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Background: Cardiac resynchronization therapy (CRT) is a well-established therapy for patients with heart failure (HF). However, 30% of HF patients do not show any improvement in clinical status after CRT implantation. In this study, we report our echocardiography-based CRT optimization methodology, in daily practice at our CRT referral center. Methods: We included 350 ambulatory patients, who were referred to our center for optimization after CRT implantation. A protocol-driven echocardiographic approach for adjusting mechanical dyssynchrony, whereby adjusting for ventriculoventricular (VV) delays with strain and atrioventricular (AV) delays with Doppler echocardiography was performed. We defined changes in left ventricular ejection fraction (LVEF) and New York Heart Association (NYHA) classes as outcome variables in the evaluation of the CRT outcomes. Results: Optimization was obtained in 288 (82%) patients. VV and AV timings were adjusted to 61% and 51%, respectively. In 3%, biventricular pacing was turned off and in 3% left ventricular (LV) only pacing was programmed. The LVEF and NYHA class showed significant improvements in all patients who underwent CRT optimization. Conclusions: CRT optimization remains valuable in improving LVEF and functional status measured using the NYHA class in all patients receiving CRT devices.
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BACKGROUND: Truncating variants in desmoplakin (DSPtv) are an important cause of arrhythmogenic cardiomyopathy; however the genetic architecture and genotype-specific risk factors are incompletely understood. We evaluated phenotype, risk factors for ventricular arrhythmias, and underlying genetics of DSPtv cardiomyopathy. METHODS: Individuals with DSPtv and any cardiac phenotype, and their gene-positive family members were included from multiple international centers. Clinical data and family history information were collected. Event-free survival from ventricular arrhythmia was assessed. Variant location was compared between cases and controls, and literature review of reported DSPtv performed. RESULTS: There were 98 probands and 72 family members (mean age at diagnosis 43±8 years, 59% women) with a DSPtv, of which 146 were considered clinically affected. Ventricular arrhythmia (sudden cardiac arrest, sustained ventricular tachycardia, appropriate implantable cardioverter defibrillator therapy) occurred in 56 (33%) individuals. DSPtv location and proband status were independent risk factors for ventricular arrhythmia. Further, gene region was important with variants in cases (cohort n=98; Clinvar n=167) more likely to occur in the regions resulting in nonsense mediated decay of both major DSP isoforms, compared with n=124 genome aggregation database control variants (148 [83.6%] versus 29 [16.4%]; P<0.0001). CONCLUSIONS: In the largest series of individuals with DSPtv, we demonstrate that variant location is a novel risk factor for ventricular arrhythmia, can inform variant interpretation, and provide critical insights to allow for precision-based clinical management.
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Displasia Arritmogênica Ventricular Direita , Cardiomiopatias , Desmoplaquinas , Feminino , Humanos , Masculino , Arritmias Cardíacas/genética , Displasia Arritmogênica Ventricular Direita/diagnóstico , Cardiomiopatias/genética , Desmoplaquinas/genética , Fatores de RiscoRESUMO
OBJECTIVE: Scavenger receptor BI (SR-BI) is a cell surface receptor that promotes the selective uptake of cholesteryl esters from high-density lipoprotein (HDL) by the liver. In mice, SR-BI deficiency results in increased plasma HDL cholesterol levels and enhanced susceptibility to atherosclerosis. The aim of this study was to investigate the role of SR-BI deficiency on platelet function. METHODS AND RESULTS: SR-BI-deficient mice were thrombocytopenic, and their platelets were abnormally large, probably because of an increased cholesterol content. The FeCl(3) acute injury model to study arterial thrombosis susceptibility showed that SR-BI wild-type mice developed total arterial occlusion after 24±2 minutes. In SR-BI-deficient mice, however, the time to occlusion was reduced to 13±1 minutes (P=0.02). Correspondingly, in SR-BI-deficient mice, platelets circulated in an activated state and showed increased adherence to immobilized fibrinogen. In contrast, platelet-specific disruption of SR-BI by bone marrow transplantation in wild-type mice did not alter plasma cholesterol levels or affect platelet count, size, cholesterol content, or reactivity, suggesting that changes in plasma cholesterol levels were responsible for the altered responsiveness of platelets in SR-BI-deficient mice. CONCLUSIONS: The function of SR-BI in HDL cholesterol homeostasis and prevention of atherosclerosis is indirectly also essential for maintaining normal platelet function and prevention of thrombosis.
