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European Journal of Heart Failure 2001 3(1):59-67; doi:10.1016/S1388-9842(00)00114-8
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© 2001 European Society of Cardiology

Skeletal muscle characteristics, muscle strength and thigh muscle area in patients before and after cardiac transplantation

Maria Schaufelbergera,*, Bengt O. Erikssonb, Lars Lönnc, Bengt Rundqvistd, Katharina Stibrant Sunnerhagene and Karl Swedberga

a Department of Medicine, Sahlgrenska University Hospital Östra, Göteborg University Göteborg, Sweden
b Department of Pediatrics, Sahlgrenska University Hospital Östra, Göteborg University Göteborg, Sweden
c Department of Diagnostic Radiology Sahlgrenska University Hospital Sahlgrenska, Göteborg University Göteborg, Sweden
d Division of Cardiology, Sahlgrenska University Hospital Sahlgrenska, Göteborg University Göteborg, Sweden
e Department of Rehabilitation Medicine, Sahlgrenska University Hospital Sahlgrenska, Göteborg University Göteborg, Sweden

* Corresponding author. Tel.: +46-31-343-40-00; fax: +46-31-25-89-33. E-mail address: maria.schaufelberger{at}hjl.gu.se (M.Schaufelberger).


   Abstract
Top
 Abstract
1. Introduction
 2. Methods
 3. Results
 4. Discussion
 References
 
Background: Patients with chronic heart failure demonstrate several skeletal muscle abnormalities. The underlying mechanisms are unclear. After cardiac transplantation, cardiac function is restored, but exercise capacity is still impaired.

Aim: To evaluate the influence of cardiac transplantation on skeletal muscle fibre composition, fibre area and capillarization as well as muscle enzymes, lactate, thigh muscle area and strength.

Methods: Ten patients were longitudinally investigated before, 1–3 and 6–9 months after transplantation. Ten healthy individuals served as controls. A biopsy from the lateral vastus muscle was obtained and the thigh muscle area was measured with computed tomography. Muscle strength in the knee extensors and exercise capacity were also evaluated.

Results: Muscle lactate was elevated in patients vs. controls (3.6±3.0 vs. 1.5±0.7 mmol/kg wet wt., P = 0.037), and decreased to normal (1.4±0.3 mmol/kg wet wt., P = 0.038) after transplantation. Citrate synthase activity was decreased in patients (5.6±1.5 µmol/g wet wt./min) vs. controls (8.1±1.6 µmol/g wet wt./min, P = 0.0018), and did not change post transplantation. Patients had decreased number of capillaries in contact with each fibre vs. controls (2.6±0.5 vs. 3.5±1.0, P = 0.039) which persisted post transplantation. Exercise capacity increased after transplantation (74±22 vs. 118±26 W, P = 0.0002), whereas muscle strength did not improve significantly.

Conclusion: The persisting intrinsic abnormalities in skeletal muscle after cardiac transplantation may contribute to the impaired exercise capacity observed in cardiac transplant recipients.

Key Words: Heart failure • Cardiac transplantation • Skeletal muscle

Received February 15, 2000; Revised May 22, 2000; Accepted June 20, 2000


   1. Introduction
Top
 Abstract
 1. Introduction
2. Methods
 3. Results
 4. Discussion
 References
 
Patients with chronic heart failure demonstrate several skeletal muscle abnormalities including impaired skeletal muscle metabolism, decreased oxidative enzyme activity, altered fibre type composition and decreased capillarization [1–3]. Diminished muscle mass, strength and endurance have also been reported in these patients [4,5]. The underlying mechanisms behind these abnormalities are unclear. Deconditioning may be of importance, which is supported by reports that training partially reverses skeletal muscle alterations in patients with heart failure [6–9]. It seems that cardiac hemodynamics is related to skeletal muscle abnormalities [3,10]. It is also possible that the neuroendocrine and cytokine activation prevailing in heart failure influence skeletal muscle. Conventional medical treatment for heart failure may also affect skeletal muscle [3,11].

