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(Chest. 2000;117:321-332.)
© 2000 American College of Chest Physicians

Ventilatory Constraints During Exercise in Patients With Chronic Heart Failure*

Bruce D. Johnson, PhD; Kenneth C. Beck, PhD; Lyle J. Olson, MD; Kathy A. O’Malley; Thomas G. Allison, PhD; Ray W. Squires, PhD and Gerald T. Gau, MD, FCCP

* From the Divisions of Cardiovascular (Drs. Johnson, Olson, Allison, Squires, and Gau) and Thoracic Diseases (Dr. Beck and Ms. O’Malley), Department of Internal Medicine, Mayo Clinic and Foundation, Rochester, MN. The study was supported by the Mayo Foundation and Human Health Services grant MO1-RR00585, General Clinical Research Centers, Division of Research Resources, National Institutes of Health.

Correspondence to: Bruce D. Johnson, PhD, Division of Cardiovascular Diseases, Baldwin 2B, Mayo Clinic, Rochester, MN 55905; e-mail: johnson.bruce{at}mayo.edu


   Abstract
TOP
 Abstract
Introduction
 Materials and Methods
 Results
 Discussion
 References
 
We examined the degree of ventilatory constraint in patients with a history of chronic heart failure (CHF; n = 11; mean ± SE age, 62 ± 4 years; cardiac index [CI], 2.0 ± 0.1; and ejection fraction [EF], 24 ± 2%) and in control subjects (CTLS; n = 8; age, 61 ± 5 years; CI, 2.6 ± 0.3) by plotting the tidal flow-volume responses to graded exercise in relationship to the maximal flow-volume envelope (MFVL). Inspiratory capacity (IC) maneuvers were performed to follow changes in end-expiratory lung volume (EELV) during exercise, and the degree of expiratory flow limitation was assessed as the percent of the tidal volume (VT) that met or exceeded the expiratory boundary of the MFVL. CHF patients had significantly (p < 0.05) reduced baseline pulmonary function (FVC, 76 ± 4%; FEV1, 78 ± 4% predicted) relative to CTLS (FVC, 99 ± 4%; FEV1, 102 ± 4% predicted). At peak exercise, oxygen consumption (O2) and minute ventilation (E) were lower in CHF patients than in CTLS (O2, 17 ± 2 vs 32 ± 2 mL/kg/min; E, 56 ± 4 vs 82 ± 6 L/min, respectively), whereas E/carbon dioxide output was higher (42 ± 4 vs 29 ± 5). In CTLS, EELV initially decreased with light exercise, but increased as E and expiratory flow limitation increased. In contrast, the EELV in patients with CHF remained near residual volume (RV) throughout exercise, despite increasing flow limitation. At peak exercise, IC averaged 91 ± 3% and 79 ± 4% (p < 0.05) of the FVC in CHF patients and CTLS, respectively, and flow limitation was present over > 45% of the VT in CHF patients vs < 25% in CTLS (despite the higher E in CTLS). The least fit and most symptomatic CHF patients demonstrated the lowest EELV, the greatest degree of flow limitation, and a limited response to increased inspired carbon dioxide during exercise, all consistent with E constraint. We conclude that patients with CHF commonly breathe near RV during exertion and experience expiratory flow limitation. This results in E constraint and may contribute to exertional intolerance.

Key Words: ejection fraction • end-expiratory lung volume • flow limitation • left ventricular dysfunction • ventilatory limitation


   Introduction
TOP
 Abstract
 Introduction
Materials and Methods
 Results
 Discussion
 References
 
It remains controversial as to the degree that the pulmonary system contributes to exercise intolerance that is associated with chronic heart failure (CHF).1 Patients with CHF often demonstrate changes in resting pulmonary function, which may include combined obstructive and restrictive changes.2 These changes are thought to be related to weakened respiratory muscles, increased heart size, pulmonary hypertension, and chronic, "subclinical" edema. The effect of reduced pulmonary function is a reduction in breathing reserve (ie, the maximal available ventilation relative to the ventilation necessary for a given task). Despite the decreased breathing reserve, patients with CHF typically have an enhanced ventilatory demand for a given metabolic demand (increased minute ventilation [E]/carbon dioxide output [CO2]), particularly during exercise.1 Thus, the potential for mechanical constraints to ventilation in this population is enhanced.

Although studies examining the E/maximum voluntary ventilation (MVV) relationship generally do not suggest a ventilatory limitation in patients with CHF, this relationship may not be a valid index, particularly in this population. The MVV reflects a maximal volitional effort at a time when the respiratory muscles are not competing for blood flow with locomotor muscles and are in a nonfatigued state. In addition, studies have suggested an exercise-induced bronchoconstriction in this population that could change the maximal available expiratory flows (capacity).3 The breathing reserve is also dependent on where one "chooses" to breathe relative to total lung capacity and residual volume (RV; ie, the regulation of end-expiratory lung volume [EELV]). At low lung volumes, the available maximal expiratory airflows are limited due to airway narrowing or closure and the resultant shape of the expiratory flow-volume (FV) curve. At high lung volumes, while considerable airflow is available, the elastic load on inspiration increases, which may be particularly detrimental to the patient with CHF (given the proposed inspiratory muscle weakness). Thus, a more comprehensive evaluation of the degree of ventilatory constraint may provide additional insight into the etiology of severe exertional dyspnea.