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Arteriopatias Oclusivas/metabolismo , Plaquetas/metabolismo , HDL-Colesterol/sangue , Ativação Plaquetária , Receptores Depuradores Classe B/deficiência , Trombose/metabolismo , Animais , Arteriopatias Oclusivas/induzido quimicamente , Arteriopatias Oclusivas/genética , Arteriopatias Oclusivas/patologia , Arteriopatias Oclusivas/prevenção & controle , Plaquetas/patologia , Transplante de Medula Óssea , Cloretos , Colesterol na Dieta/metabolismo , Modelos Animais de Doenças , Compostos Férricos , Fibrinogênio/metabolismo , Camundongos , Camundongos Knockout , Adesividade Plaquetária , Agregação Plaquetária , Receptores Depuradores Classe B/genética , Trombocitopenia/metabolismo , Trombocitopenia/patologia , Trombose/induzido quimicamente , Trombose/genética , Trombose/patologia , Trombose/prevenção & controle , Fatores de Tempo , Regulação para CimaRESUMO
It has been shown that natural killer T (NKT) cell activation accelerates atherosclerosis in apoE(-/-) mice. ApoE is, however, an important mediator in the presentation of lipids which may complicate conclusions on the role of NKT cells in atherosclerosis. Treatment of LDLr(-/-) mice with alpha-GalCer during Western-type diet feeding is therefore of interest. Atherosclerosis was induced by Western-type diet feeding and collar placement around the carotid arteries in both LDLr(-/-) and apoE(-/-) mice. Subsequently, the mice were treated twice a week with alpha-GalCer. This resulted in an 84% reduction in plaque size in LDLr(-/-) mice (P < 0.05), while no effect was observed in apoE(-/-) mice. In-vitro incubation of splenocytes with alpha-GalCer showed that LDLr(-/-) splenocytes proliferated stronger than apoE(-/-) splenocytes. This is reflected in a larger increase in production of cytokines and especially IL-10 after in-vitro stimulation with alpha-GalCer in LDLr(-/-) mice compared with apoE(-/-) splenocytes. Additionally, feeding a Western-type diet for 1.5 weeks induced a strong increase in the number of NKT cells in LDLr(-/-) mice and this increase was slower and less prominent in apoE(-/-) mice. Administration of alpha-GalCer to LDLr(-/-) mice in combination with Western-type diet feeding reduced plaque formation, but this effect was not seen in apoE(-/-) mice. This may be explained by the decreased presentation of lipids on CD1d molecules due to the lack of apoE. In this study we proved for the first time that NKT cells may also act in an atheroprotective manner.
