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Ann Thorac Surg 2000;70:1281-1289
© 2000 The Society of Thoracic Surgeons
a Division of Cardiothoracic Surgery, Department of Surgery, Wayne State University, Detroit, Michigan, USA
b Department of Human Anatomy and Cell Biology, University of Liverpool, Liverpool, United Kingdom
Address reprint requests to Dr Stephenson, Division of Cardiothoracic Surgery, Wayne State University, Suite 2102 Harper Professional Building, 3990 John R St, Detroit, MI 48201
Presented at the Thirty-sixth Annual Meeting of The Society of Thoracic Surgeons, Fort Lauderdale, FL, Jan 31–Feb 2, 2000.
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Abstract |
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 TopFootnotes Abstract IntroductionMaterial and methodsResultsCommentAcknowledgmentsReferences |
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Methods. In 10 dogs, SMVs were constructed from the latissimus dorsi muscle, lined internally with pericardium, and conditioned by electrical stimulation to induce fatigue resistant properties. The SMVs were connected to the descending thoracic aorta via two 12-mm Gore-Tex conduits and the aorta was ligated between the two grafts. The SMV was stimulated to contract during the diastolic phase of alternate cardiac cycles. The animals were monitored at regular intervals.
Results. At initial hemodynamic assessment, SMV contraction augmented mean diastolic blood pressure by 24.6% (from 61 ± 7 to 76 ± 9 mm Hg). Presystolic pressure was reduced by 15% (from 60 ± 8 to 51 ± 7 mm Hg) after an assisted beat. Four animals died early, 1 from a presumed arrhythmia, and 3 during propranolol-induced hypotension. The other 6 animals survived for 273, 596, 672, 779, 969, 1,081, and 1,510 days. Diastolic augmentation was 27.4% at 1 year (93 ± 9 vs 73 ± 6 mm Hg; n = 5), 34.7% at 2 years (85 ± 6 vs 63 ± 7 mm Hg; n = 3), 21.2% (89 ± 10 vs 73 ± 8 mm Hg; n = 2) at 3 years, and 34.5% (78 vs 58 mm Hg; n = 1) after 4 years in circulation. After 4 years, the isolated SMV was able to maintain a pressure of over 80 mm Hg while ejecting fluid at 20 mL/s. No animal showed evidence of SMV rupture or thromboembolism.
Conclusions. The SMVs in this study provided effective and stable hemodynamic assistance over an extended period of time. There was no evidence that the working pattern imposed on the muscular wall of the SMV compromized its viability. Areas of fibrofatty degeneration were suggestive of early damage that future protocols should seek to minimize.
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Introduction |
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TopFootnotesAbstractIntroductionMaterial and methodsResultsCommentAcknowledgmentsReferences |
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Over the last 15 years, we have been seeking to establish a surgical approach to chronic cardiac assistance based on the use of muscular pumping chambers, which we call skeletal muscle ventricles (SMVs). These SMVs have been connected to the circulation in a variety of ways to provide both left and right ventricular assistance [7–10]. The configuration with which we have had the most long-term success is one in which the SMV is connected via a bifurcated graft to the descending thoracic aorta; the SMV then functions as an aortic diastolic counterpulsator, in a manner somewhat analogous to the intraaortic balloon pump. In 1994, we reported on 10 animals that had pericardium-lined SMVs placed in circulation with this configuration [11]. Here, we report hemodynamic data on this cohort of animals followed up to 4 years, together with a more detailed functional and histological assessment of the SMV that pumped chronically in circulation for 4 years.
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Material and methods |
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TopFootnotesAbstractIntroductionMaterial and methodsResultsCommentAcknowledgmentsReferences |
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The parietal pericardium was harvested between the two phrenic nerves via an eighth interspace thoracotomy. The visceral surface of this pericardium was applied to a polypropylene mandrel with the approximate shape of a truncated cone, having a base of 30 mm diameter, a height of 65 mm, and a volume of 25 mL (approximately 2.5 mL/kg body weight). The base of the mandrel was lined with a 5-mm ring of Dacron felt (USCI, Billerica, MA) and the pericardium was sewn to this ring with 6-0 polypropylene suture so that the entire surface of the mandrel was covered with pericardium. At this stage, a 16-mm ultrasonic flow probe (Transonic Systems, Inc, Ithaca, NY) was placed around the main pulmonary artery to record total cardiac output. The end of the flow probe was placed under the skin in the dorsal subcutaneous tissue.
