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European Journal of Heart Failure 2005 7(6):1017-1022; doi:10.1016/j.ejheart.2004.10.009
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© 2005 European Society of Cardiology

Alveolar-capillary membrane conductance is the best pulmonary function correlate of exercise ventilation efficiency in heart failure patients

Marco Guazzia,*, Giuseppe Reinab, Gabriele Tumminelloa and Maurizio D. Guazzic

a Cardiopulmonary Laboratory, University of Milano, Cardiology Division, San Paolo Hospital Via A. di Rudiní, 8, 20142, Milano, Italy
b Institute of Statistics and Biometry, University of Milano Milano, Italy
c Institute of Cardiology, University of Milano Milano, Italy

* Corresponding author. Tel.: +39 2 50323144; fax: +39 2 50323144. E-mail address: Marco.Guazzi{at}unimi.it


   Abstract
Top
 Abstract
1. Methods
 2. Results
 3. Discussion
 References
 
Background: In heart failure (HF), changes in lung mechanics and gas diffusion are limiting factors to exercise. Their contribution to an increased exercise ventilation to CO2 production (VE/VCO2) slope is undefined.

Methods: A total of 67 stable HF patients underwent cardiopulmonary exercise and pulmonary function tests, including forced vital capacity (FVC), forced expiratory volume in 1 s (FEV1), maximal voluntary ventilation (MVV), total lung capacity (TLC) and alveolar diffusing capacity with its subcomponents (alveolar-capillary membrane conductance (Dm) and capillary blood volume (Vc)).

Results: Patients showed a mild restrictive pattern (FEV1=85±15% and FVC=75±13% of normal predicted) and a moderate Dm reduction (32±12 ml min–1 mm Hg–1). Average peak VO2 was 15.6±4.0 ml min–1 kg–1 and the VE/VCO2 slope was 39.6±11.0. At simple Spearman correlation analysis, all variables, but Vc, correlated with peak VO2; only Dm correlated with VE/VCO2 slope. At partial Spearman correlation, all variables lost the peak VO2 correlation, and Dm still inversely correlated with VE/VCO2 slope (r=–0.35; p=0.005). In patients with a high VE/VCO2 slope (cutoff value 34), despite comparable lung volumes, Dm was significantly more depressed (30±13 vs. 35±10 ml min–1 mm Hg–1; p<0.01).

Conclusions: Pulmonary function tests and alveolar gas diffusing capacity poorly correlate with peak VO2. Dm impairment rather than lung volumes correlates with exercise ventilation efficiency. This finding further adds to the pathophysiological relevance of an abnormal gas exchange in HF patients.

Key Words: Alveolar-capillary gas diffusion • Exercise ventilation • Left ventricular dysfunction

Received April 6, 2004; Revised July 29, 2004; Accepted October 14, 2004

Lung volumes and pulmonary gas diffusing capacity at rest correlate with a reduced oxygen uptake at peak exercise (peak VO2) in patients with heart failure (HF) due to left ventricular (LV) systolic dysfunction [1–4]. Several investigators have described an excessive ventilatory response to exercise, expressed by the slope of the linear relationship of ventilation per unit of carbon dioxide production (i.e. VE/VCO2 slope), as a common pathophysiological characteristic of these patients, that provides strong and independent prognostic information [5–11]. A cause–effect relationship has been established between a peripheral chemoreflex hypersensitivity and a steep exercise VE/VCO2 slope [5,9,12,13]. Mathematically, the VE/VCO2 slope is determined by three factors: the amount of CO2 produced, the physiological dead space–tidal volume ratio (VD/VT) and the arterial CO2 partial pressure. This implies that abnormalities intrinsic to the lung and commonly encountered in HF patients, such as a restrictive lung pattern [14–17], and an abnormal gas diffusing capacity [2,3,18], may also be involved in the dynamic ventilatory response to exercise. On the other hand, it should be considered that any increase in physiological dead space is a consequence of a higher ventilation and increased breathing rate (due to a limit on tidal volume) rather than the cause of the increased VE/VCO2 slope.

