RESUMO
Atrial fibrillation (AF) and heart failure with preserved ejection fraction (HFpEF) often coexist; however, clinically available anti-AF drugs can exacerbate symptoms of HFpEF. M201-A suppressed ryanodine receptor-mediated diastolic Ca2+ leakage, possibly inhibiting common pathological processes toward AF and HFpEF. To bridge the basic information to clinical practice, we assessed its cardiohemodynamic, anti-AF and ventricular proarrhythmic profile using halothane-anesthetized dogs (n = 4). M201-A hydrochloride in doses of 0.03, 0.3 and 3 mg/kg/10 min was intravenously administered, providing peak plasma concentrations of 0.09, 0.81 and 5.70 µg/mL, respectively. The high dose of M201-A showed various cardiovascular actions. Namely, M201-A increased mean blood pressure and tended to enhance isovolumetric ventricular relaxation without suppressing ventricular contraction or decreasing cardiac output. M201-A enhanced atrioventricular conduction, but hardy affected intra-atrial/ventricular conduction. Importantly, M201-A prolonged effective refractory period more potently in the atrium than in the ventricle, indicating that it may become an atrial-selective antiarrhythmic drug. Meanwhile, M201-A prolonged QT interval/QTcV, and showed reverse frequency-dependent delay of ventricular repolarization. M201-A prolonged J-Tpeakc without prolonging Tpeak-Tend or terminal repolarization period, indicating the risk of causing torsade de pointes is negligible. Thus, M201-A is expected to become a hopeful therapeutic strategy for patients having pathology of both AF and HFpEF.
Assuntos
Antiarrítmicos , Fibrilação Atrial , Insuficiência Cardíaca , Canal de Liberação de Cálcio do Receptor de Rianodina , Volume Sistólico , Animais , Cães , Canal de Liberação de Cálcio do Receptor de Rianodina/metabolismo , Fibrilação Atrial/tratamento farmacológico , Fibrilação Atrial/fisiopatologia , Insuficiência Cardíaca/tratamento farmacológico , Insuficiência Cardíaca/fisiopatologia , Volume Sistólico/efeitos dos fármacos , Antiarrítmicos/farmacologia , Masculino , Átrios do Coração/efeitos dos fármacos , Átrios do Coração/fisiopatologia , Relação Dose-Resposta a Droga , Humanos , FemininoRESUMO
We investigated the modulatory effects of aldosterone on atrial remodeling induced by an abdominal aorto-venocaval shunt (AVS) in rats, as patients with primary hyperaldosteronism are suggested to have a higher risk of developing atrial fibrillation (AF). The rats were divided into four groups based on the basis of whether they underwent AVS surgery, received aldosterone using an intraperitoneally implanted osmotic minipump, or both. Aldosterone was started at 0.5 µg/h during the AVS surgery, and morphological and electrophysiological assessments were performed four weeks after AVS creation. The atrial structural changes induced by AVS, including atrial cell hypertrophy and fibrosis, were not modulated by aldosterone, whereas P-wave duration was longer in aldosterone-treated AVS rats than in non-treated rats. Although the average AF duration induced by burst pacing was 10-25 s in the untreated, aldosterone-treated, and AVS rats, the AF duration was approximately 100 s in the aldosterone-treated AVS rats. Meanwhile, there was no significant difference in the atrial effective refractory period among the four experimental groups. Notably, premature atrial contractions (PAC) were frequently observed in aldosterone-treated sham rats, while paroxysmal AF, in addition to PAC, was detected in aldosterone-treated AVS rats, which was not induced in non-treated AVS rats. These findings suggest that aldosterone robustly promotes AF, particularly in the presence of chronic volume overload.
Assuntos
Aldosterona , Fibrilação Atrial , Átrios do Coração , Animais , Aldosterona/sangue , Fibrilação Atrial/etiologia , Fibrilação Atrial/fisiopatologia , Masculino , Átrios do Coração/efeitos dos fármacos , Átrios do Coração/fisiopatologia , Átrios do Coração/patologia , Remodelamento Atrial/efeitos dos fármacos , Ratos , Ratos Sprague-DawleyRESUMO
BACKGROUND: Doxorubicin is an important anticancer drug, however, elicits dose-dependently cardiomyopathy. Given its mode of action, i.e. topoisomerase inhibition and DNA damage, we investigated genetic events associated with cardiomyopathy and searched for mechanism-based possibilities to alleviate cardiotoxicity. We treated rats at clinically relevant doses of doxorubicin. Histopathology and transmission electron microscopy (TEM) defined cardiac lesions, and transcriptomics unveiled cardiomyopathy-associated gene regulations. Genomic-footprints revealed critical components of Abl1-p53-signaling, and EMSA-assays evidenced Abl1 DNA-binding activity. Gene reporter assays confirmed Abl1 activity on p53-targets while immunohistochemistry/immunofluorescence microscopy demonstrated Abl1, p53&p73 signaling. RESULTS: Doxorubicin treatment caused dose-dependently toxic cardiomyopathy, and TEM evidenced damaged mitochondria and myofibrillar disarray. Surviving cardiomyocytes repressed Parkin-1 and Bnip3-mediated mitophagy, stimulated dynamin-1-like dependent mitochondrial fission and induced anti-apoptotic Bag1 signaling. Thus, we observed induced mitochondrial biogenesis. Transcriptomics discovered heterogeneity in cellular responses with minimal overlap between treatments, and the data are highly suggestive for distinct cardiomyocyte (sub)populations which differed in their resilience and reparative capacity. Genome-wide footprints revealed Abl1 and p53 enriched binding sites in doxorubicin-regulated genes, and we confirmed Abl1 DNA-binding activity in EMSA-assays. Extraordinarily, Abl1 signaling differed in the heart with highly significant regulations of Abl1, p53 and p73 in atrial cardiomyocytes. Conversely, in ventricular cardiomyocytes, Abl1 solely-modulated p53-signaling that was BAX transcription-independent. Gene reporter assays established Abl1 cofactor activity for the p53-reporter PG13-luc, and ectopic Abl1 expression stimulated p53-mediated apoptosis. CONCLUSIONS: The tyrosine kinase Abl1 is of critical importance in doxorubicin induced cardiomyopathy, and we propose its inhibition as means to diminish risk of cardiotoxicity.
