RESUMO
BACKGROUND: In acute myocardial infarction complicated by cardiogenic shock the use of mechanical circulatory support devices remains controversial and data from randomized clinical trials are very limited. Extracorporeal life support (ECLS) - venoarterial extracorporeal membrane oxygenation - provides the strongest hemodynamic support in addition to oxygenation. However, despite increasing use it has not yet been properly investigated in randomized trials. Therefore, a prospective randomized adequately powered clinical trial is warranted. STUDY DESIGN: The ECLS-SHOCK trial is a 420-patient controlled, international, multicenter, randomized, open-label trial. It is designed to compare whether treatment with ECLS in addition to early revascularization with percutaneous coronary intervention or alternatively coronary artery bypass grafting and optimal medical treatment is beneficial in comparison to no-ECLS in patients with severe infarct-related cardiogenic shock. Patients will be randomized in a 1:1 fashion to one of the two treatment arms. The primary efficacy endpoint of ECLS-SHOCK is 30-day mortality. Secondary outcome measures such as hemodynamic, laboratory, and clinical parameters will serve as surrogate endpoints for prognosis. Furthermore, a longer follow-up at 6 and 12 months will be performed including quality of life assessment. Safety endpoints include peripheral ischemic vascular complications, bleeding and stroke. CONCLUSIONS: The ECLS-SHOCK trial will address essential questions of efficacy and safety of ECLS in addition to early revascularization in acute myocardial infarction complicated by cardiogenic shock.
Assuntos
Oxigenação por Membrana Extracorpórea , Infarto do Miocárdio/terapia , Revascularização Miocárdica/métodos , Ponte de Artéria Coronária/métodos , Oxigenação por Membrana Extracorpórea/efeitos adversos , Oxigenação por Membrana Extracorpórea/métodos , Fibrinolíticos/uso terapêutico , Humanos , Infarto do Miocárdio/complicações , Infarto do Miocárdio/mortalidade , Prognóstico , Estudos Prospectivos , Qualidade de Vida , Tamanho da Amostra , Choque Cardiogênico/etiologia , Choque Cardiogênico/mortalidadeRESUMO
BACKGROUND: White blood cell-associated antibodies can lead to transfusion-related acute lung injury (TRALI). Female donors with a history of pregnancies have been identified as a main cause for these antibodies. Male or female donors without a history of pregnancy are considered as safe donors. STUDY DESIGN AND METHODS: Following the identification of two TRALI cases associated with blood products from male donors, we investigated the frequency of granulocyte-specific and human leukocyte antigen (HLA) antibodies in the entire blood donor population using a high throughput automated flow-cytometry-based granulocyte immunofluorescence test (Flow-GIFT). We investigated sera from 14,343 whole blood donors (female, n = 6974, 48.7%; male, n = 7369, 51.3%) using automated Flow-GIFT. Of the female blood donors, 60.4% had a history of pregnancy. Positive sera were retested by the standard granulocyte immunofluorescence test and granulocyte agglutination test. For the detection of HLA Class I and II immunoglobulin G antibodies, we used a commercial screening enzyme-linked immunosorbent assay. RESULTS: We detected in 924 (21.9%) of the 4212 females with a history of pregnancy antibodies against granulocyte antigens (n = 62, 1.5%), HLA Class I and/or II antigens (n = 864, 20.5%). Notably, in 3.5% (n = 96) of 2762 females without a history of pregnancy and in 2.1% (n = 154) of 7369 males antibodies against granulocyte antigens (n = 13, 0.47% and n = 45, 0.6%), HLA Class I and/or II (n = 83, 3% and n = 109, 1.4%, respectively), were also detected. CONCLUSION: Human neutrophil antigen antibodies are rare in male and females without a history of pregnancy compared to females with a history of pregnancy, but their relevance is not negligible.
