Impact of Baseline Mitral Regurgitation on Postoperative Outcomes After Left Ventricular Assist Device Implantation as Destination Therapy.

BACKGROUND: Currently, there are no guidelines for management of moderate to severe mitral regurgitation (MR) in patients undergoing left ventricular assist device (LVAD) implantation. The present study aimed to investigate the impact of baseline MR on short and midterm survival in patients who had LVAD as destination therapy (DT). METHODS: The DT-LVAD patients were classified into 2 groups based on baseline MR status: ≥ moderate MR and < moderate MR. Baseline clinical characteristics and post-LVAD implant adverse events were compared. Unadjusted mortality rates at 30 days, 1 year, and 2 years were analyzed. RESULTS: Of 91 patients studied, 62 (68%) had ≥ moderate MR before LVAD implantation; ≥ moderate MR patients had a higher incidence of concomitant pulmonary disease (11% vs 0%; P = .001) and ≥ moderate tricuspid regurgitation (55% vs 23%, P = .004) than < moderate MR patients. Other baseline clinical characteristics were similar in both groups. Post-LVAD adverse events did not differ between the 2 groups. Survival rates at 30 days, 1 year, and 2 years for both groups (≥ moderate MR vs < moderate MR) were 90% vs 100% (P = .03), 63% vs 90% (P = .001), and 52% vs 83% (P = .002), respectively. On multivariable analysis, age, female sex, ≥ moderate tricuspid regurgitation, and ≥ moderate MR at baseline were found to be independent predictors of overall all-cause mortality. Overall survival was significantly lower in the ≥ moderate MR group than the < moderate MR group (log-rank test, P = .03). CONCLUSION: In DT LVAD patients, ≥ moderate MR is common and is associated with worse survival at both short and midterm follow-up.

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.

The future direction of the adult heart allocation system in the United States.

Ensuring equitable and fair organ allocation is a central charge of the United Network for Organ Sharing (UNOS) as the Organ Procurement and Transplantation Network (OPTN) through its contract with the Department of Health and Human Services (DHHS). The OPTN/UNOS Board initiated a reassessment of the current allocation system. This paper describes the efforts of the OPTN/UNOS Heart Subcommittee, acting on behalf of the OPTN/UNOS Thoracic Organ Transplantation Committee, to modify the current allocation system. The Subcommittee assessed the limitations of the current three-tiered system, outcomes of patients with status exceptions, emerging ventricular assist device (VAD) population, options for improved geographic sharing and status of potentially disenfranchised groups. They analyzed waiting list and posttransplant mortality rates of a contemporary cohort of patient groups at risk, in collaboration with the Scientific Registry of Transplant Recipients to develop a proposed multi-tiered allocation scheme. This proposal provides a framework for simulation modeling to project whether candidates would have better waitlist survival in the revised allocation system, and whether posttransplant survival would remain stable. The tiers are subject to change, based on further analysis by the Heart Subcommittee and will lead to the development of a more effective and equitable heart allocation system.

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.

Heart and lung transplantation in the United States, 1996-2005.

This article examines the Organ Procurement and Transplantation Network/Scientific Registry of Transplant Recipients data on heart and lung transplantation in the United States from 1996 to 2005. The number of heart transplants performed and the size of the heart waiting list continued to drop, reaching 2126 and 1334, respectively, in 2005. Over the decade, post-transplant graft and patient survival improved, as did the chances for survival while on the heart waiting list. The number of deceased donor lung transplants increased by 78% since 1996, reaching 1407 in 2005 (up 22% from 2004). There were 3170 registrants awaiting lung transplantation at the end of 2005, down 18% from 2004. Death rates for both candidates and recipients have been dropping, as has the time spent waiting for a lung transplant. Other lung topics covered are living donation, recent surgical advances and changes in immunosuppression regimens. Heart-lung transplantation has declined to a small (33 procedures in 2005) but important need in the United States.

