Triggers Of Atrial Fibrillation Research Articles

Immunoproteasome Subunit β5i Promotes Ang II (Angiotensin II)-Induced Atrial Fibrillation by Targeting ATRAP (Ang II Type I Receptor-Associated Protein) Degradation in Mice.

Atrial fibrillation (AF) is the most common type of cardiac arrhythmia and increases the risk of stroke, heart failure, and death. Ang II (angiotensin II) triggers AF, mainly through stimulation of the AT1R (Ang II type I receptor). The immunoproteasome is a highly efficient proteolytic machine derived from the constitutive proteasome, but the role it plays in regulating AT1R activation and triggering AF remains unknown. Here, we show that among the catalytic subunits, β5i (PSMB8) expression, and chymotrypsin-like activity were the most significantly upregulated in atrial tissue of Ang II-infused mice or serum from patients with AF. β5i KO (β5i knockout) in mice markedly attenuated Ang II-induced AF incidence, atrial fibrosis, inflammatory response, and oxidative stress compared with WT (wild type) animals, but injection with recombinant adeno-associated virus serotype 9-β5i increased these effects. Moreover, we found that ATRAP (AT1R-associated protein) was a target of β5i. Overexpression of ATRAP significantly attenuated Ang II-induced atrial remodeling and AF in recombinant adeno-associated virus serotype 9-β5i-injected mice. Mechanistically, Ang II upregulated β5i expression to promote ATRAP degradation, which resulted in activation of AT1R-mediated NF-κB signaling, increased NADPH oxidase activity, increased TGF (transforming growth factor)-β1/Smad signaling, and altered the expression of Kir2.1 and CX43 (connexin 43) in the atria, thereby affecting atrial remodeling and AF. In summary, this study identifies β5i as a negative regulator of ATRAP stability that contributes to AT1R activation and to AF, highlighting that targeting β5i activity may represent a potential therapeutic approach for the treatment of hypertensive AF.

A review and analysis of strategies for prediction, prevention and management of post-operative atrial fibrillation after non-cardiac thoracic surgery.

Atrial fibrillation (AF) is the most common sustained arrhythmia after non-cardiac thoracic surgery and is associated with a significant increase in perioperative morbidity, intensive care unit (ICU) admission, and mortality. Practical guidance is needed to assist clinicians in managing this critical issue and direct further research. Here we aim to provide a synoptic review and analysis of the literature to distil practical recommendations for prediction, prevention and management of post-operative atrial fibrillation (POAF) suitable for clinical application and further evaluation. To predict POAF, risk factors including age, gender, elevated pre-operative heart rate and extent of surgical resection have been reproducibly identified and integrated into scoring systems. To prevent POAF, prophylactic therapy with beta-blockers, amiodarone, or magnesium have demonstrated to be effective, but need further trials in high-risk populations. To manage unstable POAF that precipitates hypotension and hypoperfusion, although rare, requires immediate electrocardioversion to restore cardiac output and adequate oxygen delivery. For hemodynamically stable patients, rate control and prevention of adverse events are the objectives. We propose an individualized approach aimed at rate control using initial incremental low dose beta-blocker or calcium channel blocker (CCB) therapy with close monitoring of a patient's response, and continuation of the drug that they respond to, along with simultaneous identification and reduction of triggers of AF, in order for spontaneous return to sinus rhythm. For patients who persistently fail to respond to rate control therapy, rhythm control may be considered using an agent selected based on the patient's comorbidities and the medications' side effect profile. While controversial and requiring further study, anticoagulation therapy is recommended in patients with risk factors for thromboembolic events after 48 hours of persistent AF. We recommend continuous prospective monitoring of incidence and severity of POAF to track the impact of protocols to predict, prevent and manage POAF.

Mind the gap: Quantification of incomplete ablation patterns after pulmonary vein isolation using minimum path search.