Assuntos
Autoanticorpos/sangue , Doadores de Sangue , Granulócitos/imunologia , Lesão Pulmonar Aguda Relacionada à Transfusão/etiologia , Ensaio de Imunoadsorção Enzimática , Feminino , Citometria de Fluxo/métodos , Antígenos HLA/sangue , Humanos , Incidência , Masculino , Programas de Rastreamento , Neutrófilos , GravidezRESUMO
Atherosclerosis is a chronic inflammatory disease. Lesion progression is primarily mediated by cells of the monocyte/macrophage lineage. IL-17A is a proinflammatory cytokine, which modulates immune cell trafficking and is involved inflammation in (auto)immune and infectious diseases. But the role of IL-17A still remains controversial. In the current study, we investigated effects of IL-17A on advanced murine and human atherosclerosis, the common disease phenotype in clinical care. The 26-wk-old apolipoprotein E-deficient mice were fed a standard chow diet and treated either with IL-17A mAb (n = 15) or irrelevant Ig (n = 10) for 16 wk. Furthermore, essential mechanisms of IL-17A in atherogenesis were studied in vitro. Inhibition of IL-17A markedly prevented atherosclerotic lesion progression (p = 0.001) by reducing inflammatory burden and cellular infiltration (p = 0.01) and improved lesion stability (p = 0.01). In vitro experiments showed that IL-17A plays a role in chemoattractance, monocyte adhesion, and sensitization of APCs toward pathogen-derived TLR4 ligands. Also, IL-17A induced a unique transcriptome pattern in monocyte-derived macrophages distinct from known macrophage types. Stimulation of human carotid plaque tissue ex vivo with IL-17A induced a proinflammatory milieu and upregulation of molecules expressed by the IL-17A-induced macrophage subtype. In this study, we show that functional blockade of IL-17A prevents atherosclerotic lesion progression and induces plaque stabilization in advanced lesions in apolipoprotein E-deficient mice. The underlying mechanisms involve reduced inflammation and distinct effects of IL-17A on monocyte/macrophage lineage. In addition, translational experiments underline the relevance for the human system.
Assuntos
Aterosclerose/imunologia , Aterosclerose/metabolismo , Interleucina-17/metabolismo , Macrófagos/metabolismo , Monócitos/metabolismo , Animais , Anticorpos Monoclonais/farmacologia , Aorta/efeitos dos fármacos , Aorta/imunologia , Aorta/metabolismo , Aorta/patologia , Apolipoproteínas E/deficiência , Apolipoproteínas E/genética , Aterosclerose/tratamento farmacológico , Aterosclerose/genética , Aterosclerose/patologia , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD4-Positivos/metabolismo , Adesão Celular/efeitos dos fármacos , Diferenciação Celular , Análise por Conglomerados , Técnicas de Cocultura , Citocinas/genética , Citocinas/metabolismo , Modelos Animais de Doenças , Progressão da Doença , Células Espumosas/patologia , Perfilação da Expressão Gênica , Humanos , Mediadores da Inflamação/metabolismo , Interleucina-17/antagonistas & inibidores , Interleucina-17/farmacologia , Metabolismo dos Lipídeos , Macrófagos/citologia , Macrófagos/efeitos dos fármacos , Macrófagos/imunologia , Masculino , Camundongos , Camundongos Knockout , Monócitos/citologia , Monócitos/efeitos dos fármacos , Monócitos/imunologia , Placa Aterosclerótica/tratamento farmacológico , Placa Aterosclerótica/imunologia , Placa Aterosclerótica/metabolismo , Placa Aterosclerótica/patologia , Adesividade Plaquetária/efeitos dos fármacos , TranscriptomaRESUMO
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.
Assuntos
Amiloidose/diagnóstico por imagem , Coração/diagnóstico por imagem , Placa Amiloide/diagnóstico por imagem , Índice de Gravidade de Doença , Idoso , Idoso de 80 Anos ou mais , Amiloidose/epidemiologia , Estudos de Coortes , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Placa Amiloide/epidemiologia , Cintilografia , Disfunção Ventricular Esquerda/diagnóstico por imagem , Disfunção Ventricular Esquerda/epidemiologiaRESUMO
BACKGROUND: Treatment options in patients with amyloidotic transthyretin (ATTR) cardiomyopathy are limited. Epigallocatechin-3-gallate (EGCG), the most abundant catechin in green tea (GT), inhibits fibril formation from several amyloidogenic proteins in vitro. Thus, it might also halt progression of TTR amyloidosis. This is a single-center observational report on the effects of GT consumption in patients with ATTR cardiomopathy. METHODS: 19 patients with ATTR cardiomyopathy were evaluated by standard blood tests, echocardiography, and cardiac MRI (n = 9) before and after consumption of GT and/or green tea extracts (GTE) for 12 months. RESULTS: Five patients were not followed up for reasons of death (n = 2), discontinuation of GT/GTE consumption (n = 2), and heart transplantation (n = 1). After 12 months no increase of left ventricular (LV) wall thickness and LV myocardial mass was observed by echocardiography. In the subgroup of patients evaluated by cardiac MRI a mean decrease of LV myocardial mass (-12.5 %) was detected in all patients. This was accompanied by an increase of mean mitral annular systolic velocity of 9 % in all 14 patients. Total cholesterol (191.9 ± 8.9 vs. 172.7 ± 9.4 mg/dL; p < 0.01) and LDL cholesterol (105.8 ± 7.6 vs. 89.5 ± 8.0 mg/dL; p < 0.01) decreased significantly during the observational period. No serious adverse effects were reported by any of the participants. CONCLUSIONS: Our observation suggests an inhibitory effect of GT and/or GTE on the progression of cardiac amyloidosis. We propose a randomized placebo-controlled investigation to confirm our observation.
