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2.
J Invasive Cardiol ; 2020 Nov 10.
Artigo em Inglês | MEDLINE | ID: mdl-33168780

RESUMO

BACKGROUND: Left ventricular endomyocardial biopsy (LVEMB) is commonly performed via the transfemoral route. Radial access may help reduce vascular access complications, but there are few data on the safety and feasibility of transradial LVEMB. OBJECTIVE: Describe the safety and feasibility of transitioning from transfemoral to transradial access LVEMB. METHODS: This is a single-center, prospective, observational cohort study. Fifty procedures in 49 patients were included, 25 (50%) via the femoral route and 25 (50%) via the radial route. RESULTS: The cohort had a mean age of 47 ± 13 years and the most common indication for LVEMB was myocarditis. From June 2015 until September 2016, all procedures (n = 21) were performed via the femoral approach; thenceforth, there was a gradual transition to the radial approach. More tissue samples were obtained when the procedure was performed via the femoral approach (P<.01). The minimum sampling target of 3 specimens was not met in 4 patients (16%) via the radial approach and in 1 patient (4%) via the femoral approach. Complications occurred in 3/25 transradial procedures (12%; 2 cardiac perforations and 1 forearm hematoma) and 3/25 transfemoral procedures (12%; 1 cardiac perforation, 1 femoral artery pseudoaneurysm, and 1 ventricular fibrillation). Cardiac perforations via the transradial approach occurred during the early transition period. There were no deaths. CONCLUSIONS: Transradial LVEMB is feasible, with a similar complication profile to femoral procedures, but associated with a smaller number of specimens. Transitioning from transfemoral to transradial procedures may initially be associated with a higher risk of complications and potentially a lower diagnostic yield.

5.
Eur Heart J Cardiovasc Imaging ; 21(3): 326-336, 2020 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-31317183

RESUMO

AIMS : Myocardial scar detected by cardiovascular magnetic resonance has been associated with sudden cardiac death in dilated cardiomyopathy (DCM). Certain genetic causes of DCM may cause a malignant arrhythmogenic phenotype. The concepts of arrhythmogenic left ventricular (LV) cardiomyopathy (ALVC) and arrhythmogenic DCM are currently ill-defined. We hypothesized that a distinctive imaging phenotype defines ALVC. METHODS AND RESULTS : Eighty-nine patients with DCM-associated mutations [desmoplakin (DSP) n = 25, filamin C (FLNC) n = 7, titin n = 30, lamin A/C n = 12, bcl2-associated athanogene 3 n = 3, RNA binding motif protein 20 n = 3, cardiac sodium channel NAv1.5 n = 2, and sarcomeric genes n = 7] were comprehensively phenotyped. Clustering analysis resulted in two groups: 'DSP/FLNC genotypes' and 'non-DSP/FLNC'. There were no significant differences in age, sex, symptoms, baseline electrocardiography, arrhythmia burden, or ventricular volumes between the two groups. Subepicardial LV late gadolinium enhancement with ring-like pattern (at least three contiguous segments in the same short-axis slice) was observed in 78.1% of DSP/FLNC genotypes but was absent in the other DCM genotypes (P < 0.001). Left ventricular ejection fraction (LVEF) and global longitudinal strain were lower in other DCM genotypes (P = 0.053 and P = 0.015, respectively), but LV regional wall motion abnormalities were more common in DSP/FLNC genotypes (P < 0.001). DSP/FLNC patients with non-sustained ventricular tachycardia (NSVT) had more LV scar (P = 0.010), whereas other DCM genotypes patients with NSVT had lower LVEF (P = 0.001) than patients without NSVT. CONCLUSION: DSP/FLNC genotypes cause more regionality in LV impairment. The most defining characteristic is a subepicardial ring-like scar pattern in DSP/FLNC, which should be considered in future diagnostic criteria for ALVC.

