DREAM-ICD-II Study.

BACKGROUND: Regulatory authorities of most industrialized countries recommend 6 months of private driving restriction after implantation of a secondary prevention implantable cardioverter-defibrillator (ICD). These driving restrictions result in significant inconvenience and social implications. This study aimed to assess the incidence rate of appropriate device therapies in contemporary recipients of a secondary prevention ICD. METHODS: This retrospective study at 3 Canadian tertiary care centers enrolled consecutive patients with new secondary prevention ICD implants between 2016 and 2020. RESULTS: For a median of 760 days (324, 1190 days), 721 patients were followed up. The risk of recurrent ventricular arrhythmia was highest during the first 3 months after device insertion (34.4%) and decreased over time (10.6% between 3 and 6 months, 11.7% between 6 and 12 months). The corresponding incidence rate per 100 patient-days was 0.48 (95% CI, 0.35-0.64) at 90 days, 0.28 (95% CI, 0.17-0.45) at 180 days, and 0.21 (95% CI, 0.13-0.33) between 181 and 365 days after ICD insertion (P<0.001). The cumulative incidence of arrhythmic syncope resulting in sudden cardiac incapacitation was 1.8% within the first 90 days and subsequently dropped to 0.4% between 91 and 180 days (P<0.001) after ICD insertion. CONCLUSIONS: The incidence rate of appropriate therapies resulting in sudden cardiac incapacitation in contemporary recipients of a secondary prevention ICD is much lower than previously reported and declines significantly after the first 3 months. Lowering driving restrictions to 3 months after the index cardiac event seems safe, and revision of existing guidelines should be considered in countries still adhering to a 6-month period. Existing restrictions for private driving after implantation of a secondary prevention ICD should be reconsidered.

Same-day discharge for atrial fibrillation ablation: outcomes and impact of ablation modality.

AIMS: Same-day discharge is increasingly common after catheter ablation for atrial fibrillation (AF). However, the impact of same-day discharge on healthcare utilization after ablation and whether this differs by ablation modality remains uncertain. We examined the safety, efficacy, and subsequent healthcare utilization of a same-day discharge protocol for AF ablation, including radiofrequency (RF) and cryoballoon ablation, in a contemporary cohort. METHODS AND RESULTS: All consecutive patients for whom full healthcare utilization data were available at two centres and who underwent AF ablation from 2018 to 2019 were included. Same-day discharge was the default strategy for all patients. The efficacy and safety outcomes were proportions of same-day discharge and readmission/emergency room (ER) visits, and post-discharge complications, respectively. Of the 421 patients who underwent AF ablation (mean 63.3 ± 10.2 years, 33% female), 90.5% (381/421) achieved same-day discharge with no difference between RF and cryoballoon ablation (89.8 vs. 95.1%, adjusted P = 0.327). Readmission ≤30 days occurred in 4.8%, with ER visits ≤30 days seen in 26.1% with no difference between ablation modalities (P = 0.634). Patients admitted overnight were more likely to present to the ER (40.0 vs. 24.7% with same-day discharge, P = 0.036). The overall post-discharge complication rate was low at 4/421 (1.0%), with no difference between ablation modality (P = 0.324) and admission/same-day discharge (P = 0.485). CONCLUSION: Same-day discharge can be achieved in a majority of patients undergoing RF or cryoballoon ablation for AF. Healthcare utilization, particularly ER visits, remains high after AF ablation, regardless of ablation modality or same-day discharge.

Correlation of unipolar electrogram modification with ablation index during pulmonary vein isolation: A pilot study.

BACKGROUND: Pulmonary vein isolation (PVI) using radiofrequency catheter ablation is a widely accepted therapy for drug-refractory atrial fibrillation patients. Elimination of the negative component of the local unipolar electrogram (UEGM) during PVI is a marker of transmural lesion formation. The ablation index (AI) can predict the quality of ablation lesion. Combining these two parameters could make PVI safer and efficient. The purpose of this pilot study was to examine the correlation between UEGM modification characteristics of the different target areas of left atrium and the associated AI values during PVI. METHODS: We analyzed 10 patients who underwent PVI using radiofrequency energy. The local electrophysiological properties and ablation parameters of 15 designated areas of interest in the left atria targeted by radiofrequency catheter ablation were collected. RESULTS: Out of the 10 patients, six were men (mean age 66 years) and 80% had paroxysmal AF. The mean time to achieve the UEGM modification in the posterior wall was shorter than that of the anterior wall (8.9 seconds vs. 11.1 s, respectively). The UEGM modification for every lesion was achieved at significantly lower AI values than conventional AIs (p < .001). CONCLUSION: During PVI, the AIs deduced according to the local UEGM modification are markedly shorter than those generally recommended AIs in contemporary practice. This indicates that conventionally recommended AIs could be safely reduced while ensuring the efficacy and quality of radiofrequency ablation during PVI. This approach would probably reduce to risk of collateral thermal injuries.