The thoracolumbar fascia of the latissimus dorsi muscle graft was then attached to the Dacron sewing ring at the base of the mandrel so that the muscle was wrapped around the mandrel 2 to 2.5 times. Layers of the SMV were sewn to each other with absorbable suture, and the SMV was left in a subcutaneous position near the left axilla. The nerve lead was connected to a pulse generator (Itrel model 7421; Medtronic, Inc) that was placed beneath the left rectus abdominis muscle. Stimulation was switched on briefly to confirm that the system was functioning; the stimulator was then programmed to the "off" state and the incision closed in layers with absorbable suture.
Conditioning
The animals were allowed to recover for 3 weeks, the so-called vascular delay, to allow for some development of a collateral blood supply. After this, the stimulator was programmed to deliver continuous indirect stimulation to the SMV at a frequency of 2 Hz, with a duration of 210 µs and an amplitude of 1.0 to 2.0 V. This was continued for a 6-week period to induce transformation of the muscle to a uniform population of slow twitch, fatigue-resistant (type I) fibers, as described previously [12].
Connection to the circulation
After 9 weeks (3 weeks’ vascular delay plus 6 weeks’ conditioning), the animals were again anesthetized. The mandrel was removed from the SMV, and the inner pericardial lining inspected. The left chest was opened through a fifth interspace thoracotomy. Two 12-mm, ringed Gore-Tex conduits (W.L. Gore and Associates, Flagstaff, AZ) were anastomosed to the descending aorta in an end-to-side fashion. The two conduits were sutured to circular openings in a conically shaped base cap, which was connected to the base of the SMV via the Dacron felt ring. Figure 1 shows a schematic drawing of the SMV connected to the circulation.
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The thoracic aorta was ligated between the two conduits to direct blood flow through the SMV. With the SMVs contracting, the conduits were deaired and the clamps were removed, placing the SMV in circulation.
Hemodynamic data collection and analysis
Hemodynamic data were recorded initially at the time of connection to the circulation, again after 2 to 4 weeks in circulation, and subsequently at 2- to 3-month intervals. At the time of connection to the circulation, pressures in the femoral artery, the carotid artery, and the SMV were recorded with a fluid-filled column connected to a pressure transducer (Spectramed, Oxnard, CA). Pressures in the aortic arch and the left ventricle were measured with 5F microtransducer-tipped catheters (Millar Instruments, Inc, Houston, TX). Cardiac output was derived from the ultrasonic flow probe (Transonic Systems, Inc) that had been placed around the pulmonary artery. The data were collected with a Gould ES 1000B recording and display system (Gould Instruments, Inc, Cleveland, OH). Data were also sampled digitally with a real-time data acquisition system (AT-CODAS; Dataq Instruments, Inc, Akron, OH) at a 200-Hz sampling rate and stored on a computer. Stored data were analyzed offline with a data analysis software program (Windaq; Dataq Instruments, Inc).
Subsequent hemodynamic recordings were made with percutaneously placed, fluid-filled catheters in the femoral and carotid arteries, as long as these arteries remained patent. The flow probe was accessed subcutaneously to record cardiac output. In 9 of the animals, SMV function was assessed under hypotensive, low-cardiac output conditions induced by infusion of propranolol.
Hemodynamic data are expressed as mean ± standard deviation. Statistical significance was accepted at p value less than 0.05, determined by repeated-measures analysis of variance calculated with a statistical software package (INSTAT; Graphical Software, San Diego, CA).
Measurements on the isolated skeletal muscle ventricle
One dog was the subject of a more detailed terminal assessment, conducted electively after the SMV had been pumping in circulation for over 4 years. After the hemodynamic measurements in circulation, made as already described, the proximal and distal conduits connecting the SMV to the aorta were clamped. The femoral arterial pressure trace indicated that there was adequate distal perfusion, the result of a partial recanalization of the ligated section of aorta between the conduits. The SMV was detached by cutting the conduits, and its base was sewn to a silicone rubber connecting piece that was connected to a computer-controlled servo-pump. The neuromuscular stimulating electrodes were disconnected from the implantable cardiomyostimulator and connected to an external stimulator. The stimulator and the servo-pump were controlled by the same computer. Pressure monitored within the SMV cavity was fed back to the controller. The SMV and servo-pump were filled with a degassed saline solution, and care was taken to remove any air bubbles. The SMV was compressed manually and the corresponding position of the pump, representing zero volume of the SMV, was noted. The volume of the SMV could subsequently be determined from the position of the piston within the servo-pump. The characteristics of the SMV as an independent hydraulic pump were then determined by stimulating the muscle at a series of fixed volumes corresponding to a predetermined range of preload pressures and then at a series of flow rates imposed by the programmed movement of the piston within the servo-pump. The hydraulic performance of the SMV from the 4-year dog was compared with similar measurements taken from a SMV constructed acutely in a sheep after 6 weeks of conditioning its latissimus dorsi muscle.
