Patients with atrial fibrillation frequently experience sleep disorder breathing, and both conditions are highly prevalent in presence of heart failure (HF). We explored the association between the combination of an HF and a sleep apnoea (SA) index and the incidence of atrial high-rate events (AHRE) in patients with implantable defibrillators (ICDs). Data were prospectively collected from 411 consecutive HF patients with ICD. The IN-alert HF state was measured by the multi-sensor HeartLogic Index (>16), and the ICD-measured Respiratory Disturbance Index (RDI) was computed to identify severe SA. The endpoints were as follows: daily AHRE burden of ≥5 min, ≥6 h, and ≥23 h. During a median follow-up of 26 months, the time IN-alert HF state was 13% of the total observation period. The RDI value was ≥30 episodes/h (severe SA) during 58% of the observation period. An AHRE burden of ≥5 min/day was documented in 139 (34%) patients, ≥6 h/day in 89 (22%) patients, and ≥23 h/day in 68 (17%) patients. The IN-alert HF state was independently associated with AHRE regardless of the daily burden threshold: hazard ratios from 2.17 for ≥5 min/day to 3.43 for ≥23 h/day (P < 0.01). An RDI ≥ 30 episodes/h was associated only with AHRE burden ≥5 min/day [hazard ratio 1.55 (95% confidence interval: 1.11-2.16), P = 0.001]. The combination of IN-alert HF state and RDI ≥ 30 episodes/h accounted for only 6% of the follow-up period and was associated with high rates of AHRE occurrence (from 28 events/100 patient-years for AHRE burden ≥5 min/day to 22 events/100 patient-years for AHRE burden ≥23 h/day). In HF patients, the occurrence of AHRE is independently associated with the ICD-measured IN-alert HF state and RDI ≥ 30 episodes/h. The coexistence of these two conditions occurs rarely but is associated with a very high rate of AHRE occurrence. URL: http://clinicaltrials.gov/Identifier: NCT02275637.

The aim of the study was to systematically review evidence on the effectiveness and safety of oral mexiletine administered in monotherapy or in combination with other antiarrhythmic drugs for recurrent ventricular arrhythmia (ventricular tachycardia/ventricular fibrillation, VT/VF) in adult patients with structural heart disease (SHD) and implantable cardioverter defibrillators (ICDs). We systematically searched MEDLINE, Embase, and CENTRAL databases from inception to 27 August 2021 for prospective and retrospective studies investigating mexiletine in the target population. The main outcome was the reduction of ICD therapy. The main safety outcome was the presence of any serious adverse events (SAEs) leading to mexiletine discontinuation. Study quality was assessed using the Cochrane risk of bias tool or the Newcastle-Ottawa scale. Four studies comprising 86 mexiletine recipients were included in the review. We also obtained individual data of 50 patients from two studies. Ischaemic cardiomyopathy (ICM) was present in 86% of patients. The quality of included studies was moderate/low. A narrative review was undertaken as studies varied widely in terms of study population and treatment. Across studies, mexiletine treatment (with or without amiodarone) seemed to consistently reduce the number of ICD therapies especially in a population where catheter ablation (CA) was unsuccessful or contraindicated. In ICM patients deemed eligible for CA, mexiletine seemed to be inferior to CA. Mexiletine was discontinued in 14% of cases, mainly for gastrointestinal or neurological SAE. Mexiletine seems to be an option for the long-term treatment of recurrent VT/VF in adult patients with SHD, especially ICM, and ICD in whom CA was unsuccessful or not suitable.