The purpose of the following study was to examine the regulation of EELV, to determine the degree of ventilatory constraint (as implied by the degree of expiratory flow limitation), and to assess changes in airway function (as implied by changes in the shape of the expiratory FV envelope) in patients with a history of CHF during progressive exercise.


   Materials and Methods
TOP
 Abstract
 Introduction
 Materials and Methods
Results
 Discussion
 References
 
Subjects
Nineteen subjects, 11 with a history of CHF (7 men and 4 women) and 8 control subjects (CTLS; 5 men and 3 women with no history of cardiac or pulmonary problems) participated in the study. Entry criteria for CHF patients included at least a 1-year history of known CHF, New York Heart Association (NYHA) class II or III symptoms, ejection fraction (EF) < 30% (baseline echocardiogram), no history of dangerous arrhythmias, no pacemakers, and typically at least one prior hospitalization for CHF. Age- and gender-matched individuals who were not engaged in an exercise routine served as CTLS. Five of the 11 CHF patients (averaging < 15 pack-years) and 3 of 8 CTLS (averaging < 10 pack-years) had previously smoked. All subjects had quit smoking at least 15 years prior to the study. All subjects gave informed consent to participate in the study that had been approved by the Institutional Review Board of the Mayo Clinic and Foundation. All subjects had been exposed to exercise testing on one or more occasions prior to the study test. Four subjects had performed cycle ergometry (two CTLS and two CHF patients), and the rest had performed treadmill exercise. The majority of CHF patients were taking a combination of angiotensin-converting enzyme inhibitors, diuretics, and digoxin. None were taking ß-blockers, one was taking a calcium channel blocker, and one was taking nitrates. None of the CTLS were taking prescription medications at the time of the study.

General Protocol
All subjects performed baseline lung volume testing in a body plethysmograph (model 1085; Medical Graphics; St. Paul, MN) on a day separate from the exercise testing. Exercise was performed in the Mayo Clinic General Clinical Research Center Exercise Core Laboratory. Treadmill exercise consisted of a protocol incremented by two METs every 2 min, starting with two miles per hour (mph) and a 0% grade. (One MET is the approximate rate of O2 of an individual at rest, 3.5 mL/kg/min.) Cycle ergometry consisted of increments ranging from 10 (for CHF patients) to 30 W (for CTLS), depending on the initial fitness of the subject. All subjects exercised to a perceived exertion level of 18 to 20 on the Borg scale (6 to 20 scale).4 Dyspnea was assessed using a simple four-point scale, ranging from no shortness of breath, to mild, moderate, and severe dyspnea. A resting cardiac output was determined in triplicate for each subject for a determination of cardiac index (CI) using the acetylene rebreathe technique.5

General Setup
The subjects breathed through a low resistance Hans Rudolph (HnsR) pneumotachograph (model 3800; Hans Rudolph; Kansas City, MO) that was heated to 37°C and connected to a disposable pneumotachograph (Prevent Pneumotachs; Medical Graphics). The total dead space of the breathing apparatus was 120 mL. The HnsR pneumotachograph was connected to a transducer (Validyne Engineering; Northridge, CA) and demodulator, and the flow signal was digitized at the rate of 100 samples/s and stored on computer for later analysis. The HnsR pneumotachograph was used to measure inspired and expired flow rates for assessment of tidal exercise FV loops and the maximal volitional FV envelopes. The Medical Graphics pneumotachograph was used for the measurement of breath-by-breath ventilation, oxygen consumption (O2), and CO2 throughout exercise. Prior to beginning the study, a linearization look-up table was determined for the HnsR pneumotachograph over a range of flow rates (0 to 15 L/s). Before each exercise test, both pneumotachographs were calibrated with a 3-L syringe. Expired gases were sampled at the mouth via a mass spectrometer (model 1100; Perkin-Elmer; Norwalk, CT) that was calibrated with gravimetric-quality gases. Oxygen saturation was measured via a pulse oximeter (model N200; Nellcor Puritan Bennett; Pleasanton, CA). All subjects were followed with a 12-lead ECG using a cardiac monitor (model Q4500; Quinton; Bothell, WA).

FV Measurements
Tidal FV loops (extFVLs) were measured at rest, prior to exercise, and during the last 30 s of each exercise intensity. Maximal FV maneuvers were performed in conjunction with the tidal breaths at rest and during each exercise intensity, as well as within 5 min postexercise and again after 15 to 20 min. The extFVLs were collected without perception by the subjects. Typically, five to eight tidal breaths were collected followed by instructions to take a deep inspiration to total lung capacity (TLC), the inspiratory capacity (IC) maneuver. This was followed by an additional five breaths and a second IC maneuver followed by a FVC maneuver. On analysis, drift in the volume signal was corrected by aligning the tidal breaths according to the two IC maneuvers (assuming that TLC did not change). The IC maneuver was practiced repeatedly at rest prior to exercise to help ensure that a complete inspiration would be accomplished throughout the exercise period. The coefficient of variation for CHF patients and CTLS for multiple IC maneuvers that were performed prior to exercise averaged < 4%.

