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(Circulation. 1998;98:1742-1749.)
© 1998 American Heart Association, Inc.

Clinical Investigation and Reports

Improved Exercise Tolerance After Losartan and Enalapril in Heart Failure

Correlation With Changes in Skeletal Muscle Myosin Heavy Chain Composition

Giorgio Vescovo, MD, PhD, FESC; Luciano Dalla Libera, DChem; Francesco Serafini, MD; Cristiana Leprotti, MD; Luigi Facchin, MD; Maurizio Volterrani, MD, FESC; Claudio Ceconi, MD, FESC; ; Giovanni Battista Ambrosio, MD, FESC

From the First Department of Internal Medicine, Venice City Hospital, Venice, Italy (G.V., F.S., C.L., G.B.A.); the CNR Unit for Muscle Physiopathology, University of Padua, Padua, Italy (L.D.L.); the Department of Cardiology, Venice City Hospital, Venice, Italy (L.F.); and Cardiology and IRCCS, Gussago, Brescia, Italy (M.V., C.C.).

Correspondence to Giorgio Vescovo, MD, PhD, FESC, First Department of Internal Medicine, Venice City Hospital, 30100 Venice, Italy. E-mail ldl{at}civ.bio.unipd.it

	Abstract

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Background—In congestive heart failure, fatigue-resistant, oxidative, slow type I fibers are decreased in leg skeletal muscle, contributing to exercise capacity (EC) limitation. The mechanisms by which ACE inhibitors and AII antagonists improve EC is still unclear. We tested the hypothesis that improvement in EC is related to changes in skeletal muscle composition toward type I fibers.

Methods and Results—Eight patients with congestive heart failure, NYHA classes I through IV, were treated for 6 months with enalapril (E) 20 mg/d, and another 8 with losartan (L) 50 mg/d. EC was assessed with maximal cardiopulmonary exercise testing at baseline and after treatment. Myosin heavy chain (MHC) composition of the gastrocnemius was studied after electrophoretic separation of slow MHC1, fast oxidative MHC2a, and fast glycolytic MHC2b isoforms from needle microbiopsies obtained at baseline and after 6 months. EC improved in both groups. Peak O₂ increased from 21.0±4.7 to 27.6±4.3 mL · kg^-1 · min ^-1 (P=0.011) in the L group and from 17.5±5.0 to 25.0±5.5 mL · kg^-1 · min ^-1 (P=0.014) in the E group. Similarly, ventilatory threshold changed from 15.0±4.0 to 19.9±4.9 mL (P=0.049) with L and from 12.0±1.9 to 15.4±3.5 mL (P=0.039) with E. MCH1 increased from 61.2±11.2% to 75.4±7.6% with L (P=0.012) and from 60.6±13.1% to 80.1±10.9% (P=0.006) with E. Similarly, MHC2a decreased from 21.20±9.5% to 12.9±4.4% (P=0.05) with L and from 19.9±7.8% to 11.8±7.9% (P=0.06) with E. MHC2b changed from 17.5±6.5% to 11.7±5.2% (P=0.07) with L and from 19.5±6.4% to 8.1±4.6% (P=0.0015) with E. There was a significant correlation between net changes in MHC1 and absolute changes in peak O₂ (r²=0.29, P=0.029) and a trend to significance for MHC2a and 2b.

Conclusions—Six months' treatment with L and with E produces an improvement in EC of similar magnitude. These changes are accompanied by a reshift of MHCs of leg skeletal muscle toward the slow, more fatigue-resistant isoforms. Magnitude of MHC1 changes correlates with the net peak O₂ gain, which suggests that improved EC may be caused by favorable biochemical changes occurring in the skeletal muscle.

Key Words: heart failure • muscles • myosin • exercise

	Introduction

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Heart failure is characterized by decreased exercise capacity (EC) because of the early appearance of symptoms such as fatigue and dyspnea. The origin of these symptoms is not clear, although it has been suggested that they may depend on intrinsic skeletal muscle abnormalities.^{1 2 3 4 5 6 7 8} A shift from the slow type I fibers toward the more fatigable fast type II fibers has been described.^{9 10 11} We have observed a correlation between the percent distribution of the 3 myosin heavy chains (MHC[s]), MHC isoforms in the gastrocnemius (namely MHC1, slow aerobic; MHC2a, fast oxidative; and MHC2b, fast glycolytic), the severity of the heart failure syndrome,¹¹ and EC expressed in terms of peak O₂ and VT.¹² ACE inhibitors (ACEi) have been shown to reduce morbidity and mortality and improve EC in patients with congestive heart failure (CHF), left ventricular dysfunction, and previous myocardial infarction.¹³ These changes have been mostly attributed to the favorable effects of the blockade of the renin-angiotensin system¹³ or to a decreased bradykinin breakdown.¹⁴ Improvements in EC because of pharmacological treatment or training have been accompanied by mechanical, metabolic, and biochemical changes in the skeletal muscle.^{15 16 17 18 19 20 21 22} Moreover, there are still no explanations for improved EC after ACEi because neither central hemodynamic nor skeletal muscle blood flow seems to correlate with improved EC. Studies that examine skeletal muscle changes after treatment with ACEi have led to controversial results.^{23 24} Recently, AII antagonists (AIIa) have been introduced for the treatment of CHF. They improve EC^{24 25} and even decrease mortality.²⁶ Although several comparisons with ACEi have been performed, similarities and differences between these 2 therapeutic options remain to be better defined. In the present study, we have compared the magnitude of improvement in EC after 6 months' treatment with enalapril (E) with those occurring with losartan (L). Since we have postulated that changes in skeletal muscle fibers may contribute to it, we correlated the net improvement in EC with biochemical changes occurring in the leg skeletal muscles. We took MHCs as skeletal muscle biochemical markers and gas exchanged during maximal cardiopulmonary exercise tests as an objective measurement of EC.

