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(Circulation. 2002;106:3079.)
© 2002 American Heart Association, Inc.

Clinical Investigation and Reports

Exercise Anaerobic Threshold and Ventilatory Efficiency Identify Heart Failure Patients for High Risk of Early Death

Anselm K. Gitt, MD; Karlman Wasserman, MD, PhD; Caroline Kilkowski, MD; Thomas Kleemann, MD; Andreas Kilkowski, MD; Matthias Bangert, MD; Steffen Schneider, PhD; Armin Schwarz, MD; Jochen Senges, MD, FESC

From Herzzentrum Ludwigshafen (A.K.G., C.K., T.K., A.K., M.B., S.S., A.S., J.S.), Department of Cardiology, Ludwigshafen, Germany; and Harbor–UCLA Medical Center (K.W.), Torrance, Calif.

Correspondence to Anselm K. Gitt, MD, Herzzentrum Ludwigshafen, Bremser Str 79, 67063 Ludwigshafen, Germany. E-mail gitta{at}klilu.de

	Abstract

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Background— The maximal oxygen uptake (peak O₂) is used in risk stratification of patients with chronic heart failure (CHF). Peak O₂ might be lower than maximally possible if exercise is stopped early because of lack of patient motivation or premature cessation by the investigator. In contrast, the anaerobic threshold (O₂AT) and the ventilatory efficiency (E versus CO₂ slope) are less subject to these influences. Thus, we compared these parameters with peak O₂ in identifying patients with CHF at increased risk for death within 6 months after evaluation.

Methods and Results— We performed cardiopulmonary exercise tests with gas exchange measurements in 223 consecutive patients with CHF (114 coronary artery disease, 92 dilated cardiomyopathy, 17 others) at the Herzzentrum Ludwigshafen between 1995 and 1998. We measured peak O₂, O₂AT and E versus CO₂ slope. We selected peak O₂ of 14 mL/kg per minute, O₂AT of <11 mL/kg per minute, and E versus CO₂ slope of >34 as threshold values for high risk of death. The median follow-up time was 644 days. Patients with peak O₂ of 14 mL/kg per minute had a >3-fold-increased risk (OR=3.4; CI, 1.3 to 9.1), with O₂AT <11 mL/min per kg or E versus CO₂ slope >34 a 5-fold increased risk for early death (OR=5.3; CI, 1.5 to 19.0; OR=4.8; CI, 1.7 to 13.8, respectively). In patients with both O₂AT <11 mL/kg per minute and E versus CO₂ slope >34, the risk of early death was 10-fold higher (OR=9.6; CI, 2.1 to 44.7). After correction for age, sex, left ventricular ejection fraction, and New York Heart Association class in a multivariate analysis, the combination of O₂AT <11 mL/kg per minute and E versus CO₂ slope >34 was the best predictor of 6-month mortality (RR=5.1, P=0.001).

Conclusions— O₂AT of <11 mL/kg per minute and slope of E versus CO₂ >34, combined, better identified patients at high risk for early death from CHF than did peak O₂ and should therefore be considered when prioritizing patients for heart transplantation.

Key Words: heart failure • exercise • transplantation • ventilation • prognosis

	Introduction

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Despite recent advances in pharmacological treatment of patients with chronic heart failure (CHF), including ACE inhibitors and ß-blockers,^1–4 mortality rates in patients with severe CHF remain high. Reliable risk stratification is a continuing challenge as the number of candidates for heart transplantation is increasing and the supply of donor hearts is limited. Because of the supply-demand mismatch, many patients die while they are on the waiting list for transplantation. The identification of patients at highest risk for early death from heart failure, therefore, is of special importance.

Besides classic risk factors such as left ventricular ejection fraction (LVEF), New York Heart Association class IV symptoms, and neurohormonal markers, peak O₂ was found to predict survival in patients with CHF.^5–8 Mancini et al⁹ reported that patients with heart failure with a peak O₂ >14 mL/kg per minute had a 1-year survival rate similar to that of patients receiving heart transplantation. Increasing experience has confirmed the prognostic value of peak O₂ in the evaluation for heart transplantation.^10–15 The 24th Bethesda Conference for Cardiac Transplantation¹⁶ listed peak O₂<10 mL/kg per minute with achievement of anaerobic metabolism as an accepted indication for heart transplantation. Patients with a peak O₂ 14 mL/kg per minute and major limitation of daily activities were also transplantation candidates.

