Lack of authentic atrial fibrillation in commonly used murine atrial fibrillation models

The mouse is a useful preclinical species for evaluating disease etiology due to the availability of a wide variety of genetically modified strains and the ability to perform disease-modifying manipulations. In order to establish an atrial filtration (AF) model in our laboratory, we profiled several commonly used murine AF models. We initially evaluated a pharmacological model of acute carbachol (CCh) treatment plus atrial burst pacing in C57BL/6 mice. In an effort to observe micro-reentrant circuits indicative of authentic AF, we employed optical mapping imaging in isolated mouse hearts. While CCh reduced atrial refractoriness and increased atrial tachyarrhythmia vulnerability, the left atrial (LA) excitation patterns were rather regular without reentrant circuits or wavelets. Therefore, the atrial tachyarrhythmia resembled high frequency atrial flutter, not typical AF per se. We next examined both a chronic angiotensin II (Ang II) infusion model and the surgical model of transverse aortic constriction (TAC), which have both been reported to induce atrial and ventricular structural changes that serve as a substrates for micro-reentrant AF. Although we observed some extent of atrial remodeling such as fibrosis or enlarged LA diameter, burst pacing-induced atrial tachyarrhythmia vulnerability did not differ from control mice in either model. This again suggested that an AF-like pathophysiology is difficult to demonstrate in the mouse. To continue searching for a valid murine AF model, we studied mice with a cardiac-specific deficiency (KO) in liver kinase B1 (Cardiac-LKB1), which has been reported to exhibit spontaneous AF. Indeed, the electrocardiograms (ECG) of conscious Cardiac-LKB1 KO mice exhibited no P waves and had irregular RR intervals, which are characteristics of AF. Histological evaluation of Cardiac-LKB1 KO mice revealed dilated and fibrotic atria, again consistent with AF. However, atrial electrograms and optical mapping revealed that electrical activity was limited to the sino-atrial node area with no electrical conduction into the atrial myocardium beyond. Thus, Cardiac-LKB1 KO mice have severe atrial myopathy or atrial standstill, but not AF. In summary, the atrial tachyarrhythmias we observed in the four murine models were distinct from typical human AF, which often exhibits micro- or macro-reentrant atrial circuits. Our results suggest that the four murine AF models we examined may not reflect human AF well, and raise a cautionary note for use of those murine models to study AF.

Laser balloon ablation in patients with a left common pulmonary vein.

Background: Pulmonary vein isolation (PVI) with a balloon-based visually guided laser ablation (VGLA) is regarded as a useful therapeutic tool for treating atrial fibrillation (AF). The clinical efficacy of a VGLA has never been fully investigated in patients with a left common pulmonary vein (LCPV). Objective: We investigated the procedural safety as well as clinical usefulness of VGLA in patients with an LCPV. Methods: This study consisted of 130 consecutive patients who underwent VGLA of de novo non-valvular paroxysmal AF. Results: Eleven patients (8.5%) had an LCPV (ostium maximal average diameter: 27.5 ± 4.9 mm, ostium minimal average diameter: 17.7 ± 3.5 mm). Nine out of 11 (81.8%) LCPVs were successfully occluded and isolated at the ostium with a VGLA guided PVI. The ablation procedure time was significantly shorter in the patients with than without an LCPV (61.5 ± 15.4 vs. 86.9 ± 32.9 min, p = 0.01). There was no difference regarding the atrial tachyarrhythmia recurrence between those with and without an LCPV (p = 0.18). A total of fifteen patients underwent a redo procedure, but reconnections were not observed in any of the LCPV patients. Conclusion: The VGLA guided PVI was a useful therapeutic tool even in patients with an LCPV. The presence of an LCPV was not associated with any atrial tachyarrhythmia recurrence.

The Effect of Diabetes Mellitus on the Recurrence of Atrial Fibrillation after Ablation

Diabetes mellitus (DM) plays a crucial role in the regulation of atrial fibrillation (AF). This study aimed to evaluate the outcome of pulmonary vein isolation (PVI) using a single-shot device in patients with AF and DM. A total of 531 consecutive patients undergoing initial cryoballoon (CB)-guided PVI were evaluated. Two hundred eighty-one patients (53%) suffered from paroxysmal AF (PAF; mean age 51 ± 23.2 years, 26% female), 250 patients (48%) from persistent AF (PERS; 64 ± 10.0 years old, 30% female) and 80 patients (15%) were diagnosed with coincidental DM (68 ± 19.6 years old, 30% female). Follow-up visits were performed at 3, 6 and 12 months including 7-day Holter ECGs. Primary endpoint was the first documented recurrence of atrial tachyarrhythmia. AF recurrence occurred in 26% (140 patients). PAF patients with DM presented with a significantly higher risk for arrhythmia recurrence (Kaplan Meier analysis; Log rank p < 0.001 *). Multivariate analyses found DM to be an independent predictor (IP) for AF recurrence (p = 0.009 *, hazard ratio (HR) 4.363, confidence interval (CI) 1.456–13.074). In PERS, DM was associated with a 43% increase in AF recurrence (p = 0.320, HR 1.427, CI 0.707–2.879). DM has relevant effects on AF recurrence after PVI-only ablation approaches for AF. Major differences were observed in PAF as DM seems to favor the development of individual arrhythmia substrate, which is usually not yet present in PAF. In PERS, DM effects are less pronounced as individual fibrosis has already developed. Thus, personalized paths addressing individual arrhythmia substrates are needed in this specific cohort of patients.

