Publications by authors named "Zachary Laksman"

62 Publications

Variant Re-interpretation in Survivors of Cardiac Arrest with Preserved Ejection Fraction (CASPER Registry) by Clinicians and Clinical Commercial Laboratories.

Circ Genom Precis Med 2021 May 7. Epub 2021 May 7.

Division of Cardiology, Department of Medicine, University of British Columbia, Vancouver, BC, Canada.

- Following an unexplained cardiac arrest, clinical genetic testing is increasingly becoming standard of care. Periodic review of variant classification is required, as re-interpretation can change the diagnosis, prognosis, and management of patients and their relatives. - This study aimed to develop and validate a standardized algorithm to facilitate clinical application of the 2015 American College of Medical Genetics and Association for Molecular Pathology (ACMG-AMP) guidelines for the interpretation of genetic variants. The algorithm was applied to genetic results in the Cardiac Arrest Survivors with Preserved Ejection Fraction Registry (CASPER), to assess the rate of variant re-classification over time. Variant classifications were then compared to the classifications of two commercial laboratories to determine the rate and identify sources of variant interpretation discordance. - Thirty-one percent of participants (40/131) had at least one genetic variant with a clinically significant reclassification over time. Variants of uncertain significance were more likely to be downgraded (73%) to benign than upgraded to pathogenic (27%, p= 0.03). For the second part of the study, 50% (70/139) of variants had discrepant interpretations (excluding benign variants), provided by at least one team. - Periodic review of genetic variant classification is a key component of follow-up care given rapidly changing information in the field. There is potential for clinical care gaps with discrepant variant interpretations, based in the interpretation and application of current guidelines. The development of gene and disease specific guidelines and algorithms may provide an opportunity to further standardize variant interpretation reporting in the future.
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http://dx.doi.org/10.1161/CIRCGEN.120.003235DOI Listing
May 2021

Size matters in atrial fibrillation: the underestimated importance of reduction of contiguous electrical mass underlying the effectiveness of catheter ablation.

Europace 2021 May 5. Epub 2021 May 5.

Division of Cardiology, University of British Columbia, 740 Hillside Ave, Vancouver, BC V8T 1Z4, Canada.

Evidence has accumulated over the last century of the importance of a critical electrical mass in sustaining atrial fibrillation (AF). AF ablation certainly reduces electrically contiguous atrial mass, but this is not widely accepted to be an important part of its mechanism of action. In this article, we review data showing that atrial size is correlated in many settings with AF propensity. Larger mammals are more likely to exhibit AF. This is seen both in the natural world and in animal models, where it is much easier to create a goat model than a mouse model of AF, for example. This also extends to humans-athletes, taller people, and obese individuals all have large atria and are more likely to exhibit AF. Within an individual, risk factors such as hypertension, valvular disease and ischaemia can enlarge the atrium and increase the risk of AF. With respect to AF ablation, we explore how variations in ablation strategy and the relative effectiveness of these strategies may suggest that a reduction in electrical atrial mass is an important mechanism of action. We counter this with examples in which there is no doubt that mass reduction is less important than competing theories such as ganglionated plexus ablation. We conclude that, when considering future strategies for the ablative therapy of AF, it is important not to discount the possibility that contiguous electrical mass reduction is the most important mechanism despite the disappointing consequence being that enhancing success rates in AF ablation may involve greater tissue destruction.
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http://dx.doi.org/10.1093/europace/euab078DOI Listing
May 2021

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

JACC Clin Electrophysiol 2021 Apr;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

Defining idiopathic ventricular fibrillation: A systematic review of diagnostic testing yield in apparently unexplained cardiac arrest.

Heart Rhythm 2021 Mar 26. Epub 2021 Mar 26.

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

Background: Idiopathic ventricular fibrillation (IVF) is diagnosed in patients with apparently unexplained cardiac arrest (UCA) after varying degrees of evaluation. This is largely due to the lack of a standardized approach to UCA.

Objective: We sought to develop an evidence-based diagnostic algorithm for IVF by systematically examining the yield of diagnostic testing in UCA probands.

Methods: Studies reporting the yield of diagnostic testing in UCA were identified in MEDLINE, EMBASE, Cochrane Central Register of Controlled Trials, and conference abstracts. Their methodological quality was assessed by the National Institutes of Health quality assessment tool. Meta-analyses were performed using the random effects model.

Results: A total of 21 studies were included. The pooled comprehensive diagnostic testing yield was 43% (95% confidence interval 39%-48%). A lower yield was seen when only definite diagnoses based on the prespecified criteria were used (32% vs 47%; P = .15). Epinephrine challenge, Holter monitoring, and family screening were associated with low yield (<5%), whereas cardiac magnetic resonance imaging, exercise treadmill test, and sodium-channel blocker challenge were associated with high yield (≥5%). Coronary spasm provocation, electrophysiology study, and systematic genetic testing were reported to be abnormal in a high proportion of UCA probands (>10%).

Conclusion: We developed a stepwise algorithm for UCA evaluation and criteria to assess the strength of IVF diagnosis on the basis of the diagnostic yield of UCA testing.
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http://dx.doi.org/10.1016/j.hrthm.2021.03.030DOI Listing
March 2021

THE ROLE OF PHOSPHORYLATION IN ATRIAL FIBRILLATION: A FOCUS ON MASS SPECTROMETRY APPROACHES.

