Progression of Atrial Fibrillation after Cryoablation or Drug Therapy.

BACKGROUND: Atrial fibrillation is a chronic, progressive disorder, and persistent forms of atrial fibrillation are associated with increased risks of thromboembolism and heart failure. Catheter ablation as initial therapy may modify the pathogenic mechanism of atrial fibrillation and alter progression to persistent atrial fibrillation. METHODS: We report the 3-year follow-up of patients with paroxysmal, untreated atrial fibrillation who were enrolled in a trial in which they had been randomly assigned to undergo initial rhythm-control therapy with cryoballoon ablation or to receive antiarrhythmic drug therapy. All the patients had implantable loop recorders placed at the time of trial entry, and evaluation was conducted by means of downloaded daily recordings and in-person visits every 6 months. Data regarding the first episode of persistent atrial fibrillation (lasting ≥7 days or lasting 48 hours to 7 days but requiring cardioversion for termination), recurrent atrial tachyarrhythmia (defined as atrial fibrillation, flutter, or tachycardia lasting ≥30 seconds), the burden of atrial fibrillation (percentage of time in atrial fibrillation), quality-of-life metrics, health care utilization, and safety were collected. RESULTS: A total of 303 patients were enrolled, with 154 patients assigned to undergo initial rhythm-control therapy with cryoballoon ablation and 149 assigned to receive antiarrhythmic drug therapy. Over 36 months of follow-up, 3 patients (1.9%) in the ablation group had an episode of persistent atrial fibrillation, as compared with 11 patients (7.4%) in the antiarrhythmic drug group (hazard ratio, 0.25; 95% confidence interval [CI], 0.09 to 0.70). Recurrent atrial tachyarrhythmia occurred in 87 patients in the ablation group (56.5%) and in 115 in the antiarrhythmic drug group (77.2%) (hazard ratio, 0.51; 95% CI, 0.38 to 0.67). The median percentage of time in atrial fibrillation was 0.00% (interquartile range, 0.00 to 0.12) in the ablation group and 0.24% (interquartile range, 0.01 to 0.94) in the antiarrhythmic drug group. At 3 years, 8 patients (5.2%) in the ablation group and 25 (16.8%) in the antiarrhythmic drug group had been hospitalized (relative risk, 0.31; 95% CI, 0.14 to 0.66). Serious adverse events occurred in 7 patients (4.5%) in the ablation group and in 15 (10.1%) in the antiarrhythmic drug group. CONCLUSIONS: Initial treatment of paroxysmal atrial fibrillation with catheter cryoballoon ablation was associated with a lower incidence of persistent atrial fibrillation or recurrent atrial tachyarrhythmia over 3 years of follow-up than initial use of antiarrhythmic drugs. (Funded by the Cardiac Arrhythmia Network of Canada and others; EARLY-AF ClinicalTrials.gov number, NCT02825979.).

Cryoablation or Drug Therapy for Initial Treatment of Atrial Fibrillation.

BACKGROUND: Guidelines recommend a trial of one or more antiarrhythmic drugs before catheter ablation is considered in patients with atrial fibrillation. However, first-line ablation may be more effective in maintaining sinus rhythm. METHODS: We randomly assigned 303 patients with symptomatic, paroxysmal, untreated atrial fibrillation to undergo catheter ablation with a cryothermy balloon or to receive antiarrhythmic drug therapy for initial rhythm control. All the patients received an implantable cardiac monitoring device to detect atrial tachyarrhythmia. The follow-up period was 12 months. The primary end point was the first documented recurrence of any atrial tachyarrhythmia (atrial fibrillation, atrial flutter, or atrial tachycardia) between 91 and 365 days after catheter ablation or the initiation of an antiarrhythmic drug. The secondary end points included freedom from symptomatic arrhythmia, the atrial fibrillation burden, and quality of life. RESULTS: At 1 year, a recurrence of atrial tachyarrhythmia had occurred in 66 of 154 patients (42.9%) assigned to undergo ablation and in 101 of 149 patients (67.8%) assigned to receive antiarrhythmic drugs (hazard ratio, 0.48; 95% confidence interval [CI], 0.35 to 0.66; P<0.001). Symptomatic atrial tachyarrhythmia had recurred in 11.0% of the patients who underwent ablation and in 26.2% of those who received antiarrhythmic drugs (hazard ratio, 0.39; 95% CI, 0.22 to 0.68). The median percentage of time in atrial fibrillation was 0% (interquartile range, 0 to 0.08) with ablation and 0.13% (interquartile range, 0 to 1.60) with antiarrhythmic drugs. Serious adverse events occurred in 5 patients (3.2%) who underwent ablation and in 6 patients (4.0%) who received antiarrhythmic drugs. CONCLUSIONS: Among patients receiving initial treatment for symptomatic, paroxysmal atrial fibrillation, there was a significantly lower rate of atrial fibrillation recurrence with catheter cryoballoon ablation than with antiarrhythmic drug therapy, as assessed by continuous cardiac rhythm monitoring. (Funded by the Cardiac Arrhythmia Network of Canada and others; EARLY-AF ClinicalTrials.gov number, NCT02825979.).