Assuntos
Cardiomiopatias , Doxorrubicina , Miócitos Cardíacos , Proteínas Proto-Oncogênicas c-abl , Transdução de Sinais , Proteína Supressora de Tumor p53 , Animais , Doxorrubicina/efeitos adversos , Doxorrubicina/farmacologia , Miócitos Cardíacos/efeitos dos fármacos , Miócitos Cardíacos/metabolismo , Miócitos Cardíacos/patologia , Proteína Supressora de Tumor p53/metabolismo , Transdução de Sinais/efeitos dos fármacos , Cardiomiopatias/induzido quimicamente , Cardiomiopatias/patologia , Cardiomiopatias/metabolismo , Proteínas Proto-Oncogênicas c-abl/metabolismo , Proteínas Proto-Oncogênicas c-abl/genética , Ventrículos do Coração/patologia , Ventrículos do Coração/efeitos dos fármacos , Átrios do Coração/patologia , Átrios do Coração/efeitos dos fármacos , Átrios do Coração/metabolismo , Morte Celular/efeitos dos fármacos , Masculino , Ratos , Ratos WistarRESUMO
Background: The aim of this study is to evaluate atrial involvement by comparing pre- and post-chemotherapy left atrial mechanical and electromechanical parameters in patients treated with cardiotoxic chemotherapeutic agents. Methods: We designed our study as a prospective cohort study. Sixty-eight female patients between the ages of 18 and 50, scheduled for treatment with cardiotoxic chemotherapeutic agents, were included in our study. Atrial mechanical functions and electromechanical parameters were examined and compared with basic echocardiographic parameters before and after chemotherapy. Results: The mean age of the patients was 41.6 ± 7.9 years. After chemotherapy, lateral PA, septal PA, and tricuspid PA durations showed a significant increase (p < 0.001), but there were no statistically significant changes in the left intra-atrial electromechanical delay, the right intra-atrial electromechanical delay, or the interatrial electromechanical delay values. Following treatment, LAVmax, LAVmin, and LApreA significantly increased (p < 0.001). Additionally, the left atrial passive and active emptying volumes increased (p < 0.001), while the reservoir and pump (active emptying) functions decreased (with p-values of 0.03 and 0.01, respectively). The passive emptying function, however, showed no significant change (p = 0.65). Decreases in LVEF were observed, while LVEDD, LVESD, IVS, PW, and LA diameters increased (p-value of 0.02 for IVS and <0.001 for the others). Conclusions: Significant impairment of atrial mechanical functions and electromechanical parameters was observed after treatment with cardiotoxic chemotherapeutic agents. This suggests an elevated likelihood of atrial arrhythmia linked to the use of cardiotoxic chemotherapeutic agents.
Assuntos
Antineoplásicos , Função do Átrio Esquerdo , Ecocardiografia , Átrios do Coração , Humanos , Feminino , Adulto , Estudos Prospectivos , Pessoa de Meia-Idade , Função do Átrio Esquerdo/efeitos dos fármacos , Função do Átrio Esquerdo/fisiologia , Antineoplásicos/efeitos adversos , Antineoplásicos/uso terapêutico , Átrios do Coração/efeitos dos fármacos , Átrios do Coração/fisiopatologia , Átrios do Coração/diagnóstico por imagem , Ecocardiografia/métodos , Adolescente , Estudos de Coortes , Cardiotoxicidade/etiologia , Cardiotoxicidade/fisiopatologia , Adulto JovemRESUMO
Atrial fibrosis is associated with the occurrence of atrial fibrillation (AF) and regulated by the transforming growth factor-ß1 (TGF-ß1)/Smad2/3 signalling pathway. Unfortunately, the mechanisms of regulation of TGF-ß1/Smad2/3-induced atrial fibrosis and vulnerability to AF remain still unknown. Previous studies have shown that sirtuin3 (SIRT3) sulfhydration has strong anti-fibrotic effects. We hypothesised that SIRT3 sulfhydration inhibits angiotensin II (Ang-II)-induced atrial fibrosis via blocking the TGF-ß1/Smad2/3 signalling pathway. In this study, we found that SIRT3 expression was decreased in the left atrium of patients with AF compared to that in those with sinus rhythm (SR). In vitro, SIRT3 knockdown by small interfering RNA significantly expanded Ang-II-induced atrial fibrosis and TGF-ß1/Smad2/3 signalling pathway activation, whereas supplementation with Sodium Hydrosulfide (NaHS, exogenous hydrogen sulfide donor and sulfhydration agonist) and SIRT3 overexpression using adenovirus ameliorated Ang-II-induced atrial fibrosis. Moreover, we observed suppression of the TGF-ß1/Smad2/3 pathway when Ang-II was combined with NaHS treatment, and the effect of this co-treatment was consistent with that of Ang-II combined with LY3200882 (Smad pathway inhibitor) on reducing atrial fibroblast proliferation and cell migration in vitro. Supplementation with dithiothreitol (DTT, a sulfhydration inhibitor) and adenovirus SIRT3 shRNA blocked the ameliorating effect of NaHS and AngII co-treatment on atrial fibrosis in vitro. Finally, continued treatment with NaHS in rats ameliorated atrial fibrosis and remodelling, and further improved AF vulnerability induced by Ang-II, which was reversed by DTT and adenovirus SIRT3 shRNA, suggesting that SIRT3 sulfhydration might be a potential therapeutic target in atrial fibrosis and AF.
