Infant orthotopic cardiac transplantation

Infant orthotopic cardiac transplantation has been recently applied to various forms of congenital heart disease with encouraging short-term results. Between June 1986 and September 1987 we evaluated 16 infants for orthotopic cardiac transplantation. Fourteen had hypoplastic left heart syndrome, one had endocardial fibroelastosis with aortic atresia, and one had anomalous pulmonary arterial origin of the left main coronary. Eight families accepted the treatment program and eight families refused (two because of associated anomalies and six on philosophical grounds). Of the eight patients who were candidates for orthotopic cardiac transplantation, one died 6 hours after diagnosis, one was allowed to die after 60 days because of acquired neurologic complications, and another had congenital cytomegalic virus infection. The remaining five patients (four with hypoplastic left heart syndrome, one with anomalous pulmonary arterial origin of the left main coronary) had orthotopic cardiac transplantation. The operation was performed with absorbable polydioxanone suture with deep hypothermia and circulatory arrest in four neonates for hypoplastic left heart syndrome (average time 47 minutes) and bicaval cannulation and continuous bypass in one 11-month-old infant for anomalous origin of the left main coronary. In-house retrieval was used in all. One neonate died of complications as a result of pretransplant donor heart dysfunction and size discrepancy, whereas the remaining three neonates and one infant survived and are home 23 months, 12 months, and 8 months (the patients with hypoplastic left heart syndrome) and 17 months (the patient with anomalous origin of the left main coronary) postoperatively. Triple-drug immunosuppression included cyclosporine, azathioprine, and prednisone. Rejection was diagnosed by clinical evaluation of child activity and monocyte cell cycle analysis from peripheral blood samples without myocardial biopsies. Routine echocardiograms, electrocardiograms, and chest x-ray films were not helpful. Six episodes of rejection were successfully treated in four patients. Twelve-month postoperative catherization in one patient (hypoplastic left heart syndrome) showed appropriate graft growth, no aortic or pulmonary anastomotic strictures, normal right and left ventricular function, and no coronary artery disease. We conclude that infant orthotopic cardiac transplantation is an acceptable procedure for severe forms of untreatable congenital heart disease. The excellent short-term results warrant continued application of orthotopic cardiac transplantation.     

Clinical orthotopic cardiac transplantation

The results of orthotopic cardiac transplantation have improved dramatically since the early experiences in the late 1960s. After almost 20 years of research and experience and the introduction of cyclosporine, 1 and 5 year survival rates are now 80 percent and 60 percent, respectively. The number of potential recipients far exceeds that of available donors, which is the limiting factor in cardiac transplantation. Complications related to immunosuppressive therapy remain significant, and despite decreased length of hospitalization, costs remain high. The majority of patients have good functional rehabilitation and are free of cardiac symptoms. Moreover, orthotopic cardiac transplantation has finally become a therapeutic treatment of end-stage heart disease.     

Potassium-verapamil cardioplegia for myocardial protection: an experimental evaluation through preservation and transplantation

The efficacy of potassium-verapamil cardioplegia for myocardial protection was studied using the canine heart preservation and transplantation system. Coronary vascular washout of the grafts was performed via the aortic root both in Group I (n=8) with 4 degrees C high potassium cardioplegic solution and in Group II (n=8) with 4 degrees C high potassium and 1 mg/L verapamil solution. The heart were immersed into the same solution as used for washout and stored at 4 degrees C for 6 hours, without oxygenation and perfusion. The grafts were transplanted orthotopically under conditions of cardiopulmonary (CP) bypass. Adequate hemodynamics without the support of CP bypass was obtained in all the grafts of Group II during a 2-hour observation period. In contrast, only five out of eight grafts in Group I were able to support the recipient circulation. Contraction bands were more prominently and frequently observed in the histology in Group I. Thus, the combination of coronary vascular washout with cold potassium-verapamil cardioplegia and storage at 4 degrees C with the same solution seems to be effective for myocardial protection of the canine heart in cases of orthotopic transplantation.     

A comparative study of the most widely used solutions for cardiac graft preservation during hypothermia.

