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European Journal of Heart Failure 2002 4(4):469-472; doi:10.1016/S1388-9842(02)00093-4
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© 2002 European Society of Cardiology

Is the elevated slope relating ventilation to carbon dioxide production in chronic heart failure a consequence of slow metabolic gas kinetics?

Klaus K.A. Witte* and Andrew L. Clark

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

* Corresponding author. Tel.: +44-1482-624073; fax: +44-1482-624085 E-mail address: klauswitte{at}hotmail.com


   Abstract
Top
 Abstract
1. Introduction
 2. Methods and subjects
 3. Results
 4. Discussion
 References
 
Objective: Patients with heart failure have slow metabolic gas exchange kinetics, which may contribute to the elevated slope of the relationship between ventilation and carbon dioxide production (Ve/Vco2 slope).

Setting: A tertiary referral centre for cardiology.

Subjects: Eleven patients with stable chronic heart failure and 11 age-matched controls.

Design: Each subject underwent maximal bicycle-based peak exercise testing with metabolic gas exchange analysis and three further repeated tests at 15%, 25% and 50% of the load achieved at peak exercise. The ventilation and carbon dioxide production from each of these steady-state tests was used to re-calculate the Ve/Vco2 slope and compared with the Ve/Vco2 slope derived from the maximal test.

Results: Peak oxygen consumption [mean (S.D.)] was lower in heart failure patients [18.2 (4.0) vs. 31.2 (6.3) ml/kg per min; P<0.001] than in controls. The Ve/Vco2 slope was steeper in patients than controls [32.7 (8.3) vs. 27.1 (1.6); P<0.05]. There was no difference between the Ve/Vco2 slope reconstructed from the three steady state tests and resting data and that gained from the maximal test [35.3 (7.8) vs. 25.9 (3.2); P=0.43].

Conclusions: The elevated slope of the relationship between ventilation and carbon dioxide production is not a consequence of the short stages of a standard incremental exercise test combined with delayed metabolic gas kinetics in heart failure patients.

Key Words: Chronic heart failure • Ventilation • Breathlessness

Received September 20, 2001; Revised December 4, 2001; Accepted February 22, 2002


   1. Introduction
Top
 Abstract
 1. Introduction
2. Methods and subjects
 3. Results
 4. Discussion
 References
 
The dominant symptom of patients with chronic heart failure is exercise intolerance, due to breathlessness and fatigue. This can be assessed objectively by incremental exercise testing with metabolic gas exchange measurements used to derive peak oxygen consumption (pVo2) as an index of exercise capacity [1]. At the same time, the slope of the relation between ventilation and carbon dioxide production (Ve/Vco2 slope) can be used to characterise the ventilatory response to exercise [2,3]. Typically in chronic heart failure, pVo2 is reduced, and Ve/Vco2 is increased [4,5]. Thus, for a given carbon dioxide production, (Vco2), the ventilatory response is greater. pVo2 and Ve/Vco2 are inversely related and both are related to symptom scores and prognosis [6,7].

Metabolic gas exchange kinetics are slowed in patients with heart failure [8–11]. We have previously shown that metabolic gas exchange variables differ with different stage duration in incremental tests [12]. The measured Ve/Vco2 slope is greater if the exercise test has shorter stages. This raises the possibility that the apparent increase in Ve/Vco2 is due in part to failure to reach steady state during the standard 3-min stages of an exercise test.

The present study was designed to measure the Ve/Vco2 slope from data derived from steady state experiments to eliminate the possible influence of delayed metabolic gas kinetics and slow peripheral adaptation to work on the gradient of the relationship.


   2. Methods and subjects
Top
 Abstract
 1. Introduction
 2. Methods and subjects
3. Results
 4. Discussion
 References
 
Approval was granted by the local ethics committee, and all subjects gave written, informed, consent prior to participation in the study. The investigation conformed to the principles outlined in the Declaration of Helsinki. Eleven patients with chronic heart failure due to ischaemic heart disease and 11 age-matched controls were studied. All subjects were male. All patients had NYHA class II symptoms of breathlessness, an ejection fraction of less than 40% on echocardiography and had been taking the same medication with no evidence of clinical deterioration in the preceding 3 months. Patients with peripheral neuropathy or neuromuscular disease restricting exercise testing were excluded. No patient or subject had symptoms of airways disease or an FEV1 of less than 75% of predicted. All patients were receiving angiotensin-converting enzyme antagonists and -blockers at optimal doses. The controls were individuals of a similar age, chosen at random from the lists of local general practitioners. All had normal systolic and diastolic left ventricular function, however, two were receiving non-β-blocker based therapy for hypertension.

