Homeostatic proliferation is a barrier to transplantation tolerance.

Despite the ease of inhibiting immune responses by blockade of T-cell costimulation in naive rodent models, it is difficult to suppress those responses in animals with memory cells. Studies demonstrating the importance of alloreactive T-cell deletion during tolerance induction have promoted use of peritransplant T-cell-depleting therapies in clinical trials. But potentially complicating wide-scale, nonspecific T-cell depletion is the finding that extensive T-cell proliferation can occur under conditions of lymphopenia. This process, termed homeostatic proliferation, may induce acquisition of functional memory T cells. Here, using clinically relevant mouse models of peripheral T-cell depletion, we show that residual nondepleted T cells undergo substantial homeostatic expansion. In this setting, costimulatory blockade neither significantly suppresses homeostatic proliferation nor prevents allograft rejection. In addition, T cells that have completed homeostatic proliferation show dominant resistance to tolerance when adoptively transferred into wild-type recipients, consistent with known properties of memory cells in vivo. These findings establish the importance of homeostatic proliferation in clinically relevant settings, demonstrate the barrier that homeostatic proliferation can present to the induction of transplantation tolerance, and have important implications for transplantation protocols that use partial or complete peripheral T-cell depletion.

Non-hematopoietic allograft cells directly activate CD8+ T cells and trigger acute rejection: an alternative mechanism of allorecognition.

Despite evidence that human non-hematopoietic cells, such as vascular endothelium, can activate allogeneic T lymphocytes in vitro, the prevailing view has been that hematopoietic antigen-presenting cells are required to trigger alloimmune responses in vivo. Here we report that mouse non-hematopoietic cells activate alloreactive CD8+ T lymphocytes in vitro and in vivo. We also show that vascularized cardiac allografts are acutely rejected via CD8+ direct allorecognition even if the alloantigen is not presented by hematopoietic professional antigen-presenting cells. Because activation of alloreactive CD8+ T cells by donor-type non-hematopoietic cells can continue for the life of the allograft, these findings present a new clinically relevant mechanism of allorecognition and should be taken into consideration when developing strategies to prevent allograft vasculopathy or to induce tolerance.

Mechanisms of chronic rejection in cardiothoracic transplantation.

Despite significant improvements in early post-transplantation survival rates, long-term patient and graft survival have remained poor, due in large part to the vexing problem of chronic allograft rejection. Attempts to combat this problem with intensification of immunosuppression have led to concomitant increases in the rates of fatal malignancies and infections. In cardiac transplantation, chronic rejection is manifested primarily by a disease entity known as cardiac allograft vasculopathy, an occlusive narrowing of the coronary vessels. In lung transplantation, chronic rejection is typified by obliterative bronchiolitis, an airflow limiting narrowing of the bronchioles. From an immunologic standpoint, chronic rejection is believed to be the end result of repeated immune and non-immune insults to the graft. This review examines the pathophysiology of heart and lung chronic, with emphasis on both immune and non-immune causes.

Regulatory transplantation tolerance and "stemness": evidence that Foxp3 may play a regulatory role in SOCS-3 gene transcription.

Immune self-tolerance is controlled by a subset of T lymphocytes that are regulatory (Treg) and epigenetically programmed to suppress autoreactive immune effector cells in vivo. Treg require expression of Foxp3, a transcription factor that not only represses the interleukin-2 gene promoter, but also sequesters key mediators of T-cell signal transduction by complexing with cytoplasmic NFAT and NFkappaB. We have discovered that expression of Foxp3 is linked to two stem cell-related factors, namely leukemia inhibitory factor (LIF) and axotrophin. Because both LIF and axotrophin each influence Foxp3, we now ask if reciprocal cross-talk occurs; for example, does Foxp3 in turn influence LIF and/or axotrophin? We compared the effect of wt-Foxp3 versus mutant DeltaE251-Foxp3, which lacks transcriptional activity, on transcript levels of axotrophin, LIF, and suppressor of cytokine signaling-3 (SOCS-3; a feedback inhibitor of LIF) in the Jurkat human T-cell line. Unexpectedly, a 50-fold increase in SOCS-3 transcripts occurred in the DeltaE251-Foxp3 cells, coincident with a dramatic decrease in LIF transcription. This implies that, either directly or indirectly, transcription of SOCS-3 is negatively regulated by wt-Foxp3. Suppression of SOCS-3 by Foxp3 would support a model wherein Foxp3 promotes LIF signaling in Treg and is further evidence of reciprocity between Foxp3, LIF, and axotrophin.