Peak O₂ might be underestimated because of reduced patient motivation as well as premature termination of exercise by the examiner. The anaerobic threshold (O₂AT) measures the sustainable O₂ uptake and is an objective parameter of cardiopulmonary exercise capacity that can be derived from submaximal exercise testing and therefore is independent of the influences described above.¹⁷ However, data showing its prognostic value in CHF do not yet exist.

Recently, ventilatory efficiency, measured as the slope of E versus CO₂ below the ventilatory compensation point for exercise metabolic acidosis, was found to be a reliable predictor of prognosis in patients with CHF.^18,19 As with O₂AT, it can be derived from submaximal exercise testing and is independent of patient motivation.

In this study, we sought to determine the predictive value of O₂AT, of E versus CO₂ slope, and the combination of both for estimating the short-term (6-month) and long-term (2-year) survival of patients with CHF and to compare these parameters with survival predicted by peak O₂/kg.

	Methods

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Patients
The study included 223 consecutive patients with CHF referred to the Herzzentrum Ludwigshafen who performed progressively increasing, symptom-limited cardiopulmonary exercise testing with gas exchange measurements between February 1995 and October 1998. All patients were referred by physicians in the catchment area of the Herzzentrum Ludwigshafen, had heart failure for at least 3 months, and were receiving stable doses of their medications without exacerbation of symptoms or need for intravenous inotropic support during 4 weeks preceding exercise testing. Patients with severe concomitant extracardiac diseases limiting exercise performance were excluded. Informed consent was obtained from each patient. The baseline demographic and clinical characteristics are shown in Table 1.

View this table: [in this window] [in a new window]   TABLE 1. Clinical Characteristics of the Study Population

Cardiopulmonary Exercise Testing
All patients performed upright bicycle exercise to maximum tolerance with the use of a progressively increasing work rate at 10 to 20 W/min after a period of resting and unloaded pedaling, as recommended by Buchfuhrer et al.²⁰ Patients were encouraged to exercise until symptoms were intolerable. Investigator-determined exercise end points were severe ventricular tachycardia of >5 beats, high degree of AV block, ST-segment depression >3 mm, systolic blood pressure >250 mm Hg, or progressive decrease in blood pressure.

Breath-by-breath gas exchange measurements were performed with a MedGraphics CardiO₂ metabolic cart. Oxygen uptake (O₂), carbon dioxide output (CO₂), tidal volume (VT), and breathing rate were measured. Blood gases (PaO₂, PaCO₂) and pH were measured at rest and shortly before the end of exercise with the use of arterialized capillary blood samples from the hyperemic earlobe.

Cardiopulmonary Parameters
From the above data, minute ventilation (E), respiratory exchange ratio (CO₂/O₂), the O₂-pulse (O₂/HR), and the ventilatory equivalents for O₂ and CO₂ (E/O₂, E/CO₂) were calculated. Peak O₂ was determined as the highest O₂ achieved during exercise. The anaerobic threshold (O₂AT) was measured by the V-slope method.²¹ Typical changes in ventilatory equivalents and end-tidal gas concentrations (PETO₂ and PETCO₂) were examined to search for agreement in cases that were questionable with regard to the precise O₂AT value. Predicted peak O₂ was determined by using the regression equations of Wasserman et al.¹⁷ The E versus CO₂ slope was calculated by linear regression, excluding the nonlinear part of the data after the onset of ventilatory compensation for metabolic acidosis. Referring to published data on prognosis in patients with CHF, we selected peak O₂ of 14 mL/kg per minute⁹ or 50%normal,¹³ O₂AT <11 mL/kg per minute,^22–24 and a E versus CO₂ slope >34¹⁸ as threshold values to identify patients with CHF with an increased risk of death.

Follow-Up Data on Prognosis
All patients were followed at the Herzzentrum Ludwigshafen. The outcome data were prospectively collected by telephone interviews of the patient or the patient’s family or by information from the residents’ registration office. The median follow-up period was 644 days.

