Andrzej Tomasik

Oxidative Stress Markers and C-Reactive Protein Are Related to Severity of Heart Failure in Patients with Dilated Cardiomyopathy

Background. The aim of study was to determine relationships between functional capacity (NYHA class), left ventricle ejection fraction (LVEF), hemodynamic parameters, and biomarkers of redox state and inflammation in patients with dilated cardiomyopathy (DCM). Methods. DCM patients (n = 109, aged 45.97 ± 10.82 years), NYHA class IIV, and LVEF 2.94 ± 7.1% were studied. Controls comprised age-matched healthy volunteers (n = 28). Echocardiography and right heart catheterization were performed. Serum activities of superoxide dismutase isoenzymes (MnSOD and CuZnSOD), concentrations of uric acid (UA), malondialdehyde (MDA), and C-reactive protein (hs-CRP) were measured. Results. MnSOD, UA, hs-CRP, and MDA were significantly higher in DCM patients compared to controls. Except MDA concentration, above parameters were higher in patients in III-IV NYHA class or with lower LVEF. hsCRP correlated with of MnSOD (P < 0.05) and CuZnSOD activity (P < 0.01). Both isoenzymes positively correlated with mPAP and pulmonary capillary wedge pressure (MnSOD, resp., P < 0.01 and P < 0.05 and CuZnSOD P < 0.05; P < 0.05). UA positively correlated with MnSOD (P < 0.05), mPAP (P < 0.05), and PVRI (P < 0.05). The negative correlation between LVEF and UA (P < 0.01) was detected. Conclusion. There are relationships among the severity of symptoms of heart failure, echocardiographic hemodynamic parameters, oxidative stress, and inflammatory activation. Increased MnSOD activity indicates the mitochondrial source of ROS in patients with advanced heart failure.

Nephrotic Origin Hyperlipidemia, Relative Reduction of Vitamin E Level and Subsequent Oxidative Stress May Promote Atherosclerosis

Background: The relation between nephrotic syndrome and atherosclerosis has not yet been fully clarified, although the high levels of low-density lipoprotein cholesterol usually found in this syndrome may give rise to atherosclerosis. This study was intended to test the disturbances of antioxidant/oxidant status in children with nephrotic syndrome (NS). Methods: 8 children in the active stage (AS) of NS , 7 children during the remission stage (REM) of NS, and 14 control subjects (CTRL) were enrolled into the study. The levels of plasma total cholesterol (TC), HDL-cholesterol (HDL-chol), LDL-cholesterol (LDL-chol), triglycerides (TG), vitamin E and 7-ketocholesterol (7KCH) before and after plasma saponification were measured. Results: A significant increase in the concentrations of TC, LDL-chol, vitamin E and total 7KCH in AS patients have been found. These patients had also a lower vitamin E/LDL-chol ratio. These changes have not been observed in the remission stage of nephrotic syndrome. Higher amounts of electronegatively charged-(oxidized) LDL particles as well as different oxysterols in AS patients have also been demonstrated. Conclusion: The study revealed significant disturbances in oxidant status during NS leading to plasma accumulation of oxidized LDL and cholesterol oxidation products that exert cytotoxicity and are known to induce atherosclerosis. We suggest that this may constitute an important link between nephrotic syndrome and atherosclerosis.

Clinical Significance of Viral Genome Persistence in the Myocardium of Patients with Dilated Cardiomyopathy

Background: The impact of myocardial viral persistence on the clinical outcome of patients with dilated cardiomyopathy (DCM) is still open to question. Methods: Fifty-two patients with DCM were enrolled and followed for a median of 3.8 years with respect to death or heart transplantation. Studied patients were clinically stable for at least 6 months before hospitalization. They underwent coronary angiography and endomyocardial biopsy. Specimens were examined by histo- and immunohistochemistry, and the viral genomes of parvovirus B19, cytomegalovirus (CMV), Coxsackie B virus (CVB), and hepatitis B and C viruses were studied by real-time polymerase chain reaction. Results: Forty-two out of 52 patients were available for clinical follow-up. The viral genome was detected in the myocardium of 32 out of 42 patients. Among the viruses studied, CMV and CVB were the most frequently found. Nine out of 42 patients achieved the predefined study end point. No statistically significant correlation was found between the presence of a persistent viral genome and study end point. No statistically significant relationship between viral genomes studied and immunohistology results was detected. Conclusions: High prevalence of a viral genome in the myocardium of patients with DCM did not have an influence on their long-term clinical outcome.