Data Analysis
For each subject tested, two drift-corrected extFVLs were averaged for rest and at each exercise intensity using a computer program developed at Mayo. The average loops were then plotted separately within each subject’s maximum flow-volume envelope (MFVL; obtained at the same specific time point) to assess the degree of ventilatory constraint. For presentation, all tidal and maximal FV data were averaged for each group (CHF patients and CTLS) at rest and at three different work intensities (50%, 75%, and 100% of peak O2).

Indexes of Ventilatory Constraint
Change in EELV:
The change in EELV was determined by the change in IC (ie, TLC - IC), which assumed that TLC did not change significantly during the exercise.6 Previous studies7 have shown that EELV falls during exercise in normal subjects, but as expiratory flow limitation occurs, EELV increases to gain access to flows at the higher lung volumes. Thus the change in EELV from rest to exercise was considered to be a possible indicator of the presence of ventilatory limitation. EELV was also expressed as IC/vital capacity (VC) to help identify where EELV occurred in relation to the available VC.

Expiratory Flow Limitation:
The degree of expiratory flow limitation was defined as the degree to which the tidal flows during exercise met or exceeded the MFVL measured during the same time period.8 The expiratory flow limitation was expressed as the percent of the tidal volume (VT) over which expiratory flow met or exceeded the MFVL flow at the same lung volume.

Inspiratory Flow Capacity:
Inspiratory flow capacity was determined by how close the inspiratory phase of the tidal breath came to the maximal inspiratory flows generated by the forced inspiratory maneuvers. The point chosen during the inspiratory phase of the tidal breath was the lung volume where tidal flow was closest to maximum. This varied for each subject and often was not the peak exercise inspiratory flow, since this tended to occur at lower lung volumes. More often, this occurred at higher lung volumes, when the inspiratory flow generating capacity may be reduced due to the shortened inspiratory muscles.9

End-Inspiratory Lung Volume Expressed as a Percent of TLC:
At higher lung volumes, the load, work, and cost of breathing increase. End-inspiratory lung volume (EILV; ie, EELV + VT) is the highest lung volume achieved during a tidal breath; when expressed relative to TLC (EILV/TLC), it gives an index of elastic load presented to the inspiratory muscles.

Maximal Estimated Ventilation Available for a Given Breathing Pattern:
The maximal estimated ventilation available for a given breathing pattern (ECAP) was estimated based on the maximal available inspiratory and expiratory airflow over the range of the actual tidal breath for each exercise intensity placed at the measured EELV. ECAP is not dependent on volitional effort to the same extent as the MVV, and it takes into account the breathing pattern and dynamic changes in airway function that may occur during exercise. The methods used for the determination of ECAP have been previously described.8 Briefly, the extFVL is aligned within the MFVL according to the measured EELV. The tidal breath is divided into 50 equal volume segments ({Delta}V). An estimated minimal expiration time duration (TE) is determined by dividing each {Delta}V by the average maximal expiratory flow within each {Delta}V, and summing all such times over the expiratory phase of VT, expressed as follows:

where MEFe = average maximal expiratory flow, and {Sigma}Te = sum of the times over the expiratory phase of VT. Measured inspiratory to total breathing cycle time is used to estimate minimal inspiratory time. The sum of minimal inspiratory time and TE gives a minimal breathing cycle time and maximal breathing frequency. The product of maximal breathing frequency and measured VT equals ECAP. ECAP determined in this manner has been shown to decrease with low-level exercise in normal subjects (secondary to a decrease in EELV) and to subsequently increase significantly as VT increases through encroachment on the inspiratory reserve volume (IRV).

Limitations to Indexes of E Constraint:
The assessment of expiratory flow limitation and ECAP are dependent on appropriately defining maximal expiratory flows. We chose to make these measurements using the exercise breathing circuit and the classical maximal expiratory maneuver. However, previous studies10 have demonstrated gas compression, particularly over the lower lung volumes (the effort-independent portion of the MFVL), with excessive expiratory pressure generation. The compression is particularly apparent in patients having significant airflow obstruction, but it may result in a loss in volume of as much as 3 to 5% of the VC at 25 to 50%, respectively, of the full inflation volume in healthy subjects.10 Due to the gas compression, it is possible that the maximal expiratory flow rates measured may underestimate the flow rates that are truly available. As a result, the degree of expiratory flow limitation may be overestimated, while the estimated ECAP may be slightly underestimated using our definitions. However, we believe that these errors are likely small, given the lack of significant obstructive changes in our subjects. In addition, during exercise tidal breathing, large expiratory pressures may also be produced, which could also cause some gas compression in our subjects.9 Thus, the flows estimated in a body plethysmograph may not be fully available to the flow-limited subject. Previous studies9 10 have also demonstrated a gradual plateau in the relationship of expiratory flow to pleural pressure production as voluntary expiratory effort is increased, suggesting that flow limitation may begin to occur (ie, increase in effort out of proportion to flow) prior to "true" flow limitation (ie, increase in effort with no increase in flow). Thus, our estimate of expiratory flow limitation likely represents "near or impending" flow limitation, rather than absolute limitation; however, significant expiratory flow constraint would still exist. Clearly, flow limitation can occur throughout expiration or only over a portion of the expiratory breath. The present definition represents the percentage of the tidal breath that reaches or exceeds that described by the MFVL.