The present study was designed to identify which pulmonary variable at rest is better related with VE/VCO2 slope in patients with systolic LV dysfunction. Since, in these patients, the alveolar-capillary membrane dysfunction contributes to symptom exacerbation and exercise intolerance [1,2] and represents a strong prognosticator of clinical course [18], we addressed the hypothesis that changes in alveolar-capillary membrane conductance may be linked to the VE/VCO2 slope in these patients, and may be used as an index of exercise ventilatory efficiency.


   1. Methods
Top
 Abstract
 1. Methods
2. Results
 3. Discussion
 References
 
1.1. Study population
The study comprised patients with stable heart failure (NYHA class II–III) due to systolic LV dysfunction, secondary to ischemic (documented previous myocardial infarction) or idiopathic dilated cardiomyopathy (cardiac enlargement, reduced ejection fraction, and absence of a specific reason for cardiac impairment), who were referred to Cardiopulmonary Laboratory at San Paolo Hospital at the University of Milan, for evaluation of HF. Assessment included echocardiography, lung function tests and symptom-limited cardiopulmonary exercise testing (CPET).

Patients were in stable clinical condition, under the therapeutic regimen (Table 1) prescribed by the referring physician, and were willing to be subjected to a comprehensive pulmonary function evaluation and CPET. Their LV ejection fraction (echocardiography) averaged 35±6%. Patients were not considered eligible for the study if they 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 <70% of the predicted normal value, primary valvular heart disease, current or past history of smoking more than 10 cigarettes per day during 1 of the 5 past years. Sixty-seven consecutive patients who met the entry criteria were enrolled.


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  		Table 1 Baseline hemodynamic, lung function, cardiopulmonary exercise testing data and therapy

 
The protocol was approved by the institution Ethical Committee.

1.2. CPET Analysis
After enrolment, two symptom-limited cardiopulmonary exercise tests with respiratory gas exchange measurement were performed and a personalised ramp protocol was used. The first test was carried out for familiarization purposes and the second one as representative of the maximal exercise performance. A 12-lead electrocardiogram, heart rate and blood pressure were obtained at rest and at each minute during exertion. Respiratory gas analysis was performed using a Sensor Medics Vmax system (Yorba Linda, California, USA). Oxygen consumption (VO2), carbon dioxide production (VCO2), minute ventilation (VE), respiratory exchange ratio, VD/VT and ventilatory equivalents for O2 (VE/VO2) and CO2 (VE/VCO2) were measured continuously breath-by-breath. Peak VO2 was defined as the highest VO2 observed during the exercise test. Age-, gender-and weight-adjusted predicted VO2 values were also determined. Anaerobic threshold was obtained using the V-slope method [19]. The reproducibility of the ventilatory response to exercise as characterised by the VE/VCO2 slope had previously been assessed in our laboratory. There was good agreement between repeated measures that were carried out in 45 patients (r=0.95, p<0.001), with a mean coefficient of variation of 5.2%.

1.3. Pulmonary function
Spirometry was performed with equipment that met the American Thoracic Society performance criteria [20]. To adjust for height, age, and sex, we used published prediction equations for forced expiratory volume in 1 s (FEV1), forced vital capacity (FVC), total lung capacity (TLC) and maximal voluntary ventilation (MVV) [21]. Diffusing lung 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. DLco subdivisions, i.e., the alveolar-capillary membrane diffusion capacity (Dm) and the capillary pulmonary blood volume available for gas exchange (Vc), were determined according to the classic Roughton and Forster method [22].

This method partitions diffusing capacity into its component resistances: the diffusive resistance of the alveolar-capillary membrane (1/Dm) and the reactive resistance due to capillary blood (1/{theta}Vc, where {theta}=the rate of reaction of CO with haemoglobin) according to the following equation, which assumes that the red blood cell membrane has a negligible resistance to gas exchange:


Formula

where Hb is the subject's hemoglobin concentration (g dL–1) and PAO2 is the alveolar O2 partial pressure. Measuring DLco at different PAO2 values, a plot of 1/DLco against 1/{theta} will yield a straight line with a Y-intercept of 1/Dm and a gradient of 1/Vc.

