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European Journal of Heart Failure 2008 10(1):85-88; doi:10.1016/j.ejheart.2007.10.010
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© 2008 European Society of Cardiology

Combining the ventilatory response to exercise and peak oxygen consumption is no better than peak oxygen consumption alone in predicting mortality in chronic heart failure

Lee Inglea, Klaus K. Wittec,*, John G.F. Clelandb and Andrew L. Clarkb

a Carnegie Research Institute, Leeds Metropolitan University Leeds, UK
b Academic Department of Cardiology, University of Hull Hull, UK
c Department of Cardiology, Leeds General Infirmary Leeds, UK

* Corresponding author. Leeds General Infirmary, Great George Street, Leeds, LS1 3EX, United Kingdom. Tel.: +44 113 2787206. E-mail address: klauswitte{at}hotmail.com (K. K. Witte).


   Abstract
Top
 Abstract
1. Introduction
 2. Methods
 3. Results
 4. Conclusions
 5. Limitations
 References
 
Background: A low peak oxygen uptake (pVO2) and steep VE/VCO2 slope are independently associated with a worse prognosis in patients with chronic heart failure (CHF). We wished to confirm whether combining these variables as a ratio would lead to a more accurate predictor of prognosis than using either alone.

Methods: 388 CHF patients completed a treadmill-based cardiopulmonary exercise test (CPET) to volitional exhaustion using a modified Bruce protocol.

Results: 212 CHF patients completed the CPET with a peak RER ≥1.0. Of these, 48 patients died and one was transplanted during follow-up. In surviving patients, the median follow-up period was 42 months (IQR 34–49 months). The ratio VE/VCO2 slope/pVO2 was calculated for each individual and its ability to predict outcome compared with other variables. The Cox multivariable survival analysis showed that pVO2 was the strongest independent predictor of mortality in CHF patients.

Conclusion: Our study shows that the composite variable VE/VCO2 slope/pVO2 is a less effective prognosticator than pVO2 alone in patients with CHF.

Key Words: Exercise testing • Cardiopulmonary exercise testing • Prognosis

Received June 28, 2007; Revised September 21, 2007; Accepted October 18, 2007


   1. Introduction
Top
 Abstract
 1. Introduction
2. Methods
 3. Results
 4. Conclusions
 5. Limitations
 References
 
The cardinal symptom of chronic heart failure (CHF) is exercise intolerance, usually due to breathlessness and fatigue.[1] This can be objectively assessed as a reduction in peak oxygen consumption (pVO2) during cardiopulmonary exercise testing (CPET).[2] Patients also have an increased ventilatory response throughout exercise as shown by an increase in the slope relating ventilation to carbon dioxide production (VE/VCO2 slope).[3-5] Rather than examining each of these two variables separately, a combination, presented as a ratio, might be better at predicting outcome in patients with a range of heart failure than either alone. In 100 CHF patients, the ratio VE/VCO2 slope/pVO2 related to prognosis more closely than either variable alone.[6] However, many exercise variables are highly related, and deviations of single data-points can change the order of prognostic information particularly when one variable is a composite of two others included in a multivariate model. We wished therefore to assess, in a larger unselected population of ambulatory CHF patients followed for a longer period of time, with a larger number of endpoints, whether combining pVO2 and VE/VCO2 slope as a ratio leads to more accurate prediction of prognosis than using either alone.


   2. Methods
Top
 Abstract
 1. Introduction
 2. Methods
3. Results
 4. Conclusions
 5. Limitations
 References
 
The Hull and East Riding Ethics Committee approved the study, and all patients provided informed consent for participation. We reviewed baseline exercise tests of 388 CHF patients under follow-up at a community heart failure centre. All patients were symptomatic with a left ventricular ejection fraction <45%, but had been stable without exacerbation, hospital admission or medication change for the preceding 3 months. We did not include patients with neurological conditions, limiting anginal pain or pulmonary disease (FEV1 <80% of predicted).

