(Circulation. 2000;101:2213.)
© 2000 American Heart Association, Inc.
Basic Science Reports |
Clenbuterol-Supported Dynamic Training of Skeletal Muscle Ventricles Against Systemic Load
A Key for Powerful Circulatory Assist?
Presented in part at the 71st Scientific Sessions of the American Heart Association, Dallas, Tex, November 9–12, 1998, and published in abstract form (Circulation. 1998;98[suppl I]:I-751).
From the Clinic of Cardiac Surgery (N.W.G., P.K., M.S., H.-H.S.) and the Institutes of Anesthesiology (M.G.), Anatomy (E.R.), and Animal Care (R.N.), Medical University of Lübeck, Germany.
Correspondence to Priv Doz Dr med Norbert W. Guldner, Klinik für Herzchirurgie, Medizinische Universität zu Lübeck, Ratzeburger Allee 160, D-23538 Lübeck, Germany. E-mail guldner{at}medinf.mu-luebeck.de
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Abstract |
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Background—The profound loss of power that occurs in skeletal muscle after electrical conditioning has been the major limiting factor in its clinical application. This study investigates a 3-fold approach for chronic conditioning of skeletal muscle ventricles (SMVs) combining electrical transformation, dynamic training against systemic load, and pharmacological support with clenbuterol.
Methods and Results—In 10 adult male goats, SMVs were constructed from latissimus dorsi muscle wrapped around an intrathoracic training device with windkessel characteristics. SMVs were stimulated electrically and trained dynamically by shifting volume against systemic load. Group 1 goats were controls (n=5), and group 2 goats (n=5) were supported with clenbuterol (150 µg 3 times a week). SMV dynamics were recorded weekly over 5 to 8 months: peak pressure (Pmax), stroke volume (SV), volume displacement per minute (VD), stroke work per day (SW/d), and maximum rates of pressure generation, +dP/dtmax, and decay, -dP/dtmax. In group 1, after 149.5±2.7 days (n=4), data were Pmax=70.8±4.7 mm Hg, SV=3.2±1.2 mL, VD=62.3±21.1 mL/min, SW/d=0.8±0.4 kJ, +dP/dtmax=64±13 mm Hg/s, and -dP/dtmax=156±32 mm Hg/s. These parameters were significantly improved (P<0.007) in the clenbuterol-treated group 2 after 151±2.7 days: Pmax=176.2±43.8 mm Hg, SV=23.3±6.1 mL, VD=568.2±186.1 mL/min, SW/d=9.1±2.2 kJ, +dP/dtmax=1134±267 mm Hg/s, and -dP/dtmax=1028±92 mm Hg/s. In 2 SMVs of group 2, VD increased to 1090 and 1235 mL/min after 202 and 246 days of training, respectively. At termination, myosin heavy chains were totally transformed into myosin heavy chain-1 in all SMVs.
Conclusions—This clenbuterol-supported dynamic training provides powerful SMVs that may have important clinical implications for the treatment of end-stage heart failure by muscular blood pumps.
Key Words: muscles • electrical stimulation • contraction • circulation • clenbuterol
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Introduction |
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The incidence of heart failure is increasing in western countries.1 Medical treatment and heart transplantation are the most accepted therapies. As adjunct or even alternative treatments, biomechanical circulatory assist using the autologous skeletal muscle as in cardiomyoplasty or aortomyoplasty or as skeletal muscle ventricles (SMVs) are highly attractive approaches and have been investigated experimentally and clinically for several decades.2 3 4 5 6 7 8 9 10 11 12 The profound loss of power that occurs in skeletal muscle after electrical conditioning has been the major limiting factor in its clinical application.13 14
A 2-fold approach to skeletal muscle conditioning, including a gentle stimulation protocol in combination with dynamic training, has been shown to improve muscle performance.15 16 17 A power-increasing effect of the ß2-adrenergic receptor agonist clenbuterol in electrically conditioned latissimus dorsi muscle (LDM) was recently demonstrated over an evaluation period of 60 minutes in growing sheep.18 Theoretically, a 3-fold approach to skeletal muscle conditioning combining electrical transformation, dynamic training, and pharmacological modulation by clenbuterol may further enhance mechanical performance of muscle-powered circulatory assist.
