RESUMO
Atrial fibrillation (AF) is the most prevalent cardiac arrhythmia seen in clinical settings, which has been associated with substantial rates of mortality and morbidity. However, clinically available drugs have limited efficacy and adverse effects. We aimed to investigate the mechanisms of action of andrographolide (Andr) with respect to AF. We used network pharmacology approaches to investigate the possible therapeutic effect of Andr. To define the role of Andr in AF, HL-1 cells were pro-treated with Andr for 1 h before rapid electronic stimulation (RES) and rabbits were pro-treated for 1 d before rapid atrial pacing (RAP). Apoptosis, myofibril degradation, oxidative stress, and inflammation were determined. RNA sequencing (RNA-seq) was performed to investigate the relevant mechanism. Andr treatment attenuated RAP-induced atrial electrophysiological changes, inflammation, oxidative damage, and apoptosis both in vivo and in vitro. RNA-seq indicated that oxidative phosphorylation played an important role. Transmission electron microscopy and adenosine triphosphate (ATP) content assay respectively validated the morphological and functional changes in mitochondria. The translocation of nuclear factor erythroid 2-related factor 2 (Nrf2) to the nucleus and the molecular docking suggested that Andr might exert a therapeutic effect by influencing the Keap1-Nrf2 complex. In conclusions, this study revealed that Andr is a potential preventive therapeutic drug toward AF via activating the translocation of Nrf2 to the nucleus and the upregulation of heme oxygenase-1 (HO-1) to promote mitochondrial bioenergetics.
Assuntos
Fibrilação Atrial , Animais , Coelhos , Fibrilação Atrial/tratamento farmacológico , Fibrilação Atrial/prevenção & controle , Fibrilação Atrial/metabolismo , Proteína 1 Associada a ECH Semelhante a Kelch/metabolismo , Transdução de Sinais , Fator 2 Relacionado a NF-E2/metabolismo , Fator 2 Relacionado a NF-E2/farmacologia , Simulação de Acoplamento Molecular , Estresse Oxidativo , Metabolismo Energético , Mitocôndrias/metabolismo , Inflamação/tratamento farmacológico , Inflamação/metabolismo , Heme Oxigenase-1RESUMO
The voltage-gated K+ channel plays a key role in atrial excitability, conducting the ultra-rapid rectifier K+ current (IKur) and contributing to the repolarization of the atrial action potential. In this study, we examine its regulation by hydrogen sulfide (H2S) in HL-1 cardiomyocytes and in HEK293 cells expressing human Kv1.5. Pacing induced remodeling resulted in shorting action potential duration, enhanced both Kv1.5 channel and H2S producing enzymes protein expression in HL-1 cardiomyocytes. H2S supplementation reduced these remodeling changes and restored action potential duration through inhibition of Kv1.5 channel. H2S also inhibited recombinant hKv1.5, lead to nitric oxide (NO) mediated S-nitrosylation and activated endothelial nitric oxide synthase (eNOS) by increased phosphorylation of Ser1177, prevention of NO formation precluded these effects. Regulation of Ikur by H2S has important cardiovascular implications and represents a novel and potential therapeutic target.
Assuntos
Fibrilação Atrial , Sulfeto de Hidrogênio , Canais de Potássio de Abertura Dependente da Tensão da Membrana , Humanos , Sulfeto de Hidrogênio/farmacologia , Sulfeto de Hidrogênio/metabolismo , Fibrilação Atrial/metabolismo , Células HEK293 , Canal de Potássio Kv1.5/genética , Canal de Potássio Kv1.5/metabolismo , Miócitos Cardíacos/metabolismoRESUMO
Melatonin has been proven to have antiarrhythmic potential; however, several studies have recently challenged this view. Herein, using a mouse model of obesity-induced atrial fibrillation (AF), we tentatively explored whether exogenous melatonin supplementation could increase AF susceptibility in the context of obesity. We observed that an 8-week drinking administration of melatonin (60 µg/ml in water) induced a greater susceptibility to AF in obese mice, although obesity-induced structural remodeling was alleviated. An investigation of systemic insulin sensitivity showed that melatonin treatment improved insulin sensitivity in obese mice, whereas it inhibited glucose-stimulated insulin secretion. Notably, melatonin treatment inhibited protein kinase B (Akt) signaling in the atria of obese mice and palmitate-treated neonatal rat cardiomyocytes, thereby providing an AF substrate. Melatonin increased lipid stress in obesity, as evidenced by elevated lipid accumulation and lipolysis-related gene expression, thus contributing to the impairment in atrial Akt signaling. Taken together, our results demonstrated that melatonin could increase AF susceptibility in obesity, probably due to increased lipid stress and resultant impairment of atrial Akt signaling. Our findings suggest that special precautions should be taken when administering melatonin to obese subjects.
