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BACKGROUND: Sporadic studies have examined the impact of OSA on ACS patients by homocysteine (Hcy) level. This study attempted to comprehensively evaluate the effects of the interaction between Hcy and OSA on long-term cardiovascular outcomes in ACS patients. METHODS: In this prospective, large-scale cohort study, 2160 patients admitted for ACS were recruited to undergo overnight sleep monitoring. OSA was diagnosed when apnea-hypopnea index ≥ 15 events/h. Patients with normohomocysteinemia (NHcy) were defined as having serum Hcy ≤ 15 µmol/L, and the others had hyperhomocysteinemia (HHcy). The primary endpoint was major adverse cerebrocardiovascular event (MACCE), a composite of cardiovascular death, myocardial infarction, stroke, ischemia-driven revascularization and hospitalization for unstable angina and heart failure. RESULTS: A total of 1553 eligible ACS patients (average age: 56.3 ± 10.5 years) were enrolled, among which 819 (52.7%) had OSA, and 988 (63.6%) were with NHcy. OSA did not significantly affect the level of Hcy. During a median follow-up of 2.9 (1.6, 3.5) years, after adjustment for clinical confounders, OSA was associated with increased risk for MACCE occurrence versus non-OSA ones in ACS patients with NHcy (adjusted hazard ratio [HR] = 1.36, 95% confidence interval [CI] 1.02-1.83, P = 0.039), but not in those with HHcy (adjusted HR = 0.92, 95%CI 0.62-1.36, P = 0.668). There was an absence of interaction between homocysteine level and OSA in relation to MACCE (interaction P = 0.106). CONCLUSIONS: OSA was independently associated with worse prognosis in ACS patients with NHcy. Our study emphasized the necessity to identify potential presence of OSA in such a population. TRIAL REGISTRATION: ClinicalTrials.gov; Number: NCT03362385; URL: www. CLINICALTRIALS: gov .
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Síndrome Coronariana Aguda , Apneia Obstrutiva do Sono , Humanos , Pessoa de Meia-Idade , Idoso , Prognóstico , Síndrome Coronariana Aguda/diagnóstico , Síndrome Coronariana Aguda/epidemiologia , Estudos Prospectivos , Estudos de Coortes , Apneia Obstrutiva do Sono/diagnóstico , Apneia Obstrutiva do Sono/epidemiologia , Apneia Obstrutiva do Sono/complicações , Homocisteína , Fatores de RiscoRESUMO
BACKGROUND: Angiogenesis plays a critical role on post-infarction heart failure (PIHF), the presence of which facilitates additional blood supply to maintain the survival of residual cardiomyocytes. The sigma-1 receptor (S1R) has been substantiated to stimulate angiogenesis, with the effect on a model of PIHF remaining unknown. AIMS: This study aims to investigate the effects of S1R on PIHF and the underlying mechanisms involved. METHODS: Rats were implemented left anterior descending artery ligation followed by rearing for 6 weeks to induce a phenotype of heart failure. Daily intraperitoneal injection of S1R agonist or antagonist for 5 weeks was applied from 2nd week after surgery. The effects exerted by S1R were detected by echocardiography, hemodynamic testing, western blot, Sirius red dyeing, ELISA, immunohistochemistry and fluorescence. We also cultured HUVECs to verify the mechanisms in vitro. RESULTS: Stimulation of S1R significantly ameliorated the cardiac function resulted from PIHF, in addition to the observation of reduced fibrosis in the peri-infarct region and the apoptosis of residual cardiomyocytes, which were associated with augmentation of microvascular density in peri-infarct region through activation of the JAK2/STAT3 pathway. We also indicated that suppression of JAK2/STAT3 pathway by specific inhibitor in vitro reversed the pro-angiogenic effects of S1R on HUVECs, which further confirmed that angiogenesis, responsible for PIHF amelioration, by S1R stimulation was in a JAK2/STAT3 pathway-dependent manner. CONCLUSION: S1R stimulation improved PIHF-induced cardiac dysfunction and ventricular remodeling through promoting angiogenesis by activating the JAK2/STAT3 pathway.
