Exercise capacity and skeletal muscle structure and function before and after balloon mitral valvuloplasty

Exercise Capacity and Skeletal Muscle Structure and Function Before and After Balloon Mitral Valvuloplasty Clifford W. Barlow, FRCS, Jeremy E.H. Long, FCP(SA), Garry Brown, PhD, Pravin Manga, FCP(SA), Theo E. Meyer, FCP(SA), and Peter A. Robbins, DPhil This study evaluated the effects of balloon mitral valvuloplasty (BMV) on exercise capacity and skeletal muscle structure and function in 10 subjeck with mitral stenosis (mean age f SD 33 + 5.5). Measurements were obtained before, and 2 weeks and 4 months after BMV to provide baseline data, to examine the effects of improved hemodynamics, and to examine the effects of resum tion of normal physical activity, respectively. Valvulop Pasty caused an increase in mitral valve area (0.89 + 0.04 to 1.75 + 0.07 cm*; mean f SE), and an increase in resting cardiac output (3.8 f 0.18 to 4.6 f 0.19 L/min, p 4.05). At early follow-up after 2 weeks, sub’ects did more work (31% increase, p ~0.01) and hda greater maximal oxygen consumption (11% increase, p ~0.01). However, measurements reflecting skeletal muscle histology, biochemistry, and function were unaltered at this stage. Four months after BMV, subjects had a further increase in exercise capacity compared with both baseline (58% increase, p
and early follow-up (20% increase, p ~0.05). There were associated late increases compared with b&line in quadriceps cross-sectional area (66 + 5.8 vs 61 + 5.5 cm*, p ~0.05) and torque production (125 f 14 vs 118 f 16 Nm, p ~0.05). The percentage of slow twitch type I fibers increased compared with baseline (41 f 2.0% vs 33 f 3.1%, p <0.05), as did the size of type II fibers (5.9 f 0.49 vs 4.9 + 0.57 pm* X 103, p *0.05). Citrate s thase activity at late follow-up was also greater tr an itwas before BMV (193 f 32.1 vs 131 + 16.2 nmol/mg/min, p <0.05), although cytochrome oxidase activity remained unaltered. Thus, skeletal muscle abnormalities are found in patients with mitral stenosis. An early increase in exercise capacity occurs after BMV without changes in skeletal muscle structure and biochemistry. However, longer term improvements in exercise performance are associated with alterations in skeletal muscle. (Am J Cardiol 1995;76:684-688)

ercutaneousballoon mitral valvuloplasty (BMV) is P a favorable alternative to surgery for many patients with mitral stenosis. Hemodynamic and symptomatic

From the University laboratory of Physiology, University of Oxford, rtment of Cardiology, UniOxford, United Kingdom, and the De versity of the Witwatersrand, Johannes r urg, South Africa. This study was supported in part by an Oxford Nuffield Medical Fellowship and the Oxford Medical Research Fund, Oxford, United Kingdom. Manuscript received November 14, 1994; revised manuscript received and accepted Jul 5, 1995. Address for reprints: C Ylfford W. Barlow, FRCS, University laboratory of Physiology, University of Oxford, Parks Road, Oxford OX1 3PT, United Kingdom.

matic tight mitral stenosis were studied. All subjects were in sinus rhythm and all were limited by breathlessnessor muscle fatigue. All gave informed written consent before entering the study. Subjectsundertook practice studies before the initial quadriceps strength and fatigue tests,and also before the first invasive exercise tests, to familiarize themselves with the protocols. No subject took p blockers or digoxin within 24 hours of any exercise test. The initial series of invasive tests, to establish baseline measurements before BMV, took place within a 3-day period before the procedure. The second series of invasive tests, to establish the effects of improved hemodynamics, took place about 2 weeksafter BMV During this interval subjects restricted their activity and avoided exercise that produced breathlessnessor fatigue. The third series of invasive tests, to establish the effects of both improved hemodynamics and increased physical activity, were scheduled for about 4 months after BMV During the period before this third study, subjects were encouraged to participate in activities and exercise that produced breathlessnessand fatigue. Exercise testing: Upright cycle exercise testing took place on an ergometer (model 400L, Medical Fitness Equipment, Maarn, Holland) with continuous ECG monitoring. The work rate was increasedin 25 W stages every 3 minutes to a voluntary maximum. Gas exchange was recordedby measuring inspired volumes and mixed expiratory oxygen and carbon dioxide concentrationsby using oxygen and carbon dioxide analyzers(model OX4, Mijnhardt-Oxycon, Mijnhardt, Holland).