Evidence for functional inter-relationships between FOXP3, leukaemia inhibitory factor, and axotrophin/MARCH-7 in transplantation tolerance.

In an ex vivo mouse model, regulatory transplantation tolerance is not only linked to Foxp3, but also to release of leukaemia inhibitory factor (LIF) and to expression of axotrophin (also known as MARCH-7), a putative ubiquitin E3 ligase associated with feedback control of T cell activation and of T cell-derived LIF. Given this coordinate correlation with tolerance, we now ask if Foxp3 expression is influenced by LIF or by axotrophin. In spleen cells from allo-rejected mice we found that exogenous LIF reduced interferon gamma release in response to donor antigen by 50%, but LIF had no direct effect on levels of Foxp3 protein in allo-primed cells that were either tolerant, or aggressive, for donor antigen. However, we did find an effect of axotrophin on Foxp3: in the axotrophin null mouse, thymic Foxp3 transcripts were reduced compared to axotrophin wildtype littermates. To test whether these findings in the mouse were of potential significance in man we measured transcript levels of axotrophin and LIF in peripheral blood cell samples collected for a recently published clinical study concerning haematopoietic stem cell recipients. In controls, human peripheral blood CD4+CD25+cells contained significantly more FOXP3 and axotrophin than CD4+CD25-cells. In bone marrow autograft recipients, where peripheral blood cell samples directly represent both the grafted tissue and the immune response, both FOXP3 and axotrophin negatively correlated with graft versus host disease (GVHD). These data suggest that (i) thymic Foxp3+T cell development is influenced by axotrophin; and (ii) clinical auto-GVHD inversely correlates with axotrophin transcript expression as has been previously reported for FOXP3.

Consensus conference report: maximizing use of organs recovered from the cadaver donor: cardiac recommendations, March 28-29, 2001, Crystal City, Va.

The shortage of available donor hearts continues to limit cardiac transplantation. For this reason, strict criteria have limited the number of patients placed on the US waiting list to approximately 6000 to 8000 per year. Because the number of available donor hearts has not increased beyond approximately 2500 per year, the transplant waiting list mortality rate remains substantial. Suboptimal and variable utilization of donor hearts has compounded the problem in the United States. In 1999, the average donor yield from 55 US regions was 39%, ranging from 19% to 62%. This report provides the detailed cardiac recommendations from the conference on "Maximizing Use of Organs Recovered From the Cadaver Donor" held March 28 to 29, 2001, in Crystal City, Va. The specific objective of the report is to provide recommendations to improve the evaluation and successful utilization of potential cardiac donors. The report describes the accuracy of current techniques such as echocardiography in the assessment of donor heart function before recovery and the impact of these data on donor yield. The rationale for and specific details of a donor-management pathway that uses pulmonary artery catheterization and hormonal resuscitation are provided. Administrative recommendations such as enhanced communication strategies among transplant centers and organ-procurement organizations, financial incentives for organ recovery, and expansion of donor database fields for research are also described.

Depletion of recipient CD4+ but not CD8+ T lymphocytes prevents the development of cardiac allograft vasculopathy.