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Aterosclerose/etiologia , Aterosclerose/imunologia , Células T Matadoras Naturais/imunologia , Animais , Apolipoproteínas E/deficiência , Apolipoproteínas E/genética , Aterosclerose/tratamento farmacológico , Aterosclerose/patologia , Doenças das Artérias Carótidas/tratamento farmacológico , Doenças das Artérias Carótidas/etiologia , Doenças das Artérias Carótidas/imunologia , Doenças das Artérias Carótidas/patologia , Citocinas/biossíntese , Dieta Aterogênica , Modelos Animais de Doenças , Galactosilceramidas/farmacologia , Técnicas In Vitro , Ativação Linfocitária/efeitos dos fármacos , Masculino , Camundongos , Camundongos Knockout , Células T Matadoras Naturais/efeitos dos fármacos , Receptores de LDL/deficiência , Receptores de LDL/genéticaRESUMO
OBJECTIVE: Vascular endothelial growth factor receptor 2 (VEGFR2)-overexpressing cells may form an interesting target for the treatment of atherosclerosis because of their involvement in processes that contribute to this disease, such as angiogenesis. METHODS AND RESULTS: We vaccinated mice against VEGFR2 by an orally administered DNA vaccine, comprising a plasmid, encoding murine VEGFR2, carried by live attenuated Salmonella typhimurium. This vaccine induces cellular immunity against cells that overexpress VEGFR2. Vaccination of hypercholesterolemic mice against VEGFR2 resulted in a marked induction of CD8+ cytotoxic T cells specific for VEGFR2 and led to an inhibition of angiogenesis in a hindlimb ischemia model. Interestingly, VEGFR2 vaccination attenuated the progression of preexisting advanced atherosclerotic lesions in the brachiocephalic artery of apoE-/- mice. Furthermore, VEGFR2 vaccination strongly reduced the initiation of collar-induced atherosclerosis in the carotid arteries of LDLr-/- mice. In addition, denudation of the carotid artery, as a model for postinterventional lesion formation, resulted in delayed endothelial replacement and significantly increased neointima formation on VEGFR2 vaccination. CONCLUSIONS: These data indicate the prominent role of VEGFR2+ cells in cardiovascular diseases and show that induction of cellular immunity against atherosclerosis-associated cells by means of DNA vaccination may contribute to the development of novel therapies against atherosclerosis.
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Aterosclerose/prevenção & controle , Hipercolesterolemia/terapia , Imunoterapia Ativa/métodos , Neovascularização Patológica/prevenção & controle , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/imunologia , Administração Oral , Animais , Aterosclerose/patologia , Linfócitos T CD8-Positivos/imunologia , Técnicas de Cocultura , Células Endoteliais/imunologia , Células Endoteliais/patologia , Feminino , Membro Posterior , Histocitoquímica , Imunidade Celular/imunologia , Isquemia/terapia , Camundongos , Vacinas de DNA/administração & dosagemRESUMO
Recent human studies reveal that hyperglycemia induces procoagulant and antifibrinolytic effects in blood that may contribute to a greater risk of arterial thrombosis, but the direct relationship between high blood glucose levels and thrombosis has not yet been investigated. We performed a number of experiments to clarify whether hyperglycemia was causally related to arterial thrombosis and whether the combined stimulus of hyperglycemia and inflammation would enhance the thrombotic effect. In a model of ferric-chloride-induced carotid artery thrombosis, hyperglycemia did not influence the time to occlusion in mice pretreated with streptozotocin, but the rate of thrombus formation was accelerated. This effect was associated with increased thrombin generation and could not be explained by changes in vessel-wall tissue factor activity. The prothrombotic effect of hyperglycemia was assessed in a separate experiment, showing that collagen/thrombin-induced platelet procoagulant activity was increased in hyperglycemic mice. The effect of inflammation was studied by injecting a low dose of endotoxin that caused a systemic inflammatory state after 24 h (increased plasma levels of tumor necrosis factor alpha, interleukin-6 and monocyte chemotactic protein 1 in diabetic and nondiabetic mice) associated with a mild delay in thrombus formation. This reduced rate of thrombus formation was attenuated by hyperglycemia. Together, these data establish a discrete but clear contribution of hyperglycemia in experimental arterial thrombosis.
