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European Journal of Heart Failure 2001 3(1):53-58; doi:10.1016/S1388-9842(00)00112-4
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© 2001 European Society of Cardiology

Is there a relationship between muscle fatigue resistance and cardiovascular responses to isometric exercise in mild chronic heart failure?

Charlotte A. Carringtona,*, Wendy J. Fishera, Michael K. Daviesb and Michael J. Whitea

a School of Sport and Exercise Sciences, University of Birmingham Edgbaston, Birmingham, UK
b Department of Cardiology, University Hospital Birmingham NHS Trust UK

* Corresponding author. Tel.: +44-121-414-4111; fax: +44-121-414-4121. E-mail address: c.a.carrington{at}bham.ac.uk (C.A. Carrington).


   Abstract
Top
 Abstract
1. Introduction
 2. Methods
 3. Results
 4. Discussion
 References
 
Background: Exercise intolerance in chronic heart failure (CHF) may be due to altered fatigue resistance and muscle afferent input to the cardiovascular system from dysfunctional skeletal muscle.

Aim: To determine whether calf muscle fatigue resistance was associated with the magnitude of a muscle afferent driven cardiovascular response to isometric exercise.

Methods and results: Cardiovascular responses were recorded in eight stable CHF patients (ejection fraction 20–40%) and nine healthy, age-matched controls during voluntary and electrically evoked isometric plantar flexion and post-exercise circulatory occlusion. The force developed by the plantar flexors during a 2-min submaximal electrically evoked fatigue test was measured. There was no relationship between ischaemic muscle fatigue and cardiovascular changes during and after voluntary contraction in either group nor evoked contraction in the CHF group. In the control group, the change in diastolic blood pressure (DBP) at the end of evoked contraction was related to the severity of fatigue at 90 s and 120 s (FI=0.01{Delta}DBP+0.3, r=0.81, P<0.05 and FI=0.02{Delta}DBP+0.8, r=0.84, P<0.01, respectively).

Conclusion: Muscle fatigue resistance did not relate to the magnitude of the cardiovascular stress generated by isometric exercise of the same muscle in these patients.

Key Words: Heart failure • Fatigue • Isometric exercise

Received March 9, 2000; Revised June 13, 2000; Accepted June 20, 2000


   1. Introduction
Top
 Abstract
 1. Introduction
2. Methods
 3. Results
 4. Discussion
 References
 
The mechanisms underlying the exertional fatigue experienced by CHF patients are unclear. Recently, it has been suggested that it, and other CHF symptoms, may be due to altered afferent input to the cardiorespiratory system from dysfunctional skeletal muscle, the so called ‘muscle hypothesis’ [1].

The cardiovascular response to exercise is affected by the muscle contractile character [2], the contractile protein profile [3] and the training status [4,5] of the active muscle. In CHF, intrinsic skeletal muscle abnormalities occur which include muscle fibre atrophy, a relative increase in type IIb fibre area [6] a decrease in oxidative capacity and a reliance on anaerobic metabolism during exercise [7,8]. All of these factors are associated with decreased fatigue resistance [9] and muscle fatigue resistance is linked to sympathoexcitation [10]. Furthermore, the metabolic products of exercise, particularly anaerobic exercise, are known to stimulate muscle afferents [11]. Therefore, the fatigue resistance of a muscle may influence the magnitude of the muscle afferent drive that this muscle produces during exercise. Muscle afferent drive is best assessed during isometric exercise and post-exercise circulatory occlusion (PECO). Additionally, if the exercise is electrically evoked the influence of central command can be removed [12]. In a recent study [4] local muscle training attenuated the cardiovascular response of the trained muscle to evoked isometric exercise and increased the fatigue resistance of the trained muscle. Moreover, the attenuated blood pressure rise seen during evoked isometric exercise correlated with the increased fatigue resistance. It is possible, therefore, that muscle fatigue resistance may be related to the magnitude of the blood pressure rise during isometric exercise in patients with CHF. If this were true then it might be a predictor of the cardiovascular response to exercise in this patient group.