Cardiovasc Res 2021 Mar 21. Epub 2021 Mar 21.

Faculty of Medicine, University of British Columbia, Vancouver, British Columbia, Canada.

Atrial fibrillation (AF) is the most common arrhythmia worldwide. It is associated with significant increases in morbidity in the form of stroke and heart failure, and a doubling in all-cause mortality. The pathophysiology of AF is incompletely understood, and this has contributed to a lack of effective treatments and disease-modifying therapies. An important cellular process that may explain how risk factors give rise to AF includes post-translational modification (PTM) of proteins. As the most commonly occurring PTM, protein phosphorylation is especially relevant. Although many methods exist for studying protein phosphorylation, a common and highly resolute technique is mass spectrometry (MS). This review will discuss recent evidence surrounding the role of protein phosphorylation in the pathogenesis of AF. MS-based technology to study phosphorylation and uses of MS in other areas of medicine such as oncology will also be presented. Based on these data, future goals and experiments will be outlined that utilize MS technology to better understand the role of phosphorylation in AF and elucidate its role in AF pathophysiology. This may ultimately allow for the development of more effective AF therapies.
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http://dx.doi.org/10.1093/cvr/cvab095DOI Listing
March 2021

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

Europace 2021 Mar 3. Epub 2021 Mar 3.

Section of Cardiac Electrophysiology, Division of Cardiology, Department of Medicine, Western University, London, ON, Canada.

Aims: Atrial fibrillation (AF) is a complex heritable disease whose genetic underpinnings remain largely unexplained, though recent work has suggested that the arrhythmia may develop secondary to an underlying atrial cardiomyopathy. We sought to evaluate for enrichment of loss-of-function (LOF) and copy number variants (CNVs) in genes implicated in ventricular cardiomyopathy in 'lone' AF.

Methods And Results: Whole-exome sequencing was performed in 255 early onset 'lone' AF cases, defined as arrhythmia onset prior to 60 years of age in the absence of known clinical risk factors. Subsequent evaluations were restricted to 195 cases of European genetic ancestry, as defined by principal component analysis, and focused on a pre-defined set of 43 genes previously implicated in ventricular cardiomyopathy. Bioinformatic analysis identified 6 LOF variants (3.1%), including 3 within the TTN gene, among cases in comparison with 4 of 503 (0.80%) controls [odds ratio: 3.96; 95% confidence interval (CI): 1.11-14.2; P = 0.033]. Further, two AF cases possessed a novel heterozygous 8521 base pair TTN deletion, confirmed with Sanger sequencing and breakpoint validation, which was absent from 4958 controls (P = 0.0014). Subsequent cascade screening in two families revealed evidence of co-segregation of a LOF variant with 'lone' AF.

Conclusion: 'Lone' AF cases are enriched in rare LOF variants from cardiomyopathy genes, findings primarily driven by TTN, and a novel TTN deletion, providing additional evidence to implicate atrial cardiomyopathy as an AF genetic sub-phenotype. Our results also highlight that AF may develop in the context of these variants in the absence of a discernable ventricular cardiomyopathy.
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http://dx.doi.org/10.1093/europace/euaa421DOI Listing
March 2021

Role of Common Genetic Variation in Lone Atrial Fibrillation.

Circ Genom Precis Med 2021 Feb 1;14(1):e003179. Epub 2021 Feb 1.

Section of Cardiac Electrophysiology, Division of Cardiology, Department of Medicine (A.C.S., L.J.G., A.S.T., J.D.R.), Western University, London, Ontario, Canada.

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http://dx.doi.org/10.1161/CIRCGEN.120.003179DOI Listing
February 2021

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

J Cardiovasc Electrophysiol 2021 03 15;32(3):856-859. Epub 2021 Feb 15.

Heart Rhythm Services, Division of Cardiology, Center for Cardiovascular Innovation, University of British Columbia, Vancouver, British Columbia, Canada.

Introduction: Patients undergoing evaluation for an inherited arrhythmia syndrome undertake a series of ambulatory investigations including 24-h Holter monitor, exercise treadmill testing (ETT), and others. Patch monitors may simplify the evaluation, providing accurate arrhythmia evaluation and QT assessment.

Methods And Results: Patients referred for evaluation of an inherited arrhythmia syndrome underwent standard investigations, including 12-lead electrocardiography (ECG), 24-h Holter monitoring, ETT, along with supplemental monitoring using a 7-day ECG patch monitor. Heart rates (HR), corrected QT intervals (QTc), and ectopic burden were compared across monitoring modalities. Among 35 patients that wore the patch monitor, the median age was 39 years (54% male). There was intermediate correlation between resting HR across modalities (r = .58-.66) and poor correlation of peak HR (r = .27-.39). There was intermediate correlation between resting QTc intervals across modalities (r = .72-.77) but negligible correlation between QTc intervals at peak HR across modalities (r = -.01 to -.06). There was good correlation in PAC and PVC ectopic burden across the Holter and patch monitor.