Cardiac transplantation is a valuable treatment option for some patients with advanced chronic heart failure. Since cardiac transplantation improves hemodynamics and tissue perfusion as well as sympathetic neural activity [12,13], a regression in skeletal muscle abnormalities would be expected post transplantation. Although there is a marked improvement in cardiac performance, hemodynamics and symptoms soon after heart transplantation, maximal exercise capacity is still impaired [14]. It has been suggested that persistent skeletal muscle abnormalities may contribute to the impaired exercise capacity found in heart transplant recipients [15].

The objective was to investigate if skeletal muscle abnormalities are reversible after cardiac transplantation in a longitudinal study of patients with chronic heart failure. We hypothesised that increased physical activity, an improved cardiac function and sympathetic activity post transplant [12,13], would result in an amelioration of skeletal muscle metabolism, histochemistry, muscle area and strength.


   2. Methods
Top
 Abstract
 1. Introduction
 2. Methods
3. Results
 4. Discussion
 References
 
2.1. Patient population
Ten patients, seven males and three females, with chronic heart failure in New York Heart Association (NYHA) functional class III–IV awaiting heart transplantation were investigated (Table 1). Patients were not included in this study if they had diabetes mellitus, intermittent claudication, significant pulmonary disease, symptom-limiting angina pectoris or other disorders limiting physical performance. Ten healthy subjects, matched for age and gender, served as control group (Table 1). The Ethics Committee of the Göteborg University approved the protocol, and written informed consent was obtained from each subject.


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  		Table 1 Characteristics of patients with chronic heart failure awaiting cardiac transplantation and control subjects

 
2.2. Study protocol
A skeletal muscle biopsy was obtained from the lateral vastus muscle at admittance to hospital for evaluation before heart transplantation. Echocardiogram was used to evaluate ejection fraction according to Simpson's biplane formula. Tissue determinations (adipose tissue, muscle tissue) were determined by computed tomography. Muscle strength test of the knee extensors was also performed. The investigations were repeated 1–3 months and 6–9 months after cardiac transplantation. Dynamic exercise tests were performed at baseline and at the second follow-up. All patients participated in the ordinary post transplant training program including both supervised stationary cycling and limb muscle training five times per week.

2.3. Skeletal muscle biopsy
Percutaneous skeletal muscle biopsies were obtained in local anaesthesia with a conchotome from the middle part of the lateral vastus muscle in the right leg [16]. Two samples were immediately frozen in liquid nitrogen, stored at –70°C and used for analysis of lactate and enzymes. A third sample was trimmed and mounted in embedding media, frozen in cooled isopentane and stored at –70°C. This sample was used for histochemical analysis.

One biopsy sample was weighed and fluorometrically analysed for lactate, expressed in mmol/kg wet wt., according to the modified Lowry and Passoneau methods as described by Karlsson [17]. A second biopsy sample was weighed and the activities of phosphorylase and lactate dehydrogenase, as well as citrate synthase and 3-hydroxyacyl-CoA dehydrogenase were analysed with fluorometric technique [18–21]. The enzyme activities are expressed in µmol/g wet wt./min.

Muscle fibre classification and calculation of capillaries were performed according to Dubowitz [22] and Andersen and Henriksson [23]. Measurements of fibre areas were made with a semi-automated method (Comfas system, Bio-Rad Scan Beam A/S, Hadsund, Denmark).

2.4. Muscle strength test
The patients were seated with support for the back and a seat-belt around the waist, with both legs hanging freely. The knee angle was 90°. An inelastic strap was placed around the ankle and attached to a pressure transducer with amplifier (Steve Strong, Stig Starke HB, Göteborg, Sweden). The subjects were instructed to pull the ankle strap maximally for 3 s by extending the knee. The best of three efforts in the right leg was reported as maximal isometric quadriceps force (in Newton). Muscle strength test was not performed in the control group.

