Post-heart transplant diastolic dysfunction is a risk factor for mortality.

OBJECTIVES: The purpose of this study was to evaluate the incidence and prognostic implication of diastolic dysfunction (DD) occurring in the first year after transplant. BACKGROUND: Diastolic dysfunction is a recognized complication in heart transplant recipients, but its true incidence and natural history has been poorly characterized. We studied the prognostic implication of DD, as defined by elevated filling pressures with normal systolic function, occurring in the first year after transplant. METHODS: Between June 1992 and June 2002, all patients who underwent heart transplantation at a single institution were included in the study (231 at 6 weeks and 250 at 6 months and 1 year). Diastolic dysfunction was defined as right atrial pressure (RAP) >/=15 mm Hg (right ventricular [RV] DD) or pulmonary capillary wedge pressure >/=18 mm Hg (left ventricular [LV] DD) with normal systolic function by echocardiogram and without severe mitral or tricuspid insufficiency. In addition, RV DD was defined by a RAP/stroke volume (SV) ratio. RESULTS: The incidence of DD was 22%, 8%, and 12% at 6 weeks, 6 months, and 1 year, respectively. The incidence of LV DD was more frequent than that of RV DD at any time point (p < 0.0001). By multivariable analysis RV DD, as manifested by an elevated RAP/SV, but not LV DD was a strong predictor of cardiac mortality at all time points. CONCLUSIONS: Diastolic dysfunction is common early after transplant, and its incidence decreases during the first year. Right ventricular DD, as measured by an elevated RAP/SV ratio, but not LV DD is a strong predictor of cardiac mortality. Further studies are needed to evaluate the functional status of patients with RV or LV DD and whether aggressive medical therapy for early DD could alter outcome.

Efficacy of bosentan in a small cohort of adult patients with pulmonary arterial hypertension related to congenital heart disease.

OBJECTIVES: This study was designed to assess the tolerability and efficacy of the oral endothelin receptor antagonist bosentan in adult patients with pulmonary arterial hypertension (PAH) related to congenital heart disease (CHD). BACKGROUND: Severe PAH in the setting of CHD is a debilitating syndrome for which there are limited treatment options. This is the first long-term study experience in adults reporting on the tolerability and efficacy of therapy with bosentan for this patient population. METHODS: A 12-month single-center experience with 19 women and 5 men with PAH associated with CHD (79% in New York Heart Association [NYHA] class III) was analyzed. Hemodynamic responses, exercise capacity, and Borg dyspnea index were assessed prior to the administration of bosentan, and again at 3, 6, and 12 months after the study began. Clinical assessments were performed monthly for up to 12 months. The change from baseline was tested using the Wilcoxon pairs test. RESULTS: There was significant improvement in hemodynamics from baseline to 12 months (mean [+/- SD] systolic pulmonary arterial pressure, 99 +/- 30 to 87 +/- 28 mm Hg [p

Response of doxorubicin-induced cardiomyopathy to the current management strategy of heart failure.

BACKGROUND: Doxorubicin (D) (Adriamycin) is a potent and efficacious chemotherapeutic agent in the treatment of various forms of cancer, but its use has been limited by the development of cardiac toxicity. Historically, D-induced cardiomyopathy (CMP) has been refractory to therapy. We report our experience with this form of CMP at the University of Alabama at Birmingham. METHODS: Twenty-five patients (20 women, 5 men) with a clinical diagnosis of D-CMP were referred to our program from 1990 to 2003. Patient data were extracted from office charts. RESULTS: Patients were followed-up for 71 +/- 58 months. On presentation, the average left ventricular ejection fraction (LVEF) was 26 +/- 9.2%, and 88% of patients were New York Heart Association (NYHA) Class III or IV. Patients were treated with angiotensin-converting enzyme inhibitors (ACEi; n = 23) or angiotensin-receptor blocker (ARB; n = 2), and 15 were treated with a combination of ACEi and beta-blockers (BB). With medical therapy, LVEF improved significantly (26 +/- 9.2% vs 35 +/- 16.5%, p = 0.022), as did the NYHA class (p < 0.003). All survivors (n = 19) were NYHA Class I or II with medical therapy, with 10 (53%) being Class I. In the group of patients treated with ACEi + BB, there was a statistically significant improvement in LVEF (26 +/- 10.0% vs 37 +/- 17.6%, p = 0.028), which not seen in the ACEi group, with a strong trend toward normalization of LV function (47% vs 10%, p = 0.054). CONCLUSIONS: In the current era of management of heart failure, D-CMP carries a better prognosis than previously described. Early addition of BB may further improve LVEF.

