Gas Exchange Efficiency in Congestive Heart FailureRobert L. Johnson, Jr, MD

The lungs and heart are irrevocably linked in theiroxygen and CO2 transport functions. Functional im-pairment of the lungs often affects heart function, and

functional impairment of the heart often affects lung function.In patients with chronic congestive heart failure (CHF),exertional dyspnea is a common symptom, and ventilatoryeffort is increased at a given exercise workload despitenormal arterial blood gases. In this issue ofCirculation, theincreased exercise ventilation in CHF is reported to containprognostic information that extends beyond that provided bymaximal oxygen uptake (V˙ O2max), left ventricular ejectionfraction, or the NYHA functional classification.1 Their dataindicate that the steepness with which ventilation increasesrelative to CO2 production during incremental exercise, eitheralone or in combination with V˙ O2max, left ventricular ejectionfraction, and NYHA classification, can be a sensitive tool forpredicting event-free survival of patients with CHF. Such atool can be important for evaluating the need for hearttransplantation or for following the efficacy of therapeuticmeasures; it can be evaluated at submaximal work loads andis easier to measure than V˙ O2max.

See p 2803

The high ventilation (V˙ E) with respect to CO2 production(V̇CO2) in CHF is not a new observation,2–6 but its potentialusefulness as a prognostic tool to evaluate the severity ofCHF is relatively new. Perhaps even more important, how-ever, is what the studies of Kleber et al,1 using this tool, tellus about impaired gas exchange in CHF and its relationship toimpaired gas exchange in lung disease.

Because the high level of ventilatory drive in heart failurecan predict survival, it must contain important information onhow left ventricular dysfunction affects either the lung orventilatory control. The first thing that we need to examine,then, is what basic information is contained in the slope of therelationship between ventilation (V˙ E) and CO2 production(V̇CO2). The modified alveolar equation7 concisely describesthe determinants of the steepness with which V˙ E rises withrespect to V˙ CO2:

V̇E5F 863

PaCO2z~12VD/VT!G zV̇CO2,

whereF 863

PaCO2z~12VD/VT!G5slope,

PaCO2 5arterial CO2 tension, andVD/VT 5fraction of the tidal volume

(VT) that goes to dead space(VD).

The relationship between V˙ E and V̇CO2 by Equation 1 islinear over a wide range, and its slope is determined by just2 factors: (1) behavior of arterial CO2 tension during exerciseand (2) the VD/VT ratio. If PaCO2 is driven down by a highventilatory drive from peripheral chemoreceptors or by ergo-receptors in skeletal muscle, the slope of the V˙ E/V̇CO2

relationship will increase, or if VD/VT is high, the V̇E/V̇CO2

slope will increase. Increased chemoreceptor gain is oftenseen in severe CHF,8 eg, in patients with Cheyne-Stokesbreathing, but increased chemoreceptor gain alone will notdrive the PaCO2 down unless the set point about which PaCO2

is controlled is depressed or unless hypoxic drive or ergore-ceptor drive is high. Most studies suggest that blood gases arenormal in patients with CHF4 and that PaCO2 either stays thesame or declines modestly from rest to peak exercise, nodifferently than in normal controls. There are 2 potentialsources for a high VD/VT ratio: (1) a low tidal volume (VT)with respect to a normal anatomic dead space or (2) anabnormally high physiological dead space. Patients with CHFoften have a reduced tidal volume at heavy exercise, whichwould increase the VD/VT ratio; however, it has been esti-mated that only'33% of the increased dead space ventilationin CHF can be explained by a low VT.2,5

Current information suggests that the major source for anabnormally steep V˙ E/V̇CO2 slope in CHF is increased nonuni-formity of ventilation-perfusion ratios (V˙ /Q̇), causing ineffi-cient gas exchange. However, a word of caution is stillnecessary. The above conclusion is based on indirect evi-dence. No direct comparisons have been made of PaCO2 anddead space ventilation in CHF patients with and without ahigh V̇E/V̇CO2 slope during exercise. Such comparisons areneeded.

