Skip Navigation

European Journal of Heart Failure 2005 7(4):612-617; doi:10.1016/j.ejheart.2004.05.006
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 Witte, K. K.A.
Right arrow Articles by Clark, A. L.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Witte, K. K.A.
Right arrow Articles by Clark, A. L.
Social Bookmarking
Add to CiteULike   Add to Connotea   Add to Del.icio.us  
What's this?

© 2005 European Society of Cardiology

The effects of long-term β-blockade on the ventilatory responses to exercise in chronic heart failure

Klaus K.A. Witte*, Simon Thackray, Nikolay P. Nikitin, John G.F. Cleland and Andrew L. Clark

Academic Cardiology, Castle Hill Hospital Castle Road, Cottingham Hull HU16 5JQ, UK

* Corresponding author. Tel.: +44-1482-624073; Fax: +44-1482-624071. E-mail address: klauswitte{at}hotmail.com


   Abstract
Top
 Abstract
1. Introduction
 2. Methods
 3. Results
 4. Discussion
 5. Conclusions
 6. Limitations
 References
 
Aims: Chronic heart failure (CHF) patients complain of breathlessness and fatigue. Beta-blockers improve symptoms, echocardiograpahic variables and prognosis in CHF, but their effect on exercise capacity remains unclear. The aim of this study was to describe the effects of long-term beta-blocker therapy on metabolic gas exchange variables and ventilation during exercise in CHF patients.

Methods: 42 patients with symptomatic heart failure due to left ventricular systolic dysfunction (ejection fraction 33.2 (8.2)) on loop diuretics and angiotensin-converting enzyme inhibitors or angiotensin II antagonists, underwent exercise testing with metabolic gas exchange. They were then initiated onto and uptitrated to the maximum tolerated dose of beta-blockers. After 1 year of follow-up, patients were invited back for repeat testing.

Results: 35 patients attended for repeat exercise testing. Four patients had died, and three had not tolerated beta-blockade. After 1 year, exercise time was increased (487 (221) vs. 500 (217), p<0.05), and peak oxygen consumption and VE/VCO2 slope were unchanged (20.9 (5.0) vs. 20.0 (5.4), p=0.15 and 36.7 (8.3) vs. 37.3 (7.8), p=0.70). Peak ventilation, (61.5 (12.9) vs. 57.1 (13.4), p<0.05), peak carbon dioxide production (1629 (404) vs. 1496 (375), p<0.02) and hence respiratory exchange ratio (1.02 (0.08) vs. 0.98 (0.06) p<0.02) and p<0.05) were reduced. Submaximal oxygen consumption and carbon dioxide production were lower at matched workloads. The slope relating symptoms to ventilation (Borg/VE slope) was less steep following beta-blockade (0.18 (0.09) vs. 0.15 (0.06), p<0.05).

Conclusion: Long term beta-blocker therapy increases exercise time but not peak oxygen consumption, and reduces peak carbon dioxide production. CHF patients are less symptomatic for a given ventilation during exercise following beta-blocker treatment.

Key Words: Breathlessness • Beta-blockers • Chronic heart failure

Received August 13, 2003; Revised March 22, 2004; Accepted May 5, 2004


   1. Introduction
Top
 Abstract
 1. Introduction
2. Methods
 3. Results
 4. Discussion
 5. Conclusions
 6. Limitations
 References
 
Patients with chronic heart failure complain of exercise intolerance, usually due to breathlessness and fatigue [1]. This can be objectively assessed as a reduction in peak oxygen consumption (pVO2) during incremental exercise testing with metabolic gas exchange analysis [2]. Patients also have an increased ventilatory response to exercise as shown by an increase in the slope relating ventilation to carbon dioxide production (VE/VCO2 slope) [3,4]. The VE/VCO2 slope is abnormal throughout exercise [5], and correlates inversely with pVO2, so that the greater the ventilatory response, the lower the exercise capacity [3,4].

