RESUMO
Atrial fibrillation (AF) is prevalent in diabetes mellitus (DM); however, the basis for this is unknown. This study investigated AF susceptibility and atrial electrophysiology in type 1 diabetic Akita mice using in vivo intracardiac electrophysiology, high-resolution optical mapping in atrial preparations, and patch clamping in isolated atrial myocytes. qPCR and western blotting were used to assess ion channel expression. Akita mice were highly susceptible to AF in association with increased P-wave duration and slowed atrial conduction velocity. In a second model of type 1 DM, mice treated with streptozotocin (STZ) showed a similar increase in susceptibility to AF. Chronic insulin treatment reduced susceptibility and duration of AF and shortened P-wave duration in Akita mice. Atrial action potential (AP) morphology was altered in Akita mice due to a reduction in upstroke velocity and increases in AP duration. In Akita mice, atrial Na+ current (INa) and repolarizing K+ current (IK) carried by voltage gated K+ (Kv1.5) channels were reduced. The reduction in INa occurred in association with reduced expression of SCN5a and voltage gated Na+ (NaV1.5) channels as well as a shift in INa activation kinetics. Insulin potently and selectively increased INa in Akita mice without affecting IK Chronic insulin treatment increased INa in association with increased expression of NaV1.5. Acute insulin also increased INa, although to a smaller extent, due to enhanced insulin signaling via phosphatidylinositol 3,4,5-triphosphate (PIP3). Our study reveals a critical, selective role for insulin in regulating atrial INa, which impacts susceptibility to AF in type 1 DM.
Assuntos
Fibrilação Atrial/metabolismo , Remodelamento Atrial/fisiologia , Diabetes Mellitus Experimental/complicações , Diabetes Mellitus Tipo 1/complicações , Insulina/metabolismo , Potenciais de Ação/efeitos dos fármacos , Potenciais de Ação/fisiologia , Animais , Fibrilação Atrial/diagnóstico , Fibrilação Atrial/etiologia , Fibrilação Atrial/fisiopatologia , Remodelamento Atrial/imunologia , Células Cultivadas , Diabetes Mellitus Experimental/induzido quimicamente , Diabetes Mellitus Experimental/metabolismo , Diabetes Mellitus Tipo 1/genética , Diabetes Mellitus Tipo 1/metabolismo , Modelos Animais de Doenças , Ecocardiografia , Eletrocardiografia , Átrios do Coração/citologia , Átrios do Coração/metabolismo , Átrios do Coração/patologia , Átrios do Coração/fisiopatologia , Humanos , Insulina/administração & dosagem , Insulina/genética , Canal de Potássio Kv1.5/metabolismo , Masculino , Camundongos , Camundongos Transgênicos , Miócitos Cardíacos/efeitos dos fármacos , Miócitos Cardíacos/patologia , Miócitos Cardíacos/fisiologia , Canal de Sódio Disparado por Voltagem NAV1.5/metabolismo , Técnicas de Patch-Clamp , Potássio/metabolismo , Cultura Primária de Células , Sódio/metabolismo , Estreptozocina/toxicidadeRESUMO
Background Systemic inflammation is a strong predictor of atrial fibrillation. A key role for electrical remodeling is increasingly recognized, and experimental data suggest that inflammatory cytokines can directly affect connexins resulting in gap-junction dysfunction. We hypothesized that systemic inflammation, regardless of its origin, promotes atrial electric remodeling in vivo, as a result of cytokine-mediated changes in connexin expression. Methods and Results Fifty-four patients with different inflammatory diseases and elevated C-reactive protein were prospectively enrolled, and electrocardiographic P-wave dispersion indices, cytokine levels (interleukin-6, tumor necrosis factor-α, interleukin-1, interleukin-10), and connexin expression (connexin 40, connexin 43) were measured during active disease and after reducing C-reactive protein by >75%. Moreover, peripheral blood mononuclear cells and atrial tissue specimens from an additional sample of 12 patients undergoing cardiac surgery were evaluated for atrial and circulating mRNA levels of connexins. Finally, in vitro effects of interleukin-6 on connexin expression were studied in HL-1 mouse atrial myocytes. In patients with active inflammatory diseases, P-wave dispersion indices were increased but rapidly decreased within days when C-reactive protein normalizes and interleukin-6 levels decline. In inflammatory disease patients, both P-wave dispersion indices and interleukin-6 changes were inversely associated with circulating connexin levels, and a positive correlation between connexin expression in peripheral blood mononuclear cells and atrial tissue was demonstrated. Moreover, interleukin-6 significantly reduced connexin expression in HL-1 cells. Conclusions Our data suggest that regardless of specific etiology and organ localization, systemic inflammation, via interleukin-6 elevation, rapidly induces atrial electrical remodeling by down-regulating cardiac connexins. Although transient, these changes may significantly increase the risk for atrial fibrillation and related complications during active inflammatory processes.
