RESUMO
AIMS: Hospital admissions are frequently preceded by increased pulmonary congestion in heart failure (HF) patients. This study evaluated whether early automated fluid status alert notification via telemedicine improves outcome in HF patients. METHODS AND RESULTS: Patients recently implanted with an implantable cardioverter defibrillator (ICD) with or without cardiac resynchronization therapy were eligible if one of three conditions was met: prior HF hospitalization, recent diuretic treatment, or recent brain natriuretic peptide increase. Eligible patients were randomized (1:1) to have fluid status alerts automatically transmitted as inaudible text message alerts to the responsible physician or to receive standard care (no alerts). In the intervention arm, following a telemedicine alert, a protocol-specified algorithm with remote review of device data and telephone contact was prescribed to assess symptoms and initiate treatment. The primary endpoint was a composite of all-cause death and cardiovascular hospitalization. We followed 1002 patients for an average of 1.9 years. The primary endpoint occurred in 227 patients (45.0%) in the intervention arm and 239 patients (48.1%) in the control arm [hazard ratio, HR, 0.87; 95% confidence interval (CI), 0.72-1.04; P = 0.13]. There were 59 (11.7%) deaths in the intervention arm and 63 (12.7%) in the control arm (HR, 0.89; 95% CI, 0.62-1.28; P = 0.52). Twenty-four per cent of alerts were not transmitted and 30% were followed by a medical intervention. CONCLUSION: Among ICD patients with advanced HF, fluid status telemedicine alerts did not significantly improve outcomes. Adherence to treatment protocols by physicians and patients might be challenge for further developments in the telemedicine field.
Assuntos
Insuficiência Cardíaca , Terapia de Ressincronização Cardíaca , Desfibriladores Implantáveis , Hospitalização , Humanos , Telemedicina , Resultado do TratamentoRESUMO
Liver-derived acute phase proteins (APPs) emerged as powerful predictors of cardiovascular disease and cardiovascular events, but their functional role in atherosclerosis remains enigmatic. We report that the gp130 receptor, which is a key component of the inflammatory signaling pathway within hepatocytes, influences the risk of atherosclerosis in a hepatocyte-specific gp130 knockout. Mice on an atherosclerosis-prone genetic background exhibit less aortic atherosclerosis (P < 0.05) with decreased plaque macrophages (P < 0.01). Translating these findings into humans, we show that genetic variation within the human gp130 homologue, interleukin 6 signal transducer (IL6ST), is significantly associated with coronary artery disease (CAD; P < 0.05). We further show a significant association of atherosclerotic disease at the ostium of the coronary arteries (P < 0.005) as a clinically important and heritable subphenotype in a large sample of families with myocardial infarction (MI) and a second independent population-based cohort. Our results reveal a central role of a hepatocyte-specific, gp130-dependent acute phase reaction for plaque development in a murine model of atherosclerosis, and further implicate IL6ST as a genetic susceptibility factor for CAD and MI in humans. Thus, the acute phase reaction should be considered an important target for future drug development in the management of CAD.
Assuntos
Aterosclerose/metabolismo , Receptor gp130 de Citocina/fisiologia , Animais , Aorta/metabolismo , Vasos Coronários/metabolismo , Receptor gp130 de Citocina/metabolismo , Predisposição Genética para Doença , Hepatócitos/metabolismo , Humanos , Inflamação , Macrófagos/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Polimorfismo Genético , RiscoRESUMO
Understanding the transcriptional regulation of angiogenesis could lead to the identification of novel therapeutic targets. We showed here that the transcription factor GATA6 is expressed in different human primary endothelial cells as well as in vascular endothelial cells of mice in vivo. Activation of endothelial cells was associated with GATA6 nuclear translocation, chromatin binding, and enhanced GATA6-dependent transcriptional activation. siRNA-mediated down-regulation of GATA6 after growth factor stimulation led to a dramatically reduced capacity of macro- and microvascular endothelial cells to proliferate, migrate, or form capillary-like structures on Matrigel. Adenoviral overexpression of GATA6 in turn enhanced angiogenic function, especially in cardiac endothelial microvascular cells. Furthermore, GATA6 protected endothelial cells from undergoing apoptosis during growth factor deprivation. Mechanistically, down-regulation of GATA6 in endothelial cells led to increased expression of transforming growth factor (TGF) ß1 and TGFß2, whereas enhanced GATA6 expression, accordingly, suppressed Tgfb1 promoter activity. High TGFß1/ß2 expression in GATA6-depleted endothelial cells increased the activation of the activin receptor-like kinase 5 (ALK5) and SMAD2, and suppression of this signaling axis by TGFß neutralizing antibody or ALK5 inhibition restored angiogenic function and survival in endothelial cells with reduced GATA6 expression. Together, these findings indicate that GATA6 plays a crucial role for endothelial cell function and survival, at least in part, by suppressing autocrine TGFß expression and ALK5-dependent signaling.