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improvements occur immediately and persist at longterm follow-up,1-3 although maximal oxygen consumption (VO,max) may be unchanged after 48 hours.’ It is possible that the late improvement in exercise capacity after BMV results from a gradual recovery of the skeletal muscle,’ since several studies have found that skeletal muscle histology and biochemistry are altered in patients with heart failure due to left ventricular dysfunction.4-9 The presentstudy investigated skeletal muscle structure, function, and recovery in young patients with mitral stenosis before and after BM‘C! The three studies-before, and 2 weeks and 4 months after BMV-provided baseline measurements, determined the effects of improved hemodynamics, and determined the effects of increased physical activity, respectively.

METHODS Subjects and study design: Ten consecutive patients (8 women and 2 men) undergoing BMV for sympto-

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Computed tomography: The cross-sectional area of the right quadriceps muscle was measuredby computed tomography according to a previously described method.‘OAn initial scan of the femur ensured that the cross-sectional slices were midway between the top of the greater trochanter and the bottom of the lateral femoral condyle. Cross-sectional areas were calculated automatically after generating an outline around the perimeter of the muscle (Figure 1). The method allowed for computed tomography scansto be taken at an identical site on all 3 occasions. Quadriceps torque and fatigue testing: Dynamic maximal quadriceps torque and fatigue were measuredusing an isokinetic device (model Cybex II, Lumex, New York). The lever arm was attached to the tibia and subjects performed maximal knee extensions from 90” to 0”. The method of adjusting the equipment is described more fully elsewhere.l’ To determine maximal quadriceps torque, subjects performed 5 maximal isokinetic contractions at 6O”/s. The mean of the highest 2 values was considered to be the maximal quadriceps torque at this angular velocity. To determine quadriceps fatigue, maximal contractions at 18O”/swere performed for 1 minute. Fatigue was measured as the maximal torque production at the end of 1 minute, expressedas a percentageof the initial maximal value. Muscle histology and biochemistry: Quadriceps muscle biopsy was undertaken once the exercise, force, and fatigue testsfor each seriesof procedureshad been completed. Generally a needle biopsy was performed under local anesthesia (lidocaine 2%) taking routine aseptic precautions.l2 On a few occasions biopsy was undertaken using an open technique in an operating theater, with the patient also under local anesthesia. Specimensfor histology were frozen in isopropanol that had been cooled in liquid nitrogen and kept in a freezer at -70°C before processing.Sampleswere cut in

FIGURE 1. Computed tomography scan of the right thigh showing traced outline of the quadriceps muscle.

a cryostat at -20°C and stained for myosin adenosine triphosphataseactivity, after preincubation at pH 9.4, for classification of fibers as type I or II (Figure 2).i3 Mean cross-sectionalareasof the individual fiber types and the percent distribution of each type were determined by a semiautomated method.14The samples taken for biochemical analysis were assayedfor citrate synthaseand for cytochrome oxidase activity using spectrophometric techniques.I5 Balloon

mitral vaivuloplasty

and echocardiography:

Valvuloplasty was performed using the Inuoe balloon catheter (Toray, Japan). The technique of BMV and the methods for obtaining hemodynamic measurements before and immediately afterward are describedin detail elsewhere.i6 The transmitral diastolic gradient was recorded, triplicate measurementsof cardiac output using thermodilution were obtained, and mitral valve areawas calculated using the Gorlin formula.17 Patients underwent 2-dimensional echocardiography with Doppler color flow mapping before BMV and on each of 2 subsequentoccasions. Mitral valve area was calculated by the Doppler pressurehalf-time method.18 Statistical analysis: Results are expressedas mean f SE unless otherwise stated.Differences in the variables on the 3 different occasions were assessedby analysis of variance. This was followed, when appropriate, by paired 2-tailed Student’s t tests. A p value co.05 was considered statistically significant.