	Methods

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Patients
We studied 16 male patients with CHF in different NYHA classes. The cause of CHF was diagnosed with clinical criteria, ECG, echocardiogram, cardiac catheterization, and coronary angiogram. Clinical characteristics are described in Table 1. Symptoms of heart failure had begun at least 2 months before they entered the study, and these included dyspnea, orthopnea, peripheral edema, and gallop. All patients except 2 were on frusemide with dosage ranging from 20 to 120 mg/d. Diuretic treatment was optimized and stabilized before randomization. None of them had previous treatment with ACEi or AIIa. None had diabetes mellitus, peripheral vascular disease (excluded by a Winsor ankle/brachial index 1), neuromuscular diseases, heart valve disease, or lung disease. Patients underwent echocardiogram, maximal treadmill cardiopulmonary exercise testing, and medial gastrocnemius needle biopsy and were afterward randomly assigned either to E or to L treatment so that 2 groups of 8 patients were formed. Patients randomized to L started with 25 mg once a day, which was titrated up to 50 mg after a week, whereas patients randomized to E were started on 5 mg twice a day, which was titrated up to 10 mg after a week. After 6 months' treatment, all the patients had another echocardiogram, maximal cardiopulmonary exercise testing, and second needle biopsy. Eight age-matched, detrained, sedentary, healthy volunteers with negative medical history and physical examination, normal blood pressure (BP), and resting ECG functioned as controls and underwent gastrocnemius biopsy. The study was approved by the ethics committee of the Venice City Hospital, and written informed consent was obtained.

View this table: [in this window] [in a new window]   Table 1. Clinical Characteristics of Patients at Baseline and After 6 Months' Treatment

Echocardiograms were performed with color-Doppler technique by use of a Hewlett-Packard Sonos 2000. Ejection fraction (EF), left ventricle end-diastolic diameter (LVEDD), and left ventricle end-systolic diameter (LVESD) were measured with an apical 4-chamber approach. All the patients were classified according to NYHA classes.

Diuretic consumption score was assigned to each patient according to the following classes: class 1, no diuretic; class 2, 20 to 40 mg/d frusemide or a thiazide diuretic; class 3, 40 mg/d frusemide; class 4, 80 mg/d; and class 5, 120 mg/d.²⁷

Cardiopulmonary Exercise Testing
All CHF patients underwent maximal symptom-limited cardiopulmonary exercise testing with a modified Naughton protocol.¹² A Schiller Cardiovit CS100 with a 1308 capnograph was used. Oxygen consumption at maximum exercise was expressed as peak oxygen consumption (peak O₂), defined as the mean oxygen consumption of the last 30 seconds of an incremental exercise test. The anaerobic ventilatory threshold (VT) was automatically calculated by use of Wasserman's criteria.²⁸ The degree of muscle atrophy was expressed as the gastrocnemius cross-sectional area (CSA)/body mass index (BMI). The CSA was calculated on a CT scan slice obtained one-third distal to the right popliteal space.¹¹

Skeletal muscle needle biopsies were taken from the right medial gastrocnemius with a 17-gauge soft-tissue Menghini needle (Sterylab Histo-cut). With this method,^{11 12} we were able to obtain 50 to 200 µg of tissue that was immediately frozen in liquid nitrogen. The electrophoretic separation of MHCs was carried out with the method described by Carraro.²⁹ Samples were solubilized in 2.3% SDS, 10% glycerol, 0.5% mercaptoethanol, and 62.5 mmol/L Tris-HCl pH 6 and loaded on a 7% polyacrylamide slab gel. Gels containing 0.2 µg of protein per band are usually stained with 0.1% Coomassie's Brilliant Blue in 5% acetic acid/40% methanol. Gels with <0.1 µg protein were stained with the silver method. Individual MHCs were identified by immunoblotting the gel bands with a panel of monoclonal antibodies (gift of Prof S. Schiaffino, University of Padua, Italy).^{11 12 30} The percent distribution of MHCs was determined by gel densitometry (Hofer Scientific GS300 transmittance reflectance scanner connected to a McIntosh SE Apple computer). Data were analyzed with GS370 densitometry software. A linear response was attained on densitometry when 0.1 to 2 µg of individual MHC was analyzed.²⁹ Within this range, there was no variability in MHC percent distribution when different protein concentrations of the same sample were loaded. Quantitative densitometry was performed by use of internal MHC standards with known percent distribution of MHCs. The coefficient of variation for interassay and intra-assay (same sample tested on different gels and the same sample tested on the same gel, respectively) was <2%. The reproducibility of the bioptic sampling is fairly high and is the coefficient of variation in CHF patients of 5% for MHC1, 5% for MHC2a, and 6% for MHC2b, as previously shown in 5 biopsies taken on consecutive days from the same patient.¹¹