Assuntos
Neuropatias Amiloides Familiares/tratamento farmacológico , Cardiomiopatias/tratamento farmacológico , Catequina/análogos & derivados , Chá/química , Idoso , Neuropatias Amiloides Familiares/fisiopatologia , Cardiomiopatias/fisiopatologia , Catequina/isolamento & purificação , Catequina/farmacologia , Colesterol/sangue , Estudos de Coortes , Progressão da Doença , Feminino , Seguimentos , Ventrículos do Coração/efeitos dos fármacos , Ventrículos do Coração/patologia , Humanos , Masculino , Pessoa de Meia-Idade , Valva Mitral/metabolismo , Extratos Vegetais/farmacologiaAssuntos
Síndrome Hipereosinofílica/diagnóstico , Síndrome Hipereosinofílica/tratamento farmacológico , Hipertrofia Ventricular Esquerda/diagnóstico , Hipertrofia Ventricular Esquerda/tratamento farmacológico , Proteínas de Fusão Oncogênica/biossíntese , Piperazinas/uso terapêutico , Pirimidinas/uso terapêutico , Receptor alfa de Fator de Crescimento Derivado de Plaquetas/biossíntese , Fatores de Poliadenilação e Clivagem de mRNA/biossíntese , Adulto , Benzamidas , Doença Crônica , Humanos , Síndrome Hipereosinofílica/genética , Hipertrofia Ventricular Esquerda/genética , Mesilato de Imatinib , Masculino , Resultado do TratamentoRESUMO
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.
Assuntos
Amiloidose/diagnóstico , Troponina T , Amiloidose/patologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Miocárdio/patologia , Prognóstico , Análise de Sobrevida , Troponina T/sangueRESUMO
Angiograms of cardiac transplant (HTx) recipients were to be evaluated in a ring experiment and a joint consensus on criteria of angiographic evaluation of coronary arteries of HTx patients was to be reached. Twenty-four coronary angiograms from 11 hospitals were circulated. One hundred eighty-eight blinded evaluations were returned. A joint evaluation by six experienced cardiologists was used as reference standard and a consensus evaluation form was developed. Significant lesions (stenosis 75%, 50% in the left main coronary artery) were diagnosed in 10/23 abnormal coronary angiograms (41.7%). Interventional revascularization was recommended in 8/10 (80%). In 21 coronary angiograms distal pruning was found and in 11/21 (52.4%) cases with distal pruning occlusion of at least one peripheral vessel was detected. The best kappa value (0.7) was found for the presence of at least one clinically significant stenosis. Agreement on the site and grade of local stenosis was much less. Some agreement on remodeling was found in assessing diffuse narrowing in the LCA (kappa=0.371, P<0.001). The kappa value for peripheral obliteration was 0.331 (P=0.001). Angiographic evaluation of cardiac allograft vasculopathy, particularly of diffuse and peripheral disease and remodeling, needs standardization. This should be performed in a downward compatible improvement process.
