Unloading the infarcted heart affect MMPs-TIMPs axis in a rat cardiac heterotopic transplantation model.

Ventricular assist devices may function as a bridge to recovery or heart transplantation, however, little is known about its mechanisms. This study examined the role of matrix metalloproteinases (MMP)-tissue inhibitors of metalloproteinases (TIMP) axis in the process of recovery after unloading in a rat ischemic-induce heart failure (HF) model. Myocardial infarction model was created with the coronary artery ligation. The infarcted rats hearts were unloaded by heterotopic cardiac transplantation (n=14). 2 weeks later, the function of normal and infarcted hearts with or without loading was evaluated by Langendorff perfusion model. The hearts were then harvested and prepared for the study of expression of MMPs and TIMPs. Developed pressure in the unloading group was higher than the loading group (P=0.0074). Unloading increased the ratio of TIMP-1-MMP-1(1.38±0.11 vs. 0.76±0.09, P<0.05), TIMP-2-MMP-2 (1.06±0.10 vs. 0.33±0.07, P<0.01), TIMP-3-MMP-9(1.07±0.08 vs. 0.59±0.06, P<0.05). Although MMP-1, 2, 9 were downregulated (P<0.01, 0.01, 0.05, respectively), TIMP-2 and TIMP-3 upregulated (P<0.01, 0.05, respectively), MMP-7 and TIMP-1 was not affected significantly. The infarcted cardiac function could be improved by unloading. It was attributed to downregulation of MMP-1, 2 and 9, and upregulation of TIMP-2 and -3, and furthermore, the ratio of TIMPs to MMPs was increased, which might be more sensitive than sole MMPs or TIMPs for the judgment of myocardial matrix homeostasis.

Specification of mouse telencephalic and mid-hindbrain progenitors following heterotopic ultrasound-guided embryonic transplantation.

We have demonstrated the utility of ultrasound backscatter microscopy for targeted intraparenchymal injections into embryonic day (E) 13.5 mouse embryos. This system has been used to test the degree of commitment present in neural progenitors from the embryonic ventral telencephalon and mid-hindbrain region. Many E13.5 ventral telencephalic progenitors were observed to integrate and adopt local phenotypes following heterotopic transplantation into telencephalic or mid-hindbrain targets, whereas mid-hindbrain cells of the same stage were unable to integrate and change fate in the telencephalon. In contrast, many mid-hindbrain cells from an earlier developmental stage (E10.5) were capable of integrating and adopting a forebrain phenotype after grafting into the telencephalon, suggesting that mouse mid-hindbrain progenitors become restricted in their developmental potential between E10.5 and E13.5.

Cardiac preservation is enhanced in a heterotopic rat transplant model by supplementing the nitric oxide pathway.

Nitric oxide (NO) is a novel biologic messenger with diverse effects but its role in organ transplantation remains poorly understood. Using a porphyrinic microsensor, the first direct measurements of coronary vascular and endocardial NO production were made. NO was measured directly in the effluent of preserved, heterotopically transplanted rat hearts stimulated with L-arginine and bradykinin; NO concentrations fell from 2.1 +/- 0.4 microM for freshly explanted hearts to 0.7 +/- 0.2 and 0.2 +/- 0.08 microM for hearts preserved for 19 and 38 h, respectively. NO levels were increased by SOD, suggesting a role for superoxide-mediated destruction of NO. Consistent with these data, addition of the NO donor nitroglycerin (NTG) to a balanced salt preservation solution enhanced graft survival in a time- and dose-dependent manner, with 92% of hearts supplemented with NTG surviving 12 h of preservation versus only 17% in its absence. NTG similarly enhanced preservation of hearts stored in University of Wisconsin solution, the clinical standard for preservation. Other stimulators of the NO pathway, including nitroprusside, L-arginine, or 8-bromoguanosine 3',5' monophosphate, also enhanced graft survival, whereas the competitive NO synthase antagonist NG-monomethyl-L-arginine was associated with poor preservation. Likely mechanisms whereby supplementation of the NO pathway enhanced preservation included increased blood flow to the reperfused graft and decreased graft leukostasis. NO was also measured in endothelial cells subjected to hypoxia/reoxygenation and detected based on its ability to inhibit thrombin-mediated platelet aggregation and serotonin release. NO became undetectable in endothelial cells exposed to hypoxia followed by reoxygenation and was restored to normoxic levels on addition of SOD. These studies suggest that the NO pathway fails during preservation/transplantation because of formation of oxygen free radicals during reperfusion, which quench available NO. Augmentation of NO/cGMP-dependent mechanisms enhances vascular function after ischemia and reperfusion and provides a new strategy for transplantation of vascular organs.

