A Comparison between splenic fossa and subhepatic fossa auxiliary partial heterotopic liver transplantation in a porcine model.

To test the alternative possible locations for the placement of a liver graft and the relevant surgical technique issues, we developed a porcine model of auxiliary partial heterotopic liver transplantation (APHLT) and evaluated the difference between 2 styles of liver transplantation, either subhepatic fossa or splenic fossa APHLT, by comparing survival and biochemical indexes. Thirty-eight miniature pigs were randomly divided into 2 groups. A left hemihepatic graft without the middle hepatic vein (HV) was procured from the living donor. In group A (n = 9), an 8 mm diameter polytetrafluoroethylene (PTFE) graft approximately 2.5 cm long was connected to the left HV while another PTFE graft of the same size was connected to the left portal vein (PV). The liver graft was implanted in the right subhepatic fossa following splenectomy and right nephrectomy. In group B (n = 10), a PTFE graft of the same size was connected to the left HV while the liver graft was implanted in the splenic fossa following splenectomy and left nephrectomy. Survival rate and complications were observed at 2 weeks after transplantation. Data were collected from 5 animals in group A and 6 animals in group B that survived longer than 2 weeks. The liver function and renal function of the recipients returned to normal at 1 week after surgery in both groups. Eighty-eight percent (14/16) of the PTFE grafts remained patent at 2 weeks after surgery, but 44% of the PTFE grafts (7/16) developed mural thrombus. No significant differences in the survival rate and biochemistry were found between the 2 groups. In conclusion, the splenic fossa APHLT can achieve beneficial outcomes similar to the subhepatic fossa APHLT in miniature pigs, although it also has a high morbidity rate due to hepatic artery thrombosis, PV thrombosis, and PTEF graft mural thrombus formation. Liver Transplantation 22 812-821 2016 AASLD.

Heterotopic heart transplantation: the United States experience.

INTRODUCTION: More than 3 decades have passed since the first heterotopic heart transplantation (HHT) was reported. Nowadays, this surgical technique is used rarely, and only in patients who do not qualify for standard orthotopic heart transplantation (OHT). Current indications mainly comprise refractory pulmonary hypertension and a donor-recipient size mismatch (>20%). The objective of this study was to analyze the United States experience with HHT. PATIENTS AND METHODS: The United Network for Organ Sharing (UNOS) database between 1987 and 2007 was analyzed. Patients who underwent heart transplantation were enrolled in this study. Patients with missing transplant dates or history of retransplantation were excluded. RESULTS: A total of 41,379 patients underwent OHT and 178 HHT; 32,361 and 111 patients, respectively, were enrolled. Overall 1-, 5-, and 10-year survival was significantly (P < .001) better in OHT (87.7%, 74.4%, 54.4%) than HHT patients (83.8%, 59%, 35.1%). Survival in patients with transpulmonary gradients (TPG) >15 mmHg was 86.6 %, 73.3%, and 57.4% in the OHT and 93.8%, 64.8%, and 48.6% in the HHT group (P = .35). Pretransplant criteria (HHT versus OHT) with statistically significant differences (P < .05) were as follows (mean + SD): recipient weight, 78.9 + 19.9 versus 74.1 + 23.4 kg; recipient height, 174.9 + 13.9 versus 168 + 25.1 cm; and TPG 12.1 + 7.2 versus 9.6 + 6.3 mmHg. CONCLUSIONS: The results show that HHT remains a feasible option in a highly selected patient population, with overall good results.

[Establishment of the model of heterotopic uterine transplantation in syngeneic rats].

OBJECTIVE: To develop a surgical method for establishment of a heterotopic uterine transplantation model in syngeneic rats and evaluate its feasibility. METHODS: Thirty pairs of Wistar rats aged 8 - 10 weeks were used as donor and recipient. Heterotopic uterine transplantation was conducted, and the duration of the operation was recorded. The recipient rats were killed 7 days after surgery. The morphology of the transplanted uteri was evaluated. RESULTS: Thirty heterotopic uterine transplantations were conducted. The survival rate increased from 40% (6/15) in the first 15 pairs of recipient rats to 75% (12/15) in the last 15 pairs of recipient rats. Among the 18 living recipient rats, 15 transplanted uteri were viable. The viable rate of uterine transplantation was 83%. Compared with the first 15 pairs of rats, the duration of donor procedures, recipient procedures vascular anastomosis and the total time of the surgery decreased to (65 +/- 10) min, (89 +/- 22) min, (36 +/- 8) min and (154 +/- 23) min respectively in the last 15 pairs of rats. CONCLUSION: It is feasible to establish the model of heterotopic uterine transplantation in Wistar rats.

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.

A highly selective inhibitor of Rho-associated coiled-coil forming protein kinase, Y-27632, prolongs cardiac allograft survival of the BALB/c-to-C3H/He mouse model.

