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European Journal of Heart Failure 2006 8(1):68-73; doi:10.1016/j.ejheart.2005.04.009
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© 2005 European Society of Cardiology

Does symptom-limited cycle exercise cause low frequency diaphragm fatigue in patients with heart failure?

Mark J. Dayera,*, Nicholas S. Hopkinsona, Ewen T. Rossb, Sophie Jonvillea, Tarek Sharshara, Mark Kearneyc, John Moxhamd and Michael I. Polkeya

a Respiratory Muscle Laboratory, Royal Brompton and Harefield N.H.S Trust Royal Brompton Hospital, London, UK
b Department of Respiratory Medicine Gartnavel General Hospital, Glasgow, UK
c Department of Cardiology, Guy's, King's and St. Thomas' School of Medicine Kings College Hospital, London, UK
d Department of Respiratory Medicine, Guy's, King's and St. Thomas' School of Medicine Kings College Hospital, London, UK

* Corresponding author. Tel.: +44 020 7351 8029; fax: +44 020 7351 8939. E-mail address: markdayer{at}gmail.com


   Abstract
Top
 Abstract
1. Introduction
 2. Methods
 3. Results
 4. Discussion
 References
 
Background: Reduced diaphragm contractility occurs in some healthy subjects when they exercise to exhaustion. This indicates low frequency fatigue, which may contribute to task failure. We hypothesised that patients with congestive heart failure (CHF) might be especially vulnerable to the development of low frequency diaphragm fatigue after exhaustive exercise.

Aims: To study the effect of exhaustive incremental cycle exercise on diaphragm contractility in patients with CHF.

Methods: 12 patients with CHF with an ejection fraction of 36.5±7.3% and 12 healthy age-matched control subjects performed an incremental cycle test to exhaustion. The unpotentiated twitch transdiaphragmatic pressure (twitch Pdi) in response to bilateral anterolateral magnetic phrenic nerve stimulation (BAMPS) was measured before and after exercise.

Results: Twitch Pdi at baseline was 20.2±6.7 cmH2O in the CHF group and 20.3±3 cmH2O in the controls (p=0.957). 25 and 35 min post exercise the values were 19.9±5.4 and 20.0±5.1 cmH2O in the CHF group and 20.6±4.3 and 21.2±3.4 cmH2O in the control group; neither change was significant (F(2,27)=0.007, p=0.993; F(2,33)=0.144, p=0.866, respectively).

Conclusion: When patients with CHF cycle to exhaustion, low frequency fatigue of the diaphragm does not occur, and this is unlikely to be an important factor limiting exercise capacity of such patients.

Key Words: Heart failure • Congestive • Respiratory muscles • Muscle fatigue

Received December 8, 2004; Accepted April 18, 2005


   1. Introduction
Top
 Abstract
 1. Introduction
2. Methods
 3. Results
 4. Discussion
 References
 
In patients with congestive heart failure (CHF), breathlessness at relatively low workloads is frequent despite optimum medical therapy. The pathophysiological basis for dyspnea in CHF is not clear; in particular breathlessness is poorly correlated with the extent of left ventricular dysfunction at rest, or with central haemodynamic changes during exercise [1,2]. Furthermore, altering central haemodynamics does not improve exercise capacity acutely [3,4].

The muscle hypothesis of CHF proposes that impaired skeletal muscle function, which develops as a consequence of a chronic low cardiac output, contributes to symptom generation [5]. There is evidence to suggest that the respiratory muscles are abnormal in CHF, although their strength appears relatively well preserved [6]. Several studies indicate that in patients with CHF there is an imbalance between the load placed upon the respiratory muscles and their capacity. During exercise, patients with CHF tend to increase their respiratory rate more than their tidal volume compared with healthy controls [7], a pattern of breathing associated with respiratory muscle fatigue. Moreover, excessive loading of the inspiratory muscles occurs, as evidenced by a slowing of the inspiratory muscle relaxation rate, after exhaustive exercise [8], although slowing of the muscle relaxation rate precedes overt fatigue [9]. Other important physiological abnormalities potentially deleterious to muscle function have been demonstrated, particularly respiratory muscle deoxygenation during exercise [10]. A reduced blood supply to the diaphragm during exercise may reduce its functional capacity and render it more vulnerable to fatigue. Finally, reducing the work of breathing using heliox [11] or non-invasive ventilation [12] improves patients' ability to exercise.

