Your browser doesn't support javascript.
Mostrar: 20 | 50 | 100
Resultados 1 - 6 de 6
Filtros adicionais

Intervalo de ano
J Am Heart Assoc ; 8(2): e008968, 2019 01 22.
Artigo em Inglês | MEDLINE | ID: mdl-30638108


Background Myocarditis is an important cause of acute and chronic heart failure. Men with myocarditis have worse recovery and an increased need for transplantation compared with women, but the reason for the sex difference remains unclear. Elevated sera soluble (s) ST2 predicts mortality from acute and chronic heart failure, but has not been studied in myocarditis patients. Methods and Results Adults with a diagnosis of clinically suspected myocarditis (n=303, 78% male) were identified according to the 2013 European Society of Cardiology position statement. Sera sST2 levels were examined by ELISA in humans and mice and correlated with heart function according to sex and age. Sera sST2 levels were higher in healthy men ( P=8×10-6) and men with myocarditis ( P=0.004) compared with women. sST2 levels were elevated in patients with myocarditis and New York Heart Association class III - IV heart failure ( P=0.002), predominantly in men ( P=0.0003). Sera sST2 levels were associated with New York Heart Association class in men with myocarditis who were ≤50 years old ( r=0.231, P=0.0006), but not in women ( r=0.172, P=0.57). Sera sST2 levels were also significantly higher in male mice with myocarditis ( P=0.005) where levels were associated with cardiac inflammation. Gonadectomy with hormone replacement showed that testosterone ( P<0.001), but not estradiol ( P=0.32), increased sera sST2 levels in male mice with myocarditis. Conclusions We show in a well-characterized subset of heart failure patients with clinically suspected and biopsy-confirmed myocarditis that elevated sera sST2 is associated with an increased risk of heart failure based on New York Heart Association class in men ≤50 years old.

Am J Respir Crit Care Med ; 197(1): 127-129, 2018 01 01.
Artigo em Inglês | MEDLINE | ID: mdl-29155600
Am J Physiol Regul Integr Comp Physiol ; 304(4): R267-77, 2013 Feb 15.
Artigo em Inglês | MEDLINE | ID: mdl-23255589


Recent findings indicate that TLR3 polymorphisms increase susceptibility to enteroviral myocarditis and inflammatory dilated cardiomyopathy (iDCM) in patients. TLR3 signaling has been found to inhibit coxsackievirus B3 (CVB3) replication and acute myocarditis in mouse models, but its role in the progression from myocarditis to iDCM has not been previously investigated. In this study we found that TLR3 deficiency increased acute (P = 5.9 × 10(-9)) and chronic (P = 6.0 × 10(-7)) myocarditis compared with WT B6.129, a mouse strain that is resistant to chronic myocarditis and iDCM. Using left ventricular in vivo hemodynamic assessment, we found that TLR3-deficient mice developed progressively worse chronic cardiomyopathy. TLR3 deficiency significantly increased viral replication in the heart during acute myocarditis from day 3 through day 12 after infection, but infectious virus was not detected in the heart during chronic disease. TLR3 deficiency increased cytokines associated with a T helper (Th)2 response, including IL-4 (P = 0.03), IL-10 (P = 0.008), IL-13 (P = 0.002), and TGF-ß(1) (P = 0.005), and induced a shift to an immunoregulatory phenotype in the heart. However, IL-4-deficient mice had improved heart function during acute CVB3 myocarditis by echocardiography and in vivo hemodynamic assessment compared with wild-type mice, indicating that IL-4 impairs cardiac function during myocarditis. IL-4 deficiency increased regulatory T-cell and macrophage populations, including FoxP3(+) T cells (P = 0.005) and Tim-3(+) macrophages (P = 0.004). Thus, TLR3 prevents the progression from myocarditis to iDCM following CVB3 infection by reducing acute viral replication and IL-4 levels in the heart.