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Methods |
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Animals
Experimental investigations were carried out in 10 adult male Boor goats, 3.7±1.1 years old, with a weight of 77.6±6.0 kg. They were castrated 4 weeks before the operation to keep them together and avoid injuries between them. The experiments were performed in accordance with the Guide for the Care and Use of Laboratory Animals published by the National Institutes of Health. They were supervised by a representative of the District President of the local Society for Prevention of Cruelty to Animals.
Myostimulators and Electrodes
Commercially available myostimulators were used (Medtronic model
7420/7424 and Telectronics model 7220). An epimysial electrode 30
mm long (custom-made, Medtronics, Bakken Research
Center)19 was attached to the muscle close to the branches
of the nervus thoracodorsalis. On the opposite side of the muscle, an
electrode 60 mm long (Medtronics SP5591–500-60-NMS) was placed
subfascially.
Training Device
The training device (Figure 1
) was
made of silicone rubber (Q3, Dow Corning) and has been described in
detail before.15 Briefly, it consists of a central chamber
and 2 compliant side bladders filled with saline solution. The
barrel-shaped central chamber and the side bladders have volumes of 150
mL and 50 mL each, respectively. The side bladders are constructed with
a compliance of 1.0 to 1.3 mL/mm Hg, simulating the windkessel
characteristics of the arterial system in normal subjects
with 1.07 mL/mm Hg.20
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Operative Procedure
The operation was performed under general anesthesia
as described before.15 16 17 21 In brief, the left LDM was
dissected free, folded to a double layer, and wrapped around the
central chamber of the training device. The SMV was transferred into
the thorax and fixed at the thoracic wall.
Training Procedure
The training procedure was a combination of an electrical
conditioning by burst stimulation and a dynamic training with
contractions against a constant filling pressure of 60 to 70
mm Hg within the elastic training device. Each SMV contraction shifted
volume into the expanding side bladders, generating a pressure
increase. After muscle contraction, the expanded side bladders shifted
the fluid back to the pumping chamber before the next contraction cycle
could commence. Electrical conditioning was performed as shown in Table 1 and described in detail before.21 Dynamic training is
characterized by auxotonic contractions with simultaneous
increase of muscle tension and decrease of muscle length.
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Experimental Groups and Clenbuterol Medication
The 10 male goats were assigned alternately to the different
groups without remarkable differences in age and weight (groups 1/2:
age, 3.5±1.0/3.8±1.0 years and body weight, 77.2±6.4/78.0±6.3 kg).
Animals in group 1 were controls (n=5), and animals in group 2 (n=5)
were treated with clenbuterol (Boehringer-Ingelheim). A dosage
of 150-µg capsules 5 times a week for the first 2 weeks was
administered orally, followed by the same dosage 3 times per week.
Data Acquisition
With the goats unsedated, pressure changes inside the training
device induced by SMV contractions were measured once a week by
piercing of a subcutaneous vascular access port, which communicated
with the lumen of the training device via a 5F, 40-cm-long catheter
(Figure 1
). The piercing needle (Surecan, Braun) was connected
with a 100-cm stiff plastic tube to an electromechanical pressure
transducer (Hewlett Packard, model 1290 C). Pressure data were
recorded and stored in a PC (AT 486, 33 MHz; resolution, 12 bit;
sampling rate, 200 Hz). At each measurement, the filling pressure was
adjusted to 60 mm Hg by addition of usually <3 mL of 10%
hyperosmolar saline solution via the subcutaneous vascular access port.
Thereafter, 5 series of couples of pressure traces were recorded.
Then, with the myostimulator switched off, the compliance of the side
bladders was determined as described in detail
elsewhere.22
Analysis of Compliance
The compliance of the side bladders was compared between the 2
groups after the first week and after 1, 3, and 5 months after surgery.
As a representative value for the compliance, the
pressure increase after injection of 30 mL of saline solution into the
training device in addition to the load of 70 mm Hg was defined
as 
P30 mL.
