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Ann Thorac Surg 1995;59:961-969
© 1995 The Society of Thoracic Surgeons

Anabolic Steroids (Metenolone) Improve Muscle Performance and Hemodynamic Characteristics in Cardiomyoplasty

Dirk Fritzsche, MD, Ralf Krakor, MD, Gerhard Asmussen, PhD, Ralf Widera, PhD, Paul Caffier, MD, Julia Berkei, MD, Markus Cesla, MD

Clinic for Cardiovascular Surgery, University of Leipzig, Leipzig, Germany

Accepted for publication November 22, 1994.


   Abstract
Top
 Footnotes
 Abstract
Introduction
 Study Protocol
 Material and Methods
 Results
 Comment
 References
 
The loss of force and mass in the conditioned latissimus dorsi muscle are principal reasons for the poor improvement in hemodynamic functioning attained by cardiomyoplasty. Using 24 sheep, we investigated the effect of anabolic steroids on the hemodynamic, histologic, and myophysiologic characteristics in the setting of cardiomyoplasty. In 12 of the animals (group A), the latissimus dorsi muscles were electrically conditioned with an Itrel pulse generator; in the remaining 12 animals (group B), the electrical conditioning was combined with the administration of an anabolic hormone (metenolone; 100 mg/week). The hemodynamic measurements were performed during isolated perfusion of the subclavian artery (maintenance of pressure in the muscles), while all other circulation variables were held at the exact and reproducible value of zero by inducing ventricular fibrillation. Maximum force and muscle mass showed a significant increase in group B (maximum force: group A, 4.23 ± 0.55 kp, and group B, 6.0 ± 3.14 kp; muscle mass: group A, +11.07% ± 1.06%, and group B, +79.9% ± 40.8%). The ratio of type I to type II fibers after 12 weeks was 65.2% to 34.8% in group A and 96.7% to 3.3% in group B, as opposed to 19.9% to 80.1% in the control group. No side effects of the anabolic steroids were observed during the experiment. In the hemodynamic studies, we were able to demonstrate a further significant increase in the left ventricular pressure, fractional fiber shortening value, ejection fraction, stroke volume, cardiac output, and stroke work when using conditioned latissimus dorsi muscles that were additionally treated with metenolone. In our reproducible heart failure model, the administration of anabolic steroids led to an acceleration of the fast-to-slow transformation, an increase in the force capacity and muscle mass of the conditioned latissimus dorsi muscles, as well as an improvement in hemodynamic functioning, while the pharmacologic effects remained confined to the chronically stimulated muscle. It seems likely, therefore, that anabolically conditioned latissimus dorsi muscles can help cardiac insufficiency in two ways. On the one hand, they can produce a significant direct increase in contractility. On the other hand, the considerable increase in thickness can be expected to cause a reduction in wall tension and in myocardial oxygen consumption according to Laplace's law.


   Introduction
Top
 Footnotes
 Abstract
 Introduction
Study Protocol
 Material and Methods
 Results
 Comment
 References
 
See also 969.

Since its introduction into clinical use by Carpentier and Chachques [1] in 1985, cardiomyoplasty (CMP) has become the object of intensive clinical and theoretical research. So far, the procedure has been performed in more than 400 patients worldwide, and initial results are encouraging [2]. It is therefore not inappropriate to consider whether CMP could develop into a viable alternative to heart transplantation, particularly in those instances in which transplantation is contraindicated. To date, however, there has been no conclusive proof of the way in which CMP works: Although a clinically impressive improvement in the New York Heart Association functional class and in survival rates has been demonstrated [3], attempts at identifying objective hemodynamic characteristics have been disappointing. The effect of CMP could, on the one hand, consist of producing a direct increase in ventricular augmentation [4, 5]. One factor tending to support this hypothesis is the measurable (but slight) increase in the left ventricular ejection fraction. On the other hand, a rise in the contraction amplitude of the left ventricular posterior wall has been observed, even in the ``off'' mode. The muscle wrapped around the heart appears to cause a decrease in wall tension, which theoretically contributes to a reduction in oxygen consumption according to Laplace's law, and thus to optimization of the contraction variables [5, 6]. It is probably the combination of both effects that is responsible for the remarkable improvement in the patient's clinical condition. We hypothesized that the hemodynamic benefit of CMP thus depends on two variables: the force capacity and the thickness of the latissimus dorsi muscles (LDs).

