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European Journal of Heart Failure 2007 9(10):1024-1031; doi:10.1016/j.ejheart.2007.07.001
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© 2007 European Society of Cardiology

Excessive ventilation during early phase of exercise: A new predictor of poor long-term outcome in patients with chronic heart failure

Ewa A. Jankowskaa, Tomasz Witkowskia, Beata Ponikowskab, Krzysztof Reczucha, Ludmila Borodulin-Nadziejab, Stefan D. Ankerc, Massimo F. Piepolid, Waldemar Banasiaka and Piotr Ponikowskia,*

a Cardiology Department, Military Hospital Weigla 5, 50-981 Wroclaw, Poland
b Department of Physiology, Wroclaw Medical University Poland
c Division of Applied Cachexia Research, Department of Cardiology, Charite Medical School Berlin, Germany
d Heart Failure Unit, Cardiac Department, G. da Saliceto Polichirurgico Hospital Piacenza, Italy

* Corresponding author. Tel.: +48 71 7660 237; fax: +48 71 7660 228. E-mail address: piotrponikowski{at}4wsk.pl (P. Ponikowski)


   Abstract
Top
 Abstract
1. Introduction
 2. Methods
 3. Results
 4. Discussion
 5. Study limitations
 References
 
Background: Studies demonstrating prognostic value of excessive exercise ventilation in chronic heart failure (CHF) have focused on data derived from the whole cardiopulmonary exercise test (CPET). Whether ventilatory response to early phase of exercise is useful for risk stratification in CHF is unknown.

Methods and results: We evaluated 216 patients with systolic CHF who underwent CPET (age: 60±11 years, NYHA class [I/II/III/IV]: 18/104/77/17). Ventilatory response to exercise (slope of regression line relating ventilation to carbon dioxide production) was calculated from the whole exercise test (VE-VCO2-all) and from the first 3min of exercise (early phase — VE-VCO2-3min). During follow-up (mean: 40± 20months, >3years in survivors), 89 (41%) CHF patients died. High VE-VCO2-all and VE-VCO2-3min predicted poor outcome in single predictor analyses, and in multivariable models when adjusted for prognosticators (age, NYHA class, ejection fraction, peak VO2) (P<0.0001). In receiver operating characteristic curve analysis, areas under curve for 3-year follow-up were similar for VE-VCO2-all and VE-VCO2-3min. VE-VCO2-3min maintained its prognostic value in patients taking β-blockers (P<0.0001) and those unable to perform maximal CPET (P=0.0009).

Conclusions: In CHF patients, excessive ventilation assessed over the first 3min predicts poor outcome. Assessment of ventilatory response to exercise for prognostic stratification may be extended to patients unable to perform maximal CPET.

Key Words: Heart failure • Exercise ventilation • Prognosis

Received October 12, 2006; Revised March 27, 2007; Accepted July 2, 2007


   1. Introduction
Top
 Abstract
 1. Introduction
2. Methods
 3. Results
 4. Discussion
 5. Study limitations
 References
 
Augmented ventilatory response to exercise is common in chronic heart failure (CHF) [1,2], and is probably due to the numerous abnormalities present in the CHF syndrome, including impaired haemodynamics [1,3], perfusion-ventilation mismatch in the lungs [4,5], and disordered control of ventilation with abnormal cardio-respiratory reflex control [6,7]. Augmented ventilatory response to exercise is an indicator of worsening CHF, and is an independent marker of poor prognosis in a broad spectrum of patients with CHF [2,7-9].

Despite the acknowledged pathophysiological and clinical importance of excessive exercise ventilation in CHF, an optimal assessment method has not been established. Ventilatory response to exercise is usually expressed as ventilation per unit of carbon dioxide production, calculated either as a ratio at certain time-point of exercise [10,11] or as a slope of regression line (i.e. VE-VCO2 slope) [2-11]. Until now, VE-VCO2 slope was calculated from the metabolic data derived from the whole symptom-limited cardiopulmonary exercise test (CPET) [2-11]. However, this approach excludes a large number of CHF patients who are unable to perform maximal effort.

