INTRODUCTION

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Breathlessness and the sensation of fatigue during physical exertion are common in chronic heart failure (CHF), yet these symptoms correlate poorly with indices of left ventricular function (1). Peripheral muscle wasting (so-called cardiac cachexia) has long been recognized in CHF and alteration in skeletal muscle function is now thought to contribute to exercise limitation (2). It is likely that the respiratory muscles are equally susceptible to these changes, and since there is an increased respiratory work load in CHF (3, 4), reduced respiratory muscle strength may play a role in the development of dyspnea. However, the evidence that respiratory muscle weakness occurs in CHF is mainly derived from volitional maneuvers, particularly static maximal mouth pressures (5). An obvious concern with these tests when used clinically is that suboptimal muscle activation can be difficult to exclude even if the results are reproducible (8), making interpretation of the findings difficult. Less variable results are obtained if the subject is asked to make a short maximal sniff during which esophageal and transdiaphragmatic pressures (Sn Pes, Sn Pdi) are recorded (9, 10). This technique is easier for the subject to perform, and it also provides specific data on the diaphragm, the most important inspiratory muscle.

Measurement of twitch transdiaphragmatic pressure (Tw Pdi) using electrical phrenic nerve stimulation provides a nonvolitional method of assessing diaphragm strength in vivo (11), but it can be uncomfortable for the subject. Furthermore, difficulty in locating the phrenic nerves, resulting in subjects being unable to relax, can lead to potentiation and inaccurate results (12). Recently, magnetic phrenic nerve stimulation has provided an alternative nonvolitional technique (13) that is well tolerated and increasingly used in clinical situations where accurate determination of muscle strength is important (14). We therefore performed a study using a combination of magnetic phrenic nerve stimulation and maximum voluntary sniffs to further assess respiratory muscle strength and in particular the diaphragm in patients with stable CHF.

Changes in muscle fiber composition have been shown in CHF with increased proportions of type I (slow) fibers (15) in human diaphragm biopsies, and alteration in the force-frequency relationship in animal models (16). Measuring the in vivo force frequency characteristics of the human diaphragm with tetanic stimulation is impossible because of the discomfort produced and the difficulty in maintaining constant stimulation. However, as the force frequency relationship can be analyzed using pairs of stimuli (17, 18), we performed paired phrenic nerve stimulation in a subgroup of patients to investigate possible adaptation of the force-frequency characteristics of the diaphragm.

	METHODS

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Subjects

Twenty male patients with stable CHF were recruited from our outpatient clinics. None had any previous history of neurologic or chronic respiratory disease. All of them were receiving diuretics, and 19 of the 20 were receiving angiotensin-converting enzyme inhibitors; none had received adjustments to his medication in the month prior to these studies, and all had been clinically stable for this period. Two patients were in New York Heart Association functional Class I, 13 in Class II, and five in Class III. Etiology of CHF was dilated cardiomyopathy in three and ischemic heart disease in the remainder. Data from a control group of 15 age-matched male subjects were used for comparison. These subjects were either colleagues or drawn from registers of healthy volunteers. The study protocol was approved by the hospital ethics committee, and all the subjects gave written informed consent.

Measurements

Spirometry was obtained with a wedge bellows spirometer (Vitalograph, Buckinghamshire, UK), the best of three efforts was used. Lung volumes were determined from whole-body plethysmography (Jaeger, Würzburg, Germany), using the best of at least two reproducible measurements. Predicted values of the European Respiratory Society guidelines were used.

Mouth pressures were measured using a flanged mouthpiece attached to a brass tube incorporating a valve and 2-mm leak to prevent glottic closure. Esophageal and transdiaphragmatic pressures were measured from latex balloons mounted on 110-cm polythene catheters (P.K. Morgan, Rainham, Kent, UK) passed pernasally and positioned in the esophagus and stomach. All pressures were measured with Validyne MP-45 transducers (± 200 cm H₂O) and Validyne amplifiers (Validyne Corp., Northridge, CA). Transdiaphragmatic pressure was displayed on-line by subtraction of gastric pressure from esophageal pressure. Signals were passed via a 12-bit NB-MIO-16 analogue-digital converter (National Instruments, Austin, TX) to a Macintosh Centris computer (Apple Computers, Cupertino, CA) running LabView software (National Instruments) and sampling at 100 Hz.

In the CHF subjects left ventricular ejection fraction (LVEF) was measured using multi-uptake nuclear angiography and maximal oxygen uptake (MO₂) determined using an incremental treadmill walk to exhaustion (Bruce protocol).

Maneuvers

MIP and MEP were measured from residual volume (RV) and TLC, respectively, while the subjects were seated and wearing noseclips (19). Maximum effort was encouraged verbally, with simultaneous visual feedback from a monitor. Maneuvers were separated by at least 30-s rest periods and continued until no further increase in pressure could be obtained.

