Publications by authors named "Thomas M Roston"

40 Publications

Burst Exercise Testing Can Unmask Arrhythmias in Patients With Incompletely Penetrant Catecholaminergic Polymorphic Ventricular Tachycardia.

JACC Clin Electrophysiol 2021 04;7(4):437-441

Centre for Cardiovascular Innovation, Division of Cardiology, University of British Columbia, Vancouver, British Columbia, Canada. Electronic address:

Catecholaminergic polymorphic ventricular tachycardia (CPVT) is characterized by cardiac arrest during sudden exertion. However, standard exercise stress testing (EST) lacks sensitivity, leading to misdiagnosis and undertreatment. After a nondiagnostic standard gradual EST, we report 6 patients who underwent a novel burst exercise test characterized by sudden high workload at the outset of testing. In 5 of 6 patients, the burst EST induced new and more complex arrhythmias versus standard EST, which compelled medication initiation in 3 patients. We postulate that this simple EST modification better mimics a typical CPVT triggering event and could improve diagnostic sensitivity and therapeutic decision making.
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http://dx.doi.org/10.1016/j.jacep.2021.02.013DOI Listing
April 2021

Pregnancy in catecholaminergic polymorphic ventricular tachycardia: therapeutic optimization and multidisciplinary care are key to success.

Herzschrittmacherther Elektrophysiol 2021 Jun 21;32(2):199-206. Epub 2021 Apr 21.

Centre for Cardiovascular Innovation, Division of Cardiology, Department of Medicine, The University of British Columbia, Vancouver, Canada.

Women of child-bearing age comprise a large proportion of the patients followed by inherited arrhythmia clinics. Despite being a rare and dangerous diagnosis, cardiac and obstetric care providers should know that catecholaminergic polymorphic ventricular tachycardia (CPVT) is not a contraindication to pregnancy. In fact, pregnancy was not associated with an increased risk of CPVT-associated arrhythmias in a recent large cohort study, and most guideline-based anti-arrhythmic drug treatments are life-saving and carry a low risk of teratogenesis. In principle, the potential for CPVT destabilization may be more likely to occur after anti-arrhythmic drugs are decreased or stopped during pregnancy, when an implantable cardioverter defibrillator (ICD) shock exacerbates catecholamine release, or if adrenaline surges are triggered by labor and delivery. Therefore, all pregnant women should be followed by a cardio-obstetrics team with extensive knowledge of CPVT diagnosis, as well as arrhythmia risk stratification fand management. This multidisciplinary care should begin preconception and involve counseling on preimplantation genetic testing, choosing safe and effective anti-arrhythmic drugs, stopping contraindicated medications, optimal programming of ICDs, and planning for the brief hyper-adrenergic period of labor and delivery. The latest data on pregnancy in CPVT is reviewed here and the optimal care for this rare and complex patient population outlined.
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http://dx.doi.org/10.1007/s00399-021-00755-6DOI Listing
June 2021

Cardiac ryanodine receptor calcium release deficiency syndrome.

Sci Transl Med 2021 Feb;13(579)

Department of Cardiology, Aarhus University Hospital, and Department of Clinical Medicine, Health, Aarhus University, Palle Juul-Jensens Blv 99, DK-8200 Aarhus N, Denmark.

Cardiac ryanodine receptor (RyR2) gain-of-function mutations cause catecholaminergic polymorphic ventricular tachycardia, a condition characterized by prominent ventricular ectopy in response to catecholamine stress, which can be reproduced on exercise stress testing (EST). However, reports of sudden cardiac death (SCD) have emerged in EST-negative individuals who have loss-of-function (LOF) RyR2 mutations. The clinical relevance of RyR2 LOF mutations including their pathogenic mechanism, diagnosis, and treatment are all unknowns. Here, we performed clinical and genetic evaluations of individuals who suffered from SCD and harbored an LOF RyR2 mutation. We carried out electrophysiological studies using a programed electrical stimulation protocol consisting of a long-burst, long-pause, and short-coupled (LBLPS) ventricular extra-stimulus. Linkage analysis of RyR2 LOF mutations in six families revealed a combined logarithm of the odds ratio for linkage score of 11.479 for a condition associated with SCD with negative EST. A RyR2 LOF mouse model exhibited no catecholamine-provoked ventricular arrhythmias as in humans but did have substantial cardiac electrophysiological remodeling and an increased propensity for early afterdepolarizations. The LBLPS pacing protocol reliably induced ventricular arrhythmias in mice and humans having RyR2 LOF mutations, whose phenotype is otherwise concealed before SCD. Furthermore, treatment with quinidine and flecainide abolished LBLPS-induced ventricular arrhythmias in model mice. Thus, RyR2 LOF mutations underlie a previously unknown disease entity characterized by SCD with normal EST that we have termed RyR2 Ca release deficiency syndrome (CRDS). Our study provides insights into the mechanism of CRDS, reports a specific CRDS diagnostic test, and identifies potentially efficacious anti-CRDS therapies.
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http://dx.doi.org/10.1126/scitranslmed.aba7287DOI Listing
February 2021

Causal Genetic Variants in Stillbirth.

N Engl J Med 2020 12;383(27):2687

Boston Children's Hospital, Boston, MA

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http://dx.doi.org/10.1056/NEJMc2032136DOI Listing
December 2020

Potential overdiagnosis of long QT syndrome using exercise stress and QT stand testing in children and adolescents with a low probability of disease.

J Cardiovasc Electrophysiol 2021 Feb 13;32(2):500-506. Epub 2021 Jan 13.

Department of Pediatrics, Division of Cardiology, British Columbia Children's Hospital and The University of British Columbia, Vancouver, Canada.