Various methods have been used to evaluate skeletal muscle fatigue in CHF, the most precise of which is to measure the force developed during muscle contractions (see [13] for review). Previous studies that have used this method have measured forces developed from voluntary muscle contractions [14–16]. Because voluntary contractions, whether isometric or dynamic, may be affected by motivation and/or fear of over-exertion, the resulting measure of fatigue resistance may not be reliable. Electrically evoked contractions, on the other hand, enable fatigue resistance to be determined independently of subject volition. However, the few studies that have used direct electrical stimulation to activate the muscle have used either a very small muscle mass [17] or have had difficulties with patients tolerating supramaximal tetanic stimulation of a larger muscle group [18]. In the present study a validated, electrically evoked submaximal fatigue test was used on a large postural muscle group, the ankle plantar flexors [19]. Our hypothesis was that calf muscle fatigue resistance assessed by electrically evoked contractions would relate to the cardiovascular response to involuntary isometric exercise of the calf muscles.


   2. Methods
Top
 Abstract
 1. Introduction
 2. Methods
3. Results
 4. Discussion
 References
 
2.1. Subjects
Eight patients (two women) with stable chronic heart failure (CHF) due to ischaemic heart disease took part in the study. All had New York Heart Association (NYHA) class II–III heart failure of mean duration 2.3±2.2 years; range 0.5–7 years. All had left ventricular dysfunction with an echocardiographic ejection fraction of ≤40% (range 20–40%). Physical and clinical characteristics are given in Table 1. Patients did not have diabetes, any neuromuscular disorders, chronic lung or significant valvular heart disease. Other exclusion criteria included atrial fibrillation, peripheral vascular disease and β-blockade.


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  		Table 1 Physical and clinical characteristics of the subjectsa

 
Nine sex- and age-matched control subjects (two women) were studied. All were healthy, normotensive subjects with no history of heart disease, peripheral vascular disease or musculoskeletal disease, and none were taking any prescribed medication. Table 1 shows the physical characteristics of the control subjects. The local ethical committee approved experimental procedures and the subjects gave written informed consent before participation in the study. The investigation conforms with the principles outlined in the Declaration of Helsinki.

2.2. Experimental protocol
Established methods were used to measure evoked and voluntary pressor responses [12,19]. The subject was seated with the preferred leg clamped in the dynamometer. The thigh was horizontal whilst the knee and ankle joints were at 1.4 rad (85°). Upward force generated by the calf muscles transmitted to the transducer. Output from the transducer was amplified and transmitted to an analogue to digital converter (Cambridge Electronic Design 1401 plus) and was displayed on a personal computer (Vale Platinum TX) and a chart recorder. Maximum voluntary contractile force (MVC) was determined as being the best of three attempts. The twitch interpolation technique was used to ascertain that maximal activation of muscle was achieved [20]. Thirty percent MVC was calculated and was displayed on a chart recorder. For voluntary contractions subjects maintained the required force by matching the deflection produced on the chart recorder to the pre-determined 30% MVC line. For evoked contractions tetanic stimulation at 20 Hz, 50 µs pulse width, was used and small adjustments of stimulus current (Digitimer D56) maintained force output of 30% MVC. These levels of stimulation are not painful and were tolerated easily by the subjects. Blood pressure was recorded from the middle finger using a Finapres (Omeda) and heart rate was recorded using a three-lead electrocardiogram (ECG) and heart rate monitor (Cardiorater CR7, Cardiac Records Ltd). Analogue blood pressure and analogue ECG signals were transmitted to an analogue to digital converter (Cambridge Electronic Design 1401plus). For each signal, the sampling frequency of analogue to digital conversion was 1000 Hz. Blood pressure and heart rate waveform data were displayed and analysed on a personal computer (Vale Platinum TX).

Subjects were habituated to the procedures during preliminary visits to the laboratory. On experimental days, two 8-min protocols were performed involving either voluntary or electrically evoked isometric plantar flexion. Before the start of a protocol the subject rested for 10 min, positioned in the dynamometer, in order to attain a stable basal circulatory state. A 2-min control period was followed immediately by a 2-min electrically evoked contraction at 30% MVC. Just prior to the start of the contraction, a pneumatic thigh cuff was inflated to 200 mmHg and was maintained throughout the 2-min contraction. At the end of the contraction the thigh cuff remained inflated at 200 mmHg for 2 min post-exercise circulatory occlusion (PECO) and was then released for a 2-min recovery period. Heart rate and blood pressure were recorded continuously throughout the 8-min protocol. At the end of the experiment the subject rested for at least 20 min before the second protocol was performed. Subjects repeated the experiments on one further occasion when the order in which the voluntary and involuntary contractions were performed was reversed. At each time point, average values for the two experiments performed under each experimental condition were then calculated for every subject.