Sniffs were performed from FRC without a noseclip while the subject was seated in front of a monitor screen for simultaneous visual feedback. Sniffs were recorded with verbal encouragement until no further increase in pressures could be obtained.

Phrenic nerve stimulation was performed using a Magstim 200 HP stimulator (Magstim Co., Whitland, Wales) and a circular 90-mm coil (P/N 9784-00) positioned dorsally over the cervical spine (13). Subjects rested for 20 min before stimulation to minimize twitch potentiation. A series of low-power stimulations were then delivered at varying sites between approximately C4 and C7, until an optimal response was reached. This point was marked and used subsequently for stimulations at 100% power output with the subject seated with trouser belt undone and wearing a noseclip. Pressure traces were available on-line to the investigator, who instructed the subject to relax with mouth closed at end-expiratory lung volume. At least three satisfactory twitches were recorded for each subject.

Paired stimulation was performed using two Magstim 200 stimulators linked by a BiStim timing module (Magstim Co.), accurate to 0.01 ms, powering a single 90-mm coil. Briefly, delivery of a pair of stimulations separated by a short time interval produces a pressure response (pTw) that is the sum of the tension produced by the first twitch (T1) and the second twitch (T2). The relationship between time interval and force increment for the second twitch, calculated by subtraction of T1 from pTw, reflects the contractile properties of the muscle. Diaphragm T2 force-frequency curves were therefore studied on a separate occasion in a subgroup of eight patients and eight control subjects by delivering at least three stimulations at interpulse intervals of 200, 100, 50, 33, and 10 ms corresponding to 5, 10, 20, 30, and 100 Hz.

Analysis

MIP was defined as the most negative value that could be sustained for 1 s; the best effort was selected for analysis. Similarly, for expiratory pressure, MEP was defined as the greatest pressure sustainable for 1 s. Traces for Sn Pes, Sn Pdi, Tw Pdi, and pTw Pdi were accepted for analysis if the patient was relaxed at end-expiration at FRC, as determined by the esophageal (Pes) and gastric (Pgas) traces and defined as the height from baseline to peak pressure. Values quoted for Tw Pdi are the mean of all acceptable traces, whereas for Sn Pes and Sn Pdi the greatest single value obtained is presented.

Paired stimulation data were analyzed using specially written LabView software that allowed average pTw responses for each interpulse time to be calculated. Subtracting an averaged 1 Hz twitch allowed T2 Pdi to be calculated for each interpulse time (18, 20).

Data obtained were compared with values from male control subjects similarly free from chronic neurologic or respiratory disease. None had any previous cardiac history or current exercise limitation. Most had previously participated in a range of physiologic studies, including respiratory muscle strength measurement, and some of these data have been previously presented (20).

Statistical significance was tested using simple regression analysis and Student's t test (StatView 4.0; Abacus Concepts, Berkeley, CA) accepting p < 0.05 as significant.

	RESULTS

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Anthropologic, cardiac and pulmonary function data are summarized in Table 1. There was no significant difference in terms of age, body habitus, or spirometry between patients and control subjects. The participants tolerated the protocols without difficulty. One patient declined magnetic phrenic nerve stimulation. Data for Sn Pdi in 20 patients and Tw Pdi in 19 patients were therefore available for analysis.

Global Respiratory Muscle Strength

There was considerable overlap between patients and control subjects for all the indices measured (Figure 1); however, muscle strength was lower in the CHF group for all maneuvers. Although a significant reduction was seen between patients and control subjects for MIP (p = 0.01) (Table 2), when global inspiratory muscle strength was measured by sniff esophageal pressure the difference did not achieve significance (p = 0.2). Similarly, the difference in maximal expiratory pressure between the two groups was not significant (p = 0.09).

View larger version (19K): [in this window] [in a new window]   Figure 1.   Box plots of respiratory muscle strength. The line within the box represents the 50th percentile (median), the box itself represents the interquartile range (25th and 75th percentiles). The outermost lines represent the 10th and 90th percentiles. Units: cm H2O. *Significant difference between control subjects and patients with CHF, p < 0.05.

Diaphragm Strength

Diaphragm strength was significantly lower in the CHF group when measured with both twitch Pdi and sniff Pdi, although in absolute terms the reduction in strength was mild (Table 2). The results of paired phrenic nerve stimulation in the subgroup of eight patients and eight control subjects, with individual data normalized for single twitch Pdi to allow comparison, are shown in Figure 2. A trend to increased twitch summation in CHF at all frequencies was observed from the pTw Pdi and T2 data, most notably at frequencies within the physiologic firing frequency range of 5 to 20 Hz.

