Ann Thorac Surg 2000;70:1291-1295
© 2000 The Society of Thoracic Surgeons
Original articles: cardiovascular
Dynamic cardiomyoplasty in a growing organism
Bernhard Voss, MDa,
Matthias Thielmann, MDa,
Mohamed El-Mehsena,
Philipp Albert Schnabel, MDa,
Siegfried Hagl, MDa,
Rüdiger Lange, MDa
a Department of Cardiac Surgery, Deutsches Herzzentrum Munich, Munich, and Departments of Cardiac Surgery and Pathology, University Hospital Heidelberg, Heidelberg, Germany
Address reprint requests to Dr Voss, Deutsches Herzzentrum Munich, Lazarettstr 36, 80636 Munich, Germany
e-mail: voss{at}dhm.nhn.de
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Abstract
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Background. Until now cardiomyoplasty has been a treatment option for adults only. However, there may be a demand for cardiomyoplasty in children. The purpose of this study was to investigate the possibility of applying the method of cardiomyoplasty before growth is completed.
Methods. The latissimus dorsi muscle (LD) was wrapped around the heart of 20 Göttinger Minipigs (9.1 ± 1.2 kg body weight). The LD was fixed to the pericardium in group 1 (n = 11) and to the epimyocardium in group 2 (n = 9) and stimulated with burst impulses. After 5.6 ± 1.8 months hemodynamic and histologic follow-up-examinations were carried out in 13 surviving animals (weight 32.4 ± 5.3 kg).
Results. In group 1 (n = 6) only the left ventricle was covered by the LD. In 4 animals the LD contracted strongly; in 2, the outer border of the muscle was atrophied. In group 2 (n = 7) both ventricles were covered by the LD in all animals and showed strong contractions. In 2 animals the outer border of the muscle was atrophied. In both groups the contracting parts of the LD showed an intact muscle structure, but compared with the contralateral LD, there was a higher percentage of interstitial fat and connective tissue. Hemodynamic measurements and the well-being of the animals suggest that restriction of cardiac chamber diameter did not occur. The electrical stimulation of the LD caused a minimal increase of left ventricular pressure and aortic peak flow in group 2.
Conclusions. Cardiomyoplasty can be applied in a growing organism. There is growth of the LD with the heart. The muscle structure remains intact. To prevent dislocation of the LD, it seems to be important to fix the LD directly onto the epimyocardium.
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Introduction
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For now, heart transplantation is the only treatment option for children with end-stage dilated cardiomyopathy [1]. Heart transplantation in the pediatric patient becomes increasingly successful in terms of survival, however, the procedure is limited by the lack of donor organs [2]. Moreover, morbidity due to infection and rejection is still present. In the first year after transplant, 45.1% and in the second year, 31.6%, of the children require nonroutine rehospitalization [3]. Furthermore, the life expectancy of transplanted children is limited owing to transplant vasculopathy [4]. Therefore, alternative methods are needed for the treatment of end-stage heart disease in children. One possibility could be dynamic cardiomyoplasty (CMP). So far this procedure has been used only in adult patients and its potential application in children is unknown. Therefore, in an experimental animal study we investigated the following questions: Is it technically possible to perform dynamic CMP on a small animal? Does the skeletal muscle grow after transposition on the heart? How does chronic stimulation influence muscle structure? Is the growing heart impaired by the muscle wrap?
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Material and methods
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The experimental part of this study was carried out at the University of Heidelberg.
Cardiomyoplasty operation
Twenty young Göttinger Minipigs (age 3.9 ± 0.3 months, weight 9.2 ± 1 kg) were used. All animals received humane care in compliance with the "Guide for the Care and Use of Laboratory Animals" published by the National Institutes of Health (National Institutes of Health publication 85-23, revised 1985).
General anesthesia was induced using intravenous ketamine (2 mg/kg body weight) and maintained with propofol (0.1 mg · kg-1 · min-1) and ketamine (0.03 mg · kg-1 · min-1). Each pig was placed in the right lateral position. Under sterile conditions the left LD was dissected, taking care to preserve the thoracodorsal neurovascular bundle. Two perimysial electrodes (Medtronic Model 4753, Medtronic, Inc, Minneapolis, MN) were secured above the nerve (Fig 1). The thorax was opened by dissection of the second rib and the muscle translocated into the thorax. Another thoracotomy was performed between the fourth and fifth ribs and the pericardium was opened.
