Heterotopic Position Research Articles

Urothelium Patterns Bladder Smooth Muscle Location

Smooth muscle differentiation is induced in the embryonic bladder by the centrally located urothelium in the undifferentiated mesenchyme in the periphery adjacent to the serosa. We hypothesize that under the appropriate signal the entire undifferentiated bladder mesenchyme is capable of smooth muscle differentiation and that the urothelium patterns fibromuscular development. Embryonic bladders of wild-type and Green Fluorescent Protein mice were separated into urothelial and mesenchymal components before smooth muscle differentiation (E12.5-E13). The urothelial layer green fluorescent protein was recombined and grafted with the mesenchyme (wild-type) in an orthotopic position, heterotopic position and ectopic position. In all cases, a zone of smooth muscle inhibition was observed adjacent to the epithelium whether the urothelium was in an orthotopic or heterotypic position. Bladder mesenchyme and bladder epithelium grafted alone did not grow. In conclusion, the full thickness of bladder mesenchyme is capable of smooth muscle differentiation dependent on the location of urothelium. These experiments support the hypothesis that urothelium secretes a diffusible factor that at high concentrations inhibits smooth muscle and at low concentrations induces smooth muscle, thus patterning mesenchymal cell differentiation across the full thickness of the fibromuscular bladder wall.

Abstract 1855: Transmural Myocardial Repair with Engineered Heart Tissue Grafts

Engineered Heart Tissue (EHT) can be utilized to partially repair infarcted myocardium in rats. Here, we investigated the feasibility of EHT-grafts as transmural wall replacement in a heterotopic transplantation model. Methods: EHTs (diameter: 15 mm, thickness: 1– 4 mm) were generated from 12.5 ×10 6 neonatal rat heart cells, collagen type I, and matrigel. Similarly, non-contractile constructs were generated from rat cardiac fibroblasts (FB) and mesenchymal stem cells (MSC). Grafts were surgically inserted into large transmural defects (diameter: 6 mm) in the left ventricle of explanted donor hearts. Subsequently, “treated” hearts were transplanted into weight-matched (308±12 g; n=14), immune suppressed (cyclosporine, azathioprine, prednisolone) Wistar rats in heterotopic position. All transmural defects were also covered with an aortic patch to prevent bleeding from the ventricles. Sham surgeries included aortic patch implantations only. Heterotopic hearts were harvested after 28 days and subjected to morphological analyses by confocal laser scanning microscopy (CLSM). Results: Heart transplant weight at the time of implantation was 1.1±0.02 g (n=14). Heterotopic heart weight increased substantially in Sham (2.4±0.3 g, n=3) and FB-graft (2.1±0.1 g, n=3) animals, whereas MSC- (1.7±0.2 g, n=4) and EHT-graft (1.3±0.1 g, n=4; p<0.05 vs. Sham) animals showed a smaller or no increase in weight, respectively. EHT grafts remained contractile throughout the observation period. CLSM revealed that EHT-grafts established oriented muscle bundles (actin and actinin staining) inside the transmural defects and were strongly vascularized (CD31 and smooth muscle actin staining; lectin labeling) leading to partial reconstitution of the myocardial continuity. This was not observed in animals with FB- and MSC-grafts. However, MSC-grafts, but not FB-grafts, contained newly formed vessels with a markedly larger diameter than observed in EHT-grafts (21±6 vs. 5±0.7 μm; p<0.05). Conclusion: EHTs can be utilized as myocardial tissue grafts to reconstruct and prevent pathological enlargement of the left ventricle. This study constitutes a first step to establish a novel transmural myocardial repair technology involving fully bioengineered heart muscle.

Rejection patterns in allogeneic uterus transplantation in the mouse

Transplantation of the uterus in the mouse has been developed as a model system for research towards human uterine transplantation. Previous studies in a mouse model have demonstrated that a syngeneic uterus transplant can give rise to normal offspring. The aim of this study was to characterize the time course of rejection in a fully allogeneic mouse uterus transplantation model. Uteri of BALB/c mice were transplanted to a heterotopic position in C57BL/6 recipients, whose native uteri were left in situ. The blood flow of the uteri, their gross appearance and general histology and the density of T-lymphocytes were examined on postoperative days 2-28. Macroscopic signs of rejection were apparent from day 5. At the light microscopy level, minimal inflammatory changes were seen from day 5 and massive inflammation was seen from day 10 to day 15. At day 28, necrosis and fibrosis were seen. The density of T-lymphocytes (CD3(+)) was increased in the grafted uterus from day 2 in the myometrium and from day 5 in the endometrium. Blood flow in the grafted uteri was reduced from day 15. A murine model to study rejection of allogeneic uterus transplants was characterized. Signs of rejection were seen from day 2 to day 5 and severe rejection was seen from day 10 to day 15. The data will be useful in future studies on immunosuppressants in this model.

