Atrial Atrial Fibrillation Research Articles

Melatonin inhibits angiotensin II–induced atrial fibrillation through preventing degradation of Ang II Type I Receptor–Associated Protein (ATRAP)

Angiotensin II (Ang II) induced Atrial fibrillation (AF) often accompanied with reduced ATRAP which is a negative modulator of Ang II type 1 receptor (AT1R). Melatonin can protect against AF, but the underlying molecular mechanism remains poorly understood. In this study, Ang II was used to induce AF, and AF inducibility and duration were documented telemetrically. Ang II-infused mice had a higher AF incidence, which was associated with atrial fibrosis, inflammation, and oxidative stress. Melatonin partially inhibited these effects, and enforced expression of siRNA-ATRAP in atria counteracted the beneficial role of melatonin. Specifically, melatonin inhibited expression of Ang II-induced proteasome and immunoproteasome subunits β2, β2i, β5, and β5i as well as their corresponding trypsin-like and chymotrypsin-like activities and blocked ATRAP degradation. In turn, this inhibited AT1R-mediated NF-κB signaling, transforming growth factor (TGF)-β1/Smad signaling in the atria, and thereby affected atrial remodeling and AF. Melatonin receptor inhibition by the chemical inhibitor luzindole partially inhibited the inhibitory effects of melatonin on proteasome activity and also Ang II-induced pathological changes in the atria. Overall, our study demonstrates that melatonin protects against Ang II-induced AF by inhibiting proteasome activity and stabilizing ATRAP expression, and these effects are partially dependent on melatonin receptor activation.

Role of the succinate pathway in the electrophysiological properties of right atria in a persistent atrial fibrillation sheep model

Atrial fibrillation (AF) is the most sustained arrhythmia and increases morbidity and mortality. However, development and maintenance of AF is a still poorly understood process. Metabolic remodelling could induce transition from paroxysmal to persistent AF. Succinate levels are increased in AF patients indicating a potential role for metabolic remodelling. To assess the impact of the succinate pathway on the electrophysiological properties of right atria (RA) in persistent AF sheep model. Optical experiments were performed in ex vivo RA from a burst pacing AF sheep model. RA were perfused by Tyrode solution with glucose (5.6 mM), subsequently replaced by succinate (10 mM) to increase mitochondrial reactive oxygen species (ROS) production which are known to modulate excitation-contraction coupling (ECC) and study metabolic remodelling. An activator of the succinate β-adrenergic receptor (GPR91), cis-epoxysuccinic acid (300 μM), was used to study the GPR91 involvement in atrial electrophysiology and AF. Action potential duration at 80% of repolarization (APD80) were assessed from 2 to 5 Hz pacing frequency and during sinus rhythm (SR). We used an S1S2 pacing protocol to determine effective refractory period (ERP) and a burst pacing protocol (30 Hz) to assess ex vivo AF vulnerability. Finally, an organ donation program allowed us to investigate these properties in a human RA from an AF patient. During succinate perfusion SR is decreased in Sham (1,5 vs 1,2 Hz; P = 0,03), AF (1,5 vs 1 Hz; P = 0,003) and resistant (1,3 vs 1 Hz; P = 0,01) sheep, ERP is increased in AF sheep (184 vs 344 ms; P = 0,0007) and APD80 is increased in Sham (217 vs 264 ms; P = 0,0004) and AF sheep (195 vs 275 ms; P = 0,003). We also observed an increase in amplitude alternans which can induce re-entries and therefore be pro-arrhythmic. These results seems to be confirmed on human AF RA by increasing APD80 (257 vs 309 ms), ERP (260 vs 330 ms) and spontaneous arrhythmias. GPR91 activation led to a slowing of SR (1,7 vs 1,3 Hz; P = 0,03), a shortening of APD80 (200 vs 170 ms; P = 0,007) and an increase in spontaneous arrhythmias. A dysregulation of ECC could explain our results consistently with the ROS involvement and metabolic remodelling in AF. For the first time, we also demonstrated that GPR91 pathway is involved in atrial electrophysiology and could be involved in AF mechanisms.

Neonatal Scn1b-null mice have sinoatrial node dysfunction, altered atrial structure, and atrial fibrillation.

Loss-of-function (LOF) variants in SCN1B, encoding the voltage-gated sodium channel β1/β1B subunits, are linked to neurological and cardiovascular diseases. Scn1b-null mice have spontaneous seizures and ventricular arrhythmias and die by approximately 21 days after birth. β1/β1B Subunits play critical roles in regulating the excitability of ventricular cardiomyocytes and maintaining ventricular rhythmicity. However, whether they also regulate atrial excitability is unknown. We used neonatal Scn1b-null mice to model the effects of SCN1B LOF on atrial physiology in pediatric patients. Scn1b deletion resulted in altered expression of genes associated with atrial dysfunction. Scn1b-null hearts had a significant accumulation of atrial collagen, increased susceptibility to pacing induced atrial fibrillation (AF), sinoatrial node (SAN) dysfunction, and increased numbers of cholinergic neurons in ganglia that innervate the SAN. Atropine reduced the incidence of AF in null animals. Action potential duration was prolonged in null atrial myocytes, with increased late sodium current density and reduced L-type calcium current density. Scn1b LOF results in altered atrial structure and AF, demonstrating the critical role played by Scn1b in atrial physiology during early postnatal mouse development. Our results suggest that SCN1B LOF variants may significantly impact the developing pediatric heart.