Pulmonary vein isolation (PVI) is a common procedure for the treatment of atrial fibrillation (AF) since the initial trigger for AF frequently originates in the pulmonary veins. A successful isolation produces a continuous lesion (scar) completely encircling the veins that stops activation waves from propagating to the atrial body. Unfortunately, the encircling lesion is often incomplete, becoming a combination of scar and gaps of healthy tissue. These gaps are potential causes of AF recurrence, which requires a redo of the isolation procedure. Late-gadolinium enhanced cardiac magnetic resonance (LGE-CMR) is a non-invasive method that may also be used to detect gaps, but it is currently a time-consuming process, prone to high inter-observer variability. In this paper, we present a method to semi-automatically identify and quantify ablation gaps. Gap quantification is performed through minimum path search in a graph where every node is a scar patch and the edges are the geodesic distances between patches. We propose the Relative Gap Measure (RGM) to estimate the percentage of gap around a vein, which is defined as the ratio of the overall gap length and the total length of the path that encircles the vein. Additionally, an advanced version of the RGM has been developed to integrate gap quantification estimates from different scar segmentation techniques into a single figure-of-merit. Population-based statistical and regional analysis of gap distribution was performed using a standardised parcellation of the left atrium. We have evaluated our method on synthetic and clinical data from 50 AF patients who underwent PVI with radiofrequency ablation. The population-based analysis concluded that the left superior PV is more prone to lesion gaps while the left inferior PV tends to have less gaps (p < .05 in both cases), in the processed data. This type of information can be very useful for the optimization and objective assessment of PVI interventions.

Profibrotic, Electrical, and Calcium-Handling Remodeling of the Atria in Heart Failure Patients With and Without Atrial Fibrillation.

Atrial fibrillation (AF) and heart failure (HF) are common cardiovascular diseases that often co-exist. Animal models have suggested complex AF-promoting atrial structural, electrical, and Ca2+-handling remodeling in the setting of HF, but data in human samples are scarce, particularly regarding Ca2+-handling remodeling. Here, we evaluated atrial remodeling in patients with severe left ventricular (LV) dysfunction (HFrEF), long-standing persistent (‘chronic’) AF (cAF) or both (HFrEF-cAF), and sinus rhythm controls with normal LV function (Ctl) using western blot in right-atrial tissue, sharp-electrode action potential (AP) measurements in atrial trabeculae and voltage-clamp experiments in isolated right-atrial cardiomyocytes. Compared to Ctl, expression of profibrotic markers (collagen-1a, fibronectin, periostin) was higher in HFrEF and HFrEF-cAF patients, indicative of structural remodeling. Connexin-43 expression was reduced in HFrEF patients, but not HFrEF-cAF patients. AP characteristics were unchanged in HFrEF, but showed classical indices of electrical remodeling in cAF and HFrEF-cAF (prolonged AP duration at 20% and shorter AP duration at 50% and 90% repolarization). L-type Ca2+ current (ICa,L) was significantly reduced in HFrEF, cAF and HFrEF-cAF, without changes in voltage-dependence. Potentially proarrhythmic spontaneous transient-inward currents were significantly more frequent in HFrEF and HFrEF-cAF compared to Ctl, likely resulting from increased sarcoplasmic reticulum (SR) Ca2+ load (integrated caffeine-induced current) in HFrEF and increased ryanodine-receptor (RyR2) single-channel open probability in HFrEF and HFrEF-cAF. Although expression and phosphorylation of the SR Ca2+-ATPase type-2a (SERCA2a) regulator phospholamban were unchanged in HFrEF and HFrEF-cAF patients, protein levels of SERCA2a were increased in HFrEF-cAF and sarcolipin expression was decreased in both HFrEF and HFrEF-cAF, likely increasing SR Ca2+ uptake and load. RyR2 protein levels were decreased in HFrEF and HFrEF-cAF patients, but junctin levels were higher in HFrEF and relative Ser2814-RyR2 phosphorylation levels were increased in HFrEF-cAF, both potentially contributing to the greater RyR2 open probability. These novel insights into the molecular substrate for atrial arrhythmias in HF-patients position Ca2+-handling abnormalities as a likely trigger of AF in HF patients, which subsequently produces electrical remodeling that promotes the maintenance of the arrhythmia. Our new findings may have important implications for the development of novel treatment options for AF in the context of HF.