What might be the source of an increased nonuniformity ofpulmonary V̇/Q̇ ratios in CHF and why would it provideprognostic information not provided by V˙ O2max? Lung vol-umes and ventilatory function in the CHF patients studied byKleber et al1 were relatively normal, and arterial bloodoxygen saturation at peak exercise was normal, as is generallythe case in CHF in the absence of coexisting lung disease.This pattern of a high VD/VT ratio with normal arterial bloodgases suggests that nonuniformity of V˙ /Q̇ ratios in the lung is

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

From the Division of Pulmonary and Critical Care, Department ofInternal Medicine, University of Texas Southwestern Medical Center,Dallas, Tex.

Correspondence to Robert L. Johnson, Jr, MD, Pulmonary and CriticalCare, University of Texas Southwestern Medical Center, 5323 HarryHines Blvd, Dallas, TX 75390-9034. E-mail robert.johnson@emailswmed.edu

(Circulation. 2000;101:2774-2776.)© 2000 American Heart Association, Inc.

Circulation is available at http://www.circulationaha.org

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more likely caused by increased nonuniformity of perfusionthan of ventilation. When ventilatory capacity remains nor-mal, inefficient gas exchange caused by abnormal distributionof perfusion usually can be well compensated during exerciseby raising ventilation enough to maintain a normal PaCO2 andnormal arterial blood O2 saturation. This is not true in severechronic obstructive lung disease, in which not only areventilation and perfusion poorly matched, but also, compen-satory increases in ventilation are restricted by the highresistance to air flow; during exercise, PaCO2 rises and arterialblood O2 saturation falls. In the CHF patients studied byKleber et al1 with high V̇E/V̇CO2 slopes, mean total lungcapacity (TLC), vital capacity (VC), and lung diffusingcapacity (DLCO) were significantly lower than in patients witha normal V̇E/V̇CO2 slope, yet arterial O2 saturation remainednormal at peak exercise. DLCO is usually reduced in severeCHF9–12 and correlates significantly with V˙ O2max. A modestreduction in DLCO may reflect a more severe reduction of truemembrane diffusing capacity (DMCO), because the low DMCO

in CHF can be counterbalanced by a high pulmonary capil-lary blood volume (Vc). In patients with severe CHF (NYHAclass III) studied by Puri et al,9 DMCO was 35% of control,whereas DLCO was reduced only to 55% of control because ofa high Vc (144% of control). The low DMCO implies thatoxygen diffusing capacity (DLO2) is correspondingly reduced,which in turn will reduce the rate of oxygenation of bloodperfusing the lungs, and if the cardiac output is high enough,will cause oxygen saturation of blood leaving the lung to fallduring exercise. Some of these changes in diffusing capacityand dead space ventilation are reversible with ACE inhibitorsand diuretics, reflecting subclinical interstitial pulmonaryedema.5,13 However, persistence of a low DLCO after hearttransplantation14 implies additional structural changes inmicrovasculature, which is confirmed by morphological stud-ies. Muscular arteries and arterioles show medial hypertrophyand intimal and adventitial fibrosis with narrowing vascularlumens.15 Matrix proteins are increased in the alveolar walls,and capillary basement membranes are thickened16,17; thesechanges probably begin very early in response to a chronicincrease in pulmonary capillary blood pressure from anycause.18

In the face of an abnormally high VD/VT ratio and asignificant reduction of DLO2 in patients with severe CHF,why is maximal oxygen transport not partially limited byimpaired gas exchange associated with a rise in PaCO2 and fallin arterial O2 saturation during exercise, as usually occurs inlung disease with similar abnormalities? There are 2 reasons:

(1) Maximal ventilatory capacity is well maintained in CHFand can compensate for the high VD/VT, bringing the PaCO2

down to normal levels at peak exercise and maintaining anormal or high alveolar oxygen tension. (2) Maximal cardiacoutput (Q̇max) in CHF is reduced more than is the DLO2; hence,the ratio of DLO2/Q̇ never falls low enough during exercise tocause a fall of O2 saturation of blood leaving the lung.7

It is the low maximal cardiac output and impaired periph-eral O2 extraction that primarily impairs oxygen transport inCHF,4,19 not pulmonary gas exchange; arterial blood gasesremain normal. However, the reduced efficiency of gasexchange in CHF reflected by the steep relationship betweenV̇E and V̇CO2 is probably a major source of the exertionaldyspnea with normal arterial blood gases.