Relationship Between Muscle Strength and Size and Contractile Proteins Pattern
In 7 other patients with CHF of different causes (1 from congenital heart disease; 3 from DCM; and 3 from ischemic heart disease) and different NYHA classes (4, class II; 2, class III; and 1, class IV), gastrocnemius isometric strength in the dominant leg was measured with a CYBEX ORTHOTRON device. A maximum of 5 voluntary contractions was accepted as maximal strength. This was expressed in newtons. Gastrocnemius CSA was measured on CT scan sections and the strength/unit area was calculated. A skeletal muscle biopsy was taken from the same muscle immediately afterward. The correlation between MHC composition, muscle strength, muscle CSA, and strength/unit area was then calculated.

Statistical Analysis
Mean±SD was used. Student's t test for paired and unpaired data was used when appropriate. Linear regression was also used. A 5% difference was considered statistically significant.

	Results

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Control Patients
Mean age of control subjects was 55.4±8.5 (P=NS versus CHF). The gastrocnemius MHC composition showed the prevalence of MHC1 (73.0±4.6%, P=0.03 versus CHF baseline). MHC2a was 16.13±7.04 (P=0.33) and MHC2b 11.12±5.54 (P=0.015). These data are similar to those previously reported by our group.¹¹

CHF Patients
Baseline
Patient Characteristics

The 2 groups of patients did not differ in terms of baseline demographics, and clinical parameters (age, body weight, and systolic and diastolic blood pressure) (Tables 1 and 2). In terms of the cause of heart failure, NYHA class, and diuretic class the 2 groups were well balanced.

View this table: [in this window] [in a new window]   Table 2. Comparison Between Losartan and Enalapril at Baseline and After 6 Months' Treatment

Measurements

Measurements showed no statistically different values between L and E for EF, LVEDD, and LVESD. Gas exchange measurements of peak O₂, VT, and E were not significantly different between L and E. O₂ pulse was also similar (12.1±3.0 mL · kg^-1 · min^-1 · hr^-1 in L group versus 11.9±2.5 mL · kg^-1 · min^-1 · hr^-1 [P=NS] in E group). Exercise duration was also similar in E and L. MHC composition of the medial gastrocnemius was almost identical for all 3 isoforms in L and E groups. For CSA/BMI, the degree of gastrocnemius atrophy was similar in both L and E groups (0.63±0.18 versus 0.60±0.21, P=NS).

Six Months' Treatment
Patient Characteristics

Body weight and systolic and diastolic blood pressure were substantially similar in the 2 treatment groups (Tables 1 and 2). NYHA classes in the L group were I in 3 patients, II in 3, and III in 2, whereas in the E group they were I in 1 patient, II in 4, III in 2, and IV in 1. Similarly, there were no differences in diuretic class between the 2 treatment groups.

Measurements

EF, LVEDD, and LVESD did not show differences between L and E. Peak O₂, VT, and E were not different in L and E groups. O₂ pulse was also similar (15.3±4.11 versus 13.00±3.4 mL · kg^-1 · min^-1 · hr^-1, P=NS). The exercise duration was 12.2±2.8 minutes for L versus 10.6±3.6 minutes for E (P=NS). None of the 3 MHC isoforms differed between L and E. The degree of muscle atrophy after 6 months' treatment was similar in L and E (0.64±0.16 versus 0.62±0.21, P=NS) and therefore substantially unchanged when compared with baseline values.

Comparison of Baseline and 6 Months' Treatment
Losartan

Blood pressure was statistically unchanged after 6 months' treatment, though a slight trend toward lower values was observed both for systolic and diastolic BP. EF showed a slight, though not significant, increase after 6 months' treatment. LVEDD and LVESD were not significantly different. After 6 months' L treatment, there was a significant increase in EC in that the mean exercise time was significantly increased. This was reflected by a significant improvement in peak O₂ (Figure 1) and VT (Figure 2). There was also a trend for E to be significantly increased (P=0.5). MHC composition is shown in Figure 3. The percent distribution of the MHCs in the medial gastrocnemius showed a significant increase of the MHC1 after 6 months' treatment (P=0.012) (Figure 4a). This was paralleled by a decrease of both MHC2a (P=0.05) (Figure 4b) and MHC2b (P=0.07) (Figure 4c).