1.4. Statistical analysis
All data are presented as mean value±1 S.D. The initial data analysis was designed to identify simple Spearman linear correlations between pulmonary variables at rest and peak VO2 and VE/VCO2 slope. Partial Spearman correlations were then performed. Differences between patients presenting with a VE/VCO2 slope ≤34 (upper normal limit) and those presenting with a VE/VCO2 slope >34 were assessed using the unpaired Student's t-test (all test statistics two-tailed). Differences were considered significant if the null hypothesis could be rejected at p<0.05. Statistics were performed by means of Stata 6.0 package.


   2. Results
Top
 Abstract
 1. Methods
 2. Results
3. Discussion
 References
 
2.1. Clinical characteristics
Baseline hemodynamic, lung function, cardiopulmonary exercise testing data and drug therapy distribution are reported in Table 1.

Average peak VO2 was 15.6±4.0 ml min–1 kg–1 and average VE/VCO2 slope was 39.6±11.0. No patient complained of chest discomfort or developed ECG signs of myocardial ischemia during exercise. The reason for stopping exercise was muscle fatigue in 50% of patients, dyspnea in 30% and a combination of both symptoms in the remaining 20% of cases. Since aspirin may impair Dm and gas exchange [3], it seems relevant to underline that only 15% of patients were on aspirin treatment. No differences were detected between patients who received aspirin and those who did not, possibly because most patients on aspirin were in NYHA functional class II and were receiving a low aspirin dose (100 mg/day or less).

Table 2 reports the pulmonary variables in patients with a VE/VCO2 slope <34 (n=24) and those (n=43) with a VE/VCO2 slope >34. No differences were detected in FEV1, FVC, TLC and MVV; on the contrary, the difference in Dm was highly significant (p<0.01).


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  		Table 2 Subgroup comparison of individual pulmonary variables

 
2.2. Simple and partial Spearman correlation
At simple Spearman correlation analysis, all pulmonary variables considered, but Vc, were significantly related with peak VO2 (Table 3). As to the VE/VCO2 slope, only Dm showed a significant inverse correlation (r=–0.36; p=0.002) (Table 4 and Fig. 1). Spearman partial correlation of pulmonary parameters with peak VO2 did not show any statistical significance (Table 3), whereas Dm maintained a significant correlation with VE/VCO2 (r=–0.35; p=0.005) (Table 4).


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  		Table 3 Spearman simple and partial correlations between pulmonary variables and peak VO2

 


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  		Table 4 Spearman simple and partial correlations between pulmonary variables and VE/VCO2 slope

 


Figure 1
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  		Fig. 1 Linear correlation between Dm and VE/VCO2 slope.

 

   3. Discussion
Top
 Abstract
 1. Methods
 2. Results
 3. Discussion
References
 
Findings in the present report confirm the study-generating hypothesis. They document that, among lung function variables, the alveolar-capillary gas exchange, and specifically the Dm component of lung diffusion, is the best pulmonary function correlate of the exercise VE/VCO2 slope in patients with HF due to left ventricular dysfunction. To our knowledge, no previous study has addressed the potential for a link between changes in lung function and an abnormally steep exercise VE/VCO2 slope.

There is a large body of evidence suggesting that, in HF patients, a steep VE/VCO2 slope is a powerful and independent prognostic indicator [5–9]. Likewise, Dm is the only powerful independent resting lung function predictor of survival [18]. Consistently, when patients were grouped according to a VE/VCO2 slope cut-off value of 34 (upper normal limit) [5], no differences were detected in FEV1, FVC, TLC, MVV and Vc, whereas Dm significantly differentiated the two patient groups.

Even though a lung restrictive pattern [13–15,23] and a depressed lung diffusion [2,3] are common features in HF patients, their pathophysiological and clinical significance may be quite disparate [24]. Abnormalities in lung mechanics improve after tailored therapy [14] and reverse after fluid withdrawal by ultrafiltration [25] or cardiac transplantation [14]; on the contrary, alveolar Dm component poorly responds to drug therapy and fluid removal by ultrafiltration [25] and, despite a "modulatory" effect by ACE-inhibition [3,26], no improvement is observed after cardiac transplantation [27], suggesting an irreversible alveolar damage. For these reasons, alterations in Dm more than those in lung volumes seem to be a sensitive marker of the structural changes that take place in the lung parenchyma as a consequence of LV dysfunction [24]. There is a tight structure–function correspondence between anatomical alveolar-capillary membrane derangement and reduced alveolar gas diffusion, and its components are noninvasive indicators of the state of integrity of the pulmonary microvascular bed [24].