RESULTS The 10 consecutive patients who agreed to participate in the study were relatively young (mean age f SD 33 + 5.5 years). They all completed the initial baseline study and underwent successful BMV All 10 patients returned for early reassessment(after 12 + 4.2 days; mean + SD), and 8 of them completed the late followup study (after 15f 2.3 weeks; mean+ SD). Two patients did not complete the late follow-up study; 1 became pregnant and was excluded. The other, who lived in a remotearea,was lost to all clinical follow-up. The results from these2 patients were not included with results from the other 8 when statistical comparisons were made between all 3 study periods. All of the patients were in sinus rhythm initially and at the time of the follow-up

FIGURE 2. Needle biopsy specimen of the right quadriceps muscle stained for myosin adenosine triphosphatase. Type I fibers are pa/e and type II fibers are dark.

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TABLE I Hemodynamic

Measurements

1

2 3 4 5 6 7 8 9 10

& Sex

Before

23 25 26 30 30 33 34 37 38 43

0.97 0.70 0.81 0.82 0.90

F F F F F M F F M F

1.10

After, and Late After (15 + 2.3 weeks) LAP (mm Hg)

V02max (ml/kg/min)

After

Before

After

Before

After

1.50

1.64 1.83

1.77 1.70

16 25

1.97

2.46

1.50

1.68 1.60 2.10 1.38 1.47

22 31

7 16 8 12 18

12.7 17.0 10.6 18.9 21.0

30 16 28 20 22

13 14 17 14 12

18.4

3.4 7.0 5.6 2.9 8.0 3.2 5.1 7.2 5.6 5.5

28 49 24 45 38 64 20 40 32 30

18 34 26 30 38 40 24 35 21 16

4.4 3.0 3.6 3.7 5.3 3.4 3.8 3.7 4.8 3.2

4.9 4.4 5.1 5.0 6.1 3.9 3.9 4.0 4.8 5.0

15

Mitral

Before

Early

Late

1

17.0 16.5 11.6

18.5 17.0 16.5

23.1 18.4 -

4.5

16.1

19.3

19.8

4.0

10

of Right Quadriceps Valvuloplasty

Area,

Exercise Duration (min)

9.3 29.0 13.5 10.0

5.0 2.5

Quad.

and Fatigue Before,

Area

Quad.

(cm*)

Early After (12 * 4.2 days), and

Max.

Quad.

Torque

Fatigue (“7

(Nml

Early

Late

Before

Early

Late

Before

Early

Late

8.0 3.5 8.0

11.5 .O

58.3 53.5 36.9

58.7 57.6 41.6

62.1 60.9 -

102 70

112 -

43

40

6.0 10.5 6.0

40.4 43.8 72.4 55.5 69.8 89.4 48.9

39.8 45.7 74.1 52.3 73.0 89.7 50.4

42.0

45 45 58 49

25 52

8% 62.6 74.8 85.7

ii 98 150 95 128 202

ii

45

51.1

81

45 30 50 42 42 36 34 35 37

30 -

4.5 6.5 8.5 6.0 8.0

108 85 108 64 81 146 85 122 195 85

36 31 30

20 30 32 40

15.8

12.8 13.0

14.7 12.2

11.3

14.6

15.6

23.7

24.4

29.5

16.0

17.0

15.5

18.5

19.2

4.0

7.5

4.5

Strength,

Before

8.9 13.3

6.0 6.0 6.0

= mitral valve area (Doppler); MVG = mitral valve gradient; PAP =

tote

Early

12.9

-

CO (L/min)

(mm Hg)

Before

4 5 6 7 8 9

PAP (mm Hg)

MVG Before

Patient

:

Valvuloplasty

After

TABLE II Exercise Data and Measurements Balloon

Mitral

Before

CO = cardiac output; Immed. = immediately; LAP = mean left atria1 pressure; WA “WO” DUt~OW.lN Cll’kN DrSS”Te.

Late After (15 + 2.3 weeks)

Balloon

tote

(cm*)

1.60 1.54 1.74 1.40 1.59

0.84 0.80 0.92 0.88

Immediately

Immed.