Assuntos
Fibrilação Atrial , Resistência à Insulina , Melatonina , Camundongos , Ratos , Animais , Fibrilação Atrial/genética , Fibrilação Atrial/metabolismo , Melatonina/farmacologia , Proteínas Proto-Oncogênicas c-akt , Camundongos Obesos , Obesidade/metabolismo , LipídeosRESUMO
Atrial fibrillation (AF) is the most prevalent cardiac arrhythmia seen in clinical settings, which has been associated with substantial rates of mortality and morbidity. However, clinically available drugs have limited efficacy and adverse effects. We aimed to investigate the mechanisms of action of andrographolide (Andr) with respect to AF. We used network pharmacology approaches to investigate the possible therapeutic effect of Andr. To define the role of Andr in AF, HL-1 cells were pro-treated with Andr for 1 h before rapid electronic stimulation (RES) and rabbits were pro-treated for 1 d before rapid atrial pacing (RAP). Apoptosis, myofibril degradation, oxidative stress, and inflammation were determined. RNA sequencing (RNA-seq) was performed to investigate the relevant mechanism. Andr treatment attenuated RAP-induced atrial electrophysiological changes, inflammation, oxidative damage, and apoptosis both in vivo and in vitro. RNA-seq indicated that oxidative phosphorylation played an important role. Transmission electron microscopy and adenosine triphosphate (ATP) content assay respectively validated the morphological and functional changes in mitochondria. The translocation of nuclear factor erythroid 2-related factor 2 (Nrf2) to the nucleus and the molecular docking suggested that Andr might exert a therapeutic effect by influencing the Keap1-Nrf2 complex. In conclusions, this study revealed that Andr is a potential preventive therapeutic drug toward AF via activating the translocation of Nrf2 to the nucleus and the upregulation of heme oxygenase-1 (HO-1) to promote mitochondrial bioenergetics.
Assuntos
Animais , Coelhos , Fibrilação Atrial/metabolismo , Proteína 1 Associada a ECH Semelhante a Kelch/metabolismo , Transdução de Sinais , Fator 2 Relacionado a NF-E2/farmacologia , Simulação de Acoplamento Molecular , Estresse Oxidativo , Metabolismo Energético , Mitocôndrias/metabolismo , Inflamação/metabolismo , Heme Oxigenase-1RESUMO
BACKGROUND: Dietary consumption of ω-3 fatty acids is correlated with a reduced incidence of cardiovascular events. Here, we investigated the effect of dietary ω-3 fatty acids on atrial fibrillation (AF) vulnerability in a canine model of AF and explored the related mechanisms. METHODS: Twenty four male beagle dogs (weight, 8-10 kg) were randomly divided into four groups: (a) sham-operated group (normal chow); (b) AF+FO [AF and normal chow supplemented with fish oil (FO): 0.6 g n-3 polyunsaturated fatty acids (ω-3 PUFA) /kg/day]; (c) AF group (normal chow); (d) sham-operated FO group (chow supplemented with FO: 0.6 g ω-3 PUFA/kg/day). AF was induced by rapid atrial pacing (RAP: 400 bpm for 4 weeks). Daily oral administration of FO was initiated 1 week before surgery and continued for 4 weeks post operation. RESULTS: Atrial electric remodeling was significantly attenuated and AF vulnerability were significantly reduced in AF+FO group compared to AF group. Endoplasmic reticulum (ER) stress-related protein expression levels of glucose-regulated protein78, C/EBP homologous protein, cleaved-Caspase12, and phosphorylation of protein kinase R-like ER kinase as well as inflammatory cytokines interleukin-1ß, interleukin-6, tumor necrosis factor-α in left atrium (LA) were significantly downregulated in AF+FO group than in AF group (all p<0.05). In addition, Masson staining revealed lower extent of LA interstitial fibrosis in AF+FO group than in AF group (p<0.01). Myocardial apoptosis was also significantly reduced in AF+FO group than in AF group (p<0.05). CONCLUSIONS: Dietary ω-3 fatty acids could significantly reduce RAP-induced AF vulnerability, possibly via attenuating myocardial ER stress, inflammation, and apoptosis in this canine model of AF.
Assuntos
Fibrilação Atrial , Ácidos Graxos Ômega-3 , Animais , Cães , Masculino , Fibrilação Atrial/etiologia , Fibrilação Atrial/metabolismo , Fibrilação Atrial/prevenção & controle , Modelos Animais de Doenças , Estresse do Retículo Endoplasmático , Ácidos Graxos Ômega-3/farmacologia , Inflamação/complicaçõesRESUMO
Background Recent clinical trials have demonstrated the possible pleiotropic effects of SGLT2 (sodium-glucose cotransporter 2) inhibitors in clinical cardiovascular diseases. Atrial electrical and structural remodeling is important as an atrial fibrillation (AF) substrate. Methods and Results The present study assessed the effect of canagliflozin (CAN), an SGLT2 inhibitor, on atrial remodeling in a canine AF model. The study included 12 beagle dogs, with 10 receiving continuous rapid atrial pacing and 2 acting as the nonpacing group. The 10 dogs that received continuous rapid atrial pacing for 3 weeks were subdivided as follows: pacing control group (n=5) and pacing+CAN (3 mg/kg per day) group (n=5). The atrial effective refractory period, conduction velocity, and AF inducibility were evaluated weekly through atrial epicardial wires. After the protocol, atrial tissues were sampled for histological examination. The degree of reactive oxygen species expression was evaluated by dihydroethidium staining. The atrial effective refractory period reduction was smaller (P=0.06) and the degree of conduction velocity decrease was smaller in the pacing+CAN group compared with the pacing control group (P=0.009). The AF inducibility gradually increased in the pacing control group, but such an increase was suppressed in the pacing+CAN group (P=0.011). The pacing control group exhibited interstitial fibrosis and enhanced oxidative stress, which were suppressed in the pacing+CAN group. Conclusions CAN and possibly other SGLT2 inhibitors might be useful for preventing AF and suppressing the promotion of atrial remodeling as an AF substrate.
