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(Circulation. 2000;101:2803.)
© 2000 American Heart Association, Inc.

Clinical Investigation and Reports

Impairment of Ventilatory Efficiency in Heart Failure

Prognostic Impact

F. X. Kleber, MD; G. Vietzke, MD; K. D. Wernecke, PhD; U. Bauer, MD; C. Opitz, MD; R. Wensel, MD; A. Sperfeld, MD; S. Gläser, MD

From Medizinische Klinik und Poliklinik I, Universitätsklinikum Charité, Arbeitsgruppe Medizinische Biometrie, Humboldt-Universität zu Berlin, Berlin, Germany.

	Abstract

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Background—Impairment of ventilatory efficiency in congestive heart failure (CHF) correlates well with symptomatology and contributes importantly to dyspnea.

Methods and Results—We investigated 142 CHF patients (mean NYHA class, 2.6; mean maximum oxygen consumption [O₂max], 15.3 mL O₂ · kg^-1 · min^-1; mean left ventricular ejection fraction [LVEF], 27%). Patients were compared with 101 healthy control subjects. Cardiopulmonary exercise testing was performed, and ventilatory efficiency was defined as the slope of the linear relationship of CO₂ and ventilation (VE). Results are presented in percent of age- and sex-adjusted mean values. Forty-four events (37 deaths and 7 instances of heart transplantation, cardiomyoplasty, or left ventricular assist device implantation) occurred. Among O₂max, NYHA class, LVEF, total lung capacity, and age, the most powerful predictor of event-free survival was the VE versus CO₂ slope; patients with a slope 130% of age- and sex-adjusted normal values had a significantly better 1-year event-free survival (88.3%) than patients with a slope >130% (54.7%; P<0.001).

Conclusions—The VE versus CO₂ slope is an excellent prognostic parameter. It is easier to obtain than parameters of maximal exercise capacity and is of higher prognostic importance than O₂max.

Key Words: prognosis • heart failure • ventilation

	Introduction

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Ventilatory efficiency is defined by ventilation relative to CO₂ production. Its most important determinant is the matching of ventilation and perfusion. In most patients with congestive heart failure (CHF), as in normal control subjects, ventilatory efficiency improves with exercise. It correlates very well with exercise capacity respectively O₂max¹ and closely relates to symptomatology.^{2 3} Both NYHA class and O₂max have been proven to be good predictors of prognosis in CHF. Therapy with ACE inhibitors known to improve prognosis also betters ventilatory efficiency.³ Ventilatory efficiency can be derived from a moderate effort well before exhaustion and is highly reproducible.¹

Therefore, we investigated the impact of ventilatory efficiency in CHF on outcome and compared it with other prognostic parameters like left ventricular ejection fraction (LVEF), NYHA class, and O₂max. To maximize the physiological information from cardiopulmonary exercise testing (CPX), we normalized O₂max and the slope of ventilation (VE) versus CO₂ for age and sex using our own control population.^{4 5}

	Methods

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Patients
We monitored 142 consecutive patients (117 men, 25 women; mean age, 51.6±10 years; range, 21 to 73 years) with CHF after performing CPX between June 1993 and November 1996. Mean and median follow-up until death or end of follow-up was 16 months. The cause of CHF was coronary artery disease (n=70), dilated cardiomyopathy (n=66), valvular heart disease (n=4), graft failure (n=1), and hypertensive heart disease (n=1). Eleven patients were in NYHA class IV, 78 in class III, and 45 in class II; 8 patients did not complain of symptomatic limitation (class I).

Symptoms were attributed to heart and not lung disease in all patients, albeit the mild abnormality of pulmonary function tests in some patients was thought to be secondary to heart disease. Current smoking status and smoking history are presented in Table 1.

View this table: [in this window] [in a new window]   Table 1. Lung Function Tests and Smoking Status

Origin and severity of CHF were determined by echocardiography (n=130), chest radiograph (n=114), or cardiac catheterization (n=95). Inclusion criteria were a O₂max <25 mL O₂ · kg^-1 · min^-1 and either cardiothoracic ratio >0.5, echocardiographic left ventricular end-diastolic diameter 57 mm, or LVEF determined by contrast ventriculography or echocardiography 45%. Mean LVEF was 27% (median, 26%). One hundred nineteen patients were in sinus rhythm, 19 had atrial fibrillation, and 4 had pacemaker rhythm.

