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European Journal of Heart Failure 2007 9(6-7):625-629; doi:10.1016/j.ejheart.2007.01.007
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© 2007 European Society of Cardiology

Response of the oxygen uptake efficiency slope to exercise training in patients with chronic heart failure

Christophe Van Laethema,b,c,*, Nico Van De Veired,1, Guy De Backerc,d, Salhi Bihijac,e, Tony Seghersc, Dirk Cambiere, Marc Vanderheydenb and Johan De Sutterc,d,1

a Department of Physiotherapy, Artevelde Institute of Higher Education Ghent, Belgium
b Cardiovascular Center, Onze Lieve Vrouw Hospital Aalst, Belgium
c Cardiac Rehabilitation Unit, University Hospital Ghent, Belgium
d Department of Cardiology, University Hospital Ghent, Belgium
e Department of Rehabilitation Sciences and Physiotherapy, University Ghent, Belgium

* Corresponding author. University Hospital Gent, 1K4, De Pintelaan 185, 9000 Ghent, Belgium. Tel: +32 9 240 69 24; fax: +32 9 240 38 11. E-mail address: christophe.vanlaethem{at}arteveldehs.be


   Abstract
Top
 Notes
 Abstract
1. Introduction
 2. Methods
 3. Results
 4. Discussion
 5. Limitations
 6. Conclusion
 References
 
Background: The oxygen uptake efficiency slope (OUES) is a new exercise parameter that provides prognostic power in patients with CHF. Little is known about the effects of exercise training (ET) on OUES.

Aim: To describe the response of OUES to 6 months of ET in CHF patients and compare its evolution to that of other exercise variables.

Methods: 35 patients with CHF (NYHA II–III, age 54±9y, LVEF 31±10%) performed 3 maximal exercise tests, i.e. at the start, middle and end of a 6 month ET program. OUES, PeakVO2, ventilatory anaerobic threshold (VAT) and slope VE/VCO2 were determined.

Results: OUES, peakVO2, VAT, slope VE/VCO2, peak Watt, 6MWT and NYHA-class improved during the first part of the ET period (p<0.05). Only VAT, peak Watt and 6MWT continued to improve during the second part of the ET period (p>0.05) Improvements in OUES correlated better with improvements in peakVO2 (r=0.77, p<0.001), than changes in other prognostic variables.

Discussion: OUES improves significantly after 6 months of ET. Changes in peakVO2 correlate best with changes in OUES. OUES is sensitive to ET and can be used to evaluate the progression of exercise capacity in CHF patients.

Key Words: Exercise training • Heart failure • Ventilation

Received April 14, 2006; Revised October 24, 2006; Accepted January 18, 2007


   1. Introduction
Top
 Notes
 Abstract
 1. Introduction
2. Methods
 3. Results
 4. Discussion
 5. Limitations
 6. Conclusion
 References
 
Chronic heart failure (CHF) is characterized by progressive exercise intolerance and exertional dyspnoea during minimal exercise, resulting in poor quality of life. Since the original work of Mancini et al. [1] peak oxygen consumption (peakVO2) has become an important independent factor in the prognostic stratification of patients with CHF. In recent years, new exercise variables like the Ventilatory Anaerobic Threshold (VAT) and peak oxygen pulse have been suggested to have additional prognostic value [2,3] in particular, the ventilatory response to exercise, expressed as the slope of the linear relation between minute ventilation and carbon dioxide output, i.e. VE/VCO2 slope, provides superior prognostic information in patients with intermediate or preserved exercise capacity, compared to peakVO2 [4,5]. There is a general consensus that exercise training beneficially influences these prognostic indicators in CHF [6,7].

In 1996, Baba et al. [8] introduced and validated a new linear measure of the ventilatory response to exercise, called the oxygen uptake efficiency slope (OUES), in young patients with congenital heart disease. The OUES is derived from the single-segment logarithmic relation between oxygen uptake and minute ventilation during incremental exercise. Its physiological background is based on the development of metabolic acidosis, the physiological dead space and the arterial carbon dioxide partial pressure. As a result, OUES incorporates in a single index not only cardiovascular and peripheral factors that determine oxygen uptake but also pulmonary factors that influence the ventilatory response to exercise [8]. Previously, we and others have shown that OUES is significantly correlated to peakVO2 in patients with CHF and is not influenced by the duration of the exercise test, nor by achieved exercise intensity [8-10]. Very recently, Davies et al. suggested the superior independent prognostic value of OUES over peakVO2 and VE/VCO2 slope in a 6-year follow-up of 243 patients with CHF [11]. However, no data are available on the response of this new prognostic indicator to exercise training in this particular group of deconditioned CHF patients.

