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Funding Acknowledgements Type of funding sources: None. Background Sacubitril/valsartan (S/V) has demonstrated a significant benefit in decreasing mortality and morbidity in patients with heart failure with reduced ejection fraction (HFrEF) when compared to angiotensin inhibition. Recent studies demonstrated that the benefits of S/V encompass a positive cardiac remodeling, leading to a reduction of ventricular arrhythmias. The effect of S/V on the supraventricular arrhythmic burden is still unknown. Purpose To evaluate the effect of sacubitril/valsartan on the supraventricular arrhythmic burden in HFrEF patients with an implantable cardioverter defibrillator (ICD) or cardiac resynchronisation therapy-defibrillator (CRT-D) and remote monitoring. Methods The SAVE THE RHYTHM is a multicentre, observational, prospective registry is enrolling all patients with HFrEF, ICD or CRT-D actively followed through remote monitoring and starting treatment with sacubitril/valsartan. All patients are followed-up at least one year after sacubitril/valsartan start. The primary endpoint is the number of sustained atrial tachycardia or AF (AT/AF). Secondary endpoints include incidence of AT/AF in the total population, total burden of AT/AF (defined as the percentage of time in AT/AF per day), mean number of premature ventricular contractions (PVC) per hour and percentage of biventricular pacing per day (in patients with CRT-D). All primary and secondary endpoints are collected through remote monitoring. Results At the time of the second ad interim analysis, 188 patients (85.2% male, age 68 ± 10 years) were consecutively enrolled. In patients without permanent AF, treatment with S/V was associated with a reduced incidence of AT/AF episodes, which changed from 32.6% (before treatment start) to 24.3%, 20.5% and 6.9% according to the sacubitril/valsartan dose (24/26 mg, 49/51 mg and 97/103 mg respectively; p= 0.041). A significant decrease in the median annual number of AT/AF episodes was also seen in these patients (16/year before treatment; 12/year at 24/26 mg; 6/year at 49/51 mg and 1/year at 97/103 mg; p = 0.046). No significant differences were reported in terms of PVC or biventricular pacing (all p = NS). Patients with permanent AF experienced no benefits from sacubitril/valsartan therapy in terms of arrhythmic burden reduction. No new diagnosis of clinical AF was made after starting treatment with sacubitrl/valsartan in all patients. Conclusions Preliminary data suggest that therapy with S/V could reduce the episodes of AT/AF in patients with HFrEF and remote monitoring, and the benefit seems related to the maximum tolerated dose of S/V. No positive effect has been noted in patients with permanent AF.

Brugada syndrome (BrS) is a disorder characterized by cardiac conduction system dysfunctions, which increases the risk of sudden cardiac death, without heart structural alterations. The diagnosis is based on the ECG tracing analysis: BrS patients have common anomalies. The typical ECG pattern, however, can remain latent and patients can be asymptomatic: the first symptom often coincides with death. Recently, a new mutation associated with BrS has been identified and characterized by HEK 293 cells. This study aims to analyse, through numerical simulation of the O ‘Hara-Rudy (ORd) model, the mutation effects on the ventricular action potential (AP). Under normal conditions, the simulation results do not show significant alterations in the mutant AP. For this reason, we hypothesized that the pathological BrS phenotype could be triggered by other factors.