The aim of this study was therefore to prospectively assess, whether an evaluation of ventilation during the early stage of exercise (i.e. first 3 min) could provide clinically relevant prognostic information in CHF. VE-VCO2 slope during the first 3 min of exercise can be measured readily in nearly all CHF patients from the data routinely acquired during CPET. In light of recent reports of the limited predictive value of CPET-derived indices in CHF patients treated with β-blockers [12,13], this was also addressed in our study.


   2. Methods
Top
 Abstract
 1. Introduction
 2. Methods
3. Results
 4. Discussion
 5. Study limitations
 References
 
2.1. Study population
All consecutive patients with systolic CHF who underwent CPET in our institution between January 1999 and September 2002 and who met the following inclusion criteria were considered for the study: 1) a >3-month documented history of CHF; 2) left ventricular ejection fraction (LVEF) ≤45% as assessed by echocardiography; 3) clinical stability and unchanged CHF medication for ≥2 weeks preceding the study; 4) CPET of ≥3-minute duration. Exclusion criteria included: 1) pulmonary disease which may significantly contribute to symptoms of exercise intolerance; 2) musculoskeletal disorder; 3) acute coronary syndrome or coronary revascularisation within 3 months preceding the study.

The study protocol was approved by the local ethics committee and all subjects gave written informed consent. The study was conducted in accordance with the Helsinki Declaration.

2.2. Cardiopulmonary exercise testing
After a period of 5-minute rest, all patients underwent a symptom-limited treadmill exercise test (modified Bruce's protocol) with respiratory gas exchange analysis. Minute ventilation (VE), oxygen consumption (VO2) and carbon dioxide production (VCO2) were assessed every 10 s (BREEZE EX, Cardiorespiratory Diagnostic Software 1991-1996, Medical Graphics, USA). Peak oxygen consumption (peak VO2, mL min–1 kg–1) was measured as an average of the last 30 s of exercise. Ventilatory response to exercise, expressed as the slope of the regression line relating VE to VCO2 (VE-VCO2 slope) was calculated: 1) from the whole exercise test (VE-VCO2-all), and 2) from the first 3 min of exercise (early phase, VE-VCO2-3 min).

2.3. Clinical follow-up
All measurements (CPET, clinical assessment, laboratory tests, echocardiography) were performed on the same day, which was considered as baseline.

Patients were seen regularly by the study investigators in the outpatient CHF clinic with a follow-up duration of at least 3 years in all who survived. Survival data (as of 30/11/2005) was obtained directly from patients or their relatives, from the CHF clinic database or from the hospital system. No patient was lost to follow-up. The primary end-point for the analysis was all-cause mortality.

2.4. Statistical analyses
Continuous variables were expressed as mean±standard deviation. The inter-group differences were tested using the t-Student test, the {chi}2 test, or the one-way ANOVA where appropriate. Single predictor and multivariable regression analyses were applied to establish variables determining values of VE-VCO2-all and VE-VCO2-3 min in patients with CHF.

The associations between analysed variables and survival in patients with CHF were assessed using Cox proportional hazards analysis (both single predictor and multivariable models). In the single predictor analyses, we included clinical parameters (age, sex, NYHA class, LVEF, CHF aetiology), and parameters assessed during CPET (peak VO2, VE-VCO2-all, VE-VCO2-3 min). During the construction of multivariable Cox models, we included all variables which had been shown to be related to survival in single predictor regression models. The assumptions of proportional hazard were tested for all the covariates.

In order to evaluate prognostic accuracy for both VE-VCO2 slopes in predicting death, we applied receiver operating characteristic (ROC) curve analysis for a 3-year follow-up with an estimation of area under curve (AUC), and established the cut-off values of both slopes with the best sensitivity and specificity for this time point.

In order to estimate the effect of ventilatory response to exercise (assessed separately for the whole exercise test and the first 3 min of exercise) on 3-year mortality rates, Kaplan-Meier curves for cumulative survival were constructed with the application of cut-off values for both slopes established in ROC analysis. Differences in survival rates were tested using the Cox-Mantel log-rank test.

A value of P<0.05 was considered statistically significant.


