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European Journal of Heart Failure 2005 7(2):183-188; doi:10.1016/j.ejheart.2004.06.001
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© 2005 European Society of Cardiology

Home-based exercise training modulates pro-oxidant substrates in patients with chronic heart failure

Josef Niebauera,b,*, Andrew L. Clarkc, Katharine M. Webb-Peploea, Rainer Bögerd and Andrew J.S. Coatsa,e

a Cardiac Medicine, Royal Brompton Hospital and NHLI London, UK
b Herzzentrum der Universität Leipzig Leipzig, Germany
c Cardiac Medicine, University of Hull UK
d Clinical Pharmacology, University of Hamburg Germany
e University of Sydney Australia

* Corresponding author. Herzzentrum der Universität Leipzig, Oberarzt der Abetilung fur Innere Medizin/Kardiologie, Strümpellstr. 39, 04289 Leipzig, Germany. Tel.: +49 341 865 0; fax: +49 341 865 1461. E-mail address: j.niebauer{at}medizin.uni-leipzig.de


   Abstract
Top
 Abstract
1. Introduction
 2. Methods
 3. Results
 4. Discussion
 References
 
Background: In chronic heart failure, oxidative stress is thought to lead to endothelial dysfunction. In this study, we assessed the effect of home-based exercise training on variables of the NO and purine pathways.

Methods and results: Eighteen patients and nine controls were randomly assigned in cross-over design to 8 weeks of exercise training (5 days/week, submaximal bicycle ergometer training, 30 min/day; calisthenics 9 min/day) and 8 weeks of sedentary lifestyle. Hypoxanthine, xanthine, L-arginine, asymmetric dimethylarginine (ADMA), symmetric DMA (SDMA) and nitrite were measured. In patients, exercise training led to an increase in peak VO2 (p<0.003). At baseline hypoxanthine—a pro-oxidant substrate and marker of hypoxia—was higher in patients than in controls (24.6±4.3 vs. 11.9±4.2 µmol/l; p<0.05). After training there was a reduction in hypoxanthine (p<0.01). Nitrite levels were lower in patients (416±31 µmol/l) than in healthy controls (583±35 µmol/l, p<0.001). Although nitrite levels were highest after exercise, the changes did not reach statistical significance (p=n.s.). L-Arginine, ADMA, and SDMA levels were not different between groups and were not altered by exercise training.

Conclusions: Chronic heart failure is associated with increased levels of hypoxanthine and decreased levels of nitrite. This imbalance can be beneficially modulated by chronic home-based exercise training.

Key Words: Heart failure • Exercise • Nitric oxide • Hypoxanthine

Received March 22, 2004; Revised April 25, 2004; Accepted June 8, 2004


   1. Introduction
Top
 Abstract
 1. Introduction
2. Methods
 3. Results
 4. Discussion
 References
 
Chronic heart failure is characterized by exercise intolerance. In part, this may be related to impaired flow-dependent vasodilation in conductance vessels as compared with normal subjects, which suggests that there is vascular endothelial dysfunction of large conduit vessels [1]. Altered endothelial function might thus contribute to impaired tissue perfusion in heart failure. Exercise training programs produce an increase in exercise capacity and at the same time an improvement in endothelial function [2,3]. The cause of the impaired endothelial function has not yet been fully elucidated. It may be related to abnormalities of the vasodilator nitric oxide (NO), although there are conflicting reports concerning the effects of heart failure on NO in the literature [4]. Oxidative stress secondary to increased free radical formation is reported to be common in chronic heart failure, and has an adverse effect on cardiac function and outcome [5,6]. Free radicals can inactivate NO and its biological activity [7].

NO is synthesized from the amino acid precursor L-arginine by nitric oxide synthases [8]. Asymmetric dimethylarginine (ADMA) is an endogenous inhibitor of NO synthesis produced by breakdown of methylated proteins [9]. Symmetrical DMA is produced when the methylation of amino acid residues has been symmetrical, and it has no effect on NO metabolism. Where ADMA accumulates, for example, in renal failure, it may cause endothelial dysfunction which is potentially reversible by L-arginine [10]. It may be involved in changes in NO metabolism in heart failure [11]. The ratio of L-arginine to ADMA gives an indication of the availability of L-arginine available for NO synthesis.

In normal conditions, the enzyme xanthine dehydrogenase (XDH) converts endogenous purines to xanthine and then urate for excretion. The enzyme can be converted to xanthine oxidase (XO), particularly in response to ischemia and reperfusion. The reduction of hypoxanthine to urate is accompanied by free radical production, particularly peroxide and superoxide [12], which can serve as precursors of highly damaging molecules, such as the hydroxyl radical. These may then contribute to oxidative stress and tissue damage following ischemia/reperfusion.

