Impact of donor left ventricular hypertrophy on survival after heart transplant.

Left ventricular hypertrophy (LVH) of the donor heart is believed to increase the risk of allograft failure after transplant. However this effect is not well quantified, with variable findings from single-center studies. The United Network for Organ Sharing database was used to analyze the effect of donor LVH on recipient survival. Three cohorts, selected in accordance with the American Society of Echocardiography guidelines, were examined: recipients of allografts without LVH (<1.1 cm), with mild LVH (1.1-1.3 cm) and with moderate-severe LVH (≥ 1.4 cm). The study group included 2626 patients with follow-up of up to 3.3 years. Mild LVH was present in 38% and moderate-severe LVH in 5.6% of allografts. Predictors of mortality included a number of donor and recipient characteristics, but not LVH. However, a subgroup analysis showed an increased risk of death in recipients of allografts with LVH and donor age >55 years, and in recipients of allografts with LVH and ischemic time ≥ 4 h. In the contemporary era, close to half of all transplanted allografts demonstrate LVH, and survival of these recipients is similar to those without LVH. However, the use of allografts with LVH in association with other high-risk characteristics may result in increased mortality.

B cells in transplantation.

B cell responses underlie the most vexing immunological barriers to organ transplantation. Much has been learned about the molecular mechanisms of B cell responses to antigen and new therapeutic agents that specifically target B cells or suppress their functions are available. Yet, despite recent advances, there remains an incomplete understanding about how B cell functions determine the fate of organ transplants and how, whether or when potent new therapeutics should optimally be used. This gap in understanding reflects in part the realization that besides producing antibodies, B cells can also regulate cellular immunity, contribute to the genesis of tolerance and induce accommodation. Whether non-specific depletion of B cells, their progeny or suppression of their functions would undermine these non-cognate functions and whether graft outcome would suffer as a result is unknown. These questions were discussed at a symposium on "B cells in transplantation" at the 2015 ISHLT annual meeting. Those discussions are summarized here and a new perspective is offered.

The paradox of obesity in patients with heart failure.

PURPOSE: Heart failure (HF) patients often have comorbid conditions that confound management and adversely affect prognosis. The purpose of this study was to determine whether the obesity paradox is also present in hospitalized HF patients in an integrated healthcare system. DATA SOURCES: A cohort of 2707 patients with a primary diagnosis of HF was identified within an integrated, 20-hospital healthcare system. Patients were identified by ICD-9 codes or a left ventricular ejection fraction < or =40% dating back to 1995. Body mass index (BMI) was calculated using the first measured height and weight when hospitalized with HF. Survival rates were calculated using Kaplan Meier estimation. Hazard ratios for 3-year mortality with 95% confidence intervals were assessed using Cox regression, controlling for age, gender, and severity of illness at time of diagnosis. CONCLUSIONS: Three-year survival rates paradoxically improved for patients with increasing BMI. Survival rates for the larger three BMI quartiles were significantly better than for the lowest quartile after adjusting for severity of illness, age, and gender. IMPLICATIONS FOR PRACTICE: While obesity increases the risk of developing HF approximately twofold, reports involving stable outpatients suggest that obesity is associated with improved survival after the development of HF. This finding is paradoxical because obesity increases the risk and worsens the prognosis of other cardiovascular diseases.

Incidence of adenomatous colorectal polyps in cardiac transplant recipients.

BACKGROUND: The present study evaluates the effects of long-term immunosuppression after cardiac transplantation on the risk for adenomatous polyps. METHODS: The endoscopic procedures performed at LDS and University Hospitals in cardiac transplant recipients were reviewed and compared with results from a previously studied control group. RESULTS: A total of 123 endoscopic procedures were performed in 98 heart transplant patients (59% for cancer screening and 41% for gastrointestinal complaints). Eighty-five percent of patients were male and 15% were female; their mean age was 57 years. In the group <3 years posttransplant, adenomatous polyps were present in 25%, hyperplastic polyps were present in 10%, and synchronous lesions in 3 patients. In the group >3 years posttransplant, adenomatous polyps were present in 16%, hyperplastic polyps were present in 22%, and synchronous lesions in were evident in 3 patients. No significant difference with results from a previously studied control group. CONCLUSIONS: Long-term immunosuppression does not increase the risk for adenomatous polyps of the colon.

