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.

An International Multicenter Evaluation of Type 5 Long QT Syndrome: A Low Penetrant Primary Arrhythmic Condition.

BACKGROUND: Insight into type 5 long QT syndrome (LQT5) has been limited to case reports and small family series. Improved understanding of the clinical phenotype and genetic features associated with rare KCNE1 variants implicated in LQT5 was sought through an international multicenter collaboration. METHODS: Patients with either presumed autosomal dominant LQT5 (N = 229) or the recessive Type 2 Jervell and Lange-Nielsen syndrome (N = 19) were enrolled from 22 genetic arrhythmia clinics and 4 registries from 9 countries. KCNE1 variants were evaluated for ECG penetrance (defined as QTc >460 ms on presenting ECG) and genotype-phenotype segregation. Multivariable Cox regression was used to compare the associations between clinical and genetic variables with a composite primary outcome of definite arrhythmic events, including appropriate implantable cardioverter-defibrillator shocks, aborted cardiac arrest, and sudden cardiac death. RESULTS: A total of 32 distinct KCNE1 rare variants were identified in 89 probands and 140 genotype positive family members with presumed LQT5 and an additional 19 Type 2 Jervell and Lange-Nielsen syndrome patients. Among presumed LQT5 patients, the mean QTc on presenting ECG was significantly longer in probands (476.9±38.6 ms) compared with genotype positive family members (441.8±30.9 ms, P<0.001). ECG penetrance for heterozygous genotype positive family members was 20.7% (29/140). A definite arrhythmic event was experienced in 16.9% (15/89) of heterozygous probands in comparison with 1.4% (2/140) of family members (adjusted hazard ratio [HR] 11.6 [95% CI, 2.6-52.2]; P=0.001). Event incidence did not differ significantly for Type 2 Jervell and Lange-Nielsen syndrome patients relative to the overall heterozygous cohort (10.5% [2/19]; HR 1.7 [95% CI, 0.3-10.8], P=0.590). The cumulative prevalence of the 32 KCNE1 variants in the Genome Aggregation Database, which is a human database of exome and genome sequencing data from now over 140 000 individuals, was 238-fold greater than the anticipated prevalence of all LQT5 combined (0.238% vs 0.001%). CONCLUSIONS: The present study suggests that putative/confirmed loss-of-function KCNE1 variants predispose to QT prolongation, however, the low ECG penetrance observed suggests they do not manifest clinically in the majority of individuals, aligning with the mild phenotype observed for Type 2 Jervell and Lange-Nielsen syndrome patients.

Post-operative pain following cardiac implantable electronic device implantation: insights from the BRUISE CONTROL trials.

AIMS: Post-operative pain following cardiac implantable electronic device (CIED) insertion is associated with patient dissatisfaction, emotional distress, and emergency department visits. We sought to identify factors associated with post-operative pain and develop a prediction score for post-operative pain. METHODS AND RESULTS: All patients from the BRUISE CONTROL-1 and 2 trials were included in this analysis. A validated Visual Analogue Scale (VAS) was used to assess the severity of pain related to CIED implant procedures. Patients were asked to grade the most severe post-operative pain, average post-operative pain, and pain on the day of the first post-operative clinic. Multivariable regression analyses were performed to identify predictors of significant post-operative pain and to develop a pain-prediction score. A total of 1308 patients were included. Multivariable regression analysis found that the presence of post-operative clinically significant haematoma {CSH; P value < 0.001; odds ratio (OR) 3.82 [95% confidence interval (CI): 2.37-6.16]}, de novo CIED implantation [P value < 0.001; OR 1.90 (95% CI: 1.47-2.46)], female sex [P value < 0.001; OR 1.61 (95% CI: 1.22-2.12)], younger age [<65 years; P value < 0.001; OR 1.54 (95% CI: 1.14-2.10)], and lower body mass index [<20 kg/m2; P value < 0.05; OR 2.05 (95% CI: 0.98-4.28)] demonstrated strong and independent associations with increased post-operative pain. An 11-point post-operative pain prediction score was developed using the data. CONCLUSION: Our study has identified multiple predictors of post-operative pain after CIED insertion. We have developed a prediction score for post-operative pain that can be used to identify individuals at risk of experiencing significant post-operative pain.