Conclusion: Patch monitors may simplify the evaluation of patients for an inherited arrhythmia syndrome and provide resting QT assessment over time. However, QTc interval comparison at peak HRs remains variable, and may be limited by the single-lead ECG vector when using the patch monitor. Apart from QTc intervals at peak HR, patch monitors demonstrated good correlation with the ECG and Holter monitor for other parameters.
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http://dx.doi.org/10.1111/jce.14917DOI Listing
March 2021

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

Exp Physiol 2021 Mar 5;106(3):683-699. Epub 2021 Feb 5.

IUCPQ-UL Research Center, Laval University, Québec, QC, Canada.

New Findings: What is the role of SCN5A-C683R? SCN5A-C683R is a novel variant associated with an uncommon phenotype of adrenaline-triggered ventricular arrhythmia in the absence of a distinct ECG phenotype. What is the main finding and its importance? Functional studies demonstrated that Na 1.5/C683R results in a mixed electrophysiological phenotype with gain-of-function (GOF) and loss-of-function (LOF) properties compared with Na 1.5/wild type. Gain-of-function properties are characterized by a significant increase of the maximal current density and a hyperpolarizing shift of the steady-state activation. The LOF effect of Na 1.5/C683R is characterized by increased closed-state inactivation. Electrophysiological properties and clinical manifestation of SCN5A-C683R are different from long-QT-3 or Brugada syndrome and might represent a distinct inherited arrhythmia syndrome.

Abstract: Mutations of SCN5Ahave been identified as the genetic substrate of various inherited arrhythmia syndromes, including long-QT-3 and Brugada syndrome. We recently identified a novel SCN5A variant (C683R) in two genetically unrelated families. The index patients of both families experienced adrenaline-triggered ventricular arrhythmia with cardiac arrest but did not show a specific ECG phenotype, raising the hypothesis that SCN5A-C683R might be a susceptibility variant and the genetic substrate of distinct inherited arrhythmia. We conducted functional cellular studies to characterize the electrophysiological properties of Na 1.5/C683R in order to explore the potential pathogenicity of this novel variant. The C683R variant was engineered by site-directed mutagenesis. Na 1.5/wild type (WT) and Na 1.5/C683R were expressed in tsA201 cells. Electrophysiological characterization of C683R was performed using the whole-cell patch-clamp technique. Adrenergic stimulation was mimicked by exposure to the protein kinase A activator 8-CPT-cAMP. The impact of β-blockers was tested by exposing Na 1.5/WT and Na 1.5/C683R currents to propranolol and nadolol. C683R resulted in a co-association of gain-of-function and loss-of-function properties of Na 1.5. Gain-of-function properties were characterized by a significant increase of the maximal Na 1.5 current density compared with Na 1.5/WT (861 ± 309 vs. 627 ± 489 pA/pF; P < 0.05, n ≥ 9) that was potentiated in Na 1.5/C683R with 8-CPT-cAMP stimulation (869 ± 287 vs. 607 ± 320 pA/pF; P < 0.05, n ≥ 12). C683R also resulted in a significant hyperpolarizing shift in the voltage of steady-state activation (-65.4 ± 3.0 vs. -57.2 ± 4.8 mV; P < 0.001), resulting in an increased window current compared with WT. The loss-of-function effect of Na 1.5/C683R was characterized by significantly increased closed-state inactivation compared with Na 1.5/WT (P < 0.05). C683R is a novel SCN5A variant resulting in a co-association of gain-of-function and loss-of-function properties of the cardiac sodium channel Na 1.5. The phenotype is characterized by adrenaline-triggered ventricular arrhythmias. Electrophysiological properties and clinical manifestations are different from long-QT-3 or Brugada syndrome and might represent a distinct inherited arrhythmia syndrome.
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http://dx.doi.org/10.1113/EP089088DOI Listing
March 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 gene 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

Anticoagulation for Patients With Atrial Fibrillation and End-Stage Renal Disease on Dialysis: A National Survey.

Can J Cardiol 2020 Dec 10. Epub 2020 Dec 10.

Division of Cardiology, University of British Columbia, Vancouver, British Columbia, Canada.

Patients with atrial fibrillation (AF) have a significant increased risk of embolic stroke. Patients with end-stage renal disease who are on dialysis have an increased risk of both embolic stroke and bleeding. Stroke-prevention studies with the use of anticoagulation for AF patients have excluded patients on dialysis, so there remains no consensus on their management. We developed and implemented a pan-Canadian multidisciplinary survey to explore the current beliefs and practices concerning patients with AF on dialysis. We developed an online investigator-designed survey with both quantitative and qualitative responses with the use of a secure university-affiliated electronic service. The survey was distributed to physicians via the QxMD platform and directly to internal medicine, cardiology, and nephrology residency program directors for distribution to faculty members. 130 participants responded, including 46 cardiologists, 45 nephrologists, 30 general internists, and 9 other physicians. The preferred anticoagulant was warfarin. The CHADS score used to initiate anticoagulation was highly variable, with specialties differing in use of a CHADS threshold of ≥ 1 (P < 0.001) and the impact of previous transient ischemic attack/stroke (P = 0.02). Calciphylaxis history affected the decision to prescribe anticoagulation. Specialties differed in thresholds used to consider direct oral anticoagulants for dialysis patients, with nephrologists more likely to prescribe anticoagulation at higher CHADS scores. Our survey demonstrated significant heterogeneity of anticoagulation use for stroke prevention in patients with AF on dialysis. Physician specialty and patient risk profiles contributed to the observed variability. This study reemphasises the need for clinical trials, large observational studies, and consensus guidelines to address evidence-based equipoise.
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http://dx.doi.org/10.1016/j.cjca.2020.12.005DOI Listing
December 2020

The Hearts in Rhythm Organization: A Canadian National Cardiogenetics Network.