Assuntos
Remodelamento Atrial/imunologia , Conexinas/genética , Inflamação/imunologia , Interleucina-6/imunologia , Miócitos Cardíacos/metabolismo , Adulto , Idoso , Idoso de 80 Anos ou mais , Animais , Antibacterianos/uso terapêutico , Anti-Inflamatórios/uso terapêutico , Artrite Reumatoide/tratamento farmacológico , Artrite Reumatoide/imunologia , Remodelamento Atrial/genética , Proteína C-Reativa/imunologia , Procedimentos Cirúrgicos Cardíacos , Conexina 43/efeitos dos fármacos , Conexina 43/genética , Conexina 43/metabolismo , Conexinas/efeitos dos fármacos , Conexinas/metabolismo , Eletrocardiografia , Feminino , Regulação da Expressão Gênica , Átrios do Coração/citologia , Humanos , Infecções/tratamento farmacológico , Infecções/imunologia , Inflamação/tratamento farmacológico , Inflamação/metabolismo , Inflamação/fisiopatologia , Interleucina-1/imunologia , Interleucina-10/imunologia , Interleucina-6/farmacologia , Masculino , Camundongos , Pessoa de Meia-Idade , RNA Mensageiro/metabolismo , Fator de Necrose Tumoral alfa/imunologia , Adulto Jovem , Proteína alfa-5 de Junções ComunicantesRESUMO
Cardiac dysfunction with progressive inflammation and fibrosis is a hallmark of Chagas disease caused by persistent Trypanosoma cruzi infection. Osteopontin (OPN) is a pro-inflammatory cytokine that orchestrates mechanisms controlling cell recruitment and cardiac architecture. Our main goal was to study the role of endogenous OPN as a modulator of myocardial CCL5 chemokine and MMP-2 metalloproteinase, and its pathological impact in a murine model of Chagas heart disease. Wild-type (WT) and OPN-deficient (spp1 -/-) mice were parasite-infected (Brazil strain) for 100days. Both groups developed chronic myocarditis with similar parasite burden and survival rates. However, spp1 -/- infection showed lower heart-to-body ratio (P<0.01) as well as reduced inflammatory pathology (P<0.05), CCL5 expression (P<0.05), myocyte size (P<0.05) and fibrosis (P<0.01) in cardiac tissues. Intense OPN labeling was observed in inflammatory cells recruited to infected heart (P<0.05). Plasma concentration of MMP-2 was higher (P<0.05) in infected WT than in spp1 -/- mice. Coincidently, specific immunostaining revealed increased gelatinase expression (P<0.01) and activity (P<0.05) in the inflamed hearts from T. cruzi WT mice, but not in their spp1 -/- littermates. CCL5 and MMP-2 induction occurred preferentially (P<0.01) in WT heart-invading CD8+ T cells and was mediated via phospho-JNK MAPK signaling. Heart levels of OPN, CCL5 and MMP-2 correlated (P<0.01) with collagen accumulation in the infected WT group only. Endogenous OPN emerges as a key player in the pathogenesis of chronic Chagas heart disease, through the upregulation of myocardial CCL5/MMP-2 expression and activities resulting in pro-inflammatory and pro-hypertrophic events, cardiac remodeling and interstitial fibrosis.
Assuntos
Remodelamento Atrial , Cardiomiopatia Chagásica , Quimiocina CCL5/metabolismo , Metaloproteinase 2 da Matriz/metabolismo , Miocardite , Osteopontina/fisiologia , Remodelação Ventricular , Animais , Remodelamento Atrial/genética , Remodelamento Atrial/imunologia , Células Cultivadas , Cardiomiopatia Chagásica/genética , Cardiomiopatia Chagásica/imunologia , Cardiomiopatia Chagásica/metabolismo , Cardiomiopatia Chagásica/patologia , Modelos Animais de Doenças , Fibrose Endomiocárdica/genética , Fibrose Endomiocárdica/metabolismo , Fibrose Endomiocárdica/patologia , Inflamação/genética , Inflamação/metabolismo , Inflamação/patologia , Masculino , Camundongos , Camundongos Endogâmicos C3H , Camundongos Endogâmicos C57BL , Camundongos Knockout , Miocardite/genética , Miocardite/imunologia , Miocardite/metabolismo , Miocardite/patologia , Miocárdio/imunologia , Miocárdio/metabolismo , Miocárdio/patologia , Osteopontina/genética , Remodelação Ventricular/genética , Remodelação Ventricular/imunologiaRESUMO
PURPOSE OF REVIEW: Atrial fibrillation is the most common sustained arrhythmia, but its mechanisms are poorly understood. In particular, little is known about the factors that contribute to the establishment of persistent or permanent atrial fibrillation. This review addresses possible common signaling pathways that might promote both structural and electrical remodeling of the atria, thus contributing to atrial fibrillation perpetuation. RECENT FINDINGS: Sustained atrial fibrillation may trigger an inflammatory response leading to activation of myofibroblasts and to the release of cytokines such as transforming growth factor-ß and platelet-derived growth factor, as well as profibrotic proteins such as galectin-3. Activation of signaling cascades involving such proteins is critical for the development of fibrosis and may also lead to ion channel dysfunction, which, along with myocyte apoptosis and extracellular matrix generation and turnover, likely contributes to both electrical and structural remodeling and predisposes to atrial fibrillation. SUMMARY: Identifying upstream strategies targeting molecular pathways that are common to fibrosis and electrical remodeling leading to atrial fibrillation perpetuation is highly desirable. This would facilitate finding new target genes with pleiotropic effects on the expression of ion channel proteins in myocytes and profibrotic molecules in nonmyocyte cells that are important for pathologic remodeling, which could become an important goal in persistent atrial fibrillation therapy.