View larger version (53K): [in this window] [in a new window]   Figure 1. Peak O2 at baseline and after 6 months' treatment. Los Base indicates L baseline; En Base, E baseline; Los Treat, L treatment; and En Treat, E treatment.

View larger version (47K): [in this window] [in a new window]   Figure 2. Ventilatory threshold (VT) at baseline and after 6 months' treatment. Abbreviations as in Figure 1.

View larger version (25K): [in this window] [in a new window]   Figure 4. MHC composition at baseline and after 6 months' treatment. A, MHC1; B, MHC2a; C, MHC2b. Abbreviations as in Figure 1.

Enalapril

Blood pressure decreased after 6 months' treatment without reaching statistical significance for systolic or diastolic pressures. There was a slight, though not significant, increase in EF. Ventricular diameters did not show any significant change. Similar to L treatment, 6 months' E treatment produced an increase in EC. Exercise duration (P=0.03), peak O₂ (P=0.014) (Figure 1), and ventilatory threshold (VT) (P=0.039) (Figure 2) increased significantly. E showed only a trend to significance (P=0.4). MHC composition is shown in Figure 3. As it did with L, 6 months' treatment with E produced an increase in the percent of MHC1 (P=0.006) (Figure 4a) and a decrease in both MHC2a (P=0.06) (Figure 4b) and MHC2b (P=0.0015) (Figure 4c).

View larger version (43K): [in this window] [in a new window]   Figure 3. SDS-PAGE of MHCs. Arrows indicate the 3 isoforms separated on the basis of their relative mobility: in order from the fastest to the slowest, MHC1, MHC2a, and MHC2b. Lanes a and b: L, baseline; c and d, E baseline; a' and b', L after 6 months' treatment; and c' and d', E after 6 months' treatment.

Correlation Between Changes in MHCs and Cardiopulmonary Exercise Test Measurements
At baseline, we found a significant correlation between peak O₂ and the percent distribution of MHCs. The correlation was positive for MHC1 (P=0.007) (Figure 5a) and negative for MHC2a (Figure 5b) (P=0.008) and MHC2b (P=0.058) (Figure 5c). When data were analyzed for the single L and E groups, there was an equally positive correlation between peak O₂ and MHC1 (r²=0.59, P=0.026 for L and r²=0.36, P=0.1 for E), and MHC2a (r²=0.73, P=0.007 for L and r²=0.32, P=0.1 for E). At baseline, there was a trend for MHCs to be correlated with VT and E (MHC1 versus VT, P=0.11; MHC2a versus VT, P=0.11; MHC2b versus VT, P=0.4; MHC1 versus E, P=0.5; MHC2a versus E, P=0.6; and MHC2b versus E, P=0.6). We also correlated the absolute changes in MHC (MHC) composition after treatment with the changes in peak O₂ (O₂), and VT (VT). O₂ was correlated with MHC1 (P=0.029) (Figure 6) and MHC2a (P=0.06), whereas for MHC2b it did not reach statistical significance (P=0.3). When the O₂ was correlated with MHC1 for L and E groups separately, it was r²=0.57, P=0.05 and r²=0.28, P=0.2, respectively. The correlation between VT and MHCs was r²=0.2, P=0.6 for MHC1; r²=0.21, P=0.8 for MHC2a; and r²=0.11, P=0.7 for MHC2b.

View larger version (11K): [in this window] [in a new window]   Figure 5. Correlation between peak O2 and MHC composition at baseline. A, MHC1; B, MHC2a; C, MHC2b.

View larger version (13K): [in this window] [in a new window]   Figure 6. Correlation between absolute changes in peak O2 (O2) and MHC1 (MHC1) after 6 months' treatment (all patients).

Statistically, NYHA class at baseline was highly correlated with peak O₂ (r²=0.54, P<0.0011). We could not find any correlation between EF, LVEDV, LVESV, diuretic score, and indexes of cardiopulmonary exercise testing. Similar results were obtained for the 2 groups of treatment when analyzed separately. NYHA class at baseline was negatively correlated with MHC1 (r²=0.26, P=0.05) and positively with MHC2a and MHC2b (r²=0.28, P=0.04). After 6 months' treatment, there was no correlation between the hemodynamic indexes (EF, LVEDD, and LVESD) and gas measurements (peak O₂, VT, and E). EF, LVEDD, and LVESD did not correlate with O₂ or with MHCs. NYHA class was, however, still significantly correlated (r²=0.45, P=0.004) with peak O₂.

Relationship Between Skeletal Muscle Strength and MHC Composition
In the 7 patients in whom gastrocnemius strength was measured, MHC composition was similar to that of CHF patients randomized either to L or E (MHC1 59.4±8.9%, MHC2a 18.3±8.5%, and MHC2b 22.3±5.5%). We could not find any relationship between MHC composition and muscle strength, CSA, or strength/unit area. In fact, for MHC1 this was r²=0.1, P=0.5 for strength (Figure 7a); r²=0.2, P=0.3, for CSA (Figure 7b); and r²=0.3, P=0.2 for strength/unit area (Figure 7c). There was an even lower correlation between MHC2a and MHC2b and the same parameters.