Decreased estimated glomerular filtration rate predicts long-term recurrence after catheter ablation of atrial fibrillation in mild to moderate renal insufficiency

Background Catheter ablation is an established therapy for atrial fibrillation (AF), but recurrence after ablation remains a great challenge. Additionally, little is known about the effect of renal function on the efficiency of AF ablation. This study aimed to evaluate the predictors of the prognosis of catheter ablation for AF, especially the effect of renal function. Methods A total of 306 drug-refractory symptomatic patients with AF who underwent first-time catheter ablation were enrolled in the present study. Individuals underwent circumferential pulmonary vein isolation for paroxysmal AF and stepwise ablation for persistent AF. Results The follow-up time was 27.2 ± 19.5 months, 202 patients (66.01%) were free of atrial tachyarrhythmia (non-recurrence group), and the other 104 patients experienced recurrence (recurrence group). The recurrence group had a larger left atrial diameter (LAD) and left atrial volume (LAV), a higher LAV index (LAVI) (both, p < 0.01), and a lower estimated glomerular filtration rate (eGFR) (53.5 ± 14.4 vs. 65.5 ± 13.3 ml/min/1.732, p < 0.001) and creatinine clearance rate (CCr) (85.2 ± 26.1 vs. 101.5 ± 29.4 ml/min, p < 0.05). Multivariate logistic regression indicated both eGFR (p = 0.002) and LAVI (p < 0.001) as independent associated factors for long-term recurrence after single catheter ablation; multivariate Cox proportional hazard regression with backward feature selection identified both eGFR (HR: 0.93, 95% CI: 0.91–0.95, p < 0.001) and LAVI (HR: 1.32, 95% CI: 1.25–1.40, p < 0.001) as independent prognostic factors for recurrence when adjusting other clinical variables. Conclusions Decreased eGFR and elevated LAVI may facilitate the long-term recurrence of atrial tachyarrhythmia after catheter ablation for AF.

Impact of a time-to-effect guided ablation protocol in cryoballoon ablation on durability of pulmonary vein isolation

Background: Cryoballoon (CB) based pulmonary vein isolation (PVI) has proven to be as effective as radiofrequency (RF) based ablation. Different ablation protocols took the individual time-to-isolation (TTI) into account aiming at shorter but equally or even more effective freeze-cycles. The current study sought to assess the impact of the TTI on PVI durability in patients undergoing a repeat procedure for recurrence of atrial tachyarrhythmia (ATA). Methods and Results: In 205 patients with ATA recurrence after previous CB-based PVI a total of 806 PVs were identified. One hundred-twenty-six out of 806 PVs (16%) were previously treated with a TTI guided ablation (protocol #1; TTI+120 sec.), in 92/806 (11%) PVs TTI was only monitored (m) but fixed freeze-cycles were applied (protocol #2; mTTI) and in 588/806 (73%) a fixed freeze-cycle was applied without TTI-monitoring. There was no difference in the PV-reconduction rate between the groups (P=0.23). The right inferior pulmonary vein (RIPV) showed overall significantly higher reconduction rates compared to the other PVs (RIPV – left inferior PV (LIPV) p<0.003, -left superior PV (LSPV) p<0.001, - right superior PV RSPV p<0.013). In 21 patients (10%) only for the RIPV reconduction was assessed. Conclusions: TTI based CB ablation did not show significant differences regarding PV-reconduction rates compared to the other protocols.

Impact of Left Atrial Posterior Wall Isolation Technique on the Outcome of Ablation in Persistent Atrial Fibrillation