Lipid peroxidation and vitamin E in human coronary atherosclerotic lesions

BACKGROUND We aimed to assess the oxidant/antioxidant status within the ex vivo human coronary endarterectomy samples. METHODS To achieve this, we measured products of lipid oxidation (malondialdehyde, 7-ketocholesterol), lipids (cholesterol, cholesteryl esters) and vitamin E in endarterectomy samples. RESULTS Content of malondialdehyde in the plaque ranged from 0.23 to 37.36 microg/g. Unesterified cholesterol content ranged from 0.30 to 1.94 mg/g. It was 9.04+/-4.32% of total cholesterol. Total cholesterol content ranged from 1.73 to 23.69 mg/g. Cholesteryl palmitate content ranged from 0.57 to 19.10 mg/g, which is 11.43-60.86% of the total esters (mean+/-SD 40.27+/-18.42%). Cholesteryl oleate content ranged from 0.24 to 5.76 mg/g, being 9.97-21.81% of total esters (mean+/-SD 14.35+/-4.51%). Cholesteryl linoleate content ranged from 1.05 to 8.21 mg/g, being 17.84-45.15% of total esters (mean+/-SD 30.78+/-11.69%). Cholesteryl arachidonate content ranged from 0.51 to 4.20 mg/g, which is 7.56-22.87% of total esters (mean+/-SD 14.60+/-5.60%). The cholesteryl linoleate/cholesteryl oleate ratio (CL/CO) ranged from 1.01 to 4.33. Content of 7-ketocholesterol in the plaque ranged from 0.0 to 577.5 ng/g of wet weight. The 7-ketocholesterol/total cholesterol ratio was 0.003+/-0.003% (range from 0.0% to 0.008%). The 7-ketocholesterol/unesterified cholesterol ratio was 0.024+/-0.023% (range from 0.0% to 0.066%). The plaque content of vitamin E ranged from 0.0 to 40.9 microg/g of wet weight. CONCLUSION The present study, comprising measurements of lipids, products of lipid peroxidation and vitamin E in 12 human coronary endarterectomy samples, lends the evidence for ongoing lipid peroxidation within an atherosclerotic lesion.

Neopterin and Beta-2 Microglobulin Relations to Immunity and Inflammatory Status in Nonischemic Dilated Cardiomyopathy Patients

Background. The aim of the study was to assess the relationships among serum neopterin (NPT), β2-microglobulin (β2-M) levels, clinical status, and endomyocardial biopsy results of dilated cardiomyopathy patients (DCM). Methods. Serum NPT and β-2 M were determined in 172 nonischaemic DCM patients who underwent right ventricular endomyocardial biopsy and 30 healthy subjects (ELISA test). The cryostat biopsy specimens were assessed using histology, immunohistology, and immunochemistry methods (HLA ABC, HLA DR expression, CD3 + lymphocytes, and macrophages counts). Results. The strong increase of HLA ABC or HLA DR expression was detected in 27.2% patients—group A—being low in 72.8% patients—group B. Neopterin level was increased in patients in group A compared to healthy controls 8.11 (4.50–12.57) versus 4.99 (2.66–8.28) nmol/L (P < 0.05). β-2 microglobulin level was higher in DCM groups A (2.60 (1.71–3.58)) and B (2.52 (1.51–3.72)) than in the control group 1.75 (1.28–1.96) mg/L, P < 0.001. Neopterin correlated positively with the number of macrophages in biopsy specimens (P < 0.05) acute phase proteins: C-reactive proteins (P < 0.05); fibrinogen (P < 0.01); and NYHA functional class (P < 0.05) and negatively with left ventricular ejection fraction (P < 0.05). Conclusions. Neopterin but not β-2 microglobulin concentration reflected immune response in biopsy specimens. Neopterin correlated with acute phase proteins and stage of heart failure and may indicate a general immune and inflammatory activation in heart failure.