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Trombose das Artérias Carótidas/fisiopatologia , Endotoxinas/sangue , Fibrinolíticos/sangue , Hiperglicemia/fisiopatologia , Animais , Coagulação Sanguínea/efeitos dos fármacos , Trombose das Artérias Carótidas/induzido quimicamente , Trombose das Artérias Carótidas/prevenção & controle , Cloretos , Diabetes Mellitus Experimental/sangue , Diabetes Mellitus Experimental/induzido quimicamente , Diabetes Mellitus Experimental/fisiopatologia , Modelos Animais de Doenças , Endotoxinas/farmacologia , Feminino , Compostos Férricos , Fibrinolíticos/farmacologia , Hiperglicemia/sangue , Hiperglicemia/induzido quimicamente , Camundongos , Camundongos Endogâmicos C57BL , Estreptozocina , Trombina/efeitos dos fármacos , Tempo de Trombina/métodos , Tromboflebite/tratamento farmacológico , Tromboflebite/metabolismoRESUMO
OBJECTIVE: HIV combination therapy using protease inhibitors is associated with elevated plasma levels of atherogenic lipoproteins and increased risk for atherosclerosis. We investigated whether the HIV entry inhibitor TAK-779 affects lipoprotein levels and atherogenesis in low-density lipoprotein receptor-deficient mice. TAK-779 is an antagonist for the chemokine receptors CCR5 and CXCR3, which are expressed on leukocytes, especially T-helper 1 cells, and these receptors may be involved in recruitment of these cells to atherosclerotic plaques. METHODS AND RESULTS: TAK-779 treatment of low-density lipoprotein receptor-deficient mice did not elevate the levels of atherogenic lipoproteins, whereas it dramatically reduced atherosclerosis in the aortic root and in the carotid arteries. The number of T cells in the plaque was reduced by 95%, concurrently with a 98% reduction in the relative IFN-gamma area. TAK-779-treated animals showed a decreased percentage of CD4+ and CD8+ T cells in peripheral blood and in mediastinal lymph nodes compared with control-treated animals. CONCLUSIONS: TAK-779 not only suppresses HIV entry via blockade of CCR5 but also attenuates atherosclerotic lesion formation by blocking the influx of T-helper 1 cells into the plaque. TAK-779 treatment may be especially beneficial for young HIV patients as they face lifelong treatment, and this drug impairs atherogenesis.
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Amidas/farmacologia , Fármacos Anti-HIV/farmacologia , Aterosclerose/tratamento farmacológico , Compostos de Amônio Quaternário/farmacologia , Receptores de LDL/genética , Células Th1/efeitos dos fármacos , Animais , Aterosclerose/genética , Aterosclerose/imunologia , Antagonistas dos Receptores CCR5 , Quimiocina CCL4 , Quimiocina CCL5/genética , Quimiocina CCL5/metabolismo , Colesterol/sangue , Feminino , Ligantes , Contagem de Linfócitos , Proteínas Inflamatórias de Macrófagos/genética , Proteínas Inflamatórias de Macrófagos/metabolismo , Camundongos , Camundongos Mutantes , RNA Mensageiro/análise , Receptores CCR5/genética , Receptores CCR5/metabolismo , Receptores CXCR3 , Receptores de Quimiocinas/genética , Receptores de Quimiocinas/metabolismo , Receptores de LDL/deficiência , Baço/efeitos dos fármacos , Baço/imunologia , Células Th1/fisiologiaRESUMO
The aim of this cohort study was to evaluate the value of echocardiographic multilayer strain analysis in the identification of arrhythmogenic cardiomyopathy (AC) in its earliest stages in which sudden cardiac death can occurs. Twenty seven asymptomatic relatives of AC probands (mean age 39.6 ± 19.5 years, 37 % male) with a desmosomal pathogenic mutation but no additional criteria for AC (group II) were compared to age and sex-matched healthy controls (group I). In addition, 70 patients harboring a pathogenic desmosomal mutation with "definitive" diagnosis of AC (group IV), and 19 subjects with "borderline" diagnosis (group III) were also studied. A standard echocardiographic evaluation plus left (LV) and right ventricular global and regional transmural, endocardial, and epicardial longitudinal strain (LS) analysis, was performed. In group II, while LV ejection fraction, fractional shortening, and S' were not significantly reduced compared to controls, transmural global LS was significantly reduced to 19.3 ± 1.8 % in group II versus 20.9 ± 1.1 % in controls (p = 0.0003). Compared to controls, group II presented significant (p < 0.05) regional LS decrease in the basal infero-lateral, antero-lateral, latero-apical, infero-septal, and septo-apical segments. Moreover, LS of the latero-apical and the basal antero-lateral segments was significantly altered in the epicardium (p < 0.05) but not significantly in the endocardium. Global and regional LV LS analysis allows detection of AC in an early or non-diagnostic stage of the disease. Moreover, epicardial LS analysis allows the detection of abnormalities earlier than endocardial LS.