Assuntos
Comunicação Autócrina/fisiologia , Células Endoteliais/metabolismo , Fator de Transcrição GATA6/metabolismo , Neovascularização Fisiológica/fisiologia , Proteínas Serina-Treonina Quinases/metabolismo , Receptores de Fatores de Crescimento Transformadores beta/metabolismo , Transdução de Sinais/fisiologia , Animais , Apoptose/fisiologia , Células Cultivadas , Células Endoteliais/citologia , Fator de Transcrição GATA6/genética , Regulação da Expressão Gênica/fisiologia , Humanos , Camundongos , Proteínas Serina-Treonina Quinases/genética , Receptor do Fator de Crescimento Transformador beta Tipo I , Receptores de Fatores de Crescimento Transformadores beta/genética , Proteína Smad2/genética , Proteína Smad2/metabolismo , Fator de Crescimento Transformador beta1/genética , Fator de Crescimento Transformador beta1/metabolismo , Fator de Crescimento Transformador beta2/genética , Fator de Crescimento Transformador beta2/metabolismoRESUMO
BACKGROUND: Fibroblast growth factor 9 (FGF9) is secreted from bone marrow cells, which have been shown to improve systolic function after myocardial infarction (MI) in a clinical trial. FGF9 promotes cardiac vascularization during embryonic development but is only weakly expressed in the adult heart. METHODS AND RESULTS: We used a tetracycline-responsive binary transgene system based on the α-myosin heavy chain promoter to test whether conditional expression of FGF9 in the adult myocardium supports adaptation after MI. In sham-operated mice, transgenic FGF9 stimulated left ventricular hypertrophy with microvessel expansion and preserved systolic and diastolic function. After coronary artery ligation, transgenic FGF9 enhanced hypertrophy of the noninfarcted left ventricular myocardium with increased microvessel density, reduced interstitial fibrosis, attenuated fetal gene expression, and improved systolic function. Heart failure mortality after MI was markedly reduced by transgenic FGF9, whereas rupture rates were not affected. Adenoviral FGF9 gene transfer after MI similarly promoted left ventricular hypertrophy with improved systolic function and reduced heart failure mortality. Mechanistically, FGF9 stimulated proliferation and network formation of endothelial cells but induced no direct hypertrophic effects in neonatal or adult rat cardiomyocytes in vitro. FGF9-stimulated endothelial cell supernatants, however, induced cardiomyocyte hypertrophy via paracrine release of bone morphogenetic protein 6. In accord with this observation, expression of bone morphogenetic protein 6 and phosphorylation of its downstream targets SMAD1/5 were increased in the myocardium of FGF9 transgenic mice. CONCLUSIONS: Conditional expression of FGF9 promotes myocardial vascularization and hypertrophy with enhanced systolic function and reduced heart failure mortality after MI. These observations suggest a previously unrecognized therapeutic potential for FGF9 after MI.
Assuntos
Fator 9 de Crescimento de Fibroblastos/farmacologia , Insuficiência Cardíaca/prevenção & controle , Infarto do Miocárdio/complicações , Animais , Proteína Morfogenética Óssea 6/genética , Proteína Morfogenética Óssea 6/metabolismo , Fator 9 de Crescimento de Fibroblastos/administração & dosagem , Fator 9 de Crescimento de Fibroblastos/genética , Expressão Gênica/efeitos dos fármacos , Coração , Insuficiência Cardíaca/mortalidade , Hipertrofia Ventricular Esquerda/induzido quimicamente , Camundongos , Camundongos Transgênicos , Neovascularização Patológica/induzido quimicamente , Fosforilação , Ratos , Tetraciclina/farmacologiaRESUMO
BACKGROUND: Iron deficiency may impair aerobic performance. This study aimed to determine whether treatment with intravenous iron (ferric carboxymaltose) would improve symptoms in patients who had heart failure, reduced left ventricular ejection fraction, and iron deficiency, either with or without anemia. METHODS: We enrolled 459 patients with chronic heart failure of New York Heart Association (NYHA) functional class II or III, a left ventricular ejection fraction of 40% or less (for patients with NYHA class II) or 45% or less (for NYHA class III), iron deficiency (ferritin level <100 microg per liter or between 100 and 299 microg per liter, if the transferrin saturation was <20%), and a hemoglobin level of 95 to 135 g per liter. Patients were randomly assigned, in a 2:1 ratio, to receive 200 mg of intravenous iron (ferric carboxymaltose) or saline (placebo). The primary end points were the self-reported Patient Global Assessment and NYHA functional class, both at week 24. Secondary end points included the distance walked in 6 minutes and the health-related quality of life. RESULTS: Among the patients receiving ferric carboxymaltose, 50% reported being much or moderately improved, as compared with 28% of patients receiving placebo, according to the Patient Global Assessment (odds ratio for improvement, 2.51; 95% confidence interval [CI], 1.75 to 3.61). Among the patients assigned to ferric carboxymaltose, 47% had an NYHA functional class I or II at week 24, as compared with 30% of patients assigned to placebo (odds ratio for improvement by one class, 2.40; 95% CI, 1.55 to 3.71). Results were similar in patients with anemia and those without anemia. Significant improvements were seen with ferric carboxymaltose in the distance on the 6-minute walk test and quality-of-life assessments. The rates of death, adverse events, and serious adverse events were similar in the two study groups. CONCLUSIONS: Treatment with intravenous ferric carboxymaltose in patients with chronic heart failure and iron deficiency, with or without anemia, improves symptoms, functional capacity, and quality of life; the side-effect profile is acceptable. (ClinicalTrials.gov number, NCT00520780).