Relationship between electrical activity and left atrial volume during atrial fibrillation

Abstract Funding Acknowledgements Type of funding sources: None. Introduction Pulmonary veins (PV) ostia were previously identified as the left atrium (LA) areas with the shortest refractory period during sinus rhythm. Pulmonary veins isolation (PVI) became standard of care, but clinical results are still suboptimal. Currently, atrial fibrillation (AF) cycle length mapping (CLM) is possible due to a special tool of the Carto® electroanatomical mapping, which identifies areas in the left atria with shortest refractory period, during AF. Purpose Using this new EAM feature, our study aimed to assess the relationship between short refractory period LA areas and left atrial volume and AF type, known predictors of AF relapse. Methods Retrospective analysis of an unicentric registry of individuals with symptomatic drug-refractory AF who underwent PVI AF ablation with Carto® EAM. CLM was performed. CL maps were created with a high-density mapping Pentaray® catheter before and after PVI. We assessed areas of short cycle length (SCL) (defined as 120 to 250ms), and their relationships with complex fractionated atrial electrograms (CFAE), and low-voltage zones (from 0.1 to 0.3mV). Results A total of 35 patients (21 men, median age 62 IQR 53-71 years) were included. Most patients presented with persistent AF (n=23, 66%), and 8 patients (23%) had a previous PVI. The mean shortest measured cycle length in AF was 134ms (SD ± 23ms). There was a negative correlation between LA volume and SCL areas after PVI (Spearman Correlation coefficient [ρ] = - 0.47, P = 0.037). There was no correlation between LA volume and SCL areas before the PVI procedure (ρ = -0.06, P = 0.776), nor between AF type and SCL (ρ = -0.118, P = 0.620). All patients presented areas of SCL located in the PVs or their insertion, 76% in the posterior/roof region adjacent to the left superior pulmonary vein (LSPV) and 76% in the anterior region of the wall adjacent to the right superior pulmonary vein (RSPV). These two areas remained the fastest even after PVI. The anterior mitral region rarely presented SCL (16%). SCL were related to low-voltage areas in 93% and were adjacent to CFAE in 84% of the cases. Low-voltage areas and CFAE were more frequent and had a larger LA dispersion than SCL. Conclusion Our study shows that LA volume, not AF type, is correlated with remaining SCL areas after a pulmonary vein isolation procedure. This finding suggests a possible causal link between increased LA volume and AF relapse post-PVI. More studies are needed to assess the role of the SCL areas as a potential ablation target and their impact on AF ablation outcomes.

Usefulness of the physiological single chamber pacemaker VDD in elderly patients with normal sinus rhythm

Abstract Funding Acknowledgements Type of funding sources: None. Background In frail elderly patients or when atrioventricular block (AVB) is paroxysmal, and pacing anticipated to be infrequent, single chamber pacing (VVI or VDD) may be considered as it carries a lower complication rate compared with DDD devices. For sinus rhythm patients, the single lead VDD, by preserving atrial sensing, is a more physiological mode than VVI devices, with comparable time procedure and complication rates. However, there are few data assessing the performance of VDD pacemakers in elderly patients, with AVB and sinus rhythm. Purpose We want to evaluate the 3-years performance of VDD pacemakers (PM) in frailty elder patients with AVB. Methods We conducted a retrospective, observational study of 200 elderly (³75 years) patients with AVB and normal sinus rhythm who consecutively implanted VDD PM between 2016 and 2018. Baseline clinical characteristics were analyzed, and a 3-years follow-up was performed: atrial undersensing, atrial fibrillation (AF), heart failure (HF) hospitalization, cardiovascular (CV) and non-CV death. Results Mean age was 84±5 years and 55% were female. The study population presented several comorbidities: 74% had atrial hypertension, 49% dyslipidemia, 35% chronic kidney disease and 28% diabetes. After 3-years follow-up most of the patients (90%; n=162) were still programmed in their original mode with good atrial sensing. Due to permanent AF, 4%(n=8) patients had been switched to VVIR mode and 5.5% (n=11) due to P-wave undersensig. 0ne-third (n=65) died during follow-up, 89% (n=58) due to non-CV causes. Low amplitude P-wave (<0.5mV) at baseline had a numerical, non-statistically significant association with atrial undersensig and AF at 3-years (p=0.14 and p=0.77, respectively). Atrial undersensing during follow-up didn’t relate with all-cause death and HF hospitalization (p=0.58 and p=0.64, respectively), but was associated with atrial fibrillation (12.7% vs 31.6%, p=0.038). Conclusion A significantly larger number of VDD-paced elderly patients maintain their original mode program with good atrial sensing. Moreover, atrial undersensing did not influence mortality or HF hospitalization rate. These results reinforce the benefit of VDD use among frail and elderly patients.