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Arritmias Cardíacas/complicações , Cardiomiopatias/diagnóstico por imagem , Ecocardiografia Doppler , Pericárdio/diagnóstico por imagem , Função Ventricular Esquerda , Adulto , Arritmias Cardíacas/diagnóstico , Arritmias Cardíacas/fisiopatologia , Cardiomiopatias/etiologia , Cardiomiopatias/fisiopatologia , Estudos de Casos e Controles , Diagnóstico Precoce , Feminino , Humanos , Londres , Masculino , Pessoa de Meia-Idade , Contração Miocárdica , Pericárdio/fisiopatologia , Valor Preditivo dos Testes , Estresse Mecânico , Volume Sistólico , Adulto JovemRESUMO
Restenosis after angioplasty occurs in 30-40% of the treated patients. To develop a strategy to deliver drugs to restenotic lesions, we selected phages that bind to proliferating vascular smooth muscle cells (VSMC), from a random constraint 15-mer peptide phage display library. Phages were selected for binding to cultured primary aortic VSMC (in vitro biopanning) and selected for binding to denudated carotid arteries in mice (in vivo biopanning). In vitro biopanning did not result in a consensus sequence, but recurring FLGW and LASR amino acid motifs were identified. In vivo biopanning resulted in two consensus peptides 5G6 (CNIWGVVLSWIGVFPEC) and 5E5 (CESLWGGLMWTIGLSDC). Surprisingly, these two sequences were recovered after both in vitro and in vivo biopanning, but predominantly in vivo. Moreover, a strong recurring motif, IGR, was identified in the in vivo clones. The consensus phages 5G6 and 5E5 bind selectively to VSMC compared to other cell types. Furthermore, they bind preferentially to proliferating VSMC compared to VSMC that were growth arrested, and are effectively internalized by their target cells. The specific binding capacities of 5G6 and 5E5 phages suggest that these peptide sequences can be used for targeting of restenotic lesions, in which proliferating VSMC are the dominant cell type.
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Oclusão de Enxerto Vascular/patologia , Músculo Liso Vascular/metabolismo , Peptídeos/administração & dosagem , Sequência de Aminoácidos , Animais , Divisão Celular , Sistemas de Liberação de Medicamentos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Biblioteca de Peptídeos , Homologia de Sequência de AminoácidosRESUMO
BACKGROUND: TIE2(+) cells play a crucial role in processes that are involved in atherosclerosis, such as angiogenesis. Therefore, the specific deletion of TIE2(+) cells by means of DNA vaccination may affect atherosclerosis. METHODS: Cellular immunity against cells that overexpress TIE2 was established in LDLr(-/-) mice by a novel oral DNA vaccination technique, in which an attenuated Salmonella typhimurium strain was used as a carrier for plasmid pcDNA3.1 encoding TIE2. After three oral vaccinations with 2-week time intervals LDLr(-/-) mice were put on a Western type diet and atherosclerosis was induced. RESULTS: Eight weeks after vaccination FACS analysis of circulating peripheral blood mononuclear cells (PBMCs) revealed a significant decrease (33%, p<0.05) in TIE2(+) cells upon vaccination against TIE2, indicating the successful induction of cellular immunity following vaccination against TIE2. Six weeks after collar placement vaccination against TIE2 resulted in significantly decreased carotid atherosclerosis, as indicated by 30% (p<0.05) reduced intima area and 27% (p<0.05) reduced intima/lumen ratios. Furthermore, atherosclerosis was attenuated in the aortic root by 42% (p<0.05), further underlining the anti-atherosclerotic effect of vaccination against TIE2. Adventitial angiogenesis was reduced by 61% (p<0.05) upon vaccination against TIE2 providing a mechanism via which vaccination against TIE2 inhibits lesion formation. Histochemical analysis of the atherosclerotic lesion composition revealed a 1.6-fold (carotid artery, p<0.05) and 1.9-fold (aortic root, p<0.05) increase in collagen content upon vaccination against TIE2, indicating a more stable plaque phenotype. CONCLUSIONS: We demonstrate that vaccination against TIE2 induces cellular immunity against cells that overexpress TIE2 and results in smaller atherosclerotic lesions with a more stable phenotype. Therefore, vaccination strategies that target cells that contribute to atherosclerosis, may be of potential use in the development of novel treatments of atherosclerosis.
