Skip Navigation

European Journal of Heart Failure 2005 7(6):1033-1039; doi:10.1016/j.ejheart.2004.11.009
This Article
Right arrow Abstract Freely available
Right arrow FREE Full Text (PDF) Freely available
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Add to My Personal Archive
Right arrow Download to citation manager
Right arrowRequest Permissions
Right arrow Disclaimer
Google Scholar
Right arrow Articles by Castro, P.
Right arrow Articles by Lavandero, S.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Castro, P.
Right arrow Articles by Lavandero, S.
Social Bookmarking
Add to CiteULike   Add to Connotea   Add to Del.icio.us  
What's this?

© 2005 European Society of Cardiology

Effects of carvedilol on oxidative stress and chronotropic response to exercise in patients with chronic heart failure

Pablo Castroa,*, José Luis Vukasovicb, Mario Chiongc, Guillermo Díaz-Arayac, Hernán Alcainoc, Miguel Copajac, Rodrigo Valenzuelac, Douglas Greiga, Osvaldo Péreza, Ramón Corbalana and Sergio Lavanderob,c,d

a Cardiovascular Diseases, Universidad Católica de Chile Santiago, Chile
b Faculty of Medicine, Universidad de Chile Santiago, Chile
c Faculty of Chemical and Phamarceutical Sciences, Universidad de Chile Santiago, Chile
d FONDAP Center for Molecular Studies of the Cell, Universidad de Chile Santiago, Chile

* Corresponding author. Tel.: +56 2 2434161. E-mail address: pcastro{at}med.puc.cl


   Abstract
Top
 Abstract
1. Introduction
 2. Methods
 3. Results
 4. Discussion
 5. Conclusions
 Acknowledgments
 References
 
Background: Our previous studies suggest that the increase in heart rate from rest to peak exercise is reduced in patients with chronic heart failure (CHF) and this is associated with increased oxidative stress, as determined by malondialdehyde (MDA) plasma levels.

Aim: To investigate the effects of carvedilol on the heart rate response to exercise and oxidative stress in patients with CHF.

Methods and results: Thirty stable NYHA classes II—III CHF patients received carvedilol therapy for 6 months, at a mean maintenance dose of 25 mg (range 6.25—50 mg/day). After treatment, the patients showed a significant improvement in their functional NYHA class (p=0.013), increased left ventricular ejection fraction (LVEF) (24±1.4% to 31±2.3%, p=0.003) and 6-min walk distance (499±18 to 534±18 m, p=0.03), without changes in the peak VO2. At baseline, norepinephrine (NE) plasma levels increased with exercise (510±51 to 2513±230 pg/mL, p<0.001), and these levels were not affected by carvedilol. Chronotropic responsiveness index (increase in heart rate divided by the increase in NE from rest to peak exercise) was not changed by carvedilol (0.049±0.001 to 0.042±0.001, p=0.6). MDA levels of CHF patients decreased after treatment with carvedilol (2.4±0.2 to 1.1±0.2 µM, p<0.001), without changes in antioxidant enzyme activities.

Conclusions: Carvedilol treatment in patients with CHF results in reduced oxidative stress without restoration of the chronotropic responsiveness index.

Key Words: β-Adrenergic antagonist • Carvedilol • Oxidative stress • Chronic heart failure

Received March 23, 2004; Revised September 9, 2004; Accepted November 11, 2004


   1. Introduction
Top
 Abstract
 1. Introduction
2. Methods
 3. Results
 4. Discussion
 5. Conclusions
 Acknowledgments
 References
 
Oxidative stress is an imbalance between the production of reactive oxygen species (ROS) and endogenous antioxidant defense mechanisms, including enzymatic and non-enzymatic mechanisms [1,2]. Various mechanisms of ROS production in the failing myocardium have been proposed; the most important sources include the mitochondrial respiratory chain enzymes, xanthine oxidase, non-phagocytic NADPH oxidase, neutrophil NADPH oxidase and auto-oxidation of catecholamines [3]. Oxidative stress has also been implicated in the pathogenesis and development of chronic heart failure (CHF), causing cardiomyocyte death, abnormalities in transduction of myocardial β-adrenergic receptor signaling, as well as contractile dysfunction [1,4]. There is a significant correlation between oxidative stress and the severity of CHF [5,6], despite some contradictory views [7]. A more direct relationship has been established between the markers of oxidative stress and indexes of functional capacity [3].