The values of both these variables, however, decline significantly in the course of the conditioning process: force capacity and thickness are sacrificed in favor of increased resistance to fatigue. If it were possible to use pharmacologic means to induce a thicker and stronger muscle than is obtainable with electrical conditioning alone, then a combined pharmacologic and electrical approach could be expected to confer distinct hemodynamic benefits for the patient. This was the line of thinking that prompted us to investigate the effect of anabolic steroids on the contraction characteristics of stimulated LDs and on the changes in the hemodynamic functioning after CMP using anabolically treated muscles.


   Study Protocol
Top
 Footnotes
 Abstract
 Introduction
 Study Protocol
Material and Methods
 Results
 Comment
 References
 
First Study
This study was carried out in 12 female adult merino sheep (average weight, 45.5 ± 3.6 kg [mean ± standard deviation]). The left LD of each animal was stimulated using a myostimulator (Itrel; Medtronic, Minneapolis, MN). Six sheep received 100 mg of metenolone (Primobolan S Depot 100) intramuscularly per week (group IB). The remaining 6 sheep, which were subjected to electrical conditioning alone, formed group IA. The nonstimulated contralateral LDs of all 12 animals constituted the control group. After a conditioning period of 12 weeks, all 24 LDs underwent identical physiologic and morphologic investigations.

Second Study
This study was performed in 12 adult female merino sheep (average weight, 47.9 ± 6.3 kg). After 12 weeks of chronic electrostimulation, the transformed muscles were wrapped around the heart and acute hemodynamic measurements were started using a specially developed experimental model. As in the first study, animals treated additionally with anabolic hormones formed group IIB; the remaining sheep constituted group IIA.

Animals and Animal Care
The surgical procedure performed in all these animals was done in strict accordance with the guidelines of the Federal Republic of Germany's legislation for the prevention of cruelty to animals. Premedication consisted of 0.03 mg/kg of atropine plus 1.0 mg/kg of diazepam. Narcosis was induced with 0.22 mg/kg of xylazine (Rompun) plus 11.0 mg/kg of ketamine (Ketanest), and was maintained by appropriate doses. All animals received twice-daily injections of an analgesic (tramadol) for 8 days postoperatively. At the end of the experiments, the animals in group II were sacrificed with an overdose of phenobarbital.

Stimulation Procedure
After a postoperative recovery period of 10 to 14 days, the left LDs of the animals were conditioned using an Itrel myostimulator. Two intramuscular leads (SP 5577-90/-30; Medtronic) were placed very close to the branches of the thoracodorsal nerve, as proximally as possible (cathode) and about 6 cm distally (anode). The myostimulator was placed subcutaneously in the interscapular region.

Stimulation was started with a burst frequency of 5 Hz, a 210-µs pulse width, and a 0.5 second ``on'' and 1.5 second ``off'' time. The pulse amplitude was initially programmed at 5 V. Stimulation variables were increased gradually every other week, ultimately reaching a burst frequency of 30 Hz and a pulse amplitude of 10.5 V. The burst frequency was increased in increments of 5 Hz; the pulse amplitude was varied by 0.5 to 1 V, depending on whether contraction was clearly palpable and visible. In the 14th week, the contraction characteristics (groups IA and IB) were investigated and all LD biopsies or hemodynamic measurements were performed (groups IIA and IIB).


   Material and Methods
Top
 Footnotes
 Abstract
 Introduction
 Study Protocol
 Material and Methods
Results
 Comment
 References
 
Mechanical Measurements
The muscle was prepared as far as the humeral origin, keeping the neurovascular bundle intact and severing the costal insertion completely. Perforating collaterals to the muscle were cauterized. Approximately 1 cm of the distal portion was wrapped around a metal rod and secured with a continuous suture. The rod was connected by means of a thin wire to a Hottinger force transducer (Z6-4; Hottinger-Baldwin, Darmstadt, Germany). The signals were sampled at a frequency of 1,000 Hz. A biopsy specimen (approximately 1 cm3) was taken from a defined region of the LD (constant for all animals) and was quickly frozen and stored in liquid nitrogen for later use. Once the operating field had been prepared, the LDs were first stimulated with 7.5 V and burst frequencies of 5, 10, 15, 20, and 30 Hz until contraction became tetanic. The contraction characteristics were then investigated under the effect of impulses of up to 10.5 V, with burst frequencies marginally exceeding those required to induce fused tetanic contractions. Finally, the conditioned muscles were subjected to a 90-minute fatigue test. Upon completion of the bilateral investigations, the LDs were severed at the humeral origin and weighed. Curve analysis was performed by computer using UDAS-Analyse software (Cortex, Friedrichsdorf, Germany). Of special interest were the contraction time (in milliseconds), half-relaxation time (in milliseconds), frequency required to induce fused tetanic contraction (VFR, in hertz), maximal force at VFR (in kiloponds), force under supramaximal stimulation patterns (in kiloponds), and the force--time curve (in kiloponds per second).