View larger version (9K): [in this window] [in a new window]   Figure 7. A, correlation between MHC1 and muscle strength; B, CSA; and C, muscle strength/unit area in the gastrocnemius of CHF patients.

	Discussion

Top Abstract Introduction Methods Results Discussion References

 
ACEi have been shown to improve EC, quality of life, and survival¹³ in CHF. Recently, similar data have been reported for AIIa.^{25 26} In this article, we describe an improved EC of similar magnitude after 6 months' treatment with L and E. This is demonstrated by NYHA class and exercise duration but especially by the objective measurements of EC such as peak O₂, VT, and E. Since the treatment groups look homogeneous in terms of demographics, clinical characteristics, and causes, the differences appear true. The reason why ACEi produce favorable changes in EC are not entirely clear. Central hemodynamics improve with therapy but do not correlate with peak O₂. The modulation of the neurohormonal cascade, the decrease in peripheral resistances, the improvement in skeletal muscle blood flow,³¹ and the local increase of the bradykinin concentration³² have been proposed as possible mechanisms. We can speculate that the latter mechanism is unlikely to be involved in that L, though showing similar effects of E, does not possess this therapeutic property.

CHF is characterized by skeletal muscle myopathy accompanied by a reduced number of type I, slow, aerobic, fatigue-resistant fibers that express MHC1, and by an increased number of type 2a and 2b fast fibers, which express MHC2a and MHC2b, respectively.^{9 33 34 35 36 37} These latter fibers reach anaerobic metabolism earlier and are more prone to fatigue. It has been recently demonstrated^{2 12 38} that there is a close correlation between indexes of EC and muscle characteristics, and we have hypothesized that skeletal muscle MHC composition plays an important role in determining EC in CHF.¹² In this study, at baseline, patients with different degrees of CHF show the presence of typical skeletal muscle myopathy with a statistically significant correlation between MCH composition, clinical and functional parameters of CHF, and expiratory gases. After 6 months' treatment with L and E, the skeletal muscle MHC composition of the gastrocnemius reshifts toward MHC1. This occurred in both treatment groups, and the results were statistically significant for all 3 MHC components; the magnitude was the same. Schaufelberger et al²³ found that 3 months' therapy with E was able to increase skeletal muscle fiber size without changes in fiber-type distribution. The present study was twice as long and looked at MHC distribution rather than fibers distribution, and this can account for the observed differences. Our data are, however, in agreement with Munzel et al,²⁴ who showed that with ACEi an increased concentration of mitochondria per fiber correlated with an increased endurance to fatigue. Our results are consistent with changes in fiber type obtained with 6 months' physical training in patients with CHF; EC was improved and paralleled by an increase in type I fibers.¹⁸ Low-intensity exercise training has also been shown to improve EC and oxidative metabolism by increasing mitochondria concentration.³⁹ We observed a statistically significant correlation between PEAKo₂ and MHCs and a trend toward significance for VT, which suggests that the reshift of the MHC pattern toward the slow, more fatigue-resistant, aerobic MHCs could be, at least in part, responsible for the improvement in cardiopulmonary parameters that closely reflect the EC in CHF patients. These data are supported by our previous observations^{11 12} and also by those of Massie et al,³⁸ who found that in the skeletal muscle of patients with CHF there was an inverse relationship between the appearance of fatigue and the fiber type II excess. The correlation between PEAKO₂ and MHC1 was present in the E and L groups separately, which suggests that both drugs were able to produce the same biological effects. If this is because of a common mechanism of action, it cannot be established by the present study. We can speculate that these drugs could act directly on the muscle fibers, or they could modulate circulating substances. The sympathetic drive to the skeletal muscle and the AII-mediated norepinephrine release could be reduced with consequent savings in oxidative substrates.⁴⁰ E and L could also block tumor necrosis factor-⁴¹ or insulin-like growth factor⁴² that have been shown to produce contractile protein waste in the CHF myopathy.⁴³ As previously observed,^{44 45} central hemodynamic parameters do not seem to interfere with EC or with fiber-type composition; in fact, in our study, none of them changed with treatment and no correlation was found with respect to clinical parameters, gas exchange measurements, and MHC pattern. Muscle atrophy has been postulated to limit EC in CHF,^{46 47} which suggests a correlation with muscle function.⁴⁸ We did not observe substantial changes in muscle trophism after 6 months' treatment, in keeping with the hypothesis that disuse atrophy may not play a role in the genesis of the CHF myopathy.^{11 30 49} In fact, we could not find any relationship between MHC composition and muscle strength, CSA, or strength/unit area. It is known that MHC composition in the skeletal muscle does not account for force, but it determines speed of shortening and relaxation, ATP, and oxygen consumption.⁵⁰ Muscle strength is known to be related to muscle mass, and strength/unit area does not change in leg muscle in CHF,⁵¹ except in cardiac cachexia.⁴³ Gastrocnemius CSA/BMI did not change significantly in our patients and we therefore assume that muscle strength did not change after 6 months' treatment. The contribution of the observed changes in MHC pattern to improving EC has to be ascribed to the enhanced muscle endurance derived from intrinsic characteristics of MHC1 that are more fatigue resistant.