Clonal T-large granular lymphocyte proliferation in solid organ transplant recipients.

Large granular lymphocytic (LGL) leukemia is a rare disorder, usually caused by clonal proliferation of CD3+ CD57+ T-LGL cells. T-cell clonality is confirmed by rearrangements of the T-cell receptor (TCR) gene. Characteristic features of T-LGL leukemia include neutropenia, anemia, and constitutional symptoms such as fatigue. Many solid organ transplant recipients experience similar symptoms and have neutropenia and anemia often attributed to immunosuppressive therapy. The purpose of this study was to determine the prevalence of T-LGL proliferation in solid organ transplant recipients and demonstrate its association with leukopenia and anemia. Twenty-three cardiac and renal transplant patients were evaluated by peripheral smear examination, flow cytometry, and TCR gene rearrangement study by polymerase chain reaction. Ten of 14 (71%) cardiac transplant patients and 4 of 9 (44%) renal transplant patients, without evidence of either allograft rejection or a viral syndrome, were found to have clonal expansion of T-LGL cells. Constitutional symptoms were present in 30% of these patients. Anemia of <10 g/dL was seen in 75% of renal transplant and 10% of cardiac transplant patients. None of these patients had significant neutropenia defined as absolute neutrophil count of 1500 mu/L. Most of the patients did not require any specific therapeutic intervention. Although TCR gene rearrangement is considered a hallmark of T-LGL leukemia, we believe that this monoclonality is not a true form of posttransplant lymphoproliferative disorder. Constant antigenic stimulus from the allograft may be the underlying etiology of clonal expansion and may contribute to cytopenias and fatigue seen in transplant patients.

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.

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.

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.

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.

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.

Giant cell myocarditis: most fatal of autoimmune diseases.

OBJECTIVE: To increase awareness of giant cell myocarditis (GCM), its pathogenesis, and treatment. METHODS: Review of relevant publications from the English-language literature. RESULTS: GCM is a rare, frequently fatal inflammatory disorder of cardiac muscle of unknown origin, characterized by widespread degeneration and necrosis of myocardial fibers.Congestive heart failure and ventricular tachycardia are common clinical manifestations. GCM occurs primarily in previously healthy adults, although it is frequently associated with various systemic diseases, primarily of autoimmune causes. The inflammatory infiltrate is characterized by the presence of multinucleated giant cells and is distinct from cardiac sarcoidosis. Animal models of GCM are similar to models of other autoimmune disorders such as rheumatoid arthritis. The prognosis, which is poor despite partial responsiveness to immunosuppressive medications, is improved with cardiac transplantation. CONCLUSIONS: The clinical and immunopathogenetic similarities with classical rheumatologic diseases, the differential diagnosis with sarcoidosis and other inflammatory conditions, and the use of standard immunosuppressive medications make GCM a disease process that should be added to the rheumatologist's expertise.

Cardiac transplantation in New Jersey.

Heart transplantation is an effective treatment for end-stage congestive heart failure resulting in a one-year survival of 80 percent and a return to normal function in 90 percent of survivors. Refinements in the pre- and postoperative medical management of transplant recipients portend further benefits.

Lung transplantation in New Jersey.

Single- or bilateral-lung transplantation is an effective treatment for end-stage pulmonary diseases. Refinements in the surgical technique and postoperative management of recipients have resulted in a return to normal function in most cases and a one-year survival in 70 percent of patients.

Immunosuppression: tomorrow and beyond.

Balancing the benefits and side effects of immunosuppressive therapy is important in transplant patients. Several new agents appear to be safer, more effective, and more specific than the available standard immunosuppressive drugs. Many of the agents are likely to be used with present drugs.

High-risk heart surgery in the heart transplant candidate.