Assuntos
Anemia Ferropriva/tratamento farmacológico , Compostos Férricos/uso terapêutico , Insuficiência Cardíaca/tratamento farmacológico , Hematínicos/uso terapêutico , Deficiências de Ferro , Maltose/análogos & derivados , Idoso , Anemia Ferropriva/complicações , Doença Crônica , Feminino , Compostos Férricos/efeitos adversos , Ferritinas/sangue , Seguimentos , Insuficiência Cardíaca/sangue , Insuficiência Cardíaca/complicações , Insuficiência Cardíaca/fisiopatologia , Hematínicos/efeitos adversos , Humanos , Masculino , Maltose/efeitos adversos , Maltose/uso terapêutico , Qualidade de Vida , Volume Sistólico/efeitos dos fármacos , Disfunção Ventricular Esquerda/etiologiaRESUMO
BACKGROUND: Because a delayed arterial healing response after drug-eluting stent implantation has raised concerns about safety in diabetic patients, long-term effects of treatment with sirolimus-eluting stent (SES), as compared with bare-metal stent (BMS), have to be established. The aim of the 5-year follow-up of the randomized, controlled, open-label multicenter SCORPIUS study was to assess long-term safety and efficacy of the CYPHER (Cordis, Johnson & Johnson, Bridgewater, NJ) SES in percutaneous coronary intervention of diabetic patients. METHODS: A total of 190 patients with type 2 diabetes mellitus were randomized to receive either a SES (n = 95) or a BMS (n = 95). Dual-antiplatelet therapy (aspirin plus clopidogrel) was prescribed for at least 6 months. Clinical follow-up data were scheduled at 1, 8, and 12 months and 5 years. RESULTS: Treatment with SES resulted in a 16% decrease in the rate of major adverse cardiac events (36% vs 52%; hazard ratio 0.6, 95% CI 0.4-0.9; P = .02). This reduction in major adverse cardiac events with SES at 5 years was mostly attributable to a lower number of repeat target lesion revascularization (13% vs 29%; hazard ratio 0.4, 95% CI 0.2-0.7; P = .003). No differences between groups were observed for safety end points (all-cause mortality 21% vs 21%, cardiac death 15% vs 13%, repeat myocardial infarction 8% vs 9%, and stent thrombosis 5% vs 6%) at 5 years. CONCLUSIONS: The 5-year follow-up of the SCORPIUS trial demonstrates the long-term antirestenotic efficacy of SES in diabetic patients with significantly reduced target lesion revascularization and comparable rates of mortality, myocardial infarction, and stent thrombosis compared with BMS.
Assuntos
Angioplastia Coronária com Balão/métodos , Estenose Coronária/cirurgia , Diabetes Mellitus Tipo 2/complicações , Stents Farmacológicos , Sirolimo/farmacologia , Idoso , Angiografia Coronária , Estenose Coronária/complicações , Estenose Coronária/diagnóstico por imagem , Método Duplo-Cego , Feminino , Seguimentos , Alemanha , Humanos , Imunossupressores/farmacologia , Masculino , Estudos Prospectivos , Desenho de Prótese , Fatores de Tempo , Resultado do TratamentoRESUMO
Toll-like receptors (TLRs) are known primarily as pathogen recognition receptors of the innate immunity, initiating inflammatory pathways to organize the immune defense. More recently, an involvement of TLRs in various physiologic and pathologic processes has been reported. Because many of these processes implicate angiogenesis, we here elucidated the role of a TLR2/6-dependent pathway on angiogenesis using the TLR2/6 agonist macrophage-activating lipopeptide of 2 kDa (MALP-2), a common bacterial lipopeptide. In vivo and in vitro Matrigel assays demonstrated that MALP-2 promoted angiogenesis in a TLR2/6-dependent manner. Moreover, MALP-2 induced endothelial cell proliferation and migration and a strong secretion of granulocyte-macrophage colony-stimulating factor (GM-CSF). GM-CSF release in response to MALP-2 from isolated vascular segments was completely prevented when the endothelium was removed. MALP-2 containing Matrigel implants exhibited vascular structures as well as CD45(+) cells. MALP-2 induced migration of leukocytes and likewise GM-CSF release, particularly from the monocyte population. Inhibition of GM-CSF by siRNA or antibodies suppressed MALP-2-induced angiogenesis in vitro and in vivo. These results clearly identified a TLR2/6-dependent induction of angiogenesis by the bacterial lipopeptide MALP-2, which is mediated by GM-CSF. This might represent a general mechanism to enhance or restore blood flow and recruit immune cells for pathogen defense and tissue regeneration.
Assuntos
Células Endoteliais/metabolismo , Fator Estimulador de Colônias de Granulócitos e Macrófagos/metabolismo , Neovascularização Fisiológica/fisiologia , Receptor 2 Toll-Like/metabolismo , Receptor 6 Toll-Like/metabolismo , Animais , Anticorpos/farmacologia , Aorta/citologia , Movimento Celular/efeitos dos fármacos , Movimento Celular/fisiologia , Células Cultivadas , Células Endoteliais/citologia , Células Endoteliais/imunologia , Fator Estimulador de Colônias de Granulócitos e Macrófagos/genética , Fator Estimulador de Colônias de Granulócitos e Macrófagos/imunologia , Humanos , Sistema Imunitário/fisiologia , Leucócitos/citologia , Leucócitos/imunologia , Leucócitos/metabolismo , Lipopeptídeos/metabolismo , Lipopeptídeos/farmacologia , Camundongos , Camundongos Endogâmicos C57BL , Neovascularização Fisiológica/efeitos dos fármacos , RNA Interferente Pequeno , Regeneração/fisiologia , Receptor 2 Toll-Like/genética , Receptor 6 Toll-Like/genética , Veias Umbilicais/citologiaRESUMO
AIMS: Mice with a cardiomyocyte (CM)-restricted knockout of signal transducer and activator of transcription 3 (STAT3-KO) develop spontaneous heart failure. We investigated the impact of STAT3-mediated regulation of microRNAs for pathophysiological alterations in the heart. METHODS AND RESULTS: MicroRNAchip and qRT-PCR analysis revealed elevated cardiac expression of miR-199a in STAT3-KO mice. Lentiviral shRNA-mediated STAT3-knock-down in neonatal rat CMs markedly increased miR-199a promoter activity and miR-199a levels indicative of a suppressive effect of STAT3 on miR-199a transcription. Up-regulated miR-199a in CM by pre-miR-199a transfection (pre-miR-199a-CM) reduced expression of components of the ubiquitin-proteasome system (UPS), i.e. the ubiquitin-conjugating enzymes Ube2g1 (mRNA and protein) and Ube2i (protein). Pre-miR-199a-CM or CM with siRNA-mediated down-regulation of Ube2i and Ube2g1 (siRNA-Ube2i/2g1-CM) displayed massive down-regulation of α- and ß-myosin heavy chain expression associated with disrupted sarcomere structures. In addition, protein arginine methyltransferase I (PRMT-I) expression and asymmetric dimethylarginine (ADMA) synthesis were increased in pre-miR-199a-CM or in siRNA-Ube2i/2g1-CM. Increased ADMA in cell culture supernatant (SN) from pre-miR-199a-CM or siRNA-Ube2i/2g1-CM lowered nitric oxide (NO) bioavailability of rat cardiac endothelial cells while lowering ADMA concentration in CM SNs by the PRMT inhibitor arginine methyltransferase inhibitor 1 (AMI-1) (100 µM) improved NO bioavailability. In STAT3-KO hearts Ube2i and Ube2g1 expression were markedly reduced. Human terminal failing hearts harbouring low STAT3 protein levels displayed increased miR-199a levels and decreased Ube2g1 expression. CONCLUSION: This study identifies a novel pathophysiological circuit in the heart between reduced STAT3 protein levels, increased miR-199a expression, and subsequent impairment of the UPS that disrupts CM sarcomere structure and impairs via the release of ADMA endothelial cell function.