   3. Results
Top
 Abstract
 1. Introduction
 2. Methods
 3. Results
4. Discussion
 5. Study limitations
 References
 
During the study period, we evaluated 229 patients with stable systolic CHF who underwent CPET in our institution and were considered candidates for the study. Of these, 13 patients were not able to complete the first 3-minute stage of CPET for the following reasons: (1) shortness of breath, hyperventilation and/or atypical chest discomfort occurring immediately after start of exercise with unwillingness to continue CPET (7 patients: 6 men, age: 65±11 years, LVEF: 32±7%, NYHA class II/III: 5/2 patients), (2) mouthpiece intolerance (6 patients: 5 men, age: 63±12 years, LVEF: 30±8%, NYHA class II/III: 4/2). These patients were not included in the study. The remaining 216 subjects, who performed CPET and had an exercise duration ≥3 min, formed the study population and were included in the subsequent analyses. The detailed characteristics of the study population are presented in Table 1.


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  		Table 1 Baseline characteristics for the 216 patients with chronic heart failure, who performed the cardiopulmonary exercise test for at least 3 min

 
All 216 patients performed cardiopulmonary exercise testing of at least 3-minute duration with mean peak VO2 of 14.8±4.9 mL min–1 kg–1 (limits: 4.5-32.0 mL min–1 kg–1). Ventilatory response to early exercise (mean VE-VCO2-3 min: 35.0±11.2, limits: 16.0-106.6) was significantly lower than to the whole exercise testing (mean VE-VCO2-all: 37.0±11.9, limits: 20.5-117.2), with a mean difference of –2.0±5.3 (P<0.0001). Values of VE-VCO2-3 min and VE-VCO2-all were strongly interrelated (r=0.90, P<0.0001) (Fig. 1).


Figure 01
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  		Fig. 1 Linear regression between VE-VCO2 slope calculated from the whole exercise test (VE-VCO2-all) and from the first 3-minute phase of exercise (VE-VCO2-3 min) performed in 216 patients with chronic heart failure, all of whom performed the cardiopulmonary exercise test for at least 3 min.

 
3.1. Clinical determinants of ventilatory response to exercise in patients with CHF
In single predictor models, VE-VCO2-all and VE-VCO2-3 min were related to peak VO2 (r=–0.39 and r=–0.36, respectively, P<0.0001 for both) and NYHA class (R=0.30, P<0.0001; results of ANOVA — F=6.13, P=0.0005, VE-VCO2-all in NYHA I vs. II vs. III vs. IV — 30.9±8.9 vs. 34.8±8.2 vs. 40.4±15.4 vs. 41.6±10.8; R=0.27, P<0.0001; results of ANOVA — F=5.92, P=0.0007, VE-VCO2-3 min in NYHA I vs. II vs. III vs. IV — 28.3±6.4 vs.33.3±7.4 vs. 38.0±15.2 vs. 39.5±10.8, respectively). LVEF mildly correlated with VE-VCO2-all and VE-VCO2-3 min (r=–0.16, P=0.02 and r=–0.12, P=0.08). Patients with ischaemic CHF had marginally higher VE-VCO2-all (37.9±12.7) and VE-VCO2-3 min (36.0±12.3) than patients with CHF of non-ischaemic aetiology (34.5±9.4 and 32.6±7.9, respectively, P=0.06). Neither age nor sex determined values of VE-VCO2-all and VE-VCO2-3 min (all P>0.2).

In a multivariable forward stepwise regression model, only peak VO2 (P<0.0001 for each slope) and NYHA class (P=0.02 and P=0.01 — for VE-VCO2-all and VE-VCO2-3 min) remained independent determinants of both VE-VCO2-all and VE-VCO2-3 min.

3.2. Ventilatory response to exercise and prognosis in patients with CHF
At the end of follow-up (mean follow-up duration — 1201±593 days, median — 1231 days, limits: 4-2506 days, >3 years in all who survived), there were 89 deaths (41%) (mean time to death — 704±454 days, median — 646 days, limits: 4-2021 days). The cumulative survival of all patients was 88%, 77% and 67% at 1, 2 and 3 years, respectively.

The proportionality assumption and the assumption of a log-linear relationship between the prognosticators and the hazard function were fulfilled for all tested variables.

3.2.1. Single predictor analyses
In single predictor Cox proportional-hazards models, the following variables were related to increased mortality in patients with CHF: age (per 1 year — HR=1.03, 95% CI: 1.01-1.05; {chi}2=6.14, P=0.01), NYHA class (per NYHA class, with NYHA I as a reference group — HR=1.55, 95% CI: 1.19-2.02; {chi}2=10.33, P=0.001), LVEF (per 1% — HR=0.96, 95% CI: 0.93-0.98; {chi}2=10.05, P=0.002), but not CHF aetiology or sex (both P>0.1).

