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.

Abstract P640: Incident Atrial Fibrillation and Cardiovascular Risk Increases in Patients With Increased Burden of Atrial Ectopy

Introduction: Atrial fibrillation (AF) is a major risk factor for cerebral ischemia in North America. Atrial ectopy has been associated with incident AF and increased stroke risk on short-duration ECG monitoring. The objective of this study was to characterize the relationship between the burden of atrial ectopy with future AF, stroke, and cardiovascular events on prolonged ECG monitoring. Methods: A retrospective, observational study was conducted at a single centre enrolling patients >18 years old referred from TIA clinic. Data was collected from 7- and 14-day Holter monitor reports, patient charts, and cardiac investigations. The final sample included 1124 patients; a subgroup of 759 patients had echocardiograms. Univariate and multivariate logistic regression determined the odds ratio (OR) of developing the composite outcome (AF, TIA/stroke, ACS, death) or secondary outcomes (AF or TIA/stroke). Results: The population was high-risk with a mean CHA 2 DS 2 -VASc of 4.0 (±1.8); during 1-year of follow-up, the primary outcome occurred amongst 116 (10.3%) patients. Univariate analysis ORs are displayed in Table 1. There was a statistically significant relationship (p<0.001) between percentage of PACs and the composite outcome (OR 4.066), and AF (11.886) for patients with 2-5% PACs. PAC runs/day was significant if >5/day for AF (OR 5.989, p<0.01) and for the composite (OR 2.231, p<0.05). Long PAC runs (>30 beats) also had significant ORs for AF (2.849, p<0.01) and the composite (5.320, p<0.01). In the subgroup analysis, reduced ejection fraction had an OR of 2.172 (1.407-5.771) for the composite outcome, and atrial dilatation had an OR of 2.778 (1.390-5.551) for AF. Conclusions: Increased burden of atrial ectopy is associated with increased odds of developing AF and a composite of cardiovascular events. Patients with increased ectopy should be considered for further, future ECG monitoring and risk stratification with echocardiogram.

Premature ventricular contraction is associated with increased risk of atrial fibrillation: a nationwide population-based study

Premature ventricular contraction (PVC) and atrial fibrillation (AF) are common arrhythmias affecting 1–2% of the general population. During PVC, retrograde ventriculo-atrial activation can occur and act like an atrial ectopy. However, the clinical significance of this phenomenon is not fully understood. We aimed to elucidate whether the clinical diagnosis of PVC can increase the risk of new-onset AF. We performed a nationwide population-based analysis using the Korean National Health Insurance Service database. A total of 9,537,713 people without prior history of PVC and AF were identified. Among these people, 4135 developed PVC in 2009, and people with and without PVC were followed until 2018. People who had PVC showed an increased risk of new-onset AF as compared with people without PVC (hazard ratio [HR] = 2.705; 95% confidence interval [CI] = 2.428–3.013; p < 0.001). The risk of ischemic stroke was also significantly increased in people with PVC (HR 1.160; 95% CI 1.048–1.284; p = 0.0041). New-onset AF developed in 72 people (19.3%) among 374 people with PVC who had ischemic stroke during their follow-up. A significant interaction was observed between PVC and age with people < 65 years at greater risk of new-onset AF for having PVC. In this observational analysis, the risk of new-onset AF and ischemic stroke was increased in people with PVC. Additional evaluation to identify AF in people with PVC can be helpful.

Short coupling with high burden of atrial ectopy in twenty-four hour holter recording predicts recurrence of atrial arrhythmia after atrial fibrillation ablation

Background Atrial arrhythmia recurrence is experienced in up to 20% of patients after initially receiving a catheter ablation for atrial fibrillation (AF). Therefore, it is important to define predictors of atrial arrhythmia recurrence. Atrial ectopy (AE) with short coupling interval (S-AE) has been reported to be a trigger of AF. On the other hand, high burden of AE has been reported to be a useful predictor of atrial arrhythmia recurrences after AF ablation. Thus, the combination of the incidence of S-AE and AE burden during a 24-hour Holter recording could be a useful predictor of atrial arrhythmia recurrence after AF ablation. Purpose To investigate this hypothesis, we performed a retrospective case-controlled study. Methods We enrolled 180 patients who underwent their first catheter ablation procedure for AF and performed a 24-hour Holter recording between 90 to 365 days after their ablation procedure. Patients who performed an additional ablation procedure before the Holter recording were excluded. Finally, we analyzed 173 patients (age: 65±10 years, female: 28.3%, non-paroxysmal: 27.7%). The Holter recordings were analyzed by the same experienced technicians. We defined AE as a narrow QRS complex occurring &gt;25% than prior R-R interval, and S-AE as AE occurring &gt;55% earlier than expected. The relationship between the characteristics of AE during the Holter recording and atrial arrhythmia recurrences was investigated. Results The Holter recordings were performed at a median of 103 (IQR: 98–138) days after ablation. The median number of AE were 144 (IQR: 54–699) beats per day, and S-AE was recorded in 49 patients (28.3%). Forty-two patients (24.3%) had a recurrence of atrial arrhythmia during a median 488-day follow up period. Patients with S-AE had a recurrence of atrial arrhythmia more frequently than those without S-AE (44.9% vs 16.1%, p&lt;0.001). We found the cut-off point of AE burden as 241 beats per day by the receiver operating characteristic curve with 74% sensitivity and 70% specificity to predict atrial arrhythmia recurrence. We divided the patients into four groups according to the presence or absence of S-AE and high AE burden. In the Kaplan-Meier analysis, patients with S-AE and high AE burden had the highest atrial arrhythmia recurrence rate (Log-rank test: p&lt;0.001). In the Cox multivariate analysis, S-AE with high AE burden was an independent predictor of atrial arrhythmia recurrence (HR: 4.27, 95% CI: 2.32–7.85, p&lt;0.001). Conclusion For AF patients who underwent their first catheter ablation, S-AE (&gt;55% earlier than expected) with high AE burden (&gt;241 beats per day) during the 24-hour Holter recording predicted recurrences of atrial arrhythmia. These results can help to develop follow-up strategies after AF ablation. Funding Acknowledgement Type of funding source: None