An epicardial approach is an effective means to detect and eliminate residual potentials in non-transmural lesions created during prior endocardial ablation. We sought to determine the impact of a combined epicardial and endocardial approach compared with a conventional endocardial approach, on recurrence-free survival after redo ablation. Participants with recurred persistent atrial fibrillation after prior endocardial ablation were randomized (1:1) to undergo treatment with the combined approach (epicardial followed by endocardial ablation) for the treatment group or conventional approach (endocardial ablation only) for the control group. The primary outcome was the time to recurrence of atrial fibrillation or atrial tachycardia following a 90-day blanking period within 12 months after the procedure. The secondary safety outcome was the occurrence of procedure-related complications within 24 h after the procedure. Of 100 randomized participants {median age, 59.0 [(interquartile range (IQR): 53.8-64.3] years, including 16% women, with one prior ablation (IQR: 1-1)}, 93 (93%) completed the trial. Events relevant to the primary outcome occurred in 16 patients in the treatment group and in 21 patients in the control group {Kaplan-Meier estimator percentages, 32 vs. 42%; hazard ratio, 0.71 [95% confidence interval (CI): 0.37-1.37]}. The periprocedural complication rate was lower in the treatment group [2 vs. 16%; odds ratio, 0.11 (95% CI: 0.00-0.87)] with similar achievement of the procedural endpoint in the two groups. In the redo procedure for persistent atrial fibrillation, the combined approach had no significant difference of recurrence-free survival and a lower procedural complication rate compared with the conventional approach.

Abstract Funding Acknowledgements Type of funding sources: Public grant(s) – National budget only. Main funding source(s): NIH, R01 HL149134, R01HL83359 Background Both Sleep Apnea (SA) and Atrial Fibrillation/flutter (AF) are known risk factors for stroke, and both are increasing in prevalence. They are both under-diagnosed in young adults &amp;lt;60 Y. There is an urgent need to define stroke risk portended by SA and AF yet there a paucity of data in adults aged 20-60 years. Purpose To define the relationship between stroke, SA, and AF in a very large cohort of 2 million young-middle aged adults aged 20-60 Y in Northern California. Methods We probed the Stanford Research Repository of electronic health data from 01/01/2008 to 11/30/2021 for the diagnoses of stroke, transient ischemic attacks, AF and SA using relevant codes (stroke: 433.X, 434.X, 436.X, I63.X, I65.X, I66.X, G45.X, G46.X; AF: I48.X; SA: G47.X, 327.27). Results We identified 2267485 patients aged 20-60Y (55% F; 32% White, 12% Asian, 3% Black), of whom SA was diagnosed in 52730 (2.3%), AF in 10230 (0.4%) and incident stroke in 10385 (0.4%) (Figure 1A) In patients with SA, 1.5% developed incident stroke. Stroke was more common in patients with SA than those without, regardless of co-existing diagnosis of AF; OR with AF: 1.5 [1.3-1.7, p&amp;lt;0.001] and OR without AF: 3.0 [2.8-3.3 p&amp;lt;0.0001]. Risk of stroke with SA than without was noted to be higher in the younger age subgroups (Figure 1B) regardless of AF. Although AF was more common in patients with SA than without (odds ratio, OR: 10.1 [9.6-10.6, p&amp;lt;0.0001]), the majority of SA patients (63% with CHADS2VASC ≥2) with stroke did not have a diagnosis of AF (75%), of whom 96% were not anticoagulated (Fig 1, left panel). Of the remaining patients with SA and incident stroke, who did have AF (25%), only 26% were taking OACs at the time of stroke despite median CHADS2 VASC score=3 (Fig 1A, left panel). Finally, 7% of AF patients developed incident stroke. Of these, 73% had CHADS2VASC ≥2, yet 44% were not anticoagulated. Patients with SA comprised a third of all AF patients with stroke and, compared to AF patients with stroke and without SA, had higher CHADS2VASC (median 3 vs 2, p&amp;lt;0.001) and a similarly low use of anticoagulation (56% vs 54% on OAC) (Fig 1A, right panel). Conclusions In &amp;gt;2 million young individuals, we uncover a novel association between SA and incident stroke, regardless of the diagnosis of AF. Surprisingly, three quarters of patients with SA developed incident stroke in the absence of AF, and were not anticoagulated. These results underscore the need to screen for AF and sleep apnea in young adults.