BACKGROUND: Reports conflict on the benefits of preservative solutions. We investigated the efficacy of the most widely used cardioplegic solutions by comparing extracellular solutions such as Celsior solution, St. Thomas Hospital solutions 1 and 2 (STH-1, STH-2), the modified University of Wisconsin solution (UW-1), Lyon Preservation solution (LYPS) from our laboratory, and intracellular solutions such as standard University of Wisconsin solution (UW), Bretschneider solution (HTK), Stanford solution (STF), and Euro-Collins solution (EC). METHODS: Male rats (n = 110) were randomized into 11 groups: LYPS, Celsior, STH-1, STH-2, UW-1, UW, HTK, STF, EC, and normal saline solution groups, and a control group. All hearts, except controls, were preserved by cold storage (8 hours at 4 degrees C) in the various solutions. We used an isolated non-working-heart model and biopsy specimens to assess heart preservation (n = 5/group). RESULTS: Hearts stored in the EC and saline solutions had poor left ventricular developed pressure (LVDP) x heart rate (HR) (1,407.5 +/- 154 and 1,390 +/- 439 mm Hg/mn, respectively). In contrast, hearts stored in LYPS and Celsior had a LVDP x HR close to control hearts (31,349 +/- 1,847, 27,620 +/- 1,207, and 36,627 +/- 1,322 mm Hg/mn, respectively), whereas hearts stored in STH-1, STH-2, UW-1, UW, HTK, and STF had intermediate functional response (14,278 +/- 2,176, 12,402 +/- 1,571, 11,428 +/- 1,629, 11,603 +/- 2,521, 7,045 +/- 537, and 7,086 +/- 1,206 mm Hg/mn, respectively). Hearts preserved with STH-2, UW, HTK, STF, EC, and saline solution showed significantly increased release of creatine kinase and lactate dehydrogenase than did control hearts or hearts preserved in Celsior, LYPS, STH-1, and UW-1. The energetic charge (EC = [(0.5 adenosine diphosphate + adenosine triphosphate) / (adenosine triphosphate + adenosine diphosphate + adenosine monophosphate)]) in STH-2, UW, HTK, STF, EC, and saline groups was significantly lower (p < 0.05) than in the other groups. CONCLUSION: Extracellular-type solutions provided better preservation than did intracellular-type solutions. However, UW and UW-1 (intracellular- and extracellular-type solutions) provided equivalent preservation of cardiac function. Preservation quality may be attributed to calcium, often added to extracellular solutions. Among extracellular solutions, Celsior and LYPS solution showed comparable efficacy on left ventricular function and seemed to offer better preservation than the other solutions tested in this study.     

A comparative study of Celsior and University of Wisconsin solutions based on 12-hr preservation followed by transplantation in canine models

BACKGROUND: Celsior is a recently developed extracellular-type preservation solution that is effective in organ preservation. This experimental study was designed to compare the effects of Celsior and University of Wisconsin (UW) solutions in myocardial protection, using 12-hour preservation followed by orthotopic transplantation. METHODS: Fourteen pairs of adult mongrel dogs were divided into 2 groups. In the UW group (n = 7), UW solution at 4 degrees C was used for coronary vascular washout and storage following cardiac arrest with glucose-insulin-potassium (GIK) solution. In the Celsior group (n = 7), Celsior solution was used to produce cardiac arrest, for coronary vascular washout, and for storage. After 12-hour cold preservation, orthotopic transplantation was performed under cardiopulmonary bypass (CPB). The rate of recovery (%) of cardiac function of donor hearts was compared 1 and 2 hours after weaning from CPB, and then the transplanted hearts were harvested for histological study. RESULTS: Hemodynamic parameters including cardiac output, left ventricular pressure (LVP), and the maximum rates of positive and negative increase of LVP after transplantation were significantly (p < 0.05) higher in the Celsior group than in the UW group 2 hours after weaning from CPB. The transmission electron microscopic study found that degeneration of the mitochondria in the Celsior group was less extensive than in the UW group. CONCLUSION: Celsior solution enhanced the cardiac function of hearts preserved for 12 hours prior to transplantation compared to UW solution. Our results indicate that Celsior solution is equivalent or superior to UW solution for cardiac preservation.     