Assuntos
Células Endoteliais/fisiologia , Insuficiência Cardíaca/enzimologia , MicroRNAs/metabolismo , Miócitos Cardíacos/fisiologia , Fator de Transcrição STAT3/fisiologia , Enzimas de Conjugação de Ubiquitina/fisiologia , Animais , Arginina/análogos & derivados , Arginina/metabolismo , Regulação para Baixo , Endotélio Vascular/fisiologia , Insuficiência Cardíaca/fisiopatologia , Humanos , Camundongos , Camundongos Knockout , Óxido Nítrico Sintase Tipo III/fisiologia , Ratos , Fator de Transcrição STAT3/metabolismo , Regulação para CimaRESUMO
BACKGROUND: Growth-differentiation factor-15 (GDF-15) is emerging as a prognostic biomarker in patients with coronary artery disease. Little is known about GDF-15 as a biomarker in patients with heart failure. METHODS AND RESULTS: The circulating concentration of GDF-15 was measured at baseline (n=1734) and at 12 months (n=1517) in patients randomized in the Valsartan Heart Failure Trial (Val-HeFT). GDF-15 levels at baseline ranged from 259 to 25 637 ng/L and were abnormally high (>1200 ng/L) in 85% of patients. Higher levels were associated with features of worse heart failure and biomarkers of neurohormonal activation, inflammation, myocyte injury, and renal dysfunction. Baseline GDF-15 levels (per 100 ng/L) were associated with the risks of mortality (hazard ratio, 1.017; 95% confidence interval, 1.014 to 1.019; P<0.001) and first morbid event (hazard ratio, 1.020; 95% confidence interval, 1.017 to 1.023; P<0.001). In a comprehensive multiple-variable Cox regression model that included clinical prognostic variables, B-type natriuretic peptide, high-sensitivity C-reactive protein, and high-sensitivity troponin T, GDF-15 remained independently associated with mortality (hazard ratio, 1.007; 95% confidence interval, 1.001 to 1.014; P=0.02) but not first morbid event. At 12 months, the GDF-15 levels had increased by a similar amount in the placebo and valsartan groups (P=0.94). Increases in GDF-15 over 12 months were independently associated with the risks of future mortality and first morbid event also after adjustment for clinical prognostic variables, B-type natriuretic peptide, high-sensitivity C-reactive protein, and high-sensitivity troponin T and their changes. CONCLUSIONS: GDF-15 reflects information from several pathological pathways and provides independent prognostic information in heart failure. GDF-15 levels increase over time, suggesting that GDF-15 reflects a pathophysiological axis that is not completely addressed by the therapies prescribed in Val-HeFT.
Assuntos
Fator 15 de Diferenciação de Crescimento/sangue , Insuficiência Cardíaca/fisiopatologia , Tetrazóis/uso terapêutico , Valina/análogos & derivados , Idoso , Bloqueadores do Receptor Tipo 1 de Angiotensina II/uso terapêutico , Fibrilação Atrial/complicações , Biomarcadores/sangue , Angiopatias Diabéticas/epidemiologia , Feminino , Insuficiência Cardíaca/sangue , Insuficiência Cardíaca/tratamento farmacológico , Insuficiência Cardíaca/mortalidade , Humanos , Hipertensão/complicações , Masculino , Pessoa de Meia-Idade , Placebos , Prognóstico , Análise de Regressão , Medição de Risco , Fatores de Risco , Índice de Gravidade de Doença , Valina/uso terapêutico , ValsartanaRESUMO
BACKGROUND: Atherosclerosis is a systemic inflammatory disease characterized by the formation of atherosclerotic plaques. Both innate immunity and adaptive immunity contribute to atherogenesis, but the mode of interaction is poorly understood. Chemokine receptor 7 (CCR7) is critically involved in the transition from innate to adaptive immune activation by coordinating the migration to and positioning of antigen-presenting dendritic cells and T cells in secondary lymphoid organs. More recently, it was shown that CCR7 is also responsible for T-cell migration into inflamed tissues and T-cell egress from these tissues via the afferent lymph. Thus, we investigated the influence of a systemic CCR7 deficiency on atherogenesis in atherosclerosis-prone low-density lipoprotein receptor (ldlr) knockout mice. METHODS AND RESULTS: CCR7 deficiency resulted in reduced atherosclerotic plaque development. CCR7(-/-) T cells showed impaired entry and exit behavior from atherosclerotic lesions. Oxidized low-density lipoprotein, a key molecule for atherogenesis with antigenic features, was used to pulse dendritic cells and to expand T cells ex vivo. Adoptive transfer of C57BL/6 wild-type T cells but not ccr7(-/-)-derived T cells primed with oxidized low-density lipoprotein-pulsed dendritic cells resulted in a reconstitution of atherogenesis in ccr7(-/-)/ldlr(-/-) mice. CONCLUSION: These results demonstrate that both CCR7-dependent T-cell priming in secondary lymphoid organs and CCR7-dependent recirculation of T cells between secondary lymphoid organs and inflamed tissue are crucially involved in atherosclerotic plaque development.