Therefore, the aim of this study was to explore the response of the OUES to a six month training program in stable patients with CHF and to compare its evolution to that of other well known exercise variables that hold important prognostic information.


   2. Methods
Top
 Notes
 Abstract
 1. Introduction
 2. Methods
3. Results
 4. Discussion
 5. Limitations
 6. Conclusion
 References
 
2.1. Study population
Twenty-six males and 9 females with stable CHF, all free of exercise-limiting co-morbidities, such as cerebrovascular disease, musculoskeletal impairment or vascular disease of the lower extremities, were enrolled in a 40-session cardiac rehabilitation program (two sessions each week for 6 months). Patient characteristics are presented in Table 1. All 35 patients performed three maximal cardiopulmonary exercise tests, i.e. at the start, in the middle and at the end of the rehabilitation program. All patients were in New York Heart Association (NYHA) class II-III and had no clinical signs of overt congestive heart failure at the time of the study. Six patients were currently smokers, while 22 had a history of smoking, 5 patients had insulin-dependent diabetes mellitus. Medications were not significantly altered during the course of the clinical study.


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  		Table 1 Baseline patient characteristics

 
The study protocol conforms with the principles outlined in the Declaration of Helsinki (Br Med J 1964; ii:177) and was approved by the local Ethics Committee of the University Hospital Gent. All subjects gave written informed consent before entering the study.

2.2. Exercise testing and respiratory gas measurements
Patients were tested on a computer-driven cyclo-ergometer (Marquette Case, Marquette Electronics, Milwaukee, Wisc., USA) using a gradual protocol starting at 25 W with gradual increase of 10 W every minute. Twelve-lead ECG and heart rate were recorded continuously during the test, and blood pressure was measured with a manual sphygmomanometer every two minutes. Subjects were encouraged to exercise to the self-determined limits of their functional capacities or until the physician stopped the test because of severe adverse events, such as increasing chest pain, dizziness, potentially life-threatening arrhythmias, significant ST-segment deviations, marked systolic hypotension or hypertension.

Respiratory gas measurements were obtained using an Oxycon Pro spirometer (Jaeger-Viasys Healthcare, Hoechberg, Germany).The oxygen consumption (VO2), carbon dioxide production (VCO2), minute ventilation (VE), tidal volume, respiratory rate and mixed expiratory carbon dioxide concentration were measured continuously with breath-by-breath analysis. Before calculating the variables described below, we averaged all separate breath plots over 15 second time intervals.

PeakVO2 was expressed as the highest attained VO2 during the final 30 s of exercise. Ventilatory anaerobic threshold was defined as the level of oxygen uptake during exercise, where either the increase in VE/VO2 was non-linear and was not associated with a simultaneously increase in VE/VCO2; or where the linear relationship between VCO2 and VO2 (using V-slope method) disappeared [12]. VE/VCO2 slope which reflects the rate of increase in minute ventilation per unit increase in CO2-production, was obtained by linear regression analysis of the relation between VE and VCO2 during exercise using the data of the whole exercise test (including respiratory compensation) [13]. The Oxygen Uptake Efficiency Slope describes the relationship between oxygen uptake and ventilation during incremental exercise, via a single-segment logarithmic expression of ventilation and is defined as the regression slope "a" in VO2=axlog10 VE+b. A steeper slope or higher OUES represents a more efficient oxygen uptake, whereas a shallower slope or lower OUES represents a higher amount of ventilation required for any given oxygen uptake. The OUES was calculated using respiratory data from the first 90% of exercise time (OUES90%) as well as using all respiratory data plots up to 100% (OUES). The percent of age-adjusted predicted OUES was calculated as OUES divided by predicted OUES derived by using the gender-specific equations reported by Hollenberg and Tager [9] where for women, OUES=1175 –(15.5xage)+(841xBSA); for men OUES=1320–(26.7xage)+(1394xBSA).

Flow meters and gas analysers were calibrated for accuracy and linearity.

Finally, all patients performed a standardized, self-paced 6 minute walk test (6MWT) in a 15 m long corridor in our rehabilitation centre at the three pre-determined test points (start middle and end of the rehabilitation program). Before the 6MWT, patients were instructed to cover as much distance as possible within 6 minutes without running. Patients were allowed to stop at any time during the test, but were encouraged to restart as soon as possible. During the test, patients were instructed and encouraged with standardized comments and encouragements. The distance covered in 6 minutes was measured to the nearest meter.