In ischemic tissue, purine substrates for XDH/XO build up, due to aberrant ATP catabolism [13], which occurs both in the heart [14] and in other areas [15]. Following ischemia in the heart, the availability of purine substrates for xanthine oxidase is more important for the generation of reactive oxygen species than the conversion of XDH to XO [16]. Hypoxanthine and uric acid may act as an indicator of oxidative stress.

We aimed to assess the role of hypoxanthine and xanthine in patients with chronic heart failure and to study whether a home-based program of exercise training induced changes in hypoxanthine and xanthine. We also studied the effects of training on the stable end products of nitric oxide metabolism, nitrite and nitrate, and on the substrate for NO production, L-arginine, and the NO-synthesis inhibitor, ADMA.


   2. Methods
Top
 Abstract
 1. Introduction
 2. Methods
3. Results
 4. Discussion
 References
 
2.1. Study design and population
We studied 18 patients and nine age-matched controls. Subjects were entered into a randomized cross-over study of unsupervised exercise training exclusively performed at home vs. rest (Fig. 1).


Figure 1
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  		Fig. 1 Study design.

 
Patients were recruited if they had had heart failure for at least 3 months, and had been clinically stable with no admissions and no changes in medication for 3 months. Heart failure was defined as symptoms of exercise limitation by breathlessness or fatigue in the presence of objective evidence of left ventricular systolic dysfunction on echocardiography (left ventricular end diastolic dimension (LVEDD) greater than 6.5 cm, and a shortening fraction less than 25%). No patient was limited by angina or had sustained ventricular arrhythmia on Holter monitoring. All patients had a serum creatinine of <125 mmol/l and were biochemically euthyroid. None of the patients or control subjects had obstructive lung disease as assessed by spirometry.

The nine healthy volunteers had no symptoms suggestive of heart disease and no history of hypertension, effort induced chest pain, or undue shortness of breath. There was no evidence of significant heart disease on echocardiography and no ischemic electrocardiographic change on maximal exercise testing.

The study was approved by the Ethics Committee of the Royal Brompton Hospital, London, UK. All patients gave written informed consent before starting the trial.

2.2. Exercise program
Patients and healthy subjects were randomized to start with either 8 weeks of exercise training or 8 weeks of rest (Fig. 1). Exercise training was unsupervised and carried out in patients' homes. Patients were asked to train at least on 5 days a week. The training program consisted of a combination of calisthenics and bicycle ergometry, performed at home. Participants were asked to do the first nine exercises in the Canadian airforce XBX program. The XBX Plan is a physical fitness program in which the work load increases as physical fitness improves. The time limit for each exercise remains the same (9 min in total), but the number of times the exercise is performed within this time limit is increased at each level. The exercises are made more difficult from each level to the next higher one.

In addition, subjects were lend a bicycle ergometer (Tunturi original ergometer W1 electronics) and asked to exercise on it for 20 min a day. They were asked to warm up by pedaling at a work load of 25 W at 50 rpm for 3 min and then to increase the resistance until their pulse rate was between 70% and 80% of the maximum pulse rate achieved on their initial maximal treadmill test. They then pedaled at 50 rpm for 20 min before decreasing the resistance to 25 W to cool down for 2–3 min.

During the 8-week rest period, the exercise bicycles were withdrawn (where the subjects had been randomized to training first) and subjects were asked to avoid any strenuous activity that might lead to shortness of breath or exhaustion.

The subjects were investigated at the Royal Brompton Hospital over 2 days at the start and end of each phase of the trial. After the first phase, they crossed over immediately to the second phase of the trial. Investigations were carried out at the same time of day at each visit.

2.3. Cardiopulmonary exercise testing
Subjects exercised using an incremental treadmill protocol. We used the Bruce protocol modified by the addition of a 3-min "stage 0" at the onset of exercise (1 mph at 5% gradient). During the test, expired air was collected and analyzed with a respiratory mass spectrometer (Amis 2000, Innovision, Odense Denmark). Oxygen consumption (VO2), carbon dioxide (VCO2), and minute ventilation (VE) were measured online. Peak oxygen consumption was calculated off line.

2.4. Blood tests
After 40 min lying supine (for heart rate variability monitoring) blood was taken from the antecubital vein and sent for routine analysis of urea and electrolytes. Blood samples for analysis of nitrite, nitrate, hypoxanthine, and xanthine were put on ice, immediately centrifuged at 4 °C and 1300 rpm. Plasma was then transferred into Eppendorf tubes and stored at –80 °C until further analysis.