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Insuficiência Cardíaca , Receptores sigma , Animais , Infarto , Ratos , Receptores sigma/agonistas , Receptores sigma/metabolismo , Roedores/metabolismo , Fator de Transcrição STAT3/metabolismo , Receptor Sigma-1RESUMO
BACKGROUND: Oxidative stress is an important factor involved in the progress of heart failure. The current study was performed to investigate whether pinocembrin was able to ameliorate post-infarct heart failure (PIHF) and the underlying mechanisms. METHODS: Rats were carried out left anterior descending artery ligation to induce myocardial infarction and subsequently raised for 6 weeks to produce chronic heart failure. Then pinocembrin was administrated every other day for 2 weeks. The effects were evaluated by echocardiography, western blot, Masson's staining, biochemical examinations, immunohistochemistry, and fluorescence. In vitro we also cultured H9c2 cardiomyocytes and cardiac myofibroblasts to further testify the mechanisms. RESULTS: We found that PIHF-induced deteriorations of cardiac functions were significantly ameliorated by administrating pinocembrin. In addition, the pinocembrin treatment also attenuated collagen deposition and augmented vascular endothelial growth factor receptor 2 in infarct border zone along with an attenuated apoptosis, which were related to an amelioration of oxidative stress evidenced by reduction of reactive oxygen species (ROS) in heart tissue and malondialdehyde (MDA) in serum, and increase of superoxide dismutase (SOD). This were accompanied by upregulation of nuclear factor erythroid 2-related factor 2 (Nrf2)/ heme oxygenase-1 (HO-1) pathway. In vitro experiments we found that specific Nrf2 inhibitor significantly reversed the effects resulted from pinocembrin including antioxidant, anti-apoptosis, anti-fibrosis and neovascularization, which further indicated the amelioration of PIHF by pinocembrin was in a Nrf2/HO-1 pathway-dependent manner. CONCLUSION: Pinocembrin ameliorated cardiac functions and remodeling resulted from PIHF by ROS scavenging and Nrf2/HO-1 pathway activation which further attenuated collagen fibers deposition and apoptosis, and facilitated angiogenesis.
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Flavanonas/farmacologia , Insuficiência Cardíaca/etiologia , Insuficiência Cardíaca/metabolismo , Heme Oxigenase-1/metabolismo , Infarto do Miocárdio/complicações , Fator 2 Relacionado a NF-E2/metabolismo , Transdução de Sinais/efeitos dos fármacos , Animais , Antioxidantes/química , Antioxidantes/farmacologia , Biomarcadores , Gerenciamento Clínico , Modelos Animais de Doenças , Suscetibilidade a Doenças , Ecocardiografia , Flavanonas/química , Insuficiência Cardíaca/diagnóstico , Insuficiência Cardíaca/tratamento farmacológico , Imuno-Histoquímica , Masculino , Infarto do Miocárdio/diagnóstico , Infarto do Miocárdio/etiologia , Miócitos Cardíacos/efeitos dos fármacos , Miócitos Cardíacos/metabolismo , Miofibroblastos/imunologia , Miofibroblastos/metabolismo , Fator 2 Relacionado a NF-E2/antagonistas & inibidores , Estresse Oxidativo/efeitos dos fármacos , Ratos , Espécies Reativas de Oxigênio/metabolismoRESUMO
BACKGROUND: MicroRNAs (miRNAs) have been identified as important participants in the development of atherosclerosis (AS). The present study explored the role of miR-128-3p in the dysfunction of vascular smooth muscle cells (VSMCs) and the underlying mechanism. METHODS: Human VSMCs and ApoE knockout (ApoE-/-) C57BL/6J mice were used to establish AS cell and animal models, respectively. Expression levels of miR-128-3p, forkhead box O4 (FOXO4) and matrix metallopeptidase 9 (MMP9) were detected using qRT-PCR and Western blot, respectively. CCK-8, BrdU, and Transwell assays as well as flow cytometry analysis were performed to detect the proliferation, migration and apoptosis of VSMCs. Levels of inflammatory cytokines and lipids in human VSMCs, mice serum and mice VSMCs were also determined. The binding site between miR-128-3p and 3'UTR of FOXO4 was confirmed using luciferase reporter gene assay. RESULTS: MiR-128-3p was found to be decreased in AS patient serum, ox-LDL-treated VSMCs, AS mice serum and VSMCs of AS mice. Transfection of miR-128-3p mimics suppressed the proliferation and migration of VSMCs, accompanied by the promoted apoptosis and the decreased levels of inflammatory cytokines. Further experiments confirmed the interaction between miR-128-3p and FOXO4. Augmentation of FOXO4 or MMP9 reversed the effects of miR-128-3p. Besides, miR-128-3p inhibited triglyceride (TG), total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C) but increased high-density lipoprotein cholesterol (HDL-C) in the serum of AS mice. CONCLUSION: MiR-128-3p repressed the proliferation and migration of VSMCs through inhibiting the expressions of FOXO4 and MMP9.