2.3. Training protocol
Each 1 h-training session started and ended with a 5-minute warm-up/ cool-down and stretching period and involved an exercise "circuit" consisting of muscle strengthening exercises for upper and lower limbs, alternating with aerobic exercises (treadmill walking, stepping and cycling). The strengthening exercises concentrated on plantar extension, knee extension and flexion, hip extension and flexion, elbow flexion and extension and seated dual pectoral flexion. Before the start of the program, patients were instructed in the correct lifting technique and were instructed on how to avoid Valsalva manoeuvre during each exercise. The initial exercise intensity was kept low (±50% of 1 Repetition Maximum or 1 RM). Each exercise was repeated in 3 sets of 15 repetitions, with a 1 minute rest between sets. Aerobic cycling, stepping and treadmill walking intensities were maintained at 70-85% of peak heart rate of the first cardiopulmonary exercise test. The total aerobic exercise time was 25 min/session. Exercise intensity was progressively increased as individually tolerated.

2.4. Statistics
Data were analyzed using a commercially available statistical software program (SPSS 12.0, SPSS Inc, Chicago, Illinois (USA). Continuous variables are presented as mean±standard deviation. General Linear Model with appropriate post-hoc analysis was used to look for significant differences between repeated measurements at the three different assessment times during the training period. A non-parametric Friedman and Wilcoxon signed ranks test was used for analysis of the evolution in NYHA-class. Spearman or Pearson correlation coefficients were used for appropriate associations between exercise and clinical variables. To assess significant differences between achieved correlations, we calculated 95% confidence intervals and performed significance t-tests on Pearson's correlation coefficients. Statistical significance was set at a two-tailed probability level of less than 0.05.


   3. Results
Top
 Notes
 Abstract
 1. Introduction
 2. Methods
 3. Results
4. Discussion
 5. Limitations
 6. Conclusion
 References
 
3.1. Response of the oxygen uptake efficiency slope and other exercise parameters to exercise training
On average patients attended 38±4 training sessions (range 25-41) during the 6-month training program. All exercise parameters improved significantly over the entire course of the 6-month exercise program (p<0.05) (Table 2).


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  		Table 2 Evolution of exercise and clinical variables after 3 and 6 months of exercise training

 
During the first three months of the training program, most exercise parameters improved significantly. Peak VO2 increased by an average of 17.5%, VAT by an average of 20 % and peak Watt and cumulative Watts by an average of 24% and 63% respectively. Oxygen uptake efficiency slope improved significantly during the first three months of the training program by an average of 14%, i.e. from 51% to 56% of the predicted value, whereas VE/VCO2 slope decreased by an average of 6%. The distance covered during the 6MWT increased significantly. Finally, NYHA-class improved in most patients (all p<0.05). There were no significant changes in peak O2-pulse, peak respiratory exchange rate (peak RER) and body mass index (BMI).

During the second part of the training program (i.e. between the 3rd and 6th month of training) only VAT, peak Watt, cumulative Watts and the distance covered during the 6MWT continued to increase significantly (p<0.05), whereas all the other exercise parameters remained statistically unaltered.

Submaximal OUES (calculated at 90% of total exercise duration) was highly correlated to the maximal OUES (calculated from all respiratory data of the entire CPX test) (r=0.973; p<0.0001) and followed the same evolution as OUES during the training program. The improvements in OUES (expressed as absolute delta-values and percentages of delta-values) after the first and second parts of the exercise training period, correlated highly with the respective improvements in peakVO2 (r ranging from 0.64 to 0.77, p<0.001). Besides changes in OUES, both changes in VAT and peak Watt were also significantly correlated to the changes in peakVO2 (r ranging between 0.37 and 0.55, p<0.05) The correlation between changes in OUES and peakVO2 was significantly stronger than the correlation between changes in peakVO2 and any other included exercise parameter. (p<0.01) No measure of changes in ventilatory efficiency, i.e. changes in OUES, slope VE/VCO2, peak VE/VO2 or peak VE/VCO2, was significantly correlated with changes in distance during 6MWT. In contrast, changes in peakVO2 between the first and second CPX test were significantly related to changes in 6MWT (r=0.29, p<0.05). The improvements in OUES were equally correlated to the improvements in VAT and VE/VC02 slope (r=0.46 and r=0.43 respectively, p<0.01).


   4. Discussion
Top
 Notes
 Abstract
 1. Introduction
 2. Methods
 3. Results
 4. Discussion
5. Limitations
 6. Conclusion
 References
 
To the best of our knowledge, this study is the first to describe the effects of exercise training on OUES in patients with stable CHF. Our results show that exercise training beneficially affects OUES and that the marked improvements in OUES best reflect the observed improvements in peakVO2, compared to training-induced changes in other measures of (sub)maximal exercise capacity.