CJC Open 2020 Nov 29;2(6):652-662. Epub 2020 May 29.

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

Background: The Hearts in Rhythm Organization (HiRO) is a team of Canadian inherited heart rhythm and cardiomyopathy experts, genetic counsellors, nurses, researchers, patients, and families dedicated to the detection of inherited arrhythmias and cardiomyopathies, provision of best therapies, and protection from the tragedy of sudden cardiac arrest.

Methods: Recently, existing disease-specific registries were merged into the expanded National HiRO Registry, creating a single common data set for patients and families with inherited conditions that put them at risk for sudden death in Canada. Eligible patients are invited to participate in the registry and optional biobank from 20 specialized cardiogenetics clinics across Canada.

Results: Currently, there are 4700 participants enrolled in the National HiRO Registry, with an average of 593 participants enrolled annually over the past 5 years. The capacity to enable knowledge translation of research findings is built into HiRO's organizational infrastructure, with 3 additional working groups (HiRO Clinical Care Committee, HiRO Active Communities Committee, and HiRO Annual Symposium Committee), supporting the organization's current goals and priorities as set alongside patient partners.

Conclusion: The National HiRO Registry aims to be an integrated research platform to which researchers can pose novel research questions leading to a better understanding, detection, and clinical care of those living with inherited heart rhythm and cardiomyopathy conditions and ultimately to prevent sudden cardiac death.
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http://dx.doi.org/10.1016/j.cjco.2020.05.006DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7710951PMC
November 2020

Drug screening platform using human induced pluripotent stem cell-derived atrial cardiomyocytes and optical mapping.

Stem Cells Transl Med 2021 Jan 14;10(1):68-82. Epub 2020 Sep 14.

Molecular Cardiac Physiology Group, Departments of Biomedical Physiology and Kinesiology and Molecular Biology and Biochemistry, Simon Fraser University, Burnaby, British Columbia, Canada.

Current drug development efforts for the treatment of atrial fibrillation are hampered by the fact that many preclinical models have been unsuccessful in reproducing human cardiac physiology and its response to medications. In this study, we demonstrated an approach using human induced pluripotent stem cell-derived atrial and ventricular cardiomyocytes (hiPSC-aCMs and hiPSC-vCMs, respectively) coupled with a sophisticated optical mapping system for drug screening of atrial-selective compounds in vitro. We optimized differentiation of hiPSC-aCMs by modulating the WNT and retinoid signaling pathways. Characterization of the transcriptome and proteome revealed that retinoic acid pushes the differentiation process into the atrial lineage and generated hiPSC-aCMs. Functional characterization using optical mapping showed that hiPSC-aCMs have shorter action potential durations and faster Ca handling dynamics compared with hiPSC-vCMs. Furthermore, pharmacological investigation of hiPSC-aCMs captured atrial-selective effects by displaying greater sensitivity to atrial-selective compounds 4-aminopyridine, AVE0118, UCL1684, and vernakalant when compared with hiPSC-vCMs. These results established that a model system incorporating hiPSC-aCMs combined with optical mapping is well-suited for preclinical drug screening of novel and targeted atrial selective compounds.
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http://dx.doi.org/10.1002/sctm.19-0440DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7780813PMC
January 2021

Establishing reference ranges for ambulatory electrocardiography parameters: meta-analysis.

Heart 2020 Nov 20;106(22):1732-1739. Epub 2020 Jul 20.

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

Objective: Despite the widespread and increasing use of ambulatory electrocardiography (ECG), there is no consensus on reference ranges for ambulatory electrocardiogram parameters to guide interpretation. We sought to determine population distribution-based reference ranges for parameters measured during ambulatory electrocardiogram in healthy adults, based on existing literature.

Methods: We searched multiple databases from 1950 to 2020. Articles reporting original data from ≥24-hour ambulatory electrocardiogram monitoring in healthy adults were included. Data extraction and synthesis were performed according to Meta-analysis of Observational Studies in Epidemiology guidelines. The prevalence/mean and SD for common parameters (sinus pauses, conduction abnormalities and ectopy) were extracted by age group (18-39, 40-59, 60-79 and 80+ years).

Results: We identified 33 studies involving 6466 patients. Sinus pauses of >3 s were rare (pooled prevalence <1%) across all ages. Supraventricular ectopy of >1000/24 hours increased with age, from 0% (95% CI 0% to 0%) in those aged 18-39 years to 6% (95% CI 0% to 17%) in those aged 60-79 years. Episodes of supraventricular tachycardia increased from 3% (95% CI 1% to 6%) in those aged 18-39 years to 28% (95% CI 9% to 52%) in those aged 60-79 years. Ventricular ectopy of >1000/24 hours also increased with age, from 1% (95% CI 0% to 2%) in those aged 18-39 years to 5% (95% CI 1% to 10%) in those aged 60-79 years. Episodes of non-sustained ventricular tachycardia ranged from 0% (95% CI 0% to 1%) in those aged 18-39 years to 2% (95% CI 0% to 5%) in those aged 60-79 years.