Assuntos
Fibrilação Atrial , Remodelamento Atrial/efeitos dos fármacos , Canagliflozina/farmacologia , Átrios do Coração , Estresse Oxidativo/efeitos dos fármacos , Transportador 2 de Glucose-Sódio/metabolismo , Animais , Fibrilação Atrial/metabolismo , Fibrilação Atrial/patologia , Fibrilação Atrial/fisiopatologia , Cães , Técnicas Eletrofisiológicas Cardíacas/métodos , Átrios do Coração/patologia , Átrios do Coração/fisiopatologia , Sistema de Condução Cardíaco/metabolismo , Sistema de Condução Cardíaco/fisiopatologia , Espécies Reativas de Oxigênio/análise , Inibidores do Transportador 2 de Sódio-Glicose/farmacologia , Resultado do TratamentoRESUMO
Point mutation in alcohol dehydrogenase 2 (ALDH2), ALDH2*2 results in decreased catalytic enzyme activity and has been found to be associated with different human pathologies. Whether ALDH2*2 would induce cardiac remodeling and increase the attack of atrial fibrillation (AF) remains poorly understood. The present study evaluated the effect of ALDH2*2 mutation on AF susceptibility and unravelled the underlying mechanisms using a multi-omics approach including whole-genome gene expression and proteomics analysis. The in-vivo electrophysiological study showed an increase in the incidence and reduction in the threshold of AF for the mutant mice heterozygous for ALDH2*2 as compared to the wild type littermates. The microarray analysis revealed a reduction in the retinoic acid signals which was accompanied by a downstream reduction in the expression of voltage-gated Na+ channels (SCN5A). The treatment of an antagonist for retinoic acid receptor resulted in a decrease in SCN5A transcript levels. The integrated analysis of the transcriptome and proteome data showed a dysregulation of fatty acid ß-oxidation, adenosine triphosphate synthesis via electron transport chain, and activated oxidative responses in the mitochondria. Oral administration of Coenzyme Q10, an essential co-factor known to meliorate mitochondrial oxidative stress and preserve bioenergetics, conferred a protection against AF attack in the mutant ALDH2*2 mice. The multi-omics approach showed the unique pathophysiology mechanisms of concurrent dysregulated SCN5A channel and mitochondrial bioenergetics in AF. This inspired the development of a personalized therapeutic agent, Coenzyme Q10, to protect against AF attack in humans characterized by ALDH2*2 genotype.
Assuntos
Aldeído-Desidrogenase Mitocondrial/fisiologia , Fibrilação Atrial/patologia , Metabolismo Energético , Mitocôndrias/patologia , Mutação , Canais de Sódio/metabolismo , Transcriptoma , Animais , Fibrilação Atrial/etiologia , Fibrilação Atrial/metabolismo , Redes Reguladoras de Genes , Masculino , Camundongos , Mitocôndrias/metabolismo , Transdução de Sinais , Canais de Sódio/genéticaRESUMO
Pharmaco-therapeutic strategies of atrial fibrillation (AF) are moderately effective and do not prevent AF onset and progression. Therefore, there is an urgent need to develop novel therapies. Previous studies revealed heat shock protein (HSP)-inducing compounds to mitigate AF onset and progression. Such an HSP inducing compound is L-glutamine. In the current study we investigate the effect of L-glutamine supplementation on serum HSP27 and HSP70 levels and metabolite levels in patients with AF patients (n = 21). Hereto, HSP27 and HSP70 levels were determined by ELISAs and metabolites with LC-mass spectrometry. HSP27 levels significantly decreased after 3-months of L-glutamine supplementation [540.39 (250.97-1315.63) to 380.69 (185.68-915.03), p = 0.004] and normalized to baseline levels after 6-months of L-glutamine supplementation [634.96 (139.57-3103.61), p < 0.001]. For HSP70, levels decreased after 3-months of L-glutamine supplementation [548.86 (31.50-1564.51) to 353.65 (110.58-752.50), p = 0.045] and remained low after 6-months of L-glutamine supplementation [309.30 (118.29-1744.19), p = 0.517]. Patients with high HSP27 levels at baseline showed normalization of several metabolites related to the carbohydrates, nucleotides, amino acids, vitamins and cofactors metabolic pathways after 3-months L-glutamine supplementation. In conclusion, L-glutamine supplementation reduces the serum levels of HSP27 and HSP70 within 3-months and normalizes metabolite levels. This knowledge may fuel future clinical studies on L-glutamine to improve cardioprotective effects that may attenuate AF episodes.
Assuntos
Fibrilação Atrial/metabolismo , Suplementos Nutricionais , Glutamina/farmacologia , Proteínas de Choque Térmico/metabolismo , Metaboloma , Metabolismo Energético/efeitos dos fármacos , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , FenótipoRESUMO
Background The tandem of P domains in a weak inward rectifying K+ channel (TWIK)-related acid-sensitive K+ channel (TASK-1; hK2P3.1) two-pore-domain potassium channel was recently shown to regulate the atrial action potential duration. In the human heart, TASK-1 channels are specifically expressed in the atria. Furthermore, upregulation of atrial TASK-1 currents was described in patients suffering from atrial fibrillation (AF). We therefore hypothesized that TASK-1 channels represent an ideal target for antiarrhythmic therapy of AF. In the present study, we tested the antiarrhythmic effects of the high-affinity TASK-1 inhibitor A293 on cardioversion in a porcine model of paroxysmal AF. Methods and Results Heterologously expressed human and porcine TASK-1 channels are blocked by A293 to a similar extent. Patch clamp measurements from isolated human and porcine atrial cardiomyocytes showed comparable TASK-1 currents. Computational modeling was used to investigate the conditions under which A293 would be antiarrhythmic. German landrace pigs underwent electrophysiological studies under general anesthesia. Paroxysmal AF was induced by right atrial burst stimulation. After induction of AF episodes, intravenous administration of A293 restored sinus rhythm within cardioversion times of 177±63 seconds. Intravenous administration of A293 resulted in significant prolongation of the atrial effective refractory period, measured at cycle lengths of 300, 400 and 500 ms, whereas the surface ECG parameters and the ventricular effective refractory period lengths remained unchanged. Conclusions Pharmacological inhibition of atrial TASK-1 currents exerts antiarrhythmic effects in vivo as well as in silico, resulting in acute cardioversion of paroxysmal AF. Taken together, these experiments indicate the therapeutic potential of A293 for AF treatment.