Background: Long QT syndrome (LQTS) is a dangerous arrhythmia disorder that often presents in childhood and adolescence. The exercise stress test (EST) and QT-stand test may unmask QT interval prolongation at key heart rate transition points in LQTS, but their utility in children is debated.

Objective: To determine if the QT-stand test or EST can differentiate children with a low probability of LQTS from those with confirmed LQTS.

Methods: This retrospective study compares the corrected QT intervals (QTc) of children (<19 years) during the QT-stand test and EST. Patients were divided into three groups for comparison: confirmed LQTS (n = 14), low probability of LQTS (n = 14), and a control population (n = 9).

Results: Using the Bazett formula, confirmed LQTS patients had longer QTc intervals than controls when supine, standing, and at 3-4 min of recovery (p ≤ .01). Patients with a low probability of LQTS had longer QTc duration upon standing (p = .018) and at 1 min of recovery (p = .016) versus controls. There were no significant QTc differences at any transition point between low probability and confirmed LQTS. Using the Fridericia formula, differences in QTc between low probability and confirmed LQTS were also absent at the transition points examined, except at 1 min into exercise, where low probability patients had shorter QTc intervals (437 vs. 460 ms, p = .029).

Conclusion: The diagnostic utility of the QT stand test and EST remains unclear in pediatric LQTS. The formula used for heart rate correction may influence accuracy, and dynamic T-U wave morphology changes may confound interpretation in low probability situations.
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http://dx.doi.org/10.1111/jce.14865DOI Listing
February 2021

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

Can J Cardiol 2020 Dec 26. Epub 2020 Dec 26.

Centre for Heart Lung Innovation, University of British Columbia, Vancouver, British Columbia, Canada; Experimental Medicine Program, Department of Medicine, University of British Columbia, Vancouver, British Columbia, Canada. Electronic address:

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) and higher risk of dilated cardiomyopathy in AF patients (aHR 10.39, 95% CI 5.31-20.33; P = 8.37 × 10). 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.
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http://dx.doi.org/10.1016/j.cjca.2020.12.024DOI Listing
December 2020

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

Circulation 2020 Sep 22;142(10):932-947. Epub 2020 Jul 22.

Section of Cardiac Electrophysiology, Division of Cardiology, Department of Medicine, Western University, London, ON, Canada (K.N., J.W., A.S.T., A.C.S., J.M., J.D.R.).

Background: Genetic variants in calsequestrin-2 () 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 -CPVT was sought through an international multicenter collaboration.

Methods: Genotype-phenotype segregation in -CPVT families was assessed, and the impact of genotype on arrhythmic risk was evaluated using Cox regression models. Putative dominant 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 variant, were identified. Among 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 heterozygous family members had undergone clinical evaluation, and 17 of 51 (33.3%) met diagnostic criteria for CPVT. Relative to heterozygotes, homozygote/compound heterozygote genotype status in probands was associated with a 3.2-fold (95% CI, 1.3-8.0; =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; <0.001) increased hazard in genotype-positive family members. In vitro turbidity assays revealed that p.R33Q and all 6 candidate dominant 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 -CPVT redefines its heritability and confirms that pathogenic heterozygous 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.
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http://dx.doi.org/10.1161/CIRCULATIONAHA.120.045723DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7484339PMC
September 2020

The Effect of Carbetocin Dose on Transmural Dispersion of Myocardial Repolarization in Healthy Parturients Scheduled for Elective Cesarean Delivery Under Spinal Anesthesia: A Prospective, Randomized Clinical Trial.

Anesth Analg 2021 02;132(2):485-492

From the Department of Anesthesia, BC Women's Hospital, Vancouver, British Columbia, Canada.

Background: QT interval prolongation is associated with torsade de pointes but remains a poor predictor of drug torsadogenicity. Increased transmural dispersion of myocardial repolarization (TDR), measured as the time interval between the peak and end of the T wave (Tp-e), is a more reliable predictor. Carbetocin is recommended as an uterotonic in patients undergoing cesarean delivery (CD), but its effect on Tp-e is unknown. We evaluated the effect of carbetocin dose on Tp-e and Bazett-corrected QT intervals (QTc) during elective CD under spinal anesthesia.

Methods: On patient consent, 50 healthy parturients undergoing elective CD with a standardized spinal anesthetic and phenylephrine infusion were randomized to receive an intravenous (IV) bolus of carbetocin 50 µg (C50) or 100 µg (C100) via an infusion pump over 1 minute. A 12-lead electrocardiogram (ECG) was obtained at baseline, 5 minutes after spinal anesthesia, then 5 and 10 minutes after carbetocin administration. A cardiologist blinded to group and timing of ECGs measured QTc and Tp-e using Emori's criteria. Primary outcome was the change in Tp-e at 5 minutes after carbetocin administration between the C50 and C100 groups and within each group compared to baseline values. Secondary outcomes included occurrence of arrhythmias, changes in QTc at 5 and 10 minutes after carbetocin, changes in both QTc and Tp-e after spinal anesthesia compared to baseline between and within groups.

Results: Data from 41 parturients with a mean (standard deviation [SD]) age of 39.0 (0.7) years and weight of 75.0 (12.0) kg were analyzed. Between groups, at 5 minutes after carbetocin administration, Tp-e in C100 was 4.1 milliseconds longer compared to C50 (95% confidence interval [CI], 0.8-7.5; P = .01). Within groups, at 5 minutes after carbetocin administration, C50 did not significantly increase Tp-e compared to baseline (mean difference [MD] 1.9 milliseconds; 95% CI, -0.95 to 4.81 milliseconds; P = .42) but C100 did (MD 5.1 milliseconds; 95% CI, 2.1-8.1; P = .003). QTc increased significantly within C50 and C100 groups at 5 and 10 minutes after carbetocin administration (all P < .001), with no between-group differences. There were no arrhythmias.