BACKGROUND: We have described that chimeric rat hearts bearing recipient-type antigen-presenting cells (APCs) do not reject acutely, but develop cardiac allograft vasculopathy (CAV) in untreated recipients. This suggests that CAV is triggered either by CD8+ direct allorecognition or by CD4+ indirect allorecognition. To determine the allorecognition pathway responsible for CAV in this model, recipients of chimeric hearts underwent either CD8+ or CD4+ T cell depletion. METHODS: Chimeric hearts were created via bone marrow transplantation in two fully major histocompatibility-mismatched rat strain combinations. DA recipients were thymectomized and treated with Ox8 and Ox38 murine monoclonal antibodies, which deplete CD8+ and CD4+ T cells, respectively. Chimeric PVG hearts bearing DA APCs, abbreviated PVG(DA), were heterotopically transplanted into recipients undergoing thymectomy alone or recipients undergoing thymectomy plus either CD4+ or CD8+ T cell depletion. RESULTS: PVG(DA) allografts survived 100 days, but developed CAV in thymectomized recipients and in those permanently depleted of CD8+ T cells. In contrast, chimeric hearts transplanted into permanently CD4+ T cell-depleted recipients survived 100 days and demonstrated no evidence of CAV. CONCLUSIONS: In this specific strain combination, recipient CD8+ T cells are neither necessary nor sufficient for the development of CAV, whereas recipient CD4+ T cells are required for the development of CAV. These findings suggest that CAV is dependent on CD4+ indirect allorecognition and that CD8+ direct allorecognition stimulated by nonprofessional APCs plays a minor role.

Aggressive pharmacologic donor management results in more transplanted organs.

BACKGROUND: Brain death results in adverse pathophysiologic effects in many cadaveric donors, resulting in cardiovascular instability and poor organ perfusion. Hormonal resuscitation (HR) has been reported to stabilize and improve cardiac function in brain-dead donors. The goal of this study was to examine the effect of HR on the brain-dead donor on the number of organs transplanted per donor. METHODS: A retrospective analysis of all brain-dead donors recovered in the United States from January 1, 2000, to September 30, 2001, was conducted. HR consisted of a methylprednisolone bolus and infusions of vasopressin and either triiodothyronine or L-thyroxine. Univariate analyses and multivariate logistic regression analyses were used to detect differences between the HR group and those donors who did not receive HR. RESULTS: Of 10,292 consecutive brain-dead donors analyzed, 701 received three-drug HR. Univariate analysis showed the mean number of organs from HR donors (3.8) was 22.5% greater than that from nonhormonal resuscitation donors (3.1) (P <0.001). Multivariate analyses showed that HR was associated with the following statistically significant increased probabilities of an organ being transplanted from a donor: kidney 7.3%, heart 4.7%, liver 4.9%, lung 2.8%, and pancreas 6.0%. Extrapolation of these probabilities to the 5,921 brain-dead donors recovered in 2001 was calculated to yield a total increase of 2,053 organs. CONCLUSION: HR stabilizes certain brain-dead donors and is associated with significant increases in organs transplanted per donor.

Hormonal resuscitation yields more transplanted hearts, with improved early function.

BACKGROUND: Brain death results in cardiovascular instability and poor organ perfusion in many brain-dead donors. Hormonal resuscitation stabilizes certain brain-dead donors and is associated with significant increases in the numbers of organs transplanted per donor. The goal of this study was to examine the quality of hearts recovered from donors treated with hormonal resuscitation. METHODS: A retrospective analysis of 4,543 recipients of hearts recovered from brain-dead donors, reported to the United Network for Organ Sharing/Organ Procurement and Transplantation Network database between November 1, 1999, and December 31, 2001, was conducted. Hormonal resuscitation consisted of a methylprednisolone bolus and infusions of vasopressin and either triiodothyronine or l-thyroxine. Univariate and multivariate analyses were used to evaluate the quality of hearts from donors who received three-drug hormonal resuscitation (3HR) treatment versus donors who did not receive all three drugs (non-3HR). Death within 30 days and early graft dysfunction were used as endpoints. RESULTS: Hearts from 3HR donors demonstrated a 1-month survival rate of 96.2%, compared with a 92.1% survival rate for non-3HR donor hearts (P<0.01). Early graft dysfunction occurred in 5.6% of 3HR donor hearts and 11.6% of non-3HR donor hearts (P<0.01). Multivariate results demonstrated a 46% reduced odds of death within 30 days and a 48% reduced odds of early graft dysfunction. Steroids alone and steroids plus triiodothyronine/l-thyroxine also significantly reduced prolonged graft dysfunction. CONCLUSIONS: This study suggests that 3HR treatment of brain-dead donors results in increased numbers of transplanted hearts, with improved short-term graft function.