Although the assessment of ECAP offers a specific index of ventilatory capacity based on the shape of the maximal expiratory flows, the VT achieved, and the regulation of EELV during exercise, it may slightly overestimate the available breathing capacity, particularly when the tidal breath occurs at high lung volumes. The calculation of ECAP assumes an instantaneous increase in flow at the onset of expiration. At high lung volumes, this would require extremely large expiratory pressures, which make it unlikely that such a pattern would be adopted during exercise. At lower lung volumes, where most normal tidal breathing occurs, ECAP likely represents a reasonable assessment of the ‘true’ ventilation that is available.8


   Results
TOP
 Abstract
 Introduction
 Materials and Methods
 Results
Discussion
 References
 
Baseline Characteristics
Table 1 lists the subject characteristics of the CHF and control groups. No significant differences were observed between the groups for age, height, and weight, although the CTLS tended to be slightly taller and lighter. The CI was lower in the CHF group relative to the control group. The majority of CHF patients were NYHA class III, and the average EF was 24%, as determined by echocardiography.


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  		Table 1. Subject Characteristics*

 
Pulmonary Function
Baseline lung volumes and maximal flow rates are shown in Table 2 for CHF patients and CTLS. The CHF patients demonstrated primarily a restrictive pattern, with a reduced TLC, VC, and functional residual capacity (FRC) relative to CTLS, while RV was similar to CTLS and predicted values. The RV/TLC relationship was increased and the FEV1/FVC relationship was slightly reduced (74% vs 80%, respectively), also suggesting a mild obstruction in CHF patients. Figure 1 clearly illustrates the reduction in lung volumes that was observed in patients with CHF relative to the age- and gender-matched CTLS. The mean MFVL was plotted for each group and was placed according to the mean absolute lung volumes for CHF patients and CTLS. Although at a given lung volume, flows were similar or increased in CHF patients, FEV1 and forced expiratory flow after 50% of vital capacity had been expelled (FEF50) were reduced consistent with a decrease in flow reserve.


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  		Table 2. Maximal Lung Volumes and Flow Rates*

 


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  		Figure 1. Average MFVLs for CHF patients (dashed) and CTLS (solid) for maneuvers performed preexercise, plotted according to mean absolute lung volumes for each group. Patients with a history of CHF demonstrated primarily restrictive changes but also had reduced FEV1 and FEF50, significantly reducing the available ventilatory capacity for use during exercise.

 
Ventilatory and Metabolic Changes During Exercise
The ventilatory and metabolic changes associated with exercise are shown in Table 3 for each group. The data shown are from at rest, and at 50%, 75%, and 100% of peak exercise. Peak O2 was 65% and 116% of predicted for the CHF patients and CTLS, respectively. The CHF patients had a significantly smaller increase in VT during exercise, but achieved a similar percent of their VC relative to the CTLS. E/CO2 was significantly elevated throughout exercise in the CHF patients. Oxygen saturation measured by ear oximetry decreased 3% from rest to peak exercise in CTLS (97% vs 94%, respectively) and a similar amount in CHF patients (95% vs 92%, respectively).


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  		Table 3. Ventilatory and Metabolic Changes During Exercise*

 
Ventilatory and metabolic changes at matched Es are shown in Table 4 . On average, the work intensity was 2.1 mph with an 11.7% grade for CTLS, and 1.9 mph with a 9.2% grade for CHF patients, or an estimated 136 W and 132 W for each group, respectively. At approximately 50 L/min, the CHF patients were more tachypneic with a reduced VT relative to the control subjects and at the matched Es, the CHF group used a greater percent of VC. As expected, from the elevated E/CO2 (Table 1) , the O2 at the similar E is significantly reduced in CHF patients relative to CTLS.


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  		Table 4. Ventilatory Changes and Indexes of Ventilatory Constraint at Iso-E During Exercise*

 
FV Responses to Exercise and Changes in EELV
Figure 2 shows the FV responses to exercise in CTLS (left panel) and CHF patients (right panel). Shown are the mean responses for each group at rest, and at 50%, 75%, and 100% of peak exercise. Maximal volitional FV envelopes are shown for rest and peak exercise only. Table 5 lists the mean indexes of ventilatory constraint for each extFVL that is plotted in Figure 2 . The CTLS demonstrated a significant (p < 0.05) decrease in EELV with mild to moderate exercise; however, as expiratory flow limitation developed, EELV increased slightly over the lowest values that were observed. In CHF patients, EELV was reduced at rest (relative to CTLS) and decreased slightly with low to moderate exercise. With increased ventilatory demands of heavier exercise intensities, EELV remained near RV despite significant expiratory flow limitation and apparent room to increase EELV by encroachment on the IRV. By peak exercise, expiratory tidal flows reached maximal available flows over 47% of the VT in CHF patients, relative to 24% of the VT in CTLS. EILV reached a higher percent of TLC in CTLS than in CHF patients, and the inspiratory flows generated during exercise reached a similar percent of the maximal available inspiratory flow. Interestingly, the point where tidal inspiratory flows came closest to maximal available flows occurred at a higher lung volume (relative to TLC) in CTLS than in CHF patients. Figure 3 shows an extreme example of a CHF patient with altered regulation of EELV with an IC that approaches or equals the VC throughout exercise.