The values calculated were checked for significance using Student's t test for paired values. All results are reported as the mean ± standard deviation.

Hemodynamic Measurements
Cardiomyoplasty was performed in a posteroanterior manner. The muscle was secured with a running 3-0 Prolene suture (Ethicon, Somerville, NJ) in the atrioventricular groove to prevent dislocation, then the truncus brachiocephalicus was prepared. This is the only vessel arising from the aortic arch in sheep. After the animal was heparinized (500 U/kg), all pressure transducers and perfusion cannulas were put in place. The pressure in the radial artery was measured by a Statham P23 XL (Spectramed). Left ventricular pressure and aortic pressure were registered by means of two tip catheters (VPC 684D; Millar Instruments, Houston, TX), which were introduced through the aortic wall and secured with pursestring sutures. For the pressure monitoring in the right atrium (central venous pressure), right ventricle, and pulmonary artery (pulmonary artery pressure/pulmonary capillary wedge pressure), we used thermodilution catheters (Opticath P 7110; Abbot). Flow measurements were performed using a new extravascular Doppler flow probe and cardiac output monitoring system (Extravascular Doppler EVD TM, ABCOM; Pro-Medica). The probe was fitted directly onto the aorta approximately 3 cm downstream from the valve. Stroke work (in erg x 106) was calculated using the following formula: (aortic pressure - left ventricular end-diastolic pressure) x stroke volume x 1330. Both the truncus brachiocephalicus and the jugular vein were cannulated, and circulation plus oxygenation were started. After a final check of the entire equipment, the truncus brachiocephalicus was cross-clamped and the heart put into fibrillation.

With this model, we were able to calculate all variables resulting from muscle contraction alone, as cardiac output and other circulation variables were held at the exact and reproducible value of zero. If we had not perfused the truncus brachiocephalicus (from which the thoracodorsal artery for the LD arises), the muscle would have fatigued shortly after the start of fibrillation, as it would in no case been able to maintain the necessary perfusion pressure for itself by compressing the heart.

We then started muscle contraction with the Itrel myostimulator (33 pulses per second, 210-µs pulse width, 10.5 V, 0.5 second ``on'', 1.5 second ``off''). Registration was theoretically possible for hours, but was abandoned after 15 to 20 minutes. The perfusion pressure of the LD was maintained at 90 mm Hg, which was about the same as the mean aortic pressure before cross-clamping and fibrillation (Fig 1Go).



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  		Fig 1. . The experimental model. To simplify the explanation, the drawing does not include the pressure transducers, flow probe, or oxygenator between the vein and roller pump.

 
During registration, we performed transmuscular (epicardial) M-mode and two-dimensional echocardiography with a 3.75-MHz standard probe. As a base station we used an Echocardiograph SSH 140 A (Toshiba). From these data we calculated the fractional fiber shortening, ejection fraction, stroke volume, stroke work, and cardiac output. Furthermore we recorded blood flow in the left and right ventricular outflow tract with Doppler and color-flow imaging.

Morphologic Investigations
The biopsy specimens were transferred to a cryostat (American Optical, Southbridge, MA), and cross-sections (12 µm thick) were cut. The following histologic and enzyme histochemical reactions were performed on serial sections: hematoxylin-eosin staining, staining according to the van Gieson method, succinic-dehydrogenase, myosin-adenosine-triphosphatase. For the myosine-adenosine-triphosphatase reaction, the different fiber types were distinguished by using preincubations within a range of acidic (4.0 to 4.6) and alkaline (10.0 to 10.6) pH values. The diameters of the fibers were determined using an ocular micrometer.

A sample of liver parenchyma was taken from each group II animal at the very beginning of the final experiment by means of a laparotomy. These samples from both groups (IIA and IIB) was investigated by both light and electron microscopy, and no differences or evidence of deterioration were found in any of the ultrastructural features.


   Results
Top
 Footnotes
 Abstract
 Introduction
 Study Protocol
 Material and Methods
 Results
Comment
 References
 
Fiber Type Composition
The data described here are based on the investigations conducted on 12 electrically stimulated LDs (groups IA and IIA), 12 conditioned muscles also treated with anabolic hormones, (groups IB and IIB), and 24 nonstimulated contralateral muscles (control group).

