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European Journal of Heart Failure 2003 5(2):171-174; doi:10.1016/S1388-9842(02)00251-9
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© 2002 European Society of Cardiology

Anti-oxidative properties of beta-blockers and angiotensin-converting enzyme inhibitors in congestive heart failure

Bernard S.P. China, Nigel J. Langfordb, Sarah L. Nuttallb, Christopher R. Gibbsa, Andrew D. Blanna and Gregory Y.H. Lipa,*

a University of Birmingham, Division of Medical Sciences City Hospital, Birmingham, UK
b Queen Elizabeth Hospital Birmingham, UK

* Corresponding author. University Department of Medicine, City Hospital, Birmingham B18 7QH, UK. Tel.: +44-121-5075080; fax: +44-121-554-4083 E-mail address: g.y.h.lip{at}bham.ac.uk


   Abstract
Top
 Abstract
1. Introduction
 2. Patients and methods
 3. Results
 4. Discussion
 References
 
Background: Chronic elevation of plasma catecholamines and sympathetic stimulation in chronic heart failure (CHF) leads to increased production of free radicals, and so possibly to endothelial damage/dysfunction and atheroma formation. Abnormal oxidative stress may therefore be related to some of the high mortality and morbidity in CHF. The objective of the present prospective open study was to compare the effects of β-blockers and ACE inhibitors in relation to oxidative stress and endothelial damage in CHF.

Methods: We studied 66 outpatients with CHF: 46 patients were established on an ACE inhibitor and were then started on a β-blocker, and 20 patients not previously on ACE-inhibitors were started on lisinopril. Baseline levels of the measured parameters were compared to 22 healthy control subjects. Serum lipid hydroperoxides (LHP) and total antioxidant capacity (TAC) were determined as indices of oxidative damage and antioxidant defence, and plasma von Willebrand factor (vWf) as an index of endothelial damage/dysfunction.

Results: Baseline indices for the measures of oxidative damage and endothelial function in the 66 CHF patients were significantly higher than healthy control subjects [median LHP 7.5 (5.9–12.6) vs. 4.8 µmol/l, P=0.0022; TAC 428 (365–567) vs. 336 Trollox Eq. Units, P=0.0005; mean vWf 134±27 vs. 89±23 IU/dl, P<0.0001]. Following 3 months of maintenance therapy with β-blockers, there was significant reduction in LHP levels, but not TAC or vWf. ACE inhibitor therapy also significantly reduced vWf levels, but failed to have any statistically significant effects on LHP or TAC.

Conclusion: This pilot study suggests that oxidative stress in CHF may be due to increased free radical production or inefficient free radical clearance by scavengers. β-Blockers, but not ACE inhibitors, reduced lipid peroxidation in patients with CHF. No relation was demonstrated between a reduction in oxidative damage and endothelial damage/dysfunction.

Key Words: Beta-blockers • Congestive heart failure • ACE inhibitors • Oxidative stress • Endothelial damage/dysfunction

Received August 27, 2002; Revised October 9, 2002; Accepted December 2, 2002


   1. Introduction
Top
 Abstract
 1. Introduction
2. Patients and methods
 3. Results
 4. Discussion
 References
 
Oxidative stress occurs when there is increased free radical production or deficient, reduced or inefficient scavenging of these reactive free radicals [1,2]. Chronic elevation of plasma catecholamines and sympathetic stimulation in chronic heart failure (CHF) leads to increased production of free radicals, leading to other pathophysiological abnormalities such as endothelial damage/dysfunction [3–5] and excessive atheroma formation. Abnormal oxidative stress may therefore be related to some of the high mortality and morbidity in CHF.

The angiotensin converting enzyme (ACE) inhibitors and β-adrenoceptor blockers have been shown to be of benefit in CHF [6]. One mechanism by which these agents reduce mortality may be via their anti-oxidant effects. β-Blockers, which reduce inotropy and heart rate, improve the efficiency of oxygen utilisation [6,7] thus reducing oxidative stress. In fact, the third generation non-selective β-blocker, carvedilol, has been shown in vitro and in animal models to inhibit lipid peroxidation and to increase scavenging of free radicals [8]. However, it is unclear whether or not such mechanisms exist in vivo. One possible consequence of increased oxidant stress may be damage to the endothelium, leading to dysfunction, as implied by raised levels of endothelial cell markers von Willebrand factor (vWf), known to be present in CHF [9].