BACKGROUND: Current studies provide evidence that a small G protein, RhoAp21, and its target protein, Rho-associated coiled-coil forming protein kinase (ROCK), regulate not only cell shape but also cell migration. However, contribution of Rho/ROCK signaling to graft rejection is unknown. The purpose of this study was to evaluate the inhibitory effect of Y-27632, a highly selective ROCK inhibitor, on rejection of heterotopic cardiac transplantation in mice. METHODS: BALB/c (H-2(d)) hearts were transplanted into C3H/He (H-2(k)) as allografts that were full histoincompatibility combinations. The recipients received several doses of Y-27632, commencing 1 day before cardiac transplantation until rejection. We used immunohistochemical study to detect the expression of myocardial intercellular adhesion molecule 1 (ICAM-1) and vascular cell adhesion molecule 1 (VCAM-1), and we immunoenzymatically measured serum interleukin (IL)-6. Furthermore, we evaluated cardiac allograft vasculopathy treated with either FK506 or Y-27632 at Day 100. RESULTS: The Y-27632-treated (2 mg/kg/day) allografts prolonged the mean survival time (49.6 +/- 10.1 days, n = 12) as compared with the untreated allografts (8.1 +/- 0.4 days, n = 7, p < 0.001). Histologic examinations of the Y-27632-treated allografts at Day 7 showed greatly reduced leukocyte infiltration compared with the untreated allografts. The Y-27632-treated allografts revealed faint expression of myocardial ICAM-1 and VCAM-1 at Day 7. The serum IL-6 levels also decreased in the Y-27632-treated mice. In the long-surviving Y-27632-treated allografts at Day 100, we saw neither active rejection nor apparent thickening of vascular intima. CONCLUSION: Our results suggest that ROCK plays a major role in cardiac rejection in the BALB/c-to-C3H/He mouse model. Inhibition of this Rho/ROCK signaling may be an alternative therapeutic option for managing acute and chronic rejection.

Attenuation of waiting time mortality with heterotopic heart transplantation.

As the number of heart transplants and the number of transplant programs has increased, so has the waiting time for a suitable organ. To more accurately assess the magnitude of this increase and the influence of recipient size, we reviewed waiting times for large (body surface area greater than or equal to 1.95 m2) and small (body surface area less than 1.95 m2) patients with respect to era of transplantation. Patients who underwent transplantation early (1984 to December 31, 1986) waited 35 +/- 47 days (mean +/- standard deviation), whereas patients who underwent transplantation in the late era (1987 to September 30, 1989) waited 83 +/- 102 days (p = 0.001). Large patients waited longer (130 +/- 142 days) in the late era than did small patients (60 +/- 67 days; p = 0.008). During the heterotopic era (October 1, 1989 to June 30, 1990), waiting times for large patients who received a heterotopic transplant (67 +/- 46 days) were significantly shorter than those for patients who received an orthotopic transplant (166 +/- 157 days; p = 0.05). Waiting times for small patients remained unchanged. In addition, waiting time mortality decreased from 24% to 9% (p less than 0.05). Comparison of orthotopic and heterotopic procedures performed during the same era revealed no significant differences in recipient age, preoperative status, graft ischemic time, donor age, early and midterm survival, or early postoperative functional status. Heterotopic heart transplantation may effectively increase the size of the donor pool, decrease the waiting time, and decrease waiting time mortality without increasing the morbidity of the procedure.

Heterotopic heart transplantation and recipient heart operation in ischemic heart disease.

The role of heterotopic heart transplantation in coronary heart disease has not been defined. Between 1983 and 1988, 28 patients with end-stage ischemic heart disease were managed by heterotopic heart transplantation and adjunctive operation on the recipient heart: coronary artery bypass grafts and aneurysmectomy, 20; coronary artery bypass grafts, 5; and aneurysmectomy, 3. Indications were feasibility of operative procedures to the recipient heart and small donor size (61% of the donors were less than 15 years). The 1-year and 5-year actuarial survival was 79% and 63%. Of the 22 patients who survived to 2-year follow-up, all of whom had been severely limited (New York Heart Association grade III/IV) preoperatively, 20 were in grades I or II at 2-year follow-up (p less than 0.001). In 14 of 22 patients (64%), the recipient heart augmented the donor cardiac output substantially, and in 4 the recipient heart supported the patient when the donor heart failed to eject. In conclusion, this series demonstrates the efficacy of heterotopic transplantation combined with operation to the recipient heart in the management of patients with end-stage ischemic heart disease.

Improved multiorgan function after prolonged univentricular support.