Right Ventricular Outflow Tract Reconstruction With an Allograft Conduit in Non-Ross Patients: Risk Factors for Allograft Dysfunction and Failure

Allograft conduits (AC) are used for reconstruction of the right ventricular outflow tract (RVOT) in children with RVOT hypoplasia or atresia and for pulmonary valve replacement in children undergoing Ross aortic valve replacement (AVR). Children undergoing the Ross AVR are generally older and have their AC inserted in the orthotopic position as opposed to the heterotopic position used for most cases of complex RVOT obstruction. The orthotopic position of the AC combined with the fact that the AC in the Ross patients are larger and can be oversized are the three factors that increase the right ventricular-pulmonary artery (RV-PA) conduit durability in the Ross AVR group. A retrospective evaluation of our experience with use of AC in non-Ross patients for reconstruction of the RVOT was conducted to determine the risk factors for failure. Between January 1985 and December 2003, 117 non-Ross patients received AC (94 pulmonary and 23 aortic) for RVOT reconstruction. Median age at implantation was 8 months (mean 4.3 +/- 7.1 years; range, 6 days to 43 years). There were 57 children (49%) less than 12 months of age. Endpoints were AC failure (valve explant, balloon dilatation), and AC dysfunction (AC stenosis >40 mm Hg and AC insufficiency more than 2+). There were no device-related deaths. Overall patient survival was 80% at 15 years. Freedom from AC failure was 60% at 5 years and 43% at 15 years. Freedom from failure was worse in infants (42% and 34% at 5 and 15 years, respectively). Freedom from AC dysfunction was 40% at 5 years and 23% at 15 years. Freedom from dysfunction was worse in infants (21% and 16% at 5 and 15 years, respectively). Univariate analysis identified younger patient age, smaller AC size, diagnosis of truncus arteriosus, and the presence of aortic AC as risk factors for AC dysfunction and failure. Multivariate analysis identified smaller AC size and the presence truncus arteriosus as risk factors for AC dysfunction and failure. Right ventricular outflow tract reconstruction with an AC in non-Ross patients has poor performance at midterm follow-up with AC dysfunction and failure of, respectively, 60% and 40% for the entire group and 79% and 58% in the infant group at 5 years. An alternate conduit for this application must be considered.

Cardiac xenotransplantation: Early success in the orthotopic position

A suggested threshold for clinical application of cardiac xenotransplantation is a median 90-day survival of the transgenic pig heart in the life-supporting orthotopic position in a nonhuman primate recipient. We have achieved consistent xenotransplant heart function in the heterotopic position for >90 days. This report is our initial experience in the orthotopic position.

Heterotopic Heart Transplantation: An Expanding Role in the Twenty-First Century?

Background Heterotopic heart transplantation was first performed in humans in 1974, the main advantage being the continuing function of the patient's native heart, in the event of life-threatening acute rejection. The effect of cyclosporine on acute rejection saw the heterotopic transplantation technique wane. Our unit revisited heterotopic transplantation in response to a growing number of waiting list patients with high pulmonary artery pressures. We also anticipated an increased cardiac allograft utilization, and improvement of our waiting list times. Methods We retrospectively analyzed 151 patients undergoing heart transplantation by our unit between August 1997 and September 2003. Twenty received allografts in the heterotopic position. This cohort was compared with the 131 contemporary orthotopic heart transplant recipients with respect to their outcomes. Results The indication for transplantation was ischemic cardiomyopathy in 14 (70%) of the heterotopic cohort and 47 (36%) of the orthotopic cohort ( p = 0.004), and dilated cardiomyopathy in 3 (15%) and 48 (37%) in the heterotopic and orthotopic groups, respectively ( p = 0.06). Heterotopic recipients were significantly older than orthotopic recipients, and they had higher pulmonary artery pressures. The heterotopic donors were also older and the ischemic times were longer. A subgroup analysis was made among those patients who had high pulmonary artery pressures as these groups were better matched. Major morbidity in the heterotopic heart transplantation group consisted of reversible allograft dysfunction in 4 patients, renal dysfunction requiring hemofiltration in 3 patients, profound myopathy in 4 patients, and cerebrovascular events in 2 patients. There were two early deaths in the heterotopic transplant group and eight in the orthotopic group ( p = 0.87). Kaplan-Meier survival analysis of survival was performed. Conclusions Heterotopic heart transplantation is a viable transplant option for selected high-risk heart transplant recipients in spite of somewhat poorer outcomes.