Assuntos
Doenças da Aorta/prevenção & controle , Aterosclerose/prevenção & controle , Receptores CCR7/deficiência , Imunidade Adaptativa/fisiologia , Animais , Doenças da Aorta/metabolismo , Doenças da Aorta/fisiopatologia , Aterosclerose/metabolismo , Aterosclerose/fisiopatologia , Peso Corporal/fisiologia , Linfócitos T CD4-Positivos/efeitos dos fármacos , Linfócitos T CD4-Positivos/patologia , Movimento Celular/fisiologia , Modelos Animais de Doenças , Imunidade Inata/fisiologia , Lipoproteínas LDL/farmacologia , Macrófagos/efeitos dos fármacos , Macrófagos/patologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Receptores CCR7/genéticaRESUMO
BACKGROUND: In patients with myocardial infarction, high serum levels of interleukin-6 cytokines predict a poor outcome. The common receptor of interleukin-6 cytokines, glycoprotein-130 (gp130), signals via janus kinase/signal transducer and activator of transcription (STAT), cytoplasmic protein tyrosine phosphatase/extracellular signal-regulated kinase, and phosphoinositide-3-kinase/Akt pathways, and the regulation of these pathways depends at least in part on the gp130 tyrosine-757 residue. By analyzing cardiomyocyte-specific gp130(Y757F) mutant mice, we investigated the effect of disturbed gp130 signaling after myocardial infarction. METHODS AND RESULTS: The cardiomyocyte-restricted alpha-myosin heavy chain-Cre-recombinase-loxP system was used to generate mice with gp130(Y757F) mutant cardiomyocytes (alphaMHC-Cre(tg/-);gp130(fl/Y757F) [Y(757)F]); all other cells carried at least 1 functional gp130 gene, ensuring normal gp130 signaling. Y(757)F mice displayed normal cardiac function and morphology at 3 months of age comparable to their nonmutant littermates. In response to myocardial infarction, Y(757)F mice displayed higher mortality associated with increased left ventricular rupture rate, sustained cardiac inflammation, and heart failure. These adverse effects were associated with prolonged and enhanced STAT3 activation and increased expression of interleukin-6 and of the complement-activating mannose-binding lectin C. Pharmacological inhibition of the complement system by cobra venom factor attenuated inflammation, prevented left ventricular rupture, and improved cardiac function in Y(757)F mice. Stronger effects were observed with a genetic reduction of STAT3 (STAT3(flox/+)) restricted to cardiomyocytes in Y(757)F mice, which prevented extensive upregulation of interleukin-6, complement activation, and sustained inflammation and lowered left ventricular rupture rate, heart failure, and mortality in subacute myocardial infarction. CONCLUSIONS: Impaired downregulation of gp130-mediated STAT3 activation in subacute infarction promotes cardiac inflammation, adverse remodeling, and heart failure, suggesting a potential causative role of high interleukin-6 serum levels after myocardial infarction.
Assuntos
Receptor gp130 de Citocina/metabolismo , Infarto do Miocárdio/metabolismo , Miocardite/metabolismo , Fator de Transcrição STAT3/metabolismo , Animais , Receptor gp130 de Citocina/genética , Regulação para Baixo/genética , Humanos , Interleucina-6/sangue , Interleucina-6/genética , Camundongos , Camundongos Mutantes , Mutação de Sentido Incorreto , Infarto do Miocárdio/genética , Infarto do Miocárdio/patologia , Miocardite/genética , Miocardite/patologia , Miócitos Cardíacos/metabolismo , Miócitos Cardíacos/patologia , Ruptura Espontânea/genética , Ruptura Espontânea/metabolismo , Fator de Transcrição STAT3/genéticaRESUMO
BACKGROUND: High-density lipoprotein (HDL)-raising therapies are currently under intense evaluation, but the effects of HDL may be highly heterogeneous. We therefore compared the endothelial effects of HDL from healthy subjects and from patients with type 2 diabetes mellitus and low HDL (meeting the criteria for metabolic syndrome), who are frequently considered for HDL-raising therapies. Moreover, in diabetic patients, we examined the impact of extended-release (ER) niacin therapy on the endothelial effects of HDL. METHODS AND RESULTS: HDL was isolated from healthy subjects (n=10) and patients with type 2 diabetes (n=33) by sequential ultracentrifugation. Effects of HDL on endothelial nitric oxide and superoxide production were characterized by electron spin resonance spectroscopy analysis. Effects of HDL on endothelium-dependent vasodilation and early endothelial progenitor cell-mediated endothelial repair were examined. Patients with diabetes were randomized to a 3-month therapy with ER niacin (1500 mg/d) or placebo, and endothelial effects of HDL were characterized. HDL from healthy subjects stimulated endothelial nitric oxide production, reduced endothelial oxidant stress, and improved endothelium-dependent vasodilation and early endothelial progenitor cell-mediated endothelial repair. In contrast, these beneficial endothelial effects of HDL were not observed in HDL from diabetic patients, which suggests markedly impaired endothelial-protective properties of HDL. ER niacin therapy improved the capacity of HDL to stimulate endothelial nitric oxide, to reduce superoxide production, and to promote endothelial progenitor cell-mediated endothelial repair. Further measurements suggested increased lipid oxidation of HDL in diabetic patients, and a reduction after ER niacin therapy. CONCLUSIONS: HDL from patients with type 2 diabetes mellitus and metabolic syndrome has substantially impaired endothelial-protective effects compared with HDL from healthy subjects. ER niacin therapy not only increases HDL plasma levels but markedly improves endothelial-protective functions of HDL in these patients, which is potentially more important. CLINICAL TRIAL REGISTRATION: clinicaltrials.gov. Identifier: NCT00346970.