Assuntos
Angiotensina II , Fibrilação Atrial , Fibrose , Átrios do Coração , Sulfeto de Hidrogênio , Transdução de Sinais , Sirtuína 3 , Proteína Smad2 , Proteína Smad3 , Fator de Crescimento Transformador beta1 , Idoso , Animais , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Ratos , Angiotensina II/farmacologia , Fibrilação Atrial/metabolismo , Fibrilação Atrial/patologia , Fibrilação Atrial/prevenção & controle , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Átrios do Coração/efeitos dos fármacos , Átrios do Coração/metabolismo , Átrios do Coração/patologia , Sulfeto de Hidrogênio/farmacologia , Sulfeto de Hidrogênio/metabolismo , Ratos Sprague-Dawley , Transdução de Sinais/efeitos dos fármacos , Sirtuína 3/metabolismo , Sirtuína 3/genética , Proteína Smad2/metabolismo , Proteína Smad3/metabolismo , Fator de Crescimento Transformador beta1/metabolismoRESUMO
Cardiac remodeling in rats with post-infarction chronic heart failure caused by anterior transmural myocardial infarction leads to an atypical location of areas of positive and negative cardioelectric potentials on the body surface before the onset of the PII-wave on the ECG in the limb leads, which is a sign of increased heterogeneity of atrial depolarization associated with the appearance of additional excitation focus in the left atrium. A course of therapy with fabomotizole leads to a decrease in the heterogeneity of atrial depolarization at the initial stages of the formation of the cardioelectric field of the atria on the body surface before the onset of the PII-wave, thereby producing an antiarrhythmic effect.
Assuntos
Mapeamento Potencial de Superfície Corporal , Átrios do Coração , Insuficiência Cardíaca , Infarto do Miocárdio , Animais , Ratos , Insuficiência Cardíaca/tratamento farmacológico , Insuficiência Cardíaca/fisiopatologia , Infarto do Miocárdio/fisiopatologia , Infarto do Miocárdio/tratamento farmacológico , Infarto do Miocárdio/complicações , Átrios do Coração/efeitos dos fármacos , Átrios do Coração/fisiopatologia , Masculino , Mapeamento Potencial de Superfície Corporal/métodos , Morfolinas/farmacologia , Morfolinas/uso terapêutico , Eletrocardiografia , Ratos Wistar , Benzimidazóis/farmacologia , Benzimidazóis/uso terapêutico , Antiarrítmicos/uso terapêutico , Antiarrítmicos/farmacologiaRESUMO
The present study examined three hallucinogenic amphetamine derivatives, namely, 2,5-dimethoxy-4-iodoamphetamine (DOI) as well as 2,5-dimethoxy-4-methylamphetamine (DOM) and 4-methylmethcathinone (mephedrone). The objective of this study was to test the hypothesis that DOI, DOM, and mephedrone would increase the contractile force in isolated human atrial preparations in a manner similar to amphetamine. To this end, we measured contractile force under isometric conditions in electrically stimulated (1 Hz) human atrial preparations obtained during open surgery. DOI and DOM alone or in the presence of isoprenaline reduced the contractile force concentration-dependently in human atrial preparations. These negative inotropic effects of DOM and DOI were not attenuated by 10 µM atropine. However, mephedrone increased the contractile force in human atrial preparations in a concentration- and time-dependent manner. Furthermore, these effects were attenuated by the subsequent addition of 10 µM propranolol or pretreatment with 10 µM cocaine in the organ bath. Therefore, it can be concluded that amphetamine derivatives may exert opposing effects on cardiac contractile force. The precise mechanism by which DOI and DOM exert their negative inotropic effects remains unknown at present. The cardiac effects of mephedrone are probably due to the release of cardiac noradrenaline.
Assuntos
Alucinógenos , Átrios do Coração , Contração Miocárdica , Humanos , Átrios do Coração/efeitos dos fármacos , Contração Miocárdica/efeitos dos fármacos , Alucinógenos/farmacologia , Masculino , Feminino , Isoproterenol/farmacologia , Metanfetamina/farmacologia , Metanfetamina/análogos & derivados , Atropina/farmacologia , Anfetaminas/farmacologia , Pessoa de Meia-Idade , Propranolol/farmacologia , Anfetamina/farmacologia , AdultoRESUMO
ABSTRACT: Previous studies have found that anxiety disorders may increase the incidence of atrial fibrillation (AF). More and more studies have shown that α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors (AMPARs) are involved in the occurrence and development of cardiovascular diseases. However, the role of AMPARs in AF associated with anxiety disorder remains unclear. The aim of this study was to investigate the effect of AMPARs on AF susceptibility in rats with anxiety disorder and its possible mechanism. The anxiety disorder rat model was established by unpredictable empty bottle stimulation and was treated with AMPARs agonist and antagonist. Our results showed that AMPARs antagonist treatment significantly reduced sympathetic activity, improved heart rate variability, shortened action potential duration, prolonged effective refractory period, reduced AF induction rate, and improved cardiac electrical remodeling and the expression of inflammatory factors. In addition, inhibition of AMPARs reduced the phosphorylation of IκBα and p65. Our experimental results suggest that inhibition of AMPARs can reduce autonomic remodeling, improve atrial electrical remodeling, and suppress myocardial inflammation, which provides a potential therapeutic strategy for the treatment of AF associated with anxiety disorder.