6.
Circ Heart Fail ; 12(11): e005250, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31718319

RESUMO

BACKGROUND: Coxsackie-B-viruses (CVB) are frequent causes of acute myocarditis and dilated cardiomyopathy, but an effective antiviral therapy is still not available. Previously, we and others have demonstrated that treatment with an engineered sCAR-Fc (soluble coxsackievirus-adenovirus receptor fused to the carboxyl-terminus of human IgG) efficiently neutralizes CVB3 and inhibits the development of cardiac dysfunction in mice with acute CVB3-induced myocarditis. In this study, we analyzed the potential of sCAR-Fc for treatment of chronic CVB3-induced myocarditis in an outbred NMRI mouse model. METHODS: NMRI mice were infected with the CVB3 strain 31-1-93 and treated with a sCAR-Fc expressing adeno-associated virus 9 vector 1, 3, and 7 days after CVB3 infection. Chronic myocarditis was analyzed on day 28 after infection. RESULTS: Initial investigations showed that NMRI mice develop pronounced chronic myocarditis between day 18 and day 28 after infection with the CVB3 strain 31-1-93. Chronic cardiac infection was characterized by inflammation and fibrosis as well as persistence of viral genomes in the heart tissue and by cardiac dysfunction. Treatment of NMRI mice resulted in a distinct reduction of cardiac inflammation and fibrosis and almost complete elimination of virus RNA from the heart by day 28 after infection. Moreover, hemodynamic measurement revealed improved cardiac contractility and diastolic relaxation in treated mice compared with mice treated with a control vector (mean±SD; maximal pressure, 81.9±9.2 versus 69.4±8.6 mm Hg, P=0.02; left ventricular ejection fraction, 68.9±8.5 versus 54.2±11.5%, P=0.02; dP/dtmax, 7275.2±1674 versus 4432.6±1107 mm Hg/s, P=0.004; dP/dtmin, -4046.9±776 versus -3146.3±642 mm Hg/s, P=0.046). The therapeutic potential of sCAR-Fc is limited, however, since postponed start of sCAR-Fc treatment either 3 or 7 days after infection could not attenuate myocardial injury. CONCLUSIONS: Early therapeutic employment of sCAR-Fc, initiated at the beginning of the primary viremia, inhibits the development of chronic CVB3-induced myocarditis and improves the cardiac function to a level equivalent to that of uninfected animals.

7.
Ann Surg Oncol ; 26(9): 2943-2951, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31243666

RESUMO

BACKGROUND: This study aimed to compare the outcomes of two distinct patient populations treated within two neighboring UK cancer centers (A and B) for advanced epithelial ovarian cancer (EOC). METHODS: A retrospective analysis of all new stages 3 and 4 EOC patients treated between January 2013 and December 2014 was performed. The Mayo Clinic surgical complexity score (SCS) was applied. Cox regression analysis identified the impact of treatment methods on survival. RESULTS: The study identified 249 patients (127 at center A and 122 in centre B) without significant differences in International Federation of Gynecology and Obstetrics (FIGO) stage (FIGO 4, 29.7% at centers A and B), Eastern Cooperative Oncology Group (ECOG) performance status (ECOG < 2, 89.9% at centers A and B), or histology (serous type in 84.1% at centers A and B). The patients at center A were more likely to undergo surgery (87% vs 59.8%; p < 0.001). The types of chemotherapy and the patients receiving palliative treatment alone were equivalent between the two centers (3.6%). The median SCS was significantly higher at center A (9 vs 2; p < 0.001) with greater tumor burden (9 vs 6 abdominal fields involved; p < 0.001), longer median operation times (285 vs 155 min; p < 0.001), and longer hospital stays (9 vs 6 days; p < 0.001), but surgical morbidity and mortality were equivalent. The independent predictors of reduced overall survival (OS) were non-serous histology (hazard ratio [HR], 1.6; 95% confidence interval [CI] 1.04-2.61), ECOG higher than 2 (HR, 1.9; 95% CI 1.15-3.13), and palliation alone (HR, 3.43; 95% CI 1.51-7.81). Cytoreduction, of any timing, had an independent protective impact on OS compared with chemotherapy alone (HR, 0.31 for interval surgery and 0.39 for primary surgery), even after adjustment for other prognostic factors. CONCLUSIONS: Incorporating surgery into the initial EOC management, even for those patients with a greater tumor burden and more disseminated disease, may require more complex procedures and more resources in terms of theater time and hospital stay, but seems to be associated with a significant prolongation of the patients overall survival compared with chemotherapy alone.


Assuntos
Adenocarcinoma de Células Claras/mortalidade , Adenocarcinoma Mucinoso/mortalidade , Cistadenocarcinoma Seroso/mortalidade , Procedimentos Cirúrgicos de Citorredução/mortalidade , Neoplasias do Endométrio/mortalidade , Neoplasias Ovarianas/mortalidade , Padrões de Prática Médica/normas , Adenocarcinoma de Células Claras/patologia , Adenocarcinoma de Células Claras/cirurgia , Adenocarcinoma Mucinoso/patologia , Adenocarcinoma Mucinoso/cirurgia , Adulto , Idoso , Idoso de 80 Anos ou mais , Cistadenocarcinoma Seroso/patologia , Cistadenocarcinoma Seroso/cirurgia , Neoplasias do Endométrio/patologia , Neoplasias do Endométrio/cirurgia , Feminino , Seguimentos , Humanos , Pessoa de Meia-Idade , Neoplasias Ovarianas/patologia , Neoplasias Ovarianas/cirurgia , Prognóstico , Estudos Retrospectivos , Taxa de Sobrevida , Carga Tumoral , Adulto Jovem
8.
Eur Heart J ; 40(40): 3318-3332, 2019 Oct 21.
Artigo em Inglês | MEDLINE | ID: mdl-31004144