Pacemaker or defibrillator surgery without interruption of anticoagulation.

BACKGROUND: Many patients requiring pacemaker or implantable cardioverter-defibrillator (ICD) surgery are taking warfarin. For patients at high risk for thromboembolic events, guidelines recommend bridging therapy with heparin; however, case series suggest that it may be safe to perform surgery without interrupting warfarin treatment. There have been few results from clinical trials to support the safety and efficacy of this approach. METHODS: We randomly assigned patients with an annual risk of thromboembolic events of 5% or more to continued warfarin treatment or to bridging therapy with heparin. The primary outcome was clinically significant device-pocket hematoma, which was defined as device-pocket hematoma that necessitated prolonged hospitalization, interruption of anticoagulation therapy, or further surgery (e.g., hematoma evacuation). RESULTS: The data and safety monitoring board recommended termination of the trial after the second prespecified interim analysis. Clinically significant device-pocket hematoma occurred in 12 of 343 patients (3.5%) in the continued-warfarin group, as compared with 54 of 338 (16.0%) in the heparin-bridging group (relative risk, 0.19; 95% confidence interval, 0.10 to 0.36; P<0.001). Major surgical and thromboembolic complications were rare and did not differ significantly between the study groups. They included one episode of cardiac tamponade and one myocardial infarction in the heparin-bridging group and one stroke and one transient ischemic attack in the continued-warfarin group. CONCLUSIONS: As compared with bridging therapy with heparin, a strategy of continued warfarin treatment at the time of pacemaker or ICD surgery markedly reduced the incidence of clinically significant device-pocket hematoma. (Funded by the Canadian Institutes of Health Research and the Ministry of Health and Long-Term Care of Ontario; BRUISE CONTROL ClinicalTrials.gov number, NCT00800137.).

Failed anti-tachycardia pacing can be used to differentiate atrial arrhythmias from ventricular tachycardia in implantable cardioverter-defibrillators.

BACKGROUND: Atrial fibrillation/tachycardia (AF/AT) may result in inappropriate therapies in implantable cardioverter-defibrillators (ICDs). The post-pacing interval (PPI) and tachycardia cycle length difference (PPI - TCL) has been previously demonstrated to indicate the proximity of the pacing site to a tachycardia origin. AIMS: We postulated that the PPI and PPI - TCL would be greater in AT/AF vs. ventricular tachycardia (VT) after episodes of failed anti-tachycardia pacing (ATP). METHODS AND RESULTS: This was a single-centre, retrospective study evaluating consecutive patients implanted with dual (DR)/biventricular (BIV) ICDs. Stored electrograms were used to determine whether the ATP captured the arrhythmia and the arrhythmia did not present with primary or secondary termination. Measurements were done using manual calipers. A total of 155 patients were included. There were 79 BIV and 76 DR devices. In total, 39 episodes were identified in 20 patients over a 23-month follow-up period. A total of 76 sequences of ATP (burst/ramp) were delivered, 28 (37%) of them inappropriate. Fifty-one events (18 AT/AF and 33 VT) were compared. The mean PPI was 693 ± 96 vs. 512 ± 88 ms (P < 0.01) and the mean PPI - TCL was 330 ± 97 vs. 179 ± 103 ms (P < 0.01) for AT/AF and VT, respectively. Cut-offs of 615 ms for the PPI [area under curve (AUC) 0.93; 95% confidence interval (CI): 0.84-1.00; P < 0.01] and 260 ms for PPI - TCL (AUC 0.86; 95% CI: 0.74-0.98; P < 0.01) were identified. CONCLUSION: The PPI and PPI - TCL after failed ATP differs significantly between AF/AT and VT and are therefore useful indices to discriminate between supraventricular tachycardia and VT in ICDs.

Survival after implantable cardioverter-defibrillator implantation in the elderly.