Importance of genetic testing in unexplained cardiac arrest.

AIMS: Genetic testing is recommended in specific inherited heart diseases but its role remains unclear and it is not currently recommended in unexplained cardiac arrest (UCA). We sought to assess the yield and clinical utility of genetic testing in UCA using whole-exome sequencing (WES). METHODS AND RESULTS: Survivors of UCA requiring external defibrillation were included from the Cardiac Arrest Survivor with Preserved Ejection fraction Registry. Whole-exome sequencing was performed, followed by assessment of rare variants in previously reported cardiovascular disease genes. A total of 228 UCA survivors (mean age at arrest 39 ± 13 years) were included. The majority were males (66%) and of European ancestry (81%). Following advanced clinical testing at baseline, the likely aetiology of cardiac arrest was determined in 21/228 (9%) cases. Whole-exome sequencing identified a pathogenic or likely pathogenic (P/LP) variant in 23/228 (10%) of UCA survivors overall, increasing the proportion of 'explained' cases from 9% only following phenotyping to 18% when combining phenotyping with WES. Notably, 13 (57%) of the 23 P/LP variants identified were located in genes associated with cardiomyopathy, in the absence of a diagnosis of cardiomyopathy at the time of arrest. CONCLUSIONS: Genetic testing identifies a disease-causing variant in 10% of apparent UCA survivors. The majority of disease-causing variants was located in cardiomyopathy-associated genes, highlighting the arrhythmogenic potential of such variants in the absence of an overt cardiomyopathy diagnosis. The present study supports the use of genetic testing including assessment of arrhythmia and cardiomyopathy genes in survivors of UCA.

Characterization of arrhythmia substrate to ablate persistent atrial fibrillation (COAST-AF): Randomized controlled trial design and rationale.

BACKGROUND: Atrial low voltage area (LVA) catheter ablation has emerged as a promising strategy for ablation of persistent atrial fibrillation (AF). It is unclear if catheter ablation of atrial LVA increases treatment success rates in patients with persistent AF. OBJECTIVE: The primary aim of this trial is to assess the potential benefit of adjunctive catheter ablation of atrial LVA in addition to pulmonary vein isolation (PVI) in patients with persistent AF, when compared to PVI alone. The secondary aims are to evaluate safety outcomes, the quality of life and the healthcare resource utilization. METHODS/DESIGN: A multicenter, prospective, parallel-group, 2-arm, single-blinded randomized controlled trial is under way (NCT03347227). Patients who are candidates for catheter ablation for persistent AF will be randomly assigned (1:1) to either PVI alone or PVI + atrial LVA ablation. The primary outcome is 18-month documented event rate of atrial arrhythmia (AF, atrial tachycardia or atrial flutter) post catheter ablation. Secondary outcomes include procedure-related complications, freedom from atrial arrhythmia at 12 months, AF burden, need for emergency department visits/hospitalization, need for repeat ablation for atrial arrhythmia, quality of life at 12 and 18 months, ablation time, and procedure duration. DISCUSSION: Characterization of Arrhythmia Mechanism to Ablate Atrial Fibrillation (COAST-AF) is a multicenter randomized trial evaluating ablation strategies for catheter ablation. We hypothesize that catheter ablation of atrial LVA in addition to PVI will result in higher procedural success rates when compared to PVI alone in patients with persistent AF.

Augmented wide area circumferential catheter ablation for reduction of atrial fibrillation recurrence (AWARE) trial: Design and rationale.

BACKGROUND: Recurrence of atrial fibrillation (AF) after a pulmonary vein isolation procedure is often due to electrical reconnection of the pulmonary veins. Repeat ablation procedures may improve freedom from AF but are associated with increased risks and health care costs. A novel ablation strategy in which patients receive "augmented" ablation lesions has the potential to reduce the risk of AF recurrence. OBJECTIVE: The Augmented Wide Area Circumferential Catheter Ablation for Reduction of Atrial Fibrillation Recurrence (AWARE) Trial was designed to evaluate whether an augmented wide-area circumferential antral (WACA) ablation strategy will result in fewer atrial arrhythmia recurrences in patients with symptomatic paroxysmal AF, compared with a conventional WACA strategy. METHODS/DESIGN: The AWARE trial was a multicenter, prospective, randomized, open, blinded endpoint trial that has completed recruitment (ClinicalTrials.gov NCT02150902). Patients were randomly assigned (1:1) to either the control arm (single WACAlesion set) or the interventional arm (augmented- double WACA lesion set performed after the initial WACA). The primary outcome was atrial tachyarrhythmia (AA; atrial tachycardia [AT], atrial flutter [AFl] or AF) recurrence between days 91 and 365 post catheter ablation. Patient follow-up included 14-day continuous ambulatory ECG monitoring at 3, 6, and 12 months after catheter ablation. Three questionnaires were administered during the trial- the EuroQuol-5D (EQ-5D) quality of life scale, the Canadian Cardiovascular Society Severity of Atrial Fibrillation scale, and a patient satisfaction scale. DISCUSSION: The AWARE trial was designed to evaluate whether a novel approach to catheter ablation reduced the risk of AA recurrence in patients with symptomatic paroxysmal AF.