As expected, the chronic electrostimulation resulted in a transformation of fast type II fibers to slow type I fibers. The unstimulated control muscles contained about 20% type I and 80% type II fibers (Fig 2AGo). After 12 weeks of stimulation, the percentage of type I fibers increased to 65% and the percentage of type II fibers decreased to 35% (Fig 2BGo). However, in the muscles from animals receiving metenolone, the fiber transformation was almost complete: 97%, type I; and 3%, type II (Figs 2C, 3GoGo).



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  		Fig 2. . (A) Unstimulated latissimus dorsi stained with acid adenosine triphosphatase (pH, 4.1). Type I fibers are stained dark. (B) Stimulated latissimus dorsi preparation from a group A animal (without anabolic steroids). (C) Stimulated latissimus dorsi preparation from a group B animal (with anabolic steroids). (Calibration bar, 50 µm.)

 


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  		Fig 3. . Fiber type composition in the unstimulated and stimulated latissimus dorsi muscles. The administration of an anabolic hormone led to an almost complete transition in the steroid group and to a significant acceleration of the transformation process.

 
Mechanical Measurements
The data reported here were obtained from the 12 sheep making up group I (first study). The contraction time at VFR was 345.3 ± 11.9 and 432.3 ± 54.7 ms for the contralateral, nonstimulated muscles of group IA (p < 0.01) and group IB (p < 0.05), respectively. There was a corresponding increase in the half-relaxation time at VFR: 170 ± 36.2 ms for group IA and 163.1 ± 13.9 ms for group IB versus 93 ± 7.94 and 107.6 ± 60.5 ms (p = not significant [NS]) for the contralateral, unstimulated muscles of groups IA and IB, respectively. The maximum force under stimulation at 7.5 V and tetanic frequencies (maximum force at VFR) was 1.15 ± 0.7 kp in group IA and 4.13 ± 1.2 kp in group IB (p < 0.05). The values measured for the corresponding contralateral, nonstimulated muscles were 4.27 ± 0.57 and 4.95 ± 1.1 kp, respectively (p = NS) (Fig 4Go). The conditioned muscles of group IA reached a force--time curve at VFR of 0.64 ± 0.23 kp/s; the corresponding value for group IB was 4.9 ± 1.97 kp/s (p < 0.05). The contralateral, unstimulated muscles displayed force--time curve values of 13.5 ± 0.74 and 15.5 ± 2.18 kp/s in groups IA and IB, respectively.



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  		Fig 4. . Maximal force capacity under stimulation frequencies that were just tetanic. (LD = latissimus dorsi.)

 
Renewed determination of the same contraction characteristics, this time under supramaximal stimulation patterns (10.5 V, burst frequency &gt; VFR), produced the following constellation of results. The contraction time was 383.6 ± 83.7 ms for group IA and 494.17 ± 30.5 ms for group IB, compared with 161 ± 19.52 ms for the contralateral, unstimulated muscles (p < 0.05 versus group IA). The half-relaxation time also showed an increase, but this result fell short of the threshold of statistical significance. Maximum force was determined to be 4.23 ± 0.55 kp in group IA and 6.0 ± 3.14 kp in group IB (p = NS). Under identical stimulation conditions, the contralateral muscles were stronger in group IA (6.1 ± 2.3 kp), but weaker in group IB (5.25 ± 1.57 kp; p = NS). The maximal force--time relation for group IA was calculated as 6.7 ± 1.05 kp/s versus a control value of 16.4 ± 1.36 kp/s (p < 0.001). The corresponding value for group IB was 5.13 ± 2.19 kp/s versus a control value of 15.8 ± 2.16 kp/s (p < 0.05).

In the fatigue test, none of the conditioned muscles in groups IA and IB displayed any fall-off in developed force during the 90 minutes of the test. The force of the contralateral, nonstimulated muscles in both groups declined after 2.25 minutes (± 28 seconds) to 80% of the initial values.

The muscle weight of the stimulated LDs in group IA was 172.6 ± 10.0 g versus 155 ± 7.51 g for the contralateral, unstimulated muscles. In group IB, there was a remarkable increase in the muscle weight of 249.17 ± 91.4 g versus 145.67 ± 57.96 g in the contralateral, unstimulated muscles (p < 0.05) (Fig 5Go). The relative increase in weight of the conditioned muscles in group IA was 11.07% ± 1.06%; in group IB it was 79.97% ± 40.8% (p < 0.05). The calculated maximal force per 100 g of muscle tissue did not differ significantly between the two groups: group IA, 2.42 ± 0.17 kp/100 g versus 3.87 ± 1.46 kp/100 g in contralateral, unstimulated muscles; group IB, 2.52 ± 0.48 kp/100 g versus 3.95 ± 1.45 kp/100 g in contralateral, unstimulated muscles (p = NS).