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  		Figure 2. The FV response to exercise in CTLS (left panel) and CHF patients (right panel). Shown are the mean extFVLs obtained at rest and during exercise at 50% of peak O2 (exercise stage 1 [Exer1]), at 75% of peak O2 (exercise stage 2 [Exer2]), and at 100% of peak O2 (exercise stage 3 [Exer3]), plotted within the mean MFVL obtained at rest and during peak exercise. In CTLS, EELV fell with mild to moderate exercise but increased to minimize expiratory flow limitation. In contrast, CHF patients had a reduced EELV at rest that remained persistently reduced throughout exercise, resulting in significant expiratory airflow limitation and a reduced breathing reserve.

 

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  		Table 5. Indices of Ventilatory Constraint*

 


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  		Figure 3. The FV response to exercise in a patient (Subject M) with NYHA Class III CHF (O2, 16.2 mL/kg/min; EF, 21%). This patient represents an extreme example of an altered regulation of EELV during exercise (IC/VC, 100%). Pre-Exer = preexercise; pk = peak; peak exer = peak exercise.

 
At a matched ventilation (Table 4) , differences in the degree of ventilatory constraint and the breathing pattern between CHF patients and CTLS were more apparent. Flow limitation was present over 47% of the VT in CHF patients compared to 13% in CTLS, and inspiratory flows in CHF patients reached a higher percent of the available flows, but at a lower lung volume. EILV reached a similar percent of TLC, and the ratio of E to ECAP demonstrated a significantly reduced breathing reserve in CHF patients.

Changes in Ventilatory Capacity With Exercise
The coefficient of variation for FVC, FEF50, and FEV1 for repeat MFVLs within a workload during exercise averaged 2.03 ± 0.31%, 3.94 ± 0.47%, and 3.77 ± 0.3%, respectively, in CHF patients and 3.46 ± 0.80%, 2.51 ± 0.60%, and 2.47 ± 0.70%, respectively, in CTLS. Figure 4 shows the average MFVLs for CHF patients and CTLS for preexercise, for each exercise stage, and postexercise. A progressive increase in the expiratory boundary of the MFVL occurred during exercise in both groups; however, this was significant only in CTLS. The percent increase in the FEF50 averaged 6% for CHF patients and 38% in CTLS. The increase in the maximal expiratory flows resolved during the early recovery period. None of the subjects showed a drop in flows postexercise of > 10% (negative exercise asthma response). ECAP increased only slightly in CHF patients from an estimated 62 to 73 L/min by peak exercise. The lack of a significant increase was due not only to the lack of bronchodilation, but primarily due to the persistently reduced EELV and expiratory flow limitation. In CTLS, the ECAP increased from 88 to 146 L/min due to bronchodilation, an increase in VT (encroachment on the IRV), and movement of the extFVL away from the lower maximal expiratory flows by the small increase in EELV (by peak exercise).



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  		Figure 4. Changes in ventilatory capacity with exercise in CTLS (left panel) and in CHF patients (right panel). Mean MFVLs are shown for preexercise (Pre), and at 50% (Exer1), 75% (Exer2), and 100% of peak O2 (Exer3), and postexercise (Post). The CTLS demonstrated a progressive increase in FEV1 and FEF50 throughout exercise that resolved during postexercise maneuvers. The CTLS demonstrated a significantly greater increase in FEV1 and FEF50 during exercise relative to the CHF subjects, (p < 0.05). See Figure 2 for expansion of abbreviations.

 
Changes in Perceived Exertion and Dyspnea During Exercise
Both CHF patients and CTLS exercised to a similar mean level of perceived exertion (17.7 ± 0.4 and 17.6 ± 0.3, respectively). Only one control subject complained of moderate to severe shortness of breath by peak exercise (mean, 2.1 ± 0.2), while three CHF patients complained of moderate shortness of breath and three complained of severe shortness of breath (mean, 2.8 ± 0.4). It should be noted, however, that it was not always possible in the CHF patients to assess ratings of dyspnea, along with the other exercise measurements (ie, perceived exertion, IC, and MFVL maneuvers) prior to completion of exercise due to the abruptness of symptoms that terminated the test. In these cases, the ratings were obtained from the patients postexercise on how they felt during exercise. With this limitation in mind, there was a tendency for the degree of dyspnea to be associated with the amount of expiratory flow limitation and the IC/VC ratio in CHF patients (r2 = 0.53 and 0.61, respectively; p < 0.05), but not in CTLS. The CHF patients with the greatest expiratory flow limitation also demonstrated the highest IC/VC ratios (r2 = 0.54; p < 0.05), indicating that the flow limitation was associated with lower EELVs.


   Discussion
TOP
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
References
 
The present investigation examined the FV responses to progressive exercise relative to the capacities established by the maximal volitional FV envelope in patients with a history of CHF compared to age- and gender-matched healthy subjects. The CHF group displayed primarily restrictive changes in baseline lung volumes, which, along with decreased expiratory flow rates, significantly decreased the available E capacity (~ 30%). At rest and during exercise, IC remained at a high percentage of the VC (EELV near RV) and significant expiratory flow limitation was present. Despite the degree of expiratory flow limitation, the CHF patients continued to breathe at reduced EELVs; by peak exercise, the IC was > 90% of the measured VC. This was in contrast to the healthy subjects, who increased EELV as expiratory flow limitation developed. The persistently reduced EELV and flow limitation in the CHF patients occurred despite apparent reserve to increase both VT and inspiratory flow further by encroachment on the IRV and the inspiratory flow capacity. Based on the small difference between E and ECAP at peak exercise, significant E constraint was observed and may contribute to the limited exercise tolerance and dyspnea observed in patients with more severe CHF.