Conclusion: Despite the limitations of existing published data, this meta-analysis provides evidence-based reference ranges for ambulatory electrocardiogram parameters and highlights significant age-dependent differences that should be taken into account during interpretation.
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http://dx.doi.org/10.1136/heartjnl-2020-316925DOI Listing
November 2020

Variation in RARG increases susceptibility to doxorubicin-induced cardiotoxicity in patient specific induced pluripotent stem cell-derived cardiomyocytes.

Sci Rep 2020 06 25;10(1):10363. Epub 2020 Jun 25.

Centre for Heart Lung Innovation, Department of Medicine, University of British Columbia, Vancouver, Canada.

Doxorubicin is a potent anticancer drug used to treat a variety of cancer types. However, its use is limited by doxorubicin-induced cardiotoxicity (DIC). A missense variant in the RARG gene (S427L; rs2229774) has been implicated in susceptibility to DIC in a genome wide association study. The goal of this study was to investigate the functional role of this RARG variant in DIC. We used induced pluripotent stem cell derived cardiomyocytes (iPSC-CMs) from patients treated with doxorubicin. iPSC-CMs from individuals who experienced DIC (cases) showed significantly greater sensitivity to doxorubicin compared to iPSC-CMs from doxorubicin-treated individuals who did not develop DIC (controls) in cell viability and optical mapping experiments. Using CRISPR/Cas9, we generated isogenic cell lines that differed only at the RARG locus. Genetic correction of RARG-S427L to wild type resulted in reduced doxorubicin-induced double stranded DNA breaks, reactive oxygen species production, and cell death. Conversely, introduction of RARG-S427L increased susceptibility to doxorubicin. Finally, genetic disruption of the RARG gene resulted in protection from cell death due to doxorubicin treatment. Our findings suggest that the presence of RARG-S427L increases sensitivity to DIC, establishing a direct, causal role for this variant in DIC.
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http://dx.doi.org/10.1038/s41598-020-65979-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7316788PMC
June 2020

Efficacy and Safety of Same-Day Discharge for Atrial Fibrillation Ablation.

JACC Clin Electrophysiol 2020 06 29;6(6):609-619. Epub 2020 Apr 29.

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

Objectives: The purpose of this study was to evaluate the efficacy, health care utilization, and safety of a same-day discharge protocol.

Background: Catheter ablation of atrial fibrillation (AF) is the most common ablation performed. Increasing volumes of AF ablation are placing demands on hospital resources. In response, our institutions developed a same-day discharge protocol for AF ablation.

Methods: This was a multicenter cohort study of all patients undergoing AF ablation from 2010 to 2014 at 2 major centers. The primary efficacy outcome was the proportion of successful same-day discharges. The primary health care utilization outcome was 30-day hospital readmission for any reason. The primary safety outcome was a composite of 30-day death, stroke/transient ischemic attack or embolism, or bleeding requiring hospitalization.

Results: A total of 3,054 patients underwent AF ablation from 2010 to 2014 and met inclusion criteria. Same-day discharge was achieved in 79.2% (2,418 of 3,054). Hospital readmission at 30 days was 7.7% for the same-day discharge group, 10.2% for those who remained in the hospital overnight without complications (p = 0.055 for comparison with same-day discharge), and 19.5% (p < 0.001) for those who remained in the hospital with procedural complications (7.7%). Complication rates from discharge to 30 days (excluding immediate procedural complications) were 0.37% for the same-day discharge group, 0.36% (p = 0.999) for those kept overnight without complications, and 2.5% (p = 0.044) for those with initial procedural complications.

Conclusions: Same-day discharge after AF ablation is feasible in the majority of patients with use of a standardized protocol. This approach was not associated with higher hospital readmission or complication rates after discharge.
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http://dx.doi.org/10.1016/j.jacep.2020.02.009DOI Listing
June 2020

Driving Restrictions and Early Arrhythmias in Patients Receiving a Primary-Prevention Implantable Cardioverter-Defibrillator (DREAM-ICD) Study.

Can J Cardiol 2020 08 28;36(8):1269-1277. Epub 2020 May 28.

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

Background: Current guidelines recommend 4 weeks of private driving restriction after implantation of a primary-prevention implantable cardioverter-defibrillator (ICD). These driving restrictions result in significant inconvenience and social implications. Advances in medical treatment and ICD programming have lowered the overall rate of device therapies. The objective of this study was to assess the incidence of ICD therapies at 30, 60, and 180 days after implantation.

Methods: Driving Restrictions and Early Arrhythmias in Patients Receiving a Primary-Prevention Implantable Cardioverter-Defibrillator (DREAM-ICD) was a retrospective cohort study conducted at 2 Canadian university centres enrolling patients with new implantation of a primary-prevention ICD. Device programming was standardised according to current guidelines. A total of 803 patients were enrolled.

