Skeletal muscle contractile characteristics and fatigue resistance in patients with chronic heart failure

Transcription

1 European Heart Journal (1996) 17, Skeletal muscle contractile characteristics and fatigue resistance in patients with chronic heart failure S. D. R. Harridge, G. Magnusson and A. Gordon* Department of Physiology and Pharmacology, Physiology III, Karolinska Institute; Stockholm, Sweden; *Department of Medicine, Huddinge Hospital, Huddinge, Sweden Whole muscle contractile characteristics and fatigue resistance were studied in male patients with chronic heart failure (n = 6) and in healthy control subjects (n = 6). Maximum voluntary isometric strength in the major muscle groups of leg (plantar flexors and knee extensors) and arm (elbow extensors and elbow flexors), was found to be similar for both groups of subjects. However, a faster isometric twitch time course was observed in the plantar flexor and knee extensor muscles of heart failure chronic patients. The poor resistance to fatigue in the knee extensors of chronic heart failure patients was confirmed in the present study, but using twitch interpolation this was shown not to be due to poor activation. The plantar flexors of chronic heart failure patients also showed a tendency to be less resistant to fatigue, even when the muscle was activated by direct electrical stimulation. The present study shows that independent of muscle strength, patients with chronic heart failure may possess muscles that are faster to contract and less resistant to fatigue. However, it seems this increased fatigability is not due to poor muscle activation. (Eur Heart J 1996; 17: ) Key Words: Heart failure, muscle contraction, fatigue, activation. Introduction Whole body exercise tolerance is markedly reduced in patients with chronic heart failure, with a decrease in muscle strength and an increase in local muscle fatigability being implicated as potential causes 1 ' 1. To establish whether muscle strength per se is a contributory factor to reduced whole body exercise capacity, it is important that strength is measured in a number of major muscle groups covering both the upper and lower extremities. Lower muscle strength in chronic heart failure patients has partly been attributed to their smaller muscle mass' 2 ' 31, but impairment of the descending motor pathways and an inability to activate the muscle fully during maximum voluntary contraction cannot be excluded. Independent of muscle strength, it is possible that the skeletal muscles of patients with chronic heart failure may contract faster due to a significantly higher proportion of type II 141 and particu- Revision submitted 29 August 1995, and accepted 20 September Correspondence- S. D. R. Harridge, University Department of Geriatric Medicine, Royal Free Hospital School of Medicine, Pond Street, London NW3 2QG, U.K X/96/ $18.00/0 lady type lib fibres 15 ' 61. Since type II fibres are inherently less resistant to fatigue than type I fibres' 71 it is possible that the reduced ability of patients with chronic heart failure to maintain force output during repeated contractions' 3 ' 8 ' 91 is due to alterations in fibre distribution and to changes in the metabolic profile of the working muscles' 4 " 61. However, the lower fatigue resistance in these patients may also be as a result of poor motivation, due to a fear of over-exertion. The reduced endurance of the tibialis anterior in chronic heart failure patients recently reported by Minotti et a/.' 91 was partly a result of central fatigue, but the patients were no different to controls in this respect. However, with maximal exercise of the larger muscle groups such as the knee extensors a greater physiological challenge is presented to these patients, with potentially more relevance to the fear of over-exertion. The aim of the present investigation was thus to determine muscle strength in the major muscle groups of the arm and leg in chronic heart failure patients, to determine any differences in the time course of the muscle twitch and to establish whether muscle force production during maximal single and repeated contractions of major muscle groups was affected by poor activation The European Society of Cardiology

