As originally published in 1992: Skeletal muscle ventricles in the pulmonary circulation: up to 16 weeks' experience. Updated in 1998.
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Animals↗
Biomedical subjects
A D Spanta
Publications and source records attributed to A D Spanta.
Aqueous oxygen: a highly O2-supersaturated infusate for regional correction of hypoxemia and production of hyperoxemia.
BACKGROUND: High levels of hyperoxemia may have utility in the treatment of regional tissue ischemia, but current methods for its implementation are impractical. A catheter-based method for infusion of O2, dissolved in a crystalloid solution at extremely high concentrations, ie, 1 to 3 mL O2/g (aqueous oxygen [AO]), into blood without bubble nucleation was recently developed for the potential hyperoxemic treatment of regional tissue ischemia. METHODS AND RESULTS: To test the hypotheses that hypoxemia is correctable and that hyperoxemia can be produced locally by AO infusion, normal saline equilibrated with O2 at 3 MPa (30 bar; 1 mL O2/g) was delivered into arterial blood in two different animal models. In 15 New Zealand White rabbits with systemic hypoxemia, AO was infused into the midabdominal aorta at 1 g/min. Mean distal arterial PO2 increased to 236+/-113 and 593+/-114 mm Hg on 1-hour periods of air and O2 breathing, respectively, from a baseline of 70+/-10 mm Hg (P<.01). In contrast, infusion of ordinary normal saline in a control group (n=7) had no effect on arterial PO2. No differences between groups (P>.05) in temporal changes in blood counts and chemistries were identified. In 10 dogs, low coronary blood flow in the circumflex artery was delivered with a roller pump through the central channel of an occluding balloon catheter. Hypoxemic, normoxemic, and AO-induced hyperoxemic blood perfusates (mean PO2, 52+/-4, 111+/-22, and 504+/-72 mm Hg, respectively) were infused for 3-minute periods in a randomized sequence. Short-axis two-dimensional echocardiography demonstrated a significant decrease (P<.05) in left ventricular ejection fraction compared with baseline physiological values with low-flow hypoxemic and normoxemic perfusion but not with low-flow hyperoxemic perfusion. CONCLUSIONS: Intra-arterial AO infusion was effective in these models for regional correction of hypoxemia and production of hyperoxemia.
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Skeletal muscle ventricles, left ventricular apex-to-aorta configuration. 1 to 11 weeks in circulation.
BACKGROUND: Skeletal muscle ventricles (SMVs) have been used in animals in a variety of configurations to provide circulatory assistance. Long-term survival and function have been demonstrated. Our laboratory recently obtained promising short-term hemodynamic data in a left ventricular apex-to-aorta model. METHODS AND RESULTS: SMVs were constructed from the left latissimus dorsi muscle in five adult mongrel dogs. After a 3-week period of vascular delay and 5 to 7 weeks of electrical conditioning, valved conduits were used to connect the left ventricular apex to the SMV and the SMV to the descending aorta. The SMV was then stimulated to contract during cardiac diastole. Initial measurements showed a significant increase in the mean femoral diastolic pressure (62 +/- 6 versus 51 +/- 5 mm Hg, P < .05). There was also a decrease in the left ventricular tension-time index (11.5 +/- 2.5 versus 14.6 +/- 2.1 mm Hg.s, P < .05), indicating a decrease in the work requirement of the left ventricle. During SMV stimulation, the majority of flow (65%) was through the SMV circuit and was associated with reversal of flow in the proximal descending thoracic aorta. The longest-surviving animal survived 76 days, at which time pressure augmentation was still seen (mean femoral diastolic pressure, 63 +/- 0.9 versus 50 +/- 1.2 mm Hg, P < .05). CONCLUSIONS: Survival beyond the acute setting is possible with this model. Diastolic pressure augmentation can be effectively maintained over time.
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Endothelial lined skeletal muscle ventricles: open and percutaneous seeding techniques.
Twelve bilateral skeletal muscle ventricles (SMVs) were constructed in six dogs by wrapping each latissimus dorsi muscle around a cylindrical, plastic mandrel (volume 30 cc). After 6 to 10 weeks, five dogs had one of their SMVs seeded with allogeneic cultured canine endothelial cells (8 x 10(6) cells/pouch) via an open technique, whil the contralateral SMV was seeded by percutaneous injection of cells into the space around the mandrel. After 1 week, the SMVs were excised. Viable, adherent endothelial cells were present in all seeded pouches; this was confirmed via fluorescent microscopy with several endothelial cell markers; KLH-2, dilacetylated low-density lipoprotein and antibodies to von Willebrand factor. The inner lining of the SMVs were also examined with scanning and transmission electron microscopy; the highest concentration of cells were seen at the apex where a continuous endothelial monolayer was observed. No significant difference in the distribution or the morphology of the endothelial lining was noted between the open and percutaneous seeding techniques. These data show that SMVs can be seeded with an endothelial monolayer using both open and percutaneous techniques.
