Exercise ventilation inefficiency and cardiovascular mortality in heart failure: the critical independent prognostic value of the arterial CO2 partial pressure

Marco Guazzi1,*, Giuseppe Reina2, Gabriele Tumminello1 and Maurizio D. Guazzi3

1Cardiopulmonary Laboratory, Cardiology Division, University of Milano, San Paolo Hospital, Via A. di Rudinì, 8, 20142, Milano, Italy
2Institute of Statistics and Biometry, University of Milano, Italy
3Institute of Cardiology, University of Milano, Italy

Received 3 March 2004; revised 16 October 2004; accepted 28 October 2004; online publish-ahead-of-print 14 December 2004.

* Corresponding author. Tel/fax: +39 02 50323144. E-mail address: marco.guazzi{at}unimi.it

See page 426 for the editorial comment on this article (doi:10.1093/eurheartj/ehi141)


    Abstract
 Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 Acknowledgements
 References
 
Aims In chronic heart failure (CHF) patients, the ventilation (VE) needed to eliminate metabolically produced CO2 during exercise (i.e. the VE/VCO2 slope) is a strong prognosticator. VE/VCO2 slope determinants are the dead space–tidal volume (VD/VT) ratio and the arterial CO2 partial pressure (PaCO2). We aimed at defining the respective prognostic role of these two variables.

Methods and results One hundred and twenty-eight stable CHF patients (average left ventricular ejection fraction 34±10%) underwent cardiopulmonary exercise testing and blood gas analysis. The prognostic relevance of the VE/VCO2 slope, VD/VT, and PaCO2 at peak exercise was evaluated by the Kaplan–Meier approach with log-rank testing and by multivariate Cox regression analysis. During a mean period of 31.3±20 months, 24 patients died from cardiac causes. In univariate analysis, predictors of death included the use of anti-aldosterone drugs, low peak VO2, peak VE/VO2, peak PaCO2 and high VE/VCO2 slope, and peak VD/VT. Multivariate analysis identified a low peak PaCO2 (<35 mmHg) as the strongest independent prognostic indicator [hazard ratio 4.65, 95% confidence interval (CI) (1.695–12.751), P=0.003] that primarily accounts for the VE/VCO2 slope prognostic power.

Conclusion These findings imply that regulatory mechanisms involved in the tight control of ventilatory command and blood gas tension, rather than lung function abnormalities, play a critical pathophysiological role in the exercise ventilation inefficiency of CHF patients.

Key Words: Heart failure • PaCO2 • Prognosis • Ventilation


    Introduction
 Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 Acknowledgements
 References
 
Identification of chronic heart failure (CHF) patients at high risk for early death remains a basic challenge. This challenge has two major complementary approaches: (i) the search for new and more sensitive prognostic indicators, and (ii) the refinement of already known prognostic markers through a more in-depth study and characterization of their determinants.

In recent years, there has been growing and convincing evidence that inefficient ventilation during physical performance is a very sensitive indicator of poor outcome in CHF patients.17 Interestingly, a number of reports suggest that the excessive amount of ventilation (VE) needed to eliminate metabolically produced CO2 (i.e. the VE/VCO2 slope) is a prognostic indicator even more powerful than oxygen consumption measured at peak exercise (peak VO2).2,3,7

The VE/VCO2 slope determinants are the physiological dead space–tidal volume (VD/VT) ratio and the arterial CO2 partial pressure (PaCO2). Studies investigating the pathophysiological basis for an increased VE/VCO2 slope in CHF have reported conflicting results. Some investigators have stressed the importance of an increased VD/VT secondary to ventilation/perfusion mismatching, especially in patients with moderate to severe heart failure with a preserved or minimally impaired neural control of ventilation.8,9 Others have provided evidence that overactive chemoreflex and ergoreflex responses drive the ventilatory pattern during exercise.1,4 Information regarding PaCO2 changes during exercise is limited, and despite balanced evidence in favour for5,1013 and against8,9,14 a significant decrease in PaCO2 at peak exercise, the assumption is generally accepted that ventilation inefficiency occurs in the absence of significant changes in CO2 tension.15

A salient point that has not been addressed before and that represents the primary objective of this study is the exploration of the relative contribution of VD/VT and PaCO2 to the prognostic information provided by the VE/VCO2 slope. This may represent a step forward to a more precise identification of the mechanisms underlying an excessive exercise ventilation, and possibly toward more appropriate therapeutic interventions.