2.5. Thigh muscle area
A computed tomography scan at the mid-thigh region half-way between the knee joint and the iliac crest was obtained. Tissue discrimination is possible knowing different intervals of pixel values, i.e. attenuation values expressed in Hounsfield units (HU). A comprehensive description of the application is given by Chowdbury et al. [24].

Thigh muscle area was not investigated in the control group.

2.6. Exercise testing
At baseline and at the second follow-up patients performed a maximal upright bicycle exercise test with an increase of workload of 10 W every minute until exhaustion. No exercise test was performed in the control group.

2.7. Statistical analysis
Data are expressed as mean±S.D. An unpaired two-sided Student's t-test was used to evaluate possible differences for between-group comparisons and a paired two-sided Student's t-test was used for intra-group comparisons. The relations between variables were examined by simple regression analysis. P<0.05 was considered significant. However, the exploratory nature of this study makes significance levels uncertain because of repeated tests.


   3. Results
Top
 Abstract
 1. Introduction
 2. Methods
 3. Results
4. Discussion
 References
 
Ejection fraction increased in all patients (mean 70±9% at follow-up 1 and 71±6% at follow-up 2). All heart transplant recipients were treated with cyclosporine, glucocorticoids and azathioprin throughout the post-transplant study period. The mean dose of cyclosporine was 440±66 mg and 382±64 mg at times of follow-up 1 and 2, respectively. The mean dose of prednisolone was 9.0±1.7 mg and 7.5±0 mg and of azathioprine 123±46 mg and 103±56 mg at follow-up 1 and 2, respectively. No signs of graft rejection were present at time of follow-up. The first post-transplant biopsy was performed when the patients were ready to leave the hospital, in all but two patients at 5–6 weeks after transplantation. One patient developed transient severe left and right heart failure and remained in hospital for 10 weeks. Another patient developed transient right heart failure and uraemia, which initially required hemodialysis. The first post-transplant follow-up was performed after 3 months in this patient, when he had not had dialysis for 3 weeks. At the first follow-up all patients had improved symptomatically and all were in NYHA class II. Six patients required diuretics due to oedema and six patients had developed hypertension, which was treated with calcium antagonists. At the second follow-up, after 6–9 months, five patients were in NYHA class I and five patients were in NYHA class II. Four patients still received diuretic treatment and six patients were treated with calcium antagonists due to post-transplant hypertension.

3.1. Skeletal muscle biochemistry
Skeletal muscle lactate was significantly elevated in patients at baseline compared with controls (3.6±3.0 mmol/kg wet wt. vs. 1.5±0.7 mmol/kg wet wt., P=0.037), and decreased early after transplantation (1.4±0.3 mmol/kg wet wt., P=0.038). Before transplantation patients had lower activities of phosphorylase and citrate synthase compared to controls, whereas 3-hydroxyacyl-CoA dehydrogenase and lactate dehydrogenase did not differ between the groups (Fig. 1). One patient had extremely low phosphorylase activity (varying from 0.3 to 0.8 µmol/g wet wt./min). When this patient was excluded no significant difference in phosphorylase activity was demonstrated between patients and controls. The enzyme activities did not change significantly throughout the study (Fig. 1).


Figure 1
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  		Fig. 1 Skeletal muscle enzyme activities in control subjects and in patients before cardiac transplantation, 1–3 months and 6–9 months after transplantation.

 
3.2. Skeletal muscle histochemistry
In three patients, there was not sufficient material for a histochemical evaluation. At baseline there was a tendency towards changed fibre type composition in the patients with an increased percentage of type II B fibres (Fig. 2). No alteration in muscle fibre area was observed between the groups. The patients had significantly decreased capillarization in comparison with healthy controls (Fig. 3). In one patient who developed left and right heart failure post-transplant, fibre area decreased markedly and capillaries/mm2 increased as a function of decreased fibre area, early after transplantation. However, no significant changes were observed in the whole group after cardiac transplantation (Figs. 2 and 3).


Figure 2
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  		Fig. 2 Fibre type composition in skeletal muscle in control subjects and in patients before cardiac transplantation, 1–3 months and 6–9 months after transplantation.