We therefore hypothesised that a sustained imbalance between the load placed on the respiratory muscles and their capacity may cause low frequency diaphragm fatigue which would in turn contribute to exertional dyspnea. To test this hypothesis we measured diaphragm contractility before and after exhaustive exercise in patients with congestive cardiac failure and controls.


   2. Methods
Top
 Abstract
 1. Introduction
 2. Methods
3. Results
 4. Discussion
 References
 
2.1. Subjects
All subjects gave written informed consent to the experimental procedures which were approved by the Ethics Committee of the Royal Brompton Hospital. The investigation conformed with the principles outlined in the Declaration of Helsinki.

Twelve male patients, aged 56.9±9.9 years, of height 1.75±0.09 m, and weight 93.8±18.2 Kg with a diagnosis of chronic CHF, were recruited from specialist CHF clinics between March 2002 and September 2004. The diagnosis of CHF was based upon a clinical history and either echocardiography (n=9) or magnetic resonance imaging (n=3). Their mean ejection fraction was 36.5±7.3%. Exclusion criteria included any history of lung disease, neuromuscular limitation to exercise, significant peripheral vascular disease, uncontrolled hypertension, exercise-induced angina, exercise-induced ventricular arrhythmias, or the presence of a permanent pacemaker (which is a contraindication to magnetic stimulation). All patients had been clinically stable for the previous month. Two were in New York Heart Association class I, eight were in class II and two were in class III. The aetiology of left ventricular dysfunction was ischaemic in four and idiopathic-dilated in eight. In addition four were in atrial fibrillation and one had a diagnosis of type II diabetes. All were taking ACE-inhibitors or angiotensin II receptor antagonists. 11 of the 12 were taking beta-blockers, and 11 were taking loop diuretics. Six patients were also taking spironolactone.

Twelve age-matched (57.6±16.4 years), healthy volunteers (10 men), of height 1.73±0.10 m, and weight 76.1±15.8 Kg, with no history of heart or lung disease were also recruited. None were on any regular medications. The control subjects were significantly lighter than the patients (p=0.016).

2.2. Study design
Spirometry was performed (Jaeger Toennies, Wurzburg, Germany) according to British Thoracic Society guidelines [13]. Predicted values were taken from the European Respiratory Society guidelines [14] and Cotes and Hall [15].

To record oesophageal and gastric pressures, two balloon catheters were introduced per nasally, after the application of topical anaesthesia, and positioned in the oesophagus and stomach in the conventional manner [16]. Oesophageal pressure (Poes) was measured using a 10 cm latex balloon attached to a 110 cm plastic catheter (Ackrad Laboratories Inc., Cranford, New Jersey, USA) and inflated with 0.5 ml of air. Gastric pressure (Pgas) was measured using a similar balloon catheter inflated with 2 ml of air. All pressures were measured with Validyne transducers (Range±300 cmH2O; Validyne M.P.-45; Validyne, Northridge, Ca, USA) linked to amplifiers (P. K. Morgan Ltd., Gillingham, Kent, UK). Signals were passed through a BNC board (BNC-2090, National Instruments, Austin, TX, USA) to an analogue to digital converter sampling at 100 Hz (DAQCard-AI-16XE-50), displayed in real time, and stored on a computer running LabView 6.1 software (National Instruments, Austin, TX, USA). Transdiaphragmatic pressure (Pdi) was displayed in real time by subtracting the oesophageal pressure from the gastric pressure.

Sniffs were performed from functional residual capacity without a nose clip with the subjects seated in front of a monitor screen. Sniffs were repeated with vigorous encouragement and visual feedback until no further increase in pressure was seen [17].

