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European Journal of Heart Failure 2002 4(2):193-199; doi:10.1016/S1388-9842(02)00002-8
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© 2002 European Society of Cardiology

Addition of candesartan to angiotensin converting enzyme inhibitor therapy in patients with chronic heart failure does not reduce levels of oxidative stress

Gethin R. Ellisa,*, Angus K. Nightingaleb,c, Daniel J. Blackmand, Richard A. Andersonb,c, Catherine Mumfordb,c, Graham Timminsb,c, Derek Lange, Simon K. Jacksonf, Michael D. Penneyg, Malcolm J. Lewisd, Michael P. Frenneauxb,c and Jayne Morris-Thurgoodb,c

a Department of Cardiology Royal Glamorgan Hospital, Llantrisant, Rhondda Cynon Taf, UK
b Wales Heart Research Institute University of Wales College of Medicine, Heath Park, Cardiff CF14 4XN, UK
c Department of Cardiology University of Wales College of Medicine, Cardiff, UK
d Department of Cardiology Northampton General Hospital, Northampton, UK
e Department of Pharmacology UWCM, Cardiff, UK
f Department of Medical Microbiology UWCM, Cardiff, UK
g Clinical Biochemistry Royal Gwent Hospital, Newport, Gwent, UK

* Corresponding author. Tel.: +44-1443-443580; fax: +44-1443-443371. E-mail address: gethin.ellis{at}pr-tr.nhs.wales.uk


   Abstract
Top
 Abstract
1. Introduction
 2. Methods
 3. Results
 4. Discussion
 5. Conclusions
 References
 
Background: Angiotensin II exerts a number of harmful effects in patients with chronic heart failure (CHF) and, through an increase in oxidative stress, is thought to be critical in the development of endothelial dysfunction. Angiotensin II may be elevated in CHF despite treatment with angiotensin converting enzyme (ACE) inhibitors, producing a rationale for adjunctive angiotensin receptor blockade. We investigated whether the addition of angiotensin antagonism to ACE inhibition would reduce oxidative stress and improve endothelial function and exercise tolerance in patients with chronic heart failure.

Methods and results: Twenty-eight heart failure patients, who were on stable ACE inhibitor therapy, were randomised to receive adjunctive therapy with candesartan or placebo. Plasma lipid-derived free radicals, TBARS and neutrophil O2-generation, markers of oxidative stress, were measured in venous blood. Arterial endothelial function was assessed as the response of the brachial artery to flow-related shear stress. Exercise capacity was determined by cardiopulmonary exercise testing. Compared with placebo, candesartan had no effect on changes in lipid derived free radicals (–0.1±1.2 vs. –0.1±1.0 units, respectively, P = NS), TBARS (–2.2±1.1 vs. –2.6±2.2 µmol/l, respectively, P = NS) or neutrophil O2-generating capacity (–7.3±5.1 vs. –8.4±7.9 mV/5x105 neutrophils, respectively, P = NS). There was no effect on changes in brachial artery flow-mediated dilatation (0.5±1.0 vs. 0.8±1.3%, respectively, P = NS) nor peak VO2 (1.6±0.7 ml/kg per min vs. 1.8±0.6 ml/kg per min; P = NS).

Conclusion: The addition of the candesartan to ACE inhibitor therapy had no effect on oxidative stress and did not improve endothelial function or exercise capacity in patients with CHF.