 


Figure 3
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  		Fig. 3 Capillarization of the lateral vastus muscle in control subjects and in patients before cardiac transplantation, 1–3 months and 6–9 months after transplantation.

 
3.3. Muscle strength of the knee extensors and exercise capacity
It was not possible to test muscle strength in one patient due to technical problems and another patient was too symptomatic to perform a maximal exercise test at baseline. Muscle strength was decreased at time of the first follow-up and increased again at the second follow-up although the increase was not significant compared to baseline (Table 2). There was no significant change in strength/unit muscle throughout the study (Table 2). Exercise capacity increased from baseline to the second follow-up (Table 2).


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  		Table 2 Exercise capacity, muscle strength in the knee extensors and thigh muscle area in patients with chronic heart failure before and after cardiac transplantationa

 
3.4. Thigh muscle area
Two patients did not want to participate in this part of the investigation. Muscle cross-sectional area of the thigh was significantly increased at the second follow-up compared with baseline values and first follow-up values (Table 2).

3.5. Correlations
Seven patients performed maximal exercise test, muscle strength test and muscle cross-sectional area at baseline. Maximal exercise capacity was related to thigh muscle cross-sectional area (r=0.86, P=0.013, n=7) and to muscle strength in the knee extensors (r=0.77, P=0.025, n=8) at baseline (Fig. 4). These relations persisted late after transplantation (r=0.84, P=0.010, n=8 and r=0.64, P=0.010, n=9) where eight patients performed all three tests.


Figure 4
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  		Fig. 4 Relation between thigh muscle cross-sectional area and work rate before heart transplantation at the late follow-up, and between thigh muscle strength and work rate before heart transplantation and at the late follow-up.

 

   4. Discussion
Top
 Abstract
 1. Introduction
 2. Methods
 3. Results
 4. Discussion
References
 
In this longitudinal study we have investigated skeletal muscle characteristics in patients with chronic heart failure before, at 1–3 months and 6–9 months after cardiac transplantation, and compared with a healthy control group. The enzymatic and histochemical alterations found at baseline in the patients did not improve after transplantation. These persistent abnormalities may contribute to the lower exercise capacity and muscle strength found in cardiac transplant recipients.

The skeletal muscle changes found in our patients awaiting transplantation are in accordance with several other investigations of patients with chronic heart failure [2–5,25]. However, significantly decreased phosphorylase activities has not been described before. One of our patients had extremely low phosphorylase activity (varying from 0.3 to 0.8 µmol/g wet wt./min). When this patient was excluded no significant difference in phosphorylase activity was demonstrated between patients and controls.

We hypothesised that increased physical activity, an improved cardiac function and sympathetic activity post transplant [13,14], would result in an amelioration of skeletal muscle metabolism, histochemistry, muscle area and strength. However, we could not confirm our hypothesis. The elevated muscle lactate level noted at baseline decreased already early after transplantation, suggesting a decreased lactate production or increased lactate washout. No change in enzyme activity was noticed after transplantation despite a regular training program and marked physical improvement. Our finding of decreased oxidative enzyme activity may explain the persisting skeletal muscle metabolic abnormalities, demonstrated as lower pH and lower phosphocreatine to phosphocreatine and inorganic phosphate ratio, after cardiac transplantation found by Stratton et al. [26], and remaining diminished respiratory muscle endurance noticed by Mancini et al. [27].

Bussières et al. found an increase in β-hydroxyacyl CoA dehydrogenase and phosphofructokinase activities already 3 months after transplantation, whereas citrate synthase did not change [28]. The reason for the discrepancy between their results and ours might depend on that our patients did not have decreased β-hydroxyacyl CoA dehydrogenase activity at baseline. Difference in medication and training programs might also have an impact on the results.