Eleven cardiac transplant candidates (all male; mean age, 43.3 years) with multiorgan (hepatic, pulmonary, and/or renal) dysfunction were sustained for prolonged periods (> 30 days) with the HeartMate (Thermo Cardiosystems, Inc, Woburn, MA) left ventricular assist device. We evaluated the effect of extended support on end-organ recovery and on the ultimate outcome of cardiac transplantation. In addition to cardiac failure, 9 patients had hepatic dysfunction, 8 had pulmonary dysfunction, and 6 had renal dysfunction (4 of whom required hemodialysis before left ventricular assist device support). Mean duration of support was 115 days (range, 31 to 233 days). All patients underwent successful transplantation; 10 of these patients survived a mean of 24 months. One patient, who had required hemodialysis and ventilatory support during and after support, experienced progressive multiorgan failure and died 7 weeks after transplantation. Two late deaths after transplantation were unrelated to the device. Overall, patients experienced improvement in cardiac functional class status, and most participated in cardiac rehabilitation programs before transplantation. During left ventricular assist device support, hepatic function returned to normal in 8 patients, pulmonary function recovered in 7, and renal function returned to normal in 4. One patient who required hemodialysis underwent renal transplantation after cardiac transplantation and had complete recovery of renal function. In the current era of donor shortages, gravely ill patients can benefit from a strategy of prolonged left ventricular assist device support. This strategy has proved safe, has allowed for reversal of multiorgan dysfunction, and has produced healthier transplant candidates.

Endocrine and exocrine function of pancreatic fragments autotransplanted into hepatic parenchyma.

We studied the use of hepatic parenchyma as a recipient site for pancreatic fragment transplantation. Endocrine and exocrine pancreatic functions were evaluated following pancreatic autotransplantation in 26 mongrel dogs that had undergone total pancreatectomy. The endocrine function of the pancreatic tissue transplanted to hepatic parenchyma was significantly inferior to that of normal controls. Cholecystic bile amylase concentrations were markedly elevated in six dogs that had been implanted with pancreatic fragments in their hepatic parenchyma and had survived more than 2 months. Also, choledochal bile amylase concentrations increased significantly following pancreozymin-secretion (PS) injection. In contrast, cholecystic bile amylase concentrations in normal dogs were low and choledochal bile amylase concentrations did not respond to a PS load. Histological examination of pancreatic autografts in hepatic parenchyma revealed marked proliferation of exocrine tissue with abundant zymogen granules and reconstruction of pancreatic lobules with a few islets.

Heterotopic heart transplantation: experimental development and clinical experience.

Heterotopic heart transplantation was initially developed in the laboratory for experimental transplantation. While it was more widely utilized in the pre-cyclosporine era to provide adjunct circulatory support in combination with the native heart, associated complications as well as improved long-term graft survival have now established orthotopic transplantation as the procedure of choice. Heterotopic heart transplantation is currently reserved for highly selected patients. The technique is only performed at selected transplantation centers, and indications include significant donor recipient size mismatch or irreversible recipient pulmonary hypertension. The foreseeable introduction of clinical porcine xenotransplantation may lead to renewed interest in the technique of heterotopic heart transplantation as a bridge to potential native heart recovery or allotransplantation in selected patients.

Heterotopic heart transplantation--a means to increase donor availability.

From November 1985 to August 1989, 105 patients underwent heart transplantation at our institution of whom 8 (7%) underwent heterotopic heart transplantation (HHTx). There were 7 males and 1 female with a mean age of 49 +/- 6 years (range, 41-58 years), 7 of whom had ischaemic cardiomyopathy and 1 had dilated cardiomyopathy. The indications for HHTx were gross donor/recipient size mismatch, unreliable donor heart, elevated pulmonary vascular resistance and the need for urgent transplantation or their combination. HHTx was performed as a left ventricular bypass in 6 patients and as biventricular bypass in 2 combined with various surgical procedures on the native heart in 5. There was one perioperative death with a mean follow-up of the survivors of 17 +/- 10 months (range, 6-30 months). Comparison of preoperative and postoperative (1 year) 2-D echocardiographic studies of the native heart showed haemodynamic stability of the latter with no substantial changes in left ventricular ejection fraction and cardiac index, while left ventricular end-diastolic volume tended to increase in 2 patients. In conclusion, preservation of the native heart allows recovery or growth of a graft considered unsuitable for orthotopic transplantation. Our experience confirms that HHTx may still be considered a valuable alternative to orthotopic transplantation in selected patients, thus expanding donor utilization.

Prolongation of heterotopic heart allograft survival by portal venous injection of alloantigen: the role of hepatic nonparenchymal cells.