Key Words: Heart failure • Angiotensin • Drugs • Endothelium • Free radicals

Received November 12, 2001; Accepted November 28, 2001


   1. Introduction
Top
 Abstract
 1. Introduction
2. Methods
 3. Results
 4. Discussion
 5. Conclusions
 References
 
In recent years, considerable advances have been made in the treatment of chronic heart failure (CHF). In particular, blockade of the renin–angiotensin system by ACE inhibitors has resulted in clear prognostic and mortality benefits in CHF. Angiotensin II (AII) exerts a number of harmful effects on the cardiovascular system and, through an increase in oxidative stress achieved in a number of potential ways including direct increases in vascular smooth muscle production of superoxide anion, is thought to be critical in the development of endothelial dysfunction [1,19]. This may be achieved by ACE inhibitors decrease levels of AII but these may rise again with prolonged treatment [2,3]. In this situation, the addition of angiotensin II type I receptor (AT1-R) antagonists might be expected to be of benefit [4]. One study has shown an increase in exercise capacity with combined ACE inhibition and AT1-R blockade [5] although another smaller study did not show any improvement in exercise capacity or neurohormones [6]. A larger study, investigating the effect of candesartan alone, enalapril alone or combination therapy showed no difference in mortality between the three groups, although there were improvements in left ventricular dimensions and function with combination therapy [7]. Improvements in exercise capacity have been described 3 weeks following the introduction of either an ACE inhibitor or an AT1-R antagonist alone to patients with CHF [24] and we hypothesised that combination therapy for 4 weeks with ACE inhibitors and candesartan cilexetil would result in lower levels of oxidative stress, thereby improving endothelial function and exercise capacity compared to ACE inhibition alone.


   2. Methods
Top
 Abstract
 1. Introduction
 2. Methods
3. Results
 4. Discussion
 5. Conclusions
 References
 
2.1. Subject population
We screened 43 patients, mean age 62 years (range 39–78 years), all of whom had documented impaired left ventricular systolic function (ejection fraction ≤35%) and stable NYHA class II to IV symptoms of CHF. The patients were on medical therapy unchanged for at least three months. All subjects were treated with an ACE inhibitor, which had been titrated to the maximal tolerated dose prior to inclusion in the study. We excluded patients with significant renal impairment (serum creatinine >250 mmol/l), hepatic impairment (twice normal serum transaminase levels) or evidence of active infective illness. Clinical characteristics are shown in Tables 1 and 2. The study was approved by the Bro Taf Local Research Ethics Committee and written informed consent was obtained from all subjects. From the initial group of 43 patients, 33 patients fulfilled the inclusion/exclusion criteria and were randomised to receive either candesartan or placebo.


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  		Table 1 Clinical characteristics

 


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  		Table 2 Effects of candesartan on hemodynamics and exercise capacity

 
2.2. Study protocol
On the first day of the study, at 09:00 h after an overnight fast, venous blood was obtained for measurement of oxidative stress and assessment of renal function, brain natriuretic peptide (BNP) and cholesterol [8]. Pulse wave analysis was then performed after subjects had rested for 20 min. Arterial endothelial function was then assessed and following this, subjects performed an incremental treadmill cardiopulmonary exercise test. The patients were randomly allocated to receive candesartan, or placebo for 1 month in addition to their usual therapy. The initial starting dose of candesartan or placebo was 8 mg once daily. Then, subject to clinical review, including blood pressure and renal function, this was increased to 16 mg daily after 1 week. Following a month of treatment, all the measurements were repeated.

2.3. Measurement of BNP
Concentrations of BNP in plasma were measured by immunoradiometric assay (Shionoria assay, Shionogi & Co Ltd, Osaka, Japan). Blood was collected into tubes containing EDTA as an anticoagulant (1.8 mg K2/ml) and apoprotinin (500 kIU/ml: Bayer AG, Germany). The plasma was separated by centrifugation and frozen at –40 °C until assayed. The assay has a detection limit of 2 pg/ml and concentrations in normal healthy adult male and female volunteers are <18 pg/ml. Between-batch imprecision of the assay over the range of values measured was between 4.0 and 7.5%.

2.4. Measurement of oxidative stress
2.4.1. Measurement of venous free radicals (FR)
Venous blood samples were taken directly into the pre-prepared spin-trap-containing vacutainer bottles and centrifuged at 2000 rev./min for 5 min. Lipid-derived FR levels were measured as previously described by us [9]. Results are expressed as arbitrary units.

2.4.2. Thiobarbituric acid reactive substances (TBARS)
Plasma levels of TBARS (an indicator of lipid peroxides) were determined as previously described using a colorimetric assay available as a standard commercially available kit (Oxis International Inc.) [9,10]. The results are expressed as µmol/l and give values for malonaldehyde and 4-hydroxyalkenals combined.

2.4.3. Superoxide anion generation by neutrophils
We employed a refined lucigenin-enhanced chemiluminescent assay of NADPH oxidase activity to measure basal and post-activation levels of O2– generation by neutrophils [11] which we have previously described in detail [9].