Assuntos
Diabetes Mellitus Tipo 2/tratamento farmacológico , Hipolipemiantes/administração & dosagem , Lipoproteínas HDL/sangue , Síndrome Metabólica/tratamento farmacológico , Niacina/administração & dosagem , Idoso , Animais , Células Cultivadas , Preparações de Ação Retardada , Diabetes Mellitus Tipo 2/metabolismo , Angiopatias Diabéticas/tratamento farmacológico , Angiopatias Diabéticas/metabolismo , Células Endoteliais/efeitos dos fármacos , Células Endoteliais/metabolismo , Feminino , Radicais Livres/metabolismo , Humanos , Peroxidação de Lipídeos/efeitos dos fármacos , Masculino , Síndrome Metabólica/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Mutantes , Camundongos Nus , Pessoa de Meia-Idade , NADPH Oxidases/metabolismo , Óxido Nítrico/metabolismo , Peroxidase/metabolismo , Superóxidos/metabolismo , Vasodilatação/efeitos dos fármacos , Vasodilatação/fisiologiaRESUMO
BACKGROUND: Endothelial dysfunction and injury are considered to contribute considerably to the development and progression of atherosclerosis. It has been suggested that intense exercise training can increase the number and angiogenic properties of early endothelial progenitor cells (EPCs). However, whether exercise training stimulates the capacity of early EPCs to promote repair of endothelial damage and potential underlying mechanisms remain to be determined. The present study was designed to evaluate the effects of moderate exercise training on in vivo endothelial repair capacity of early EPCs, and their nitric oxide and superoxide production as characterized by electron spin resonance spectroscopy analysis in subjects with metabolic syndrome. METHODS AND RESULTS: Twenty-four subjects with metabolic syndrome were randomized to an 8 weeks exercise training or a control group. Superoxide production and nitric oxide (NO) availability of early EPCs were characterized by using electron spin resonance (ESR) spectroscopy analysis. In vivo endothelial repair capacity of EPCs was examined by transplantation into nude mice with defined carotid endothelial injury. Endothelium-dependent, flow-mediated vasodilation was analysed using high-resolution ultrasound. Importantly, exercise training resulted in a substantially improved in vivo endothelial repair capacity of early EPCs (24.0 vs 12.7%; p < 0.05) and improved endothelium-dependent vasodilation. Nitric oxide production of EPCs was substantially increased after exercise training, but not in the control group. Moreover, exercise training reduced superoxide production of EPCs, which was not observed in the control group. CONCLUSIONS: The present study suggests for the first time that moderate exercise training increases nitric oxide production of early endothelial progenitor cells and reduces their superoxide production. Importantly, this is associated with a marked beneficial effect on the in vivo endothelial repair capacity of early EPCs in subjects with metabolic syndrome.
Assuntos
Endotélio Vascular/fisiologia , Terapia por Exercício/métodos , Exercício Físico/fisiologia , Síndrome Metabólica/reabilitação , Recuperação de Função Fisiológica/fisiologia , Células-Tronco/fisiologia , Vasodilatação/fisiologia , Animais , Células Cultivadas , Espectroscopia de Ressonância de Spin Eletrônica , Endotélio Vascular/citologia , Teste de Esforço , Feminino , Seguimentos , Humanos , Masculino , Síndrome Metabólica/metabolismo , Síndrome Metabólica/patologia , Camundongos , Camundongos Nus , Pessoa de Meia-Idade , Óxido Nítrico/metabolismo , Superóxidos/metabolismoRESUMO
BACKGROUND: Prevalence of patent foramen ovale (PFO) with detectable right-to-left shunt is higher in young adults with transient ischemic attack (TIA) and stroke compared to the general population. So far, published series included different occluder systems, various indications and regimens of postprocedural anticoagulation. In our experience, occluder systems may be associated with an increased prevalence of thrombus formation, which has also reported by other groups. The aim of the present study was to evaluate the follow-up results after implantation of the Amplatzer® occluder in patients with PFO using a consistent anticoagulation regimen. METHODS AND RESULTS: One-hundred and fourteen patients with PFO (60 men; age: 47 ± 13 years) and ≥1 thromboembolic event were included. Other causes for embolism were excluded. PFO-closure was successful in all patients. All patients were treated with aspirin (100 mg/day) and clopidogrel (75 mg/day) for 6 months. TEE was repeated at a mean of 10.3 months. Mean clinical follow-up period was 18 ± 9 months. After a mean of 10 months, no patient had either a significant residual shunt nor a suspected thrombus formation on the occluder. During follow-up, 5 patients suffered from neurological events (1 stroke, 2 TIAs, 2 epileptic seizures), though complete closure of the PFO was documented by TEE. One patient suffered from bleeding complications (upper GI-bleeding). CONCLUSION: Percutaneous closure of PFO in symptomatic patients by Amplatzer® occluder represents an effective therapy with a low incidence of peri-interventional complications and recurrent thromboembolism. Thrombus formations on the occluder system were not detected in this cohort.