Short-coupled ventricular fibrillation represents a distinct phenotype among latent causes of unexplained cardiac arrest: a report from the CASPER registry.

AIMS: The term idiopathic ventricular fibrillation (IVF) describes survivors of unexplained cardiac arrest (UCA) without a specific diagnosis after clinical and genetic testing. Previous reports have described a subset of IVF individuals with ventricular arrhythmia initiated by short-coupled trigger premature ventricular contractions (PVCs) for which the term short-coupled ventricular fibrillation (SCVF) has been proposed. The aim of this article is to establish the phenotype and frequency of SCVF in a large cohort of UCA survivors. METHODS AND RESULTS: We performed a multicentre study including consecutive UCA survivors from the CASPER registry. Short-coupled ventricular fibrillation was defined as otherwise unexplained ventricular fibrillation initiated by a trigger PVC with a coupling interval of <350 ms. Among 364 UCA survivors, 24/364 (6.6%) met diagnostic criteria for SCVF. The diagnosis of SCVF was obtained in 19/24 (79%) individuals by documented ventricular fibrillation during follow-up. Ventricular arrhythmia was initiated by a mean PVC coupling interval of 274 ± 32 ms. Electrical storm occurred in 21% of SCVF probands but not in any UCA proband (P < 0.001). The median time to recurrent ventricular arrhythmia in SCVF was 31 months. Recurrent ventricular fibrillation resulted in quinidine administration in 12/24 SCVF (50%) with excellent arrhythmia control. CONCLUSION: Short-coupled ventricular fibrillation is a distinct primary arrhythmia syndrome accounting for at least 6.6% of UCA. As documentation of ventricular fibrillation onset is necessary for the diagnosis, most cases are diagnosed at the time of recurrent arrhythmia, thus the true prevalence of SCVF remains still unknown. Quinidine is effective in SCVF and should be considered as first-line treatment for patients with recurrent episodes.

Right Ventricular Function at Cardiac MRI Predicts Cardiovascular Events in Patients with an Implantable Cardioverter-Defibrillator.

Background Right ventricular ejection fraction (RVEF) is an independent predictor of death and adverse cardiovascular outcomes in patients with various cardiac conditions. Purpose To investigate whether RVEF, measured with cardiac MRI, is a predictor of appropriate shock or death in implantable cardioverter-defibrillator (ICD) recipients for primary and secondary prevention of sudden cardiac death. Materials and Methods This retrospective, multicenter, observational study included patients who underwent cardiac MRI before ICD implantation between January 2007 and May 2017. Right ventricular end-diastolic and end-systolic volumes and RVEF were measured with cardiac MRI. The primary end point was a composite of all-cause mortality or appropriate ICD shock. The secondary end point was all-cause mortality. The association between RVEF and primary and secondary outcomes was evaluated by using multivariable Cox regression analysis. Potential interactions were tested between primary prevention, ischemic cause, left ventricular ejection fraction (LVEF), and RVEF. Results Among 411 patients (mean age ± standard deviation, 60 years; 315 men) during a median follow-up of 63 months, 143 (35%) patients experienced an appropriate ICD shock or died. In univariable analysis, lower RVEF was associated with greater risks for appropriate ICD shock or death and for death alone (log-rank trend test, P = .003 and .005 respectively). In multivariable Cox regression analysis adjusting for age at ICD implantation, LVEF, ICD indication (primary vs secondary), ischemic heart disease, and late gadolinium enhancement, RVEF was an independent predictor of the primary outcome (hazard ratio [HR], 1.21 per 10% lower RVEF; 95% CI: 1.04, 1.41; P = .01) and all-cause mortality (HR, 1.25 per 10% lower RVEF; 95% CI: 1.01, 1.55; P = .04). No evidence of significant interactions was found between RVEF and primary or secondary prevention (P = .49), ischemic heart disease (P = .78), and LVEF (P = .29). Conclusion Right ventricular ejection fraction measured with cardiac MRI was a predictor of appropriate implantable cardioverter-defibrillator shock or death. © RSNA, 2021 See also the editorial by Nazarian and Zghaib in this issue. An earlier incorrect version of this article appeared online. This article was corrected on August 24, 2021.

Myocardial strain assessment using cardiovascular magnetic resonance imaging in recipients of implantable cardioverter defibrillators.