Assuntos
Antiarrítmicos/farmacologia , Fibrilação Atrial/tratamento farmacológico , Frequência Cardíaca/efeitos dos fármacos , Miócitos Cardíacos/efeitos dos fármacos , Proteínas do Tecido Nervoso/antagonistas & inibidores , Bloqueadores dos Canais de Potássio/farmacologia , Canais de Potássio de Domínios Poros em Tandem/antagonistas & inibidores , Sulfonamidas/farmacologia , ortoaminobenzoatos/farmacologia , Animais , Fibrilação Atrial/diagnóstico , Fibrilação Atrial/metabolismo , Fibrilação Atrial/fisiopatologia , Modelos Animais de Doenças , Eletrocardiografia , Técnicas Eletrofisiológicas Cardíacas , Feminino , Humanos , Masculino , Potenciais da Membrana/efeitos dos fármacos , Simulação de Acoplamento Molecular , Miócitos Cardíacos/metabolismo , Proteínas do Tecido Nervoso/genética , Proteínas do Tecido Nervoso/metabolismo , Canais de Potássio de Domínios Poros em Tandem/genética , Canais de Potássio de Domínios Poros em Tandem/metabolismo , Estudo de Prova de Conceito , Período Refratário Eletrofisiológico/efeitos dos fármacos , Sus scrofa , Fatores de Tempo , Xenopus laevisRESUMO
Mitochondrial dysfunction and oxidative stress play an important role in the pathogenesis of both atrial fibrillation (AF) and diabetes mellitus (DM). Wenxin Keli (WXKL), an antiarrhythmic traditional Chinese medicine, has been shown to prevent cardiac arrhythmias through modulation of cardiac ion channels. This study tested the hypothesis that WXKL can improve atrial remodeling in diabetic rats by restoring mitochondrial function. Primary atrial fibroblasts of neonatal SD rats were divided into four groups: control, hydrogen peroxide (H2O2), H2O2+WXKL 1 g/L, and H2O2+WXKL 3 g/L groups. Intracellular mitochondrial membrane potential (MMP), reactive oxygen species (ROS), and mitochondrial oxygen consumption were measured. SD male rats were randomly divided into three groups: control, DM, and DM+WXKL groups. Rats in the DM+WXKL group were treated with daily gavage of WXKL at 3 g/kg. After eight weeks, echocardiography, hemodynamic examination, histology, electrophysiology study, mitochondrial respiratory function, and western blots were assessed. H2O2 treatment led to increased ROS and decreased intracellular MMP and mitochondrial oxygen consumption in primary atrial fibroblasts. WXKL improved the above changes. DM rats showed increased atrial fibrosis, greater left atrial diameter, lower atrial conduction velocity, higher conduction heterogeneity, higher AF inducibility, and lower mitochondrial protein expression, and all these abnormal changes except for left atrial diameter were improved in the DM+WXKL group. WXKL improves atrial remodeling by regulating mitochondrial function and homeostasis and reducing mitochondrial ROS in diabetic rats.
Assuntos
Antiarrítmicos/uso terapêutico , Fibrilação Atrial/tratamento farmacológico , Remodelamento Atrial/efeitos dos fármacos , Diabetes Mellitus Experimental/complicações , Medicamentos de Ervas Chinesas/uso terapêutico , Mitocôndrias Cardíacas/efeitos dos fármacos , Estresse Oxidativo/efeitos dos fármacos , Animais , Fibrilação Atrial/etiologia , Fibrilação Atrial/metabolismo , Fibrilação Atrial/fisiopatologia , Medicamentos de Ervas Chinesas/farmacologia , Ecocardiografia , Fibroblastos/efeitos dos fármacos , Fibroblastos/metabolismo , Átrios do Coração/citologia , Átrios do Coração/efeitos dos fármacos , Átrios do Coração/metabolismo , Átrios do Coração/fisiopatologia , Peróxido de Hidrogênio/toxicidade , Masculino , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Mitocôndrias Cardíacas/metabolismo , Mitocôndrias Cardíacas/patologia , Ratos , Ratos Sprague-Dawley , Espécies Reativas de Oxigênio/metabolismoAssuntos
Antagonistas Adrenérgicos beta/uso terapêutico , Antiarrítmicos/uso terapêutico , Anticoagulantes/uso terapêutico , Fibrilação Atrial/tratamento farmacológico , Bloqueadores dos Canais de Cálcio/uso terapêutico , Antagonistas Adrenérgicos beta/farmacocinética , Animais , Antiarrítmicos/farmacocinética , Anticoagulantes/farmacocinética , Fibrilação Atrial/epidemiologia , Fibrilação Atrial/metabolismo , Bloqueadores dos Canais de Cálcio/farmacocinética , Ensaios Clínicos como Assunto/métodos , Dabigatrana/farmacocinética , Dabigatrana/uso terapêutico , Humanos , Rivaroxabana/farmacocinética , Rivaroxabana/uso terapêuticoRESUMO
OBJECTIVE: Both atrial fibrillation (AF) and heart failure (HF) are increasingly prevalent and related to high hospitalization rate and mortality. AF is a cause as well as a consequence of HF, with complicated interactions resulting in impairment of cardiac systolic and diastolic function. Conversely, the complex structural and neurohormonal alterations in HF contribute to the occurrence and development of AF. However, the molecular mechanism remains unclear. This study aims to explore the effect of Exchange-protein activated by cAMP 1 (EPAC1) on AF in isoproterenol (ISO)-induced HF and the potential molecular mechanism. MATERIALS AND METHODS: Mice and cultured isolated adult cardiomyocytes were treated with ISO and or not EPAC1 inhibitor CE3F4. Programmed electrical stimulation (PES) was performed to induce AF. EPAC1 expression was determined by Reverse Transcriptase-Polymerase Chain Reaction (RT-PCR) and Western blot. Cellular electrophysiology was examined by whole cell patch clamp. RESULTS: Both mRNA and protein levels of EPAC1 were upregulated in HF mice. ISO increased the AF susceptibility, and the negative effect was deteriorated by CE3F4. ISO mediated high AF susceptibility of HF via prolonging action potential and exciting L-type calcium channel (LTCC). These could also be reversed by CE3F4 treatment. CONCLUSIONS: EPAC1 increased the AF susceptibility in ISO-induced HF mouse model via alternating LTCC.
