Eur Heart J 1997 Schaufelberger

European Heart Journal (1997) 18, 971-980

Skeletal muscle alterations in patients with chronicheart failure

M. Schaufelberger*, B. O. Erikssonf, G. Grimbyi, P. Held* and K. Swedberg**Department of Medicine, ^Department of Pediatrics, Ostra University Hospital, %Department of Rehabilitation

Medicine, Sahlgrenska University Hospital, Goteborg University, Sweden

Aims To investigate skeletal muscle in patients withchronic heart failure and controls, and relate skeletal mus-cle variables to functional class, exercise capacity, centralhaemodynamics, muscle strength and medical treatment.

Methods Biopsy from the lateral vastus muscle was ob-tained in 43 patients and 20 controls. Right sided heartcatheterization was performed in 19 patients and maximalexercise testing in 26 patients. In nine patients musclestrength was measured. Patients had higher lactate levels,higher lactate dehydrogenase activity, and lower oxidativeenzymes activity than controls. In patients, the percentageof type I fibres and capillarization were decreased while thepercentage of type II B fibres were increased. Lactate

dehydrogenase activity correlated with exercise capacity,muscle strength and right atrial pressure. Digoxin-treatedpatients had significantly lower oxidative enzyme activitythan patients without digoxin treatment.

Conclusion Patients with chronic heart failure have sev-eral skeletal muscle abnormalities. Central haemodynamicsand medical treatment may, in addition to inactivity, beimportant in skeletal muscle changes.(Eur Heart J 1997; 18: 971-980)

Key Words: Heart failure, skeletal muscle, central haemo-dynamics, exercise capacity.

IntroductionCardiac performance as well as extra cardiac factorsmay contribute to symptomatology in chronic heartfailure. Reduced skeletal muscle volume''1, strength andendurance have been reported'1'2', as has skeletal muscleblood flow'3'41. A relationship between skeletal musclevolume, muscle blood flow and peak VO2 has beenobserved'561. However, muscle blood flow corrected formuscle volume ceased to be correlated with peak VO2'51,which may indicate that muscle volume is of greaterimportance than blood flow for peak VO2 in heartfailure. Intrinsic abnormalities in skeletal muscle mightalso contribute to symptomatology. Abnormal skeletalmuscle metabolism during exercise has been demon-strated with 31P nuclear magnetic resonancespectroscopy'7"91, unrelated to blood flow1'0"1. There isalso evidence of a decrease in type I and an increase intype II B muscle fibres'12"141. Capillarization is alsoaltered, but the results are conflicting'12"141. A reductionin oxidative enzyme activity has been reported'12"151, butthis has not been confirmed by others'16-171.

Revision submitted 13 September 1996, and accepted 18 September1996.

Correspondence: Maria Schaufelberger, MD, Department of Medi-cine, Ostra University Hospital, S-416 85 Goteborg, Sweden.

Although several investigators have reportedskeletal muscle changes, the results are not consistentand factors contributing to the abnormalities havenot been fully explored. Inactivity and decreased car-diac performance may contribute. Pharmacologicaltreatment in patients with heart failure may also poten-tially be of importance. Digoxin is, to a great extent,bound to skeletal muscle'181. Whether this affectsskeletal muscle metabolism and enzyme activities ornot, is to our knowledge not known. Beta-blockertreatment, which improves symptoms in some patientswith heart failure'191, might influence skeletal musclemetabolism during exercise'2021'. Treatment with theangiotensin converting enzyme inhibitor enalapril in-creases muscle fibre area and lactate dehydrogenaseactivity in skeletal muscle of patients with chronicheart failure'22'.

The objective of this study was to evaluate towhat extent skeletal muscle metabolism, enzymatic ac-tivities, fibre composition, fibre area and capillarizationare altered in patients with chronic heart failure. An-other aim was to investigate if duration of heart failure,functional class, central haemodynamic variables at rest,exercise capacity and muscle strength are related toskeletal muscle abnormalities. Further objectives were tostudy the relationships between skeletal muscle variablesand treatment with digoxin and beta-blockers.

0195-668X/97/060971 +10 $18.00/0 y 1997 The European Society of Cardiology

by guest on April 30, 2010eurheartj.oxfordjournals.org

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972 M. Schaufelberger et al.