BACKGROUND: The benefit of implantable cardioverter-defibrillators (ICDs) among elderly patients is controversial and may be attenuated by nonarrhythmic death. We examined the impact of age on device-delivered therapies and outcomes after primary or secondary prevention ICD. METHODS AND RESULTS: In a prospective, inclusive registry of 5399 ICD recipients in Ontario, Canada (February 2007 to September 2010), device-delivered therapies and complications were determined at routine clinic visits. Among primary prevention ICD recipients aged 18 to 49 (n=317), 50 to 59 (n=769), 60 to 69 (n=1336), 70 to 79 (n=1242), and ≥80 (n=275) years, mortality increased with age, as follows: 2.1, 3.0, 5.4, 6.9, and 10.2 deaths per 100 person-years, respectively (P<0.001). Secondary prevention ICD recipients aged 18 to 49 (n=114), 50 to 59 (n=244), 60 to 69 (n=481), 70 to 79 (n=462), and ≥80 (n=159) years also exhibited increasing mortality, as follows: 2.2, 3.8, 6.1, 8.7, and 15.5 deaths per 100 person-years, respectively (P<0.001). However, rates of appropriate shock were similar across age groups: from 6.7 (18-49 years) to 4.2 (≥80 years) per 100 person-years after primary prevention ICDs (P=0.139) and from 11.4 (18-49 years) to 11.9 (≥80 years) per 100 person-years after secondary prevention ICDs (P=0.993). Covariate-adjusted competing risk analysis demonstrated higher risk of death (Ptrend<0.001 for both primary and secondary prevention) but no significant decline in appropriate shocks with older age after primary (P=0.130) or secondary (P=0.810) prevention ICD implantation. CONCLUSIONS: Whereas elderly patients exhibited increased mortality after ICD implantation, rates of appropriate device shocks were similar across age groups. Decisions regarding ICD candidacy should not be based on age alone but should consider factors that predispose to mortality despite defibrillator implantation.

Radiofrequency catheter ablation for the treatment of idiopathic premature ventricular contractions originating from the right ventricular outflow tract: a systematic review and meta-analysis.

BACKGROUND: Frequent idiopathic premature ventricular contractions (PVCs) have been associated with left ventricular cardiomyopathy. Idiopathic PVCs often originate from the right ventricular outflow tract (RVOT), and radiofrequency catheter ablation (RFCA) is being used as a treatment to alleviate symptoms. A meta-analysis was performed to evaluate RFCA for the treatment of frequent idiopathic PVCs on heart function. METHODS AND RESULTS: A literature search was conducted using Medline and Embase to identify studies evaluating the effects of RFCA as treatment for PVCs originating from the RVOT. Articles were chosen if they reported the effect of RFCA on the quantity of PVCs or ventricular function. Only studies in English were included. Articles were excluded if they did not separate results for PVCs originating from areas other than the RVOT. A total of 450 articles were retrieved from electronic searches, and 14 articles were included in this systematic review. Six of these were meta-analyzed (N = 70) and showed a reduction in the total number of PVCs in 24 hours after RFCA by a mean of -30089.44 confidence interval [CI]: -31658.47, -28520.40, P < 0.00001). Left ventricular ejection fraction (LVEF) was reported in five of the 14 studies, which included 108 patients. RFCA significantly improved LVEF by a mean of 10.36 (CI: 8.75, 11.97, P < 0.00001) in patients with frequent PVCs from the RVOT. The remaining studies reported their results differently and were not included in the meta-analyses but were described separately. CONCLUSIONS: RFCA reduces the number of PVCs and improves the cardiac function in patients with idiopathic frequent PVCs originating from the RVOT.

Heart rate variability and procedural outcome in catheter ablation for atrial fibrillation.