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  		Fig 5. . Average muscle weight for both groups and its relative increase during the conditioning process. (abs. = absolute; LD = latissimus dorsi.)

 
The average relative weight gain of all animals amounted to 7% over the duration of the experiment, and is certainly to be explained by the general conditions (diet and exercise) under which the animals were kept. The weight gain of the anabolically treated animals was not significantly greater or more rapid than that of the untreated animals (Fig 6Go).



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  		Fig 6. . Relative body mass of all animals during the stimulation period. There was no evidence that the administration of an anabolic hormone led to any water or sodium retention.

 
Hemodynamic Measurements
The data reported here are based on the investigations performed in the 12 sheep of group II (second study). Table 1Go summarizes the hemodynamic situation before cross-clamping and starting fibrillation.


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  		Table 1. . Hemodynamic Situation in Groups IIA and IIB Before Cross-Clamping of Truncus and Start of Fibrillation
 
The values for ``hemodynamic work'' presented in the next paragraph refer to the performance of the LD under conditions of cardiac fibrillation, with isolated perfusion of the LD. The results were obtained from three successive contractions, in most cases at the beginning of the recording period.

Table 2Go summarizes the characteristics of hemodynamic work of the isolated perfused LD. The LDs of group IIA produced a pressure amplitude of 25.3 mm Hg (left ventricular pressure, 35.3/10 mm Hg), whereas the muscles of group IIB produced an increase of 36.2 mm Hg (left ventricular pressure, 49.7/13.5 mm Hg; p < 0.05). The left ventricular pressure amplitude of group IIA corresponded to an increase in the aortic pressure, averaging 14.4 mm Hg; in group IIB, the aortic pressure increased by 17.4 mm Hg (p = NS). The maximum rate of rise of left ventricular pressure was 682.6 ± 344.7 mm Hg/s for both groups. The pressure amplitude in the right ventricle and pulmonary artery did not differ significantly. Whereas the fractional fiber shortening for group IIA was calculated as 0.28 ± 0.03, it was significantly greater in group IIB (0.43 ± 0.05; p < 0.05). Analogously, the ejection fraction was 0.35 ± 0.074 in group IIA, as opposed to 0.44 ± 0.06 in group IIB, but the difference fell short of the threshold of statistical significance. It is clear, however, that much greater compression of the ventricles is produced by the stronger, anabolically treated LDs than by muscles subjected exclusively to electrostimulation (Fig 7Go). The stroke volume (determined echocardiographically) was 4.66 ± 0.7 mL in group IIA versus 8.1 ± 0.8 mL in group IIB (p < 0.05). The calculated mean values for the cardiac output (30 contractions/min; 0.5 second ``on'' and 1.5 second ``off'') were 127 ± 20.7 mL/min for group IIA as opposed to 244 ± 40.7 mL/min for group IIB (p < 0.05). Stroke work for the LD wrapped around the fibrillating heart was calculated as 0.18 ± 0.05 erg x 106 in group IIA and 0.43 ± 0.072 erg x 106 for group IIB (p < 0.05).


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  		Table 2. . Registered Variables of Hemodynamic Work of the Isolated Perfused Latissimus Dorsi Muscles of Groups IIA and IIB
 


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  		Fig 7. . Two-dimensional and M-mode echocardiography (short-axis view). The circumferential compression of both ventricles by the latissimus dorsi (LD) in the ``on'' mode of the myostimulator is clearly visible. (IVS = ; LV = left ventricle; MV = mitral valve; PW = ; RV = right ventricle.)

 

   Comment
Top
 Footnotes
 Abstract
 Introduction
 Study Protocol
 Material and Methods
 Results
 Comment
References
 
Since its clinical introduction by Carpentier and Chachques [2] in 1985, dynamic CMP has aroused considerable clinical interest, and is now in the clinical trial stage as an option for the surgical treatment of terminal cardiac insufficiency. The more rapid implementation of CMP as an alternative to heart transplantation is currently hindered by a number of experimental and clinical observations that have been made.