The sympathetic nervous system is overactive in chronic heart failure [6] and has an influence on the reflexes contributing to the control of ventilation such as skeletal muscle ergoreceptors [7,8] and central chemoreceptors [9,10]. Exogenously infused catecholamines increase ventilation in control subjects [11–13] and yohimbine, which increases catecholamine release, increases ventilation during exercise in normal subjects [14]. Beta-blockade in chronic heart failure improves echocardiographic variables of cardiac function, patients' symptoms and their prognosis [15,16], but randomised trials have failed to demonstrate a consistent improvement on maximal [17,18] or submaximal [19–21,23] exercise capacity. A sub-study of patients with CHF randomised to atenolol or placebo recently showed a modest benefit on pVO2 in 23 heart failure patients compared with 20 taking placebo [24].

We have previously demonstrated a reduction in ventilation early in exercise, and respiratory exchange ratio (RER) following acute beta- and alpha blockade [25]. This might be a consequence of a change in substrate utilization. The ratio of oxygen consumption to carbon dioxide production at the mouth (RER) is lower (~0.7) when lipids are metabolised than when carbohydrates are used (~1.0). The change in peak RER might therefore represent a shift from carbohydrate to lipid use due to acute sympathetic inhibition. There is a suggestion that training might lead to reduced anaerobic metabolism with increased energy production for the same oxygen consumption [26].

The aim of the present study was to assess the influence of long-term beta-blockade has on the ventilatory response to exercise and symptoms of breathlessness in patients with chronic heart failure.


   2. Methods
Top
 Abstract
 1. Introduction
 2. Methods
3. Results
 4. Discussion
 5. Conclusions
 6. Limitations
 References
 
We enrolled 42 patients into the study. Chronic heart failure was defined as the presence of symptoms of fatigue or breathlessness on exertion and a left ventricular ejection fraction on echocardiography of less than 40% with no other cause of breathlessness apparent. To be included in the analysis, the condition had to be of at least 3 months duration prior to the initial visit, with no recent exacerbation or change in medication and no beta-blocker therapy. We did not include patients with neurological conditions, inducible ischaemia or a history of pulmonary disease, or if their FEV1 was less than 80% of predicted. A control group was considered unethical in view of the overwhelming evidence of benefit of beta-blockers.

At the initial visit each patient received a complete echocardiographic examination using a Vingmed Vivid 5 scanner (Horten, Norway) using M-mode to determine left ventricular end-diastolic diameter (LVEDD) and the modified Simpson's rule to calculate left ventricular volumes and ejection fraction (LVEF). They then underwent symptom-limited treadmill-based maximal exercise testing using a Bruce protocol modified by the addition of a ‘stage 0’ at onset consisting of 3 min of exercise at 1.61 km/h (1 mile/h) with a 5% gradient. Patients were encouraged to exercise to exhaustion. During the tests patients wore a tightly fitting facemask to which was connected a capnograph and a sample tube enabling on-line ventilation and metabolic gas exchange measurements (Jaeger Oxycon Delta, Würtzburg, Germany). A respiratory exchange ratio (RER), (VCO2/VO2) of 1.1 was taken to indicate maximal effort. The anaerobic threshold was calculated using the VO2/VCO2 slope method [27]. Standard spirometry (FEV1 and FVC) was also performed prior to the exercise test. The subjects were asked to score their symptoms of breathlessness or fatigue between 0 and 10 (0 being no symptoms and 10 being maximal) on a standard scale of perceived exertion [28] at the end of each stage during the test. We related symptoms to ventilation by plotting the Borg score against ventilation and calculated the slope of this relationship for each test (Borg/VE slope) [29]. All patients underwent an initial exercise test to familiarise them with the equipment. We used the second test as our baseline.

The patients were then referred to the local nurse-led heart failure clinic for initiation and uptitration of beta-blocker therapy. They were seen within 3 weeks and commenced on beta-blockers (either carvedilol or bisoprolol) in accordance with local guidelines. Carvedilol was the first line agent. The beta-antagonists were uptitrated following recognized trial protocols [30] with visits every 2 weeks until target or maximally tolerated doses were achieved. Reasons for accepting doses below target levels were a resting heart rate <50 beats/min or symptomatic postural hypotension. The patients were seen at regular intervals for the subsequent 12 months and invited back for a further exercise test and echocardiogram after 1 year of beta-blocker therapy. No training program was undertaken by any patient between the baseline and repeated tests. However, physical activity was not discouraged.