The objective of the present prospective open study was to test the hypothesis that β-blockers and ACE inhibitors reduce oxidative stress and therefore improve endothelial dysfunction in patients with CHF. Our markers of oxidative stress were levels of lipid hydroperoxides (LHP), that we expected to be higher in CHF, and total antioxidant capacity (TAC), that we expected to be reduced in CHF [10–12].


   2. Patients and methods
Top
 Abstract
 1. Introduction
 2. Patients and methods
3. Results
 4. Discussion
 References
 
2.1. Subjects
We studied 66 outpatients with compensated CHF: (i) 46 patients (23 males; mean age 64 years, S.D. 13) who were established on an ACE inhibitor (lisinopril) and were then started on a β-blocker [either bisoprolol (n=26) initially 1.25 mg and titrated to 10 mg once daily or carvedilol (n=20) initially 6.25 mg titrated to 50 mg total daily]; and (ii) 20 CHF patients (11 males; mean age 68 years, S.D. 8) who were not previously on ACE-inhibitors, who were prospectively started on lisinopril 2.5 mg and titrated to 20 mg. Both β-blockers or ACE inhibitors were titrated to the maximum tolerated dose according to a standard protocol over a 2-month period. Patients were then followed up for a further 3 months. All patients were free from acute illnesses or recent admissions (>3 months). Baseline levels of the measured parameters were compared to 22 healthy control subjects (20 males; mean age 61 years, S.D. 7).

2.2. Laboratory
Serum lipid hydroperoxides (LHP) and total antioxidant capacity (TAC) were determined as indices of oxidative damage and antioxidant defence, and plasma vWf as an index of endothelial damage/dysfunction [9]. LHP were assessed by the ferrous-oxidation of the colorimetric dye xylenol orange at a wavelength of 560 nm in conjunction with the specific hydroperoxide discriminant triphenylphosphine [10]. TAC was determined by enhanced chemiluminescence [11], and vWf by ELISA (Dako-Patts, Ely, UK) [9]. Intra- and inter-assay coefficients of variation for all assays were <5% and <10%, respectively.

2.3. Power calculation and statistical methods
We hypothesised: (a) that levels of LHP or TAC would be different in CHF than in healthy control subjects by 1 S.D.; and (b) that 3 months treatment by β-blockade or ACE inhibition would reduce levels of lipid hydroperoxides by 0.5 of a standard deviation. In the cross-section analysis, for a difference of two-thirds of a standard deviation at P<0.05 and 1–β=0.85, the sample size requirement is 34. However, in view of multiple measurements, we extended this figure to provide additional confidence. Similarly, in the intervention study, we hypothesised the same reduction due to therapy, which again calls for a minimum of 34 data points (i.e. 17 subjects before and after treatment). Therefore we have again exceeded our sample requirement [13,14].

Continuously variable data was subjected to the Shapiro–Wilks test to define distribution. That distributed normally is presented as mean and S.D., and analysed by the t-test. Data distributed non-normally are presented as median and interquartile range (IQR) and were compared with the Mann–Whitney U-test. Data before and after treatment were analysed by paired t testing or Wilcoxon's rank sum test. Correlations were sought with Spearman's method.


   3. Results
Top
 Abstract
 1. Introduction
 2. Patients and methods
 3. Results
4. Discussion
 References
 
The patients in the ACE inhibitor and β-blockers arms of the study were comparable in age and co-morbidity (Table 1).


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  		Table 1 Clinical features in patients with chronic heart failure

 
Baseline indices for the measures of oxidative damage and scavenging (LHP and TAC) and endothelial function in the 66 CHF patients were significantly higher than the 22 healthy control subjects (Table 2). Median LHP (P=0.0022) and TAC (P=0.0005), and mean vWf (P<0.001) levels were higher in CHF patients compared to controls (Table 2). These differences (after logarithmic transformation) indicate we have sufficient power to test our hypotheses and minimise the risks of types 1 and 2 error.


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  		Table 2 Oxidative stress and endothelial dysfunction in chronic heart failure compared to control subjects

 
Following 3 months of maintenance therapy with β-blockers, there was significant reduction in blood pressure and LHP levels, but not TAC or vWf (Table 3). ACE inhibitor therapy also significantly reduced blood pressure, as well as vWf levels, but failed to have any statistically significant effects on LHP or TAC. There were no correlations between LHP, TAC and vWf (nor the changes with therapy) in the groups studied (data not shown).