Assuntos
Fibrilação Atrial/diagnóstico , Canais de Cálcio Tipo L/metabolismo , Fatores de Troca do Nucleotídeo Guanina/genética , Fatores de Troca do Nucleotídeo Guanina/metabolismo , Insuficiência Cardíaca/complicações , Isoproterenol/efeitos adversos , Animais , Fibrilação Atrial/etiologia , Fibrilação Atrial/genética , Fibrilação Atrial/metabolismo , Células Cultivadas , Modelos Animais de Doenças , Técnicas Eletrofisiológicas Cardíacas , Insuficiência Cardíaca/induzido quimicamente , Insuficiência Cardíaca/genética , Insuficiência Cardíaca/metabolismo , Masculino , Camundongos , Miócitos Cardíacos/citologia , Miócitos Cardíacos/efeitos dos fármacos , Miócitos Cardíacos/metabolismo , Quinolinas/farmacologia , Regulação para Cima/efeitos dos fármacosRESUMO
AIM: We aimed to study the effect of allocryptopine (All) on the late sodium current (INa,Late) of atrial myocytes in spontaneously hypertensive rats (SHR). METHODS: The enzyme digestion method was used to separate single atrial myocytes from SHR and Wistar-Kyoto (WKY) rats. INa,Late was recorded using the patch-clamp technique, and the effect of All was evaluated on the current. RESULTS: Compared with WKY rat cells, an increase in the INa,Late current in SHR myocytes was found. After treatment with 30 µM All, the current densities were markedly decreased; the ratio of INa,Late/INa,peak of SHR was reduced by 30 µM All. All reduced INa,Late by alleviating inactivation of the channel and increasing the window current of the sodium channel. Furthermore, INa,Late densities of three SCN5A mutations declined substantially with 30 µM All in a concentration-dependent manner. CONCLUSIONS: The results clearly show that an increase in INa,Late in SHR atrial myocytes was inhibited by All derived from Chinese herbal medicine.
Assuntos
Antiarrítmicos/farmacologia , Fibrilação Atrial/prevenção & controle , Alcaloides de Berberina/farmacologia , Átrios do Coração/efeitos dos fármacos , Hipertensão/tratamento farmacológico , Miócitos Cardíacos/efeitos dos fármacos , Canal de Sódio Disparado por Voltagem NAV1.5/efeitos dos fármacos , Sódio/metabolismo , Potenciais de Ação , Animais , Fibrilação Atrial/etiologia , Fibrilação Atrial/metabolismo , Fibrilação Atrial/fisiopatologia , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Células HEK293 , Átrios do Coração/metabolismo , Frequência Cardíaca , Humanos , Hipertensão/complicações , Hipertensão/metabolismo , Hipertensão/fisiopatologia , Masculino , Mutação , Miócitos Cardíacos/metabolismo , Canal de Sódio Disparado por Voltagem NAV1.5/genética , Canal de Sódio Disparado por Voltagem NAV1.5/metabolismo , Ratos Endogâmicos SHR , Ratos Endogâmicos WKY , Fatores de TempoRESUMO
BACKGROUND: The heat shock protein (HSP) inducer, geranylgeranylacetone (GGA), was previously found to protect against atrial fibrillation (AF) remodeling in experimental model systems. Clinical application of GGA in AF is limited, due to low systemic concentrations owing to the hydrophobic character of GGA. OBJECTIVES: To identify novel HSP-inducing compounds, with improved physicochemical properties, that prevent contractile dysfunction in experimental model systems for AF. METHODS: Eighty-one GGA-derivatives were synthesized and explored for their HSP-inducing properties by assessment of HSP expression in HL-1 cardiomyocytes pretreated with or without a mild heat shock (HS), followed by incubation with 10 µM GGA or GGA-derivative. Subsequently, the most potent HSP-inducers were tested for preservation of calcium transient (CaT) amplitudes or heart wall contraction in pretreated tachypaced HL-1 cardiomyocytes (with or without HSPB1 siRNA) and Drosophilas, respectively. Finally, CaT recovery in tachypaced HL-1 cardiomyocytes posttreated with GGA or protective GGA-derivatives was determined. RESULTS: Thirty GGA-derivatives significantly induced HSPA1A expression after HS, and seven showed exceeding HSPA1A expression compared to GGA. GGA and nine GGA-derivatives protected significantly from tachypacing (TP)-induced CaT loss, which was abrogated by HSPB1 suppression. GGA and four potent GGA-derivatives protected against heart wall dysfunction after TP compared to non-paced control Drosophilas. Of these compounds, GGA and three GGA-derivatives induced a significant restoration from CaT loss after TP of HL-1 cardiomyocytes. CONCLUSION: We identified novel GGA-derivatives with improved physicochemical properties compared to GGA. GGA-derivatives, particularly GGA*-59, boost HSP expression resulting in prevention and restoration from TP-induced remodeling, substantiating their role as novel therapeutics in clinical AF.