Histology, histochemistry, and immunocytochemistry
At the end of the experiment, the SMV was removed from the animal that had survived for 4 years, and samples were taken for histological, histochemical, and immunocytochemical analysis. Samples were taken at three levels (proximal, middle, and distal, where proximal means nearest to the basal, or open end of the SMV) and at four cardinal points (designated north, south, east, west, looking at the basal end, where south was nearest the chest and north nearest the skin). In addition, samples were taken from the pedicle, that is to say, the unwrapped portion of the muscle used to construct the SMV. Nine biopsies were taken from the contralateral latissimus dorsi muscle. Three samples were taken across the muscle at each of three levels (proximal, middle, distal, where proximal was nearest to the narrow, humeral insertion). Each sample was mounted on a cork disc, which was marked to indicate the orientation and then placed in melting isopentane above liquid nitrogen. The frozen specimen was wrapped in cooled aluminum foil and maintained below -77°C, pending use.
Cryostat sections of 10-µm thickness were stained by the regressive hematoxylin and eosin method for general morphological assessment, by the hematoxylin-van Gieson method to demonstrate connective tissue structures, and histochemically for the demonstration of succinic dehydrogenase, and for myofibrillar ATPase with acid and alkali preincubation. Serial sections were reacted with monoclonal antibodies specific for the heavy chains of fast, slow and neonatal myosin, which were visualized by a peroxidase technique [13].
Sections were viewed by transmitted light in a Leitz Diaplan microscope equipped with a Vario Orthomat 2 camera system (Leica UK, Milton Keynes, UK) and photographed on Kodak Ektachrome 160T film for color transparencies or Ilford Pan F for black-and-white negatives.
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Results |
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TopFootnotesAbstractIntroductionMaterial and methodsResultsCommentAcknowledgmentsReferences |
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Relaxation of the SMV produced a significant decrease in arterial pressure immediately preceding the next left ventricular ejection (presystolic pressure). The magnitude of the presystolic pressure drop ranged from 11% to 32% of control values for stimulation at 33 Hz. There was a modest reduction, of 1% to 11% of control values, in the peak systolic pressure generated by the left ventricle during the cycle after SMV relaxation.
In 1 dog, the SMV functioned effectively for over 4 years in circulation. In this animal, diastolic augmentation at 4 years was 34.5% at 33 Hz (39% at 50 Hz). In the cycle after SMV contraction, presystolic pressure was reduced by 32% at 33 Hz (48% at 50 Hz). Figure 2 shows pressure tracings obtained during hemodynamic measurements on this animal at various time points. The hemodynamic performance of this animal over time is compared with the rest of the group in Figure 3.
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In each animal, the SMV was examined echocardiographically for signs of thrombus formation inside the SMV at the time that the hemodynamic measurements were performed. No evidence of thrombus was seen in any of the serial echocardiographs.
Post mortem examination
Each of the animals in this study underwent a complete autopsy at the time of its death. This included examination of the SMV, the heart and lungs, the abdominal organs, including the kidneys, and also the spinal cord. No animal showed evidence of distal embolization to any of the organs or spinal cord. The inner linings of the SMVs were smooth and showed no sign of thrombus formation. In the dogs that died early, a separate lining could be identified, although it was adherent to the SMV wall. In the longer term dogs, the pericardium could not be identified as a discrete structure.
