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European Journal of Heart Failure 2006 8(4):420-427; doi:10.1016/j.ejheart.2005.10.003
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© 2006 European Society of Cardiology

VE/VCO2 slope is associated with abnormal resting haemodynamics and is a predictor of long-term survival in chronic heart failure

Serafim N. Nanasa,*, John N. Nanasb, Dimitrios Ch. Sakellarioua, Stavros K. Dimopoulosa, Stavros G. Drakosb, Smaragdo G. Kapsimalakoua, Christina A. Mpatzioub, Ourania G. Papazachoua, Anargyros S. Dalianisb, Maria I. Anastasiou-Nanab and Charis Roussosa

a Pulmonary and Critical Care Medicine Department, Cardiopulmonary Exercise Testing And Rehabilitation Laboratory, "Evgenidio" Hospital, National and Kapodestrian University of Athens Greece
b Clinical Therapeutics Department, "Alexandra" Hospital, National and Kapodestrian University of Athens Greece

* Corresponding author. National and Kapodestrian University, Pulmonary and Critical Care Medicine Department, Evgenidio Hospital 20, Papadiamantopoulou str, Athens 115 28, Greece. Tel.: +30 210 7236743; fax: +30 210 7242785. E-mail address: snanas{at}cc.uoa.gr


   Abstract
Top
 Abstract
1. Introduction
 2. Results
 3. Discussion
 References
 
Background: Patients with chronic heart failure (CHF) present with exercise-induced hyperpnea, but its pathophysiological mechanism has not been thoroughly investigated. We aimed to determine the relationship between exercise-induced hyperpnea, resting haemodynamic measurements and the validity of ventilatory response (VE/VCO2 slope) as a mortality predictor in CHF patients.

Methods: Ninety-eight CHF patients (90M/8F) underwent a symptom-limited treadmill cardiopulmonary exercise test (CPET). Right heart catheterization and radionuclide ventriculography were performed within 72 h of CPET.

Results: Twenty-seven patients died from cardiac causes during 20±6 months follow-up. Non-survivors had a lower peak oxygen consumption (VO2p), (16.5±4.9 vs. 20.2±6.1, ml/kg/min, p=0.003), a steeper VE/VCO2 slope (34.8±8.3 vs. 28.9±4.8, p<0.001) and a higher pulmonary capillary wedge pressure (PCWP) (19.5±8.6 vs. 11.7±6.5 mm Hg, p=0.008) than survivors. By multivariate survival analysis, the VE/VCO2 slope as a continuous variable was an independent prognostic factor ({chi}2: 8.5, relative risk: 1.1, 95% CI: 1.03–1.18, p=0.004). Overall mortality was 52% in patients with VE/VCO2 slope ≥34 and 18% in those with VE/VCO2 slope <34 (log rank: 18.5, p<0.001). In a subgroup of patients (VO2p: 10–18 ml/kg/min), VE/VCO2 slope was a significant predictor of mortality (relative risk: 6.2, 95% CI: 1.7–22.2, p=0.002). Patients with high VE/VCO2 slope had higher resting PCWP (19.9±9.1 vs. 11.3±5.7 mmHg, p<0.001) and VE/VCO2 slope correlated significantly with PCWP (r: 0.57, p<0.001).

Conclusions: The VE/VCO2 slope, as an index of ventilatory response to exercise, improves the risk stratification of CHF patients. Interstitial pulmonary oedema may be a pathophysiological mechanism of inefficient ventilation during exercise in these patients.

Key Words: Ventilatory response • Heart failure • Cardiopulmonary exercise testing • Interstitial pulmonary oedema • Risk stratification

Received January 24, 2005; Revised July 1, 2005; Accepted October 3, 2005


   1. Introduction
Top
 Abstract
 1. Introduction
2. Results
 3. Discussion
 References
 
Exercise intolerance is one of the main characteristics of chronic heart failure (CHF) and these patients commonly suffer from hyperpnea at rest and during mild exercise. Hyperpnea during exercise is ascertained by increased ventilation (VE) in relation to CO2 output (VCO2), the VE/VCO2 slope, with normal O2 saturation [1]. Recent reports suggest that the VE/VCO2 slope may be a better risk stratifier than peak VO2 (VO2p) in patients with CHF [2-4].