Results are reported as means (SD). Beta-blocker doses are reported as a percentage of target dose (25 mg bd for Carvedilol and 10 mg od for Bisoprolol).

We used paired Student's t-tests for within group comparisons of the ventilatory and haemodynamic data. A p-value of <0.05 was taken to be significant.


   3. Results
Top
 Abstract
 1. Introduction
 2. Methods
 3. Results
4. Discussion
 5. Conclusions
 6. Limitations
 References
 
Table 1 shows patient characteristics. Four patients had died at 1 year of follow-up and three others had not tolerated beta-blockade. All the remaining 35 patients attended for repeat exercise testing after 1 year of therapy. The mean oxygen consumption was 20.9 (5.0) ml/kg/min. Eleven patients were taking bisoprolol and 24 carvedilol. Seven patients were in atrial fibrillation. At the end of the uptitration period, none of these remained on digoxin. All of these 35 patients had been on optimal-dose angiotensin converting enzyme inhibitors or angiotensin II antagonists at baseline. There was no difference in baseline age, height, weight, severity of heart failure, LVEDD, left ventricular end diastolic volumes (LVEDV) and LVEF, duration of therapy, pulmonary function, or for any of the baseline rest and peak exercise test data between the patients on carvedilol and bisoprolol. A higher percentage of recommended daily dose of carvedilol was taken (Table 2), but the duration of therapy was not different.


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

  		Table 1 Subject characteristics

 


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

  		Table 2 Beta-blocker doses and duration of therapy

 
There was no significant change in weight after 1 year of beta-blockade, but the average NYHA class had improved from 2.5 (0.9) to 1.9 (0.7); p<0.05. FEV1 was significantly reduced after 1 year of beta-blocker therapy (from 84 (17%) to 79 (21%)) (Table 3) but FVC was not changed.


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

  		Table 3 Echocardiographic and peak exercise variables before and after beta-blocker therapy

 
3.1. Haemodynamic data
Resting and peak heart rates and peak blood pressure readings were reduced significantly by beta-blockade (Table 4). There was however, no reduction in resting blood pressure with either of the beta-blockers. There was no difference in the response of heart rate or blood pressure between carvedilol and bisoprolol.


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

  		Table 4 Haemodynamic data before and after long-term beta-blockade

 
3.2. Echocardiographic data
Left ventricular end diastolic volume and diameter were reduced after a year of beta-blocker therapy (Table 3) and the ejection fraction was increased.

3.3. Peak exercise
There was no change in peak oxygen consumption or VE/VCO2 slope after beta-blocker therapy (Table 3). There was, however, a small but significant increase in exercise time. There was also a reduction in peak ventilation and although the tidal volume at peak was not altered, the frequency of ventilation was reduced. RER at peak was also reduced due to a reduction in peak carbon dioxide production. Beta-blocker therapy reduced the gradient of the Borg/VE slope significantly (Table 3). There were no differences in changes in maximal data between the two beta-blockers. No resting variables were different after beta-blockade.

3.4. Submaximal exercise
The number of patients exercising past each stage increased following beta-blockade (31 vs. 34 and 23 vs. 28 for the first two stages, respectively). There were no differences in frequency, tidal volume and ventilatory equivalent for carbon dioxide at any of the early stages of exercise. However, there was a significant reduction in oxygen consumption and carbon dioxide production (Fig. 1a and b), and a reduction in submaximal ventilation for the first two stages (p<0.02) (Fig. 1c) following beta-blockade. The RER at matched submaximal workloads was not reduced (Fig. 1d). Symptoms of breathlessness were significantly reduced at the end of the first stage (Borg score, 1.15 (0.2) to 0.72 (0.2), p<0.05).