Histological, histochemical, and immunocytochemical findings
The SMV that had pumped in circulation for over 4 years had, like the others, been placed in the subcutaneous tissue between the skin and the chest wall of the dog. One reason for taking samples of the SMV wall from four cardinal points at three levels was to ascertain whether this subcutaneous placement had resulted in pressure necrosis. The histological condition of the muscle wall varied greatly. The best preserved muscle was indistinguishable morphologically from control tissue, even in terms of fiber size and the thickness of interfascicular septa (Fig 6A). This was the appearance found at the locations identified as proximal west and south, middle north and east, and distal south and east (see Material and Methods for sampling scheme). In the least well-preserved samples, muscle tissue had been replaced largely or entirely by fibrous and fatty connective tissue; this was the nature of the wall at distal north and west. Other sites had an intermediate appearance (Fig 6B). There appeared to be no systematic trend in these observations; in particular, the deep and superficial sampling sites (south and north, respectively) appeared to be no less viable than the more lateral (west and east) sites. We assume that the damage observed was related primarily to the need to fold and to suture the muscle during surgical configuration as a ventricle, rendering some areas more vulnerable to ischemia. This would be consistent with the results of a previous study, in which we evaluated 44 SMVs after various times in circulation; we noted then that most of the fibrotic changes occurred in the first 3 weeks and that the muscle condition subsequently remained stable [14].
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Because of the heterogeneous condition of the muscular wall, it was not possible, without having systematically sampled the whole SMV, to estimate what fraction of the SMV wall consisted of healthy muscle tissue. The functional status of the wall is reflected more appropriately in the ability of the SMV to develop pressure in circulation (Figs 2, 3, 4A) and to eject fluid under standardized conditions (Fig 5).
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Comment |
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TopFootnotesAbstractIntroductionMaterial and methodsResultsCommentAcknowledgmentsReferences |
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In the present study, the procedures for constructing the SMVs incorporated a number of modifications designed to reduce the risk of these two complications. It was felt that the use of pericardium to line the blood-contacting surface of the SMV would help to decrease the risk of thrombus development in the SMV, and it may also have contributed to protection against SMV rupture. Stress at the muscle/sewing ring interface was reduced by including a wide strip of thoracolumbar fascia in the SMV-sewing ring anastomosis and by using a conical base cap.
The success of these measures may be judged by the fact that of the 10 animals in the present series, none suffered SMV rupture or embolic complications. Two dogs were terminated electively. With one exception (a presumed arrhythmia), death in all the other animals was a direct or indirect consequence of hemodynamic monitoring or pharmacological intervention, procedures that were necessary to the experimental evaluation of the SMVs but were unrelated to the normal functioning of the SMV.
At the time of connecting the SMVs in circulation, we undertook and reported an extensive evaluation of the hemodynamic effects of SMV contraction on left ventricular function [11]. Performance parameters derived from those measurements included end-systolic elastance, preload recruitable stroke work, and endocardial viability ratio, and illustrated the ability of the SMV to share the workload, and to improve the efficiency, of the native left ventricle. We would have liked to record the same hemodynamic data throughout the study, but this proved impossible because cannulating repeatedly for retrograde placement of a left ventricular micromanometer resulted in carotid occlusions that denied us further access to the left ventricle. However, arterial pressure tracings recorded at 2- to 3-month intervals for up to 4 years were essentially stable (see Fig 2), so it is likely that the influence of SMV contraction on left ventricular mechanics was similarly maintained.
A unique feature of our terminal evaluation of the SMV that pumped for over 4 years was the data collected after isolating the ventricle from the circulation and connecting it to a servo-controlled hydraulic apparatus. By stimulating the SMV to pump under these closely controlled conditions, we could examine its ability to eject fluid against different pressures. It was encouraging to find that the data collected in this way agreed closely with data that we had obtained from similar SMVs constructed acutely in the sheep. This agreement is suggestive of underlying relationships that are, to some extent at least, independent of the animal model and time in circulation. By extension, they suggest that these animal experiments would be of some predictive value if extrapolated to clinical application in humans.
In this experiment, SMVs were used to assist the normal heart. To examine the potential for providing assistance during heart failure, 9 dogs in the study were assessed acutely for 1 hour under low-output conditions induced by propranolol infusion. The SMVs continued to provide diastolic augmentation and afterload reduction during this simulation of profound heart failure [11]. These results are not necessarily indicative of the performance to be expected in long-standing heart failure, but it is equally possible that SMVs would function even more effectively in more clinically relevant situations, where the level of heart failure tends to be less extreme and more gradual in onset.