Statistical Analysis
Continuous variables are expressed as mean±1 SD. Discrete variables are shown as absolute values and/or percentages ±SD. Simple linear regression analysis was used to examine E versus CO₂ slope as a function of peak O₂ and O₂AT. ² testing was used for analysis of categoric variables. The log rank test was used to compare differences among subgroups of the patients with CHF. Diagnostic test analysis was performed to calculate sensitivity, specificity, and positive predictive and negative predictive values for the different threshold values. The prognostic values of E versus CO₂ slope, peak O₂, O₂AT, LVEF, and NYHA class were assessed by using a multiple Cox regression analysis. Survival curves were constructed by using the Kaplan-Meier product limit method and were compared with the log rank test. We used a likelihood ratio test according to Wald in the logistic regression model to test for differences between odds ratios. A value of P<0.05 was considered significant. All calculations were performed with the use of the SAS statistical package, version 6.12 (SAS Institute, Inc).

	Results

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Baseline Characteristics
Descriptive characteristics of the study population are presented in Table 1. Ischemic cardiomyopathy was the predominant underlying cause of CHF (114 patients, 51%). LVEF was reduced to 28.7±8.1%; the left ventricular end-diastolic diameter was 65±7 mm. All patients had symptomatic heart failure, with a mean NYHA class of 2.1±0.7. The medical treatment included ACE inhibitors in 95%, ß-blockers in 43%, diuretics in 71%, digitalis in 69%, aspirin in 31%, and anticoagulants in 38% of the patients. Twenty patients (9%) had pacemakers and another 36 patients (16%) had an implanted cardioverter-defibrillator (ICD).

Follow-Up on Survival
None of the patients were lost to follow-up. During the median follow-up of 644 days, 46 patients died (nonsurvivors). Four patients with an ICD had ventricular fibrillation, detected and successfully treated by the ICD. Twenty patients died within the first 6 months of follow-up. None of the patients underwent heart transplantation. The clinical characteristics of the survivors and nonsurvivors are presented in Table 1. The nonsurvivors were similar to the survivors in sex, body mass index, and in the cause of CHF but were older, more symptomatic, and had a lower LVEF (Table 1).

Lung Function Test
The mean vital capacity (VC) of all patients was 88% of predicted with a normal FEV₁/VC ratio (Table 2). The nonsurvivors showed a more restrictive pattern expressed by a lower VC than survivors. The nonsurvivors had a slightly lower average PaCO₂ at rest and at peak exercise compared with survivors. Dead space fractions of E (VD/VT) were increased to 0.62 and 0.49, during rest and peak exercise, respectively (Table 2).

View this table: [in this window] [in a new window]   TABLE 2. Lung Function, Blood Gases, Exercise Characteristics of the Study Population (n=223), and Differences Between Survivors and Nonsurvivors

Cardiopulmonary Exercise Testing
Exercise was stopped for dyspnea in 141 patients, angina in 22 patients, and fatigue or exhaustion in 40 patients. The remaining 20 patients were stopped for investigator-determined end points described in the Methods section. The anaerobic threshold could not be determined in 17 patients (8%) because of mitigating oscillatory gas exchange patterns or premature end of exercise. All measurements of exercise capacity were lower in nonsurvivors than survivors (Table 2). There was no difference in heart rate at rest or at maximal exercise between both groups. The O₂-pulse was lower in nonsurvivors. E at maximal exercise was lower in nonsurvivors because of their lower maximal work rate.

Cardiopulmonary Predictors of Long-Term Mortality
Peak O₂ 14, peak O₂ 50% normal, E versus CO₂ slope >34, and O₂AT <11 were significant predictors of death in CHF during the median follow-up of 644 days (Figure 1). Peak O₂ 14 and O₂AT <11 were more predictive, with odds ratios of 3.9 and 3.7 than the percent of predicted peak O₂ and the E versus CO₂ slope with odds ratios of 2.5 and 3.0, respectively. O₂AT <11 identified 4 additional nonsurvivors not identified by peak O₂ 14 (Figure 2). In patients with peak O₂ 14 and E versus CO₂ slope >34, the increased risk of death was 6.1 times (Figure 1); whereas the combination of E versus CO₂ slope >34 and O₂AT <11 increased risk of death 7.0 times during follow-up (P<0.001, Figure 1). Thirty-six of 46 nonsurvivors had O₂AT <11 and 31 of 46 had a E versus CO₂ slope >34. Only 6 of 46 nonsurvivors had nonpathological values for either O₂AT <11 and the E versus CO₂ slope >34 (Figure 3).