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Fig 1. (A) Epimysial lead. (B) Preparation of the left m. latissimus dorsi and epimysial lead placement.
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With the heart slightly moved from the pericardial sac, 5 stitches in the area of the atrioventricular groove were placed on the pericardium in group 1 and directly on the epicardium in group 2 for attachment to the muscle. The LD was wrapped around the heart in a clockwise fashion begins at the pulmonary artery to the inferior vena cava, so that the spinal rim of the muscle was fixed to the posterior wall of the left ventricle (LV). A myocardial sensing electrode was attached to the LV. The cardiomyostimulator (Medtronic Model 4710) was placed under the neck muscle and the electrodes were connected, having been tunneled under the scapula. The surplus cable was coiled in reverse for further growth. After drains were put in place, the wound was closed in layers. The drains were removed on the first postoperative day.
Postoperative growth phase
The skeletal muscle was stimulated with progressively longer bursts in accordance with the standard operation procedure (Table 1). The burst stimulation was synchronized with every second heart beat. The amplitude for muscle stimulation was chosen for each animal in such a way that a powerful contraction was palpated at the entrance of the LD into the thorax. The weight of the animals was checked every week. The aim was to increase the body weight by three to four times.
Final examination
After the expected weight was achieved, a final, acute experiment was performed. The anesthetic was delivered by intravenous propofol (0.1 mg · kg-1 · min-1) and ketamine (0.04 mg · kg-1 · min-1). Micro-Tip catheters (Millar Instruments Inc, Houston, TX) for blood pressure monitoring were introduced in the LV, the aorta ascendens, and the vena cava superior. The chest was opened by a median sternotomy. After the dissection of adhesions an electromagnetic flow probe was placed around the aorta ascendens. Heart rate, aortic pressure, LV pressure, central venous pressure, dp/dt, and aortic flow were monitored simultaneously on a multichannel printer. The hemodynamic measurements were started 10 minutes after the chest was closed. The LD was stimulated with every third heartbeat.
For statistical comparisons, the mean values of 5 supported and 5 unsupported heart beats during a 15-second period were entered into the Student’s t test. After these measurements had been obtained, the thorax was reopened and the heart-skeletal muscle complex was exposed to assess the contraction of the LD in all areas.
For further histologic examination, biopsies (0.5 x 0.5 cm) of the middle part of the LD were taken. The samples were fixated by immersion of 8%-formalin solution. Paraffin slides of 4 µm were prepared and stained with hematoxylin and eosin. These were viewed light microscopically with 25- to 1,000-magnification for qualitative and quantitative results. The percentage volume of myocyts, fat, and connective tissue was morphometrically assessed with the help of an integration lattice [5]. As control samples, we used muscle sections from the middle of the contralateral LD, which were assessed in the same manner. At the end of the examination the heart-skeletal muscle complex was completely removed. The coronary arteries and the a. thoracodorsalis were flushed with dextran solution containing 0.1% procain, then glutaraldehyde 3% solution was injected for preservation. From this, cross-sectional slides were made.
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Results
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Technical feasibility of cardiomyoplasty
In 15 animals the operation was performed without complications (group 1, n = 8; group 2, n = 7). Five animals (group 1, n = 3; group 2, n = 2) died during the operation because of irreversible ventricular fibrillation during luxation of the heart. This complication occurred during the first experiments. In the later experiments the heart was moved with utmost care and ventricular fibrillation did not occur any more. Furthermore, it became obvious that the standard intramuscular electrodes were too large to be implanted without damaging the muscular vessels and nerves. Therefore, perimysial leads were applied, stitched onto the surface of the muscle near the nerve (Fig 1).
Growth phase
In group 1 a pig had to be killed prematurely owing to a wound infection with abscess. Another pig developed ascites and was also killed prematurely. Postmortem examination revealed that this animal had an atrophy of the wrapped muscle so that the right ventricular diastolic wall motion was disturbed. The other animals showed normal growth development. The extra-anatomical use of the LD caused no visible physical disability.
