Psychological Distress and Quality of Life in Participants Undergoing Genetic Testing for Arrhythmogenic Right Ventricular Cardiomyopathy Caused by TMEM43 p.S358L: Is It Time to Offer Population-Based Genetic Screening?

PURPOSE: We have identified 27 families in Newfoundland and Labrador (NL) with the founder variant TMEM43 p.S358L responsible for 1 form of arrhythmogenic right ventricular cardiomyopathy. Current screening guidelines rely solely on cascade genetic screening, which may result in unrecognized, high-risk carriers who would benefit from preemptive implantable cardioverter-defibrillator therapy. This pilot study explored the acceptability among subjects to TMEM43 p.S358L population-based genetic screening (PBGS) in this Canadian province. METHODS: A prospective cohort study assessed attitudes, psychological distress, and health-related quality of life (QOL) in unselected individuals who underwent genetic screening for the TMEM43 p.S358L variant. Participants (n = 73) were recruited via advertisements and completed 2 surveys at baseline, 6 months, and 1 year which measured health-related QOL (SF-36v2) and psychological distress (Impact of Events Scale). RESULTS: No variant-positive carriers were identified. Of those screened through a telephone questionnaire, >95% felt positive about population-genetic screening for TMEM43 p.S358L, though 68% reported some degree of anxiety after seeing the advertisement. There were no significant changes in health-related QOL or psychological distress scores over the study period. CONCLUSION: Despite some initial anxiety, we show support for PBGS among research subjects who screened negative for the TMEM43 p.S358L variant in NL. These findings have implications for future PBGS programs in the province.

An International Multicenter Evaluation of Inheritance Patterns, Arrhythmic Risks, and Underlying Mechanisms of CASQ2-Catecholaminergic Polymorphic Ventricular Tachycardia.

BACKGROUND: Genetic variants in calsequestrin-2 (CASQ2) cause an autosomal recessive form of catecholaminergic polymorphic ventricular tachycardia (CPVT), although isolated reports have identified arrhythmic phenotypes among heterozygotes. Improved insight into the inheritance patterns, arrhythmic risks, and molecular mechanisms of CASQ2-CPVT was sought through an international multicenter collaboration. METHODS: Genotype-phenotype segregation in CASQ2-CPVT families was assessed, and the impact of genotype on arrhythmic risk was evaluated using Cox regression models. Putative dominant CASQ2 missense variants and the established recessive CASQ2-p.R33Q variant were evaluated using oligomerization assays and their locations mapped to a recent CASQ2 filament structure. RESULTS: A total of 112 individuals, including 36 CPVT probands (24 homozygotes/compound heterozygotes and 12 heterozygotes) and 76 family members possessing at least 1 presumed pathogenic CASQ2 variant, were identified. Among CASQ2 homozygotes and compound heterozygotes, clinical penetrance was 97.1% and 26 of 34 (76.5%) individuals had experienced a potentially fatal arrhythmic event with a median age of onset of 7 years (95% CI, 6-11). Fifty-one of 66 CASQ2 heterozygous family members had undergone clinical evaluation, and 17 of 51 (33.3%) met diagnostic criteria for CPVT. Relative to CASQ2 heterozygotes, CASQ2 homozygote/compound heterozygote genotype status in probands was associated with a 3.2-fold (95% CI, 1.3-8.0; P=0.013) increased hazard of a composite of cardiac syncope, aborted cardiac arrest, and sudden cardiac death, but a 38.8-fold (95% CI, 5.6-269.1; P<0.001) increased hazard in genotype-positive family members. In vitro turbidity assays revealed that p.R33Q and all 6 candidate dominant CASQ2 missense variants evaluated exhibited filamentation defects, but only p.R33Q convincingly failed to dimerize. Structural analysis revealed that 3 of these 6 putative dominant negative missense variants localized to an electronegative pocket considered critical for back-to-back binding of dimers. CONCLUSIONS: This international multicenter study of CASQ2-CPVT redefines its heritability and confirms that pathogenic heterozygous CASQ2 variants may manifest with a CPVT phenotype, indicating a need to clinically screen these individuals. A dominant mode of inheritance appears intrinsic to certain missense variants because of their location and function within the CASQ2 filament structure.

Exercise and arrhythmic risk in TMEM43 p.S358L arrhythmogenic right ventricular cardiomyopathy.