The process of fast-to-slow twitch transformation produced by chronic electrostimulation has been extensively described for skeletal muscle for various species [7–10]. The induced resistance to fatigue is accompanied, on the one hand, by a significant reduction in the force capacity. On the other hand, a loss of mass has been observed in the chronically stimulated muscle due to the conversion of fibers to type I. Dynamic CMP leads to a measurable increase in the left ventricular ejection fraction, but this increase is not correlated with the patient's clinical improvement [11]. Apparently the wrapped muscle has a synergistically acting and verifiable ``squeezing'' effect on ventricular performance. There can be no doubt that the regional wall mobility of the insufficient heart is measurably greater during the LD contraction cycle [5]. However, it has also been observed that the contraction amplitude of the left ventricular posterior wall is greater in the ``off'' mode of the cardiomyostimulator than it is preoperatively (R. Lange, oral communication). This may mean that the lessening in the wall tension of the insufficient, dilated heart is brought about by the presence of the wrapped muscle. According to Laplace's law, this should lead to a reduction in myocardial oxygen consumption. Whether a thick muscle could have a higher compliance and might even cause the early diastolic filling time to be prolonged has not, to our knowledge, been demonstrated clearly. Further long-term animal studies will be required to provide evidence of this.

Apparently it was the general nonacceptance of anabolic steroids by the medical profession that led to the rejection of the data from such studies. However, in light of the findings yielded by investigations into anabolic side effects carried out at the former East German Research Institute for Physical Culture and Sport in Leipzig, we have concluded that side effects can be expected to occur primarily in the growing organism, as a function of dosage levels and length of treatment. In any case, side effects occasionally seen in connection with the long-term uptake of anabolic steroids are always completely reversible, at least as far as 17ß estered steroids (such as metenolone) are concerned. However, there is little evidence that the long-term oral uptake of 17{alpha} acylated substances over months or years could precipitate peliosis hepatis and, very rarely, liver carcinoma. So far, there is no single case described in which 17ß estered testosterone derivatives are suspected of inducing serious side effects, either in the liver or in any other tissue [12]. Of course, the use of any kind of anabolic steroid is strongly proscribed in children and in patients with breast cancer.

Given the average age and life expectancy of patients for whom CMP is a clinical option, the dangers of anabolic side effects would appear to lose much of their (in most cases overestimated) significance. In fact, in our investigations we found no evidence of either systemic (eg, water and sodium retention) or hepatocellular changes, such as might have been a feared result of anabolic steroid administration.

The influence of chronic stimulation and anabolic steroids was previously studied in the LD of dogs by Hohenhaus and associates [13]. In contrast to our findings, they found an almost complete fiber transformation in both the anabolically treated and nontreated stimulated LDs. They stated that anabolic steroids have no additional effects on the changes in muscle properties after chronic stimulation. The discrepancies between our results and those of Hohenhaus and colleagues are explained by the fact that the influence of anabolic steroids as well as chronic stimulation is highly species and muscle specific [14, 15]. One should therefore be cautious about extrapolating data obtained in one species to another, or to human beings. Furthermore, the stimulation patterns used in this study (see Material and Methods) are completely different from those used by Hohenhaus' group. They used a tonic stimulation pattern of 2 Hz administered continuously, whereas we used a more phasic pattern, with short, high-frequency pulse trains, as is the generally accepted practice in clinical studies. In particular, the changes in the muscle properties after chronic stimulation depend on both the overall amount of stimuli and the stimulation pattern [14]. We therefore assume that the pattern of activity used in our study was insufficient to induce complete fiber transition in sheep within a time span of 12 weeks, but sufficient to do so in combination with anabolic steroids.

In group IA, the loss of maximal force was significant; it was less marked in group IB, and, under maximal stimulation (10.5 V), the left LDs actually displayed a higher force development than did the contralateral muscles. The large standard deviation in group IB was certainly not caused by different drug administration (dosage or duration). Obviously the animals responded in a highly individual fashion to the steroid. In a further study (paper submitted for publication), in which we were primarily concerned with measuring the time course of the morphologic changes in muscle tissue, the morphometric data were in the same range and the standard deviation was smaller in a more homogenic animal material.

The maximal force capacity of the contralateral, unstimulated muscles remained unchanged in both group IA and group IB. This means that anabolic steroids per se do not appear to have any protein-synthesizing or ``training'' effect on the unstimulated LD in terms of a force increase. However, the use of anabolic steroids antagonized the loss of force capacity in the course of the transformation process. No differences in the maximal force capacity per 100 g of muscle tissue occurred in our study. In other words, the increase in the contractile potential must be due solely to the mass increase in the conditioned muscles of group IB. The protein-anabolic effect was not observable in the absence of chronic stimulation (contralateral muscles). The chief effect of the anabolic steroids consisted of an increased synthesis of structural and functional proteins. Apparently the steroids also have a synergistic effect on the extent and the completeness of the transformation process. We are currently preparing a detailed histologic analysis of the muscle tissue. However, the whole findings are too extensive to be presented in this paper.

