Atrial Fibrillation Induction Rate Research Articles

NR4A3 prevents diabetes induced atrial cardiomyopathy by maintaining mitochondrial energy metabolism and reducing oxidative stress

Atrial cardiomyopathy (ACM) is responsible for atrial fibrillation (AF) and thromboembolic events. Diabetes mellitus (DM) is an important risk factor for ACM. However, the potential mechanism between ACM and DM remains elusive. Atrial tissue samples were obtained from patients diagnosed with AF or sinus rhythm (SR) to assess alterations in NR4A3 expression, and then two distinct animal models were generated by subjecting Nr4a3-/- mice and WT mice to a high-fat diet (HFD) and Streptozotocin (STZ), while db/db mice were administered AAV9-Nr4a3 or AAV9-ctrl. Subsequently, invivo and invitro experiments were conducted to assess the impact of NR4A3 on diabetes-induced atrial remodeling through electrophysiological, biological, and histological analyses. RNA sequencing (RNA-seq) and metabolomics analysis were employed to unravel the downstream mechanisms. The expression of NR4A3 was significantly decreased in atrial tissues of both AF patients and diabetic mice compared to their respective control groups. NR4A3 deficiency exacerbated atrial hypertrophy and atrial fibrosis, and increased susceptibility to pacing-induced AF. Conversely, overexpression of NR4A3 alleviated atrial structural remodeling and reduced AF induction rate. Mechanistically, we confirmed that NR4A3 improves mitochondrial energy metabolism and reduces oxidative stress injury by preserving the transcriptional expression of Sdha, thereby exerting a protective influence on atrial remodeling induced by diabetes. Our data confirm that NR4A3 plays a protective role in atrial remodeling caused by diabetes, so it may be a new target for treating ACM. This study was supported by the major research program of National Natural Science Foundation of China (NSFC) No: 82370316 (to Q-S. W.), No. 81974041 (to Y-P. W.), and No. 82270447 (to Y-P. W.) and Fundation of Shanghai Hospital Development Center (No. SHDC2022CRD044 to Q-S. W.).

Inhibition of α-Amino-3-Hydroxy-5-Methyl-4-Isoxazolepropionic Acid Receptors Ameliorates Atrial Inflammation and Vulnerability to Atrial Fibrillation in Rats with Anxiety Disorders.

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.

SIRT3/AMPK Signaling Pathway Regulates Lipid Metabolism and Improves Vulnerability to Atrial Fibrillation in Dahl Salt-Sensitive Rats.

Hypertension may result in atrial fibrillation (AF) and lipid metabolism disorders. The Sirtuins3 (SIRT3)/AMP-activated protein kinase (AMPK) signaling pathway has the capacity to regulate lipid metabolism disorders and the onset of AF. We hypothesize that the SIRT3/AMPK signaling pathway suppresses lipid metabolism disorders, thereby mitigating salt-sensitive hypertension (SSHT)-induced susceptibility to AF. The study involved 7-week-old male Dahl salt-sensitive that were fed either a high-salt diet (8% NaCl; DSH group) or a normal diet (0.3% NaCl; DSN group). Then DSH group was administered either oral metformin (MET, an AMPK agonist) or intraperitoneal injection of Honokiol (HK, a SIRT3 agonist). This experimental model allowed for the measurement of Systolic blood pressure (SBP), the expression levels of lipid metabolism-related biomarkers, pathological examination of atrial fibrosis, and lipid accumulation, as well as AF inducibility and AF duration. DSH decrease SIRT3, phosphorylation-AMPK, and very long-chain acyl-CoA dehydrogenase, (VLCAD) expression, increased FASN and FABP4 expression and concentrations of free fatty acid and triglyceride, atrial fibrosis and lipid accumulation in atrial tissue, enhanced level of SBP, promoted AF induction rate and prolonged AF duration, which are blocked by MET and HK. Our results also showed that the degree of atrial fibrosis was negatively correlated with VLCAD expression, but positively correlated with the expression of FASN and FABP4. We have confirmed that a high-salt diet can result in hypertension, and associated atrial tissue lipid metabolism dysfunction. This condition is linked to the inhibition of the SIRT3/AMPK signaling pathway, which plays a significant role in the progression of susceptibility to AF in SSHT rats.

High-Salt Diet Inhibits the Expression of Bmal1 and Promotes Atrial Fibrosis and Vulnerability to Atrial Fibrillation in Dahl Salt-Sensitive Rats.