2 Skeletal muscle and fatigue resistance in patients with CHF 897 Table 1 Physical characteristics of the subjects Age (years) Weight (kg) Height (cm) Ejection fraction (%) VO 2 max (ml. kg ~ '. min ~ ') Patients (n = 6) 55-7 ± ± ± ± * ±2-4 (n=6) 62-7 ± ± ± ±4-2 'Patients with chronic heart failure significantly different controls. Methods Patients Six male patients with chronic heart failure as a result of left ventricular systolic dysfunction participated in the study. Four patients had idiopathic dilated cardiomyopathy and two had heart failure based on previous myocardial function. Five patients were in New York Heart Association Functional Class II and one in Class III. Left ventricular ejection fraction as determined by echocardiography ranged from 18-45%. Physical characteristics are given in Table 1. All of the patients were medicated with ACE inhibitors and diuretics. Four were taking digoxin, two atenolol and one warfarin. The patients had suffered from the disease for 6-3 ± 4-5 (1-11) years and had been clinically stable for at least 1 month prior to the study. They exercised by walking or cycling at least 2 h a week. Six healthy age-matched men volunteered as control subjects. All had a normal electrocardiograph response to exercise and none was taking medication. They were also habitually active, walking for a couple of hours per week. Muscle testing All measurements were made on the dominant limb. To test contractile properties and voluntary strength of the knee extensors, the subjects were seated upright in a rigid chair with knee flexed to an angle of 90 (see 1 ' 01 ). The lower leg was strapped in a steel brace attached by a rigid bar to a strain gauge load cell (Bofors KRG-4, 2 kn, Nobel Electronic, Sweden). Percutaneous stimulating electrodes (15 x 6 cm Tenzecare-3M) were placed over the proximal and distal portions of the quadriceps femoris. To test the plantar flexors, the subjects were seated upright in a purpose-built dynamometer with the thigh horizontal and the ankle positioned at an angle of 85" 1 " 1. A specially shaped clamp placed over the distal portion of the thigh close to the kiiee prevented heel lift to during contractions. The ankle joint was aligned with the centre of rotation of a footplate 0-3 m from a load cell (see above). Stimulating electrodes (6x10 cm) were placed over the belly of the soleus (- ve) and over the heads of the gastrocnemius (+ve). To test the elbow flexors and extensors the subjects were seated upright in a tall-backed rigid chair, firmly attached with steel pins to a fixed bench. The shoulder was positioned so that the upper arm was in a horizontal position and the elbow was flexed to 90. The elbow joint was fixed to a purpose-built dynamometer fixed on the bench. The wrist was clamped between two steel brackets to the lever arm of the dynamometer, and movement in the shoulder region was prevented with an adjustable clamp. The dynamometer was designed such that all force resulting from elbow extension and flexion was transmitted through a 015 m lever system to a load cell (see above). Four chronic heart failure patients and an equal number of controls performed this part of the study. No electrically evoked contractions were performed on the arm muscles. The torque signals from the load cell were amplified (BKJ-5 Nobel Electronik, Sweden and Gould, U.S.A.) and processed by an analogue-to-digital converter (Cambridge Electronic Etesign 1401, U.K.) attached to a personal computer, which sampled the data at a rate of 4 khz for twitch and 2 khz for the maximum voluntary contraction measurements. All muscle contractions were evoked using direct current square wave pulses of ms duration delivered by a battery powered stimulator 1 ' 21, where a PC controls output from a Krone-Hite (Avon, MA, U.S.A.) waveform generator. Maximum voluntary grip strength of the hand was tested using a handgrip dynamometer (Cardionics, AB Sweden) with the arm in a straightened position. Test procedure For the plantar flexors and the knee extensors each procedure began with the determination of the maximal twitch response. A maximal twitch was defined where a stepwise increment in voltage delivered every 30 s resulted in no further increase in torque. Three maximal twitches were performed and the average values for peak torque (PJ, time to peak torque (TPT) and half relaxation time (1/2RT) were used for analysis. One chronic heart failure patient did complete the knee extensor twitch protocol and one control subject did not complete the plantar flexor twitch protocol. Following a short rest, 4-5 maximum voluntary contractions were performed where the subjects were asked to generate their maximum force as fast as possible and maintain the contraction for 2-3 s. At least 1 min of rest was taken between contractions. During the final two maximum voluntary contractions of the knee extensors and plantar flexors a maximal electrical impulse was delivered to the muscle in an attempt to monitor the ability of the subjects to activate fully each respective muscle.