Maximum inspiratory manoeuvres were performed with the subjects seated and wearing a nose clip. A flanged mouthpiece attached to a tube incorporating a valve and a 2 mm diameter leak to prevent glottic closure was used. Maximum effort was encouraged verbally and there was simultaneous visual feedback of pressures achieved. Manoeuvres were repeated from residual volume until three reproducible efforts were obtained. The one second average of negative mouth pressure was recorded (MIP) [18].

The twitch transdiaphragmatic pressure (Twitch Pdi) was measured at baseline by stimulating the phrenic nerves bilaterally using two Magstim 200 Monopulse stimulators and two 45 mm figure of eight coils (Magstim Co., Whitland, Wales, UK) positioned anteriorly over each sternocleidomastoid muscle at the level of the cricoid cartilage (Bilateral anterolateral magnetic phrenic nerve stimulation, BAMPS) [19]. Subjects rested for at least 20 min before stimulation to minimize twitch potentiation [20]. A minimum of six stimuli was delivered at 100% intensity with the subjects' breath holding at functional residual capacity.

An incremental exercise test to exhaustion was performed on a cycle ergometer. The increments were set at 10 W per minute for patients with CHF and 20 W per minute for healthy controls. Full metabolic data was collected using a metabolic cart (Oxycon Pro and Labmanager software v4.53, Eric Jaeger GmbH, Hochberg, Germany) and peak oxygen uptake (VO2) and the ratio of ventilation to carbon dioxide production (VE/VCO2 slope) calculated. The VO2 data and other data acquired breath by breath were averaged over seven breaths. To compensate for the difference in weight between the control subjects and patients, peak VO2 was also corrected for weight. The percent predicted VO2 for each subject was also calculated using published formulae [21]. The subjects were asked to rate dyspnea and leg fatigue using a modified 10-point Borg scale [22,23] at peak exercise, and were also asked to choose the symptom which had caused them to stop exercising.

Following exercise, subjects sat quietly without speaking to depotentiate; at 25 and 35 min after exercise BAMPS was repeated as described above.

2.3. Statistics
All data were analysed using SPSS (Chicago, USA, version 11.0.0). Between-group variability was analysed using unpaired t-tests or Mann-Whitney U tests where Kolmogorov-Smirnov testing indicated non-normal distribution of data. Changes in variables over time were analysed by repeated-measures analysis of variance.


   3. Results
Top
 Abstract
 1. Introduction
 2. Methods
 3. Results
4. Discussion
 References
 
3.1. Lung function
Patients with CHF had a significantly reduced percent-predicted forced expiratory volume in one second (FEV1) (86.3±17.2 vs. 103.0±11.6%, p=0.009) and forced vital capacity (FVC) (91.2±12.6 vs. 112.0±15.7%, p=0.003) compared to normal subjects, although the FEV1/FVC ratio was preserved (0.75±0.08 vs. 0.74±0.04, p=0.694).

3.2. Respiratory muscle testing
Tests of voluntary function were reduced in one patient with CHF (Sniff Poes 41 cmH2O, MIP 38 cmH2O), although this patient's twitch Pdi was in the normal range (19.4 cmH2O) suggesting poor technique (Table 1). There was no significant difference in either volitional or non-volitional measure of respiratory muscle strength between the groups.


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  		Table 1 Respiratory muscle testing

 
3.3. Cardiopulmonary exercise testing
Patients and control subjects exercised for a similar length of time (657±237 vs. 597±196 s, p=0.497). The load at peak exercise was significantly lower for patients with CHF (113±50 vs. 194±68 W, p=0.003). The peak VO2, adjusted for weight, was significantly lower in the CHF group (16.0±.7 vs. 25.3±.5 mls/kg/minute, p=0.003). Similarly the percent predicted peak VO2 was significantly lower in the patient group (61.9±17.1% vs. 91.7±20.4%, p=0.001). There was, furthermore, a significantly steeper VE/VCO2 slope in the patient group, however estimated (data before respiratory compensation point: 36.5±15.1 vs. 27.3±4.4, p=0.014, all data 43.6±15.8 vs. 33.4±6.3, p=0.03). At the termination of exercise 7/12 CHF patients stopped because of shortness of breath as did 7/12 of the subjects in the control group. The mean Borg scores for breathlessness and leg discomfort at peak exercise were not significantly, higher in the heart failure group (breathlessness: 5.2±2.0 vs. 4.9±1.8, p=0.94; leg discomfort 6.2±2.4 vs. 5.5±2.2, p=0.45). The peak minute ventilation as a percent of the subjects predicted value was similar in the heart failure (73±23%) and control (73±16%, p=0.98).