Calcium in the Pathophysiology of Atrial Fibrillation and Heart Failure.

Atrial fibrillation (AF) is commonly associated with heart failure. A bidirectional relationship exists between the two—AF exacerbates heart failure causing a significant increase in heart failure symptoms, admissions to hospital and cardiovascular death, while pathological remodeling of the atria as a result of heart failure increases the risk of AF. A comprehensive understanding of the pathophysiology of AF is essential if we are to break this vicious circle. In this review, the latest evidence will be presented showing a fundamental role for calcium in both the induction and maintenance of AF. After outlining atrial electrophysiology and calcium handling, the role of calcium-dependent afterdepolarizations and atrial repolarization alternans in triggering AF will be considered. The atrial response to rapid stimulation will be discussed, including the short-term protection from calcium overload in the form of calcium signaling silencing and the eventual progression to diastolic calcium leak causing afterdepolarizations and the development of an electrical substrate that perpetuates AF. The role of calcium in the bidirectional relationship between heart failure and AF will then be covered. The effects of heart failure on atrial calcium handling that promote AF will be reviewed, including effects on both atrial myocytes and the pulmonary veins, before the aspects of AF which exacerbate heart failure are discussed. Finally, the limitations of human and animal studies will be explored allowing contextualization of what are sometimes discordant results.

Persistent left superior vena cava as an arrhythmogenic source in atrial fibrillation: results from a multicenter experience.

Persistent left superior vena cava (PLSVC) is one of the most frequently reported congenital anomalies and may be an important source of trigger of atrial fibrillation (AF). This was a multicenter retrospective experience including 28 patients with PLSVC who were referred for catheter ablation for drug-refractory symptomatic AF. Pulmonary vein and PLSVC isolation were performed (3.5-mm open irrigated tip ablation catheter at maximum power of 20W, maximum temperature 43°C with flow rate of 17ml/min). Clinical outcomes such as complications and long-term freedom from AF were measured. The mean age of the population was 61 ± 8years, 21% were females, and AF duration was 60 ± 33months. Sixty-one percent paroxysmal AF (17/28), 25% (7/28) persistent AF, and 14% (4/28) had long-standing persistent AF. There were no major complications that required any intervention. PLSVC isolation was achieved in 96% (27/28). Freedom from AF at 1year without antiarrhythmic drugs was seen in 75% (21/28) of patients. In PLSVC patients with AF, segmental isolation of PLSVC appears to be feasible and safe and can translate into favorable clinical outcomes.

Does Caffeine Consumption Increase the Risk of New-Onset Atrial Fibrillation?

Objective: Caffeine has been considered a trigger for atrial fibrillation (AF). We conducted a meta-analysis including a dose-response analysis to assess the relationship between caffeine consumed and incidence of AF. Methods: Data from selected studies represented 176,675 subjects (AF in 9,987 [5.7%]). Caffeine content varied widely, ranging from 40 to 180 mg per cup of coffee. For purposes of the calculations in this study, we assumed 140 mg of caffeine in a standard 12-oz cup of coffee. Results: No significant difference was found in AF incidence when the subjects consuming less than 2 cups of coffee per day were compared to subjects with higher consumption, 1.068 (0.937–1.216). The risk of AF was higher among subjects consuming less than 2 cups of coffee daily when compared to higher daily consumption subjects. A lower incidence of AF was found among people consuming more than 436 mg daily. Conclusion: The incidence of AF is not increased by coffee consumption. In fact, we found a lower incidence of AF when caffeine consumption exceeded 436 mg/day. Therefore, based on available evidence there is no association between caffeine intake and AF risk.