Muscle contractile characteristics were measured from electrically evoked maximal twitch responses under isometric conditions, according to the methods of Davies et al. [21]. Three maximal responses were recorded from which the mean time-to-peak tension (TPT), half-relaxation time (1/2 RT) and peak tension (PT) were calculated.

The electrically evoked submaximal fatigue test was performed on the last visit and consisted of trains of stimuli at 20 Hz lasting 300 ms repeated 1 s–1 for 2 min. The calf muscles were activated using 20 Hz, 300 ms tetanus and the current was increased until there was no further rise in force. The force produced at this supramaximal stimulus was measured and 60% was calculated. The current required to evoke tetanic contraction to this level was found and used during the fatigue test. All tests were performed under conditions of local circulatory arrest. Immediately before the fatigue test started a thigh cuff was inflated to 200 mmHg and was maintained during the 2-min test. Fatigue indices were calculated at 30, 60, 90, and 120 s by dividing the force at each time point by the initial force.

Data are reported as group means±standard deviation unless otherwise stated. Comparisons of the data at key time points were made using a Mann–Whitney U-test for between group analysis and Wilcoxen Signed Rank Test for within group analysis. Some of the contractile data (not the fatigue data) and the cardiovascular data have been reported elsewhere [22].


   3. Results
Top
 Abstract
 1. Introduction
 2. Methods
 3. Results
4. Discussion
 References
 
3.1. Muscle contractile characteristics
The muscle twitch characteristics, MVC forces produced prior to contraction, and tetanic force at 20 Hz, were not significantly different between chronic heart failure patients and control subjects (Table 2). The mean fatigue test data for both groups are shown in Fig. 1. At each time point that fatigue indices were calculated, the CHF patients’ calf muscles were more fatigable than those of the control subjects and this difference was significant at 60 s and 90 s (P<0.01).


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  		Table 2 Muscle characteristics of the CHF and control groupsa

 


Figure 1
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  		Fig. 1 Comparison between CHF patients (open squares) and control subjects (closed squares) of the mean change in fatigue index during 2 min submaximal electrically evoked fatigue test (bars indicate mean±S.E.M). *Significantly different between groups, P<0.01.

 
3.2. Cardiovascular responses
Control subjects had an initial resting SBP of 131±19.5 mmHg, DBP of 72±9.48 mmHg and HR of 75±8.73 beats min–1. In comparison, CHF patients had significantly (P<0.05) lower resting blood pressure values, SBP 110±21.32 mmHg and DBP 59±10.35 mmHg but a similar resting heart rate 78±17.45 beats min–1. The cardiovascular changes at the end of voluntary and evoked contractions for both CHF and control groups are given in Table 3.


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  		Table 3 Group mean changes in cardiovascular responses at the end of contractiona

 
At the end of the evoked contraction the rise in SBP and DBP was significantly smaller (P<0.05) in the CHF group compared with the control group. Similarly, at the end of the voluntary contraction, the rise in SBP was significantly smaller (P<0.05) in the CHF patients than in the control group.

3.3. Relationship between resistance to fatigue and cardiovascular responses
In the CHF group there was no relationship between the fatigue index values and the changes in blood pressure or heart rate. In the control group the change in DBP at the end of evoked contraction was related to the fatigue index at 90 s (FI=0.01{Delta}DBP+0.3, r=0.81, P<0.05) and at 120 s (FI=0.02{Delta}DBP+0.8, r=0.84, P<0.01).


