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(Chest. 2003;124:580-586.)
© 2003 American College of Chest Physicians

Prolonged Oxygen Uptake Kinetics During Low-Intensity Exercise Are Related to Poor Prognosis in Patients With Mild-to-Moderate Congestive Heart Failure*

Christoph Schalcher, MD; Hans Rickli, MD; Manuel Brehm, MD; Daniel Weilenmann, MD; Erwin Oechslin, MD; Wolfgang Kiowski, MD and Hans Peter Brunner-La Rocca, MD

* From the Division of Cardiology, Department of Internal Medicine, University Hospital, Zurich, Switzerland.

Correspondence to: Hans Peter Brunner-La Rocca, MD, Division of Cardiology, University Hospital, Petersgraben 4, 4031 Basel, Switzerland; e-mail: brunnerh{at}uhbs.ch


   Abstract
TOP
 Abstract
Introduction
 Materials and Methods
 Results
 Discussion
 Conclusions
 References
 
Study objective: To investigate the prognostic value of oxygen uptake (O2) kinetics during low-intensity exercise in patients with congestive heart failure.

Design: Prospective cohort study.

Setting: Tertiary care center.

Patients: One hundred forty-six consecutive patients (128 men) with chronic heart failure, followed up for a mean (± SD) duration of 25 ± 15 months.

Measurements: A treadmill exercise test was performed with "breath by breath" gas-exchange monitoring. O2 kinetics were defined as the O2 deficit (ie, {Delta}O2 x time[rest to steady state] - {Sigma}O2[rest to steady state]) and mean response time (MRT) [ie, O2 deficit/{Delta}O2]. Cardiac death, urgent cardiac transplantation, and hospitalization due to worsening heart failure were considered as the end points.

Results: Thirty patients (21%) died, 11 patients (8%) underwent urgent transplantation, and 32 patients (22%) were hospitalized. In univariate analysis, MRT was the most powerful predictor of survival, survival free of urgent transplantation, and survival free of hospitalization (hazard ratios [HRs] per 10 s, 1.65, 1.72, and 1.61, respectively; all p < 0.0001). The predictive value of MRT exceeded that of peak O2 (HR per mL/kg/min, 0.90; p = 0.02, 0.91; p = 0.007, and 0.95; p = 0.08, respectively). In multivariate analysis, MRT (HR per 10 s, 1.73; p = 0.0002), resting systolic BP (HR per 10 mm Hg, 0.65; p = 0.003), and the slope of the ventilatory response to exercise (HR per 10 U, 1.68; p = 0.02) were independent predictors of survival.

Conclusions: Our results suggest that O2 kinetics are strongly related to outcome in heart failure patients. Since it has several additional advantages over peak exercise testing (eg, less time-consuming, less demanding for the patients, less dependent on motivation, and applicable in patients with limitations other than cardiopulmonary disease), it has the potential to become a prognostic test for the assessment of heart failure patients.

Key Words: congestive heart failure • exercise test • oxygen consumption • prognosis


   Introduction
TOP
 Abstract
 Introduction
Materials and Methods
 Results
 Discussion
 Conclusions
 References
 
Risk stratification in patients with congestive heart failure is important because of a growing patient population, the shortage of heart transplant donors, and increasing economic constraints. Selecting patients for heart transplantation or other treatment modalities such as left ventricular assist devices requires a careful weighing of the risk associated with these therapies against the risk of medical treatment. However, risk stratification in patients with congestive heart failure is difficult and often fails in individual patients. Exercise testing with gas exchange measurement is one of the pivotal methods for prognostic assessment. Peak oxygen uptake (O2peak) is related to the severity of congestive heart failure, and, accordingly, to mortality and morbidity.1 However, O2peak has limitations as a parameter of cardiovascular capacity. Thus, it may be influenced by conditions other than congestive heart failure and may be dependent on the patient’s motivation and the physician’s termination criteria.2 Accordingly, there has been an increasing interest in submaximal exercise testing in heart failure patients.3 4 5 6

The rate of change of oxygen uptake (O2) at exercise onset (ie, O2 kinetics) is one of the measures of submaximal exercise performance and is altered in patients with congestive heart failure.7 8 9 Since the increase in cardiac output at exercise onset may be delayed while the maximal cardiac output is still normal,8 the assessment of O2 kinetics may be a measure of cardiovascular performance independent of changes in O2peak. Furthermore, a small pilot study10 found an association between delayed O2 kinetics and prognosis. This study was conducted to investigate prospectively whether O2 kinetics predict prognosis in patients with congestive heart failure at least as well as does O2peak.