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.

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.

Patch monitors for arrhythmia monitoring in patients for suspected inherited arrhythmia syndrome.

INTRODUCTION: Patients undergoing evaluation for an inherited arrhythmia syndrome undertake a series of ambulatory investigations including 24-h Holter monitor, exercise treadmill testing (ETT), and others. Patch monitors may simplify the evaluation, providing accurate arrhythmia evaluation and QT assessment. METHODS AND RESULTS: Patients referred for evaluation of an inherited arrhythmia syndrome underwent standard investigations, including 12-lead electrocardiography (ECG), 24-h Holter monitoring, ETT, along with supplemental monitoring using a 7-day ECG patch monitor. Heart rates (HR), corrected QT intervals (QTc), and ectopic burden were compared across monitoring modalities. Among 35 patients that wore the patch monitor, the median age was 39 years (54% male). There was intermediate correlation between resting HR across modalities (r = .58-.66) and poor correlation of peak HR (r = .27-.39). There was intermediate correlation between resting QTc intervals across modalities (r = .72-.77) but negligible correlation between QTc intervals at peak HR across modalities (r = -.01 to -.06). There was good correlation in PAC and PVC ectopic burden across the Holter and patch monitor. CONCLUSION: Patch monitors may simplify the evaluation of patients for an inherited arrhythmia syndrome and provide resting QT assessment over time. However, QTc interval comparison at peak HRs remains variable, and may be limited by the single-lead ECG vector when using the patch monitor. Apart from QTc intervals at peak HR, patch monitors demonstrated good correlation with the ECG and Holter monitor for other parameters.

Effectiveness of medical therapy for treatment of idiopathic frequent premature ventricular complexes.

INTRODUCTION: The relative effectiveness of medical therapy compared with a conservative approach of monitoring in patients with idiopathic frequent premature ventricular complexes (PVCs) is uncertain. We evaluated the effectiveness of medical versus conservative therapy for frequent PVCs. METHODS: Patients with frequent PVCs (≥5%) were prospectively enrolled in this cohort study between 2016 and 2020. In patients with normal cardiac function and no structural heart disease, those receiving medical therapy were compared with controls without therapy. Patients were followed longitudinally for change in PVC burden and with serial echocardiography. RESULTS: Overall, 120 patients met inclusion criteria (mean: 56.5 ± 14.6 years, 54.2% female) with 53 on beta-blockers or calcium channel blockers (BBs/CCBs), 27 on Class I or III antiarrhythmic drugs (AADs), and 40 patients treated conservatively. Median initial PVC burden ranged from 15.5% to 20.6%. The median relative reduction of PVCs was 32.7%, 30.5%, and 81.3%, in the conservative therapy, BBs/CCBs, and AADs cohorts, respectively. AADs had greater PVC reduction compared with BBs/CCBs (p = 0.017) and conservative therapy (p = 0.045). PVC reduction to <1% was comparable across groups at 35.0%, 17.0%, 33.3%, respectively. Four patients (4/120, 3.3%) developed left ventricular dysfunction. Rates of adverse drug reactions and medication discontinuation were similar between groups, with no serious adverse events noted. CONCLUSION: In patients with idiopathic frequent PVCs, BB, and CCB have limited effectiveness in PVC reduction. Class I and III AADs have superior effectiveness for medical therapy in symptomatic patients, but only achieved complete PVC resolution suppression in one-third of patients.

SCN5A-C683R exhibits combined gain-of-function and loss-of-function properties related to adrenaline-triggered ventricular arrhythmia.

