Report From the American Society of Transplantation Conference on Donor Heart Selection in Adult Cardiac Transplantation in the United States.

Cardiac transplantation remains the only definitive treatment for end-stage heart failure. Transplantation rates are limited by a shortage of donor hearts. This shortage is magnified because many hearts are discarded because of strict selection criteria and concern for regulatory reprimand for less-than-optimal posttransplant outcomes. There is no standardized approach to donor selection despite proposals to liberalize acceptance criteria. A donor heart selection conference was organized to facilitate discussion and generate ideas for future research. The event was attended by 66 participants from 41 centers with considerable experience in cardiac donor selection. There were state-of-the-art presentations on donor selection, with subsequent breakout sessions on standardizing the process and increasing utilization of donor hearts. Participants debated misconceptions and established agreement on donor and recipient risk factors for donor selection and identified the components necessary for a future donor risk score. Ideas for future initiatives include modification of regulatory practices to consider extended criteria donors when evaluating outcomes and prospective studies aimed at identifying the factors leading to nonacceptance of available donor hearts. With agreement on the most important donor and recipient risk factors, it is anticipated that a consistent approach to donor selection will improve rates of heart transplantation.

Everolimus versus mycophenolate mofetil in heart transplantation: a randomized, multicenter trial.

In an open-label, 24-month trial, 721 de novo heart transplant recipients were randomized to everolimus 1.5 mg or 3.0 mg with reduced-dose cyclosporine, or mycophenolate mofetil (MMF) 3 g/day with standard-dose cyclosporine (plus corticosteroids ± induction). Primary efficacy endpoint was the 12-month composite incidence of biopsy-proven acute rejection, acute rejection associated with hemodynamic compromise, graft loss/retransplant, death or loss to follow-up. Everolimus 1.5 mg was noninferior to MMF for this endpoint at month 12 (35.1% vs. 33.6%; difference 1.5% [97.5% CI: -7.5%, 10.6%]) and month 24. Mortality to month 3 was higher with everolimus 1.5 mg versus MMF in patients receiving rabbit antithymocyte globulin (rATG) induction, mainly due to infection, but 24-month mortality was similar (everolimus 1.5 mg 10.6% [30/282], MMF 9.2% [25/271]). Everolimus 3.0 mg was terminated prematurely due to higher mortality. The mean (SD) 12-month increase in maximal intimal thickness was 0.03 (0.05) mm with everolimus 1.5 mg versus 0.07 (0.11) mm with MMF (p < 0.001). Everolimus 1.5 mg was inferior to MMF for renal function but comparable in patients achieving predefined reduced cyclosporine trough concentrations. Nonfatal serious adverse events were more frequent with everolimus 1.5 mg versus MMF. Everolimus 1.5 mg with reduced-dose cyclosporine offers similar efficacy to MMF with standard-dose cyclosporine and reduces intimal proliferation at 12 months in de novo heart transplant recipients.

Myocardial mechanisms causing heart failure early after cardiac transplantation.

Early after heart transplantation, some patients have heart failure (HF) with preserved left ventricular ejection fraction (LVEF), in the absence of rejection. The purpose of this study was to define the mechanisms causing HF early after transplantation and to determine whether these mechanisms involve changes that occur in active or passive myocardial properties. Eleven consecutive patients 1 week after heart transplantation underwent right heart catheterization and echocardiography with an endomyocardial biopsy. Hemodynamic measurements were obtained at spontaneous heart rate, and then were repeated at three atrially paced rates increased in 20-bpm increments above spontaneous heart rate. At baseline, 5 patients (group 1) had clinical HF and a pulmonary capillary wedge pressure (PCWP) > or = 16 mmHg, and 6 patients (group 2) had no clinical evidence of HF and a PCWP < 16 mmHg. LVEF was normal in all 11 patients. The relationships between cardiac index versus heart rate (HR) and PCWP versus HR were normal in all 11 patients. These normal function-versus-frequency relationships suggested that there were no significant abnormalities in the active myocardial processes of contraction or relaxation. In group 1 patients, the PCWP was significantly increased but the left ventricular end diastolic dimension was normal, suggestive of diastolic stiffness. Early after transplantation, there was a significant increase in LV wall thickness in group 1 patients as compared with preexplantation values despite myocardial biopsies in all 11 patients, showing no evidence of rejection, cardiomyocyte hypertrophy, or interstitial fibrosis thus suggestive of myocardial edema.

Heart transplant rejection with hemodynamic compromise: a multiinstitutional study of the role of endomyocardial cellular infiltrate. Cardiac Transplant Research Database.

BACKGROUND: The natural history of patients experiencing hemodynamic compromise with rejection has been incompletely characterized. This multiinstitutional study examined the outcome of such episodes, particularly with regard to the extent of cellular infiltrate on the index endomyocardial biopsy. METHODS: From January 1, 1990, through June 30, 1994, 3367 patients in the Cardiac Transplant Research Database experienced 4137 episodes of rejection. Severe hemodynamic compromise occurred in approximately 5% of the rejection episodes, and this proportion remained relatively constant over time. RESULTS: Recipient risk factors for rejection with severe hemodynamic compromise included black race, female recipient sex, and diabetes. The 3-month actuarial survival rate was 60% after rejection with severe hemodynamic compromise versus 95% after rejection with no or mild compromise. Low initial biopsy score conferred a higher early survival, but a lower survival at 2 years after rejection with severe hemodynamic compromise. Among patients who survive an initial rejection episode with severe hemodynamic compromise, survival at 2 years after an episode was 46% among those who had a low initial biopsy score versus 84% with a high biopsy score. CONCLUSIONS: Rejection with hemodynamic compromise, although rare, represents a major complication of heart transplantation with a poor long-term outcome. Survivors of hemodynamically compromising rejection episodes associated with low biopsy scores in the International Society for Heart and Lung Transplantation grading system have a significantly worse long-term outcome than survivors of episodes associated with high scores. These findings suggest that immunologic mechanisms other than lymphocytic infiltration of the cardiac allograft are important and distinct causes of allograft dysfunction.

Tricuspid valve repair for biopsy-induced regurgitation after cardiac transplantation.

Tricuspid regurgitation is a recognized complication of cardiac transplantation. Damage to the tricuspid valve and subvalvar apparatus has been suggested as a possible cause. We have repaired the tricuspid valves of 2 patients in whom severely symptomatic tricuspid regurgitation developed after transplantation. Gore-Tex sutures were used to replace ruptured chordae anchoring the septal and posterior leaflets. The repair was supported with a Carpentier-Edwards ring. The repairs remain durable at 2 year and 3 years. Both patients demonstrated a similar lesion that we believe to be characteristic of endomyocardial biopsy-induced tricuspid regurgitation.

The cardiac transplant donor: identification, assessment, and management.

In the previous 2 decades, there have been many advances in the treatment of coronary and valvular heart disease. However, these treatments remain imperfect, and more patients are surviving only to have congestive heart failure develop later in life. During the same 2 decades, advances in surgical techniques and immunosuppression made cardiac transplantation the treatment of choice for severe, end-stage heart failure. Despite concomitant legislation designed to promote organ donation, there remains a severe shortfall in the number of organ donors compared with the number of potential recipients. This article discusses identification of the potential organ donor, assessment of the heart for donation, medical management of the brain-dead organ donor from pronouncement to procurement, and finally, some of the ethical issues raised in the wake of further efforts to increase the potential donor pool.

Early hormonal therapy stabilizes hemodynamics during donor procurement.

BACKGROUND: Hemodynamic instability has been implicated in the loss of otherwise transplantable organs. We examined the hypothesis that administration of hormonal therapy early during donor management would stabilize hemodynamics and increase the number of organs procured. METHODS: We retrospectively analyzed 133 consecutive donor records from a single organ procurement organization. Controls (C) received no early hormonal therapy. A steroid group (S) received methylprednisolone only and a combination hormonal therapy group (CH) received thyroxine, methylprednisolone, dextrose, and insulin at the start of donor management (t(0h)). Adrenergic support was adjusted to maintain mean arterial blood pressure (MAP) at > or =60 mm Hg. Doses of adrenergic agents were assessed at t(0h), 4 hours (t(4h)), and just prior to procurement (t(proc)). RESULTS: Baseline characteristics were similar in all groups. Dosages of adrenergic agents decreased over time in all groups. A significant decrease in adrenergic requirements was seen in the CH group compared with the C group at t(4h) and t(proc). A trend toward decreased adrenergic requirements was noted in S compared with C at t(4h) and t(proc). Slightly more total organs were procured from S and CH compared with C. CONCLUSIONS: Significantly less adrenergic support was required with early use of CH. A similar (although nonsignificant) reduction was seen with S. The benefit(s) of CH vs corticosteroids alone remains uncertain and requires further study.