Conclusions
In conclusion, the present study shows that L and E improve EC in patients with CHF due to different causes and with different levels of severity. The improvement in EC is paralleled by a reshift of the contractile proteins toward more fatigue-resistant, oxidative fibers. Since there is a correlation between the magnitude of isozymic shift and net improvement in peak O₂, it can be argued that the increased EC could be explained (in part) by the favorable biochemical changes occurring in the skeletal muscle.

Limitations of the Study
This study was done with 16 patients. A larger sample could have led to statistically significant differences for those parameters that only showed trends to significance (such as O₂ and MHC2b or VT and MHCs), which would have eventually strengthened our hypothesis. We think that the lack of central hemodynamic data did not bias or weaken our study because of the known absence of correlation between central hemodynamics, severity of CHF syndrome, and severity of myopathy.⁵² Whether the increased expression of MCH1 after L and E is a direct effect of the drugs on the skeletal muscle or is secondary to other factors, such as improvement in exercise activity, is something that can only be speculated. Further studies are needed.

	Acknowledgments

 
This study was supported by a grant from the Veneto Region. We acknowledge Roberta Zennaro, PhD, for the electrophoretic analysis; Carlo La Monaca, MD, for performing CT scans; and Raffaele Santoro, MD, for measuring muscle strength.

Received March 16, 1998; revision received June 19, 1998; accepted June 23, 1998.

	References

Top Abstract Introduction Methods Results Discussion References

 
1. Minotti JR, Pillay P, Chang L, Wells L, Massie BM. Neurophysiological assessment of skeletal muscle fatigue in patients with congestive heart failure. Circulation. 1992;86:903–908.[Abstract/Free Full Text]

2. Harridge SPR, Magnusson G, Gordon A. Skeletal muscle contractile characteristics and fatigue resistance in patients with chronic heart failure. Eur Heart J. 1996;17:896–901.[Abstract/Free Full Text]

3. Wiener DH, Fink LI, Maris J, Jones RA, Chance B, Wilson JR. Abnormal skeletal muscle bioenergetics during exercise in patients with heart failure: role of reduced muscle blood flow. Circulation. 1986;73:1127–1136.[Abstract/Free Full Text]

4. Arnolda R, Conway M, Dolecki M, Sharif H, Rajagopalan B, Ledingham JGG, Sleight P, Radda GK. Skeletal muscle metabolism in heart failure: a ³¹P nuclear magnetic resonance spectroscopy study of leg muscle. Clin Sci. 1990;79:583–589.[Medline] [Order article via Infotrieve]

5. Mancini DM, Ferraro N, Tuchler M, Chance B, Wilson JR. Detection of abnormal calf muscle metabolism in patients with heart failure using phosphorus-31 nuclear magnetic resonance. Am J Cardiol. 1988;62:1234–1240.[Medline] [Order article via Infotrieve]

6. Massie BM, Conway M, Rajagopalan B. Skeletal muscle metabolism during exercise under ischemic conditions in congestive heart failure: evidence for abnormalities unrelated to blood flow. Circulation. 1988;78:320–326.[Abstract/Free Full Text]

7. Massie B, Conway M, Yonge R. ³¹P nuclear magnetic resonance evidence of abnormal skeletal muscle metabolism in patients with congestive heart failure. Am J Cardiol. 1987;60:309–315.[Medline] [Order article via Infotrieve]

8. Wilson JR, Fink LI, Maris J, Ferraro N, Power-Vanwart J, Eleff S, Chance B. Evaluation of energy metabolism in skeletal muscle of patients with heart failure with gated phosphorus-31 nuclear magnetic resonance. Circulation. 1985;71:57–62.[Abstract/Free Full Text]

9. Lipkin DP, Jones DA, Round JM, Poole-Wilson PA. Abnormalities of skeletal muscle in patients with chronic heart failure. Int J Cardiol. 1988;18:187–195.[Medline] [Order article via Infotrieve]

10. Sullivan MJ, Green HJ, Cobb FR. Skeletal muscle biochemistry and histology in ambulatory patients with long-term heart failure. Circulation. 1990;81:518–527.[Abstract/Free Full Text]

11. Vescovo G, Serafini F, Facchin L, Tenderini L, Carraro U, Dalla Libera L, Catani C, Ambrosio GB. Specific changes in skeletal muscle myosin heavy chain composition in cardiac failure: differences with disuse atrophy as assessed on microbiopsies by a new electrophoretic micromethod. Heart. 1996;76:337–343.[Abstract/Free Full Text]

12. Vescovo G, Serafini F, Dalla Libera L, Leprotti C, Facchin L, Tenderini P, Ambrosio GB. Skeletal muscle myosin heavy chain composition in CHF: correlation between the magnitude of the isoenzymatic shift, exercise capacity, and gas exchange measurements. Am. Heart J. 1998;135:130–137.[Medline] [Order article via Infotrieve]

13. Garg R, Yusuf S. Overview of randomized trials of Angiotensin-converting enzyme on mortality and morbidity in patients with congestive heart failure. Collaborative Group on ACE Inhibitor Trials [published erratum appears in JAMA. 1995;274:462]. JAMA. 1995;273:1450–1458.