NEW FINDINGS: What is the role of SCN5A-C683R? SCN5A-C683R is a novel variant associated with an uncommon phenotype of adrenaline-triggered ventricular arrhythmia in the absence of a distinct ECG phenotype. What is the main finding and its importance? Functional studies demonstrated that NaV 1.5/C683R results in a mixed electrophysiological phenotype with gain-of-function (GOF) and loss-of-function (LOF) properties compared with NaV 1.5/wild type. Gain-of-function properties are characterized by a significant increase of the maximal current density and a hyperpolarizing shift of the steady-state activation. The LOF effect of NaV 1.5/C683R is characterized by increased closed-state inactivation. Electrophysiological properties and clinical manifestation of SCN5A-C683R are different from long-QT-3 or Brugada syndrome and might represent a distinct inherited arrhythmia syndrome. ABSTRACT: Mutations of SCN5Ahave been identified as the genetic substrate of various inherited arrhythmia syndromes, including long-QT-3 and Brugada syndrome. We recently identified a novel SCN5A variant (C683R) in two genetically unrelated families. The index patients of both families experienced adrenaline-triggered ventricular arrhythmia with cardiac arrest but did not show a specific ECG phenotype, raising the hypothesis that SCN5A-C683R might be a susceptibility variant and the genetic substrate of distinct inherited arrhythmia. We conducted functional cellular studies to characterize the electrophysiological properties of NaV 1.5/C683R in order to explore the potential pathogenicity of this novel variant. The C683R variant was engineered by site-directed mutagenesis. NaV 1.5/wild type (WT) and NaV 1.5/C683R were expressed in tsA201 cells. Electrophysiological characterization of C683R was performed using the whole-cell patch-clamp technique. Adrenergic stimulation was mimicked by exposure to the protein kinase A activator 8-CPT-cAMP. The impact of ß-blockers was tested by exposing NaV 1.5/WT and NaV 1.5/C683R currents to propranolol and nadolol. C683R resulted in a co-association of gain-of-function and loss-of-function properties of NaV 1.5. Gain-of-function properties were characterized by a significant increase of the maximal NaV 1.5 current density compared with NaV 1.5/WT (861 ± 309 vs. 627 ± 489 pA/pF; P < 0.05, n ≥ 9) that was potentiated in NaV 1.5/C683R with 8-CPT-cAMP stimulation (869 ± 287 vs. 607 ± 320 pA/pF; P < 0.05, n ≥ 12). C683R also resulted in a significant hyperpolarizing shift in the voltage of steady-state activation (-65.4 ± 3.0 vs. -57.2 ± 4.8 mV; P < 0.001), resulting in an increased window current compared with WT. The loss-of-function effect of NaV 1.5/C683R was characterized by significantly increased closed-state inactivation compared with NaV 1.5/WT (P < 0.05). C683R is a novel SCN5A variant resulting in a co-association of gain-of-function and loss-of-function properties of the cardiac sodium channel NaV 1.5. The phenotype is characterized by adrenaline-triggered ventricular arrhythmias. Electrophysiological properties and clinical manifestations are different from long-QT-3 or Brugada syndrome and might represent a distinct inherited arrhythmia syndrome.

Enrichment of loss-of-function and copy number variants in ventricular cardiomyopathy genes in 'lone' atrial fibrillation.

AIMS: Atrial fibrillation (AF) is a complex heritable disease whose genetic underpinnings remain largely unexplained, though recent work has suggested that the arrhythmia may develop secondary to an underlying atrial cardiomyopathy. We sought to evaluate for enrichment of loss-of-function (LOF) and copy number variants (CNVs) in genes implicated in ventricular cardiomyopathy in 'lone' AF. METHODS AND RESULTS: Whole-exome sequencing was performed in 255 early onset 'lone' AF cases, defined as arrhythmia onset prior to 60 years of age in the absence of known clinical risk factors. Subsequent evaluations were restricted to 195 cases of European genetic ancestry, as defined by principal component analysis, and focused on a pre-defined set of 43 genes previously implicated in ventricular cardiomyopathy. Bioinformatic analysis identified 6 LOF variants (3.1%), including 3 within the TTN gene, among cases in comparison with 4 of 503 (0.80%) controls [odds ratio: 3.96; 95% confidence interval (CI): 1.11-14.2; P = 0.033]. Further, two AF cases possessed a novel heterozygous 8521 base pair TTN deletion, confirmed with Sanger sequencing and breakpoint validation, which was absent from 4958 controls (P = 0.0014). Subsequent cascade screening in two families revealed evidence of co-segregation of a LOF variant with 'lone' AF. CONCLUSION: 'Lone' AF cases are enriched in rare LOF variants from cardiomyopathy genes, findings primarily driven by TTN, and a novel TTN deletion, providing additional evidence to implicate atrial cardiomyopathy as an AF genetic sub-phenotype. Our results also highlight that AF may develop in the context of these variants in the absence of a discernable ventricular cardiomyopathy.

