In Silico TRials guide optimal stratification of ATrIal FIbrillation patients to Catheter Ablation and pharmacological medicaTION: the i-STRATIFICATION study.

AIMS: Patients with persistent atrial fibrillation (AF) experience 50% recurrence despite pulmonary vein isolation (PVI), and no consensus is established for secondary treatments. The aim of our i-STRATIFICATION study is to provide evidence for stratifying patients with AF recurrence after PVI to optimal pharmacological and ablation therapies, through in silico trials. METHODS AND RESULTS: A cohort of 800 virtual patients, with variability in atrial anatomy, electrophysiology, and tissue structure (low-voltage areas, LVAs), was developed and validated against clinical data from ionic currents to electrocardiogram. Virtual patients presenting AF post-PVI underwent 12 secondary treatments. Sustained AF developed in 522 virtual patients after PVI. Second ablation procedures involving left atrial ablation alone showed 55% efficacy, only succeeding in the small right atria (<60 mL). When additional cavo-tricuspid isthmus ablation was considered, Marshall-PLAN sufficed (66% efficacy) for the small left atria (<90 mL). For the bigger left atria, a more aggressive ablation approach was required, such as anterior mitral line (75% efficacy) or posterior wall isolation plus mitral isthmus ablation (77% efficacy). Virtual patients with LVAs greatly benefited from LVA ablation in the left and right atria (100% efficacy). Conversely, in the absence of LVAs, synergistic ablation and pharmacotherapy could terminate AF. In the absence of ablation, the patient's ionic current substrate modulated the response to antiarrhythmic drugs, being the inward currents critical for optimal stratification to amiodarone or vernakalant. CONCLUSION: In silico trials identify optimal strategies for AF treatment based on virtual patient characteristics, evidencing the power of human modelling and simulation as a clinical assisting tool.

What determines the optimal pharmacological treatment of atrial fibrillation? Insights from in silico trials in 800 virtual atria.

The best pharmacological treatment for each atrial fibrillation (AF) patient is unclear. We aim to exploit AF simulations in 800 virtual atria to identify key patient characteristics that guide the optimal selection of anti-arrhythmic drugs. The virtual cohort considered variability in electrophysiology and low voltage areas (LVA) and was developed and validated against experimental and clinical data from ionic currents to ECG. AF sustained in 494 (62%) atria, with large inward rectifier K+ current (IK1 ) and Na+ /K+ pump (INaK ) densities (IK1 0.11 ± 0.03 vs. 0.07 ± 0.03 S mF-1 ; INaK 0.68 ± 0.15 vs. 0.38 ± 26 S mF-1 ; sustained vs. un-sustained AF). In severely remodelled left atrium, with LVA extensions of more than 40% in the posterior wall, higher IK1 (median density 0.12 ± 0.02 S mF-1 ) was required for AF maintenance, and rotors localized in healthy right atrium. For lower LVA extensions, rotors could also anchor to LVA, in atria presenting short refractoriness (median L-type Ca2+ current, ICaL , density 0.08 ± 0.03 S mF-1 ). This atrial refractoriness, modulated by ICaL and fast Na+ current (INa ), determined pharmacological treatment success for both small and large LVA. Vernakalant was effective in atria presenting long refractoriness (median ICaL density 0.13 ± 0.05 S mF-1 ). For short refractoriness, atria with high INa (median density 8.92 ± 2.59 S mF-1 ) responded more favourably to amiodarone than flecainide, and the opposite was found in atria with low INa (median density 5.33 ± 1.41 S mF-1 ). In silico drug trials in 800 human atria identify inward currents as critical for optimal stratification of AF patient to pharmacological treatment and, together with the left atrial LVA extension, for accurately phenotyping AF dynamics. KEY POINTS: Atrial fibrillation (AF) maintenance is facilitated by small L-type Ca2+ current (ICaL ) and large inward rectifier K+ current (IK1 ) and Na+ /K+ pump. In severely remodelled left atrium, with low voltage areas (LVA) covering more than 40% of the posterior wall, sustained AF requires higher IK1 and rotors localize in healthy right atrium. For lower LVA extensions, rotors can also anchor to LVA, if the atria present short refractoriness (low ICaL ) Vernakalant is effective in atria presenting long refractoriness (high ICaL ). For short refractoriness, atria with fast Na+ current (INa ) up-regulation respond more favourably to amiodarone than flecainide, and the opposite is found in atria with low INa . The inward currents (ICaL and INa ) are critical for optimal stratification of AF patient to pharmacological treatment and, together with the left atrial LVA extension, for accurately phenotyping AF dynamics.