View larger version (29K): [in this window] [in a new window]   Figure 1. Cardiopulmonary predictors of total mortality rate during follow-up of median 644 days: Univariate analysis. Numbers are odds ratios. Bars are 95% CI.

View larger version (19K): [in this window] [in a new window]   Figure 2. Distribution of O2AT and peak O2 in survivors and in nonsurvivors. Horizontal and vertical lines mark cutoff values of parameters. O2AT identified all nonsurvivors who also had peak O2 14 and an additional 4 nonsurvivors.

View larger version (19K): [in this window] [in a new window]   Figure 3. Distribution of O2AT and E versus CO2 slope in survivors and nonsurvivors. Horizontal and vertical lines mark cutoff values of parameters. Combination of both parameters identified all but 6 nonsurvivors.

Survival Analysis
The Kaplan-Meier survival curves of single and combined predictors of death are shown in Figure 4. All parameters were significant predictors of death for the total follow-up of 644 days.

View larger version (40K): [in this window] [in a new window]   Figure 4. Kaplan-Meier survival curves using peak O2 14 (A), peak O2 <50% predicted normal (B), E versus CO2 slope >34 (C), O2AT <11 mL/kg per minute (D), the combination of peak O2 14 and E versus CO2 slope >34 (E), as well as O2AT <11 and E versus CO2 slope >34 (F) as cutoff points. We found significant differences in survival at 6 months after initial evaluation in A, C, D, E, and F.

Cardiopulmonary Predictors of Six-Month Mortality
During the first 6 months of follow-up after the initial evaluation, peak O₂ <50% of predicted was not predictive of early death (Figure 5). Patients with peak O₂ 14 had a >3-fold risk, whereas patients with E versus CO₂ slope >34 had a 4.8-fold risk of early death. However, the best single predictor of early death was O₂AT <11 with a 5.3-fold-increased risk (Figure 5). Combining peak O₂ 14 with E versus CO₂ slope >34, the increased risk of death was 6.1-fold; the combination of E versus CO₂ slope >34 and O₂AT <11 was 9.6-fold (P<0.001, Figure 5). Patients who had both O₂AT <11 and E versus CO₂ slope >34 showed a 6-month mortality rate of 21.7% compared with only 2.6% in patients without these changes.

View larger version (22K): [in this window] [in a new window]   Figure 5. Cardiopulmonary predictors of early death within 6 months: Univariate analysis. Numbers are odds ratios. Bars are 95% CI.

The diagnostic test analysis for the different single and combined cardiopulmonary predictors of 6-month mortality showed that the combination of E versus CO₂ slope >34 with O₂AT <11 was superior to the single cardiopulmonary parameters in predicting death within 6 months, with a positive predictive value of 20.

After correcting for sex, age, LVEF, and NYHA class, all parameters were significant predictors of increased mortality rates within 6 months (Table 3). The combination of O₂AT <11 and E versus CO₂ slope >34 was superior to other parameters (OR=5.1, P=0.001, Table 3). The chronic ß-adrenergic blocker therapy was not taken into account in this multivariate analysis because it failed to predict death in univariate as well as in multivariate analysis in our patient population. The likelihood ratio test, according to Wald, in the logistic regression model to test for differences between odds ratios of different risk indicators, failed to show significance because of the large 95% CI and—for this kind of statistical test—a too-small number of patients and events in the subgroups.