Documenting the descent - remote monitoring and adult-onset Catecholaminergic Polymorphic Ventricular Tachycardia associated with ventricular fibrillation and bradycardia.

This image highlights a 38-year-old female with ventricular fibrillation and spontaneous return to sinus rhythm found on an implantable loop recorder inserted for recurrent syncope. Ultimately, she was diagnosed with catecholaminergic polymorphic ventricular tachycardia, a rare inherited arrhythmia disorder.

Mutation location effect on severity of phenotype during exercise testing in type 1 long-QT syndrome: impact of transmembrane and C-loop location.

BACKGROUND: Targeted mutation site-specific differences have correlated C-loop missense mutations with worse outcomes and increased benefit of beta-blockers in LQT1. This observation has implicated the C-loop region as being mechanistically important in the altered response to sympathetic stimulation known to put patients with LQT1 at risk of syncope and sudden cardiac death. OBJECTIVE: The objective of this study was to determine if there is mutation site-specific response to sympathetic stimulation and beta-blockers using exercise testing. METHODS: This study is a retrospective review of LQT1 patients undergoing exercise testing at 3 academic referral centers. RESULTS: A total of 123 patients (age 28 ± 17 years, 59 male) were studied including 34 patients (28%) with C-loop mutations. There were no significant differences in supine, standing, peak exercise and 1-minute recovery QTc duration between patients with C-loop mutations and patients with alternate mutation sites. In 37 patients that underwent testing on and off beta-blockers, beta-blocker use was associated with a significant reduction in supine, standing and peak exercise QTc. This difference was not seen in the small group of patients (7/37) with C-loop mutations. There was no difference in QTc at 1 and 4 minutes into recovery. CONCLUSIONS: Genetically confirmed LQT1 patients in this study cohort with C-loop mutations did not demonstrate the expected increase in QTc in response to exercise, or resultant response to beta-blocker. The apparent increased risk of cardiac events associated with C-loop mutation sites and the marked benefit received from beta-blocker therapy are not reflected by exercise-mediated effects on QTc in this study population.

Perceived self-efficacy and empowerment in patients at increased risk of sudden cardiac arrest.

Background: The role of multidisciplinary clinics for psychosocial care is increasingly recognized for those living with inherited cardiac conditions (ICC). In Canada, access to healthcare providers differ between clinics. Little is known about the relationship between access to specialty care and a patient's ability to cope with, and manage their condition. Methods: We leveraged the Hearts in Rhythm Organization (HiRO) to conduct a cross-sectional, community-based survey of individuals with ICC and their family members. We aimed to describe access to services, and explore the relationships between participants' characteristics, cardiac history and self-reported health status and self-efficacy (GSE: General Self-Efficacy Scale) and empowerment (GCOS-24: Genetic Counseling Outcome Scale). Results: We collected 235 responses from Canadian participants in 10 provinces and territories. Overall, 63% of participants reported involvement of a genetic counsellor in their care. Access to genetic testing was associated with greater empowerment [mean GCOS-24: 121.14 (SD = 20.53) vs. 105.68 (SD = 21.69); p = 0.004]. Uncertain genetic test results were associated with lower perceived self-efficacy (mean GSE: uncertain = 28.85 vs. positive = 33.16, negative = 34.13; p = 0.01). Low global mental health scores correlated with both lower perceived self-efficacy and empowerment scores, with only 11% of affected participants reporting involvement of psychology services in their care. Conclusion: Differences in resource accessibility, clinical history and self-reported health status impact the perceived self-efficacy and empowerment of patients with ICC. Future research evaluating interventions to improve patient outcomes is recommended.

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.

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.

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.

A Population-Based Study of Unexplained/Lone Atrial Fibrillation: Temporal Trends, Management, and Outcomes.