All subjects underwent a treadmill-based symptom-limited cardiopulmonary exercise test (CPET) with metabolic gas exchange (Jaeger Oxycon Delta, Viasys, USA) using an incremental 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. A peak respiratory exchange ratio (RER), (VCO2/VO2) of ≥1.0 was taken to indicate maximal effort [7]. Peak oxygen uptake (pVO2) was calculated as the average VO2 for the last 30 s of exercise. The VE/VCO2 slope (full) was calculated by linear regression by analysing breath-by-breath values obtained throughout the full test from all data points.[8] The anaerobic threshold (AT) was calculated using the VO2/VCO2 slope method, [9] The VE/VCO2 slope to pVO2 ratio (VE/VCO2/pVO2) was calculated for each patient. Patients were excluded from the survival analysis if they completed the CPET with a peak RER (pRER) <1.0. Follow-up was censored on 1st July 2006.

Results are reported as median±inter-quartile range (IQR). Categorical data are presented as percentages. Cox regression models were developed to predict candidate univariate predictors of mortality using all baseline variables. All variables in Table 1 (pRER ≥1.0) were entered as potential candidate predictors of mortality. We checked for collinearity between candidate univariate predictors by calculating Pearson's correlation coefficients using a cut-off of r>0.3. Model building was based on backwards elimination (P-value for entry was <0.05; P-value for removal >0.1). We then constructed a Cox regression model to calculate hazard ratios with 95% CI. SPSS (version 13.0) was used to analyze the data. An arbitrary level of 5% statistical significance was used throughout (two-tailed).


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  		Table 1 Baseline clinical characteristics dichotomised by RER group

 

   3. Results
Top
 Abstract
 1. Introduction
 2. Methods
 3. Results
4. Conclusions
 5. Limitations
 References
 
Table 1 shows data for all patients dichotomised by those achieving a pRER more or less than 1.0. Clinical profile and functional characteristics were similar between groups. From an initial population of 388, 212 patients completed the CPET with a pRER ≥1.0, of whom 48 patients died and one was transplanted representing an event rate of 22.9%. In surviving patients, the median follow-up time was 42 months (IQR 34-49 months). In CHF patients, Kaplan-Meier survival curves showing cumulative survival according to pVO2, VE/VCO2 slope (full), and VE/VCO2 slope/pVO2 are reported in Figs. 1-3GoGo. Six variables were significantly associated with mortality on univariate Cox analysis. Each was included in the final multivariable Cox model (Table 2), and each was an independent predictor of mortality.


Figure 01
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  		Fig. 1 Kaplan-Meier survival curves showing peak oxygen uptake (mL kg–1.min–1) (quartile ranges) in patients with pRER ≥1.0.

 


Figure 02
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  		Fig. 2 Kaplan-Meier survival curves showing VE/VCO2 slope (full test) (quartile ranges) in patients with pRER ≥1.0.

 


Figure 03
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  		Fig. 3 Kaplan-Meier survival curves showing VE/VCO2 slope/pVO2 ratio (quartile ranges) in patients with pRER ≥1.0.

 


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  		Table 2 Cox multivariable regression model in patients with pRER ≥1.0

 
However, when we ran a correlation analysis to identify collinearity between variables we were forced to eliminate the following; VE/VCO2 slope/pVO2, peak heart rate, VE/VCO2 slope (full), VE/VCO2@AT, and anaerobic threshold (r>0.3; P<0.001). Peak oxygen uptake remained in the model as it had the highest {chi}2 value (46.2). Thus, the strongest independent predictor of events was pVO2 (in CPETs with a pRER ≥1.0). VE/VCO2 slope/pVO2 was the next strongest predictor (Table 3). We also ran a sub-group analysis on beta-blocked patients only, VE/VCO2 slope/pVO2 was removed from the final multivariable model (loss in Chi-Square=4.2) at Step 1, and pVO2 remained the most potent prognosticator (HR=0.763; P=0.002; 95% CI=0.640-0.909).


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  		Table 3 Correlation matrix

 