Anthracycline-Induced Atrial Structural and Electrical Remodeling Characterizes Early Cardiotoxicity and Contributes to Atrial Conductive Instability and Dysfunction.

Aims: Cancer patients treated with anthracyclines are susceptible to atrial fibrillation (AF), while the mechanisms remain unclear. Due to sudden and unpredictable features, prediction of anthracycline-induced AF at early phase is difficult. Clinically, we tested whether anthracycline-induced early atrial remodeling in patients could be detected by echocardiography. Experimentally, we investigated the mechanisms of doxorubicin-induced atrial remodeling and AF in mice, and the protective effects of dexrazoxane and antioxidants. Methods and Results: Postsurgery breast cancer patients with an anthracycline-containing or anthracycline exclusion regimen were recruited for echocardiography before chemotherapy, and 3 and 6 months after chemotherapy. Mice were injected with doxorubicin or vehicle (5 mg/kg/week, 4 weeks), and left atrial diameter, electrical transmission, and AF inducibility were measured. Meanwhile, the level of reactive oxygen species (ROS), activity of antioxidant enzymes, cardiomyocyte size, vacuolization, inflammation, and fibrosis were also measured in mouse atria. The therapeutic effects of dexrazoxane and antioxidants on doxorubicin-induced changes in the aforementioned parameters were also determined. While ventricular parameters and functions were unchanged in cancer patients receiving anthracyclines before and after chemotherapy, left atrial reservoir and conduit function were decreased at 3 months postchemotherapy versus prechemotherapy. Doxorubicin-induced susceptibility to AF occurred in mice before onset of ventricular dysfunction. Doxorubicin-induced AF was via inducing structural remodeling (cardiomyocyte death, hypotrophy, and vacuolization) and electrical remodeling (reduction and redistribution of connexin 43) in atria, which was effectively prevented by dexrazoxane or antioxidants through inhibiting ROS generation or enhancing ROS elimination. Innovation and Conclusion: AF inducibility was induced after doxorubicin injection, which can be inhibited by repressing the ROS level. Antioxid. Redox Signal. 37, 19-39. The Clinical Trial Registration number is PJ-KS-KY-2019-73.

Adjunctive Left Atrial Posterior Wall Isolation in Treating Atrial Fibrillation: Insight From a Large Secondary Analysis.

This study evaluated the role of adjunctive left atrium posterior wall isolation (PWI) in preventing atrial fibrillation (AF) recurrence. The left atrium posterior wall is an arrhythmogenic substrate that contributes to the development of AF. This was an updated pooled analysis that included clinical data regarding PWI plus pulmonary vein isolation (PVI) in treating AF. The primary outcome was recurrence of atrial tachyarrhythmias. A total of 26 studies with 3,287 patients with AF (age 61.7 ± 10.8 years) were included. Mean follow-up was 15.2± 8.4months. Procedural success to achieve PWI was 92.8%. In paroxysmal AF, adjunctive PWI did not reduce the recurrence of all atrial arrhythmias (P=0.21) or AF (P=0.37); however, in persistent AF, adjunctive PWI was associated with substantially lower recurrence of all atrial arrhythmias (risk ratio: 0.74; P< 0.001) and AF (risk ratio: 0.67; P=0.01), particularly when randomized data were included. Subgroup analyses based on meta-regression demonstrated that patients with older age, a larger left atrial diameter, and persistent AF benefited more significantly from the adjunctive PWI. Adjunctive PWI using either radiofrequency or a cryoballoon reduced AF recurrence, whereas using radiofrequency seemed to be associated with higher recurrence rate of atrial tachycardias and/or atrial flutter. Non-BOX adjunctive PWI rather than BOX PWI was associated with significantly lower recurrence of AF. The incidence of procedural adverse events between the PVI+PWI (3.2%) and PVI (2.8%) groups was low and similar. PVI+PWI needed longer ablation and/or procedural time but had similar fluoroscopy time. Adjunctive PWI can be achieved in most patients without compromising safety. Patients with persistent AF appear to benefit from this approach. The ablation technology and/or approach may affect the clinical outcome of PWI.