BACKGROUND: High-level exercise has been associated with a malignant phenotype in desmosomal and genotype-negative forms of arrhythmogenic right ventricular cardiomyopathy (ARVC). This is the first study to examine this issue with ARVC secondary to the TMEM43 p.S358L mutation. OBJECTIVE: The purpose of this study was to evaluate the impact of exercise on arrhythmic risk and cardiac death in TMEM43 p.S358L ARVC. METHODS: Individuals with the TMEM43 p.S358L mutation enrolled in a prospective registry who had received a primary prevention implantable cardioverter-defibrillator (ICD) were invited to complete the modified Paffenbarger Physical Activity Questionnaire to assess their physical activity in the year before their ICD implantation. Time-to-event analyses using unadjusted and adjusted Cox proportional hazards models evaluated associations between physical activity and first appropriate ICD discharge secondary to malignant ventricular arrhythmia or cardiac death. RESULTS: In 80 subjects with the TMEM43 p.S358L mutation, exercise ≥9.0 metabolic equivalent of task (MET)-hours/day (high level) in the year before ICD implantation was associated with an adjusted 9.1-fold increased hazard of first appropriate ICD discharge (there were no deaths) relative to physical activity <9.0 MET-hours/day (moderate level) (95% confidence interval [CI] 3.3-24.6 MET-hours/day; P < .001). The median age from birth to first appropriate ICD discharge was 58.5 years (95% CI 56.5-60.5 years) vs 35.8 years (95% CI 28.2-43.4 years) (P < .001) in subjects in moderate- and high-level exercise groups, respectively. CONCLUSION: Exercise ≥9.0 MET-hours/day is associated with an increased risk of malignant ventricular arrhythmias in the TMEM43 p.S358L subtype of ARVC. Extrapolating these data, we suggest molecular testing be offered in early childhood to inform exercise choices reflective of the genotype.

Cardiac arrest in a mother and daughter and the identification of a novel RYR2 variant, predisposing to low penetrant catecholaminergic polymorphic ventricular tachycardia in a four-generation Canadian family.

BACKGROUND: Catecholaminergic polymorphic ventricular tachycardia (CPVT) is a rare inherited arrhythmia syndrome characterized by adrenergically driven ventricular arrhythmia predominantly caused by pathogenic variants in the cardiac ryanodine receptor (RyR2). We describe a novel variant associated with cardiac arrest in a mother and daughter. METHODS: Initial sequencing of the RYR2 gene identified a novel variant (c.527G > T, p.R176L) in the index case (the mother), and her daughter. Structural analysis demonstrated the variant was located within the N-terminal domain of RyR2, likely leading to a gain-of-function effect facilitating enhanced calcium ion release. Four generation cascade genetic and clinical screening was carried out. RESULTS: Thirty-eight p.R176L variant carriers were identified of 94 family members with genetic testing, and 108 family members had clinical evaluations. Twelve carriers were symptomatic with previous syncope and 2 additional survivors of cardiac arrest were identified. Thirty-two had clinical features suggestive of CPVT. Of 52 noncarriers, 11 had experienced previous syncope with none exhibiting any clinical features of CPVT. A documented arrhythmic event rate of 2.89/1000 person-years across all carriers was calculated. CONCLUSION: The substantial variability in phenotype and the lower than previously reported penetrance is illustrative of the importance of exploring family variants beyond first-degree relatives.

Regional differences in aortic valve replacements: Atlantic Canadian experience.

BACKGROUND: Transcatheter aortic valve implantation (TAVI) is evolving rapidly and is increasingly being adopted in the treatment of aortic valve disease. The goal of this study was to examine regional differences in surgical aortic valve replacement (SAVR) and TAVI across Atlantic Canada. METHODS: We identified all patients who underwent SAVR or TAVI between Jan. 1, 2010, and Dec. 31, 2014, in New Brunswick, Nova Scotia and Newfoundland and Labrador. Data obtained included patient demographic characteristics and surgical procedure details. We performed univariate descriptive analyses and calculated crude and age- and sex-adjusted incidence rates. RESULTS: A total of 3042 patients underwent SAVR or TAVI during the study period, 1491 in Nova Scotia, 1042 in New Brunswick and 509 in Newfoundland and Labrador. Patient demographic characteristics were similar across regions. A much higher proportion of patients in Newfoundland and Labrador (43.6%) than in Nova Scotia (4.2%) or New Brunswick (13.6%) received a mechanical versus a bioprosthetic valve. Rates of TAVI increased over the study period, with New Brunswick adopting their program before Nova Scotia (144 v. 74 procedures). Adjusted rates of all AVR procedures remained stable in Nova Scotia (40-50 per 100 000 people). Adjusted rates were lower in New Brunswick and Newfoundland and Labrador than in Nova Scotia; they increased slowly in New Brunswick over the study period. CONCLUSION: Despite geographical proximity and similar patient demographic characteristics, there existed regional differences in the management of aortic valve disease within Atlantic Canada. Further study is required to determine whether the observed differences in age- and sex-adjusted rates of AVR may be explained by geographical disease-related differences, varying practice patterns or barriers in access to care.