Conclusions: Tp-e was unaffected by C50 IV given after CD in healthy parturients under spinal anesthesia, but minimally prolonged by C100. The increase in QTc after carbetocin administration was statistically significant, but with no apparent dose-dependent effect. The minimal Tp-e prolongation at the higher dose is unlikely to have any clinically significant impact on TDR and therefore the risk of inducing torsade de pointes is low.
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http://dx.doi.org/10.1213/ANE.0000000000004712DOI Listing
February 2021

Arrhythmias in Cardiac Amyloidosis: Challenges in Risk Stratification and Treatment.

Can J Cardiol 2020 03 12;36(3):416-423. Epub 2019 Dec 12.

Division of Cardiology, University of British Columbia, Vancouver, British Columbia, Canada. Electronic address:

Cardiac amyloidosis occurs secondarily to the deposition of insoluble protein fibrils in cardiac tissue leading to progressive myocardial dysfunction, clinical heart failure, and arrhythmia. In recent years, increasing awareness and improved screening have resulted in an increased prevalence of cardiac amyloidosis, with contemporary estimates reporting a prevalence of 18-55 cases per 100,000 person-years, accounting for > 13% of heart failure hospitalizations. The arrhythmic manifestations of cardiac amyloidosis can range from conduction-system disease and bradyarrhythmias to atrial fibrillation and sudden cardiac death. Bradyarrhythmias and conduction system disease may occur secondarily to amyloid infiltration, but the timing of pacemaker implantation remains unclear. When available, biventricular pacing should be considered in symptomatic patients, particularly in those expected to receive a high burden of ventricular pacing (> 40%). The management of atrial fibrillation can be challenging, because contemporary agents for rate and rhythm control may be poorly tolerated in patients with cardiac amyloidosis. Patients with cardiac amyloidosis also have a high rate of intracardiac thrombus and should be anticoagulated in the presence of atrial fibrillation (regardless of CHADS score). We generally consider transesophageal echocardiography before cardioversion regardless of anticoagulation status or duration of arrhythmia. Ventricular arrhythmias may also occur in patients with cardiac amyloidosis, and decisions surrounding implantable cardioverter-defibrillator implantation should balance the risks of ventricular arrhythmia and sudden cardiac death with the competing risks of worsening heart failure and noncardiac death. In this review, we cover the primary arrhythmic manifestations of cardiac amyloidosis and discuss their management considerations.
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http://dx.doi.org/10.1016/j.cjca.2019.11.039DOI Listing
March 2020

Heart Rate Recovery After Exercise Is Associated With Arrhythmic Events in Patients With Catecholaminergic Polymorphic Ventricular Tachycardia.

Circ Arrhythm Electrophysiol 2020 03 16;13(3):e007471. Epub 2020 Feb 16.

Department of Pediatrics, Children's Heart Centre, Division of Cardiology, British Columbia Children's Hospital, Vancouver, BC, Canada (T.M.R., S.S.).

Background: Risk stratification in catecholaminergic polymorphic ventricular tachycardia remains ill defined. Heart rate recovery (HRR) immediately after exercise is regulated by autonomic reflexes, particularly vagal tone, and may be associated with symptoms and ventricular arrhythmias in patients with catecholaminergic polymorphic ventricular tachycardia. Our objective was to evaluate whether HRR after maximal exercise on the exercise stress test (EST) is associated with symptoms and ventricular arrhythmias.

Methods: In this retrospective observational study, we included patients ≤65 years of age with an EST without antiarrhythmic drugs who attained at least 80% of their age- and sex-predicted maximal HR. HRR in the recovery phase was calculated as the difference in heart rate (HR) at maximal exercise and at 1 minute in the recovery phase (ΔHRR1').

Results: We included 187 patients (median age, 36 years; 68 [36%] symptomatic before diagnosis). Pre-EST HR and maximal HR were equal among symptomatic and asymptomatic patients. Patients who were symptomatic before diagnosis had a greater ΔHRR1' after maximal exercise (43 [interquartile range, 25-58] versus 25 [interquartile range, 19-34] beats/min; <0.001). Corrected for age, sex, and relatedness, patients in the upper tertile for ΔHRR1' had an odds ratio of 3.4 (95% CI, 1.6-7.4) of being symptomatic before diagnosis (<0.001). In addition, ΔHRR1' was higher in patients with complex ventricular arrhythmias at EST off antiarrhythmic drugs (33 [interquartile range, 22-48] versus 27 [interquartile range, 20-36] beats/min; =0.01). After diagnosis, patients with a ΔHRR1' in the upper tertile of its distribution had significantly more arrhythmic events as compared with patients in the other tertiles (=0.045).

Conclusions: Catecholaminergic polymorphic ventricular tachycardia patients with a larger HRR following exercise are more likely to be symptomatic and have complex ventricular arrhythmias during the first EST off antiarrhythmic drug.
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http://dx.doi.org/10.1161/CIRCEP.119.007471DOI Listing
March 2020

Initially unexplained cardiac arrest in children and adolescents: A national experience from the Canadian Pediatric Heart Rhythm Network.

Heart Rhythm 2020 06 6;17(6):975-981. Epub 2020 Feb 6.

Children's Heart Centre, Division of Cardiology, Department of Pediatrics, British Columbia's Children's Hospital, Vancouver, British Columbia, Canada. Electronic address:

Background: Unexplained cardiac arrest (UCA) is rare in children. Despite investigations, the etiology in up to one-half of patients remains unknown.

Objective: The purpose of this study was to assess the management and outcomes of pediatric UCA survivors through the Canadian Pediatric Heart Rhythm Network.