Intraportal transplantation of pancreatic islets into livers of diabetic rats. Reinnervation of islets and regulation of insulin secretion by the hepatic sympathetic nerves.

Two weeks after intraportal transplantation of 2,000 neonatal pancreatic islets, recipient rats completely recovered from streptozotocin-induced diabetes. The reversal of diabetes could be documented by the normalization of blood glucose levels, by a restored weight gain, by normal glucagon and insulin levels in blood, and by a disappearance of polyuria and polydipsia. The reversal remained stable for at least 9 months. This study determined whether intraportally transplanted pancreatic islets were reinnervated after transplantation and whether the secretion of insulin and glucagon from pancreatic islets might be modulated by the vegetative innervation of recipient livers. Predominantly catecholaminergic but also cholinergic nerve fibers were detected not only within the portal tracts around hepatic arteries, portal veins, and bile ducts, but also at the borderline of hepatocytes and beta-cells and in islet cell complexes between beta-cells. Corresponding electron micrographs showed beta-cells in close contact with axons of nonmyelinated nerve fibers. Isolated livers were single pass perfused via both the hepatic artery and the portal vein. An increase in glucose level from 5 to 14 mmol/l enhanced hepatic glucose uptake and increased insulin secretion from transplanted islets with a biphasic secretion profile but had no effect on glucagon output. Stimulation of the nerve plexus around the hepatic artery and the portal vein (7.5 Hz, 2 min), which activates primarily the sympathetic system, not only reduced glucose uptake and perfusion flow but also completely reversed the glucose-stimulated increase in insulin secretion. Nerve stimulation did not influence glucagon secretion.(ABSTRACT TRUNCATED AT 250 WORDS)

Development of an ectopic site for islet transplantation, using biodegradable scaffolds.

Clinical islet transplantation in liver has achieved normoglycemia. However, this site may not be ideal for islet survival. To create a more optimal site for islet transplantation, we have developed a construct with biodegradable scaffolds. Islets were seeded in scaffolds and transplanted into the epididymal fat pad of diabetic BALB/c mice. Controls included islets transplanted underneath the kidney capsule or into the fat pad without scaffolds. All animals with islets in scaffolds or the kidney became normoglycemic and maintained this metabolic state. When islets were transplanted without scaffolds the time to achieve normoglycemia was significantly increased and less than 45% of mice survived. An oral glucose tolerance test was performed on the scaffold and kidney groups with similar blood glucose levels and area under the curve values between the groups. Grafts were removed at more than 100 days posttransplantation and all animals became hyperglycemic. There was no significant difference in insulin content between the grafts and all grafts were well vascularized with insulin-positive beta cells. Therefore, islets in scaffolds function and restore diabetic animals to normoglycemic levels, similar to islets transplanted underneath the kidney capsule, suggesting scaffolds can be used to create a site for islet transplantation.

Na+/H+ exchange inhibition and antioxidants lack additive protective effects after reperfusion injury in the working heterotopic rat heart isograft.

