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.

Multicenter Analysis of Immune Biomarkers and Heart Transplant Outcomes: Results of the Clinical Trials in Organ Transplantation-05 Study.

Identification of biomarkers that assess posttransplant risk is needed to improve long-term outcomes following heart transplantation. The Clinical Trials in Organ Transplantation (CTOT)-05 protocol was an observational, multicenter, cohort study of 200 heart transplant recipients followed for the first posttransplant year. The primary endpoint was a composite of death, graft loss/retransplantation, biopsy-proven acute rejection (BPAR), and cardiac allograft vasculopathy (CAV) as defined by intravascular ultrasound (IVUS). We serially measured anti-HLA- and auto-antibodies, angiogenic proteins, peripheral blood allo-reactivity, and peripheral blood gene expression patterns. We correlated assay results and clinical characteristics with the composite endpoint and its components. The composite endpoint was associated with older donor allografts (p < 0.03) and with recipient anti-HLA antibody (p < 0.04). Recipient CMV-negativity (regardless of donor status) was associated with BPAR (p < 0.001), and increases in plasma vascular endothelial growth factor-C (OR 20; 95%CI:1.9-218) combined with decreases in endothelin-1 (OR 0.14; 95%CI:0.02-0.97) associated with CAV. The remaining biomarkers showed no relationships with the study endpoints. While suboptimal endpoint definitions and lower than anticipated event rates were identified as potential study limitations, the results of this multicenter study do not yet support routine use of the selected assays as noninvasive approaches to detect BPAR and/or CAV following heart transplantation.

A unique case of rituximab-related posterior reversible encephalopathy syndrome in a heart transplant recipient with posttransplant lymphoproliferative disorder.

Rituximab is commonly used as a first line therapy to treat posttransplant lymphoproliferative disorders (PTLDs). It has also proved useful in the management of refractory antibody mediated graft rejection. We report an unusual case in which a heart transplant recipient being treated with rituximab for PTLD developed altered mental status, hallucinations and visual symptoms and magnetic resonance imaging (MRI) findings of symmetrical enhancement suggestive of posterior reversible leukoencephalopathy syndrome (PRES). Resolution of these clinical symptoms and radiological findings after discontinuation of therapy confirmed the diagnosis. This is the first case of PRES seen due to rituximab in a heart transplant recipient. Another unique feature of the case is the development of PRES after second cycle of rituximab as compared to prior reports in nonheart transplant patients in which the syndrome developed after first dose administration. The objective of this case report is to increase the awareness of this rare entity amongst immunocompromised transplant patients.

A novel therapeutic approach to the treatment of scleroderma-associated pulmonary complications: safety and efficacy of combination therapy with imatinib and cyclophosphamide.

OBJECTIVE: Scleroderma-related interstitial lung disease (SSc-ILD) has limited therapeutic options due to unclear pathogenesis. Recently, PDGF receptor (PDGFR) amplification has been postulated to cause fibrosis. We hypothesized that a combination of immunosuppressive agents, e.g. cyclophosphamide (CYC) and imatinib (PDGFR inhibitor), might be useful for treating SSc-related ILD. Our objective was to evaluate the safety and efficacy of this combination therapy in scleroderma-related pulmonary disease. METHODS: Five patients with advanced SSc-ILD underwent comprehensive cardiopulmonary evaluation, followed by administration of oral imatinib (200 mg/day) and intravenous CYC (500 mg every 3 weeks). Safety was assessed by close monitoring of complete blood count, liver and cardiac functions. Efficacy was evaluated by measuring pulmonary functions at 6 and 12 months. RESULTS: Of the five patients in the study, four had severe and one had mild restrictive lung disease. All patients tolerated the combination treatment without myelosuppression, deterioration of liver functions or cardiac status. Only one patient had mild fluid overload requiring diuretics. Two patients completed 1 yr of treatment. Only the patient with mild restrictive lung disease showed improvement in pulmonary function. CONCLUSION: The combination of intravenous CYC and oral imatinib was well-tolerated without major side effects. Clinical improvement was seen in only the patient with mild restrictive disease. To our knowledge, this is the first study examining the safety, tolerability and efficacy of imatinib in combination with CYC in scleroderma-related pulmonary disease. Large prospective trials are needed to further determine optimal timing, dose and duration of this regimen.

Improved survival with statins, angiotensin receptor blockers, and steroid weaning after heart transplantation.