We have recently shown that the increase in heart rate from rest to peak exercise is reduced in patients with CHF at any given increase in circulating norepinephrine (NE) [8]. These data suggest that the sino-atrial node has a lower sensitivity to β-adrenergic stimulation in CHF, because the increase in heart rate is primarily mediated by the action of the sympathetic nervous system on β-adrenergic receptors [5]. In addition, we and others have demonstrated that patients with CHF have higher levels of oxidative stress, as determined by malondialdehyde (MDA) test [9,10]. There are also preliminary data suggesting that oxidative stress may attenuate the β-adrenergic receptor-mediated signal transduction in the heart, by changing the functions of Gs proteins and the catalytic subunit of adenyl cyclase [11].

Carvedilol is an {alpha}- and β-adrenergic receptor-antagonist with antioxidant activity, with demonstrated effect in reducing the risk of cardiovascular morbidity or death in patients with CHF, [12–14]. The exact mode by which carvedilol improves the prognosis of CHF is not known, but possible mechanisms include: (a) up-regulation of β-adrenergic receptors in the heart and (b) modulation of the downstream inhibitory G proteins [15]. In addition, there is some evidence that catecholamines can provoke oxidative stress in terminally differentiated myocardial cells, and this process can subsequently trigger apoptosis; a condition that could also be prevented by carvedilol [16].

The purpose of the present study was to investigate the effects of carvedilol on the heart rate response to exercise and upon oxidative stress, in patients with CHF.


   2. Methods
Top
 Abstract
 1. Introduction
 2. Methods
3. Results
 4. Discussion
 5. Conclusions
 Acknowledgments
 References
 
2.1. Patients
The present study comprised a series of 30 patients with CHF, either secondary to coronary artery disease (n=16) or due to idiopathic cardiomyopathy (n=14). The criteria for inclusion were: (a) chronic stable HF in NYHA functional classes II to III; (b) ability to complete a symptom-limited treadmill exercise test; (c) evidence of left ventricular dilatation and left ventricular ejection fraction (LVEF) less than 40%, as determined by radionuclide gated pool scan; and (d) treatment with diuretics, digitalis and vasodilators.

Criteria for exclusion were: (a) coronary artery bypass surgery, angioplasty or myocardial infarction during the past 6 months; (b) chronic angina; (c) uncontrolled hypertension: systolic blood pressure (BP) >160 mm Hg or diastolic BP >90 mm Hg; (d) hypertensive cardiomyopathy; (e) change in maintenance therapy or use of β-blockers during the past 2 months; (f) implanted pacemaker; (g) atrial fibrillation; (h) significant valvular disease; (i) presence of any other conditions affecting the accurate determination of oxidative stress status, including renal insufficiency (plasma creatinine >2 mg/dL), autoimmune diseases, malignant tumours, advanced liver or pulmonary disease and acute or chronic inflammation.

All patients signed an informed consent approved by our Institutional Review Board and Ethics Committee. All patients received carvedilol. The initial dose was 3.12 mg twice daily, which was doubled (if tolerated) at two weekly intervals up to a maximum of 25 b.i.d. All patients were evaluated before treatment and after 6 months of the treatment.

2.2. Clinical assessment
NYHA functional class and the Mahler clinical score (range 0–12 points) were used [17]. Briefly, the Mahler score evaluates the severity of dyspnoea. The score depends on ratings for three different categories: (a) functional impairment, (b) magnitude of task and (c) magnitude of effort. Dyspnoea is rated in five degrees from 0 (severe) to 4 (unimpaired) for each category. The ratings for each of the three categories are added to form the score. LVEF was determined by radionuclide ventriculography. A 6-min corridor walk test and a maximal exercise test with gas exchange were also performed.

2.3. Measurement of plasma NE levels
Plasma NE samples were collected from an indwelling venous line, when the patient had been in the supine position in a quiet room for 30 min. Measurements were repeated at maximal exercise. Determination was performed by HPLC, using a commercial kit (Chromsystems Instruments and Chemicals, Munich, Germany). The inter-assay and intra-assay variation reported for this method was 6%.

2.4. Chronotropic responsiveness index
Increase in heart rate divided by the increase in NE from rest to peak exercise was used to calculate the chronotropic responsiveness index.