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  		Table 3 Effects of therapy on oxidative stress and endothelial dysfunction in chronic heart failure

 

   4. Discussion
Top
 Abstract
 1. Introduction
 2. Patients and methods
 3. Results
 4. Discussion
References
 
In the present study we have shown that LHP levels were higher in CHF patients compared with control subjects, suggesting increased oxidative stress in these patients. TAC was also raised, as was vWf (the latter confirming our previous report [9]). Failure of increased TAC to prevent or minimise free-radical-mediated lipid peroxidation and muscle damage has previously been demonstrated following prolonged exercise [15], and the present results indicate that TAC in CHF, although raised, but may be impaired or inefficient. Indeed, raised TAC may be a physiological response to raised LHP, although lack of correlation fails to support this concept precisely. Lack of correlation between LHP and vWf at baseline suggests that the former alone may not directly damage the endothelium.

The reduction in LHP with β-blockers may be one of many mechanisms by which this class of drug is beneficial in CHF, and the change is unrelated to the fall of blood pressure or a reduction in endothelial cell damage, as a similar effect was not seen with the ACE inhibitors. The fall in vWf levels with the ACE inhibitor is in keeping with the beneficial effects of ACE inhibitors on endothelial function [16] and may be related to the improvement of blood pressure regulation in these patients as we have previously demonstrated a link between hypertension and endothelial damage [17].

This study is limited by the cross-sectional comparison between baseline indices and the open-label design and relatively small size of the intervention arms, but the numbers recruited are in fulfilment of our power calculation. We acknowledge that our CHF group have associated comorbidity such as diabetes and smoking, but the prime objective of this study was to test the hypothesis that β-blockers and ACE inhibitors reduce oxidative stress and therefore improve endothelial dysfunction in patients with CHF, rather than to assess the effect of comorbidity on our research indices, for which we are probably underpowered: the reason for including the healthy control group was not to emphasise a case/control comparison (as previously addressed by many other authors [3,5,9,15]), but to indicate approximate ‘normal’ levels of the haemostasis markers for comparisons with the CHF patient group. We also acknowledge that there are various ways of measuring oxidative stress in vivo, but we chose to measure serum levels of LHP and TAC because of their proven reliability and previous associations with heart failure [3,5]. Similarly, we have measured vWf as our index of endothelial damage/dysfunction, in keeping with our previous reports [9,17], but we accept that a continuum is likely to exist between endothelial dysfunction (which may be reversible) and clear damage (which may be irreversible)—the distinction between dysfunction and damage may well be unclear, but several different approaches to assessing endothelial integrity are available, ranging from flow-mediated dilatation of the brachial artery to measurement of plasma markers, such as vWf [18]. Finally, we have not attempted subgroup analyses of the beta-blocker arm, as the prime objective of the study was to test the hypothesis that β-blockers and ACE inhibitors reduce oxidative stress and therefore improve endothelial dysfunction in patients with CHF, rather than a comparison between the beta-blockers, which has been previously shown to be no different between metoprolol and carvedilol [19].

In conclusion, measures of oxidative stress and endothelial function are abnormal in CHF. These are modified by therapy: β-blockers reduce lipid peroxidation independently of its blood-pressure lowering action, whilst ACE inhibitors reduced endothelial damage/dysfunction. These effects may have implications for the pathophysiology of vascular complications in CHF.


   Acknowledgements
 
We acknowledge the support of the Pulse Trust, the Peel Medical Research Trust and the City Hospital Research and Development programme for the Haemostasis Thrombosis and Vascular Biology Unit.


   References
Top
 Abstract
 1. Introduction
 2. Patients and methods
 3. Results
 4. Discussion
 References
 

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  4. Katz S.D. Mechanisms and implications of endothelial dysfunction in congestive heart failure. Curr Opin Cardiol (1997) 12:259–264.[Web of Science][Medline]
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  10. Nourooz-Zadeh J., Tajaddini-Samardi J., Wolff S.P. Measurement of plasma hydroperoxide concentrations by the ferrous-oxidation-xylenol orange assay in conjunction with triphenylphosphine. Anal Biochem (1994) 220:403–409.[CrossRef][Web of Science][Medline]
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