PO-690-05 NOVEL LAPAROSCOPY-BASED RENAL DENERVATION FOR MODULATING AF INDUCIBILITY USING A SWINE MODEL

Renal denervation (RDN) may control atrial fibrillation (AF) by modulating autonomic tone. The study aimed to validate the acute effects of a novel laparoscopy-based RDN for modulating AF inducibility using a swine model. Each 4 swine were assigned for the sham operation and laparoscopy-based RDN. Vagal nerve stimulation (VNS; 10 Hz, 50 ms, 5-20 V, 30 sec) was performed at the right vagal nerve to enhance AF inducibility. Burst atrial pacing (100 ms, 1-5 V, 90 sec) at the right atrium was used to induce AF. Atrial effective refractory period (AERP) and AF duration were compared before and after the sham operation or RDN. Laparoscopy-based RDN was done using an instrument with linear bipolar electrodes that wraps around the renal artery (Figure 1A). It delivers the radiofrequency energy to the adventitia to ablate renal sympathetic nerves. Both proximal and distal parts of renal artery were ablated (Figure 2A). Renal arterial biopsy was done and stained with tyrosine hydroxylase to identify sympathetic nerves and compared between both groups. For the sham group, VNS significantly reduced AERP from median 180 to 150 ms and 170 to 150 ms before and after the sham operation, respectively (both p =0.009) (Figure 2A). VNS numerically increased AF duration from median 4.5 to 10.5 sec and 6.0 to 9.5 sec before and after the sham operation (p =0.06 and 0.11, respectively) (Figure 2B). The effect of VNS on AF duration was significant (p =0.005), while the sham operation did not (p =0.79). For the RDN group, VNS numerically reduced AERP from 160 to 130 ms and 180 to 160 ms before and after RDN (p =0.24 and 0.54, respectively) (Figure 2A). VNS did not induce significant difference in AF duration regardless of RDN. However, RDN significantly reduced AF duration regardless of VNS (from mean 23.0 to 4.8 sec; difference between means 18.3 sec (95% CI 6.4-30.1 sec); p =0.03) (Figure 2B). The effect of RDN on AF duration was significant (p =0.003). In histology analysis, renal sympathetic nerve tissue was degenerated after laparoscopic RDN, whereas normal renal sympathetic nerves were intact in the sham group (Figure 2B). A novel laparoscopy-based RDN significantly reduced AF inducibility in swine models. The long-term effect of this novel laparoscopy-based RDN would be investigated.View Large Image Figure ViewerDownload Hi-res image Download (PPT)

BS-526-02 ROLE OF THE SUCCINATE PATHWAY IN THE ELECTROPHYSIOLOGICAL PROPERTIES OF RIGHT ATRIA IN A PERSISTENT ATRIAL FIBRILLATION SHEEP MODEL

The progression from paroxysmal to persistent atrial fibrillation (AF) is still a poorly understood process. Succinate levels are increased in AF patients indicating a potential role for metabolic remodeling in this transition process. To assess the impact of the succinate pathway on the electrophysiological properties of right atria (RA) in a persistent AF sheep model. Optical mapping was performed on ex vivo RA from a burst pacing AF sheep model, including 8 sham, 7 persistent AF, and 3 resistant animals. RA were perfused by Tyrode solution with glucose (5.6mM), subsequently replaced by succinate (10mM), known to increase mitochondrial Reactive Oxygen Species (ROS). An activator of the succinate β-adrenergic receptor (GPR91), cis-epoxysuccinic acid (300μM), was also used to study the GPR91 involvement in atrial electrophysiology and AF (N=6). Action potential duration at 80% of repolarization (APD80) were assessed from 2 to 5Hz pacing frequency and during sinus rhythm (SR). We used an S1S2 pacing protocol to determine effective refractory period (ERP) and a burst pacing protocol (30Hz) to assess ex vivo AF vulnerability. Finally, an organ donation program allowed us to investigate these properties in a human RA from an AF patient. During succinate perfusion SR is decreased in Sham (1,5 vs 1,2 Hz ; p=0,03), AF (1,5 vs 1 Hz ; p=0,003) and resistant (1,3 vs 1 Hz ; p=0,01) sheep, ERP is increased in AF sheep (184 vs 344 ms ; p=0,0007) and APD80 is increased in Sham (217 vs 264 ms ; p=0,0004) and AF sheep (195 vs 275 ms ; p=0,003). We also observed an increase in amplitude alternans and decrease in frequencies at which alternans was observed. These results appear to be confirmed in a human AF RA where succinate increased APD80 (257 vs 309 ms), ERP (260 vs 330 ms) and the occurrence of spontaneous arrhythmias. Finally, in sheep, GPR91 activation led to a slowing of SR (1,7 vs 1,3 Hz ; p=0,03), a shortening of APD80 (200 vs 170 ms ; p=0,007) and an increase in spontaneous arrhythmias. Succinate induces significant electrophysiological modifications, especially in persistent AF, and increases vulnerability to AF. We have shown that the GPR91 pathway is involved in atrial electrophysiology and succinate-induced arrhythmogenesis, most likely in combination with increased ROS production.

IP3R1/GRP75/VDAC1 complex mediates endoplasmic reticulum stress-mitochondrial oxidative stress in diabetic atrial remodeling

