Aldosterone synthesis and cytokine production in human peripheral blood mononuclear cells.

Previously, we reported that spironolactone reduced cytokine production in cultured human peripheral blood mononuclear cells (PBMCs) with angiotensin (Ang) II stimulation. To address the mechanisms underlying this effect, we examined the contribution of aldosterone to cytokine production in cultured human PBMCs with Ang II stimulation. PBMCs expressed the messenger RNA (mRNA) of Ang II type 1 receptor (AT1R) and mineralocorticoid receptor (MR) both spontaneously and after Ang II stimulation, but expressed Ang II type 2 receptor (AT2R) under neither condition. After 24 h of incubation, exogenous Ang II induced the expression of CYP11B2 (a key enzyme of aldosterone synthesis) mRNA and caused aldosterone synthesis. CV-11974 (an AT1R antagonist) reduced Ang II-induced aldosterone synthesis, whereas PD-123319 (an AT2R antagonist) had no effect. The concentration of aldosterone peaked earlier than those of monocyte chemoattractant protein-1 (MCP-1) and tumor necrosis factor-alpha (TNF-alpha). After 48 h of incubation (under the influence of synthesized aldosterone), CV-11974 and spironolactone significantly reduced the Ang II-enhanced production of MCP-1 and TNF-alpha, whereas PD-123319 also had no effect. In conclusion, Ang II induces aldosterone synthesis through AT1R and enhances cytokine production through an AT1R-dependent mechanism and, at least partly, through a MR-dependent mechanism in human PBMCs.

Continuous positive airway pressure ameliorated severe pulmonary hypertension associated with obstructive sleep apnea.

A 52-year-old obese woman was admitted to our institution for evaluation of dyspnea and pulmonary hypertension (PH). Polysomnography revealed severe obstructive sleep apnea (OSA) with an apnea hypopnea index of 99.8. Treatment with nocturnal continuous positive airway pressure (CPAP) resulted in correction of daytime hypoxemia, hypercapnia, and near-normalization of pulmonary artery pressure. To our knowledge, this is the most severe case of OSA-associated PH (approximately70 mmHg) reported to date, and it was successfully treated with nocturnal CPAP. This case demonstrates that OSA should be considered and polysomnography performed in all patients with PH, irrespective of severity, and that nocturnal CPAP has therapeutic effects on both OSA and daytime PH.

Relationship between oxidative stress and systolic dysfunction in patients with hypertrophic cardiomyopathy.

BACKGROUND: Progression of hypertrophic cardiomyopathy (HCM) to left ventricular dilatation and systolic dysfunction sometimes occurs. However, the mechanism is not known. We examined whether oxidative stress was elevated in myocardia of HCM patients and whether the levels were correlated with left ventricular dilatation and systolic dysfunction. METHODS AND RESULTS: Endomyocardial biopsy samples obtained from the right ventricular side of the septum of 31 patients with HCM, and 10 control subjects were studied immunohistochemically for the expression of 4-hydroxy-2-nonenal (HNE)-modified protein, which is a major lipid peroxidation product. Expression of HNE-modified protein was found in all myocardial biopsy samples from patients with HCM. Expression was distinct in the cytosol of cardiomyocytes. The expression levels in patients with HCM were significantly increased compared with those in control subjects (P = .0005). The expression levels in patients with HCM were correlated with left ventricular end-diastolic diameter (r = 0.483, P = .0053) and end-systolic diameter (r = 0.500, P = .0037) determined by echocardiography. The expression levels were inversely correlated with left ventricular ejection fraction determined by left ventriculography (r = -0.640, P = .0001). CONCLUSION: Oxidative stress was elevated in myocardia of HCM patients and the levels were correlated with left ventricular dilatation and systolic dysfunction. Oxidative stress is involved in the pathogenesis of heart failure in patients with HCM.

Risk of alveolar hemorrhage in patients with primary pulmonary hypertension--anticoagulation and epoprostenol therapy.