Figure 1
View larger version (12K):
[in this window]
[in a new window]
[Download PowerPoint slide]
  		Fig. 1 (a) Oxygen consumption during the first two stages before (unfilled columns) and after beta-blockade (filled columns). *p<0.05, **p<0.001 (n=31 for first stage and 23 for second stage). (b) Carbon dioxide production during the first two stages before (unfilled columns) and after beta-blockade (filled columns). *p<0.05, **p<0.001 (n=31 for first stage and 23 for second stage). (c) Ventilation during the first two stages of exercise before (unfilled columns) and after (filled columns) beta-blockade. *p<0.05 (n=31 for first stage and 23 for second stage). (d) RER during the first two stages of exercise before (unfilled columns) and after (filled columns) beta-blockade (n=31 for first stage and 23 for second stage).

 

   4. Discussion
Top
 Abstract
 1. Introduction
 2. Methods
 3. Results
 4. Discussion
5. Conclusions
 6. Limitations
 References
 
The present study demonstrates a reduction in oxygen consumption at submaximal matched workloads in patients with chronic heart failure most likely to be due to the effects of long-term beta-blockade. There was a no increase in peak oxygen consumption. However, peak carbon dioxide production was reduced and thus the peak RER (VCO2/VO2) was reduced. There was also a reduction in peak ventilation, but it was of a lower magnitude than the reduction in peak carbon dioxide production. There was no change in the VE/VCO2 slope.

The finding that beta-blockade allows patients to do more exercise for a given oxygen consumption with less carbon dioxide production and a reduction in RER suggests the possibility of increased ‘efficiency’ of energy production in skeletal muscle with less anaerobic metabolism. The submaximal data demonstrating reduced oxygen consumption and carbon dioxide production in the early stages of exercise are in line with this hypothesis. Increased ‘efficiency’ of energy production has previously been demonstrated following training programs [26]. None of the patients had been involved in a training program or had been on a treadmill between the baseline test and the reassessment. However, it is possible that with an improvement in their general condition, patients did more exercise than prior to beta-blocker therapy leading to a degree of ‘auto-training’.

During early exercise the major substrates used for energy production are fatty acids, whose metabolism leads to an RER of 0.7. As exercise progresses, the influence of the sympathetic nervous system leads to a so-called cross-over effect of down-regulation of fatty acid metabolism and an increase in the relative importance of glycogenolysis and glucose utilization with recruitment of fast twitch fibres [31,32]. This causes the RER to rise to 1. The influence of the sympathetic nervous system has been demonstrated in rats whose adrenal medulla has been destroyed. In this model, fatty acids from adipose tissue are burnt instead of muscle glycogen during exercise [33]. The utilization of muscle glycogen during exercise in these rats was restored by infusing adrenaline. We have previously demonstrated a reduced peak RER after acute sympathetic inhibition [25], suggesting lower peak carbon dioxide production, which might also be a consequence of altered muscle metabolism.

The present study describes clearly the benefit on echocardiographically derived variables of ventricular function following long-term beta-blockers, but did not demonstrate any benefit on peak oxygen consumption. This confirms previous data demonstrating a poor relationship between improvements in haemodynamic variables and exercise capacity, following vasodilator therapy [34,35], inotropes [36], cardiac transplantation [37], and beta-blocker treatment [17,19,21,22,38]. The greatest predictor of benefit might not be the change in central haemodynamics but the improvement in leg blood flow, hinting that peripheral factors may be involved [39]. No consistent benefit on exercise capacity has been shown with the use of beta-blockers in large randomised trials. Peak oxygen consumption is a powerful prognostic marker, but does not improve despite the benefits on prognosis of beta-blockers, and their beneficial effects on other prognostic markers such as ejection fraction. The reasons for this discrepancy remain elusive.

In our study, the effect of the beta-blockers on symptoms of breathlessness was also significant. A reduction in Borg score at the end of the first stage of exercise with no parallel reduction in ventilation was accompanied by a reduction in the gradient of the slope relating perceived exertion to ventilation (Borg/VE slope) [29]. This implies a sympathetic contribution to both ventilation and the symptoms of breathlessness in chronic heart failure, perhaps by increasing the sensitivity of peripheral receptors whether they are chemoreceptors or ergoreceptors responding to stretch.