Hypertension is a risk factor for atrial fibrillation (AF), and brain and muscle arnt-like protein 1 (Bmal1) regulate circadian blood pressure and is implicated in several fibrotic disorders. Our hypothesis that Bmal1 inhibits atrial fibrosis and susceptibility to AF in salt-sensitive hypertension (SSHT) and our study provides a new target for the pathogenesis of AF induced by hypertension. The study involved 7-week-old male Dahl salt-sensitive that were fed either a high-salt diet (8% NaCl; DSH group) or a normal diet (0.3% NaCl; DSN group). An experimental model was used to measure systolic blood pressure (SBP), left atrial ejection fraction (LAEF), left atrial end-volume index (LAEVI), left atrial index (LAFI), AF inducibility, AF duration, and atrial fibrosis pathological examination and the expression of Baml1 and fibrosis-related proteins (TNF-α and α-SMA) in left atrial tissue. DSH increased TNF-α and α-SMA expression in atrial tissue, level of SBP and LAESVI, atrial fibrosis, AF induction rate, and AF duration, and decreased Bmal1 expression in atrial tissue, the circadian rhythm of hypertension, and level of LAEF and LAFI. Our results also showed that the degree of atrial fibrosis was negatively correlated with Bmal1 expression, but positively correlated with the expression of TNF-α and α-SMA. We demonstrated that a high-salt diet leads to circadian changes in hypertension due to a reduction of Bmal1 expression, which plays a crucial role in atrial fibrosis and increased susceptibility to AF in SSHT rats.

Mechanisms by which spinal cord stimulation intervenes in atrial fibrillation: The involvement of the endothelin-1 and nerve growth factor/p75NTR pathways.

Can the spinal cord stimulation (SCS) regulate the autonomic nerves through the endothelin-1 (ET-1) and nerve growth factor (NGF)/p75NTR pathways and thus inhibit the occurrence of atrial fibrillation (AF)? In our research, 16 beagles were randomly divided into a rapid atrial pacing (RAP) group (n = 8) and a RAP + SCS group (n = 8), and the effective refractory period (ERP), ERP dispersion, AF induction rate, and AF vulnerability window (WOV) at baseline, 6 h of RAP, 6 h of RAP + SCS were measured. The atrial tissue was then taken for immunohistochemical analysis to determine the localization of ET-1, NGF, p75NTR, NF-kB p65, and other genes. Our results showed that SCS attenuated the shortening of ERP in all parts caused by RAP, and after 6 h of SCS, the probability of AF in dogs was reduced compared with that in the RAP group. Moreover, the expression of ET-1, NGF, and p75NTR in the atrial tissues of dogs in the RAP + SCS group was significantly increased, but the expression of NF-kB p65 was reduced. In conclusion, SCS promotes the positive remodeling of cardiac autonomic nerves by weakening NFκB p65-dependent pathways to interfere with the ET-1 and NGF/p75NTR pathways to resist the original negative remodeling and inhibit the occurrence of AF.

Sacubitril/valsartan reduces susceptibility to atrial fibrillation by improving atrial remodeling in spontaneously hypertensive rats

AimSacubitril/valsartan (Sac/Val, LCZ696), the world's first angiotensin receptor-neprilysin inhibitor (ARNi), has been widely used in the treatment of heart failure. However, the use of Sac/Val in the treatment of atrial fibrillation (AF), especially AF with hypertension, has been less reported. We investigated the effect of Sac/Val on atrial remodeling and hypertension-related AF. MethodsThe AF induction rate and electrophysiological characteristics of spontaneously hypertensive rats (SHRs) treated with Sac/Val or Val were detected by rapid atrial pacing and electrical mapping/optical mapping. The whole-cell patch-clamp and Western blot were used to observe electrical/structural remodeling of atrial myocytes/tissue of rats and atrium-derived HL-1 cells cultured under 40 mmHg in vitro. ResultsSac/Val was superior to Val in reducing blood pressure, myocardial hypertrophy and susceptibility of AF in SHRs. The shorten action potentials duration (APD), decreased L type calcium channel current (ICa,L) and Cav1.2, increased ultrarapid delayed rectified potassium current (Ikur) and Kv1.5 in atrial myocytes/tissue of SHRs could be better improved by Sac/Val, as well as the levels of atrial fibrosis. While the protein expression of angiotensin-converting enzyme-1 (ACE-1), angiotensin, angiotensin II type I AT1 receptor (AT1R) and neprilysin (NEP) were increased, which could be more effective ameliorated by Sac/Val than Val. Furthermore, Val + Sacubitrilat (LBQ657) (an active NEP inhibitor) was also superior to LBQ657 or Val in improving the electrical and structural remodeling of HL-1 cells through inhibiting NEP. ConclusionSac/Val can improve atrial structural and electrical remodeling induced by hypertension and reduce the AF susceptibility by inhibiting RAS and NEP. The above effects of Sac/Val were superior to Val alone.