Table 1 Characteristics of 43 patients with chronic heart failure and 20 controlsubjects

Age (years)*Sex (male/female)Weight (kg)*Diagnosis:

Coronary artery diseaseDilated cardiomyopathyHypertension

Duration of heart failure (months)*NYHA class:

IIIIIIIV

Ejection fraction (%)*Beta-blockersVasodilatorsACE inhibitorsDigoxinWorkload (W)*

Patients

61-9 11132/11

780 15 6

28123

36 40

318184

26 814163631

86 25 (n = 26)

Controls

65-8 7-415/5

75-4 9-8

190 41 (n=10)

P

nsnsns

00001

*Data are mean SD; ACE = angiotensin converting enzyme; NYHA=New York HeartAssociation.

MethodsPatient population

Forty-three patients with chronic heart failure, in NewYork Heart Association class (NYHA) I-IV, and 20age- and sex-matched healthy individuals, were studied(Table 1). Eleven patients were investigated as part of aclinical evaluation for heart transplantation. All patientshad a left ventricular ejection fraction of

Skeletal muscle in CHF 973

Table 3 Capillary supply of the lateral vastus muscle in patients

Capillary density (cap . mm"2)Capillary/fibreNumber of capillaries in contact with each fibre

Type IType IIType IIAType I IBAverage

Fibre area in relation to capillaries in contact with each fibre (urn2 x 103)Type IType IIAType IIB

with

n

3131

3131313131

313131

chronic heart failurePatients

mean SD

244 10111 0-2

30 0-62-4 0-42-6 0-42-2 0-42-6 0-4

1-9 0-620 0-921 11

n

88

88888

888

and normal subjectsControls

mean SD

286 1081-4 0-3

3-6 0-82-7 0-630 0-62-5 0-53-1 0-7

1-7 0-81-9 0-91-9 1-0

p

ns0008

004ns

005ns

0-02

nsnsns

in embedding media, frozen in cooled isopentaneand stored at - 70C. This sample was used for histo-chemical analysis.

One biopsy sample was weighed and fluorometri-cally analysed for adenosine triphosphate, creatine phos-phate, glycogen, glucose, glucose-6-phosphate andlactate according to the modified Lowry and Passoneaumethods, as described by Karlsson'231. All values areexpressed in mmol. kg ~' ww. A second biopsy samplewas weighed and the activities of phosphorylase andlactate dehydrogenase, as well as citrate synthetase and3-hydroxyacyl-CoA dehydrogenase, were analysed usinga fiuorometric technique'24"271. The enzyme activities areexpressed in umol. g ~ ' ww . min ~' .

Muscle fibre classification and calculation ofcapillaries were performed in 35 patients and eightcontrol subjects, in a blinded manner, according toDubowitz, and Andersen and Henriksson'28'29'. Fibreareas were measured with a semi-automated method(Comfas system, Bio-Rad Scan Beam A/S, Hadsund,Denmark).

Exercise testing and right-sided heartcatheter ization

Exercise tests were performed in the upright position ona bicycle ergometer in 26 patients and 10 control sub-jects. In 16 patients and among the control subjects aramp protocol was utilized where the workload wasincreased by 10 W every minute until exhaustion. In tenpatients evaluated for heart transplantation, the exercisetests started at 30 W. All exercise tests were performedwithin 12 days of muscle biopsy except in four caseswhere they were performed up to 2 months before thebiopsy. All patients were clinically stable between theperformance of the test and that of the biopsy.

Right-sided heart catheterization through theinternal jugular vein was performed in the supine posi-tion in 19 patients, who all, except one, performed anexercise test within a week of muscle biopsy. Right

atrial, pulmonary artery and pulmonary capillary wedgepressures were determined from a Swan-Ganz catheter.Cardiac output was measured with the thermodilutiontechnique.

Muscle strength testMuscle strength in the knee extensors was measured innine patients, all investigated haemodynamically. Thepatients were seated with the back supported, a seat-beltaround the waist, with both legs hanging freely. Theknee angle was 90. A non-elastic strap was placedaround the ankle and attached to a pressure transducerwith amplifier (Steve Strong, Stig Starke HB, Goteborg,Sweden). The subjects were instructed to pull the anklestrap maximally for 3 s. The best of three efforts in theright leg was reported as maximal isometric quadricepsforce (in Newton, N).

Statistical analysisData are expressed as mean SD. An unpaired two-sided Student's t-test was used to evaluate possibledifferences between groups. The relationship betweenvariables was examined by simple regression analysis./>


Controls All CHF NYHA NYHAiii in - rv

Controls All CHF NYHA NYHAiii in- rv

5o

3

: p < 0.02

i i

ns

i

3 0.8oi

J3

ga.