RESUMO

AIMS: Heart failure with preserved ejection fraction (HFpEF) and pathological cardiac aging share a complex pathophysiology, including extracellular matrix remodelling (EMR). Protease-activated receptor 2 (PAR2) deficiency is associated with EMR. The roles of PAR1 and PAR2 have not been studied in HFpEF, age-dependent cardiac fibrosis, or diastolic dysfunction (DD). METHODS AND RESULTS: Evaluation of endomyocardial biopsies from patients with HFpEF (n = 14) revealed that a reduced cardiac PAR2 expression was associated with aggravated DD and increased myocardial fibrosis (r = -0.7336, P = 0.0028). In line, 1-year-old PAR2-knockout (PAR2ko) mice suffered from DD with preserved systolic function, associated with an increased age-dependent α-smooth muscle actin expression, collagen deposition (1.7-fold increase, P = 0.0003), lysyl oxidase activity, collagen cross-linking (2.2-fold increase, P = 0.0008), endothelial activation, and inflammation. In the absence of PAR2, the receptor-regulating protein caveolin-1 was down-regulated, contributing to an augmented profibrotic PAR1 and transforming growth factor beta (TGF-ß)-dependent signalling. This enhanced TGF-ß/PAR1 signalling caused N-proteinase (ADAMTS3) and C-proteinase (BMP1)-related increased collagen I production from cardiac fibroblasts (CFs). PAR2 overexpression in PAR2ko CFs reversed these effects. The treatment with the PAR1 antagonist, vorapaxar, reduced cardiac fibrosis by 44% (P = 0.03) and reduced inflammation in a metabolic disease model (apolipoprotein E-ko mice). Patients with HFpEF with upstream PAR inhibition via FXa inhibitors (n = 40) also exhibited reduced circulating markers of fibrosis and DD compared with patients treated with vitamin K antagonists (n = 20). CONCLUSIONS: Protease-activated receptor 2 is an important regulator of profibrotic PAR1 and TGF-ß signalling in the heart. Modulation of the FXa/FIIa-PAR1/PAR2/TGF-ß-axis might be a promising therapeutic approach to reduce HFpEF.

9.
FASEB J ; : fj201701408R, 2018 Jun 04.
Artigo em Inglês | MEDLINE | ID: mdl-29863913

RESUMO

Regulatory T (Treg) cells offer new therapeutic options for controlling undesired systemic and local immune responses. The aim of the current study was to determine the impact of therapeutic Treg administration on systemic and cardiac inflammation and remodeling in coxsackievirus B3 (CVB3) -induced myocarditis. Therefore, syngeneic Treg cells were applied intravenously in CVB3-infected mice 3 d after infection. Compared with CVB3 + PBS mice, CVB3 + Treg mice exhibited lower left ventricular (LV) chemokine expression, accompanied by reduced cardiac presence of proinflammatory Ly6ChighCCR2highCx3Cr1low monocytes and higher retention of proinflammatory Ly6CmidCCR2highCx3Cr1low monocytes in the spleen. In addition, splenic myelopoiesis was reduced in CVB3 + Treg compared with CVB3 + PBS mice. Coculture of Treg cells with splenocytes isolated from mice 3 d post-CVB3 infection further demonstrated the ability of Treg cells to modulate monocyte differentiation in favor of the anti-inflammatory Ly6ClowCCR2lowCx3Cr1high subset. Treg-mediated immunomodulation was paralleled by lower collagen 1 protein expression and decreased levels of soluble and insoluble collagen in LV of CVB3 + Treg compared with CVB3 + PBS mice. In agreement with these findings, LV systolic and diastolic function was improved in CVB3 + Treg mice compared with CVB3 + PBS mice. In summary, adoptive Treg transfer in the inflammatory phase of viral-induced myocarditis protects the heart against inflammatory damage and fibrosis via modulation of monocyte subsets.-Pappritz, K., Savvatis, K., Miteva, K., Kerim, B., Dong, F., Fechner, H., Müller, I., Brandt, C., Lopez, B., González, A., Ravassa, S., Klingel, K., Diez, J., Reinke, P., Volk, H.-D., Van Linthout, S., Tschöpe, C. Immunomodulation by adoptive regulatory T-cell transfer improves Coxsackievirus B3-induced myocarditis.