Salmons and associates [15] were able to demonstrate a clear myotrophic effect of an anabolic steroid (nandrolone decanoate) in the tibialis anterior muscles of rabbits. After 12 weeks, the muscles of the treated animals showed highly significant increases in wet weight (38%), twitch tension (66%), maximum isometric tension (48%), maximum cross-sectional area (27%), and specific tension (17%). The experiments provided clear physiologic and morphologic evidence of a steroid-induced hypertrophy that was not attributable to fluid retention or changes in body weight.

In short, the findings described in the papers cited are in agreement with the findings from our two studies in recognizing an anabolic effect of anabolic steroids on chronically stimulated muscle tissue. Whereas Hohenhaus and Salmons and their colleagues were unsuccessful in their attempt to antagonize the loss of force capacity and muscle mass caused by the transformation process, we were able to demonstrate such an effect. Although the chronic discontinuous burst stimulation we used did not enable us to demonstrate a complete transformation, the loss of force capacity was significant. The administration of metenolone facilitated both an increase in the proportion of fatigue-resistant type I fibers to 97% and a complete antagonism of the loss of force capacity. This was achieved through a significant increase in muscle mass (amounting to 80%). Given a simultaneous increase in the number of fibers and a reduction in their transverse sectional area, this growth can be attributed to hyperplasia of the muscle, and we were in fact able to observe the formation of new muscle fibers from satellite cells.

In our study, the volume of blood transported per minute by the LD contraction (cardiac output) was of the order of 140 mL/min, as compared with a cardiac output of approximately 2.5 L/min under the initial conditions. Thus the LD, at 30 contractions/min, transported 5.6% of the physiologic cardiac output in the sheep. Let us assume that the resistance in the circulatory system under consideration has not altered since the commencement of fibrillation, and is thus of the order of the measured value of 600 dyn x s/cm5. Given the equation


(1)

(where PAP is the pulmonary artery pressure, PCWP is the pulmonary capillary wedge pressure, and CO is cardiac output) and constant resistance, the expected change in pressure ({Delta}P) cannot be greater than about 6%, and is thus at the threshold of statistical significance.

Nevertheless, the left ventricular pressure and aortic pressure in group IIB showed a significant increase due to the anabolically treated LD; the increase in the left ventricular pressure was significant even by comparison with the results for group IIA. By analogy with the remarks made previously, we may assume that the reason for our failure to demonstrate a significant pressure increase in the pulmonary circulation for group IIB stems from the much lower resistance of the pulmonary vascular bed.

As far as the other variables are concerned, we were able to demonstrate a significant increase by comparison with the conditions of circulatory standstill. The additional improvement in stroke volume, cardiac output, stroke work, and fractional fiber shortening due to the anabolically treated LDs of group IIB was statistically significant. The ejection fraction in group IIB was increased from 0.28 (group IIA) to 0.44, but, with the given standard deviation and the relatively small number of cases, this result failed to exceed the threshold of significance (p = 0.462).

These findings suggest that the effect of systolic augmentation plays an important role in relation to CMP, and that it is worthwhile trying to increase this effect by improving the skeletal muscle force capacity. The complex way in which CMP works has not yet been fully explained. To what extent information may be provided by recent studies investigating CMP pressure--volume loops or by dynamic three-dimensional magnetic resonance imaging reconstruction of the assisted and unassisted kinetics of the heart after CMP remains an open question.

Acker and associates [16] in their studies calculated a stroke work of 0.4 erg x 106 for double-wrapped mock circulation devices. Hammond and colleagues [17] measured an average value of 0.2 erg x 106 for skeletal muscle ventricles with a filling volume of 45 mL. Mannion and co-workers [18, 19] wrapped 45-mL bladders with a conditioned canine LD and connected these to a vertical tube filled with water. In this configuration, at a contraction rate of 45 contractions/min, the muscle pumped 260 mL, which corresponded to 13% of the cardiac output of the dogs studied.