0.2 -

Controls All CHF NYHA NYHAIII III-IV

o

ns

i J ^1ns

BControls All CHF NYHA NYHA

H I III-IV

Controls All CHF NYHA NYHAI I I III-IV

Controls All CHF N\'HA NYHAIII III-IV

Figure 1 Skeletal muscle adenosine nucleotides, glycolytic intermediates and glycogen in patientswith chronic heart failure (NYHA III, NYHA III-IV) and control subjects. CHF=chronic heartfailure.

NYHA III and III-IV (Fig. 2). Adenosine triphos-phate, creatine phosphate, glucose-6-phosphate, glucoseand glycogen did not differ between patients and con-trols (Fig. 1). No significant difference was found inphosphorylase activity between the groups (Fig. 2).Citrate synthetase and 3-hydroxyacyl-CoA dehydro-genase activities were lower among patients than thenormal subjects, but again there was no differencebetween patients in NYHA I-II and III-IV (Fig. 2).

Although there was a decreased percentage oftype I fibres and an increase in type II B fibres in patients

compared with controls (Fig. 3), no difference in thepercentage of type II A and II C fibres was notedbetween the groups (Fig. 3), or between the fibre areas(Fig. 4). The patients had fewer capillaries per fibre andfewer capillaries in contact with each fibre than thecontrol subjects (Table 3), but capillary density and fibrearea in relation to capillaries in contact with each fibredid not differ between the groups (Table 3).

No relationship between the duration of heartfailure and skeletal muscle variables was seen. There wasno difference in biochemical and histochemical variables

Eur Heart J, Vol. 18, June 1997


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" 7

300

250

200

150

100

50

0

P < 0.05

1 1ns

1 1

Controls All CHF NYHA NYHA

I-II III-IVControls All CHF NYHA NYHA

I-II III-IV

Controls All CHF NYHA NYHAI-II III-IV

r 8

a

ta 4o

i 2n

I P < 0.02' ' ns

i i

I 1 1I i 181Controls All CHF NYHA NYHA

I-II III-IV

Figure 2 Skeletal muscle enzyme activity in patients with chronic heart failure (NYHA I-II,NYHA III-IV) and control subjects.

between patients who performed an exercise test andright sided heart catheterization and those who did not.The activities of citrate synthetase and 3-hydroxyacyl-CoA dehydrogenase were not related to central haemo-dynamic variables. Right atrial pressure correlated withlactate dehydrogenase activity (Fig. 5). There was alsoa relationship between maximal workload, musclestrength in the knee extensors and lactate dehydrogenaseactivity (Fig. 5), but none between histochemical vari-ables and central haemodynamic measurements; exercisecapacity was positively correlated to the percentage oftype I fibres (Fig. 5).

Skeletal muscle variables did not differ betweenpatients treated with beta-blockers vs without beta-blockers. Patients treated with digoxin had lower citratesynthetase and 3-hydroxyacyl-CoA dehydrogenase ac-tivity than patients without digoxin treatment (3-8 10vs 5-6 1-8; />


70

60

I 50I 40ta

"g. 3 0

^ 20

10

0

- ^H

" " i"

" i"

" i

P < 0.03

U Tr ir

IIS

1

T


Controls All CHF NYHA NYHAI-Il III-IV

60

50

i 40

I 3i. 20

10

0

P < 0.04

2O

6 -

4 -

2



Figure 3 Fibre type distribution in skeletal muscle in patients with chronic heart failure (NYHAIII, NYHA III-IV) and control subjects.

A reduction of glycogen'13'341, as well as of ad-enosine triphosphate and phosphocreatine in skeletalmuscle at rest134', has been reported in patients withchronic heart failure. These observations must be inter-preted cautiously since in another study'351 the resultscould not be replicated and half of the patients investi-gated by Broqvist and co-workers'341 suffered from dia-betes mellitus. We found elevated levels of lactate in theskeletal muscle of patients with heart failure. In otherstudies the same tendencies have been noted but havenot reached statistical significance, most probably due tothe limited number of patients investigated and the widedistribution of the material'13'351. The increased lactatelevels in this investigation may be explained by theincrease in glycolytic metabolism which was alreadypresent at rest.