2.5. Determination of MDA concentrations and antioxidant enzyme activities
Twenty milliliters of blood were obtained by venipuncture at baseline and during the reperfusion at 0.5 and 24 h. Each sample was centrifuged at 1250xg for 10 min at 4 °C. Plasma was separated and stored at –20 °C; erythrocytes were washed three times with saline solution, homogenized and centrifuged in the same manner. Lysates, prepared by adding 0.1 mL cell pellet to 0.4 mL of water, were stored at –20 °C.

2.6. MDA assay
Lipid peroxide formation was determined by the presence of thiobarbituric acid reactive substances (TBARS), as described previously [18]. Commercially available MDA was used as standard. To 1.5 mL microcentrifuge tubes, the following solutions were added: 0.375 mL 0.15 M phosphoric acid, 0.125 mL 42 mM thiobarbituric acid and 0.025 mL serum, MDA standards or 0.1 M HCl (blank). The mixtures were vortexed and placed in boiling water for 30 min. Absorbances at 532 nm were measured and concentrations were expressed as µM.

2.7. Determination of superoxide dismutase (SOD) activity
SOD was extracted from the hemolysed blood, according to McCord and Fridovich [19]. The enzyme activity was assayed as described by Misra and Fridovich [20]. This method is based on the principle that the rate of alkaline oxidation of epinephrine is decreased by SOD activity. Oxidation yields a chromophore that was detected at 480 nm. SOD activity was expressed as unit (U) per gram of hemoglobin (Hb).

2.8. Catalase (CAT) activity
Enzymatic activity was determined as described by Beers and Sizer [21]. Briefly, 1 mL of diluted hemolysed blood was added to a cuvette. The reaction was initiated by addition of 1 mL of 30 mM H2O2, and the change in absorbance at 240 nm was monitored at 25 °C for 1 min. A portion of the remaining sample was used for hemoglobin determination. Specific activity was expressed in units (mmol H2O2/min) per gram Hb.

2.9. Glutathione peroxidase (GSH-Px) activity
Enzymatic activity was determined as described by Paglia and Valentine [22]. The lysate was mixed with an equal volume of double-strength Drabkin's reagent. In a reaction tube, 0.1 mL of this mixture was added to 2.58 mL 50 mM phosphate buffer (pH 7.0) containing 5 mM EDTA. The following reagents were then added in turn: 0.1 mL of NADPH (8.4 mM), 0.01 mL glutathione reductase (30 U/mL), 0.01 mL sodium azide (1.125 M) and 0.1 mL GSH (150 mM). The enzymatic reaction was initiated by addition of 0.1 mL of pre-warmed H2O2 (2.2 mM). NADPH conversion to NADP was followed by continuous recording of the change in absorbance at 340 nm, between 2 and 4 min after initiation of the reaction. The non-enzymatic oxidation of GSH was determined by simultaneous assay of a system identical to the first, except for replacement of the hemolysate by an equal volume of water. The values of the latter were subtracted from those of the former, to calculate the true enzymatic activity. Enzymatic activity was expressed as units (nmol NADPH oxidized/min) per gram Hb.

2.10. Statistical analysis
Results are presented as mean±S.E.M. Differences in LV ejection fraction, 6-min walk distance, blood pressure, heart rate, peak VO2, exercise plasma catecholamine levels and oxidative stress parameters were analyzed using two-sample t-tests. Linear regression analysis was performed to evaluate the correlations between MDA levels and index of chronotropic responsiveness. The correlations at baseline and after treatment with carvedilol were compared using z-test. Any p-value ≤0.05 was considered statistically significant.


   3. Results
Top
 Abstract
 1. Introduction
 2. Methods
 3. Results
4. Discussion
 5. Conclusions
 Acknowledgments
 References
 
3.1. Clinical parameters of the patients
The study included 30 patients with CHF. Mean age was 59±2 (range 47–71) and 23 were males. Sixteen patients were categorized in NYHA class II and 14 in NYHA class III. Sixteen patients had ischemic dilated cardiomyopathy, five of them having undergone previous myocardial re-vascularization surgery. Fourteen patients had idiopathic dilated cardiomyopathy (Table 1). In addition, 10 patients had a left bundle branch block (LBBB) and 2 had a right bundle branch block (RBBB). Nine patients had evidence of a previous myocardial infarction by ECG criteria.


