Search

Background: Senile systemic amyloidosis (SSA) is a common aging phenomenon in the elderly population. Nevertheless, pre-mortem diagnosis of SSA is rare. Thus, data on clinical characterization and disease severity are limited., Methods: 36 consecutive SSA patients (71.6 [64.7-82.7]years) were evaluated by electrocardiography, echocardiography, laboratory tests, and (99m)Technetium-3,3-diphosphono-1,2-propanodicarboxylic acid ((99m)Tc-DPD) scintigraphy (n=20)., Results: In addition to cardiac involvement, amyloid deposition was found in rectum (n=6), peripheral nerves (n=2), and urinary bladder (n=2). Five patients showed low voltage pattern. Thickness of interventricular septum (IVS) was 20 [12-27]mm. LV longitudinal function was diminished (TDI-s 5 [3-11] cm/s; MAPSE 6.5 [2.5-19]mm; TAPSE 12.5 [2-24]mm). LV systolic function (LV-EF<45%) was markedly decreased in 19 patients. Plasma levels of troponin T (0.05 [0.01-0.23]µg/L) and NT-proBNP (4318 [205-16597]ng/L) were elevated. (99m)Tc-DPD heart retention was 7.8 [2.4-11.0]% and correlated with MAPSE (ρ=-0.716; p=0.0018), TAPSE (ρ=-0.491; p<0.05), and IVS (ρ=0.556; p=0.0153). Heart-to-body ratio correlated with MAPSE (ρ=-0.771; p=0.0018), IVS (ρ=0.603; p=0.0086). Twelve patients died during follow-up of 27.4 [0.1-106.2]months. Exclusively (99m)Tc-DPD heart retention, diastolic dysfunction and in trend MAPSE were associated with patient's outcome. Interestingly, risk predictors that were well established in patients with AL amyloidosis were not predictive for survival in patients with SSA., Conclusions: This study gave first evidence that (99m)Tc-DPD HR may be capable to display the extent of cardiac amyloid deposition. Moreover, this study suggested that (99m)Tc-DPD HR, diastolic dysfunction and in trend MAPSE are associated with poor outcome. Nevertheless, these findings need to be established in a larger prospective trial., (Crown Copyright © 2011. Published by Elsevier Ireland Ltd. All rights reserved.)

Cardiac biomarkers provide prognostic information in light-chain amyloidosis (AL). Thus, a novel high-sensitivity cardiac troponin T (hs-TnT) assay may improve risk stratification. hs-TnT was assessed in 163 patients. Blood levels were higher with cardiac than renal or other organ involvement and were related to the severity of cardiac involvement. Increased sensitivity was not associated with survival benefit. Forty-seven patients died during follow-up (22.3 ± 1.0 months). Nonsurvivors had higher hs-TnT than survivors. Outcome was worse if hs-TnT more than or equal to 50 ng/L and best less than 3 ng/L. Survival of patients with hs-TnT 3 to 14 ng/L did not differ from patients with moderately increased hs-TnT (14-50 ng/L), but was worse if interventricular septum was more than or equal to 15 mm. Discrimination according to the Mayo staging system was only achieved by the use of the hs-TnT assay, but not by the fourth-generation troponin T assay. Multivariate analysis revealed hs-TnT, NT-proBNP, and left ventricular impairment as independent risk factors for survival. hs-TnT and NT-proBNP predicted survival, even after exclusion of patients with impaired renal function. Plasma levels of the hs-TnT assay are associated with the clinical, morphologic, and functional severity of cardiac AL amyloidosis and could provide useful information for clinicians on cardiac involvement and outcome.