CONTEXTE: Le remplacement valvulaire aortique par cathéter, une méthode en pleine évolution, est de plus en plus utilisé pour le traitement des valvulopathies aortiques. Cette étude visait à examiner les différences régionales quant au remplacement valvulaire aortique par cathéter ou par chirurgie dans les provinces de l'Atlantique. MÉTHODES: Nous avons recensé tous les patients ayant subi un remplacement valvulaire aortique entre le 1er janvier 2010 et le 31 décembre 2014 au Nouveau-Brunswick, en Nouvelle-Écosse et à Terre-Neuve-et-Labrador. Nous avons recueilli des données sur les caractéristiques démographiques des patients et les interventions chirurgicales, puis nous avons réalisé une analyse descriptive univariée et avons calculé les taux d'incidence bruts et corrigés selon l'âge et le sexe. RÉSULTATS: En tout, 3042 patients ont subi un remplacement valvulaire aortique par cathéter ou par chirurgie pendant la période à l'étude : 1491 en Nouvelle-Écosse, 1042 au Nouveau-Brunswick et 509 à Terre-Neuve-et-Labrador. Les caractéristiques démographiques des patients étaient semblables d'une région à l'autre. La proportion des patients recevant une prothèse mécanique plutôt qu'une bioprothèse était beaucoup plus élevée à Terre-Neuve-et-Labrador (43,6 %) qu'en Nouvelle-Écosse (4,2 %) ou au Nouveau-Brunswick (13,6 %). Les taux de remplacement par cathéter ont augmenté au cours de la période à l'étude; le Nouveau-Brunswick a adopté un programme à ce sujet avant la Nouvelle-Écosse (144 c. 74 interventions). Les taux corrigés pour tous les remplacements étaient stables en Nouvelle-Écosse (40-50 par 100 000 habitants); ils étaient plus faibles au Nouveau-Brunswick et à Terre-Neuve-et-Labrador, mais ont augmenté lentement au Nouveau-Brunswick pendant la période à l'étude. CONCLUSION: Malgré la proximité géographique des provinces de l'Atlantique et les caractéristiques démographiques semblables des patients, il existait des différences dans la prise en charge des valvulopathies aortiques. D'autres études seront nécessaires pour déterminer si les variations dans les taux de remplacement corrigés selon l'âge et le sexe pourraient s'expliquer par des différences géographiques dans le nombre de cas, des différences dans les pratiques ou des obstacles à l'accès aux soins.

Primary Cardiac T Cell Lymphoma Mimicking ST-Elevation Myocardial Infarction.

Primary cardiac T cell lymphoma is an extremely rare condition with only a handful of biopsy-proven cases worldwide. We present a 62-year-old female presenting with nonspecific chest discomfort, shortness of breath, and anterolateral ST-elevation on electrocardiogram mimicking a ST-elevation myocardial infarction. Imaging revealed a cardiac mass and cardiac catheterization showed diffuse noncritical coronary disease with an occluded 2nd diagonal branch. Biopsy via minimally invasive cardiac surgery showed a pathologically proven diagnosis of primary cardiac T cell lymphoma. To our knowledge, this is the first documented case worldwide of primary cardiac T cell lymphoma that has resulted in ST-elevation mimicking a myocardial infarction.

Disappearance of pathologic anteroseptal Q waves after reperfusion with percutaneous coronary intervention (PCI) in a 61 year old female: A case report.

We report a case of a 61 year old female with disappearance of anteroseptal Q waves following an anterior STEMI. At presentation a 12 lead ECG revealed frank anteroseptal Q waves and T wave inversion (V1-V3). The patient underwent percutaneous coronary intervention (PCI) with drug eluting stenting to a critically stenosed left anterior descending artery. At a five month follow-up visit a 12 lead ECG demonstrated the complete resolution of anteroseptal Q waves and normal R wave progression was seen in the precordial leads. Here we discuss this observation with a review of the literature regarding Q wave resolution.

"There are days I wish it wasn't there, and there's days I realize I'm lucky": A qualitative study of psychological sequelae to the implantable cardioverter defibrillator as a treatment for the prevention of sudden cardiac death in arrhythmogenic right ventricular cardiomyopathy.