10.
Sci Rep ; 8(1): 5575, 2018 04 03.
Artigo em Inglês | MEDLINE | ID: mdl-29615815

RESUMO

Cardiac fibroblasts play an important role in the regulation of the extracellular matrix and are newly recognized as inflammatory supporter cells. Interferon (IFN)-γ is known to counteract transforming growth factor (TGF)-ß1-induced myofibroblast differentiation. This study aims at investigating in vitro how IFN-γ affects TGF-ß1-induced monocyte attraction. Therefore, C4 fibroblasts and fibroblasts obtained by outgrowth culture from the left ventricle (LV) of male C57BL6/j mice were stimulated with TGF-ß1, IFN-γ and TGF-ß1 + IFN-γ. Confirming previous studies, IFN-γ decreased the TGF-ß1-induced myofibroblast differentiation, as obviated by lower collagen I, III, α-smooth muscle actin (α-SMA), lysyl oxidase (Lox)-1 and lysyl oxidase-like (LoxL)-2 levels in TGF-ß1 + IFN-γ- versus TGF-ß1-stimulated cardiac fibroblasts. TGF-ß1 + IFN-γ-stimulated C4 and cardiac fibroblasts displayed a higher CC-chemokine ligand (CCL) 2, CCL7 and chemokine C-X3-C motif ligand (Cx3CL1) release versus sole TGF-ß1-stimulated fibroblasts. Analysis of migrated monocyte subsets towards the different conditioned media further revealed that sole TGF-ß1- and IFN-γ-conditioned media particularly attracted Ly6Clow and Ly6Chigh monocytes, respectively, as compared to control media. In line with theses findings, TGF-ß1 + IFN-γ-conditioned media led to a lower Ly6Clow/Ly6Chigh monocyte migration ratio compared to sole TGF-ß1 treatment. These differences in monocyte migration reflect the complex interplay of pro-inflammatory cytokines and pro-fibrotic factors in cardiac remodelling and inflammation.


Assuntos
Movimento Celular , Monócitos/citologia , Miocárdio/citologia , Miofibroblastos/citologia , Animais , Diferenciação Celular/efeitos dos fármacos , Movimento Celular/efeitos dos fármacos , Colágeno/biossíntese , Interações Medicamentosas , Regulação Enzimológica da Expressão Gênica/efeitos dos fármacos , Interferon gama/farmacologia , Masculino , Metaloproteinase 2 da Matriz/metabolismo , Camundongos , Monócitos/efeitos dos fármacos , Monócitos/metabolismo , Miofibroblastos/efeitos dos fármacos , Miofibroblastos/metabolismo , Fenótipo , Fator de Crescimento Transformador beta1/farmacologia
12.
Sci Rep ; 8(1): 2820, 2018 02 12.
Artigo em Inglês | MEDLINE | ID: mdl-29434214

RESUMO

Inflammation in myocarditis induces cardiac injury and triggers disease progression to heart failure. NLRP3 inflammasome activation is a newly identified amplifying step in the pathogenesis of myocarditis. We previously have demonstrated that mesenchymal stromal cells (MSC) are cardioprotective in Coxsackievirus B3 (CVB3)-induced myocarditis. In this study, MSC markedly inhibited left ventricular (LV) NOD2, NLRP3, ASC, caspase-1, IL-1ß, and IL-18 mRNA expression in CVB3-infected mice. ASC protein expression, essential for NLRP3 inflammasome assembly, increased upon CVB3 infection and was abrogated in MSC-treated mice. Concomitantly, CVB3 infection in vitro induced NOD2 expression, NLRP3 inflammasome activation and IL-1ß secretion in HL-1 cells, which was abolished after MSC supplementation. The inhibitory effect of MSC on NLRP3 inflammasome activity in HL-1 cells was partly mediated via secretion of the anti-oxidative protein stanniocalcin-1. Furthermore, MSC application in CVB3-infected mice reduced the percentage of NOD2-, ASC-, p10- and/or IL-1ß-positive splenic macrophages, natural killer cells, and dendritic cells. The suppressive effect of MSC on inflammasome activation was associated with normalized expression of prominent regulators of myocardial contractility and fibrosis to levels comparable to control mice. In conclusion, MSC treatment in myocarditis could be a promising strategy limiting the adverse consequences of cardiac and systemic NLRP3 inflammasome activation.


Assuntos
Inflamassomos/metabolismo , Células-Tronco Mesenquimais/fisiologia , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Animais , Cardiomiopatias/metabolismo , Caspase 1/metabolismo , Infecções por Coxsackievirus/virologia , Coração/fisiologia , Humanos , Inflamação/patologia , Interleucina-1beta/metabolismo , Macrófagos/metabolismo , Masculino , Células-Tronco Mesenquimais/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Miocardite/virologia , Miocárdio/metabolismo , Proteína 3 que Contém Domínio de Pirina da Família NLR/fisiologia
13.
Eur Heart J ; 39(10): 876-887, 2018 03 07.
Artigo em Inglês | MEDLINE | ID: mdl-29136142

RESUMO

Aims: Foxo3 is a transcription factor involved in cell metabolism, survival, and inflammatory disease. However, mechanistic insight in Foxo3 effects is still limited. Here, we investigated the role of Foxo3 on natural killer (NK) cell responses and its effects in viral myocarditis. Methods and results: Effects of Foxo3 on viral load and immune responses were investigated in a model of coxsackie virus B3 myocarditis in wild-type (WT) and Foxo3 deficient mice. Reduced immune cell infiltration, viral titres, and pro-inflammatory cytokines in cardiac tissue were observed in Foxo3-/- mice 7 days post-infection (p.i.). Viral titres were also attenuated in hearts of Foxo3-/- mice at Day 3 while interferon-γ (IFNγ) and NKp46 expression were up-regulated suggesting early viral control by enhanced NK cell activity. CD69 expression of NK cells, frequencies of CD11b+CD27+ effector NK cells and cytotoxicity of Foxo3-/- mice was enhanced compared to WT littermates. Moreover, microRNA-155 expression, essential in NK cell activation, was elevated in Foxo3-/- NK cells while its inhibition led to diminished IFNγ production. Healthy humans carrying the longevity-associated FOXO3 single nucleotide polymorphism (SNP) rs12212067 exhibited reduced IFNγ and cytotoxic degranulation of NK cells. Viral inflammatory cardiomyopathy (viral CMI) patients with this SNP showed a poorer outcome due to less efficient virus control. Conclusion: Our results implicate Foxo3 in regulating NK cell function and suggest Foxo3 playing an important role in the antiviral innate immunity. Thus, enhanced FOXO3 activity such as in the polymorphism rs12212067 may be protective in chronic inflammation such as cancer and cardiovascular disease but disadvantageous to control acute viral infection.