Clinical utility of non-contact charge density 'SuperMap' algorithm for the mapping and ablation of organized atrial arrhythmias.

AIMS: SuperMap is a novel non-contact algorithm for the mapping of organized atrial arrhythmias. We prospectively evaluated SuperMap during mapping and ablation of atrial tachycardias (ATs) and paced rhythms and compared to conventional high-density contact mapping. METHODS AND RESULTS: Consecutive patients undergoing SuperMap guided ablation of pre-existing ATs or AT developed during atrial fibrillation ablation procedures were included together with maps obtained during pacing to assess block in linear lesions. The time taken to obtain diagnostic maps was measured together with the number of electrogram (EGM) points and accuracy compared to the arrhythmia diagnosis confirmed using a combination of map findings, entrainment, and response to ablation. In a subgroup of patients, concurrent contact mapping was performed with contact and SuperMap analysed by separate operators blinded to the other technique. The time taken to generate a diagnostic map, EGM number, and map accuracy was compared. Thirty-one patients (62 maps) were included with contact mapping performed in 19 [39 maps (33 for AT)]. SuperMap acquisition time was 314 s [interquartile range (IQR) 239-436]. The median number of EGM points used per map was 5399 (IQR 3279-8677). SuperMap was faster than contact mapping [394 ± 219 s vs. 611 ± 331 s; difference 217 s, 95% confidence interval (CI) 116-318, P < 0.0005]. The number of EGM points used per map was higher for SuperMap (7351 ± 5054 vs. 3620 ± 3211; difference 3731, 95% CI 2073-5388, P < 0.0005). SuperMap and contact mapping were accurate in 92% and 85% of maps, respectively, P = 0.4805. CONCLUSION: SuperMap non-contact charge density mapping is a rapid and reliable approach to guide the ablation of complex atrial arrhythmias.

Caged-in: Successful percutaneous closure of left atrial appendage with Watchman-FLX in the presence of proximal thrombus.

Percutaneous mechanical closure of the left atrial appendage (LAA) is a valuable stroke prevention strategy in patients with atrial fibrillation and contraindication to oral anticoagulation. LAA thrombus is a common finding in patients with atrial fibrillation and frequently fails to resolve despite therapeutic anticoagulation. In this scenario, LAA occlusion device implant is generally discouraged due to the high risk of thrombus dislodgement and embolization; however, alternative management options are limited. We report the first case of a successful LAA occlusion device (Watchman-FLX) implant in the presence of a proximal thrombus.

"Real-world" performance of the Confirm Rx™ SharpSense AF detection algorithm: UK Confirm Rx study.

Introduction: The novel Confirm Rx™ implantable cardiac monitor (ICM) with SharpSense™ technology incorporates a new P-wave discriminator designed to improve AF detection. This study aimed to evaluate the diagnostic performance of the Confirm Rx™ ICM in detecting AF episodes of varying durations. Methods: We conducted a multicenter retrospective analysis of consecutive patients implanted with a Confirm Rx™ ICM (v1.2) across nine UK hospitals, all with documented AF lasting at least 6 min. Electrocardiograms (ECGs) were manually adjudicated by cardiologists. To account for intra- and inter-reviewer variability, a random sample of 10% of ECGs underwent additional review. Disagreements were resolved by a third reviewer. Diagnostic performance was determined by calculating the gross and patient-averaged positive predictive value (PPV) for AF episodes of different duration. The source of false positive (FP) detection was also categorized. Results: Overall, 16,230 individual ECGs from 232 patients were included. The median AF episode duration was 14 min. R-wave amplitude remained stable during follow-up (0.52 ± 0.27 mV [initial] vs. 0.54 ± 0.29 mV [end of follow-up], p = .10). The gross and patient-averaged PPV were 75.0% and 67.0%, respectively. Diagnostic performance (gross) increased with progressively longer AF episodes: 88.0% for ≥1 h, 97.3% for 6 h, and 100% for 24 h. The main source of FP during tachycardia was T-wave oversensing (54.2%), while in non-tachycardic episodes it was predominantly ectopy (71.2%). The AF burden precision was excellent (93.3%). Conclusion: The Confirm Rx™ ICM diagnostic performance was modest for all AF episodes (75%), with accuracy increasing for longer AF episodes.

High-density electroanatomic activation mapping to guide slow pathway modification in patients with persistent left superior vena cava.