A comparative study on changes in hemostasis in orthotopic and auxiliary liver transplantation in pigs

We compared blood loss and hemostasis in pigs which had undergone either orthotopic liver transplantation (OLT) (group A, n=12) or auxiliary heterotopic partial liver transplantation (APLT) (group B, n=11). Blood samples were taken at regular intervals during and after the operations. In both groups, nine animals survived longer than 24 h and data from these animals were used for analysis. Median (range) intraoperative blood loss was 825 ml (250–1500 ml) in OLT and 425 ml (300–750) in APLT (P<0.01). Routine clotting times, as the activated partial thromboplastin time, prothrombin time and thrombin time, showed no major intraoperative changes in either group. Fibrinogen levels decreased in both groups, but no significant difference was found between the two groups. The only significant difference between group A and B was a more sustained increase in fibrinolytic activity after graft recirculation in group A. Post-operatively, restoration of fibrinogen, antithrombin-III and ₂-antiplasmin levels was slightly faster in group B, resulting in significantly higher levels during the first day. We conclude that, in this animal model, APLT is associated with significantly lower blood loss and less severe fibrinolytic activity, than OLT. This difference might result from the lack of an anhepatic period and the reduced surgical trauma in auxiliary heterotopic liver transplantation.     

hDAF porcine cardiac xenograft maintains cardiac output after orthotopic transplantation into baboon--a perioperative study

BACKGROUND: Only limited data are available on the physiological functional compatibility of cardiac xenografts after orthotopic pig to baboon transplantation (oXHTx). Thus we investigated hemodynamic parameters including cardiac output (CO) before and after oXHTx. METHODS: Orthotopic xenogeneic heart transplantation from nine hDAF transgeneic piglets to baboons was performed. We used femoral arterial thermodilution for the invasive assessment of CO and stroke volume. RESULTS: Baseline CO of the baboons after induction of anesthesia was 1.36 (1.0-1.9) l/min. 30 to 60 min after termination of the cardiopulmonary bypass, CO of the cardiac xenograft was significantly increased to 1.72 (1.3-2.1) l/min (P < 0.01). The stroke volumes of the baboon heart before transplantation and the cardiac xenograft was comparable [14.9 (11-26) vs. 11.8 (10-23) ml]. Thus the higher CO was achieved by an increase in heart rate after oXHTx [75.0 (69-110) vs. 140.0 (77-180)/min; P < 0.01]. Despite the increased CO, oxygen delivery was reduced [256 (251-354) vs. 227 (172-477) ml/min; P < 0.01] due to the inevitable hemodilution during the cardiopulmonary bypass and the blood loss caused by the surgical procedures. CONCLUSION: Our results demonstrate that in the early phase after orthotopic transplantation of hDAF pig hearts to baboons, cardiac function of the donor heart is maintained and exceeds baseline CO. However, in the early intraoperative phase this was only possible by using inotropic substances and vasopressors due to the inevitable blood loss and dilution by the priming of the bypass circuit.     

心脏死亡供体经典原位肝移植的单中心临床研究

目的总结心脏死亡器官捐献（donation after cardiac death,DCD）供体供肝获取及应用于肝移植的临床经验和可行性。方法2011年11月至2012年9月,西安交通大学第一附属医院采用Maastricht标准或中国标准,共获取18例DCD供肝,于该院完成经典原位肝移植14例,送往其他移植中心3例,放弃1例。对18例供体与在该院完成肝移植的14例受体的临床资料进行回顾性分析,了解供肝情况、受体围手术期及随访结果。结果18例供体中符合Maastricht标准Ⅲ类5例、V类2例,符合中国标准Ⅲ类（即脑一心双死亡标准器官捐献,donation after brain death plus cardiac death, DBCD）11例。按规范器官获取流程取得供肝。供肝的热缺血时间为11～18min,平均为14．5min;冷缺血时间为90—600min,平均为350min。14例受体均顺利完成移植手术。其中12例受体预后良好,肝功能逐渐恢复,未出现原发性移植肝无功能、血栓形成、排斥反应,但2例出现胆道狭窄并发症,经胆道支架置人术后引流通畅;重症监护室（ICU）治疗时间平均7d,术后住院时间平均23d,病情稳定后出院。1例受体术后2d死于肝衰竭,其供体原发病为冠状动脉粥样硬化性心脏病,需给予大量多巴胺维持其血压;另1例于术后当日死于腹腔内大出血,其供体为重症哮喘、心肺复苏后死亡。12例受体者平均随访时间为6个月,总体存活率为85％,肿瘤患者尚未发现复发转移。结论DCD可以扩大供肝来源且近期效果良好,具有可行性。实施可控型DCD捐献,严格掌握供者适应证、加强器官评估、缩短热缺血时间和冷缺血时间,是保障供肝质量的重要因素。     

Cariporide (HOE-642) improves cardiac allograft preservation in a porcine model of orthotopic heart transplantation