Response to Inhaled Nitric Oxide, But neither Sodium Nitroprusside nor Sildenafil, Predicts Survival in Patients with Dilated Cardiomyopathy Complicated with Pulmonary Hypertension

Introduction: Pulmonary hypertension in patients with dilated cardiomyopathy is associated with higher mortality. Objectives: The aim of the study was to assess the predictive value of the vasodilator response to three different drugs, sodium nitroprusside, inhaled nitric oxide, and oral sildenafil, in patients with dilated cardiomyopathy complicated with pulmonary hypertension. Patients and methods: Twenty-nine patients with dilated cardiomyopathy complicated with postcapillary pulmonary hypertension (left ventricle ejection fraction (LVEF) 20.6 ± 8.2%, mean pulmonary artery pressure (mPAP) 42.49 ± 7.27 mmHg, transpulmonary gradient (TPG)>12 mmHg or pulmonary vascular resistance index (PVRI)>5 WU/m2) underwent single-session vaso reactivity testing with sodium nitroprusside, inhaled nitric oxide (120 ppm), oral sildenafil (50 mg), and a combination of sildenafil and inhaled nitric oxide. The vasodilator responders were defined as those participants who achieved a reduction of PVRI<5 WU/m2 and TPG<12 mmHg. The primary study endpoint was death in the 30-month-long follow-up. Kaplan-Meier analysis and Cox proportional hazard modelling were used to identify the predictors of survival. Results: In the follow-up, eight patients died (six patients with irreversible pulmonary hypertension). Six patients underwent successful heart transplantation. Multivariate Cox proportional hazard analysis disclosed a response to nitric oxide as the only predictor of longer survival (HR=11.77, 95% CI=1.12-123.9 at P=0.04). Conclusions: Vasodilator response to inhaled nitric oxide predicts longer survival in patients with dilated cardiomyopathy complicated with pulmonary hypertension.

Post-Dilatation Intravascular Brachytherapy Trials on Hypercholesterolemic Rabbits Using 32P-Phosphate Solutions in Angioplasty Balloons

Abstract Response of peripheral arteries to post-dilatation intravascular brachytherapy (IVBT) using 32P liquid sources was studied in a rabbit model. The applied sources were angioplasty balloons filled with aqueous solutions of Na2H32PO4, NaCl and iodinated contrast. Dose distribution was calibrated by thermoluminescence dosimetry. The uncertainty of in vitro determinations of the activity–dose dependence was ± 15–30%. The animal experiments were performed on rabbits with induced hypercholesterolemia. The 32P sources were introduced into a randomly chosen (left or right) iliac artery, immediately after balloon injury. Due to the low specific activity of the applied sources, the estimated 7–49 Gy doses on the internal artery surface required 30–100 min irradiations. A symmetric, balloon-occluded but non-irradiated artery of the same animal served as control. Radiation effects were evaluated by comparing the thicknesses of various components of irradiated versus untreated artery walls of each animal. The treatment was well tolerated by the animals. The effects of various dose ranges could be distinguished although differences in individual biological reactions were large. Only the 49 Gy dose at “zero” distance (16 Gy at 1.0 mm from the balloon surface) reduced hypertrophy in every active layer of the artery wall. The cross-sectional intimal thicknesses after 7, 12, 38 and 49 Gy doses were 0.277, 0.219, 0.357 and 0.196 mm2 respectively, versus 0.114, 0.155, 0.421 and 0.256 mm2 in controls (p < 0.05). The lowest radiation dose on the intima induced the opposite effect. Edge intimal hyperplasia was not avoided, which agrees with other reports. The edge restenosis and the variability of individual response to identical treatment conditions must be considered as limitations of the post-dilatation IVBT method. Only application of highest irradiation doses was effective. The irradiation dose should be planned and calculated for adventitia.

32P liquid sources—comparison of the effectiveness of postangioplasty versus poststenting intravascular brachytherapy in hypercholesterolemic rabbits: Adjunctly implanted titanium stent does not attenuate the effect of endovascular irradiation

PURPOSE Endovascular application of ionizing radiation is a promising but still not sufficiently studied means of restenosis prevention. To test the effects of radiation on restenosis, and especially their dependence on whether the angioplasty was followed by stent implantation or not, we performed an in-stent versus no-stent intravascular brachytherapy study in an animal model. Balloon-based, continuous and self-centering, liquid 32P sources seemed the most convenient for the purpose. METHOD The radial dose distribution around angioplasty balloons filled with solutions of Na(2)H32PO(4) was calibrated by thermoluminescence dosimetry, both in the absence and presence of stents. The animal experiments were performed on rabbits with induced hypercholesterolemia. The balloons containing 32P were introduced into iliac artery immediately after stent implantation or after angioplasty alone. Radiation effects were evaluated postmortem by comparing thickness of various components of the artery wall. RESULTS In the presence of titanium stents (TTS), irradiation with 16 Gy dose at 1.0 mm from the balloon surface was no less effective in reducing hypertrophy in every active layer of the artery wall than without a stent. CONCLUSION In the animal model, IVBT basing on P(32) liquid sources was no less effective in the stented arteries than in the nonstented ones.