Results: The cumulative rates of appropriate ICD therapies at 30, 60, and 180 days were 0.12%, 0.50%, and 0.75%, respectively. There was no syncope during the first 6 months. The median duration to the first appropriate ICD therapy was 208 (range 23-1109) days after implantation. The rate of inappropriate ICD therapies at 30 days was only 0.2%. Overall, < 13.6% of all appropriate ICD therapies occurred within the first 6 months after implantation.

Conclusions: The rate of appropriate ICD therapies within the first 30 days after device insertion is extremely low in contemporary primary prevention cohorts with guideline-concordant device programming. There was no increased risk for ventricular arrhythmia early after ICD insertion. The results of DREAM-ICD suggest the need for a revision of the existing driving restrictions for primary-prevention ICD recipients.
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http://dx.doi.org/10.1016/j.cjca.2020.05.029DOI Listing
August 2020

Guidance on Minimizing Risk of Drug-Induced Ventricular Arrhythmia During Treatment of COVID-19: A Statement from the Canadian Heart Rhythm Society.

Can J Cardiol 2020 06 8;36(6):948-951. Epub 2020 Apr 8.

University of British Columbia, Vancouver, British Columbia, Canada.

The COVID-19 pandemic has led to efforts at rapid investigation and application of drugs which may improve prognosis but for which safety and efficacy are not yet established. This document attempts to provide reasonable guidance for the use of antimicrobials which have uncertain benefit but may increase risk of QT interval prolongation and ventricular proarrhythmia, notably, chloroquine, hydroxychloroquine, azithromycin, and lopinavir/ritonavir. During the pandemic, efforts to reduce spread and minimize effects on health care resources mandate minimization of unnecessary medical procedures and testing. We recommend that the risk of drug proarrhythmia be minimized by 1) discontinuing unnecessary medications that may also increase the QT interval, 2) identifying outpatients who are likely to be at low risk and do not need further testing (no history of prolonged QT interval, unexplained syncope, or family history of premature sudden cardiac death, no medications that may prolong the QT interval, and/or a previous known normal corrected QT interval [QTc]), and 3) performing baseline testing in hospitalized patients or those who may be at higher risk. If baseline electrocardiographic testing reveals a moderately prolonged QTc, optimization of medications and electrolytes may permit therapy. If the QTc is markedly prolonged, drugs that further prolong it should be avoided, or expert consultation may permit administration with mitigating precautions. These recommendations are made while there are no known effective treatments for COVID-19 and should be revisited when further data on efficacy and safety become available.
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http://dx.doi.org/10.1016/j.cjca.2020.04.003DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7195336PMC
June 2020

Fracture of an epicardial left ventricular lead implanted at open-heart surgery in anticipation of future need for cardiac resynchronization therapy.

Clin Case Rep 2020 Feb 22;8(2):383-386. Epub 2020 Jan 22.

Division of Cardiology Cardiac Rhythm Services University of British Columbia Vancouver BC Canada.

Epicardial left ventricular leads can be implanted at open-heart surgery for cardiac resynchronization therapy. We report a 2-year-old fractured epicardial left ventricular lead detected at generator implant. It highlights the importance of good surgical implant technique and of rigorous lead evaluation for signs of impending failure at generator implant.
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http://dx.doi.org/10.1002/ccr3.2669DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7044377PMC
February 2020

The Potential Impact of Intrathoracic Impedance on Defibrillation Threshold Testing in S-ICDs.

Can J Cardiol 2019 Nov 25;35(11):1604.e13-1604.e16. Epub 2019 Jul 25.

Heart Rhythm Services, St Paul's Hospital, University of British Columbia, Vancouver, British Columbia, Canada. Electronic address:

A man with an ischemic cardiomyopathy and chronic obstructive pulmonary disease underwent subcutaneous implantable cardioverter-defibrillator (S-ICD) placement under general anesthesia. Following induction of ventricular fibrillation (VF), defibrillation testing (65J) failed, requiring external rescue. Repeat shock testing with reversed polarity (65J) failed. A third shock and external defibrillation failed (80J and 200J), followed by a second external defibrillation (200J), which did not immediately terminate VF, and a device shock 2 seconds later (80J, successful). Repeat shock testing (80J) under conscious sedation without mechanical ventilation was successful. We discuss this case of failed defibrillation testing during S-ICD placement, potentially due to lung hyperinflation, requiring double sequential defibrillation.
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http://dx.doi.org/10.1016/j.cjca.2019.07.624DOI Listing
November 2019

Molecular Autopsy Implicates Primary Carnitine Deficiency in Sudden Unexplained Death and Reversible Short QT Syndrome.

Can J Cardiol 2019 09 16;35(9):1256.e1-1256.e2. Epub 2019 May 16.

BC Inherited Arrhythmia Program, Vancouver, British Columbia, Canada. Electronic address:

We report a case of sudden unexplained death in a young asymptomatic woman in whom postmortem genetic testing after a negative autopsy identified a homozygous pathogenic mutation in SLC22A5 which leads clinically to primary carnitine deficiency (PCD). Her brother was subsequently diagnosed clinically with short QT syndrome, received an implantable defibrillator, and was then found to carry the same pathogenic homozygous mutation and critically low levels of carnitine. His QT interval improved with the use of carnitine supplementation, highlighting the close relationship between electrophysiology and biochemistry, and the importance of postmortem genetic testing in the clinical management of surviving relatives.
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http://dx.doi.org/10.1016/j.cjca.2019.05.014DOI Listing
September 2019

Type 8 long QT syndrome: pathogenic variants in CACNA1C-encoded Cav1.2 cluster in STAC protein binding site.