The decreased levels of oxidative enzyme activityis in accordance with several other studies I'2"151, but thelack of changes noticed by others may be due to thelimited number of patients investigated I16-17'. Immobili-zation decreases oxidative enzyme activity'31'361, whereastraining has the opposite effect on both healthy individ-uals'371 and patients with heart failure'381. Use of digoxinwas related to the decrease in oxidative enzyme activity.About 50% of digitalis is bound to skeletal muscle'181and increases contractility both in cardiac and skeletalmuscle'391. In cat and mouse, ouabain is predominantlybound to the type I fibres'40'4'1, which have high oxidat-

ive capacity. The sodium, potassium-pump is importantfor excitability and contractility, and is the cellulardigitalis glycoside receptor'421. It may be that the digitalisbinding to skeletal muscle influences oxidative enzymeactivity. Another explanation may be that the stimula-tion of skeletal muscle by digitalis is so intense that theoxidative enzymes are down-regulated.

In this investigation, lactate dehydrogenase ac-tivity was increased among the patients compared to thecontrol group. Others have not reported such an eleva-tion'12'131. We have demonstrated an increase in lactatedehydrogenase activity in skeletal muscle in patientswith heart failure after 3 months treatment with theangiotensin converting enzyme inhibitor enalapril'221.This may explain the discrepancy between our resultsand others, since 84% of the patients in the presentinvestigation were treated with angiotensin convertingenzyme inhibitors. The increased lactate dehydrogenaseactivity may thus be due to angiotensin convertingenzyme inhibitor treatment. Another possibility is thatthe patients had a higher percentage of type II B fibres,which have high glycolytic activity.

Exercise capacity and muscle strength in theright leg were related to lactate dehydrogenase activity.This might be due to a defect in the oxidative pathwayand impaired oxygen delivery to working muscles, whichmay increase the demand on the anaerobic metabolism.Another possibility is that the decreased muscle volume



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10

8

6

4

2

n

ns usi 1 f 1

- ^

|111liiiiControls All CHF NYHA

IIINYHAIII-IV

Controls All CHF NYHA NYHAiii m - r v

Figure 4 Skeletal muscle fibre area in patients with chronic heart failure (NYHA III, NYHAIII-IV) and control subjects.

found in patients with chronic heart failure1'1 mightincrease the demand on each muscle fibre, leading to anincreased anaerobic metabolism. There was a weakrelationship between lactate dehydrogenase activity andright atrial pressure which is difficult to interpret. It isconceivable that decreased cardiac output, decreasednutritive flow to skeletal muscle and exercise capacityare related to low oxidative enzyme activities, but wecould not show such a relationship in patients with heartfailure. Magnusson and co-workers saw no relationshipbetween exercise capacity and oxidative enzyme activityin patients with heart failure'431.

The altered fibre type distribution found in thisstudy is in accordance with other reports'12"141. Musclefibre area was not altered in the patients with heartfailure in comparison with normal subjects. A varietyof muscle fibre area abnormalities has been de-scribed ['2,13,16,44,45^

w i t h atrophy of the type II B fibresas the most consistent finding. Disuse leads to musclefibre atrophy, but change in fibre composition is not aconsistent finding in healthy individuals'30"321. The di-verging results between the investigations concerningmuscle fibre area may be due to the different degree ofphysical activity in the patients. We noticed decreasedcapillarization, which is in accordance with results ofSullivan and coworkers'13', but not with others'121, andmay have been due to inactivity or decreased blood flow.Capillarization and fibre area increase after training in

patients with chronic heart failure, but the fibre typecomposition does not change'461. Altered fibre type com-position was also reported in respiratory muscles ofpatients with chronic heart failure'471 but after hearttransplantation, no change in fibre type compositionand capillarization was observed'48'. However, treatmentwith steroids and cyclosporin after heart transplantationmay influence skeletal muscle. The fibre type distribu-tion found in our patients with heart failure resemblesthat in patients with non-insulin dependent diabetesmellitus'491. It is possible that hormonal disturbancesmight contribute to altered fibre type compositionin these disorders. Increased cytokine levels found inadvanced heart failure'50'5'1 might also influence theskeletal muscle.

Limitations of the studyIn this study, a set of test methods and possible contrib-uting factors have been applied to elucidate skeletalmuscle abnormalities in patients with heart failure.Although this is the largest group of patients with heartfailure where muscle biopsies have been investigatedbiochemically and histochemically, some subjects werenot investigated fully. Another objection may be thatthe metabolic and enzymatic results are expressed inmmol. kg ~' ww and umol. g 1

ww . min ', respect-



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Eur Heart J 1997 Schaufelberger