Background: Cardiac light-chain amyloidosis carries a high risk for death predominantly from progressive cardiomyopathy or sudden death (SCD). Independent risk factors for SCD are syncope and complex nonsustained ventricular arrhythmias., Objective: The purpose of this study was to test whether prophylactic placement of an implantable cardioverter-defibrillator (ICD) reduces SCD in patients with cardiac amyloidosis., Methods: Nineteen patients with histologically proven cardiac amyloidosis and a history of syncope and/or ventricular extra beats (Lown grade IVa or higher) received an ICD., Results: During a mean follow-up of 811 +/- 151 days, two patients with sustained ventricular tachyarrhythmias were successfully treated by the ICD. Two patients underwent heart transplantation, and seven patients died due to electromechanical dissociation (n = 6) or glioblastoma (n = 1). Nonsurvivors more often showed progression of left ventricular wall thickness, low-voltage pattern, ventricular arrhythmias (Lown grade IVa or higher), and higher N-terminal pro-brain natriuretic peptide levels than did survivors. Bradycardias requiring ventricular pacing (VVI 40/min <1%, DDD 60/min 6% +/- 1%) occurred only rarely., Conclusion: Patients with cardiac amyloidosis predominantly die as a result of electromechanical dissociation and other diagnoses not amenable to ICD therapy. Selected patients with cardiac amyloidosis may benefit from ICD placement. Better predictors of arrhythmia-associated SCD and randomized trials are required to elucidate the impact of ICD placement in high-risk patients with cardiac amyloidosis.

Background: Cardiac amyloidosis (CA) is the most problematic cause of heart failure because medical treatment strategies are not well tolerated. Due to its high mortality, identification of patients at high risk is crucial for treatment strategies such as heart transplantation prior to chemotherapy for amyloid disease., Methods: Left ventricular wall thickness (LVT) progression was retrospectively compared with electrocardiographic and echocardiographic parameters for risk prediction in 39 patients with histologically proven cardiac amyloidosis., Results: Seventeen deaths occurred, equivalent to 1- and 3-year survival rates of 62.1% and 55.0%, respectively. LVT progression in deceased patients was 2.02 +/- 0.85 mm/month compared with 0.19 +/- 0.03 mm/month in survivors (p < 0.001). Autologous stem-cell transplantation (n = 22, or 54%) reduced LVT progression as compared with not receiving stem cells (0.21 +/- 0.04 mm/month vs 1.45 +/- 0.57 mm/month, p < 0.005). LVT progression correlated with maximal LVT and absolute LVT increase. Progression of LVT was more rapid in patients with impaired LV ejection fraction (LVEF) than preserved LVEF (2.16 +/- 1.04 mm/month vs 0.30 +/- 0.13 mm/month, p < 0.001). LVT closely correlated with survival, whereas initial, maximum or absolute increase in LVT did not. Further predictors of survival were LVEF, autologous stem-cell transplantation and low voltage, but not diastolic dysfunction. Multivariate analysis identified LVT progression as the strongest independent parameter for survival., Conclusions: LVT progression is a powerful risk predictor in light-chain CA, superior to parameters such as LVEF, LVT or a low-voltage pattern. Improved survival by high-dose chemotherapy and stem-cell transplantation is paralleled by a reduction in LVT progression. Repetitive echocardiographic assessment appears indicated in CA patients to identify candidates for heart transplantation in amyloidosis.

Adhesion of leukocytes is an early step in the formation of adaptive or innate immunity. In chronic inflammatory pathologies like atherosclerosis, regulation of adhesiveness is pivotal for the accumulation of leukocytes within the vessel wall. Therefore, the quantification of adhesion is crucial for the understanding and monitoring of immune responses in patients. However, so far, functional analysis of leukocyte adhesion has been time consuming and required prior purification of cell populations from peripheral blood. This reduced the number of samples and cell populations that could be analysed from limited patient material. Here, we introduce a novel method involving rapid quantification of integrin-mediated leukocyte adhesion in human whole blood using flow cytometry. The quantification relies on soluble multivalent immunocomplexes and is thus called "ligand-complex-based adhesion assay" (LC-AA). LC-AA evaluates both integrin affinity and avidity in T-cells, NK-cells and monocytes from as little as 20 mul of whole blood. In marked contrast to T-cells and NK-cells, unstimulated monocytes show non-blockable background binding of the complexes. Therefore, for this subset only, the stimulation-induced integrin activation is measurable. With the LC-AA, for the first time, measurement of adhesiveness of extremely rare cell populations like CD34+ peripheral blood stem cells can be assessed in the absence of prior purification steps. Finally, the small blood volumes needed for adhesion analysis with the LC-AA allow the evaluation of multiple cell subpopulations in large sample collectives, e.g. required in clinical studies.

