Xenogeneic orthotopic heart transplantation: Where are we now?

Cardiac xenotransplantation is a promising option for satisfying the unmet need for cardiac replacement. Mechanical hearts have been in development for over 40 years and only one device is currently available “off the shelf” for implantation in the United States. It took 39 years for this first approved device to be available. This device approval arose from outcomes from the rematch trial (2001) when survival in the ventricular assist device group was fifty‐two percent and twenty‐three percent at 1 and 2 years, compared with twenty‐five percent and eight percent in the medically treated group. Quality of life was significantly improved at 1 year in the ventricular assist device group. While mechanical support continues to improve, intrinsic disadvantages remain, such as thromboembolism, the need for careful anticoagulation, infection, lack of physiological response, durability and power supply. Pursuit of cardiac xenotransplantation therefore remains a potentially important contributor to the treatment of heart failure clinically. With the addition of human complement regulating proteins to the pig genome using a micro‐injection technique and the subsequent development of Gal knockout pigs using cloning technology, pre‐clinical median survival of heterotopic cardiac xenotransplants is now in excess of 3 months. A three months median survival of orthotopic cardiac xenotransplants has been proposed as a possible threshold for a clinical trial. Attention has therefore focused on the orthotopic cardiac xenotransplant pig to baboon model. There have been six operative survivors ranging from 2 to 57 days. Immunosuppression in these recipients consisted of ATG induction, tacrolimus, sirolimus, anti‐CD20 and a steroid taper. No anticoagulation was used. None of the animals died of rejection. The causes of failure largely related to the challenges of the model system. In four of the six cases rejection was minimal and the remaining two mild to moderate. Recipients were healthy and well during the post‐operative period. Biochemistry was stable. Challenges encountered during these studies have included early peri‐operative heart failure which has markedly improved with peri‐operative management. These studies have shown maintenance of normal cardiac function for up to 2 months following pig to baboon transplantation. In addition, hearts from the recipients who survived showed peri‐operative myocardial dysfunction that completely recovered post‐operatively within a few days. Outcomes of pre‐clinical orthotopic cardiac xenotransplantation continue to improve with this report describing the longest survivors to date. Porcine hearts can function normally in primates for at least 2 months. Peri‐operative cardiac dysfunction is likely avoidable and is recoverable. Reparative processes are intact in the xenotransplant setting. Cardiac xenograft rejection is well controlled on tolerable immunosuppressants. Model limitations remain a serious challenge. The powerful advantage of biologic cardiac replacement (complete implantability, intrinsic power supply, lack of need for anticoagulation and physiological responsiveness) justifies continued pre‐clinical studies. In the first instance the goal of clinical cardiac xenotransplantation will be to provide additional treatment alternatives for patients with end‐stage organ failure. The comparison on outcomes will be with other available treatments and not allotransplantation in the first instance. Research programme supported by NIH Grant A166310.     

Does total orthotopic heart transplantation offer improved hemodynamics during cellular rejection events?

BACKGROUND: We hypothesized that total orthotopic heart transplantation (TOHT) improves hemodynamics during cellular rejection compared with biatrial transplantation (SOHT). METHODS: We reviewed 1942 biopsies from 134 patients (pts) and right heart catheterization data obtained at endomyocardial biopsy. Biopsies that displayed cellular rejection grade 1B as classified according to International Society for Heart and Lung Transplantation (ISHLT) criteria were analyzed. Pts with pacemakers, atrial fibrillation, or beta-blocker therapy at the time of biopsy were excluded. Twenty-three pts after TOHT and 38 after SOHT were identified to match these criteria. RESULTS: Demographic data and pretransplant hemodynamics were similar. TOHT pts had a higher mean cardiac index than SOHT recipients (3.3 +/- 0.8 vs 2.7 +/- 0.5 L/min/m(2); P =.002). Right atrial mean pressure was lower after TOHT (8 +/- 4 vs 11 +/- 4 mm Hg; P =.006). Pulmonary pressures, pulmonary vascular resistance, and heart rate were similar. CONCLUSIONS: TOHT offers improved hemodynamics during cellular rejection grade 1B as evidenced by higher cardiac output and index with lower right atrial pressures. Future studies must examine the potential benefits of TOHT during more severe rejection events.     