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Proteínas de Ciclo Celular/genética , Fatores de Transcrição Forkhead/genética , Regulação da Expressão Gênica , Metaloproteinase 9 da Matriz/genética , MicroRNAs/genética , Músculo Liso Vascular/metabolismo , Miócitos de Músculo Liso/metabolismo , Regiões 3' não Traduzidas , Idoso , Idoso de 80 Anos ou mais , Animais , Proteínas de Ciclo Celular/metabolismo , Movimento Celular/efeitos dos fármacos , Proliferação de Células , Feminino , Fatores de Transcrição Forkhead/metabolismo , Humanos , Masculino , Metaloproteinase 9 da Matriz/metabolismo , Camundongos , Pessoa de Meia-IdadeRESUMO
AIM: A close relationship exists between resting heart rate (RHR) and obstructive sleep apnea (OSA). Still, the prognostic importance of nighttime RHR in patients with acute coronary syndrome (ACS) with or without OSA remains unclear. METHODS: In this prospective cohort study, OSA was defined as an apnea-hypopnea index of ≥ 15 events/h, and the high nighttime RHR (HNRHR) was defined as a heart rate of ≥ 70 bpm. The primary endpoint was a major adverse cardiovascular and cerebrovascular event (MACCE), including cardiovascular death, myocardial infarction, stroke, ischemia-driven revascularization, or hospitalization for heart failure. RESULTS: Among the 1875 enrolled patients, the mean patient age was 56.3±10.5 years, 978 (52.2%) had OSA, and 425 (22.7%) were in HNRHR. The proportion of patients with HNRHR is higher in the OSA population than in the non-OSA population (26.5% vs. 18.5%; Pï¼0.001). During 2.9 (1.5, 3.5) years of follow-up, HNRHR was associated with an increased risk of MACCE in patients with OSA (adjusted HR: 1.56, 95% CI: 1.09-2.23, P=0.014), but not in patients without OSA (adjust HR: 1.13, 95% CI: 0.69-1.84, P=0.63). CONCLUSIONS: In patients with ACS, a nighttime RHR of ≥ 70 bpm was associated with a higher risk of MACCE in those with OSA but not in those without it. This identifies a potential high-risk subgroup where heart rate may interact with the prognosis of OSA. Further research is needed to determine causative relationships and confirm whether heart rate control impacts cardiovascular outcomes in patients with ACS-OSA.
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Síndrome Coronariana Aguda , Frequência Cardíaca , Apneia Obstrutiva do Sono , Humanos , Síndrome Coronariana Aguda/fisiopatologia , Síndrome Coronariana Aguda/complicações , Apneia Obstrutiva do Sono/fisiopatologia , Apneia Obstrutiva do Sono/complicações , Pessoa de Meia-Idade , Masculino , Feminino , Frequência Cardíaca/fisiologia , Prognóstico , Estudos Prospectivos , Seguimentos , Idoso , Fatores de Risco , Descanso/fisiologiaRESUMO
BACKGROUND: The prognostic benefit of complete revascularization in elderly patients (aged over 75 years) with multi-vessel disease and acute coronary syndrome (ACS) is currently unclear. This study aimed to determine the long-term prognostic impact of complete revascularization in this population. METHODS: We conducted this study using data obtained from the BleeMACS (Bleeding complications in a Multicenter registry of patients discharged after an Acute Coronary Syndrome) registry, which was carried out from 2003 to 2014. The objective was to categorize older patients diagnosed with ACS into two groups: those who underwent complete revascularization and those who did not. Propensity score matching and the Kaplan-Meier analysis were employed to examine differences in one-year clinical outcomes. The primary endpoint was major adverse cardiovascular event (MACE), which encompassed a combination of all-cause mortality and myocardial infarction. RESULTS: Out of 1263 patients evaluated, 445 patients (35.2%) received complete revascularization. Patients who underwent complete revascularization had a higher prevalence of hypertension and prior percutaneous coronary intervention compared to those who did not. During the one-year follow-up period, complete revascularization was associated with a significantly decreased risk of MACE [13.7% vs. 20.5%, hazard ratio (HR) = 0.63, 95% CI: 0.45-0.88, P = 0.007] and a lower risk of myocardial infarction (5.9% vs. 9.9%, HR = 0.55, 95% CI: 0.33-0.92, P = 0.02). However, it was not linked to a lower risk of all-cause death (9.5% vs. 13.5%, HR = 0.68, 95% CI: 0.45-1.02, P = 0.06). Similar results were observed in the subgroup analysis. CONCLUSIONS: Long-term clinical improvements were observed in ACS patients aged over 75 years with multi-vessel disease who achieved complete revascularization. Therefore, adhering to guidelines for complete revascularization should be recommended for elderly patients.