Study on the pharmacological mechanisms of sodium-glucose co-transporter 2 inhibitors in obesity-related atrial fibrillation based on network pharmacology and experimental verification.

Obesity is an independently risk factor of atrial fibrillation (AF). It is likely that the global burden of AF will escalate due to the current obesity epidemic. Weight loss can effectively reduce the risk of AF, while sodium-glucose co-transporter 2 inhibitors (SGLT2i) can reduce body weight, so SGLT2i are potentially effective for obesity-related AF. SGLT2i are a novel type of oral medication. This current study used network pharmacology to examine the potential mechanisms of SGLT2i in the treatment of obesity-related AF, and the therapeutic effects were assessed in vivo. Potential gene targets for SGLT2i in treating obesity-related AF were identified from public database. Cytoscape V3.7.1 was used to construct the "Drug-Target" and "Drug-Target-Disease" networks. The STRING database was applied to investigate the protein-protein interactions (PPIs). Additionally, the Bioconductor tools were used to analyze the Gene Ontology (GO) biological functions and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway. The efficacy of SGLT2i in treating obesity-related AF was investigated in vivo using a diet-induced obese C57BL/6J male mouse model. A number of indicators were assessed, including invasive electrophysiology, testing of blood samples, and expression detection of pathway targets. These experiments were used to verify the targets mined by network pharmacology. The results indicated that SGLT2i had 80 potential target genes during the treatment of obesity-related AF, and 10 hub genes were obtained by further screening. It was predicted that the treatment of obesity-related AF by SGLT2i involved the advanced glycation end product (AGE)-receptor for advanced glycation end product (RAGE) signaling pathway and other signaling pathways. In in vivo experiments, administration of SGLT2i (the SGLT2i + DIO group) resulted in a lower AF induction rate (P<0.05), decreased serum AGEs/soluble RAGE (sRAGE) ratio (P<0.01), and decreased expression of NADPH oxidase 2 (NOX2) (P<0.05) compared to untreated DIO mice (the DIO group). In this study, pharmacological network analysis and in vivo experiments demonstrated that SGLT2i acts on obesity-related AF by inhibiting the AGE-RAGE signaling pathway. These results offer fresh perspectives on the pharmacological actions of SGLT2i in treating obesity-related AF.

Electrical, structural, and autonomic atrial remodeling underlies atrial fibrillation in inflammatory atrial cardiomyopathy.

There is growing evidence indicating a close relationship between inflammation and atrial fibrillation (AF). Although underlying inflammatory atrial cardiomyopathy may contribute to the development of AF, the arrhythmogenic remodeling caused by atrial inflammation has not been elucidated in detail. Herein, we examined electrical, structural, and autonomic changes in the atria in a mouse model of autoimmune myocarditis. BALB/c mice were immunized with cardiac myosin peptide (MyHC-α614-629) conjugated with complete Freund's adjuvant on days 0 and 7. Susceptibility to AF was assessed using right-atrial burst pacing. The mice immunized with MyHC-α614-629 showed an inflammatory atrial cardiomyopathy phenotype, with enlarged atria; a high degree of inflammatory cell infiltration primarily consisting of CD4+ T cells, CD8+ T cells, Ly6GlowCD11b+ macrophages, and CD11c+ dendritic cells; and severe interstitial fibrosis with collagen deposition. These mice demonstrated significantly enhanced susceptibility to AF, as indicated by their increased AF induction rate and duration. In addition, the expression of potassium channels (Kcnh2, Kcnd3, and Kcnj2) and calcium handling-associated genes (Cacna1c, Camk2, Ryr2, and Atp2a2) was downregulated. Connexin 40 expression was significantly downregulated, leading to frequent lateralization to the inflamed atrium. Sympathetic and parasympathetic innervation and neurotrophin expression (nerve growth factor and brain-derived neurotrophic factor) were upregulated in the inflamed atria. Inflammatory atrial cardiomyopathy promotes susceptibility to AF via arrhythmogenic electrical, structural, and autonomic remodeling of the atria.

Vericiguat reduces electrical and structural remodeling in a rabbit model of atrial fibrillation.