   Materials and Methods
TOP
 Abstract
 Introduction
 Materials and Methods
Results
 Discussion
 Conclusions
 References
 
One hundred forty-six consecutive patients (18 women) with chronic heart failure who had been referred to our heart failure clinic and had been in stable condition for at least 3 months were included in the study. Left ventricular ejection fraction was < 45% in all patients. The cause of heart failure was coronary artery disease in 46 patients (32%), dilated cardiomyopathy in 80 patients (55%), valvular heart disease in 9 patients (6%), hypertensive heart disease in 4 patients (3%), and combined cardiac etiologies in 7 patients (5%). All patients were receiving therapy with angiotensin-converting enzyme inhibitors or angiotensin II-receptor blockers, 133 patients (91%) were receiving diuretics, 86 patients (59%) were receiving digitalis, 47 patients (32%) were receiving ß-blockers, and 32 patients (22%) were receiving amiodarone. Thirty-five patients (24%) were smokers. The results were not influenced by smoking habits. Patients were excluded from the study if their exercise capacity was limited by reasons other than chronic heart failure.

All patients underwent a physical examination, an exploration of their medical history, and a standard multipanel laboratory screening. Subsequently, an exercise test was performed on a treadmill. Other diagnostic tests were performed according to the discretion of the treating physicians. In 100 patients, right heart catheterization was performed at a second visit that occurred within 3 months of the initial visit. Fluid-filled Swan-Ganz catheters advanced under radiographic control were used for pressure measurements. Cardiac output was determined using the Fick method. Blood was taken from the radial artery and the right pulmonary artery to measure arterial and central venous oxygen saturation.

Gas exchange was assessed using a breath-by-breath system (CPX/D; Medical Graphics Corporation; St. Paul, MN), which was calibrated before each test. Patients started walking after reaching a steady-state gas exchange condition while standing quietly. To define precisely the starting point of walking, patients stood on the edges of the treadmill and started walking after the device had reached a programmed speed and elevation. A two-step protocol was used.11 Initially, the patients walked at 1.0 mile per hour (mph) with an elevation of 6% for 6 min, corresponding to approximately 0.5 W/kg body weight. Thereafter, both speed and elevation were increased to augment workload by approximately 0.15 W/kg body weight/min until exhaustion. Workload was assessed by rearrangement of the following formula used by the American College of Sports Medicine12 :

where "elevation" is expressed in percent, speed is expressed in meters per second (ie, mph x 1,609/3,600), and g is the gravitation constant (ie, 9.81).

Oxygen deficit was calculated according to the formula11 :

where t is the time from rest to steady state (in minutes), {Delta}O2 is the difference of O2 from rest to steady state (in milliliters per minute), and {Sigma}O2 is the sum of the consumed O2 (in milliliters). To calculate the O2 deficit, a software package was used (BreezeEx, version 3.02; Medical Graphics Corporation). All O2 deficit calculations were performed by two observers blinded to the follow-up data (ie, CS and MB), and, in case of disagreement, a third observer reanalyzed the data (ie, HPB).

The mean response time of O2 (MRT) [ie, the time constant of O2] was calculated using the following formula9 :

O2peak was defined by averaging five of seven consecutive breaths. The anaerobic threshold was determined using the V-slope method,13 and the ventilatory response to exercise (E/CO2) was defined as previously described.14

Patient status was determined by interview of the referring physicians and/or patients and by chart review. In addition to cardiac death, urgent transplantation (defined as the need for therapy with positive inotropic agents or a left-ventricular assist device) and hospitalization due to worsening congestive heart failure were considered as end points. In case of elective heart transplantation (11 patients), follow-up was censored at the time of transplantation for survival analysis, because O2peak data were used for making the decision to list patients for cardiac transplantation. The mean (± SD) duration of follow-up in these 11 patients was 374 ± 273 days. One patient committed suicide. His follow-up was censored at the time of the event.