TRANSPLANTATION OF THE MOUSE UTERUS: REJECTION PATTERN SIMILAR TO OTHER ORGAN TRANSPLANTS.

P1225 Aims: We have previously, in a syngeneic mouse model, demonstrated that the transplanted uterus has the capacity of harbouring pregnancies to term and deliver offsprings, which will develop into normal adults. The aim of the present study was to characterize the development of rejection in an allogeneic mouse uterus transplantation model. Methods: Uterus of BalbC mice was surgically removed and transplanted into a heterotopic position by vascular anastomosis to C57BL/6 recipients, which had their native uterus preserved. The tissue blood flow measured by Laser Doppler Flowmetry, gross morphology and histology by light microscopy of the grafted uterus were examined and compared to the native uterus on postoperative day (POD) 2 (n=3), 5 (n=5), 10 (n=4), 15 (n=4) and 28 (n=3). Results: The blood flow in the transplanted uterus was reduced already on POD 2 compared to the native uterus and a progressive decrease in blood flow was seen over time. Macroscopic examination of the transplanted uteri on POD 2 demonstrated normal uterine size and colour, but after 5 days a slight oedema was seen. On POD 10 and 15 the grafts of most animals were oedematous and showed signs of necrosis. Two weeks later the transplanted uteri were totally necrotic. On POD 2 only slight inflammatory changes were seen, but three days later a marked increase in the number of inflammatory cells were observed. On POD 10 and 15 the grafts were heavily inflamed throughout the uterine wall and numerous lymphocytes were present in the glandular epithelium. Focal apoptosis was seen but no necrosis was evident. The blood vessels were congested and endarteritis was seen. Finally, by POD 28 no viable parenchyma was left in the grafts. Conclusions: The rejection pattern in this model of mouse uterus transplantation is similar to other transplanted solid organs. Progressive deterioration in microcirculation, a gradual increase in inflammatory cells and glandular inflammation culminated in fully established rejection by the end of the second week posttransplant. This model will be used for further studies of suitable immunosuppression in uterine transplantation.

A subcutaneous heterotopic limb transplantation model in the mouse for prolonged allograft survival.

A heterotopic position of a limb allograft is advantageous in the fragile mouse model to reduce mortality but is prone to autotomy. The purpose of this study was to describe a new heterotopic limb transplantation model in the mouse for prolonged allograft survival. Eleven lower hindlimbs were transplanted in a heterotopic subcutaneous position in the groin of the recipient animal with the donor skin inset as a skin paddle for monitoring. Seven transplants were syngeneic (Balb/c) and four were allogeneic (C57Bl/6 donor). The overall success rate (acute survival < 7 days) was 73% (8/11) and the mortality rate was 18% (2/11). Five of seven syngeneic transplants survived for 60 days and were harvested for histology. Recipients of successful allogeneic transplants (n = 3) received no immunosuppression and rejected their allografts between 8 and 11 days postoperatively. Mixed lymphocyte culture and flow cytometry demonstrated secondary immune responses by pre-sensitized animals, and histology showed lymphocytic infiltration and necrosis consistent with acute rejection.

