Dragan Simic

Evaluation of Oxidative Stress after Repeated Intravenous Iron Supplementation

Parenteral iron has been recommended for the treatment of iron deficiency in the majority of maintenance hemodialyzed (HD) patients. However, iron supplementation and consequent over saturation of transferrin and high iron levels, may aggravate oxidative stress already present in these patients. This study aimed to further clarify the role of repeated intravenous iron therapy as a supplementary cause of oxidative stress in HD patients. Markers of free radical activities (carbonyl reactive derivatives, CRD, thiol groups, SH, malondialdehyde, MDA) and antioxidant enzyme activities (superoxide dismutase, SOD and glutathione peroxidase, GPX) were determined in plasma and red blood cells (RBC) of 19 hemodialysis patients given a total iron dose of 625 mg (ferrogluconat, Ferrlecit, 62.5 mg). Blood samples were taken before the first and after the last dose of iron. Twenty apparently normal subjects served as healthy controls. Before iron treatment, HD patients exhibited increased concentrations of MDA and CRD in plasma and red blood cells, accompanied with impaired antioxidant capacity. All patients responded to iron therapy with a significant increase in their serum ferritin, serum iron, hemoglobin, and red blood cells levels. However, iron treatment resulted in enhanced oxidative stress in plasma of HD patients, since significant increase in plasma MDA and CRD concentrations, together with a decrease in nonprotein SH groups levels were detected. Supplementation with iron did not significantly influence plasma SOD and GPX activities, nor did any of the red blood cell parameters tested. Our data show that, despite improvement in hematological parameters, an increase in iron stores due to supplementation could also contribute to increased free radical production in HD patients.

Markers of oxidative damage in chronic heart failure: role in disease progression

Abstract Background: We aimed to study the relationship between markers of oxidative lipid or protein damage and ventricular remodeling and the validity of 8-epi-prostaglandin F2α (8-epi-PGF2α) as an indicator of disease severity in patients with ischemic chronic heart failure (CHF). Patients and methods: We enrolled four groups of 12 patients with varying CHF according to the New York Heart Association (NYHA) classification and 25 controls. Urinary 8-epi-PGF2α and plasma malondialdehyde and protein thiol (P-SH) groups were correlated with echocardiographic indices of remodeling. The reliability of isoprostanes was analyzed by a receiver operating characteristics (ROC) curve. Results: NYHA class III and IV patients exhibited elevated 8-epi-PGF2α levels, increased malondialdehyde concentrations and decreased P-SH groups when compared to controls and NYHA I and II patients. 8-Epi-PGF2α and P-SH groups correlated significantly with indices of remodeling. The ROC curve drawn for 8-epi-PGF2α allowed us to differentiate NYHA class III and IV patients from NYHA class I and II patients with a sensitivity of 95.8% and specificity of 95.8% (cut off 0.84 ng/mg creatinine; area under curve 0.99; P < 0.001). Conclusions: Markers of oxidative damage are unlikely to play a significant role in early stages of CHF. However, they might become important in the course of CHF when their concentrations reach critical levels. Urinary 8-epi-PGF2α is a reliable indicator of symptomatic CHF.

The Role of Serum VCAM‐1 and TNF‐α as Predictors of Mortality and Morbidity in Patients with Chronic Heart Failure

To assess the prognostic significance of four inflammatory markers (TNF‐α, high sensitive C‐reactive protein (hs‐CRP), intercellular cell adhesion molecule‐1 (ICAM‐1), vascular cell adhesion molecule‐1 (VCAM‐1)) in chronic heart failure (CHF) patients with respect to individual outcomes, especially disease exacerbation and mortality.

Metabolic syndrome and left ventricular function: Is the number of criteria actually important?