BACKGROUND: Anticoagulation therapy and continuous intravenous infusion of epoprostenol are the standard treatment for primary pulmonary hypertension (PPH). Because epoprostenol has an antiplatelet effect, concomitant use of an anticoagulant could increase the likelihood of hemorrhagic complications. METHODS AND RESULTS: In the present study, 31 consecutive patients with PPH (10 men, 21 women, mean +/- SD age, 28.5+/-10.1 years) treated with anticoagulation and epoprostenol between April 1999 and December 2003 were retrospectively evaluated. Clinical and hematological data at the time of the bleeding episode were retrieved from the medical records. Nine patients (22.6%) experienced 11 bleeding episodes: 9 episodes (81.8%) were alveolar hemorrhage and 2 patients were in severe respiratory distress. The mean dose of epoprostenol at the time of the first bleeding episode was 89.0 +/-40.5 ng.kg(-1).min(-1) (range, 28.1-164.0). More of the patients who did not have a bleeding episode remain alive than did patients with bleeding episodes (59% vs 33%) nor did they require lung transplantation. CONCLUSIONS: A considerable number of patients with PPH who received combined anticoagulant and high-dose epoprostenol therapy developed alveolar hemorrhage, which can be fatal.

Failure of disopyramide to improve right ventricular outflow tract obstruction after living-donor lobar lung transplantation.

Right ventricular (RV) outflow tract obstruction (RVOTO) is an uncommon complication of lung transplantation in patients with pulmonary hypertension (PH) and both medical management and surgical intervention are required. A 28-year-old female with primary PH was referred and because she did not respond to medical treatment, living-donor lobar lung transplantation was performed. The operation was successful, but dyspnea and exercise intolerance developed during rehabilitation and transthoracic echocardiography revealed RVOTO. Intravenous disopyramide during cardiac catheterization reduced the pressure gradient from 35 mmHg to 16 mmHg without decreasing RV systolic pressure. However, electrical and hemodynamic parameters were adversely affected by disopyramide and thus, after cardiac catheterization, administration of fluid and a low dose of atenolol was started, and her symptoms improved. Transthoracic echocardiography showed improvement in the RVOTO. This case suggests that disopyramide should be avoided for patients with RVOTO following lung transplantation and that other negative inotropic agents, such as beta-blockers, are more effective for relief of RVOTO.

Effect of a kink in unilateral pulmonary artery anastomosis on velocities of blood flow through bilateral pulmonary vein anastomoses in living-donor lobar lung transplantation.

Intraoperative transesophageal echocardiography is generally performed to detect vascular complications during lung transplantation. We report a case with a kink in pulmonary artery (PA) anastomosis suggested by an abnormal flow profile of pulmonary vein (PV) anastomoses during living-donor lobar lung transplantation. During the transplantation, velocity of blood flow through the right PV anastomosis showed abnormal elevation. Then, the patient's PA pressure elevated abnormally and a kink in the left PA anastomosis was found. Careful monitoring of PV anastomoses may enable detection of not only an abnormality of PV anastomoses but also that of PA anastomoses, especially in living-donor lobar lung transplantation.

Differences between flow profiles of pulmonary vein anastomoses affected by peripheral atelectasis in cadaveric and bilateral living-donor lobar lung transplantations.

We report two cases of peripheral atelectasis during cadaveric and living-donor lobar lung transplantation, which had different effects on the flow profile of pulmonary vein (PV) anastomoses. In the patient who underwent living-donor lobar lung transplantation, we detected the increase in the velocity of blood flow through the left PV anastomosis by intraoperative transesophageal echocardiography. Then peripheral atelectasis occurred in the transplanted left lung lobe. On the other hand, in the patient who underwent cadaveric bilateral lung transplantation, peripheral atelectasis occurred, but no changes in velocities of blood flow through PV anastomoses were detected by intraoperative transesophageal echocardiography. This difference may have been caused by the difference in sizes of pulmonary beds of transplanted grafts. These findings indicate the necessity of careful monitoring of PV anastomoses, especially in cases of living-donor lobar lung transplantation.

Relationships between depolarization abnormality and repolarization abnormality in patients with Brugada syndrome: using body surface signal-averaged electrocardiography and body surface maps.

