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(Circulation. 2001;103:916.)
© 2001 American Heart Association, Inc.

Editorial

Gas Exchange Efficiency in Congestive Heart Failure II

Robert L. Johnson, Jr, MD

From the Department of Internal Medicine, University of Texas Southwestern Medical Center at Dallas.

Correspondence to Robert L. Johnson, Jr., MD, Pulmonary and Critical Care Division, Department of Internal Medicine, 5323 Harry Hines Blvd, Dallas, TX 75390-9034. E-mail Robert.Johnson{at}utsouthwestern.edu

Key Words: Editorials • heart failure • ventilation

It has become increasingly apparent that congestive heart failure (CHF) affects not only the cardiovascular system, but every organ system involved with oxygen transport, including the respiratory system, skeletal muscles, and the hormonal and neural feedback control systems for breathing, cardiac output, blood pressure, blood volume, and distribution of blood flow. One segment of this transport system cannot be isolated from the rest. The ventilatory response to exercise in patients with CHF is augmented despite normal arterial O₂ saturation and a normal or low end-tidal PCO_2.^{1 2 3 4 5 6} The augmented ventilatory response is measured as a steep slope of the increase in ventilation with respect to CO₂ output (E/CO₂) or as a high E/CO₂ ratio at peak exercise. The source of this ventilatory augmentation has been controversial, but its pathophysiological significance is clear. A high slope at submaximal exercise or a high E/CO₂ ratio at peak exercise is a powerful index of poor prognosis in patients with CHF.^{4 7} As indicated by Ponikowski et al⁸ in the current issue of Circulation, this prognostic power is retained in patients with CHF, even when the maximal O₂ uptake (O₂ max) is near the normal range.

A high E/CO₂ ratio has 2 possible sources: (1) increased ventilation, which is required to overcome a large dead space to maintain a normal arterial CO₂ tension (PaCO₂), or (2) increased central drive to ventilation, which drives the PaCO₂ below what is normally expected. Ponikowski et al⁸ present convincing evidence that the augmented ventilatory response to exercise in CHF is significantly correlated with other markers of abnormal cardiorespiratory reflex control (ie, central and peripheral chemoreceptor control of ventilation, ergoreceptor drive to ventilation, and both autonomic and baroreceptor control of the circulation). Thus, the high E/CO₂ seems related to altered chemoreceptor gain and ergoreceptor drive to ventilation, as well as to impaired reflex control of the heart and circulation. Impaired autonomic and baroreceptor control become manifest in severe heart failure by an abnormally reduced variability in heart rate and an increased variability in blood pressure, with predisposition to arrhythmias and sudden death.^{9 10} These observations provide a major link between augmented exercise ventilation in CHF and poor prognosis.

Is the augmented ventilation during exercise an integral part of the deranged cardiorespiratory reflex controls in CHF or a manifestation of structural changes in the lung that impair ventilation/perfusion matching, as I suggested in a previous editorial?¹¹ Ponikowski et al⁸ and others^{6 12} from the same laboratory provide indirect support for a high ventilatory drive related to increased chemoreceptor gain and ergoreceptor drive in skeletal muscle. However, if present, such an increased ventilatory drive should force the PaCO₂ below expected levels during exercise and generate a negative correlation between PaCO₂ and E/CO₂ at peak exercise. No convincing data from arterial blood gases indicate that this occurs. Wasserman et al⁵ provided comprehensive data on alveolar arterial blood gas exchange in 130 patients with CHF and 52 normal controls. They concluded that "the increase in ventilatory response in CHF is due primarily to 2 mechanisms: (1) the increased CO₂ output relative to O₂, owing to bicarbonate buffering of accumulating lactic acid, and (2) the increase in VD/VT ratio due to reduced perfusion of ventilated lung." Arterial PCO₂ was not depressed from rest to heavy exercise, although end-tidal PCO₂ was depressed because of a high alveolar dead space. There was no evidence for increased central or peripheral drive to ventilation.