New UNOS rules: historical background and implications for transplantation management. United Network for Organ Sharing.

The algorithm for the allocation of donor hearts used by the United Network for Organ Sharing (UNOS) was changed in January 1999. The new scheme alters the medical urgency criteria from a 2-tiered to a 3-tiered system. Blood type O and blood type B candidates are less disadvantaged and pediatric candidates are somewhat advantaged with regard to adolescent donors. The new allocation algorithm allows an individual with life-threatening ventricular arrhythmias to be listed in the highest urgency status. Increased regulation will occur with the establishment of a review for the highest urgency status and the establishment of regional review boards.

Avoidance of cellular blood product transfusions in LVAD recipients does not prevent HLA allosensitization.

BACKGROUND: Transfusion of cellular blood products during left ventricular assist device (LVAD) implantation has been associated with HLA allosensitization, resulting in the need for a negative prospective cross-match and prolonged transplant waiting times. In order to prevent this risk, we developed a protocol to avoid transfusion of cellular blood products. METHODS: The protocol included preoperative patient stabilization, perioperative recombinant erythropoietin and blood conservation strategies, and postoperative monitoring of mixed venous oxygen saturation (SVO2) to assure adequate peripheral oxygen delivery. Panel reactive antibody (PRA) was measured in all patients pre and post LVAD placement to assess HLA sensitization. RESULTS: Seven consecutive patients underwent LVAD implantation without transfusion of blood or platelets, one of whom expired perioperatively. Mean hematocrit was 35.2% preoperatively, and 21.8% postoperatively, reaching a nadir of 20.2%. Postoperative SVO2 was >60% in all patients. In the six survivors, mean hematocrit reach 24.3%, 27.3%, and 33.0% by postoperative day seven, fourteen, and thirty, respectively. PRA in three patients was 0% preoperatively and remained 0% until transplantation after 33, 34, and 50 days of support. In two patients, preoperative PRA was 7% and 17%, dropped to 3% and 0% after thirty days, then progressively rose to 96% and 100% after 60 and 90 days, respectively. In one other patient, preoperative PRA was 0%, remained at 0% after thirty days, then rose to 96% by 60 days. CONCLUSIONS: Avoiding transfusion of cellular blood products in LVAD recipients is safe and well tolerated, but does not universally protect from HLA allosensitization. Other factors may also produce sensitization, such as immunogenic components of the LVAD, soluble antigen in fresh frozen plasma, or latent sensitization which is not initially evident in critically ill and possibly anergic patients.

Electromagnetic interference of automatic implantable cardioverter defibrillator and HeartWare left ventricular assist device.

The use of continuous-flow left ventricular assist devices (LVAD) have markedly improved outcomes in patients with advanced heart failure (HF). The HeartWare LVAD is a miniaturized centrifugal pump implanted within the pericardial space. Implantable cardioverter-defibrillators (ICDs) are susceptible to oversensing of extracardiac signals (electromagnetic interference [EMI]). We report two cases of EMI in patients that received a HeartWare LVAD as destination therapy for advanced HF. The patients were 75 and 78 years old, both with severe ischemic dilated cardiomyopathy (ejection fraction < 0.20) and New York Heart Association class 4 heart failure. Both patients had a St. Jude Medical Unify ICD with a 7 Fr dual coil St. Jude Medical Durata ICD lead. In both patients, the lead location was in the right ventricular apex with an inferior orientation. Both patients experienced immediate ICD therapies after LVAD placement, requiring the tachytherapies to be disabled. ICD programming changes to increase sensitivity and the detection windows were ineffective. Both patients underwent ICD system revision. In one patient, the existing lead was moved to an anteroseptal location that stopped the EMI. In the other patient, the ICD system was changed to allow a separate right ventricular sensing lead in an anteroseptal location and a dual coil ICD lead placed in an apical location, a strategy used to obtain an acceptable defibrillation threshold. The patients have had no subsequent EMI detected on clinical and remote monitoring. Patients with a right ventricular apical ICD lead placement that undergo placement of a HeartWare LVAD are susceptible to EMI and inappropriate ICD therapies. These cases suggest the primary mechanism is proximity of the ICD lead to the device and as such relocation to an anteroseptal location can overcome the problem. These data suggest that all patients that receive a HeartWare LVAD with an ICD should have the device carefully checked at maximum LVAD output to determine if EMI may be present. ASAIO Journal 2013;59:136-139. Key Words: left ventricular assist device, electromagnetic interference, improper ICD shocks, end-stage heart failure.