Statistical Analysis
Values are expressed as the mean ± SD and frequencies as indicated. Survival and survival free of the need for urgent transplantation or hospitalization were calculated using Kaplan-Meier curves. Patients were divided into three groups according to the MRT (ie, <= 40 s, 40 to 60 s, and >= 60 s). The strata were derived from the pilot study,10 based on findings in healthy control subjects (a cutoff time of 40s corresponds approximately to the mean value, and a cutoff time of 60s corresponds approximately to the mean + 2SD in age-matched control subjects [data were derived from the original data set of the study by Lewalter et al15 ]). Hazard ratio (HR) was assessed by univariate Cox regression analysis. Multivariate Cox regression analysis was performed by including significant predictors of outcome in the univariate analysis. Additionally, survival analysis was separately performed in patients with preserved and reduced exercise capacity (ie, O2peak < 18 mL/kg/min and >= 18 mL/kg/min16 ).

Receiver operating characteristic curves for 1-year survival and survival free of the need for urgent transplantation or hospitalization were analyzed by nonparametric Z-statistics. Statistical analysis was performed using a statistical software package (SPSS, version 9.0; SPSS Inc; Chicago, IL).


   Results
TOP
 Abstract
 Introduction
 Materials and Methods
 Results
Discussion
 Conclusions
 References
 
Patient characteristics are listed in Table 1 . Thirty patients (21%) died due to a cardiac cause, and 11 patients (8%) needed urgent transplantation (mean follow-up time, 762 ± 454 days; median, 722 days). Thirty-two patients (22%) were hospitalized due to worsening heart failure after a mean duration of 530 ± 432 days (median, 368 days). Fifty-three patients (36%) reached the end point of death or hospitalization due to worsening congestive heart failure. After 1, 2, and 3 years, the cardiac survival rates were 87 ± 3%, 80 ± 4%, and 75 ± 4%, respectively, the rates of survival free of the need for urgent transplantation were 83 ± 3%, 74 ± 4%, and 68 ± 5%, respectively, and the rates of survival free of hospitalization were 80 ± 3%, 69 ± 4%, and 57 ± 5%, respectively.


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  		Table 1.. Baseline Characteristics*

 
Table 2 shows the significant predictors of outcome. MRT was the most significant predictor of all end points, irrespective of the smoking status of the patients. O2peak also was related to outcome, however, its predictive value was less than that of O2 kinetics and E/CO2. Resting BP, severity of symptoms, and serum sodium and creatinine levels were other parameters that were related to outcome. All other clinical and morphologic parameters and measures that had been obtained during right heart catheterization did not predict outcome.


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  		Table 2.. Significant Predictors of Cardiac Mortality, Urgent Transplantation, or Hospitalization Due to Worsening Heart Failure in Univariate Analysis*

 
An MRT of <= 40 s was found in 36 patients (25%), an MRT of 40 to 60s was found in 72 patients (49%), and an MRT of >= 60 s was found in 38 patients (26%). Figure 1 depicts the Kaplan-Meier curves in patients subdivided according to the three strata of MRT, showing poor outcome in patients with prolonged MRT compared with those with normal MRT.



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  		Figure 1.. Kaplan-Meier plots of cardiac survival (top, A), cardiac survival free of uTPL (middle, B), and survival free of hospitalization (hosp) [bottom, C] for the following three categories of MRT: > 60 s, 40 to 60 s, and < 40 s. The table between top, A, and middle, B, denotes the number of patients in each category of MRT at baseline, and after 1, 2, 3, and 4 years with respect to cardiac survival and cardiac survival free of urgent transplantation, respectively. The table below bottom, C, denotes the number of patients with respect to cardiac survival free of hospitalization. See Table 2 for abbreviation not used in text.

 
Table 3 depicts the predictive power of important parameters of exercise testing in patients with reduced and preserved exercise capacity. Interestingly, results did not differ significantly between these two subgroups. Particularly, MRT retained its prognostic power in both subgroups.