   4. Discussion
Top
 Abstract
 1. Introduction
 2. Methods
 3. Results
 4. Discussion
References
 
The purpose of the study was to determine whether there was an association between calf muscle fatigue resistance, assessed by electrically evoked contractions, and the magnitude of the cardiovascular response to isometric exercise in both CHF patients and control subjects. In agreement with earlier studies, we found that during involuntary exercise the patients were more fatigable than the control subjects [17,18]. This could not be attributed to lack of motivation or fear of over-exertion since the test was electrically evoked. Neither could the greater fatigability be attributed to impaired central circulation and muscle blood flow, since local muscle blood flow was occluded during the test. In addition, we found that the pressor response to isometric exercise was attenuated in the CHF patients compared to the controls. This was true of both voluntary and evoked contractions. Thus, under ischaemic measurement conditions the patients were more fatigable yet produced a lower pressor response. The attenuated pressor response in the patients is unlikely to be due to any drug therapy. Nitrates were taken by only three patients and it is improbable that this alone would lead to a significant effect in a small population of eight patients. Furthermore, the group mean changes for the three patients on nitrates were similar to those of the five who were not. There is clear evidence that ACE-inhibitor therapy does not impair the ability of the sympathetic nervous system to increase activity during exercise nor does it appear to effect the relative magnitude of the change from baseline. A study of CHF patients who were taking ACE-inhibitors found that the percentage increases in muscle sympathetic nerve activity and skin sympathetic nerve activity were at least as great as those of control subjects during standardised handgrip exercise [23]. In addition, the pressor response in patients on ACE-inhibitor therapy has been reported as equal to [24] or greater than that of control subjects [25] during handgrip exercise. Since all of the above studies involved patients on similar standard drug therapy to our own it seems unlikely that our finding of an attenuated pressor response during calf muscle exercise can be explained on the basis of drug effects on sympathoexcitation.

The relationship between local muscle fatigue resistance and cardiovascular responses to exercise was not as we expected in either the control subjects or CHF patients. In the control subjects we found a significant association between fatigue index in the latter phases of the test and the magnitude of the blood pressure response during electrically evoked exercise, which is independent of central command. The more fatigable the muscle the smaller was the diastolic blood pressure increase at the end of the exercise period. This is not readily explained by a theory based on simple co-dependence of fatigue and muscle afferent activation linked to metabolite accumulation. Muscle afferent activation is linked to sympathoexcitation [26] in fresh and in fatigued muscle [10]. The increased muscle sympathetic nerve activity causes increased vascular resistance which is best reflected in diastolic blood pressure change. If fatigue, i.e. a low fatigue index, was directly linked to metabolite production and these metabolites caused muscle afferent activation, it would be expected that fatigue index and change in diastolic blood pressure during involuntary exercise would be inversely related. Our finding of the opposite outcome requires a different explanation. The twitch time to peak data in the control subjects indicate a muscle with a preponderance of type I fibres [2]. The relative reduction of type II fibre area may reduce the production of the metabolites associated with muscle afferent activation [11,27]. The result is a smaller pressor response, a greater fatigue resistance and the significant relationship between diastolic blood pressure change and fatigue index that we observed. In the patient group, despite their probable similar muscle composition to the control group, there was no association between fatigability and the pressor response. The two processes seem independent of each other. The increased fatigability of the patients’ muscle is apparent quite early in the fatigue test (Fig. 1.) as indicated by their rapid loss of force seen in the first 30 s. This can have nothing to do with impaired supply of oxygen or substrate during this ischaemic test. It is likely that even with similar muscle composition to control subjects, the patients will have muscle with decreased oxygen stores and oxidative capacity and, therefore, a greater dependence on anaerobic metabolism [8,7]. Since the products of anaerobic metabolism are known to stimulate muscle afferents [11] this might be expected to lead to greater muscle afferent stimulation in CHF patients and, therefore, a greater pressor response. However, in direct conflict with this hypothesis, there is evidence that chronic exposure to such conditions may cause muscle afferent desensitisation in CHF patients [28] resulting in an attenuation of the pressor response seen during involuntary exercise and PECO [28]. Our patients had all attempted to maintain an active lifestyle, within the limitations of their condition, therefore, the attenuated pressor response would be consistent with muscle afferent desensitisation in this postural muscle group [22].

In conclusion, it seems that our objective test of muscle fatigue resistance does not relate to the magnitude of the cardiovascular stress experienced during isometric exercise of the same muscle in the CHF patients we studied. However, our patients with mild heart failure might be viewed as above average in their attempts to remain active despite their NYHA classification and, therefore, may have a training induced adaptation of their muscle afferent activity [4]. A study of more limited or less well motivated patients might reveal a relationship between local muscle fatigue resistance and cardiovascular stress during exercise.


   Acknowledgements
 
This work was supported by the British Heart Foundation Grant PG/97085.


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

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