Celina Wojciechowska

Randomized, Placebo-Controlled Study for Immunosuppressive Treatment of Inflammatory Dilated Cardiomyopathy Two-Year Follow-Up Results

Background—Previous studies have shown disappointing results for immunosuppressive treatment in patients with dilated cardiomyopathy. Therefore, we studied the effectiveness of such therapy in patients with HLA upregulation on biopsy. Methods and Results—Of 202 patients with dilated cardiomyopathy, 84 patients with increased HLA expression were randomized to receive either immunosuppression or placebo for 3 months; they were then followed for 2 years. After 2 years, there were no significant differences in the primary end point (a composite of death, heart transplantation, and hospital readmission) between the 2 study groups (22.8% for the immunosuppression group and 20.5% for the placebo). The secondary efficacy end point included changes in ejection fraction, end-diastolic diameter, end-diastolic volume, end-systolic volume and NYHA class; left ventricular ejection fraction increased significantly in the immunosuppression group compared with the placebo group (95% CI, 4.20 to 13.12;P <0.001) after 3 months of follow-up. The early favorable effects of immunosuppressive therapy on left ventricular volume, left ventricular diastolic dimension, and New York Heart Association class were also present. This improvement was maintained in the immunosuppression group at 2 years (ejection fraction: 95% CI, 6.94 to 19.04;P <0.001). In addition, on the basis of the protocol-specified definition of improvement, 71.8% patients in the immunosuppression group versus 20.9% patients in the placebo group met the criteria of improvement after 3 months (P <0.001). At the end of the follow-up period, 71.4% patients from the immunosuppression group versus 30.8% patients from the placebo group were improved (P =0.001). Conclusions—These data demonstrate a long-term benefit of immunosuppressive therapy in patients with dilated cardiomyopathy and HLA upregulation on biopsy specimens. Thus, restoration of immunosuppressive therapy for such patients should be considered.

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.

Associations between metabolic syndrome, serum thyrotropin, and thyroid antibodies status in postmenopausal women, and the role of interleukin-6

INTRODUCTION The prevalence of metabolic syndrome increases after menopause; however, the role of concomitant subclinical hypothyroidism has not been completely elucidated. The aim of the study was to identify associations between thyrotropin, immune status, inflammation, and metabolic syndrome in postmenopausal women. The specific goals were: to assess thyrotropin (TSH) and interleukin-6 (IL-6) concentrations in the serum of subclinical hypothyroid postmenopausal women with and without metabolic syndrome and compare them with euthyroid controls; to test whether immune status is related to metabolic syndrome in postmenopausal women and determine the role of IL-6; to examine the relationships between TSH and different features of metabolic syndrome: insulin resistance, waist circumferences, waist-to-hip ratio (WHR), BMI, metabolic parameters (triglycerides, total cholesterol and high-density lipoprotein cholesterol), and inflammatory cytokines (IL-6). MATERIAL AND METHODS Three hundred and seventy-two postmenopausal women were included in the study: 114 women had subclinical hypothyroidism (10.0 uIU/mL > TSH ≥ 4.5 uIU/mL, normal fT4), and 258 women were in euthyreosis (TSH 0.35-4.5 uIU/mL, normal fT4); both groups were matched by age. Anthropometric measurements were conducted (BMI, waist circumference, WHR) and blood pressure was measured. In all subjects the following were assessed in serum: lipid profile, glucose, insulin, TSH, fT4, thyroid antibodies (T-Abs) - TPO-Abs, TG-Abs, and IL-6 concentrations. RESULTS The prevalence of metabolic syndrome was 49.12% in subclinical hypothyroid women and 46.89% in euthyroid women. However, the proportion of subjects with one or two abnormalities was significantly higher in the subclinical hypothyroid group (45.61%) than in the euthyroid group (32.17%). When we compared subclinical hypothyroid women with and without metabolic syndrome, subjects with metabolic syndrome had higher BMI, abdominal circumferences, WHR, and HOMA-I. They presented higher systolic and diastolic blood pressure. Serum concentrations of cholesterol, triglycerides, fasting glucose, IL-6, TSH, T-Abs were also higher and serum cHDL was lower. There were no significant differences in fT4 concentrations. A similar comparison was made for euthyroid women with and without metabolic syndrome. Higher BMI, waist circumference, WHR, HOMA-I, and systolic blood pressure were observed in subjects with metabolic syndrome. Serum concentrations of TSH, triglycerides, glucose, and IL-6 were also higher, but the concentration of cHDL was significantly lower. There were no significant differences in fT4, T-Abs, cholesterol levels, and diastolic pressure. When we compared euthyroid women T-Abs (+) and T-Abs (-), the prevalence of metabolic syndrome was similar (48.68% vs. 46.15%). There were no differences in BMI, waist circumference, WHR, lipid profile, glucose, and HOMA-I, fT4. However, thyroid autoimmunity was associated with elevated TSH and IL-6 levels. When we analysed subclinical hypothyroid women with and without thyroid autoimmunity, there were no significant differences in glucose and lipid profile. However, Hashimoto`s subjects were more obese, had higher waist circumference, WHR, HOMA-I, and higher prevalence of metabolic syndrome. Serum concentrations of TSH and IL-6 were also higher and fT4 was lower. Among all of the women, serum TSH concentration was significantly correlated with BMI, waist circumference, WHR, systolic blood pressure, cholesterol, triglycerides, and TPO-Abs. When the variables of subjects with upper quartile of TSH were compared with lower quartile of TSH, we found significantly higher BMI, waist circumference, WHR, increased concentration of IL-6, cholesterol, triglycerides, and T-Abs, and concentrations of cHDL and fT4 were lower. OR for metabolic syndrome in subjects with upper quartile TSH vs. lower quartile was 1.35 (95% confidence interval [CI] 1.10-1.60). CONCLUSIONS Our study confirms that metabolic syndrome in both euthyroid and subclinical hypothyroid women is connected with obesity, visceral fat accumulation, and higher TSH and IL-6 concentrations. Immune thyroiditis is associated with higher TSH and IL-6 levels. Obese subclinical hypothyroid women with Hashimoto`s thyroditis have a higher prevalence of metabolic syndrome when compared with subclinical hypothyroid women without thyroid autoimmunity. It is possible that in the crosstalking between subclinical hypothyroidism and metabolic syndrome, enhanced proinflammatory cytokine release in the course of immunological thyroiditis plays a role.