OBJECTIVES: Arrhythmogenic right ventricular cardiomyopathy caused by a TMEM43 p.S358L mutation is a fully penetrant autosomal dominant cause of sudden cardiac death where prophylactic implantable cardioverter defibrillator therapy significantly reduces mortality by returning lethal cardiac rhythms to normal. This qualitative study assessed the psychological ramifications of the implantable cardioverter defibrillator on recipients, their spouses and their mutation negative siblings. DESIGN: Qualitative interview study. PARTICIPANTS: Twenty-one individuals (nine mutation positive, eight mutation negative and four spouses) from 15 families completed semi-structured interviews. RESULTS: No theoretical assumptions about the data were made: inductive sub-coding was accomplished with the constant comparison method and cohesive themes across all respondent interviews were determined. All interviewees had a family history of sudden cardiac death and appropriate implantable cardioverter defibrillator therapy in themselves or family members. Average length of time with an implantable cardioverter defibrillator was 10 years. Major themes included: (1) acceptance and gratitude, (2) grudging acceptance, (3) psychological effects (on emotional and psychological well-being; functioning of the broader family unit; and relationships), and (4) practical concerns (on clothes, travel, loss of driving licence and the effects of an implantable cardioverter defibrillator discharge). These affected all family members, regardless of mutation status. CONCLUSIONS: Despite the survival advantage of implantable cardioverter defibrillator therapy, the intervention carries psychological and practical burdens for family members from kindreds manifesting p.S358L TMEM43 ARVC that does not appear to dissipate with time. A move towards integrating psychology services with the cardiac genetics clinic for the extended family may provide benefit.

Bundle Branch Re-Entrant Ventricular Tachycardia: Novel Genetic Mechanisms in a Life-Threatening Arrhythmia.

OBJECTIVES: This study sought to investigate for an underlying genetic etiology in cases of apparent idiopathic bundle branch re-entrant ventricular tachycardia (BBRVT). BACKGROUND: BBRVT is a life-threatening arrhythmia occurring secondary to macro-re-entry within the His-Purkinje system. Although classically associated with dilated cardiomyopathy, BBRVT may also occur in the setting of isolated, unexplained conduction system disease. METHODS: Cases of BBRVT with normal biventricular size and function were recruited from 6 North American centers. Enrollment required a clinically documented wide complex tachycardia and BBRVT proven during invasive electrophysiology study. Study participants were screened for mutations within genes associated with cardiac conduction system disease. Pathogenicity of identified mutations was evaluated using in silico phylogenetic and physicochemical analyses and in vitro biophysical studies. RESULTS: Among 6 cases of idiopathic BBRVT, each presented with hemodynamic compromise and 2 suffered cardiac arrests requiring resuscitation. Putative culprit mutations were identified in 3 of 6 cases, including 2 in SCN5A (Ala1905Gly [novel] and c.4719C>T [splice site mutation]) and 1 in LMNA (Leu327Val [novel]). Biophysical analysis of mutant Ala1905Gly Nav1.5 channels in tsA201 cells revealed significantly reduced peak current density and positive shifts in the voltage-dependence of activation, consistent with a loss-of-function. The SCN5A c.4719C>T splice site mutation has previously been reported as disease-causing in 3 cases of Brugada syndrome, whereas the novel LMNA Leu327Val mutation was associated with a classic laminopathy phenotype. Following catheter ablation, BBRVT was noninducible in all cases and none experienced a clinical recurrence during follow-up. CONCLUSIONS: Our investigation into apparent idiopathic BBRVT has identified the first genetic culprits for this life-threatening arrhythmia, providing further insight into its underlying pathophysiology and emphasizing a potential role for genetic testing in this condition. Our findings also highlight BBRVT as a novel genetic etiology of unexplained sudden cardiac death that can be cured with catheter ablation.

Do Biologics Protect Patients With Psoriasis From Myocardial Infarction? A Retrospective Cohort.