Because of the limited supply of donor hearts, transplant physicians are searching for alternative treatments for patients referred for orthotopic heart transplantation. A group of 20 patients (7% of patients accepted for heart transplantation at Loyola University Medical Center) were nonrandomly sent for conventional heart surgery. Of 20 patients, 17 survived their hospitalization, and 11 of the original 20 have avoided heart transplantation or having their names added to the transplant list. This group represents a high-risk subset of patients. Patients with poor ventricular function and ventricular arrhythmias or with poor ventricular function who underwent first-time revascularization were well served by more conventional heart surgery (all 10 patients survived surgery). Patients with poor ventricular function who required redo bypass operation had a poor result (three of six died), and such patients should be considered carefully for initial heart transplantation.

Influence of preoperative transpulmonary gradient on late mortality after orthotopic heart transplantation.

We reviewed the transpulmonary gradient, pulmonary arterial systolic pressure, pulmonary vascular resistance (Wood units), and pulmonary vascular resistance index (Wood units X Body surface area), recorded preoperatively in 109 recipients aged 44.6 +/- 13.5 (mean +/- SD) years who underwent orthotopic heart transplantation between March 1984 and March 1988, to identify which measure of pulmonary hypertension most accurately predicts poor outcome after orthotopic heart transplantation. These recipients were followed up as many as 57 (24.7 +/- 14.5) months after their transplant procedure. Preoperative hemodynamic values were as follows: transpulmonary gradient, 10.4 +/- 4.7 mm Hg; pulmonary artery systolic pressure, 53.6 +/- 14.8 mm Hg; pulmonary vascular resistance, 2.7 +/- 1.8 Wood units; pulmonary vascular resistance index, 4.9 +/- 2.7. Nineteen recipients died within 1 year after orthotopic heart transplantation. Causes of death were acute rejection (8), chronic rejection (1), infection (2), nonspecific orthotopic heart transplant failure (4), bowel ischemia (1), pancreatitis (1), lymphoma (1), and liver failure (1). Preoperative pulmonary arterial systolic pressure, pulmonary vascular resistance, and pulmonary vascular resistance index were not predictive of 1-month, 6-month, or 1-year mortality. One-month mortality rates of orthotopic heart transplant recipients with transpulmonary gradient greater than or equal to 12 mm Hg and of those with transpulmonary gradient less than 12 mm Hg were not significantly different (11% vs 3%; p = 0.12). The 6-month mortality rate of orthotopic heart transplant recipients with transpulmonary gradient greater than or equal to 12 mm Hg, however, was five times greater than that of orthotopic heart transplant recipients with transpulmonary gradient less than 12 mm Hg (24% vs 5%; p = 0.003), and 12-month mortality of orthotopic heart transplant recipients with transpulmonary gradient greater than or equal to 12 mm Hg was increased sevenfold when compared with that of orthotopic heart transplant recipients with transpulmonary gradient less than 12 mm Hg (36% vs 5%; p = 0.0005). These results suggest that presently used measures of pulmonary hypertension do not predict mortality in the first month after orthotopic heart transplantation, but that elevated preoperative transpulmonary gradient is associated with a significant increase in mortality at 6 and 12 months after orthotopic heart transplantation. Prospective randomized trials are needed to determined whether extended preload and afterload reduction before and/or after transplant will favorably influence long-term prognosis of orthotopic heart transplant recipients with elevated preoperative transpulmonary gradient.

Prospective randomized trial of OKT3- versus horse antithymocyte globulin-based immunosuppressive prophylaxis in heart transplantation.