The pathophysiological mechanisms behind this exercise inefficient ventilation are not fully understood. They may be related to the observation that patients with CHF have obstructive and restrictive respiratory abnormalities [5,6], decreased diffusing capacity [7], respiratory muscle weakness [8,9], abnormal cardio-respiratory reflex control [10], ventilation-perfusion mismatch [11] and alveolar oedema [12]. The relationship between the VE/VCO2 slope value and hemodynamic measurements has apparently not been quantified in patients with CHF in studies where the correlation between hemodynamic measurements and exercise capacity was determined [13,14].

The objectives of this study were to evaluate the prognostic power of the ventilatory response to exercise in a group of patients with CHF, and to examine the relationship between hemodynamic parameters at rest and the ventilatory response to exercise to clarify the pathophysiological basis of this increased ventilation.

1.1. Study population and methods
All stable, optimally treated CHF patients at our centre undergo CPET every 6 months to evaluate global functional capacity. This study included 98 patients, consecutively referred for CPET at the Heart Failure Clinic of our Institute. All patients were in a stable clinical condition and were receiving optimal medical treatment at the time of CPET. The anthropometric and clinical characteristics of all patients, measured at baseline are shown in Table 1. The diagnosis of CHF was based on a detailed clinical and laboratory evaluation, including blood chemistry, electrocardiogram (ECG), echocardiogram, right-heart catheterization, radionuclide ventriculography and coronary angiography in all patients and, when clinically indicated, myocardial biopsy. Sixty-two patients (63%) had dilated cardiomyopathy, 34 patients (35%) had ischaemic cardiomyopathy and 2 (2%) had valvular disease. The mean duration of heart failure from the time of first diagnosis was 18±6 months. Three patients had a history of type II diabetes mellitus, and were receiving optimal treatment with oral anti-diabetic agents. Two patients were receiving L-thyroxine for hypothyroidism due to amiodarone intake, but had normal fT3, fT4, and TSH at the time of CPET. No other concomitant diseases were observed. Angiotensin-converting enzyme inhibitors were administered in 97% of patients, diuretics in 85%, digitalis in 82%, β-adrenergic blockers in 27% and nitrates in 44% of patients. Patients with myocardial infarction within the previous 2 months, or suffering from neuromuscular, orthopaedic or other non-cardiac, exercise limiting, disorders were excluded. Other exclusion criteria were angina pectoris, light-headedness, major arrhythmias and ECG findings consistent with ischaemia during exercise testing. Informed consent was formally obtained from each participant. The study protocol was approved by the Human Study Committee of our institution.


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  		Table 1 Baseline characteristics of the overall patient population and of the survivors and non-survivors

 
1.2. Haemodynamic measurements
Right heart catheterization was performed within 72 h of CPET. Left ventricular ejection fraction (LVEF) was measured by radionuclide ventriculography. The cardiac index (CI) was also measured just prior to CPET by the non-invasive single breath acetylene technique [15].

1.3. Cardiopulmonary exercise testing
All patients performed a symptom-limited, incremental CPET on a treadmill (model 2000, Marquette Electronics, Milwaukee, WI). A modified Bruce or modified Naughton ramp exercise protocol was chosen, according to the New York Heart Association (NYHA) functional class, to attain a target test duration of 8-12 min.

Gas exchange was measured with the patient breathing through a low resistance valve with the nose clamped with a model Vmax 229 (Sensormedics, Yorba Linda, CA) calibrated with a known gas mixture before each test. The oxygen uptake (VO2), carbon dioxide output (VCO2) and minute ventilation (VE) were measured breath-by-breath with the on-line system.

All variables were recorded for 2 min at rest before exercise, throughout exercise and for the first 5 min of recovery. Baseline VO2 was taken as the average of measurements for 2 min before the onset of exercise with the patient standing. Ventilation frequency was recorded throughout the exercise test and during recovery. Peripheral O2 saturation was monitored continuously by pulse oximetry. Heart rate (HR) and rhythm were monitored by a MAX 1, 12-lead ECG system (Marquette Electronics, General Electric Healthcare) and blood pressure was measured every 2 min with a mercury sphygmomanometer. All patients were verbally encouraged to exercise to exhaustion, as defined by intolerable leg fatigue or dyspnea.