Assuntos
Proteína Forkhead Box O3 , Células Matadoras Naturais/imunologia , Miocardite , Adulto , Animais , Infecções por Coxsackievirus/imunologia , Infecções por Coxsackievirus/virologia , Citocinas/metabolismo , Modelos Animais de Doenças , Feminino , Proteína Forkhead Box O3/genética , Proteína Forkhead Box O3/imunologia , Proteína Forkhead Box O3/metabolismo , Coração/virologia , Humanos , Masculino , Camundongos , Camundongos Knockout , Pessoa de Meia-Idade , Miocardite/imunologia , Miocardite/patologia , Miocardite/virologia , Miocárdio/imunologia , Miocárdio/patologia , Polimorfismo de Nucleotídeo Único
14.
Circ Heart Fail ; 10(11)2017 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-29158436

RESUMO

BACKGROUND: The alarmins S100A8 and S100A9 are damage-associated molecular patterns, which play a pivotal role in cardiovascular diseases, inflammation, and viral infections. We aimed to investigate their role in Coxsackievirus B3 (CVB3)-induced myocarditis. METHODS AND RESULTS: S100A8 and S100A9 mRNA expression was 13.0-fold (P=0.012) and 5.1-fold (P=0.038) higher in endomyocardial biopsies from patients with CVB3-positive myocarditis compared with controls, respectively. Elimination of CVB3 led to a downregulation of these alarmins. CVB3-infected mice developed an impaired left ventricular function and displayed an increased left ventricular S100A8 and S100A9 protein expression versus controls. In contrast, CVB3-infected S100A9 knockout mice, which are also a complete knockout for S100A8 on protein level, showed an improved left ventricular function, which was associated with a reduced cardiac inflammatory and oxidative response, and lower CVB3 copy number compared with wild-type CVB3 mice. Exogenous application of S100A8 to S100A9 knockout CVB3 mice induced a severe myocarditis similar to wild-type CVB3 mice. In CVB3-infected HL-1 cells, S100A8 and S100A9 enhanced oxidative stress and CVB3 copy number compared with unstimulated infected cells. In CVB3-infected RAW macrophages, both alarmins increased MIP-2 (macrophage inflammatory protein-2) chemokine expression, which was reduced in CVB3 S100A8 knockdown versus scrambled siRNA CVB3 cells. CONCLUSIONS: S100A8 and S100A9 aggravate CVB3-induced myocarditis and might serve as therapeutic targets in inflammatory cardiomyopathies.


Assuntos
Calgranulina A/metabolismo , Calgranulina B/metabolismo , Infecções por Coxsackievirus/metabolismo , Enterovirus Humano B/patogenicidade , Miocardite/metabolismo , Miócitos Cardíacos/metabolismo , Adulto , Animais , Calgranulina A/deficiência , Calgranulina A/genética , Calgranulina B/genética , Estudos de Casos e Controles , Quimiocina CXCL2/metabolismo , Infecções por Coxsackievirus/diagnóstico , Infecções por Coxsackievirus/genética , Infecções por Coxsackievirus/virologia , Modelos Animais de Doenças , Enterovirus Humano B/genética , Feminino , Fibrose , Interações Hospedeiro-Patógeno , Humanos , Macrófagos/metabolismo , Macrófagos/virologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Pessoa de Meia-Idade , Miocardite/diagnóstico , Miocardite/genética , Miocardite/virologia , Miócitos Cardíacos/patologia , Miócitos Cardíacos/virologia , Infiltração de Neutrófilos , Estresse Oxidativo , Células RAW 264.7 , Interferência de RNA , RNA Mensageiro/genética , Receptor para Produtos Finais de Glicação Avançada/metabolismo , Transdução de Sinais , Transfecção , Função Ventricular Esquerda
15.
Circ Heart Fail ; 10(9)2017 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-28912259