Current medication included ACE inhibitors (89%), diuretics (69%), nitrates (67%), digitalis (52%), anticoagulants (30%), and antiarrhythmics (6%). Ten percent were on calcium antagonists, mainly for rate control, and 31% were on aspirin for coronary disease.

Control Subjects
One hundred one healthy volunteers 16 to 75 years of age (mean, 37±14 years) underwent CPX testing to establish age- and sex-corrected normal values. Forty-five were female (weight, 60±8 kg; height, 165±6 cm), 56 were male (weight, 78±12 kg; height, 179±9 cm). Results have been published in part elsewhere.⁴ Linear regression analysis for age versus oxygen consumption and VE versus CO₂ slope revealed the following mean normal value formulas: VE versus CO₂ slope: 0.13xage+19.9 for men and 0.12xage+24.4 for women; O₂ at the gas exchange anaerobic threshold (O₂AT): -0.17xage+28.6 for men and -0.16xage+24.2 for women; O₂max: -0.36xage+51.5 for men and -0.34xage+44.6 for women.

For prognostic analysis, oxygen consumption and VE versus CO₂ slope values are presented as percent predicted (PP) from the individual age- and sex-corrected mean normal values.

Exercise Testing
In all patients and control subjects, a symptom-limited CPX test was performed according to the modified Naughton protocol⁶ with a Medical Graphics CPX/D system. Details of our test protocol have been published earlier.⁴

Great effort was undertaken not to stop exercise prematurely. However, indications to stop the test were a higher degree of AV block or ventricular tachycardia >5 consecutive beats at a rate >120/min, new atrial fibrillation, ST-segment depression >3 mm, or systolic blood pressure >260 mm Hg, as well as a progressive decrease in blood pressure.

O₂max was defined as the peak O₂ measured, always occurring well beyond the anaerobic threshold. O₂ at O₂AT was detected by the V-slope method,^{7 8} supplemented by simultaneous observation of end-tidal gas concentrations (PETO₂/CO₂).

Ventilatory efficiency on exercise was measured by plotting VE against CO₂. This plot revealed a linear relationship (r=0.98 to 0.99). The ventilatory efficiency on exercise is represented by its slope. The nonlinear part of this relationship after onset of acidotic drive to ventilation⁸ was excluded.

Lung Function Tests
Routine lung function tests, including total lung capacity (TLC), forced expiratory volume in 1 second (FEV₁), inspiratory vital capacity (IVC), and diffusion capacity for carbon monoxide (DLCO), were expressed as percent predicted of normal PP. Oxygen saturation was continuously measured percutaneously by pulse oximetry on the ear lobe. Breathing reserve was calculated as 100-(100xVE_max/resting FEV₁x41).⁹

Follow-Up Data on Prognosis
Follow-up events included overall deaths, cardiac transplantation (HTX), implantation of a left ventricular assist device (LVAD), or cardiomyoplasty. Most patients had a follow-up of >1 year. Minimal follow-up was 6 months. One patient was lost to follow-up.

Statistical Analysis
Results are presented as mean±SD. For comparison between groups, the Mann-Whitney U test was used; to compare prognostic parameters, linear and logistic regression analyses were performed. Correlations were determined according to Bravais-Pearson or Spearman. The follow-up data were analyzed by Kaplan-Meier life-table analysis and the log-rank test. To define the cutoffs giving the best discrimination in defining the likelihood of event-free survival, univariate log-rank tests (Mantel-Haenszel)¹⁰ were used. A multiple Cox regression analysis was performed using LVEF, O₂max, VE versus CO₂ slope, age, TLC, and NYHA class.¹¹

Classification trees (CART) were constructed with subgroups internally as homogeneous and externally as heterogeneous as possible, measured on the corresponding log-rank test.^{12 13} The successive splits of the tree correspond to the features with the greatest prognostic importance. For diagnostic testing sensitivity, accuracy and ORs were estimated.

	Results

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Exercise Testing
Eighty-nine patients terminated exercise because of dyspnea, 15 because of angina, 13 because of fatigue, 10 because of nonspecific symptoms like vertigo and anxiety, and 15 because of the above-defined criteria. All exercise tests in control subjects were limited by exhaustion.