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Chronic morphologic changes of skeletal muscle ventricles in circulation.
Skeletal muscle ventricles (SMVs) were constructed either extrathoracically or intrathoracically in 44 dogs using the left latissimus dorsi muscle. These SMVs functioned as aortic counterpulsators for from several hours to 216 days. In this study, the relationship between the morphologic changes in the SMVs and their time course in the circulation was evaluated retrospectively. The average volume of the SMV chamber after it had been excised and fixed in formalin was 21.3 +/- 11.0 mL (mean +/- the standard deviation) for extrathoracic SMVs and 20.0 +/- 7.5 mL for intrathoracic SMVs. The volume of the SMV chamber did not correlate with the time course in the circulation. The SMV wall was mainly composed of three components: muscular, fibrous, and fatty aspects. The overall thickness of the wall appeared to be preserved over time in the circulation. However, the thickness of the muscular component tended to decrease over time. SMV rupture occurred in 15 dogs between postoperative days 4 and 39. All ruptures occurred at the suture line between the SMV and the vascular conduits. There was some degree of thrombus in 24 SMVs. Before SMVs can be applied clinically for the purpose of cardiac assist, problems with rupture and thrombus formation must be solved. A better understanding of the morphologic changes that take place in the SMV over time also is needed.
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Skeletal muscle ventricles with efferent valved homograft.
Skeletal muscle ventricles (SMVs) were constructed from the latissimus dorsi muscle in seven beagles. Following 3 weeks of vascular delay and 6 weeks of electrical conditioning, the SMVs were connected in series with the thoracic aorta using a valved aortic homograft for the efferent limb. The SMVs were stimulated to contract synchronously during diastole. Effective aortic diastolic counterpulsation was achieved in all dogs, with an average 24.2% +/- 15.3% improvement in diastolic pressure. In two animals surviving beyond 3 months, increase in SMV function was noted over time. Appropriate aortic homograft valve function was documented by echocardiogram. Acute reversible heart failure was induced with propranolol in one dog alive after 126 days. A 61.3% reduction in cardiac output and a 37.6% reduction in mean arterial blood pressure were achieved. During profound low cardiac output, SMV stimulation with 33 Hz and 50 Hz improved cardiac output by 16.9% and 17.8%, improved the tension time index by 14.9% and 16.1%, and improved the endocardial viability ratio by 34.1% and 34.1%, respectively. These results again demonstrate the long-term effectiveness of SMVs as aortic counterpulsators. A valve in the efferent limb of the SMV system functions appropriately over time and may improve the efficiency of the system.
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Update on skeletal muscle ventricles as aortic diastolic counterpulsators.
Skeletal muscle ventricles are constructed from canine latissimus dorsi muscle. These skeletal muscle ventricles can be placed subcutaneously on the chest wall or inside the chest cavity. Skeletal muscle ventricles are connected to the descending thoracic aorta and activated to pump blood as aortic diastolic counterpulsators. The skeletal muscle ventricle in 1 animal pumped blood in the circulation for 27 months. Skeletal muscle ventricles can also function effectively under the condition of low cardiac output. Although thrombus has been detected in some skeletal muscle ventricles, thromboembolism to distal organs has been detected only rarely during the past few years. This research appears promising; however, skeletal muscle ventricle rupture remains a problem and currently accounts for about 30% of the mortality in the long-term experiments. It occurs at the site between the skeletal muscle ventricle outlet and the Dacron sewing ring that is necessary to connect conduits from the skeletal muscle ventricle to the animal's circulation. We believe that skeletal muscle ventricle rupture is likely to be a solvable problem. Once a solution has been found, skeletal muscle ventricles may be ready for clinical use in patients with chronic congestive heart failure.
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Skeletal muscle ventricles with improved thromboresistance: 28 weeks in circulation.