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OBJECTIVE: Ventricular arrhythmias (VAs) are a common complication of chronic ischaemic heart failure (CIHF). The purpose of this study is to investigate the efficacy of pinocembrin in a rat model of VAs induced by CIHF and further examine the possible mechanism. METHODS: Rats were subjected to ligation of left anterior descending coronary artery to mimic CIHF and then received pinocembrin treatment daily for 2 months. The vivo electrophysiology were performed to determine the effect of pinocembrin on ventricular electrical activity. The expression of Cav1.2, Kv4.2, and NGF was determined by Western blot. The structural change of ventricle was tested by the Echocardiography, Masson staining, and HE staining. The effect of pinocembrin on sympathetic nerve-related markers was detected by the immunostaining and the ELISA was used to test for biomarkers associated with heart failure. RESULTS: Pinocembrin increased the expression of ion channel protein Cav1.2 and Kv4.3, ameliorated the shortening of action potential duration (APD) and reduced the incidence and duration of ventricular fibrillation (VF). Pinocembrin also reduced the expression of nerve growth factor (NGF) and improved the autonomic nerve remodelling. In addition, pinocembrin reduced the area of infarct area and myocardial fibrosis, accompanied by increasing the expression of connexin protein 43 (CX43). CONCLUSION: We demonstrate that pinocembrin reduces cardiac nerve remodelling and protects against Vas induced by CIHF. The findings suggest that pinocembrin can be a promising candidate for the treatment of VAs.
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Flavanonas/uso terapêutico , Insuficiência Cardíaca , Infarto do Miocárdio , Animais , Arritmias Cardíacas/etiologia , Arritmias Cardíacas/prevenção & controle , Modelos Animais de Doenças , Insuficiência Cardíaca/tratamento farmacológico , Insuficiência Cardíaca/etiologia , Insuficiência Cardíaca/prevenção & controle , Humanos , Fator de Crescimento Neural , RatosRESUMO
RATIONALE: It has been reported that patients with major depressive disorder (MDD) are prone to developing ventricular arrhythmias. Moreover, the Sigma-1 receptor not only plays a crucial role in MDD but has also been shown to have antiarrhythmic properties. The Sigma-1 receptor is a common receptor related to depression and ventricular arrhythmias. OBJECTIVE: We analyzed the effects of the Sigma-1 receptor on depression and ventricular repolarization-related ion remodeling in MDD rats. METHODS: MDD was induced in rats by chronic unpredictable mild stress (CUMS), and 28 days later, the rats were subjected to behavior tests. Protein expression was measured by western blotting, and cardiac morphological changes were observed by Masson staining. Electrophysiological measurement of the myocardium was performed with the whole-cell patch-clamp technique. RESULTS: Compared with the control rats, the MDD rats exhibited lower transient outward potassium current (Ito) and L-type calcium current (ICa-L) amplitudes. On the other hand, a trend of depolarization of Ito and hyperpolarization of ICa-L was observed in the MDD rats. Thus, we investigated the effect of fluvoxamine, a Sigma-1 receptor agonist, on Ito and ICa-L. Fluvoxamine enhanced Ito and altered its current kinetics, as shown by acceleration of activation and recovery from inactivation. In contrast, fluvoxamine inhibited the Ca2+ by hyperpolarizing the steady-state activation of ICa-L. All these effects were blocked by BD1047. CONCLUSION: Taken together, our results indicate that Sigma-1 receptor modulates the functions of Ito and ICa-L to possibly exert antiarrhythmic effects.