INTRODUCTION: Repolarization and depolarization abnormalities have been reported to be related to Brugada syndrome. METHODS AND RESULTS: We evaluated the relationships between repolarization abnormality and depolarization abnormality using 48-lead unipolar signal-averaged electrocardiograms and 87-lead unipolar body surface maps in 15 patients with Brugada-type ECGs. Data were compared with those from healthy control subjects (n = 5) and within subgroups of Brugada syndrome with (n = 8) and without (n = 7) ventricular arrhythmias (VA) induced by programmed electrical stimulation (PES). Eighty-seven-lead body surface maps were recorded, and potential maps were constructed to evaluate elevation of the ST segment 20 ms after the J point. Forty-eight-lead signal-averaged ECGs were recorded, and isochronal maps of duration of the delayed potential (dDP) were constructed to evaluate the dDP in each lead. Potential maps showed that patients with Brugada-type ECG, especially those with VA induced by programmed electrical stimulation, had greater elevation of the ST segment in the right ventricular outflow tract, especially at E5. Isochronal maps of dDP in the Brugada-type ECG group showed that maximum dDP was located at E5 and that the area with long dDP was larger than that in the control subjects. The dDPs at E7, E5, F7, and F5 in the VA-inducible group were significantly longer than those in the VA-noninducible group. These results showed that the location of greater elevation in the ST segment coincided with the location of longer dDP. CONCLUSION: Repolarization abnormality and depolarization abnormality in the walls of both ventricles, especially in the right ventricular outflow tract, are related to the VA of Brugada syndrome.

Significance of the level of monocyte chemoattractant protein-1 in human atherosclerosis.

BACKGROUND: Monocyte chemoattractant protein-1 (MCP-1), a potent chemoattractant for monocytes, plays an important role in the earliest events of atherogenesis. However, direct evidence of the effects of MCP-1 on atherosclerosis in chronic hemodialysis (HD) patients has not been reported. METHODS AND RESULTS: The serum MCP-1 concentrations and the intimal - medial thickness (IMT) in the carotid arteries were measured in 42 non-diabetic chronic HD patients and 20 age-matched controls. The expression of MCP-1 was examined immunohistochemically in radial arterial tissues obtained from the HD patients. IMT and the serum concentration of MCP-1 in the HD patients were both significantly greater than in controls. Multiple regression analysis revealed that the serum concentration of MCP-1 was an independent factor influencing IMT. Tissue immunostaining showed that MCP-1 is expressed in both endothelial and smooth muscle cells and that its level of expression correlates with the serum concentration of MCP-1. CONCLUSIONS: An increase in MCP-1 may be an important factor in the progression of atherosclerosis in non-diabetic HD patients.

Sinus node function in patients with Brugada-type ECG.

BACKGROUND: Some studies have shown that patients with Brugada syndrome (BS) have atrioventricular conduction disturbance, but their sinus node function has not been evaluated. METHODS AND RESULTS: The patients group consisted of 59 male patients and 1 female patient with BS. Supraventricular and ventricular programmed electrical stimulation (PES) was performed. Ventricular fibrillation (VF) or sustained polymorphic ventricular tachycardia was induced by ventricular PES in 26 patients with BS (VF group), but was not induced in the other 34 patients (non-VF group). Sinus node function and conduction of the atrioventricular (AV) node in the control group, non-VF group and VF group were evaluated. Sinus node function was attenuated and the His - ventricle interval was prolonged in the VF group (corrected sinus node recovery time: 452+/-126 ms (VF group), 324+/-146 ms (non-VF group), Sino-atrial conduction time: 179+/-60 ms (VF group), 127+/-60 ms (non-VF group), His-ventricle interval: 41+/-9 ms (VF group), 35+/-8 ms (non-VF group)). CONCLUSION: The function of both the sinus node and AV node are attenuated in patients with PES-induced VF.

Usefulness of body surface mapping to differentiate patients with Brugada syndrome from patients with asymptomatic Brugada syndrome.

We attempted to determine the usefulness of body surface mapping (BSM) for differentiating patients with Brugada syndrome (BS) from patients with asymptomatic Brugada syndrome (ABS). Electrocardiograms (ECG) and BSM were recorded in 7 patients with BS and 35 patients with ABS. Following the administration of Ic antiarrhythmic drugs, BSM was recorded in 5 patients with BS and 16 patients with ABS. The maximum amplitudes at J0, J20, J40 and J60 were compared between the 2 groups, as were 3-dimensional maps. The maximum amplitudes at J0, J20 and J60 under control conditions were larger in patients with BS than in patients with ABS (P < 0.05). A three-dimensional map of the ST segments under control conditions in patients with BS showed a higher peak of ST elevation in the median precordium compared to that for patients with ABS. Increases in ST elevation at J20, J40 and J60 following drug administration were greater in patients with BS than in patients with ABS (P < 0.05). Evaluation of the change in amplitude of the ST segment at E5 caused by Ic drug administration was also useful for differentiating between the 2 groups. In conclusion, BSM was useful for differentiating patients with BS from those with ABS.