BACKGROUND: Previous studies on lone/unexplained atrial fibrillation and atrial flutter (AF) did not exclude patients with contemporary secondary AF triggers. We characterized unexplained AF using a strict definition, and compared it to secondary AF. METHODS: In this population-based study, unexplained AF was defined by the lack of any identifiable triggering medical/surgical diagnosis. Comparisons by AF type (unexplained vs secondary), age-of-onset (≤ / > 65 years), and sex were undertaken. Data were acquired by linking 6 population databases maintained by the Alberta Ministry of Health over a 9-year period (April 2006 to March 2015). The primary composite outcome of stroke, transient ischemic attack, thromboembolism, and/or death was assessed. RESULTS: There were 33,150 incident AF diagnoses identified, including 1145 patients (3.5%) with unexplained AF, 931 (81.2%) of whom were aged ≤ 65 years (2.8% of diagnoses, and 79% male). Patients with unexplained AF less often received rate/rhythm-control drugs (P < 0.0001), but they more often underwent electrical cardioversion (P < 0.0001) vs secondary AF patients. Men were younger at unexplained AF diagnosis (45 [interquartile range: 34-59] vs 58 [interquartile range: 40-69] years; P < 0.001). After adjusting for age at diagnosis, there were no sex-based differences in the primary outcome. Event-free survival in young unexplained AF (age ≤ 65 years) was 99.4% at 1 year and 98.3% at 3 years. At 3 years, hospitalization(s)/emergency visit(s) for noncardiovascular reasons and for AF occurred in 56.6% and 23.8% of these patients, respectively. CONCLUSIONS: Using a strict contemporary definition of unexplained AF, this study shows that the condition is rare, predominantly male, and has excellent event-free survival. However, the high rate of acute hospital utilization after diagnosis is concerning.

CONTEXTE: Les études précédentes sur le flutter auriculaire et la fibrillation auriculaire (FA) idiopathiques/inexpliqués n'excluaient pas les patients présentant des déclencheurs contemporains de FA secondaire. Nous avons caractérisé la FA inexpliquée en utilisant une définition stricte, et l'avons comparée à la FA secondaire. MÉTHODOLOGIE: Dans cette étude basée sur une population, la FA inexpliquée a été définie par l'absence de tout diagnostic médical/chirurgical de déclencheur identifiable. Des comparaisons par type de FA (inexpliquée vs secondaire), par âge d'apparition (≤ / > 65 ans) et par sexe ont été effectuées. Les données ont été acquises en reliant six bases de données de population maintenues par le ministère de la Santé de l'Alberta sur une période de neuf ans (avril 2006 à mars 2015). Le paramètre d'évaluation principal comprenant l'accident vasculaire cérébral (AVC), l'accident ischémique transitoire, la thromboembolie et/ou le décès a été évalué. RÉSULTATS: Au total, 33 150 diagnostics de FA ont été recensés, dont 1 145 patients (3,5 %) présentant une FA inexpliquée, parmi lesquels 931 (81,2 %) étaient âgés de ≤ 65 ans (2,8 % des diagnostics, et 79 % d'hommes). Les patients atteints de FA inexpliquée ont moins souvent reçu de médicaments pour contrôler la fréquence ou le rythme cardiaque (p < 0,0001), mais ils ont plus souvent subi une cardioversion électrique (p < 0,0001) par rapport aux patients atteints de FA secondaire. Les hommes étaient plus jeunes au moment du diagnostic d'une FA inexpliquée (45 [intervalle interquartile : 34 à 59] vs 58 [intervalle interquartile : 40 à 69] ans; p < 0,001). Après un ajustement pour l'âge au moment du diagnostic, il n'y avait pas de différence entre les sexes quant au paramètre d'évaluation principal. La survie sans événement chez les patients jeunes ayant présenté une FA inexpliquée (âge ≤ 65 ans) était de 99,4 % à un an, et de 98,3 % à trois ans. À trois ans, une ou plusieurs hospitalisations/consultations à l'urgence pour des raisons non cardiovasculaires et pour une FA sont survenues chez 56,6 % et 23,8 % de ces patients, respectivement. CONCLUSIONS: En utilisant une définition contemporaine stricte de la FA inexpliquée, cette étude montre que cette affection est rare, majoritairement masculine, et qu'elle est associée à une excellente survie sans événement. Cependant, le taux élevé d'utilisation de soins actifs dans les hôpitaux après le diagnostic est préoccupant.