Purpose: The molecular etiology of atrial fibrillation (AF) and its treatment are poorly understood. AF involves both electrical and structural features. Vericiguat can ameliorate cardiac remodeling in heart failure. The effects of vericiguat on AF, however, are unclear. Here, the actions of vericiguat on atrial structural and electrical remodeling in AF and its possible mechanisms were investigated. Methods and Results: Thirty-six rabbits were randomly allocated to four groups, namely, sham, RAP (pacing with 600 beats/min over three weeks), vericiguat-treated (three weeks' pacing plus daily oral dose of 1.5 mg/kg of vericiguat), and vericiguat-treated only. HL-1 cells received rapid pacing with or without vericiguat. Parameters including electrophysiology, echocardiography, histology, Ca2+ levels, and ICaL density, as well as levels of TRPC6, CaN, NFAT4, p-NFAT4, Cav1.2, collagen I, collagen III, and ST2 were measured. Significant changes of above proteins expression level, circulating biochemical indices, Ca2+ concentrations, and ICaL density in both animals and cell models, these effects were significantly restored by vericiguat. Vericiguat also reversed the enlarged atrium and significantly reduced myocardial fibrosis, together with preventing reduced atrial effective refractory periods (AERPs) and AF induction rate. Conclusion: Vericiguat thus ameliorated AF-associated structural and electrical remodeling. These findings suggest the potential of vericiguat for treating AF.

Effects of Sacubitril/Valsartan on the Expression of CaMKII/Cav1.2 in Atrial Fibrillation Stimulation Rabbit Model.

Overall, 18 rabbits were randomly divided into control, pacing (600 beats/min), and pacing+sac/val groups. The rabbits in the pacing+sac/val cohort received oral sac/val (10 mg/kg twice daily) across the 21-day investigation period. After three weeks, the atrial effective refractory period (AERP) and AF induction rate were compared. HL-1 cultures were exposed to fast pacing (24 h) with and without LBQ657 (active sacubitril form)/valsartan. Western blots were used for detecting Cav1.2 and CaMKII expression within atrial muscles of the rabbits and HL-1 cultures of AF model. In comparison to the sham cohort, the AF induction rate was markedly increased together with AERP reduction within pacing cohort. Such changes were markedly rescued through sac/val treatment in pacing+sac/val cohort. The proteomic expression profiles of CaMKII and Cav1.2 showed that the CaMKII expression was markedly upregulated, while Cav1.2 expression was downregulated in the pacing cohort. Importantly, these effects were absent in pacing+sac/val cohort. Results of this study show that sac/val treatment regulates the expression of CaMKII/Cav1.2 and could alter this pathway in atrial rapid electrical stimulation models. Therefore, this investigation could contribute to a novel strategy in AF therapeutics in clinical settings.

Study of electrophysiological, structural, and mitochondrial metabolism remodelling in a sheep model of atrial fibrillation monitored by telemetry

Atrial Fibrillation (AF) stabilization depends on remodelling processes affecting the electrophysiological, metabolic, and structural properties of the atrial muscle. Develop an AF Sheep model to study the electrophysiogical, structural and bioenergetic remodelling of the cardiac tissue. An algorithm controlled pacemaker stimulating repeatedly the right atria at 10 Hz during 30 sec followed by 5 sec of sinus rhythm (SR) detection was used to induce AF. Its development was monitored by telemetry. Electrophysiological remodelling was studied in vivo by contact mapping and ex vivo by optical mapping. Structural remodelling was studied at the organ level using computed tomography (μCT) and at the mitochondrial level by electronic microscopy. Bioenergetic remodelling was evaluated on isolated mitochondria. AF sheep were kept 75 days before being studied. AF induction rate was 80%. AF developed and stabilized after 25 and 48 days, respectively. Animals remained less than 0.02 ± 0.03% in SR once AF was installed. In vivo contact mapping revealed a decreased voltage in AF atria compared to Sham. The highest AF frequencies were localised in the pulmonary veins. When compared to Sham, AF induced: (1) a 50% decrease of the atrial effective refractory periods; (2) a left atrial decrease in action potential duration; (3) an increase in atrial volumes; (4) Fat infiltration; (5) a decrease in mitochondrial cristae density; (6) a decrease in ATP synthesis rate; (7) an increased oxidation of the mitochondrial NAD(P)H pool; (9) an increased mitochondrial H2O2 emission, independently of the respiratory substrates used to fuel the electron transport chain. The AF Sheep model developed is characterized by occurrence of remodelling processes at different levels. Further studies will establish the time course of development of remodelling processes in order to improve AF therapeutics strategies by targeting atrial remodelling.