At the beginning of muscle stimulation in group 1, 2.1 ± 1.4 V were required for strong contractions of the muscle and had to be increased to 4.2 ± 1.5 V by the end of the experiment. In group 2 stimulation energy was increased from 2.1 ± 0.3 V to 3.1 ± 0.69 V.
Final experiment
Group 1, muscle fixation to the pericardium
After 7.6 ± 0.4 months, 6 pigs had achieved a weight of 37.0 ± 1.5 kg. In the anesthetized animals the aortic pressure did not change upon muscle stimulation (Table 2). In all animals the LD, which originally covered both ventricles, was dislocated in such a way that only the left ventricle was covered. In 4 animals the LD contracted well in all areas. In 2 animals only the apex of the muscle contracted.
Group 2, muscle fixation on the epicardium
After 4 ± 0.4 months, 7 animals achieved a weight of 28 ± 2.8 kg. The hemodynamic values without stimulation did not differ from those of group 1. The stimulation of the skeletal muscle caused a minimal increase of left ventricular pressure and peak aortic flow (Table 3). In all animals both ventricles were covered by the muscle. Five muscles were contracting in all areas, whereas two only contracted around the apex. Figure 2 shows an excised heart skeletal muscle complex.
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Fig 2. Heart-skeletal muscle complex (group 2). The left ventricle with the overlying m. latissimus dorsi is exposed by a longitudinal incision.
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Histology
The light microscopic examination of the contracting muscle sections showed an intact muscle structure. In comparison with the contralateral right LD, the left LD that was wrapped around the heart displayed a higher percentage of fat and connective tissue (Table 4, Fig 3, and Fig 4). The cross-sectional slides (Fig 5) revealed that the wrapped LD becomes thinner at the periphery. Between the epicardium and the skeletal muscle, a layer of fat and connective tissue was found. New blood vessels between the heart and the skeletal muscle were not seen.
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Fig 4. Histologic section of the left m. latissimus dorsi used for cardiomyoplasty (x 40). In comparison with the normal muscle (see Fig 3), the amount of fatty and fibrous tissue is increased.
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Fig 5. Cross-section through an entire heart-skeletal muscle complex of group 2. (LV = left ventricle, A = atrium.)
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Comment
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Cardiomyoplasty was first described in 1985 by Carpentier and Chachques [6] as a surgical method for the treatment of end-stage heart failure. The procedure may be applied to patients with ischemic or dilated cardiomyopathy who present with contraindications for heart transplantation [7]. Up until now this method has only been used on adults.
From 1982 until 1997, 2,758 patients under the age of 16 had heart transplantation [8]. Especially in the age group from 6 to 15 years (n = 1,190) the indication for transplantation was predominantly for cardiomyopathy (62.0%) and not for congenital diseases (28.1%). The 3-year survival after transplantation in children of this age group was 71%. However, the application of heart transplantation to children is limited owing to the lack of suitable donor organs. A multicenter study (21 centers) [9] emphasizes this problem: From 264 children (aged 3 days to 17.9 years, average age 4.7 years) who were listed for heart transplantation in 1993, only 60% had been transplanted after 6 months, 14% were still waiting for a transplantation, and 23% died while waiting. The complications after successful heart transplantation can be representatively shown by the long-term experience at Stanford University [10]: Between 1977 and 1993 heart transplantation was performed on 73 patients less than 18 years old (average age 9.0 ± 6.4 years; indications were congenital heart disease 33%, cardiomyopathy 64%). The mean follow-up was 3.9 years. After 5 years only 3.2% ± 3% had had no rejection and 20% ± 7.3% no infection. Angiography exhibited coronary sclerosis after 10 years in 21% ± 8.5%. Neoplasm developed in 5 children (6.9%); and 29 children died from infection (28%), rejection (24%), coronary sclerosis (17%), pulmonary hypertension (14%), or other reasons (17%).