RESUMO

BACKGROUND: The cytoplasmatic pattern recognition receptor, NOD2 (nucleotide-binding oligomerization domain 2), belongs to the innate immune system and is among others responsible for the recognition of single-stranded RNA. With Coxsackievirus B3 (CVB3) being a single-stranded RNA virus, and the recent evidence that the NOD2 target, NLRP3 (NOD-like receptor family, pyrin domain containing 3) is of importance in the pathogenesis of CVB3-induced myocarditis, we aimed to unravel the role of NOD2 in CVB3-induced myocarditis. METHODS AND RESULTS: Endomyocardial biopsy NOD2 mRNA expression was higher in CVB3-positive patients compared with patients with myocarditis but without evidence of persistent CVB3 infection. Left ventricular NOD2 mRNA expression was also induced in CVB3-induced myocarditis versus healthy control mice. NOD2 knockdown(-/-) mice were rescued from the detrimental CVB3-mediated effects as shown by a reduced cardiac inflammation (less cardiac infiltrates and suppression of proinflammatory cytokines), cardiac fibrosis, apoptosis, lower CAR (Coxsackievirus and adenovirus receptor) expression and CVB3 copy number, and an improved left ventricular function in NOD2-/- CVB3 mice compared with wild-type CVB3 mice. In agreement, NOD2-/- decreased the CVB3-induced inflammatory response, CVB3 copy number, and apoptosis in vitro. NOD2-/- was further associated with a reduction in CVB3-induced NLRP3 expression and activity as evidenced by lower ASC (apoptosis-associated speck-like protein containing a CARD) expression, caspase 1 activity, or IL-1ß (interleukin-1ß) protein expression under in vivo and in vitro CVB3 conditions. CONCLUSIONS: NOD2 is an important mediator in the viral uptake and inflammatory response during the pathogenesis of CVB3 myocarditis.


Assuntos
Infecções por Coxsackievirus/metabolismo , Enterovirus Humano B/metabolismo , Miocardite/metabolismo , Miocárdio/metabolismo , Proteína Adaptadora de Sinalização NOD2/metabolismo , Animais , Apoptose , Proteínas Reguladoras de Apoptose/metabolismo , Proteínas Adaptadoras de Sinalização CARD , Estudos de Casos e Controles , Caspase 1/metabolismo , Linhagem Celular , Infecções por Coxsackievirus/imunologia , Infecções por Coxsackievirus/prevenção & controle , Infecções por Coxsackievirus/virologia , Modelos Animais de Doenças , Enterovirus Humano B/genética , Enterovirus Humano B/imunologia , Predisposição Genética para Doença , Interações Hospedeiro-Patógeno , Humanos , Interleucina-1beta/metabolismo , Masculino , Camundongos Endogâmicos C57BL , Camundongos Knockout , Miocardite/imunologia , Miocardite/prevenção & controle , Miocardite/virologia , Miocárdio/imunologia , Miocárdio/patologia , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Proteína Adaptadora de Sinalização NOD2/deficiência , Proteína Adaptadora de Sinalização NOD2/genética , Fenótipo , Interferência de RNA , Transdução de Sinais , Transfecção , Regulação para Cima
16.
PLoS One ; 12(8): e0182643, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28800592

RESUMO

Studies on inflammatory disorders elucidated the pivotal role of the CX3CL1/CX3CR1 axis with respect to the pathophysiology and diseases progression. Coxsackievirus B3 (CVB3)-induced myocarditis is associated with severe cardiac inflammation, which may progress to heart failure. We therefore investigated the influence of CX3CR1 ablation in the model of acute myocarditis, which was induced by inoculation with 5x105 plaque forming units of CVB3 (Nancy strain) in either CX3CR1-/- or C57BL6/j (WT) mice. Seven days after infection, myocardial inflammation, remodeling, and titin expression and phosphorylation were examined by immunohistochemistry, real-time PCR and Pro-Q diamond stain. Cardiac function was assessed by tip catheter. Compared to WT CVB3 mice, CX3CR1-/- CVB3 mice exhibited enhanced left ventricular expression of inflammatory cytokines and chemokines, which was associated with an increase of immune cell infiltration/presence. This shift towards a pro-inflammatory immune response further resulted in increased cardiac fibrosis and cardiomyocyte apoptosis, which was reflected by an impaired cardiac function in CX3CR1-/- CVB3 compared to WT CVB3 mice. These findings demonstrate a cardioprotective role of CX3CR1 in CVB3-infected mice and indicate the relevance of the CX3CL1/CX3CR1 system in CVB3-induced myocarditis.


Assuntos
Quimiocina CX3CL1/imunologia , Infecções por Coxsackievirus/genética , Enterovirus Humano B/patogenicidade , Interações Hospedeiro-Patógeno/imunologia , Miocardite/genética , Receptores de Quimiocinas/imunologia , Animais , Apoptose , Receptor 1 de Quimiocina CX3C , Moléculas de Adesão Celular/genética , Moléculas de Adesão Celular/imunologia , Quimiocina CX3CL1/genética , Infecções por Coxsackievirus/imunologia , Infecções por Coxsackievirus/patologia , Infecções por Coxsackievirus/virologia , Modelos Animais de Doenças , Enterovirus Humano B/crescimento & desenvolvimento , Regulação da Expressão Gênica , Testes de Função Cardíaca , Humanos , Interleucinas/genética , Interleucinas/imunologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Miocardite/imunologia , Miocardite/patologia , Miocardite/virologia , Miócitos Cardíacos/imunologia , Miócitos Cardíacos/patologia , Fosforilação , Proteínas Quinases/genética , Proteínas Quinases/imunologia , Receptores de Quimiocinas/deficiência , Receptores de Quimiocinas/genética
17.
Cardiovasc Res ; 113(8): 906-914, 2017 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-28402411