Modulative effects of lncRNA TCONS_00202959 on autonomic neural function and myocardial functions in atrial fibrillation rat model.

Atrial fibrillation (AF) is a typical cardiac arrhythmia. The autonomic nervous system can modulate the myocardial system with complicated mechanisms. Long non-coding RNA (lncRNA) is involved in myocardial diseases, and lncRNA TCONS_00202959 is down-regulated in AF. However, the detailed effects of AF on automatic functions or cardiomyocytes are not well known yet. Sprague-Dawley (SD) rats were randomly divided into control group, AF group (which was prepared by injecting the acetylcholine-CaCl2 solution) and treatment group (receiving lentiviral transfection of lncRNA TCONS_00202959 on AF rats). Real Time-quantitative PCR (RT-PCR) was used to measure the expression of lncRNA TCONS_00202959. Atrial effective refractory period (AERP) and AF induction rate were measured, along with heart rate variability (HRV) analysis to reveal autonomic nervous function. The expression of tyrosine hydroxylase (TH) and choline acetyltransferase (CHAT) was analyzed in atrial tissues. The expression of lncRNA TCONS_00202959 was decreased in the AF group compared to the control group (p < 0.05), which also had shortened AERP and elevated AF induction rate. The analysis of the autonomic nervous function revealed lower standard deviation of NN intervals (SDNN), SDNN of atrial (SDANN), root mean square of successive differences (RMSSD) and SDNN intervals in all 5-min segments (SDNNindx), plus elevated power ratio of low frequency (LF)/high frequency (HF). TH expression was increased whilst CHAT expression was decreased (p < 0.05). The treatment group showed enhanced expression of lncRNA TCONS_00202959, elongated AERP plus decreased AF induction rate. The treatment rats also had higher SDNN, SDANN, RMSSD and SDNNindx, lower LF/HF ratio, decreased TH expression and increased CHAT expression (p < 0.05 compared to the AF group). AF rats had decreased expression of lncRNA TCONS_00202959, which can help to prevent AF pathogenesis by suppressing cardiac autonomic nervous function.

Time-dependent cervical vagus nerve stimulation and frequency-dependent right atrial pacing mediates induction of atrial fibrillation.

Objective:This study aimed to investigate the effects of right cervical vagus trunk simulation (RVTS) and/or right atrial pacing (RAP) on the induction of atrial fibrillation (AF).Methods:Twenty-four healthy adult dogs were randomly divided into four groups: RAP groups comprising RAP500 (RAP with 500 beats/min) and RAP1000 (RAP with 1000 beats/min) and RVTS groups comprising RVTS and RAP500+RVTS. All dogs underwent 12-h intermittent RAP and/or RVTS once every 2 h. The AF induction rate, AF duration, atrial effective refractory period (ERP), and dispersion of ERP (dERP) were compared after every 2 h of RAP or/and RVTS.Results:All groups had successful AF induction. The RAP1000 group had the highest AF induction rate and the longest AF duration. The RAP1000 group also had a shortened ERP in comparison to the other groups as well as the maximum dERP. Compared to the RAP500 group, RAP500+RVTS had an increased capacity to induce AF as measured by the AF induction rates, AF duration, ERP, and dERP.Conclusion:Increased tension in the vagus nerve and the intrinsic cardiac autonomic nervous system plays an important role in AF induction through different potential mechanisms. Interventions involving the vagus nerve and/or intrinsic cardiac autonomic nervous system can be a future potential therapy for AF.

Prevention of Atrial Fibrillation by Using Sarcoplasmic Reticulum Calcium ATPase Pump Overexpression in a Rabbit Model of Rapid Atrial Pacing.