Methods: A retrospective case series of children (age 1-19 years) who presented with UCA between January 1, 2004, and November 1, 2017, was conducted. Patients with known heart disease pre-UCA were excluded. UCA details, investigations, genetic test results, treatment, implantable cardioverter-defibrillator (ICD) data, subsequent diagnoses, and family screening data were collected.

Results: Forty-six patients (61% male) were survivors of sudden unexpected death and met inclusion criteria at 8 participating sites. Median age at UCA was 13.8 years (interquartile range [IQR] 9-16 years). Baseline retrievable investigations included electrocardiogram (96%), echocardiogram (85%), exercise stress test (73%), and cardiac magnetic resonance imaging (57%). The presumed etiology for the UCA was identified in 24 (52%), mainly long QT syndrome or catecholaminergic polymorphic ventricular tachycardia. Genetic testing was performed in 33 of 46 (72%), with pathogenic/likely pathogenic variants identified in 13 of 33 (39%) and variants of uncertain significance in 8 of 33 (24%). ICDs were implanted in 35 of 46 (76%). Over median follow-up of 36 months (IQR 17-57 months), 8 of 35 had arrhythmia events captured on device interrogation. Families of 26 of 46 patients(57%) underwent screening, leading to a cardiac diagnosis in 6 of 26 families.

Conclusion: A cause for UCA was not identified in nearly 50% of patients despite extensive investigations, including cascade screening. A large proportion (75%) of ICD shocks occurred in patients without a diagnosis.
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http://dx.doi.org/10.1016/j.hrthm.2020.01.030DOI Listing
June 2020

To play or not to play? sports participation and shared decision-making in athletes with inherited heart rhythm disorders.

Br J Sports Med 2020 Oct 24;54(19):1126-1128. Epub 2020 Jan 24.

The University of British Columbia, Vancouver, British Columbia, Canada

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http://dx.doi.org/10.1136/bjsports-2019-101236DOI Listing
October 2020

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

Circulation 2020 02 16;141(6):429-439. Epub 2020 Jan 16.

European Reference Network for Rare and Low Prevalence Complex Diseases of the Heart (A.M., I.T., L.C., A.B., D.K., B.S., C.S., Y.D.W., S.D., A.A.M.W., E.R.B., J.T.-H., J.P.K., F.D., P.J.S., E.S.-B., S.G.P.).

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 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. 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 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, <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]; =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], =0.590). The cumulative prevalence of the 32 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 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.
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http://dx.doi.org/10.1161/CIRCULATIONAHA.119.043114DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7035205PMC
February 2020

The merits of the ICD for inherited heart rhythm disorders: A critical re-appraisal.

Trends Cardiovasc Med 2020 10 24;30(7):415-421. Epub 2019 Oct 24.

Division of Cardiology, Department of Pediatrics, University of British Columbia, 4480 Oak Street, 1F Clinic, Vancouver, BC V6H 0B3, Canada.

The implantable cardioverter defibrillator (ICD) is often considered a routine intervention for an inherited heart rhythm disorder (IHRD) despite there being little to no randomized data for non-ischemic indications. Furthermore, existing IHRD studies often do not report adverse ICD outcomes, and observational data increasingly show that complications are under-recognized. Only recently have tools emerged to address the rational use of ICDs for specific forms of IHRD, although the acceptable risk of device complications remains unestablished. Here, we summarize the evidence of ICD benefit and harm in IHRD, highlight current knowledge gaps, and propose alternative and adjunctive options to the transvenous ICD.
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http://dx.doi.org/10.1016/j.tcm.2019.10.004DOI Listing
October 2020

Caring for the pregnant woman with an inherited arrhythmia syndrome.

Heart Rhythm 2020 02 7;17(2):341-348. Epub 2019 Aug 7.

Division of Cardiology, University of British Columbia, Vancouver, British Columbia, Canada. Electronic address:

Pregnancy is a period of increased cardiovascular risk in a woman's life. In the setting of an inherited arrhythmia syndrome (IAS), cardiologists and obstetricians may be unfamiliar with cardiovascular optimization and risk stratification in pregnancy. Historically, there were little data addressing the safety of pregnancy in these rare disorders. Recent advances suggest that no type of IAS represents an absolute contraindication to pregnancy. However, it is imperative that obstetric and cardiovascular clinicians understand the major forms of IAS and how they affect the risks and course of pregnancy. This includes any disease-specific proarrhythmic triggers unique to pregnancy, such as the postpartum period in long QT syndrome (especially type 2), which poses the greatest risk of arrhythmias, and the adrenergic nature of labor and delivery, which is relevant to catecholaminergic polymorphic ventricular tachycardia. Fortunately, several effective antiarrhythmic options exist that pose little fetal risk. IAS-specific optimization of implantable cardioverter-defibrillator algorithms, drug therapy, and a maternal cardiac plan addressing the antepartum, labor, and delivery and postpartum periods reduces the risk. Where evidence does not exist, there are plausible mechanistic considerations to guide clinicians. To achieve optimal outcomes, early involvement of an expert pregnancy heart team comprising obstetrics, genetics, cardiology, and anesthesiology team members and a shared decision-making approach to IAS issues in pregnancy are needed.
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http://dx.doi.org/10.1016/j.hrthm.2019.08.004DOI Listing
February 2020

Chronotropic incompetence as a risk predictor in children and young adults with catecholaminergic polymorphic ventricular tachycardia.

J Cardiovasc Electrophysiol 2019 10 11;30(10):1923-1929. Epub 2019 Jul 11.

Division of Cardiology, Department of Pediatrics, Children's Heart Centre, BC Children's Hospital, University of British Columbia, Vancouver, Canada.