BACKGROUND: Cardiovascular magnetic resonance (CMR) is increasingly used in the evaluation of patients who are potential candidates for implantable cardioverter-defibrillator (ICD) therapy to assess left ventricular (LV) ejection fraction (LVEF), myocardial fibrosis, and etiology of cardiomyopathy. It is unclear whether CMR-derived strain measurements are predictive of appropriate shocks and death among patients who receive an ICD. We evaluated the prognostic value of LV strain parameters on feature-tracking (FT) CMR in patients who underwent subsequent ICD implant for primary or secondary prevention of sudden cardiac death. METHODS: Consecutive patients from 2 Canadian tertiary care hospitals who underwent ICD implant and had a pre-implant CMR scan were included. Using FT-CMR, a single, blinded, reader measured LV global longitudinal (GLS), circumferential (GCS), and radial (GRS) strain. Cox proportional hazards regression was performed to assess the associations between strain measurements and the primary composite endpoint of all-cause death or appropriate ICD shock that was independently ascertained. RESULTS: Of 364 patients (mean 61 years, mean LVEF 32%), 64(17.6%) died and 118(32.4%) reached the primary endpoint over a median follow-up of 62 months. Univariate analyses showed significant associations between GLS, GCS, and GRS and appropriate ICD shocks or death (all p < 0.01). In multivariable Cox models incorporating LVEF, GLS remained an independent predictor of both the primary endpoint (HR 1.05 per 1% higher GLS, 95% CI 1.01-1.09, p = 0.010) and death alone (HR 1.06 per 1% higher GLS, 95% CI 1.02-1.11, p = 0.003). There was no significant interaction between GLS and indication for ICD implant, presence of ischemic heart disease or late gadolinium enhancement (all p > 0.30). CONCLUSIONS: GLS by FT-CMR is an independent predictor of appropriate shocks or mortality in ICD patients, beyond conventional prognosticators including LVEF. Further study is needed to elucidate the role of LV strain analysis to refine risk stratification in routine assessment of ICD treatment benefit.

The effect of left ventricular pacing on transmural activation delay in myopathic human hearts.

Aims: Left ventricular (LV) epicardial pacing (LVEpiP) in human myopathic hearts does not decrease global epicardial activation delay compared with right ventricular (RV) endocardial pacing (RVEndoP); however, the effect on transmural activation delay has not been evaluated. To characterize the transmural electrical activation delay in human myopathic hearts during RVEndoP and LVEpiP compared with global epicardial activation delay. Methods and results: Explanted hearts from seven patients (5 male, 46 ± 10 years) undergoing cardiac transplantation were Langendorff-perfused and mapped using an epicardial sock electrode array (112 electrodes) and 25 transmural plunge needles (four electrodes, 2 mm spacing), for a total of 100 unipolar transmural electrodes. Electrograms were recorded during LVEpiP and RVEndoP, and epicardial (sock) and transmural (needle) activation times, along with patterns of activation, were compared. There was no difference between the global epicardial activation times (LVEpiP 147 ± 8 ms vs. RVEndoP 156 ± 17 ms, P = 0.46). The mean LV transmural activation time during LVEpiP was significantly shorter than that during RVEndoP (125 ± 44 vs. 172 ± 43 ms, P < 0.001). During LVEpiP, of the transmural layers endo-, mid-myocardium and epicardium, LV endocardial layer was often the earliest compared with other transmural layers. Conclusion: In myopathic human hearts, LVEpiP did not decrease global epicardial activation delays compared with RVEndoP. LV epicardial pacing led to early activation of the LV endocardium, revealing the importance of the LV endocardium even when pacing from the LV epicardium.

ICD Implantation Rates in Cardiac Arrest Survivors in Canada.

Background: Patients resuscitated from out-of-hospital cardiac arrest (OHCA) are at high risk of recurrence, posing a substantial burden on healthcare systems. Despite the established benefit of implantable cardioverter defibrillator (ICD) therapy in many such patients, and recommendations by guidelines, few studies have described the proportion of OHCA patients who receive guideline-concordant care. Methods: The Canadian Institute for Health Information Discharge Abstract Database dataset was used to identify OHCA patients admitted to hospitals across Canada, excluding Quebec. We analyzed all patients without a probable ischemic or bradycardia etiology of cardiac arrest, who survived to discharge, to estimate the ICD implantation rates in patients who were potentially eligible to have an ICD. Results: Between 2013 and 2017, a total of 10,435 OHCA patients who were admitted to the hospital were captured in the database; 4486 (43%) survived to hospital discharge, and 2580 survivors (57.5%) were potentially eligible to receive an ICD. Among these potentially eligible patients, 757 (29.3%) received an ICD during their index admission or within 30 days after discharge from the hospital. The ICD implantation rate during index admission increased from 13.8% in 2013 to 19.6% in 2017 (P-value for time trend < 0.05). The rate of ICD implantations in potentially eligible patients was higher in urban than in rural settings (19.5% vs 11.1%) and in teaching vs community hospitals (34.7% vs 9.8%). Conclusions: Although ICD implantation rates show an increasing trend among patients with OHCA who are likely eligible for secondary prevention, significant underutilization of ICDs persists in these patients.