Assuntos
Cateterismo Cardíaco/métodos , Embolia Paradoxal/terapia , Forame Oval Patente/terapia , Dispositivo para Oclusão Septal/estatística & dados numéricos , Aspirina/uso terapêutico , Cateterismo Cardíaco/instrumentação , Clopidogrel , Ecocardiografia Transesofagiana , Embolia Paradoxal/diagnóstico por imagem , Embolia Paradoxal/cirurgia , Feminino , Forame Oval Patente/diagnóstico por imagem , Forame Oval Patente/cirurgia , Humanos , Ataque Isquêmico Transitório , Masculino , Pessoa de Meia-Idade , Inibidores da Agregação Plaquetária/uso terapêutico , Estudos Prospectivos , Fatores de Risco , Acidente Vascular Cerebral , Inquéritos e Questionários , Tromboembolia , Ticlopidina/análogos & derivados , Ticlopidina/uso terapêuticoRESUMO
Navigating animals combine multiple perceptual faculties, learn during exploration, retrieve multi-facetted memory contents, and exhibit goal-directedness as an expression of their current needs and motivations. Navigation in insects has been linked to a variety of underlying strategies such as path integration, view familiarity, visual beaconing, and goal-directed orientation with respect to previously learned ground structures. Most works, however, study navigation either from a field perspective, analyzing purely behavioral observations, or combine computational models with neurophysiological evidence obtained from lab experiments. The honey bee (Apis mellifera) has long been a popular model in the search for neural correlates of complex behaviors and exhibits extraordinary navigational capabilities. However, the neural basis for bee navigation has not yet been explored under natural conditions. Here, we propose a novel methodology to record from the brain of a copter-mounted honey bee. This way, the animal experiences natural multimodal sensory inputs in a natural environment that is familiar to her. We have developed a miniaturized electrophysiology recording system which is able to record spikes in the presence of time-varying electric noise from the copter's motors and rotors, and devised an experimental procedure to record from mushroom body extrinsic neurons (MBENs). We analyze the resulting electrophysiological data combined with a reconstruction of the animal's visual perception and find that the neural activity of MBENs is linked to sharp turns, possibly related to the relative motion of visual features. This method is a significant technological step toward recording brain activity of navigating honey bees under natural conditions. By providing all system specifications in an online repository, we hope to close a methodological gap and stimulate further research informing future computational models of insect navigation.
RESUMO
BACKGROUND: Angiotensin-receptor blockers (ARBs) are effective treatments for patients with heart failure, but the relation between dose and clinical outcomes has not been explored. We compared the effects of high-dose versus low-dose losartan on clinical outcomes in patients with heart failure. METHODS: This double-blind trial was undertaken in 255 sites in 30 countries. 3846 patients with heart failure of New York Heart Association class II-IV, left-ventricular ejection fraction 40% or less, and intolerance to angiotensin-converting-enzyme (ACE) inhibitors were randomly assigned to losartan 150 mg (n=1927) or 50 mg daily (n=1919). Allocation was by block randomisation stratified by centre and presence or absence of beta-blocker therapy, and all patients and investigators were masked to assignment. The primary endpoint was death or admission for heart failure. Analysis was by intention to treat. This study is registered with ClinicalTrials.gov, number NCT00090259. FINDINGS: Six patients in each group were excluded because of poor data quality. With 4.7-year median follow-up in each group (IQR 3.7-5.5 for losartan 150 mg; 3.4-5.5 for losartan 50 mg), 828 (43%) patients in the 150 mg group versus 889 (46%) in the 50 mg group died or were admitted for heart failure (hazard ratio [HR] 0.90, 95% CI 0.82-0.99; p=0.027). For the two primary endpoint components, 635 patients in the 150 mg group versus 665 in the 50 mg group died (HR 0.94, 95% CI 0.84-1.04; p=0.24), and 450 versus 503 patients were admitted for heart failure (0.87, 0.76-0.98; p=0.025). Renal impairment (n=454 vs 317), hypotension (203 vs 145), and hyperkalaemia (195 vs 131) were more common in the 150 mg group than in the 50 mg group, but these adverse events did not lead to significantly more treatment discontinuations in the 150 mg group. INTERPRETATION: Losartan 150 mg daily reduced the rate of death or admission for heart failure in patients with heart failure, reduced left-ventricular ejection fraction, and intolerance to ACE inhibitors compared with losartan 50 mg daily. These findings show the value of up-titrating ARB doses to confer clinical benefit. FUNDING: Merck (USA).
Assuntos
Bloqueadores do Receptor Tipo 1 de Angiotensina II/administração & dosagem , Insuficiência Cardíaca/tratamento farmacológico , Losartan/administração & dosagem , Idoso , Relação Dose-Resposta a Droga , Método Duplo-Cego , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Resultado do TratamentoRESUMO
OBJECTIVES: To evaluate the relation of echocardiographic parameters of diastolic function, exercise capacity (expressed as peakVO(2)) and NT-proBNP in patients with transposition of the great arteries (TGA) and Mustard procedure. METHODS: Diastolic function was determined by measuring tricuspid flow velocities (Ea/Aa ratio), isovolumic relaxation time (IVRT), and deceleration time (DT). E/Ea ratios were calculated. For assessment of systolic function, CMR was applied. RESULTS: E/A (r = 0.07, p = 0.66), E/Ea medial (r = 0.03, p = 0.84), E/Ea lateral (r = -0.01, p = 0.92), IVRT (r = -0.13, p = 0.44), and DT (r = -0.05, p = 0.76) were not correlated with peakVO(2). NT-proBNP showed a significant correlation with IVRT (r = 0.44, p = 0.004) and Ea/Aa medial (r = -0.34, p = 0.025). No correlation was found between RV systolic function and peakVO(2) (r = 0.07, p = 0.63). CONCLUSIONS: Exercise capacity in patients with TGA and Mustard procedure is not related to echocardiographic parameters of diastolic function. NT-proBNP is associated with selected echocardiographic parameters of diastolic function.