INTRODUCTION: In patients with normal hearts, increased vagal tone is associated with onset of paroxysmal atrial fibrillation (AF). Vagal denervation of the atria renders AF less inducible. Circumferential pulmonary vein isolation (CPVI) is effective for treating paroxysmal and persistent AF, and has been shown to impact heart rate variability (HRV) indices, in turn, reflecting vagal denervation. We examined the impact of CPVI on HRV indices, and evaluated the relationship between vagal modification and AF recurrence. METHODS: Electrocardiogram recordings were collected from 83 consecutive patients (63 male, 20 female, age 56.9 ± 9.3 years) undergoing CPVI for paroxysmal (n = 56) or persistent (n = 27) AF. Recordings were obtained over 10 minutes preprocedure, and at intervals up to 12 months. Antiarrhythmic medications were suspended prior to CPVI, and were resumed for 3 months following. Success was defined as no recurrence of atrial arrhythmia lasting longer than 30 seconds. RESULTS: In patients with successful procedures (n = 56, 42 paroxysmal, 14 persistent), HRV indices were significantly altered, with respect to preprocedure levels, over a sustained period. However, patients with recurrence (n = 27, 14 paroxysmal, 13 persistent) demonstrated similar HRV to their preprocedure levels over the follow-up period. CONCLUSION: Our results suggest that patients experiencing recurrence after a single CPVI have HRV attenuated by the procedure only intermittently, whereas patients with one successful CPVI experience a sustained change. A short-term HRV recording is a convenient and potentially important marker for recurrence of atrial arrhythmia in a population undergoing CPVI.

Predicting long-term survival after de novo cardioverter-defibrillator implantation for primary prevention: A population based study.

Background: Implantable cardioverter-defibrillators (ICDs) reduce the risk of sudden cardiac death in patients with left ventricular dysfunction. While short-term mortality benefit of ICD insertion has been established in landmark randomized controlled trials, little is known about the long-term outcomes of patients with ICDs in clinical practice. In this paper, we describe the long-term survival of patients following de novo ICD implantation for primary prevention in clinical practice and determine the factors which help predict survival after ICD implant. Methods: Retrospective population-based study of all patients receiving a de novo ICD for primary prevention in Ontario, Canada from 2007 to 2011 using the Ontario ICD Database housed within ICES. Simple random selection was used to split the population into a derivation and internal validation cohort in a ratio of 2:1. Cox proportional hazards regression was used to determine predictors of interest and predict 10-year survival, model performance was assessed using calibration and validation. Results: In the derivation cohort (n = 3399), mean age was 65.3 years (standard deviation [SD] = 11.0), 664 patients were female (19.5 %) and 2344 patients (69.0 %) had ischemic cardiomyopathy. Ten year survival was 45.7 % (95 % confidence interval [CI] 44.0 %-47.4 %). The final prediction model included age, sex, disease factors (ischemic vs nonischemic cardiomyopathy, left ventricular ejection fraction) and patient factors (symptoms, comorbidities), and biomarkers at the time of ICD assessment. This model had good discrimination and calibration in derivation (0.79, 95 % CI 0.77, 0.81) and validation samples (0.78, 95 % CI 0.76, 0.79). Conclusions: A combination of demographic and clinical factors determined at baseline can be used to predict 10-year survival in patients with implantable cardioverter-defibrillators with good accuracy. Our findings help to identify individuals at risk of long-term mortality and may be useful in targeting future prevention strategies to enhance longevity in this high-risk population.

Canadian Cardiovascular Society 2023 Guidelines on the Fitness to Drive.

Cardiovascular conditions are among the most frequent causes of impairment to drive, because they might induce unpredictable mental state alterations via diverse mechanisms like myocardial ischemia, cardiac arrhythmias, and vascular dysfunction. Accordingly, health professionals are often asked to assess patients' fitness to drive (FTD). The Canadian Cardiovascular Society previously published FTD guidelines in 2003-2004; herein, we present updated FTD guidelines. Because there are no randomized trials on FTD, observational studies were used to estimate the risk of driving impairment in each situation, and recommendations made on the basis of Canadian Cardiovascular Society Risk of Harm formula. More restrictive recommendations were made for commercial drivers, who spend longer average times behind the wheel, use larger vehicles, and might transport a larger number of passengers. We provide guidance for individuals with: (1) active coronary artery disease; (2) various forms of valvular heart disease; (3) heart failure, heart transplant, and left ventricular assist device situations; (4) arrhythmia syndromes; (5) implantable devices; (6) syncope history; and (7) congenital heart disease. We suggest appropriate waiting times after cardiac interventions or acute illnesses before driving resumption. When short-term driving cessation is recommended, recommendations are on the basis of expert consensus rather than the Risk of Harm formula because risk elevation is expected to be transient. These recommendations, although not a substitute for clinical judgement or governmental regulations, provide specialists, primary care providers, and allied health professionals with a comprehensive list of a wide range of cardiac conditions, with guidance provided on the basis of the level of risk of impairment, along with recommendations about ability to drive and the suggested duration of restrictions.