Various immunosuppressive and adjunctive pharmacological regimens exist for cardiac transplantation, though the associations between these regimens and long-term survival are unclear. We reviewed demographic, clinical, and pharmacological data from 220 consecutive adult heart transplant recipients between 1986 and 2003 who survived beyond 3 months. Immunosuppression was cyclosporine-based (n=94) or tacrolimus-based (n=126), and 104 patients were weaned off steroids (all receiving tacrolimus). Covariates of mortality were assessed in a Cox proportional hazards analysis. The mean age was 5.2+/-13 years. Survival was 96%, 88%, and 81% at 1, 3, and 5 years, respectively. Significant covariates associated with mortality included pretransplant diabetes mellitus (hazard ratio [HR] 2.83, 95% confidence interval [CI] 1.45 to 5.04), black race (HR 1.41, 95% CI 1.01 to 1.94), higher pretransplant creatinine clearance (HR 0.99, 95% CI 0.98 to 1.00), steroid withdrawal (HR 0.60, 95% CI 0.39 to 0.85), and exposure to a statin (HR 0.53, 95% CI 0.40 to 0.70) or an angiotensin receptor blocker (HR 0.50, 95% CI 0.20 to 0.95) after transplantation. Treatment with a statin, an angiotensin receptor blocker, and steroid withdrawal were each associated with improved survival in heart transplant recipients. These findings warrant prospective study, with specific emphasis on identifying the clinical effects of these medications in transplant recipients.

De novo immunosuppression with sirolimus and tacrolimus in heart transplant recipients compared with cyclosporine and mycophenolate mofetil: a one-year follow-up analysis.

BACKGROUND: Limited data exist regarding the safety and efficacy of sirolimus in combination with a calcineurin inhibitor in heart transplant recipients. METHODS: From January 2001 to June 2002, 31 de novo heart transplant recipients (treatment group) received a combination of sirolimus, tacrolimus, low-dose rabbit antithymocyte globulin, and glucocorticoids. Outcomes, such as actuarial survival, rate of rejection, incidence of infection, probability of developing diabetes mellitus, renal function, platelet and white blood cell counts, and incidence of coronary artery disease at 1 year, were compared with a cohort of 25 patients (control group) who underwent transplantation primarily in 2000 and in early 2002 treated with cyclosporine, mycophenolate mofetil, and glucocorticoids. All patients were followed up for at least 12 months. RESULTS: Kaplan-Meier actuarial 1-year survival rates were equivalent between groups (97% for the treatment group and 88% for the control group), as was freedom from allograft rejection (48% and 42% for treatment and control groups, respectively). No cases of transplant arteriopathy were noted within the first posttransplantation year. Renal function was not significantly affected in either group. There was a striking increased incidence of mediastinitis in the treatment group (19%) versus 0% in the control group (P = .02). Tacrolimus-sirolimus therapy was associated with a nearly 11-fold increased incidence of new-onset diabetes mellitus as well (P = .004). CONCLUSION: Tacrolimus, sirolimus, and steroids (following low-dose rabbit antithymocyte globulin) were associated with an increased incidence of mediastinitis and posttransplantation diabetes mellitus. No obvious long-term benefit on survival, arteriopathy, or renal function was noted.

Treatment of congestive heart failure: guidelines for the primary care physician and the heart failure specialist.

During the past 10 years, the philosophy of heart failure treatment has evolved from symptom control to a combined prevention and symptom-management strategy. Recent clinical trials have proved that early detection can delay progression. Treatment of asymptomatic left ventricular dysfunction is as important as treatment of symptomatic disease. The purpose of this review is to simplify recent guidelines for pharmacological management of chronic systolic heart failure for the primary care physician and the heart failure specialist. Early recognition and prevention therapies, combined with lifestyle modification, are essential in the treatment of heart failure. Therapy with angiotensin-converting enzyme inhibitors, beta-blockers, and diuretics is now standard. Digoxin is added to improve clinical symptoms, especially in patients with atrial fibrillation. Aldosterone antagonists may be recommended in select patients with stable New York Heart Association class III or IV heart failure. If angiotensin-converting enzyme inhibitors are not tolerated, angiotensin receptor blockers, hydralazine hydrochloride, and isosorbide dinitrate are recommended. The data on antiarrhythmic and anticoagulation therapies are inconclusive.

Tacrolimus monotherapy in adult cardiac transplant recipients: intermediate-term results.

BACKGROUND: Tacrolimus (FK506) is a macrolide antibiotic that inhibits T-cell activation and proliferation. To date, all published trials have used tacrolimus and steroids in combination with either azathioprine or mycophenolate mofetil. Previous experience with pediatric cardiac transplant patients at our institution suggested that use of tacrolimus alone provides an adequate level of immunosuppression and that withdrawal of steroids is readily achieved in most recipients. Between January 1, 1996, and July 7, 1999, we performed 77 adult cardiac transplants. Forty-three of these patients received tacrolimus and prednisone as primary immunosuppression, without azathioprine or mycophenolate mofetil. Thirty-two of the 43 patients started on tacrolimus have been weaned off steroids and are maintained on monotherapy. These latter patients form the basis of this report. The mean time for achieving monotherapy was 246 +/- 127 days (range, 106 to 730). Grade > or = 2 rejection occurred at 0.40 episodes per patient in the first 90 days (a combination of Grades 2 and 3A/3B rejections). The freedom from treated rejection (includes all 3A/3B and Grade 2 rejection in the first 90 days) was 69% at 90 days and 52% at 1 year. One patient (of 32) had documented cytomegalovirus infection (gastritis) diagnosed at 8 months post-transplant. We observed 1 case of transplant vasculopathy and 1 case of post-transplant lymphoproliferative disorder during the follow-up period. Our results show that use of tacrolimus alone after steroid weaning provides effective immunosuppression with low incidence of rejection, cytomegalovirus infection, transplant arteriopathy, or post-transplant lymphoproliferative disease.