Background: Anemia after heart transplantation is common; however, there are scant data on etiology and treatment. This study evaluates type of anemia and the effects of erythropoietin therapy., Methods: In 37 anemic heart transplant recipients (31 male/59.1+/-10.3 years/hemoglobin <12.0 g/dl), complete anemia work-up was performed including erythropoietin determination. For three months, 12 anemic patients with renal failure (9 male/64.1+/-13.6 years) were treated with 1-3x4000 IU of epoietin beta/week; treatment endpoints were hemoglobin levels and quality of life as determined by questionnaire., Results: In 31 patients no other cause of anemia than renal insufficiency (mean creatinine 1.9+/-0.9 mg/dl, mean calculated GFR 50.8+/-21.5 ml/min, no hemodialysis) was found; in 93.5% of these patients with renal insufficiency, measured erythropoietin levels were markedly lower than predicted [Beguin Y, Clemons GK, Pootrakul P, Fillet G. Quantitative assessment of erythropoiesis and functional classification of anemia based on measurements of serum transferrin receptor and erythropoietin. Blood 1993; 81(4):1067-1076.]. There was an inverse correlation of hemoglobin levels with serum creatinine/creatinine clearance and a strong trend for inverse correlation of erythropoietin levels. All 12 patients treated with erythropoietin showed a significant increase in hemoglobin levels after three months returning to pre-treatment values within 3 months of cessation of therapy (before study 10.8+/-1.1 g/dl, end of study 14.1+/-1.7 g/dl, three months after end of study 11.6+/-2.1 g/dl; p<0.005). Quality of life was significantly improved in eight patients (75%)., Conclusions: Anemia after heart transplantation is associated with moderate renal failure and low erythropoietin levels in most patients. Erythropoietin therapy resulted in increased hemoglobin levels in all and improved quality of life in 75% of patients. Erythropoietin may be a superior marker of functional renal impairment after heart transplantation; its therapeutic substitution allows effective anemia management and improves quality of life.

Background: Recent studies have suggested that the peroxynitrite-poly(ADP-ribose) polymerase (PARP) pathway is activated during acute allograft rejection. Therefore, we investigated whether PARP inhibition improves transplant outcome and the extent to which immunologic factors contribute to the effects of PARP inhibition., Methods: Isogeneic Lewis-to-Lewis and allogeneic Dark Agouti (DA)-to-Lewis rat cardiac transplants were studied under treatment with placebo, the PARP inhibitor INO-1001 (1 mg/kg/day), cyclosporine (2.5 or 5 mg/kg/day) or the combination of INO-1001 and low-dose cyclosporine. Functional, biochemical and histologic analyses were performed 3 and 5 days after transplantation in control and INO-1001-treated animals. In addition, stimulated T cells and endothelial cells were treated with INO-1001 to evaluate the potential immunosuppressive effects of PARP inhibition., Results: PARP inhibition alone and in combination with cyclosporine significantly prolonged graft survival. Acute rejection led to a typical sequence of initial endothelial dysfunction and reduced contractile reserve followed by progressive systolic and diastolic dysfunction, which were reduced by PARP inhibition. PARP inhibition led to reduced antigen-specific and non-specific proliferation in stimulated T cells and dose-dependently inhibited intracellular adhesion molecule-1 (ICAM-1) up-regulation in stimulated endothelial cells., Conclusions: PARP inhibition was found to prolong graft survival and improve cardiac function during acute cardiac rejection. Direct immunosuppressive properties contribute at least partially to the beneficial effects of PARP inhibitors in graft rejection.