Contexte: Les patients ayant survécu à un arrêt cardiaque extra-hospitalier (ACEH) présentent un risque élevé de récidive, ce qui impose un lourd fardeau aux systèmes de soins de santé. Malgré l'avantage établi de la mise en place d'un défibrillateur cardioverteur implantable (DCI) chez un grand nombre de ces patients, et les recommandations des lignes directrices, peu d'études décrivent la proportion de patients victimes d'un ACEH ayant reçu des soins conformes aux lignes directrices. Méthodologie: Nous avons recensé les admissions à l'hôpital de patients ayant subi un ACEH au Canada, à l'exception du Québec à partir de l'ensemble de données de la Base de données sur les congés des patients de l'Institut canadien d'information sur la santé. Nous avons inclus dans notre analyse tous les patients pour lesquels la cause de l'arrêt cardiaque n'était probablement pas ischémique ou bradycardique et qui avaient survécu jusqu'à leur congé de l'hôpital, afin d'estimer les taux d'implantation d'un DCI chez les patients potentiellement admissibles à cette intervention. Résultats: Entre 2013 et 2017, un total de 10 435 patients ayant subi un ACEH ont été hospitalisés selon la base de données; 4 486 (43 %) avaient survécu jusqu'à leur congé de l'hôpital, et 2 580 survivants (57,5 %) étaient potentiellement admissibles à l'implantation d'un DCI. Parmi les patients potentiellement admissibles, 757 (29,3 %) avaient reçu un DCI au moment de leur admission initiale ou dans les 30 jours suivant leur congé de l'hôpital. Le taux d'implantation de DCI lors de l'admission initiale est passé de 13,8 % en 2013 à 19,6 % en 2017 (valeur p pour la tendance au fil du temps < 0,05). Le taux d'implantation d'un DCI chez les patients potentiellement admissibles était plus élevé en milieu urbain qu'en milieu rural (19,5 % contre 11,1 %) et dans les hôpitaux d'enseignement/universitaires par comparaison avec les hôpitaux communautaires (34,7 % contre 9,8 %). Conclusions: Bien que les taux d'implantation de DCI affichent une tendance à la hausse chez les patients ayant subi un ACEH qui sont probablement admissibles à des interventions de prévention secondaire, les DCI demeurent largement sous-utilisés chez ces patients.

Incremental value of the signal-averaged ECG for diagnosing arrhythmogenic cardiomyopathy.

BACKGROUND: Arrhythmogenic right ventricular cardiomyopathy (ARVC) is currently diagnosed using a combination of clinical features, imaging, electrocardiography, and genetic investigations. An abnormal signal-averaged electrocardiogram (SAECG) is defined as a minor diagnostic criterion by the 2010 Task Force Criteria, but doubts remain about the value of this investigation. OBJECTIVE: We evaluated the utility of the SAECG in diagnosing ARVC using the Canadian Arrhythmogenic Right Ventricular Cardiomyopathy Registry, a population representative registry of probands with ARVC and relatives, less influenced by referral bias. METHODS: Probands with ARVC and family members from the Canadian Arrhythmogenic Right Ventricular Cardiomyopathy Registry underwent phenotype review. SAECG parameters were compared individually and in combination between those with varying degrees of ARVC severity and healthy controls (family members of probands with ARVC and unexplained sudden death, free of evidence of cardiac disease). RESULTS: A total of 196 patients with ARVC and 205 controls were included (mean age 44 ± 15 years; 186 of 401 men [46%]). SAECG abnormalities were seen in 83 of 205 controls (40%), 33 of 68 patients with ARVC and mild disease (51%), and 31 of 42 with severe disease (74%). The SAECG associated strongly with imaging abnormalities (major: odds ratio 3.0, 95% confidence interval 1.3-6.9; minor: odds ratio 3.5, 95% confidence interval 0.7-16.5) but not with other aspects of phenotype. Patients carrying pathogenic variants but with minimal phenotype had similar SAECGs to healthy controls (filtered QRS duration 111.2 ± 11.2 ms vs 111 ± 7.6 ms, P = .93; duration of low amplitude signals < 40 µV 32.3 ± 8.9 ms vs 34.2 ± 7.2 ms, P = .32; root mean square of the terminal 40 ms of the filtered QRS complex 43.1 ± 25.2 ms vs 38.2 ± 20.2 ms, P = .38). CONCLUSION: The SAECG appears to be a surrogate marker for structural abnormalities seen on imaging in those with ARVC. Great caution is required in interpreting SAECG findings in those without other corroborating evidence of an ARVC phenotype.

The Prevalence and Characteristics of Arrhythmic Mitral Valve Prolapse in Patients With Unexplained Cardiac Arrest.