BACKGROUND: The utility of combining strategies of myocardial protection was studied in intact rat hearts subjected to 1 hour of ischemia and 40 minutes blood reperfusion. METHODS: Lewis rats (n = 48) were divided into 4 transplant groups. Twenty-four hearts were arrested by coronary perfusion with hypothermic Celsior solution at 60 mm Hg. The aortic valve was punctured to introduce volume into the left ventricle (LV), and the hearts were abdominally isografted. Animals were either given both the antioxidant probucol (300 mg/kg) and the sodium-hydrogen exchange inhibitor cariporide (5 mg/kg) (CP; n = 6), just cariporide (CAR; n = 6), just probucol (PROB; n = 6), or neither drug (CON; n = 6). After 40 minutes of blood reperfusion, transplanted hearts were rearrested. The control recipients' native hearts (native; n = 6) were also arrested. Postmortem LV compliance relations and myocardial water content (MWC) were measured. RESULTS: Grafts protected by probucol were significantly more compliant than controls and significantly less compliant than grafts protected by cariporide alone and with both cariporide and probucol (p = 0.0001, analysis of variance). Compliance relations for CP overlapped those for CAR. All grafts were less compliant than natives. MWC was significantly greater in controls and PROB than in natives. CONCLUSIONS: Pretreatment with cariporide in the setting of ischemia-reperfusion injury provides greater protection against the development of diastolic abnormalities than probucol when Celsior solution is used for both arrest and preservation. In this model, there is no advantage to combining the drugs, supporting the hypothesis that there is an overlapping mechanism of protection.

Heart transplantation changes the expression of distinct gene families.

We took advantage of the combination of a rat heart transplantation model with a modified differential display RT-PCR method to identify transcriptome changes in the right atria from transplanted compared with native hearts. Based on sequence homology search, the 37 cDNAs differentially displayed both 2 and 7 days posttransplantation were categorized into 7 unknown transcripts, 16 expressed sequence tags (ESTs), and 14 partially or completely characterized genes. The last group cDNAs, validated by relative RT-PCR, belonged to diverse gene families involved in specific metabolisms, protein synthesis, cell signaling, and transcription. Furthermore, we identified differential transcripts corresponding to denervation and fetal gene reexpression. We found coordinate downregulation of genes involved in energy metabolism and protein synthesis regulation, similar to that reported for senescent skeletal muscle. From these transcriptome changes, we propose that heart transplants and senescent muscles share common molecular mechanisms.

Long-term ovarian function evaluation after autografting by implantation with fresh and frozen-thawed human ovarian tissue.

The transplantation of ovarian tissue has recently been the focus of intense investigation with the aim of avoiding premature ovarian failure mainly in patients receiving chemotherapy or radiotherapy for malignant disease. Here, we present an evaluation of the long-term function of both fresh (patients 1, 2, and 3) and cryopreserved (patient 4) ovarian autografts in four premenopausal patients aged 46-49 yr who underwent heterotopic ovarian transplantation and were followed over a 1-yr period without receiving gonadotropins to stimulate follicular growth. In patients 1 and 2, approximately 1 cm(3) ovarian cortical autograft was placed sc in the inner aspect of the arm, whereas and in patients 3 and 4 minced ovarian tissue was placed into a muscle pocket in the abdominal wall. In patients 1, 2, and 4 the ovarian hormone secretion (as suggested by sequential estradiol and FSH serum measurements) was reestablished 3-4 months after autotransplantation, and graft function was not improved by immediate rather than delayed heterotopic ovarian autografting. Despite a reestablished ovarian function, a 2- to 7-fold increase in peripheral FSH concentration was evidenced. The cases reported here suggest that hormonal protection can be restored after fresh or cryopreserved heterotopic ovarian transplantation in women, albeit for only a short reproductive span.

Retinal transplants in congenitally blind mice: patterns of projection and synaptic connectivity.

Embryonic retinae were transplanted onto the midbrain of neonatal congenitally anophthalmic mice and neonatal mice from which both eyes had been removed. When donor mice of the AKR strain were used, the detailed patterns of the transplant projections to the host brain were demonstrated with an antibody to Thy-1.1, which specifically stains neural tissue derived from AKR donors. Many of the subcortical visual centers were innervated, and only small differences were encountered between anophthalmic and eye-enucleated mice. The terminal arbors of transplant-derived axons could not be classified as in normal animals, although several distinct arbor types were seen. In the superior colliculus, the laminar arrangements that characterize normal retinal arbors were disrupted. Despite this, the synaptic patterns formed by transplant-derived axons in the superior colliculus of anophthalmic mice compared very closely with those of retinal axons in normal, sighted animals. These observations indicate that the ability of a retinal transplant to innervate the host brain and to form the synaptic arrays characteristic of optic terminals are not dependent on prior innervation, nor do they appear to be influenced by the events that follow eye removal.