O₂AT and O₂max were 10.7±3.2 and 15.2±4.7 mL O₂ · kg^-1 · min^-1 (median, 57 and 47 PP), respectively, in the patient group. The VE versus CO₂ slope was 39.3±16.4 (median, 128 PP). There was no difference between the 2 major etiologic subgroups.

At termination of exercise, patients used 44±15% of maximal breathing capacity; healthy volunteers, 59±12%. In patients and in all NYHA subgroups, O₂max was reached earlier after O₂AT than in normal subjects (O₂AT/O₂max in patients, 71±11%; in normal subjects, 58±9%; P<0.001; see Table 2). Termination of exercise because of angina or by the physician did not influence the O₂AT/O₂max ratio. Patients with normal and reduced ventilatory efficiency had similar O₂AT/O₂max ratios (71±11% versus 72±10%).

View this table: [in this window] [in a new window]   Table 2. VO2 and VE versus CO2 Slope in Subsets With Different Severity of CHF

Oxygen Desaturation and Lung Function Testing
In 6 of 142 patients, a significant decrease in oxygen saturation (4%) was found (mean, 96% to 87%). Five of these were in NYHA class III, and 1 was in class IV. One had a small atrial septum defect, and 1 had suspected pulmonary embolism with extremely elevated VE versus CO₂ slope (140) normalized at reevaluation. The other 4 had severe CHF (O₂AT, 4.7 to 9.0; O₂max, 6.1 to 11.2 mL O₂ · kg^-1 · min^-1; VE versus CO₂ slope, 57 to 85), and all 4 died within 2 years. Lung function and smoking status are given in Table 1.

Relationship Between Ventilatory Efficiency, Symptoms, and Exercise Capacity
Ventilatory efficiency was impaired (VE versus CO₂ slope >35) in 46% of patients. Patients with reduced ventilatory efficiency had lower LVEF (20±7% versus 25±8%; P<0.001) and O₂max (12.2±3.6 versus 17.8±3.9; P<0.001) than patients without reduced ventilatory efficiency.

Results in various NYHA classes are presented in Table 2. The VE versus CO₂ slope but not O₂AT or O₂max was significantly different in all NYHA classes (P<0.05), but the correlation between VE versus CO₂ slope and NYHA class was not very good (r=0.44; P<0.001). Exercise ventilatory efficiency correlated with O₂AT (r=-0.70, P<0.001), O₂max (r=-0.70; P<0.001), and exercise time (r=-0.53; P<0.001) but only weakly with LVEF (r=-0.17; P=0.048).

The correlations between exercise capacity and ventilatory efficiency were similar using the PP values (VO₂max PP and slope PP: r=-0.64; P<0.001; O₂AT PP and slope PP: r=0.65; P<0.001).

Follow-Up of Vital Status
Thirty-seven deaths occurred during follow-up. An additional 7 patients survived HTX, cardiomyoplasty, or LVAD implantation. Eight deaths occurred at various time intervals after prior HTX, LVAD, or cardiomyoplasty. Median event-free survival was 38 months (overall survival, 39 months). Univariate Kaplan-Meier analysis of event-free survival revealed significant survival differences (log-rank test) with cutoff points for O₂AT at 10 mL · kg^-1 · min^-1 or 30, 45, and 50 PP; O₂max at 10, 12, and 14 mL · kg^-1 · min^-1 or 45 PP; and VE versus CO₂ slope at 35 and 40 L/L CO₂ or 125 and 130 PP.

Figure 1 shows the event-free survival for the total group, and Figure 2a and 2b shows Kaplan-Meier life-table analyses (event-free survival) for the best cutoffs, ie, O₂max (>45 versus 45 PP) and VE versus CO₂ slope (130 versus >130 PP). The best cutoff for O₂AT was >50 versus 50 PP (life table not shown).

View larger version (10K): [in this window] [in a new window]   Figure 1. Event-free survival for total patient group.

View larger version (16K): [in this window] [in a new window]   Figure 2. Kaplan-Meier life-table analysis for O2max >45% vs 45% predicted (a) and for VE vs CO2 slope 130% vs >130% predicted (b).