Thus, left ventricular heart failure has important effects onlung function, just as lung disease has important effects oncardiovascular function. The application of a measurementthat quantifies efficiency of gas exchange during exercise asan index of the severity of CHF and life expectancy in CHFemphasizes the important functional linkage between theheart and the lungs. The measurement used is simple and canbe applied even at low levels of exercise. It must beemphasized, however, that the measurement, ie, the slope ofthe relationship between V˙ E and V̇CO2 during exercise, isnonspecific and is frequently abnormally steep in primarylung disease as well as in CHF, although usually associatedwith abnormal arterial blood gases in lung disease. Hence, themeasurement used by Kleber et al1 must be interpreted incontext. To emphasize this, a comparison of the primarydeterminants of impaired gas exchange in CHF, chronicobstructive lung disease, and interstitial lung disease withalveolar capillary block20 are shown in the Table.

In the Table, the arrows, pointing either up or down,indicate the change in direction of the key determinants ateach step in oxygen transport for each condition. The Table isoversimplified but is conceptually useful. In CHF, the pri-mary impairment of oxygen transport is imposed by areduced maximal cardiac output (Q˙

max), indicated by a bold-face arrow pointing down. In patients with chronic obstruc-tive pulmonary disease, primary impairment of oxygen trans-port is imposed by a reduced maximal ventilation (V˙ Emax)with inefficient gas exchange, and in patients with interstitiallung disease with alveolar capillary block, the primaryimpairment is imposed by a reduced DLO2. In all of thesedisorders, uneven V˙ /Q̇ matching increases the VD/VT ratioand impairs the efficiency of CO2 excretion from the lung; ifventilation can be increased enough during increasing exer-

Determinants of Gas Exchange at Maximal Exercise in Patients With CHF andWith Primary Lung Disease

Q̇max V̇Emax DLO2 VD/VT V̇E/V̇CO2 Slope DLO2/Q̇ PaCO2 SaO2

CHF f N 2 1 1 N N N

COPD 2 f 2 1 V 2 V 2

IPF 2 2 f 1 1 f 2 f

COPD indicates chronic obstructive lung disease; IPF, interstitial pulmonary fibrosis; V, variable(can be high, normal, or low); N, normal;2, decreased;1, increased; and boldface arrow, a primarychange. In CHF, the primary determinant of V̇O2max is a low Q̇max; in COPD, the primary determinantis V̇Emax; and in IPF with alveolar capillary block, the primary determinant of V̇O2max is a low DLO2.

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cise to prevent the PaCO2 from rising, the V̇E/V̇CO2 slope willbe steeper than normal in lung disease as well as in CHF, asindicated by the bracketed term in Equation 1. In severechronic obstructive pulmonary disease, PaCO2 will rise asexercise load increases, and the V˙ E/V̇CO2 slope may becomelow even though VD/VT is high.19 Coexistent lung disease cansignificantly alter the expected pattern of gas exchange inCHF. Thus, it must be cautioned that if a patient with CHFhas significant coexistent lung disease, application of theV̇E/V̇CO2 slope to predict survival, as proposed by Kleber etal,1 becomes invalid.

In summary, available data suggest that chronic CHFinduces structural changes as well as interstitial pulmonaryedema in the lungs, which impair the efficiency of gasexchange; the extent of these changes reflects the severity ofthe CHF and probably its duration. Physiologically, thesestructural changes are manifested by an increased ratio ofdead space to tidal volume (VD/VT), which causes an abnor-mally high ventilation during exercise. They are also usuallymanifested by a reduction in diffusing capacity of the lung(DLCO), which varies with the severity of CHF. Although themagnitude of these physiological changes in lung functioncan reflect the severity of CHF and be an important predictorof survival, inefficiency of gas exchange is not the primarycause of impaired exercise capacity. Reduced maximal oxy-gen transport in CHF is caused by a low maximal cardiacoutput and perhaps impaired peripheral oxygen extraction;arterial PaCO2 and arterial O2 saturation at peak exerciseremain normal. Even though arterial blood gases remainnormal, inefficient gas exchange can be a major source ofexertional hyperpnea and dyspnea. The pattern of abnormalgas exchange during exercise in CHF clearly differs from thatin primary lung disease; problems of interpretation arisewhen CHF and primary pulmonary disease coexist.