View this table: [in this window] [in a new window]   TABLE 3. Cox Regression Analysis, Including Sex, Age, LVEF, and NYHA Class, for Calculation of Risk of Death at 6 Months

	Discussion

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Study Findings
To our knowledge, this is the first prospective study of cardiopulmonary exercise data in consecutive patients with CHF to compare O₂AT <11 as a predictor of early 6-month mortality with the established prognostic parameters of peak O₂ 14 or peak O₂ 50% predicted. By itself and in combination with E versus CO₂ slope >34, it identifies patients with a 2.7- and a 5.1-fold-increased risk of death within 6 months after initial evaluation, respectively, independent of sex, age, left ventricular function, and NYHA class (Table 3).

Study Population
The population of this study consisted of unselected patients with CHF treated at the Herzzentrum Ludwigshafen. Most previous studies of cardiopulmonary exercise testing in CHF were conducted in preselected patients evaluated for heart transplantation.^{9,11,14,15,25} In comparison, the patients in our study were approximately 10 years older (mean age, 63 years) and had a higher mortality rate. The underlying cause was ischemic and nonischemic heart disease in approximately equal distribution, in contrast to a higher number of dilated cardiomyopathy in earlier studies.^9,15

Most studies on the prognostic value of cardiopulmonary exercise parameters were conducted before ß-adrenergic blockers were shown to be beneficial in CHF. Recent published data reported ß-adrenergic blocker use in only 31% of patients with CHF.¹⁴ Forty-three percent of our study population were taking long-term ß-adrenergic blocker therapy. However, the role of ß-adrenergic blockade on the prognostic significance of these exercise parameters awaits a larger study with greater statistical power.

Cardiopulmonary Exercise Testing and Prognosis in Heart Failure
Peak O₂ related to body weight has been the most widely used parameter to predict survival in patients with CHF.^11,15 A value of <14 was recommended for selecting potential candidates for heart transplantation. Patients with peak O₂ <10 had the worst prognosis. However, an actual cutoff for decision probably does not exist. Rather, there is an increasing risk of death with decreasing values of peak O₂, as previously described.^5,11 We confirmed that a peak O₂ 14 signifies a worse prognosis than a higher peak O₂ in our population of unselected patients with CHF.

A given value of peak O₂/kg may signify a different degree of abnormality when comparing young male patients and elderly female patients. Therefore, some investigators recommended peak O₂ expressed as percentage of the predicted maximal value, taking sex, age, and nonobese weight into account.¹³ Stevenson¹¹ reported that peak O₂/kg and the percent predicted value might be interchangeable. In our study population, peak O₂ 50% normal could identify patients at increased risk for long-term but not 6-month mortality.

Chua et al¹⁸ and Kleber et al¹⁹ demonstrated the prognostic value of the ventilatory efficiency (E versus CO₂ slope) during exercise. We used the cutoff value of E versus CO₂ slope >34 to discriminate between patients at high and low risk for death.

There are no data on the prognostic value of the anaerobic threshold in patients with CHF. Stevenson¹¹ reported that O₂AT was essentially interchangeable with peak O₂. Referring to the Weber classification^23,24 and to studies of cardiopulmonary exercise testing in preoperative evaluation of elderly patients by Older and Hall,²² we have chosen O₂AT <11 as a cutoff value for high risk. We compared the O₂AT with the peak O₂ to determine their respective prognostic strengths for early (6 months) and long-term (2 years) mortality. O₂AT <11 identified additional patients to be at high risk. This parameter was as good as peak O₂ in the identification of patients at increased risk for assessing long-term mortality but provided greater prognostic strength for predicting 6-month mortality. By multivariate analysis, correcting for sex, age, LVEF, and NYHA class, O₂AT <11 identified patients to have a 2.7-fold-increased risk of death at 6 months (P=0.02) (Table 3).

We found the same prognostic strength for the E versus CO₂ slope as for O₂AT (Table 3). Both parameters can be derived simultaneously from the same exercise test. In contrast to peak O₂, which is strongly dependent on patient motivation to perform a maximal effort exercise, O₂AT and E versus CO₂ slope can be determined from a submaximal effort exercise test. We therefore combined O₂AT <11 with E versus CO₂ slope >34 for risk stratification. This combination surpassed all other parameters in their prognostic strength even after multivariate adjustment for age, sex, LVEF, and NYHA class (OR=5.1, P<0.01, Table 3).