Histone deacetylase inhibition attenuates atrial arrhythmogenesis in sterile pericarditis

Cardiac surgery is complicated with atrial fibrillation (AF). Histone deacetylase (HDAC) inhibition reduces AF occurrence. In pericarditis, HDAC inhibition may modulate AF trigger and substrate. We recorded electrocardiograms in control and pericardiotomic (op) rabbits without and with an intraperitoneal injection of MPT0E014 (HDAC inhibitor). Conventional microelectrodes recorded action potentials (APs) in pulmonary veins (PVs), the right and left atrium (LA). Masson's trichrome was used to identify collagen fibers in PVs and the LA. Electrocardiograms showed frequent atrial premature contractions in op rabbits, but not in the other 3 groups. The beating rates in PVs and opPVs were decreased by MPT0E014 treatment. Spontaneous burst firings occurred in opPVs (36.4%), but not in control PVs. H2O2 induced greater burst firings in opPVs (72.7%) than in control PVs (11.1%), MPT0E014-treated PVs (16.7%), and MPT0E014-treated opPVs (12.5%). The AP duration at a repolarization extent of 90% (APD90) was shorter in the opLA than that in the control LA. In the presence of isoproterenol (1 μM), rapid atrial pacing (RAP, 20 Hz) induced a higher incidence of burst firings in the opLA (90%) than in the other groups. In contrast, acetylcholine (5 mM) and RAP induced a lower incidence of burst firing in the MPT0E014-treated LA (33.3%) than in the other groups. Fibrosis prevailed in opPVs and the opLA compared to the respective control PVs and LA, which was attenuated in those that received MPT0E014. In conclusion, a pericardiotomy increased fibrosis and arrhythmogenesis in PVs and the LA, which were prevented by HDAC inhibition.

Levosimendan differentially modulates electrophysiological activities of sinoatrial nodes, pulmonary veins, and the left and right atria.

Calcium overload increases the risk of atrial fibrillation (AF). Levosimendan, a calcium sensitizer, increases myofilament contractility. Clinical reports suggested that levosimendan might increase AF occurrence, but the electrophysiological effects of levosimendan on AF substrates and triggers (pulmonary veins, PVs) are not clear. Conventional microelectrodes were used to record action potentials (APs) in isolated rabbit PVs, sinoatrial nodes (SANs), the left atrium (LA), and right atrium (RA) before and after application of different concentrations of levosimendan with or without milrinone (a phosphodiesterase [PDE] III inhibitor), and glibenclamide (an ATP-sensitive potassium channel [KATP ] inhibitor). Levosimendan (0.03, 0.1, 0.3, and 1 μM) significantly increased spontaneous rates from 2.1 ± 0.2 to 2.5 ± 0.2, 2.5 ± 0.2, 2.5 ± 0.1, and 2.7 ± 0.2Hz, respectively, in PVs (n=10), but had no effects on denudated PVs (n=9). Additionally, levosimendan significantly induced burst firing and/or triggered beats in intact PVs, but not in denudated PVs. In contrast, levosimendan at 0.3 and 1 μM increased the SAN spontaneous rate. In the presence of milrinone (10 μM), levosimendan (1 μM) did not increase the PV spontaneous activity. Moreover, glibenclamide (100 μM) prevented acceleration of the levosimendan-induced SAN and PV rates. In the LA, levosimendan at 0.3 and 1 μM shortened the AP duration, and increased contractility at 0.03, 0.1, 0.3, and 1 μM. In contrast, levosimendan did not change the RA contractility, and shortened the AP duration only at 1 μM. Levosimendan increased PV arrhythmogenesis through activating endothelial PDE III and the KATP , and modulating PV tension.

Atrial Fibrillation Triggers in Patients with Coronary Artery Disease and Subclinical Thyrotoxicosis

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Hydrogen sulphide increases pulmonary veins and atrial arrhythmogenesis with activation of protein kinase C.