Franciosa et al² reported both arterial blood gas and hemodynamic data at rest and peak exercise in 28 patients with CHF. They concluded that "exercise intolerance in patients with severe CHF is associated with marked elevation of pulmonary capillary wedge pressure and anaerobic metabolism without hypoxemia or altered carbon dioxide tension." The mean PaCO₂ (35±7 mm Hg) was the same at rest and peak exercise; hence, similar to the data from Wasserman et al,⁵ there was no evidence suggesting a high ventilatory drive. Fortunately, however, Franciosa et al² provided the blood gas and hemodynamic data on each subject in a table, which allowed a more comprehensive analysis. Both the E/CO₂ and dead-space gas volume to tidal gas volume (VD/VT) ratios can be calculated at peak exercise from the tabulated data and plotted with respect to PaCO₂ (Figure 1). This yields a highly significant inverse correlation between E/CO₂ and PaCO₂ (Figure 1A) that supports Ponikowski et al’s⁸ hypothesis. There is also a highly significant, direct correlation between E/CO₂ and the VD/VT ratio (Figure 1B), confirming an uneven distribution of ventilation with respect to perfusion in the lung. Thus, the PaCO₂ is driven to low levels during peak exercise in CHF, despite inefficient gas exchange from a high VD/VT ratio.

View larger version (19K): [in this window] [in a new window]   Figure 1. Relationship of augmented ventilation with respect to CO2 output (E/CO2) to arterial CO2 tension (PaCO2) and to dead-space ventilation (VD/VT) at peak exercise in patients with CHF, derived from data of Franciosa et al.2 Averaged data from Clark et al6 fall within same range. Results indicate that augmented ventilatory response in patients with heart failure is a consequence of both an increase in ventilatory drive and a corresponding increase in dead-space ventilation.

From whence might this increased drive arise? Ponikowski et al⁸ show high chemoreceptor gains for PO₂ and PCO₂ in CHF that positively correlate with a high E/CO₂ slope. Normal individuals who have high chemoreceptor gain also have an augmented ventilatory response to exercise.^{13 14 15} In Figure 2, I compare the relationship between E/CO₂ and PaCO₂ at peak exercise in the CHF patients studied by Franciosa et al² with that in the normal subjects studied by Martin et al.¹⁵ The normal subjects had different chemoreceptor gains for PO₂ and PCO₂ at rest, which were augmented at exercise; those normal subjects with high chemoreceptor gains had higher ratios of E/CO₂ and a lower PaCO₂. The point of the graph is to illustrate from the regression lines that that ventilation had to be about twice that in the normal subjects to achieve the same PaCO₂ because of the inefficient gas exchange (ie, the high VD/VT ratio). This means that ventilatory drive had to be, on average, twice as high in the CHF patients than in the normal subjects studied by Martin et al.¹⁵ It is hard to explain this increased drive by a simple increase in chemoreceptor gain, however, because chemoreceptor gain does not represent a unidirectional drive; rather, it represents the strength of feedback control to minimize any deviation of arterial PO₂ and PCO₂ in either direction from their respective set points. This is like the gain of the thermostat in a home air-conditioning system. Exercise must alter the set point of the control system, perhaps by increased sympathetic stimulation or from increased stimulation from skeletal muscle ergoreceptors, both of which are augmented in CHF. A high chemoreceptor gain would then tighten the control and ensure a smaller error signal at full response. It would be of interest to know whether normal subjects who have a high chemoreceptor gain and a high ventilatory response to exercise also have a high ergoreceptor drive from skeletal muscle.

View larger version (25K): [in this window] [in a new window]   Figure 2. Data from Franciosa et al2 plotted in Figure 1A is compared with similar data in normal subjects studied by Martin et al,15 who also showed a positive correlation between chemoresponsiveness to hypoxia and hypercapnia similar to that in patients with CHF. Normal subjects with high chemosensitivity had a lower PaCO2 and higher E/CO2 than subjects with low chemosensitivity, but ventilation at same CO2 output in patients must be, on average, twice that in normal subjects to achieve same PaCO2 as a consequence of inefficient gas exchange.

The augmented ventilatory response to exercise in CHF correlates with control and reflex abnormalities and with hemodynamic alterations. The latter relationships can also be illustrated from the data of Franciosa et al² (Figure 3). There is a strong inverse correlation of E/CO₂ with cardiac index (Figure 3A) and with pulmonary artery pressure (Figure 3B). Hence, there are multiple reasons why this simple ratio of E/CO₂, or the slope of the increase in E with respect to CO₂ during exercise, provides a powerful prognostic index in heart failure. It seems to reflect the severity of derangement in almost all aspects of CHF; it is also an objective measurement that can be made easily.