RationaleEndoplasmic reticulum (ER) stress and mitochondrial dysfunction are important mechanisms of atrial remodeling, predisposing to the development of atrial fibrillation (AF) in type 2 diabetes mellitus (T2DM). However, the molecular mechanisms underlying these processes especially their interactions have not been fully elucidated. ObjectiveTo explore the potential role of ER stress–mitochondrial oxidative stress in atrial remodeling and AF induction in diabetes. Methods and resultsMouse atrial cardiomyocytes (HL-1 cells) and rats with T2DM were used as study models. Significant ER stress was observed in the diabetic rat atria. After treatment with tunicamycin (TM), an ER stress agonist, mass spectrometry (MS) identified several known ER stress and calmodulin proteins, including heat shock protein family A (HSP70) member [HSPA] 5 [GRP78]) and HSPA9 (GRP75, glucose-regulated protein 75). In situ proximity ligation assay indicated that TM led to increased protein expression of the IP3R1–GRP75–VDAC1 (inositol 1,4,5-trisphosphate receptor 1–glucose-regulated protein 75–voltage-dependent anion channel 1) complex in HL-1 cells. Small interfering RNA silencing of GRP75 in HL-1 cells and GRP75 conditional knockout in a mouse model led to impaired calcium transport from the ER to the mitochondria and alleviated mitochondrial oxidative stress and calcium overload. Moreover, GRP75 deficiency attenuated atrial remodeling and AF progression in Myh6-Cre+/Hspa9flox/flox + TM mice. ConclusionsThe IP3R1–GRP75–VDAC1 complex mediates ER stress–mitochondrial oxidative stress and plays an important role in diabetic atrial remodeling.

Structural Remodeling and Rotational Activity in Persistent/Long-Lasting Atrial Fibrillation: Gender-Effect Differences and Impact on Post-ablation Outcome.

BackgroundStructural and post-ablation gender differences are reported in atrial fibrillation (AF). We analyzed the gender differences in structural remodeling and AF mechanisms in patients with persistent/long-lasting AF who underwent wide area circumferential pulmonary vein isolation (WACPVI).Materials and MethodsUltra-high-density mapping was used to study atrial remodeling and AF drivers in 85 consecutive patients. Focal and rotational activity (RAc) were identified with the CartoFinder system and activation sequence analysis. The impact of RAc location on post-ablation outcomes was analyzed.ResultsThis study included 64 men and 21 women. RAc was detected in 73.4% of men and 38.1% of women (p = 0.003). RAc patients had higher left atrium (LA) voltage (0.64 ± 0.3 vs. 0.50 ± 0.2 mV; p = 0.01), RAc sites had higher voltage than non-RAc sites 0.77 ± 0.46 vs. 0.53 ± 0.37 mV (p < 0.001). Women had lower LA voltage than men (0.42 vs. 0.64 mV; p < 0.001), including pulmonary vein (PV) antra (0.16 vs. 0.30 mV; p < 0.001) and posterior wall (0.34 vs. 0.51 mV; p < 0.001). RAc in the posterior atrium was recorded in few women (23.8 vs. 54.7% in men; p = 0.014). AF recurrence rate was higher in patients with RAc outside WACPVI than those with all RAc inside WACPVI or no RAc (63.4 vs. 11.1 and 31.0%; p = 0.008 and p = 0.01). Comparison of selected patients using propensity score matching confirmed lower atrial voltage (0.4 ± 0.2 vs. 0.7 ± 0.3 mV; p = 0.007) and less RAc (38 vs. 75%; p = 0.02) in women.ConclusionWomen have shown more advanced structural remodeling at ablation, which is associated with a lower incidence of RAc (usually located outside the WACPVI). These findings could explain post-ablation gender differences.

Autonomic Afferent Dysregulation in Atrial Fibrillation.

This study sought to evaluate the role of cardiac afferent reflexes in atrial fibrillation (AF). Efferent autonomic tone is not associated with atrial remodeling and AF persistence. However, the role of cardiac afferents is unknown. Individuals with nonpermanent AF (n=48) were prospectively studied (23 in the in-AF group and 25 in sinus rhythm [SR]) with 12 matched control subjects. We performed: 1) low-level lower body negative pressure (LBNP), which decreases cardiac volume, offloading predominantly cardiac afferent (volume-sensitive) low-pressure baroreceptors; 2) Valsalva reflex (predominantly arterial high-pressure baroreceptors); and 3) isometric handgrip reflex (both baroreceptors). We measured beat-to-beat mean arterial pressure (MAP) and heart rate (HR). LBNP elicits reflex vasoconstriction, estimated using venous occlusion plethysmography-derived forearm blood flow (∝1/vascular resistance), maintaining MAP. To assess reversibility, we repeated LBNP (same day) after 1-hour low-level tragus stimulation (in n=5 in the in-AF group and n=10 in the in-SR group) and >6weeks post-cardioversion (n=7). The 3 groups were well matched for age (59 ± 12 years, 83% male), body mass index, and risk factors (P=NS). The in-AF group had higher left atrial volume (P< 0.001) and resting HR (P = 0.01) but similar MAP (P = 0.7). The normal LBNP vasoconstriction (-49 ± 5%) maintaining MAP (control subjects) was attenuated in the in-SR group (-12 ± 9%; P = 0.005) and dysfunctional in the in-AF group (+11 ± 6%; P< 0.001), in which MAP decreased and HR was unchanged. Valsalva was normal throughout. Handgrip MAP response was lowest in the in-AF group (P = 0.01). Interestingly, low-level tragus stimulation and cardioversion improved LBNP vasoconstriction (-48 ± 15%; P = 0.04; and -32 ± 9%; P = 0.02, respectively). Cardiac afferent (volume-sensitive) reflexes are abnormal in AF patients during SR and dysfunctional during AF. This could contribute to AF progression, thus explaining "AF begets AF." (Characterisation of Autonomic function in Atrial Fibrillation [AF-AF Study]; ACTRN12619000186156).