Introduction: Risk stratification tools for catecholaminergic polymorphic ventricular tachycardia (CPVT) are limited. The exercise stress test (EST) is the most important diagnostic and prognostic test. We aimed to determine whether heart rate (HR) and blood pressure (BP) response during EST were associated with the risk of arrhythmias.

Materials And Methods: We studied the association between HR and BP response and ventricular arrhythmia burden on EST in 20 CPVT patients. HR reserve values <80% and ≤62% were used to define chronotropic incompetence (CI) off and on therapy, respectively. Symptoms and ventricular arrhythmia score (VAS) in all patients with respect to CI and BP during index EST off therapy and on maximal therapy were compared.

Results: CI in CPVT patients off therapy was associated with a worse VAS during EST (P = .046). Patients with CI also more frequently presented with syncope and/or cardiac arrest compared to patients with a normal chronotropic response (P = .008). Once on therapy, patients with CI had similar VAS compared to patients without CI (P = .50), suggesting that treatment attenuates risk related to CI. Patients with CI also had a lower peak systolic BP (P = .041) which persisted on maximal therapy (P = .033).

Conclusion: Untreated CPVT patients with CI have more ventricular arrhythmias than those without CI. This may serve as a simple disease prognosticator that can be modified by antiarrhythmic therapy. A mechanistic link between CI and arrhythmia susceptibility remains unknown. Larger studies are needed to confirm and establish the mechanism of these findings.
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http://dx.doi.org/10.1111/jce.14043DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6786920PMC
October 2019

Implantable cardioverter-defibrillators in previously undiagnosed patients with catecholaminergic polymorphic ventricular tachycardia resuscitated from sudden cardiac arrest.

Eur Heart J 2019 09;40(35):2953-2961

Department of Cardiology, Centre for Cardiological Innovation, Oslo University Hospital, Rikshospitalet, Sognsvannsveien 20, Oslo, Norway.

Aims: In patients with catecholaminergic polymorphic ventricular tachycardia (CPVT), implantable cardioverter-defibrillator (ICD) shocks are sometimes ineffective and may even trigger fatal electrical storms. We assessed the efficacy and complications of ICDs placed in patients with CPVT who presented with a sentinel event of sudden cardiac arrest (SCA) while undiagnosed and therefore untreated.

Methods And Results: We analysed 136 patients who presented with SCA and in whom CPVT was diagnosed subsequently, leading to the initiation of guideline-directed therapy, including β-blockers, flecainide, and/or left cardiac sympathetic denervation. An ICD was implanted in 79 patients (58.1%). The primary outcome of the study was sudden cardiac death (SCD). The secondary outcomes were composite outcomes of SCD, SCA, appropriate ICD shocks, and syncope. After a median follow-up of 4.8 years, SCD had occurred in three patients (3.8%) with an ICD and none of the patients without an ICD (P = 0.1). SCD, SCA, or appropriate ICD shocks occurred in 37 patients (46.8%) with an ICD and 9 patients (15.8%) without an ICD (P < 0.0001). Inappropriate ICD shocks occurred in 19 patients (24.7%) and other device-related complications in 22 patients (28.9%).

Conclusion: In previously undiagnosed patients with CPVT who presented with SCA, an ICD was not associated with improved survival. Instead, the ICD was associated with both a high rate of appropriate ICD shocks and inappropriate ICD shocks along with other device-related complications. Strict adherence to guideline-directed therapy without an ICD may provide adequate protection in these patients without all the potential disadvantages of an ICD.
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http://dx.doi.org/10.1093/eurheartj/ehz309DOI Listing
September 2019

The challenge of implantable cardioverter-defibrillator programming and shock interpretation in treatment-refractory catecholaminergic polymorphic ventricular tachycardia.

J Cardiovasc Med (Hagerstown) 2019 Aug;20(8):569-571

Department of Pediatrics, Children's Heart Centre, BC Children's Hospital, University of British Columbia, Vancouver, British Columbia, Canada.

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http://dx.doi.org/10.2459/JCM.0000000000000814DOI Listing
August 2019

Switching Between β-Blockers: An Empiric Tool for the Cardiovascular Practitioner.

Can J Cardiol 2019 04 31;35(4):539-543. Epub 2019 Jan 31.

Division of Cardiology, St Paul's Hospital and Vancouver General Hospital, University of British Columbia, Vancouver, British Columbia, Canada. Electronic address:

β-Blockers are a cornerstone of therapy for cardiovascular disease, but their clinical benefits are not consistent across the class and specific agents are preferred for certain indications. Further, when prescribed, a patient's clinical status might change, requiring the cardiologist to switch to an alternate agent. Examples of such scenarios include the development or a worsening of chronic noncardiac diseases (eg, hyperthyroidism, renal failure), new cardiac-related disease (eg, heart failure, atrial fibrillation), or practical/safety issues (eg, pregnancy, cost, side effects). However, guidelines on how to best switch to a different β-blocker are lacking. Additionally, most hospital-based formularies and guidelines do not provide recommendations around common challenges, like medication intolerance or adjustments for acute illness. We present a practical approach to switching between commonly prescribed β-blockers, which considers drug interchangeability for various indications, rationale for switching, necessary initial adjustments to dose/frequency, and differences in target/maximal doses.
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http://dx.doi.org/10.1016/j.cjca.2019.01.013DOI Listing
April 2019

Pregnancy in Catecholaminergic Polymorphic Ventricular Tachycardia.

JACC Clin Electrophysiol 2019 03 26;5(3):387-394. Epub 2018 Dec 26.