MVA

Age(yr) Patient

Before,

10.0 19.0

8.5

114 85 -

160 98 142 213 89

Max. = maximal; Quad. = quadriceps; VOlmox = maximal oxygen consumption

Valvuloplasty resulted in substantial decreasesin mean left atrial pressure,mitral valve gradient, and mean pulmonary artery pressure(Table I). Mitral valve area,determined using the Gorlin formula, increased from 0.86 f 0.07 to 1.82 f 0.13 cm2 after BMV At late follow-up, echocardiographic estimation of mitral valve area remained increasedat 1.76+ 0.13 cm2 (n = 8). Resting cardiac output increasedfrom 3.8 + 0.18 to 4.6 + 0.19 L/min immediately after BMV (Table I). Exercise responses:Exercise responsesand measurements of skeletal muscle strength and fatigue for the 10 subjects, listed in order of increasing age, are listed in Table II. VO,max increasedfrom 15.3f 1.56ml/kg/min (n = 8) at baseline to 17.2 f 1.36 ml/kg/min (p ~0.01; n = 8) at early follow-up. VO,max at late follow-up (19.9 + 1.91 ml/kg/mm, n = 8) was greater than that at both baseline (p ~0.01) and early follow-up (p ~0.05). There

were significant increasesin total exerciseduration both 2 weeks after BMV (p ~0.01) and at late follow-up study when values were significantly greaterthan those at baseline (p ~0.01) and at early follow-up (p ~0.05). The 2 patients who did not return after 4 months (patients 2 and 5) had similar increasesin exercise performance at the time of early follow-up (Table II). Correlation analysis did not reveal a significant relation between the magnitude of the change in hemodynamics with valvuloplasty (assessedas percent reduction in mitral valve gradient) and the magnitude of the change in V02max. Quadriceps area, torque, and fatigue: The effects of BMV on total quadriceps cross-sectionalarea, maximal dynamic torque production, and quadriceps fatigue are listed in Table II. No change in cross-sectionalarea was detected by computed tomography 2 weeks after BMV compared with before BMV (62 + 5.7 vs 61 + 5.5 cm2, respectively; n = 8). However, the quadriceps cross-sectional areameasurementat late follow-up (66 f 5.8 cm*; n = 8) was greater than both previous values (p ~0.05). This pattern was mirrored by the tests for quadriceps force production. Maximal dynamic torque was not altered at early follow-up comparedwith baseline value (114 f 15 vs 118+ 16 Nm; n = 8) but had increased 4 months after BMV (125 f 14 Nm; n = 8); this measurementat late follow-up was significantly greater than that obtained at baseline (p ~0.05) and at early followup (p ~0.01). No significant increase in torque was

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studies. Medication doses tended to be reduced after BMV Five patients were taking B blockers and 1 was taking digoxin before BMV Only 1 patient continued taking a B blocker and none of the patients were taking digoxin after valvuloplasty. Early clinical improvements, as assessedby New York Heart Association functional class, remained constant 4 months later. All subjects reported considerably increased physical activity levels comparedwith thosebefore BMV No significant adverse effects were encountered during the study. Hemodynamic effects of balloon mitral valvuloplasty:

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TABLE III Skeletal Muscle Mitral Valvuloplasty

Histology

Before

Before,

Type I Fiber Size

Type I Fiber Distribution (%) Patient

and Biochemistry

(km*X

103)

Early After (12 * 4.2 days],

Type II Fiber Size (pm2X103)

and Late After (15 * 2.3 weeks)

Citrate Synthase (nmol/mg/min)

Balloon

Cytochrome Oxidase (nmol/mg/min)