Background: Growth factors such as platelet-derived growth factor (PDGF) and fibroblast growth factor (FGF) appear to play a key role in immunologic reactions in the long-term course after heart transplant. Their expression in the early phase after transplant has been recently described. The aim of the present study was, therefore, to examine the growth factor expression in the early and later periods, up to three years after transplant in the same patient cohort., Methods: Right ventricular endomyocardial biopsies were obtained from 29 heart transplant recipients before implantation, after one and two weeks, and after one, two, and three years after heart transplant, and immediately frozen in liquid nitrogen. The growth factor expression was examined immunohistochemically., Results: The PDGFs were mainly expressed in vascular structures and they were less pronounced in cardiomyocytes. Especially after the first week, a significant increase was found in the expression of PDGF A and B as well as PDGF-receptors alpha and beta. In the yearly biopsies, PDGF expression was rarely found. The bFGF expression was merely weak in the later period three years after transplant and the aFGF was only expressed in the early phase. A comparison of recipients with short and long ischemic time did not reveal any significant differences in the intensity of expression., Conclusions: The increased expression of PDGF and FGF in the first postoperative week can be interpreted as an unspecific reaction to peritransplant injury. This might be related to important reparative, angioprotective, and wound-healing processes shortly after the heart transplant had taken place. The weak expression in the later period appears to be linked to a stable transplant function and a direct influence by the immunosuppressive therapy.

Background: The effect of pre- or post-operatively acquired diabetes mellitus on survival after heart transplantation remains controversial. The influence of transplant era on diabetes-associated survival is unknown., Methods: A retrospective database analysis was performed on all cardiac transplant recipients followed up at our institution between 1986 and 2003. Diabetes mellitus was diagnosed based on oral glucose tolerance testing., Results: Survival was analyzed in 243 patients (80% male, mean age 52.2 years, mean follow-up 5.22 years). Kaplan-Meier survival analysis demonstrated significantly worse (p = 0.0001) survival both early (months 0 to 12) and late (>5 years) after transplantation in pre-operative diabetics (n = 53) compared with non-diabetics (n = 190). Pre-operative diabetes was identified as the only independent risk factor for decreased long-term (>1 year) survival (p = 0.004). In contrast, no effect on survival (p = 0.5) was demonstrated in patients becoming diabetic only after heart transplantation (n = 39). At 12 months post-transplant renal function was significantly impaired in diabetics (p = 0.025); acute rejection, cytomegalovirus (CMV) infection and transplant vasculopathy occurred with similar frequency. Causes of death were similar in diabetics and non-diabetics. Reduced long-term survival in pre-operative diabetics was seen in the early transplant era (1986 to 1994) (p < 0.0001), but not in the more recent era (1995 to 2003) (p = 0.5)., Conclusions: Pre-transplant but not post-transplant diabetes confers an adverse risk for survival (short and long term). Diabetes-associated long-term survival appears to have improved in the recent era, supporting continued transplantation in diabetics under close surveillance and aggressive medical management.