   5. Conclusions
Top
 Abstract
 1. Introduction
 2. Methods
 3. Results
 4. Discussion
 5. Conclusions
6. Limitations
 References
 
This is the first study to examine in detail the effects of long-term beta-blockade on metabolic gas exchange during exercise in patients with chronic heart failure. Beta-blockers can reduce oxygen utilisation at matched submaximal workloads and lead to an increase in exercise time with no increase in peak oxygen consumption. It is possible that sympathetic inhibition leads to a more efficient use of substrates or a shift towards the use of fats and proteins and away from simple sugars and glycogen.


   6. Limitations
Top
 Abstract
 1. Introduction
 2. Methods
 3. Results
 4. Discussion
 5. Conclusions
 6. Limitations
References
 
Due to the overwhelming data suggesting prognostic benefit of beta-blockade in patients with LVEF reduction, the present study is observational and not a randomised controlled trial. However we were non-selective in the patients we included in the initial exercise tests, and only seven of those enrolled were lost to follow-up. We were unable to comment on differences between beta-blockers. A comparison between beta-blockers would require a much larger double-blind randomised study [40].


   Acknowledgements
 
The authors wish to thank Mrs Elaine Allison for administrative assistance.


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

  1. Clark A.L., Sparrow J.L., Coats A.J.S. Muscle fatigue and dyspnoea in chronic heart failure: two sides of the same coin? Eur. Heart J. (1995) 16:49–52.[Free Full Text]
  2. Clark A.L., Poole-Wilson P.A., Coats A.J.S. Exercise limitation in chronic heart failure: central role of the periphery. J. Am. Coll. Cardiol. (1996) 28:1092–1102.[Abstract]
  3. Buller N.P., Poole-Wilson P.A. Mechanism of the increased ventilatory response to exercise in patients with chronic heart failure. Br. Heart J. (1990) 63:281–283.[Abstract/Free Full Text]
  4. Davies S.W., Emery T.M., Watling M.I.L., et al. A critical threshold of exercise capacity in the ventilatory response to exercise in chronic heart failure. Br. Heart J. (1991) 65:179–183.[Abstract/Free Full Text]
  5. Witte K.K.A., Clark A.L. Is the elevated slope relating ventilation to carbon dioxide production in chronic heart failure a consequence of slow metabolic gas kinetics? Eur. J. Heart Fail. (2002) 4:469–472.[Abstract/Free Full Text]
  6. Francis G.S., Cohn J.N., Johnson G., et al. Plasma norephinephrine, plasma rennin activity and congestive heart failure. Relations to survival and the effects of therapy in V-HeFT II follow-up. Circulation (1993) 87(Suppl_VI):40–48.[Web of Science]
  7. Piepoli M., Clark A.L., Coats A.J.S. Muscle metaboreceptors in the hemodynamic, autonomic and ventilatory responses to exercise in man. Am. J. Physiol. (1995) 269:H1428–H1436. [Heart Circ. Physiol. 38].[Web of Science][Medline]
  8. Piepoli M., Clark A., Volterrani M., et al. Contribution of muscle afferents to the hemodynamic, autonomic and ventilatory responses to exercise in patients with chronic heart failure. Circulation (1996) 93:940–952.[Abstract/Free Full Text]
  9. Narkiewicz K., Pesek C.A., van de Borne P.J.H., et al. Enhanced sympathetic and ventilatory responses to central chemoreflex activation in heart failure. Circulation (1999) 100:262–267.[Abstract/Free Full Text]
  10. Chua T.P., Clark A.L., Amadi A., Coats A.J.S. Relationship between chemosensitivity and the ventilatory response to exercise in chronic heart failure. J. Am. Coll. Cardiol. (1996) 27:650–657.[Abstract]
  11. Wheelan R.F., Young I.M. The effect of adrenaline and noradrenaline infusions on respiration in man. Br. J. Pharmacol. (1953) 8:98–102.[Medline]
  12. Heistad D.D., Wheeler R.C., Mark A.L., et al. Effects of adrenergic stimulation on ventilation in man. J. Clin. Invest. (1972) 51:1469–1475.[Web of Science][Medline]
  13. Butland R.J.A., Pang J.A., Geddes D.M. The selectivity of the β adrenoceptor for ventilation in man. Br. J. Clin. Pharmacol. (1982) 14:707–711.[Web of Science][Medline]
  14. Clark A.L., Galloway S., MacFarlane N., et al. Catecholamines contribute to exertional dyspnoea and to the ventilatory response to exercise in normal humans. Eur. Heart J. (1997) 18:1829–1833.[Abstract/Free Full Text]
  15. Packer M., Bristow M.R., Cohn J.N., et al. The effect of carvedilol on morbidity and mortality in patients with chronic heart failure. N. Engl. J. Med. (1996) 334:1349–1355.[Abstract/Free Full Text]
  16. CIBIS II Investigators. The cardiac insufficiency bisoprolol study II (CIBIS II). Lancet (1999) 353:9–13.[CrossRef][Web of Science][Medline]
  17. Australia/New Zealand Heart Failure Research Collaborative Group. Randomised, placebo-controlled trial of carvedilol in patients with congestive heart failure due to ischaemic heart disease. Lancet (1997) 349:375–380.[CrossRef][Web of Science][Medline]