CPET-derived parameters were predictors of survival in patients with CHF, i.e.: peak VO2 (per 1 mL min–1 kg–1 — HR=0.90, 95% CI: 0.85-0.94; {chi}2=19.13, P<0.0001), VE-VCO2-all slope (per 1 — HR=1.05, 95% CI: 1.04-1.07; {chi}2=41.92, P<0.0001), and VE-VCO2-3 min slope (per 1 HR=1.05, 95% CI: 1.04—1.07; {chi}2=38.28, P<0.0001).

3.2.2. Multivariable analyses
In a 2-variable model, VE-VCO2-all and VE-VCO2-3 min slopes, independently of peak VO2, were related to increased risk of death in patients with CHF (both P<0.0001, Table 2).


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  		Table 2 Predictors of mortality (multivariable Cox proportional hazard analyses) in 216 patients with chronic heart failure, all of whom performed the cardiopulmonary exercise test for at least 3 min

 
Both VE-VCO2-all and VE-VCO2-3 min slopes remained independent predictors of survival also in multivariable models, which included all variables that had been shown to be related to survival in single predictor models (both P<0.0001, Table 2).

3.2.3. Diagnostic accuracy in predicting death
AUCs for a 3-year follow-up were similar for VE-VCO2-all (0.662, 95% CI: 0.595-0.725) and VE-VCO2-3 min (0.682, 95% CI: 0.616-0.744) (P>0.4), indicating comparative predictive power at this time-point (Fig. 2).


Figure 02
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  		Fig. 2 Mortality predictive accuracy of VE-VCO2-all and VE-VCO2-3 min slopes at 3-year-follow-up, as illustrated by ROC curves for sensitivity and specificity performed in 216 patients with chronic heart failure, all of whom performed cardiopulmonary exercise test for at least 3 min.

 
ROC analysis revealed the following cut-off values as having best diagnostic accuracy for predicting death at 3-year follow-up: 32.81 for VE-VCO2-all slope (sensitivity: 73%, specificity: 55%, positive predictive value: 44%, negative predictive value: 81%) and 40.26 for VE-VCO2-3 min slope (sensitivity: 41%, specificity: 88%, positive predictive value: 63%, negative predictive value: 75%).

Kaplan-Meier analysis, using the cut-off values of ventilatory slopes established in the ROC analysis, revealed that 3-year survival was, respectively: 56% (95% CI: 47-65%) for CHF patients with high VE-VCO2-all (i.e. >32.81) as compared to 81% (95% CI: 73-89%) in those with VE-VCO2-all≤32.81 ({chi}2=17.26, P<0.0001); and 37% (95% CI: 23-51%) for CHF patients with high VE-VCO2-3 min (i.e. >40.26) as compared to 75% (95% CI: 69-81%) in those with VE-VCO2-3 min≤40.26 ({chi}2=30.89, P<0.0001) (Fig. 3A and B). Whereas a 1-year survival was 72% (95% CI: 59-85%) for CHF patients with VE-VCO2-3 min>40.26 as compared to 92% (95% CI: 88-96%) in those with VE-VCO2-3 min≤40.26 ({chi}2=14,86, P=0.0001).


Figure 03
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  		Fig. 3 Kaplan-Meier survival curves over 3 years for the 216 patients who performed CPET for at least 3 min. VE-VCO2 slopes are depicted either from the entire test (VE-VCO2-all) (A) or from the first 3-minute phase of exercise (VE-VCO2-3 min) (B). Survival differences were significant for both VE-VCO2-all and VE-VCO2-3 min (p<0.0001).

 
3.3. Ventilatory response to exercise and prognosis in subgroup of patients with CHF
3.3.1. NYHA class
Excessive ventilatory response to a whole exercise test (VE-VCO2-all) was a predictor of poor outcome regardless of CHF severity as assessed by NYHA class, i.e. in patients in NYHA class I-II (per 1 — HR=1.06, 95% CI: 1.03-1.09; {chi}2=15.85, P<0.0001) and those in NYHA class III-IV (per 1 — HR=1.04, 95% CI: 1.02-1.06; {chi}2=17.35, P<0.0001).