The influence of obstructive sleep breathing disturbances on echocardiographic and pulmonary haemodynamic parameters in patients with dilated cardiomyopathy.

BACKGROUND It is important to identify the clinical indicators of poor prognosis and treatable conditions that might contribute to the progression of heart failure (HF) and pulmonary hypertension (PH) in the group of patients with dilated cardiomyopathy (DCM) and concomitant obstructive sleep apnoea (OSA). AIM To evaluate the influence of OSA on echocardiographic and haemodynamic parameters in patients with DCM, and the outcome in long-term follow-up. METHODS We enrolled patients with DCM and severely impaired ejection fraction (EF < 30%). Each patient underwent polygraphy, echocardiography, and right heart catheterisation. Subjects were divided into groups based on the apnoea-hypopnoea index (AHI): > 0 and < 5 (group I), ≥ 5 and ≤ 15 (group II), > 15 and ≤ 30 (group III), and > 30 (group IV). We compared the OSA-free (AHI < 5) subjects with those with OSA (AHI ≥ 5). The evaluated clinical end-points were death and orthotropic heart transplant. RESULTS The study population comprised 51 patients. Mean EF was 22%; 59% of patients were suffering from OSA. The increased severity of OSA correlated with worse pulmonary haemodynamics. Patients with OSA had higher mean pulmonary arterial pressure and pulmonary vascular resistance than individuals without OSA (p = 0.044, p = 0.032, respectively). The highest chamber diameters assessed in echocardiography were found in group IV (p < 0.05). A total of 10 end-points occurred during follow-up (8.9 ± 5.1 months), with significant differences observed between groups I-IV and the highest rate in group IV (p < 0.001). CONCLUSIONS The increasing severity of OSA worsens the prognosis of DCM patients, independently of severe HF and coexistent PH. Systematic OSA screening in patients with HF might facilitate identification of individuals at high risk of progression of pulmonary haemodynamic impairment and end-point rate.

Prognostic Factors in Patients with an Implanted Pacemaker after 80 Years of Age in a 4-Year Follow-Up

Background: The controversy over electrotherapy for patients aged >80 years occurs already at the stage of qualification for this treatment type and concerns optimal device selection, the implantation strategy, and the overall benefit from pacemaker therapy. The group also has a considerable number of cardiovascular risk factors, and the data from the literature on the impact of the pacing mode on the remote prognosis of this group are ambiguous. Objective: Assessment of the risk factors for death among patients with implanted pacemakers >80 years of age in a 4-year follow-up. Methods: The study group consisted of 140 consecutive patients (79 women) aged 84.48 ± 3.65 years with single- or dual-chamber pacemakers implanted >80 years of age because of symptomatic bradycardia. In univariate and multivariate Cox regression analyses, demographic, echocardiographic, and laboratory parameters, pharmacotherapy, and factors related to the implanted device - i.e., indications, pacemaker type, and the implantation position of the tip of the right ventricular lead - were included. The endpoint was death for any reason in a 4-year follow-up. Results: During follow-up, 68 patients (48.6%) died. Although atrial fibrillation with a slow ventricular response constituted 20% of the indications for implantation, 60.8% of the patients received a single-chamber system (VVI/VVIR). In the whole group, the multivariate Cox regression analysis showed both a favourable prognostic significance of DDD pacing system implantation (HR = 0.507; 95% CI: 0.294-0.876) and coexisting hypertension (HR = 0.520; 95% CI: 0.299-0.902). The risk factors were fasting glycaemia (HR = 1.180; 95% CI: 1.038-1.342) and, potentially, female sex (HR = 1.672; 95% CI: 0.988-2.830; p = 0.056). In the female subgroup a more favourable prognosis was related to the use of angiotensin-converting enzyme inhibitors (HR = 0.435; 95% CI: 0.202-0.933) and DDD pacemaker implantation (HR = 0.381; 95% CI: 0.180-0.806). In the male subgroup a more favourable prognosis was related to concerned patients with coexisting hypertension (HR = 0.349; 95% CI: 0.079-0.689). Conclusions: DDD mode pacing seems to serve as a factor which decreases mortality among patients aged >80 years in long-term follow-up. The potentially poorer prognosis for the female patients in this group may result from a combination of the dominant VVI pacing mode, potential propagation of atrial fibrillation, a low proportion of antithrombotic therapy, and sex-related predispositions to thromboembolic complications.