Permeability to blood-borne protein and 3HGABA in CNS tissue grafts. I. Intraventricular grafts.

In the present study, solid grafts of fetal CNS tissue from the rat neocortex, cerebellum, or ventral mesencephalon were placed into the lateral, III or IV ventricles of young adult hosts. Survival periods ranged from 2 days to 20 months. To study the permeability to protein and potential changes in the blood-brain barrier (BBB), macromolecules such as HRP, HRP-human serum albumin, and HRP-human IgG were administered intravascularly and circulated for periods between 3 minutes and 1 hour. Younger grafts were completely filled with the protein, even at 2 days, when the graft vasculature already contained host macrophages, whereas all older grafts showed variability in permeation with protein ingress initiating at the graft-host interface and subsequently diffusing through the extracellular spaces. Permeation was from several sources: permeable vessels of the circumventricular organs and the choroid plexus which grew into the grafts, the perivascular spaces surrounding these vessels, or from the normally impermeable vessels of the pia mater, which, because of their engulfment by the graft and subsequent angiogenesis, may have been rendered permanently leaky. Invading vessels were often "cuffed" by lymphocytic cells. Many grafts were only partially filled by the glycoprotein conjugates; ventral mesencephalic grafts allowed the least diffusion even when vascularized by choroidal vessels. Fenestrated vessels were not directly observed even though petechial leaks were evident and vessels indigenous to the CNS grafts retained BBB properties. To determine endogenous protein exudation, noninjected animals were immunocytochemically examined for rat serum albumin (RSA). The distribution of RSA mimicked that of the injected proteins at interface regions, although in most instances the entire graft was filled by a light, diffuse labeling suggesting a steady-state protein leakage over the life of the graft. When HRP was delivered intraventricularly, the intraventricular grafts were nearly filled with reaction product by 20 minutes. The depth of penetration in the grafts from the CSF interface was generally threefold greater than in normal brain. The increase in permeation suggests that solutes may flow through these grafts (out of or into the CSF) at an increased rate. Lastly the neurotransmitter tritiated gamma-aminobutyric acid (3HGABA) which does not cross the BBB was vascularly administered to hosts bearing neocortical grafts. These experiments not only confirmed the permeability in these grafts but showed that the blood-borne amino acid could be directly sequestered by grafted neurons or glia.(ABSTRACT TRUNCATED AT 400 WORDS)

Intraoperative hemodynamics in liver transplantation comparing orthotopic with heterotopic transplantation in the pig.

The intraoperative hemodynamic changes and several graft function parameters were studied comparing orthotopic liver transplantation with auxiliary partial liver transplantation (APLT) in the pig. Thirty-one Yorkshire pigs (ca. 25 kg b.w.) were randomly allocated to OLT (n = 16) or APLT (n = 15). During the construction of portal anastomosis the median cardiac output dropped to 67% of the initial value in OLT and to 49% in APLT (P less than 0.02). Median duration of the portal flow interruption was shorter in APLT: 15 min versus 48 min in OLT (P less than 0.002). After unclamping of the aorta, the median systolic blood pressure dropped to 75 mmHg in OLT and to 90 mmHg in APLT (P less than 0.02). APLT is less time-consuming: median duration of transplantation was 128 min versus 165 min in OLT (P less than 0.002). SGOT levels were lower in APLT than in OLT (median SGOT on the first postoperative day 67 was IU/L versus 177 IU/L, P less than 0.002). It is concluded that APLT is a shorter procedure than OLT with a shorter portal flow interruption, being less offensive to the recipient.

The isolated perfused rat spleen. An original method for studying the function of hepatocytes transplanted into the spleen.