Similarly, high VE-VCO2-3 min slope was related to increased mortality in analogous subgroups of patients, i.e. in patients in NYHA class I-II (per 1 — HR=1.07, 95% CI: 1.03-1.11; {chi}2=11.32, P=0.0008) and those in NYHA class III-IV (per 1 — HR=1.04, 95% CI: 1.02-1.07; {chi}2=18.31, P<0.0001).

In patients in NYHA class I-II, both ventilatory indices demonstrated comparable prognostic power as evidenced by similar AUCs (0.675 for VE-VCO2-all vs. 0.649 for VE-VCO2-3 min, respectively, P>0.4). However, in patients with NYHA III-IV, VE-VCO2-3 min appeared to be a stronger prognosticator (AUCs: 0.612 for VE-VCO2-all vs. 0.675 for VE-VCO2-3 min, respectively, P=0.048).

3.3.2. Patients with CHF performing submaximal CPET
In 49 (23%) patients with CHF, the respiratory gas exchange ratio (RER=VCO2/VO2) at peak exercise did not exceed 1.00, indicating submaximal exertion during CPET. There were no differences in clinical characteristics and CPET parameters between those with RER≤1.0 vs. RER>1.0 — age: 62±11 vs. 59±12 years, men: 86% vs. 87%, LVEF: 32±8 vs. 31±8%, NYHA class: 2.4±0.7 vs. 2.4±0.8, peak VO2: 14.1±4.8 vs. 15.0±4.9 mL min–1 kg–1, VE-VCO2-all: 36.6±17.7 vs. 37.1±19.7, VE-VCO2-3 min: 36.4±16.7 vs. 34.6±9.3, P≥0.10 in all comparisons.

In this subgroup, excessive ventilatory response to exercise predicted poor outcome, both when expressed as VE-VCO2-all slope (per 1 — HR=1.06, 95% CI: 1.03-1.10; {chi}2=15.94, P<0.0001), and VE-VCO2-3 min slope (per 1 — HR=1.08, 95% CI: 1.04-1.12; {chi}2=17.16, P<0.0001).

Kaplan-Meier analysis performed in these 49 CHF patients with RER≤1.00, using the cut-off values of ventilatory slopes established in the ROC analysis, revealed that 3-year survival was, respectively: 55% (95% CI: 33-77%) for CHF patients with high VE-VCO2-all (i.e. >32.81) as compared to 72% (95% CI: 56-88%) in those with VE-VCO2-all≤32.81 ({chi}2=2.63, P=0.11), and 22% (95% CI: 0-50%) for CHF patients with high VE-VCO2-3 min (i.e. >n40.26) as compared to 75% (95% CI: 62-88%) in those with VE-VCO2-3 min≤40.26 ({chi}2=19.77, P<0.0001) (Fig. 4A and B).


Figure 04
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  		Fig. 4 Kaplan-Meier survival curves over 3 years for the 49 patients who did not complete a maximal CPET (i.e. RER≤1). VE-VCO2 slopes are depicted either from the entire test (VE-VCO2-all) (A) or from the first 3-minute phase of exercise (VE-VCO2-3 min) (B). Survival differences trended towards significance for VE-VCO2-all (p=0.11) and were significant for VE-VCO2-3 min (p<0.0001).

 
3.3.3. CHF patients treated with β-blockers
At the time of exercise testing 177 (82%), patients were being treated with β-blockers. During follow-up, in this subgroup 69 CHF patients died (3-year mortality: 26%). There was no significant difference in clinical characteristics (age, sex, CHF aetiology, NYHA class, LVEF, peak VO2, VE-VCO2 slopes) between those with and without β-blockers.

Among CHF patients treated with β-blockers, both elevated VE-VCO2 slopes predicted poor outcome in single predictor models (for VE-VCO2-3 min: per 1 — HR=1.06, 95% CI: 1.04-1.08; {chi}2=34.76, P<0.0001, for VE-VCO2-all: per 1 — HR=1.05, 95% CI: 1.04-1.07; {chi}2=36.44, P<0.0001).