Assuntos
Transtornos de Ansiedade , Fibrilação Atrial , Modelos Animais de Doenças , Átrios do Coração , Ratos Sprague-Dawley , Receptores de AMPA , Animais , Fibrilação Atrial/fisiopatologia , Fibrilação Atrial/tratamento farmacológico , Fibrilação Atrial/metabolismo , Masculino , Transtornos de Ansiedade/tratamento farmacológico , Transtornos de Ansiedade/metabolismo , Transtornos de Ansiedade/fisiopatologia , Átrios do Coração/efeitos dos fármacos , Átrios do Coração/fisiopatologia , Átrios do Coração/metabolismo , Átrios do Coração/patologia , Receptores de AMPA/metabolismo , Remodelamento Atrial/efeitos dos fármacos , Frequência Cardíaca/efeitos dos fármacos , Mediadores da Inflamação/metabolismo , Potenciais de Ação/efeitos dos fármacos , Fosforilação , Transdução de Sinais , Sistema Nervoso Simpático/fisiopatologia , Sistema Nervoso Simpático/efeitos dos fármacos , Sistema Nervoso Simpático/metabolismo , Fator de Transcrição RelA/metabolismo , Ratos , Anti-Inflamatórios/farmacologia , Período Refratário Eletrofisiológico/efeitos dos fármacos , Inibidor de NF-kappaB alfa/metabolismoRESUMO
BACKGROUND: Sodium-glucose cotransporter-2 (SGLT2) inhibitors have demonstrated reduction in heart failure outcomes in patients with type 2 diabetes mellitus, although the exact mechanism of benefit remains unclear. Alteration in left atrial (LA) function due to chronic pressure or volume overload is a hallmark of heart failure. OBJECTIVE: To evaluate the effect of the SGLT2 inhibitor empagliflozin on LA volume and function. METHODS: 90 patients with coronary artery disease and type 2 diabetes (T2DM) were randomized to empagliflozin (n = 44) or placebo (n = 46), and underwent cardiac magnetic resonance (CMR) imaging at baseline and after 6 months. The main outcome was change in LA volume; LA function, including active and passive components, was also measured by a blinded reader. RESULTS: At baseline, there was no significant difference in LA volumes between the empagliflozin (indexed maximum LA volume 26.4 ± 8.4mL/m2, minimum LA volume 11.1 ± 5.7mL/m2) and placebo (indexed maximum LA volume 28.7 ± 8.2mL/m2, minimum LA volume 12.6 ± 5.0mL/m2) groups. After 6 months, changes in LA volumes did not differ with adjusted difference (empagliflozin minus placebo): 0.99 mL/m2 (95% CI: -1.7 to 3.7 mL/m2; p = 0.47) for indexed maximum LA volume, and 0.87 mL/m2 (95% CI: -0.9 to 2.6 mL/m2; p = 0.32) for indexed minimum LA volume. Changes in total LA emptying fraction were also similar, with between-group adjusted mean difference - 0.01 (95% CI: -0.05 to 0.03, p = 0.59). CONCLUSION: SGLT2 inhibition with empagliflozin for 6 months did not have a significant impact on LA volume and function in patients with T2DM and coronary artery disease. (Effects of Empagliflozin on Cardiac Structure in Patients with Type 2 Diabetes [EMPA-HEART]; NCT02998970).
Assuntos
Função do Átrio Esquerdo , Compostos Benzidrílicos , Doença da Artéria Coronariana , Diabetes Mellitus Tipo 2 , Glucosídeos , Inibidores do Transportador 2 de Sódio-Glicose , Humanos , Glucosídeos/uso terapêutico , Glucosídeos/efeitos adversos , Compostos Benzidrílicos/uso terapêutico , Compostos Benzidrílicos/efeitos adversos , Diabetes Mellitus Tipo 2/tratamento farmacológico , Diabetes Mellitus Tipo 2/diagnóstico , Diabetes Mellitus Tipo 2/fisiopatologia , Diabetes Mellitus Tipo 2/complicações , Inibidores do Transportador 2 de Sódio-Glicose/uso terapêutico , Inibidores do Transportador 2 de Sódio-Glicose/efeitos adversos , Masculino , Doença da Artéria Coronariana/tratamento farmacológico , Doença da Artéria Coronariana/fisiopatologia , Doença da Artéria Coronariana/diagnóstico por imagem , Feminino , Pessoa de Meia-Idade , Idoso , Função do Átrio Esquerdo/efeitos dos fármacos , Resultado do Tratamento , Fatores de Tempo , Método Duplo-Cego , Remodelamento Atrial/efeitos dos fármacos , Átrios do Coração/fisiopatologia , Átrios do Coração/efeitos dos fármacos , Átrios do Coração/diagnóstico por imagemRESUMO
CONTEXT: Chlordecone (CLD) is a carcinogenic organochlorine pesticide. CLD was shown to disturb the activity of cardiac Na+-K+-ATPase and Ca2+-Mg2+-ATPase. Conditions affecting these transmembrane pumps are often associated with cardiac arrhythmias (CA). However, little is known about the role of CLD on atrial fibrillation (AF) incidence, the most common type of CA. HYPOTHESES: 1) Daily ingestion of CLD induces arrhythmogenic cardiac remodeling. 2) A phase of CLD withdrawal can reduce CLD-induced AF susceptibility. METHODS: Adult male Wistar rats (250 g-275 g) ingested daily-doses of CLD (0 µg/L, 0.1 µg/L, or 1 µg/L) diluted in their quotidian water for 4 weeks. From day (D)29 to D56, all rats received CLD-free water. Vulnerability to AF and cardiac function were evaluated at D28 and D56 by electrophysiological study, echocardiography, and optical-mapping. Levels of genes and proteins related to inflammation, fibrosis, and senescence were quantified by qPCR and immunoassays. RESULTS: Twenty-eight days of CLD exposure were associated with significantly increased AF vulnerability compared to CLD-free rats. Contamination with 1 µg/L CLD significantly reduced atrial conduction velocity (ERP, APD). CLD-weaning normalized food consumption and weight intake. However, after the CLD-withdrawal period of 28 days, AF inducibility, atrial inflammation (IL6, IL1ß), and atrial fibrosis (Masson's trichrome staining) remained significantly higher in rats exposed to 1 µg/L CLD compared to 0 µg/L. CONCLUSIONS: Prolonged CLD ingestion provokes atrial conduction slowing and increased risk of AF. Although CLD-weaning, some persistent damages occurred in the atrium like atrial fibrosis and atrial senescence signals, which are accompanied by atrial inflammation and arrhythmogenicity.