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efficiency in heart failure: prognostic impact.Circulation. 2000;101:2803–2809.

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4. Sullivan MJ, Higginbotham MB, Cobb FR. Increased exercise ventilationin patients with chronic heart failure: intact ventilatory control despitehemodynamic and pulmonary abnormalities.Circulation. 1988;77:552–559.

5. Reindl I, Kleber FX. Exertional hyperpnea in patients with chronic heartfailure is a reversible cause of exercise intolerance.Basic Res Cardiol.1996;91(suppl 1):37–43.

6. Chua TP, Ponikowski P, Harrington D, et al. Clinical correlates andprognostic significance of the ventilatory response to exercise in chronicheart failure.J Am Coll Cardiol. 1997;29:1585–1590.

7. Hsia CCW, Johnson RL Jr. Exercise physiology and lung disease. In:Bone R, ed.Comprehensive Textbook of Pulmonary and Critical CareMedicine. St Louis, Mo: Mosby-Yearbook; 1993:sec B, 1–20.

8. Ponikowski P, Chua TP, Piepoli M, et al. Augmented peripheral chemo-sensitivity as a potential input to baroreflex impairment and autonomicimbalance in chronic heart failure.Circulation. 1997;96:2586–2594.

9. Puri S, Baker BL, Dutka DP, et al. Reduced alveolar-capillary membranediffusing capacity in chronic heart failure: its pathophysiological rel-evance and relationship to exercise performance.Circulation. 1995;91:2769–2774.

10. Kraemer MD, Kubo SH, Rector TS, et al. Pulmonary and peripheralvascular factors are important determinants of peak exercise oxygenuptake in patients with heart failure.J Am Coll Cardiol. 1993;21:641–648.

11. Siegel JL, Miller A, Brown LK, et al. Pulmonary diffusing capacity in leftventricular dysfunction.Chest. 1990;98:550–553.

12. Wright RS, Levine MS, Bellamy PE, et al. Ventilatory and diffusionabnormalities in potential heart transplant recipients.Chest. 1990;98:816–820.

13. Guazzi M, Marenzi G, Alimento M, et al. Improvement of alveolar-capillary membrane diffusing capacity with enalapril in chronic heartfailure and counteracting effect of aspirin.Circulation. 1997;95:1930–1936.

14. Schwaiblmair M, von Scheidt W, U¨ berfuhr P, et al. Lung function andcardiopulmonary exercise performance after heart transplantation:influence of cardiac allograft vasculopathy.Chest. 1999;116:332–339.

15. Smith RC, Burchell HB, Edwards JE. Pathology of the pulmonaryvascular tree, IV: structural changes in pulmonary vessels in chronic leftventricular failure.Circulation. 1954;10:801–808.

16. Harris P, Heath D. Structural changes in the lung associated with pulmo-nary venous hypertension. In:The Human Pulmonary Circulation: ItsForm and Function in Health and Disease. 2nd ed. New York: ChurchillLivingstone; 1977:332–351.

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18. Parker JC, Breen EC, West JB. High vascular and airway pressuresincrease interstitial protein mRNA expression in isolated rat lungs.J ApplPhysiol. 1997;83:1697–1705.

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KEY WORDS: Editorials n exercisen dyspnean hyperpnean blood gases

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Robert L. Johnson, JrGas Exchange Efficiency in Congestive Heart Failure

Print ISSN: 0009-7322. Online ISSN: 1524-4539 Copyright © 2000 American Heart Association, Inc. All rights reserved.

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