BACKGROUND: There is growing evidence that mitral valve prolapse (MVP) is associated with otherwise unexplained cardiac arrest (UCA). However, reports are hindered by the absence of a systematic ascertainment of alternative diagnoses. OBJECTIVES: This study reports the prevalence and characteristics of MVP in a large cohort of patients with UCA. METHODS: Patients were enrolled following an UCA, defined as cardiac arrest with no coronary artery disease, preserved left ventricular ejection fraction, and no apparent explanation on electrocardiogram. A comprehensive evaluation was performed, and patients were diagnosed with idiopathic ventricular fibrillation (IVF) if no cause was found. Echocardiography reports were reviewed for MVP. Patients with MVP were divided into 2 groups: those with IVF (AMVP) and those with an alternative diagnosis (nonarrhythmic MVP). Patient characteristics were then compared. The long-term outcomes of AMVP were reported. RESULTS: Among 571 with an initially UCA, 34 patients had MVP (6%). The prevalence of definite MVP was significantly higher in patients with IVF than those with an alternative diagnosis (24 of 366 [6.6%] vs 5 of 205 [2.4%]; P = 0.03). Bileaflet prolapse was significantly associated with AMVP (18 of 23 [78%] vs 1 of 8 [12.5%]; P = 0.001; OR: 25.2). The proportion of patients with AMVP who received appropriate implantable cardioverter-defibrillator therapies over a median follow-up of 42 months was 21.1% (4 of 19). CONCLUSIONS: MVP is associated with otherwise UCA (IVF), with a prevalence of 6.6%. Bileaflet prolapse appears to be a feature of AMVP, although future studies need to ascertain its independent association. A significant proportion of patients with AMVP received appropriate implantable cardioverter-defibrillator therapies during follow-up.

Standard vs Augmented Ablation of Paroxysmal Atrial Fibrillation for Reduction of Atrial Fibrillation Recurrence: The AWARE Randomized Clinical Trial.

Importance: Recurrent atrial fibrillation (AF) commonly occurs after catheter ablation and is associated with patient morbidity and health care costs. Objective: To evaluate the superiority of an augmented double wide-area circumferential ablation (WACA) compared with a standard single WACA in preventing recurrent atrial arrhythmias (AA) (atrial tachycardia, atrial flutter, or atrial fibrillation [AF]) in patients with paroxysmal AF. Design, Setting, and Participants: This was a pragmatic, multicenter, prospective, randomized, open, blinded end point superiority clinical trial conducted at 10 university-affiliated centers in Canada. The trial enrolled patients 18 years and older with symptomatic paroxysmal AF from March 2015 to May 2017. Analysis took place between January and April 2022. Analyses were intention to treat. Interventions: Patients were randomized (1:1) to receive radiofrequency catheter ablation for pulmonary vein isolation with either a standard single WACA or an augmented double WACA. Main Outcomes and Measures: The primary outcome was AA recurrence between 91 and 365 days postablation. Patients underwent 42 days of ambulatory electrocardiography monitoring after ablation. Secondary outcomes included need for repeated catheter ablation and procedural and safety variables. Results: Of 398 patients, 195 were randomized to the single WACA (control) arm (mean [SD] age, 60.6 [9.3] years; 65 [33.3%] female) and 203 to the double WACA (experimental) arm (mean [SD] age, 61.5 [9.3] years; 66 [32.5%] female). Overall, 52 patients (26.7%) in the single WACA arm and 50 patients (24.6%) in the double WACA arm had recurrent AA at 1 year (relative risk, 0.92; 95% CI, 0.66-1.29; P = .64). Twenty patients (10.3%) in the single WACA arm and 15 patients (7.4%) in the double WACA arm underwent repeated catheter ablation (relative risk, 0.72; 95% CI, 0.38-1.36). Adjudicated serious adverse events occurred in 13 patients (6.7%) in the single WACA arm and 14 patients (6.9%) in the double WACA arm. Conclusions and Relevance: In this randomized clinical trial of patients with paroxysmal AF, additional ablation by performing a double ablation lesion set did not result in improved freedom from recurrent AA compared with a standard single ablation set. Trial Registration: ClinicalTrials.gov Identifier: NCT02150902.

Association of the Timing and Extent of Cardiac Implantable Electronic Device Infections With Mortality.