Validation of a novel algorithm for quantification of the percentage of signal fractionation in atrial fibrillation.

AIMS: Catheter ablation for paroxysmal atrial fibrillation (AF) is rapidly becoming a standard practice. There is literature to support that catheter ablation of persistent AF requires additional 'substrate modification'. In clinical practice, operators rely on automated fractionation maps created by three-dimensional anatomic mapping systems to rapidly assess complex 'fractionated' signals (CFAE). These systems use differing algorithms to automate the process. The agreement between operators and contemporary algorithms has not been examined. We sought to assess the agreement between operators and a novel method of quantification calculating percentage fractionation (PF). METHODS AND RESULTS: Expert opinion on 80 atrial electrogram 4 s signals of varying levels of activity were gathered and pooled for comparison. Twelve independent experts visually quantified the signal fractionation and offered a threshold level for ablation. We developed an algorithm to find sites with high continuous electrical activity, or high PF. Correlation between experts and PF was 0.78 [P < 0.01, 95% confidence interval (CI) (0.68-0.86)]. Receiver operating characteristics curve sensitivity and specificity for PF were 0.7727 and 0.8103 at the optimal cut-off point of 58.45 PF with area under curve 0.89 CI (0.80-0.99). CONCLUSION: The PF statistic represents a more robust and intuitive measure to represent fractionated atrial activity; importantly it demonstrates excellent agreement with expert users and presents a new standard for algorithm assessment. Use of a PF statistic should be considered in automated mapping systems.

Cardiac rhythm device contact dermatitis.

We present a series of three cases of patch testing confirmed cardiac rhythm device induced contact dermatitis. In the first two cases, there was complete resolution with device extraction and reimplantation with another device with either an absence of the offending agent or a coating with another resin or metal. These cases illustrate the difficulties in diagnosing pain, tenderness, and dermatological manifestations in patients with cardiac rhythm devices (pacemakers and implantable cardioverter defibrillators).

Sex differences in implantable cardioverter-defibrillator outcomes: findings from a prospective defibrillator database.

BACKGROUND: Sex differences in the use and outcomes of implantable cardioverter-defibrillators (ICDs) have not been fully studied. OBJECTIVE: To examine potential sex differences in ICD implantation and device outcomes. DESIGN: Health payer-mandated, prospective study of patients referred for ICD implantation, with comprehensive, longitudinal follow-up for complications, deaths, and device outcomes. SETTING: 18 ICD implantation and follow-up centers in Ontario, Canada. PATIENTS: 6021 patients (4733 men) referred for ICD implantation from February 2007 to July 2010. MEASUREMENTS: Multivariate-adjusted ICD implantation rate, complications up to day 45, multivariate-adjusted complications, device outcomes (including appropriate shocks and therapies), and deaths occurring during 1-year follow-up. RESULTS: Rates of ICD implantation were similar in men and women (relative risk, 0.99 [95% CI, 0.97 to 1.02]; P = 0.60). However, women were significantly more likely to experience major complications by 45 days (odds ratio, 1.78 [CI, 1.24 to 2.58]; P = 0.002) and 1 year (hazard ratio [HR], 1.91 [CI, 1.48 to 2.47]; P < 0.001) after implantation. Occurrence of any major or minor complication was also increased in women at both 45-day follow-up (odds ratio, 1.50 [CI, 1.12 to 2.00]; P = 0.006) and 1-year follow-up (HR, 1.55 [CI, 1.25 to 1.93]; P < 0.001). After implantation, women were less likely than men to receive appropriate ICD shock (HR, 0.69 [CI, 0.51 to 0.93]; P = 0.015) or appropriate therapy via shock or antitachycardia pacing (HR, 0.73 [CI, 0.59 to 0.90]; P = 0.003). Total mortality among defibrillator recipients did not differ between men and women (HR, 1.00 [CI, 0.64 to 1.55]; P = 0.99). LIMITATION: The differential effects of sex on prereferral events were not examined. CONCLUSION: Although ICD implantation rates were similar after referral to an electrophysiologist, women who underwent ICD implantation had greater risks for complications and were less likely to experience appropriate ICD-delivered therapies than men. PRIMARY FUNDING SOURCE: Canadian Institutes of Health Research and Ontario Ministry of Health and Long-Term Care.