View larger version (18K): [in this window] [in a new window]   Figure 3. High E/CO2 ratio in CHF also correlates significantly with hemodynamic abnormalities, as demonstrated here using data of Franciosa et al2 for cardiac index at peak exercise and for resting pulmonary artery (PA) pressure.

Footnotes

The opinions expressed in this editorial are not necessarily those of the editors or of the American Heart Association.

References

1. Weber KT, Kinasewitz GT, Janicki JS, et al. Oxygen utilization and ventilation during exercise in patients with chronic heart failure. Circulation. 1982;65:1213–1223.[Abstract/Free Full Text]
   
2. Franciosa JA, Ledy CL, Willen M, et al. Relation between hemodynamic and ventilatory responses in determining exercise capacity in severe congestive heart failure. Am J Cardiol. 1984;53:127–134.[Medline] [Order article via Infotrieve]
   
3. Clark AL, Poole-Wilson PA, Coats AJ. Relation between ventilation and carbon dioxide production in patients with chronic heart failure. J Am Coll Cardiol. 1992;20:1326–1332.[Abstract]
   
4. Chua TP, Ponikowski P, Harrington D, et al. Clinical correlates and prognostic significance of the ventilatory response to exercise in chronic heart failure. J Am Coll Cardiol. 1997;29:1585–1590.[Abstract]
   
5. Wasserman K, Zhang YY, Gitt A, et al. Lung function and exercise gas exchange in chronic heart failure. Circulation. 1997;96:2221–2227.[Abstract/Free Full Text]
   
6. Clark AL, Volterrani M, Swan JW, et al. The increased ventilatory response to exercise in chronic heart failure: relation to pulmonary pathology. Heart. 1997;77:138–146.[Abstract/Free Full Text]
   
7. Kleber FX, Vietzke G, Wernecke KD, et al. Impairment of ventilatory efficiency in heart failure: prognostic impact. Circulation. 2000;101:2803–2809.[Abstract/Free Full Text]
   
8. Ponikowski P, Francis DP, Piepoli MF, et al. Enhanced ventilatory response to exercise in patients with chronic heart failure and preserved exercise tolerance: marker of abnormal cardiorespiratory reflex control and predictor of poor prognosis. Circulation. 2001;103:967–972.[Abstract/Free Full Text]
   
9. Goldberger AL, Rigney DR, Mietus J, et al. Nonlinear dynamics in sudden cardiac death syndrome: heart rate oscillations and bifurcations. Experientia. 1988;44:983–987.[Medline] [Order article via Infotrieve]
   
10. Poon CS, Merrill CK. Decrease of cardiac chaos in congestive heart failure. Nature. 1997;389:492–495.[Medline] [Order article via Infotrieve]
    
11. Johnson RL Jr. Gas exchange efficiency in congestive heart failure. Circulation. 2000;101:2774–2776.[Free Full Text]
    
12. Piepoli M, Clark AL, Volterrani M, et al. Contribution of muscle afferents to the hemodynamic, autonomic, and ventilatory responses to exercise in patients with chronic heart failure: effects of physical training. Circulation. 1996;93:940–952.[Abstract/Free Full Text]
    
13. Rebuck AS, Jones NL, Campbell EJ. Ventilatory response to exercise and to CO₂ rebreathing in normal subjects. Clin Sci. 1972;43:861–867.[Medline] [Order article via Infotrieve]
    
14. Weil JV, Byrne-Quinn E, Sodal IE, et al. Augmentation of chemosensitivity during mild exercise in normal man. J Appl Physiol. 1972;33:813–819.[Free Full Text]
    
15. Martin BJ, Weil JV, Sparks KE, et al. Exercise ventilation correlates positively with ventilatory chemoresponsiveness. J Appl Physiol. 1978;45:557–564.[Abstract/Free Full Text]
    

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This Article Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Johnson, R. L. Search for Related Content PubMed PubMed Citation Articles by Johnson, R. L., Jr Related Collections Congestive Exercise testing Pulmonary circulation and disease Other diagnostic testing Autonomic, reflex, and neurohumoral control of circulation