Hydrogen sulphide (H2S), one of the most common toxic air pollutants, is an important aetiology of atrial fibrillation (AF). Pulmonary veins (PVs) and left atrium (LA) are the most important AF trigger and substrate. We investigated whether H2S may modulate the arrhythmogenesis of PVs and atria. Conventional microelectrodes and whole‐cell patch clamp were performed in rabbit PV, sinoatrial node (SAN) or atrial cardiomyocytes before and after the perfusion of NaHS with or without chelerythrine (a selective PKC inhibitor), rottlerin (a specific PKC δ inhibitor) or KB‐R7943 (a NCX inhibitor). NaHS reduced spontaneous beating rates, but increased the occurrences of delayed afterdepolarizations and burst firing in PVs and SANs. NaHS (100 μmol/L) increased IKATP and INCX in PV and LA cardiomyocytes, which were attenuated by chelerythrine (3 μmol/L). Chelerythrine, rottlerin (10 μmol/L) or KB‐R7943 (10 μmol/L) attenuated the arrhythmogenic effects of NaHS on PVs or SANs. NaHS shortened the action potential duration in LA, but not in right atrium or in the presence of chelerythrine. NaHS increased PKC activity, but did not translocate PKC isoforms α, ε to membrane in LA. In conclusion, through protein kinase C signalling, H2S increases PV and atrial arrhythmogenesis, which may contribute to air pollution‐induced AF.

Abstract P022: The Association of Sleep Apnea With Atrial Fibrillation and Ectopy Using Ambulatory Electrocardiogram in the Atherosclerosis Risk in Communities (ARIC) Study

Introduction: Sleep apnea (SA) is associated with burden of atrial fibrillation (AF), but studies of SA and ectopic beats, potential triggers of AF, are sparse. Our study contributes by examining the association of SA with AF, premature atrial contractions (PACs), and premature ventricular contractions (PVCs) from 48-hour continuous ambulatory electrocardiogram (aECG) monitoring. Methods: The study population includes 716 black and 438 white participants from the ARIC 48-hour aECG ancillary study, after excluding those with a paced rhythm (n=43) or poor quality measures (n=8). SA was defined as self-reported physician diagnosis or hospital discharge records with ICD-9-CM codes for SA. Prevalent AF was defined using 48-hour aECG monitoring, study visit ECGs, or hospital discharge code (427.3) since study baseline in 1986-1987. PACs and PVCs were defined if ectopy was present 1-5% (occasional) and &gt;5% (frequent) of the recording time versus &lt;1% of the recording time (referent). Multivariable logistic regression was used to examine this association with inverse variance weighting to account for the sampling and non-response. Results: Participants with SA (unweighted N=217) were more likely to be female (55%), white race (52%), current smokers (57%), have hypertension (82%), and be obese (57%). Participants with SA were 7.3 (95% CI: 3.7, 14.5) times more likely to have AF compared to those without SA after adjusting for covariates. Compared to participants without SA, the relative odds of occasional and frequent PACs versus the referent was increased by 20% and 50% respectively among participants with SA after adjusting for confounders, although not statistically significant. The association was similar and not statistically significant for frequent PVCs. Conclusions: In a community-based population using standardized 48-hour aECG monitoring, SA was associated with prevalent AF, but not significantly associated with PACs or PVCs. Further study is needed to establish mechanisms that link SA and cardiac arrhythmias.

What Is the Role of Left Atrial Appendage Closure in the Rhythm Control of Atrial Fibrillation?

Interventional catheter ablation approaches to the rhythm control of atrial fibrillation (AF) have advanced significantly in the past decade. The foundation of the catheter ablation in AF is electrical isolation of the pulmonary veins (PVI). However, PVI only in more advanced stages of AF (persistent AF) has only modest to poor success rates prompting a search for alternative and adjunctive procedures to improve the outcomes of ablation in persistent AF. The left atrial appendage (LAA) is well understood to be a primary source of emboli in AF but less well known be a trigger or driver for AF. Therefore, LAA exclusion is an attractive target to potentially improve AF ablation outcomes in more advanced stages of AF and possibly as an alternative to chronic oral anticoagulation in the prevention of stroke and systemic embolism in AF. However, the precise role of LAA closure in the interventional approach to AF is still to be elucidated with ongoing clinical investigations.