Evaluation of the usefulness of recording the ECG in the 3rd intercostal space and prevalence of Brugada-type ECG in accordance with recently established electrocardiographic criteria.

BACKGROUND: It has been reported that recording electrocardiograms (ECGs) in the 3rd intercostal space (ICS) is one method that can be used for detecting Brugada syndrome; however, the prevalence of Brugada-type ECGs recorded in the 3rd ICS and the usefulness of recording the ECG in the 3rd ICS in accordance with recently established electrocardiographic criteria is unknown. METHODS AND RESULTS: ECGs were recorded in both the 4th and 3rd ICS in 17 Brugada-type ECG patients (group A) and in 206 consecutive male subjects (group B). Brugada-type ECGs were divided into 3 types. In group A, the prevalence of type 1 ECG, which is a coved-type ECG with ST-segment elevation of >/=2 mm, increased from 23.5% to 64.7% when ECG was recorded in the 3rd ICS. The conversion to type 1 ECG was found to be related to induction of ventricular arrhythmia. In group B, the prevalence of Brugada-type ECG increased from 1.5% to 5.8% when the ECG was recorded in the 3rd ICS. CONCLUSIONS: Recording the ECG in the 3rd ICS is useful for identifying high-risk patients with Brugada-type ECG and for detecting concealed Brugada-type ECG.

Ventricular arrhythmia induced by sodium channel blocker in patients with Brugada syndrome.

OBJECTIVES: We administered pilsicainide chloride, a class Ic pure sodium channel blocker, to patients with Brugada syndrome (BS) and evaluated the occurrence of ventricular arrhythmia (VA) and T-wave alternans (TWA). BACKGROUND: Ventricular arrhythmia and TWA are sometimes induced by a sodium channel blocker challenge test in BS patients, but the significance of the induced VA and TWA is not known. METHODS: Pilsicainide was administered to 65 patients with BS (10 symptomatic and 55 asymptomatic patients), and the occurrence of VA, TWA, and change of electrocardiogram were evaluated. Electrophysiologic study was performed in 57 patients, and the induction of VA by programmed electrical stimulation (PES) was evaluated. RESULTS: Ventricular arrhythmia was not induced by administration of pilsicainide in 55 patients (no-VA group). Administration of pilsicainide-induced VA in 10 patients (Pil-VA group) and polymorphic ventricular tachycardia in four patients. Pilsicainide-induced VA in 60% of the symptomatic patients but in only 7% of asymptomatic patients (p < 0.01). ST level, QTc, and indexes of cardiac conduction in the Pil-VA group were not different from those in the no-VA group. Ventricular fibrillation was induced by PES in 67% of the patients in the Pil-VA group and in 33% of the patients in the no-VA group. In six cases, macroscopic TWA occurred in association with pilsicainide-induced VA, but TWA occurred in only one patient without pilsicainide-induced arrhythmia. CONCLUSIONS: Administration of a sodium channel blocker results in induction of not only ST-elevation but also VA and TWA in patients with BS.

Site-specific arrhythmogenesis in patients with Brugada syndrome.

INTRODUCTION: It has been believed that electrophysiologic abnormality of the epicardial region of the right ventricular free wall may play an important role in arrhythmogenesis of phase 2 reentry in Brugada syndrome, but clinical evidence of the occurrence of ventricular arrhythmias at the right ventricular free wall has not been evaluated. In this study, we evaluated the site-specific inducibility of ventricular fibrillation (VF) and the origin of spontaneous premature ventricular contractions (PVCs) in patients with Brugada syndrome. METHODS AND RESULTS: Forty-five patients with Brugada-type ECG were enrolled in this study. Spontaneous PVCs were recorded in 9 patients. Programmed electrical stimulation (PES) was performed at the right ventricular apex (RVA), the free wall and septal region of the right ventricular outflow tract (RVOT), and the left ventricle (LV). The inducibility of PVT/VF was evaluated at each ventricular site, and the origin of PVC was determined by pace mapping. Sustained VF was induced in 17 patients. VF was induced in all 17 patients by PES at RVOT. Although PES at the septal region of the RVOT induced VF in only 5 patients (29%), PES at the free-wall region of the RVOT induced PVT/VF in 13 patients (76%). PES at RVA induced VF in only 2 patients (12%), and PES at LV failed to induce any arrhythmic events. Ventricular pace mapping showed that 64% of PVCs occurred at the free-wall region of the RVOT, 18% at the septal region of the RVOT, 9% at RVA, and 9% at LV. CONCLUSION: VF in patients with Brugada syndrome frequently is induced at the free-wall region of the RVOT area. The origin of PVC appears to be related to the site of PVT/VF induction by PES.