Mechanism of T cell-mediated endothelial apoptosis.

BACKGROUND: Cytotoxic T lymphocyte (CTL)-mediated destruction of allogeneic vascular endothelium is important in the pathogenesis of both acute and chronic allograft rejection. Despite the importance of this phenomenon, the effector mechanisms responsible for endothelial cell killing are not well defined, and conflicting conclusions have been reached based on variation in experimental methodology. METHODS: We used a recently described method for isolating mouse vascular endothelium to evaluate endothelial cell lysis by CTLs. Endothelial cell destruction was assessed in vitro both by 51Cr release and DNA fragmentation using wild-type and lpr (Fas deficient) endothelium of C3H/HeJ (H2(k)) mice by MHC alloantigen-specific T cells of wild-type, gld (Fas ligand deficient), and perforin-deficient mice on a C57BL/6 (H2(b)) background. RESULTS: Although maximal lysis of 56.6+/-0.8% was seen when using wild-type targets and effectors, only a moderate decrease in apoptosis to 37.6+/-4.0% was detected when the Fas/Fas ligand death receptor pathway was eliminated. This decrease in cytotoxicity occurred despite the preserved functional capacity of this pathway. Alternatively, a significant decrease in cytotoxicity to 17.4+/-4.7% was seen when the perforin/granzyme exocytosis pathway was eliminated. CONCLUSIONS: These data indicate that CTLs destroy vascular endothelium primarily by the perforin/granzyme exocytosis pathway with only a minor contribution to apoptosis by the Fas/Fas ligand death receptor pathway. These data are critical for the proper interpretation of studies evaluating acute and chronic allograft rejection and for the design of rational strategies to ameliorate vascular injury concomitant to the rejection process.

CD3 monitoring of antithymocyte globulin therapy in thoracic organ transplantation.

BACKGROUND: Antithymocyte globulin is frequently used as a component of induction therapy in thoracic organ transplantation. This study evaluates the utility of monitoring peripheral CD3 lymphocytes to rationally adjust antithymocyte globulin therapy in this patient population. METHODS: A total of 17 heart and 19 lung transplant recipients received antithymocyte globulin (ATGAM or thymoglobulin) as induction therapy or to treat steroid-resistant acute or chronic rejection. Absolute CD3 counts were maintained between 50 and 100 cells/microl. RESULTS: With CD3 monitoring, the doses of antithymocyte globulin were reduced from 10-15 mg/kg to 1-5 mg/kg during the course of therapy. The total amount of antithymocyte globulin given to each CD3 monitored patient was reduced by 48%. Dose reduction did not alter the number of acute rejection or infectious episodes, and hematological side effects were infrequent. CONCLUSION: CD3 monitoring of antithymocyte globulin therapy in thoracic organ recipients reduced the amount of drug received by each patient, while maintaining CD3 counts less than 100 cells/microl.

The role of passenger leukocyte genotype in rejection and acceptance of rat liver allografts.