In a multivariable models, high VE-VCO2-all and analogously VE-VCO2-3 min (P<0.0001 for each slope) and low LVEF (P=0.04 and P=0.03 — for VE-VCO2-all and VE-VCO2-3 min) remained independent predictors of survival in CHF patients treated with β-blockers, but not age, NYHA class, peak VO2 and exercise time (all P>0.1).


   4. Discussion
Top
 Abstract
 1. Introduction
 2. Methods
 3. Results
 4. Discussion
5. Study limitations
 References
 
This study shows that elevated VE-VCO2 slope measured during the first 3 min of CPET is an independent predictor of poor outcome in patients with CHF. Augmented ventilatory response to the early phase of exercise also has prognostic value in patients on β-blocker therapy, and in those who are not able to perform maximal exercise. The latter finding may be of particular practical relevance due to the limited evidence on CPET applicability for risk stratification in these CHF patients.

Exercise testing with gas exchange analysis has become a routine tool for the evaluation of patients with CHF [14,15]. Of several indices derived from CPET data, peak VO2 has been traditionally used for prognostic stratification with various cut-off values proposed for decision-making [14-18]. Recently, it has become evident that assessment of ventilatory response to exercise also carries prognostic information, independently of conventional prognosticators in CHF [2,7-9,19,20].

Excessive exercise ventilation in CHF is due to either ventilation-perfusion mismatching in the lungs (indicating abnormalities within the lungs or compromised haemodynamics) [3,4], or abnormal control of ventilation (which in turns indicates impaired reflex control within the cardio-respiratory system) [3,6,7,21]. Thus, augmented ventilatory response to exercise very likely reflects the severity of derangements in almost all pathophysiological aspects of the CHF syndrome, which may well explain its prognostic value.

It has not yet been established how to optimally characterize ventilatory response to exercise. Most often, it is expressed as the steepness of the slope of the regression line relating ventilation to carbon dioxide production (VE-VCO2 slope), calculated either from the onset of exercise to the point of ventilatory threshold [5,8,10,11,20] or utilizing all CPET data [2,6,7,19]. The first approach is based on the premise that the relationship between ventilation and carbon dioxide production is not linear throughout the exercise, with a disproportionate increase in ventilation towards the end of exercise [11,22]. However, ventilatory threshold is not detectable in a sizable number of CHF patients, which constitutes a practical disadvantage of this method. Therefore, VE-VCO2 slope calculated from the whole metabolic dataset seems to be more practical, additionally comprising information from the whole exercise test. Again, however, its potential weakness is a dependence on the patient’s motivation. Cessation of exercise testing prior to achieving a maximal effort may cause falsely low values of VE-VCO2 slope. This is of particular importance in patients with CHF who tend to avoid strenuous efforts and restrict themselves to submaximal exercise during daily activities.

To address the question of how to best apply assessment of ventilatory response to exercise in risk stratification of patients with CHF, we prospectively evaluated whether early response to exercise might provide prognostic information. We identified the first 3 min of exercise testing, as an arbitrarily defined period of early phase of exercise, which could be easily determined in the vast majority of CHF patients, and calculated VE-VCO2 slope from this pre-defined metabolic dataset.

In our study, of 216 unselected patients with CHF, high values of VE-VCO2-3 min predicted poor long-term outcome independently of the other clinical risk factors. The steepness of the VE-VCO2-3 min slope identified patients with more severe exercise intolerance, but did not correlate with systolic function of the heart and was not influenced by age or CHF aetiology in multivariable models. Our study confirms previous observations [23,24] that ventilation during early and whole exercise are significantly interrelated, but they can not be used interchangeably since the former is significantly lower than the latter.