Cardiomiopatia Dilatada/virologia , Infecções por Coxsackievirus/imunologia , Enterovirus Humano B/fisiologia , Interleucina-4/imunologia , Miocardite/virologia , Receptor 3 Toll-Like/imunologia , Doença Aguda , Animais , Cardiomiopatia Dilatada/genética , Cardiomiopatia Dilatada/imunologia , Doença Crônica , Infecções por Coxsackievirus/genética , Citocinas/biossíntese , Citocinas/imunologia , Modelos Animais de Doenças , Humanos , Interleucina-4/análise , Macrófagos/imunologia , Macrófagos/virologia , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Miocardite/genética , Miocardite/imunologia , Linfócitos T Reguladores/imunologia , Linfócitos T Reguladores/virologia , Receptor 3 Toll-Like/genética , Replicação Viral/imunologia
Circ Heart Fail ; 5(3): 366-75, 2012 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-22454393


BACKGROUND: IL-33 through its receptor ST2 protects the heart from myocardial infarct and hypertrophy in animal models but, paradoxically, increases autoimmune disease. In this study, we examined the effect of IL-33 or ST2 administration on autoimmune heart disease. METHODS AND RESULTS: We used pressure-volume relationships and isoproterenol challenge to assess the effect of recombinant (r) IL-33 or rST2 (eg, soluble ST2) administration on the development of autoimmune coxsackievirus B3 myocarditis and dilated cardiomyopathy in male BALB/c mice. The rIL-33 treatment significantly increased acute perimyocarditis (P=0.006) and eosinophilia (P=1.3×10(-5)), impaired cardiac function (maximum ventricular power, P=0.0002), and increased ventricular dilation (end-diastolic volume, P=0.01). The rST2 treatment prevented eosinophilia and improved heart function compared with rIL-33 treatment (ejection fraction, P=0.009). Neither treatment altered viral replication. The rIL-33 treatment increased IL-4, IL-33, IL-1ß, and IL-6 levels in the heart during acute myocarditis. To determine whether IL-33 altered cardiac function on its own, we administered rIL-33 to undiseased mice and found that rIL-33 induced eosinophilic pericarditis and adversely affected heart function. We used cytokine knockout mice to determine that this effect was due to IL-33-mediated signaling but not to IL-1ß or IL-6. CONCLUSIONS: We show for the first time to our knowledge that IL-33 induces eosinophilic pericarditis, whereas soluble ST2 prevents eosinophilia and improves systolic function, and that IL-33 independently adversely affects heart function through the IL-33 receptor.

Cardiomiopatia Dilatada/etiologia , Cardiomiopatia Dilatada/prevenção & controle , Eosinofilia/etiologia , Coração/fisiopatologia , Interleucinas/efeitos adversos , Pericardite/etiologia , Receptores de Interleucina/uso terapêutico , Animais , Doenças Autoimunes/etiologia , Doenças Autoimunes/prevenção & controle , Doenças Autoimunes/virologia , Cardiomiopatia Dilatada/metabolismo , Infecções por Coxsackievirus/complicações , Modelos Animais de Doenças , Eosinofilia/prevenção & controle , Eosinofilia/virologia , Coração/efeitos dos fármacos , Proteína 1 Semelhante a Receptor de Interleucina-1 , Interleucina-1beta/deficiência , Interleucina-1beta/genética , Interleucina-1beta/metabolismo , Interleucina-33 , Interleucina-6/deficiência , Interleucina-6/genética , Interleucina-6/metabolismo , Interleucinas/farmacologia , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Camundongos Knockout , Miocárdio/metabolismo , Pericardite/prevenção & controle , Pericardite/virologia , Proteínas Recombinantes/efeitos adversos , Proteínas Recombinantes/farmacologia , Proteínas Recombinantes/uso terapêutico
Am J Physiol Heart Circ Physiol ; 302(8): H1726-36, 2012 Apr 15.
Artigo em Inglês | MEDLINE | ID: mdl-22328081