Assuntos
Procedimentos Cirúrgicos Cardíacos/métodos , Tolerância ao Exercício/fisiologia , Peptídeo Natriurético Encefálico/sangue , Fragmentos de Peptídeos/sangue , Transposição dos Grandes Vasos , Adulto , Biomarcadores/sangue , Diástole/fisiologia , Ecocardiografia , Teste de Esforço , Feminino , Humanos , Masculino , Consumo de Oxigênio/fisiologia , Sístole/fisiologia , Transposição dos Grandes Vasos/diagnóstico por imagem , Transposição dos Grandes Vasos/fisiopatologia , Transposição dos Grandes Vasos/cirurgia , Função Ventricular Direita/fisiologiaRESUMO
AIMS: We have recently observed that intracoronary autologous bone marrow cell (BMC)-transfer improves parameters of diastolic function in patients after acute myocardial infarction at 6 and 18 months. There is no clinical study addressing the long-term effect of BMC transfer on diastolic function. Therefore, we conducted a 5-year follow-up of the BOOST trial to evaluate a sustained benefit on echocardiographic parameters on diastolic function. METHODS AND RESULTS: After successful primary percutaneous coronary intervention (PCI) for acute ST-elevation MI, patients were randomized to a control (n = 28) or BMC transfer group (n = 28). Echocardiography was performed at 4.5 +/- 1.5 days after PCI, at 6, 18, and 60 months. Diastolic function was determined by measuring transmitral flow velocities (E/A ratio), diastolic myocardial velocities (E(a)/A(a) ratio), isovolumic relaxation time (IVRT), and deceleration time (DT). All analyses were performed in a blinded fashion. There was an overall treatment effect of BMC transfer on E/A (0.25 +/- 0.10; 95% CI 0.05-0.44; P = 0.01). E/A ratio was significantly lower at 6 (Control 0.90 +/- 0.07; BMC 1.23 +/- 0.14; P = 0.03) and 18 months (Control 0.87+/-0.04; BMC 1.13 +/- 0.09; P = 0.01) in the control group, whereas E/A ratio was not different at 60 months between both groups (Control 0.90 +/- 0.06; BMC 1.05 +/- 0.07; P = 0.12). We found no overall effect of BMC transfer on E(a)/A(a) ratio (0.21 +/- 0.14; 95% CI -0.03 to 0.46; P = 0.09), DT (-12 +/- 11 ms; 95% CI -21 to 28; P = 0.75), IVRT -6 +/- 7 ms; 95% CI -9 to 19; P = 0.43), and E/E(a) ratio (0.58 +/- 0.88; 95% CI -1.18 to 2.34; P = 0.51). CONCLUSION: Intracoronary autologous BMC transfer provides an overall treatment effect on echocardiographic parameters of diastolic function in patients after AMI. However, this effect is basically related to an early improvement of parameters of diastolic function without a sustained effect on long-term follow-up.
Assuntos
Transplante de Medula Óssea , Infarto do Miocárdio/terapia , Disfunção Ventricular Esquerda/diagnóstico por imagem , Análise de Variância , Angioplastia Coronária com Balão , Intervalos de Confiança , Diástole , Ecocardiografia Doppler , Humanos , Imagem Cinética por Ressonância Magnética , Pessoa de Meia-Idade , Infarto do Miocárdio/diagnóstico por imagem , Fatores de Tempo , Resultado do Tratamento , Disfunção Ventricular Esquerda/terapiaRESUMO
BACKGROUND: Symptomatic severe aortic stenosis is associated with increased mortality and morbidity. Early identification of these patients by echocardiography is crucial. We conducted this study to evaluate a handheld ultrasound device (HCU) in patients with suspected severe aortic stenosis (AS) in comparison to a standard echocardiography device (SE). METHODS: A HCU (Vivid I; GE Healthcare) and a SE device (Philips iE 33) were used to evaluate 50 consecutive patients with suspected severe AS. Two consecutive echocardiographic studies were performed by two experienced and blinded examiners using HCU and SE device. AS was graded by mean transaortic pressure, aortic valve area (AVA), and indexed AVA (AVA adjusted for body surface area). RESULTS: Mean difference for mean transaortic gradient, AVA and indexed AVA for the SE and HCU device were 1.28 mmHg (-0.70 to 3.26 mmHg), -0.02 cm(2) (-0.06 to 0.01 cm(2)), and -0.01 cm(2)/m(2) (-0.03 to 0.01 cm(2)/m(2)), respectively. Discrepancies between both devices were not associated with misinterpretation of the degree of AS. CONCLUSION: Our study demonstrates that HCU can be used to evaluate patients with suspected AS. (ECHOCARDIOGRAPHY 2010;27:481-486).
Assuntos
Estenose da Valva Aórtica/diagnóstico por imagem , Ecocardiografia Doppler/instrumentação , Idoso , Desenho de Equipamento , Feminino , Humanos , Masculino , Reprodutibilidade dos Testes , TransdutoresRESUMO
AIMS: This study investigated the effects of irbesartan vs. enalapril, with early vs. late treatment, on markers of inflammation and ischaemic heart disease in patients with non-ST-segment elevation acute coronary syndrome (NSTEACS). METHODS AND RESULTS: Patients hospitalized with ischaemic symptoms and evidence of NSTEACS were randomized to early (at hospitalization) or late (at hospital discharge) treatment with irbesartan 150 mg/day followed by 300 mg/day on day 15 (n = 212) or enalapril 10 mg/day followed by 20 mg/day on day 15 (n = 217) to day 60. The primary endpoint was the change from baseline in high-sensitivity C-reactive protein (hs-C-reactive protein) at day 60; secondary endpoints included changes in troponin I, B-type natriuretic peptide, microalbuminuria, interleukin 6, myeloperoxidase, secretory non-pancreatic type II phospholipase A2, ischaemia-modified albumin, soluble CD40 ligand, matrix metalloproteinase-9, aldosterone, and blood pressure. High-sensitivity C-reactive protein levels were comparable in both the irbesartan and enalapril treatment arms. There were no treatment-related differences in any of the biomarkers measured. Changes in inflammatory markers were unaffected by the timing of treatment initiation. Both treatments were well tolerated, with no differences in major adverse cardiac events. CONCLUSION: In patients with NSTEACS, inflammatory markers decreased over time in both treatment arms, with no differences between irbesartan and enalapril.