Assuntos
Angiografia Coronária/métodos , Transplante de Coração/métodos , Transplante Homólogo/métodos , Cardiologia/métodos , Constrição Patológica/terapia , Angiografia Coronária/normas , Vasos Coronários/diagnóstico por imagem , Vasos Coronários/patologia , Alemanha , Guias como Assunto , Transplante de Coração/diagnóstico por imagem , Transplante de Coração/normas , Humanos , Revascularização Miocárdica/métodos , Variações Dependentes do Observador , Sensibilidade e Especificidade , Resultado do Tratamento , UltrassonografiaRESUMO
INTRODUCTION: The prevalence, pathophysiology, and clinical indicators of valvular amyloid deposition have not been clarified yet. METHODS: One hundred fifty surgically resected heart valve specimens [67.4+/-1.0 years; aortic stenosis (AS), n=100; aortic regurgitation, n=19; mitral stenosis, n=7; mitral regurgitation, n=24] were qualitatively, semiquantitatively, and immunohistochemically analyzed and correlated with clinical data. RESULTS: Amyloid was found in 83/150 specimens with highest prevalence in AS (74/100), intermediate prevalence in mitral stenosis (2/7) and regurgitation (7/24), and lowest prevalence in aortic regurgitation (2/19). Severe and polymorphic amyloid deposits were almost exclusively found in AS (35/100). Filamentous cloudy amyloid patterns occurred with the same frequency in AS (29/100). A combination of both was found only in AS (n=7/100). By immunohistochemistry, none of the most common amyloid proteins was identified except for a weak staining by the apolipoprotein AI antibody, but more intense adjacent to amyloid deposits. Amyloid correlated with valvular thickening (P<.05), hyperlipidemia (P=.07), coronary artery disease (P=.084), and obesity (P=.082). CONCLUSIONS: Localized valvular amyloid is predominantly found in stenotic aortic valves. It appears to depend on atheroinflammatory conditions and high shear-stress hemodynamics. Further studies are needed to identify the underlying protein.
Assuntos
Amiloide/metabolismo , Amiloidose/patologia , Aterosclerose/patologia , Doenças das Valvas Cardíacas/patologia , Valvas Cardíacas/patologia , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Amiloidose/complicações , Amiloidose/metabolismo , Insuficiência da Valva Aórtica/complicações , Insuficiência da Valva Aórtica/metabolismo , Insuficiência da Valva Aórtica/patologia , Estenose da Valva Aórtica/complicações , Estenose da Valva Aórtica/metabolismo , Estenose da Valva Aórtica/patologia , Aterosclerose/complicações , Aterosclerose/metabolismo , Criança , Doença da Artéria Coronariana/complicações , Doença da Artéria Coronariana/metabolismo , Doença da Artéria Coronariana/patologia , Feminino , Doenças das Valvas Cardíacas/complicações , Doenças das Valvas Cardíacas/metabolismo , Valvas Cardíacas/metabolismo , Valvas Cardíacas/cirurgia , Humanos , Hiperlipidemias/complicações , Hiperlipidemias/metabolismo , Hiperlipidemias/patologia , Processamento de Imagem Assistida por Computador , Masculino , Pessoa de Meia-Idade , Insuficiência da Valva Mitral/complicações , Insuficiência da Valva Mitral/metabolismo , Insuficiência da Valva Mitral/patologia , Estenose da Valva Mitral/complicações , Estenose da Valva Mitral/metabolismo , Estenose da Valva Mitral/patologia , Obesidade/complicações , Obesidade/metabolismo , Obesidade/patologia , Adulto JovemRESUMO
BACKGROUND: The prognostic value of NT-proBNP has been recognized in patients with amyloidosis complicated by cardiac involvement. We aimed to use contrast enhanced cardiac magnetic resonance imaging (CMR) to identify functional and structural alterations related to levels of NT-proBNP better to understand the mechanisms of its release in cardiac amyloidosis. METHODS AND RESULTS: CMR was performed on a 1.5-T scanner in 34 patients with biopsy proven amyloid light chain (AL; n = 27) or hereditary transthyretin related (TTR; n = 7) amyloidosis. NT-proBNP was higher in patients with (n = 25) compared to patients without cardiac involvement (n = 9) (2931 (IQR: 972-8629; min-max: 25-27,277) pg/ml vs. 177 (IQR: 71-1431; min-max: 22-7935) pg/ml, p = 0.008). ROC analysis identified a NT-proBNP of <2426.5 pg/ml as optimal discriminator for event free survival (682 +/- 65 days). NT-proBNP did not correlate with LV- ejection fraction, end-diastolic and end-systolic volumes or stroke volume. There was a moderate correlation between NT-proBNP and LV-mass (R = 0.52, p = 0.003) and extent of late gadolinium enhancement (LGE; R = 0.41, p = 0.04). CONCLUSIONS: This study confirms the prognostic value of NT-proBNP in patients with AL and TTR amyloidosis and provides the novel finding that NT-proBNP correlates with surrogates of myocardial amyloid burden such as LV-mass and LGE, supporting the concept of NT-proBNP as a biomarker reflecting the severity of cardiac amyloid infiltration.