RESUMO

Aim: To address the mechanisms responsible for the increase in LV filling pressures induced by acute hypertension transients in patients with heart failure with preserved ejection fraction (HFpEF). Methods and results: Multiple-beat pressure-volume loops were recorded during inferior vena cava occlusion in 39 HFpEF patients and 20 controls during handgrip and atrial pacing. We measured the contribution of relaxation, elastic recoil, and stiffness to instantaneous diastolic pressure using a novel processing method. Fibrosis was quantified from endomyocardial biopsies. HFpEF patients showed higher diastolic pressures and stiffness constant than controls (P < 0.05 for all). As opposed to controls, all intrinsic global diastolic properties were sensitive to acute changes in systolic pressure in the HFpEF group. In fact, the stiffness constant increased by more than 50% during handgrip in HFpEF patients (P < 0.05), tightly related to changes in systolic pressure (fixed-effect = 0.26 mm Hg per mm Hg [95% CI = 0.15-0.37]; P < 0.0001). Incomplete relaxation contributed to increasing pressure before atrial contraction, but changes in end-diastolic pressure was mostly caused by the increase in stiffness. The degree of pressure-sensitivity of stiffness correlated with myocardial collagen volume and crosslinking (R = 0.40 to 0.82 for all). Conclusion: Acute chamber stiffening is the main mechanism responsible for rising late-diastolic pressures when HFpEF patients undergo hypertension transients. This stiffening behaviour is related to impaired dynamic systolic-diastolic interactions and correlates with matrix remodelling. Ventricular-vascular relationships are a promising target in HFpEF and should be taken into account when assessing diastolic function.


Assuntos
Diástole/fisiologia , Hipertensão/fisiopatologia , Disfunção Ventricular Esquerda/fisiopatologia , Adulto , Idoso , Feminino , Força da Mão/fisiologia , Insuficiência Cardíaca/fisiopatologia , Humanos , Hipertensão/complicações , Masculino , Pessoa de Meia-Idade , Volume Sistólico/fisiologia
18.
Nat Commun ; 7: 13710, 2016 12 14.
Artigo em Inglês | MEDLINE | ID: mdl-27966531

RESUMO

Interstitial fibrosis plays a key role in the development and progression of heart failure. Here, we show that an enzyme that crosslinks collagen-Lysyl oxidase-like 2 (Loxl2)-is essential for interstitial fibrosis and mechanical dysfunction of pathologically stressed hearts. In mice, cardiac stress activates fibroblasts to express and secrete Loxl2 into the interstitium, triggering fibrosis, systolic and diastolic dysfunction of stressed hearts. Antibody-mediated inhibition or genetic disruption of Loxl2 greatly reduces stress-induced cardiac fibrosis and chamber dilatation, improving systolic and diastolic functions. Loxl2 stimulates cardiac fibroblasts through PI3K/AKT to produce TGF-ß2, promoting fibroblast-to-myofibroblast transformation; Loxl2 also acts downstream of TGF-ß2 to stimulate myofibroblast migration. In diseased human hearts, LOXL2 is upregulated in cardiac interstitium; its levels correlate with collagen crosslinking and cardiac dysfunction. LOXL2 is also elevated in the serum of heart failure (HF) patients, correlating with other HF biomarkers, suggesting a conserved LOXL2-mediated mechanism of human HF.


Assuntos
Aminoácido Oxirredutases/fisiologia , Insuficiência Cardíaca/metabolismo , Miocárdio/patologia , Aminoácido Oxirredutases/sangue , Aminoácido Oxirredutases/metabolismo , Animais , Fibrose/metabolismo , Humanos , Camundongos Knockout , Miocárdio/metabolismo , Estresse Fisiológico
19.
J Mol Med (Berl) ; 94(6): 645-53, 2016 06.
Artigo em Inglês | MEDLINE | ID: mdl-27080394