Multi-organ transplantation: is there a protective effect against acute and chronic rejection?

BACKGROUND: Heart-lung transplantation (Tx) is known to offer a protective effect against acute cardiac rejection. This study was undertaken to evaluate acute and chronic heart and/or lung rejection in the setting of multiple-transplanted organs from the same donor compared with single-organ transplantation. METHODS: Acute (treated rejection episodes of heart or lungs) and chronic (allograft vasculopathy in hearts and bronchiolitis obliterans syndrome [BOS] in lungs) rejection events were analyzed in 348 heart transplant (H) recipients, 24 heart-lung (HL) recipients, 82 double-lung (L) recipients and 8 heart-kidney (HK) recipients >18 years of age, who were transplanted between 1990 and 2002. RESULTS: Survival at 3 years differed among groups as follows: HK, 100%; H, 82%; HL, 74%; and L, 70%. The probability of acute rejection within the first 3 months was higher in H recipients than in HL (81% vs 22%; p < 0.0001) or HK (81% vs 12%; p = 0.00009) recipients. Acute cardiac rejection occurred more frequently during the first 2 years in isolated H recipients compared with HL (2.8 vs 0.27 episodes; p < 0.0001) and HK (2.8 vs 0.54; p < 0.001) recipients. Acute lung rejection occurred more frequently in the first 2 years in L than HL (2.4 vs 1.0 episodes; p = 0.02) recipients. Chronic cardiac rejection (allograft vasculopathy) was more likely within 3 years after H compared with HL (32% vs 16%; p = 0.04) or HK (32% vs 0%; p = 0.14). The onset of chronic lung rejection (BOS) within 3 years was similar in HL and L recipients (39% vs 40%; p = 0.9). CONCLUSIONS: Recipients of multiple organs from a single donor undergo less acute rejection of the heart or lungs compared with isolated heart or lung transplant recipients. Cardiac allograft vasculopathy is decreased significantly when cardiac transplantation is combined with a lung allograft. A lower incidence of cardiac allograft vasculopathy is observed when cardiac transplantation is combined with a renal allograft, and may prove statistically significant when more cases have been accumulated. These phenomena may result from immune modulation of the recipient by simultaneous transplant of disparate tissues or introduction of immune-modulating hematopoietic elements.

Palliation of allograft vasculopathy with transluminal angioplasty: a decade of experience.

OBJECTIVES: The goal of this study was to examine the outcomes of percutaneous coronary interventions (PCI) and the predictors for restenosis after cardiac transplantation. BACKGROUND: The role of PCI as definitive therapy for allograft coronary disease (ACD) remains contentious. METHODS: Between January 1, 1990 and December 31, 2000, 62 patients (1.5 to 15.5 years after transplant) underwent 151 procedures resulting in PCIs of 219 lesions. Follow-up after PCI angiography was usually obtained at three and six months, then yearly. Repeat PCI was routinely done to lesions with >60% restenosis. RESULTS: The primary procedural success was 97%. Repeat PCI occurred in 74 of 219 lesions (34%); PCI-related mortality was 2.6% (4 of 151). The freedom from re-PCI (of same vessel site) was 75% at six months, 65% at one year, and 57% at four years. The freedom from restenosis was 95% at one month, 81% at three months, and 57% at six months. Multivariate predictors of freedom from restenosis were the use of stents, higher anti-proliferative immunosuppressant dose, and an era effect. In the setting of one-vessel disease at first PCI, the two-year freedom for ACD death or graft loss was 74%, compared with 75% for two-vessel and 27% for three-vessel disease (p = 0.009). CONCLUSIONS: Despite the increasing effectiveness of PCI for localized ACD, the survival after development of advanced ACD remains poor. Stents appear to increase effectiveness of PCI for ACD, but other factors in the current era contribute to improved outcomes.

Selection of patients and techniques of heart transplantation.