View this table:
[in this window]
[in a new window]

  		Table 1 Baseline clinical characteristics of the patients

 
3.2. Effects of carvedilol on cardiac function parameters
All patients were treated with carvedilol, with a mean maintenance dose of 25 mg (range 6.25–50 mg/day). As shown in Table 2, there was an improvement in functional class and in the Mahler clinical score after 6 months of therapy. Table 2 also shows that LVEF increased from 23±1% to 31±2% (p=0.003) and there was an increase in the 6-min walk distance without significant changes in the peak VO2 (499±17 to 534±18 m, p=0.03 and 17±1 to 17±1 mL/kg/min, p=0.13 respectively). From baseline to 6 months, supine resting heart rates fell by 7 bpm. At maximum exercise, heart rate fell by 18 bpm. Supine resting systolic and diastolic blood pressure was reduced by 5 and 2 mm Hg, respectively, and by 20 and 7 mm Hg at maximum exercise. As shown in Table 2, there was a significant reduction in exercise heart rate–systolic blood pressure product (from 21,981±1137 to 16,844±1368, p=0.001) after carvedilol treatment.


View this table:
[in this window]
[in a new window]

  		Table 2 Evaluation of the patients at baseline and after 6 months of treatment with carvedilol

 
3.3. Effect of carvedilol on plasma NE levels
At baseline, the resting NE plasma levels were 510±51 pg/mL and they increased significantly with exercise (to 2513±230 pg/mL, p<0.001). No significant changes in these resting or peak exercise NE levels were observed after treatment with carvedilol (456±56 and 2575±363 pg/mL, respectively).

3.4. Effect of carvedilol on chronotropic responsiveness index
Table 2 also shows that, after treatment with carvedilol, the index of chronotropic responsiveness did not change.

3.5. Effects of carvedilol on plasma MDA levels and antioxidant enzyme activities
Table 3 shows that CHF patients had a significant elevation in their MDA levels (2.4±0.2, normal value=0.9±0.1 µM, p=0.014), and they decreased significantly after treatment with carvedilol (to 1.1±0.2 µM, p<0.001). No changes were observed in anti-oxidant enzyme activities, however.


View this table:
[in this window]
[in a new window]

  		Table 3 Oxidative stress parameters in the patients at baseline and after 6 months of carvedilol therapy

 
3.6. Effects of carvedilol on plasma NE and MDA levels and chronotropic responsiveness index
At baseline, there was a significant correlation between the peak exercise NE and MDA plasma levels (r=0.7, p<0.001) and between the index of chronotropic responsiveness and MDA (r=–0.44, p=0.01). After 6 months of carvedilol therapy, however, these correlations were not significant (r=0.2, p=0.3 and r=0.28, p=0.17, respectively) any longer (Fig. 1).


Figure 1
View larger version (45K):
[in this window]
[in a new window]
[Download PowerPoint slide]
  		Fig. 1 Effect of carvedilol on the ejection fraction determined by radionuclide ventriculography. A: Baseline, B: after a 6-month treatment with carvedilol.

 

   4. Discussion
Top
 Abstract
 1. Introduction
 2. Methods
 3. Results
 4. Discussion
5. Conclusions
 Acknowledgments
 References
 
In the present study, we found that 6-months treatment with carvedilol in patients with stable CHF resulted in partial improvement of oxidative stress, as determined by plasma MDA levels. However, despite the reduction in MDA levels, the index of chronotropic responsiveness did not change.

Patients with CHF have an attenuated heart rate response to peak exercise. This has been attributed to desensitization of the β-adrenergic pathway in the sino-atrial node [11]. During exercise, the heart rate at any given increase in NE level was found to be less in CHF patients as compared with healthy controls. Since the increase in heart rate is mediated primarily by the action of the sympathetic nervous system on β-adrenergic receptors, these data suggest that the sino-atrial node may be less sensitive to β-adrenergic stimulation in CHF patients. Experimental studies have reported a reduction in isoproterenol-stimulated adenylcyclase activity in heart membranes, following treatment with high concentrations of H2O2 [11]. In patients with normal LV function, Mak and Newton suggested that the intra-coronary infusion of vitamin C increased the coronary blood flow response to β-adrenergic stimulation [23].

In the present study, patients treated with carvedilol had an alleviation of their symptoms, improved LV ejection fraction and better sub-maximal exercise performance, as determined by the 6-min walk distance. The 5% increase in LV ejection fraction and the absence of clear benefit of carvedilol on maximal exercise duration is similar to that observed in previous trials with β-blockers [24]. From baseline to 6 months, both the supine maximum heart rates and systolic blood pressure fell significantly. That this exercise performance was maintained at a lower rate-pressure product suggests an improved cardiac efficiency and is also consistent with the increased LV ejection fraction.