Assuntos
Fibrilação Atrial , Fibrose , Ratos Wistar , Animais , Masculino , Fibrilação Atrial/induzido quimicamente , Inseticidas/toxicidade , Ratos , Coração/efeitos dos fármacos , Átrios do Coração/efeitos dos fármacos , Átrios do Coração/patologia , Miocárdio/patologia , Miocárdio/metabolismoRESUMO
Atrial fibrillation (AF) is the most common sustained cardiac arrhythmia. Excessive stimulation of the inositol (1,4,5)-trisphosphate (IP3) signaling pathway has been linked to AF through abnormal calcium handling. However, little is known about the mechanisms involved in this process. We expressed the fluorescence resonance energy transfer (FRET)-based cytosolic cyclic adenosine monophosphate (cAMP) sensor EPAC-SH187 in neonatal rat atrial myocytes (NRAMs) and neonatal rat ventricular myocytes (NRVMs). In NRAMs, the addition of the α1-agonist, phenylephrine (PE, 3 µM), resulted in a FRET change of 21.20 ± 7.43%, and the addition of membrane-permeant IP3 derivative 2,3,6-tri-O-butyryl-myo-IP3(1,4,5)-hexakis(acetoxymethyl)ester (IP3-AM, 20 µM) resulted in a peak of 20.31 ± 6.74%. These FRET changes imply an increase in cAMP. Prior application of IP3 receptor (IP3R) inhibitors 2-aminoethyl diphenylborinate (2-APB, 2.5 µM) or Xestospongin-C (0.3 µM) significantly inhibited the change in FRET in NRAMs in response to PE. Xestospongin-C (0.3 µM) significantly inhibited the change in FRET in NRAMs in response to IP3-AM. The FRET change in response to PE in NRVMs was not inhibited by 2-APB or Xestospongin-C. Finally, the localization of cAMP signals was tested by expressing the FRET-based cAMP sensor, AKAP79-CUTie, which targets the intracellular surface of the plasmalemma. We found in NRAMs that PE led to FRET change corresponding to an increase in cAMP that was inhibited by 2-APB and Xestospongin-C. These data support further investigation of the proarrhythmic nature and components of IP3-induced cAMP signaling to identify potential pharmacological targets.NEW & NOTEWORTHY This study shows that indirect activation of the IP3 pathway in atrial myocytes using phenylephrine and direct activation using IP3-AM leads to an increase in cAMP and is in part localized to the cell membrane. These changes can be pharmacologically inhibited using IP3R inhibitors. However, the cAMP rise in ventricular myocytes is independent of IP3R calcium release. Our data support further investigation into the proarrhythmic nature of IP3-induced cAMP signaling.
Assuntos
AMP Cíclico , Citosol , Transferência Ressonante de Energia de Fluorescência , Átrios do Coração , Receptores de Inositol 1,4,5-Trifosfato , Miócitos Cardíacos , Animais , Miócitos Cardíacos/metabolismo , Miócitos Cardíacos/efeitos dos fármacos , Receptores de Inositol 1,4,5-Trifosfato/metabolismo , AMP Cíclico/metabolismo , Átrios do Coração/metabolismo , Átrios do Coração/efeitos dos fármacos , Átrios do Coração/citologia , Citosol/metabolismo , Ratos , Ratos Sprague-Dawley , Células Cultivadas , Animais Recém-Nascidos , Compostos de Boro/farmacologia , Fenilefrina/farmacologia , Sinalização do Cálcio/efeitos dos fármacos , Inositol 1,4,5-Trifosfato/metabolismo , Sistemas do Segundo Mensageiro/efeitos dos fármacosRESUMO
The current study aimed to investigate the anti-atrial fibrillatory (AF) effects of a combination of valsartan and a calcium channel blocker (cilnidipine or amlodipine) in Dahl salt-sensitive (Dahl S) rats. Seven-week-old male Dahl S rats were fed an 8% salt diet. Six weeks later, valsartan (60 mg/kg, Val group), cilnidipine + valsartan (10 + 60 mg/kg, CV group), amlodipine + valsartan (3 + 60 mg/kg, AV group), or vehicle was orally administered daily for 5 weeks. Echocardiography and atrial electrophysiological evaluations were performed on the last day of treatment. Blood pressure in each drug treatment group was lower than in the Vehicle group. The duration of AF induced by atrial burst stimulation was shorter in the Val group (3.2 ± 1.6 s) than in the Vehicle group (11.2 ± 6.0 s), which was further shortened in the CV and AV groups (1.1 ± 0.3 and 1.3 ± 0.3 s, respectively). Left ventricular ejection fraction and left ventricular fractional shortening were greater in the CV and AV groups than those in the Vehicle group. Urinary albumin excretion in the CV group was the lowest among the drug-treated groups. The results collectively suggest that the combination of a calcium channel blocker with valsartan could be useful in terms of its anti-AF action as well as for improving cardiac and renal functions.
Assuntos
Pressão Sanguínea , Bloqueadores dos Canais de Cálcio , Di-Hidropiridinas , Ratos Endogâmicos Dahl , Valsartana , Animais , Valsartana/farmacologia , Di-Hidropiridinas/farmacologia , Masculino , Bloqueadores dos Canais de Cálcio/farmacologia , Pressão Sanguínea/efeitos dos fármacos , Fibrilação Atrial/tratamento farmacológico , Quimioterapia Combinada , Rim/efeitos dos fármacos , Ratos , Anlodipino/farmacologia , Função Ventricular Esquerda/efeitos dos fármacos , Átrios do Coração/efeitos dos fármacosRESUMO
We studied the effect of Refralon on the electrophysiological properties of the supraventricular myocardium against the background of adrenergic (epinephrine) influence in the zone of the pulmonary veins, the area where 50-90% of atrial arrhythmias is triggered. The experiments were carried out on isolated tissue preparations of Wistar rats. The multichannel microelectrode array technique was used to record action potentials simultaneously in the atrium and in the ostium and distal parts of the pulmonary veins. Epinephrine application (12-50 nM) led to depolarization of the resting potential and the conduction block in the distal part of the pulmonary veins. Refralon (30 µg/kg) restored the resting potential in the distal part of the pulmonary veins. Against the background of epinephrine, Refralon did not significantly change the duration of the action potential at 90% repolarization in comparison with control. At the same time, the comparison drug E-4031 against the background of epinephrine significantly increased the duration of action potential in the atrium and in the ostium of the pulmonary veins, and sotalol increased it only in the ostium. Neither E-4031, nor sotalol restored conduction in their distal part. Refralon has a biphasic effect under conditions of adrenergic stimulation: the fast component is responsible for stabilizing the resting potential in the pulmonary vein and reduces the dispersion of action potential duration in the atrium and pulmonary vein and is also quickly washed away, and the slow component is responsible for the increase of the action potential duration and is slowly washed away.