ОТДАЛЕННЫЕ РЕЗУЛЬТАТЫ МИНИИНВАЗИВНОЙ ЭПИКАРДИАЛЬНОЙ ВИДЕОАССИСТИРОВАННОЙ РАДИОЧАСТОТНОЙ ИЗОЛЯЦИИ ЛЕГОЧНЫХ ВЕН ПРИ ИЗОЛИРОВАННОЙ ФИБРИЛЛЯЦИИ ПРЕДСЕРДИЙ

Aim. To analyze long-term results of the use of minimally invasive epicardial video-assisted radiofrequency ablation (RFA) of the pulmonary veins (PV) in patients with various forms of isolated atrial fibrillation (AF). Materials and methods. Since February 2011 to December 2014, 22 patients (male/female – 21/1) with paroxysmal / persistent / long-standing persistent idiopathic form of AF were operated on the basis of the Republican Scientific and Practical Center “Cardiology”, 7 (31.8%) / 9 (41%) / 6 (27.2%) cases respectively. Mean age was 48.33 ± 9.37 (31–66) years old. The average duration of the history of AF before the operation was 58.6 ± 32.5 months. RFA was performed through a bilateral mini-thoracotomy approach using video endoscopy with the application of bipolar irrigated Gemini X ablative clamp electrodes. All patients underwent bilateral antral RFA isolation of the PVs. In 100% of patients it was possible to achieve a conduction block from the PV collectors. Results. During the hospital period, there were not no lethal cases, conversions to sternotomy, and neurological complications. The long-term period was studied in 100% of patients, the average follow-up period was 7.4+0.5 years. The final rhythm was assessed using Holter monitoring in 3, 6, and 12 months after surgery, then annually. In 6 (28%) cases in patients with initial non-paroxysmal AF, endocardial RFA of the isthmus of the right atrium or PV orifices was performed at different times after surgery due to the presence of atrial flutter (4/19%) or AF (2/9.5%). Implantation of the pacemaker was required in 2 cases (9.0%). The ef fectiveness of bipolar antral RFA isolation of the PV using the Gemini X device, depending on the initial form of AF in the long-term period: paroxysmal – 100%, persistent – 66.7%, long-term persistent – 33.3%. Conclusion. Epicardial minimally invasive bipolar antral PV isolation is a highly effective treatment for paroxysmal AF. In non-paroxysmal forms of AF, it is necessary to expand isolation of arrhythmogenic zones in the atria.

Interleukin-6-Mediated-Ca2+ Handling Abnormalities Contributes to Atrial Fibrillation in Sterile Pericarditis Rats.

Pre-existing Ca2+ handling abnormalities constitute the arrhythmogenic substrate in patients developing postoperative atrial fibrillation (POAF), a common complication after cardiac surgery. Postoperative interleukin (IL)-6 levels are associated with atrial fibrosis in several animal models of POAF, contributing to atrial arrhythmias. Here, we hypothesize that IL-6-mediated-Ca2+ handling abnormalities contribute to atrial fibrillation (AF) in sterile pericarditis (SP) rats, an animal model of POAF. SP was induced in rats by dusting atria with sterile talcum powder. Anti-rat-IL-6 antibody (16.7 μg/kg) was administered intraperitoneally at 30 min after the recovery of anesthesia. In vivo electrophysiology, ex vivo optical mapping, western blots, and immunohistochemistry were performed to elucidate mechanisms of AF susceptibility. IL-6 neutralization ameliorated atrial inflammation and fibrosis, as well as AF susceptibility in vivo and the frequency of atrial ectopy and AF with a reentrant pattern in SP rats ex vivo. IL-6 neutralization reversed the prolongation and regional heterogeneity of Ca2+ transient duration, relieved alternans, reduced the incidence of discordant alternans, and prevented the reduction and regional heterogeneity of the recovery ratio of Ca2+ transient. In agreement, western blots showed that IL-6 neutralization reversed the reduction in the expression of ryanodine receptor 2 (RyR2) and phosphorylated phospholamban. Acute IL-6 administration to isolated rat hearts recapitulated partial Ca2+ handling phenotype in SP rats. In addition, intraperitoneal IL-6 administration to rats increased AF susceptibility, independent of fibrosis. Our results reveal that IL-6-mediated-Ca2+ handling abnormalities in SP rats, especially RyR2-dysfunction, independent of IL-6-induced-fibrosis, early contribute to the development of POAF by increasing propensity for arrhythmogenic alternans.

Pharmacological inhibition of acetylcholine-regulated potassium current (I K,ACh) prevents atrial arrhythmogenic changes in a rat model of repetitive obstructive respiratory events.