14. Linz W, Scholkens BA. A specific B-2 bradykinin receptor antagonist HOE 140 abolishes the anti-hypertrophic effect of ramipril. Br J Pharmacol. 1992;104:771–779.[Medline] [Order article via Infotrieve]

15. Minotti JR, Johnson EC, Hudson TL, Zuroske G, Fukushima E, Murata G, Wise LE, Chick TW, Icenogle MV. Training-induced skeletal muscle adaptations are independent of systemic adaptations. J Appl Physiol. 1990;68:289–294.[Abstract/Free Full Text]

16. Minotti JR, Johnson EC, Hudson TL, Zuroske G, Murato G, Fukushima E, Cagle TG, Chick TW, Massie BM, Icenagle MV. Skeletal muscle response to exercise training in congestive heart failure. J Clin Invest. 1990;86:751–758.

17. Coats AJS, Adamopoulos S, Radaelli A, McCance A, Meyer TE, Bernardi L, Solda PL, Davey P, Ormerord O, Forfar C, Conway J, Sleight P. Controlled trial of physical training in chronic heart failure. Circulation. 1992;85:2119–2131.[Abstract/Free Full Text]

18. Belardinelli R, Georgiou D, Scocco V, Barstow TJ, Purcaro A. Low intensity exercise training in patients with chronic heart failure. J Am Coll Cardiol. 1995;26:975–982.[Abstract]

19. Gollnick PD, Saltin B. Significance of skeletal muscle oxidative enzyme enhancement with endurance training. Clin Physiol. 1982;2:1–12.[Medline] [Order article via Infotrieve]

20. Holloszy JO, Booth FW. Biochemical adaptations to endurance exercise in muscle. Annu Rev Physiol. 1976;38:273–291.[Medline] [Order article via Infotrieve]

21. Sullivan MJ, Higginbotham MB, Cobb FR. Exercise training in patients with chronic heart failure delays ventilatory anaerobic threshold and improves submaximal exercise performance. Circulation. 1989;79:324–329.[Abstract/Free Full Text]

22. Hambrecht R, Fiehn E, Yu J, Niebauer J, Weigl C, Hilbrich L, Adams V, Riede U, Schuler G. Effects of endurance training on mitochondrial ultrastructure and fiber type distribution in skeletal muscle of patients with stable chronic heart. J Am Coll Cardiol. 1997;29:1067–1073.[Abstract]

23. Schaufelberger M, Andersson G, Eriksson BO, Grimby G, Held P, Swedberg K. Skeletal muscle changes in patients with chronic heart failure before and after treatment with enalapril. Eur Heart J. 1996;17:1678–1685.[Abstract/Free Full Text]

24. Munzel T, Kurz S, Drexler H. Are alterations of skeletal muscle ultrastructure in patients with heart failure reversible under treatment with ACE inhibitors? Herz. 1993;18(suppl 1):400–405.

25. Gottleib SS, Dickstein K, Fleck E, Kostis J, Levine TB, LeJemtel T, DeKeck M. Hemodynamic and neurohumoral effects of the angiotensin II antagonist losartan in patients with congestive heart failure. Circulation. 1993;88:1602–1609.[Abstract/Free Full Text]

26. Pitt B, Segal R, Martinez FA, Murers G, Cowley AJ, Thomas I, Deedwania PC, Ney DE, Snavely DB, Chang PI. Randomised trial of losartan versus captopril in patients over 65 with heart failure (evaluation of losartan in the elderly study, ELITE). Lancet. 1997;349:747–752.[Medline] [Order article via Infotrieve]

27. Harding SE, Jones SM, O'Gara P, Dal Monte F, Vescovo G, Poole-Wilson PA. Isolated ventricular myocytes from failing and non-failing human hearts: the relation of age and clinical status of patients to isoproterenol response. J Mol Cell Cardiol. 1992;24:549–564.[Medline] [Order article via Infotrieve]

28. Wasserman K. The anaerobic threshold measurement to evaluate exercise performance. Am Rev Respir Dis. 1984;129(suppl):S35–S40.

29. Carraro U, Catani C. A sensitive SDS-PAGE method for separating MHC isoforms of rat skeletal muscles reveals the heterogeneous nature of the embryonic myosins. Biochem Biophys Res Commun. 1983;116:793–802.[Medline] [Order article via Infotrieve]

30. Vescovo G, Ceconi C, Bernocchi P, Ferrari R, Carraro U, Ambrosio GB, Dalla Libera L. Skeletal muscle myosin heavy chain expression in rats with monocrotaline-induced cardiac hypertrophy and failure: relation to blood flow and degree of muscle atrophy. Cardiovasc Res. In press.