Myocarditis and dilated cardiomyopathy (DCM) are often caused by viral infections and occur more frequently in men than in women, but the reasons for the sex difference remain unclear. The aim of this study was to assess whether gene changes in the heart during coxsackievirus B3 (CVB3) myocarditis in male and female BALB/c mice predicted worse DCM in males. Although myocarditis (P = 4.2 × 10(-5)) and cardiac dilation (P = 0.008) were worse in males, there was no difference in viral replication in the heart. Fibrotic remodeling genes, such as tissue inhibitor of metalloproteinase (TIMP)-1 and serpin A 3n, were upregulated in males during myocarditis rather than during DCM. Using gonadectomy and testosterone replacement, we showed that testosterone increased cardiac TIMP-1 (P = 0.04), serpin A 3n (P = 0.007), and matrix metalloproteinase (MMP)-8 (P = 0.04) during myocarditis. Testosterone increased IL-1ß levels in the heart (P = 0.02), a cytokine known to regulate cardiovascular remodeling, and IL-1ß in turn increased cardiac serpin A 3n mRNA (P = 0.005). We found that 39 of 118 (33%) genes identified in acute DCM patients were significantly altered in the heart during CVB3 myocarditis in mice, including serpin A 3n (3.3-fold change, P = 0.0001). Recombinant serpin A 3n treatment induced cardiac fibrosis during CVB3 myocarditis (P = 0.0008) while decreasing MMP-3 (P = 0.04) and MMP-9 (P = 0.03) levels in the heart. Thus, serpin A 3n was identified as a gene associated with fibrotic cardiac remodeling and progression to DCM in male myocarditis patients and mice.

Proteínas da Fase Aguda/farmacologia , Infecções por Coxsackievirus/fisiopatologia , Interleucina-1beta/farmacologia , Miocardite/fisiopatologia , Serpinas/farmacologia , Testosterona/farmacologia , Remodelação Ventricular/efeitos dos fármacos , Proteínas da Fase Aguda/metabolismo , Animais , Doenças Autoimunes/fisiopatologia , Citocinas/metabolismo , Progressão da Doença , Feminino , Fibrose , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Análise em Microsséries , Dados de Sequência Molecular , Miocardite/genética , Miocardite/patologia , Miocárdio/metabolismo , Miocárdio/patologia , Orquiectomia , Ovariectomia , Reação em Cadeia da Polimerase em Tempo Real , Proteínas Recombinantes/farmacologia , Serpinas/metabolismo , Caracteres Sexuais , Remodelação Ventricular/fisiologia , Ensaio de Placa Viral
Clin Dev Immunol ; 2012: 129486, 2012.
Artigo em Inglês | MEDLINE | ID: mdl-22013485


Viral infections are able to induce autoimmune inflammation in the heart. Here, we investigated the role of virus-activated Toll-like receptor (TLR)3 and its adaptor TRIF on the development of autoimmune coxsackievirus B3 (CVB3) myocarditis in mice. Although TLR3- or TRIF-deficient mice developed similarly worse acute CVB3 myocarditis and viral replication compared to control mice, disease was significantly worse in TRIF compared to TLR3-deficient mice. Interestingly, TLR3-deficient mice developed an interleukin (IL)-4-dominant T helper (Th)2 response during acute CVB3 myocarditis with elevated markers of alternative activation, while TRIF-deficient mice elevated the Th2-associated cytokine IL-33. Treatment of TLR3-deficient mice with recombinant IL-33 improved heart function indicating that elevated IL-33 in the context of a classic Th2-driven response protects against autoimmune heart disease. We show for the first time that TLR3 versus TRIF deficiency results in different Th2 responses that uniquely influence the progression to chronic myocarditis.

Proteínas Adaptadoras de Transporte Vesicular/metabolismo , Infecções por Coxsackievirus/imunologia , Enterovirus/fisiologia , Miocardite/imunologia , Receptor 3 Toll-Like/metabolismo , Doença Aguda , Proteínas Adaptadoras de Transporte Vesicular/genética , Proteínas Adaptadoras de Transporte Vesicular/imunologia , Animais , Autoimunidade/genética , Doença Crônica , Infecções por Coxsackievirus/complicações , Infecções por Coxsackievirus/genética , Infecções por Coxsackievirus/fisiopatologia , Progressão da Doença , Enterovirus/patogenicidade , Regulação da Expressão Gênica/imunologia , Interleucina-33 , Interleucina-4/genética , Interleucina-4/imunologia , Interleucina-4/metabolismo , Interleucinas/genética , Interleucinas/imunologia , Interleucinas/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Miocardite/etiologia , Miocardite/genética , Miocardite/fisiopatologia , Células Th2/imunologia , Células Th2/virologia , Receptor 3 Toll-Like/genética , Receptor 3 Toll-Like/imunologia , Replicação Viral