Baseline Lung Volumes and Flow Rates
Previous studies have examined baseline changes in lung volumes and maximal flow rates in patients with stable CHF.2 14 Differing patterns have been reported, including little change from age and height predicted, mainly restrictive changes, obstructive changes,3 15 and combined restrictive and obstructive changes.1 16 17 18 Multiple factors can contribute to the restrictive changes, including increased heart size, weakened inspiratory muscles, and chronic pulmonary hypertension. More recently, it has also been suggested that increased levels of circulating cytokines in patients with CHF may also contribute to the observed changes.19 It is, however, difficult to separate changes in pulmonary function due to the history of CHF as opposed to changes due to smoking history, environmental exposure, and previous coronary artery bypass surgery. Three of the CHF patients in the present study had previous coronary artery bypass surgery, while two of these patients along with three others had a prior smoking history that could have accounted for some of the observed mild obstructive changes.

Breathing Reserve During Exercise
The reduced volume and flow capacities in CHF patients clearly reduces the available breathing reserve during exercise. Previous studies, however, have focused on the relationship of the peak exercise E to the MVV or some estimate of the maximal breathing capacity, such as FEV1 multiplied by 35 or 40.1 20 In these studies, as well as in our own, peak exercise E only approaches 50 to 70% of these estimates of the maximal breathing capacity; therefore, it has been concluded that pulmonary mechanical constraints do not likely contribute to the observed dyspnea or exercise intolerance in patients with CHF. However, this approach to the assessment of ventilatory constraint ignores where subjects "choose" to breathe in relationship to the constraints imposed by the MFVL. Clearly, at low lung volumes (near RV), due to the shape of the MFVL, expiratory flow limitation can occur with minimal increases in tidal flows. On the other hand, breathing at high lung volumes (even in healthy subjects) increases the elastic load and the cost of breathing.21

In the present study, we estimated a ventilatory capacity (ECAP) that was dependent on the size of the tidal breath and the regulation of EELV as well as the shape of the MFVL. Using this approach, the patients with CHF were already at 43% of their ventilatory capacity at rest relative to 18% using the traditional estimates (FEV1 multiplied by 35 or 40); by peak exercise, they were at almost 90% of their estimated ECAP. This was in contrast to the age-matched subjects who reached only 60% of their estimated ECAP by peak exercise. Although both the CHF patients and CTLS were at a similar percentage of their estimated MVV (FEV1 x 40) during exercise, because the CHF patients breathed at such low EELVs, little true expiratory flow reserve and thus breathing reserve was available.

The degree of ventilatory constraint is not only dependent on the E capacity, but also on the E demands associated with exercise. We have previously shown that highly trained young endurance athletes will develop fairly severe E constraint, however at metabolic demands that significantly exceed that of their sedentary counterpart.22 Similarly, older fit adults also approach the capacities of their lung and chest wall for producing expiratory flow and inspiratory pleural pressures during exercise.7 9 In these groups of healthy subjects with normal lung function, E demand plays a critical role in defining the degree of constraint. In contrast, the CHF subjects, despite poor exercise tolerance and relatively reduced E demands, also demonstrated significant E constraint. Interestingly, the least fit of the CHF patients tended to have the lowest EELVs, the greatest degree of expiratory flow limitation, and the smallest baseline FVCs (r2 for IC/VC; percent VT flow limited at peak exercise vs peak O2; and % predicted FVC vs O2 peak was 0.45, 0.50 and 0.42 respectively, p < 0.05), suggesting that exercise capacity did not play a significant role in this population in defining the degree of constraint, but rather the breathing strategy and baseline pulmonary function, as well as the fact that the subjects with the lowest O2 peaks tended to have a higher E demand for a given CO2.

We also noted bronchodilation in the older healthy subjects that was not apparent in CHF patients. The exercise-induced increase in the expiratory boundary of the MFVL has been previously reported7 in older adults and plays a significant role in increasing ECAP. The mechanism for the increase in airflow with exercise remains controversial but may include the release of vagal tone, increased plasma catecholamines, and/or other exercise-induced modulators of airway tone.9 It is unclear why such a response was not noted in CHF patients; however, previous studies3 have suggested increased bronchial reactivity in CHF patients with methacholine and exercise. It is also possible that an increased pulmonary blood flow in the CTLS may transiently alter lung compliance and thus improve recoil, reducing airway compression during the FVC maneuvers. If the lungs of CHF patients are less compliant prior to exercise, exercise-induced changes in expiratory air flows may be less evident.

Expiratory Flow Limitation and Regulation of EELV
A previous study by Duguet et al23 suggested that some patients with acute left heart failure may experience expiratory flow limitation at rest, as assessed by the negative inspiratory pressure technique. The majority of the flow limitation was only observed when the patients were in the supine position (which tends to decrease EELV), and the flow limitation tended to be related to the reported orthopnea. Expiratory flow limitation may be expected with acute exacerbations of left ventricular (LV) dysfunction, as pulmonary edema results in obstructive airway changes, but may not be expected in patients with stable LV dysfunction and a minimal smoking history. Interestingly, in the present study, expiratory flow limitation was observed at rest in 6 of 11 patients in the seated position and was present in all subjects by peak exercise.

