Use of Anti-Thymocyte Globulin for Induction Therapy in Cardiac Transplantation: A Review.

The most common causes of death after heart transplantation (HTx) include acute rejection and multi-organ failure in the early period and malignancy and cardiac allograft vasculopathy (CAV) in the late period. Polyclonal antibody preparations such as rabbit anti-thymocyte globulin (ATG) may reduce early acute rejection and the later occurrence of CAV after HTx. ATG therapy depletes T cells, modulates adhesion and cell-signaling molecules, interferes with dendritic cell function, and induces B-cell apoptosis and regulatory and natural killer T-cell expansion. Evidence from animal studies and from retrospective clinical studies in humans indicates that ATG can be used to delay calcineurin inhibitor (CNI) exposure after HTx, thus benefiting renal function, and to reduce the incidence of CAV and ischemia-reperfusion injury in the transplanted heart. ATG may reduce de novo antibody production after HTx. ATG does not appear to increase cytomegalovirus infection rates with longer prophylaxis (6-12 months). In addition, ATG may reduce the risk of lymphoproliferative disease and does not appear to confer an additive effect on acquiring lymphoma after HTx. Randomized, controlled trials may provide stronger evidence of ATG association with patient survival, graft rejection, renal protection through delayed CNI initiation, as well as other benefits. It can also help establish optimal dosing and patient criteria to maximize treatment benefits.

Combined Heart and Kidney Transplantation: A 23-Year Experience.

BACKGROUND: We report clinical experience with combined heart and kidney transplantation (HKTx) over a 23-year time period. METHODS: From June 1992 to August 2015, we performed 83 combined HKTx procedures at our institution. We compared the more recent cohort of 53 HKTx recipients (group 2, March 2009 to August 2015) with the initial 30 previously reported HKTx recipients (group 1, June 1992 to February 2009). Pre-operative patient characteristics, peri-operative factors, and post-operative outcomes including survival were examined. RESULTS: The baseline characteristics of the two groups were similar, except for a lower incidence of ethanol use and higher pre-operative left-ventricular ejection fraction, cardiac output, and cardiac index in group 2 when compared with group 1 (P = .007, .046, .037, respectively). The pump time was longer in group 2 compared with group 1 (153.30 ± 38.68 vs 129.60 ± 37.60 minutes; P = .007), whereas the graft ischemic time was not significantly different between the groups, with a trend to a longer graft ischemic time in group 2 versus group 1 (195.17 ± 45.06 vs 178.07 ± 52.77 minutes; P = .056, respectively). The lengths of intensive care unit (ICU) and hospital stay were similar between the groups (P = .083 and .39, respectively). In addition, pre-operative and post-operative creatinine levels at peak, discharge, 1 year, and 5 years and the number of people on post-operative dialysis were similar between the groups (P = .37, .75, .54, .87, .56, and P = .139, respectively). Overall survival was not significantly different between groups 2 and 1 for the first 5 years after transplant, with a trend toward higher survival in group 2 (P = .054). CONCLUSIONS: The most recent cohort of combined heart and kidney transplant recipients had similar ICU and hospital lengths of stay and post-operative creatinine levels at peak, discharge, and 1 and 5 years and a similar number of patients on post-operative dialysis when compared with the initial cohort. Overall survival was not significantly different between the later and earlier groups, with a trend toward higher overall survival at 5 years in the more recent cohort of patients. In selected patients with co-existing heart and kidney failure, combined heart and kidney transplantation is safe to perform and has excellent outcomes.

Tacrolimus-associated Diffuse Gastrointestinal Ulcerations and Pathergy: A Case Report.

Tacrolimus is a common immunosuppressive modality with a range of therapeutic applications, including for rheumatologic disease, nephrotic syndrome, and inflammatory bowel disease. The medication also plays an integral role in organ transplantation. However, tacrolimus has a significant side effect profile, which commonly includes nephrotoxicity, neurotoxicity, infection risk, and anemia. We describe an unusual case of tacrolimus toxicity in a cardiac transplant patient, manifesting as diffuse gastrointestinal ulcerations and pathergy. Our goal was to further characterize the toxicity of tacrolimus to include this rare presentation.