Assuntos
Amiloidose/sangue , Amiloidose/patologia , Cardiomiopatias/sangue , Cardiomiopatias/patologia , Gadolínio , Imageamento por Ressonância Magnética/métodos , Peptídeo Natriurético Encefálico/sangue , Fragmentos de Peptídeos/sangue , Amiloide/metabolismo , Meios de Contraste , Feminino , Humanos , Masculino , Pessoa de Meia-IdadeRESUMO
AIMS: The prognosis of advanced cardiac light-chain amyloidosis is poor. Heart transplantation might enable causative therapy and ultimately improve prognosis. METHODS AND RESULTS: Nineteen patients with cardiac amyloidosis but no obvious involvement of other organs were scheduled for heart transplantation. Four to 6 months later, high-dose melphalan chemotherapy and autologous stem cell transplantation (HDM-ASCT) was planned in patients not in complete remission. Seven of nineteen patients died while waiting for heart transplantation. The remaining 12 patients (complete remission, n = 4) underwent surgery. Chemotherapy in patients not in complete remission consisted of HDM-ASCT (n = 5/12; subsequent complete remission, n = 2; partial remission, n = 3) or melphalan-prednisolone (partial remission, n = 1). Two of twelve patients were ineligible for any chemotherapy. Three of twelve patients died [423.5 (105-2131) days] from progressive disease, relapse, or sepsis. The 1- and 3-year survival rates were 83 and 83%, respectively, similar to those of patients undergoing heart transplantation for standard indications. Corresponding survival rates stratified by haematological response were 100 and 100% for complete remission (partial remission, 100 and 100%; progressive disease, 0 and 0%). CONCLUSION: Heart transplantation in advanced cardiac amyloidosis is a promising approach to interrupting the vicious circle of ineligibility for potential curative chemotherapeutic treatment and extremely poor prognosis of cardiac amyloidosis without chemotherapy. Highly urgent heart transplantation combined with subsequent HDM-ASCT appears to offer a successful treatment option to improve the poor outcome of cardiac amyloidosis. However, it should be restricted to highly selected patients in specialized centres.
Assuntos
Amiloidose/tratamento farmacológico , Amiloidose/cirurgia , Cardiopatias/tratamento farmacológico , Cardiopatias/cirurgia , Transplante de Coração/métodos , Amiloidose/diagnóstico , Amiloidose/mortalidade , Estudos de Coortes , Terapia Combinada , Intervalo Livre de Doença , Feminino , Rejeição de Enxerto , Sobrevivência de Enxerto , Cardiopatias/diagnóstico , Cardiopatias/mortalidade , Transplante de Coração/efeitos adversos , Transplante de Células-Tronco Hematopoéticas/métodos , Humanos , Estimativa de Kaplan-Meier , Masculino , Melfalan/uso terapêutico , Probabilidade , Prognóstico , Estudos Retrospectivos , Medição de Risco , Índice de Gravidade de Doença , Taxa de Sobrevida , Transplante Autólogo , Resultado do Tratamento , Listas de EsperaRESUMO
BACKGROUND: Endothelial progenitor cells (EPC) home to sites of vascular repair and therefore have potential implications in allogenic transplantation settings and in various vascular diseases. This study was performed to investigate the antigen-presenting capacity of peripheral blood mononuclear cells-derived EPC and their T-cell co-stimulatory capacity compared with human vascular endothelial cells (HUVEC) or monocytes. METHODS: EPC were isolated from peripheral blood mononuclear cells by adhesion to fibronectin. Antigen presentation and co-culture assays of EPC, HUVEC, monocytes, and dendritic cells with allogenic CD4 T cells were quantified by thymidine incorporation (cpm) and by quantitative reverse-transcriptase polymerase chain reaction (LightCycler) for cytokine production. RESULTS: Flow cytometric analyses revealed an expression of endothelial antigens (e.g., KDR) as well as monocytic antigens (e.g., CD14) in EPC. EPC effectively presented Mycobacterium tuberculosis antigen MTB 85B to DB3 hybridoma, a cell line specifically recognizing MTB 85B presented by means of human leukocyte antigen-DR3. In phytohemaglutinin-based CD4 T-cell co-stimulation assays, EPC-induced proliferation and cytokine production was comparable with monocytes and dendritic cells, whereas HUVEC-induced T-cell co-stimulation was markedly weaker. In contrast to HUVEC, EPC as well as monocytes activated naïve CD4/CD45RA T cells. Blocking experiments using CTLA-4-IgG fusion protein identified the CD28/CD80/86 system as a major co-stimulatory pathway for EPC-dependent T-cell activation. CONCLUSIONS: Although EPC exhibit endothelial-like surface markers, functional characteristics place these cells in a monocytic lineage. EPC also display antigen-presenting capacity similar to monocytes and much stronger than human vascular EC. Significant T-cell-activating potential will have to be expected from EPC when potentially used therapeutically, especially in allogenic transplant settings.