The effects of early and delayed immunosuppression in experimental tracheal transplantation with omentopexy

Background/Purpose : Best results in experimental tracheal allotransplantation are obtained when metachronous revascularization by omentopexy and immunosuppression are used. Nevertheless, this method of revascularization implies in a 4-day period of ischemia to the graft. The aim of this study was to assess the influence of the 4-day period of ischemia on host sensitization as well as the effect of early or delayed immunosuppression on the outcome of the grafts. Methods : Thirty rabbits were submitted to tracheal allotransplantation and divided according to position of the graft (orthotopic or heterotopic transplants) and the initiation of immunosuppression (early or delayed). The quality of the revascularization was evaluated by the identification of Indian ink, perfused through the abdominal aorta, inside the submucosal vessels. The outcome of the grafts was evaluated by histological analysis according to a semiquantitative scale of alterations. Results : Grafts were better revascularized in heterotopic position. Grafts with late immunosuppression presented good outcome only when heterotopically positioned. No significant differences were observed in grafts placed heterotopically or orthotopically when immunosuppression was initiated early after the transplant. Conclusions : Transient ischemia produced by metachronous revascularization is not the single factor responsible for the histological alterations observed in tracheal allografts. These alterations probably also are produced by the activation of immune responses. This activation is more intense in more ischemic grafts, but can be suppressed by early administration of immunosuppression.

The right neuron at the wrong place: biology of heterotopic neurons in cortical neuronal migration disorders, with special reference to associated pathologies.

During the development of the neocortex, neurogenesis and neuronal differentiation occur in two separate locations. Thus neurons have to migrate through the future white matter. Arrested or excessive migration leads neurons to differentiate in a heterotopic position. Such neuronal migration disorders (NMDs) occur sporadically in normal development but are markedly increased as a consequence of genetic defects or after exposure to toxic drugs during the period of migration. Anatomofunctional studies in rodents with NMDs have revealed that heterotopic neurons form essentially normal afferent and efferent connections, which has been interpreted as evidence that the connection pattern of cortical neurons is specified prior to migration. In addition, recent data show that heterotopic neurons can be contacted by environmental, that is local, fibres that normally never innervate the neocortex. This dual connectivity leads heterotopias to form bridges between their environmental and original network. Such an abnormal pattern of connectivity could contribute to the pathophysiology of disorders associated with NMDs such as epilepsy.

Heterotopic Neurogenesis in a Rat with Cortical Heterotopia

Early cellular development was studied in the neocortex of the tish rat. This neurological mutant is seizure-prone and displays cortical heterotopia similar to those observed in certain epileptic patients. The present study demonstrates that a single cortical preplate is formed in a typical superficial position of the developing tish neocortex. In contrast, two cortical plates are formed: one in a normotopic position and a second in a heterotopic position in the intermediate zone. As the normotopic cortical plate is formed, it characteristically separates the subplate cells from the superficial Cajal-Retzius cells. In contrast, the heterotopic cortical plate is not intercalated between the preplate cells because of its deeper position in the developing cortex. Cellular proliferation occurs in two zones of the developing tish cortex. One proliferative zone is located in a typical position in the ventricular/subventricular zone. A second proliferative zone is located in a heterotopic position in the superficial intermediate zone, i.e., between the two cortical plates. This misplaced proliferative zone may contribute cells to both the normotopic and heterotopic cortical plates. Taken together, these findings indicate that misplaced cortical plate cells, but not preplate cells, comprise the heterotopia of the tish cortex. Heterotopic neurogenesis is an early developmental event that is initiated before the migration of most cortical plate cells. It is concluded that misplaced cellular proliferation, in addition to disturbed neuronal migration, can play a key role in the formation of large cortical heterotopia.

Neocortex in the hippocampus: an anatomical and functional study of CA1 heterotopias after prenatal treatment with methylazoxymethanol in rats.

Migration disorders cause neurons to differentiate in an abnormal heterotopic position. Although significant insights have been gained into the etiology of these disorders, very little is known about the anatomy of heterotopias. We have studied heterotopic masses arising in the hippocampal CA1 region after prenatal treatment with methylazoxymethanol (MAM) in rats. Heterotopic cells were phenotypically similar to neocortical supragranular neurons and exhibited the same temporal profile of migration and neurogenesis. However, they did not express molecules characteristic of CA1 neurons such as the limbic-associated membrane protein. Horseradish peroxidase injections in heterotopia demonstrated labeled fibers not only in the neocortex and white matter but also in the CA1 stratum radiatum and stratum lacunosum. To study the pathophysiological consequences of this connectivity, we compared the effects of neocortical and limbic seizures on the expression of Fos protein and on cell death in MAM animals. After metrazol-induced seizures, Fos-positive cells were present in CA1 heterotopias, the only hippocampal region to be activated with the neocortex. By contrast, kainic acid-induced seizures caused a prominent delayed cell death in limbic regions and in CA1 heterotopias. Together, these results suggest that neocortical heterotopias in the CA1 region are integrated in both the hippocampal and neocortical circuitry.