Abstract Funding Acknowledgements Type of funding sources: Public grant(s) – EU funding. Main funding source(s): This publication is part of a project that has received funding from the European Union’s Horizon 2020 research and innovation program under grant agreement No 954783. Background Stereotactic arrhythmia radio-ablation (STAR) is a promising strategy for the non-invasive treatment of ventricular arrhythmias (VA). The management of the cardio-respiratory motion of the target and the reduction of the uncertainties related to patients’ positioning are two of the main challenges that STAR has to overcome. A prototype of a system was developed that can automatically acquire and interpret echocardiographic images using an artificial intelligence (AI) algorithm to calculate cardiac displacement in real-time. Purpose To evaluate the feasibility of this automatic acquisition system in patients with a history of VA. Methods We conducted a single center, feasibility study enrolling consecutive patients with a history of VA. Echocardiographic images were automatically acquired from the parasternal and apical views with a dedicated probe. The system was designed to hold the probe fixed to the chest in the supine position during both free-breathing and short expiratory breath-hold sequences, to simulate STAR treatment. The primary endpoint was the percentage of patients reaching a score ≥2 in a multi-parametric assessment evaluating the quality of automatically acquired images in terms of: A - allowing a proper identification of the cardiac cycle phase using the AI algorithm, B - allowing a correct measurement of the heart displacement by the AI algorithm, C - ability to visually distinguish typical cardiac structures, and D - stability of the image throughout the respiration cycle. Moreover, we investigated the potential impact of clinical and demographic characteristics on achieving the primary outcome. Results From May to September 2021, we enrolled 24 patients (63±14 years, 21% females). All of them had a history of VA and 21 (88%) had an ICD. Eight patients (33%) had coronary artery disease, 12 (50%) had non-ischemic cardiomyopathy, and 3 had idiopathic VA. Parasternal as well as apical images were obtained from all patients except from one, in whom parasternal view could not be collected due to the patient’s inability to maintain the supine position. The primary outcome was achieved in 23 patients (96%) for the apical view, in 20 patients (87%) for the parasternal view, and in all patients in at least one of the two views. The images quality was maximal (i.e. score=4) in at least one of the two windows in 19 patients (79%). Atrial fibrillation arrhythmia was the only clinical characteristics associated with a poor score outcome in both imaging windows (apical p=0,022, parasternal p=0,014). Conclusion An automatic ultrasonographic image acquisition system associated with an AI algorithm is feasible for real-time monitoring of cardiac motion in patients with a history of VA. The possibility of real-time, non-invasive monitoring of cardiac position would lead to a significant improvement in the quality and safety of STAR treatment, particularly in case of treatment with heavy particles such as protons and carbon ions.

Abstract Funding Acknowledgements Type of funding sources: Public grant(s) – EU funding. Main funding source(s): European Union Horizon 2020 CATCH ME; Cardiovascular Research Netherlands RACE V Background Little is known about changes in the atrial transcriptome associated with paroxysmal and persistent atrial fibrillation (AF). Purpose To identify major molecular mechanisms in AF, we determined consistent differential expression (DE) between atrial tissue samples from well-characterized patients with paroxysmal or persistent AF and patients without a history of AF (no AF) in two independent patient cohorts. Methods Poly-A tailed RNA from left and right atrial appendage tissue samples from independent discovery and replication cohorts CATCH ME (n=192) and RACE V (n=122) was sequenced and analyzed according to patient AF history. Analyses were performed stratified by atrial side, adjusting for age, sex, heart failure and a combination of clinical characteristics determined by principal component analysis. Transcripts were considered DE in CATCH ME if their fold change reached transcriptome-wide significance (false discovery rate (FDR) &amp;lt; 0.05). DE transcripts in each rhythm comparison were replicated in RACE V if we observed a concordant direction of effect and a within-set FDR &amp;lt; 0.05 in