RESUMO

UNLABELLED: Ischemia impairs the adenine nucleotide translocase (ANT), which transports ADP and ATP across the inner mitochondrial membrane. We investigated whether ANT1 overexpression has protective effects on ischemic hearts. Myocardial infarction was induced in wild-type (WT) and heart-specific ANT1-transgenic (ANT1-TG) rats, and hypoxia was set in isolated cardiomyocytes. ANT1 overexpression reduced the myocardial infarct area and increased the survival rate of infarcted rats. Reduced ANT1 expression and increased 4-hydroxynonenal modification of ANT paralleled to impaired ANT function in infarcted WT hearts. ANT1 overexpression improved ANT expression and function. This was accompanied by reduced mitochondrial cytochrome C release and caspase-3 activation. ANT1-TG hearts suffered less from oxidative stress, as shown by lower protein carbonylation and 4-hydroxynonenal modification of ANT. ANT1 overexpression also increased cell survival of hypoxic cardiomyocytes and attenuated reactive oxygen species (ROS) production. This was linked to higher stability of mitochondrial membrane potential and lower activity of ROS detoxifying catalase. ANT1-TG cardiomyocytes also showed higher resistance against H2O2 treatment, which was independent of catalase activity. In conclusion, ANT1 overexpression compensates impaired ANT activity under oxygen-restricted conditions. It reduces ROS production and oxidative stress, stabilizes mitochondrial integrity, and increases survival, making ANT1 a component in ROS management and heart protection during ischemia. KEY MESSAGES: ANT1 overexpression reduces infarct size and increases survival after infarction. ANT1 overexpression compensates restricted ANT expression and function in infarcted hearts. Increased ANT1 expression enhances mitochondrial integrity. ANT1-overexpressing hearts reduce oxidative stress by decreasing ROS generation. ANT1 is a component in ROS management and heart protection.


Assuntos
Translocador 1 do Nucleotídeo Adenina/genética , Mitocôndrias Cardíacas/genética , Infarto do Miocárdio/genética , Miócitos Cardíacos/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Translocador 1 do Nucleotídeo Adenina/metabolismo , Aldeídos/metabolismo , Animais , Caspase 3/genética , Caspase 3/metabolismo , Catalase/genética , Catalase/metabolismo , Hipóxia Celular , Sobrevivência Celular , Citocromos c/metabolismo , Regulação da Expressão Gênica , Peróxido de Hidrogênio/farmacologia , Masculino , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Potencial da Membrana Mitocondrial/genética , Mitocôndrias Cardíacas/efeitos dos fármacos , Infarto do Miocárdio/mortalidade , Infarto do Miocárdio/patologia , Infarto do Miocárdio/prevenção & controle , Miócitos Cardíacos/efeitos dos fármacos , Miócitos Cardíacos/patologia , Estresse Oxidativo , Cultura Primária de Células , Carbonilação Proteica/efeitos dos fármacos , Ratos , Ratos Transgênicos , Transdução de Sinais , Análise de Sobrevida
20.
Arch Gynecol Obstet ; 294(3): 607-14, 2016 09.
Artigo em Inglês | MEDLINE | ID: mdl-27040418

RESUMO

OBJECTIVE: To assess surgical morbidity and mortality of maximal effort cytoreductive surgery for disseminated epithelial ovarian cancer (EOC) in a UK tertiary center. METHODS/MATERIALS: A monocentric prospective analysis of surgical morbidity and mortality was performed for all consecutive EOC patients who underwent extensive cytoreductive surgery between 01/2013 and 12/2014. Surgical complexity was assessed by the Mayo clinic surgical complexity score (SCS). Only patients with high SCS ≥5 were included in the analysis. RESULTS: We evaluated 118 stage IIIC/IV patients, with a median age of 63 years (range 19-91); 47.5 % had ascites and 29 % a pleural effusion. Median duration of surgery was 247 min (range 100-540 min). Median surgical complexity score was 10 (range 5-15) consisting of bowel resection (71 %), stoma formation (13.6 %), diaphragmatic stripping/resection (67 %), liver/liver capsule resection (39 %), splenectomy (20 %), resection stomach/lesser sac (26.3 %), pleurectomy (17 %), coeliac trunk/subdiaphragmatic lymphadenectomy (8 %). Total macroscopic tumor clearance rate was 89 %. Major surgical complication rate was 18.6 % (n = 22), with a 28-day and 3-month mortality of 1.7 and 3.4 %, respectively. The anastomotic leak rate was 0.8 %; fistula/bowel perforation 3.4 %; thromboembolism 3.4 % and reoperation 4.2 %. Median intensive care unit and hospital stay were 1.7 (range 0-104) and 8 days (range 4-118), respectively. Four patients (3.3 %) failed to receive chemotherapy within the first 8 postoperative weeks. CONCLUSIONS: Maximal effort cytoreductive surgery for EOC is feasible within a UK setting with acceptable morbidity, low intestinal stoma rates and without clinically relevant delays to postoperative chemotherapy. Careful patient selection, and coordinated multidisciplinary effort appear to be the key for good outcome. Future evaluations should include quality of life analyses.


Assuntos
Procedimentos Cirúrgicos de Citorredução/métodos , Neoplasias Epiteliais e Glandulares/cirurgia , Neoplasias Ovarianas/cirurgia , Adulto , Idoso , Idoso de 80 Anos ou mais , Carcinoma Epitelial do Ovário , Feminino , Humanos , Pessoa de Meia-Idade , Morbidade , Neoplasias Epiteliais e Glandulares/mortalidade , Neoplasias Ovarianas/mortalidade , Estudos Prospectivos , Qualidade de Vida , Adulto Jovem
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