Europace 2019 Nov;21(11):1725-1732

Division of Cardiology, University of British Columbia, 1033 Davie St., Rm 211, Vancouver, BC, Canada.

Aims: Pathogenic gain-of-function variants in CACAN1C cause type-8 long QT syndrome (LQT8). We sought to describe the electrocardiographic features in LQT8 and utilize molecular modelling to gain mechanistic insights into its genetic culprits.

Methods And Results: Rare variants in CACNA1C were identified from genetic testing laboratories. Treating physicians provided clinical information. Variant pathogenicity was independently assessed according to recent guidelines. Pathogenic (P) and likely pathogenic (LP) variants were mapped onto a 3D modelled structure of the Cav1.2 protein. Nine P/LP variants, identified in 23 patients from 19 families with non-syndromic LQTS were identified. Six variants, found in 79% of families, clustered to a 4-residue section in the cytosolic II-III loop region which forms a region capable of binding STAC SH3 domains. Therefore, variants may affect binding of SH3-domain containing proteins. Arrhythmic events occurred in similar proportions of patients with II-III loop variants and with other P/LP variants (53% vs. 48%, P = 0.41) despite shorter QTc intervals (477 ± 31 ms vs. 515 ± 37 ms, P = 0.03). A history of sudden death was reported only in families with II-III loop variants (60% vs. 0%, P = 0.03). The predominant T-wave morphology was a late peaking T wave with a steep descending limb. Exercise testing demonstrated QTc prolongation on standing and at 4 min recovery after exercise.

Conclusion: The majority of P/LP variants in patients with CACNA1C-mediated LQT8 cluster in an SH3-binding domain of the cytosolic II-III loop. This represents a 'mutation hotspot' in LQT8. A late-peaking T wave with a steep descending limb and QT prolongation on exercise are commonly seen.
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http://dx.doi.org/10.1093/europace/euz215DOI Listing
November 2019

Outcomes of untreated frequent premature ventricular complexes with normal left ventricular function.

Heart 2019 09 29;105(18):1408-1413. Epub 2019 May 29.

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

Objective: The natural history of frequent premature ventricular complexes (PVCs) in association with preserved left ventricular ejection fraction (LVEF) is uncertain. The optimal management of this population is thus undefined. We studied the outcomes of untreated patients with frequent PVCs and preserved LVEF.

Methods: This cohort study prospectively evaluated consecutive patients from 2012 to 2017, with asymptomatic or minimally symptomatic frequent idiopathic PVCs (≥5% PVCs in 24 hours; normal LVEF; no cause identified on comprehensive evaluation). No suppressive therapy (ablation or antiarrhythmic drugs) were used and patients were followed with serial ambulatory ECG monitoring and echocardiography. The primary arrhythmic outcome was reduction in PVC burden to <1% on serial ambulatory monitoring. The primary echocardiographic outcome was a reduction of LVEF to <50%.

Results: One hundred patients met inclusion criteria (mean age 51.8 years, 57% female) with a median PVC burden of 18.4%. Reduction to <1% PVCs occurred in 44 of 100 patients (44.0%) at a median of 15.4 months (range 2.6 to 64.3). Recurrence was uncommon (4/44, 9.1%). Four patients (4.3%) with a persistently elevated PVC burden developed left ventricular dysfunction (LVEF <50%) during the follow-up period at a range of 53-71 months. The initial PVC burden did not predict subsequent resolution (HR 1.00(0.97, 1.03); p=0.86).

Conclusions: A strategy of active surveillance is appropriate for the majority of patients with frequent idiopathic PVCs in association with preserved LVEF, owing to the low risk of developing left ventricular systolic dysfunction and the high rate of spontaneous resolution.
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http://dx.doi.org/10.1136/heartjnl-2019-314922DOI Listing
September 2019

Ibrutinib Displays Atrial-Specific Toxicity in Human Stem Cell-Derived Cardiomyocytes.

Stem Cell Reports 2019 05 25;12(5):996-1006. Epub 2019 Apr 25.

Simon Fraser University, 8888 University Drive, Burnaby, BC V5A 1A6, Canada; University of British Columbia, 170-6371 Crescent Road, Vancouver, BC V6T 1Z2, Canada. Electronic address:

Ibrutinib (IB) is an oral Bruton's tyrosine kinase (BTK) inhibitor that has demonstrated benefit in B cell cancers, but is associated with a dramatic increase in atrial fibrillation (AF). We employed cell-specific differentiation protocols and optical mapping to investigate the effects of IB and other tyrosine kinase inhibitors (TKIs) on the voltage and calcium transients of atrial and ventricular human pluripotent stem cell-derived cardiomyocytes (hPSC-CMs). IB demonstrated direct cell-specific effects on atrial hPSC-CMs that would be predicted to predispose to AF. Second-generation BTK inhibitors did not have the same effect. Furthermore, IB exposure was associated with differential chamber-specific regulation of a number of regulatory pathways including the receptor tyrosine kinase pathway, which may be implicated in the pathogenesis of AF. Our study is the first to demonstrate cell-type-specific toxicity in hPSC-derived atrial and ventricular cardiomyocytes, which reliably reproduces the clinical cardiotoxicity observed.
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http://dx.doi.org/10.1016/j.stemcr.2019.03.011DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6524928PMC
May 2019

Comparison of Ajmaline and Procainamide Provocation Tests in the Diagnosis of Brugada Syndrome.