Background: Brugada syndrome (BrS) is a cardiac disorder characterized by conduction abnormalities that can lead to sudden death; syncope and cardiac arrest are clinical manifestations which are often associated with an enhancement of the vagal activity. Mutations in the SCN5A gene (Na v 1.5 channel) are the most common cause of the inherited forms of BrS. Objective: To characterize the functional behavior of mutant Na v 1.5 channels expressing a novel heterozygous mutation (S805L) recently identified in an Italian family affected by the BrS. Methods: HEK cells were used as experimental model to express both the wild-type (WT) and the mutated S805L channels (alone, Homo or in combination, Hetero) and the accessory β-subunit (SCN1B). Patch-clamp and western blot experiments were carried out to assess the dysfunctional role of the mutation. Results: When compared to the WT current, the S508L mutation significantly (P&It0.05) decreases the peak current density by about 65% for the Homo condition (WT: -120.2±10.2, n=28); Homo: -40.3±4.2, n=16) and by 35% for the Hetero condition (Hetero: -78.2±8.3, n=27). Densitometric analysis carried out on western blot data further support the conclusion that S805L channels are less abundant in the plasma membrane. We also observed that the S805L mutation positively shifts the V½ values of the voltage dependence of the inactivation of both Homo and Hetero currents (V½: WT -85.5±0.2 mV, n=55; Homo -80.9±0.3 mV, n=22; Hetero -81.9±0.2 mV, n=25; P&It0.05); a positive shift of the V½ of the activation was also observed but only in the Homo condition (V½: WT -33.0±0.4 mV, n=28; Homo -30.0±0.5, n=16, P&It0.05). The kinetics of recovery from inactivation and the amplitude of the late sodium current were also evaluated but they were unaffected by the mutation. Conclusion: When expressed in the Hetero condition, the S805L mutation causes a reduction in the channel expression, however, the positive shift of the inactivation curve suggests an increase in Na channel availability. We thus believe that the precise quantitative balance between these two phenomena and their relation with vagal activity may underlie the clinical manifestation of the disease.

Background— Remote magnetic navigation–guided ablation with 3-dimensional (3D)-image integration could provide maximum benefit in patients with complex anatomy. We reviewed supraventricular tachycardia (SVT) ablation in adult patients with congenital heart disease to assess the contribution of these technologies. Methods and Results— One hundred fifty-four SVT ablation procedures (228 SVTs) using a 3D-electroanatomic mapping system in 116 adult patients with congenital heart disease (mean age, 41; 76 male) were classified into 3 groups: Group A, manual mapping/ablation (n=60 procedures); Group B, remote magnetic navigation–guided mapping/ablation with normal femoral vein access (49); and Group C, remote magnetic navigation–guided mapping/ablation with difficult access (45). Group A included simple anomalies with less SVTs. Group B comprised predominantly Fontan patients with more SVTs. Group C included more complex defects, such as intra-atrial baffle or interrupted inferior venous access, in which retrograde aortic and superior venous accesses were used exclusively with more frequent use of image integration (97.8%; P P =0.370). In group C, fluoroscopy time was the shortest (median, 4.2 min; P P P =0.787) during a mean 20-months follow-up period. Conclusions— The combination of remote magnetic navigation, 3D-image integration, and electroanatomic mapping system facilitated safe and feasible ablation with very low fluoroscopy exposure even in patients with complex anomalies.

Background: Although indexed left atrial volume (iLAV) is the most accurate measure of left atrial size, it has not been evaluated prospectively as predictor of recurrence of atrial fibrillation (AFib) after successful cardioversion (CV). Methods: We prospectively selected 76 patients (mean age 66.1 ± 13.6 years, 65.8% men) with AFib who underwent successful CV. Baseline clinical and echocardiographic characteristics were obtained before CV. LAV was measured using Simpson's method and indexed to body surface area. All patients were scheduled for follow-up visit at 1, 6, 12 months, and then annually. A 24-hour Holter ECG was performed within 6 months and each time the patients reported symptoms suggestive of arrhythmia. Results: The 52 patients (68.4%) with AFib recurrence had larger iLAV (35.5 ± 8.9 mL/m2 vs 27.0 ± 6.7 mL/m2, P < 0.001). Anteroposterior LA diameter was not associated with AFib relapse (OR 1.08, 95% CI: 0.96–1.21, P = 0.09). Each unit increase in iLAV was associated with a 1.15-fold increased risk of recurrence (OR 1.15, 95% CI: 1.06–1.25, P < 0.001). In a multivariable model, iLAV remained the only independent predictor of relapse (adjusted OR 1.14, 95% CI: 1.02–1.28, P = 0.02). The area under ROC curves, generated to compare LA diameter, and iLAV as predictors of AFib recurrence were 0.56 (SE 0.07) versus 0.78 (SE 0.05), respectively (P = 0.003). Conclusion: This is the first prospective study to show that larger iLAV, as a more accurate measure of LA remodeling than anteroposterior diameter, is strongly and independently associated with a higher risk of AFib recurrence after CV. (Echocardiography 2012;29:276-284)