DIRECT PULMONARY VEIN ABLATION WITHOUT STENOSIS: CHRONIC EFFICACY OF A NOVEL ELECTROPORATION TECHNIQUE

Despite the primary trigger for atrial fibrillation (AF) being within the pulmonary vein, current treatments avoid direct ablation of this substrate because of the prohibitive incidence of pulmonary vein (PV) stenosis. Given the suboptimal results with contemporary thermal AF ablation, we previously

Porcine heart interatrial septum anatomy

BackgroundThe left-sided atrial septal pouch (SP), a recently re-discovered anatomical structure within the human interatrial septum, has emerged as a possible source of thrombi formation and a trigger for atrial fibrillation, thereby potentially increasing the risk for ischemic stroke. In many studies, the swine interatrial septum has been used as model of the human heart. Also, possible new strategies and devices for management of the SPs may first be tested in this pig model. Therefore, in this study, we aimed to evaluate swine interatrial septum morphology and to compare it with the human analog, especially in the light of SP occurrence. MethodsA total of 75 swine (Sus scrofa f. domestica) hearts were examined. The interatrial septum morphology was assessed, and SPs were measured. ResultsThe most common variant of the interatrial septum was smooth septum (26.6%) followed by the patent foramen ovale channel and right SP (both 22.7%). No left or double SPs were observed. In 28.0% of all cases the fold of tissue (left septal ridge) was observed on the left side of the interatrial septum in the location where the left-sided SP should be expected. The mean length of the patent foramen ovale channel was 7.1±1.5mm. The mean right SP depth was 6.3±2.2mm, and its ostium width and height were 5.8±1.2 and 5.3±1.6mm, respectively. ConclusionsThere are significant differences between human and porcine interatrial septum morphology that should be taken into account during experimental studies. The absence of the left SP in swine results in the inability to use porcine heart as an experimental model for left-sided SP management.

Systemic inflammation as a trigger of Atrial Fibrillation

Systemic inflammation as a trigger of Atrial Fibrillation

Targeting nonpulmonary vein triggers during atrial fibrillation ablation: is the game worth the candle?

Triggers for atrial fibrillation are found outside the pulmonary veins in 12-20% of cases. The role of addressing these triggers during catheter ablations has not been well defined. Therefore, the aim of this review is to summarize the effect of ablation of nonpulmonary vein triggers in addition to pulmonary vein isolation across the spectrum of atrial fibrillation in patients receiving catheter ablation. In paroxysmal atrial fibrillation, an inducible nonpulmonary vein trigger is an independent predictor of recurrence. These triggers are inducible by adenosine and isoproterenol infusion. Nonpulmonary vein triggers cause a significant proportion of atrial fibrillation recurrence seen during repeat procedure and addressing them decreases such recurrence. Targeting inducible nonpulmonary vein triggers also decreases recurrence in persistent atrial fibrillation and was associated with a 25-30% relative reduction in arrhythmia recurrence compared with pulmonary vein isolation alone. In persistent atrial fibrillation, the addition of left atrial appendage isolation was associated with 55% reduction in arrhythmia recurrence. There was no benefit to the empirical ablation of the superior vena cava and the addition of extensive linear lines. There was insufficient evidence to assess the effects of empirical ablation of the coronary sinus, crista terminalis, left atrial posterior wall and the vein of Marshall on arrhythmia recurrence. Evidence suggests that the presence of an inducible nonpulmonary vein trigger is a strong predictor of arrhythmia recurrence. Efforts to detect and ablate nonpulmonary vein triggers are warranted. Further studies are required to fully identify the role nonpulmonary vein trigger ablation.

Subxiphoid Minimally Invasive Epicardial Ablation (Convergent Procedure) With Left Thoracoscopic Closure of the Left Atrial Appendage

The Convergent Procedure is a combined epicardial and endocardial ablation performed by a cardiac surgeon and electrophysiologist to treat symptomatic persistent and long standing persistent atrial fibrillation. The epicardial ablation is performed on the entire width of the posterior left atrial wall using monopolar radiofrequency via a subxiphoid incision. There is no sternotomy and cardiopulmonary bypass is not utilized. The surgical ablation is then followed by endocardial voltage mapping and ablation, allowing for complete lesion set creation. Left atrial appendage exclusion can be performed via left thoracoscopic approach at the same time as the surgical ablation. The Convergent Procedure is a truly hybrid, collaborative procedure which combines the strengths of minimally invasive cardiac surgery and percutaneous electrophysiologic techniques to treat a challenging disease process.