BACKGROUND: Psoriasis is a chronic immune-mediated inflammatory disorder that affects approximately 2% to 3% of the population, which translates to 17 million in North America and Europe and approximately 170 million people worldwide. Although psoriasis can occur at any age, most cases develop before age 40 years. Some larger studies have noted bimodal age at onset with the first peak occurring at approximately age 30 years and the second peak at around 55 to 60 years, but most patients have a younger age of onset (15-30 years). Psoriasis is associated with multiple comorbidities, decreased quality of life, and decreased longevity of life. Two recent systematic reviews and a meta-analysis concluded that psoriasis patients are at increased risk of major adverse cardiovascular events. Multiple studies confirm that many of the comorbidities found in patients with psoriasis are also important risk factors for cardiovascular disease, stroke, diabetes mellitus, hypertension, hyperlipidemia, obesity, and metabolic syndrome. METHODS: We conducted a retrospective cohort study using charts from a dermatology clinic combined with an administrative database of patients with moderate to severe psoriasis in Newfoundland and Labrador, Canada. We examined the role of clinical predictors (age of onset of psoriasis, age, sex, biologic use) in predicting incident myocardial infarction (MI). RESULTS: Logistic regression revealed that age of onset (odds ratio [OR], 8.85; P = .005), advancing age (OR, 1.07; P < .0001), and being male (OR, 3.64; P = .018) were significant risk factors for the development of MI. Neither biologic therapy nor duration of biologic therapy were statistically significant risk factors for the development of MI. Our study found that in patients with psoriasis treated with biologics, there was a nonsignificant trend in reduced MI by 78% (relative risk, 0.18; 95% confidence interval, 0.24-1.34; P = .056). CONCLUSION: Our study demonstrated a trend toward decreased MI in patients with moderate to severe psoriasis on biologics. Patients with an early age of onset of psoriasis (<25 years) were nearly 9 times more likely to have an MI. Clinicians should consider appropriate cardiovascular risk reduction strategies in patients with psoriasis.

Long-Term Clinical Outcome of Arrhythmogenic Right Ventricular Cardiomyopathy in Individuals With a p.S358L Mutation in TMEM43 Following Implantable Cardioverter Defibrillator Therapy.

BACKGROUND: We previously showed a survival benefit of the implantable cardioverter defibrillator (ICD) in males with arrhythmogenic right ventricular cardiomyopathy caused by a p.S358L mutation in TMEM43. We present long-term data (median follow-up 8.5 years) after ICD for primary (PP) and secondary prophylaxis in males and females, determine whether ICD discharges for ventricular tachycardia/ventricular fibrillation were equivalent to an aborted death, and assess relevant clinical predictors. METHODS AND RESULTS: We studied 24 multiplex families segregating an autosomal dominant p.S358L mutation in TMEM43. We compared survival in 148 mutation carriers with an ICD to 148 controls matched for age, sex, disease status, and family. Of 80 male mutation carriers with ICDs (median age at implantation 31 years), 61 (76%) were for PP; of 68 females (median age at implantation 43 years), 66 (97%) were for PP. In males, irrespective of indication, survival was better in the ICD groups compared with control groups (relative risk 9.3 [95% confidence interval 3.3-26] for PP and 9.7 [95% confidence interval 3.2-29.6] for secondary prophylaxis). For PP females, the relative risk was 3.6 (95% confidence interval 1.3-9.5). ICD discharge-free survival for ventricular tachycardia/ventricular fibrillation ≥ 240 beats per minute was equivalent to the control survival rate. Ectopy (≥ 1000 premature ventricular complexes/24 hours) was the only independent clinical predictor of ICD discharge in males, and no predictor was identified in females. CONCLUSIONS: ICD therapy is indicated for PP in postpubertal males and in females ≥ 30 years with the p.S358L TMEM43 mutation. ICD termination of rapid ventricular tachycardia/ventricular fibrillation can reasonably be considered an aborted death.

Values and Preferences of Physicians and Patients With Nonvalvular Atrial Fibrillation Who Receive Oral Anticoagulation Therapy for Stroke Prevention.

BACKGROUND: Real-world data on patients' and physicians' values related to the use of oral anticoagulant (OAC) therapy for stroke prevention in patients with nonvalvular atrial fibrillation are currently lacking. We sought to assess the values, preferences, and experience of patients who receive OAC therapy, and of physicians who prescribe OAC therapy. METHODS: A national survey of randomly selected patients (n = 266) and physicians (n = 178) was conducted between May and September 2014. Each was asked to evaluate the importance of individual OAC attributes and identify which of 2 medication profiles they would prefer (individual attributes were progressively modified to determine which were the most valued and/or influenced treatment choice). Medication adherence and prescription practice was also assessed. RESULTS: The preferences of patients and physicians regarding OAC therapy differed but largely focused on characteristics related to safety and, to a lesser extent, efficacy. When based solely on the basis of the attribute profile (blinded to the specific agent), physicians were more likely to select apixaban (61%), whereas patients showed no significant preference among apixaban, rivaroxaban, and warfarin. Despite this, 49% of physicians spontaneously stated rivaroxaban as their preferred agent (vs 25% apixaban). Patients prescribed and taking once daily medications (rivaroxaban or warfarin) showed better compliance with their OAC therapy (approximately 30% of twice daily medications being taken once daily, with significantly more missed doses compared with once daily medications). CONCLUSIONS: Real-world prescriptions do not reflect reported values, which suggests that other factors influence patient-physician decision-making around OAC therapy. Data on self-reported adherence to OAC therapy and discordance in the use of OACs from prescribed regimens are concerning and warrant further investigation.