1.4. Cardiopulmonary variables
The gas exchange measurements from the CPET were used to calculate anaerobic threshold (AT), O2 pulse (VO2/HR) and the VE/VCO2 slope. The peak values of gas exchange (VO2p, VCO2p and VEp) were calculated as the average of the measurements made during the 20 s period before the end of exercise. The AT was determined using the V-slope technique [16]. The results were confirmed graphically, from a plot of ventilatory equivalent for oxygen (VE/VO2) and carbon dioxide (VE/VCO2) against time. The ventilatory response to exercise was calculated as the slope by linear regression of VE vs. VCO2 from the beginning of exercise to AT, where the relationship is linear [17,18]. The breathing reserve (BR) at maximal exercise was calculated as: (MVV–VEp)/MVV, where MVV was the maximal voluntary ventilation obtained from 40x forced expired volume in 1 s (FEV1).

Patients were retrospectively classified into 4 classes according to the Weber classification. Class A included patients with VO2p>20 ml/kg/min, class B: 16-20, class C: 10-15 and class D: <10 ml/kg/min [19].

1.5. Patient follow up
The patients were regularly seen by the study investigators in a dedicated outpatient CHF clinic. The outcome data were obtained from the hospital records or from telephone interviews with the patient or the patient's family. The median follow up period was 20±6 months.

1.6. Statistical analyses
Results are presented as means±standard deviation (SD) unless otherwise specified. Pearson's correlation coefficient was used to evaluate the bivariate relationships. Analysis of variance with the Bonferroni correction of the post hoc test of significance was used for the statistical evaluation of the differences between Weber groups. The chi-squared test was used for evaluation of categorized variables. The prognostic value of the variables was assessed using a univariate Cox hazard regression model. To evaluate the independent prognostic value of the VE/VCO2 slope and of the other clinical variables statistically significant by univariate analysis, multivariate Cox regression analyses were performed. Receiver operator characteristic (ROC) analysis was carried out to determine the cut-off values of the parameters used in the Cox regression analysis. Survival curves were constructed by the Kaplan Meier method and were compared with the log-rank test. The lowest level for statistical significance was chosen as p<0.05.


   2. Results
Top
 Abstract
 1. Introduction
 2. Results
3. Discussion
 References
 
The mean age of the overall population was 51±12 years and the survivors were slightly, though not significantly older than non-survivors (Table 1). LVEF averaged 31%, FEV1 was 87% of predicted and forced vital capacity (FVC) was 93% of predicted. The carbon monoxide diffusing capacity (DLCO) was 77% of predicted. The mean cardiac index (CI) was 2.4 l/min/m2 and the mean pulmonary capillary wedge pressure (PCWP) was 13.8 mmHg. Survivors had a significantly higher mean LVEF (Table 2). There were no significant differences in pulmonary function measurements between the two groups, although the mean DLCO was lower in the non-survivors. The PCWP and the pulmonary artery pressure (PAP) were significantly higher in non-survivors than survivors, while CI was similar in both groups (Table 2).


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  		Table 2 Initial resting pulmonary function and hemodynamic measurements in the overall patient population and in the survivors and non-survivors

 
Table 3 indicates that non-survivors had a lower VO2p, AT and peak HR than survivors, but a higher VE/VCO2 slope value. There were no significant differences in VEp, VO2/HR or BR between the two groups.


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  		Table 3 Initial cardiopulmonary exercise measurements in the overall patient population and in survivors and non-survivors

 
When the patients hemodynamic measurements were stratified according to Weber class, there were significant differences in PCWP and VO2p between class A and B and in VE/VCO2 slope (Fig. 1) and VO2p between class B and C/D. Fig. 2 illustrates the highly significant correlations (p<0.001) between the ventilatory response to exercise, represented by the VE/VCO2 slope, and the resting PCWP and VO2p (r-values=0.57 and –0.56, respectively). When patients with VE/VCO2 slope>45 or resting PCWP >30 mm Hg (outliers) were excluded, the correlations between the VE/VCO2 slope, and the resting PCWP and VO2p remained significant at the same level (p<0.001) with r-values=0.48 and 0.61, respectively. Table 4 shows that patients with VE/VCO2≥34 had a significantly reduced LVEF, VO2p, peak HR and VO2/HR, FEV1 and DLCO, and a higher PCWP.