Analysis of Fluid Dynamic Parameters
SV was assessed relating the pressure increase during a muscular
contraction to the determined compliance curve of the side bladders of
the device as described before.15 22 In vitro, it was
shown that this method of indirect SV evaluation was valid, relying on
a nonexpandable central chamber
(R=0.996).22 In vivo, it was demonstrated
that the compliance curve is solely an expression of the side bladders
into which the SV was expelled. After a volume of 100 mL had been added
into the training device, it was shown by x-ray examination that there
was no change in diameters of the central chamber (n=4). For an
approximate control of the shifted volume, the difference of the radii
of the 2 side bladders was determined by x-ray examination. Therefore,
the side bladders were regarded as spheres and the volume shift as the
difference of sphere volumes before and after contraction. This SV
validation by x-ray examination was performed in test situations with a
volume shift between 14 and 83 mL and was found to be comparable to the
indirect SV calculation described above.22
Stroke work, W, was evaluated by means of numerical integration of the
pressure-volume curve of the training device determined at each
measurement15 22
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Stroke work was standardized to LDM weight, which was then called specific stroke work (J/kg). Stroke work per day was approximated by multiplying stroke work by the number of contractions per day. Maximum rate of pressure development (+dP/dtmax) and maximum rate of pressure decay (-dP/dtmax) were calculated by the first derivation of pressure trace, filtered with a low pass of 30 Hz. Time to peak pressure, tPmax, and relaxation half-time, trelax 1/2, were standardized to SV to neutralize the influence of SV variability.
Analysis of MHCs
Muscle samples for analysis of myosin baseline
composition were taken intraoperatively from the free wall of the SMV
opposite the muscle pedicle. Further samples of the muscle were
harvested after training from the same location of the SMV and from the
corresponding contralateral part of the LDM. Muscle samples were frozen
under liquid nitrogen, stored at -80°C, and pulverized, then used
for myosin extraction by the method of Ho et al23 and
brought to electrophoresis on acrylamide gel for a
separation for 20 hours at 150 V. The gel was fixed for 24 hours with
methanol. All gels underwent a silver staining by the method of Oakly
et al.24 The gel electrophoresis was photo documented, and
after a computer scanning, was quantified by Gel-Pro Analyzer
version 3.0 for Windows software.
Statistics
Data are presented as mean±SD. A Mann-Whitney
U test was performed for comparison between groups.
Differences were considered significant at values of
P<0.05. All statistical calculations were performed with
Winstat 3.0 software (Kalmia Co).
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Results |
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Animals and Operative Procedure
All 10 male Boor goats survived the operative procedure. There was no failure in the myostimulators and electrodes. In 1 animal of group 1, an elastic training device failed as a result of leakage on postoperative day 49, and the goat was excluded from the study. The average training time of group 1 (n=4) was 149.5±2.7 days and that of group 2 (n=5), 151±2.7 days. Two goats of group 2 were observed up to 202 and 246 days, respectively. Mean body weight of group 1 decreased during the training period minimally from 77.2±5.9 to 76.5±9.5 kg, and it increased significantly in the clenbuterol-treated group 2 from 78.0±6.3 to 87.8±9.3 kg (P=0.02) after 151±2.7 days of training. There was no significant difference in body weight at the beginning of the training between groups 1 and 2 (P=0.23).
Mechanical Performance
Performance data of each SMV at the end of the training
period are listed in Table 1.
Clenbuterol increased contraction and relaxation performance
significantly (P<0.007).
Pressure
In group 1 (4 animals; average follow-up, 149.5±2.7 days), an
increased peak pressure, Pmax, was observed
during the first 60 days, followed by a continuous decline
corresponding to a poor fluid dynamic outcome (Figures 2 and 3;
Table 2). End-stage peak pressure of
group 1 was 70.8±4.7 mm Hg. SMVs of group 2 (n=5) showed much
better mechanical performance (Figures 2 and 3,
Table 2) with maintained or increasing maximum pressure values
after 151±2.7 days of dynamic training. Maximum pressure values of
group 2 (n=5) were 176.2±43.8 mm Hg (P<0.007).
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Two goats of group 2 showed suprasystemic pressure of 210 and 251 mm Hg after 202 and 246 days of clenbuterol-supported dynamic training, respectively.
Compliance
During the training period, compliance decreased remarkably, as
demonstrated by an increased P30 mL value.
P30 mL after the first postoperative week was:
group 1, 33.0±10.4 mm Hg; group 2, 37±12.0 mm Hg
(P=0.31); after 1 month: group 1, 44.3±25.3 mm Hg;
group 2, 64.2±30.3 mm Hg (P=0.29); after 3 months,
group 1, 79.6±52.7 mm Hg; group 2, 87.3±84.2 mm Hg
(P=0.44); and after 5 months: group 1, 158.0±126
mm Hg; group 2, 192.3±146 mm Hg (P=0.02). No
significance was found between groups up to the third postoperative
month. After 5 months of dynamic training, compliance was significantly
different between the 2 groups.