Aims We analysed the type and mechanism of supraventricular arrhythmias encountered in a series of symptomatic adults with atrial isomerism undergoing catheter ablation procedures. Methods and results The study population included consecutive adults with atrial isomerism who had previously undergone surgical repair or palliation of the associated anomalies. Patients underwent electrophysiological study for symptomatic arrhythmia in our institution between 2010 and 2012 using magnetic navigation in conjunction with CARTO RMT and three-dimensional (3D) image integration. Eight patients (five females) with a median age of 33 years [interquartile range (IQR) 24–39] were studied. Access to the cardiac chambers of interest was obtained retrogradely via the aorta using remotely navigated magnetic catheters in six patients. Radiofrequency ablation successfully targeted twin atrioventricular (AV) nodal reentrant tachycardia in two patients, atrial fibrillation (AF) in three, focal atrial tachycardia (AT) mainly originating in the left-sided atrium in four patients, and macro-reentrant AT dependent on a right-sided inferior isthmus in three patients. The median fluoroscopy time was 3.0 min (IQR 2–11). After a median follow-up of 10 months (IQR 6–21), five of the ablated patients are free from arrhythmia; two patients experienced episodes of self-terminated AF and AT, respectively, within one month post-ablation; the remaining patient had only non-sustained AT during the electrophysiological study and was managed medically. Conclusion Various supraventricular tachycardia mechanisms are possible in adults with heterotaxy syndrome, all potentially amenable to radiofrequency ablation. The use of remote magnetic navigation along with 3D mapping facilitated the procedures and resulted in a short radiation time.

Aims Atrial fibrillation (AFib) induces remodelling of the left atrium (LA). Indexed LA volume (iLAV) as more accurate measure of LA size has not been evaluated as predictor of recurrence of AFib after cardioversion. Methods and results We identified 411 adults (mean age 64.1 ± 11.4 years, 34.5% women) who underwent successful cardioversion and with no history of other atrial arrhythmia, stroke, congenital heart disease, valvular dysfunction, surgery, thyroid dysfunction, acute or chronic inflammatory disease, and pacemaker. All echocardiographic data were retrieved from the laboratory database. iLAV was measured off-line using Simpson's method. Clinical characteristics and recurrence of clinical AFib were determined by review of medical records. Patients with scheduled follow-up of at least 6 months were included. About 250 patients (60.8%) developed AFib recurrence after a median (25th–75th percentile) follow-up of 345.0 (210.0–540.0) days. Patients with AFib recurrence had significantly greater iLAV than patients without AFib recurrence (39.7 ± 8.4 vs. 31.4 ± 4.6, P < 0.001). Each mL/m2 increase in iLAV was associated with a 30% increased risk of AFib recurrence [odds ratio (OR) 1.30, confidence interval (CI) 1.23–1.38, P < 0.001]. In a multivariable model, each mL/m2 increase in iLAV was independently associated with a 21% increase in the risk of AFib recurrence (OR 1.21, CI 1.11–1.30, P < 0.001). The areas under receiver operating characteristic curves, generated to compare LA diameter and iLAV as predictors of AFib recurrence, were 0.59 ± 0.3 and 0.85 ± 0.2, respectively ( P < 0.001). Conclusion The present study is the first to show that larger iLAV before cardioversion, as a more accurate measure of LA remodelling than LA diameter, is strongly and independently associated with higher risks of AFib recurrence.