Background: Cytolytic induction therapy with anti-thymocyte globulin (ATG) should induce effective immunosuppression, with a low rate of rejection in the initial phase after heart transplantation. Induction therapy with ATG allows post-operative renal recovery without the negative effects of highly nephrotoxic cyclosporine levels. An increased rate of infection is a common problem, however, and has been associated with "over-immunosuppression" early after transplantation. Therefore, we investigated whether reduced T-cell-adapted ATG induction therapy could be performed without increasing the risk of graft loss by rejection and whether reductions in infection rates and costs are possible., Methods: Between March 1999 and December 2002, T-cell-adapted ATG induction therapy with ATG (Sangstat) (1.5 mg/kg) was given to 62 heart transplant recipients (study group) starting on post-operative Days 1 to 6. T-lymphocyte sub-populations were screened daily using flow cytometry. If total lymphocytes were <100/microl (reference 1,300 to 2,300/microl), T-helper lymphocytes (CD4+) <50/microl (reference >500/microl) and T-suppressor cells (CD8+) <50/microl (reference >300/microl), then no ATG was given. Further immunosuppression was continued with triple therapy consisting of methylprednisolone, azathioprine and cyclosporine. An historic group of heart transplant recipients given a full-dose ATG regimen for 8 days served as controls. These recipients were treated with ATG (Merieux 1.5 mg/kg) until reaching monoclonal cyclosporine levels of >300 mg/dl. Additional immunosuppressive treatment did not differ. Patients in both groups received systemic antibiotics (Imipenem) peri-operatively. Results of routine endomyocardial biopsies and rates of infections were examined., Results: Study group patients were older (52 +/- 10 vs 49 +/- 14 years). In the study group, mean cumulative ATG dose was reduced significantly to 596 +/- 220 mg (p < 0.05) for 3.9 +/- 1.6 days compared with 1,159 +/- 376 mg for 6.9 +/- 1.1 days in the control group. The rate of cytomegalovirus (CMV) seroconversion was 23% in the study group compared with 13% in the control group. Rate of deep sternal infections was lower in the study group (1.6% vs 3.2%). The mean rejection rate in the first 3 months was 0.4 +/- 0.7 for the study patients (185 biopsies) vs 1.1 +/- 1.7 for controls (237 biopsies). All biopsies with ISHLT Grade >2 were treated successfully with 1,000 mg of methylprednisolone intravenously for 3 days. Both groups showed a similar 1-year survival rate (study 88%, control 89%)., Conclusions: T-cell-adapted ATG induction therapy can be a helpful tool for individualized immunosuppression. It is not associated with an increased rate of rejection. Lower doses of immunosuppression help to minimize the rates of infection. In addition, cytolytic induction therapy combined with reduced ATG results in significant cost reduction.

Background: The significance of International Society of Heart and Lung Transplantation (ISHLT) grade >/=3A rejection detected by routine endomyocardial biopsies beyond 2 years post-transplant remains uncertain., Methods: We performed a retrospective analysis of our single-institution database consisting of 4,041 biopsies (188 patients) from 1986 to 2001. Incidence, clinical correlates and outcome of ISHLT grade >/=3A rejection beyond 2 years post-transplant were analyzed., Results: A total of 307 ISHLT grade >/=3A rejection episodes was diagnosed up to 10 years after transplantation, 69 of which occurred later than 2 years post-transplant in 33 of 139 patients ("late rejection") at therapeutic levels of immunosuppression. Late rejection was only marginally correlated with the incidence of moderate rejection within the first 2 post-transplant years (p = 0.09). The incidence of moderate rejection per patient-year decreased from 1.05 in Year 1 over 0.11 in Year 5 to 0.04 in Year 10. The technical failure rate of biopsies remained low throughout the post-transplant period (range 0.7% to 2.4%). Spontaneous resolution of ISHLT grade >/=3A rejection beyond 2 years post-transplant occurred in all 17 patients in whom specific anti-rejection therapy had been electively withheld. Mortality beyond 2 years post-transplant was lower (p = 0.033) in the "late rejecting" group (n = 33) than in the control group (n = 106)., Conclusions: Endomyocardial biopsy continues to detect episodes of moderate rejection even very late after heart transplantation, without a close correlation with the rejection frequency in the early post-transplant period. Even without specific treatment, late rejection carries a benign clinical prognosis and may represent a separate biologic entity. Potential long-term effects-for instance, on the pathogenesis of transplant vasculopathy-need further elucidation.