Background Left atrial posterior wall (LAPW) isolation is an adjunct to pulmonary vein isolation (PVI) for persistent atrial fibrillation (AF). Objective To compare the effect of LAPW box isolation with LAPW point-by-point ablation and PVI in persistent AF on 12-month arrhythmia-free survival and procedure complications. Methods 77 consecutive patients who underwent LAPW box isolation, 24 patients who underwent LAPW point-by-point ablation and 101 patients who underwent PVI for persistent AF were compared. All patients had undergone no prior ablation for AF and were followed up for one year. Results Mean time to atrial tachyarrhythmia recurrence was similar with LAPW box isolation (9.8 months, 95% CI = 9-10.7) and LAPW point-by-point ablation (10 months, 95% CI = 8.6-11.3), both were longer than PVI (8.2 months, 95% CI = 7.4-9.1, log-rank p = 0.003). There was no difference in peri-procedural complications (LAPW box isolation: 5/77, LAPW point-by-point ablation: 1/24, PVI: 6/101, p = 0.91). At 12 months, no difference in atrial tachyarrhythmia recurrence was observed between box isolation (23/77, 30%) and point-bypoint ablation (11/24, 46%, p = 0.15), but significantly higher recurrence occurred with PVI alone (58/101, 57%, p &lt; 0.001). Procedure time was similar with both approaches, with longer fluoroscopy with point-by-point ablation (median: 38 min, IQR: 29-47.75) vs box isolation (median: 28 min, IQR: 7.5-39.5, p = 0.2). Conclusion In persistent AF, there was no difference between LAPW box isolation and point-by-point ablation in terms of mean arrhythmia-free survival, 12-month recurrence or procedure complications. Arrhythmia-free survival with either technique was longer than PVI alone, with no increase in complications.

Prediction of Recurrent Atrial Tachyarrhythmia After Receiving Atrial Flutter Ablation in Patients With Prior Cardiac Surgery for Valvular Heart Disease

Background: Surgical scars cause an intra-atrial conduction delay and anatomical obstacles that facilitate the perpetuation of atrial flutter (AFL). This study aimed to investigate the outcome and predictor of recurrent atrial tachyarrhythmia after catheter ablation in patients with prior cardiac surgery for valvular heart disease (VHD) who presented with AFL.Methods: Seventy-two patients with prior cardiac surgery for VHD who underwent AFL ablation were included. The patients were categorized into a typical AFL group (n = 45) and an atypical AFL group (n = 27). The endpoint was the recurrence of atrial tachyarrhythmia during follow-up. A multivariate analysis was performed to determine the predictor of recurrence.Results: No significant difference was found in the recurrence rate of atrial tachyarrhythmia between the two groups. Patients with concomitant atrial fibrillation (AF) had a higher recurrence of typical AFL compared with those without AF (13 vs. 0%, P = 0.012). In subgroup analysis, typical AFL patients with concomitant AF had a higher incidence of recurrent atrial tachyarrhythmia than those without it (53 vs. 14%, P = 0.006). Regarding patients without AF, the typical AFL group had a lower recurrence rate of atrial tachyarrhythmia than the atypical AFL group (14 vs. 40%, P = 0.043). Multivariate analysis showed that chronic kidney disease (CKD) and left atrial diameter (LAD) were independent predictors of recurrence.Conclusions: In our study cohort, concomitant AF was associated with recurrence of atrial tachyarrhythmia. CKD and LAD independently predicted recurrence after AFL ablation in patients who have undergone cardiac surgery for VHD.

Thoracoscopic surgical atrial fibrillation ablation in patients with an extremely enlarged left atrium

Purpose Efficacy of pulmonary vein isolation (PVI) for atrial fibrillation (AF) decreases as left atrial (LA) volume increases. However, surgical AF ablation with unknown efficacy is being performed in patients with a giant LA (GLA). We determined efficacy of thoracoscopic AF ablation in patients with compared to without a GLA. Methods Patients underwent thoracoscopic PVI with additional left atrial ablations lines (in persistent AF) and were prospectively followed up. GLA was defined as LA volume index (LAVI) ≥ 50 ml/m2. Follow-up was performed with ECGs and 24-h Holters every 3 months. After a 3-month blanking period, all antiarrhythmic drugs were discontinued. The primary outcome was freedom of any atrial tachyarrhythmia ≥ 30 s during 2 years of follow-up. Results At baseline, 68 (15.4%) patients had a GLA (LAVI: 56.7 [52.4–62.8] ml/m2), while 374 (84.6%) had a smaller LA (LAVI: 34.8 [29.2–41.3] ml/m2). GLA patients were older (61.9 ± 6.9 vs 59.4 ± 8.8 years, p = 0.02), more often diagnosed with persistent AF (76.5% vs 58.6%, p = 0.008). Sex was equally distributed (with approximately 25% females). GLA patients had more recurrences compared to non-GLA patients at 2-year follow-up (42.6% vs 57.2%, log rank p = 0.02). Freedom of AF was 69.0% in non-GLA paroxysmal AF patients compared to 43.8–49.3% in a combined group of GLA and/or persistent AF patients(log rank p < 0.001). Furthermore, freedom was 62.4% in non-GLA male patients, compared to 43.8–47.4 in a combined group of GLA and/or female sex(log rank p = 0.02). Conclusion Thoracoscopic AF ablation is an effective therapy in a substantial part of GLA patients. Thoracoscopic AF ablation may serve as a last resort treatment option in these patients.