Skeletal muscle ventricles (SMVs) were constructed from the left latissimus dorsi in 22 mongrel dogs. The configuration of these SMVs was different from those previously reported. The animals were divided into two groups: group A (n = 11) SMVs rested for 10 weeks after construction; group B (n = 11) SMVs rested for 18 weeks. At the end of the delay period, SMVs were tested in vivo with a mock circulation device. The SMVs in group B developed stroke work greater than those in group A. After acute testing, SMVs (n = 12) were connected to the descending thoracic aorta and stimulated to contract during diastole. Aortic diastolic counterpulsation was achieved in all dogs, with 9 animals surviving from 1 to beyond 28 weeks. In all of the dogs surviving 1 week or more, the SMVs remained free of thrombus. Aspirin was used as the only antithrombotic agent. Skeletal muscle ventricles in this study were able to develop stroke work similar to that previously reported, intermediate between that of the right and left ventricular stroke work, with a significantly decreased incidence of thromboembolism.
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Skeletal muscle ventricles in the pulmonary circulation: up to 16 weeks' experience.
Skeletal muscle ventricles (SMVs) were constructed from the right latissimus dorsi muscle of 8 mongrel dogs. After a 3-week vascular delay period, each SMV was electrically preconditioned with 2-Hz continuous stimulation of the thoracodorsal nerve for 6 weeks. A porcine-valved conduit was then anastomosed between the right ventricle and the SMV, with a second valved conduit connecting the SMV to the main pulmonary artery. The pulmonary artery was then ligated proximal to the conduit. The SMVs were stimulated to contract in 1:2 diastolic mode with a 33-Hz burst frequency. Effective right ventricular assist was achieved in all dogs. Cardiac output increased by 22.6% (1,799 +/- 97 versus 1,467 +/- 84 mL/min; p less than 0.001), systemic systolic arterial pressure by 9.3% (90.1 +/- 3.5 versus 82.4 +/- 3.9 mm Hg; p less than 0.005), and peak pulmonary artery pressure by 31.8% (27.8 +/- 2.0 versus 21.1 +/- 1.7 mm Hg; p less than 0.001) at the initiation of this study. In 6 dogs, effective right heart assist was sustained for periods of between 1 week and 12 weeks. Two dogs survived for longer than 3 months, though with evidence of deteriorating SMV function. These results demonstrate the feasibility of providing sustained right ventricular assist using this modified "Rastelli-SMV" configuration, which obviates the limitations imposed by low right atrial preload.
Adaptation, Physiological↗
The long-term effect of jejunoileal autotransplantation on intestinal function.
Disturbed intestinal absorption has been demonstrated almost uniformly early after intestinal autotransplantation. Our aim was to study the long-term effects of autotransplantation on intestinal absorptive function. Studies of nutritional status and absorptive function were performed on groups of dogs at three intervals after autotransplantation: I (less than 6 months; n = 4), II (6 to 12 months; n = 4), and III (12 to 18 months; n = 4). At death samples of intestinal fluid were obtained for bacteriologic analysis, and studies of morphology and in vitro absorption were performed on intact and autotransplanted intestine. Similar studies were performed on a group of five control animals. Although body weight and serum albumin levels remained stable in dogs that had undergone autotransplantation and initial diarrhea improved, stool moisture was persistently elevated and late defects in fat and D-xylose absorption developed (4.8% +/- 3.2% stool fat at 12 months vs 2.1% +/- 0.6% before surgery and 3.4 +/- 2.0 x 10(-2) mmol/L xylose/hr at 12 months vs 8.8 +/- 5.4 x 10(-2) mmol/L xylose/hr before surgery; p less than 0.05). In vitro glucose uptake and villus height were similar in autotransplanted and adjacent intact intestine at death. Compared with control animals, animals that had undergone autotransplantation demonstrated significant overgrowth of fecal flora in jejunum and ileum (14/18 segments greater than 10(5) bacteria vs 6/15 segments; p less than 0.05). Thus delayed defects in intestinal absorption of fat and D-xylose occurred more than 12 months after autotransplantation. Because intestinal structure and function of the autotransplanted intestine were similar to those of adjacent intact intestine, this malabsorption may be related to bacterial overgrowth or other in vivo factors.
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The effect of intestinal autotransplantation on serum diamine oxidase activity.