Histological examination of the wall of the SMV that pumped in circulation for more than 4 years revealed a very heterogeneous appearance, with excellent preservation of muscle tissue in some areas and conversion to fibrofatty tissue in others. The results of a previous study [14] would suggest that the degenerative changes had occurred at an early stage after configuration and connection of the SMV in circulation. Certainly, there was no evidence of ongoing degenerative/regenerative changes at the time of examination. The fact that some of the muscle was of completely normal appearance, even after functioning for this length of time, confirms that the working conditions were sustainable. Earlier observations [18] showed that stimulation causes damage only when combined with other factors, such as ischemia and reduced resting tension, that compromise the ability of the muscle to meet the metabolic challenge. Recent work [19–21] indicates that a moderate regime of electrical stimulation delivered before surgical mobilization could significantly enhance blood flow to the distal part of the latissimus dorsi muscle graft, and may therefore be a route to achieving improved viability of the muscle when it is mobilized and configured as a ventricle.
Parallel work, completed since the present study was initiated, suggests that changes in the patterns for stimulation and activation of the SMV could contribute further to the success of the procedure. Conditioning of the muscles in these experiments followed an established protocol that induces a full fast-to-slow fiber type transformation. Recently, we have shown that a stable fast-fatigue resistant state, similar to that of naturally occurring type 2A fibers, can be induced and maintained by stimulation patterns that deliver fewer impulses to the muscle [13, 22, 23]. Such a state would confer the advantages of better preservation of mass, force-generating capacity, contractile speed, and power [24], and some authors are already advocating this approach in the context of cardiomyoplasty [25].
In terms of the chronic application of the SMV approach, we have had the most experience, and best long-term success, with SMVs connected in an aorto-aortic configuration, as in the present study, with stimulation timed to provide diastolic counterpulsation. This is not, however, the only possible configuration, and we have also investigated an approach in which the SMV is connected between the left ventricular apex and the aorta [9, 26]. Our results suggest that the reduction in left ventricular stroke work available in this configuration is greater than for the aorto-aortic connection, although there is a higher risk of thromboembolism originating within either the SMV or the valved conduits. Other configurations currently under investigation elsewhere have a SMV placed directly in series [27] or in parallel with the aorta [28].
Useful diastolic augmentation may also be obtained by wrapping the latissimus muscle around the aorta. This procedure, known as aortomyoplasty, has been performed clinically in about 30 cases [29]. Aortomyoplasty has the advantage that it does not expose blood to a new interface. However, cardiac assist is constrained by the existing geometry of the aorta to a small stroke volume. In the descending aorta, this can be enlarged only by sacrificing arterial branches to the spinal cord, with the associated risk of paraplegia. In addition, the small diameter of the descending aorta results in a wall tension that fails to load the skeletal muscle wrap adequately. The muscle cannot then operate under the conditions required for optimum power. From a hydraulic point of view, the ascending aorta has a better geometry, but the presence of great vessels requires splitting the latissimus dorsi flap, and the short available length can be compensated only by creating an artificial aneurysm. The SMV, on the other hand, is not limited by existing structures, and its geometry can be optimized to produce maximum pumping power, resulting in significant flow as well as pressure augmentation.
In summary, we have shown that SMVs can provide effective cardiac assistance for periods up to and exceeding 4 years. Improvements in the procedure have resulted in a low incidence of complications related directly to the SMV. After pumping blood continuously in circulation for over 4 years in the longest surviving animal, SMV contraction was still augmenting diastolic pressure by 34.5%, and reducing peak systolic pressure by 10% and presystolic pressure by 32%. Areas of fibrofatty degeneration were found in the muscular wall of this SMV, but the stability of its hemodynamic performance over time suggests that such damage occurred early, probably as an immediate consequence of mobilizing and configuring the muscle as a ventricle. This view is supported by the fact that there was no immunocytochemical evidence of ongoing degenerative/regenerative events. It follows that skeletal muscle pumps can sustain this working level for very prolonged periods. Further refinement of the protocol for mobilizing, conditioning, and configuring the grafted muscle should result in a more uniformly viable muscular wall and improvements in pumping performance. There is every indication from this study that the eventual transfer of this technique to provide long-term cardiac assistance in a clinical setting is an achievable target. Currently, we are focusing experimental efforts towards documenting SMV performance for this and other circulatory configurations in models of chronic left ventricular failure as a necessary step before clinical application.
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TopFootnotesAbstractIntroductionMaterial and methodsResultsCommentAcknowledgmentsReferences |
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