The aim of this study was to assess directly the function of isolated hepatocytes 1 year after transplantation into the spleen, using an original model of isolated rat-spleen perfusion. Three specific liver functions, albumin synthesis, indocyanine-green clearance, and antipyrine oxidation, were studied. Five x 10(6) isolated hepatocytes were injected into the spleen of syngenic Wistar-Furth rats. One year later, splenectomy was performed, and the splenic pedicle was carefully isolated in order to allow a selective ex vivo perfusion for 3 hr. De novo albumin synthesis was studied by qualitatively using immunoelectrophoresis and autoradiography, and quantitatively using (35S)-methionine incorporation in albumin. De novo albumin synthesis was observed in spleens containing transplanted hepatocytes but not in controls (P less than 0.001); (35S)-methionine incorporation was significantly higher in spleens containing transplanted hepatocytes than in controls (132 +/- 67 cpm/spleen/hr vs. 14 +/- 6 cpm/spleen/hr, P less than 0.001). Antipyrine clearance was significantly higher in spleens with transplanted hepatocytes than in controls (67.4 +/- 4.9 microliters/min/g vs. 0.2 +/- 0.4 microliters/min/g, P less than 0.01). No statistically significant difference was observed with indocyanine-green clearance (4.2 +/- 6.0 microliters/min/g, vs. 5.2 +/- 5.1 microliters/min/g, P greater than 0.05); this was probably due to the absence of compartmentation between the sinusoid and biliary sectors in this model. In conclusion, using this original isolated rat-spleen perfusion model, it was directly observed that 1 year after transplantation, intrasplenic hepatocytes can perform two liver-specific functions, i.e., de novo albumin synthesis and antipyrine clearance.

Prolonged function of canine pancreatic fragments autotransplanted to the spleen by venous reflux.

The long-term viability and function of pancreatic islets transplanted as nonvascularized dispersed grafts has not been well established. We report maintenance of nondiabetic carbohydrate metabolism for up to 36 months (17.8 +/- 1.4 months) in 77% of 40 consecutive canine recipients of nonpurified islet grafts transplanted to the spleen by venous reflux. Spontaneous loss of graft function occurred in 9 dogs during the follow-up period. Failure usually occurred within 1 year of implantation and was predicted by low K value and low insulin output on intravenous glucose tolerance tests 1 and 3 months postimplant. High K values and insulin output correlated strongly with maintenance of function beyond 24 months. A sufficient mass of implanted islets can provide satisfactory metabolic control for prolonged periods.

The effect of insulin treatment on function of intraportally grafted islets in streptozotocin-diabetic rats.

This study examines whether a 10-week period of daily insulin injections following intraportal islet transplantation improves the metabolic state in streptozotocin-diabetic recipients of a suboptimal number of beta cells. In recipients receiving 0.5 million beta cells, insulin treatment increased the number of animals with normal basal glycemia (from 2/6 to 7/8) and normal serum fructosamine (from 1/6 to 6/8). However, during the four weeks following a 10-week insulin regimen, this beneficial effect was lost and no differences were noticed in glucose tolerance curves and hepatic insulin reserves of insulin-treated and untreated recipients. In recipients receiving 1.1 million beta cells, administration of insulin did not influence the number of animals with normal basal glycemia (7/7 in both groups) or with normal serum fructosamine (5/7 versus 4 to 6/7) during the period of treatment or during the subsequent 4 weeks; prior insulin treatment did not improve glucose tolerance curves but reduced the hepatic insulin reserves by one-third. It is concluded that insulin injections can improve the metabolic state in recipients of an insufficient islet mass but do not enhance the metabolic capacity or insulin reserves of a hepatic islet implant. The reduced hepatic insulin content in one group of insulin-treated recipients raises the possibility that supplements of insulin injections reduce the size of grafted insulin reserves.

Reinnervation of transplanted pancreatic islets. A comparison among islets implanted into the kidney, spleen, and liver.