Since the introduction of the oxygen uptake efficiency slope as a new measure of cardio respiratory exercise capacity its reproducibility, stability and validity has been established in healthy subjects [9,14], children [8] and adult patients with cardiac [10,11,15,16,17] or other metabolic diseases [18]. Very recently, Davies et al. [11] were the first to report on the prognostic value of OUES in patients with CHF. We have previously shown that, contrary to peakVO2 and slope VE/CO2, OUES remains stable during the second part of a maximal cardiopulmonary exercise test, which makes it a very interesting effort-independent parameter to use in the clinical evaluation of patients with left ventricular dysfunction, even in those unable to perform a maximal exercise test [10].

Few studies have reported on the effects of exercise training on the OUES. Our results are the first to show that OUES improves in patients with stable CHF after 6 months of combined strength and aerobic exercise training. We found an overall average increase of 17% for OUES, which is very similar to the overall improvement observed for peakVO2, resulting in high correlations between absolute and percentage changes in OUES and peakVO2 during the initial and the last part of our 6-month exercise program. This observation extends the results from Defoor et al. [16], who reported on 425 patients with CAD after 3 months of training and those from Tsuyuki et al. [18], who trained 17 chronic haemodialysis patients for 5 months. However, our results are in contrast with those from Mourot et al. [19], who trained 8 young healthy women for 6 weeks and found no improvements in OUES, whereas peakVO2 and VAT improved significantly compared to non-trained controls. They concluded that the OUES response was highly variable and was not a sensitive marker of the response to exercise training in healthy well-trained women. Contrary to the healthy, well-trained subjects in their study, patients with CHF have an impaired skeletal muscle metabolism as well as an inappropriately high ventilatory response to exercise, due to altered muscle receptor reflexes and increased ventilatory dead space. Both factors are known to improve with exercise training in CHF, resulting in a significant reduction in blood lactate accumulation and more efficient ventilation during exercise. These improvements have a direct influence on the value of the OUES. Our data suggest that both mechanisms (expressed by VAT and VE/VCO2 slope) contribute equally to the observed improvements in OUES. However, further studies with more appropriate designs need to be performed to confirm this observation. Although exercise training results in significant improvements in OUES, it was still severely impaired in our patients. After training, patients only reached 60% of their predicted values, using the equations developed by Hollenberg et al. [9] Keeping in mind the impaired peakVO2 together with the elevated VE/VCO2 slope after training in our patients, this is not a surprising observation. However, the Hollenberg equations were calculated using a progressive modified Bruce treadmill protocol. It is currently unknown whether values of OUES are ergometer and/or protocol dependent. Nonetheless, since it is generally accepted that the achieved maximal exercise capacity, in terms of peakVO2, is about 5-25% higher with a treadmill protocol [20-23] and since OUES is highly correlated to peakVO2 in all published studies (using treadmill or bicycle ergometers) [8-11,16-19] this is very likely to be the case. As a result, we believe that the predicted values of OUES proposed by Hollenberg et al. could be overestimating the true OUES values, obtained during a progressive bicycle exercise protocol, as in our study.


   5. Limitations
Top
 Notes
 Abstract
 1. Introduction
 2. Methods
 3. Results
 4. Discussion
 5. Limitations
6. Conclusion
 References
 
In the interpretation of our study results, some limitations should be considered. Although we performed appropriate power-analysis to be able to detect statistically significant changes before starting the study, the number of included patients is still quite small. Our results need to be confirmed in larger exercise trials in this specific population. In addition, we did not include a control group of matched CHF patients that were not included in the ET program. Therefore, we can not fully exclude a learning or habituation effect. Furthermore, we used a combined exercise program, containing both general aerobic and localized strengthening exercises. Our study was not designed to dissociate the specific influences of both types of exercise on the response of OUES. Finally, whether the observed improvements in OUES after exercise training provide additional prognostic information is not clear. Further research is needed to clarify these interesting issues.


   6. Conclusion
Top
 Notes
 Abstract
 1. Introduction
 2. Methods
 3. Results
 4. Discussion
 5. Limitations
 6. Conclusion
References
 
The oxygen uptake efficiency slope is an easy to calculate submaximal exercise parameter that is very stable during the second part of a maximal exercise test. The OUES improves significantly after 6 months of exercise training. The training-induced changes in peakVO2 correlate better with the changes in OUES than with changes in other prognostic exercise parameters. We conclude that OUES is sensitive to exercise training and can be used as a new objective and intensity-independent parameter in the evaluation of the progression of exercise capacity in patients with stable CHF after exercise training.


   Notes
Top
 Notes
Abstract
 1. Introduction
 2. Methods
 3. Results
 4. Discussion
 5. Limitations
 6. Conclusion
 References
 
1 Nico Van de Veire is a research assistant and Johan De Sutter a senior clinical investigator of the Fund for Scientific Research Flanders (Belgium). Back


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

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