Prior to exercise testing each subject underwent echocardiography with assessment of left ventricular end-diastolic volume and diameter and ejection fraction using Simpson's method. After an initial familiarisation test, each subject underwent a symptom-limited peak bicycle-based exercise test (Rehcor, Cardiokinetics, Salford, UK). The load was increased by 25 watts every 3 min after an initial unloaded stage until the subject was exhausted. We used 3-min stages for the peak test, as this is currently standard practice for both treadmill- and bicycle-based exercise tests. Expired air was collected continuously and metabolic gas exchange analysis performed (Oxycon system, Jaeger, Germany). The system was recalibrated prior to each test. Peak Vo2 and the anaerobic threshold (AT), using the Vo2/Vco2 slope method [13] were determined. The Ve/Vco2 slope was calculated by performing linear regression and recording the slope obtained.

The tests were then repeated on a separate occasion at fixed workloads of 15%, 25% and 50% of the resistance achieved at peak exercise. Each test was continued until steady state was achieved. This was taken to be the point at which no further changes in ventilatory or metabolic gas levels had occurred for at least 1 min. The tests were performed in random order and each subject had a 30 min recovery period between each steady-state test. The ventilation and carbon dioxide production readings taken for the final minute of steady state exercise were averaged giving the ventilatory equivalent for CO2 (VeqCO2). The Ve and Vco2 data from the steady state tests were plotted and a Ve/Vco2 slope calculated and compared with the Ve/Vco2 slope from the maximal test.

For within group analyses we used Student's paired t-test and for between group analyses we employed ANOVA with Bonferroni correction.


   3. Results
Top
 Abstract
 1. Introduction
 2. Methods and subjects
 3. Results
4. Discussion
 References
 
Subject characteristics are shown in Table 1. The two groups were of similar age, height and weight. The pVo2 in the patient group was significantly lower than that of the controls. There was no difference in the respiratory exchange ratio (RER) at peak exercise suggesting similar levels of exertion. Left ventricular end-diastolic diameter was greater and ejection fraction on echocardiography was significantly lower in the patients than in the controls. The average Ve/Vco2 slope as obtained from the peak test in the patients was greater than in the controls (Table 2).


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  		Table 1 Subject characteristics

 


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  		Table 2 Ve/Vco2 slopes from the four methods

 
All of the patients and controls reached steady state during each of the repeated tests. The averaged rating of perceived exertion using a standard (0–10) Borg scoring system [14], VeqCO2 and load for each of the steady-state tests are shown in Table 3.


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  		Table 3 Results from the steady state tests

 
There was no difference in the Ve/Vco2 slopes obtained from the steady state exercises and those obtained from the peak exercise tests (P=0.43) (Fig. 1). As two of the patients and one elderly control subject exercised above the anaerobic threshold calculated from the peak test during the highest steady state test (50%), we repeated the comparison of the Ve/Vco2 slopes using only the 15%, 25% and resting data and compared this reconstructed slope with the sub-anaerobic results from the peak exercise test. Again, there was no difference (P=0.28).


Figure 1
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  		Fig. 1 Results from a typical heart failure patient. The Ve/Vco2 slope from an incremental test of 53.0 (small data points) with a reconstructed slope of 53.0 superimposed (large data points).

 

   4. Discussion
Top
 Abstract
 1. Introduction
 2. Methods and subjects
 3. Results
 4. Discussion
References
 
The Ve/Vco2 slope during exercise in patients with heart failure is important, both because it quantifies the ventilatory response and because it carries prognostic information [6,7]. The slope is increased in chronic heart failure. This has been explained by an increase in dead space [15] and by an increase in ventilatory stimuli from the periphery [1]. One possibility is that the slope is increased artefactually by the delay in achieving steady state gas exchange in heart failure patients [16] due to the slow metabolic gas kinetics [8,9,11]. Ventilation kinetics seem not to be slowed, however, leading to a relative increase in ventilation for a given carbon dioxide production. Short stages (1 min) in patients with chronic heart failure lead to an even steeper Ve/Vco2 slope [12]. It may be that a centrally mediated sensation of altered activity stimulates an increase in ventilation before the working muscles begin to release greater quantities of CO2.

The present study demonstrates that the elevated Ve/Vco2 slope in patients with chronic heart failure is not a consequence of the 3-min stages being too short in an incremental exercise test. The repeated tests had to be below the anaerobic threshold to allow steady state to be achieved, as this does not occur above the anaerobic threshold, but also to avoid the potentially confusing slow component of high intensity exercise [17]. We designed the study with the steady state tests at 15%, 25% and 50% to avoid the altered kinetics above the anaerobic threshold, but two of the patients and one control exercised above their anaerobic threshold during the highest steady state test (50%). We therefore compared the slope from the three steady state tests with that from the peak test, and the sub-anaerobic slope was compared with the steady state tests at 15% and 25% of peak.