Importance: Cardiac implantable electronic device (CIED) infection is a potentially devastating complication with an estimated 12-month mortality of 15% to 30%. The association of the extent (localized or systemic) and timing of infection with all-cause mortality has not been established. Objective: To evaluate the association of the extent and timing of CIED infection with all-cause mortality. Design, Setting, and Participants: This prospective observational cohort study was conducted between December 1, 2012, and September 30, 2016, in 28 centers across Canada and the Netherlands. The study included 19 559 patients undergoing CIED procedures, 177 of whom developed an infection. Data were analyzed from April 5, 2021, to January 14, 2023. Exposures: Prospectively identified CIED infections. Main Outcomes and Measures: Time-dependent analysis of the timing (early [≤3 months] or delayed [3-12 months]) and extent (localized or systemic) of infection was performed to determine the risk of all-cause mortality associated with CIED infections. Results: Of 19 559 patients undergoing CIED procedures, 177 developed a CIED infection. The mean (SD) age was 68.7 (12.7) years, and 132 patients were male (74.6%). The cumulative incidence of infection was 0.6%, 0.7%, and 0.9% within 3, 6, and 12 months, respectively. Infection rates were highest in the first 3 months (0.21% per month), reducing significantly thereafter. Compared with patients who did not develop CIED infection, those with early localized infections were not at higher risk for all-cause mortality (no deaths at 30 days [0 of 74 patients]: adjusted hazard ratio [aHR], 0.64 [95% CI, 0.20-1.98]; P = .43). However, patients with early systemic and delayed localized infections had an approximately 3-fold increase in mortality (8.9% 30-day mortality [4 of 45 patients]: aHR, 2.88 [95% CI, 1.48-5.61]; P = .002; 8.8% 30-day mortality [3 of 34 patients]: aHR, 3.57 [95% CI, 1.33-9.57]; P = .01), increasing to a 9.3-fold risk of death for those with delayed systemic infections (21.7% 30-day mortality [5 of 23 patients]: aHR, 9.30 [95% CI, 3.82-22.65]; P < .001). Conclusions and Relevance: Findings suggest that CIED infections are most common within 3 months after the procedure. Early systemic infections and delayed localized infections are associated with increased mortality, with the highest risk for patients with delayed systemic infections. Early detection and treatment of CIED infections may be important in reducing mortality associated with this complication.

Management of Inherited Arrhythmia Syndromes: A HiRO Consensus Handbook on Process of Care.

Inherited arrhythmia syndromes are rare genetic conditions that predispose seemingly healthy individuals to sudden cardiac arrest and death. The Hearts in Rhythm Organization is a multidisciplinary Canadian network of clinicians, researchers, patients, and families that aims to improve care for patients and families with inherited cardiac conditions, focused on those that confer predisposition to arrhythmia and sudden cardiac arrest and/or death. The field is rapidly evolving as research discoveries increase. A streamlined, practical guide for providers to diagnose and follow pediatric and adult patients with inherited cardiac conditions represents a useful tool to improve health system utilization, clinical management, and research related to these conditions. This review provides consensus care pathways for 7 conditions, including the 4 most common inherited cardiac conditions that confer predisposition to arrhythmia, with scenarios to guide investigation, diagnosis, risk stratification, and management. These conditions include Brugada syndrome, long QT syndrome, arrhythmogenic right ventricular cardiomyopathy and related arrhythmogenic cardiomyopathies, and catecholaminergic polymorphic ventricular tachycardia. In addition, an approach to investigating and managing sudden cardiac arrest, sudden unexpected death, and first-degree family members of affected individuals is provided. Referral to specialized cardiogenetic clinics should be considered in most cases. The intention of this review is to offer a framework for the process of care that is useful for both experts and nonexperts, and related allied disciplines such as hospital management, diagnostic services, coroners, and pathologists, in order to provide high-quality, multidisciplinary, standardized care.

Les syndromes d'arythmie héréditaires sont des troubles génétiques rares qui prédisposent des personnes en apparence en bonne santé à un arrêt cardiaque soudain et à la mort. L'organisation Hearts in Rhythm Organization est un réseau multidisciplinaire canadien qui regroupe des cliniciens, des chercheurs ainsi que des patients et leurs proches dans le but d'améliorer les soins prodigués aux patients atteints de maladies cardiaques héréditaires et à leur famille, en particulier dans le cas des maladies qui entraînent une prédisposition à l'arythmie et à un arrêt cardiaque soudain et/ou à la mort. Puisque ce champ de recherche évolue rapidement, la mise au point d'un guide pratique et simple à l'intention des professionnels de la santé pour le diagnostic et le suivi des patients enfants et adultes présentant une maladie cardiaque héréditaire serait donc un outil intéressant pour améliorer l'utilisation du système de santé et la prise en charge clinique de ces maladies tout en orientant la recherche à ce propos. La présente synthèse expose les trajectoires de soins faisant l'objet d'un consensus pour sept maladies, dont les quatre maladies cardiaques héréditaires les plus courantes qui prédisposent à l'arythmie. Elle présente aussi des scénarios pour orienter les examens, le diagnostic, la stratification du risque et la prise en charge des patients. Ces maladies sont le syndrome de Brugada, le syndrome du QT long, la cardiomyopathie arythmogénique du ventricule droit et les cardiomyopathies arythmogènes associées, et la tachycardie ventriculaire polymorphe catécholaminergique. En outre, une approche pour la prise en charge de l'arrêt cardiaque soudain, de mort subite inattendue et des membres de la famille immédiate de la personne touchée est proposée. L'orientation vers des cliniques spécialisées en cardiogénétique doit être envisagée dans la plupart des cas. L'objectif est d'établir un cadre de soins qui soit utile pour les experts et les non-experts ainsi que pour les professionnels des domaines connexes, par exemple le personnel de l'administration hospitalière et des services diagnostiques, les coroners et les pathologistes, en vue d'offrir des soins multidisciplinaires normalisés de grande qualité.