View larger version (19K): [in this window] [in a new window]   Figure 2.   Mean (± SEM) in patients with CHF and control subjects for (a) paired phrenic nerve stimulation and (b) T2 response. Data points are normalized for Tw Pdi at 1 Hz for each subject. There is increased tension addition in patients with CHF at all frequencies, but most notably between 5 and 20 Hz, demonstrated by the upward shift of the data points for CHF.

Hemodynamic Relationships

Mean Tw Pdi was significantly lower in the NYHA III group patients than in the NYHA I patients (p = 0.02), but the numbers of patients in these two categories were small. Overall there was no significant relationship between Tw Pdi and left ventricular ejection fraction or maximal oxygen uptake.

Reproducibility

Mean within-occasion coefficient of variability for Tw Pdi was 5.3% (range, 1.3 to 13.1%). Seven subjects revisited the laboratory for reproducibility studies between 4 and 10 mo apart, mean between-occasion coefficient of variation for Tw Pdi was 5.4% (range, 1.3 to 11.7%), and for Sn Pdi it was 10.1% (range, 1.8 to 20.2%).

	DISCUSSION

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In our group of stable patients with mild to moderate CHF we found that global respiratory pressure generation was well preserved. We did, however, find evidence of reduced diaphragm strength, although the magnitude of difference was small. Paired phrenic nerve stimulation suggested that a shift to the left of the frequency-force curve may occur in CHF, a change that could be due to adaptation in the diaphragm with a relative increase in the proportion of slow fibers. Before discussing the significance of these findings some important points in the methodology will be reviewed.

Subjects

Our patients with CHF were well motivated and not grossly limited by their symptoms. Although the correlation between hemodynamic parameters and symptoms may be poor, our patients had left ventricular ejection fraction and exercise performance broadly similar to those of previous studies (5, 21). The subjects in the control group were matched for body habitus, age, and sex, and their values for respiratory muscle strength were similar to those previously reported for normal subjects (9, 14, 20). It should be noted that because of the use of a flanged mouthpiece our values for MEP are slightly lower than those previously reported with a tube mouthpiece. We have previously investigated the magnitude of the difference caused by mouthpiece choice (22), and the values obtained for our control group are comparable to other studies of normal subjects using a flanged mouthpiece.

Maneuvers for Assessing Strength

We used several techniques to assess respiratory muscle strength. The data show that patients with CHF can generate a greater (more negative) pressure using the sniff rather than the MIP maneuver, and, using this method, the difference between the two groups for global inspiratory pressure was less than hitherto demonstrated (6, 7). The possible reasons for the observed disparity between MIP and Sn Pes in the patients with CHF require further discussion: one possibility is that transmission delays between thorax and mouth meant that mouth pressure (Pmo) was not a reliable measure of Pes, even during a static maneuver. In fact, Pmo closely tracked Pes, and this theory cannot explain our data. A second possibility is that, because MIP is taken over 1 s, the value is numerically lower than the sniff, which is a dynamic maneuver; to address this possibility we analyzed our data looking at Pmo_max, the maximum mouth pressure developed during the MIP maneuver. The mean value of Pmo_max was 81.7 cm H₂O, which was substantially less than the mean Sn Pes of 95.2 cm H₂O, suggesting that this also is not the explanation. The remaining possibility is that the patients with CHF may have experienced difficulty with the MIP maneuver, and in CHF, as with other conditions, a sniff may be a more accurate method for measuring maximal inspiratory pressures (9, 10).

Two previous studies (23, 24) have specifically addressed diaphragm strength in CHF. Evans and colleagues (24) found a maximal sniff Pdi of 103 cm H₂O, whereas using a Muller maneuver, Mancini and colleagues (23) found a maximum voluntary Pdi of 82 cm H₂O. Although trained subjects can voluntarily develop a greater transdiaphragmatic pressure with a modified Muller maneuver than with a sniff, the former is difficult for naive subjects. By using a twitch interpolation technique, Mancini and colleagues estimated the maximum Pdi to be 104 cm H₂O, confirming that submaximal activation can be a problem in naive subjects. We sought to avoid this difficulty by using magnetic phrenic nerve stimulation to measure twitch Pdi, which is reproducible, well tolerated, and independent of patient effort. In order to make valid comparisons between groups using this technique a number of factors need to be controlled, including the age and probably the sex of the subjects. We are confident that our protocol excluded potentiation or change in muscle length for the observed difference in Tw Pdi. Cervical magnetic phrenic nerve stimulation is not entirely specific for the diaphragm (25) as coactivation of upper thoracic intercostal muscles occurs. This leads to difficulty in demonstrating supramaximality of diaphragm stimulation because recruitment of intercostal muscles occurs with increasing stimulator output (25, 26). We used a high output stimulator and applied an identical stimulation technique to the patient and control groups. We think it unlikely that submaximal stimulation could explain the observed difference in Tw Pdi. In the only previous report of Tw Pdi in CHF, which used electrical stimulation, the investigators found a reduction in Tw Pdi of a similar magnitude to that in the present study, but the numbers studied were small and the difference not statistically significant (23).