Cardiac transplantation remains the primary therapeutic choice for most patients under 65 years of age with advanced heart failure who remain symptomatic despite maximal medical therapy. Cardiac transplantation should be reserved for those patients most likely to benefit in terms of both life expectancy and quality of life. The concept of survival benefit margin must be balanced with the principles of utility in the selection process. A critical component of outcomes research for advanced heart failure will be the generation of accurate data and analyses which predict long-term survival and quality of life with various therapeutic modalities. Patients with multiple comorbidities have inferior survival and might be considered for alternative therapies. We currently recommend the bicaval techniques as the transplant technique of choice except in small infants and children.

Regulated interleukin-10 expression prevents chronic rejection of transplanted hearts.

OBJECTIVE: Interleukin-10 is a pleiotrophic cytokine with variable effects on the alloimmune response, depending on the experimental model system. The purpose of this study was to determine the role of regulated interleukin-10 expression on the development of chronic rejection in heart transplantation, or cardiac allograft vasculopathy. METHODS: Donor hearts from B6.C-H2(bm12) mice were transplanted into wild-type and interleukin-10 transgenic recipients. In interleukin-10 transgenic recipients, murine interleukin-10 cytokine is produced under the control of human interleukin-2 promoter. Donor hearts were sacrificed at days 7 and 24. No immunosuppression was used. Intimal proliferation was measured morphometrically. Intragraft cellular infiltrate was defined by both immunohistochemistry and flow cytometry. Intracellular cytokine staining assay was performed to determine both the type and source of intragraft cytokines. RESULTS: Hearts transplanted into wild-type recipients developed severe cardiac allograft vasculopathy by 24 days. Intimal lesions were absent in the donor hearts transplanted into interleukin-10 transgenic recipients. The number of graft-infiltrating T lymphocytes and the percentage of interleukin-2/interferon-gamma producing T lymphocytes were markedly reduced in interleukin-10 transgenic recipients. Finally, the overexpression of interleukin-10 resulted in the decline of graft-infiltrating macrophages at all time points. CONCLUSIONS: Regulated expression of interleukin-10 inhibits cardiac allograft vasculopathy development via reduction of mononuclear cell recruitment and alteration of their cytokine profile. This strategy may prove beneficial in controlling the alloimmune response in solid organ transplants.

Allogeneic bone marrow inhibits T-cell activation and clonal expansion in vitro.

BACKGROUND: Donor bone marrow infusion has long been used to enhance graft survival or induce tolerance in T cell depleted solid organ allograft recipients. However, the mechanisms through which bone marrow cells affect tolerance remain obscure. We studied the affect of allogeneic bone marrow cells on the activation of allospecific T cells in vitro. METHODS: Carboxyfluorescein-diacetate succinimidyl ester-labeled CBA/Ca strain CD8+ splenocytes, bearing T-cell receptor alpha and beta transgenes from the BM3.3 T-cell clone specific for the major histocompatibility complex class I antigen Kb, were placed in culture with irradiated C57BL/6J stimulator cells in the presence of increasing numbers of C57BL/6J or Balb/cJ bone marrow cells for 1 to 3 days. Responder cells were individually analyzed for proliferative history, expression of activation-associated antigens, and intracellular cytokine production. RESULTS: Allogeneic bone marrow cells exert a dose-dependent inhibitory effect on proliferation of allospecific CD8+ T cells in mixed lymphocyte culture. However, the inhibited T-cell subpopulations show physiologic changes associate with the early stages of T-cell activation, including expression of CD69 and early decrease of surface T-cell expression. Unlike cells not co-cultured with bone marrow, these cells fail to reexpress the T-cell receptor (TCR) by 72 hr of culture. The observed inhibitory effect is also associated with a decrease in the proportion of CD8+ cells expressing interleukin-2 and interferon-gamma. CONCLUSIONS: Collectively, these results suggest that peripheral allospecific T cells undergo the initial stages of activation on exposure to antigen in the presence of bone marrow cells, but the cell cycle is arrested and TCR reexpression is inhibited. We speculate that bone marrow cells effect this inhibition through a receptor-ligand interaction that modulates the transmembrane signal pathway for the TCR.

Infection in ventricular assist devices: prevention and treatment.

Infection is one of the most important challenges to the use of implanted mechanical circulatory support systems (MCSS), particularly as we enter the era of permanent device use in patients who are not candidates for cardiac transplantation. This paper describes the pathogenesis of MCSS infection, with particular attention to the role of biofilm-forming bacteria. Suggestions are presented for the prevention and treatment of infections in implanted MCSS.