Islets transplanted beneath the kidney capsule become reinnervated during the first 3-4 months after implantation by both afferent and efferent nerve fibers. To evaluate the importance of the implantation organ for this process, the present study compared both the degree and the types of nerve fibers reinnervating islets transplanted into the liver, kidney, and spleen. For this purpose, 150 syngeneic islets were grafted under the kidney capsule of C57BL/6 mice. In addition, the same animals were injected with 150 islets into the spleen or liver. All animals were killed 14 weeks after transplantation, after which the graft-bearing organs were processed for indirect immunofluorescence for neuropeptides and tyrosine hydroxylase (TH), and with acetyl cholinesterase (AchE) staining to visualize nerve fibers. Both afferent (containing substance P and/or calcitonin gene-related peptide) and parasympathetic (containing vasoactive intestinal peptide or AchE) nerve fibers were absent from islets implanted into the spleen; an occasional CGRP fiber was seen in islets implanted into the liver; and all these fibers were regularly seen in islets implanted beneath the renal capsule. The islets implanted into the liver or spleen contained a dense network of sympathetic (containing neuropeptide Y and TH) nerve fibers that was often more dense than in the islet grafts under the kidney capsule. One-fifth of islets implanted into the liver were, however, completely devoid of demonstrable nerve fibers. In conclusion, there are marked differences with regard to the pattern of reinnervation of islets transplanted to different implantation sites.

Protection of rat heart from damage due to ischemia-reperfusion during procurement and grafting by defibrotide.

We studied the efficacy of defibrotide, a prostacyclin-stimulating agent, in preventing ischemia reperfusion injury in Wistar rat heart by using three experimental models: (1) hearts from donors were perfused with the drug (32 mg/kg/hr) during 15, 30, 45, and 60 min of cold ischemia following 5, 10, and 15 min of warm ischemia; (2) hearts from donors treated with the drug were cold-stored for 12 or 24 hr; and (3) procured hearts perfused with the drug were isografted, after 30 or 60 min of warm ischemia, in recipient rats treated daily with defibrotide. Hearts perfused with saline and/or vehicle of the drug were used as controls. At the end of established ischemia times, and after 30 min, and 2, 4, 7 and 14 days from transplantation, hearts were rapidly cooled in liquid nitrogen. ATP, ADP, AMP, cAMP contents, and NAD+/NADH ratios were evaluated in prepared tissue extracts. Cardiac ATP and ADP levels and NAD+/NADH ratios were significantly higher in defibrotide-treated organs than in controls. Isografted defibrotide-treated hearts were also significantly preserved, with respect to controls, from the loss of ATP levels until rejection occurred. Our results demonstrate the protective activity of the drug against the myocardial metabolic damage due to ischemia-reperfusion.

Heterotopic intestinal transplantation aggravates the insult of chronic rejection.

BACKGROUND: 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. METHODS: 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. RESULTS: 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). CONCLUSIONS: 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.

Hemodynamic evaluation of heterotopic heart transplantation.

To assess the relative contribution of native and donor hearts to total circulatory performance after heterotopic transplantation, we used cardiac catheterization to examine 10 patients. Left and right ventricular filling pressures significantly decreased by 41% and 36%, respectively, cardiac index increased by 25%, and pulmonary arteriolar resistance was reduced by 61%. Patients were subdivided into two groups according to the presence of one (group I) or two (group II) peaks on the aortic pressure curve. In group I, the donor left ventricle assumed total left ventricular work and 80% of right ventricular work. Because the native left ventricle could not generate enough pressure to open the aortic valve, its entire stroke volume was ejected into the common left atrium. In addition, in all four patients a native aortic regurgitation occurred in diastole and systole. In contrast, in group II, native left ventricular systolic pressure always exceeded aortic diastolic pressure. The donor left ventricle contributed 68% to systemic blood flow and the donor right ventricle 51% to pulmonary blood flow. Mild native aortic regurgitation was demonstrated in two patients only. Native left ventricular function deteriorated postoperatively in all patients (ejection fraction decreased from 0.22 +/- 0.09 to 0.14 +/- 0.08), but this deterioration was more marked in group I. Postoperative depression of native left ventricular function could not be ascribed to progression of coronary artery disease but was mainly due to reduced preload (competitive filling) and increased afterload. Thus in group I patients with more severe preoperative left ventricular dysfunction, the donor heart behaved like a total biventricular assist device. In contrast, in group II patients the donor heart acted like a partial biventricular assist device.