Study Limitations
Included in this study population were only those patients who had stable CHF and who had been able to perform a symptom-limited exercise test with gas exchange measurements. Patients unable to exercise because of contraindications such as severe aortic valve disease or unstable heart failure are not represented by our study.

Although we found clear differences in the relative prognostic value of the odds ratios of the various physiological measurements, there was a lack of statistical power to reach significance because of the number of patients and the number of events during the follow-up.

A further limitation is the need to study a larger number of patients who are being treated with ß-adrenergic blockade to determine the prognostic value of parameters of exercise gas exchange in this population.

Clinical Implications
In addition to already-established prognostic values of cardiopulmonary exercise testing, our study demonstrates the high prognostic strength of O₂AT for early and long-term mortality in CHF. The combination of O₂AT <11 and the E versus CO₂ slope >34 better identifies patients at risk for early death from CHF than peak O₂ who therefore should be considered as candidates for early heart transplantation.

Received July 24, 2002; revision received September 24, 2002; accepted September 24, 2002.

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				M. M. Hoeper, M. W. Pletz, H. Golpon, and T. Welte Prognostic value of blood gas analyses in patients with idiopathic pulmonary arterial hypertension Eur. Respir. J., May 1, 2007; 29(5): 944 - 950. [Abstract] [Full Text] [PDF]

				C. Raphael, C. Briscoe, J. Davies, Z. Ian Whinnett, C. Manisty, R. Sutton, J. Mayet, and D. P Francis Limitations of the New York Heart Association functional classification system and self-reported walking distances in chronic heart failure Heart, April 1, 2007; 93(4): 476 - 482. [Abstract] [Full Text] [PDF]

				K. Dimopoulos, D. O. Okonko, G.-P. Diller, C. S. Broberg, T. V. Salukhe, S. V. Babu-Narayan, W. Li, A. Uebing, S. Bayne, R. Wensel, et al. Abnormal Ventilatory Response to Exercise in Adults With Congenital Heart Disease Relates to Cyanosis and Predicts Survival Circulation, June 20, 2006; 113(24): 2796 - 2802. [Abstract] [Full Text] [PDF]

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				M. Guazzi, J. Myers, and R. Arena Cardiopulmonary Exercise Testing in the Clinical and Prognostic Assessment of Diastolic Heart Failure J. Am. Coll. Cardiol., November 15, 2005; 46(10): 1883 - 1890. [Abstract] [Full Text] [PDF]

				M. Wonisch, P. Lercher, D. Scherr, R. Maier, R. Pokan, P. Hofmann, and S. P. von Duvillard Influence of Permanent Right Ventricular Pacing on Cardiorespiratory Exercise Parameters in Chronic Heart Failure Patients With Implanted Cardioverter Defibrillators Chest, March 1, 2005; 127(3): 787 - 793. [Abstract] [Full Text] [PDF]

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				M. Guazzi, G. Reina, G. Tumminello, and M. D. Guazzi Exercise ventilation inefficiency and cardiovascular mortality in heart failure: the critical independent prognostic value of the arterial CO2 partial pressure Eur. Heart J., March 1, 2005; 26(5): 472 - 480. [Abstract] [Full Text] [PDF]

				H. Ohuchi, H. Takasugi, H. Ohashi, O. Yamada, K. Watanabe, T. Yagihara, and S. Echigo Abnormalities of Neurohormonal and Cardiac Autonomic Nervous Activities Relate Poorly to Functional Status in Fontan Patients Circulation, October 26, 2004; 110(17): 2601 - 2608. [Abstract] [Full Text] [PDF]

				F.X Kleber, P Waurick, and M Winterhalter CPET in heart failure Eur. Heart J. Suppl., August 1, 2004; 6(suppl_D): D1 - D4. [Abstract] [Full Text] [PDF]

				A. L. T. Uusitalo, T. Laitinen, S. B. Vaisanen, E. Lansimies, and R. Rauramaa Physical training and heart rate and blood pressure variability: a 5-yr randomized trial Am J Physiol Heart Circ Physiol, May 1, 2004; 286(5): H1821 - H1826. [Abstract] [Full Text] [PDF]