Donor PAI-1 expression inhibits the intimal response of early allograft vascular disease.

BACKGROUND: The development of allograft vascular disease (AVD) may be related to altered expression of the fibrinolytic system. We determined the extent to which plasminogen activator inhibitor type 1 (PAI-1) expression in donor tissue influences intimal proliferation (IP) in a mouse model of AVD. METHODS: We utilized an end-to-end abdominal aortic transplant model in mice to investigate the development of IP in 3 groups of 6 recipients. Group A (negative control) utilized C57BL/6J strain mice as both donors and recipients. In Groups B (positive control) and C, C57BL/6J mice were vessel donors and CBA/J mice were recipients. Both groups received intraperitoneal anti-CD4 and anti-CD8 monoclonal antibodies (250 microg/week for 5 weeks). Group C recipients, however, were transplanted with vessels from C57BL/6J PAI-1 knockout mice. Animals were killed at 50 days. Transplanted aortas were removed and intimal areas calculated using morphometric analysis. RESULTS: Group A (mean intimal area 6421 +/- 8507 microm(2)) demonstrated very little IP in comparison to the other groups. IP was significantly higher in Group B (mean intimal area 56357 +/- 35629 microm(2)) than Group A (p = 0.008). Group C (mean intimal area 288195 +/- 123279 microm(2)) demonstrated significantly more intimal proliferation than either Groups A or B (vs B, p = 0.003; vs A, p < 0.001). The significance of these results is maintained if intimal thickness is measured as a stand-alone reference for the intimal response. CONCLUSIONS: Lack of PAI-1 expression in donor tissue greatly exaggerates the extent of IP after allogeneic transplantation and suggests that PAI-1 is important in limiting the early phase of AVD.

Giant cell myocarditis in a young man responsive to T-lymphocyte cytolytic therapy.

We describe a case of a 40-year-old man who presented with recent-onset, rapidly decompensating heart failure, and who was found to have giant cell myocarditis (GCM) on biopsy. The patient responded to myocardial rest on a biventricular assist device, as well as immunosuppression that included eradication of T cells using OKT3 therapy, coupled with high-dose steroids. The patient was successfully weaned off mechanical support, and ultimately discharged home, where he continues to do well. Based on a review of the clinical and experimental literature, we believe treatment with T-lymphocytic cytolytic therapy may be beneficial. Further studies using this therapy in the treatment of GCM are warranted.

Overexpression of interleukin-10 by activated T lymphocytes inhibits atherosclerosis in LDL receptor-deficient Mice by altering lymphocyte and macrophage phenotypes.

Previous studies demonstrated that interleukin-10 (IL-10) overexpression decreases formation of early fatty-streak lesions in mice independent of lipoprotein levels. The present studies, using bone marrow transplantation, demonstrate that overexpression of IL-10 by T cells inhibits advanced atherosclerotic lesions in LDL receptor-null mice fed an atherogenic diet. In mice receiving bone marrow from the IL-10 transgenic mice compared with those receiving wild-type marrow, there was a 47% decrease in lesion size and a marked decrease in lesion complexity with an 80% reduction in the necrotic core. Accumulation of cholesterol and phospholipid oxidation products in the aorta was decreased by 50% to 80%, unrelated to plasma lipid or IL-10 levels. Our studies also provide insight into the mechanism of the IL-10-mediated decrease in lesion size. Although a strong influence toward a Th1 phenotype has previously been demonstrated in atherosclerotic models, T lymphocytes in the IL-10 transgenic (Tg) group revealed a marked shift to a Th2 phenotype, with decreased IFN-gamma production and an increase in IL-10. Evaluation of specific immunoglobulin subclasses demonstrated a preponderance of IgG(1) isotype, characteristic of a Th2 influence on B cell immunoglobulin class-switching in the IL-10 Tg group. A major finding of these studies was altered monocyte/macrophage function in the IL-10 Tg group. Monocytes showed a decrease in activation resulting in decreased expression of IFN-gamma. Furthermore, macrophage foam cells within lesions of the IL-10 Tg group exhibited markedly decreased apoptosis. These studies demonstrate that T lymphocyte IL-10 can influence the function of other immune cells to reduce the development of advanced atherosclerotic lesions in mice.