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.

Serum Galectin-3 and ST2 as predictors of unfavorable outcome in stable dilated cardiomyopathy patients

Dilated cardiomyopathy (DCM) is the third cause of heart failure and the most frequent cause of heart transplantation (HT). The value of biomarkers in prognostic stratification may be important to identification the patients for more advanced treatment. Assessment of serum Galectin-3 (Gal-3) and ST2 as biomarkers of unfavorable outcome (death and combined endpoint: HT or death or left ventricular assist device implantation) in stable DCM patients. 107 DCM patients age 39-56 years were included into the study and followed-up for mean 4.8 years. Gal-3 and ST2 concentrations were measured ELISA tests. Clinical data, treatment, laboratory parameters, NT-proBNP, Gal-3 and ST2 measured at time of inclusion were assessed as risk factors for reaching the study endpoints using log rank test and Cox proportional-hazards model. During follow-up 27 patients died, 40 achieved combined endpoint. ROC curves indicated cut-off value of ST2-17.53 ng/ml, AUC-0.65 (0.53-0.76) and of NT-proBNP-669 pg/ml, AUC 0.61 (0.50-0.73) for prediction of death. In multivariate analysis ST2 was predictor of death (HR per unit increase in log ST2 2.705, 95 % CI 1.324-5.528, P=0.006) and combined endpoint (HR per unit increase in log ST2 2.753, 95 % CI 1.542-4.914, P<0.001). NT-proBNP was predictive variable only for death in multivariate analysis. Gal-3 concentration was not associated with adverse outcome. ST2 but not Gal-3 may be useful for predicting adverse outcome in stable dilated cardiomyopathy patients.

Diagnostic Contribution of Cardiac Magnetic Resonance in Patients with Acute Coronary Syndrome and Culprit-Free Angiograms

Background In spite of robust knowledge about underlying ischemic myocardial damage, acute coronary syndromes (ACS) with culprit-free angiograms raise diagnostic concerns. The present study aimed to evaluate the additional value of cardiac magnetic resonance (CMR) over commonly available non-CMR standard tests, for the differentiation of myocardial injury in patients with ACS and non-obstructed coronary arteries. Material/Methods Patients with ACS, elevated hs-TnT, and a culprit-free angiogram were prospectively enrolled into the study between January 2009 and July 2013. After initial evaluation with standard tests (ECG, echocardiography, hs-TnT) and provisional exclusion of acute myocardial infarction (AMI) in coronary angiogram, patients were referred for CMR with the suspicion of myocarditis or Takotsubo cardiomyopathy (TTC). According to the result of CMR, patients were reclassified as having myocarditis, AMI, TTC, or non-injured myocardium as assessed by late gadolinium enhancement. Results Out of 5110 patients admitted with ACS, 75 had normal coronary angiograms and entered the study; 69 of them (92%) were suspected for myocarditis and 6 (8%) for TTC. After CMR, 49 patients were finally diagnosed with myocarditis (65%), 3 with TTC (4%), 7 with AMI (9%), and 16 (21%) with non-injured myocardium. The provisional diagnosis was changed or excluded in 23 patients (31%), with a 9% rate of unrecognized AMI. Conclusions The study results suggest that the evaluation of patients with ACS and culprit-free angiogram should be complemented by a CMR examination, if available, because the initial work-up with non-CMR tests leads to a significant proportion of misdiagnosed AMI.

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.