Assuntos
Fibrilação Atrial/tratamento farmacológico , Diterpenos/farmacologia , Proteínas de Choque Térmico/metabolismo , Miócitos Cardíacos/efeitos dos fármacos , Animais , Fibrilação Atrial/metabolismo , Diterpenos/síntese química , Diterpenos/química , Relação Dose-Resposta a Droga , Drosophila , Avaliação Pré-Clínica de Medicamentos , Estrutura Molecular , Miócitos Cardíacos/metabolismo , Relação Estrutura-AtividadeRESUMO
BACKGROUND: Bradyarrhythmia is a common clinical manifestation. Although the majority of cases are acquired, genetic analysis of families with bradyarrhythmia has identified a growing number of causative gene mutations. Because the only ultimate treatment for symptomatic bradyarrhythmia has been invasive surgical implantation of a pacemaker, the discovery of novel therapeutic molecular targets is necessary to improve prognosis and quality of life. METHODS: We investigated a family containing 7 individuals with autosomal dominant bradyarrhythmias of sinus node dysfunction, atrial fibrillation with slow ventricular response, and atrioventricular block. To identify the causative mutation, we conducted the family-based whole exome sequencing and genome-wide linkage analysis. We characterized the mutation-related mechanisms based on the pathophysiology in vitro. After generating a transgenic animal model to confirm the human phenotypes of bradyarrhythmia, we also evaluated the efficacy of a newly identified molecular-targeted compound to upregulate heart rate in bradyarrhythmias by using the animal model. RESULTS: We identified one heterozygous mutation, KCNJ3 c.247A>C, p.N83H, as a novel cause of hereditary bradyarrhythmias in this family. KCNJ3 encodes the inwardly rectifying potassium channel Kir3.1, which combines with Kir3.4 (encoded by KCNJ5) to form the acetylcholine-activated potassium channel ( IKACh channel) with specific expression in the atrium. An additional study using a genome cohort of 2185 patients with sporadic atrial fibrillation revealed another 5 rare mutations in KCNJ3 and KCNJ5, suggesting the relevance of both genes to these arrhythmias. Cellular electrophysiological studies revealed that the KCNJ3 p.N83H mutation caused a gain of IKACh channel function by increasing the basal current, even in the absence of m2 muscarinic receptor stimulation. We generated transgenic zebrafish expressing mutant human KCNJ3 in the atrium specifically. It is interesting to note that the selective IKACh channel blocker NIP-151 repressed the increased current and improved bradyarrhythmia phenotypes in the mutant zebrafish. CONCLUSIONS: The IKACh channel is associated with the pathophysiology of bradyarrhythmia and atrial fibrillation, and the mutant IKACh channel ( KCNJ3 p.N83H) can be effectively inhibited by NIP-151, a selective IKACh channel blocker. Thus, the IKACh channel might be considered to be a suitable pharmacological target for patients who have bradyarrhythmia with a gain-of-function mutation in the IKACh channel.
Assuntos
Fibrilação Atrial , Bloqueio Atrioventricular , Bradicardia , Canais de Potássio Corretores do Fluxo de Internalização Acoplados a Proteínas G , Doenças Genéticas Inatas , Mutação de Sentido Incorreto , Substituição de Aminoácidos , Animais , Animais Geneticamente Modificados , Fibrilação Atrial/genética , Fibrilação Atrial/metabolismo , Fibrilação Atrial/patologia , Fibrilação Atrial/fisiopatologia , Bloqueio Atrioventricular/genética , Bloqueio Atrioventricular/metabolismo , Bloqueio Atrioventricular/patologia , Bloqueio Atrioventricular/fisiopatologia , Benzopiranos/farmacologia , Bradicardia/genética , Bradicardia/metabolismo , Bradicardia/patologia , Bradicardia/fisiopatologia , Técnicas Eletrofisiológicas Cardíacas , Feminino , Canais de Potássio Corretores do Fluxo de Internalização Acoplados a Proteínas G/antagonistas & inibidores , Canais de Potássio Corretores do Fluxo de Internalização Acoplados a Proteínas G/genética , Canais de Potássio Corretores do Fluxo de Internalização Acoplados a Proteínas G/metabolismo , Doenças Genéticas Inatas/genética , Doenças Genéticas Inatas/metabolismo , Doenças Genéticas Inatas/patologia , Doenças Genéticas Inatas/fisiopatologia , Humanos , Masculino , Xenopus laevis , Peixe-ZebraRESUMO
Qiliqiangxin (QL) can attenuate myocardial remodeling and improve cardiac function in some cardiac diseases, including heart failure and hypertension. This study was to explore the effects and mechanism of QL on atrial structural remodeling in atrial fibrillation (AF). Twenty-one rabbits were randomly divided into a sham-operation group, pacing group (pacing with 600 beats per minute for 4 weeks), and treatment group (2.5 g/kg/day). Before pacing, the rabbits received QL-administered p.o. for 1 week. We measured atrial electrophysiological parameters in all groups to evaluate AF inducibility and the atrial effective refractory period (AERP). Echocardiography evaluated cardiac function and structure. TUNEL detection, hematoxylin and eosin (HE) staining, and Masson's trichrome staining were performed. Immunohistochemistry and western blotting (WB) were used to detect alterations in calcium channel L-type dihydropyridine receptor α2 subunit (DHPR) and fibrosis-related regulatory factors. AF inducibility was markedly decreased after QL treatment. Furthermore, we found that AERP and DHPR were reduced significantly in pacing rabbits compared with sham rabbits; treatment with QL increased DHPR and AERP compared to the pacing group. The QL group showed significantly decreased mast cell density and improved atrial ejection fraction values compared with the pacing group. Moreover, QL decreased interventricular septum thickness (IVSd) and left ventricular end-diastolic diameter (LVEDD). Compared with the sham group, the levels of TGFß1 and P-smad2/3 were significantly upregulated in the pacing group. QL reduced TGF-ß1 and P-smad2/3 levels and downstream fibrosis-related factors. Our study demonstrated that QL treatment attenuates atrial structural remodeling potentially by inhibiting TGF-ß1/P-smad2/3 signaling pathway.