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.

The right ventricular septum presents the optimum site for maximal electrical separation during left ventricular pacing.

UNLABELLED: Cardiac resynchronization therapy (CRT) benefits selected heart failure (HF) patients. The optimal placement of the right ventricle (RV) lead during biventricular pacing has not been assessed. Greater electrical separation (ES) between left ventricle (LV) and RV leads has been associated with better clinical outcomes. The site of maximal electrical separation(MES) in the RV is unknown. METHODS: Prospective study of 50 CRT patients. The LV lead was placed in a postero-lateral branch of the coronary sinus. ES was recorded at 6 sites within the RV during LV pacing at 600 milliseconds cycle length (CL). The median ES was recorded with a roving deflectable catheter at the RV outflow tract (RVOT), high septum, inflow septum, mid-septum, apical septum and apex. RESULTS: Mean age was 67 ± 7 years, 39 were male (78%). Thirty had ischemic etiology (60%). Mean left ventricular ejection fraction (LVEF) was 25 ± 7%, QRS duration pre and post was 165 ± 26 milliseconds and 138.5 ± 15.6 milliseconds (P < 0.001). Mapping ES showed a difference between 20 and 50 milliseconds distributed across the RV in the majority of patients (40/49). However, 7 subjects demonstrated delay distribution of between 50 and 82 milliseconds. ES was significant greater in the RV mid-septum (161.2 ± 23.7 milliseconds) compared with RVOT (154.1 ± 20.8 milliseconds) and apex (148.0 ± 25.5 milliseconds; P < 0.001). The site of Maximal ES was most commonly found at the mid-septum (40 patients, 80%) and only rarely at the RVOT (5, 10%) and apex (5, 10%; P < 0.01). CONCLUSION: MES was observed most commonly at the RV septum and rarely at the RV apex. Better correction of electrical and mechanical dyssynchrony by CRT may be achieved by placing the RV lead in a site outside of the apex in the majority of patients. Clinical studies exploring RV septal pacing in CRT seem warranted.

Sentinel symptoms in patients with unexplained cardiac arrest: from the cardiac arrest survivors with preserved ejection fraction registry (CASPER).

BACKGROUND: Warning symptoms may provide an opportunity to diagnose genetic disorders leading to preventative therapy. We explored the symptom history of patients with apparently unexplained cardiac arrest to determine the frequency of sentinel symptoms. METHODS: Patients with apparently unexplained cardiac arrest and no evident cardiac disease underwent systematic clinical evaluation. Patients and first-degree relatives were interviewed to determine the presence of cardiac symptoms, and those with syncope underwent 2 structured Calgary Syncope Score questionnaires to determine the probable mechanism of syncope. RESULTS: One hundred consecutive cardiac arrest patients (age 43.0 ± 13.4 years, 60% male) and 63 first-degree relatives (age 37.6 ± 16.3 years, 54% female) were enrolled. Previous cardiac symptoms were present in 69% of cardiac arrest patients compared to 43% of family members (P = 0.001). Prior syncope was present in 26% of cardiac arrest patients, compared to 22% of family members (P = 0.59). Twenty-four of 25 cardiac arrest patients who completed the syncope questionnaires had a syncope versus seizure score <1 favoring syncope. The area under the receiver operator curve (ROC) for the syncope mechanism score was 0.79 for identifying patients with subsequent cardiac arrest (95% CI, 0.6328-0.9395, P = 0.004). A score of ≤-2 had a sensitivity of 68% and specificity of 85%. Thirty percent of patients with a proven genetic cause had preceding syncope versus 19% in patients with noninherited or idiopathic causes (P = 0.032). CONCLUSIONS: Syncope that may represent a sentinel event is present in a modest proportion of patients and family members, and is often suggestive of an arrhythmia.

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.