INTRODUCTION

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In chronic heart failure (CHF) a combination of disuse, underperfusion, and neurohormonal mechanisms lead to reduced peripheral muscle strength and endurance (1, 2). Although these changes may explain limb fatigue during exercise in CHF, it is less clear if exertional dyspnea can be attributed to similar mechanisms affecting the respiratory muscles. Although it is known that pulmonary compliance is reduced in CHF (3, 4), increasing the work of breathing, we have recently shown using detailed tests (5) that respiratory muscle strength is largely preserved in CHF. However, other observations suggest that an imbalance between the load applied to and the capacity of the inspiratory muscle pump could contribute to exercise-induced dyspnea in CHF. In particular it has been observed that exercise capacity can be extended if the work of breathing is reduced using a helium-oxygen mixture (6) or inspiratory pressure support (7). However, direct evidence supporting this hypothesis is currently lacking.

When skeletal muscle operates under conditions of excessive load the maximum rate of relaxation slows; this property, which is an active process, can be determined for the inspiratory muscles from the esophageal pressure trace after a voluntary sniff (Sn Pes) (8, 9). We have previously shown that this method can detect changes in the maximum relaxation rate (MRR) of inspiratory (8) muscle in normal subjects after hyperventilation and in patients with chronic obstructive pulmonary disease (COPD) after exhaustive treadmill walking (10).

In the present study we used measurement of MRR to test the hypothesis that exercise in CHF results in excessive loading of the inspiratory muscles; we therefore measured sniff esophageal pressure maximum relaxation rate (Sn Pes MRR) in patients with CHF walking to exhaustion on a treadmill. Our rationale was that slowing of Sn Pes MRR would support this hypothesis and suggest a possible contribution to the etiology of breathlessness in CHF.

	METHODS

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Subjects

The age and lung function of the subjects, together with New York Heart Association (NYHA) status and cardiac ejection fraction measured by nuclear angiography for the CHF patients are presented in Table E1 in the online repository. Although the control subjects were younger (mean difference, 9.8 yr; p = 0.18; 95% CI, 5.1 to +24.7 yr) this difference did not achieve statistical significance. Both FEV₁ and VC were reduced in patients with CHF (p = 0.006 and p = 0.009, respectively, but there was no difference between the two groups with regard to their global maximum inspiratory muscle strength as determined by Sn Pes_max. Eight stable male patients with CHF were studied, in three the cause of heart failure was dilated cardiomyopathy and in the remaining five it was ischemic heart disease. None of the patients was an active smoker and none had symptoms to suggest chronic lung disease, although one patient had undergone a lobectomy for tuberculosis 40 yr previously. Patients were selected if they had previous experience of walking on a treadmill and could do so without developing angina, dysrhythmias, or severe leg fatigue. For comparison, nine healthy control subjects were studied. All were familiar with physiological experiments, including measurements of respiratory muscle strength; in the case of the elderly control subjects this was because of previous participation in another study (11). The study was approved by the hospital ethics review committee, and all subjects gave written informed consent.

Equipment

Spirometry was performed using a wedge bellows spirometer (Vitalograph, Bucks, UK) and lung volumes were measured using a whole-body plethysmograph (Jaeger, Würzburg, Germany). Predicted values were taken from the European Respiratory Society guidelines (12).

Esophageal pressure (Pes) was measured using a 10-cm latex balloon attached to a 110-cm plastic catheter and inflated with 0.5 ml air. Gastric pressure (Pga) was measured using a similar balloon catheter inflated with 2 ml air. The two balloon catheters were introduced pernasally and positioned in the esophagus and stomach in the conventional manner. The catheters were connected to Validyne transducers (± 200 cm H₂O; Validyne Corp., Northridge, CA). Electrical signals were amplified (Validyne) and passed via an analogue-to-digital converter (NB-MIO-16; National Instruments, Austin, TX) to an Apple Macintosh computer running LabView software (National Instruments) and sampling at 100 Hz.

Subjects exercised on a treadmill with monitoring of pulse oximetry and ECG. Minute ventilation and expired gas composition were measured breath by breath using an orifice pneumotachograph and mass spectrometer (Benchmark system; PK Morgan, Rainham, Kent, UK).