BackgroundIn obstructive sleep apnea (OSA), intermittent hypoxemia and intrathoracic pressure fluctuations may increase atrial fibrillation (AF) susceptibility by cholinergic activation.ObjectiveTo investigate short-term atrial electrophysiological consequences of obstructive respiratory events, simulated by intermittent negative upper airway pressure (INAP), and the role of atrial acetylcholine-regulated potassium current (IK,ACh) activated by the M2 receptor.MethodsIn sedated (2% isoflurane), spontaneously breathing rats, INAP was applied noninvasively by a negative pressure device for 1 minute, followed by a resting period of 4 minutes. INAP was applied repeatedly throughout 70 minutes, followed by a 2-hour recovery period. Atrial effective refractory period (AERP) and AF inducibility were determined throughout the protocol. To study INAP-induced IK,ACh activation, protein levels of protein kinase C (PKCƐ) were determined in membrane and cytosolic fractions of left atrial (LA) tissue by Western blotting. Moreover, an IK,ACh inhibitor (XAF-1407: 1 mg/kg) and a muscarinic receptor inhibitor (atropine: 1 μg/kg) were investigated.ResultsIn vehicle-treated rats, repetitive INAP shortened AERP (37 ± 3 ms vs baseline 44 ± 3 ms; P = .001) and increased LA membrane PKCƐ content relative to cytosolic levels. Upon INAP recovery, ratio of PKCƐ membrane to cytosol content normalized and INAP-induced AERP shortening reversed. Both XAF-1407 and atropine increased baseline AERP (control vs XAF-1407: 61 ± 4 ms; P > .001 and control vs atropine: 58 ± 3 ms; P = .011) and abolished INAP-associated AERP shortening.ConclusionShort-term simulated OSA is associated with a progressive, but transient, AERP shortening and a PKCƐ translocation to LA membrane. Pharmacological IK,ACh and muscarinic receptor inhibition prevented transient INAP-induced AERP shortening, suggesting an involvement of IK,ACh in the transient arrhythmogenic AF substrate in OSA.

Abstract 10429: Atrial Pitx2c Overexpression Increased Atrial Arrhythmias with Altered Calcium Handling

Introduction: We have previously reported that the atrial cardiomyocyte-specific Pitx2c overexpression impaired sinus node function. It is well known that sinus node dysfunction is associated with atrial fibrillation (AF) and PITX2C increases in patients with chronic AF. Although Pitx2c overexpression in the atrium may be susceptible to atrial arrhythmias, the mechanism is not well understood. Hypothesis: Pitx2c overexpression in the atrium induces atrial arrhythmias with altered calcium handling. Methods: We generated the atrial cardiomyocyte-specific Pitx2c overexpression mice by crossing two types of mice. Then, we examined AF inducibilities, the expressions of genes related to left-right axis determination and AF, and monophasic action potential durations of B6-Tg ( CAG-LSL-Pitx2c ); SLN Cre/+ (overexpression: OE) and B6 (wild type: WT) mice. Results, Conclusions: Pitx2c was up-regulated in the right atrium (RA) of OE than WT mice. AF increased significantly following burst pacing in OE (52%, n=6) than WT (7%, n=9) mice. Furthermore, episodes of atrial arrhythmias such as premature atrial conduction and AF were increased in OE mice. TBX3 , Shox2 and Scn5a were down-regulated, and Kcne1 was up-regulated significantly in the atrium of OE than WT mice (n=8, each group). Especially in the RA of OE mice, Cacna1c and Serca2 , which were calcium regulatory genes, were significantly down-regulated. In addition, we found that monophasic action potential duration was shorter in RA of the OE mice than WT mice. In conclusion, cardiomyocyte-specific Pitx2c overexpression in RA induces atrial arrhythmias with altered calcium handling. The transcription factor Pitx2c promotes electrical remodeling similar to clinical data.

Attenuating persistent sodium current-induced atrial myopathy and fibrillation by preventing mitochondrial oxidative stress.

Mechanistically driven therapies for atrial fibrillation (AF), the most common cardiac arrhythmia, are urgently needed, the development of which requires improved understanding of the cellular signaling pathways that facilitate the structural and electrophysiological remodeling that occurs in the atria. Similar to humans, increased persistent Na+ current leads to the development of an atrial myopathy and spontaneous and long-lasting episodes of AF in mice. How increased persistent Na+ current causes both structural and electrophysiological remodeling in the atria is unknown. We crossbred mice expressing human F1759A-NaV1.5 channels with mice expressing human mitochondrial catalase (mCAT). Increased expression of mCAT attenuated mitochondrial and cellular reactive oxygen species (ROS) and the structural remodeling that was induced by persistent F1759A-Na+ current. Despite the heterogeneously prolonged atrial action potential, which was unaffected by the reduction in ROS, the incidences of spontaneous AF, pacing-induced after-depolarizations, and AF were substantially reduced. Expression of mCAT markedly reduced persistent Na+ current–induced ryanodine receptor oxidation and dysfunction. In summary, increased persistent Na+ current in atrial cardiomyocytes, which is observed in patients with AF, induced atrial enlargement, fibrosis, mitochondrial dysmorphology, early after-depolarizations, and AF, all of which can be attenuated by resolving mitochondrial oxidative stress.