Stroke Volume
In group 1, in accordance with the time course of pressure, stroke
volume (SV) increased slightly and dropped to a low level. SV
after 149.5±2.7 days of training was 3.2±1.2 mL per beat,
corresponding to a volume displacement (VD) of 62.3±21.1 mL/min.
In group 2, the SV time course characteristics showed a more pronounced
increase at the beginning, followed by a relatively rapid decline,
reaching an individual plateau that was maintained during further
training. Maximum SV was 2 times higher at the beginning (type II
fibers) than at the end (100% type I fibers) of training. This effect
was observed in all cases in group 2. SV per beat was 23.3±6.1 mL
after 151±2.7 days of training, corresponding to a VD after 5 months
of training of 568±186 mL (Table 2). Differences from group 1
were significant (P<0.007). In 2 goats, after a training of
202 and 246 days, respectively, continuous pumping capacity of >1
L/min (1090 and 1235 mL/min) was obtained (Table 2).
Stroke Work
Stroke work per day in group 1 was poor, achieving 0.8±0.4 kJ
after 149.5±2.7 days of training. In group 2, in accordance with the
time course of pressure, SV, and contraction frequency, stroke work per
day increased continuously up to 9.1±2.2 kJ (P<0.007).
End-stage stroke work of the 2 goats after 202 and 246 days of training
was 26.8 and 27.8 kJ/d, respectively.
Contraction
In group 1, after 149.5±2.7 days of training, maximum rate of
pressure rise, +dP/dtmax, was low, 64±13
mm Hg/s, and in group 2, it was high, with a
+dP/dtmax of 1134±267 mm Hg/s
(P<0.007). +dP/dtmax of the 2 goats
after 202 and 246 days of training resulted in 1027 and 1102
mm Hg/s, respectively.
In group 1, time to peak pressure normalized to SV, tPmax/SV, resulted in 60.8±22.8 ms/mL, and it was significantly shorter in group 2, with a tPmax/SV of 11.8±4.5 ms/mL (P<0.007). tPmax/SV was 11.6 and 6.9 ms/mL after a prolonged training of 202 and 246 days, respectively.
Relaxation
The maximum rate of pressure decay was low in group 1 with a
-dP/dtmax of 156±32 mm Hg/s and high in
group 2 with a -dP/dtmax of 1028±92
mm Hg/s (P<0.007).
The relaxation half-time, trelax 1/2, was measured as 54.4±12.5 ms/mL in group 1 and 6.0±1.7 ms/mL in group 2 (P<0.007).
After 202 and 246 days of clenbuterol-supported dynamic training, -dP/dtmax was evaluated at 923 and 901 mm Hg/s, respectively, and the corresponding relaxation half-time normalized to SV was evaluated at 6.0 and 6.8 ms/mL.
Morphology
The muscle morphology of the SMVs was related to its power
delivery. A thin muscle wall (Figure 4A)
with low power in group 1 showed histologically severe
muscle damage, with a fiber substitution by fat cells. In the thick
muscles of group 2, supported by clenbuterol (Figure 4B) with
high power delivery, muscle fibers were mainly preserved, fewer fat
cells were integrated, and there were obvious signs of
hypertrophy and less connective tissue. This muscular
tissue has to undergo further morphometric analysis.
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Myosin Heavy Chains
Myosin heavy chain (MHC) composition of prospectively
harvested LDM was similar in the 2 groups: group 1, 22.1±6.5% MHC-1
and 77.9±6.5% MHC-2 and in group 2, 28.8±7.7% MHC-1 and 71.2±7.7%
MHC-2. SMVs after training of both groups showed a total transformation
into 100% MHC-1.
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Discussion |
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To the best of our knowledge, this study provides the first evidence that a 3-fold approach to skeletal muscle conditioning by a combination of electrical stimulation, dynamic training, and pharmacological modulation with clenbuterol provides a power source with a high potential for effective circulatory assistance. In our training device, which mimics systemic loading conditions, the addition of clenbuterol to electrical transformation and dynamic training resulted in a remarkable improvement in muscular performance, with a continuous pumping capacity of >1 L/min with a 300-g muscle, which has not been demonstrated before in adult muscular tissue. LDM in patients usually weighs
600 g. Therefore, a higher pumping capacity
may be expected, even considering that morphological and biochemical
abnormalities are known to occur in the skeletal muscle of patients
with end-stage heart failure and may persist despite normalization of
central hemodynamics.18
Dynamic Training
The contraction power needed for dynamic training against a load
of 60 to 70 mm Hg from the beginning was much higher than under a
low load of 5 to 10 mm Hg tested before.15 21
That is why 2 additional conditions were established to increase
contraction power. First, muscle mass was doubled by the use of male
goats with an LDM weight of 300 g instead of female goats with an
LDM weight of 150 g, which were used before.21
Second, the stroke power was supposed to be increased by application of
the ß2-stimulator clenbuterol, which was shown
elsewhere to be power-generating in nonfatiguing type I
fibers.18
ß2-Adrenergic Receptor Agonist Clenbuterol
Several drugs are known to improve muscle
hypertrophy and function.25 26 27 28 Clenbuterol, a
selective ß2-adrenergic receptor agonist,
induces skeletal muscle hypertrophy and power in the
rat25 and also cardiac hypertrophy with
preservation of certain physiological features,
such as systolic and diastolic cardiac function.