    Methods
 Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 Acknowledgements
 References
 
Study population
The study comprised patients with CHF due to either ischaemic or idiopathic dilated cardiomyopathy, who were referred to the Cardiopulmonary Laboratory at San Paolo Hospital or at the Institute of Cardiology, University of Milan, for CHF evaluation. Assessment included echocardiography, lung function, and symptom-limited cardiopulmonary exercise testing.

We restricted the analysis to patients who had been in a stable clinical condition for at least 4 months before evaluation, and under a stable therapeutic regimen prescribed by the referring physician, which was optimized during the hospital stay. We excluded patients who presented with anginal symptoms, had undergone a coronary artery bypass procedure in the previous 6 months, had primary pulmonary disorders and/or a forced expiratory volume in 1 s (FEV1)/forced vital capacity (FVC) ratio<70% of the predicted normal value, had primary valvular heart disease, or had a history of smoking more than 10 cigarettes per day during one of the past 5 years. The primary endpoint was death for cardiac reasons.

To assess vital status we resorted to the combined use of administrative and clinical databases; records during re-admission and outpatient records during follow-up (most patients attended our outpatient clinic) were reviewed. When vital status could not be determined by these methods, patients or their families were interviewed by telephone.

Echocardiography
Two-dimensional and Doppler echocardiography was performed by standard methods. Left ventricular end-systolic and end-diastolic chamber dimensions and volumes were quantified by standard techniques, using the area–length method to measure ejection fraction.

Pulmonary function tests
Spirometry was performed with equipment (Vmax Spectra, Sensomedics, Yorba Linda, CA, USA.) that met the American Thoracic Society performance criteria.16 To adjust for height, age, and sex, published prediction equations for FEV1 and FVC17 were used. Lung diffusion capacity for carbon monoxide (DLCO) was determined twice with washout intervals of at least 4 min (the average was taken as the final result) with a standard single breath technique.

Cardiopulmonary exercise testing
Patients underwent symptom-limited cardiopulmonary exercise testing with a respiratory gas exchange measurement. A personalized ramp protocol was used.18 A 12-lead electrocardiogram, heart rate, and blood pressure were obtained at rest and at each minute during exertion. For breath-by-breath gas exchange measurements, a Sensor Medics metabolic cart (Vmax Spectra, Sensomedics, Yorba Linda, CA, USA) was utilized. Minute ventilation [VE, BTPS (body temperature, atmospheric pressure saturated with water vapour)], O2 uptake [VO2, STPD (standard temperature and pressure dry)], CO2 output (VCO2, STPD), and other exercise variables were computer-calculated breath-by-breath, interpolated second-by-second, and averaged at 10 s intervals.

The VD/VT ratio was derived from PaCO2, according to the following formula:19

where PECO2 is the mean expiratory pressure of CO2 and VDapp is the dead space of the breathing apparatus.

The VE/VCO2 slope was measured by linear regression, excluding the non-linear part of the data after the onset of ventilatory compensation for metabolic acidosis. Peak VO2 was defined as the highest VO2 observed during the exercise test. Age-, gender-, and weight-adjusted predicted VO2 values were also determined by using the regression equations of Wasserman et al.18 Anaerobic threshold (AT) was determined using the V-slope method.20

Blood gases (PaO2, PaCO2) and pH were measured at rest and just before peak exercise, on arterialized capillary blood samples from the hyperaemic earlobe.

Statistical methods
The prognostic value of VE/VCO2 slope, peak PaCO2 and peak VD/VT, and other clinical variables (age, ejection fraction, drug therapy, peak VO2, and peak VT) were analysed by means of the Kaplan–Meier approach with log-rank testing and by univariate Cox regression analysis. Considering that, for the assessment of ventilatory efficiency, some authors have simply used the VE/VCO2 ratio at peak exercise2 or the VE/VCO2 ratio at AT,21,22 these two variables were also included in the univarate approach.

The cut-off values for high VE/VCO2 slope, peak VE/VCO2 ratio, VE/VCO2 ratio at AT, age, VD/VT, and those for low EF, peak VO2 and peak VT were based on median values derived from the heart failure cohort. Selection of median values as cut-off was motivated by the lack of an established clinical predictive cut-off for exercise peak PaCO2 and peak VD/VT (this is the first study investigating the prognostic power of these variables).

Multivariate Cox regression models together with Shoenfeld residual analysis was used to assess the prognostic relevance of the VE/VCO2 slope, of its determinants PaCO2 and VD/VT, and of other possible predictors. Model construction was based on a backward approach with initial selection of covariates on the basis of results of univariate analyses.