We could not demonstrate any effect of carvedilol on resting or peak exercise NE levels in our patients. There is some previous evidence suggesting that the elevation of plasma NE represents a combined effect of reduced clearance and increased spillover from the sympathetic nervous system. These two parameters are not influenced by carvedilol [25]. These findings suggest that the principal mode of action of β-blockade in heart failure is probably mediated by protection against the toxic effects of catecholamines on the heart [26].

After therapy with carvedilol, our patients showed decreased MDA levels without changes in anti-oxidant enzyme activities. Such a reduction in plasma oxidative stress markers in patients with stable CHF has been reported not only with carvedilol but also with metoprolol, a β-blocker without intrinsic anti-oxidant properties [27]. Bernstein et al. demonstrated in a rat model that metoprolol, decreased oxidative stress in the heart after myocardial infarction [28]. Nakamura et al. detected elevated myocardial oxidative stress in CHF patients [29], administration of carvedilol resulted in decreased oxidative stress level, together with improved cardiac function.

There is increasing evidence to support the view that levels of substances in the pericardial fluid closely correlate with their levels in the cardiac interstitium [30]. In our recent study, we demonstrated that oxidative stress in plasma correlated with oxidative stress in pericardial fluid. In addition, the oxidative levels of both plasma and pericardial fluid had a negative correlation with the ventricular function markers, including: left ventricular diastolic and systolic dimensions [31]. Therefore, MDA plasma levels can be considered as a reliable marker of oxidative stress in the heart.

Despite the established reduction in oxidative stress, the index of chronotropic responsiveness did not change after carvedilol. This might be attributed to a reduction in the heart rate by the β-blocker or to the effects of other factors not analyzed in this study, but potentially involved in the attenuated response to exercise in patients with CHF.

Our data showed that catecholamines and chronotropic indexes were not significantly changed after carvedilol treatment, while MDA levels were decreased. Although the exact mechanism by which carvedilol improves the prognosis of CHF remains unknown, the present results suggest that the main effect of this β-blocker in CHF patients could be related to its actions as an anti-oxidant rather than as an antagonist of the β-adrenergic receptor. However, further studies are required to fully elucidate this issue.

The main limitations of the present study are the relatively limited number of patients and the lack of a placebo group. This open-label study design might potentially introduce a bias, especially in the clinical assessment of the patients. However, all the clinical evaluations as well as the measurements of oxidative stress and exercise parameters were performed in a blinded fashion by independent individuals. β-Blockers are a part of the standard treatment of CHF, and the enrollment of patients did follow strict inclusion and exclusion criteria, without compromising their standard treatment. In addition, the regulation of heart rate is complex and includes the effects of local NE, circulating NE and circulating epinephrine on the sympathetic side, and vagal activity from the parasympathetic side. Thus, the mere determination of the NE plasma level gives an incomplete picture of the complex regulation of the heart rate. Finally, any improvement in the sinus response due to a reduction in oxidative stress could be masked by the β-blocker effect.


   5. Conclusions
Top
 Abstract
 1. Introduction
 2. Methods
 3. Results
 4. Discussion
 5. Conclusions
Acknowledgments
 References
 
Our data are consistent with the hypothesis that carvedilol treatment in patients with CHF reduces oxidative stress without restoration of the index of chronotropic responsiveness.


   Acknowledgments
Top
 Abstract
 1. Introduction
 2. Methods
 3. Results
 4. Discussion
 5. Conclusions
 Acknowledgments
References
 
We gratefully acknowledge the excellent technical assistance of Mr. Fidel Albornoz and Ivonne Padilla. This work was supported in part by FONDECYT Grants 1010992 (P.C.) and FONDAP 15010006 (S.L.).