Case report: a 32-year-old woman with familial parangangliomas and acute cardiomyopathy.

We describe the first case of a patient with familial paragangliomas, acute postoperative catecholamine-induced cardiomyopathy, and the subsequent diagnosis of an unsuspected adrenal pheochromocytoma. Relevant literature is reviewed, and treatment options are discussed.

Mycobacterium xenopi infection after heart transplantation: an unreported pathogen.

Mycobacterial infections are a well-known, potentially serious, albeit infrequent complication of solid-organ transplantation. Nontuberculous mycobacteria generally account for less than 50% of all such isolates in this patient population. Mycobacterium xenopi, an environmentally ubiquitous organism and common contaminant of hospital hot water systems, is a particularly uncommon isolate after transplantation and has never been reported in heart allograft recipients. We report the occurrence of cavitary M. xenopi infection in an immunocompromised heart transplant recipient in which all the diagnostic criteria of the American Thoracic Society were met. To our knowledge, this is the first such case in a heart transplant recipient described in the literature. Despite therapy, to which the isolates were sensitive in vitro, the patient developed extensive lung cavitation and nodules and succumbed 5 months later to allograft rejection, chronic allograft vasculopathy, and pneumonia.

Cardiac transplantation in the older recipient: excellent long-term survival based on pretransplant screening.

BACKGROUND: Cardiac transplantation has become the established treatment of choice for eligible patients with end-stage congestive heart failure. Older recipients (over the age of 60) are sometimes regarded as too high risk for transplant. Because chronological age is frequently disparate from physiologic age, we hypothesized that with careful selection after a comprehensive screening evaluation we would be able to achieve comparable survival and quality of life in an older population. METHODS: Between January 1989 and December 2002, 240 de novo adult cardiac transplants were performed for 74 female and 176 male patients. Prior to listing for cardiac transplantation, the patients were evaluated to exclude significant comorbidities that would limit survival or functional capacity postsurgery. In patients over the age of 60, particularly rigorous testing was conducted to eliminate significant extracardiac disease. RESULTS: The patients are divided in this analysis into three groups based on age at transplant (age 18 to 45, 46 to 59, and 60 years or older). Older recipients experienced similar rates of moderately severe cellular rejection (ISHLT grade 3A/ B). Survival as derived by Kaplan-Meier analysis was equivalent for all groups by Mantel-Cox logrank test (P = NS). The survival for patients older than age 60 was 83.1%, 73.7%, 67.7%, 57.4%, and 43.1% at 1,3, 5, 7, and 10 years posttransplant, respectively. CONCLUSION: We conclude that chronological age over 60 years old should not exclude a patient from the potential long-term benefit of cardiac transplant, ensuring added longevity and excellent quality of life.

Refractory humoral cardiac allograft rejection successfully treated with a single dose of rituximab.

Despite improvements in immunosuppression over the last two decades, the risk of allograft rejection is still high in the early postoperative period. Cellular rejection accounts for the majority of these episodes. However, humoral rejection is a distinct phenomenon that carries a high rate of graft loss and mortality. The currently available treatments for this serious clinical problem include anti-lymphocyte antibodies, immune globulin infusions, as well as plasmapheresis, all of which have limitations. We describe a case of refractory humoral cardiac rejection successfully treated with a single dose of rituximab (375 mg/m2). No further episodes occurred with 2 years of follow-up.

Can initial tacrolimus trough levels be predicted from clinical variables?

In eligible patients, cardiac transplantation has become the definitive treatment for end-stage heart failure. The initial posttransplantation course is marked by many potential difficulties, including renal insufficiency, hemodynamic instability, and perioperative bleeding. It is important to prevent early rejection; calcineurin inhibitors, such as tacrolimus or cyclosporine, are integral parts of such management. However, these drugs are associated with renal toxicity in some patients. Previous work suggests that limiting the increase in tacrolimus levels is associated with less renal insufficiency. The hypothesis of the current study was that a combination of clinical or laboratory variables could identify patients at risk for rapid changes in tacrolimus target levels. No single variable was strongly associated with high resultant trough levels following a standard 1-mg oral "test dose" of tacrolimus. However, the combination of 2 indices of liver metabolism (alanine aminotransferase and total bilirubin) along with serum creatinine did identify patients who tended toward elevated levels of tacrolimus (> or =4.5 ng/dL). Other variables, such as demographics, and even functional variables, such as right ventricular function by echocardiography, did not enhance the predictive value of this simple scoring system.