In order to evaluate the independent prognostic value of VE/VCO2 slope, of peak PaCO2 and peak VD/VT, two multivariate Cox regression analyses were carried out. Specifically, the first model was performed in order to confirm the VE/VCO2 slope prognostic power. As VE/VCO2 is a function of VD/VT and PaCO2, the second analysis was performed by excluding VE/VCO2 and including its two determinants PaCO2 and VD/VT. Both models were adjusted for the clinical variables statistically significant at the univariate analysis.

Four Kaplan–Meier curves for 6.5 year survival were plotted: one, for the patients with normal and for those with high VE/VCO2 slope (Figure 1); two, using as the discriminatory parameter peak PaCO2 (Figure 2) and peak VD/VT (Figure 3), respectively; one relating survival to the combination of both peak PaCO2 and peak VD/VT (Figure 4).



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Figure 1 Kaplan–Meier plot relating survival to VE/VCO2 slope.

 


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Figure 2 Kaplan–Meier plot relating survival to peak exercise PaCO2.

 


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Figure 3 Kaplan–Meier plot relating survival to peak exercise VD/VT.

 


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Figure 4 Kaplan–Meier plot relating survival to combination of peak PaCO2 and peak VD/VT.

 
The Student's t-test for unpaired values was used to compare the means of groups for quantitative variables. Data are presented as means ± SD. The level of statistical significance was set at two-tailed P value < 0.05.

Pearson correlation analyses were used to assess the association between VE/VCO2 slope and peak VD/VT and peak PaCO2.

All the analyses were performed with the statistical package STATA 7.0 (New Station, TX, USA).


    Results
 Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 Acknowledgements
 References
 
Follow-up on survival
One hundred and twenty-eight consecutive patients who met the entry criteria were selected for follow-up. No patients were lost to follow-up. The mean duration of follow-up was 31.3±20 months (median 25 months). During this period there were 24 deaths for cardiac reasons. Three patients with an implantable cardioverter defibrillator (ICD) had ventricular fibrillation successfully terminated by the ICD. None of the patients underwent heart transplantation.

Baseline characteristics
Table 1 reports the clinical characteristics of the patient population. Mean age of participants was 60±9 years and left ventricular ejection fraction averaged 34±10%. Ischaemic cardiomyopathy was the predominant (56%) cause of CHF. All patients had symptomatic heart failure with a mean New York Heart Association (NYHA) class of 2.0±0.8. Current medical therapy included ACE-inhibitors (76%), digoxin (34%), diuretics (72%) ß-blockers (30%), amiodarone (32%), and aldosterone antagonists (33%).


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Table 1 Clinical characteristics of the study population
 
Lung function test and blood gases
The mean FEV1, FVC, and DLco were 85, 75, and 76% of predicted normal value, respectively. When patients were grouped according to the median value of peak VD/VT (0.22) and of peak PaCO2 (35 mmHg), significant differences in FEV1, FVC, and DLco were detected between the two groups (P<0.05; Tables 2 and 3). In the whole population, average values of arterial blood gases both at rest and at peak exercise were within normal limits. However, when patients were grouped according to the median peak VD/VT and peak PaCO2 cut-off, there were significant differences in PaCO2 and pH at peak exercise (Tables 2 and 3).


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Table 2 Pulmonary function, cardiopulmonary exercise testing data, and arterial blood gases in the study population according to exercise peak VD/VT median value
 

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Table 3 Pulmonary function, cardiopulmonary exercise testing data, and arterial blood gases in the study population according to exercise peak PaCO2 median value
 
Cardiopulmonary exercise testing
As shown in Table 1, patients presented with a moderate exercise limitation (average peak VO2: 16.5±4.4 mL · min–1 · kg–1 corresponding to 60% of maximum predicted). Again, when patients were grouped according to peak VD/VT and peak PaCO2 median value, those with the lower VD/VT and higher PaCO2 presented with significantly higher peak VO2, VO2 at AT O2 pulse and peak tidal volume, and lower peak VD/VT, peak VE/VO2, VE/VCO2 AT, peak VE/VCO2, and VE/VCO2 slope (Tables 2 and 3).

Univariate analysis
Results of the univariate analysis of factors known to influence prognosis are reported in Table 4. VE/VCO2 slope and peak exercise PaCO2 emerged as stronger predictors. Among the therapeutic drug regimen, aldosterone antagonists were found to be the only significant predictors of survival.