Clenbuterol is the most frequently used and most potent of the
ß2-agonists, because it results in a 10% to
20% increase in mass of skeletal muscle in 8 to 14 days as well as an
increase in myocardium of 18%.25 A dosage
of clenbuterol of 150 µg/d was chosen to test quantities that are
expected to apply clinically later on. The time intervals of
application were calculated to try to avoid an accumulation of this
drug, considering an elimination half-time of 34
hours.29
Myosin Heavy Chains
The fiber composition of LDM preoperatively was not
significantly different before dynamic training of both groups and thus
could not have influenced the outcome of training. MHC-1 was found in
100% of group 1 goats as well as in the clenbuterol-supported group 2
goats after chronic stimulation and pumping. Thus, the hypothesis of
preserved MHC-2 resulting from increased power delivery could not be
verified.
Compliance
In normal subjects, the total compliance of the
arterial system was found to be 1.07
mL/mm Hg.20 Values of 0.9 mL/mm Hg were assumed in
advanced age because of hypertension and
arteriosclerosis.26 27 In our
compliant training device in the clenbuterol-supported group 2 animals,
compliance varied from 0.08 to 0.34, with a stroke work per day of 5.5
to 11.8 kJ. These low, nonphysiological compliance
values (Table 1) are regarded as the main limitations of this
study. The less compliant device is found to be combined with the
lowest stroke work per day and the most compliant bladders with the
greatest energy delivery (Table 2). This impressive high power
is thought to be even more favorable if dynamic training is performed
against physiological compliance of the
arterial system.
Application
The positive effect of clenbuterol observed on the power
development of SMVs during dynamic training against systemic load
(Figure 2, right, and Figure 3, right) may not be
sufficient to speculate that this
ß2-stimulation may strongly improve the
hemodynamic efficacy of other muscle-powered cardiac
assist procedures. Indeed, in dynamic cardiomyoplasty, LDM surrounding
dilated hearts should require more power than in SMVs with small
diameters (Laplace’s law).
Muscle contraction and relaxation were faster in clenbuterol-treated
ventricles than in those without drug supply (Table 2).
Preservation of a high +dP/dtmax of
1134±267 mm Hg/s and -dP/dtmax of
1028±92 mm Hg/s is a sign of powerful SMVs with remarkably good
SVs. Relaxation of -dP/dtmax of human left
ventricle levels off at 2000 mm Hg/s.18 That is why
the relaxation characteristics in our study also indicate that this
kind of conditioning may predispose the skeletal muscle more to a
counterpulsator application as SMVs or aortomyoplasty than a direct
cardiac assist in the form of a cardiomyoplasty.18
As shown before, dynamic training against increasing load results in increasing muscular power.15 However, this training procedure would imply a 2-stage surgical procedure with primary training up to a systemic load and a subsequent integration into the circulation. A 2-step operation as shown elsewhere4 6 7 may not be practicable for patients with end-stage heart failure. A successful training against systemic load, however, combined with a 1-step operation, may be a more practical approach for clinical application of muscular blood pumps.
To summarize this experimental work, clenbuterol-supported dynamic training may be regarded as a key for powerful muscular blood pumps. SMVs trained as described are expected to become clinically effective as muscular blood pumps performed in a 1-step operation and trained within circulation.
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Acknowledgments |
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We thank Boehringer-Ingelheim, Germany, for the gift of clenbuterol. A special thanks to P.A. Grandjean, MSc, Bakken Research Center, Maastricht, Netherlands, for his comments and to Britta Keding for her excellent support and evaluations.
Received August 10, 1999; revision received November 9, 1999; accepted November 19, 1999.
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