31. Jondeau G, Katz SD, Toussaint JF, Dubourg O, Monrad ES. Regional specificity of peak hyperemic response in patients with congestive heart failure: correlation with peak aerobic capacity. J Am Coll Cardiol. 1993;22:1399–1402.[Abstract]

32. Guazzi M, Agostoni PG, Marenzi GC, Melzi G, Guazzi MD. Similar efficacy (but different mechanisms) on exercise capacity of losartan (LOS) and enalapril (EN) in chronic heart failure (CHF). J Am Coll Cardiol. 1997;29(2A):205. Abstract.

33. Mancini DM, Coyle E, Coggan A. Contribution of intrinsic skeletal muscle changes to 31P NMR skeletal muscle metabolic abnormalities in patients with chronic heart failure. Circulation. 1989;80:1338–1346.[Abstract/Free Full Text]

34. Massie BM, Conway M, Yonge R. Skeletal muscle metabolism in patients with congestive heart failure: relation to clinical severity and blood flow. Circulation. 1987;76:1009–1019.[Abstract/Free Full Text]

35. Minotti JR, Christoph I, Oka R, Weiner MW, Wells L, Massie BM. Impaired skeletal muscle function in patients with congestive heart failure: relationship to systemic exercise performance. J Clin Invest. 1991;88:2077–2082.

36. Drexler H, Riede U, Munzel T, Konig H, Funke E, Jiust H. Alterations of skeletal muscle in chronic heart failure. Circulation. 1992;85:1751–1759.[Abstract/Free Full Text]

37. 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.[Abstract/Free Full Text]

38. Massie BM, Simonini A, Sahgal P, Wells L, Dudley GA. Relation of systemic and local muscle exercise capacity to skeletal muscle characteristics in men with congestive heart failure. J Am Coll Cardiol. 1996;27:140–145.[Abstract]

39. Belardinelli R, Scocco V, Purcaro A. Low intensity exercise training improves skeletal muscle oxidative capacity without changes in capillary growth in chronic heart failure. Circulation. 1995;92:I-399. Abstract.

40. Dickstein K, Chang P, Willenheimer R, Haunso S, Remes J, Hall C, Kjekshus J. Comparison of the effects of losartan and enalapril on clinical status and exercise performance in patients with moderate or severe chronic heart failure. J Am Coll Cardiol. 26:438–445.

41. McMurray J, Abdullah I, Dargie HJ, Shapiro D. Increased concentrations of tumor necrosis factor in "cachectic" patients with severe chronic heart failure. Br Heart J. 1994;15:1528–1532.

42. Brink M, Wellen J, Delafontaine P. Angiotensin II causes weight loss and decreases circulating insulin-like growth factor I in rats through a pressor independent mechanism. J Clin Invest. 1996;97:2509–2516.[Medline] [Order article via Infotrieve]

43. Anker SD, Swan JW, Volterrani M, Chua TP, Clark AL, Poole-Wilson PA, Coats AJS. The influence of muscle mass, strength, fatigability, and blood flow on exercise capacity in cachectic and non-cachectic patients with chronic heart failure. Eur Heart J. 1996;18:259–269.

44. Sullivan MJ, Knight JD, Higginbotham MB, Cobb FR. Relation between central and peripheral hemodynamics during exercise in patients with chronic heart failure. Circulation. 1989;80:769–780.[Abstract/Free Full Text]

45. Fink LI, Wilson J R, Ferraro N. Exercise ventilation and pulmonary artery wedge pressure in chronic stable heart failure. Am J Cardiol. 1986;57:249–253.[Medline] [Order article via Infotrieve]

46. Minotti JR, Oka RK, Wells LM, Christoph I, Massie BM. Significance of muscle atrophy in heart failure. Circulation. 1991;84(suppl II):II-50. Abstract.

47. 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;85:1364–1373.[Abstract/Free Full Text]

48. Minotti JR, Pillay P, Oka R, Wells L, Christoph I, Massie BM. Skeletal muscle size: relationship to muscle function in heart failure. J Appl Physiol. 1993;75(1):373–381.

49. Simonini A, Lang CS, Dudley GA, Yue P, McElhinny J, Marrie BM. Heart failure in rats causes changes in skeletal muscle morphology and gene expression that are not explained by reduced activity. Circ Res. 1996;79:128–136.[Abstract/Free Full Text]

50. Ruegg JC. Calcium in Muscle Contraction: Cellular & Molecular Physiology. 2nd ed. New York, NY: Springer Verlag, 1992:125.

51. Chapmans SJ, Grindrod SR, Jones DA. Cross-sectional area and force production of the quadriceps muscle. J Physiol. 1984;353–53P. Abstract.

52. Sullivan MJ, Higginbotham MB, Cobb FR. Increased exercise ventilation in patients with chronic heart failure: intact ventilatory control despite hemodynamic and pulmonary abnormalities. Circulation. 1988;77:552–559.[Abstract/Free Full Text]

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