   4. Conclusions
Top
 Abstract
 1. Introduction
 2. Methods
 3. Results
 4. Conclusions
5. Limitations
 References
 
Our findings suggest that pVO2 is a more effective prognosticator than VE/VCO2 slope (full), VE/VCO2@AT, or the composite variable VE/VCO2 slope/pVO2 in CHF patients. This finding is in conflict with that of Guazzi et al. [6] who reported on 100 CHF patients (mean age 59 years). Over their follow-up period of 26±19 months, 21 patients died from cardiovascular causes. Cox multivariable analysis revealed that the VE/VCO2 slope was a stronger predictor of mortality than pVO2; however, the composite VE/VCO2 slope/pVO2 ratio more effectively predicted outcome than either variable alone. Our findings are in a larger and older group of patients with a longer follow-up period (42±28 months vs 26±19 months). It should be noted that our primary end-point was all-cause mortality while Guazzi included cardiovascular deaths only. In addition, beta-blocker use in our patients was higher (68% vs 30%). However, although the increased ventilation seen in CHF is related to sympathetic activity, [10] there is little influence of long term beta-blockade on the VE/VCO2 slope [11] and these agents also do not significantly alter pVO2.[11-13] Beta-blockers do however reduce mortality and for a given pVO2, a patient taking a beta-blocker has a lower overall mortality than a patient not taking one.

It has been suggested that pVO2 might be less powerful a predictor of outcome in patients with mild-moderate heart failure.[14] However, in our study more than 75% of patients had NYHA class I/II symptoms, and median LVEF was 34% (29-40), yet pVO2 remained the most potent prognostic indicator. Our findings thereby also disagree with studies that have argued that an elevated VE/VCO2 slope is a more powerful outcome measure than pVO2.[15,16]

In conclusion, our findings indicate that the composite variable VE/VCO2 slope/pVO2 is a less effective prognosticator than pVO2 alone in patients with CHF. The VE/VCO2 slope/pVO2 ratio is however a better predictor of mortality than other well-researched univariate predictors including VE/VCO2 slope (full), and VE/VCO2 slope@AT.


   5. Limitations
Top
 Abstract
 1. Introduction
 2. Methods
 3. Results
 4. Conclusions
 5. Limitations
References
 
Only just over half of our patients achieved a pRER >1.0 on our modified Bruce protocol. The use of this protocol on a treadmill may be too challenging for our patients, and alternative modes/methods of exercise testing such as a more gentle ramping treadmill protocol or cycle ergometry, may yield greater success.

Despite a greater number of endpoints in our study, a major limitation of such an analysis remains that the variables gained from an exercise test are closely related, and deviations in single data-points can lead to changes in ranking of prognostic ability, particularly when one of the variables included in the model is a composite of two others.


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

  1. Clark A.L., Sparrow J.L. Coats AJS. 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., Wannamethee G., Lipkin D.P. 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(4):469–472.[Abstract/Free Full Text]
  6. Guazzi M., De Vita S., Cardano P., Barlera S., Guazzi M.D. Normalization for peak oxygen uptake increases the prognostic power of the ventilatory response to exercise in patients with chronic heart failure. Am Heart J (2003) 146:542–548.[CrossRef][Web of Science][Medline]
  7. Mezzani A., Corra U., Bosimini E., Giordano A., Giannuzzi P. Contribution of peak respiratory exchange ratio to peak VO2 prognostic reliability in patients with chronic heart failure and severely reduced exercise capacity. Am Heart J (2003) 145:1102–1107.[CrossRef][Web of Science][Medline]
  8. Ingle L, Goode K, Carroll S, et al. Prognostic value of the VE/VCO2 slope calculated from different time intervals in patients with suspected heart failure. Int J Cardiol (2007) 12;118(3):350–355.
  9. 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]
  10. 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]
  11. Witte K.K., Thackray S.D., Nikitin N.P., Cleland J.G., 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]
  12. Guazzi M., Agostoni P., Matturri M, Pontone G, Guazzi MD. 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]
  13. Wolk R, Johnson BD, Somers VK, et al. Effects of beta-blocker therapy on ventilatory responses to exercise in patients with heart failure. J Card Fail (2005) 11:333–339.[CrossRef][Web of Science][Medline]
  14. Meyers J, Gullestad L. The role of exercise testing and gas exchange measurements in the prognostic assessment of patients with heart failure. Curr Opin Cardiol (1998) 13:145–155.[Web of Science][Medline]
  15. Robbins M, Francis G, Pashkow FJ, et al. Ventilatory and heart rate response to exercise: better predictors of heart failure mortality than peak oxygen consumption. Circulation (1999) 100:2411–2417.[Abstract/Free Full Text]
  16. Kleber FX, Vietzke G, Wernecke KD, et al. Impairment of ventilatory efficiency in heart failure. Circulation (2000) 101:2803–2809.[Abstract/Free Full Text]

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