In previous studies, emphasis has been placed on the pathophysiological importance of both changes in lung mechanics and gas diffusion in relation with peak VO2 [1,2,5]. However, a potential limitation of these studies was the statistical approach that consisted of a simple correlation analysis. In the present report, when simple correlations between lung variables and peak VO2 were further tested by partial Spearman correlation, the significance of these relationships was lost. This is in agreement with the multiplicity of factors that contribute to peak VO2, and the relevance of one variable at rest may be concealed by others and vice versa. In this case, vascular, muscular and neurohumoral factors may be more relevant than the pulmonary variables.

Although there are good reasons to believe that an impaired ventilatory efficiency may be related with abnormalities in gas exchange, this subject has not been addressed in previous reports. A series of studies by Ponikowsky [9], and by others in the same laboratory [5,7,11,12], have documented that, in patients with left ventricular systolic dysfunction, an increased VE/VCO2 slope is primarily related with increased chemoreceptor gain and ergoreceptor stimulation from skeletal muscles. The rationale for testing the pathophysiological relationship between changes in lung function and exercise VE/VCO2 slope [9] is weakened by the close correlation that has been found between an increased chemoreceptor and metaboreceptor sensitivity and a steep VE/VCO2 slope, and by the lack of a relationship between lung volumes (FEV1 and FVC, TLC and MVV) and VE/VCO2 slope. This partially explains why the issue has previously been neglected. On the other hand, Wasserman et al. [28], in 106 patients with variable HF severity, invariably found that restrictive lung changes sustain the occurrence of an increased physiological dead space and a reduced tidal volume increase during incremental exercise, suggesting that alterations in lung function may account for the ventilatory performance during exercise. In these studies, however, alveolar gas diffusion was not measured and its relative contribution to an excessive exercise ventilation was not tested. Our findings do not provide evidence of a link between lung volumes and VE/VCO2 slope; they, according to results of a stepwise correlation analysis, suggest the existence of a link between excessive exercise ventilation and impaired alveolar membrane gas conductance. Further systematic analyses are warranted to elucidate the real nature of this association, mainly regarding the relative contribution of abnormalities in muscular reflexes vs. abnormalities intrinsic to the lung and involving the alveolar-capillary unit. A few speculations, however, are in order. Intrinsic abnormalities of the alveolar-capillary membrane, as produced by an increased extracellular matrix collagen synthesis and a reduced ability of type II alveolar cells to maintain constant fluid clearance from the alveoli to the interstitium, can lengthen the path for gas diffusion from the alveolus to its uptake by hemoglobin. This, however, may not systematically result in significant changes in exercise blood gas tension and may not sufficiently explain the relationship found between Dm and VE/VCO2 slope. Thickening of the alveolar surface due to reactive interstitial fibrosis, as typical of HF patients, is, however, a relevant contributory factor to an increased dead space that can be perceived by the respiratory centers as a stimulus demanding additional ventilation. Our data point towards a cause–effect relationship between Dm and VE/VCO2 slope even though they might simply be markers of severity of the disease. Both, in fact, are independent predictors of survival, and retain remarkable prognostic power [5–10,18].

In conclusion, this study shows that in patients with left ventricular dysfunction, conventional pulmonary function tests and alveolar gas diffusing capacity poorly correlate with peak VO2. Impairment in the alveolar-capillary membrane conductance rather than abnormalities in lung volumes is linked to a steep exercise VE/VCO2 slope. Because of this, Dm could represent an index of exercise ventilation efficiency, further adding to the clinical utility of measuring lung diffusion capacity in HF patients.


   Acknowledgements
 
This study was supported in part by a grant of the "Luigi Berlusconi" Foundation, Milano, Italy.


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

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