2.5. Measurement of plasma nitrite and nitrate
In aqueous solutions NO has a very short half-life and is oxidized to nitrite and nitrate. NO production was determined by measuring the accumulation of these breakdown products in the plasma by a two-step procedure. Nitrite was measured immediately by the Griess reaction. Nitrate was measured in the same samples by the Griess reaction following reduction back to nitrite. Total NO production was then taken to be the sum of nitrite and nitrate, denoted by NOx. Patients taking oral nitrates (n=8) were compared with those not taking nitrates (n=10).

2.6. Measurement of plasma hypoxanthine and xanthine
High-performance liquid chromatographic (HPLC) analysis of plasma hypoxanthine and xanthine was based on a technique described in full elsewhere [17].

2.7. Measurement of L-arginine and dimethylarginines
Plasma concentrations of L-arginine, NG,NG'-dimethylarginine (ADMA), and NG,NG-dimethylarginine (SDMA) were measured by high-performance liquid chromatography (HPLC) and precolumn derivatization with o-phthaldialdehyde (OPA) by a previously published method [18].

2.8. Statistical analyses
Data are presented as mean±standard deviation and were analyzed according to the recommendation of Altman [19] for cross-over trials. Statistical analysis was performed using a standard statistical program package (StatView 4.5, SAS Institute, Cary, NC, U.S.A.). Numerical values are presented as mean±S.D. For all statistical tests differences were considered significant if the two-sided probability of the observed result under the null hypothesis was ≤0.05. Baseline characteristics and comparisons between two groups (patients vs. healthy volunteers) were made using unpaired t-test. The results after rest and after exercise training were compared using paired t-test.


   3. Results
Top
 Abstract
 1. Introduction
 2. Methods
 3. Results
4. Discussion
 References
 
3.1. Baseline characteristics
The patients and controls were matched for age and sex (Table 1). There were no significant differences between the subjects randomized to begin with training (n=14) as compared to those randomized to rest first (n=13). Three of the patients were receiving a thiazide diuretic and 11 received an average of 117±93 mg furosemide or its equivalent daily. All were receiving an angiotensin converting enzyme inhibitor (an angiotensin receptor blocker in one subject), one was taking a beta adrenoceptor antagonist. Eight patients were on oral nitrates (47.5±5.5 mg/day).There were no differences in echocardiographic variables between the patients randomized to rest or training first.


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  		Table 1 Subject characteristics at the beginning of the study

 
Patients had a higher level of hypoxanthine and urate, and lower levels of ADMA than controls. There was also a trend for lower levels of NO and L-arginine. There was no significant relation between the L-arginine/ADMA ratio and any of the components of the purine breakdown pathway. There was no relation between daily dose of diuretic and hypoxanthine (R=0.17), xanthine (R=0.01) or urate (R=0.34).

3.2. Training effect
There was an increase in peak VO2 in the patient group from 25.3±1.8 to 28.0±2.1 ml kg-1 min-1 (p<0.003), whereas there was no significant increase in the controls. There was a significant fall in hypoxanthine (p<0.01) to levels otherwise only seen in healthy subjects (Fig. 2), whereas no further changes in the XO/XDH pathway were observed (Table 2).


Figure 2
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  		Fig. 2 At baseline, hypoxanthine levels were significantly higher in CHF patients than in healthy controls. Exercise training led to a significant fall in hypoxanthine (p<0.01) to levels otherwise only seen in healthy subjects.

 


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  		Table 2 Training-induced changes in the nitrate pathway; comparison between patients and controls after 8 weeks of training vs. 8 weeks of sedentary lifestyle

 
At baseline, NO levels were significantly lower in CHF patients who were not on oral nitrates as compared to healthy controls. This difference was not seen in patients on oral nitrates where NO levels were almost normalized (Fig. 3).


Figure 3
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  		Fig. 3 At baseline, NO levels were significantly lower in CHF patients who were not on oral nitrates as compared to healthy controls. This difference was not seen in patients on oral nitrates where NO levels were almost normalized.

 
In both the control and patient groups, there was no effect of training on any of the components of the nitrate pathways studied (NOx, L-arginine, ADMA, SDMA). There was a relation of varying strength between training and rest values for the measured variables: urate, R=0.93; hypoxanthine 0.40; xanthine 0.31; L-arginine –0.12; SDMA –0.28; and ADMA –0.04. (see Table 2) in the XO/XDH pathway. There was no relation between change in peak VO2 and change in any of the measured variables.


   4. Discussion
Top
 Abstract
 1. Introduction
 2. Methods
 3. Results
 4. Discussion
References
 
This is the first study to evaluate the effects of home-based exercise training in patients with chronic heart failure on the NO and purine pathways.