BACKGROUND: Slow pathway (SP) mapping and modification can be challenging in patients with persistent left superior vena cava (PLSVC) due to anatomic variance of the Koch triangle (KT) and coronary sinus (CS) dilation. Studies using detailed 3-dimensional (3D) electroanatomic mapping (EAM) to investigate conduction characteristics and guide ablation targets in this condition are lacking. OBJECTIVES: The purpose of this study was to describe a novel technique of SP mapping and ablation in sinus rhythm using 3D EAM in patients with PLSVC after validation in a cohort with normal CS anatomy. METHODS: Seven patients with PLSVC and dual atrioventricular (AV) nodal physiology who underwent SP modification with the use of 3D EAM were included. Twenty-one normal heart patients with AV nodal reentrant tachycardias formed the validation group. High-resolution, ultra-high-density local activation timing mapping of the right atrial septum and proximal CS in sinus rhythm was performed. RESULTS: SP ablation targets were consistently identified by an area in the right atrial septum with the latest activation time and multicomponent atrial electrogram adjacent to a region with isochronal crowding (deceleration zone). In PLSVC patients, these targets were located at or within 1 cm of the midanterior CS ostium. Ablation in this area led to successful SP modification, reaching standard clinical endpoints with a median of 43 seconds of radiofrequency energy or 14 minutes of cryoablation without complications. CONCLUSION: High-resolution activation mapping of the KT in sinus rhythm can facilitate localization and safe SP ablation in patients with PLSVC.

Transvenous or subcutaneous implantable cardioverter defibrillator: a review to aid decision-making.

The implantable cardioverter-defibrillator (ICD) is a proven treatment for preventing sudden cardiac death. Transvenous leads are associated with significant mortality and morbidity, and the subcutaneous ICD (S-ICD) addresses this. However, it is not without limitations, in particular the absence of anti-tachycardia pacing. The decision of which device is most suitable for an individual patient is often complex. Here, we review the relative merits and weaknesses of both the transvenous and S-ICD. We summarise the available evidence for each device in particular patient cohorts, namely: ischaemic and non-ischaemic cardiomyopathy, idiopathic ventricular fibrillation, Brugada syndrome, long QT syndrome, arrhythmogenic right ventricular cardiomyopathy, and hypertrophic cardiomyopathy.

Impact of Adenosine on Wavefront Propagation in Persistent Atrial Fibrillation: Insights From Global Noncontact Charge Density Mapping of the Left Atrium.

Background Adenosine shortens action potential duration and refractoriness and provokes atrial fibrillation. This study aimed to evaluate the effect of adenosine on mechanisms of wavefront propagation during atrial fibrillation. Methods and Results The study included 22 patients undergoing catheter ablation for persistent atrial fibrillation. Left atrial mapping was performed using the AcQMap charge density system before and after administration of intravenous adenosine at 1 or more of 3 time points during the procedure (before pulmonary vein isolation, after pulmonary vein isolation, and after nonpulmonary vein isolation ablation). Wave-front propagation patterns were evaluated allowing identification and quantification of localized rotational activation (LRA), localized irregular activation, and focal firing. Additional signal processing was performed to identify phase singularities and calculate global atrial fibrillation cycle length and dominant frequency. A total of 35 paired maps were analyzed. Adenosine shortened mean atrial fibrillation cycle length from 181.7±14.3 to 165.1±16.3, (mean difference 16.6 ms; 95% CI, 11.3-21.9, P<0.0005) and increased dominant frequency from 6.0±0.7 Hz to 6.6±0.8 Hz (95% CI, 0.4-0.9, P<0.0005). This was associated with a 50% increase in the number of LRA occurrences (16.1±7.6-24.2±8.1; mean difference 8.1, 95% CI, 4.1-12, P<0.0005) as well as a 20% increase in the number of phase singularities detected (30.1±7.8-36.6±9.3; mean difference 6.5; 95% CI, 2.6-10.0, P=0.002). The percentage of left atrial surface area with LRA increased with adenosine and 42 of 70 zones (60%) with highest density of LRA coincided with high density LRA zones at baseline with only 28% stable across multiple maps. Conclusions Adenosine accelerates atrial fibrillation and promotes rotational activation patterns with no impact on focal activation. There is little evidence that rotational activation seen with adenosine represents promising targets for ablation aimed at sites of stable arrhythmogenic sources in the left atrium.

Rationale and design of a randomised trial of intravenous iron in patients with heart failure.