Summary Background Metabolic syndrome (MS) is a clustering of cardiovascular risk factors responsible for the development of target organ damage. The aim of this study was to determine the effect of the increasing number of MS risk factors on left ventricular function assessed by noninvasive methods. Material/Methods The study included 204 subjects with MS and 76 controls with no MS risk factors. MS was defined by the presence of 3 or more of ATP-NCEP III criteria. MS subjects were grouped according to the number of criteria they fulfilled: 3 criteria (n=91), 4 criteria (n=65) and 5 criteria (n=48). All subjects underwent laboratory blood tests, complete 2-dimensional, pulse and tissue Doppler echocardiography. Echocardiography was used to assess systolic (LVEF, sseptal), diastolic function, by pulse-wave Doppler (E/A ratio) and tissue Doppler imaging (E/e′average), and global left ventricular function (Tei index). Appropriate time intervals for the estimation of the Tei index were obtained by tissue Doppler. Results Transmitral E/A ratio decreased significantly and progressively from the 3 criteria to the 5 criteria group (0.82±0.25 vs. 0.79±0.24 vs. 0.67±0.14, p<0.001). The transmitral E/E′average ratio was significantly and gradually increased from the 3 criteria to the 5 criteria group (7.76±1.81 vs. 9.44±2.35 vs. 10.82±2.56, p<0.001). The left ventricle Tei index progressively increased from the 3 criteria to the 5 criteria group (0.43±0.11 vs. 0.48±0.10 vs. 0.54±0.12, p<0.001). Conclusions The increasing number of MS criteria is associated with cardiac diastolic dysfunction.

Are all criteria of metabolic syndrome equally harmful

Objective The metabolic syndrome (MS) is associated with subclinical damage of diff erent organs. The aim of this study was to determine which risk factors of MS were independently associated with left ventricular structure and function (diastolic and global). Methods The study included 204 subjects with MS and 88 control subjects with no risk factors. The metabolic syndrome was defi ned by the presence of three or more of ATP-NCEP III criteria. All subjects underwent laboratory blood tests, and complete two-dimensional echocardiography which also included tissue Doppler. The echocardiography was used to assess left ventricular (LV) structure (LVmass/Ht2.7), systolic (LVEF, sseptal, slateral) and diastolic function, by pulse-wave Doppler (E/A ratio) and tissue Doppler imaging (E/e´average), and global function (Tei index). Appropriate time intervals for the estimation of the Tei index were obtained by tissue Doppler. Results The LV mass index, E/e´average and Tei index were signifi cantly higher in the MS group, whereas there was no diff erence in LV systolic function. Multiple regression analysis showed that LVmass/Ht2.7 was independently associated with systolic blood pressure (β= 0.41, P < 0.001) and waist circumference (β= 0.22, P= 0.016). The same analysis revealed that E/e´average was independently associated with systolic blood pressure (β= 0.35, P < 0.001), waist circumference (β= 0.24, P= 0.004) and triglycerides level (β= 0.21, P= 0.012); while the Tei index was independently associated with systolic blood pressure (β= 0.42, P < 0.001) and fasting glucose (β= 0.31, P < 0.001). Conclusion MS impairs left ventricular structure and diastolic and global function. Systolic blood pressure was the only MS criterion which was, at the same time, independently associated with LVmass/Ht2.7, E/e´average and the Tei index.

Predictors of global left ventricular function in metabolic syndrome

FUNDAMENTO: El sindrome metabolico (SM) representa un conjunto de factores de riesgo cardiovascular que actuan de forma sinergica. OBJETIVO: El objetivo de este estudio fue determinar cuales parametros estaban asociados de forma independiente a la funcion global del ventriculo izquierdo (VI) en individuos con SM, estimada a traves del indice Tei. METODOS: El estudio incluyo 234 individuos con SM y 96 controles ajustados por edad. El SM fue definido por la presencia de tres o mas criterios ATP-NCEP III. Todos los individuos fueron sometidos a tests de laboratorio y ecocardiograma bidimensional y con Doppler pulsado y tisular. Intervalos de tiempo apropiados en el Doppler tisular para la estimativa del indice Tei tambien fueron evaluados. RESULTADOS: El indice Tei estaba aumentado en todos los individuos con SM (0,35 ± 0,05 vs 0,49 ± 0,10, p < 0,001). Analisis de regresion multiple de los parametros clinicos mostro que la presion arterial sistolica (β = 0,289, p < 0,001), glucemia de ayuno (β = 0,205, p = 0,009), indice de masa del VI (β = 0,301, p < 0,001), E/eseptal (β = 0,267, p < 0,001) y eseptal (β = -0,176, p = 0,011) estaban independientemente asociados con la funcion ventricular izquierda global estimada por el indice Tei. CONCLUSION: El SM tuvo un impacto significativo en la funcion global del VI. La presion arterial sistolica, glucemia de ayuno, indice de masa del VI E/eseptal, y eseptal estaban independientemente asociados con la funcion global del VI. (Arq Bras Cardiol 2011;96(5):377-385)