the same comparison. Results Persistent AF compared to no AF was associated with 184 left atrial DE transcripts in CATCH ME of which 85 (46%) were replicated in RACE V, and with 208 right atrial DE transcripts in CATCH ME of which 86 (41%) were replicated in RACE V. Overall, 26 transcripts were discovered and replicated in both atria. Discovered but non-replicated transcripts often did exhibit concordant direction of effect (left: 78%, right: 83%). Replicated transcripts consisted of protein coding genes, antisense and non-coding RNAs. Protein coding genes showed involvement in pathways linking persistent AF to cardiomyocyte structure, conduction properties, fibrosis, inflammation, molecule trafficking, and endothelial dysfunction. Interestingly, paroxysmal AF was not consistently associated with DE transcripts in any comparison. Principal component analysis of the expression of the 26 transcripts strongly associated with persistent AF did however reveal a distinct paroxysmal AF expression profile in-between no AF and persistent AF patients in the first principal component scores (Figure 1). Conclusion RNA sequencing of human atrial tissue samples identified many transcripts associated with persistent AF in left and/or right atria, discovered and replicated using two independent cohorts. These consistent findings of AF-induced changes provide a starting point for targeted proteomic analysis and single-nucleus sequencing to further unravel the molecular mechanisms underlying AF progression to persistent AF, and biomarker development to quantify AF progression and enable precision medicine in individual patients.

Abstract Funding Acknowledgements Type of funding sources: None. Introduction Patients with hypertrophic obstructive cardiomyopathy (HOCM) that remain symptomatic despite optimized medical therapy are often submitted to alcohol septal ablation (ASA). One of the most frequent complications is the complete heart block (CHB), requiring permanent pacemaker (PPM) in variable rates, up to 20% of the patients. The long-term impact of PPM implantation in these patients remains unclear. Objectives This study aims to evaluate the long-term pacemaker dependency in patients with PPM after ASA and to assess the long-term impact of PPM in these patients. Methods In a tertiary center, patients who underwent ASA were retrospectively analyzed. Patients with previous PPM or implantable cardio-defibrillator were excluded. The groups with and without PPM implantation after ASA were compared regarding baseline characteristics, procedure data and outcomes. In the group who implanted PPM, the long-term pacing rates were evaluated. Results Between 2009 and 2020, 109 patients underwent ASA. 97 patients were included in this analysis (68% female, mean age 65.2 years-old). 16 patients (16.5%) required PPM implantation for CHB. In those, no vascular access, pacemaker pocket or pulmonary parenchyma complications were noted. The baseline characteristics regarding co-morbidities, symptoms, echocardiographic and electrocardiographic findings were identical in the two groups, with statistically significant differences in the mean age (70.6y/o in the PPM group versus 64.1y/o) and in the beta-blocker therapy rates previously to the intervention (56% in the PPM group versus 84%). Procedure-related data showed higher creatine kinase (CK) peaks in the PPM group (1692U/L versus 1243U/L, p0.05), without significant differences in the alcohol dose (2.1ml in both groups, p0.33). In the PPM group, the mean pacing rates at 1 month, 1 year and 2 years were 66.6±38.0, 50.4±44.1 and 50.8±42.5, respectively, with 2 patients (12.5%) having 1-5% pacing and none having pacing &amp;lt;1% at 2 years. In the group without PPM, 5 patients (6.2%) required posteriorly PPM implantation during the follow-up. There were no statistically significant differences in the two groups regarding in-hospital mortality, 1 year mortality or 1 year re-hospitalization. Despite a lower mean follow-up period in the PPM group (2.3±1.5 years versus 3.5±2.2 years, p0.05), there were no differences in the groups regarding all-cause mortality, cardiac cause mortality and cardiac cause re-hospitalization, with a statistical tendency to a lower all cause re-hospitalization in the PPM group (19% versus 43%, p0.07). Conclusions The registered pacing rates shows that all devices were adequately implanted. The long-term impact analysis suggests that the outcomes in patients who implant PPM after ASA are non-inferior to those who do not, with a tendency to reduce all cause re-hospitalizations.