BACKGROUND: Although graft-resident passenger leukocytes are known to mediate acute rejection by triggering direct allorecognition, they may also act in an immunomodulatory fashion and play an important role in tolerance induction. Our purpose in the current study was to utilize rat bone marrow chimeras to evaluate the role of the genotype of passenger leukocytes in both acute rejection and tolerance of liver allografts. METHODS: The fate of livers bearing donor-type, recipient-type, and third-party passenger leukocytes was evaluated in the MHC class I and II mismatched rejector combination ACI-->LEW and the acceptor combination PVG-->DA. RESULTS: We report that although treatment of ACI liver donors with lethal irradiation does not lead to prolongation of graft survival in the ACI-->LEW strain combination, ACI livers bearing recipient-type (LEW) or third-party passenger leukocytes (BN) are rejected at a significantly slower rate. We confirm that lethal irradiation of PVG donor animals leads to abrogation of tolerance induction with acute rejection of their livers by DA recipients. However, the majority of PVG livers carrying donor-type (PVG), recipient-type (DA), or third-party (LEW) passenger leukocytes are accepted for >100 days. These DA recipients develop immune tolerance to the donor parenchyma (PVG). CONCLUSIONS: Our findings demonstrate that long-term acceptance of liver allografts and tolerance induction is not dependent on the presence of donor-type passenger leukocytes and can be achieved with organs carrying donor-type, recipient-type, or third-party passenger leukocytes. The importance of the MHC framework on the surface of passenger leukocytes as a critical regulator of the immune response after transplantation of chimeric organs is substantiated by the delayed tempo of rejection of ACI livers bearing recipient-type or third-party passenger leukocytes in the ACI-->LEW strain combination.

Clinical risk factors for primary graft failure following lung transplantation.

STUDY OBJECTIVE: s: Primary graft failure (PGF) is a devastating acute lung injury syndrome following lung transplantation. We sought to identify donor, recipient, and operative risk factors for its development. DESIGN: We conducted a cohort study of 255 consecutive lung transplant procedures performed between October 1991 and July 2000. We defined PGF as follows: (1) diffuse alveolar opacities exclusively involving allograft(s) and developing within 72 h of transplant, (2) a ratio of PaO(2) to fraction of inspired oxygen < 200 beyond 48 h postoperatively, and (3) no other secondary cause of graft dysfunction identified. Risk factors were assessed individually and adjusted for confounding using multivariable logistic regression models. SETTING: Tertiary-care academic medical center. RESULTS: The overall incidence was 11.8% (95% confidence interval [CI], 7.9 to 15.9). Following multivariable analysis, the risk factors independently associated with development of PGF were as follows: a recipient diagnosis of primary pulmonary hypertension (PPH; adjusted odds ratio [OR], 4.52; 95% CI, 1.29 to 15.9; p = 0.018), donor female gender (adjusted OR, 4.11; 95% CI, 1.17 to 14.4; p = 0.027), donor African-American race (adjusted OR, 5.56; 95% CI, 1.57 to 19.8; p = 0.008), and donor age < 21 years (adjusted OR, 4.06; 95% CI, 1.34 to 12.3; p = 0.013) and > 45 years (adjusted OR, 6.79; 95% CI, 1.61 to 28.5; p = 0.009). CONCLUSIONS: Recipient diagnosis of PPH, donor African-American race, donor female gender, and donor age are independently and strongly associated with development of PGF.

Cardiopulmonary bypass for bilateral sequential lung transplantation in patients with chronic obstructive pulmonary disease without adverse effect on lung function or clinical outcome.