BackgroundRecent research suggests that abnormal Ca2+ handling plays a role in the occurrence and maintenance of atrial fibrillation (AF). Therefore, Ca2+ release and ingestion depend on properties of the ryanodine receptor (RyR) and sarcoplasmic reticulum Ca2+ATPase2a (SERCA2a). This study aimed to detect whether SERCA2a gene overexpression has a preventive effect on atrial fibrillation caused by rapid pacing right atrium.Material/MethodsForty-eight New Zealand white rabbits were randomly divided into a control group, AF group, AAV9/GFP group, and AAV9/SERCA2a group. The right atrium was rapidly paced at 600 beats/min for 30 days after an intraperitoneal injection of an adeno-associated virus expressing the SERCA2a gene and GFP. The AF induction rate and the effective refraction period (ERP) were measured after 0, 4, 8, 12, and 24 h of pacing. Western blot analysis was used to test for the expression of SERCA2a. Changes in atrial tissue structure were observed by H&E staining and electron microscopy.ResultsThe AF induction rate was higher in the AF groups than in the AAV9/SERCA2a group at different time points of pacing. After 12 h of pacing, ERP was significantly prolonged in the AAV9/SERCA2a group compared to the AF and AAV9/GFP groups (p<0.05). SERCA2a protein expression was significantly lower in the AF and AAV9/GFP groups compared to the control group (p<0.05), while expression was significantly higher in the AAV9/SERCA2a group than in the AF and AAV9/GFP groups (p<0.05). The myocardial structure of the AAV9/SERCA2a group was significantly improved compared with the AF group, indicating that SERCA2a overexpression relieved the structural remodeling of atrial fibrillation.ConclusionsSERCA2a overexpression is capable of suppressing ERP shortening and AF induced by rapid pacing atrium. SERCA2a gene therapy is expected to be a new anti-atrial fibrillation strategy.

Acute ivabradine treatment reduces heart rate without increasing atrial fibrillation inducibility irrespective of underlying vagal activity in dogs.

Ivabradine, a bradycardic agent, has been shown to stably reduce patient's heart rate (HR) in the setting of acute cardiac care. However, an association between atrial fibrillation (AF) risk and acute ivabradine treatment remains a controversial clinical issue, and has not been thoroughly investigated. Bradycardia and abnormal atrial refractoriness induced by ivabradine treatment may enhance vulnerability to AF induction, especially when vagal nerve is concurrently activated. We aimed to experimentally investigate the effects of acute ivabradine treatment with/without concurrent vagal activation on AF inducibility. In 16 anesthetized dogs, cervical vagal nerves were prepared for electrical stimulation (VS). AF induction rate (AFIR) was determined by atrial burst pacing. HR, atrial action potential duration (APD), atrial effective refractory period (ERP), and AFIR were obtained consecutively at baseline, during delivery of VS (VS alone), after intravenous injection of ivabradine 0.5mg/kg (n=8, ivabradine group) or saline (n=8, saline group), and again during VS delivery (drug+VS). In the ivabradine group, ivabradine alone significantly lowered HR compared to baseline, while ivabradine+VS significantly lowered HR compared to VS alone. Contrary to expectations, there were no significant differences in trends of APD, temporal dispersion of APD, ERP, and AFIR between ivabradine and saline groups. Irrespective of whether ivabradine or saline was injected, VS significantly shortened APD and ERP, and increased AFIR. Interestingly, although bradycardia in response to ivabradine injection was more intense than that to VS alone, AFIR was significantly lower after ivabradine injection than during VS alone. We conclude that, despite its intense bradycardic effect, acute ivabradine treatment does not increase AF inducibility irrespective of underlying vagal activity. This study may constitute support for the safety of using ivabradine in the setting of acute cardiac care.

Relationship between new-onset atrial fibrillation and sympathetic neural remodeling in a canine acute myocardial infarction model