The cause of the steeper gradient of this relationship remains unclear. An increase in dead space was postulated as a possible contributing factor [15], as blood gas tensions remain near normal during exercise [18,19], but we have previously demonstrated that ventilatory dead space is not significantly greater as a percentage of total ventilation in patients with chronic heart failure [20]. Heightened peripheral ergoreceptor sensitivity exists in heart failure patients and contributes significantly to the increased ventilatory response to exercise [21].

In summary, although the causes of the increased gradient of the slope relating ventilation to carbon dioxide production remain elusive, the present study confirms that the phenomenon is not a result of slowed gas-exchange kinetics but is a true and important consequence of chronic heart failure. The identification and quantification of this slope gives important prognostic information and deteriorations in patients’ condition can be quantified. We have also confirmed that three-minute stages in an incremental exercise test are long enough to allow accurate assessment of the Ve/Vco2 slope.


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

  1. 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]
  2. Wasserman K., Zhang Y.Y., Riley M.S. Ventilation during exercise in chronic heart failure. Basic Res Cardiol (1996) 91(Suppl_1):1–11.[CrossRef][Web of Science][Medline]
  3. Clark A.L., Volterrani M., Swan J.W., et al. The increased ventilatory response to exercise in chronic heart failure: relation to pulmonary pathology. Heart (1997) 77:138–146.[Abstract/Free Full Text]
  4. 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]
  5. 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 heart failure. Br Heart J (1991) 65:179–183.[Abstract/Free Full Text]
  6. Davies L.C., Francis D.P., Piepoli M., et al. Chronic heart failure in the elderly: value of cardiopulmonary exercise testing in risk stratification. Heart (2000) 83:147–151.[Abstract/Free Full Text]
  7. Francis D.P., Shamim W., Davies L.C., et al. Cardiopulmonary exercise testing for prognosis in chronic heart failure: continuous and independent prognostic value from VE/VCO(2) slope and peak VO(2). Eur Heart J (2000) 21:154–161.[Abstract/Free Full Text]
  8. Cross A.M. Jr., Higginbotham M.B. Oxygen deficit during exercise testing in heart failure. Relation to submaximal exercise tolerance. Chest (1995) 107:904–908.[Abstract/Free Full Text]
  9. Picozzi N.M., Clark A.L., Lindsay K.A., et al. Responses to constant work exercise in patients with chronic heart failure. Heart (1999) 82:482–485.[Abstract/Free Full Text]
  10. Sietsema K.E., Ben-Dov I., Zhang Y.Y., et al. Dynamics of oxygen uptake for submaximal exercise and recovery in patients with chronic heart failure. Chest (1994) 105:1693–1700.[Abstract/Free Full Text]
  11. Riley M., Porszasz J., Stanford C.F., et al. Gas exchange responses to constant work rate exercise in chronic cardiac failure. Br Heart J (1994) 72:150–155.[Abstract/Free Full Text]
  12. Clark A.L., Volterrani M., Piepoli M., et al. Factors which alter the relationship between ventilation and carbon dioxide production during exercise: implications of the understanding of the increased ventilatory response to exercise in chronic heart failure. Eur J Appl Physiol (1996) 73:144–148.[CrossRef][Web of Science]
  13. 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]
  14. Borg G. Subjective effort and physical activities. Scand J Rehab (1978) 6:108–113.
  15. Sullivan M.J., Higginbotham M.B., Cobb F.R. Increased exercise ventilation in patients with chronic heart failure: intact ventilatory control despite haemodynamic and pulmonary abnormalities. Circulation (1988) 77:552–559.[Abstract/Free Full Text]
  16. Cohen-Solal A., Laperche T., Morvan D., et al. Prolonged kinetics of recovery of oxygen consumption after maximal graded exercise in patients with chronic heart failure. Analysis with gas exchange measurements and NMR spectroscopy. Circulation (1995) 91:2924–2932.[Abstract/Free Full Text]
  17. Jones A.M., McConnell A.M. Effect of exercise modality on oxygen uptake kinetics during heavy exercise. Eur J Appl Physiol (1999) 80:213–219.[CrossRef][Web of Science]
  18. Rubin S.A., Brown H.V., Swan H.J.C. Arterial oxygenation and arterial oxygen transport in chronic myocardial failure at rest, during exercise and after hydralazine treatment. Circulation (1982) 66:143–148.[Abstract/Free Full Text]
  19. Clark A.L., Coats A.J.S. Usefulness of arterial blood gas estimations during exercise in patients with chronic heart failure. Br Heart J (1994) 71:528–530.[Abstract/Free Full Text]
  20. Clark A.L., Chua T.P., Coats A.J.S. Anatomical dead space, ventilatory pattern, and exercise capacity in chronic heart failure. Br Heart J (1995) 74:377–380.[Abstract/Free Full Text]
  21. Scott A.C., Francis D.P., Davies L.C., et al. Contribution of skeletal muscle ‘ergoreceptors’ in the human leg to respiratory control in chronic heart failure. J Physiol (2000) 529(3):863–870.[Abstract/Free Full Text]

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