OBJECTIVE: The use of cardiopulmonary bypass in lung transplantation remains controversial. Previous studies have concluded that cardiopulmonary bypass is deleterious, but these studies were confounded by the inclusion of patients with different diagnoses undergoing single- and double-lung transplantation with elective or emergency use of bypass. The goal of this study was to determine whether cardiopulmonary bypass has deleterious effects on lung function or clinical outcome by analyzing the cases of patients with a single disease entity and elective use of bypass for bilateral sequential lung transplantation. METHODS: A retrospective review of 50 patients with chronic obstructive pulmonary disease who underwent bilateral sequential lung transplantation was performed. Fourteen patients who underwent elective cardiopulmonary bypass for 218.3 +/- 75.4 minutes were compared to 36 control patients. RESULTS: After the operation, the bypass and nonbypass groups were not significantly different with respect to median duration of mechanical ventilation (1 day vs 1 day, P =.76), median stay in the intensive care unit (4 days vs 4 days, P =.44), median hospital stay (15.5 days vs 16 days, P =.74), mean increase in serum creatinine level (1.4 +/- 1.9 mg/dL vs 0.9 +/- 1.0 mg/dL, P =.33), and mean ratio of Pao(2) to fraction of inspired oxygen at 1 hour (376.6 +/- 123 vs 357.0 +/- 218, P =.75), at 24 hours (309.9 +/- 92 vs 350.6 +/- 122, P =.26), and at 48 hours (335.0 +/- 144 vs 316.2 +/- 120, P =.64). Late outcome markers compared between the bypass and nonbypass groups were the following: 1-year percentage predicted forced expiratory volume in 1 second (76.1% +/- 17.0% vs 85.3% +/- 21.7%, P =.24), 30-day mortality (7.1% vs 8.3%, P >.999), 1-year survival (85.7% vs 80.1%, P =.66), 3-year survival (64.3% vs 58.3%, P =.70), and the prevalence of bronchiolitis obliterans syndrome (0% vs 36.1%, P =.01). CONCLUSION: Cardiopulmonary bypass appears to have no deleterious effect on early lung function or clinical outcome. We hope that this pilot study removes some of the unwarranted fear of the use of bypass in lung transplantation for chronic obstructive pulmonary disease.

Fetal liver as a source of autologous progenitor cells for perinatal tissue engineering.

Mesenchymal progenitor cells, isolated from adult bone marrow, have been shown to have utility for autologous tissue engineering. The possibility of isolating from the fetal hematopoietic system a cell population with similar potential, which could be used for autologous reconstruction of prenatally diagnosed congenital anomalies, has not been explored to date. Liver stromal cells isolated from a portion of the right lateral hepatic lobe of midgestation fetal lambs were expanded in vitro. Passage 1 cells displayed a uniform fibroblast-like morphology but could be induced to differentiate into skeletal muscle, adipocytes, chondrocytes, and endothelial cells by selective medium supplementation. By manipulating the extracellular matrix in vitro, spontaneously contracting cardiac myocyte-like cells could be generated as well. Multilineage differentiation was confirmed by morphology, protein expression, and upregulation of lineage-specific mRNA. The potential for engineering myocardial tissue was then investigated by transplanting early-passage progenitor cells, organized on a three-dimensional matrix, into the ventricle of an immunocompromised rat utilizing a previously described model of left ventricular tissue engineering. Survival, incorporation into the host myocardium, and cardiomyocytic differentiation of the transplanted cells were confirmed. We have demonstrated that mesenchymal progenitor cells with multilineage potential can be isolated from the fetal liver and have potential utility for autologous tissue engineering.

Temporal changes in left ventricular systolic function in heart donors: results of serial echocardiography.

BACKGROUND: Heart donor availability continues to limit cardiac transplantation rates and many donor hearts are not transplanted because of left ventricular dysfunction. The aim of this study was to determine whether intensive donor management results in improved left ventricular systolic function as measured by serial echocardiography. METHODS: Using the California Transplant Donor Network Database, all donors who underwent serial echocardiography during donor management (from 1996 to 2000) were identified. The study includes those donors with ejection fractions <50% or regional wall-motion abnormalities shown on the initial echocardiogram. The database provides clinical data describing donor characteristics, treatments, and recipient outcomes. The mean ejection fractions at the first and second echocardiograms were compared using the Wilcoxon signed rank test. RESULTS: In 13 of 16 subjects, initial ejection fractions were <50% and improved in 12 subjects after intensive donor management. Seventy-five percent of the donors received high-dose corticosteroids, 15 of 16 received dopamine, and none received thyroid hormone. In 12 subjects, the donor hearts were transplanted with a survival rate of 92% at an average follow-up of 16 months. CONCLUSIONS: This pilot study indicates that in some cases, intensive donor management is associated with improved donor left ventricular function. Prospective studies are indicated to determine the predictors of improved donor left ventricular dysfunction and of recipient survival when sub-optimal hearts are transplanted.