BACKGROUND: Acute graft dysfunction caused by ischemia-reperfusion injury is recognized as a major source of morbidity and mortality following adult heart transplantation. The aim of this study was to determine whether treating the donor and recipient with cariporide, an inhibitor of the sodium-hydrogen exchanger, could reduce ischemia-reperfusion injury. METHODS: A porcine model of donor brain death, hypothermic ischemic preservation, and orthotopic cardiac transplantation was used. Allografts in both the control group (CON, n=6) and treatment group (CAR, n=6) were arrested and stored for 4 hours in the extracellular crystalloid cardioplegia currently used in the clinical transplantation program at our institution. In addition, both the donor and recipient animals in the CAR group received a single intravenous dose of cariporide (2 mg/kg) 15 minutes before harvesting and reperfusion, respectively. RESULTS: The initial rate of troponin I release was significantly lower in recipients of CAR hearts than in recipients of CON hearts (P =0.020). All hearts were weaned successfully from bypass. More CAR hearts were weaned successfully at the first attempt, at 1 hour post-reperfusion, than CON hearts (6 of 6 vs 3 of 6), but this did not achieve statistical significance. Left ventricular contractility (preload recruitable stroke-work relationship) and left ventricular compliance (end-diastolic pressure-volume relationship) were significantly better preserved in CAR hearts than CON hearts (both P <0.0001). CONCLUSIONS: Myocardial injury was reduced, and contractile function was better preserved in allografts that received cariporide, compared with allografts that received conventional preservation alone.     

Transgenic animals in experimental xenotransplantation models: orthotopic heart transplantation in the pig-to-baboon model

Pig organs are at risk for hyperacute and acute vascular rejection mediated by anti-pig antibodies, mainly binding to the Galalpha(1,3)Gal epitope. Acute cellular rejection is characterized by progressive infiltration of mononuclear cells. There is an ongoing search for immunosuppressive regimens that provide adequate protection against all patterns of xenograft rejection, but have no severe impact on the condition of xenograft recipients. Herein orthotopic heart transplantations were performed from hDAF or hCD46 piglets to nonsplenectomized baboons. Basic immunosuppression consisted of tacrolimus, sirolimus, GAS914, steroids, and ATG. Group 1 received basic immunosuppression. Group 2 was additionally treated with rituximab and group 3 with half-dose cyclophosphamide. Group 4 received cyclophosphamide and an anti-HLA-DR antibody. Three baboons received GAS914 and TPC. Monitoring included the regular assessment of anti-porcine antibodies, blood counts, therapeutic drug monitoring, and graft histology. Two grafts failed due to technical mistakes. In group 1, baboons died after 1 and 9 days. In group 2, maximum survival was 30 hours. In group 3, baboons lived 20 hours, 25 days, and 14 days. Group 4 survival times were 9.5 hours, 5.5 hours, 4 days, 34 hours, and 3 days. An increase of non-Galalpha(1,3)Gal antibodies was observed. Depositions of immunoglobulins and complement revealed a humoral rejection process. No cellular infiltration could be observed. In conclusion, suppressing cellular rejection with half-dose cyclophosphamide together with tacrolimus and sirolimus produced longer graft survival with a good general condition. Prevention of acute xenograft rejection further needs inhibition of non-Galalpha(1,3)Gal cytotoxicity by sufficient depression of B-cell activation.     

Safe technique for aortic anastomosis in orthotopic canine cardiac transplantation

In canine orthotopic transplantation, bleeding from the aortic suture line is often encountered, leading to the failure of the experiment. A new method for canine aortic anastomosis is described that is safe, simple to perform, and reproducible.     

原位心脏移植28例报道

目的 总结28例心脏移植的临床资料，探讨手术效果以及免疫诱导方法。方法 2000年1月至2005年5月共完成28例同种原位心脏移植术。2003年前进行心脏移植的14例受者围手术期采用环孢素A＋霉酚酸酯免疫诱导方案，2003年后的14例受者采用达利珠单抗＋霉酚酸酯免疫诱导方案。结果 28例受者均顺利完成手术，术后无出血、扭曲、右心功能不全等手术并发症。2003年前移植的受者中，有6例出现不同程度的肝、肾功能不全，3例并发不同程度的感染。2003年后移植的受者无1例术后发生肝、肾功能不全和感染。结论 心脏移植是治疗终末期心肌病变的有效手段。达利珠单抗＋霉酚酸酯诱导方法效果较好。