Does duration of donor brain injury affect outcome after orthotopic pediatric heart transplantation?

OBJECTIVE: We tested the hypothesis that duration of donor brain injury and death would have an adverse effect on recipient rejection and mortality in pediatric heart transplantation. METHODS: Ninety-three cardiac transplants were performed at our center from July 1, 1997, through June 30, 2003. The primary study end points were the number of rejection episodes and the time to first rejection. Secondary outcomes were early and late mortality. RESULTS: Among 88 recipients of 93 cardiac allografts, 5 (6%) and 1 (1%) received second and third allografts, respectively. Overall patient mortality (3 early and 2 late) was 6% (5/88), and overall graft loss was 6% (6/93). Median time from donor brain injury to declaration of brain death (brain injury interval), time from brain death to donor cardiectomy (brain death interval), and graft ischemia time were 38, 24, and 3.3 hours, respectively. Cox regression analysis (adjusting for United Network for Organ Sharing status, ventilator dependence, extracorporeal membrane oxygenation and ventricular-assist device status, diagnosis of congenital heart disease, sex and cytomegalovirus mismatches, and type of immunosuppression) demonstrated that recipients of donor hearts with relatively long periods from brain injury to death declaration or from death to organ removal had significantly improved rejection-free survival (hazard ratios 0.3, P = .01, and 0.5, P = .05, for brain injury and brain death times, respectively). Prolonged donor heart ischemia did not impact rejection rate. Increasing brain injury interval, brain death interval, and graft ischemia time had no significant effect on mortality. CONCLUSION: Longer brain injury and death intervals correlated with improved freedom from rejection but had no effect on mortality.     

Outcomes of pulmonary metastases in hepatoblastoma — is the prognosis always poor?

Background

Hepatoblastoma is a rare tumour accounting for approximately 1% of all paediatric malignancies. Hepatoblastoma complicated by pulmonary metastatic disease continues to cause management difficulties due to a lack of robust evidence and treatment guidelines.

Method

This series is the experience of a tertiary paediatric referral centre. Patients were prospectively enlisted, and their charts were retrospectively reviewed.

Results

Thirty-seven patients were treated for hepatoblastoma from 1995 to 2012 inclusive. The overall survival was 34/37(91.9%). Eight patients had lung metastases at diagnosis (LMD) and twenty-nine did not (NLMD). Two-year EFS was 62.5% in the LMD group and 89.3% in the NLMD group (p = 0.078). Overall survival in the LMD and NLMD groups was 100% and 89.7%, respectively (p = 0.389). Two patients in the LMD group required multiple thoracic resections to achieve cure. Within the NLMD group, two patients developed lung metastases whilst on treatment, and both of these patients died.

Conclusion

In this series, children presenting with lung metastases had a higher risk of relapse but excellent overall survival. However, children who developed pulmonary disease during treatment had a poor prognosis. We advocate aggressive surgical treatment of pulmonary hepatoblastoma to achieve cure.     

Endomyocardial biopsy in heart transplantation: schedule or event?

Background

Endomyocardial biopsy is the gold standard to identify rejection after heart transplantation. Due to its invasiveness, discomfort, and difficult vascular access, some patients are not willing to accept routine scheduled biopsies years after heart transplantation. The purpose of this study was to identify whether there was a difference in outcomes among the scheduled versus event biopsy groups.

Methods

We studied 411 patients who underwent heart transplantation from 1987 to 2011, reviewing biopsy results and pathology reports. There were 363 patients who followed the scheduled biopsy protocol, and 48 patients who were assigned to the event biopsy group. We extracted data on biopsy results, rejection episodes, rejection types, and survival time.