Some of the resting flow limitation in CHF patients may be due to active expiration and recruitment of expiratory muscles as a result of adding a mouthpiece with a small amount of dead space, or it may be due to the anticipation of exercise. This is implied, in part, by a slightly lower FRC obtained using IC maneuvers immediately prior to exercise compared to the values obtained using the body plethysmograph. In addition, there may be some gas compression when performing the maximal expiratory maneuvers, and thus the degree of expiratory flow limitation at rest (and during exercise) may be overestimated.10 As noted in Materials and Methods (limitations of indexes of E constraint), our definition of flow limitation likely represents impending flow limitation (ie, the shoulder of the transpulmonary pressure vs flow relationship as flow begins to plateau with increasing effort), rather than the point of absolute flow constraint.10 However, it is at this point that transpulmonary pressure begins to increase out of proportion to flow, and effort beyond it is generally avoided during exercise.9

When no flow limitation is present and there is an exponential decay of volume against time, the difference between the dynamically determined FRC (EELV), as occurs during exercise, and the relaxation volume of the respiratory system is dependent on the VT, the TE, and the time constant for emptying of the respiratory system, as described in the following equation:24

where Vr = relaxation volume of the respiratory system, trs = time constant for emptying of the respiratory system, and exponential to the base e = 2.718282. During exercise in our subjects, as VT increased and TE decreased, and if it is presumed that the time constant (resistance x compliance) does not change appreciably from rest, it would be predicted that EELV would increase. However, tonic or phasic activation of expiratory muscles increases expiratory flow rate and maintains or even reduces EELV. Thus, the patients with CHF and the CTLS must recruit expiratory muscles to increase expiratory flow rates to maintain or reduce EELV. However, with expiratory flow limitation, despite further recruitment of expiratory muscles, the expired volume that is required to maintain EELV may not be exhaled before the ensuing inspiration begins; therefore, EELV may be expected to rise (dynamic hyperinflation). This would be the presumed mechanism of the increase in EELV in CTLS. The fact that EELV does not increase in the CHF group despite the apparent expiratory flow limitation (as defined) suggests that time was adequate for maintaining a given expiratory VT and a constant level of emptying, or that the degree of expiratory flow limitation was not significant enough to cause a rise in EELV. It is likely that lung compliance is reduced in CHF patients (relative to CTLS), which would improve recoil and help reduce dynamic compression of the airways during FVC maneuvers.18 Further decreases in compliance with exercise due to a rise in pulmonary blood flow, an increase in left atrial pressure, and a concomitant rise in pulmonary vascular resistance, increasing central blood volume, may further augment lung recoil and allow CHF patients to maintain a reduced EELV.25 Further studies assessing pleural pressure development would help determine the extent of the flow-limiting pressures produced in CHF patients during exercise.

Reasons for a Reduced EELV in CHF
Potential reasons for the reduced EELV during exercise in CHF patients are speculative but may include the following: altered mechanics (due to the baseline restrictive changes and an increased elastic load), weakened inspiratory muscles, inspiratory muscle fatigue, and altered ventilatory control.

Decreased lung compliance, alone or along with an increase in thoracic and abdominal girth (secondary to increased weight) that occurs in some CHF patients, increases the inspiratory load, possibly limiting the rise in EILV.25 To maintain an adequate VT, EELV would need to be reduced. Previous studies26 have also reported reduced inspiratory muscle strength in patients with CHF. Thus, it may be beneficial to keep EELV low to optimize inspiratory muscle length and force production.9 There may also be some recoil (passive stretch) provided to the inspiratory muscles by the active expiration of expiratory muscles, which could assist the ensuing inspiration.7 9 Obesity represents another population in whom EELV is often reduced at rest and during exercise, presumably due to the inspiratory loads relative to the capacities of the inspiratory muscles. Our CHF patients did tend to be heavier than our CTLS; however, this was not significant. In the obese population, EELV was reported27 to increase during exertion when significant expiratory flow limitation developed.

Our CHF patients were at a reduced EILV/TLC ratio relative to CTLS at peak exercise; however, it is unclear if the load presented to the inspiratory muscles was similar or actually increased in the CHF patients. Both groups achieved inspiratory tidal flows that approached a similar percent of the maximal available inspiratory flows, suggesting that the inspiratory flow-generating reserve of the inspiratory muscles at peak exercise was similar (but occurred at lower lung volumes in the CHF patients).

With limited cardiac output, already weakened inspiratory muscles, and competition for blood flow between the inspiratory muscles and locomotor muscles, the likelihood of developing respiratory muscle fatigue is enhanced.1 28 High lung volumes (reduced muscle length) and an increased elastic load in this population (due to a decrease in lung compliance) would increase the work and cost of breathing, thus enhancing the potential mechanisms for fatigue.29 30 Mancini et al30 measured serratus anterior muscle oxygenation in CHF patients using near-infrared spectroscopy and found progressive deoxygenation with exercise. However, in a subsequent study, no fatigue was detected of the diaphragm after incremental exercise using phrenic nerve stimulation.31 Interestingly, there is evidence that rats may protect diaphragm blood flow during exercise despite severe LV dysfunction.32 Thus, it remains controversial whether respiratory muscle fatigue occurs and if this plays any role in altering the regulation of EELV in CHF.