Heart Rhythm Services, Division of Cardiology, University of British Columbia, Vancouver, British Columbia, Canada. Electronic address:

Objectives: This investigation was a retrospective study of catecholaminergic polymorphic ventricular tachycardia (CPVT) patients in Canada and the Netherlands to compare pregnancy, postpartum, and nonpregnant event rates.

Background: CPVT is characterized by life-threatening arrhythmias during exertion or emotional stress. The arrhythmic risk in CPVT patients during pregnancy is unknown.

Methods: Baseline demographics, genetics, treatment, and pregnancy complications were reviewed. Event rate calculations assumed a 40-week pregnancy and 24-week postpartum period.

Results: Ninety-six CPVT patients had 228 pregnancies (median 2 pregnancies per patient; range: 1 to 10; total: 175.4 pregnant patient-years). The median age of CPVT diagnosis was 40.7 years (range: 12 to 84 years), with a median follow-up of 2.9 years (range: 0 to 20 years; total 448.1 patient-years). Most patients had pregnancies before CPVT diagnosis (82%). Pregnancy and postpartum cardiac events included syncope (5%) and an aborted cardiac arrest (1%), which occurred in patients who were not taking beta-blockers. Other complications included miscarriages (13%) and intrauterine growth restriction (1 case). There were 6 cardiac events (6%) during the nonpregnant period. The pregnancy and postpartum event rates were 1.71 and 2.85 events per 100 patient-years, respectively, and the combined event rate during the pregnancy and postpartum period was 2.14 events per 100 patient-years. These rates were not different from the nonpregnant event rate (1.46 events per 100 patient-years).

Conclusions: The combined pregnancy and postpartum arrhythmic risk in CPVT patients was not elevated compared with the nonpregnant period. Most patients had pregnancies before diagnosis, and all patients with events were not taking beta-blockers at the time of the event.
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http://dx.doi.org/10.1016/j.jacep.2018.10.019DOI Listing
March 2019

Acute Management of Ventricular Arrhythmia in Patients With Suspected Inherited Heart Rhythm Disorders.

JACC Clin Electrophysiol 2019 Mar;5(3):267-283

Heart Rhythm Services, Division of Cardiology, Department of Medicine, University of British Columbia, Vancouver, British Columbia, Canada.

After the most common causes of sudden cardiac death including ischemic and structural heart disease have been ruled out, clinicians on the front lines of emergent medical care can be faced with unexplained and recurrent life-threatening arrhythmia episodes in children and adults. In these cases, an inherited arrhythmia syndrome should be suspected, and a departure from conventional advanced cardiac life support algorithms may be required. This review focuses on the electrocardiographic clues of an inherited arrhythmia syndrome that can be uncovered through a careful analysis of the baseline electrocardiogram (ECG) and classification of the presenting ventricular arrhythmia and its mode of onset. After presenting an informed working diagnosis and an explanation of the implied electrophysiologic mechanisms, discussion provides a protocol approach to acute and subacute management decisions. Careful attention to a patient's response to treatment and its ECG surrogates have the potential to facilitate tailored therapy based on the underlying arrhythmogenic substrate and pathophysiology.
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http://dx.doi.org/10.1016/j.jacep.2019.02.001DOI Listing
March 2019

Dynamic Electrocardiographic Abnormalities Captured in Timothy Syndrome.

JACC Clin Electrophysiol 2018 11;4(11):1486-1487

Department of Pediatrics, Children's Heart Centre, Division of Cardiology, British Columbia Children's Hospital, Vancouver, British Columbia, Canada. Electronic address:

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http://dx.doi.org/10.1016/j.jacep.2018.06.019DOI Listing
November 2018

Catecholaminergic polymorphic ventricular tachycardia patients with multiple genetic variants in the PACES CPVT Registry.

PLoS One 2018 7;13(11):e0205925. Epub 2018 Nov 7.

Departments of Medicine, Pediatrics, and Biochemistry & Molecular Biology, University of British Columbia, Vancouver, BC, Canada.

Background: Catecholaminergic polymorphic ventricular tachycardia (CPVT) is often a life-threatening arrhythmia disorder with variable penetrance and expressivity. Little is known about the incidence or outcomes of CPVT patients with ≥2 variants.

Methods: The phenotypes, genotypes and outcomes of patients in the Pediatric and Congenital Electrophysiology Society CPVT Registry with ≥2 variants in genes linked to CPVT were ascertained. The American College of Medical Genetics & Genomics (ACMG) criteria and structural mapping were used to predict the pathogenicity of variants (3D model of pig RyR2 in open-state).

Results: Among 237 CPVT subjects, 193 (81%) had genetic testing. Fifteen patients (8%) with a median age of 9 years (IQR 5-12) had ≥2 variants. Sudden cardiac arrest occurred in 11 children (73%), although none died during a median follow-up of 4.3 years (IQR 2.5-6.1). Thirteen patients (80%) had at least two RYR2 variants, while the remaining two patients had RYR2 variants plus variants in other CPVT-linked genes. Among all variants identified, re-classification of the commercial laboratory interpretation using ACMG criteria led to the upgrade from variant of unknown significance (VUS) to pathogenic/likely pathogenic (P/LP) for 5 variants, and downgrade from P/LP to VUS for 6 variants. For RYR2 variants, 3D mapping using the RyR2 model suggested that 2 VUS by ACMG criteria were P/LP, while 2 variants were downgraded to likely benign.

Conclusions: This severely affected cohort demonstrates that a minority of CPVT cases are related to ≥2 variants, which may have implications on family-based genetic counselling. While multi-variant CPVT patients were at high-risk for sudden cardiac arrest, there are insufficient data to conclude that this genetic phenomenon has prognostic implications at present. Further research is needed to determine the significance and generalizability of this observation. This study also shows that a rigorous approach to variant re-classification using the ACMG criteria and 3D mapping is important in reaching an accurate diagnosis, especially in the multi-variant population.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0205925PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6221297PMC
April 2019

Beyond the exercise stress test: Does the cardiac ryanodine receptor affect intellectual function?