It is possible that cyclosporine treatment influenced enzyme activities after transplantation. Mercier et al. have found a decrease in skeletal muscle mitochondrial respiration and sub maximal endurance exercise time in rats treated with cyclosporine [29]. It has been shown that cyclosporine decreases mitochondrial respiration in rat skeletal muscle in vitro through a general negative effect on the enzyme systems [30]. It is less likely that the treatment with glucocorticoids has influenced the enzyme activities, as glucocorticoids have not been shown to have any effects on the oxidative phosphorylation capacity [31]. It is also unlikely that continued deconditioning fully explains the lack of improved enzymatic activity, as the patients improved markedly in functional capacity and gained in muscle area after transplantation.

The diminished capillarization persisted throughout the study. These findings are in accordance with other reports [28,32,33], and were also found in renal transplant recipients treated with corticosteroids [31], which might suggest that treatment with corticosteroids influences capillarization. Cyclosporine induces systemic hypertension and local vasoconstriction in the kidney [34], reduction of glomerular capillaries in renal transplant biopsies [35] as well as structural and functional changes in the endothelial cells [36,37].

Although thigh muscle cross-sectional area increased late after cardiac transplantation, the area of single muscle fibres did not increase. Thus, the increase in muscle cross-sectional area cannot be explained by increased muscle fibre size. Glucocorticoids have a known myopathic action with muscle fibre atrophy [38], which could explain why muscle fibre size did not increase despite increased physical activity. An elevated fat deposition and water retention would result in increased muscle cross-sectional area without increased muscle fibre size. However, no increase in intercellular lipid deposits in skeletal muscle has been observed after cardiac transplantation [32,33]. A regeneration of skeletal muscle fibres, which has been observed after transplantation of skeletal muscle [39], might contribute to the increased muscle cross sectional area. This increase may also partly explain the increase in exercise capacity. Muscle strength was decreased at the first follow-up, most probably due to immobilisation. An increase in muscle strength to pre transplant levels was seen at the second follow-up, reflecting the influence of exercise training and increased physical activity. Braith et al. demonstrated decreased muscle strength late after cardiac transplantation compared with normals [15], which is in accordance with our results. We could not find any improvement in strength/unit muscle after transplantation, which may be explained by the persisting intrinsic muscle abnormalities found.

Although exercise capacity increased after transplantation the patients still had a decreased exercise capacity (75% of predicted). They also had a reduced maximal heart rate (80% of predicted). A reduced maximal heart rate during exercise and increased peripheral resistance has been described after cardiac transplantation [14,40]. These cardiovascular abnormalities most probably account for a great part of the limited exercise capacity post-transplantation. However, the correlation between muscle strength and area and exercise capacity seen in this study after cardiac transplantation which is in accordance with the findings by Braith et al. [15], suggests that muscle strength and area have an impact on exercise capacity after cardiac transplantation.

4.1. Study limitations
A limitation of the study is that the number of patients investigated is limited and not all patients have performed all investigations. However, our results are in accordance with earlier investigations both concerning skeletal muscle biochemistry and histochemistry before transplantation and concerning improvement in exercise capacity post transplantation.

Cardiac output increases post transplant but is lower than in normal subjects at maximal exercise [14]. Increase in heart rate response during exercise is blunted. There is also a persistent increased peripheral resistance after cardiac transplantation [14,40]. No central hemodynamics was measured in this study. Maximal heart rate was still impaired after transplantation, whereas ejection fraction at rest, measured with echocardiography was normalised. These results are in agreement with earlier studies.

4.2. Conclusion
There are persistent abnormalities in enzymatic activity and histochemical variables up to 6–9 months after cardiac transplantation. Only a slight increase in muscle area and strength was observed after 6–9 months. The persisting skeletal muscle abnormalities may contribute to the limited exercise capacity in cardiac transplant recipients.


   Acknowledgements
 
We thank Gull Andersson, Ulla Grangård, Marita Hedberg, Annagreta Jönsson and Pim Trommels for their invaluable contributions. This work was supported by grants from Swedish Society of Cardiology, Göteborg Medical Society, Swedish Heart and Lung Foundation and Swedish Medical Research Council (proj 03888).


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

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