Figure 1
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  		Fig. 1 The mean (±2SEM) VE/VCO2 slope in 3 patient groups stratified according to the Weber classification (Class A: VO2p>20 ml/kg/min, class B: 16-20, class C and D: ≤16 ml/kg/min). p<0.01 between B and C/D.

 


Figure 2
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  		Fig. 2 Scattergrams of VE/VCO2 slope vs. pulmonary capillary wedge pressure at rest and VE/VCO2 slope vs. VO2p.

 


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  		Table 4 Initial haemodynamic and exercise data according to VE/VCO2 slope <34 vs. ≥34

 
2.1. Long-term outcomes
None of the patients was lost to follow up. During the follow-up period 26 men and 1 woman died of cardiac causes, 11 suddenly and 16 from end-stage CHF. There were no additional non-cardiac deaths during the follow up period. In order to examine the prognostic significance of the variables, we assessed two models of Cox regression analysis, testing variables either as continuous or categorical. Results of the Cox regression univariate and multivariate survival analysis of continuous variables are presented in Table 5. Cut-off values were determined by ROC curve analysis. The cut-off for VE/VCO2 slope was 34 (61% sensitivity, 83% specificity, AUC=0.740±0.06, p<0.001), for LVEF was 26 (73% sensitivity, 67% specificity, AUC=0.760±0.06, p<0.001), for PCWP was 12 (70% sensitivity, 65% specificity, AUC=0.770±0.05, p<0.001) and for VO2 peak was 15 (81% sensitivity, 50% specificity, AUC=0.680±0.06, p<0.001).


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  		Table 5 Survival analysis of continuous variables

 
Table 6 shows the Cox regression univariate and multivariate survival analysis of categorical variables. In the univariate Cox proportional hazards model analysis, a high PCWP, steep VE/VCO2 slope, low VO2p, low LVEF, and NYHA functional classes III and IV were significant predictors of death (Tables 5 and 6). A VE/VCO2 slope ≥34 was the strongest predictor, followed by LVEF ≤26%. This was confirmed by the stepwise multivariate Cox proportional hazard analysis, where these two variables were considered independent predictors. The results from the Kaplan-Meier 2-year survival analysis (Fig. 3) revealed an overall mortality of 52% when the VE/VCO2 slope was ≥34, versus 18% when the slope was <34 (log rank {chi}2: 18.5, p<0.001).


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  		Table 6 Survival analysis of categorical variables

 


Figure 3
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  		Fig. 3 Kaplan-Meier survival curves according to VE/VCO2 slope (cut-off point=34).

 
In a subgroup analysis including only patients with intermediate exercise tolerance (VO2p between 10 and 18 ml/kg/min, n=45), VE/VCO2 slope ≥34 was a significant univariate predictor of mortality (Relative risk: 6.2, 95% CI: 1.7-22.2, p=0.002). Patients with VE/VCO2 slope ≥34 had a 62% mortality rate versus 13% for patients with VE/VCO2 slope <34 (log rank {chi}2: 12.2, p<0.001, Fig. 4).


Figure 4
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  		Fig. 4 Kaplan-Meier survival curves according to VE/VCO2 slope (cut-off point=34) in the subgroup of patients with VO2p between 10 and 18 ml/kg/min.

 

   3. Discussion
Top
 Abstract
 1. Introduction
 2. Results
 3. Discussion
References
 
To our knowledge, this is the first report of a direct relationship between VE/VCO2 slope and resting PCWP. This study demonstrates that an increased ventilatory response to exercise is associated with a lower survival in patients with stable CHF even in those with intermediate exercise capacity. The correlation of the VE/VCO2 slope value with resting PCWP may be an indication that, during exercise, further increases in PCWP above the resting level may result in subclinical alveolar and interstitial oedema leading to exercise limitation.