A novel small animal model of left ventricular tissue engineering.

BACKGROUND: Complex congenital cardiac anomalies involving ventricular hypoplasia require either staged palliative reconstruction, converting the circulatory system to a single ventricle based pump, or allogeneic transplantation. Tissue engineering offers the potential for complete reconstruction of these defects, but is limited by the inability to model myocardial tissue engineering in a small animal. Our goal was to develop a small animal model for ventricular tissue engineering using rat heterotopic heart transplantation. METHODS: Donor hearts were explanted after cardioplegic arrest and the left ventricular volume was augmented by the implantation of a biodegradable engineered construct. The heart was then transplanted heterotopically into syngeneic recipients creating either a volume loaded, functioning left ventricle, or a non-functioning left ventricle. Some of the engineered constructs were seeded with multipotent bone marrow-derived mesenchymal progenitor cells before implantation. Animals were evaluated by echocardiography, morphology, histology, and immunohistochemistry after 1 month. RESULTS: A scaffolding constructed from polytetrafluoroethylene, polylactide mesh, and type I and IV collagen hydrogel resulted in minimal intracardiac inflammation without aneurysmal dilatation. Successful transplantation and differentiation of mesenchymal progenitor cells was accomplished using this scaffolding. No ventricular arrhythmias resulted from this surgical manipulation and echocardiography revealed both end systolic and diastolic volume augmentation with ventricular expansion. CONCLUSION: We have developed an in vivo model of ventricular tissue engineering using heterotopic heart transplantation. Future work will focus on construction of ventricular tissue around pre-fabricated vascular networks in order increase cellular engraftment for ventricular reconstruction.

Left ventricular assist device for right side assistance in patients with transposition.

Right (systemic) ventricular dysfunction is well described after Senning operations for transposition of the great arteries, and patients with congenitally corrected transposition of the great arteries. Transplantation remains the only definitive therapy for refractory heart failure, however patients may deteriorate clinically prior to the availability of a donor heart. This report details the implantation of a TCI Heartmate (Thoratec Corp., Pleaston, CA) as a morphologic right ventricular assist device to bridge these patients to transplantation.

Pattern specification and immune response transcriptional signatures of pericardial and subcutaneous adipose tissue.

Cardiovascular disease (CVD) remains the leading cause of morbidity and mortality in the United States. Recent studies suggest that pericardial adipose tissue (PCAT) secretes inflammatory factors that contribute to the development of CVD. To better characterize the role of PCAT in the pathogenesis of disease, we performed a large-scale unbiased analysis of the transcriptional differences between PCAT and subcutaneous adipose tissue, analysing 53 microarrays across 19 individuals. As it was unknown whether PCAT-secreted factors are produced by adipocytes or cells in the supporting stromal fraction, we also sought to identify differentially expressed genes in isolated pericardial adipocytes vs. isolated subcutaneous adipocytes. Using microarray analysis, we found that: 1) pericardial adipose tissue and isolated pericardial adipocytes both overexpress atherosclerosis-promoting chemokines and 2) pericardial and subcutaneous fat depots, as well as isolated pericardial adipocytes and subcutaneous adipocytes, express specific patterns of homeobox genes. In contrast, a core set of lipid processing genes showed no significant overlap with differentially expressed transcripts. These depot-specific homeobox signatures and transcriptional profiles strongly suggest different functional roles for the pericardial and subcutaneous adipose depots. Further characterization of these inter-depot differences should be a research priority.