Cardiac Resynchronization Therapy With a Quadripolar Electrode Lead Decreases Complications at 6 Months: Results of the MORE-CRT Randomized Trial.

OBJECTIVES: The aim of this study was to test the hypothesis that a quadripolar left ventricular (LV) lead results in fewer LV lead-related events than a bipolar cardiac resynchronization therapy (CRT) system in a prospective randomized trial. BACKGROUND: Bipolar LV leads cannot be implanted at the optimal site in up to 10% of patients who need CRT, because of anatomic or technical challenges (pacing threshold, phrenic stimulation, or mechanical instability). METHODS: The MORE-CRT (More Options Available With a Quadripolar LV Lead Provide In-Clinic Solutions to CRT Challenges) trial enrolled 1,078 patients. Patients with indications for CRT defibrillator therapy were randomized into 2 groups in a 1:2 ratio: a group with a bipolar CRT lead system (the BiP group; any manufacturer) and a group with a quadripolar CRT system (the Quad group; Quartet LV lead). The primary endpoint was freedom from a composite endpoint of intraoperative and post-operative LV lead-related events at 6 months. RESULTS: A total of 1,074 of 1,078 patients (99%) were randomized and contributed to the primary endpoint. Freedom from the composite endpoint was significantly greater in the Quad than the BiP group (83.0% vs. 74.4%, p = 0.0002). The intraoperative component of the endpoint was met less frequently by Quad group patients (6.26% Quad vs. 12.1% BiP), whereas there was no difference for the post-operative component (7.1% Quad vs. 7.6% BiP). CONCLUSIONS: The Quartet LV system significantly reduced total LV lead-related events at 6 months after implantation compared with a bipolar CRT system. The reduction in events demonstrates the superiority of this quadripolar technology to effectively manage CRT patients. (More Options Available With a Quadripolar LV Lead Provide In-Clinic Solutions to CRT Challenges [MORE-CRT]; NCT01510652).

The TMEM43 Newfoundland mutation p.S358L causing ARVC-5 was imported from Europe and increases the stiffness of the cell nucleus.

AIMS: Arrhythmogenic right ventricular cardiomyopathy (ARVC) is a rare genetic condition caused predominantly by mutations within desmosomal genes. The mutation leading to ARVC-5 was recently identified on the island of Newfoundland and caused by the fully penetrant missense mutation p.S358L in TMEM43. Although TMEM43-p.S358L mutation carriers were also found in the USA, Germany, and Denmark, the genetic relationship between North American and European patients and the disease mechanism of this mutation remained to be clarified. METHODS AND RESULTS: We screened 22 unrelated ARVC patients without mutations in desmosomal genes and identified the TMEM43-p.S358L mutation in a German ARVC family. We excluded TMEM43-p.S358L in 22 unrelated patients with dilated cardiomyopathy. The German family shares a common haplotype with those from Newfoundland, USA, and Denmark, suggesting that the mutation originated from a common founder. Examination of 40 control chromosomes revealed an estimated age of 1300-1500 years for the mutation, which proves the European origin of the Newfoundland mutation. Skin fibroblasts from a female and two male mutation carriers were analysed in cell culture using atomic force microscopy and revealed that the cell nuclei exhibit an increased stiffness compared with TMEM43 wild-type controls. CONCLUSION: The German family is not affected by a de novo TMEM43 mutation. It is therefore expected that an unknown number of European families may be affected by the TMEM43-p.S358L founder mutation. Due to its deleterious clinical phenotype, this mutation should be checked in any case of ARVC-related genotyping. It appears that the increased stiffness of the cell nucleus might be related to the massive loss of cardiomyocytes, which is typically found in ventricles of ARVC hearts.

Insight into the mechanism of failure of the Riata lead under advisory.