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  		Table 3.. Comparison of Parameters of Exercise Testing Regarding Predictive Value in Patients With Reduced and Preserved Exercise Capacity*

 
Stepwise multivariate Cox regression analysis included MRT (HR per 10 s, 1.73 and 1.91, respectively; p < 0.001), resting systolic BP (HR per 10 mm Hg, 0.65 and 0.70, respectively; p < 0.01), and E/CO2 (HR per 10 U, 1.68 and 1.79, respectively; p < 0.05) as independent predictors of survival and survival free of urgent transplantation, respectively. MRT (HR per 10s, 1.69; p < 0.0001) and resting systolic BP (HR per 10 mm Hg, 0.69; p < 0.001) were independent predictors of survival free of hospitalization. Medication, particularly therapy with ß-blockers, did not influence the results.

Figure 2 shows the receiver operating characteristic curves for MRT and O2peak to predict the 1-year cardiac mortality rate. MRT tended to be more predictive than O2peak (p = 0.08) but was not significantly (p > 0.1) better than E/CO2 (mean area under the curve, 0.70 ± 0.07). The areas under the curve for predicting the 1-year combined end point of cardiac mortality and/or the need for urgent transplantation (134 patients) were similar for all three variables. The predictive value of MRT was significantly better (p <= 0.05) than the other two variables with respect to the 1-year event rate of cardiac death and hospitalization due to worsening heart failure (133 patients) [area under curve: MRT, 0.73 ± 0.05; E/CO2, 0.63 ± 0.06; and O2peak, 0.62 ± 0.06].



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  		Figure 2.. Receiver operating characteristic curves for MRT and O2peak to predict 1-year mortality (128 patients). AUC = area under the curve; * = SE.

 

   Discussion
TOP
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
Conclusions
 References
 
This study investigated the prognostic value of O2 kinetics during low-intensity, constant-workload exercise in a relatively large population of patients with chronic heart failure. It shows that MRT is a good predictor of prognosis in patients with congestive heart failure. Its predictive value was at least as good as a variety of parameters that are known to be predictive of prognosis.1 In particular, it was a better predictor of prognosis than body weight-adjusted O2peak, which is widely used in selecting patients for cardiac transplantation.17 Thus, O2 kinetics during low-intensity exercise may add important information for risk stratification in heart failure patients. Furthermore, it may serve as a substitute for O2peak in patients who are unable to exercise maximally for reasons other than chronic heart failure.

The interest in using submaximal exercise testing for the assessment of heart failure patients is increasing.3 5 9 18 The parameters of submaximal exercise may better reflect cardiac limitations during daily life than maximal exercise testing. Patients with limitations of maximal exercise capacity other than heart failure such as orthopedic or peripheral vascular occlusive diseases still may be able to perform a submaximal exercise test. Exercise-induced angina may preclude maximal exercise testing, while submaximal workload still may be unaffected by myocardial ischemia. Additionally, O2peak depends partly on the patient’s motivation and the physician’s termination criteria,2 which are confounders that do not apply to the measurement of O2 kinetics. Finally, although peak exercise testing is safe, it is more convenient for symptomatic heart failure patients to perform a low-intensity exercise test.

To date, only a relatively small number of studies19 have analyzed the parameters of submaximal exercise regarding the prediction of prognosis in heart failure patients. The value of the 6-min walk test remains controversial, and it has been shown not to be an independent predictor of survival.20 E/CO2 has been applied to submaximal exercise testing for the prognostic assessment of heart failure patients.14 21 Interestingly, E/CO2 limited to the aerobic portion was a significant predictor of survival in heart transplant candidates but was inferior to O2peak in that regard.21 Others, however, have found both E/CO2 and O2peak to be independent and highly significant predictors of survival in patients with chronic heart failure.22 It has been shown16 that E/CO2 may predict prognosis in heart failure patients with preserved exercise capacity. In our study, E/CO2 at the anaerobic threshold was an independent predictor of survival and of the need for urgent transplantation. Interestingly, both MRT and E/CO2 independently predicted these end points. This was true in patients with preserved and reduced exercise capacities (Table 3) .