Identification and in-silico characterization of splice-site variants from a large cardiogenetic national registry.

Splice-site variants in cardiac genes may predispose carriers to potentially lethal arrhythmias. To investigate, we screened 1315 probands and first-degree relatives enrolled in the Canadian Hearts in Rhythm Organization (HiRO) registry. 10% (134/1315) of patients in the HiRO registry carry variants within 10 base-pairs of the intron-exon boundary with 78% (104/134) otherwise genotype negative. These 134 probands were carriers of 57 unique variants. For each variant, American College of Medical Genetics and Genomics (ACMG) classification was revisited based on consensus between nine in silico tools. Due in part to the in silico algorithms, seven variants were reclassified from the original report, with the majority (6/7) downgraded. Our analyses predicted 53% (30/57) of variants to be likely/pathogenic. For the 57 variants, an average of 9 tools were able to score variants within splice sites, while 6.5 tools responded for variants outside these sites. With likely/pathogenic classification considered a positive outcome, the ACMG classification was used to calculate sensitivity/specificity of each tool. Among these, Combined Annotation Dependent Depletion (CADD) had good sensitivity (93%) and the highest response rate (131/134, 98%), dbscSNV was also sensitive (97%), and SpliceAI was the most specific (64%) tool. Splice variants remain an important consideration in gene elusive inherited arrhythmia syndromes. Screening for intronic variants, even when restricted to the ±10 positions as performed here may improve genetic testing yield. We compare 9 freely available in silico tools and provide recommendations regarding their predictive capabilities. Moreover, we highlight several novel cardiomyopathy-associated variants which merit further study.

Relationship Between Left Ventricular Strain Assessment by Cardiac Magnetic Resonance Imaging and Response to Cardiac Resynchronization Therapy.

Although cardiac resynchronization therapy (CRT) is an established treatment for heart failure with reduced ejection fraction, 30 to 50% patients are non-responders. In this retrospective single-centre study, 19 patients underwent cardiac MRI pre-CRT, and global left ventricular (LV) strain and late gadolinium enhancement (LGE) were measured by a blinded reader. LV reverse remodeling was independently assessed using transthoracic echocardiogram before and after CRT implant. Both LV strain and extent of LGE correlated significantly with measures of reverse LV remodeling (reduction in LV volume and improvement in LV ejection fraction). These findings suggest that CMR derived strain analysis and scar evaluation may be useful preimplant predictors of response to CRT. Larger prospective multi-center studies are needed to confirm these findings and to further evaluate the role of CMR strain imaging in guiding CRT treatment decisions.

Sex Differences and Utility of Treadmill Testing in Long-QT Syndrome.

Background Diagnosis of congenital long-QT syndrome (LQTS) is complicated by phenotypic ambiguity, with a frequent normal-to-borderline resting QT interval. A 3-step algorithm based on exercise response of the corrected QT interval (QTc) was previously developed to diagnose patients with LQTS and predict subtype. This study evaluated the 3-step algorithm in a population that is more representative of the general population with LQTS with milder phenotypes and establishes sex-specific cutoffs beyond the resting QTc. Methods and Results We identified 208 LQTS likely pathogenic or pathogenic KCNQ1 or KCNH2 variant carriers in the Canadian NLQTS (National Long-QT Syndrome) Registry and 215 unaffected controls from the HiRO (Hearts in Rhythm Organization) Registry. Exercise treadmill tests were analyzed across the 5 stages of the Bruce protocol. The predictive value of exercise ECG characteristics was analyzed using receiver operating characteristic curve analysis to identify optimal cutoff values. A total of 78% of male carriers and 74% of female carriers had a resting QTc value in the normal-to-borderline range. The 4-minute recovery QTc demonstrated the best predictive value for carrier status in both sexes, with better LQTS ascertainment in female patients (area under the curve, 0.90 versus 0.82), with greater sensitivity and specificity. The optimal cutoff value for the 4-minute recovery period was 440 milliseconds for male patients and 450 milliseconds for female patients. The 1-minute recovery QTc had the best predictive value in female patients for differentiating LQTS1 versus LQTS2 (area under the curve, 0.82), and the peak exercise QTc had a marginally better predictive value in male patients for subtype with (area under the curve, 0.71). The optimal cutoff value for the 1-minute recovery period was 435 milliseconds for male patients and 455 milliseconds for femal patients. Conclusions The 3-step QT exercise algorithm is a valid tool for the diagnosis of LQTS in a general population with more frequent ambiguity in phenotype. The algorithm is a simple and reliable method for the identification and prediction of the 2 major genotypes of LQTS.