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Canais de Cálcio/metabolismo , Transtorno Depressivo Maior/metabolismo , Ventrículos do Coração/metabolismo , Canais de Potássio/metabolismo , Receptores sigma/agonistas , Potenciais de Ação/efeitos dos fármacos , Animais , Antidepressivos de Segunda Geração/farmacologia , Arritmias Cardíacas/metabolismo , Comportamento Animal/efeitos dos fármacos , Modelos Animais de Doenças , Fluvoxamina/farmacologia , Ventrículos do Coração/citologia , Ventrículos do Coração/efeitos dos fármacos , Ligantes , Masculino , Miocárdio/metabolismo , Técnicas de Patch-Clamp , Ratos , Receptor Sigma-1RESUMO
[This corrects the article DOI: 10.3389/fphar.2020.547966.].
RESUMO
AIM: The purpose of the study was to investigate what effects the sigma-1 receptor (S1R) could exert on the cardiac myocyte ion channels in a rodent model of depression and to explore the underlying mechanisms since depression is an independent risk factor for cardiovascular diseases including ventricular arrhythmias (VAs). MATERIALS AND METHODS: To establish the depression model in rats, chronic mild unpredictable stress (CMUS) for 28 days was used. The S1R agonist fluvoxamine was injected intraperitoneally from the second week to the last week for 21 days in total, and the effects were evaluated by patch clamp, western blot analysis, and Masson staining. KEY FINDINGS: We demonstrated that depression was improved after treatment with fluvoxamine. In addition, the prolongation of the corrected QT (QTc) interval under CMUS that increased vulnerability to VAs was significantly attenuated by stimulation of S1R due to the decreased amplitude of L-type calcium current (ICa-L) and the restoration of reduced transient outward potassium current (Ito) resulting from CMUS induction. The S1R also decelerated Ito inactivation and accelerated Ito recovery by activating Ca2+/calmodulin-dependent kinase II. Moreover, the stimulation of S1R ameliorated the structural remodeling as the substrate for maintenance of VAs. All these effects were abolished by the administration of S1R antagonist BD1047, which verified the roles for S1R. SIGNIFICANCE: Activation of S1R could decrease the vulnerability to VAs by inhibiting ICa-L and restoring Ito, in addition to ameliorating the CMUS-induced depressive symptoms and structural remodeling.
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Depressão/metabolismo , Miócitos Cardíacos/metabolismo , Receptores sigma/fisiologia , Potenciais de Ação/efeitos dos fármacos , Animais , Arritmias Cardíacas/metabolismo , Depressão/fisiopatologia , Transtorno Depressivo/metabolismo , Transtorno Depressivo/fisiopatologia , Modelos Animais de Doenças , Fluvoxamina/metabolismo , Fluvoxamina/farmacologia , Ventrículos do Coração/efeitos dos fármacos , Canais Iônicos/efeitos dos fármacos , Canais Iônicos/metabolismo , Masculino , Ratos , Ratos Sprague-Dawley , Receptores sigma/metabolismo , Remodelação Ventricular/efeitos dos fármacos , Remodelação Ventricular/fisiologia , Receptor Sigma-1RESUMO
The present study aimed to assess the effect of sigma-1 receptor (S1R) stimulation on ventricular remodeling and susceptibility to ventricular arrhythmias (VAs) after myocardial infarction (MI) in rats. Wild-type male rats were placed into one of the following four treatment groups. For four weeks, animals in the Sham group and MI group received intraperitoneal (i.p.) injections of 0.9% saline (1 ml/kg/day); those in the MI + F group received fluvoxamine (FLV) (0.3 mg/kg/day); and those in the MI + F + BD group received FLV plus BD1047 (0.3 mg/kg/day). After that, the ventricular electrophysiological parameters were measured via the langendorff system. Ventricular fibrosis quantification was determined with Masson staining. Cardiac function was evaluated by echocardiography. The protein levels of S1R, connexin (Cx)43, Cav1.2, Kv4.2, Kv4.3, tyrosine hydroxylase (TH), nerve growth factor (NGF), growth-associated protein 43 (GAP43) were detected by Western blot assays. Our results indicated that fluvoxamine significantly prolonged the ventricular effective refractory period (ERP), shortened action potential duration (APD), reduced susceptibility to VAs after MI. Masson staining showed a decrease in ventricular fibrosis in the MI + F group. Furthermore, the contents of Cx43, S1R, Cav1.2, Kv4.2, Kv4.3 were increased in the MI + F group compared with the MI group (all P < 0.05). The contents of TH, NGF, GAP43 were reduced in the MI + F group compared with the MI group. (all P < 0.05). However, BD1047 reduces all of these effects of FLV. The results suggest that S1R stimulation reduces susceptibility to VAs and improves cardiac function by improving myocardial fibrosis, lightning sympathetic remodeling, electrical remodeling, gap junction remodeling and upregulating S1R content.