Risk stratification for asymptomatic patients with Brugada syndrome.

Ventricular fibrillation (VF) is induced in some asymptomatic patients with Brugada syndrome (BS), but the prognostic value of programmed electrical stimulation (PES) in such patients is controversial. The clinical characteristics of 41 asymptomatic BS patients, divided into 2 groups according to whether VF was induced by PES (inducible VF group: n=13, non-inducible VF group: n=28) were evaluated. ST levels in the right precordial leads were measured before and after administration of pilsicainide and the abnormal late potential (LP) was evaluated on the signal-averaged electrogram. The ST level at V(2) at baseline in the inducible VF group was significantly higher than that in the non-inducible VF group (p<0.05). Pilsicainide induced significant ST segment elevation in both groups and the ST level after pilsicainide in the inducible VF group was higher than that in the non-inducible VF group (p<0.01). LP was more frequent in the inducible VF group than in the non-inducible VF group. The criterion of ST level >0.15 mV at baseline with pilsicainide-induced additional ST elevation >0.10 mV and positive LP showed high sensitivity (92%) and specificity (89%) for detection of PES-induced VF in asymptomatic BS patients.

Clusters of ventricular fibrillation in a patient with an implantable cardioverter difibrillator treated with amiodarone.

A 44 year-old man with severe left ventricular dysfunction resulting from an old myocardial infarction developed clusters of ventricular fibrillation (VF). Although coronary bypass surgery was performed and heart failure was well controlled, the VF recurred during amiodarone therapy. Despite multiple deliveries of shocks by an implantable cardioverter defibrillator, the electrical storm could not be terminated. Some substrate for rapid ventricular tachyarrhythmias, refractory to class III drugs, can lead to death from arrhythmia.

Direct evidence for increased hydroxyl radicals in angiotensin II-induced cardiac hypertrophy through angiotensin II type 1a receptor.

Oxidative stress is known to contribute to numerous cardiac disease processes. However, the contribution of reactive oxygen species to cardiac hypertrophy has not yet been fully investigated. The aim of the present study was therefore to determine whether levels of reactive oxygen species were increased in angiotensin II-induced cardiac hypertrophy. We continuously administered angiotensin II (1.1 mg/kg per day) into wild-type and angiotensin II type-1a receptor knockout mice for 2 weeks. The angiotensin II treatment increased blood pressure and heart weight/body weight ratio in wild-type mice but not in knockout mice. The generation of hydroxyl radicals in heart tissue homogenate was directly assessed with electron spin resonance spectroscopy using a spin trapping agent, alpha-phenyl-N-tert butylnitrone. Angiotensin II significantly increased hydroxyl radical production 2.2-fold (p < 0.01) in the hearts of wildtype mice but not in knockout mice. The present study provided direct evidence for increased production of hydroxyl radicals in angiotensin II-induced cardiac hypertrophy through angiotensin II type-1a receptor. These findings in this study may provide important insights into the development of hypertrophy and the transition of hypertrophy to heart failure.

Atrial fibrillation and atrial vulnerability in patients with Brugada syndrome.