Assuntos
Potenciais de Ação , Antiarrítmicos , Epinefrina , Átrios do Coração , Veias Pulmonares , Ratos Wistar , Animais , Ratos , Epinefrina/farmacologia , Potenciais de Ação/efeitos dos fármacos , Antiarrítmicos/farmacologia , Veias Pulmonares/efeitos dos fármacos , Masculino , Átrios do Coração/efeitos dos fármacos , Átrios do Coração/fisiopatologia , Arritmias Cardíacas/fisiopatologia , Arritmias Cardíacas/tratamento farmacológicoRESUMO
Age is an independent risk factor for atrial fibrillation (AF), and curcumin can delay aging related disease through reducing oxidative stress and inflammation. However, its target in aging-related AF remains unclear. Transfer RNA-derived small RNA (tsRNA) is a novel short non-coding RNA (sncRNA), and exerts a potential regulatory function in aging. This study was to explore the therapeutic targets of curcumin in atrium of aged mice by PANDORA-seq. Aged mice (18 month) were treated with curcumin (100 mg/kg). Rapid transjugular atrial pacing was performed to observe AF inducibility. SA-ß-gal staining, reactive oxygen species (ROS) detection and qRT-PCR were used to assess the degree of aging and oxidative stress/inflammation levels. PANDORA-seq was performed to reveal the differentially expressed sncRNAs in the atrium of mice. The results showed that curcumin reduced the susceptibility AF of aged mice by improving aging-related atrial fibrosis. Compared to young mice (5 month) group, aged mice yielded 473 significantly altered tsRNA sequences, while 947 tsRNA sequences were significantly altered after treated with curcumin. Enrichment analysis revealed that the target genes were mainly related to DNA damage and protein modification. Compared with the 5 month group, the expression levels of mature-mt_tRNA-Val-TAC_CCA_end, mature-mt_tRNA-Glu-TTC_CCA_end, and mature-tRNA-Asp-GTC_CCA_end were up-regulated in the 18 month group, while the expression of mature-mt_tRNA-Thr-TGT_5_end was down-regulated. This trend was reversed in the 18 month + curcumin group. Increased cellular ROS levels, inflammation expression and senescence in aged mice atrium were improved by the down-regulation of mature-mt_tRNA-Val-TAC_CCA_end. In conclusion, our findings identified mature-mt_tRNA-Val-TAC_CCA_end participated in the mechanism of aging-related atrial fibrosis, providing new intervention target of aging-related AF.
Assuntos
Envelhecimento , Fibrilação Atrial , Curcumina , Átrios do Coração , Estresse Oxidativo , Animais , Curcumina/farmacologia , Fibrilação Atrial/genética , Fibrilação Atrial/metabolismo , Fibrilação Atrial/tratamento farmacológico , Camundongos , Envelhecimento/efeitos dos fármacos , Envelhecimento/genética , Átrios do Coração/efeitos dos fármacos , Átrios do Coração/metabolismo , Átrios do Coração/patologia , Estresse Oxidativo/efeitos dos fármacos , RNA de Transferência/genética , RNA de Transferência/metabolismo , Masculino , Pequeno RNA não Traduzido/genética , Pequeno RNA não Traduzido/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Fibrose , Modelos Animais de Doenças , Camundongos Endogâmicos C57BLRESUMO
Several fungi belonging to the genus Psilocybe, also called "magic mushrooms", contain the hallucinogenic drugs psilocybin and psilocin. They are chemically related to serotonin (5-HT). In addition to being abused as drugs, they are now also being discussed or used as a treatment option for depression. Here, we hypothesized that psilocybin and psilocin may act also on cardiac serotonin receptors and studied them in vitro in atrial preparations of our transgenic mouse model with cardiac myocytes-specific overexpression of the human 5-HT4 receptor (5-HT4-TG) as well as in human atrial preparations. Both psilocybin and psilocin enhanced the force of contraction in isolated left atrial preparations from 5-HT4-TG, increased the beating rate in isolated spontaneously beating right atrial preparations from 5-HT4-TG and augmented the force of contraction in the human atrial preparations. The inotropic and chronotropic effects of psilocybin and psilocin at 10⯵M were smaller than that of 1⯵M 5-HT on the left and right atria from 5-HT4-TG, respectively. Psilocybin and psilocin were inactive in WT. In the human atrial preparations, inhibition of the phosphodiesterase III by cilostamide was necessary to unmask the positive inotropic effects of psilocybin or psilocin. The effects of 10⯵M psilocybin and psilocin were abrogated by 10⯵M tropisetron or by 1⯵M GR125487, a more selective 5-HT4 receptor antagonist. In summary, we demonstrated that psilocin and psilocybin act as agonists on cardiac 5-HT4 receptors.
Assuntos
Átrios do Coração , Camundongos Transgênicos , Psilocibina , Receptores 5-HT4 de Serotonina , Psilocibina/farmacologia , Psilocibina/análogos & derivados , Animais , Humanos , Receptores 5-HT4 de Serotonina/metabolismo , Receptores 5-HT4 de Serotonina/genética , Átrios do Coração/efeitos dos fármacos , Átrios do Coração/metabolismo , Masculino , Contração Miocárdica/efeitos dos fármacos , Alucinógenos/farmacologia , Alucinógenos/toxicidade , Miócitos Cardíacos/efeitos dos fármacos , Miócitos Cardíacos/metabolismo , Camundongos , Agonistas do Receptor 5-HT4 de Serotonina/farmacologia , Frequência Cardíaca/efeitos dos fármacos , FemininoRESUMO
Human induced pluripotent stem cell (hiPSC)-derived cardiomyocytes (CMs) have found utility for conducting in vitro drug screening and disease modelling to gain crucial insights into pharmacology or disease phenotype. However, diseases such as atrial fibrillation, affecting >33 M people worldwide, demonstrate the need for cardiac subtype-specific cells. Here, we sought to investigate the base characteristics and pharmacological differences between commercially available chamber-specific atrial or ventricular hiPSC-CMs seeded onto ultra-thin, flexible PDMS membranes to simultaneously measure contractility in a 96 multi-well format. We investigated the effects of GPCR agonists (acetylcholine and carbachol), a Ca2+ channel agonist (S-Bay K8644), an HCN channel antagonist (ivabradine) and K+ channel antagonists (4-AP and vernakalant). We observed differential effects between atrial and ventricular hiPSC-CMs on contractile properties including beat rate, beat duration, contractile force and evidence of arrhythmias at a range of concentrations. As an excerpt of the compound analysis, S-Bay K8644 treatment showed an induced concentration-dependent transient increase in beat duration of atrial hiPSC-CMs, whereas ventricular cells showed a physiological increase in beat rate over time. Carbachol treatment produced marked effects on atrial cells, such as increased beat duration alongside a decrease in beat rate over time, but only minimal effects on ventricular cardiomyocytes. In the context of this chamber-specific pharmacology, we not only add to contractile characterization of hiPSC-CMs but propose a multi-well platform for medium-throughput early compound screening. Overall, these insights illustrate the key pharmacological differences between chamber-specific cardiomyocytes and their application on a multi-well contractility platform to gain insights for in vitro cardiac liability studies and disease modelling.