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Fluvoxamina/administração & dosagem , Infarto do Miocárdio/metabolismo , Receptores sigma/agonistas , Receptores sigma/metabolismo , Fibrilação Ventricular/metabolismo , Remodelação Ventricular/fisiologia , Animais , Esquema de Medicação , Masculino , Infarto do Miocárdio/complicações , Infarto do Miocárdio/tratamento farmacológico , Ratos , Ratos Sprague-Dawley , Fibrilação Ventricular/etiologia , Fibrilação Ventricular/prevenção & controle , Remodelação Ventricular/efeitos dos fármacos , Receptor Sigma-1RESUMO
Background: Depression is associated with the increased risk of mortality and morbidity and is an independent risk factor for many cardiovascular diseases. Depression may promote cardiac arrhythmias, but little is known about the mechanisms. Pinocembrin mitigated depressive-like behaviors and exhibited cardioprotective effects in several models; however, whether pinocembrin benefits ventricular arrhythmias in depression models has not been elucidated. Thus, this study was to evaluate the effects of pinocembrin on ventricular fibrillation susceptibility in rat models of depression. Methods: Male Sprague-Dawley rats were randomly assigned into control, control + pinocembrin, MDD (major depressive disorder), and MDP (MDD + pinocembrin) groups, respectively. Depressive-like behaviors, ventricular electrophysiological parameters, electrocardiogram parameters, heart rate variability, ventricular histology, serum norepinephrine, tumor necrosis factor-α, and interleukin-1ß were detected. Protein levels in left ventricle were measured by Western blot assays. Results: Compared with the MDD group, pinocembrin significantly mitigated depressive-like behaviors, prolonged ventricular effective refractory period, action potential duration, QT, and corrected QT (QTc) interval, improved heart rate variability, decreased Tpeak-Tend interval, ventricular fibrillation inducibility rate, ventricular fibrosis, ventricular positive nerve densities, and protein expression of tyrosine hydroxylase and growth associated protein-43, reduced serum norepinephrine, tumor necrosis factor-α, interleukin-1ß concentrations, and the expression levels of p-IκBα and p-p65, and increased the protein expression of Cx43, Cav1.2, and Kv.4.2 in the MDP group. Conclusion: Pinocembrin attenuates ventricular electrical remodeling, autonomic remodeling, and ion-channel remodeling, lowers ventricular fibrosis, and suppresses depression-induced inflammatory responses, providing new insights in pinocembrin and ventricular arrhythmias in depressed patients.
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AIMS: This study aimed to evaluate the effects of the sigma-1 receptor (S1R) on atrial fibrillation (AF) susceptibility in rats. MAIN METHODS: Rats were randomly assigned into three groups for intraperitoneal treatment with saline (CTL group), BD1047 (an antagonist of the S1R, BD group) or BD1047 plus fluvoxamine (an agonist of the S1R, BDâ¯+â¯F group) for 4â¯weeks. The heart rate variability (HRV) and atrial electrophysiological parameters were measured via the PowerLab system and analyzed by LabChart 8.0 software. Atrial histology was determined with Masson staining. The protein levels of connexin (Cx) 40, Cav1.2, S1R, eNOS, p-eNOS, and p-AKT were detected by western blot assays. KEY FINDINGS: Our results showed that BD1047 significantly shortened the atrial effective refractory period (ERP) and action potential duration (APD), increased AF inducibility and duration, augmented sympathetic activity, depressed parasympathetic activity, and reduced heart rate variability (HRV) compared with the CTL group. Masson staining also showed a significant increase in atrial fibrosis in the BD group. Furthermore, the expressions of S1R, Cx40, Cav1.2, p-eNOS, and p-AKT were dramatically reduced in the BD group compared with the CTL group (all Pâ¯<â¯0.01). However, fluvoxamine administration mitigated most of the abovementioned alterations. SIGNIFICANCE: Our findings indicated that S1R inhibition contributed to atrial electrical remodeling, cardiac autonomic remodeling and atrial fibrosis, which could be attenuated by fluvoxamine, thus providing new insights into the relationship between the S1R and AF.