Taking into account the geometric characteristics of the pump system concerned in each case, our results for the stroke work of conditioned LDs are identical to those reported by other authors. Of particular importance is the finding that the anabolically treated muscles of group IIB produced a doubling of the stroke work within the same system. This result does more than merely underline the effectiveness of dynamic CMP that can be expected. When applied to studies currently being conducted in the United States and elsewhere aimed at designing a suitable skeletal muscle ventricle, our finding suggests that, even in a configuration in the systemic circulatory system, a lasting significant increase in the contribution of the skeletal muscle ventricle to the total circulation can be expected. This idea appears to us to be of some importance, for several reasons. First, the hemodynamic benefit conferred by the skeletal muscle ventricle has in principle already been demonstrated in animal experiments. Second, improved design has led to thromboembolism-free survival times of more than 20 months among the animal subjects, and, third, clinical trials are increasingly becoming the subjects of discussion. This suggests that an improvement in the hemodynamic effectiveness of the skeletal muscle ventricle through the administration of anabolic steroids should be attempted in those cases in which alterations in design and geometric characteristics lead to no further increase in the performance of the skeletal muscle ventricle.

The ventricular wall tension is directly proportional to the chamber diameter and inversely proportional to the wall thickness (Laplace's law). In principle, therefore, CMP could contribute to an improvement in the hemodynamic situation by reducing preload, decreasing the end-diastolic ventricular diameter, and increasing wall thickness.

Cho and associates [20] were able to demonstrate that ventricular contraction subsequent to an assisted heartbeat commences with a significantly lower preload. Lee and colleagues [21] were also able to demonstrate that CMP produces a significant 16% reduction in the left ventricular end-diastolic pressure in the dilated heart (chronic high-frequency stimulation). Although the skeletal muscle assistance of ventricular contraction caused an increase in both pressure and the time--force curve of the left ventricle, the mean wall tension was significantly lower as a result of the reduction in ventricular diameter. This group of authors observed a 13% reduction in myocardial wall tension and a 60% increase in circumferential fiber shortening. These observations suggest that CMP can help in overcoming the abnormal functional and mechanical conditions that characterize the dilated heart. This may be the factor responsible for the longer life expectancy reported by Moreira and associates [13] for patients with dilated cardiomyopathy who undergo CMP, as compared with patients receiving only conservative therapy.

The third variable in Laplace's law is the wall thickness: an increase leads to a decrease in wall tension. After approximately 2 to 3 weeks, however, the pouch of skeletal muscle becomes firmly attached to the ventricular epicardium through the formation of fibrous adhesions, and, from a physiologic and mechanical point of view, these can be considered to be in continuity with the ventricular wall. Thus, it is highly probable that the wrapping of the heart brings about a purely passive reduction in the wall tension of the (dilated) chambers. This effect could be expected to be important precisely in the setting of dilated cardiomyopathy.

We believe that, in connection with the explanations given here, the demonstrated enormous increase in muscle mass due to the administration of anabolic steroids suggests the likelihood of further hemodynamic improvement after CMP. The results achieved-the antagonizing of the loss of force and mass while full resistance to fatigue is maintained-are highly desirable in the context of dynamic CMP, as both a strengthening of the systolic augmentation and a significant reduction in wall tension can be expected. In our hemodynamic studies, we were able to demonstrate a significant improvement in the key variables of the circulation system whenever we used an LD treated with anabolic steroids, as opposed to LDs that were only chronically electrostimulated. Ongoing experiments with phosphorus 31--nuclear magnetic resonance spectroscopy, using a chronic animal model, are required to provide evidence for this hypothesis. We hope to be able to demonstrate that LDs benefit from the application of anabolic steroids even under the conditions prevailing when the muscle is permanently wrapped.


   Footnotes
Top
 Footnotes
Abstract
 Introduction
 Study Protocol
 Material and Methods
 Results
 Comment
 References
 
Address reprint requests to Dr Fritzsche, Clinic for Cardiovascular Surgery, University Leipzig, Russenstr 19, 04289 Leipzig, Germany.


   References
Top
 Footnotes
 Abstract
 Introduction
 Study Protocol
 Material and Methods
 Results
 Comment
 References
 

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  8. Goldspink DF, Easton J, Winterburn SK, Williams PE, Goldspink GE. The role of passive stretch and repetitive electrical stimulation in preventing skeletal muscle atrophy while reprogramming gene expression. J Cardiac Surg 1991;6(Suppl 1):218–25.
  9. Pattison CW, Cumming DVE, Clayton Jones DE, Goldspink G, Dunn MJ, Yacoub MH. Variable adaption of molecular mechanisms in relation to the use of autologous striated muscle to augment myocardial function. Cardiovasc Res 1989;23:593–600.[Medline]
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  20. Cho PW, Levin HR, Curtis WE, et al. Pressure-volume analysis of changes in cardiac function in chronic cardiomyoplasty. Ann Thorac Surg 1993;56:38–45.[Abstract]
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