Protocol

Prior to exercise subjects were taught to produce short, sharp sniffs without measurable abdominal muscle activity (as judged by Pga) while seated in front of a monitor. After determining maximum sniff esophageal pressure (Sn Pes_max) (13) a series of submaximal sniffs of varying amplitude were recorded. These provided a baseline for subsequent comparison after exhaustive exercise; sniffs of varying amplitude were collected in order that sniffs obtained at exercise termination could be matched with baseline sniffs of similar amplitude. The patients with CHF then performed an incremental treadmill walk (Balke protocol) until severe breathlessness caused exercise termination. Sniffs were then recorded each minute for 5 min and also during the tenth minute after stopping. Esophageal and gastric pressures were also recorded during the treadmill walk. For the control group an identical protocol was followed except that exercise was discontinued when minute ventilation reached 100 L/min, this being greater than the highest value attained by any patient with CHF during the initial pilot studies.

Analysis

Maximum relaxation rate. In order to prevent expiratory muscle activity affecting the results, sniff traces were accepted for analysis only if the standard criteria (10) used in our laboratory were met. These were (1) Sniff maneuver performed at end-expiration, as determined by esophageal pressure. (2) Sniff duration less than 500 ms, with smooth, symmetrical upstroke and decay. (3) Decay of esophageal pressure curve returns to but does not exceed end-expiratory level. (4) Absence of abdominal muscle contraction during relaxation phase, determined by asymmetry of the gastric pressure trace. In the present study 1,507 of 2,415 sniffs (62%) met the criteria for analysis; this acceptance rate is comparable to our previous clinical studies (10, 14).

Sn Pes MRR was calculated using customized semiautomated LabView software, as the maximal rate of decay of pressure divided by peak pressure over a 50-ms epoch, with units of percent pressure loss/ 10 ms. Normalizing MRR pressure traces allowed comparison of traces with different amplitudes. As MRR varies between subjects, the effect of exercise on MRR was expressed as a percentage of baseline. As MRR recovers exponentially and returns to baseline within 5 min (8), we selected as the primary endpoint the percent slowing of MRR recorded in the first minute after cessation of exercise.

Respiratory muscle load. A measure of the pressure generated by the inspiratory muscles during the treadmill walk was obtained from the esophageal pressure time product (PTPes) and had units of cm H₂O · s/min. This was calculated by the software that integrated the esophageal trace during inspiration using a semiautomated program. In this analysis we defined inspiration by the start and finish of inspiratory airflow and for the esophageal pressure took the baseline to be zero; for a fuller discussion of this convention see Reference (15).

Statistics

Statistics were analyzed using an unpaired t test (Statview 4.0, Abacus Concepts, Berkeley, CA). A p value of < 0.05 was accepted as significant.

	RESULTS

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All the patients with CHF tolerated the protocol and all terminated walking because of intolerable dyspnea. In the online repository, Table E2 shows the exercise data obtained for the patients with CHF compared with the control subjects. Mean (SD) time to exhaustion for the patients with CHF was 9'19 (3'32) minutes and the time to achieve 100 L/min (or to severe dyspnea) was 11'32 (3'55) minutes for the control subjects (p = NS). The highest ventilation achieved by any patients with CHF was 99.9 L/min with a mean (SD) of 77.4 (8) L/min; the control subjects continued exercising until reaching a mean minute ventilation of 102.6 L/min (p < 0.009), except in the case of Subjects 8 and 9 who stopped at 31.7 L/min and 58.9 L/min, respectively. The work rate at exercise termination (calculated from treadmill speed and gradient) was not significantly different between the two groups, but maximum oxygen uptake was significantly greater at cessation in the control subjects whether expressed in absolute terms (mean difference, 13.4 mL/min/kg; 95% CI, 5 to 21 ml/min/kg; p = 0.0003) or as % predicted (mean difference, 34%; 95% CI, 19 to 50%; p = 0.0002). There were no significant differences between the two groups at the point of cessation of exercise for heart rate, respiratory rate, tidal volume, or inspiratory duty cycle. The work performed by the inspiratory muscles, estimated from the esophageal pressure time product (PTPes), during the first and last 30 s of the treadmill walk was 234 cm H₂O · s/min and 561 cm H₂O · s/min for the patients with CHF and 182 cm H₂O · s/min and 578 cm H₂O · s/min for the control subjects. There was no significant difference in PTPes between groups.