Assuntos
Células Dendríticas/imunologia , Células Endoteliais/imunologia , Endotélio Vascular/imunologia , Monócitos/imunologia , Células-Tronco/imunologia , Linfócitos T/imunologia , Animais , Especificidade de Anticorpos , Células Apresentadoras de Antígenos/imunologia , Antígenos/imunologia , Linfócitos T CD4-Positivos/imunologia , Técnicas de Cultura de Células , Citometria de Fluxo , Humanos , Hibridomas/imunologia , Ativação Linfocitária/imunologia , Camundongos , Veias UmbilicaisRESUMO
Transthyretin-derived amyloidosis (ATTR) amyloidosis is the third most prevalent amyloid type in surgical pathology and may occur as a hereditary disease with germline mutations in the TTR gene or as senile systemic amyloidosis (SSA) without mutations. Distinction between hereditary ATTR amyloidosis and SSA is of central importance, as the former necessitates genetic counseling and can be treated by liver transplantation. However, little is known about the prevalence of hereditary ATTR amyloidosis in surgical pathology specimens. We have examined the distribution of hereditary ATTR amyloidosis and SSA in a consecutive series of surgical pathology specimens with histologically and immunohistochemically confirmed ATTR amyloid. Thirty-three consecutive patients were retrieved from the Amyloid Registry of the Charité University Hospital. Genomic DNA was extracted from formalin-fixed and paraffin-embedded tissue or patient blood and examined by DNA sequencing. ATTR amyloid was found in the gastrointestinal tract, endomyocardium, peripheral nerve, carpal tunnel ligament, synovia, breast, and testicle. Amyloid fibrils were present as interstitial and vascular deposits, as evidenced by Congo red staining. TTR gene mutations were detected in 12 of 30 patients, with p.Val30Met being the most prevalent (5 patients). Furthermore, 2 novel mutations (p.Asp39Val and p.Glu54Asp) were found. In patients carrying a mutation, ATTR amyloid was found in the gastrointestinal tract, myocardium, nerve, and testicles. To conclude, the hereditary form of ATTR amyloid seems to be more common in elderly patients than previously thought. It is, therefore, important to genetically test every patient when diagnosing ATTR amyloidosis.
Assuntos
Amiloide/metabolismo , Amiloidose Familiar/genética , Mutação em Linhagem Germinativa , Pré-Albumina/genética , Adulto , Distribuição por Idade , Idade de Início , Idoso , Idoso de 80 Anos ou mais , Sequência de Bases , Feminino , Humanos , Imuno-Histoquímica , Masculino , Pessoa de Meia-Idade , Reação em Cadeia da Polimerase , Prevalência , Distribuição por SexoRESUMO
Late enhancement (LE) in cardiac magnetic resonance imaging (MRI) is a characteristic finding in patients with cardiac amyloidosis (CA) but the histomorphological explanation has not been clarified yet. Five patients with CA were evaluated by MRI prior to heart transplantation. This consisted of morphological, volumetric, and functional data, including LE analysis. For LE analysis, left ventricular (LV) short-axis sections from basal, midventricular, and apical positions were divided into 12 segments resulting in a 36-segment model. Each segment was differentiated by subendocardial, midmural, and subepicardial localization. Histological amyloid and collagenous fiber deposition was correlated with LE in corresponding MRI slides. LE was visualized in 103/180 (57.2%) predominantly subendocardial segments. Histological analysis of amyloid deposition was (peri-)vascular (n = 5), diffuse interstitial (n = 3) and/or nodular (n = 4). Extent of fibrosis was moderate to severe. Cytoplasmatic vacuolization and decline of myofibrils was seen in all patients. Fibrosis was significantly associated with LE in subendocardial and midmural localizations (p<0.05), whereas the extent of amyloid deposition was not associated with LE findings in any region. LE seems to be associated with fibrosis due to ischemia of cardiomyocytes by small vessel amyloid deposition rather than with amyloid deposition in CA, suggesting that amyloid deposition might be present prior to LE detection.