Diastolic function in the heterotopic rat heart transplant model. Effects of edema, ischemia, and rejection.

Decreased systolic ventricular function and compliance and increased left ventricular edema and mass have been demonstrated in cardiac allograft rejection. Whether decreased left ventricular compliance in rejection is caused by myocardial edema has not been examined, and compliance in the Ono-Lindsey model has not been reported. Heterotopic rat abdominal cardiac transplantation was performed in ACI isografts (n = 24) and in ACI to Lewis allografts (n = 24). Subgroups were studied on posttransplantation days 0, 1, 3, and 5 (each n = 6). Both transplanted hearts and native hearts were arrested with potassium for the assessment of myocardial water content, heart weight, and the left ventricular pressure-volume relation. In transplanted hearts, myocardial water content did not change in isografts but increased on posttransplantation day 5 in allografts (81.1% on posttransplantation day 5 versus 76.1% on day 0, 77.2% on day 1, and 77.5% on day 3, p < 0.05). Wet and dry heart weight also increased on posttransplantation day 5 in allografts (p < 0.05). The left ventricular pressure-volume relation in transplanted hearts shifted to the left when compared with that in native hearts in all subgroups; these volume differences were statistically significant (p < 0.01) for all pressures above 7.5 mm Hg. This pattern was similar in isografts and allografts on posttransplantation days 0, 1, and 3, and no significant differences between isografts and allografts were demonstrated. On posttransplantation day 5, however, the pressure after a 0.05 ml injection in allografts was greater in transplanted hearts than in native hearts (24 +/- 3 versus 3 +/- 1 mm Hg, p < 0.01). The pressure difference between transplanted and native hearts was also significantly greater in allografts than in isografts (22 +/- 2 versus 6 +/- 1 mm Hg, p < 0.01), indicating an increase in stiffness of allografts. Thus edema and impaired diastolic properties occur concurrently with allograft rejection. Left ventricular volume is abnormal from posttransplantation days 0 to 5 in transplanted hearts but not native hearts in the Ono-Lindsey model with current methods, apparently because of ischemic injury during transplantation.

The effect of basic fibroblast growth factor and omentopexy on revascularization and epithelial regeneration of heterotopic rat tracheal isografts.

Donor airway ischemia is a significant problem after clinical lung transplantation despite the use of omentopexy for accelerated local bronchial revascularization. Several growth factors have been shown to induce angiogenesis in vitro and in vivo. In the present study the quantitative effects on tracheal revascularization and epithelial regeneration of omentopexy and continuous local administration of basic fibroblast growth factor were investigated in a heterotopic rat tracheal isograft model. Tracheas were harvested from donor rats and heterotopically implanted into the omentum of syngeneic recipient rats. Animals were randomly assigned to study groups differing only in treatment of the tracheal segments: omental wrap for 2, 7, or 14 days; omental wrap plus continuous local administration of basic fibroblast growth factor for 7 or 14 days; or omental wrap plus local application of saline for 7 or 14 days. Two, 7, or 14 days after the animals were put to death, the vascularity of the tracheal segments and attached omentum and the tracheal epithelial morphology were assessed in a blinded fashion with use of light microscopy and morphometric image analysis. Vascularity in tracheal segments treated with basic fibroblast growth factor was significantly (p less than 0.05) greater than in control tracheas after 7 and 14 days. Epithelial regeneration was also improved in the basic fibroblast growth factor-treated groups at days 7 and 14 (p less than 0.05). We conclude that continuous local administration of basic fibroblast growth factor enhances early revascularization of tracheal segments induced by omentopexy and accelerates epithelial regeneration in a heterotopic rat tracheal isograft model.