Assuntos
Fibrilação Atrial/tratamento farmacológico , Remodelamento Atrial/efeitos dos fármacos , Medicamentos de Ervas Chinesas/uso terapêutico , Animais , Fibrilação Atrial/metabolismo , Fibrilação Atrial/patologia , Fibrilação Atrial/fisiopatologia , Medicamentos de Ervas Chinesas/farmacologia , Átrios do Coração/metabolismo , Átrios do Coração/patologia , Átrios do Coração/fisiopatologia , Coelhos , Proteína Smad2/metabolismo , Proteína Smad3/metabolismo , Fator de Crescimento Transformador beta1/metabolismoRESUMO
The precise mechanisms by which oxidative stress (OS) causes atrial fibrillation (AF) are not known. Since AF frequently originates in the posterior left atrium (PLA), we hypothesized that OS, via calmodulin-dependent protein kinase II (CaMKII) signaling, creates a fertile substrate in the PLA for triggered activity and reentry. In a canine heart failure (HF) model, OS generation and oxidized-CaMKII-induced (Ox-CaMKII-induced) RyR2 and Nav1.5 signaling were increased preferentially in the PLA (compared with left atrial appendage). Triggered Ca2+ waves (TCWs) in HF PLA myocytes were particularly sensitive to acute ROS inhibition. Computational modeling confirmed a direct relationship between OS/CaMKII signaling and TCW generation. CaMKII phosphorylated Nav1.5 (CaMKII-p-Nav1.5 [S571]) was located preferentially at the intercalated disc (ID), being nearly absent at the lateral membrane. Furthermore, a decrease in ankyrin-G (AnkG) in HF led to patchy dropout of CaMKII-p-Nav1.5 at the ID, causing its distribution to become spatially heterogeneous; this corresponded to preferential slowing and inhomogeneity of conduction noted in the HF PLA. Computational modeling illustrated how conduction slowing (e.g., due to increase in CaMKII-p-Nav1.5) interacts with fibrosis to cause reentry in the PLA. We conclude that OS via CaMKII leads to substrate for triggered activity and reentry in HF PLA by mechanisms independent of but complementary to fibrosis.
Assuntos
Fibrilação Atrial/metabolismo , Proteína Quinase Tipo 2 Dependente de Cálcio-Calmodulina/metabolismo , Insuficiência Cardíaca/metabolismo , Miócitos Cardíacos/metabolismo , Estresse Oxidativo/genética , Potenciais de Ação/fisiologia , Animais , Fibrilação Atrial/fisiopatologia , Fibrilação Atrial/veterinária , Sinalização do Cálcio/fisiologia , Cães , Fibrose , Átrios do Coração/patologia , Átrios do Coração/fisiopatologia , Insuficiência Cardíaca/fisiopatologia , Insuficiência Cardíaca/veterinária , Modelos Animais , Modelos Teóricos , Miócitos Cardíacos/fisiologia , Miócitos Cardíacos/ultraestrutura , Canal de Sódio Disparado por Voltagem NAV1.5/metabolismo , Canal de Liberação de Cálcio do Receptor de Rianodina/metabolismoRESUMO
PURPOSE: Shensong Yangxin (SSYX) capsule is a traditional Chinese medicine that has been used widely to treat cardiac arrhythmia. This study aimed to assess whether SSYX prevents atrial fibrillation (AF) after chronic myocardial infarction (MI)-induced heart failure and to determine the underlying mechanisms. MATERIALS AND METHODS: The study included 45 male Sprague Dawley rats. The rats underwent MI induction or sham surgery. One week after MI induction surgery, we performed serial echocardiography and administered SSYX capsule to some rats that experienced MI. After 4 weeks of treatment, AF inducibility was assessed with transesophageal programmed electrical stimulation technology. Additionally, multielectrode array assessment, histological analysis, and Western blot analysis were performed. RESULTS: AF inducibility was significantly lower in SSYX rats than in MI rats (33.3% vs 73.3%, P<0.05). Additionally, conduction velocities in the left atrium were greater in SSYX rats than in MI rats. Moreover, SSYX decreased left atrial fibrosis, downregulated TGF-ß1, MMP-9, TIMP-I, and type I and III collagen expressions, and inhibited the differentiation of cardiac fibroblasts to myofibroblasts. CONCLUSION: SSYX reduces AF inducibility after MI by improving left atrial conduction function via the inhibition of left atrial fibrosis. It prevents the development of an MI-induced vulnerable substrate for AF.