CPET is a widely accepted objective method to grade functional status [19,20], and VO2p is a common index of CPET, which is useful in predicting survival in patients with CHF [21]. For several years VO2p was the "gold standard" and remains widely used to risk stratify this type of patients [22]. However, the limitations of VO2p have prompted the search for other indices of CPET that can serve as alternative prognostic factors. The main disadvantage of VO2p is the need for maximal exercise, which may be difficult to achieve, particularly in CHF patients, whose daily activity levels are far below the effort required by the test. In addition, VO2p may be underestimated because of low patient motivation or because of premature termination of the test by the physician. In addition, the VO2p value in ml/kg/min, which is a better index of exercise capacity than when expressed in l/min [23], has the disadvantage of underestimating the exercise tolerance in obese patients, and overestimating it in cachectics [24,25].

The prognostic role of VO2p is clear from these observations, though it remains difficult to identify a distinct cut-off value. Although VO2p values <14 ml/kg/min are considered a key criterion in the selection of heart transplant candidates [26], there is no distinct threshold in the 10-18 ml/kg/min range [27] which corresponds to an intermediate exercise capacity, the level reached by the majority of patients with CHF. Thus, supplementary indices are needed to sharpen the risk stratification. After the ventilatory response to exercise was confirmed as a significant prognostic marker [28], the VE/VCO2 slope seemed to be a strong candidate as a risk predictor in CHF [29-31] even in those patients with intermediate exercise intolerance [3]. Although excess ventilation during exercise in CHF patients is well known [32], its mechanism is not clear. One possible mechanism may be the restrictive pattern of pulmonary dysfunction that is observed in patients with CHF [33], an impairment mainly attributed to subclinical alveolar and interstitial pulmonary oedema [34]. The contribution of excessive lung water to hyperpnea is supported by studies which have observed a deterioration in lung function and exercise tolerance after rapid infusion of saline solution [35]. The pathophysiological mechanism leading to water accumulation in the lung is an increased pulmonary venous pressure, manifest as a high resting PCWP.

In our study, resting PCWP correlated with VO2p and the VE/VCO2 slope. The correlation of VO2p and PCWP is concordant with other studies [12,13]. The correlation of VE/VCO2 with resting PCWP has apparently not been previously reported. This finding supports the hypothesis that interstitial pulmonary oedema may be one of the main mechanisms behind the development of exercise hyperpnea in CHF patients, because the increase in PCWP above resting levels may cause interstitial and alveolar oedema and curtail the exercise.

A significant finding in our study was the confirmation that VE/VCO2 slope is a strong, independent indicator of high risk of death in patients suffering from CHF. This observation is in agreement with other studies which have examined the prognostic significance of the VE/VCO2 slope (2-4, 29). Specifically, a VE/VCO2 slope value ≥34 identified patients who had a 3-fold increase in risk of death over a 2-year period. In addition, the VE/VCO2 slope was increased in parallel with the severity of CHF, as well as with the mean resting PCWP, suggesting that interstitial pulmonary oedema may increase the VE/VCO2 slope in heart failure. The ability to derive the VE/VCO2 slope during safe and more comfortable submaximal exercise is a major advantage of this index.

As observed in previous studies, the resting CI did not significantly differ among Weber groups [29,36]. However, in this population there was wide variability in PCWP, despite our selection of patients in a stable clinical condition. This is concordant with observations made in other studies in similar patient populations [27,36,37].

Our study population consisted of a relatively small number of patients and only a few were women, limiting our findings mainly to the male population. The mean age of patients was relatively low compared with other studies, probably because of the high proportion of patients with dilated cardiomyopathy in our study group. Only a few patients were receiving treatment with β-adrenergic blockers. The hemodynamic measurements were performed only at rest and not during exercise. Evaluation of both hemodynamic measurements during exercise and ventilatory response to exercise under submaximal or maximal exercise testing are needed in order to determine the pathophysiological mechanism of exercise induced hyperpnea in CHF patients.

In conclusion, the results of this study strongly support the value of the VE/VCO2 slope in predicting the long-term outcomes of patients with mild to moderate CHF. Furthermore, the correlation between VE/VCO2 slope and PCWP suggests that interstitial pulmonary oedema is a major pathophysiological mechanism of hyperpnea in CHF.


   Acknowledgement
 
The authors would like to thank Sotiris Gyftopoulos for his technical support. This study was funded partly by a grant from the special account for research grants of the National and Kapodestrian University of Athens, Greece and by ‘Thorax Foundation’.


   References
Top
 Abstract
 1. Introduction
 2. Results
 3. Discussion
 References
 

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