In a multivariate Cox regression analysis, the following items were included: age, LVEF, NYHA class, O₂max, VE versus CO₂ slope, and TLC. The analysis revealed the VE versus CO₂ slope to be the most powerful predictor of event-free survival, followed by O₂max. O₂max did not substantially improve the predictive value of the model. Classification trees were used to estimate the practical usefulness of the model to predict 1-year overall and event-free survival. Of the 141 patients, 105 were survivors of the first year of follow-up, and 103 survived without an event. According to the best discriminating variable and cutoffs in the log-rank statistics, we included the following parameters/cutoffs in the CART analysis: O₂AT cutoff, 50 PP; VE versus CO₂ slope, 130 PP; NYHA functional class, I/II versus III/IV and I to III versus IV; O₂max cutoff, 45 PP; age, 65 years; and LVEF, 25%. The VE versus CO₂ slope had by far the highest log-rank test value (25.65; P<0.0001), followed by O₂max (with a log-rank test value of 7.57; P=0.0059). The VE versus CO₂ slope was therefore used as the first parameter to dichotomize the patients. Analysis for event-free and overall survival revealed essentially the same: both the VE versus CO₂ slope in PP and the O₂max PP represented important information for the prognosis. Patients with a VE versus CO₂ slope 130 PP had a significantly better 1-year event-free survival (88.3%) than patients with a slope >130 PP who had a 1-year event-free survival of only 54.7% (overall survival, 88.3% versus 57.8%).

Patients with a VE versus CO₂ slope >130 PP but a O₂max >45 PP had a 79.2% 1-year event-free survival. No other parameters were useful to further characterize the prognosis of patients with a VE versus CO₂ slope 130 PP who had a good prognosis. For details, see Figure 3.

View larger version (38K): [in this window] [in a new window]   Figure 3. CART analysis with successive splits according to greatest prognostic importance of variables with respect to 1-year event-free survival (a) and CART analyses with successive splits according to various clinical decisions with respect to 1-year survival (b through e).

The sensitivity and specificity of a VE versus CO₂ slope with a cutoff of 130 PP for survival were 70.3% and 63.5%; positive and negative predictive values were 40.6% and 85.7%, accuracy was 65.3%, the OR was 4.1, and the 95% CI was 1.9 to 9.0.

	Discussion

Top Abstract Introduction Methods Results Discussion References

 
Dyspnea and Ventilatory Efficiency
The most widely used scale to measure dyspnea in CHF is the NYHA classification, which, in contrast to the Borg scale and pulmonary function tests, has been shown to contribute prognostic information independently of left ventricular function.^{14 15}

One of the most prominent features of dyspnea in CHF is hyperpnea, ie, an increase in ventilation relative to gas exchange. It is caused by early anaerobic metabolism, an increase in anatomical dead space by increased breathing rate and low tidal volumes caused by secondary restrictive physiology or respiratory muscle fatigue,¹⁶ a decreased PaCO₂ set point resulting from acidosis, disturbances of diffusion,¹⁷ activation of muscle ergoreceptors,¹⁸ and respiratory muscle deoxygenation.¹⁹ The most important cause of hyperpnea, however, is the increase in physiological dead space by alveolar hypoperfusion^{20 21} Therefore, we investigated the prognostic importance of ventilatory efficiency in patients with CHF and compared it with other currently used prognostic parameters like LVEF,^{22 23} NYHA class,^{24 25} and O₂max.

Population Under Study
Patients suffered mainly from coronary disease or dilated cardiomyopathy similar to recently reported patients.²⁶ All patients had an LVEF 45%; all NYHA I patients had an LVEF <35%.

There was no difference in smoking status in patients with reduced compared with normal ventilatory efficiency. Differences in pulmonary function tests were small and thought to be secondary to CHF. Lungs were somewhat smaller in patients with reduced ventilatory efficiency, as has been shown in normal subjects under exercise²⁷ and in persons susceptible to high-altitude pulmonary edema.²⁸ This might contribute to / mismatch by making a small ventilation-perfusion inequality more important. The slight decrease in TLC in our patients, however, is unlikely to contribute to a larger extent to the decrease in ventilatory efficiency. Forty-six percent of patients had reduced ventilatory efficiency (median, 128 PP).