Assuntos
Fibrilação Atrial/tratamento farmacológico , Medicamentos de Ervas Chinesas/farmacologia , Insuficiência Cardíaca/tratamento farmacológico , Infarto do Miocárdio/tratamento farmacológico , Animais , Fibrilação Atrial/metabolismo , Cápsulas/administração & dosagem , Cápsulas/química , Cápsulas/farmacologia , Medicamentos de Ervas Chinesas/administração & dosagem , Medicamentos de Ervas Chinesas/química , Ecocardiografia , Insuficiência Cardíaca/metabolismo , Masculino , Medicina Tradicional Chinesa , Microeletrodos , Infarto do Miocárdio/metabolismo , Ratos , Ratos Sprague-DawleyRESUMO
Background Enlargement of left atrial ( LA ) size indicates advanced disease stage in patients with atrial fibrillation ( AF ) and is associated with poor success of different AF therapies. Two dimensional echocardiographic LA measurements do not reliably reflect the true size of LA anatomy. The aim of the current study was: 1) to analyze cardiovascular magnetic resonance ( CMR )-derived LA dimensions and their association with low voltage areas ( LVA ); and 2) to investigate the association between these parameters and NT -pro ANP (N-terminal proatrial natriuretic peptide) levels. Methods and Results Patients undergoing first AF catheter ablation were included. All patients underwent CMR imaging (Ingenia 1.5T Philips) before intervention. CMR data ( LA volume, superior-inferior, transversal and anterior-posterior LA diameters) were measured in all patients. LVA were determined using high-density maps and a low voltage threshold <0.5 mV. Blood plasma samples from femoral vein were collected before catheter ablation. NT -pro ANP levels were studied using commercially available assays. There were 216 patients (65±11 years, 59% males, 56% persistent AF , 26% LVA ) included into analyses. NT -pro ANP levels in patients with LVA were significantly higher than in those without (median/interquartile range 22 [13-29] versus 15 [9-22] pg/mL, P=0.004). All CMR derived LA diameters correlated significantly with persistent AF ( r²=0.291-0.468, all P<0.001), LVA ( r²=0.187-0.306, all P<0.001), and NT -pro ANP levels ( r²=0.258-0.352, P<0.01). On logistic regression multivariable analysis, age (odds ratio=1.090, 95% confidence interval: 1.030-1.153, P=0.003), females (odds ratio=2.686, 95% confidence interval: 1.047-6.891, P=0.040), and LA volume (odds ratio=1.022, 95% confidence interval: 1.009-1.035, P=0.001) remained significant predictors for LVA . Conclusions Left atrial CMR parameters are associated with persistent AF , low voltage areas and NT -pro ANP levels. LA volume is the most significant predictor for LVA .
Assuntos
Fibrilação Atrial/diagnóstico , Fator Natriurético Atrial/sangue , Técnicas Eletrofisiológicas Cardíacas/métodos , Átrios do Coração/fisiopatologia , Imagem Cinética por Ressonância Magnética/métodos , Precursores de Proteínas/sangue , Adolescente , Adulto , Idoso , Fibrilação Atrial/metabolismo , Fibrilação Atrial/fisiopatologia , Biomarcadores/sangue , Ecocardiografia , Feminino , Átrios do Coração/diagnóstico por imagem , Humanos , Masculino , Pessoa de Meia-Idade , Prognóstico , Estudos Retrospectivos , Adulto JovemRESUMO
BACKGROUND AND OBJECTIVE: Rivaroxaban is a new oral anticoagulant for stroke prevention in patients with non-valvular atrial fibrillation (NVAF), which has less drug-food interaction than warfarin. We conducted this prospective randomized study to evaluate the metabolic benefits as well as the safety and efficacy with rivaroxaban versus warfarin in patients with NVAF following radiofrequency catheter ablation (RFCA). METHODS: From April to July 2014, 60 patients with NVAF undergoing RFCA were prospectively enrolled in our study. Following RFCA, all patients were randomly assigned to receive rivaroxaban (Group R, n=30) or warfarin (Group W, n=30). Metabolic indices including serum total protein, albumin, globulin, and high-density lipoprotein (HDL) as well as bleeding, stroke, and systemic thromboembolism events were evaluated and compared during follow-up after 15, 30, 60, and 90 d of RFCA procedure. RESULTS: Serum total protein, albumin, globulin, and HDL levels were all significantly elevated at each follow-up stage in Group R when compared to the baseline (P<0.05 respectively). In Group W, the metabolic indices decreased at first and then had an increasing trend. There were no deaths or thromboembolic complications in each group. The prevalence of total bleeding complications was similar between Group R and Group W (11/30, 36.7% vs. 10/30, 33.3%, P=0.79). CONCLUSIONS: Patients with NVAF receiving rivaroxaban after RFCA procedures appear to benefit from a metabolic perspective compared with warfarin, providing practical clinical reference for the choice of the anticoagulant. Rivaroxaban seems to be as safe and effective in preventing thromboembolic events as warfarin for these patients.