Results

The 2481 reviewed biopsies over 24 years, showed most rejection episodes (86.4%) to occur within 2 years after heart transplantation. The rejection incidence was low (2.1%) at 3 years after transplantation. The major reason for an event biopsy was poor vascular access, such as tiny central vein or congenital disease without a suitable central vein. Event biopsy group patients were younger than schedule biopsy patients (19.7 years old vs 47.6 years old; P < .05). The 10-year survival rates were 64% among the event versus 53% among the scheduled biopsy group (P = .029). The 10-year rates of freedom from rejection were similar.

Conclusions

The rejection rate was low after 3 years; episodes occurred within 2 years. Although the long-term survival in the event group was better, they had a younger man age. The rejection and freedom from rejection rates were similar. As the rejection rate was low at 3 years after transplantation, we suggest that the event principle could be applied for biopsy at 3 years after heart transplantation.     

Is early hospital discharge feasible following normothermic coronary artery surgery on the fibrillating heart?

AIM: Protocols for the earlier discharge of cardiac surgical patients are gaining popularity. We present our experience with an early hospital discharge policy following coronary artery bypass grafting (CABG) on the fibrillating heart. METHODS: Three-hundred and ninety-two consecutive patients who underwent elective CABG by a single surgeon were retrospectively reviewed. CABG was performed initially (1998-1999) in 191 patients with cardiopulmonary bypass (CPB) normothermia, intermittent aortic cross-clamping (AXC) and ventricular fibrillation and later (2001-2003) in 201 patients without CPB. Emphasis was given on short AXC and CPB times, early extubation, early mobilization and atrial fibrillation prophylaxis. Discharge criteria were as follows: walking on stairs unassisted, sinus rhythm for 24 hours, normal bowel function, apyrexia, family support at home. A 6-week follow-up clinic visit was arranged. Hospital re-admissions were carefully monitored. RESULTS: The mean (+/-SD) age of the patients was 62+/-9.6 years and the mean Parsonnet score was 6.7. The mean hospital stay was 6.1+/-2.5 days. Sixty-three (16%) and 171 (44%) patients were discharged by postoperative day 4 and 5, respectively. The following factors were independently associated with longer hospital stay: number of grafts performed (>3), requirement for postoperative inotropic support and social circumstances inadequate for early discharge. Twenty-three patients (5.8%) were re-admitted in the 6-week postoperative period. Shorter hospital stay was not associated with increased risk of re-admission. CONCLUSION: Early discharge after CABG with ventricular fibrillation is achievable, comparable to "fast-track techniques" without the use of CPB and is not associated with higher re-admission rates. We recommend the routine use of this protocol in all patients undergoing primary elective CABG.     

Does the use of pulmonary artery catheters increase the number of organs available for transplantation?

Hadjizacharia P, Salim A, Brown C, Inaba K, Chan LS, Mascarenhas A, Margulies DR. Does the use of pulmonary artery catheters increase the number of organs available for transplantation?
Clin Transplant 2010: 24: 62–66. © 2009 John Wiley & Sons A/S. Abstract: Aggressive donor management, including the placement of a pulmonary artery catheter (PAC) to monitor hemodynamic status and tissue perfusion, has been associated with a significant increase in the number of organs recovered for transplantation. Nonetheless, there has been growing scrutiny over the use of PACs because of their known complications and lack of therapeutic effect. The purpose of this study is to evaluate the use of PACs in the management of organ donors. The records of all patients who successfully donated organs between January 1, 2002 and December 31, 2005 were reviewed. A total of 96 patients underwent successful organ donation during the four‐yr study period. Of these, 49 (51.0%) were managed with a PAC. Compared with donors managed without a PAC, there were significantly more hearts recovered from donors managed with a PAC (71.4% vs. 44.7%; p = 0.0079) with no difference in the daily administration of fluids and vasopressors between the two groups. The management of organ donors with a PAC can help maximize cardiac procurement.