3.4. The effect of maximal incremental exercise on respiratory muscle function
In this study, respiratory muscle function, as determined by the twitch Pdi, did not fall significantly as a result of maximal exercise in either patients or controls.

In two subjects with CHF, one balloon became displaced during the experiment, therefore the twitch Pdi is only reported for 10 subjects. In one patient the oesophageal balloon came out, and in the other the gastric balloon migrated into the oesophagus. Therefore n=11 for the twitch Poes and twitch Pgas values.

For the subjects with CHF, the mean twitch Pdi at baseline was 20.2±6.7 cmH2O, and was 19.9±5.4 and 20.0±5.1 cmH2O for the two sets of BAMPS, at 25 and 35 min post exercise (F(2,27)=0.007, p=0.993). When the individual components of the twitch Pdi were examined, neither twitch Poes (11.5±6.2, 11.9±.3, and 12.2±5.8 cmH2O, F(2,30)=0.04, p=0.961), nor twitch Pgas (9.2±3.7, 9.1±2.9, and 9.2±2.7 cmH2O, F(2,30)=0.001, p=0.999) changed significantly over time. Only one patient in the CHF group demonstrated a consistent fall in the twitch Pdi of >15% after exercise (32.8 cmH2O at baseline, 23.4 cmH2O at 25 min, and 25.9 cmH2O at 35 min).

In the control group there were no difficulties with balloon migration. The mean twitch Pdi at baseline was 20.3±4.3 cmH2O, and was 20.6±4.3 and 21.2±3.3 cmH2O for the two sets of BAMPS post exercise (F(2,33)=0.144, p=0.866). When the individual components of the twitch Pdi were examined, neither twitch Poes (11.5±3.2, 11.6±3.2, and 12.0±2.8 cmH2O, F(2,33)=0.085, p=0.918), nor twitch Pgas (9.2±2.6, 9.7±2.7, and 10.0±2.5 cmH2O, F(2,33)=0.326, p=0.724) changed significantly over time. (Figs. 1-3GoGo).


Figure 1
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  		Fig. 1 Twitch transdiaphragmatic pressure pre and post exercise — heart failure.

 


Figure 2
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  		Fig. 2 Twitch transdiaphragmatic pressure pre and post exercise — normal controls.

 


Figure 3
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  		Fig. 3 Mean twitch pressures pre and post exercise.

 

   4. Discussion
Top
 Abstract
 1. Introduction
 2. Methods
 3. Results
 4. Discussion
References
 
Low frequency fatigue of the diaphragm is associated with injury to the diaphragmatic muscle which normalises on recovery [24,25]. We failed to demonstrate in this study that incremental exercise to exhaustion leads to low frequency diaphragm fatigue in most patients with CHF or in naïve controls. Our data are consistent with those of Kufel et al. [26] and Mancini et al. [27] though we believe that differences in the protocols employed mean that our data are a useful addition to the literature.

4.1. Critique of the method
The study by Mancini et al. [27] used transcutaneous electrical stimulation (TES) to stimulate the phrenic nerves in seven patients. Using this technique it can be difficult to locate the phrenic nerves, particularly in subjects with short thick necks, and minor changes in position can result in submaximal stimulation. TES is painful, and this may lead to an increase in respiratory rate and tidal volume which can result in twitch potentiation [20]; this was not understood at the time the study by Mancini et al. was performed. To avoid the effects of this, the first set of post exercise twitches in the current study were obtained 25 min after exercise. Although minor recovery could occur in that time, it is generally held that low frequency fatigue recovers slowly [19,28], over a period of many hours.