HETEROTOPIC INTESTINAL TRANSPLANTATION AGGRAVATES THE INSULT OF CHRONIC REJECTION1

Intestinal grafts are placed either heterotopically (out of continuity) or orthotopically (in continuity); the latter is believed to be advantageous, as intraluminal nutrients and intestinal secretions might modulate the intestinal immune status and possibly delay rejection. This study was designed to delineate the effects of heterotopic versus orthotopic allograft position on the morphology and function of intestinal smooth muscle in our rat model of chronic rejection. Syngeneic orthotopic grafts were evaluated to control for changes due to the transplantation process. Histochemistry of the graft's muscularis externa showed a significant thickening due to hyperplasia and hypertrophy, which was most pronounced in heterotopic grafts (control = 92+/-2.4 microm, syngeneic grafts = 140+/-6.7 microm, orthotopic allografts = 278+/-26.6 microm, heterotopic allografts = 456+/-50 microm). In terms of function, muscle strips from allografts only generated 23% of the total bethanechol-induced contractile force in vitro compared to unoperated controls and syngeneic grafts. The mean resting membrane potential of control and isograft muscle cells was -69 +/- 0.9 mV with a slow-wave amplitude of 20+/-0.5 mV. Chronic rejection hyperpolarized the resting membrane potential of orthotopic allografts (-66 +/- 0.5 mV) and even more so of heterotopic allografts (-58 +/- 3.4 mV). Slow-wave amplitudes were decreased in orthotopic (14+/-0.9 mV) and nearly abolished in heterotopic allografts (2+/-1.2 mV). Our data indicate that allografts in heterotopic position are most susceptible to the insult of chronic rejection exemplified by increased proliferative and hypertrophic transformation of intestinal smooth muscle and a marked decrease in mechanical and electrical activity.

Development of the striatal projection from embryonic neurons from the lateral or medial frontal cortex grafted homo- or heterotopically into the medial frontal cortex of newborn rats

The present study was designed to further investigate the effects of intrinsic or extrinsic influences on the development of the efferent connectivity of frontal neocortical neurons. The lateral or medial parts of the frontal neocortex of embryonic (E) day 16 fetuses were grafted into homo- (medial-to-medial) or heterotopic (lateral-to-medial) position in the medial part of the left frontal cortex of newborn hosts. Three to four months after grafting, a retrograde neurotracer was injected into the dorsomedial or ventrolateral quadrant of the left caudate-putamen (CPU). The ensuing retrograde labeling in the transplants was then compared to that found in an equivalent cortical area in control animals. Medial-to-medial transplants developed a striatal projection whose mediolateral organization conforms to that of the projection arising from the medial part of the intact frontal cortex. The mediolateral distribution of the projection arising from lateral-to-medial transplants was not fundamentally different from that originating from medial-to-medial transplants, a finding which stands in marked contrast with what was found recently [7]with medial-to-lateral transplants. These results indicate that inside the frontal cortex, different subregions are not totally interchangeable, at least in terms of development of efferent connectivity.