Cardiac Magnetic Resonance in the Evaluation of Patients With Frequent Premature Ventricular Complexes.

BACKGROUND: The role of cardiac magnetic resonance (CMR) in the evaluation and management of patients with frequent premature ventricular complexes (PVCs) of unknown etiology remains unclear. OBJECTIVES: This study evaluated the prevalence and prognostic significance of myocardial abnormalities detected with CMR among patients with frequent PVCs and no known structural heart disease. METHODS: This prospective cohort study included consecutive patients with frequent PVCs and a negative initial diagnostic work-up who underwent CMR with late gadolinium enhancement imaging. The clinical outcome was a composite of mortality, ventricular fibrillation, sustained ventricular tachycardia, or reduction in left ventricular ejection fraction of ≥10%. RESULTS: A total of 255 patients were included, of whom 35 (13.7%) had evidence of myocardial abnormality on CMR. Age ≥60 years (odds ratio [OR]: 6.96; 95% CI: 1.30-37.18), multifocal PVCs (OR: 10.90; 95% CI: 3.21-36.97), and non-outflow tract left ventricular PVC origin (OR: 3.00; 95% CI: 1.00-8.95) were independently associated with the presence of a myocardial abnormality on CMR. After a median follow-up of 36 months, the composite outcome occurred in 15 (5.9%) patients. The presence of a myocardial abnormality on CMR was independently associated with the composite outcome (HR: 4.35; 95% CI: 1.34-14.15; P = 0.014). CONCLUSIONS: One in 7 patients with frequent PVCs with no known structural heart disease had myocardial abnormality detected on CMR, and these abnormalities were associated with adverse clinical outcomes. These findings highlight the important role of CMR in the evaluation of patients with frequent PVCs.

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.

Return of Results Policies for Genomic Research: Current Practices and the Hearts in Rhythm Organization (HiRO) Approach.

Research teams developing biobanks and/or genomic databases must develop policies for the disclosure and reporting of potentially actionable genomic results to research participants. Currently, a broad range of approaches to the return of results exist, with some studies opting for nondisclosure of research results and others following clinical guidelines for the return of potentially actionable findings from sequencing. In this review, we describe current practices and highlight decisions a research team must make when designing a return of results policy, from informed consent to disclosure practices and clinical validation options. The unique challenges of returning incidental findings in cardiac genes, including reduced penetrance and the lack of clinical screening standards for phenotype-negative individuals, are discussed. Finally, the National Hearts in Rhythm Organisation (HiRO) Registry approach is described to provide a rationale for the selective return of field-specific variants to those participating in disease-specific research. Our goal is to provide researchers with a resource when developing a return of results policy tailored for their research program, based on unique factors related to study design, research team composition, and availability of clinical resources.

The Interplay Between Titin, Polygenic Risk, and Modifiable Cardiovascular Risk Factors in Atrial Fibrillation.

BACKGROUND: Common and rare variants, including those in the gene for the cardiac structural protein titin (TTN), have been implicated in the risk of developing atrial fibrillation (AF). However, the effect of genetic variants on risk of AF compared with established modifiable risk factors is unclear. The objective of this study was to evaluate the risk of AF and associated cardiovascular complications in TTN variant carriers and examine interactions between TTN variants or common variants and modifiable AF risk factors. METHODS: We used whole exome sequencing data of 49,881 individuals and genotyping data of 408,572 individuals from the UK Biobank to examine the associations of TTN variants, polygenic risk, and 4 risk factors (hypertension, diabetes, obesity, and smoking) with AF. Adjusted hazard ratios (aHRs) were calculated with the use of Cox proportional hazards models. RESULTS: TTN variant carrier status was associated with a higher risk of AF (aHR 2.10, 95% CI 1.59-2.79; P = 2.54 × 10-7) and higher risk of dilated cardiomyopathy in AF patients (aHR 10.39, 95% CI 5.31-20.33; P = 8.37 × 10-12). We identified additive effects between TTN variants and polygenic risk with hypertension, diabetes, obesity, and smoking on the risk of AF. CONCLUSIONS: Genetic and modifiable cardiovascular risk factors contribute to the probability of developing AF. Our findings highlight the potential utility of incorporating data from targeted sequencing or genotyping of common variants to further inform AF risk stratification and aggressive management of modifiable cardiovascular risk factors.