OBJECTIVES: For patients with a reduced left ventricular ejection fraction (LVEF) heart failure with reduced ejection fraction (HFrEF) and iron deficiency, administration of intravenous iron improves symptoms, exercise capacity and may in the following 12 months, reduce hospitalisations for heart failure. The Effectiveness of Intravenous iron treatment versus standard care in patients with heart failure and iron deficiency (IRONMAN) trial evaluated whether the benefits of intravenous iron persist in the longer term and impact on morbidity and mortality. METHODS: IRONMAN is a prospective, randomised, open-label, blinded endpoint (PROBE) event-driven trial. Patients aged ≥18 years with HFrEF (LVEF ≤45%) and evidence of iron deficiency (ferritin <100 µg/L and/or TSAT <20%) were enrolled if they had either a current or recent hospitalisation for heart failure or elevated plasma concentrations of a natriuretic peptide. Participants were randomised to receive, or not to receive, intravenous ferric derisomaltose in addition to guideline-recommended therapy for HFrEF. Every 4 months, intravenous iron was administered if either ferritin was <100 µg/L or, provided ferritin was ≤400 µg/L, TSAT was <25%. The primary endpoint is a composite of total hospitalisations for heart failure and cardiovascular death. Hospitalisation and deaths due to infection are safety endpoints. RESULTS: Trial recruitment was completed across 70 UK hospital sites in October 2021. Participants were followed until the end of March 2022. We plan to report the results by November 2022. CONCLUSIONS: IRONMAN will determine whether repeated doses of intravenous ferric derisomaltose are beneficial and safe for the long-term treatment of a broad range of patients with HFrEF and iron deficiency. TRIAL REGISTRATION NUMBER: NCT02642562.

Long-term outcomes and periprocedural safety and efficacy of percutaneous left atrial appendage closure in a United Kingdom tertiary center: An 11-year experience.

BACKGROUND: Left atrial appendage occlusion (LAAO) has been widely adopted as a strategy for stroke prevention in patients with atrial fibrillation ineligible for oral anticoagulation. OBJECTIVE: The purpose of this study was to explore longer-term "real-world" safety and efficacy outcomes in patients undergoing LAAO given varied practices in antithrombotic regimens and adoption of same-day discharge. METHODS: Analysis of acute procedural and long-term outcome data was performed for all patients undergoing LAAO implant in a United Kingdom tertiary center over an 11-year period. Rates of adverse events were calculated and compared to predicted rates in historical cohorts according to CHA2DS2-VASc and HAS-BLED scores. RESULTS: Device implantation was attempted in 229 patients, with an acute procedural success rate of 98.2% and low rate of major procedural complications of 2.6% at 30 days, including 1.3% procedure-related mortality. In the last year of enrollment, 75% of patients were discharged on the same day of the procedure. A strategy of early cessation of antithrombotic therapy was adopted, with a low rate of device-related thrombus. Over total follow-up of 889 patient-years, there were low rates of thromboembolic events (2.2/100 patient-years) and of significant bleeding events (intracranial bleed 0.6/100 patient-years; nonprocedural major bleeding 2.3/100 patient-years). CONCLUSION: LAAO with a same-day discharge strategy and early cessation of antiplatelet therapy seems to be safe and effective in reducing the risk of stroke and major bleeding over mean follow-up approaching 4 years. Although these data are reassuring, results from randomized trials with strict shorter periods of postprocedural antithrombotic therapy are eagerly awaited.

Individualized ablation strategy to treat persistent atrial fibrillation: Core-to-boundary approach guided by charge-density mapping.

BACKGROUND: Noncontact charge-density mapping allows rapid real-time global mapping of atrial fibrillation (AF), offering the opportunity for a personalized ablation strategy. OBJECTIVE: The purpose of this study was to compare the 2-year outcome of an individualized strategy consisting of pulmonary vein isolation (PVI) plus core-to-boundary ablation (targeting the conduction pattern core with an extension to the nearest nonconducting boundary) guided by charge-density mapping, with an empirical PVI plus posterior wall electrical isolation (PWI) strategy. METHODS: Forty patients (age 62 ± 12 years; 29 male) with persistent AF (10 ± 5 months) prospectively underwent charge-density mapping-guided PVI, followed by core-to-boundary stepwise ablation until termination of AF or depletion of identified cores. Freedom from AF/atrial tachycardia (AT) at 24 months was compared with a propensity score-matched control group of 80 patients with empirical PVI + PWI guided by conventional contact mapping. RESULTS: Acute AF termination occurred in 8 of 40 patients after charge-density mapping-guided PVI alone and in 21 of the remaining 32 patients after core-to-boundary ablation in the study cohort, compared with 8 of 80 (10%) in the control cohort (P <.001). On average, 2.2 ± 0.6 cores were ablated post-PVI before acute AF termination. At 24 months, freedom from AF/AT after a single procedure was 68% in the study group vs 46% in the control group (P = .043). CONCLUSION: An individualized ablation strategy consisting of PVI plus core-to-boundary ablation guided by noncontact charge-density mapping is a feasible and effective strategy for treating persistent AF, with a favorable 24-month outcome.