We have shown that:

(1) levels of NO are lower in patients with chronic heart failure as compared to healthy controls.
(2) unsupervised, home-based exercise training leads to significant improvement in physical work capacity in patients with stable chronic heart failure.
(3) in normocholesterolemic heart failure patients, levels of ADMA were not different from healthy controls and did not change with exercise training.
(4) hypoxanthine—a pro-oxidant substrate and marker of hypoxia—is raised in patients with CHF and can be normalized by exercise training.

4.1. Purine pathway
CHF is associated with increased oxidative stress, as indicated by reduced antioxidants, a depressed oxidation–reduction (redox) state and increased lipid peroxidation [20]. Oxidative stress can cause contractile dysfunction [21] which may contribute to the progression of heart failure. Xanthine oxidase is formed from xanthine dehydrogenase under conditions of both hypoxia [22] and hyperoxia [23]. The oxidase form of the enzyme utilizes molecular oxygen as a cofactor for the conversion of hypoxanthine and xanthine to uric acid, and this process results in production of both hydrogen peroxide and superoxide. Production of reactive oxygen species by xanthine oxidase has been implicated in the reoxygenation injury resulting from ischemia and reperfusion [24]. However, it has also been shown that the increased formation of purine substrates for xanthine oxidase can become more important for generating reactive oxygen species than is a major conversion of xanthine dehydrogenase to xanthine oxidase [16].

During exercise ATP is converted to ADP and AMP to supply energy for muscular contraction. When ATP breakdown exceeds resynthesis, accumulation of ADP and AMP then activates the purine nucleotide cycle and a degradation cascade producing inosine monophosphate, hypoxanthine, and in some tissues, xanthine, and uric acid [25]. Venous hypoxanthine levels are higher in CHF patients than in healthy subjects, and increase in both in response to acute exercise [26]; this is related to oxygen consumption [27]. It is thus a reflection of hypoxia and oxidative stress. Effects of chronic exercise training had not been studied previously.

Although the number of patients studied is rather small and thus presents a study limitation, this is the first study to assess levels at baseline as well as after a program of unsupervised, home-based exercise training. At baseline, levels were raised, suggesting that heart failure patients are in state of hypoxia. Exercise training was able to reduce levels of this pro-oxidant substrate (and potentially) oxidative stress.

4.2. NO metabolism
Basal release of nitric oxide in patients with chronic heart failure has been variously reported to be decreased, normal or elevated [4]. In the present study, patients without oral nitrates showed significantly lower levels of NO than healthy controls. This is in keeping with previously reported diminished endothelial function in patients with heart failure, which is due to a functional imbalance between vasodilation and vasoconstriction in favor of constricting agents [28]. Endothelial function can be improved by exercise training in normal subjects, and patients with heart failure [2]. The mechanism of benefit might be due to a shear stress induced release of both the vasodilators nitric oxide and prostacyclin and an inhibition of the release of the vasoconstrictor endothelin-1 [29]. Furthermore, when exercise training is performed chronically it is not associated with a deleterious increase in markers of proinflammatory cytokines and endothelial damage [30].

In this study, exercise training did not alter levels of NO. A previous report showed comparable baseline levels of nitrate in healthy untrained as compared to endurance trained men [31]. Although exercise training does not necessarily lead to a detectable increase in systemic nitric oxide levels, it does increase local expression of mRNA for nitric oxide synthase, augment nitric oxide activity, and enhance endothelium-dependent vasodilation at the site of increased shear stress [28,32,33]. There is thus an increased sensitivity of the endothelium and vascular smooth muscle cells to vasodilatory stimuli [2,34]. The lack of an increase in systemic levels of NO might even be beneficial, since patients with heart failure have increased inducible NO synthase activity; local overproduction of NO in cardiac tissue [35] is negatively inotropic. To date it is not clear, whether increased levels of NO secondary to the application of oral nitrates have any beneficial effects on patients' quality of life or prognosis.

ADMA is a circulating endogenous NO synthase inhibitor [36] and it is raised in heart failure where it correlates with New York Heart Association functional class. This finding is suggestive of a compensatory role of a circulating endogenous nitric oxide synthase inhibitor against induced nitric oxide synthase activity in patients with heart failure. However, levels are also elevated in patients with risk factors of atherosclerotic disease, and they correlate with the degree of hypercholesterolemia [37]. This finding could explain why in the present study, normocholesterolemic heart failure patients had rather normal ADMA levels at baseline, which did not alter with exercise training [37].

In summary, we have demonstrated for the first time that patients with chronic heart failure have increased levels of hypoxanthine and decreased levels of NO. This imbalance can be altered by a program of unsupervised home based exercise training, which leads to a normalization of hypoxanthine levels.


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

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