Editorial: Cardiac transplantation for auxiliary circulatory support

In this issue, Khaghani and associates report their experience with heterotopic cardiac transplantation in infants and children. This study is a welcome addition to the literature from the group at Harefield, which has assembled an extensive experience with this procedure. The concept of using the transplanted heart as an auxiliary pump was introduced in 1964.1Reemtsma K The heart as a test organ in transplantation studies.Ann NY Acad Sci. 1964; 120: 778-785PubMed Google Scholar, 2McGough EC Brewer PL Reemtsma K The parallel heart: studies of intrathoracic auxiliary cardiac transplants.Surgery. 1966; 60: 153-158Google Scholar These studies demonstrated that the auxiliary heart, placed in parallel with the animal's own heart, could sustain the circulation when the native heart was nonfunctional. This concept of assisted circulation now has been widely applied in the use of mechanical support, such as ventricular assist devices. It has been applied sporadically in clinical cardiac transplantation, and this report summarizes the experience in infants and children. The authors report that in a total of 1278 cardiac transplants, 104 (8.1% of the total experience) were placed in the intrathoracic, heterotopic position. This report focuses on 12 infants and children, nine of whom survive. The indications that the authors cite are (1) presence of fixed high pulmonary vascular resistance, (2) availability of undersized donors, and (3) the expectation of a degree of recipient heart recovery. It is encouraging that all patients showed a decrease in pulmonary artery pressure and all showed a normal growth pattern. It seems probable that the application of auxiliary cardiac support, both with transplants and with mechanical devices, will continue. The use of this approach for transplantation into patients with high, fixed pulmonary vascular resistance seems established. The further development of ventricular assist devices similarly will usually use this approach in preference to in situ replacement of the heart. Its usefulness in treating patients with reversible myocardial disease is intriguing but not yet established. The increasingly severe shortage of donor hearts has resulted in the use of marginally acceptable organs, and the use of such transplants as auxiliary pumps has certain advantages. Similarly, as cardiac xenografts approach clinical use, the auxiliary position rather than in situ replacement has appeal in this experimental area with uncertain outcome. Finally, a comment about nomenclature: The term heterotopic is nonspecific and refers to placement of the heart in any abnormal position. In the literature of experimental cardiac transplantation, heterotopic often refers to cervical or abdominal placement of the heart. The term piggyback is flippant and should be discarded. I recommend the terms auxiliary and parallel, as used in the original publications of this technique. These terms appropriately describe the function of the transplant, which supplements cardiac function by working in parallel with the native heart.

Orthotopic vascularized osteochondral allografts in an immunosuppressed rat model.

This study examined the survival of orthotopic, vascularized, osteochondral allografts, following 12 weeks of immunosuppression and transfer into a naive, allograft host up to 14 weeks later, and compared the results with those previously reported for similar grafts in a heterotopic position. Knee-joint allografts between DA (donor) and Lewis (recipient) rat strains were assessed by quantitative histology up to 6 months after transplantation, and graft microcirculation was examined by India-ink infusion. Graft repopulation was assessed by re-transferring the graft to a naive, non-suppressed allograft host 12 to 26 weeks after the initial transplantation. Isografts survived for as long as grafts were examined (6 months) and showed good healing of the graft/host bone junction, although long-term isografts showed some deterioration of the growth plate. Non-suppressed allografts rejected within 2 weeks. Allografts in hosts immunosuppressed for 12 weeks remained healthy and healed in a similar manner to the isografts. Following cessation of immunosuppression, allografts progressively deteriorated, with mononuclear cell infiltration apparent in graft bone marrow and muscle in the later stages examined. Transfer to second non-suppressed hosts resulted in rapid rejection of the allografts, indicating that, as shown previously in heterotopic, osteochondral allografts, little or no graft repopulation by host-derived cells had occurred during the protected period in the first host.

Expanding the donor pool

Expanding the donor pool

Auxiliary liver transplantation for acute liver failure.

In summary, the following principles are worth reiterating: 1. In the treatment of acute liver failure, protection of the native liver in anticipation that it will recover, but positioning of the allograft in a manner that optimizes its function for both the short and long term (in the event that the native liver does not recover) are important goals. Therefore, orthotopic positioning offers advantages over the heterotopic position in most cases. Development of better techniques for predicting native liver recovery might remove any of these advantages of the orthotopic position. 2. Other than the presence of fibrosis, the performance of a native liver biopsy does not appear to predict native liver recovery. The decision of whether to attempt auxiliary grafting must be based on an understanding of the natural history of the disease causing the acute liver failure. 3. The heterotopic position has the advantage of not requiring partial native hepatectomy in order to accommodate the allograft. However, except for the recent experience of Terpstra et al, this technique has carried a higher risk of venous outflow obstruction. It also requires additional space within the abdomen, usually mandating the use of prosthetic abdominal wall closures and the construction of venous conduits for portal venous inflow to the liver. There is the additional theoretical concern about competition for portal venous flow leading to eventual atrophy of the allograft liver. 4. Common events that follow liver transplantation result in changes in portal venous resistance within the liver, events that therefore alter the relative distribution of portal venous inflow between native and auxiliary livers. These events include reperfusion injury, allograft rejection, allograft viral infection (e.g., cytomegalovirus, Epstein-Barr virus, recurrent viral hepatitis), and native liver regeneration. Attempts to control portal venous flow to favor one liver over the other must account for the effect of these factors. 5. In general terms, auxiliary transplantation is not indicated for diseases in which the residual native liver either represents an ongoing threat to the recipient or is incapable of supporting life alone. This may be the case in both metabolic disorders and in cirrhosis. Most of the alleged difficulties of native hepatectomy are no longer relevant. Therefore, auxiliary transplantation is rarely if ever indicated for chronic liver disease and may not be of any additional benefit over total transplantation in the treatment of many metabolic disorders. 6. In the treatment of acute liver failure, the value of an auxiliary transplant over total transplant is obtained when the native liver recovers and the patient is withdrawn from immunosuppression. If further experience shows the effectiveness of this option, total liver transplantation with the requirement for life-long immunosuppression will no longer be appropriate for the treatment of patients with acute liver disease.