The induction of immune hyporesponsiveness in transplantation is a complex interaction between the immune system and the alloantigen. The route by which an antigen is introduced to the immune system plays an important role in the immune response. Antigen delivered via the portal circulation has the ability to induce T-cell hyporesponsiveness. In this study we examined the mechanism responsible for the induction of hyporesponsiveness by assessing immune response following portal vein (pv) injection of donor alloantigen. C57B1/6 mice were immunized via pv with splenic mononuclear cells (SMNC) from BALB/c mice. The recipient immune response was assessed in vivo by murine heterotopic heart transplant survival. SMNC and hepatic nonparenchymal cells (NPC) were isolated from pv immunized animals and used as regulatory cells in a one-way mixed lymphocyte culture (MLC) as a measure of in vitro recipient responder SMNC proliferation. Survival of murine heterotopic heart transplants was prolonged following pv injection of alloantigen (p < .04 compared to nonimmunized or systemically immunized mice). Stimulation of responder SMNCs isolated from pv immunized mice resulted in an antigen-specific hyporesponsiveness (p < .05 compared with nonimmunized or systemically immunized mice). Cocultures of responder SMNCs from nonimmunized (naive) mice with hepatic NPC from previously pv immunized mice resulted in attenuation of T-cell proliferation in MLR following stimulation with donor alloantigen (p < .05 compared to coculture with NPC from nonimmunized mice or SMNC from pv immunized mice). These data would suggest that the hepatic NPC plays an important role in the regulation of the immune response. With further identification of cell subtypes responsible for induction of hyporesponsiveness, future therapies may be directed at these specific targets, thereby minimizing the harmful side effects of current immunosuppressive therapies.

[Experience with heterotopic heart transplantation in patients with elevated pulmonary vascular resistance: late follow-up].

BACKGROUND: Along the past few years the number of papers on heterotopic cardiac transplant has been very scarce in the medical literature, including at the international level; this is particularly true in reference to the long term follow-up of these patients and the reason which led to the presentation of our report. OBJECTIVE: To report the initial clinical experience and late evolution of 4 patients undergoing heterotopic heart transplantation, indications for this procedure and its major complications. METHODS: The surgeries were performed between 1992 and 2001, and all had as indication for heterotopic transplantation the PVR, which ranged from 4.8 WU to 6.5 WU, with a transpulmonary gradient above 15 mmHg. In the 3rd patient, a direct anastomosis between the pulmonary arteries was performed without the use of a prostetic tube, and a mitral valvuloplasty and a LV aneurysmectomy were performed in the native heart. The immediate immunosuppressive regimens were double, with cyclosporine and azathioprine in the first 3 patients, and cyclosporine and mycophenolate mofetil in the 4th patient. RESULTS: One immediate death occurred from graft failure, one death occurred after 2 (1/2) years, from endocarditis in an intraventricular thrombus in the native heart, and a third death occurred 6 years after transplantation, from post-operative complications of the aortic valve surgery in the native heart. The remaining patient is well, 15 years after the transplantation. This patient is in functional class II (NYHA), 6 years after a surgical occlusion of the native heart aortic valve. CONCLUSION: Heterotopic heart transplantation results are inferior to those of orthotopic heart transplantation because they present higher RVP. The intraventricular thrombi, in the native heart, which require prolonged anticoagulation, and aortic valve complications, also in the native heart, may require surgical treatment. However, a patient's 15-year survival has demonstrated a long-term effectiveness of this option for selected patients.

A model of sequential heart and composite tissue allotransplant in rats.

BACKGROUND: Some of the 600,000 patients with solid organ allotransplants need reconstruction with a composite tissue allotransplant, such as the hand, abdominal wall, or face. The aim of this study was to develop a rat model for assessing the effects of a secondary composite tissue allotransplant on a primary heart allotransplant. METHODS: Hearts of Wistar Kyoto rats were harvested and transplanted heterotopically to the neck of recipient Fisher 344 rats. The anastomoses were performed between the donor brachiocephalic artery and the recipient left common carotid artery, and between the donor pulmonary artery and the recipient external jugular vein. Recipients received cyclosporine A for 10 days only. Heart rate was assessed noninvasively. The sequential composite tissue allotransplant consisted of a 3 x 3-cm abdominal musculocutaneous flap harvested from Lewis rats and transplanted to the abdomen of the heart allotransplant recipients. The abdominal flap vessels were connected to the femoral vessels. No further immunosuppression was administered following the composite tissue allotransplant. Ten days after composite tissue allotransplantation, rejection of the heart and abdominal flap was assessed histologically. RESULTS: The rat survival rate of the two-stage transplant surgery was 80 percent. The transplanted heart rate decreased from 150 +/- 22 beats per minute immediately after transplant to 83 +/- 12 beats per minute on day 20 (10 days after stopping immunosuppression). CONCLUSIONS: This sequential allotransplant model is technically demanding. It will facilitate investigation of the effects of a secondary composite tissue allotransplant following primary solid organ transplantation and could be useful in developing future immunotherapeutic strategies.