3 898 S. D. R. Harridge et al. Muscle activation following fatiguing exercise Fatiguing exercise of the knee extensor muscles was performed using an isokinetic dynamometer (Cybex II, Lumex Inc, N.Y., U.S.A.). Stimulating electrodes in the form of conductive silicon rubber pads (5 x 10 cm) were placed over the proximal and distal portions of the quadriceps femoris. Following a brief warm-up, where the subjects cycled at 50 watts on a cycle ergometer for 5 min and then performed some light stretching exercise, the subjects performed 50 consecutive maximal concentric contractions. Contractions were performed at an angular velocity of 180" s~' and repeated approximately once per second. Fatigue was denned as the decline in peak torque (mean of the torque generated on the best three of the last five contractions expressed as a percentage of the mean of the best three out of the first five contractions). Immediately following the final contraction, the leg was rapidly positioned and locked at an angle of approximately 60. The subjects were then instructed to push isometrically as hard as possible for 3 s. The time taken to reposition the leg and to initiate the isometric contraction was 1-2 s. A supramaximal impulse (delivered from a stimulator, Medlec, Surrey, U.K.) was then delivered to the muscle to determine the degree of activation in the fatigued state. Five of the chronic heart failure patients took part in this stage of the study and were compared with control subjects from a previous experiment [3] Electrically evoked fatigue For the plantar flexor fatigue test, the triceps surae was activated by direct electrical stimulation and stimulated for 300 ms once per second for 2 min at a frequency of 20 Hz 1 " 1. The muscle was considered to be maximally activated when prior stepwise increments in voltage (a 300 ms contraction at 20 Hz delivered once per minute) resulted in a plateau in the torque response. Of the six chronic heart failure patients tested, only two were able to tolerate a supramaximal stimulus. Three subjects were unable to tolerate a supramaximal stimulus and the test was performed at what was estimated to be 70-90% of maximum. One subject did not tolerate even mild tetanic stimulation and did not perform the test. A fatigue index was calculated as the mean of the isometric torque generated on the final three contractions expressed as a percentage of the mean torque generated by the first three contractions. The data from the patients were compared with data from a further five healthy agematched controls (mean age 57-4 ± 8-7 years), tested in very similar apparatus 1 " 1, using exactly the same test protocol and where a maximal stimulus was tolerated in all subjects. All testing of the chronic heart failure patients took place under clinical supervision. Table 2 Isometric twitch characteristics of the knee extensors and plantar flexors Patients P, (Nm) 314 ± ±60 Knee extensors TPT 81 ±5 78 ±7 1/2RT 76* ±15 94 ±8 P, (Nm) 190 ± ±3-6 Plantar flexors TPT 127* ± ± 11 1/2RT 91 ± ± 10 P, = peak torque, TPT = time to peak torque, l/2rt=halfrelaxation time. Patients significantly different from controls (/><005). Patients: n = 6 for plantar flexors, n = 5 for knee extensors.. n = 6 for knee extensors and n = 5 for plantar flexors. Statistics Values are expressed as mean ± SD in the text and Tables and ± SE in the figures. Comparisons between the chronic heart failure patients and control subjects were made using independent Student t-tests. / ) <005 was taken as the level of statistical significance. Results Peak torque generated by the maximal twitch in the plantar flexors and the knee extensors was similar for chronic heart failure patients and controls (Table 2). In the knee extensors, time to peak tension did not differ between the two groups, but a significantly faster half relaxation time was observed (/ ) <005) in the chronic heart failure patients. In the plantar flexors, both time to peak tension (F<005) and half relaxation time (P<006) were faster in chronic heart failure patients when compared with controls. Maximum voluntary torque production in the chronic heart failure patients averaged ± 30-8, 1680 ±40, 53-9 ±15-7 and 57-7 ± 20-9 Nm for the plantar flexors, knee extensors, elbow extensors and elbow flexors respectively (Fig. 1). Similar values were obtained from the four muscle groups of the control subjects. This was also the case for hand grip strength where the patients generated ± 77-1 N and the control subjects 4659±45-9N of force, but no differences in the ability to activate the plantar flexor and knee extensor muscles were observed between the chronic heart failure patients and control subjects. Following 50 isokinetic contractions of the knee extensor muscles by five of the chronic heart failure patients at 180 s~', peak torque had declined to 46 ± 13% of that generated at the onset of exercise (Fig. 2). When a maximal electrical stimulus was delivered to the muscle during a maximal isometric contraction performed immediately after the final isokinetic contraction, no further increase in torque was observed in any of the five subjects (Fig. 3).