Early

late

Before

Early

late

Before

Early

late

Before

Early

Late

Before

Early

late

38

4.6

4.4 4.9 5.5 6.3 4.1 6.8 6.6 5.4 6.4 6.8

3.8 4.8 4.5 7.9 5.5 6.1 5.9 5.3

3.4 4.3 4.3 3.5 3.3 4.0 3.8 6.6 7.7 5.4

3.5 4.8 5.9 4.6 2.8 4.7 4.7 5.5 6.9 5.2

5.1

176

156

273

11.2

21.1

12.8

6.6 3.8

92 149 130 148 78 129 122 170 -

197 159 163 166 160 -

-

8.9 33.4 13.8 26.8 -

1

19

26

2 3 4 5 6 7 8 9 10

24 39 47 35 27 29 37 29 40

27 35 43 33 30 28 39 32 38

ii 50 37 35 49 39 40

5.8 4.4 4.6 3.9 6.6 5.3 5.8 6.0 6.6

detectedonce measurementsof torque were normalized for changesin quadriceps area. Quadriceps fatigue was not significantly altered by BMV: 38 f 2.2% (n = 8) before, 41 + 1.5% (n = 8) early after, and 35 + 3.6% (n = 8) late after BMV Muscle histology and biochemistry: The early and late effects of BMV on quadriceps histology are listed in Table III. There was no effect on the percentageof slow twitch type I fibers at early follow-up (34 rf: 2.1%, n = 8) compared with those at baseline (33 + 3.1%, n = 8). However, at late follow-up, after >3 months of improved hemodynamics and increased physical activity, the percentage of type I fibers (41 f 2.0%, n = 8) increased compared with that at both baseline (p ~0.05) and early follow-up (p ~0.01). The cross-sectional area of the type I fibers was not affectedby BMV However, the area of the type II fibers was greater at late follow-up (5.9 f 0.49 pm* X 103,n = 8) than it was before (4.9 f 0.57 pm2 X lo”, n = 8) (p ~0.05) and at 2 weeks after (5.1 f 0.35 pm* X 103,n = 8) BMV (p ~0.05). Two aerobic enzymes were analyzed to determine whether BMV had any effects on their activities (Table III). Comparisons in all 8 subjects who attended all 3 occasions were not possible because of technical difficulties. Citrate synthase activity, when compared with baseline (142 f 14.5 nmol/mg/min, n = 6), was unchangedat 2 weeks after BMV (167 + 6.2 nmol/mg/ min, n = 6) (p = O.lS), but had increased at 4 months after the procedure (193 + 32.1, n = 5) (p ~0.05). No difference in cytochrome oxidase activity was detected after BMV Correlation analysis did not reveal any significant relation between the magnitude of change in hemodynamics with valvuloplasty (assessedas percent reduction in mitral valve gradient) and of changesin fiber type and citrate synthase activity. DISCUSSION

The first main finding of this study is that the skeletal muscle in mitral stenosis is altered in a manner not dissimilar to that in chronic congestive heart failure due to left ventricular dysfunction.6,T’9This was determined, not by comparing subjects with a control group, but by following the changes in skeletal muscle after BMV Second, early improvements in exercise capacity after BMV, which occur within 2 weeks of the improvement

6.3 5.0 7.4 7.9 5.2

5.3 268 130 155 137 -

16.5

14.4

14.4 15.4 22.6 15.0 11.6 28.8 -

17.1 10.2 47.2 10.7 -

in central hemodynamics, are not associatedwith early alterations in skeletal muscle structure and biochemical function. Third, after 4 months of relatively normal physical activity, further improvements in exercise performance were seen. These late improvements are associated with altered skeletal muscle structure and biochemical function. Early effects of ball oon mitral valvuloplasty: Patients in this study were young, predominantly women, and were in sinus rhythm with pliable valves.Effectsof BMV on the central hemodynamics of similar patients have been well described,20,2’and results of this study were in keeping with these results. Studies on subjectswith congestive heart failure due to left ventricular dysfunction have demonstrated that acute interventions that improve central hemodynamics do not immediately increase exercise capacity.22,2’The early follow-up tests in the present study were planned at =2 weeks after BMV, so that there was sufficient time for some of the possible effects of improved hemodynamics on reversible skeletal muscle changes to take place. However, patients were asked to avoid activities that produce breathlessnessor fatigue during these 2 weeks to minimize any early training elfect. At early follow-up, there was an increase in both exercise duration and V02max. In the only previous report on the time course of improvements in exercise capacity after BMV, no increasein VO,max was detected after 48 hours.’ Possible reasonsfor the difference in the present study are that 2 weeks had elapsed before early follow-up, and patients were younger. Skeletal muscle histologic structure and biochemical function were unaltered 2 weeks after BMV There were also no early changesin quadricepsarea,maximal torque production, or fatigue despite the early increase in exercise capacity. late effects of balloon mitral valvuloplasty: This study confirms previous reports that exercise performance is increased3 or 4 months after BMV comparedwith baseline.1,3It also showed that the early increase in exercise capacity and VO,max, detected 2 weeks after BMV, does not represent the complete response, with values being even greater after 4 months. Maximal quadriceps torque production increased 4 months after BMV This was associatedwith an increase in total quadriceps cross-sectionalarea.The findings are

