2 allele carriers was comparable among all groups : 20.4% (diabetic patients), 23.7% (nondiabetic) and 21.5% (control group) (p>0.05). There was no significant difference in frequency of A2 allele among the groups. We have not observed any association between GpIIIa polymorphism with either type 2 diabetes or STEMI.

Iatrogenic femoral pseudoaneurysms - a simple solution of inconvenient problem?

PURPOSE A femoral artery pseudoaneurysm - is the most common complication associated with invasive coronary interventions. The aim of the study was to analyze the effectiveness of various methods used for femoral pseudoaneurysm treatment and to assess how routine use of radial approach leads to reduction of these site complications. METHODS The study comprised 1854 consecutive patients who were hospitalized in years 2005-2008 and underwent coronary angiography (with or without angioplasty) via femoral artery access. Since 2009 routine radial approach has been introduced for both coronary angiography and angioplasty. In patients with symptoms suggesting entry site complications Doppler ultrasound was performed. RESULTS Femoral access site complications requiring additional procedures were observed in 63 patients (3.4%): in 56 femoral pseudoaneurysms (88.8%) and in 7 arteriovenous fistulas (11.1%) were diagnosed (all appeared after coronary angioplasty). The patients were treated in following ways: standard compression with an elastic bandage prolonged to 12 hours - in 14 cases (25%), ultrasound guided compression - in 13 patients (23.2%), finger compression followed by standard compression with an elastic bandage prolonged to 12 hours or ice compress - in 10 patients (17.8%), surgical treatment - in 3 patients (5.3%). Only 2 patients required thrombin injection (3.6%). Since the time routine radial approach was introduced extreme reduction in the rate of local complications was registered. CONCLUSION Although iatrogenic femoral pseudoaneurysms following invasive percutaneous coronary interventions are still important complications, most of them can be treated conservatively. It seems that radial access completely eliminates the risk of this complication.

The rs1801133 polymorphism of methylenetetrahydrofolate reductase gene- the association with 5-year survival in patients with ST-elevation myocardial infarction.

PURPOSE Methylenetetrahydrofolate reductase (MTHFR) is an enzyme involved in endothelial nitric oxide synthase (eNOS) coupling and homocysteine metabolism. The rs1801133 polymorphism of the MTHFR gene affects risk of coronary artery disease. We assessed its influence on 5-year survival of patients with ST-elevation acute myocardial infarction (STEMI). MATERIAL/METHODS The study group comprised consecutive patients with STEMI. Genotyping was performed with a TaqMan SNP Genotyping Assay using the ABI 7500 Real Time PCR System (Applied Biosystems). The analyzed end-point was all-cause 5-year survival. RESULTS The study group comprised 637 patients (mean age 62.3 ± 11.9 years; 25.1% females, n=160; 5-year mortality 16.3%, n=104). The percentages of TT, CT and CC genotypes were: 10.8 (n=69), 39.7 (n=253) and 49.45 (n=315), respectively. No significant differences in clinical characteristics were identified between the genotypes (p>0.05 for all parameters). Eleven (15.9%) TT homozygotes, 40 (15.8%) heterozygotes and 53 (16.8%) CC homozygotes died during follow up (p=0.99 log-rank test). TT homozygotes presented only weak and insignificant tendency towards higher mortality rates in subgroups of patients ≤75 years old (15.6 vs. 11.54%, p=0.35) or with intermediate risk according to the GRACE risk score (13.3% vs. 8.76%, p=0.42). CONCLUSIONS The rs1801133 polymorphism did not show significant association with 5-year survival.

Percutaneous Coronary Interventions Affect Concentrations of Interleukin 6 and Its Soluble Receptors in Coronary Sinus Blood in Patients With Stable Angina

Coronary stenting may create local inflammatory reaction. Interleukin 6 effects depend on the presence of soluble receptors (sIL-6R and sgp130) that facilitate or impede interleukin 6 signal transduction. Concentrations of interleukin 6 and its soluble receptors were assessed in aorta and coronary sinus after stenting in optimally treated stable angina patients scheduled for elective stenting. Baseline levels of interleukin 6 and its soluble receptors in patients did not differ from healthy controls. Initial levels of sIL-6R in aorta were significantly higher than in coronary sinus but this difference disappeared after intervention. Stenting caused interleukin 6 concentration increase to a similar extent both in coronary sinus and in aorta. Moreover, there was significantly higher sgp130 concentration in coronary sinus than in aorta. Coronary intervention increases concentration of interleukin 6 in patients with stable angina. It affects the cardiac level of interleukin 6 soluble receptors what may influence the local inflammatory reaction.