Immune function surveillance: association with rejection, infection and cardiac allograft vasculopathy.

BACKGROUND: Rejection, cardiac allograft vasculopathy (CAV), and infection are significant causes of mortality in heart transplantation recipients. Assessing the immune status of a particular patient remains challenging. Although endomyocardial biopsy (EMB) and angiography are effective for the identification of rejection and CAV, respectively, these are expensive, invasive, and may have numerous complications. The aim of this study was to evaluate the immune function and assess its utility in predicting rejection, CAV, and infection in heart transplantation recipients. METHODS: We prospectively obtained samples at the time of routine EMB and when clinically indicated for measurement of the ImmuKnow assay (IM), 12 cytokines and soluble CD30 (sCD30). EMB specimens were evaluated for acute cellular rejection, and antibody-mediated rejection (AMR). CAV was diagnosed by the development of angiographic coronary artery disease. Infectious episodes occurring during the next 30 days after testing were identified by the presence of positive bacterial or fungal cultures and/or viremia that prompted treatment with antimicrobials. RESULTS: We collected 162 samples from 56 cardiac transplant recipients. There were 31 infection episodes, 7 AMR, and 4 CAV cases. The average IM value was significantly lower during infection, (P = .04). Soluble CD30 concentrations showed significantly positive correlation with infection episodes, (P = .001). Significant positive correlation was observed between interleukin-5(IL-5) and AMR episodes (P = .008). Tumor necrosis factor-α and IL-8 showed significant positive correlation with CAV (P = .001). CONCLUSIONS: Immune function monitoring appears promising in predicting rejection, CAV, and infection in cardiac transplantation recipients. This approach may help in more individualized immunosuppression and it may also minimize unnecessary EMBs and cardiac angiographies.

Ventricular assist devices: pharmacological aspects of a mechanical therapy.

Heart failure (HF) is a global epidemic that continues to cause significant morbidity and mortality despite advances in medical therapy. Ventricular assist device technology has emerged as a therapeutic option to bridge patients with end-stage HF to heart transplantation or as an alternative to transplantation in selected patients. In some patients, mechanical unloading induced by ventricular assist devices leads to improvement of myocardial function and a possibility of device removal. The implementation of this advanced technology requires multiple pharmacological interventions, both in the perioperative and long-term periods, in order to minimize potential complications and improve patient outcomes. We herein review the latest available evidence supporting the use of specific pharmacological interventions and current practices in the care of these patients: anticoagulation, bleeding management, pump thrombosis, infections, arrhythmias, right ventricular failure, hypertension, desensitization protocols, among others. Areas of uncertainty and ground for future research are also highlighted.

Effect of blood product transfusion-induced tolerance on incidence of cardiac allograft rejection.

BACKGROUND: Blood product transfusion has been successfully used in solid-organ transplantation to induce tolerance. Whether a similar protective effect of blood product transfusion exists in heart transplantation is controversial. OBJECTIVE: To investigate the effect of cellular blood product transfusion within 2 weeks posttransplantation on the incidence of cellular and antibody-mediated rejection. PATIENTS AND METHODS: Patients were grouped on the basis of number of blood transfusions; group 1 received no transfusions, and groups 2, 3, and 4 each received an incremental number of transfusion units. All endomyocardial biopsy samples were routinely studied using immunofluorescence in the first 12 weeks posttransplantation. RESULTS: Baseline characteristics including age, sex, body mass index, history of diabetes, donor characteristics, and pretransplantation laboratory values were similar except that group 4 had a higher rate of previous sternotomy and longer ischemic time during transplantation. Approximately 9200 endomyocardial biopsy samples composed the data. Short- and long-term freedom from the International Society for Heart & Lung Transplantation grade 3A or higher cellular rejection and from antibody-mediated rejection were comparable between groups. CONCLUSIONS: Blood transfusions within the first 2 weeks post-transplantation do not seem to confer any protective effect against posttransplantation cellular rejection or antibody- mediated rejection. Whether other unmeasured confounding factors mask their effect requires further prospective studies.