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687

similar to those of Buller et al,24who reported a reduction in quadriceps cross-sectional area and force production in patients with heart failure compared with normal subjects. They also found a tendency for the quadriceps to tire more rapidly in heart failure patients than in normals. This contrastswith our findings in which the same persons were retested and thus acted as their own controls. The present study demonstratesdirect evidence of changesin skeletal muscle histologic structure with the late enhancementof exercise capacity and skeletal muscle force production. Slow twitch type I fiber distribution and easily fatigable type II fiber cross-sectionalarea both tended to increase4 months after BMV Thesefindings are entirely in accordwith 2 previous studiesof fiber composition in congestive heart failure due to left ventricular dysfunction, in which patients were compared with normal subjects.x8 However, this is the first report, to our knowledge, of such changesoccurring in the same patients before and after a corrective procedure for their cardiac pathology. Previous studies of skeletal muscle metabolism in patients with congestive heart failure have reported that the activity of mitochondrial enzymes may be attenuated.G9Citrate synthaseactivity was found to be reduced in 1 of these studies5but unaffected in another.6Cytochrome oxidase activity was found to be unaltered in heart failure patients in a previous study.9In all of these studies,69 patients were compared with controls. Although this study found no changein the activity of either enzyme in patients with mitral stenosis 2 weeks after BMV, the activity of citrate synthaseincreased4 months after BMV This is similar to the finding in patients with congestive heart failure. 6,7It provides evidence that reduced skeletal muscle aerobic enzyme activity plays a role in determining the metabolic response to exercise in mitral stenosis as it does in chronic congestive heart failure due to left ventricular dysfunction.25 However, this evidence has been obtained by following the same subjectsafter BMV, and not by studying a separatecontrol group.

1. Marzo KP, Henmann HC, Mancini DM. Effect of balloon mitral valvuloplasty on exercise capacity, ventilation and skeletal muscle oxygenation. JAm CoN Car-