Assuntos
Amiloidose/etiologia , Amiloidose/patologia , Cardiomiopatias/etiologia , Cardiomiopatias/patologia , Imageamento por Ressonância Magnética , Amiloidose/diagnóstico por imagem , Cardiomiopatias/diagnóstico por imagem , Meios de Contraste , Feminino , Gadolínio DTPA , Humanos , Aumento da Imagem , Masculino , Pessoa de Meia-Idade , RadiografiaRESUMO
INTRODUCTION: The purposes of this study are to identify a patient cohort that would benefit from the use of mechanical circulatory support (MCS) in the presence of the Eurotransplant high-urgency (HU) program. METHODS: Sixty-five patients (heart transplantation (HTx) group, 77%) underwent heart transplantation and 17 patients (D group, 20%) died while on the HU waiting list. These 82 patients were included in this retrospective study. RESULTS: The mean waiting time on HU list was 18.3+/-17.7 days in HTx group and 12.5+/-9.4 days in D group (p=0.075). The average weekly allocation rate from the active HU list was 27.7%, and the mean weekly waiting-list mortality was 12.1%. The use of intra-aortic balloon pumping (p=0.005), mechanical ventilation (p=0.007), higher dose of dobutamine (0.005), lower serum level of sodium (p=0.046), and higher serum level of C reactive protein (CRP) (0.040) at the registration of HU listing were associated with waiting-time mortality, and the serum creatinine level more than 1.5mg/dl (p=0.007, odds ratio; 14.5, 95% CI; 2.1-102.0) and the serum CRP level more than 10mg/l (p=0.026, odds ratio; 6.3, 95%CI; 1.2-31.4) were identified as significant predictors. CONCLUSION: It would be appropriate that a patient who would not be able to tolerate one or two weeks waiting time to be considered as a candidate for MCS implantation in the presence of the HU program. The patient selection criteria for MCS implantation should include not only hemodynamic parameters, but also the aspect of a beginning multi-organ failure.
Assuntos
Circulação Assistida/estatística & dados numéricos , Cardiopatias/terapia , Transplante de Coração , Seleção de Pacientes , Obtenção de Tecidos e Órgãos/métodos , Adulto , Causas de Morte , Distribuição de Qui-Quadrado , Europa (Continente) , Feminino , Cardiopatias/mortalidade , Transplante de Coração/mortalidade , Mortalidade Hospitalar , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Risco , Listas de EsperaRESUMO
Development of Epstein-Barr virus (EBV)-associated post-transplant lymphoproliferative disease (PTLD) is a serious complication following heart transplantation (HTX). This study investigates EBV DNA load in adult heart transplant recipients, its association with immunosuppression, and its potential as a marker for development of PTLD. EBV DNA load was measured prospectively by quantitative real-time polymerase chain reaction (PCR) in 172 stable HTX patients. Sixty-seven patients (39.0% of total) had a positive EBV PCR at initial examination [median 4.9 (range 1.1-16.9) years post-HTX]. In follow-up testing of 67 positive patients 6 months later, 36 patients continued to have a positive EBV PCR. Overall incidence of EBV DNA was significantly associated with calcineurin inihibitors, azathioprine medication, and with the absence of mycophenolate mofetil (MMF) treatment. In patients with positive EBV DNA levels at initial examination and negative levels at retesting, cyclosporine A levels were found to be significantly higher at initial examination (148.4 +/- 70.2 vs. 119.6 +/- 53.5 ng/ml, P < 0.05). Three patients (1.7%, 3/172) were diagnosed with PTLD during the course of the study (mean follow up 4.0 years). EBV DNA viral load determination does not appear to be useful for risk prediction or early diagnosis of PTLD in adults after HTX, but an association of EBV DNA load with qualitative and quantitative immunosuppression is demonstrated.
Assuntos
Infecções por Vírus Epstein-Barr/etiologia , Rejeição de Enxerto/prevenção & controle , Transplante de Coração/métodos , Herpesvirus Humano 4/isolamento & purificação , Terapia de Imunossupressão/efeitos adversos , Imunossupressores/efeitos adversos , Carga Viral , Adulto , Idoso , Anticorpos Antivirais/análise , DNA Viral/análise , Infecções por Vírus Epstein-Barr/epidemiologia , Feminino , Seguimentos , Alemanha/epidemiologia , Rejeição de Enxerto/imunologia , Insuficiência Cardíaca/cirurgia , Herpesvirus Humano 4/genética , Herpesvirus Humano 4/imunologia , Humanos , Incidência , Masculino , Pessoa de Meia-Idade , Reação em Cadeia da Polimerase , Prognóstico , Fatores de Risco , Fatores de TempoRESUMO
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.