OBJECTIVES: We sought to study atrial vulnerability in patients with Brugada syndrome. BACKGROUND: Atrial fibrillation (AF) often occurs in patients with Brugada syndrome, but atrial vulnerability in Brugada syndrome has not been evaluated. METHODS: The patient group consisted of 18 patients with Brugada syndrome. The control group consisted of 12 age- and gender-matched subjects who had neither organic heart disease nor AF episodes. The incidence and clinical characteristics of AF were evaluated in all 18 patients with Brugada syndrome, and an electrophysiologic study was performed in all 12 control subjects and in 14 of the 18 patients with Brugada syndrome. The atrial effective refractory period of the right atrium (RA-ERP), intra-atrial conduction time (conduction time from the stimulus at the right atrium to atrial deflection at the distal portion of the coronary sinus), duration of local atrial potential, and repetitive atrial firing (occurrence of two or more premature atrial complexes after atrial stimulation) were studied. RESULTS: Spontaneous AF occurred in 7 of the 18 patients with Brugada syndrome but in none of the control subjects. The RA-ERP was not different between the two groups. The intra-atrial conduction time was increased in the Brugada syndrome group versus the control group (168.4 +/- 17.5 vs. 131.8 +/- 13.0 ms, p < 0.001). The duration of atrial potential at the RA-ERP was prolonged in the Brugada syndrome group versus the control group (80.3 +/- 18.0 vs. 59.3 +/- 9.2 ms, p < 0.001). Repetitive atrial firing was induced in nine patients with Brugada syndrome and in six control subjects. Atrial fibrillation was induced in eight patients with Brugada syndrome but in none of the control subjects. In patients with Brugada syndrome without spontaneous AF, the intra-atrial conduction time and duration of atrial potential were also increased. CONCLUSIONS: Atrial vulnerability is increased in patients with Brugada syndrome. Abnormal atrial conduction may be an electrophysiologic basis for induction of AF in patients with Brugada syndrome.

Epicardial electrogram of the right ventricular outflow tract in patients with the Brugada syndrome: using the epicardial lead.

OBJECTIVES: We tried to record an epicardial electrogram directly, and we examined local electrograms before and after administration of a class IC anti-arrhythmic drug in patients with the Brugada syndrome. BACKGROUND: Electrical heterogeneity of the epicardium in the right ventricular outflow tract (RVOT) has been thought to be related to the Brugada syndrome. However, an epicardial abnormality has not been demonstrated in patients with the Brugada syndrome. METHODS: In five patients with a Brugada-type electrocardiogram (ECG), local unipolar electrograms were recorded at the epicardium and endocardium of the RVOT. To record the epicardial electrogram directly, we introduced an electrical guidewire into the conus branch (CB) of the right coronary artery. The duration of the local electrogram after termination of the QRS complex (DP) was measured before and after class IC anti-arrhythmic drug administration. The signal-averaged electrocardiogram (SAECG) was also obtained in all patients. RESULTS: A definite DP was observed at the epicardium, but not at the endocardium. After administration of a class IC anti-arrhythmic drug, the DP at the epicardium was prolonged from 38 +/- 10 ms to 67 +/- 24 ms. The late potential corresponding to the DP at the epicardium was observed in all patients on the SAECG. CONCLUSIONS: An epicardial electrogram can be recorded from the CB. Recording from the CB enables identification of an epicardial abnormality in patients with the Brugada syndrome. These abnormal electrograms may be related to a myocardial abnormality in the epicardium of patients with the Brugada syndrome.

Carvedilol decreases elevated oxidative stress in human failing myocardium.

BACKGROUND: Oxidative stress has been implicated in the pathogenesis of heart failure. However, direct evidence of oxidative stress generation in the human failing myocardium has not been obtained. Furthermore, the effect of carvedilol, a vasodilating beta-blocker with antioxidant activity, on oxidative stress in human failing hearts has not been assessed. This study was therefore designed to determine whether levels of lipid peroxides are elevated in myocardia of patients with dilated cardiomyopathy (DCM) and whether carvedilol reduces the lipid peroxidation level. Methods and Results- Endomyocardial biopsy samples obtained from 23 patients with DCM and 13 control subjects with normal cardiac function were studied immunohistochemically for the expression of 4-hydroxy-2-nonenal (HNE)-modified protein, which is a major lipid peroxidation product. Expression of HNE-modified protein was found in all myocardial biopsy samples from patients with DCM. Expression was distinct in the cytosol of cardiac myocytes. Myocardial HNE-modified protein levels in patients with DCM were significantly increased compared with the levels in control subjects (P<0.0001). Endomyocardial biopsy samples from 11 patients with DCM were examined before and after treatment (mean, 9+/-4 months) with carvedilol (5 to 30 mg/d; mean dosage, 22+/-8 mg/d). After treatment with carvedilol, myocardial HNE-modified protein levels decreased by 40% (P<0.005) along with amelioration of heart failure. CONCLUSIONS: Oxidative stress is elevated in myocardia of patients with heart failure. Administration of carvedilol resulted in a decrease in the oxidative stress level together with amelioration of cardiac function.