  18. Guazzi M., Agostoni P., Matturri M., Pontone G., Guazzi M.D. Pulmonary function, cardiac function, and exercise capacity in a follow-up of patients with congestive heart failure treated with carvedilol. Am. Heart J. (1999) 138:460–467.[CrossRef][Web of Science][Medline]
  19. Packer M., Colucci W.S., Sackner-Berstein J.D. for the Precise study group. Double-blind, placebo-controlled study of the effects of carvedilol in patients with moderate to severe heart failure. Circulation (1996) 94:2793–2799.[Abstract/Free Full Text]
  20. Bristow M.R., Gilbert E.M., Abraham W.T. for the MOCHA investigators. 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]
  21. Colucci W.S., Packer M., Bristow M.R. for the US carvedilol heart failure study group. Carvedilol inhibits clinical progression in patients with mild symptoms of heart failure. Circulation (1996) 94:2800–2806.[Abstract/Free Full Text]
  22. Cohn J.N., Fowler M.B., Bristow M.R. for the US carvedilol heart failure study group. Safety and efficacy of carvedilol in severe heart failure. J. Card. Fail. (1997) 3:173–179.[CrossRef][Medline]
  23. Levine T.B., Levine A.B., Keteyian S.J., Narins B. The impact of beta-receptor blocker addition to high-dose angiotensin-converting enzyme inhibitor-nitrate therapy in heart failure. Clin. Cardiol. (1998) 21:899–904.[CrossRef][Web of Science][Medline]
  24. Hulsmann M., Sturm B., Pacher R., Berger R., Bojic A., Frey B., et al. Long-term effect of atenolol on ejection fraction, symptoms, and exercise variables in patients with advanced left ventricular dysfunction. J. Heart Lung Transplant. (2001) 20:1174–1180.[CrossRef][Web of Science][Medline]
  25. Witte K.K.A., Thackray S.D.R., Nikitin N.P., Cleland J.G.F., Clark A.L. The effects of {alpha}- and β-blockade on ventilatory responses to exercise in chronic heart failure. Heart (2003) 89:1169–1173.[Abstract/Free Full Text]
  26. Clark A.L., Cleland J.G. How do you measure exercise capacity in chronic heart failure? Eur. Heart J. (2001) 22:627–628.[Free Full Text]
  27. Beaver W.L., Wasserman K., Whipp B.J. A new method for detecting the anaerobic threshold by gas exchange. J. Appl. Physiol. (1986) 60:2020–2027.[Abstract/Free Full Text]
  28. Borg G. Subjective effort and physical activities. Scand. J. Rehabil. (1978) 6:108–113.
  29. Witte K.K.A., Thackray S.D., Nikitin N.P., Cleland J.G., Clark A.L. The pattern of ventilation during exercise in chronic heart failure. Heart (2003) 89:610–614.[Abstract/Free Full Text]
  30. Pennell D.J., Ray S.G., Davies G., Burgess M., Webster J., Slomka P., et al. The carvedilol hibernation reversible ischaemia trial, marker of success (CHRISTMAS) study. Methodology of a randomised, placebo controlled, multicentre study of carvedilol in hibernation and heart failure. Int. J. Cardiol. (2000) 72:265–274.[CrossRef][Web of Science][Medline]
  31. Brooks G.A. Importance of the ‘crossover’ concept in exercise metabolism. Clin. Exp. Pharmacol. Physiol. (1997) 24:889–895.[Web of Science][Medline]
  32. Brooks G.A., Mercier J. Balance of carbohydrate and lipid utilization during exercise: the "crossover" concept. J. Appl. Physiol. (1994) 76:2253–2261.[Abstract/Free Full Text]
  33. Richter E.A., Sonne B., Mikines K.J., Ploug T., Galbo H. Muscle and liver glycogen, protein, and triglyceride in the rat. Effect of exercise and of the sympatho-adrenal system. Eur. J. Appl. Physiol. Occup. Physiol. (1984) 52:346–350.[CrossRef][Web of Science][Medline]
  34. Fink L.I., Wilson J.R., Ferraro N. Exercise ventilation and pulmonary artery wedge pressure in chronic stable congestive heart failure. Am. J. Cardiol. (1986) 57:249–253.[CrossRef][Web of Science][Medline]
  35. Massie B.M., Kramer B., Haughom F. Acute and long-term effects of vasodilator therapy on resting and exercise hemodynamics and exercise tolerance. Circulation (1981) 64:1218–1226.[Abstract/Free Full Text]
  36. Maskin C.S., Kugler J., Sonnenblick E.H., LeJemtel T.H. Acute inotropic stimulation with dopamine in severe congestive heart failure: beneficial hemodynamic effect at rest but not during maximal exercise. Am. J. Cardiol. (1983) 52:1028–1032.[CrossRef][Medline]
  37. Savin W.M., Haskell W.L., Schroeder J.S., Stinson E.B. Cardiorespiratory responses of cardiac transplant patients to graded, symptom-limited exercise. Circulation (1980 (Jul.)) 62(1):55–60.[Abstract/Free Full Text]
  38. Bristow M.R., Gilbert E.M., Abraham W.T. for the MOCHA investigators. 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]
  39. Drexler H., Banhardt U., Meinertz T., Wollschlager H., Lehmann M., Just H. Contrasting peripheral short-term and long term effects of converting enzyme inhibition in patients with congestive heart failure. A double-blind, placebo-controlled trial. Circulation (1989) 79:491–502.[Abstract/Free Full Text]
  40. Poole-Wilson P.A., Cleland J.G., Di Lenarda A., Hanrath P., Komajda M., Metra M., et al. Rationale and design of the carvedilol or metoprolol European trial in patients with chronic heart failure: COMET. Eur. J. Heart Fail. (2002) 4:321–329.[Abstract/Free Full Text]