   References
Top
 Abstract
 1. Introduction
 2. Methods
 3. Results
 4. Discussion
 5. Conclusions
 Acknowledgments
 References
 

  1. Sawyer D.B., Siwik D.A., Xiao L., et al. Role of oxidative stress in myocardial hypertrophy and failure. J. Mol. Cell Cardiol. (2002) 34:378–379.
  2. Grieve D.J., Shah A.M. Oxidative stress in heart failure. More than just damage. Eur. Heart J. (2003) 24:2161–2163.[Free Full Text]
  3. Korantzopoulos P., Galaris D., Papaioannides D., Siogas K. The possible role of oxidative stress in heart failure and the potential of antioxidant intervention. Med. Sci. Monit. (2003) 9:RA120–RA125.[Medline]
  4. Kawai K., Qin F., Shite J., et al. Importance of antioxidant and antiapoptotic effects of b-receptor blockers in heart failure therapy. Am. J. Physiol. Heart Circ. Physiol. (2004) 287:H1003–H1012.[Abstract/Free Full Text]
  5. Diaz-Velez D.R., Garcia-Castineiras G., Mendoza-Ramos E., et al. Increased malondialdehyde in peripheral blood of patients with congestive heart failure. Am. Heart J. (1996) 131:146–152.[CrossRef][Web of Science][Medline]
  6. Sawyer D.B., Colucci W.S. Mitochondrial oxidative stress in heart failure: ‘oxygen wastage— revisited. Circ. Res. (2000) 86:119–120.[Free Full Text]
  7. Mak S., Newton G.E. The oxidative stress hypothesis of congestive heart failure: radical thoughts. Chest (2001) 120:2035–2046.[CrossRef][Web of Science][Medline]
  8. Castro P.F., Greig D., Perez O., et al. Relation between oxidative stress, catecholamines, and impaired chronotropic response to exercise in patients with chronic heart failure secondary to ischemic or idiopathic dilated cardiomyopathy. Am. J. Cardiol. (2003) 92:215–218.[CrossRef][Web of Science][Medline]
  9. Castro P.F., Diaz-Araya G., Nettle D., et al. Effects of early decrease in oxidative stress after medical therapy in patients with class IV congestive heart failure. Am. J. Cardiol. (2002) 89:236–239.[CrossRef][Web of Science][Medline]
  10. Colucci W.S., Ribeiro J.P., Rocco M.B., et al. Impaired chronotropic response to exercise in patients with congestive heart failure. Circulation (1989) 80:314–323.[Abstract/Free Full Text]
  11. Persad S., Rupp H., Jindal R., et al. Modification of cardiac beta-adrenoceptor mechanisms by H2O2. Am. J. Physiol. (1998) 274:H416–H423.[Web of Science][Medline]
  12. Bristow M.R., Gilbert E.M., Abraham W.T., et al. Carvedilol produces dose-related improvements in left ventricular function and survival in subjects with chronic heart failure. Circulation (1996) 94:2807–2816.[Abstract/Free Full Text]
  13. Poole-Wilson P.A., Swedberg K., Cleland J.G., et al. Carvedilol or metoprolol european trial investigators. Comparison of carvedilol and metoprolol on clinical outcomes in patients with chronic heart failure in the Carvedilol or Metoprolol European Trial (COMET): randomised controlled trial. Lancet (2003) 362:7–13.[CrossRef][Web of Science][Medline]
  14. Packer M., Bristow M.R., Cohn J.N., et al. The effect of carvedilol on morbidity and mortality in patients with chronic heart failure. U.S. Carvedilol Heart Failure Study Group. N. Engl. J. Med. (1996) 334:1349–1355.[Abstract/Free Full Text]
  15. Bohm M., Deutsch H.J., Hartmann D., et al. Improvement of postreceptor events by metoprolol treatment in patients with chronic heart failure. J. Am. Coll. Cardiol. (1997) 30:992–996.[Abstract]
  16. Olivetti G., Abbi R., Quaini F., et al. Apoptosis in the failing human heart. N. Engl. J. Med. (1997) 336:1131–1141.[Abstract/Free Full Text]
  17. Mahler D.A., Weinberg D.H., Wells C.K., Feinstein A.R. The measurement of dyspnea. Contents, interobserver agreement, and physiologic correlates of two new clinical indexes. Chest (1984) 85:751–758.[CrossRef][Web of Science][Medline]
  18. Díaz-Araya G., Naranjo L., Godoy L., et al. Antioxidant effects of 1,4-dyhidropyridine and nitroso aril derivatives on brain cerebral slices. Gen. Pharmacol. (1998) 31:385–391.[CrossRef][Web of Science][Medline]
  19. McCord J., Fridovich I. Superoxide dismutase: an enzymic function for erythrocuprein (hemocuprein). J. Biol. Chem. (1969) 22:6049–6055.
  20. Misra H.P., Fridovich I. The role of superoxide anion in the autoxidation of epinephrine and a single assay for superoxide dismutase. J. Biol. Chem. (1972) 247:3170–3175.[Abstract/Free Full Text]
  21. Beers R., Sizer I. A spectrophotometric method for measuring the breakdown of hydrogen peroxide by catalase. J. Biol. Chem. (1952) 195:133–140.[Free Full Text]
  22. Paglia D.E., Valentine W.N. Studies on the quantitative and qualitative characterization of erythrocyte glutathione peroxidase. J. Lab. Clin. Med. (1967) 70:158–169.[Web of Science][Medline]
  23. Mak S., Newton G.E. Vitamin C augments the inotropic response to dobutamine in humans with normal left ventricular function. Circulation (2001) 103:826–830.[Abstract/Free Full Text]
  24. Australia-New Zealand Heart Failure Research Collaborative Group. Effects of carvedilol, a vasodilator-beta-blocker, in patients with congestive heart failure due to ischemic heart disease. Circulation (1995) 92:212–218.[Abstract/Free Full Text]
  25. Hasking G.J., Esler M.D., Jennings G.L., et al. Norepinephrine spillover to plasma in patients with congestive heart failure: evidence of increased overall and cardiorenal sympathetic nervous activity. Circulation (1986) 73:615–621.[Abstract/Free Full Text]
  26. Kaye D., Johnston L., Vaddadi G., et al. Mechanisms of Carvedilol action in human congestive heart failure. Hypertension (2001) 37:1216–1221.[Abstract/Free Full Text]
  27. Kukin M., Kalman J., Charney R., et al. Prospective, randomized comparison of effect of long-term treatment with metoprolol or carvedilol on symptoms, exercise, ejection fraction, and oxidative stress in heart failure. Circulation (1999) 99:2645–2651.[Abstract/Free Full Text]
  28. Bernstein M., Tyagi S.C. β-Blocker improves cardiac function by reducing oxidative stress and metalloproteinase activity after myocardial infarction. J. Appl. Res. (2001) 1:149.
  29. Nakamura K., Kusano K., Nakamura Y., et al. Carvedilol decreases elevated oxidative stress in human failing myocardium. Circulation (2002) 105:2867–2871.[Abstract/Free Full Text]
  30. Page E., Upshaw-Earley J., Goings G. Permeability of rat atrial endocardium, epicardium, and myocardium to large molecules: stretch dependent effects. Circ. Res. (1992) 71:159–173.[Abstract/Free Full Text]
  31. Vukasovic J.L., Moraga F., Díaz-Araya G., et al. Oxidative stress in pericardial fluid and plasma and its association with ventricular function. Int. J. Cardiol. (2004) [in press].