Cervical magnetic stimulation (CMS) was used in the study by Kufel et al. This approach has the disadvantage that it may also recruit neck and upper rib-cage muscles as well as the diaphragm. Although this is unimportant when diagnosing diaphragm paralysis, the partitioning of pressures produced by CMS is different from that seen with phrenic nerve stimulation [19]. We used BAMPS to determine diaphragmatic strength before and after exercise. This method is more comfortable and technically easier than TES. Importantly, it is consistently supramaximal well below maximal power output [19], and also more specific for the diaphragm than CMS [19]. A further weakness of the study by Kufel et al. is that no control group was studied.

Incremental bicycle exercise was used in this study to stress the respiratory system. The peak ventilation of the patients with CHF was on average 73.3% of their predicted maximal voluntary ventilation, and 7/12 patients stopped exercising because of breathlessness. Treadmill exercise may have given different results as bicycle exercise preferentially stresses the quadriceps muscle [29], and limb muscle fatigue could have occurred first, before respiratory muscle fatigue. In healthy elderly subjects, Mador et al. detected significant fatigue of the quadriceps, but not of the diaphragm, after constant load cycle exercise to exhaustion [30]. The use of a constant-load rather than an incremental protocol might have been more likely to generate fatigue, where higher levels of ventilation are maintained for a longer period of time. Diaphragmatic fatigue has been found in normal subjects exercising for a mean of eight minutes at more than 50% of their MVV [31] and Johnson et al. have suggested that high intensity exercise needs to be maintained for at least 10 min to generate fatigue [32].

4.2. Significance of the findings
Although some authors have postulated that low frequency fatigue has a role in determining the point of task failure [33], others have questioned whether subjects are able to drive themselves to the point at which peripheral fatigue occurs [34], and have suggested that other stimuli limit performance.

A number of studies have noted that low frequency fatigue of the diaphragm is difficult to induce, even in healthy volunteers [35]. In patients with chronic obstructive pulmonary disease, exhaustive exercise has been shown to induce a slowing of the muscle relaxation rate [36], but not low frequency fatigue [37,38]. A recent study by Laghi et al. [39] hypothesised that weaning failure in ventilated patients would be accompanied by low frequency fatigue of the diaphragm. Their findings did not confirm this hypothesis, and no low frequency fatigue was detected. They postulated that recruitment of different muscle groups and down-regulation of respiratory cortical motor output might have protected the diaphragm from fatigue. Low frequency diaphragm fatigue was also not observed in a group of patients with obstructive sleep apnoea studied soon after waking [40]. Taken together these studies suggest that low frequency fatigue of the diaphragm is seldom clinically important.

The absence of low frequency fatigue in the diaphragm begs the question of what non-cardiac factors may contribute to exercise limitation in CHF. Chronic obstructive pulmonary disease (COPD) exhibits some of the same systemic manifestations to CHF. In COPD it has been shown that quadriceps fatigue can be present after exercise [41] and this may be present in patients with CHF. Another possibility is that supraspinal factors contribute to exercise limitation. We have recently shown that treadmill exercise causes a reduction in the amplitude of both the diaphragm and quadriceps motor evoked potential elicited by magnetic stimulation of the motor cortex and it could be that this inhibition is more profound in patients with cardio-respiratory disease [42].

In conclusion, our study failed to elicit low frequency fatigue of the diaphragm after exhaustive exercise in patients with CHF or in normal control subjects, indicating that this is an unlikely contributor to the limitation of exercise in CHF. Further studies are required to determine possible non-cardiac contributors to exercise limitation in CHF.


   Acknowledgements
 
We gratefully acknowledge the support and advice of Professor Andrew Coats, Professor Philip Poole-Wilson, Professor Martin Cowie and Dr Hugh McIntyre, and the input from the lung function department at the Royal Brompton Hospital. This study was supported by a grant from the British Heart Foundation (Grant No P.G./2001042).


   References
Top
 Abstract
 1. Introduction
 2. Methods
 3. Results
 4. Discussion
 References
 

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