Heart Rhythm 2019 02 11;16(2):229-230. Epub 2018 Sep 11.

Division of Cardiology, BC Children's Hospital, University of British Columbia, Vancouver, British Columbia. Electronic address:

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http://dx.doi.org/10.1016/j.hrthm.2018.09.003DOI Listing
February 2019

Implantable cardioverter-defibrillator use in catecholaminergic polymorphic ventricular tachycardia: A systematic review.

Heart Rhythm 2018 12 3;15(12):1791-1799. Epub 2018 Jul 3.

BC Children's Hospital, Division of Cardiology, Department of Pediatrics, University of British Columbia, Vancouver, British Columbia, Canada. Electronic address:

Background: The implantable cardioverter-defibrillator (ICD) may be associated with a high risk of complications in patients with catecholaminergic polymorphic ventricular tachycardia (CPVT). However, ICDs in this population have not been systematically evaluated.

Objective: The purpose of this study was to characterize the use and outcomes of ICDs in CPVT.

Methods: We conducted a systematic review using Embase, MEDLINE, PubMed, and Google Scholar to identify studies that included patients with CPVT who had an ICD.

Results: Fifty-three studies describing 1429 patients with CPVT were included. In total, 503 patients (35.2%) had an ICD (median age 15.0 years; interquartile range 11.0-21.0 years). Among ICD recipients with a reported medication status, 96.7% were prescribed β-blockers and 13.2% flecainide. Sympathetic denervation was performed in 23.2%. Nearly half of patients received an ICD for primary prevention (47.3%), and 12.8% were prescribed optimal antiarrhythmic therapy. During follow-up, 40.1% had ≥1 appropriate shock, 20.8% experienced ≥1 inappropriate shock, 19.6% had electrical storm, and 7 patients (1.4%) died. An ICD-associated electrical storm was implicated in 4 deaths. Additional complications such as lead failure, endocarditis, or surgical revisions were observed in 96 of 296 patients (32.4%). A subanalysis of the 10 studies encompassing 330 patients with the most detailed ICD-related data showed similar trends.

Conclusion: In this population with CPVT, ICDs were common and associated with a high burden of shocks and complications. The reliance on primary prevention ICDs, and poor uptake of adjuvant antiarrhythmic therapies, suggests that improved adherence to guideline-directed management could reduce ICD use and harm.
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http://dx.doi.org/10.1016/j.hrthm.2018.06.046DOI Listing
December 2018

A Population-Based Study of Syncope in the Young.

Can J Cardiol 2018 02 11;34(2):195-201. Epub 2017 Dec 11.

Department of Medicine, University of Alberta, Edmonton, Alberta, Canada; Canadian VIGOUR Centre, University of Alberta, Edmonton, Alberta, Canada. Electronic address:

Background: The prevalence, hospitalization patterns, and outcomes of pediatric and adolescent syncope have not been rigorously characterized.

Methods: Patients < 20 years presenting to an emergency department (ED) with a primary diagnosis of syncope (International Classification of Diseases, 10th revision, code R55) between fiscal year (FY) 2006/2007 and FY 2013/2014 in the province of Alberta, Canada were grouped according to discharge status from the ED, ie, (1) admitted to hospital and (2) discharged without admission. Temporal trends and differences in baseline characteristics, medication use, and outcomes between admitted and discharged patients were examined.

Results: The prevalence of syncope increased from 143/100,000 population in FY 2006/2007 to 166/100,000 population in FY 2013/2014 (P < 0.01). The majority of the 11,488 patients who presented to the ED with syncope were discharged home (n = 11,214 [98%]). Cardiac disease was present in 12.7% and thoracic conditions were present in 8% of the study population. A majority of patients (66.2% admitted and 56.4% discharged; P = 0.018) were taking a prescription drug in the year before presentation. By 30 days, 26.1% of admitted patients had a second ED presentation and 8.1% had a rehospitalization. Among discharged patients, the 30-day repeated ED presentation rate was 11.7% and the hospitalization rate was 1.1%. By 1 year, the rates of repeated ED visits increased to 64.1% and 47.5%, and rehospitalization rates increased to 21.4% and 6.8% among admitted and discharged patients, respectively.

Conclusions: Our data suggest that pediatric and adolescent syncope is increasing in prevalence and represents a growing public health problem. This population has a high burden of comorbidities that likely contribute to increased health care resource use and polypharmacy.
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http://dx.doi.org/10.1016/j.cjca.2017.12.006DOI Listing
February 2018

Functional characterization of a novel hERG variant in a family with recurrent sudden infant death syndrome: Retracting a genetic diagnosis.

Forensic Sci Int 2018 Mar 20;284:39-45. Epub 2017 Dec 20.

Department of Biomedical Physiology and Kinesiology, Simon Fraser University, Burnaby, BC, Canada. Electronic address:

Long QT syndrome (LQTS) is the most common cardiac ion channelopathy and has been found to be responsible for approximately 10% of sudden infant death syndrome (SIDS) cases. Despite increasing use of broad panels and now whole exome sequencing (WES) in the investigation of SIDS, the probability of identifying a pathogenic mutation in a SIDS victim is low. We report a family-based study who are afflicted by recurrent SIDS in which several members harbor a variant, p.Pro963Thr, in the C-terminal region of the human-ether-a-go-go (hERG) gene, published to be responsible for cases of LQTS type 2. Functional characterization was undertaken due to the variable phenotype in carriers, the discrepancy with published cases, and the importance of identifying a cause for recurrent deaths in a single family. Studies of the mutated ion channel in in vitro heterologous expression systems revealed that the mutation has no detectable impact on membrane surface expression, biophysical gating properties such as activation, deactivation and inactivation, or the amplitude of the protective current conducted by hERG channels during early repolarization. These observations suggest that the p.Pro963Thr mutation is not a monogenic disease-causing LQTS mutation despite evidence of co-segregation in two siblings affected by SIDS. Our findings demonstrate some of the potential pitfalls in post-mortem molecular testing and the importance of functional testing of gene variants in determining disease-causation, especially where the impacts of cascade screening can affect multiple generations.
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http://dx.doi.org/10.1016/j.forsciint.2017.12.028DOI Listing
March 2018

The accessibility and utilization of genetic testing for inherited heart rhythm disorders: a Canadian cross-sectional survey study.