2.5. Measurement of flow-related endothelial function
Changes in brachial artery diameter in response to reactive hyperaemia (produced by releasing a cuff inflated at the wrist to suprasystolic pressures for 5 min), were measured non-invasively using a high-resolution ultrasonic wall-tracking system, (Vadirec Wall-Track SystemTM, resolution ±3 µm) as previously described and validated by us [9,12]. Data are presented as percentage change in brachial artery diameter from baseline and as absolute diameters.

2.6. Pulse wave analysis
Pulse wave analysis (PWA) was performed using the technique of aplanation tonometry which we and others have described in detail [13,14]. Left ventricular systolic ejection duration (ED) can be obtained from the derived central aortic pressure trace. Ejection duration is strongly related to left ventricular end diastolic pressure and to stroke volume and therefore gives useful information as to changes in central hemodynamics [15]. The reproducibility of the technique has been described elsewhere [14].

2.7. Exercise capacity
A maximal treadmill exercise test was completed by subjects according to a Weber protocol. On-line gas analysis permitted breath-by-breath measurement of expired gas concentrations. The test was symptom-limited, but subjects were encouraged to exercise to an RER >1.0. Peak VO2, exercise time and VE/VCO2 slope were calculated.

2.8. Statistical analysis
Statistical analysis was performed using SPSS 9.0. All data are presented as mean value±S.E.M. unless otherwise stated. At baseline, measures of oxidative stress, FMD, hemodynamics and exercise capacity in the two groups of patients with CHF were compared using one-way analysis of variance (ANOVA) followed by post hoc Bonferroni multiple comparisons test. We compared the effects of candesartan vs. placebo on measures of oxidative stress, endothelial function, hemodynamics and exercise capacity using analysis of covariance. Statistical significance was accepted at the level P<0.05.


   3. Results
Top
 Abstract
 1. Introduction
 2. Methods
 3. Results
4. Discussion
 5. Conclusions
 References
 
Of the 33 patients entering the study, five were withdrawn (three from the active group and two from the placebo). The dropouts in the active group were due to death (n=1) and poor drug compliance (n=2); in the placebo group, dropouts were due to worsening heart failure (n=1) and poor drug compliance (n=1). There was no change in concomitant medications in those patients that completed the study. In addition, the active and placebo groups were well matched for age, gender, NYHA status and underlying CHF aetiology (Table 1). Baseline levels of BNP, shown in Table 1, were similar in both groups and elevated compared to the normal range (<18 pg/ml) in our lab for patients without CHF. All subjects were treated with ACE inhibitors [daily mean dose of captopril was 82.5 mg (n=5), lisinopril 19.5 mg (n=14), ramipril 7 mg (n=3), enalapril 30 mg (n=5), perindopril 4 mg (n=4)]. Other treatments included digoxin (n=14), β blockers (n=5), nitrates (n=9), calcium channel blockers (n=1), diuretics (n=22), statins (n=8), aspirin (n=11) and Warfarin (n=15). One patient failed to attain the target dose of 16 mg candesartan once daily. All patients in the placebo group reached the highest dose. Results are given for the 28 patients who completed the study.

3.1. Oxidative stress
Analysis of the EPR spectra and comparison with published values indicate trapping of lipid alkoxyl and carbon-centred FR species derived from lipid peroxidation [16]. Changes in lipid derived FR and TBARS compared to baseline did not differ between the candesartan and placebo groups (lipid derived FR –0.1±1.2 vs. –0.1±0.9 units, respectively, P=NS) (Fig. 1), (TBARS –2.2±1.1 vs. –2.7±0.7 µmol/l, respectively, P=NS) (Fig. 2).


Figure 1
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  		Fig. 1 Effect of candesartan on lipid-derived free radicals.

 


Figure 2
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  		Fig. 2 Effect of candesartan on TBARS.

 
The changes in mean neutrophil O2-generating capacity in the candesartan and placebo groups when compared with baseline were similar (–7.3±8.1 vs. –8.4±7.9 mV/5x105 neutrophils respectively, P=NS) (Fig. 3).


Figure 3
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  		Fig. 3 Effect of candesartan on Neutrophil superoxide anion generating capacity.