To establish the canine model of new-onset atrial fibrillation (AF) after acute myocardial infarction (AMI), and explore the relationship between new-onset AF and sympathetic neural remodeling in this model. Twenty four adult mongrel dogs were randomly divided into 4 groups by applying random number table. Group A (n=6): ligate the left circumflex artery (LCX). Group B (n=6): ligate the LCX and right atrial anterior artery and right atrial middle artery. Group C (n=6): ligate left anterior descending artery.Group D (n=6): sham operation.Sequential electrophysiology study was performed in all dogs to determine the AF induction rate, AF duration, effective refractory period (ERP), the density of tyrosine hydroxylase (TH) and norepinephrine transporter (NET) before AMI or sham operation, and at 30 min, 2 hours and 4 hours after AMI or sham operation. (1) The highest AF induction rate of right atrium and left auricle was 96.7%(58/60) and 95.0%(57/60) in group B, 81.7%(49/60) and 38.3%(23/60) in group A, 28.3%(17/60) and 35.0%(21/60) in group C, 20.0%(12/60) and 33.3%(20/60) in group D. (2) At 4 hours after AMI, AF duration was significantly prolonged in group B(193.50±54.67) s, compared with group A(53.83±9.37) s, group C(45.00±19.50) s, and group D(16.67±4.50) s (all P<0.05). (3) In group B, the ERP of AF was prolonged at 30 minutes after AMI and shortened at 2 hours and 4 hours after AMI compared with baseline level(all P<0.05). (4) The TH density of left atrium ((3 485±694) µm2/mm2) and left auricle((2 645±454) µm2/mm2) in group A and the TH density of left atrium ((7 873±1159) µm2/mm2) and left auricle((3 070±605) µm2/mm2) in group B were significantly higher than those in group C ((1 474±475) µm2/mm2, (1 177±277) µm2/mm2) and group D ((678±206) µm2/mm2, (489±125) µm2/mm2) (all P<0.05), and the TH density of right atrium and right auricle in group B were higher than group A (all P<0.05). The NET density of left atrium((476±75) µm2/mm2) and left auricle ((414±52) µm2/mm2) in group A and the NET density of left atrium((527±81) µm2/mm2) and left auricle((429±85) µm2/mm2) in group B were lower than that in group C ((1 044±105) µm2/mm2, (867±67) µm2/mm2) and group D ((1 438±60) µm2/mm2, (1 027±119) µm2/mm2) (all P<0.05). Ligating the LCX, right atrial anterior artery and right atrial middle artery at the same time can significantly increase the success rate in establishing the canine model of new-onset atrial fibrillation after acute myocardial infarction and can also increase the AF duration.Cardiac sympathetic remodeling after acute myocardial infarction is associated with induction and duration of AF.

Renal sympathetic denervation suppresses atrial fibrillation induced by acute atrial ischemia/infarction through inhibition of cardiac sympathetic activity

ObjectiveThis study aims to explore the effects of renal sympathetic denervation (RSD) on atrial fibrillation (AF) inducibility and sympathetic activity induced by acute atrial ischemia/infarction. MethodsAcute ischemia/infarction was induced in 12 beagle dogs by ligating coronary arteries that supply the atria. Six dogs in the sham-RSD group did not undergo RSD, and six dogs without coronary artery ligation served as controls. AF induction rate, sympathetic discharge, catecholamine concentration and densities of tyrosine hydroxylase-positive nerves were measured. ResultsAcute atrial ischemia/infarction resulted in a significant increase of AF induction rate, which was decreased by RSD compared to controls (P<0.05). The root-mean-square peak value, peak area and number of sympathetic discharges were significantly augmented by atrial ischemia relative to the baseline and control (P<0.05). The number of sympathetic discharges was significantly reduced in the RSD group, compared to the control and sham-RSD groups (P<0.05). Norepinephrine and epinephrine concentrations in the atria, ventricle and kidney were elevated by atrial ischemia/infarction, but were reduced by RSD (P<0.05). ConclusionsSympathetic hyperactivity was associated with pacing-induced AF after acute atrial ischemia/infarction. RSD has the potential to reduce the incidence of new-onset AF after acute atrial ischemia/infarction. The inhibition of cardiac sympathetic activity by RSD may be one of the major underlying mechanisms for the marked reduction of AF inducibility.

β3-Adrenoceptor Impairs Mitochondrial Biogenesis and Energy Metabolism During Rapid Atrial Pacing-Induced Atrial Fibrillation

The β3-adrenoceptor (β3-AR) is implicated in cardiac remodeling. Since metabolic dysfunction due to loss of mitochondria plays an important role in heart diseases, we examined the effects of β3-AR on mitochondrial biogenesis and energy metabolism in atrial fibrillation (AF). Atrial fibrillation was created by rapid atrial pacing in adult rabbits. Rabbits were randomly divided into 4 groups: control, pacing (P7), β3-AR antagonist (L748337), and β3-AR agonist (BRL37344) groups. Atrial effective refractory period (AERP) and AF induction rate were measured. Atrial concentrations of adenine nucleotides and phosphocreatine were quantified through high-performance liquid chromatography. Mitochondrial DNA content was determined. Real-time polymerase chain reaction and Western blot were used to examine the expression levels of signaling intermediates related to mitochondrial biogenesis. After pacing for 7 days, β3-AR was significantly upregulated, AERP was reduced, and the AF induction rate was increased. The total adenine nucleotides pool was significantly reduced due to the decrease in adenosine triphosphate (ATP). The P7 group showed decreased activity of F0F1-ATPase. Mitochondrial DNA content was decreased and mitochondrial respiratory chain subunits were downregulated after pacing. Furthermore, expression of transcription factors involved in mitochondrial biogenesis, including peroxisome proliferator-activated receptor γ coactivator 1α (PGC-1α), nuclear respiratory factor 1 (NRF-1), and mitochondrial transcription factor A (Tfam), was lower in the P7 group in response to β3-AR activation. Further stimulation of β3-AR with BRL37344 exacerbated these effects, together with a significant decrease in the levels of phosphocreatine. In contrast, inhibition of β3-AR with L748337 partially restored mitochondrial biogenesis and energy metabolism of atria in the paced rabbits. The activation of β3-AR contributes to atrial metabolic remodeling via transcriptional downregulation of PGC-1α/NRF-1/Tfam pathway that are involved in mitochondrial biogenesis, which ultimately perturbs mitochondrial function in rapid pacing-induced AF. The β3-AR is therefore a potential novel therapeutic target for the treatment or prevention of AF.