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Aterosclerose/prevenção & controle , Imunidade Celular , Leucócitos Mononucleares/imunologia , Receptor TIE-2/imunologia , Vacinas de DNA/administração & dosagem , Administração Oral , Animais , Aterosclerose/imunologia , Aterosclerose/patologia , Colágeno/metabolismo , Modelos Animais de Doenças , Feminino , Vetores Genéticos , Esquemas de Imunização , Camundongos , Camundongos Knockout , Neovascularização Patológica/imunologia , Neovascularização Patológica/prevenção & controle , Fenótipo , Receptor TIE-2/genética , Receptores de LDL/deficiência , Receptores de LDL/genética , Salmonella typhimurium/genética , Vacinas Atenuadas/administração & dosagemRESUMO
Atherosclerosis is a chronic inflammatory disease that develops in the context of enhanced serum lipid levels. Nowadays, many studies focus on the modulation of inflammatory responses to reduce atherosclerosis. The most powerful strategy to achieve this is vaccination. In several immune diseases vaccination is shown to be very effective, resulting in a drastic decline in the incidence of the disease. But is vaccination also realistic in atherosclerosis? In this article, several approaches to vaccinate against atherosclerosis are described. Vaccination (based on protein or DNA) against bioactive molecules and disease-related proteins successfully reduces experimental atherosclerosis. In addition, passive immunization with antibodies against atherosclerosis-specific antigens and tolerance induction, in which antigen-specific regulatory T cells are elicited, are described. In the near future, we expect an increased interest in vaccination against atherosclerosis and, maybe, the myth may become reality when the first clinical trials are performed.
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PURPOSE OF REVIEW: Cardiovascular disease, as manifested in the formation of atherosclerotic lesions, can be described as a chronic inflammatory autoimmune-like disease that proceeds in the context of enhanced plasma lipid levels. Modulation of the immune response may therefore form a valuable therapy in addition to standardized cholesterol and blood pressure-lowering therapies. The purpose of this review is to describe a number of recent approaches to immunomodulate atherosclerosis: immunization against mediators involved in atherosclerosis, such as cytokines and modified low-density lipoprotein; intervention in cytokine pathways; intervention in co-stimulatory pathways; activation of regulatory T cells; and modulation of natural killer T cells. RECENT FINDINGS: The most recent findings point to an important role for regulatory T cells in atherosclerotic lesion formation. The function of the regulatory T cells is modulated by chemokines and by co-stimulatory pathways, whereas the function of these cells can be strongly upregulated by anti-CD3 treatment and tolerance induction. SUMMARY: In the near future the first exponents of this approach, such as immunization and enhancement of the function of regulatory T cells, may enter the first phase of clinical trials, and may ultimately add to the current therapies in atherosclerosis.