Assuntos
Átrios do Coração , Ventrículos do Coração , Células-Tronco Pluripotentes Induzidas , Contração Miocárdica , Miócitos Cardíacos , Miócitos Cardíacos/efeitos dos fármacos , Miócitos Cardíacos/fisiologia , Humanos , Células-Tronco Pluripotentes Induzidas/efeitos dos fármacos , Átrios do Coração/efeitos dos fármacos , Átrios do Coração/citologia , Contração Miocárdica/efeitos dos fármacos , Contração Miocárdica/fisiologia , Ventrículos do Coração/efeitos dos fármacos , Ventrículos do Coração/citologia , Receptores Acoplados a Proteínas G/metabolismo , Receptores Acoplados a Proteínas G/agonistas , Desenvolvimento de Medicamentos/métodos , Canais Iônicos/efeitos dos fármacos , Células Cultivadas , Avaliação Pré-Clínica de Medicamentos/métodos , Carbacol/farmacologia , Sistemas MicrofisiológicosRESUMO
OBJECTIVE: This study aims to explore the impact of sodium-glucose cotransporter-2 (SGLT-2) inhibitors, a newer class of oral antidiabetic drugs, on atrial electromechanical delay (EMD) in patients with type 2 diabetes mellitus (DM). This is particularly relevant given the significantly higher incidence of atrial fibrillation (AF) in diabetic patients compared to the general population. Atrial electromechanical delay is recognized as an important factor influencing the development of atrial fibrillation. METHODS: This study included 30 type 2 DM patients (53.3% female, mean age 60.07 ± 10.03 years), initiating treatment with SGLT-2 inhibitors. The patients were assessed using echocardiography at baseline and again at 6 months, focusing on basic echocardiographic parameters and atrial electromechanical delay times (EMD) measured via tissue Doppler imaging. RESULTS: No significant changes were observed in intra-atrial EMD times. However, significant reductions were noted in interatrial EMD times, decreasing from 15.13 ± 5.87 ms to 13.20 ± 6.12 ms (P = 0.029). Statistically significant shortening occurred in lateral pulmonary acceleration (PA) times (from 58.73 ± 6.41 ms to 54.37 ± 6.97 ms, P < 0.001), septal PA times (from 50.90 ± 6.02 ms to 48.23 ± 5), and tricuspid PA times (from 43.60 ± 6.28 ms to 41.30 ± 5.60 ms, P = 0.003). Additionally, there was a significant reduction in the E/e' ratio from 8.13 ± 4.0 to 6.50 ± 2.37 (P = 0.003). CONCLUSION: SGLT-2 inhibitors might positively influence atrial electromechanical conduction, reducing DM-related functional impairments and the risk of arrhythmias, particularly AF.
Assuntos
Fibrilação Atrial , Diabetes Mellitus Tipo 2 , Inibidores do Transportador 2 de Sódio-Glicose , Humanos , Feminino , Inibidores do Transportador 2 de Sódio-Glicose/uso terapêutico , Inibidores do Transportador 2 de Sódio-Glicose/farmacologia , Diabetes Mellitus Tipo 2/tratamento farmacológico , Diabetes Mellitus Tipo 2/complicações , Pessoa de Meia-Idade , Masculino , Fibrilação Atrial/tratamento farmacológico , Fibrilação Atrial/fisiopatologia , Átrios do Coração/diagnóstico por imagem , Átrios do Coração/efeitos dos fármacos , Átrios do Coração/fisiopatologia , Idoso , Sistema de Condução Cardíaco/efeitos dos fármacos , Sistema de Condução Cardíaco/fisiopatologia , EcocardiografiaRESUMO
OBJECTIVE: This study aimed to elucidate the molecular mechanisms by which BRD4 play a role in atrial fibrillation (AF). METHODS AND RESULTS: We used a discovery-driven approach to detect BRD4 expression in the atria of patients with AF and in various murine models of atrial fibrosis. We used a BRD4 inhibitor (JQ1) and atrial fibroblast (aFB)-specific BRD4-knockout mice to elucidate the role of BRD4 in AF. We further examined the underlying mechanisms using RNA-seq and ChIP-seq analyses in vitro, to identify key downstream targets of BRD4. We found that BRD4 expression is significantly increased in patients with AF, with accompanying atrial fibrosis and aFB differentiation. We showed that JQ1 treatment and shRNA-based molecular silencing of BRD4 blocked ANG-II-induced extracellular matrix production and cell-cycle progression in aFBs. BRD4-related RNA-seq and ChIP-seq analyses in aFBs demonstrated enrichment of a subset of promoters related to the expression of profibrotic and proliferation-related genes. The pharmacological inhibition of BRD4 in vivo or in aFB-specific BRD4-knockout in mice limited ANG-II-induced atrial fibrosis, atrial enlargement, and AF susceptibility. CONCLUSION: Our findings suggest that BRD4 plays a key role in pathological AF, at least partially by activating aFB proliferation and ECM synthesis. This study provides mechanistic insights into the development of BRD4 inhibitors as targeted antiarrhythmic therapies.