Add to CiteULike CiteULike   Add to Connotea Connotea   Add to Del.icio.us Del.icio.us    What's this?


This article has been cited by other articles:


Home page
 Eur J Heart FailHome page
H. Alcaino, D. Greig, M. Chiong, H. Verdejo, R. Miranda, R. Concepcion, J. L. Vukasovic, G. Diaz-Araya, R. Mellado, L. Garcia, et al.
Serum uric acid correlates with extracellular superoxide dismutase activity in patients with chronic heart failure
Eur J Heart Fail, July 1, 2008; 10(7): 646 - 651.
[Abstract] [Full Text] [PDF]

Home page
 Eur J Heart FailHome page
U. P. Jorde, T. J. Vittorio, M. E. Kasper, E. Arezzi, P. C. Colombo, R. L. Goldsmith, K. Ahuja, C.-H. Tseng, F. Haas, and D. S. Hirsh
Chronotropic incompetence, beta-blockers, and functional capacity in advanced congestive heart failure: Time to pace?
Eur J Heart Fail, January 1, 2008; 10(1): 96 - 101.
[Abstract] [Full Text] [PDF]

This Article
Right arrow Abstract Freely available
Right arrow FREE Full Text (PDF) Freely available
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Add to My Personal Archive
Right arrow Download to citation manager
Right arrowRequest Permissions
Right arrow Disclaimer
Google Scholar
Right arrow Articles by Castro, P.
Right arrow Articles by Lavandero, S.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Castro, P.
Right arrow Articles by Lavandero, S.
Social Bookmarking
Add to CiteULike   Add to Connotea   Add to Del.icio.us  
What's this?