 
3.2. Arterial endothelial function
Mean brachial artery end-diastolic diameters at baseline were similar in the active and placebo groups (4.4±0.2 vs. 4.3±0.1 mm, respectively, P=NS). The increase in diameter in the brachial artery in response to hyperaemia [flow-mediated dilatation (FMD)] was similar at baseline in the candesartan and placebo group (2.2±1.1 vs. 2.7±0.7%, respectively, P=NS). FMD tended to increase over 1 month in both groups, but this increase was similar in the candesartan and placebo group (0.5±1.0 vs. 0.8±1.3%, respectively, P=NS) (Fig. 4). Similarly, the change in response to 400 µg GTN during therapy was similar in the candesartan and placebo group (0.6±2.2 vs. 1.9±1.6%, respectively, P=NS).


Figure 4
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  		Fig. 4 Effect of candesartan on conduit artery endothelial function.

 
3.3. Pulse wave analysis
Blood pressure and heart rate were similar in both groups at baseline (Table 2). Following treatment with candesartan there was a slight fall in both systolic ({delta}SBP with candesartan –4.3±5.3 mmHg vs. 2.4±4.8 mmHg with placebo; P=NS) and diastolic blood pressure ({delta}DBP with candesartan –5.8±2.9 mmHg vs. –1.4±1.9 mmHg with placebo; P=NS) although this did not reach significance.

Twenty patients (10 in each group) were suitable for pulse wave analysis (in sinus rhythm with less than three ectopics per minute). Baseline parameters were well matched (Table 2). Ejection duration (ED) was inversely correlated with resting heart rate (r=–0.81; P<0.001) and positively correlated with augmentation index (AIx) (r=0.79; P<0.01). There was no improvement in ED with candesartan ({delta}ED with candesartan 4.4±6.2 ms vs. 18.1±7.9 ms with placebo; P=0.18). Similarly augmentation of central aortic pressure was not altered by treatment with candesartan ({delta}AIx with candesartan –3.3±2.6% vs. –1.3±3.8% with placebo; P=NS).

3.4. Exercise capacity
Peak VO2 was similar in both groups at baseline (15.1±1.5 ml/kg per min vs. 15.1±1.7 ml/kg per min; P=NS). At 1 month, there was a significant improvement in peak VO2 in both groups ({delta}VO2 with candesartan 1.6±0.7 ml/kg per min vs. 1.8±0.6 ml/kg per min; P<0.05 compared to baseline) but the change was similar in both groups (P=NS when changes in both groups are compared). VE/VCO2 slope and exercise time improved slightly from baseline in both groups but again there was no significant change between the groups (Table 2).


   4. Discussion
Top
 Abstract
 1. Introduction
 2. Methods
 3. Results
 4. Discussion
5. Conclusions
 References
 
The important findings of this study are that addition of the AT1-R antagonist, candesartan, to stable standard therapy, including ACE inhibitors, in patients with moderately severe CHF, did not reduce measures of oxidative stress and, furthermore, following 1 month of combination therapy there was no improvement in arterial endothelial function, left ventricular systolic ejection duration or exercise capacity.

Despite the impressive symptomatic and prognostic gains achieved with ACE inhibitors, severe CHF remains a syndrome associated with a poor quality of life, poor prognosis and frequent hospitalisation; furthermore, its prevalence is increasing [17]. This underscores the need to identify either alternate or additional therapies for CHF.

Increased oxidative stress (defined as a shift in the balance of reactive oxygen species vs. antioxidant defences in favour of the former) is believed to play a key role in the CHF syndrome [18] and is at least in part driven by high levels of AII. The patients described in our study demonstrated clear evidence of increased oxidative stress compared to normal subjects studied in our laboratory using the same techniques, despite treatment with ACE inhibitors [9] and this provided the rationale for this study. In addition, despite maximal conventional treatment, patients remained significantly symptomatic as evidenced by their relatively high NYHA class, reduced exercise capacity and elevated plasma levels of BNP providing a target for treatment.

4.1. Oxidative stress and endothelial dysfunction in CHF
ACE inhibitors have been shown to improve endothelial dysfunction in a variety of cardiovascular conditions, including CHF, hypertension, coronary artery disease and diabetes mellitus. This may be, in part, due to a reduction of AII-stimulated O2-superoxide anion generation via NADH/NADPH oxidase systems [19], but also to increased bradykinin-mediated NO release [20]. However, ACE inhibitors do not completely block AII generation, and in severe CHF, tissue AII levels may remain elevated despite the use of high dose ACE inhibitor therapy [3,21]. However, we did not measure AII levels in this group of subjects as this assay was not available to us. AT1-R antagonists (such as candesartan) offer the potential to completely block AT1-R mediated effects (including stimulation of the NADH/NADPH oxidase O2-generating enzymes). Attention has now turned to the adjunctive use of AT1-R antagonists in combination with ACE inhibitors for the treatment of moderate to severe CHF. A large multicenter study (Val-HeFT) reported that the addition of valsartan to ACE inhibitor therapy reduced hospitalisation but did not alter mortality [22]. Another large multicenter trial with candesartan is underway [23].