Assuntos
Fibrilação Atrial , Azepinas , Proteínas de Ciclo Celular , Fibrose , Átrios do Coração , Camundongos Knockout , Fatores de Transcrição , Triazóis , Fibrilação Atrial/genética , Fibrilação Atrial/metabolismo , Fibrilação Atrial/patologia , Fibrilação Atrial/tratamento farmacológico , Animais , Fatores de Transcrição/genética , Fatores de Transcrição/antagonistas & inibidores , Fatores de Transcrição/metabolismo , Átrios do Coração/patologia , Átrios do Coração/efeitos dos fármacos , Átrios do Coração/metabolismo , Humanos , Proteínas de Ciclo Celular/genética , Proteínas de Ciclo Celular/antagonistas & inibidores , Proteínas de Ciclo Celular/metabolismo , Camundongos , Azepinas/farmacologia , Azepinas/uso terapêutico , Masculino , Triazóis/farmacologia , Triazóis/uso terapêutico , Fibroblastos/efeitos dos fármacos , Fibroblastos/metabolismo , Fibroblastos/patologia , Proliferação de Células/efeitos dos fármacos , Proteínas Nucleares/genética , Proteínas Nucleares/metabolismo , Proteínas Nucleares/antagonistas & inibidores , Modelos Animais de Doenças , Camundongos Endogâmicos C57BL , Angiotensina II/farmacologia , Matriz Extracelular/metabolismo , Matriz Extracelular/efeitos dos fármacos , Terapia de Alvo Molecular , Proteínas que Contêm BromodomínioRESUMO
AIM: Atrial fibrillation (AF), the most common arrhythmia, is characterized by atrial electrical and structural remodeling. Previous studies have found that sodium-glucose cotransporter 2 inhibitor (SGLT2i) can protect myocardium in a glucose independent mechanism. But the role of SGLT2i in regulating AF remains largely unknown. This study, we aimed to investigate the effect of Dapagliflozin (DAPA) in reducing AF susceptibility via inhibiting electrical and structural remodeling. METHOD: The mouse model was established by Angiotensin II (2000 ng/kg/min) infusion for 3 weeks, and an in vitro model was generated by stimulating HL-1 and primary mouse fibroblast with Ang II (1 µM) for 24 h. Programmed electrical stimulation, ECG and whole-cell patch clamp were used to detect DAPA effect on atrial electrical remodeling induced by Ang II. To observe DAPA effect on atrial structural remodeling induced by Ang II, we used echocardiographic, H&E and Masson staining to evaluate atrial dilation. To further explore the protective mechanism of DAPA, we adopt in silico molecular docking approaches to investigate the binding affinity of Ang II and CaMKII at Met-281 site. Western blot was to detect expression level of CaMKII, ox-CaMKII, Nav1.5, Kv4.3, Kv4.2, Kchip2, Kir2.1 and Cx40. RESULTS: Ang II induced AF, atrial dilatation and fibrosis, led to atrial electrical and structural remodeling. However, these effects were markedly abrogated by DAPA treatment, a specific SGLT2i. Our observation of atrial electrical activity in mice revealed that DAPA could rescue the prolonged action potential duration (APD) and the abnormal currents of IK1, Ito and INaL triggered by Ang II infusion. DAPA could reduce the binding affinity of Ang II and CaMKII at Met-281 site, which indicated that DAPA may directly alleviate the activation of CaMKII caused by Ang II. DAPA could reduce the upregulation of ox-CaMKII caused by Ang II infusion in atrial tissues. Moreover, DAPA also ameliorated the aberrant expression levels of electrical activity related proteins (Nav1.5, Kv4.3, Kv4.2, Kchip2, Kir2.1 and Cx40) and fibrosis related signal pathways (TGF-ß1, p-smad/smad) caused by Ang II. Furthermore, we confirmed that DAPA, as well as other SGLT2i (EMPA, CANA), could reverse these abnormalities caused by Ang II incubation in HL-1 cells and primary mouse fibroblasts, respectively. CONCLUSION: Overall, our study identifies DAPA, a widely used SGLT2i, contributes to inhibiting Ang II-induced ox-CaMKII upregulation and electrical and structural remodeling to reduce AF susceptibility, suggesting that DAPA may be a potential therapy of treating AF.
Assuntos
Angiotensina II , Fibrilação Atrial , Remodelamento Atrial , Compostos Benzidrílicos , Proteína Quinase Tipo 2 Dependente de Cálcio-Calmodulina , Glucosídeos , Átrios do Coração , Simulação de Acoplamento Molecular , Inibidores do Transportador 2 de Sódio-Glicose , Animais , Angiotensina II/farmacologia , Inibidores do Transportador 2 de Sódio-Glicose/farmacologia , Fibrilação Atrial/induzido quimicamente , Fibrilação Atrial/metabolismo , Fibrilação Atrial/tratamento farmacológico , Fibrilação Atrial/fisiopatologia , Remodelamento Atrial/efeitos dos fármacos , Glucosídeos/farmacologia , Camundongos , Proteína Quinase Tipo 2 Dependente de Cálcio-Calmodulina/metabolismo , Átrios do Coração/efeitos dos fármacos , Átrios do Coração/metabolismo , Átrios do Coração/fisiopatologia , Átrios do Coração/patologia , Masculino , Compostos Benzidrílicos/farmacologia , Camundongos Endogâmicos C57BL , Modelos Animais de Doenças , Linhagem CelularRESUMO
A number of pharmacological drugs have side effects that contribute to the occurrence of atrial fibrillation, the most common type of cardiac rhythm disorders. The clinical use of antihistamines is widespread; however, information regarding their anti- and/or proarrhythmic effects is contradictory. In this work, we studied the effects and mechanisms of the potential proarrhythmic action of the first-generation antihistamine chloropyramine (Suprastin) in the atrial myocardium and pulmonary vein (PV) myocardial tissue. In PV, chloropyramine caused depolarization of the resting potential and led to reduction of excitation wave conduction. These effects are likely due to suppression of the inward rectifier potassium current (IK1). In presence of epinephrine, chloropyramine induced spontaneous automaticity in the PV and could not be suppressed by atrial pacing. Chloropyramine change functional characteristics of PV and contribute to occurrence of atrial fibrillation. It should be noted that chloropyramine does not provoke atrial tachyarrhythmias, but create conditions for their occurrence during physical exercise and sympathetic stimulation.