J Community Genet 2018 Jul 23;9(3):257-262. Epub 2017 Nov 23.

BC Inherited Arrhythmia Program, Vancouver, BC, Canada.

The genetic basis of many sudden death-related conditions has been elucidated. These include inherited arrhythmias and arrhythmogenic cardiomyopathies, termed inherited heart rhythm disorders (IHRD). Advising on and interpreting genetic testing is challenging for the general cardiologist. This has led to the development of interdisciplinary clinics for IHRD in varying stages of establishment in Canada. We sought the viewpoints and patterns of practice of Canadian IHRD experts, and assessed their ability to access genetic testing for IHRD using a national cross-sectional survey. Of 56 participants, most were physicians (68%) or genetic counselors (19%). Despite working collaboratively, most genetic counselors (59%) were either not satisfied or only somewhat satisfied with their relationships with physicians. Ninety percent of participants were involved in offering genetic evaluation, including 80% who felt that testing was usually/always accessible. Most offered genetic testing to confirm clinical diagnosis and/or direct family screening. Post-mortem genetic analysis was sought by 69% of respondents; however, a lack of retained tissue and/or poor tissue preparation hindered this process. Family screening was usually recommended in the setting of a pathogenic/likely pathogenic variant. The most commonly perceived barrier to genetic testing was cost to the healthcare system. More than a quarter of patients waited ≥ 6 months for funding. An ability to engage at-risk relatives was rated as limited/poor by 34% of participants. Despite the establishment of several interdisciplinary clinics, timely access to affordable testing, supported by strong team communication, continues to be a barrier to genetic testing in Canada.
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http://dx.doi.org/10.1007/s12687-017-0348-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6002300PMC
July 2018

Beyond the Electrocardiogram: Mutations in Cardiac Ion Channel Genes Underlie Nonarrhythmic Phenotypes.

Clin Med Insights Cardiol 2017 16;11:1179546817698134. Epub 2017 Mar 16.

British Columbia Inherited Arrhythmia Program and University of British Columbia, Vancouver, BC, Canada.

Cardiac ion channelopathies are an important cause of sudden death in the young and include long QT syndrome, Brugada syndrome, catecholaminergic polymorphic ventricular tachycardia, idiopathic ventricular fibrillation, and short QT syndrome. Genes that encode ion channels have been implicated in all of these conditions, leading to the widespread implementation of genetic testing for suspected channelopathies. Over the past half-century, researchers have also identified systemic pathologies that extend beyond the arrhythmic phenotype in patients with ion channel gene mutations, including deafness, epilepsy, cardiomyopathy, periodic paralysis, and congenital heart disease. A coexisting phenotype, such as cardiomyopathy, can influence evaluation and management. However, prior to recent molecular advances, our understanding and recognition of these overlapping phenotypes were poor. This review highlights the systemic and structural heart manifestations of the cardiac ion channelopathies, including their phenotypic spectrum and molecular basis.
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http://dx.doi.org/10.1177/1179546817698134DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5392026PMC
March 2017

The role of the autonomic nervous system in arrhythmias and sudden cardiac death.

Auton Neurosci 2017 07 31;205:1-11. Epub 2017 Mar 31.

Department of Pediatrics, University of British Columbia, BC Children's Hospital Heart Center, Room 1F9, 4480 Oak Street, V6H 3V4 Vancouver, BC, Canada. Electronic address:

The autonomic nervous system (ANS) is complex and plays an important role in cardiac arrhythmia pathogenesis. A deeper understanding of the anatomy and development of the ANS has shed light on its involvement in cardiac arrhythmias. Alterations in levels of Sema-3a and NGF, both growth factors involved in innervation patterning during development of the ANS, leads to cardiac arrhythmias. Dysregulation of the ANS, including polymorphisms in genes involved in ANS development, have been implicated in sudden infant death syndrome. Disruptions in the sympathetic and/or parasympathetic systems of the ANS can lead to cardiac arrhythmias and can vary depending on the type of arrhythmia. Simultaneous stimulation of both the sympathetic and parasympathetic systems is thought to lead to atrial fibrillation whereas increased sympathetic stimulation is thought to lead to ventricular fibrillation or ventricular tachycardia. In inherited arrhythmia syndromes, such as Long QT and Catecholaminergic Polymorphic Ventricular Tachycardia, sympathetic system stimulation is thought to lead to ventricular tachycardia, subsequent arrhythmias, and in severe cases, cardiac death. On the other hand, arrhythmic events in Brugada Syndrome have been associated with periods of high parasympathetic tone. Increasing evidence suggests that modulation of the ANS as a therapeutic strategy in the treatment of cardiac arrhythmias is safe and effective. Further studies investigating the involvement of the ANS in arrhythmia pathogenesis and its modulation for the treatment of cardiac arrhythmias is warranted.
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http://dx.doi.org/10.1016/j.autneu.2017.03.005DOI Listing
July 2017