Current practices: immunosuppression induction, maintenance, and rejection regimens in contemporary post-heart transplant patient treatment.

Cardiac transplantation is the definitive treatment for eligible patients with end-stage cardiomyopathy. Survival rates have improved dramatically during the last 10 years, especially since the advent of cyclosporine-A. Cardiac allograft rejection, previously considered a major cause of early mortality after transplantation, is no longer the limiting factor for early survival, with the use of newer and more specific immunosuppression regimens. Very few randomized, prospective trials, including comparisons between immunosuppression regimens, have been conducted in this area. Therefore, practices vary with physician and institutional experience. Most centers use a multipronged approach to immunosuppression, targeting multiple sites in the immune cascade that lead to allograft rejection. Multiple new agents in development are reviewed. Drugs such as sirolimus and its derivative, everolimus, act on specific intracellular receptors within lymphocytes, whereas other medications such as Daclizumab (Roche Laboratories, Nutley, NJ) block the interleukin-2 receptor on the surface of activated T cells. The immune response to foreign antigens is complex, with multiple redundant levels. Immunosuppression regimens continue to seek a fine balance between overimmunosuppression and insufficient protection, which may lead to allograft rejection or loss.

Effects of active vs. passive recovery on work performed during serial supramaximal exercise tests.

The current investigation was undertaken to determine the effects of active versus passive recovery on work performance during repeated bouts of supramaximal exercise. Six healthy sedentary subjects and 9 moderately trained healthy hockey players performed serial 30-second Wingate anaerobic power tests (WAnT) on a bicycle ergometer interposed with 4 minutes of active recovery at a work rate corresponding to 28 % of VO(2)max or passive recovery at rest. Peak power, mean power, total work achieved, and fatigue index were calculated for the serial WAnT. Capillary blood lactate was determined at 5-minute intervals after the last WAnT during 30 minutes of active or passive recovery. Mean power was significantly greater during active recovery in sedentary subjects when compared with passive recovery (388 +/- 42 vs. 303 +/- 37 W, p < 0.05), but did not differ according to recovery mode in moderately trained hockey players (589 +/- 22 W active vs. 563 +/- 26 W passive, p = 0.14). Total work achieved significantly increased during active when compared with passive recovery in sedentary subjects (34 890 +/- 3768 vs. 27 260 +/- 3364 J, p < 0.02) and moderately trained hockey players (86 763 +/- 9151 vs. 75 357 +/- 8281 J, p < 0.05). Capillary blood lactate levels did not differ during active when compared with passive recovery in sedentary subjects but were significantly lower during active when compared with passive recovery in moderately trained hockey players. These data demonstrate that active recovery at a work rate corresponding to 28 % of VO(2)max increases total work achieved during repeated WAnT when compared with passive recovery in sedentary subjects and moderately trained hockey players.

Validating facemask use for gas exchange analysis in patients with congestive heart failure.

PURPOSE: Functional limitation, often associated with congestive heart failure (CHF), is most accurately assessed with measurement of peak VO2 (VO2peak) during exercise testing. VO2peak strongly predicts survival in CHF patients and is used to triage patients for cardiac transplantation. However, the traditional mouthpiece/noseclip equipment used for gas exchange analysis is often cumbersome and uncomfortable. Several alternative facemask designs tested previously in healthy cohorts were inferior to the mouthpiece for measuring VO2peak. In this study, a series of facemasks designed specifically for VO2peak testing (Hans-Rudolph) was employed. Although previously validated in healthy young adults, this apparatus has not been validated in patients with severe CHF. METHODS: The Hans-Rudolph facemasks were compared with the mouthpiece apparatus in 30 patients with severe CHF. Each subject completed a cardiopulmonary exercise test with each device. Twelve subjects were randomized to evaluate a possible training effect. To enhance recruitment, 18 additional subjects were recruited after they had completed a test with the mouthpiece. RESULTS: There was no evidence of a training effect and no differences in gas exchange measurements were found between the two devices. The weight-adjusted VO2peak measurements were 17.1 +/- 5.3 ml O2/kg/min for the mouthpiece group and 17.3 +/- 5.6 ml O2/kg/min for the mask group (P = 0.54). CONCLUSIONS: The facemask was shown to be equivalent to the mouthpiece for measuring VO2peak in CHF patients. Concerns of hypoventilation and decreased VO2peak associated with previous facemask designs were not substantiated. Since successful exercise testing depends on maximal exertion, providing a choice of equipment may facilitate cooperation without sacrificing accuracy.