A final explanation may be simply due to an altered respiratory drive. Patients with CHF have high pulmonary vascular pressures, which have been proposed to cause mild chronic "subclinical" pulmonary edema; this may, in turn, stimulate receptors in the lungs that can further augment breathing.33 It is possible that with exercise, as pulmonary pressures increase, there is a further accumulation of lung water, which further enhances respiratory drive through J-receptor activation. Previous studies34 have not suggested a strong relationship between pulmonary vascular pressures and exercise-related dyspnea; however, it is unclear how lung lymph flow may be altered in patients with CHF and thus lung fluid balance. The enhanced drive to breathe has been shown to typically activate both inspiratory and expiratory muscles, possibly resulting in a reduced EELV.35

Ventilatory Constraints in CHF
Does the degree of mechanical constraint observed in the CHF patients inhibit the ventilatory response to exercise? Clearly, dyspnea becomes a significant limiting factor in the majority of our CHF patients without any overt signs of an inadequate ventilatory response. Whether the degree of constraint is contributory to the dyspnea or if other factors (ie, pulmonary vascular pressures) play a major role remains unclear. The degree of ventilatory constraint may contribute to dyspnea in a number of ways. This could occur due to the sensation of airway narrowing (dynamic compression of the airways) or due to the development of high inspiratory pressures relative to the pressure-generating capacity of the inspiratory muscles.36 37 In addition, the high work and cost of breathing may result in respiratory muscle fatigue and/or increase the competition for blood flow with locomotor muscles.38 39 Clearly, as flow limitation develops, the work and cost of breathing increases.9 Thus, approaching mechanical constraints may inhibit performance, not only by an influence on E, but also by increasing the demand for respiratory muscle blood flow.9 22

Previous studies7 22 40 have demonstrated that as ventilation approaches mechanical constraints (flow limitation, high inflation volumes, and large negative pressure swings), the response to hypoxia or hypercapnia is reduced. Additionally, if significant room was available to increase inspiratory or expiratory flow or volume, then the addition of increased inspired levels of carbon dioxide should increase E. On a subsequent day, six of the less-fit CHF patients returned for a repeat exercise study with 3% inspired carbon dioxide, along with six of the CTLS. Interestingly, as shown in Figure 5 , E at rest was elevated in CHF patients (69%) and CTLS (90%); but at peak exercise, the E was similar to air breathing for a given O2 in the CHF patients (increase of 3%), compared to a 25% increase over the air-breathing values in the CTLS. Table 6 shows the mean change in E for the given change in end-tidal carbon dioxide pressure at rest and during each work intensity in the CHF patients and CTLS. This suggests that the reduced EELV in CHF patients and the degree of expiratory flow constraint limited the ability to further increase E. However, it is also difficult to rule out an inability of the CHF patients to respond to the stimulus of increased carbon dioxide due to muscle fatigue, blood flow competition between vascular beds, and/or the general respiratory muscle load.



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  		Figure 5. Ventilatory responses to breathing room air (triangles) and 3% inspired carbon dioxide (x) in CTLS (dashed lines) and CHF patients (solid lines). With increased carbon dioxide, the CTLS demonstrated an enhanced ventilatory response at rest and throughout exercise; however, the CHF patients had a limited E response with heavier exercise (mean change in E for the given change in end-tidal carbon dioxide pressure was 1.50 ± 0.13 in CHF patients and 2.61 ± 0.80 in CTLS at rest, and 0.2 ± 0.24 in CHF patients and 1.50 ± 0.42 in CTLS near peak exercise).

 

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  		Table 6. Ventilatory Response to Increased Inspired CO2 With Progressive Exercise: {Delta}E/{Delta}End Tidal CO2*

 
In summary, patients with a history of chronic LV dysfunction have primarily restrictive changes in baseline pulmonary function, with some mild reduction in expiratory flows that reduces their available breathing reserve. Breathing reserve is further reduced by altered breathing mechanics during exercise, including a tachypneic breathing pattern and a reduced EELV, which contributes to increased expiratory flow limitation and likely a limited E response to increased levels of carbon dioxide. The severity of symptoms and reduced fitness appear to augment the observed changes.


   Acknowledgements
 
The authors thank Audrey Schroeder for help in preparing the manuscript and Dr. Michael Joyner for medical support.


   Footnotes
 
Abbreviations: CHF = chronic heart failure; CI = cardiac index; CTLS = control subjects; EELV = end-expiratory lung volume; EF = ejection fraction; EILV = end-inspiratory lung volume; extFVL = tidal flow-volume loop; FEF50 = forced expiratory flow after 50% of vital capacity has been expelled; FRC = functional residual capacity; FV = flow-volume; HnsR = Hans Rudolph; IC = inspiratory capacity; IRV = inspiratory reserve volume; LV = left ventricular; MFVL = maximum flow-volume envelope; mph = miles per hour; MVV = maximum voluntary ventilation; NYHA = New York Heart Association; RV = residual volume; TE = expiration time duration; TLC = total lung capacity; {Delta}V = volume segment; VC = vital capacity; CO2 = carbon dioxide output; E = minute ventilation; ECAP = maximal estimated ventilation available for a given breathing pattern; O2 = oxygen consumption; VT = tidal volume

Received for publication February 2, 1999. Accepted for publication June 28, 1999.


   References
TOP
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 References
 

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