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 Heart JHome page
U. Corra, A. Mezzani, A. Giordano, E. Bosimini, and P. Giannuzzi
Exercise haemodynamic variables rather than ventilatory efficiency indexes contribute to risk assessment in chronic heart failure patients treated with carvedilol
Eur. Heart J., December 2, 2009; 30(24): 3000 - 3006.
[Abstract] [Full Text] [PDF]

Home page
 J Am Coll CardiolHome page
K. K. Witte and A. L. Clark
Chronotropic Incompetence in Heart Failure
J. Am. Coll. Cardiol., August 1, 2006; 48(3): 595 - 595.
[Full Text] [PDF]

Home page
 HeartHome page
A. L Clark
Exercise and heart failure: assessment and treatment.
Heart, May 1, 2006; 92(5): 699 - 703.
[Full Text] [PDF]

Home page
 HeartHome page
K K A Witte, J G F Cleland, and A L Clark
Chronic heart failure, chronotropic incompetence, and the effects of {beta} blockade
Heart, April 1, 2006; 92(4): 481 - 486.
[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 Witte, K. K.A.
Right arrow Articles by Clark, A. L.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Witte, K. K.A.
Right arrow Articles by Clark, A. L.
Social Bookmarking
Add to CiteULike   Add to Connotea   Add to Del.icio.us  
What's this?