To compare monoclonal anti-T3-receptor antibody (OKT3) and horse antithymocyte globulin (HATG) immunoprophylaxis, 23 heart transplant recipients were randomized to OKT3 (N = 12) 5 mg IV x 14 days of HATG (N = 11) 5 mg/kg IV x 10 days and followed up for 216 +/- 137 days receiving triple immunosuppression. Recipient groups were demographically and clinically similar. First rejection occurred later in OKT3 recipients vs HATG recipients (31.7 +/- 18.3 vs 15.1 +/- 2.3 days; p less than 0.01), but the first rejection necessitating intensified immunosuppression occurred at similar times (30.9 +/- 14.6 vs 21.9 +/- 10.2 days; NS). Phenotypic characterization of peripheral blood lymphocytes by flow cytometry revealed that OKT3 and HATG recipients had similar decreases in total T lymphocytes and lymphocyte subpopulations. During the follow-up period rejection rates in the OKT3- and in the HATG-treated patients were 3.4 +/- 2.7 and 5.9 +/- 4.7, respectively (NS). The number of rejection episodes per recipient treated with intensified immunosuppression was 1.4 +/- 1.2 in the OKT3- and 2.0 +/- 3.1 in the HATG-treated patients (NS). Infection rates were 4.9 +/- 5.2 in the OKT3- and 2.7 +/- 1.7 in the HATG-treated patients (NS). The number of infection episodes that necessitated intravenous antimicrobial therapy was 2.7 +/- 2.3 in the OKT3- and 1.6 +/- 1.3 in the HATG-treated recipients (NS). The number and length of hospitalizations were similar in patients given OKT3-based or HATG-based immunoprophylaxis. We conclude that immunosuppressive prophylaxis with OKT3 vs HATG in heart transplant recipients is associated with a slightly lower incidence and severity of rejection and slightly higher infection rates.

Predictors of late acute orthotopic heart transplant rejection.

To identify predictors of late acute rejection after orthotopic heart transplantation (OHT), 53 patients who received transplants between March 1984 and March 1987 and who survived at least 1 year postoperatively were followed up for 402-1,151 days (mean, 841 days). Fourteen patients experienced 22 moderate or severe rejection episodes more than 1 year after OHT (LR); 39 were nonrejectors (NR). Twelve of 14 (86%) LR and only 14 of 39 (36%) NR had two or more moderate or severe rejection episodes within the first year after OHT (p less than 0.001). The LR had significantly higher numbers of infections more than 1 year after OHT (2.0 vs. 0.9; p less than 0.05). Nine of 22 (40%) late acute rejection episodes followed within 1 month of infection. Human leukocyte antigen reactivity before OHT, follow-up hemodynamics, length of survival, incidence of diabetes mellitus, coronary artery disease 1 year after OHT, mean cyclosporine levels, and mean daily prednisone doses were similar in LR and NR patients. We conclude that 1) OHT recipients with two or more moderate or severe rejection episodes in the first year after OHT are at higher risk of developing late acute rejection and may require closer long-term rejection surveillance and more aggressive maintenance immunosuppression and 2) the possible relation between infection and subsequent acute rejection episodes in OHT recipients requires further investigation.

Long-term follow-up of heart transplant recipients treated with murine antihuman mature T cell monoclonal antibody (OKT3): the Loyola experience.

We describe the long-term follow-up of 25 patients treated with murine antihuman mature T cell (OKT3) monoclonal antibody at Loyola University Medical Center. After OKT3 rescue therapy, 12 patients were monitored for 16.5 +/- 6.5 months. Twenty-two moderate and three severe rejection episodes occurred 11 to 469 days (166.8 +/- 126.0) after OKT3 therapy in nine of 12 patients. During the follow-up period three patients died, and one required retransplantation because of recurrent rejection. The coronary arteries of three failed allografts had severe intimal thickening and infiltration with lymphocytes. Thirteen patients received OKT3 for prophylactic immunosuppression, and their course was compared to that of 13 patients who underwent transplantation during the same period but were given prophylactic horse antihuman thymocyte globulins (HATG). There were no differences between the two drugs with respect to long-term incidence and severity of rejection and infection, cardiac allograft function, and survival. Our results indicate that, despite successful reversal with OKT3, heart transplant recipients with refractory rejection remain plagued by recurrent rejection. Cardiac allografts in recipients who die as a result of recurrent rejection show evidence of immune-mediated vasculitis, which results in severe and diffuse coronary luminal narrowing. OKT3 and HATG appear to be equally effective for rejection prophylaxis.