Paired Nerve Stimulation

Assessment of muscle contractility in terms of the force-frequency relationship is well described in laboratory preparations, but only rarely possible in vivo because of difficulty in maintaining accurate nerve localization with tetanic stimulation and the discomfort it entails (27). We therefore elected to use a technique based on paired stimulation, which we and others have found to be clinically acceptable (18, 20). Because twitch pressures are different between control subjects and patients, we were obliged to compare normalized pressure amplitude responses. The effect of change to the force-frequency relationship in CHF is therefore shown as an alteration of twitch summation rather than total pressure generation as for maximal tetanic stimulation. A relative increase in type I (slow) fibers would be expected to lead to an upward shift in the T2-frequency relationship.

Significance of Findings

Our data show no significant loss of global inspiratory or expiratory muscle strength in CHF; however, there was a definite, if minor, reduction in diaphragm strength. Our measurements of inspiratory strength, based on the sniff maneuver, suggest that some previous studies that relied on a Muller maneuver may have been affected by the aptitude and motivation of the patients. Maximal sniff transdiaphragmatic pressure has been reported in only one previous study, the mean Sn Pdi in our study (123.8 cm H₂O) exceeded that reported by Evans and colleagues (103 cm H₂O) (24), although both values remain within the range of normal values reported for this maneuver (9). The single previous study of phrenic nerve stimulation was a small one, and the present investigation is the first systematic study of Tw Pdi in CHF (23). The twitch Pdi data confirm that diaphragm strength is reduced in CHF.

Cause of the Weakness

The cause of the observed diaphragm weakness is unknown. One possible explanation is the presence of "chronic" fatigue. Granton and colleagues (28) showed that unloading the inspiratory muscles with nocturnal continuous positive airway pressure (CPAP) for 3 mo led to an increased MIP. However, the chronic fatigue hypothesis cannot be completely confirmed by the data of Granton and colleagues since long-lasting fatigue is characteristically low frequency in nature and would not be expected to lead to a significantly reduced MIP (29). Our data suggest that this hypothesis could be retested using phrenic nerve stimulation. Moreover, the presence of low frequency fatigue in CHF is not supported by our results from paired phrenic nerve stimulation that we used to further investigate changes in the force- frequency relationship of the diaphragm. We showed a trend to increased twitch addition in CHF, which is the opposite of the change observed in low frequency fatigue (30). Rather, they suggest an alteration in contractility of the diaphragm, possibly explained by an increased proportion of slow fibers. Although our data did not achieve statistical significance, human diaphragm biopsies in severe CHF have demonstrated this change (15), and animal studies using tetanic stimulation have confirmed an effect on the force-frequency relationship (16).

Angiotensin-converting enzyme inhibitors reduce the changes in diaphragm contractility attributed to heart failure in animals, and thus inclusion of patients receiving this class of drug may have also influenced our results (31). However, the values for ejection fraction, NYHA class, and MO₂ for our patients reflect a contemporary heart failure clinic population in terms of severity, the results should therefore be relevant to the majority of patients with chronic heart failure.

Clinical Significance of Diaphragm Weakness

The significance of the observed reduction in diaphragm strength is undetermined. Although gross disturbance of respiratory muscle strength results in impaired ventilatory capacity (32), there is no evidence that this is so in normal subjects. In a previous study in normal subjects we found no relationship between diaphragm strength and maximal voluntary ventilation (33). It would therefore seem unlikely that the small reduction in diaphragm strength we have demonstrated would affect maximal ventilatory performance. However, changes in respiratory muscle perfusion (34) and ventilatory load in CHF may become more important during exercise, and minor muscle weakness could then additionally contribute to breathlessness and exercise limitation. The finding of a greater proportion of fatigue-resistant muscle fibers in CHF (15), to which our data also lend support, may therefore be an important adaptation to these changes.

We conclude that global respiratory muscle strength is well preserved in CHF, and only relatively mild weakness occurs in the diaphragm that is unlikely to be clinically important. However, it remains probable that respiratory muscle function is an important factor in the exercise limitation of CHF: ventilatory load is increased (3, 23), endurance during fatiguing protocols reduced (35), and exercise duration can be extended by unloading the respiratory muscles (21). Thus, further studies investigating the clinical importance of respiratory muscle function, particularly endurance and fatigue characteristics, in CHF are warranted.