Vascular endothelial growth factor modulates pulmonary vein arrhythmogenesis via vascular endothelial growth factor receptor 1/NOS pathway

Atrial fibrillation (AF) is a common form of arrhythmia with serious public health impacts, but its underlying mechanisms are not yet fully understood. Vascular endothelial growth factor (VEGF) is highly expressed in the atrium of patients with AF, but whether VEGF affects AF pathogenesis remains unclear. Pulmonary veins (PVs) are important sources for the genesis of atrial tachycardia or AF. Therefore, this study assessed the effects of VEGF on PV electrophysiological properties and evaluated its underlying mechanisms. Conventional microelectrodes and whole-cell patch clamps were performed using isolated rabbit PV preparations or single isolated PV cardiomyocytes before and after VEGF or VEGF receptor (VEGFR), Akt, NOS inhibitor administration. We found that VEGF (0.1, 1, and 10 ng/mL) reduced the PV beating rate in a dose-dependent manner. Furthermore, VEGF (10 ng/mL) reduced late diastolic depolarization and diastolic tension. Isoproterenol increased PV beating and burst firing, which was attenuated by VEGF (1 ng/mL). In the presence of VEGFR-1 inhibition (ZM306416 at 10 μM) and L-NAME (100 μM), VEGF (1 ng/mL) did not alter PV spontaneous activity. In isolated PV cardiomyocytes, VEGF (1 ng/mL) decreased L-type calcium, sodium/calcium exchanger, and late sodium currents. In conclusion, we found that VEGF reduces PV arrhythmogenesis by modulating sodium/calcium homeostasis through VEGFR-1/NOS signaling pathway.

ATRIAL STRETCH-DEPENDENT TUMOR NECROSIS FACTOR-MEDIATED ADVERSE ATRIAL REMODELING AND ATRIAL ARRHYTHMIA INDUCIBILITY IN A MOUSE MODEL OF AORTIC REGURGITATION

<h3>BACKGROUND</h3> Atrial fibrillation (AF) is the most common sustained supraventricular arrhythmia worldwide, with its incidence linked to cardiovascular (CV) disease and, paradoxically, endurance exercise. Most conditions linked to AF are associated with elevated atrial pressures and stretch, which are powerful stimuli for atrial hypertrophy, fibrosis, and inflammation. We previously established adverse atrial changes and arrhythmogenesis required the pro-inflammatory and mechanosensitive cytokine tumor necrosis factor (TNF) in intense swim exercised mice. Thus, we hypothesize that stretch-mediated TNF-dependent signaling may provide a unifying mechanism linking AF in exercise and disease. <h3>METHODS AND RESULTS</h3> We developed a clinically-relevant mouse model of aortic regurgitation (AR), which is characterized by diastolic volume overload and elevated left ventricular end-diastolic (LVEDPs) and atrial pressures, to study atrial stretch-dependent TNF-mediated AF pathogenesis. AR was induced by retrograde puncture of the aortic valve in 8-week-old CD1 wild-type and whole-body TNF knockout (TNF-/-) mice. Four weeks after regurgitation, AR resulted in volume overload-mediated progressive LV dilatation, functional impairment, hypertrophy, and elevated LVEDPs in the absence of ventricular arrhythmia inducibility in both groups. In wild-type mice, AR resulted in adverse atrial remodeling, characterized by atrial hypertrophy and fibrosis, decreased conduction velocity, reduced atrial effective refractory period and action potential duration, and increased in vivo and ex vivo AF susceptibility. By contrast, TNF-/- prevented AR-induced adverse atrial remodeling and arrhythmia inducibility, independent of ventricular changes. <h3>CONCLUSION</h3> Our results establish that adverse atrial remodeling and AF vulnerability with AR requires TNF, providing a mechanistic link between elevated atrial pressures, adverse remodeling, and AF susceptibility with CV disease and exercise.

Sterile Pericarditis in Aachener Minipigs As a Model for Atrial Myopathy and Atrial Fibrillation.

Atrial fibrillation (AF) is the most common arrhythmia caused by structural remodeling of the atria, also called atrial myopathy. Current therapies only target the electrical abnormalities and not the underlying atrial myopathy. For the development of novel therapies, a reproducible large animal model of atrial myopathy is necessary. This paper presents a model of sterile pericarditis-induced atrial myopathy in Aachener minipigs. Sterile pericarditis was induced by spraying sterile talcum and leaving a layer of sterile gauze over the atrial epicardial surface. This led to inflammation and fibrosis, two crucial components of the pathophysiology of atrial myopathy, making the atria susceptible to the induction of AF. Two pacemaker electrodes were positioned epicardially on each atrium and connected to two pacemakers from different manufacturers. This strategy allowed for repeated non-invasive atrial programmed stimulation to determine the inducibility of AF at specified time points after surgery. Different protocols to test AF inducibility were used. The advantages of this model are its clinical relevance, with AF inducibility and the rapid induction of inflammation and fibrosis-both present in atrial myopathy-and its reproducibility. The model will be useful in the development of novel therapies targeting atrial myopathy and AF.