BACKGROUND: Cable externalization and insulation abrasion are known to occur with the St Jude Medical Riata leads under advisory. The distribution of these abnormalities and how they relate to clinical presentation have not been well described. OBJECTIVE: In this study, we sought to determine the relationship between structural lead failure and clinical presentation by using the analysis of returned Riata products in Canada. METHODS: The analyses of returned Riata products in Canada were obtained from St Jude Medical, Sylmar, CA. These data were correlated with the clinical presentation of patients just before lead removal from service. RESULTS: As of May 1, 2013, there were 263 returned Riata leads in Canada. Of these, 43 (16.8%) were found to have insulation abrasion that was due to either lead-can or lead-other device interaction (70%) or inside-out abrasion (27.9%). The predilection of lead-to-can abrasion was seen in the Riata 7-F leads (84.2% vs 58.4%; P = .07), while inside-out abrasion was more common in the Riata 8-F leads (37.5% vs 15.8%; P = .12). Electrical abnormalities were frequent (20 of 31 [65.4%]) and most often due to electrical noise (45.2%), although inappropriate shocks were present (25.8%). Death occurred in 1 of 43 (2.3%) of those patients with an insulation defect in the lead-can abrasion group. CONCLUSION: Lead-can abrasion is the most common form of insulation defect in the Riata group of leads under advisory. Management of this group of leads under advisory should not neglect the issue of lead-can abrasion, in addition to detection of cable externalization.

Snapshot of adult invasive cardiac electrophysiology in Canada: results of the web-based registry.

PURPOSE: Interventional cardiac electrophysiology (EP) has experienced a significant growth in Canada. Our aim is to establish a periodic registry as a nationwide initiative. METHODS: The registry is designed to collect information regarding EP laboratory infrastructure, human resources, and the spectrum and volumes of EP procedures. Respective administrative staff were contacted electronically. RESULTS: Out of 25 identified Canadian EP centers, 19 centers (76%) have participated in the registry. Responding centers have access on average to 5.3 lab days per week to perform EP studies/ablations; average lab time per full- and part-time (prorated to 0.5) EP physician is 0.8 day per week. Diagnostic EP studies and radio-frequency ablations are performed in all (19) centers; cryoablation is available in 83% of centers. Two centers have remote magnetic navigation systems. EnSite NavX is the most widely available 3D mapping system utilized in 15 (83%) centers, followed by CARTO and intracardiac echo which are each available in 14 (78%) centers; LocaLisa is actively used in one center. The number of full-time physicians ranges between 0 and 7, with a mean of 3.5 full-time physicians per center. The ratio of staff to trainees is 1.6:1. A total of 8,041 EP procedures are performed in the 19 centers per annum. On an annual average, 104 procedures per one operator and 159 procedures per trainee are performed. CONCLUSIONS: This registry provides contemporary information on invasive EP lab resources and procedures in Canada. It also demonstrates that Canadian EP procedural intensities of practice and training are comparable to international standards.

The Canadian experience with Durata and Riata ST Optim defibrillator leads: a report from the Canadian Heart Rhythm Society Device Committee.

BACKGROUND: The St. Jude Medical Riata family of implantable cardioverter-defibrillator (ICD) leads has demonstrated a high rate of externalized conductors and electrical failure. OBJECTIVE: Given similar design elements of Durata to Riata, the purpose of this study was to assess the rates of failure of the Riata ST Optim and Durata lead families in Canada. METHODS: All Canadian ICD-implanting centers were invited to submit follow-up information on all Optim-coated ICD leads implanted. Electrical failure was defined as a rapid change in impedance or pacing capture threshold leading to lead revision, or oversensing due to noise. Externalized conductors were defined as appearance of conductor wires outside the lead body. Systematic fluoroscopic screening for externalized conductors was not performed. RESULTS: As of December 1, 2012, 15 of 25 centers provided data on 3981 leads (44% of those sold in Canada during the same timeframe): 3477 Durata and 504 Riata ST Optim leads. The most common model numbers were 7122 (1516 leads [38%]), 7121 (707 leads [18%]), and 7120 (622 leads [16%]). Mean follow-up duration from implant to December 1, 2012, was 4.47 ± 0.48 years for Riata ST Optim leads and 2.00 ± 1.10 years for Durata leads. The annual rate of lead failure was 0.27% per year for Riata ST Optim leads and 0.24% per year for Durata leads. No instances of externalized conductors were identified in the failed leads. No deaths were attributed to lead failure; however, 2 patients experienced inappropriate shocks due to lead failure. CONCLUSION: The overall electrical failure rates of the Riata ST Optim and Durata leads appear to be low, and no instances of externalized conductors were observed.

Failure rate of the Riata lead under advisory: a report from the CHRS Device Committee.