Noninvasive assessment of myocardial bridging by coronary flow velocity reserve with transthoracic Doppler echocardiography: vasodilator vs. inotropic stimulation

BACKGROUND To consider hemodynamic assessment of myocardial bridging (MB) adequate, it is believed that inotropic stimulation with dobutamine should be estimated because its dynamic nature depends on the degree of extravascular coronary compression. This study evaluated comparative assessment of hemodynamic relevance of MB using coronary flow velocity reserve (CFVR) measurements by transthoracic Doppler echocardiography (TTDE) with vasodilatative and inotropic challenges. METHODS This prospective study included forty-four patients with angiographic evidence of isolated MB of the left anterior descending coronary artery (LAD) and systolic compression of ≥50% diameter stenosis. All patients were evaluated by exercise stress-echocardiography (ExSE) test for signs of myocardial ischemia, and CFVR of the distal segment of LAD during iv.infusion of adenosine (ADO:140μg/kg/min) and iv.infusion of dobutamine (DOB:10-40μg/kg/min), separately. RESULTS Exercise-SE was positive for myocardial ischemia in 8/44 (18%) of patients. CFVR during ADO was significantly higher than CFVR during peak DOB (2.85±0.68 vs. 2.44±0.48, p=0.002). CFVR during peak DOB was significantly lower in SE-positive group in comparison to SE-negative group (2.01±0.16 vs. 2.54±0.47, p<0.001), but not for ADO (2.47±0.51 vs. 2.89±0.70, p=0.168), respectively. Multivariable logistic analysis showed that CFVR peak DOB was the most significant predictor of functional significant MB (OR 0.011, 95%CI: 0.001-0.507, p=0.021). Receiver-operating characteristic curves have shown that TTDE-CFVR obtained by high-dose of dobutamine infusion is better than those by adenosine regarding to functional status of MB (AUC 0.861, p=0.004; AUC 0.674, p=0.179, respectively). CONCLUSIONS Non-invasive CFVR measurement by TTDE during inotropic stimulation, in comparison to vasodilation, provides more reliable functional evaluation of MB.

Associations of GSTM1*0 and GSTA1*A genotypes with the risk of cardiovascular death among hemodialyses patients.

BackgroundThe presence of glutathione transferase (GST) M1 null genotype (GSTM1-null) in end-stage renal disease (ESRD) patients is associated with lower overall survival rate in comparison to those with GSTM1-active variants. We examined association between GSTM1 and GSTT1 deletion polymorphisms as well as SNPs in GSTA1/rs3957357 and GSTP1/rs1695 genes with overall and cause-specific cardiovascular mortality in ESRD patients.MethodsTotal of 199 patients undergoing hemodialysis were included in the study. Median value of time elapsed from dialysis initiation until the death, or the end of follow-up was 8 ± 5 years. The effect of GSTM1, GSTT1, GSTP1 and GSTA1 gene polymorphisms on predicting overall and specific cardiovascular outcomes (myocardial infarction, MI or stroke) was analyzed using Cox regression model, and differences in survival were determined by Kaplan-Meier.ResultsGSTM1-null genotype in ESRD patients was found to be independent predictor of overall and cardiovascular mortality. However, after false discovery rate and Bonferroni corrections this effect was lost. The borderline effect modification by wild-type GSTA1*A/*A genotype on associations between GSTM1-null and analyzed outcomes was found only for death from stroke. Homozygous carriers of combined GSTM1*0/GSTA1*A genotype exhibited significantly shorter time to death of stroke or MI in comparison with carriers of either GSTM1-active or at least one GSTA1*B gene variant. The best survival rate regarding cardiovascular outcome was found for ESRD patients with combined GSTM1-active and mutant GSTA1*B/*B genotype.ConclusionsCombined GSTM1*0/GSTA1*A genotypes might be considered as genetic markers for cardiovascular death risk in ESRD patients, which may permit targeting of preventive and early intervention.