Assuntos
Amiloidose/complicações , Cardiomiopatias/prevenção & controle , Morte Súbita Cardíaca/prevenção & controle , Desfibriladores Implantáveis , Adulto , Cardiomiopatias/etiologia , Morte Súbita Cardíaca/etiologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Prognóstico , Estudos Prospectivos , Projetos de Pesquisa , Medição de Risco , Fatores de Risco , Fibrilação Ventricular/prevenção & controleRESUMO
OBJECTIVE: Cardiac amyloidosis (CA) is associated with a poor prognosis and a survival rate of less than 30% 2 years after clinical manifestation. Considered as a semi-malignant disease, CA is often a contraindication for HTx; however, depending on the type of CA, there are excellent treatment regimes that can be combined with HTx. In AL-amyloidosis, chemotherapy and stem cell transplantation are necessary and in TTR-amyloidosis, where the liver is the source of the pathologic protein, liver transplantation is recommended after HTx. METHODS AND RESULTS: More than 60 patients with AL-amyloidosis and more than 25 patients with ATTR-amyloidosis have been investigated at our centre. Eighteen patients showed signs of end-stage heart failure. Four patients died within 1 month after listing for HTx. Seven patients with AL (mean age 41.8 years) and five patients with ATTR-amyloidosis (mean age 42.6 years) were successfully transplanted with an actual survival rate of 91.6%. One patient died 8 months after HTx due to infection. Five AL patients received chemotherapy and SCT and one ATTR patient was liver transplanted. Three AL patients showed complete remission of amyloidosis. CONCLUSIONS: Cardiac amyloidosis is a potentially curative disease after HTx when combined with either chemotherapy and SCT or LiverTx depending on the type of the amyloidosis. Due to the natural course of the disease, urgent HTx after cardiac manifestation is mandatory. With this approach, excellent survival rates and even remission of the underlying disease is possible.
Assuntos
Amiloidose/terapia , Cardiomiopatias/terapia , Transplante de Coração/métodos , Adulto , Amiloidose/patologia , Amiloidose/fisiopatologia , Cardiomiopatias/patologia , Cardiomiopatias/fisiopatologia , Árvores de Decisões , Progressão da Doença , Feminino , Insuficiência Cardíaca/etiologia , Humanos , Transplante de Fígado , Masculino , Melfalan/uso terapêutico , Pessoa de Meia-Idade , Agonistas Mieloablativos/uso terapêutico , Índice de Gravidade de Doença , Transplante de Células-Tronco , Análise de SobrevidaRESUMO
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.
Assuntos
Amiloidose/diagnóstico por imagem , Amiloidose/mortalidade , Cardiopatias/diagnóstico por imagem , Cardiopatias/mortalidade , Ventrículos do Coração/diagnóstico por imagem , Adulto , Amiloidose/cirurgia , Progressão da Doença , Eletrocardiografia , Feminino , Coração/fisiopatologia , Cardiopatias/cirurgia , Transplante de Coração , Ventrículos do Coração/patologia , Ventrículos do Coração/fisiopatologia , Humanos , Masculino , Pessoa de Meia-Idade , Análise Multivariada , Valor Preditivo dos Testes , Prognóstico , Estudos Retrospectivos , Fatores de Risco , Análise de Sobrevida , UltrassonografiaRESUMO
A 63-year-old Caucasian male, diagnosed with dilated cardiomyopathy in 1993, remained clinically stable for several years. In 2003, a marked increase of N-terminal pro-natriuretic peptide serum level (611 ng/ml to 4926 ng/ml) was observed; left ventricular (LV) septum thickness was 10 mm. In addition, sensorimotor polyneuropathy and autonomic dysfunction occurred. Further progression of heart failure occurred despite unchanged systolic LV function. Endomyocardial biopsy in 2006 revealed transthyretin amyloidosis by Congo red and immunohistochemical staining, as well as Val94Ala substitution by transthyretin gene analysis. Cardiac amyloid deposition was quantified by technetium-99m-3,3-diphosphono-1,2-propanodicarboxylic acid (99mTc-DPD) scintigraphy. Mutational search of the relatives (n = 1) was unremarkable. The transthyretin Val94Ala mutation is characterized by sensorimotor polyneuropathy, autonomic dysfunction, and gastrointestinal and cardiac involvement with amyloid. This mutation is an addition to the growing spectrum of transthyretin mutations with late onset of clinical symptoms, but noteworthy because of progressive, finally disabling disease course. Final clinical assessment of severity of cardiac involvement in the present patient is rendered complex by possible concomitant or preceding idiopathic dilated cardiomyopathy.