BACKGROUND: A unique form of lead failure has been described in the Riata (8-F) and Riata ST (7-F) silicone defibrillation lead degradation of the outer insulation, resulting in the externalization of conductor cables. OBJECTIVE: To assess rates of lead revision due to lead failure in Riata leads affected by the Riata advisory. METHODS: Nineteen implantable cardioverter-defibrillator implant and follow-up centers were surveyed. RESULTS: As of March 1, 2012, there were 5043 known affected leads implanted in Canada. Data on 4358 (86.4%) leads were obtained; 65.3% of these were Riata (8-F) and 32.4% were Riata ST (7-F) leads. The median time from implant to last follow-up was 5 years. Electrical abnormalities were reported in 4.6% of the affected leads; 8.0% of these were found to have concomitant radiographic evidence of externalization. The rate of electrical failure was higher in the 8-F (5.2%) vs 7-F (3.3%) leads (P = .007). Oversensing with or without inappropriate shocks was reported in 39.8% of the leads with confirmed failure. Abnormally high or low impedance values (29.9%) and elevated pacing capture thresholds (43.8%) were frequently reported. One death (0.5%) attributed to lead failure was reported. Among the leads that were replaced, 21% were extracted. Two major complications (1.0%) were attributed to extraction of these leads. CONCLUSIONS: The overall rate of lead failure in the Riata (8-F) and Riata ST (7-F) leads is higher than previously reported by using passive surveillance data. The impact of recent advisories related to these leads is not yet apparent.

Recurrent missense mutations in TMEM43 (ARVD5) due to founder effects cause arrhythmogenic cardiomyopathies in the UK and Canada.

AIMS: Autosomal dominant arrhythmogenic right ventricular cardiomyopathy/dysplasia (ARVC/D) (in the group of arrhythmogenic cardiomyopathies) is a common cause of sudden cardiac death in young adults. It is both clinically and genetically heterogeneous, with 12 loci (ARVC/D1-12) and eight genes identified, the majority of which encode structural proteins of cardiac desmosomes. The most recent gene identified, TMEM43, causes disease due to a missense mutation in a non-desmosomal gene (p.S358L) in 15 extended families from Newfoundland, Canada. To determine whether mutations in TMEM43 cause ARVC/D and arrhythmogenic cardiomyopathy in other populations, we fully re-sequenced TMEM43 on 143 ARVC/D probands (families) from the UK and 55 probands (from 55 families) from Newfoundland. METHODS AND RESULTS: Bidirectional sequencing of TMEM43 including intron-exon boundaries revealed 33 variants, the majority located in non-coding regions of TMEM43. For the purpose of validation, families of probands with rare, potentially deleterious coding variants were subjected to clinical and molecular follow-up. Three missense variants of uncertain significance (p.R28W, p.E142K, p.R312W) were located in highly conserved regions of the TMEM43 protein. One variant (p.R312W) also co-segregated with relatives showing clinical signs of disease. Genotyping and expansion of the disease-associated haplotype in subjects with the p.R312W variant from Newfoundland, Canada, and the UK suggest common ancestry. CONCLUSION: Although the p.R312W variant was found in controls (3/378), identification of an ancestral disease p R312W haplotype suggests that the p.R312W variant is a pathogenic founder mutation.

Nonphysiologic noise early after defibrillator implantation in Canada: incidence and implications: a report from the Canadian Heart Rhythm Society Device Committee.

BACKGROUND: Following recent cases of nonphysiologic noise noted early after defibrillator implantation, the Canadian Heart Rhythm Society Device Committee decided to evaluate the implications of this problem. OBJECTIVE: To determine the incidence and consequences of nonphysiologic noise early after defibrillator implantation. METHODS: The Canadian Heart Rhythm Society Device Committee surveyed all Canadian defibrillator implanting centers regarding their implant volumes and number of cases where nonphysiologic noise had been noted early (< 24 hours) after implant over the preceding 2 years. For such cases, information regarding the manufacturer and occurrence of inappropriate shock or inhibition of pacing was reported. RESULTS: Responses were obtained from 20 of 23 surveyed implanting centers, with a total implant volume of 4960 defibrillators per year. The occurrence of nonphysiologic noise early after implantation was noted in 25 cases over the preceding 2 years (0.25%). Noise was detected in devices of all 3 of the leading volume device manufacturers. There were 2 cases of inappropriate shocks and 2 cases of symptomatic pacing inhibition. In 4 cases, removal of the lead from the header and retesting with the analyzer confirmed normal lead function. In all cases, the noise resolved within 24 hours. CONCLUSION: Nonphysiologic noise early after defibrillator implantation was noted in 0.25% of procedures and was not limited to one specific manufacturer. This noise may result in an inappropriate shock or inhibition of pacing in a pacemaker-dependent patient. This transient phenomenon, possibly related to fluid and/or air in the header, appears to always resolve without surgical intervention.