Because of the morbidity caused by immunosuppressive agents and long-term unsatisfactory survival rates after heart transplantation, it seemed reasonable to look for other treatment options for children with end-stage heart failure. In this respect CMP does not exclude a later heart transplantation [11] and may be applied as a bridge for transplantation.
The question of growth of the transposed LD was first addressed in a animal model by Brady and colleagues [12]. In 8 pigs (weight 18 to 22 kg) the right LD was fixed to the right ventricle. In 4 animals the muscle was stimulated by single impulses; in the other 4, the LD was not stimulated. After 10 to 14 weeks the animals doubled their body mass. Follow-up examinations showed that the skeletal muscle had grown in proportion to the increase of the size of the right ventricle. However, the design of this study was different from the conditions of clinically applied CMP. Firstly, there was a lower pressure on the LD, because it was attached only to the right ventricle and not to the left ventricle. Secondly, single pulse stimulation was used, causing a shorter-lasting contraction with a considerably lower demand on the muscle than is caused by burst stimulation, which causes a tetaniform muscle contraction.
Further studies to address CMP in a growing organism were all conducted with unstimulated muscles. In young rats (aged 6 weeks) Van Dorn and coworkers [13] performed either CMP or a mock operation (only LD mobilization and thoracotomy). After 20 weeks there was no significant difference between the two groups concerning body weight and heart size. Misara and colleagues [14] showed in an experimental study on dogs that the diastolic function of the growing heart was not impaired by a wrapped skeletal muscle.
In the present investigation CMP was carried out according to the same technical principles as in the clinical setting [15]. The size of the animals was comparable with that of children at the age of 1 year. Owing to the smaller anatomy, the operation was technically more demanding and had to be altered in respect to some technical aspects. The clinically applied intramuscular stimulation leads could not be implanted in the small skeletal muscles. With the application of epimysial electrodes we found a suitable alternative that yields a safe muscle stimulation during the observation period. By using extra long cables during growth, traction on the electrodes was avoided.
The final examination of the 13 surviving animals showed normal hemodynamics without any signs of impairment of the heart by the skeletal myoplasty. Although the LD contracted strongly in all animals, only in group 2 did the muscle stimulation cause a minimal enhancement of LV pressure and peak aortic flow. However, because the experiment was performed on healthy pig hearts no hemodynamic improvement was expected. From previous studies of cardiomyoplasty it is known that the effect of a chronically stimulated muscle on the performance of a noninsufficient heart is only minimal [16, 17].
The results of group 1 experiments revealed that the clinically used attachment of the LD on the pericardium [15] is not a safe fixation on the heart during the period of growth. Only the direct attachment on the epicardium, as done in group 2, could prevent the slipping of the muscle from the small, still-sphere-shaped hearts.
The histologic examination showed intact myocytes, except in 4 animals where atrophic muscle areas were observed. However, in comparison to the contralateral, nonstimulated LD the amount of connective tissue was significantly increased. On the basis of previous studies in animals [18] and in patients [19] these findings are typical for chronically stimulated skeletal muscles that were used for cardiomyoplasty. This finding might be an expression of muscular damage. The reason could be a lack of blood supply because of dissection of the collateral vessels during muscle preparation. Also an increased transmural pressure of the skeletal muscle under the conditions of CMP could decrease muscle perfusion. On the other hand, the muscle oxygen demand increases with the beginning of muscle stimulation [20]. Moreover, the dissection of the LD from its attachments causes a loss of tension, which can not be reproduced when the muscle is wrapped around the heart. This is associated with a higher occurrence of atrophy [21].
The present study shows that CMP can be performed in a small animal. The skeletal muscle grows with the heart. The fixation of the LD directly on the epicardium is important to prevent the dislocation of the muscle. The muscle structure of the LD used in CMP remains intact under growing conditions; however, the relative amounts of connective and fat tissue increase. The muscle wrapping causes no impairment of the growing heart.
The results encourage further examination of potential applications of skeletal muscle support in children. For instance, in another animal experiment it was shown that the pulmonary flow could be increased by a right atrial skeletal muscle plasty after a right heart bypass procedure [22].
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References
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Accepted for publication March 28, 2000.
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Abstract
Introduction