Atrial Fibrillation Initiated by Early Afterdepolarization-Mediated Triggered Activity during Acute Oxidative Stress: Efficacy of Late Sodium Current Blockade.

The mechanism of Atrial Fibrillation (AF) that emerges spontaneously during acute oxidative stress is poorly defined and its drug therapy remains suboptimal. We hypothesized that oxidative activation of Ca-calmodulin dependent protein kinase (CaMKII) promotes Early Afterdepolarization-(EAD)-mediated triggered AF in aged fibrotic atria that is sensitive to late Na current (INa-L) blockade. High-resolution voltage optical mapping of the Left and Right Atrial (LA & RA) epicardial surfaces along with microelectrode recordings were performed in isolated-perfused male Fisher 344 rat hearts in Langendorff setting. Aged atria (23-24 months) manifested 10-fold increase in atrial tissue fibrosis compared to young/adult (2-4 months) atria (P<0001. Spontaneous AF arose in 39 out of 41 of the aged atria but in 0 out of 12 young/adult hearts (P<001) during arterial perfusion of with 0.1 mm of hydrogen peroxide (H2O2). Optical Action Potential (AP) activation maps showed that the AF was initiated by a focal mechanism in the LA suggestive of EAD-mediated triggered activity. Cellular AP recordings with glass microelectrodes from the LA epicardial sites showing focal activity confirmed optical AP recordings that the spontaneous AF was initiated by late phase 3 EAD-mediated triggered activity. Inhibition of CaMKII activity with KN-93 (1 μM) (N=6) or its downstream target, the enhanced INa-L with GS-967 (1 μM), a specific blocker of INa-L (N=6), potently suppressed the AF and prevented its initiation when perfused 15 min prior to H2O2 (n=6). Increased atrial tissue fibrosis combined with acute oxidative activation of CaMK II Initiate AF by EAD-mediated triggered activity. Specific block of the INa-L with GS-967 effectively suppresses the AF. Drug therapy of oxidative AF in humans with traditional antiarrhythmic drugs remains suboptimal; suppressing INa-L offers a potential new strategy for effective suppression of oxidative human AF that remains suboptimal.

Angiotensin 1-7 modulates electrophysiological characteristics and calcium homoeostasis in pulmonary veins cardiomyocytes via MAS/PI3K/eNOS signalling pathway.

Atrial fibrillation (AF) is the most common sustained arrhythmia, and pulmonary veins (PVs) play a critical role in triggering AF. Angiotensin (Ang)-(1-7) regulates calcium (Ca2+ ) homoeostasis and also plays a critical role in cardiovascular pathophysiology. However, the role of Ang-(1-7) in PV arrhythmogenesis remains unclear. Conventional microelectrodes, whole-cell patch-clamp and the fluo-3 fluorimetric ratio technique were used to record ionic currents and intracellular Ca2+ in isolated rabbit PV preparations and in single isolated PV cardiomyocytes, before and after administration of Ang-(1-7). Ang (1-7) concentration dependently (0.1, 1, 10 and 100 nmol/L) decreased PV spontaneous electrical activity. Ang-(1-7) (100 nmol/L) decreased the late sodium (Na+ ), L-type Ca2+ and Na+ -Ca2+ exchanger currents, but did not affect the voltage-dependent Na+ current in PV cardiomyocytes. In addition, Ang-(1-7) decreased intracellular Ca2+ transient and sarcoplasmic reticulum Ca2+ content in PV cardiomyocytes. A779 (a Mas receptor blocker, 3 μmol/L), L-NAME (a NO synthesis inhibitor, 100 μmol/L) or wortmannin (a specific PI3K inhibitor, 10 nmol/L) attenuated the effects of Ang-(1-7) (100 nmol/L) on PV spontaneous electric activity. Ang-(1-7) regulates PV electrophysiological characteristics and Ca2+ homoeostasis via Mas/PI3K/eNOS signalling pathway.