Representative traces from the exercise protocol and typical sniff traces obtained in a patient with CHF before and immediately after the walk to severe dyspnea are shown in Figure 1. The mean inspiratory MRR for the first minute after termination of exercise was 22.4% slower than baseline in the CHF group and 2.8% slower than baseline in the control group (p = 0.009). The mean difference in slowing of MRR between patients with CHF and control subjects was 19.9% (95% CI, 5.7 to 34%). The effect of exercise on slowing of mean MRR showed some overlap between groups (see Table 1). The frequency of slowing was six of the eight patients with CHF and four of the nine control subjects; this difference was not statistically significant. Nevertheless, even when only those who did slow were considered, the magnitude was greater in patients with CHF (mean difference, 14.5% greater in CHF; 95% CI, 5.7 to 23.3%). The mean (SD) MRR data for the two groups for the 10 min after the exercise protocol is shown in Figure 2 and demonstrates the rapid recovery of sniff Pes MRR in line with previous observations (10, 14).

View larger version (15K): [in this window] [in a new window]   Figure 1.   (Left panel ) Representative esophageal pressure traces for the first (upper record ) and last (lower record ) 30 s of exercise in a patient with CHF. (Right panel ) Representative sniffs before (upper record ) and immediately after (lower record ) exercise in the same patient.

View larger version (18K): [in this window] [in a new window]   Figure 2.   Mean (± SD) Sn Pes MRR as a percentage of baseline after exercise protocol. (Sn Pes MRR = maximum relaxation rate of esophageal pressure after a submaximal sniff.)

	DISCUSSION

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Our data show that slowing of inspiratory muscle MRR occurs in patients with CHF following treadmill exercise to the point of severe breathlessness, this occurred with a greater magnitude than was observed in control subjects. Before considering the possible causes and implications of these findings, methodologic aspects need to be considered.

Critique of the Methods

Subjects. Patient selection was based on the presence of dyspnea, rather than limb fatigue, as the limiting symptom during exercise. In terms of CHF severity they were not as severely impaired as participants in some studies (16, 17) but are likely to be reasonably representative of a stable outpatient clinic population.

Protocol. Our patients walked until severe dyspnea prevented further exercise, whereas normal subjects exercised to achieve a minute ventilation comparable to that in patients with CHF in order to determine whether the level of ventilation attained at peak exercise in CHF was associated with excessive inspiratory muscle loading in normal subjects. It is known that slowing of inspiratory muscle relaxation rate (8) can be demonstrated in well-motivated normal subjects after maximal isocapnic ventilation at rest and that diaphragm fatigue can be elicited if very high levels of ventilation are achieved during whole body exercise (18). Thus the purpose of the control group was to allow comparison of the effect of similar levels of ventilation with those achieved by the patients with CHF at peak exercise, rather than to investigate in normal subjects whether maximal exercise could produce slowing of inspiratory muscle MRR. For this purpose we consider the control group to be appropriate in that they achieved a higher proportion of predicted O₂max with no significant differences in the pattern of breathing in terms of respiratory rate, duty cycle, or pressure-time product at the point of discontinuing exercise. We therefore believe the finding that slowing of Sn Pes MRR is more pronounced in patients with CHF than in control subjects to be due to their disease.

Sniff maneuver. Measurement of MRR is an established method for determining the effect of loading on the inspiratory muscles in normal subjects (8, 9) as well as clinical situations such as COPD and after weaning from mechanical ventilation (19). Although fatigue affects muscle MRR, other potentially confounding factors that need to be considered include muscle length, sniff amplitude, and the effect of contraction of other respiratory muscles (20, 21). Nevertheless (as discussed in the online data supplement) these factors cannot undermine the conclusions drawn from this study.