diol 1993;21:856-865. 2. Murat-Tuzcu E, Block P, Griffin B, Newell J, Palacios I. Immediate and longterm outcome of percutaneous valvotomy in patients 65 years and older. Circulation 1992;85:963-971. 3. Stefanadis C, Stratos C, Pitsavos C, Kallikazaros I, Triposkiadis F, Trikas A, Vlachopoulos C, Gavaliatsis I, Toutouzas P. Retrograde nontmnseptal balloon mitral valwloplasty: immediate results and long-term follow-up. Circulation 1992;85: 1760-1767. 4. Wilson JR, Mancini DM, Dunkman WB. Exertional fatigue due to skeletal muscle dysfunction in patients with heart failure. Circulafion 1993;87:47@475. 5. Wilson JR, Martin JL, Schwartz D, Ferraro N. Exercise intolerance in patients with chronic heart failure: role of impaired nutritive flow to skeletal muscle. Circulation 1984.69: 1079-1087. 6. Mancini DM, Coyle M, Coggan A, Beltz J, Ferraro N, Montain S, Wilson JR. Contribution of intrinsic skeletal muscle changes to 31PNMR skeletal muscle metabolic abnormalities in patients with chronic heart failure. Circulation 1989;80: 1338-1346. 7. Sullivan MJ, Green HJ, Cobb FR. Skeletal muscle biochemistry and histology in ambulatory patients with long-term heart failure. Circulation 1990;81:518-527. 8. Dunnigan A, Staley NA, Smith SA, Pielpont ME, Judd D, Benchitt DG, Benson DW. Cardiac and skeletal muscle abnormalities in cardiomyopathy: comparison of patients with tachycardia or congestive heart failure. J Am Coil Cardiol 1987;10:608-618. 9. Lipkin DP, Jones DA, Round JM, Poole-Wilson PA. Abnormalities of skeletal muscle in patients with chronic heart failure. Inf J Cardiol 1988;18:187-195. 10. Jones DA, Round JM, Edwards RHT, Grindwood SR, Tofts PS. Size and composition of the calf and quadriceps muscles in Duchenne muscular dystrophy: a tomographic and histochemical study. J Neural Sci 1983;60:307-322. I I. Thorstensson A, Grimby G, Karlsson J. Force-velocity relations and fibre composition in human knee extensor muscles. J Appl Physiol 1976;40: 12-16. 12. Dietrichson P, Coakley J, Smith PEM, Gritliths RD, Helliwell TR, Edwards RHT. Conchotome and needle percutaneous biopsy of skeletal muscle. J h’eurol Neurosurg Psychiatry 1987;50:1461-1467. 13. Round JM, Matthews Y, Jones DA. A quick, simple and reliable histochemical method for ATPase in human muscle preparations. Hisrochem J 1980;12: 707-710. 14. Round JM, Jones DA, Edwards RHT. A flexible microprocessor system for the measurement of cell size. J Clin Pathol 1982;35:620-624. 15. Wharton DC, Tzagoloff A. Cytochrome oxidase from beef heart mitochondria. Merhods Enzymol 1967;10:245-250. 16. Manga P, Singh S, Brandis S, Friedman B. Mitral valve area calculations immediately after balloon mitral valvuloplasty: effect of the atrial septal defect. J Am Co/l Cardiol 1993;21:156&1573. 17. Gorlin R, Gorlin SJ. Hydraulic formula for calculation of the areas of the stenotic mitral valve, other cardiac valves and circulatory shunts. Am Hewn J 1951;41: 1-29. 18. Hatle L, Angelsen B, Tromsdal A. Noninvasive assessment of atrioventricular pressure half-time by Doppler ultrasound. Circulation 1979;60: 109&1104. 19. Mancini DM, Walter G, Reichek N, Lenkinski R, McCully KK, Mullen JL, Wilson JR. Contribution of skeletal muscle atrophy to exercise intolerance and altered muscle metabolism in heart failure. Circulation 1992;85:13641373. 20. Rothlisberger C, Essop MR, Skudicky D, Skoularigis I, Wisenbaugh T, Sareli P. Results of percutaneous balloon mitral valvotomy in young adults. Am J Cardiol 1993;72:73-77. 21. Hemnann HC, Feldman T, Isner JM, Bashore T, Holme SDR, Rothbaum DA, Bailey SR, Dorms G, for the North American Inoue Balloon Investigators. Comparison of results of percutaneous balloon valvuloplasty in patients with mild and moderate mitral stenosis to those with severe mitral stenosis. Am J Cardiol 1993;71: 13l%1303. 22. Franciosa I, Cohn H. Immediate effects of hydralazine isosorbide dinitrate combination on exercise capacity and exercise hemodynamics in patients with left ventricular failure. Circularion 1979;59: 1085-1091. 23. Maskin C, Forman R, Sonnenblick E, LeJemtel T. Failure of dobutamine to increase exercise capacity despite hemodynamic improvement in severe chronic heart failure. Am J Cardiol 1983;51:177-182. 24. Buller NP, Jones D, Poole-Wilson PA. Direct measurement of skeletal muscle fatigue in patients with chronic heart failure. Br Hean J 1991;65:20-24. 25. Sullivan MJ, Green HJ, Cobb FR. Altered skeletal muscle metabolic response to exercise in chronic heart failure: relation to skeletal muscle aerobic enzyme activity. Circularion 1991;84:1597-1607.

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Acknowledgment:we thank Professor Pincus Sareli and Eamon Maree, MD, for allowing us to include their patients, Ms. Fiki Makhaye for assistancewith exercise testing, Ann Fennel for radiographic assistance,and Joan Round, MD, and Helen Kidd for assistancewith histologic analysis.

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