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Table 4 Univariate predictors of death (n=24)
 
Multivariate analyses
Tables 5 and 6 report the results of the Cox regression analysis and Shoenfeld test of proportional hazard assumption. Two models have been used: the first model (Table 5) included ejection fraction, use of aldosterone antagonists, peak VE/VO2, and peak VO2; an abnormally steep VE/VCO2 slope was found to be the only predictor of death [HR 5.84, CI (1.692–20.197), P=0.005]. In the second model (Table 6), after adjusting for ejection fraction, aldosterone antagonist therapy, peak VE/VO2, peak VO2, peak PaCO2, and peak VD/VT, the strongest independent predictors of death were peak PaCO2 [HR 4.65, CI (1.695–12.751), P=0.003], peak VD/VT [HR 2.51, CI (1.067–5.931), P=0.035] and ejection fraction [HR 2.96, CI (0.151–7.646), P=0.024].


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Table 5 Multivariate predictors of death: results of Cox regression analysis (model 1) and Shoenfeld test of proportional hazard assumption after adjusting for clinical variables significant in the univariate approach
 

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Table 6 Multivariate predictors of death: results of Cox regression analysis (model 2) and Shoenfeld test of proportional hazard assumption after adjusting for clinical variables significant in the univariate approach
 
Survival analysis
The Kaplan–Meier 6.5-year survival approach evidenced a survival of 38% for patients with a VE/VCO2 slope median value ≥32.6 compared with 94% survival for those with a median value <32.6 (Figure 1). When analyses were performed according to the VE/VCO2 slope determinants, PaCO2 and VD/VT at peak exercise, the survival was 40% (Figure 2) and 46% (Figure 3), respectively. Remarkably, survival of patients with both a low peak exercise PaCO2 and a high peak VD/VT was as low as 25% (Figure 4).

Correlation analyses
As shown in Figure 5A, a strong inverse correlation was found between VE/VCO2 slope and peak PaCO2 (r=–0.69; P=0.0001); 85% of non-survivors were distributed in the area with a lower peak PaCO2 (<35 mmHg) and a higher VE/VCO2 slope (≥32.4). A weaker positive correlation was found between VE/VCO2 slope and peak VD/VT (r=0.37; P=0.001) (Figure 5B); 58% of non-survivors were distributed in the area with a higher peak VD/VT (≥0.22) and a higher VE/VCO2 slope (≥32.4) (Figure 5B). No correlation was found between peak PaCO2 and peak VD/VT (r=–0.152, P=0.086).



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Figure 5 Correlation between VE/VCO2 slope and peak PaCO2 (A), and peak VD/VT (B). Survivors (open circles); non-survivors (filled circles).

 

    Discussion
 Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 Acknowledgements
 References
 
There are two novel findings in the present study. First, a low peak exercise PaCO2 and an elevated peak VD/VT are strong independent predictors of mortality in stable CHF patients. Second, a low peak exercise PaCO2 is the more significant determinant of the prognostic value of a steep VE/VCO2 slope.

A consistent association between increased levels of ventilation and cardiovascular mortality has been documented in several studies across different population groups.17 Mostly, it has been shown that an abnormally high VE/VCO2 slope predicts an increased risk of death among CHF patients to an even greater degree than peak VO2.2,3,6,7 The relationship between a high VE/VCO2 slope and survival has been further strengthened by the recent landmark finding that even in patients with normal exercise performance and peak VO2 (≥18 mL · min–1 · kg–1), an abnormal exercise ventilation significantly discriminates survival.4 In addition, the VE/VCO2 slope is independent of motivation, showing minimal variability at 30, 60, and 100% of exercise capacity,23 and retains a high prognostic power when measured at submaximal constant workloads.24 The current study confirms that VE/VCO2 slope is a stronger predictor than peak VO2, and expands, in some important respects, information provided by previous reports. In fact, it is the only study aimed at analysing the prognostic significance of the physiological determinants of ventilation in CHF patients. Furthermore, when peak PaCO2, peak VD/VT, and peak VO2 were considered together, the ventilatory variables emerged as stronger and independent predictors of death, indicating that they are not simply a function of lower workload achieved.