Arterial hypertension in the elderly

More than half of the individuals older than 65 are affected by hypertension. Isolated systolic hypertension, characterized by an increase in systolic arterial pressure without an increase in diastolic one, is the most frequent type of hypertension in persons over 50 years of age. It occurs de novo or after a long period of inadequately treated systolicdiastolic arterial hypertension. The main reason for its occurence is many years mediated increase in stiffness of the large elastic arteries. This structural change is responsible for the occurrence of high systolic pressure in the following two ways: by blood ejection from the left ventricle into the stiff arterial system of decreased distensibility, and by the increase in the pulse wave velocity with the reflection wave occurring during late systole. The increased peripheral vascular resistance, sympathetic stimulation and activities of the Renin Angiotensin Aldosteron (RAA) system play a less significant role in the incidence of arterial hypertension in the elderly than is the case with individuals affected by structural and functional changes of the aorta. Previously, vascular stiffness and an increase in systolic pulse pressure were considered as a part of the aging process and there was no insistence on treating this type of hypertension. Nowadays, when it is known that arterial hypertension in the elderly increases the risk of cardiovascular diseases three to four times more than in younger persons, it is insisted that this significant risk factor be corrected. In addition to necessary life style modifications, the advantage in medical treatment is given to thiazide diuretics and dihydropiridines from the group of calcium channel blockers. The therapy should be always adjusted to comorbidities. Elderly persons are defined as individuals at the age of 65 and older. They represent a growing segment of the population. In 1990, elderly persons comprised 13% of the total population of the USA and it is estimated that until 2040 they will constitute 20% of the population . As regards the number of elderly persons, Serbia is ranked as the fourth country in the world, after Greece, Italy and Japan. According to the data of the Statistical Office of the Republic of Serbia, approximately 17.24% of the population was elderly at the end of the last century, and it is estimated that this number will increase to 30% as far as 2025 . Similarly, the percentage of very old persons (older than 85) is constantly growing and it is assumed that there will be 16 million very old persons in the world by the middle of the 21 century . More than half of the individuals over 65 years of age have hypertension . The principal reason for the increased incidence of arterial hypertension in the elderly is the growing number of persons suffering from isolated systolic hypertension (ISH), which is also the most frequent type of hypertension found in this age group 3, . Isolated systolic hypertension is defined as an elevated systolic blood pressure ≥ 140 mmHg with the diastolic pressure value < 90 mmHg. Much more significant fact than the increased incidence of the elderly is the fact that the elderly with arterial hypertension, wheter it is isolated systolic or both systolic and diastolic, are at three to four times higher risk to develop cardiovascular diseases than young individuals. It is an important risk factor for stroke, heart failure, coronary artery disease, terminal renal failure and death .

Preditores de função ventricular esquerda global na síndrome metabólica

FUNDAMENTO: El sindrome metabolico (SM) representa un conjunto de factores de riesgo cardiovascular que actuan de forma sinergica. OBJETIVO: El objetivo de este estudio fue determinar cuales parametros estaban asociados de forma independiente a la funcion global del ventriculo izquierdo (VI) en individuos con SM, estimada a traves del indice Tei. METODOS: El estudio incluyo 234 individuos con SM y 96 controles ajustados por edad. El SM fue definido por la presencia de tres o mas criterios ATP-NCEP III. Todos los individuos fueron sometidos a tests de laboratorio y ecocardiograma bidimensional y con Doppler pulsado y tisular. Intervalos de tiempo apropiados en el Doppler tisular para la estimativa del indice Tei tambien fueron evaluados. RESULTADOS: El indice Tei estaba aumentado en todos los individuos con SM (0,35 ± 0,05 vs 0,49 ± 0,10, p < 0,001). Analisis de regresion multiple de los parametros clinicos mostro que la presion arterial sistolica (β = 0,289, p < 0,001), glucemia de ayuno (β = 0,205, p = 0,009), indice de masa del VI (β = 0,301, p < 0,001), E/eseptal (β = 0,267, p < 0,001) y eseptal (β = -0,176, p = 0,011) estaban independientemente asociados con la funcion ventricular izquierda global estimada por el indice Tei. CONCLUSION: El SM tuvo un impacto significativo en la funcion global del VI. La presion arterial sistolica, glucemia de ayuno, indice de masa del VI E/eseptal, y eseptal estaban independientemente asociados con la funcion global del VI. (Arq Bras Cardiol 2011;96(5):377-385)