4 Skeletal muscle and fatigue resistance in patients with CHF 899 Plantar Knee Elbow Elbow flexors extensors extensors flexors Figure 1 Muscle strength values for the knee extensor and plantar flexor muscle groups of the leg and the elbow flexors and extensors of the arm. Data expressed in the form of torque about the joint (n=6 for leg muscles and n=4 for arm muscles in both groups). 0 = chronic heart failure; = controls. CHF patients Figure 2 Fatigue of the knee extensor muscles in chronic heart failure patients compared to controls taken from Magnusson et al (1994) expressed as a percentage (n = 5 chronic heart failure patients, n = 8 controls). *Patients significantly different from controls (/ > <0 > 05). The mean fatigue index obtained from the electrically evoked fatigue test in the plantar flexor muscle group of the chronic heart failure patients was lower (63 ±13%), but not significantly so, when compared with control subjects (76 ± 15%, Fig. 4). Discussion Patients with chronic heart failure in the present study were similar to control subjects in terms of voluntary strength, but exhibited different contractile properties of the leg muscles as determined by the twitch response. The high degree of fatigability of the knee extensor muscles was confirmed in chronic heart failure patients, which could not be attributed to poor neural drive. Even when the muscle, in this case the plantar flexors, was involuntarily activated by direct electrical stimulation, chronic heart failure patients were found to be generally more fatiguable than control subjects. As a consequence of their condition, heart failure patients may hesitate to make a maximal effort during strength and endurance testing procedures for fear of over-exerting themselves. In order to investigate whether or not this was the case, the twitch interpolation technique was used to determine whether the chronic heart failure patients and the control subjects were able to activate fully the knee extensor and plantar flexor muscles during maximum isometric contractions. Although there was some evidence of poor activation in both the plantar flexor and knee extensor muscle groups no differences were observed between chronic heart failure patients and controls. In some studies muscle strength in patients with chronic heart failure has been reported to be lower than for controls' 3 ' 13 ' 41. This would seem to be the result of a smaller muscle mass in the subjects in these studies, as no changes in force per unit area have been reported' However, in the present study chronic heart failure patients showed comparable strength with controls in all three muscles, which is in accordance with the observations of unaltered strength in the knee extensors and ankle dorsiflexors in chronic heart failure patients in other studies' 2 ' 8 ' 91. The lack of a decline in strength in the present study is unlikely to be explained by the duration of the disease, since three of the chronic heart failure patients had suffered with the condition for approximately 10 years. However, it is likely that the more advanced and the longer the duration of heart failure, the more inactive patients become, resulting in a greater degree of muscle wasting and thus greater deterioration of muscle function. The muscle twitch provides a useful measure of involuntary muscle function which has been shown to reflect muscle composition' 151. In the present study, time to peak tension in the knee extensors was similar for both groups, however, a significantly faster half relaxation time (/ > <005) was observed in chronic heart failure patients. The twitch time course of the plantar flexors was markedly prolonged in both groups of subjects when compared to the knee extensors. This is no doubt a reflection of difference in the composition of the two muscle groups as the knee extensors, as represented by the vastus lateralis, comprise a relatively even mixture of fast (type II) and slow (type I) fibres (at least in healthy young adults)' 71, whilst the plantar flexors comprise both the gastrocnemius and soleus muscles, the latter of which is dominated by type I fibres' 161. Observations of the plantar flexors revealed a markedly faster time to peak tension (f<0-05) and half relaxation time (/><0-06) in the chronic heart failure patients as compared to control subjects. It is likely that these results are a reflection of an altered muscle composition, specifically a higher proportion of type II [4] and particularly lib fibres which have been shown to occur in the vastus lateralis' 61 and in the gastrocnemius muscles of chronic heart failure patients' 51. These data are, however, in contrast to the results of studies on isolated bundles of