Increased VE/VCO2 slope: pathophysiological bases
The precise pathophysiological substrates that predispose to, and sustain an excessive ventilation in, CHF patients remain controversial.15 Mathematically, the VE/VCO2 slope is determined by three factors: the rate of CO2 production, the physiological VD/VT, and the PaCO2. Therefore, for a given VCO2, an increased VE/VCO2 slope has multiple possible substrates: (i) an augmented central and/or peripheral command to ventilation, which drives the PaCO2 below the physiological range; (ii) a large dead space which requires an increase in ventilation to maintain a normal PaCO2; and (iii) an early occurrence of metabolic acidosis which demands ventilatory compensation. Initial studies by Sullivan et al.8 reported that an increased VD/VT, in the face of a preserved neural control of ventilation and normal blood gases, is responsible for the augmented VE/VCO2 slope. In 130 patients with different CHF severity, Wasserman et al.9 reproduced the same findings, identifying structural changes intrinsic to the lung (restrictive lung changes) and reduced lung perfusion, as responsible for the occurrence of a high VD/VT and consequent ventilation/perfusion mismatch. In these reports, changes in pH and PaCO2 between rest and peak exercise were minimal, suggesting no differences in the PaCO2 set point compared with healthy subjects. In contrast, other studies in CHF patients have reported a significant reduction in PaCO2 at peak exercise.5,10,11,13 Notably, in a population similar to ours, Hachamovitch et al.12 reported a significant reduction in PaCO2 even during a submaximal constant workload at 50 W. The link, however, between an increased VD/VT and a reduced PaCO2 remains elusive. In the present report, both an increased VD/VT and a reduced peak exercise PaCO2 were documented and for both of them a significant correlation with VE/VCO2 slope was found.

Chua et al.25 observed that an augmented ventilatory response to exercise in CHF is significantly correlated with an impaired central and peripheral control of ventilation. The same group of investigators has expanded these observations providing impressive evidence of an abnormal cardiorespiratory reflex control, related to both activation of chemoreceptors and fibres originating from the working muscle (i.e. ergoreflex stimuli),26,27 and an abnormal autonomic baroreflex control of circulation.28

PaCO2 vs. VD/VT at peak exercise: prognostic insights
It is remarkable that in CHF the only link between augmented exercise ventilation and prognosis is provided by studies assessing the ergoreflex and chemoreflex activation.1,4,27 In these reports, however, neither were blood gas measurements obtained, nor peak exercise VD/VT calculated, and their possible relationship with survival has remained undefined. Our study sheds light on the prognostic power of these variables, and multivariate Cox regression analysis has identified both arterial PaCO2 and VD/VT at peak exercise as survival predictors. PaCO2 at peak exercise, however, retained a greater prognostic significance than peak VD/VT and was associated with a higher hazard ratio (4.65 vs. 2.51). The decrease in peak exercise PaCO2 may be both the trigger (development of metabolic acidosis due to inadequate cardiac output), or the consequence (excessive ventilatory response to increasing CO2 output) of the increased ventilatory response to exercise. It is very likely that these two mechanisms were additive in influencing PaCO2 changes. Although we cannot rule out an excessive ventilatory drive secondary to chemoreflex and/or ergoreflex activation, it is noteworthy that patients who developed hypocapnia and metabolic acidosis were exposed to a higher risk of death. Whatever the underlying mechanisms, our data are in favour of a peripheral substrate, rather than of a pulmonary ventilation/perfusion mismatching as a determinant of the prognostic significance of the ventilatory response to exercise in CHF.

Study limitations
The number of patients in this study was relatively small. It should be considered, however, that the average follow-up was quite long. The analysis included only CHF patients who were in stable clinical conditions and were able to perform a symptom-limited exercise test. However, this was an unselected ambulatory CHF population. The average peak VO2 of 16.5±4.4 mL · min–1 · kg–1 reflected a mild to moderate exercise limitation, and results might not apply to advanced CHF. Nevertheless, because patients with advanced CHF and severe exercise limitation may exhibit hypocapnia and metabolic acidosis from the very early exercise stages, it is conceivable that an abnormally low arterial PaCO2 at peak exercise may bear an even more significant prognostic power in this subset of patients.

Conclusions
An excessively low peak exercise PaCO2 and an abnormally high peak VD/VT (the two determinants of ventilation for a given CO2) are both strong predictors of death among stable CHF patients and their prognostic value is independent of peak VO2.

PaCO2 emerges as the more significant determinant of the VE/VCO2 slope, suggesting that regulatory mechanisms involved in the tight control of ventilatory command and blood gas tension, rather than lung function abnormalities, play a critical pathophysiological role in the exercise ventilation inefficiency of CHF patients.


    Acknowledgements
 Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 Acknowledgements
 References
 
This study was supported, in part, by a grant from the Luigi Berlusconi Foundation.


    References
 Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 Acknowledgements
 References
 

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