Mycophenolate mofetil (MMF) in heart transplantation: rejection prevention and treatment.

Mycophenolate mofetil (MMF), the morpholinoethylester of mycophenolic acid, inhibits the de novo pathway for purine synthesis. Evidence suggests that MMF suppresses lymphocyte function more than that of neutrophils, erythrocytes, and other rapidly dividing cell lines that can utilize salvage pathways for purine synthesis. While rigorous efficacy data await the completion of an ongoing, multicenter, prospectively randomized, placebo-controlled trial, long-term safety data are, however, available from numerous uncontrolled trials in cardiac transplantation. Dose-ranging trials in 49 heart recipients suggest that doses > or = 4000 mg/d are associated with significant, reversible gastrointestinal toxicity when compared with doses < 4000 mg/d (p < 0.001). Patients receiving > or = 1000 mg/d may have fewer rejection episodes. Even in the long term, changing from azathioprine to MMF is associated with increases in hematocrit (p < 0.001), total WBC count (p < 0.005), and absolute neutrophil count (p < 0.005). Successful use of MMF in refractory cardiac allograft rejection suggests an advantage over azathioprine. MMF is safe and appears to be at least as effective as azathioprine for immunosuppression following heart transplantation.

Increased incidence of allograft rejection in stable heart transplant recipients after late conversion from mycophenolate mofetil to azathioprine.

Mycophenolate mofetil (MMF) is a safe and effective immunosuppressive agent in kidney and liver transplantation. Preliminary studies also support its use in heart transplantation. However, the cost of MMF is substantially greater than azathioprine (AZA), the current alternative. Since the majority of rejection episodes occur within the first few months of transplantation, using MMF early after transplantation and subsequently converting to AZA, after the risk of rejection has diminished, might be cost-effective. In order to evaluate the safety of such a strategy in heart transplant recipients, we reviewed the rejection profiles of a group of patients who were converted from MMF to AZA late after transplantation. Forty-three stable patients on chronic MMF therapy as part of an open-label, long-term safety study were converted to either commercially available MMF (CellCept) or AZA, at the conclusion of the study. Demographic variables, rejection histories before and after conversion, and immunosuppressive regimens were examined. Twenty-three patients were continued on commercial MMF and 20 were converted to AZA therapy. The average duration of MMF therapy prior to conversion was 41 months in each group. Baseline demographics were similar in the two groups. Treated allograft rejection occurred in 10 of 20 patients converting to AZA, as compared to only 1 of 23 patients remaining on MMF; p = 0.002. Additionally, mean scores (1-5 scale) for the three biopsies before and after conversion favored continued MMF therapy (1.5+/-0.6 before and 1.2+/-0.4 after conversion in MMF group vs. 1.3+/-0.5 before and 1.7+/-0.9 after conversion to AZA; p = 0.02). No allograft loss occurred as a result of conversion. These data suggest that conversion from MMF to AZA, even late after transplantation, can be associated with allograft rejection. The costs associated with these rejection episodes (the additional immunosuppressive agents, endomyocardial biopsies, and physician visits) may exceed the potential cost savings of converting stable heart transplant recipients from MMF to AZA.

Adjuvant intrapleural amphotericin B therapy for pulmonary mucormycosis in a cardiac allograft recipient.

Infectious complications after heart transplantation remain a major cause of morbidity and mortality. While many viral, bacterial, and protozoal infections can be successfully treated, fungal infections continue to be challenging. Mucormycosis is a rare infection in heart transplant recipients; however, mortality is exceedingly high. We report a case of cavitary Rhizopus lung infection 2 months after cardiac transplantation. The infection was complicated by inadvertent exposure of the pleural cavity to the fungus during surgical resection. Therapy consisted of standard systemic amphotericin B, surgical excision, and for the first time, the use of adjuvant intrapleural amphotericin B. Cure was achieved with no clinical or radiological evidence of disease at 3 months follow-up. Rhizopus pulmonary infection is a rare complication of cardiac transplantation. Treatment consists of the triad of systemic anti-fungal therapy, surgical resection, and control of any underlying predisposing diseases. Adjuvant intrapleural amphotericin B use could also be considered in patients with fungal pneumonias and evidence of chest wall and/or pleural cavity involvement.