Circulating levels of diamine oxidase (DAO), a mucosal enzyme found primarily in the small intestine, have been shown to reflect intestinal mucosal damage in a variety of disease states. Our aim was to assess the usefulness of both basal and postheparin DAO activity as a marker of intestinal allograft rejection by studying the influence of the nonrejection effects of intestinal transplantation on these activities. This separation of the immunological from all other effects of transplantation was achieved by studying 11 dogs who had undergone autotransplantation of the small intestine and 11 unoperated controls. Basal serum DAO activity increased during the first 3 postoperative days following autotransplantation (20.5 +/- 0.7 units/ml on Day 3 versus 6.9 +/- 4.1 units/ml preoperatively, P less than 0.05) but thereafter returned to control levels at 1 month and remained so for more than 18 months. Postheparin DAO activity was similar in both groups with a maximum increase between 15 and 60 min following heparin administration. There was no correlation between maximal DAO activity and time since operation in the transplant group. Intestinal DAO activity was similar to unoperated animals 18 months after autotransplantation. These findings suggest that postheparin serum diamine oxidase activity is not influenced by autotransplantation and thus, is a potential marker of graft rejection following intestinal allotransplantation.
Amine Oxidase (Copper-Containing)↗
Skeletal muscle ventricles: update after 18 months in circulation.
Skeletal muscle ventricles (SMVs) have been constructed from canine latissimus dorsi muscle and connected to the aorta as aortic diastolic counterpulsators. Presently one dog remains alive and well with an SMV that has been functioning continuously in circulation for 18 months, without evidence of thromboembolic complications. SMVs are able to perform cardiac-type work with an output equal to that of the left ventricle at physiologic preloads, when tested with a mock circulation device in our laboratory. SMVs have been used for right-sided cardiac assist. In acute experiments these ventricles have functioned effectively, bypassing the right side of the heart for up to 8 h. Most recently we have tested SMVs using them chronically to pump blood in the right-sided circulation, and at the time of writing they have been shown to function effectively in this configuration for up to 18 days. SMVs may be used in the future as a method of treating patients with left- or right-sided heart failure.
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Autologous skeletal muscle, an alternative for cardiac assistance.
Original attempts to use skeletal muscle for cardiac assistance were soon abandoned when the problem of muscle fatigue could not be solved. In the last 2 decades, better understanding of muscle physiology and the development of successful protocols of electrical muscle conditioning have given new impetus to researchers around the world to proceed in the effort to identify useful applications of skeletal muscle to support the heart. More than 100 patients around the world have undergone cardiomyoplasty, mostly for cardiac failure. While subjective improvement in symptoms was noticed in the majority of the patients, only recently favorable hemodynamic changes have been documented. The other alternative that has been pursued in the laboratory is the construction of skeletal muscle ventricles that, after conditioning and vascular delay, have been shown to provide significant cardiac support when used for diastolic counterpulsation or for right heart bypass in animal models.
Cardiac Surgical Procedures↗
Canine latissimus dorsi cardio-double myoplasty: acute feasibility study.
Cardio-double myoplasty was performed in eight mongrel dogs. Both latissimus dorsi muscles were dissected from the chest wall and wrapped around the heart. They were then stimulated using an R wave synchronous stimulator. Hemodynamic measurements were obtained, first with the stimulator off and then with stimulator activated. After measuring hemodynamic effects in a normal heart, acute heart failure was induced by the infusion of propranolol (5 mg/kg). Hemodynamic data were then obtained in the same fashion. In a normal heart state, cardio-double myoplasty increased the cardiac output 9.9% +/- 2.24 (p less than 0.005), the left ventricular pressure 18.7% +/- 3.53 (p less than 0.001), the pulmonary artery pressure 72.2% +/- 25.4 (p less than 0.01), and the stroke volume 13.4% +/- 5.73 (p less than 0.05). In a failing heart, the cardiac output increased 21.6% +/- 3.34 (p less than 0.005), the left ventricular pressure increased 20.8% +/- 3.34 (p less than 0.005), the pulmonary artery pressure increased 87.2% +/- 39.9 (p less than 0.05), and the stroke volume increased 46.9% +/- 22.9 (p less than 0.05). The left ventricular end-diastolic pressure decreased slightly and the central venous pressure did not change in either the normal state or during cardiac failure. Cardio-double myoplasty resulted in a significant circulatory augmentation particularly in the setting of cardiac failure.
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Skeletal muscle ventricles: a promising treatment option for heart failure.