Split liver transplantation in Europe--1988 to 1993.

The shortage of liver grafts results in the fact that 8% of potential recipients die before receiving a graft. Liver graft division has therefore been proposed to maximize the current available liver graft pool. However, the question of benefit or additional risk for the recipient that this technique might carry remains unanswered. The European Split Liver Registry was opened in March 1993 and reviewed retrospectively the clinical experience obtained at nine European centers regarding the use of split liver transplants, during the five year period from March 1988 to March 1993. From 50 donor livers, 100 grafts were prepared: 2 grafts were discarded and the other 98 were transplanted in 53 children (2 times in 3 children) and 42 adults (2/42 in heterotopic position). Sixty-three grafts were implanted in an urgent recipient (half of whom had acute hepatic failure). Portal vein thrombosis, hepatic artery thrombosis, biliary complications, and retransplantation rates were 4%, 11.5%, 18.7%, and 18.7%, respectively. Most of these complications were unrelated to the technique itself. Actual 6-month graft survivals of elective and urgent orthotopic transplants were 80% and 61.3% in children, and 72.2% and 55.6% in adults; actual 6-month patient survival rates for similar groupings were 88.9% and 61.1%, and 80% and 67.7%, respectively. Similar rates are reported after conventional transplants in Europe. It is concluded that split liver transplantation is an efficient transplant technique that benefits both urgent patients who otherwise could have died before getting a graft in time and elective patients.

Effects of canine donor heart preservation temperature on posttransplant left ventricular function and myocardial metabolism.

The generally accepted method of preserving donor heart integrity during transfer is to arrest it with cold cardioplegic solution, then store it in a plastic bag immersed in an iced electrolyte solution. Temperatures between 0 degree C and 4 degrees C are maintained by this method until the heart is transplanted. Although profound hyperthermia best inhibits metabolic processes, it may damage the myocardium. Higher myocardial temperatures may be more advantageous and may result in better preservation. The efficacy of this hypothesis has been investigated in a canine model. The hearts of 40 dogs were isolated, arrested with cold cardioplegia, removed from the animal, and stored at different temperature ranges from 0-3 degree C to 12-15 degrees C for 4 hr. After this time period, the hearts were transplanted into a recipient animal in the cervical heterotopic position. The degree and speed of myocardial functional recovery were monitored by measuring end-systolic elastance generated from pressure-diameter loops using sonomicrometry techniques. Myocardial metabolism was studied simultaneously by monitoring coronary flow, O2, glucose, lactate, pyruvate, and free fatty acid uptakes. The results were compared with those from a control group of hearts transplanted immediately after their removal. Our results indicate that donor heart function was significantly depressed 30 min after heterotopic transplantation, but returned to "control" levels after 2 hr when stored between 0 degrees C and 6 degrees C. Myocardial function remained significantly depressed throughout the 2-hr recovery period in hearts stored at higher (6-15 degrees C) temperatures. Hearts stored at all temperatures continued to extract glucose, lactate, and free fatty acids, but produced significantly higher levels of pyruvate at higher storage temperatures, which may be related to the favored use of free fatty acids. In conclusion, donor hearts stored at colder temperatures for 4 hr regain complete left ventricular function faster than hearts stored at higher temperatures. Our experiments support the presently applied methods of donor heart preservation for 4 hr.