Similar to Veterans Administration Heart Failure Trial (V-HeFT) findings,²⁹ mean O₂max was 15.2 mL · kg^-1 · min^-1, and cardiocirculatory limitation was confirmed by the high breathing reserve at the end of exercise, low rate of oxygen desaturation, and absence of pulmonary disease.

The lack of any important correlation to LVEF is not unexpected,^{23 30} and an LVEF 30% might not give very useful information regarding prognosis.^{14 31} More than 70% of our population had an LVEF 30%.

Follow-Up of Vital Status and CHF Events
Prognostic parameters in CHF²⁴ include symptoms,^{25 32 33} hemodynamics, LVEF, cardiothoracic ratio,²⁹ neurohormones,^{34 35} electrolytes,³⁶ and O₂max.^{31 37 38} We used O₂ PP derived from our own large control population. Among LVEF, NYHA class, age, and TLC, the VE versus CO₂ slope was the most powerful indicator of prognosis in a multivariate analysis.

VE/CO₂ ratio and slope are known to correlate to O₂max.³⁹ Our results demonstrate that the VE versus CO₂ slope contains prognostic information in addition to and beyond the measurement of O₂max: Patients with a VE versus CO₂ slope >130 PP had a 1-year mortality >40%, and even if O₂max were preserved, 1-year mortality was >20%. Ventilatory efficiency is easier to obtain than O₂max and can be derived from a submaximal exercise test. The high negative predictive value of a normal ventilatory efficiency (ie, slope 130 PP) is of special clinical relevance for patients with low O₂max or those who cannot exercise until exhaustion.

Underlying Physiology and Study Limitations
This study lacks an explanation of how ventilatory efficiency affects prognosis in CHF. Although normal ventilatory control in CHF⁴⁰ has been shown, an uncoupling of ventilation from CO₂ production⁴¹ has also been reported and thought to be due to activation of muscle ergoreceptors. However, substantial changes in arterial CO₂ tension have not been found,^{40 42 43} and the changes in physiological dead space suggested by increased ventilation^{40 42 43} and near-normal PCO₂ would thus be secondary.

An alternative explanation is that the increase in physiological dead space is directly caused by alveolar hypoperfusion⁴⁴ resulting from impaired endothelial vasodilatory capacity^{45 46 47} or neuroendocrine activation.^{35 48} If this theory is correct, the "muscle hypothesis" would not easily fit in.

A major diffusion disturbance^{17 49} is an unlikely explanation for the derangement of ventilatory efficiency because CO₂ diffuses much more easily than oxygen and a decrease in oxygen saturation has not been found in >95% of our patients. It might become important in severe CHF with prominent congestion.

Another limitation of our study is that not all patients stopped exercise for dyspnea or fatigue. This might introduce a considerable error through ischemic pump dysfunction. However, the reluctance to include patients with angina would not have reliably excluded silent ischemia, nor would it be meaningful to disregard some contribution of ischemia in a setting of CHF, whose leading cause is ischemic heart disease. Furthermore, dyspnea might be the only symptom of angina. Thus, in any exercise testing of CHF patients, ischemia is likely to play some part. The VE versus CO₂ relationship should, on the contrary, be of special value in this population, because it is measured well before the onset of angina or ischemia. Furthermore, the exclusion of patients who stopped exercise before the onset of dyspnea or fatigue led to a similar ratio of O₂max/O₂AT. This indicates that our patients did not stop because of angina; rather, ischemia concurred with the limitation by CHF at the end of exercise in some of them.

Despite these limitations, our results show that measurement of the VE versus VCO₂ relationship offers a unique way of estimating the prognosis of patients with CHF. During preparation of this article, similar results have been obtained by an independent group.⁵⁰ Given the possibility of therapeutic influences on ventilatory efficiency,³ this might also provide a useful tool to guide therapy, especially in severe CHF.

	Acknowledgments

 
This work was supported by grant No. 01 ZZ 9101 from the Ministry of Research, Germany.

	Footnotes

 
Reprint requests to F.X. Kleber, MD, Professor of Medicine, Humboldt University, Berlin, Director Department of Internal Medicine, Unfallkrankenhaus Berlin, Warener Straße 7, 12683 Berlin, Germany.

Received September 14, 1999; revision received January 15, 2000; accepted January 25, 2000.

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