So far, no larger studies have investigated the prognostic significance of O2 kinetics during low-intensity exercise in heart failure patients. Our data suggest that their prognostic value may be independent of, and possibly superior to, parameters of maximal exercise testing. Although this might seem to be surprising, the physiologic mechanisms of the prolongation of O2 kinetics and the reduction of O2peak may differ, at least in part. At the onset of exercise, stroke volume increases first, which depends importantly on cardiac pump function.8 The further increase in cardiac output during progressive augmentation of workload predominantly depends on an increase in heart rate.23 Therefore, the reduction in cardiac pump function, as observed in heart failure patients, may have a larger impact on the initial increase of cardiac output, which is reflected by oxygen kinetics, than on the maximal achievable cardiac output, which is reflected by O2peak. This is in line with the finding that the increase in cardiac output at exercise onset may be delayed but that maximal cardiac output is still normal,8 whereas advanced impairment of systolic function leads to a reduction of cardiac output at every stage of exercise.24 Also, a delayed or reduced increase in heart rate, as often is seen in patients with advanced heart failure,25 may contribute to this. Interestingly, the delay in the response of the heart rate at exercise onset was found similarly to correlate with O2 kinetics and O2peak in heart failure patients.11 Thus, alterations in the heart rate response may affect both O2peak and O2 kinetics. Modifications in the cardiac sympathetic nervous system may contribute to the delayed response. Such alterations are seen in patients with advanced heart failure and are related to poor outcome.26 Taken together, one may speculate that MRT is an even more sensitive marker of changes in cardiac function than is O2peak. The better correlation of O2 kinetics with neurohumoral stimulation than that of O2peak in heart failure patients supports this hypothesis.11

Limitations
Some limitations apply to the present study. The study population might not be representative of the general heart failure population. Also, the percentage of women in the study population was low (18 of 146 patients), and it is, therefore, unproven whether our findings also apply to female heart failure patients.

Like O2peak, MRT is a continuous variable, and, therefore, it is difficult to define a single threshold value for MRT beyond which transplantation should be considered. Data from different studies16 19 27 examining populations of patients with different severities of heart failure have yielded various thresholds of O2peak ranging from 10 to 18 mL/kg/min. It is probable that this also applies to MRT.

Furthermore, MRT depends on the workload,23 and for valid comparisons between different centers standardized protocols with identical workload are required. Importantly, we used a low workload, which was adjusted to the body weight (with a fixed treadmill elevation of 6% and a treadmill speed of 1 mph). This two-step protocol might not be directly comparable to other protocols. However, its major advantage is the fact that oxygen kinetics and O2peak can be measured in one single test. Importantly, the mean duration of our exercise test was in accordance with current guidelines, indicating that our protocol is appropriate for the patient population investigated. Also, our protocol may have notable advantages. It allows sick patients with advanced chronic heart failure to perform this test. Furthermore, concomitant diseases are less likely to influence the test results of oxygen kinetics.

Right heart catheterization was not prospectively planned in our study population and were performed according to the discretion of the treating physicians. Thus, this may have contributed to the lack of a predictive value of hemodynamic measurements on prognosis in our study.

Finally, the prognosis for populations with a given O2peak or MRT value depends on the current state of medical knowledge. Prognosis is improving both in congestive heart failure28 and after heart transplantation.29 Thus, there is an ongoing need for the validation of prognostic parameters in patients chronic heart failure. Still, therapy with ß-blockers did not influence our results.


   Conclusions
TOP
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 Conclusions
References
 
MRT, which is a measure of O2 kinetics at the onset of constant low-intensity exercise, is a significant predictor of outcome in patients with congestive heart failure. Our results suggest that O2 kinetics are independent from and may be even superior to O2peak in the assessment of prognosis. Since it has several additional advantages over peak exercise testing (eg, less time-consuming, less demanding for the patients, less dependent on motivation, and feasible to perform in patients with limited exercise capacity due to reasons other than congestive heart failure), it has the potential to become an essential test for the assessment of prognosis in heart failure patients. Still, further studies are required to confirm our results.


   Footnotes
 
Abbreviations: HR = hazard ratio; mph = miles per hour; MRT = mean response time of oxygen uptake; E/CO2 = ventilatory response to exercise; O2 = oxygen uptake; O2peak = peak oxygen uptake

Received for publication March 13, 2002. Accepted for publication December 5, 2002.


   References
TOP
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 Conclusions
 References
 

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