The two groups of patients in our study had considerable impairment of brachial artery FMD compared with expected age and gender predicted values for our laboratory (2.2 and 2.7% vs. 6.5%) [9], despite being on relatively high doses of ACE inhibitors. Similarly, the measures of oxidative stress we employed were also considerably higher than those seen in age and gender-matched subjects as reported by ourselves [9]. We evaluated two measures of oxidative stress in plasma, measuring relatively short-lived lipid-derived FR and also TBARS (longer-lived products of lipid peroxidation). We also assessed neutrophil O2-generation (potentially, an important source of oxidative stress in CHF). The presence of significantly enhanced oxidative stress and endothelial dysfunction in the patient population provided the potential for amelioration through a further reduction in AII effects. There was, however, not even a trend to improvement with the addition of the AT1 receptor antagonist candesartan. Similarly, despite marked exercise limitation and shortened left ventricular ejection duration prior to treatment, again we were unable to demonstrate any significant improvement.

4.2. Exercise capacity and hemodynamics in CHF
Our findings are consistent with a similar study which did not show any improvement in exercise capacity, hemodynamics or neurohormones when losartan was added to ACE inhibition [6]. It is, however, in contrast to a study which showed that the addition of losartan to ACE inhibitors for three months improved peak VO2 [5]. It is possible that the short duration of treatment (1 month) may have been insufficient. However, improvements in exercise capacity were seen by 3 weeks following the introduction of either an ACE inhibitor or an AT1-R antagonist to patients with CHF [24] and are detected at 4 [6,25] and 6 weeks in other studies [26]. No difference in exercise capacity was seen at either four or twelve weeks in a study with a similar design to the study presented here, although Houghton et al. only presented data on exercise capacity and neurohormones [6]. It is possible that differences may exist between AT1-R antagonists. However, this seems unlikely given the improvements seen in monotherapy with candesartan [27]. Our study size was relatively small, but had 95% power to detect a 3% improvement in brachial artery flow-mediated dilatation at a significance level of <0.05.

4.3. Study limitations
We did not measure plasma AII levels at baseline. However, the patients in our study had markedly limited exercise capacity, increased oxidative stress, impaired endothelial function and raised plasma BNP at baseline. Previous studies in similar patient groups have reported raised plasma AII and tissue AII generation despite ACE inhibitor therapy [3,4].

It is possible that a beneficial effect might have been seen if therapy had been maintained for a period of longer than one month and the patient numbers included in this study were also relatively small. In addition, we have recently found that reductions in oxidative stress with anti-oxidant therapy with vitamin C do not correlate with improvements in endothelial function [9]. However, previous studies have reported improvements in endothelial function and exercise capacity within 1 month of commencing ACE inhibitor therapy in patients with CHF [20,25] and in animal models, oxidative stress is reduced by ACE inhibitors [28,29]. The observation of no change in any parameter after one month of therapy is therefore persuasive and consistent with the outcome data [22].


   5. Conclusions
Top
 Abstract
 1. Introduction
 2. Methods
 3. Results
 4. Discussion
 5. Conclusions
References
 
Despite the theoretical rationale, addition of candesartan to stable ACE inhibitor therapy in patients with moderate to severe CHF did not reduce oxidative stress or improve endothelial function, exercise capacity or an indirect measure of central hemodynamics (left ventricular ejection duration). Our observations may provide a physiological basis for the absence of mortality benefit from addition of AT1-R antagonist therapy to ACE inhibitor therapy recently reported in the Val-HeFT trial [22].


   Acknowledgements
 
This study was supported by the British Heart Foundation. G.R.E. and R.A.A. were BHF Junior Research Fellows, M.P.F. holds the BHF Sir Thomas Lewis Chair of Cardiology; A.K.N., C.M., J.M.T. and G.T. are supported by the BHF. The study was also supported by a grant-in-aid from AstraZeneca Pharmaceuticals.


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

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