Significance of the Findings

Cause of slowing of MRR in CHF. Slowing of MRR is an adaptive mechanism that occurs early in a fatiguing protocol and is attributed to several factors, including depletion of ATP, intracellular acidosis, and changes in transmembrane ion conductance. Our findings are consistent with the study by Davies and colleagues (22) (reported in abstract form), which found that exercise induced slowing of inspiratory muscle relaxation rate (judged from mouth pressure during a gasp) in patients with CHF. The identification of slowing in Sn Pes MRR is consistent with the hypothesis of an imbalance between the load placed on the respiratory muscle pump and its capacity.

Although there is only a modest reduction in respiratory muscle strength in CHF (5), in vivo work has shown deoxygenation of accessory respiratory muscles in patients with CHF during exercise, suggesting reduced perfusion (23). Although slowing of MRR is independent of hypoxia (10, 24), our data support the contention that changes in the intracellular milieu of the inspiratory muscles occurs in exercising patients with CHF. The hypothesis would then be that the inability of the heart to match the requirements of the exercising respiratory musculature resulted in the manifestation of excessive loading (slowing of Sn Pes MRR). The possibility that load is also increased in CHF because of bronchial hyperresponsiveness has been previously raised (25). Our data do not exclude the possibility that load is increased in CHF, although the fact that comparable levels of inspiratory muscle pressure generation resulted in comparable levels of minute ventilation between patients and control subjects argues against this being the predominant problem.

Slowing of MRR was not seen in two of eight patients with CHF; although both subjects were well motivated this may have been due to premature cessation of exercise (especially in Patient 5) or reflect the multifactorial nature of exercise limitation in this condition. Both subjects had documented coronary artery disease; however, neither reported angina. Equally, four of nine control subjects had slowing of MRR, the greatest of which was 19.5% baseline. Nevertheless, even if the data from all participants with slowing of MRR are considered in isolation, the magnitude of slowing was greater in patients with CHF. Excessive loading causes slowing of MRR in healthy people (8), and therefore we interpret the current observations as supporting the concept that patients with CHF and control subjects represent two distinct (but overlapping) populations with respect to the effect of exercise on MRR. Patients with CHF seem to demonstrate slowing of the MRR earlier and to a greater extent than do control subjects. This is consistent with our starting hypothesis that excessive inspiratory muscle loading contributes to dyspnea. However, we acknowledge that patients with CHF seem to be "less abnormal" than patients with advanced COPD whose data we have previously reported (10). In such patients a greater mean slowing of MRR occurred at substantially lower levels of minute ventilation, and slowing was an invariable finding. In one subject MRR became faster after exercise; we speculate that this may represent abnormalities of chest wall or abdominal wall mechanics in this subject who was more obese than the remainder (BMI, 29 kg/m²).

We have shown that slowing of inspiratory muscle MRR occurs in subjects with CHF during intensive exercise. This indicates that the inspiratory muscles are operating under excessive load in CHF, but it raises the issue of whether their endurance to fatigue is reduced. Slowing of MRR does not of itself fulfill the criteria for the presence of muscle fatigue (26), to determine this would require additional studies measuring the effect of exercise on more direct measures of contractility such as twitch transdiaphragmatic pressure. We believe such studies are now warranted. Diaphragm biopsies in subjects with severe CHF show increased proportions of fatigue-resistant type I muscle fibers (27) and there are changes in diaphragm contractility studied in vivo which may reflect this (5). Therefore, slowing of inspiratory muscle MRR at a lower level of whole-body exercise and with a similar degree of respiratory muscle loading, despite these adaptations, suggests a reduced endurance capacity, possibly secondary to impaired perfusion (23). Our study is, we believe, the first to demonstrate excessive inspiratory muscle loading in a physiologically realistic model.

In patients with severe COPD unloading of the inspiratory muscle pump using noninvasive ventilation (NIV) during exercise increases exercise endurance, and as consequence is developing a role in pulmonary rehabilitation (28). The present data suggest that NIV may also have a role to play in the rehabilitation of patients with CHF.

In summary our data provide evidence of excessive loading of the inspiratory muscle pump during exhaustive exercise in patients with severe CHF. Further studies are indicated to elucidate the underlying mechanisms and clinical significance of these findings.