Atrial fibrillation electrical remodelling via ablation of the epicardial neural networks and suprathreshold stimulation of vagosympathetic nerve.

BackgroundNumerous studies have shown that the cardiac autonomic nervous system (CANS) is involved in the occurrence and persistence of atrial fibrillation (AF). The CANS is commonly considered to consist of the extrinsic and intrinsic autonomic nerves. The influence of exogenous and endogenous nerve stimulation plexus ablation on pulmonary vein sleeves and atrial myocardium provides important information in understanding the occurrence and persistence of AF. Vagosympathetic nerve stimulation and epicardial neural networks are important participants in atrial electrical remodelling (AER). Elucidation of the changes in the electrophysiological indicators of the atrial and pulmonary veins caused by epicardial neural network ablation and autonomic nerve stimulation may provide a theoretical basis for the clinical treatment of AF.Material/MethodsA total of 13 beagle dogs were randomly divided into 2 groups: the control group (n=6), which was treated with a simple rapid atrial pacing (RAP) for 6 h, and the experimental group (n=7), which was treated with RAP+vagus nerve stimulation (VNS) for 6 h. Both groups were treated with epicardial ganglia plexus (GP) ablation after 6 h. We measured the monophasic action potential (MAP), various parts of the effective refractory period (ERP), and AF induction rate before and after pacing or ablation.ResultsWith the extension of the pacing time, the atrial MAP and ERP of the 2 groups shortened and returned to normal after ablation plexus. After GP ablation, the atrial AF-induced rate did not decrease significantly compared with that of the pulmonary vein.ConclusionsVagus nerve threshold stimulation exacerbated the deterioration of electrical remodelling, whereas the epicardial neural network ablation blocked or reversed the AER.

Oxidation‐ and CaMKII‐Mediated Sarcoplasmic Reticulum Ca2+ Leak Triggers Atrial Fibrillation in Aging

Advanced age is a well-recognized predisposition to atrial fibrillation (AF). However, the cellular electrophysiological changes that underlie the heightened susceptibility to AF in aged individuals remain poorly understood. Sarcoplasmic reticulum (SR) Ca(2+) leak that results from posttranslational modification of type 2 ryanodine receptor channels (RyR2) has been implicated in arrhythmogenesis. We hypothesize that aging alters atrial myocytes Ca(2+) homeostasis and RyR2 function, which create a substrate for AF initiation. We examined the susceptibility to AF in aged (24 months) and young adult (4-5 months) mice using an intraesophageal atrial electrical stimulation protocol. Aged mice showed significant higher AF induction rate (43.3%, n = 30) than young adults (8.8%, n = 34, P < 0.01). In accordance with these in vivo findings, significantly increased diastolic SR Ca(2+) leak and arrhythmogenic Ca(2+) activities with reduced SR Ca(2+) content were observed in aged atrial myocytes. Western blot showed RyR2 oxidation and phosphorylation at Ser2814 (Ca(2+) /calmodulin-dependent protein kinase II [CaMKII] site), but not phosphorylation at Ser2808 (protein kinase A [PKA] and CaMKII site), were increased in aged atrial myocytes. The selective CaMKII inhibitor (KN-93), as well as the antioxidant reagent (DTT) reversed the diastolic Ca(2+) leak and the frequency of spontaneous Ca(2+) transients in aged atrial myocytes, whereas PKA inhibition with H-89 was ineffective. Aging increases both the oxidation and CaMKII-phosphorylation of RyR2, which result in diastolic SR Ca(2+) leak and facilitate AF initiation. These results contribute to the electrophysiological remodeling of aged atria and suggest a therapeutic strategy for AF treatment in aging.