5 900 S. D. R. Harridge et al. Angle trace Stimulus Torque trace Figure 3 An original record of a chronic heart failure patient performing maximum isokinetic contraction at 180 s~'. The record shows the final contraction followed by a rapid repositioning of the leg followed by a maximum isometric contraction. The arrow indicates the delivery of a maximal stimulus with no effect on torque production, suggesting full activation can occur whilst the muscle is in the fatigued state. CHF patients Figure 4 The fatigue index data from the plantar flexors resulting from electrically evoked isometric contractions (=5). skeletal muscle fibres from the type II fibre dominated extensor digitorum longus muscle of rats with infarction-induced chronic heart failure 1 ' 71, where twitch time course has shown to increase. This phenomenon was shown to be closely coupled to changes in sarcoplasmic reticulum Ca 2+ kinetics, which also seemed to be the cause of the ~ 50% reduction in specific tension observed during a maximal tetanus. It is evident that chronic heart failure patients have markedly reduced muscular endurance 138 ' 9 '' 31 despite similar absolute strength as control subjects' 8 ' 91. Minotti et a/.' 81 using dynamic and sustained isometric contractions of the dorsiflexors, reported that neural drive was a limiting factor to force production during fatiguing exercise, but that patients with chronic heart failure were no worse in this regard than normal healthy subjects. Compared to the dorsiflexors, the physiological demands of repeated knee extensor exercise are potentially much greater given the larger muscle mass. Thus it is possible that these patients may be more susceptible to impaired activation under these conditions. However, following 50 maximal isokinetic knee extensions the subjects appeared to be able to activate their muscle mass fully, as shown by no evidence of an interpolated twitch superimposed on an isometric contraction immediately following dynamic exercise (Fig. 3). The decline in torque over this period was in close agreement with values previously reported for chronic heart failure patients and which are markedly lower than those of healthy controls' 31. By activating the muscle through direct electrical stimulation it is possible to determine its fatigue resistance completely independent of subject volition. In the present study the plantar flexors were stimulated intermittently at a frequency of 20 Hz for 2 min. The decline in torque production was more pronounced in the patients with chronic heart failure than in the control subjects. However, in contrast to all of the control subjects, only two of the chronic heart failure patients were able to tolerate a supramaximal stimulus. Since these two showed the biggest decline in torque production, it may explain why this difference was not at the level of statistical significance, when the whole patient group was considered. The results of the fatigue experiments on the knee extensor and plantar flexor muscle groups would

6 Skeletal muscle and fatigue resistance in patients with CHF 901 seem to support the argument that local muscle fatigue in patients with chronic heart failure is due to peripheral, rather than central factors. The aetiology of muscle fatigue is complex and depends on the type and duration of the exercise performed (see 1181 for review). In the present study a relatively short duration high intensity exercise protocol was used. In this regard, lower muscle ph and higher inorganic phosphate concentrations have been observed in chronic heart failure patients following intense exercise when compared to controls' 5 ' 19 ', factors known to contribute to impaired force generation' 201. In addition lower oxidative enzyme capacity 15 ' 6 ' 21 ' and lower capillary density 161 may also contribute to the early onset of fatigue, even during relatively short exercise periods. In conclusion, voluntary strength in the major muscle groups of the arm and leg was well maintained in patients with chronic heart failure when compared with age-matched healthy individuals in the present study. However, a faster twitch response and greater fatigability were observed in the leg muscles of chronic heart failure patients. The latter finding could not be attributed to poor muscle activation, adding further weight to the argument that the decrease in local skeletal muscle fatigue resistance in patients with chronic heart failure is due to muscular and not to central limitations. The authors would like to thank Eddy Karlsson and Georg Goertz for their technical assistance. References [1] Coats AJS, Clark AL, Piepoli M, Volterrani M, Poole-Wilson PA. Symptoms and quality of life in heart failure: the muscle hypothesis. Br Heart J 1994; 72 (Suppl): S36-9. [2] Minotti JR, Pillay P, Oka R, Wells L, Christoph 1, Massie BM. 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Abnormalities of skeletal muscle in patients with chronic heart failure, Int J Cardiol 1988; 18: [14] Buller NP, Jones DA, Poole-Wilson PA,. Direct measurement of skeletal muscle fatigue in patients with chronic heart failure. Br Heart J 1991; 65: [15] White MJ, Harridge SDR, Carrington CA, Goodman M, Cummins P. The relationship between isometric contractile characteristics and isomyosin composition of the young and elderly human triceps surae. J Physiol 1994; 475: 27P. [16] Gollnick PD, Sjodin B, Karlsson J, Jansson E, Saltin B. Human soleus muscle: a comparison of fibre compositions and enzyme activities with other leg muscles. Pflug Arch 1974; 348: [17] Perreault CL, Gonzalez-Serratos, H, Liwin SE, Sun X, Franani-Armstrong C, Morgan JP. Alterations in contractility and intracellular Ca 2+ transients in isolated bundles of skeletal muscle fibers from rats with chronic heart failure. Circ Res 1993; 73: [18] Fitts RH. Cellular mechanisms of fatigue. Phys Rev 1994; 74: [19] Arnolda L, Conway M, Dolecki M et al. Skeletal muscle metabolism in heart failure; a 3I P nuclear magnetic resonance spectroscopy study of leg muscle. Clin Sci 1990; 79: [20] Cooke R, Franks K, Luciani GB, Pate E. The inhibition of skeletal muscle contraction by hydrogen ions and phosphate. J Physiol 1988; 395: [21] Ralston MA, Merola JA, Leir CV. Depressed aerobic enzyme activity of skeletal muscle in severe chronic heart failure. J Lab Clin Med 1991; 117: