In vivo cardiovascular profile of ryanodine receptor 2 inhibitor M201-A: Utility as an anti-atrial fibrillatory drug for patients suffering from heart failure with preserved ejection fraction.

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.

Evaluation of Left Atrial Electromechanical Delay and Left Atrial Phasic Functions in Patients Undergoing Treatment with Cardiotoxic Chemotherapeutic Agents.

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.

The Abl1 tyrosine kinase is a key player in doxorubicin-induced cardiomyopathy and its p53/p73 cell death mediated signaling differs in atrial and ventricular cardiomyocytes.

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.

Aldosterone Robustly Promotes Atrial Fibrillation in the Presence of Chronic Volume Overload in Rats.

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.

Salidroside treatment decreases the susceptibility of atrial fibrillation in diabetic mice by reducing mTOR-STAT3-MCP-1 signaling and atrial inflammation.

Atrial fibrillation (AF) is the most common sustained cardiac arrhythmia in clinic, and type 2 diabetes mellitus (T2DM) is an independent risk factor for AF. Salidroside (Sal), the active ingredient of the Rhodiola rosea, has hypoglycemic, anti-inflammatory, anti-fibrotic and anti-arrhythmic effects. The aim of this study is to investigate the effects and underlying molecular mechanisms of Sal on T2DM associated atrial inflammation and the pathogenesis of AF. In the in vivo study, T2DM mice model was established by high-fat diet and intraperitoneal injection of streptozotocin (STZ). Sal (25 mg/kg/d, 50 mg/kg/d, and 100 mg/kg/d) was administered orally for 4 weeks. T2DM caused atrial electrical and structural remodeling and significantly increased the susceptibility of AF. Meanwhile, mTOR-STAT3-MCP-1 signaling and inflammatory markers were also significantly enhanced in diabetic atria. However, Sal dose-dependently ameliorated cardiac dysfunction, mitigated atrial structural and electrical remodeling, and reduced atrial inflammation. Moreover, Sal-treated group exhibited remarkably down-regulated activity of mTOR-STAT3-MCP-1 pathway, and decreased atrial monocyte/macrophage infiltration. In palmitic acid (PA)-challenged HL-1 cells, Sal attenuated cytotoxicity, downregulated the expressions of TNF-α, IL-6, MCP-1, and inhibited the activation of mTOR-STAT3 signaling. However, co-treatment with MHY1485 (a mTOR agonist) reversed these effects. Taken together, the present study demonstrates that Sal treatment decreases the susceptibility of AF in diabetic mice by reducing mTOR-STAT3-MCP-1 signaling and atrial monocyte/macrophage infiltration. Sal treatment may represent a novel preventive therapy for cardiac arrhythmia and atrial fibrillation in diabetic patients.

Daily exposure to chlordecone, an organochlorine pesticide, increases cardiac fibrosis and atrial fibrillation vulnerability.

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.

Empagliflozin and left atrial function in patients with type 2 diabetes mellitus and coronary artery disease: insight from the EMPA-HEART CardioLink-6 randomized clinical trial.

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).

Opposite Contractile Effects of Amphetamine-Related Hallucinogenic Drugs in the Isolated Human Atrium.

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.

SIRT3 sulfhydration using hydrogen sulfide inhibited angiotensin II-induced atrial fibrosis and vulnerability to atrial fibrillation via suppression of the TGF-ß1/smad2/3 signalling pathway.

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.

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.

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.

Body Surface Potential Mapping during Atrial Depolarization in Rats with Post-Infarction Chronic Heart Failure against the Background of Fabomotizole Therapy.

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.

Activation of IP3R in atrial cardiomyocytes leads to generation of cytosolic cAMP.

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.

The Efficacy of I Na Block to Cardiovert Atrial Fibrillation Is Enhanced by Inhibition of I K1.

ABSTRACT: There is a need for more efficient pharmacological cardioversion of atrial fibrillation (AF). We tested the hypothesis that inhibition of I K1 significantly enhances the efficacy of I Na block to depress atrial excitability and to cardiovert AF. The study was conducted in canine isolated arterially perfused right atrial preparations with rim of ventricular tissue. AF was induced in the presence of acetylcholine (ACh; 0.5 µM). BaCl 2 (10 µM) was used to inhibit I K1 and flecainide (1.5 µM) to block I Na . Sustained AF (>45 minutes) was recorded in 100% atria (5/5) in the presence of ACh alone. Flecainide cardioverted AF in 50% of atria (4/8), BaCl 2 in 0% (0/5), and their combination in 100% (5/5). AF cardioversion occurred in 15 ± 9 minutes with flecainide alone (n = 4) and in 8 ± 9 minutes with the combination (n = 5). Following drug-induced AF cardioversion, AF was inducible in 4/4 atria with flecainide alone (≤5 minutes duration) and in 2/5 atria with the combination (≤30 seconds duration). Atrial excitability was significantly more depressed by combined versus monotherapies. There was little to no effect on ventricular excitability under any condition tested. Thus, inhibition of I K1 significantly enhances the efficacy of flecainide to depress atrial excitability and to cardiovert AF in our experimental setting. A combination of I Na and I K1 inhibition may be an effective approach for cardioversion of AF.

Nrf2 Ameliorates Atrial Fibrosis During Antithrombotic Therapy for Atrial Fibrillation by Modulating CYP2C9 Activity.

ABSTRACT: Anticoagulant therapy can significantly reduce the incidence of stroke and peripheral embolism events in patients with atrial fibrillation (AF). Although warfarin is widely used as an anticoagulant drug, a wrong dose can lead to increased risks of bleeding or blood clots. The aim of this study was to assess whether nuclear factor-erythroid-2-related factor 2 (Nrf2) can improve the efficacy of warfarin through the regulation of cytochrome P450 family 2 subfamily C member 9 (CYP2C9) using a rat model of AF. Results showed that AF significantly reduced Nrf2 in myocardial tissue of sham-operated rats. Furthermore, Nrf2 overexpression effectively reduced AF-induced atrial fibrosis by reducing collagen in the left atrium, inhibiting the expression of the fibrosis-related genes collagen I and transforming growth factor-ß1 in rats with AF. Nrf2 overexpression can activate CYP2C9, decrease the serum concentration of warfarin, and decrease prothrombin time and international normalized ratio in AF rats. In this article, Nrf2 overexpression protects against fibrosis, increased survival in AF rats, and activated CYP2C9 expression, thus broadening the therapeutic range of warfarin in AF rats.

Curcumin improves atrial fibrillation susceptibility by regulating tsRNA expression in aging mouse atrium.

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.

Anti-atrial Fibrillatory and Cardiorenal Protective Effects of the Combination of Valsartan and Cilnidipine in Dahl Salt-Sensitive Rats.

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.

Atypical Antiadrenergic Effect of Refralon as a Mechanism of High Antiarrhythmic Effectiveness.

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.

The Impact of Sodium-Glucose Cotransporter-2 Inhibitors on Atrial Electromechanical Conduction Time.

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.

Dapagliflozin: A sodium-glucose cotransporter 2 inhibitor, attenuates angiotensin II-induced atrial fibrillation by regulating atrial electrical and structural remodeling.

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.

Prostaglandin I2 signaling prevents angiotensin II-induced atrial remodeling and vulnerability to atrial fibrillation in mice.

Atrial fibrillation (AF) is the most common arrhythmia, and atrial fibrosis is a pathological hallmark of structural remodeling in AF. Prostaglandin I2 (PGI2) can prevent the process of fibrosis in various tissues via cell surface Prostaglandin I2 receptor (IP). However, the role of PGI2 in AF and atrial fibrosis remains unclear. The present study aimed to clarify the role of PGI2 in angiotensin II (Ang II)-induced AF and the underlying molecular mechanism. PGI2 content was decreased in both plasma and atrial tissue from patients with AF and mice treated with Ang II. Treatment with the PGI2 analog, iloprost, reduced Ang II-induced AF and atrial fibrosis. Iloprost prevented Ang II-induced atrial fibroblast collagen synthesis and differentiation. RNA-sequencing analysis revealed that iloprost significantly attenuated transcriptome changes in Ang II-treated atrial fibroblasts, especially mitogen-activated protein kinase (MAPK)-regulated genes. We demonstrated that iloprost elevated cAMP levels and then activated protein kinase A, resulting in a suppression of extracellular signal-regulated kinase1/2 and P38 activation, and ultimately inhibiting MAPK-dependent interleukin-6 transcription. In contrast, cardiac fibroblast-specific IP-knockdown mice had increased Ang II-induced AF inducibility and aggravated atrial fibrosis. Together, our study suggests that PGI2/IP system protects against atrial fibrosis and that PGI2 is a therapeutic target for treating AF.The prospectively registered trial was approved by the Chinese Clinical Trial Registry. The trial registration number is ChiCTR2200056733. Data of registration was 2022/02/12.