Report from a forum on US heart allocation policy.

Since the latest revision in US heart allocation policy (2006), the landscape and volume of transplant waitlists have changed considerably. Advances in mechanical circulatory support (MCS) prolong survival, but Status 1A mortality remains high. Several patient subgroups may be disadvantaged by current listing criteria and geographical disparity remains in waitlist time. This forum on US heart allocation policy was organized to discuss these issues and highlight concepts for consideration in the policy development process. A 25-question survey on heart allocation policy was conducted. Among attendees/respondents were 84 participants with clinical/published experience in heart transplant representing 51 US transplant centers, and OPTN/UNOS and SRTR representatives. The survey results and forum discussions demonstrated very strong interest in change to a further-tiered system, accounting for disadvantaged subgroups and lowering use of exceptions. However, a heart allocation score is not yet viable due to the long-term viability of variables (used in the score) in an ever-developing field. There is strong interest in more refined prioritization of patients with MCS complications, highly sensitized patients and those with severe arrhythmias or restrictive physiology. There is also strong interest in distribution by geographic boundaries modified according to population. Differences of opinion exist between small and large centers.

Left ventricular assist device in patients with body mass index greater than 30 as bridge to weight loss and heart transplant candidacy.

INTRODUCTION: In obese patients with heart failure, weight reduction may be difficult due to physical restrictions, but may be necessary to achieve heart transplant candidacy. We report the outcomes of obese patients who underwent implantation of a left ventricular assist device (LVAD) using a pulsatile (HeartMate XVE [XVE]) or continuous flow (HeartMate II [HMII]) design and the effect on body mass index (BMI). METHODS: Of 37 patients with BMI >30 kg/m(2) who underwent LVAD implantation, 29 survived at least 30 days and were followed for weight change. In the 30-day survivors, end points of the study were continued LVAD support, heart transplant, or death. One patient underwent gastric bypass surgery and was excluded. RESULTS: In the 28 patients who met inclusion criteria, BMI was 35.6 ± 4.4 kg/m(2) at baseline, and at follow-up was 33.1 ± 5.5 kg/m(2) (mean BMI change -2.5 kg/m(2); P = .063), with a mean follow-up time of 301.6 ± 255.5 days. The XVE group showed a significant BMI reduction of 3.9 kg/m(2) (P = .016 vs baseline); however, the HMII group showed 0.1 kg/m(2) increase in BMI. BMI <30 kg/m(2) at follow-up was achieved in 6 patients (21%), 5 of 19 (26%) in XVE group, and 1 of 9 (11%) in HMII group. In the 14 patients (12 XVE, 2 HMII) or 50% who received a heart transplant, the mean decrease in BMI was 4.6 kg/m(2) (P = .003). CONCLUSIONS: LVAD placement in patients with BMI >30 kg/m(2) provided significant weight loss in the pulsatile XVE group, but not in recipients of the continuous flow HMII. In patients successfully bridged to a heart transplant after LVAD insertion, mean reduction in BMI was 4.6 kg/m(2) (P = .003). LVAD implantation provides a period of hemodynamic support for obese patients with advanced heart failure, during which time opportunity may be available for weight loss. Pulsatile devices appear to be associated with greater weight loss than nonpulsatile continuous flow devices. Additional therapies may be necessary to achieve significant weight loss in recipients of the continuous flow LVAD.

Everolimus in heart transplantation: does it finally have a home?

This editorial approves the use of everolimus to wean calcineurin inhibitors (by 7­11 weeks postoperative) as safe and effective with improved first-year renal function and reduced intimal thickness by intravascular ultrasound. See article by Andreassen et al on page 1828.

Heart transplantation for Chagas cardiomyopathy in the United States.

Since an initial case in 2006, we noted multiple patients undergoing heart transplantation (HTx) for Chagas cardiomyopathy (CC) at our transplant program. The clinical characteristics, laboratory results and outcomes of patients with CC undergoing HTx in the United States have not been reported previously. In 2010, we implemented a systematic screening and management program for patients undergoing HTx for CC. Before HTx, all patients with idiopathic dilated cardiomyopathy who were born in a Chagas disease endemic country were screened for Trypanosoma cruzi (TC) infection with serology. After HTx, monitoring for TC reactivation was performed using clinical visits, echocardiography, endomyocardial biopsy and serial whole blood polymerase chain reaction (PCR) testing. Between June 2006 and January 2012, 11 patients underwent HTx for CC. One patient was empirically treated due to the presence of TC amastigotes in explanted cardiac tissue. Two patients experienced allograft dysfunction due to TC reactivation and three patients experienced subclinical reactivation (positive PCR results), which were treated. Chagas disease is a common cause of dilated cardiomyopathy in patients from endemic countries undergoing HTx at a transplant program in the United States. Reactivation is common after transplantation and can cause adverse outcomes.

Heart transplantation for end-stage heart failure due to cardiac sarcoidosis.

BACKGROUND: Cardiac sarcoidosis with end-stage heart failure has a poor prognosis without transplantation. The rates of sarcoid recurrence and rejection are not well established after heart transplantation. METHODS: A total of 19 heart transplant recipients with sarcoid of the explanted heart were compared with a contemporaneous control group of 1,050 heart transplant recipients without cardiac sarcoidosis. Assessed outcomes included 1st-year freedom from any treated rejection, 5-year actuarial survival, 5-year freedom from cardiac allograft vasculopathy (CAV), 5-year freedom from nonfatal major adverse cardiac events (NF-MACE), and recurrence of sarcoid in the allograft or other organs. Patients with sarcoidosis were maintained on low-dose corticosteroids after transplantation. RESULTS: There were no significant differences between the sarcoid and control groups in 1st-year freedom from any treated rejection (79% and 90%), 5-year posttransplantation survival (79% and 83%), 5-year freedom from CAV (68% and 78%), and 5-year freedom from NF-MACE (90% and 88%). Causes of death (n = 5) in the sarcoid group were coccidioidomycosis, pneumonia, rejection, hemorrhage, and CAV. No patient had recurrence of sarcoidosis in the cardiac allograft. Three of 19 patients (16%) experienced recurrence of extracardiac sarcoid, with no mortality. CONCLUSIONS: Patients with cardiac sarcoidosis undergoing heart transplantation have acceptable long-term outcomes without evidence of recurrence of sarcoidosis in the allograft when maintained on low-dose corticosteroids. Progression of extracardiac sarcoid was uncommon, possibly related to immunosuppression. In patients with cardiac sarcoidosis, heart transplantation is a viable treatment modality.

The future of heart transplantation.

The field of heart transplantation has seen significant progress in the past 40 years. However, the breakthroughs in long-term outcome have seen stagnation in the past decade. Through advances in genomics and transcriptomics, there is hope that an era of personalized transplant therapy lies in the future. To see where heart transplantation truly fits into the long term, searching for and understanding the alternative approaches for heart failure therapy is both important and inevitable. The application of mechanical circulatory support has contributed to the largest advancement in treatment of end stage heart failure. It has already been approved for destination therapy of heart failure, and greater portability and ease of use of the device will be the future trend. Although it is still not prime time for stem cell therapy, clinical experiences have already suggested its potential therapeutic effects. And finally, whole organ engineering is on the horizon as new techniques have opened the way for this to proceed. In the end, progress on alternative therapies largely depends on our deeper understanding of the mechanisms of heart failure and how to prevent it.

Phosphorylated S6 ribosomal protein: a novel biomarker of antibody-mediated rejection in heart allografts.

We tested the hypothesis that phosphorylation of S6 ribosomal protein (S6RP), a downstream target of the PI3K/Akt/mTOR pathway, is a biomarker of antibody-mediated rejection (AMR) in heart allografts. Primary cultures of human aortic and microvascular endothelial cells (EC) were treated with anti-HLA class I and class II antibodies (Ab) and cell lysates were studied for phosphorylation of S6 ribosmal protein at Serine235/236 (p-S6RP). Treatment of cultured EC with anti-class I and class II Ab stimulated S6RP phosphorylation. Immunohistochemical techniques were used to detect the level of p-S6RP in endomyocardial biopsies (n = 131) from 46 heart transplant recipients and the results were correlated with histopathological diagnosis of rejection, C4d staining, production of posttransplant anti-HLA Ab and clinical outcome. Increased phosphorylation of S6RP in endomyocardial biopsies was significantly associated with the diagnosis of AMR (p < 0.0001). No significant association between acute cellular rejection (ACR) and p-S6RP was observed. C4d staining was positively associated with both AMR and p-S6RP. Posttransplant anti-HLA class II Ab production was also significantly associated with a positive p-S6RP status in cardiac biopsies. These results indicate that p-S6RP is a useful biomarker for the diagnosis of AMR.

Tacrolimus with mycophenolate mofetil (MMF) or sirolimus vs. cyclosporine with MMF in cardiac transplant patients: 1-year report.

The most advantageous combination of immunosuppressive agents for cardiac transplant recipients has not yet been established. Between November 2001 and June 2003, 343 de novo cardiac transplant recipients were randomized to receive steroids and either tacrolimus (TAC) + sirolimus (SRL), TAC + mycophenolate mofetil (MMF) or cyclosporine (CYA) + MMF. Antilymphocyte induction therapy was allowed for up to 5 days. The primary endpoint of >/=3A rejection or hemodynamic compromise rejection requiring treatment showed no significant difference at 6 months (TAC/MMF 22.4%, TAC/SRL 24.3%, CYA/MMF 31.6%, p = 0.271) and 1 year (p = 0.056), but it was significantly lower in the TAC/MMF group when compared only to the CYA/MMF group at 1 year (23.4% vs. 36.8%; p = 0.029). Differences in the incidence of any treated rejection were significant (TAC/SRL = 35%, TAC/MMF = 42%, CYA/MMF = 59%; p < 0.001), as were median levels of serum creatinine (TAC/SRL = 1.5 mg/dL, TAC/MMF = 1.3 mg/dL, CYA/MMF = 1.5 mg/dL; p = 0.032) and triglycerides (TAC/SRL = 162 mg/dL, TAC/MMF = 126 mg/dL, CYA/MMF = 154 mg/dL; p = 0.028). The TAC/SRL group encountered fewer viral infections but more fungal infections and impaired wound healing. These secondary endpoints suggest that the TAC/MMF combination appears to offer more advantages than TAC/SRL or CYA/MMF in cardiac transplant patients, including fewer >/=3A rejections or hemodynamic compromise rejections and an improved side-effect profile.

Mycophenolate mofetil reduces intimal thickness by intravascular ultrasound after heart transplant: reanalysis of the multicenter trial.

UNLABELLED: The mycophenolate mofetil (MMF) trial involved 650 heart transplant patients from 28 centers who received MMF or azathioprine (AZA), both in combination with cyclosporine and corticosteroids. Baseline and 1-year intravascular ultrasound (IVUS) were performed in 196 patients (102 MMF and 94 AZA) with no differences between groups in IVUS results analyzed by morphometric analysis (average of 10 evenly spaced sites, without matching sites between studies). Baseline to first-year IVUS data can also be analyzed by site-to-site analysis (matching sites between studies), which has been reported to be more clinically relevant. Therefore, we used site-to-site analysis to reanalyze the multicenter MMF IVUS data. RESULTS: IVUS images were reviewed and interpretable in 190 patients (99 MMF and 91 AZA) from the multicenter randomized trial. The AZA group compared to the MMF group had a larger number of patients with first-year maximal intimal thickness (MIT)>or=0.3 mm (43% vs. 23%, p=0.005), a greater decrease in the mean lumen area (p=0.02) and a decrease in the mean vessel area (the area actually increased in the MMF group, p=0.03). CONCLUSION: MMF-treated heart transplant patients compared to AZA-treated patients, both concurrently on cyclosporine and corticosteroids, in this study have significantly less progression of first-year intimal thickening.

Cardiac transplant experience with cyclosporine.

The advent of cyclosporine 20 years ago was a major advance in the field of solid organ transplantation. Its use enabled directed immunosuppression with a consequent decrease in the incidence of graft failure, acute rejection, and systemic infection. The early oil-based preparation, however, was difficult to administer and had limited bioavailability and unpredictable pharmacokinetics. The drug also has a fairly narrow therapeutic window with major long-term side effects, which include nephrotoxicity, malignancy, hyperlipidemia, and hypertension. The introduction of a microemulsion preparation (Neoral) with improved bioavailability has been associated with lower rates of rejection and comparable tolerability, therefore allowing the use of lower doses. Traditionally cyclosporine toxicity has been minimized by monitoring trough levels. Monitoring of levels 2 hours after dosing may provide a more accurate determination of cyclosporine exposure. The next phase in cardiac transplantation immunosuppression will most likely see a significantly diminished role for cyclosporine with the introduction of newer, more potent immunosuppressive agents with more favorable side-effect profiles. These agents, which include mycophenolate mofetil, sirolimus, and everolimus, also hold the promise of having a major impact on the development of transplant vasculopathy, which up to now has been an important determinant of limiting long-term allograft survival.

Incidence of acute cellular rejection and non-cellular rejection in cardiac transplantation.

BACKGROUND: Rejection continues to be one of the leading causes of death during the first year after cardiac transplantation. With the advent of more potent immunosuppressive therapies, the incidence of graft rejection has been reported to be decreasing. Yet, this trend has not been well established due to differences in the interpretation of and the protocols for endomyocardial biopsy specimens. Additionally, the incidence of humoral (noncellular) rejection has not been adequately addressed. METHODS: Six thousand one hundred thirty endomyocardial biopsy specimens in 487 cardiac transplant recipients during the first year posttransplantation from 1990 to 2000 were reviewed to assess the incidences of acute cellular and treated noncellular rejection episodes. Cellular rejection was defined as ISHLT grades 3-4; noncellular rejection as a 20% decrease in echo LVEF, cardiac index <2.0, and/or inotropic support associated with ISHLT grades 0-2 necessitating treatment. RESULTS: The incidence of noncellular rejection has remained relatively unchanged at approximately 20% (P=nonsignificant for all years); in contrast, there has been a significant decrease (P <.001) in the incidence of cellular rejection from 54% to 5%. CONCLUSION: The incidence of noncellular rejection in cardiac transplant recipients has remained unchanged through the 1990s despite improved immunosuppressive therapies, which have significantly decreased the incidence of acute cellular rejection. There appears to be a need for newer immunosuppressive agents to effectively treat noncellular rejection. Clinical trials using allograft rejection as a major endpoint will need to increase the enrollment of patients to achieve adequate power to demonstrate differences between study groups.

Statins as immunosuppressive agents.

BACKGROUND: Coronary artery disease in the transplanted heart, also known as cardiac allograft vasculopathy, is one of the major causes of mortality late after heart transplantation. This accelerated form of atherosclerosis also affects the donor organs of other transplant recipients including that of liver, kidney and lung. There are multiple immune and non-immune risk factors associated with this disease process, one of which is hyperlipidemia. Use of lipid lowering agents, specifically HMG-CoA reductase inhibitors (statins) was initially reported to have outcomes benefit and possibly immunosuppressive effects in a single center study of heart transplant recipients. Other subsequent studies have supported this beneficial effect. METHOD AND RESULTS: In a recent paper by Kwak and colleagues, the specific mechanism for this immunosuppressive effect has been elucidated through the use of experiments monitoring cell surface expression assayed by fluorescence-activated cell sorting and by immunofluorescence as well as mRNA levels of major histocompatibility complex class II (MHC-II). They report that statins repress induction of MHC-II by interferon-gamma and that this in turn represses activation of T-lymphocytes and other cell types including primary human smooth muscle cells and fibroblasts, as well as in established cell lines such as ThP1, melanomas, and HeLa cells. CONCLUSION: In addition to previous clinical and laboratory publications this work by Kwak and colleagues has provided a firm scientific rationale to support the use of statins as adjunct immunosuppressive agents in organ transplantation.

Flow cytometric detection of HLA-specific antibodies as a predictor of heart allograft rejection.

BACKGROUND: Historically, panel reactive antibody (PRA) analysis to detect HLA antibodies has been performed using cell-based complement-dependent cytotoxicity (CDC) techniques. Recently, a flow cytometric procedure (FlowPRA) was introduced as an alternative approach to detect HLA antibodies. The flow methodology, using a solid phase matrix to which soluble HLA class I or class II antigens are attached is significantly more sensitive than CDC assays. However, the clinical relevance of antibodies detected exclusively by FlowPRAhas not been established. In this study of cardiac allograft recipients, FlowPRA was performed on pretransplant sera with no detectable PRA activity as assessed by CDC assays. FlowPRA antibody activity was then correlated with clinical outcome. METHODS: PRA analysis by anti-human globulin enhanced (AHG) CDC and FlowPRA was performed on sera corresponding to final cross-match specimens from 219 cardiac allograft recipients. In addition, sera collected 3-6 months posttransplant from 91 patients were evaluated. The presence or absence of antibodies was correlated with episodes of rejection and patient survival. A rejection episode was considered to have occurred based on treatment with antirejection medication and/or histology. RESULTS: By CDC, 12 patients (5.5%) had pretransplant PRA >10%. In contrast, 72 patients (32.9%) had pretransplant anti-HLA antibodies detectable by FlowPRA (34 patients with only class I antibodies; 7 patients with only class II antibodies; 31 patients with both class I and class II antibodies). A highly significant association (P<0.001) was observed between pretransplant HLA antibodies detected by FlowPRA and episodes of rejection that occurred during the first posttransplant year. Fifteen patients died within the first year posttransplant. Of nine retrospective flow cytometric cross-matches that were performed, two were in recipients who had no pretransplant antibodies detectable by FlowPRA. Both of these cross-matches were negative. In contrast, five of seven cross-matches were positive among recipients who had FlowPRA detectable pretransplant antibodies. Posttransplant serum specimens from 91 patients were also assessed for antibodies by FlowPRA. Among this group, 58 patients had FlowPRA antibodies and there was a trend (although not statistically significant) for a biopsy documented episode of rejection to have occurred among patients with these antibodies. CONCLUSIONS: Collectively, our data suggest that pre- and posttransplant HLA antibodies detectable by FlowPRA and not AHG-CDC identify cardiac allograft recipients at risk for rejection. Furthermore, a positive donor reactive flow cytometric cross-match is significantly associated with graft loss. Thus, we believe that detection and identification of HLA-specific antibodies can be used to stratify patients into high and low risk categories. An important observation of this study is that in the majority of donor:recipient pairs, pretransplant HLA antibodies were not directed against donor antigens. We speculate that these non-donor-directed antibodies are surrogate markers that correspond to previous T cell activation. Thus, the rejection episodes that occur in these patients are in response to donor-derived MHC peptides that share cryptic determinants with the HLA antigens that initially sensitized the patient.

Chronic right-sided myocarditis mimicking arrhythmogenic right ventricular dysplasia.

Arrhythmogenic right ventricular dysplasia (ARVD) is a cause of right ventricular heart failure and has been implicated in some cases of sudden death in young adults. It is well known that a large majority of patients with ARVD have histological evidence suggestive of inflammation. Here we report a unique case of chronic myocarditis limited to the right ventricle and right side of the interventricular septum which presented clinically as ARVD. The fact that right sided myocarditis can clinically mimic the genetic disease of classic arrhythmogenic right ventricular dysplasia has therapeutic implications for the patient and relatives.