Tabet et al. [23] calculated VE-VCO2 slopes from different datasets and concluded that VE-VCO2 slope derived from the first (linear) part of the ventilation-carbon dioxide production relationship significantly predicted the risk of a combined end-point of death or heart transplantation, but that it was less accurate than VE-VCO2 slope computed from all metabolic data. However, these authors [23] did not include CHF patients who were not able to complete maximal testing, which on the basis of our results may decrease the predictive power of excessive ventilation during the early phase of exercise. Additionally, the small number of deaths (11 vs. 89 in our study) and the retrospective study design, lessen its prognostic power. In contrast, Arena et al. [24] demonstrated that VE-VCO2 slope maintained prognostic value irrespective of the exercise time interval used for calculations. In another paper, the same authors [25] investigated the prognostic utility of VE-VCO2 slopes in 188 CHF patients, either by using all data from rest to peak exercise or by calculating it only from data obtained prior to ventilatory threshold. They concluded that both slope calculations were prognostically significant, but peak expression was superior [25]. This is similar to our results, which also confirm the good predictive power of VE-VCO2 slopes derived from the whole metabolic dataset. We therefore want to draw attention to the fact that in many CHF patients - when a maximal test is not feasible - a seemingly limited metabolic dataset from the first 3 min of exercise can actually provide very useful prognostic information. On the other hand, we would also like to state that our results do not diminish the prognostic value of maximal exercise testing in CHF patients, which - according to current recommendations - should be performed whenever possible [18].

There are some recent reports [12,13,18,26,27], that in CHF patients treated with β-blockers, traditionally applied cut-levels for peak VO2 derived from CPET may be of limited predictive value, particularly for listing for heart transplantation. Since β-blockers constitute a corner-stone of pharmacological therapy in CHF, this issue is clinically important. In our study, most of patients with CHF (82%) were treated with β-blockers while undergoing CPET, and both VE-VCO2 slopes maintained their independent predictive value in this group. Interestingly, in the multivariable models, reduced peak VO2 was no longer an independent predictor of poor survival either expressed as a continuous variable (as shown in Table 2) or dichotomised at the level of 10 or 14 mL/kg/min (data not shown) — both of which are considered as cut-off values for heart transplant selection. Our results indicate that indices of ventilatory response to exercise may become useful parameters for optimal prognostic evaluation in the current era of pharmacological therapy.

In order to place our results within the context of clinical applicability for heart transplantation, we also calculated Heart Failure Survival Score (HFSS) using a non-invasive model [28], which is a well-established and broadly validated approach for risk stratification and transplant selection among CHF patients. We subsequently compared HFSS with VE-VCO2 slopes. HFSS was available in 181 (84%) patients who did not differ clinically from the entire study population. It appeared that AUCs for 1-year and 3-year mortality were similar for both VE-VCO2 slopes and HFSS (p>0.5 in all comparisons), indicating a comparative predictive power at these time-points. Additionally, 1-year and 3-year survival of 72% and 37%, respectively among optimally managed CHF patients with elevated VE-VCO2-3 min slope clearly identifies those at very high risk who may well benefit from heart transplantation, in contrast to those with lower VE-VCO2-3 min slope and 1-year and 3-year mortality of 92% and 75% in whom transplantation may be deferred.


   5. Study limitations
Top
 Abstract
 1. Introduction
 2. Methods
 3. Results
 4. Discussion
 5. Study limitations
References
 
Data on the clinical usefulness of early exercise ventilatory response are already available [23-25]. To the best of our knowledge, however, none of these previous studies has applied an index of VE-VCO2 slope, calculated from only the first 3 min of exercise and prospectively demonstrated its prognostic value in a relatively large population of CHF patients, receiving an optimal therapy including beta-blockers. Due to its simplicity, this can be used in virtually all patients with CHF. Patients with poor exercise tolerance, who are not able to perform maximal CPET, seem to be most relevant for such a methodological approach. It needs to be stressed, however, that our findings need to be validated and confirmed in further studies before this novel parameter can gain more widespread application.

We were not able to address the intriguing question of why ventilatory response during the early phase of exercise was a powerful prognosticator. It is a possibility that the mechanisms responsible for augmented ventilatory response to exercise remain constant throughout the whole exercise, and therefore - similar to VE-VCO2-all - VE-VCO2-3 min also becomes a unique index describing disorders that are prognostically relevant in patients with CHF.

In summary, in patients with CHF an abnormally elevated ventilatory response in the early phase of exercise (assessed over the first 3 min) enables identification of patients at high risk of death. It may therefore also be possible to apply the assessment of VE-VCO2 slope for prognostic stratification also to patients with CHF who are not able to perform a maximal CPET, which further enhances the clinical utility of VE-VCO2 slope assessment.


   Acknowledgements
 
EAJ was supported by Training Fellowship from European Society of Cardiology.


   References
Top
 Abstract
 1. Introduction
 2. Methods
 3. Results
 4. Discussion
 5. Study limitations
 References
 

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