Our most recent work on cardiac assist with canine latissimus dorsi muscle in a skeletal muscle ventricle (SMV) configuration is reported here. One animal's SMV has been pumping blood effectively in the circulation for more than 16 months. To date there is no evidence of thromboembolism, and the dog has suffered no untoward effects. It has recently been shown, in a mock circulation study, that canine SMVs are capable of developing stroke work, at physiological preloads, much greater than that of the right ventricle and equivalent to that of the left ventricle. The improved ability of conditioned SMVs to perform work, independent of the circulation, during severe hypotension is also demonstrated. In the face of a 75% drop in left ventricular stroke work, the SMV stroke work dropped by only 50%. The continuing work on this subject suggests that a skeletal muscle ventricle may have the potential of becoming a viable alternative in the treatment of heart failure.
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Autogenously lined skeletal muscle ventricles in circulation. Up to nine months' experience.
Skeletal muscle ventricles were constructed in fifteen dogs. After a delay period of 4 weeks the skeletal muscle ventricles were connected to the descending thoracic aorta with a polytetrafluoroethylene bifurcation graft (Gore-Tex bifurcation graft, W.L. Gore & Associates, Inc., Elkton, Md.). The aorta was ligated between the two limbs of the graft so that there was obligatory blood flow through the skeletal muscle ventricle. Nine skeletal muscle ventricles were lined with autogenously derived tissue, either pleura or pericardium, whereas six had no specific lining other than an induced fibrous reaction. The skeletal muscle ventricles were activated to contract during cardiac diastole. Aortic diastolic counterpulsation was achieved in all dogs, with ten surviving from 1 week to beyond 9 months. Thrombus eventually developed in all but three of the skeletal muscle ventricles, but no dog had clinical evidence of thromboemboli. The three thrombus-free skeletal muscle ventricles were lined with pleura, including the animal surviving beyond 9 months. These results indicate that canine skeletal muscle can provide aortic diastolic counterpulsation for 9 months without clinically apparent thromboembolic complications.
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Long-term effects of jejunoileal autotransplantation on myoelectrical activity in canine small intestine.
We studied the longitudinal effects of autotransplantation on the motor function of the jejunoileum. By performing the autotransplantation procedure in a manner similar to that employed for allotransplantation, we sought to examine the long-term effects of both extrinsic denervation and the operative procedure itself on small intestinal motor function. Although initially disrupted, interdigestive myoelectrical activity demonstrated progressive organization: 88% of migrating myoelectrical complexes in animals studied between 12 and 20 months following autotransplantation demonstrated each phase of the complex in normal sequence. Longitudinal studies of several parameters of myoelectrical activity provided further evidence of progressive organization and entrainment of motor functions within the denervated intestine. Several abnormal myoelectrical patterns were observed within the autotransplanted segment, however, and coordination of either slow wave or phase III activity with the proximal innervated intestine did not recover with time. The major component of the myoelectrical response to feeding was permanently impaired with a delayed onset and shortened duration of the fed response. We conclude that the extrinsically denervated intestine recovers the ability to generate and organize all phases of the MMC but demonstrates permanent impairment of the major motor response to food. However, anoxic and cooling damage to enteric nerves and muscle, incurred during the autotransplantation procedure, may explain the persistence of abnormal motor patterns and impaired myoelectrical conduction and could play an important role, additional to that of extrinsic denervation, in the long-term motor function of the allotransplanted intestine.
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The effect of mesenteric venous hypertension on gut motility and absorption.
The effects of portal hypertension on gut function may be mediated by venous congestion and altered circulating levels of enteric hormones and neuropeptides. We designed this study to determine the effects of chronic intestinal venous hypertension (VHT), in isolation, on gut motility and absorption. In 10 dogs, a 20- to 25-cm loop of jejunum was isolated from the fecal stream, but myoneural continuity was maintained with the proximal bowel by a seromuscular bridge. In 5 dogs, VHT was created in the loop by a fixed stenosis of its venous drainage; a sham procedure was performed in a further 5 animals. Serosal monopolar electrodes were placed in all animals. Absorptive function and myoelectrical activity were studied over a 4-week period. Venous hypertension was achieved and sustained in the VHT animals; loop vein pressures for VHT vs control in cm H2O (means +/- SEM) are: initial--29.8 +/- 1.8 vs 7.5 +/- 0.4 (P less than 0.01), and at 4 weeks--17.6 +/- 6.88 vs 7.3 +/- 0.2 (P less than 0.01). Absorption of Na+, Cl-, glucose, and water was impaired in VHT loops. Normal patterns of fasting and postprandial myoelectrical activity were preserved in the VHT animals. We conclude that chronic VHT, in the absence of portosystemic shunting, results in impaired absorption of water, glucose, and electrolytes without any change in intestinal motility.
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