Management of advanced heart failure.

Congestive heart failure (CHF) due to progressive systolic dysfunction has become a modern-day epidemic. Despite the increased incidence and prevalence, significant progress has been made in the past 10 to 15 years in the treatment of CHF at all stages. The current outlook for patients with newly diagnosed, mild heart failure is encouraging. It should be noted, however, that most of the morbidity and health care expenditure is incurred by a minority of patients diagnosed with CHF who are in the advanced stages of their disease. The thrust of this article will be to provide practical advice beyond current guidelines on the management of advanced CHF.

Acute antibody-mediated rejection following heart transplantation.

Acute antibody-mediated rejection (AMR) in heart transplantation is often associated with hemodynamic compromise, and is associated with increased mortality and development of accelerated transplant coronary artery disease (TCAD). The diagnosis of AMR has historically been controversial and outcomes with aggressive immunosuppressive therapy including plasmapheresis and cyclophosphamide are poor. Advances in diagnostic techniques like the demonstration of immunopathologic evidence for antibody-mediated rejection by deposition of the complement split product C4d in tissue and detection of anti-HLA antibodies by flow cytometry will assist in further characterizing AMR. Immunosuppression targeting B-lymphocytes and use of m-TOR inhibitors to alter the predilection to develop TCAD and improve survival in AMR remains to be proven.

Improving clinical practice: should we give influenza vaccinations to heart transplant patients?

BACKGROUND: Current practice recommends that immunosuppressed patients (pts) receive yearly influenza (flu) vaccinations. However, disparity exists between current recommendations and clinical practice regarding the decision to administer flu vaccinations to heart transplant (Tx) pts. The purpose of this study was to examine the common clinical practices and outcome characteristics in Tx pts in a multi-institutional database. We assess the incidence of rejection, infection and flu in the months after administration of flu vaccinations. METHODS: Between 1990 and 2001, 5,581 pts underwent Tx at 28 institutions. Pts who were >1 year post-Tx as of January 1, 2002 (N = 3,601) constituted the study group. RESULTS: During the years 2002 and 2003, 89% of the institutions administered flu vaccines, with 7 institutions requiring pts to be >3 months (N = 1), 6 months (N = 1) and 12 months (N = 5) post-Tx. All 25 centers that vaccinated pts used trivalent inactivated vaccines during the months of October through January. Three centers did not vaccinate Tx pts due to a purported association with increased allograft rejection. There were no significant differences in the total number of rejection episodes (0.4% vs 0.3%, p = 0.7), rejection episodes by month (January: 0.4% vs 0%, p = 0.2; February: 0.5% vs 1.5%, p = 0.08; March: 0.5% vs 0%, p = 0.14), all infections (0.7% vs 0.6%, p = 0.6) and viral infections (0.1% vs 0%, p = 0.17) between centers that administered flu vaccines and those that did not, respectively. The incidence of flu was low in both groups. CONCLUSIONS: Flu vaccinations can be given safely to heart transplant pts without an increased incidence of rejection or infection. This information provides clinicians with data to improve clinical practice.

Myocarditis.

Myocarditis is difficult to diagnose owing to its diversity of presentation. Definitive treatment strategies remain elusive as well. Intuitively, therapies for viral myocarditis should be directed towards eradicating the viral infection and modulating the subsequent immune response. Antiviral agents have not yet been adequately studied. Immunomodulating therapy is difficult to develop as the immune system is both protective and injurious in this disease. Clinical trials to date suggest that there may be a window early in the disease process in which immunosuppressive therapy would be effective but this remains unproven. This possibility makes early diagnosis essential. Improved diagnostic and therapeutic measures clearly need to be developed.