JACC Clin Electrophysiol 2019 04 27;5(4):504-512. Epub 2019 Mar 27.

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

Objectives: The authors studied the response rates and relative sensitivity of the most common agents used in the sodium-channel blocker (SCB) challenge.

Background: A type 1 Brugada electrocardiographic pattern precipitated by an SCB challenge confers a diagnosis of Brugada syndrome.

Methods: Patients undergoing an SCB challenge were prospectively enrolled across Canada and the United Kingdom. Patients with no prior cardiac arrest and family histories of sudden cardiac death or Brugada syndrome were included.

Results: Four hundred twenty-five subjects underwent SCB challenge (ajmaline, n = 331 [78%]; procainamide, n = 94 [22%]), with a mean age of 39 ± 15 years (54% men). Baseline non-type 1 Brugada ST-segment elevation was present in 10%. A total of 154 patients (36%) underwent signal-averaged electrocardiography, with 41% having late potentials. Positive results were seen more often with ajmaline than procainamide infusion (26% vs. 4%, p < 0.001). On multivariate analysis, baseline non-type 1 Brugada ST-segment elevation (odds ratio [OR]: 6.92; 95% confidence interval [CI]: 3.15 to 15.2; p < 0.001) and ajmaline use (OR: 8.76; 95% CI: 2.62 to 29.2; p < 0.001) were independent predictors of positive results to SCB challenge. In the subgroup undergoing signal-averaged electrocardiography, non-type 1 Brugada ST-segment elevation (OR: 9.28; 95% CI: 2.22 to 38.8; p = 0.002), late potentials on signal-averaged electrocardiography (OR: 4.32; 95% CI: 1.50 to 12.5; p = 0.007), and ajmaline use (OR: 12.0; 95% CI: 2.45 to 59.1; p = 0.002) were strong predictors of SCB outcome.

Conclusions: The outcome of SCB challenge was significantly affected by the drug used, with ajmaline more likely to provoke a type 1 Brugada electrocardiographic pattern compared with procainamide. Patients undergoing SCB challenge may have contrasting results depending on the drug used, with potential clinical, psychosocial, and socioeconomic implications.
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http://dx.doi.org/10.1016/j.jacep.2019.01.026DOI 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

In vitro analyses of suspected arrhythmogenic thin filament variants as a cause of sudden cardiac death in infants.

Proc Natl Acad Sci U S A 2019 04 18;116(14):6969-6974. Epub 2019 Mar 18.

Molecular Cardiac Physiology Group, Simon Fraser University, Burnaby, BC V5A 1S6, Canada;

Sudden unexpected death of an infant (SUDI) is a devastating occurrence for families. To investigate the genetic pathogenesis of SUDI, we sequenced >70 genes from 191 autopsy-negative SUDI victims. Ten infants sharing a previously unknown variant in troponin I (TnI) were identified. The mutation ( R37C) is in the fetal/neonatal paralog of TnI, a gene thought to be expressed in the heart up to the first 24 months of life. Using phylogenetic analysis and molecular dynamics simulations, it was determined that arginine at residue 37 in may play a critical functional role, suggesting that the variant may be pathogenic. We investigated the biophysical properties of the R37C mutation in human reconstituted thin filaments (RTFs) using fluorometry. RTFs reconstituted with the mutant R37C TnI exhibited reduced Ca-binding sensitivity due to an increased Ca off-rate constant. Furthermore, we generated R37C mutants in human induced pluripotent stem cell derived cardiomyocytes (hiPSC-CMs) using CRISPR-Cas9. In monolayers of hiPSC-CMs, we simultaneously monitored voltage and Ca transients through optical mapping and compared them to their isogenic controls. We observed normal intrinsic beating patterns under control conditions in R37C at stimulation frequencies of 55 beats/min (bpm), but these cells showed no restitution with increased stimulation frequency to 65 bpm and exhibited alternans at >75 bpm. The WT hiPSC-CMs did not exhibit any sign of arrhythmogenicity even at stimulation frequencies of 120 bpm. The approach used in this study provides critical physiological and mechanistic bases to investigate sarcomeric mutations in the pathogenesis of SUDI.
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http://dx.doi.org/10.1073/pnas.1819023116DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6452669PMC
April 2019

The impact of steerable sheaths on unblinded contact force during catheter ablation for atrial fibrillation.

J Interv Card Electrophysiol 2020 Apr 30;57(3):417-424. Epub 2019 Jan 30.

Heart Rhythm Services, Division of Cardiology, Department of Medicine, University of British Columbia, #211-1033 Davie Street, Vancouver, BC, V6E 1M7, Canada.

Purpose: The purpose of this study was to evaluate the impact of steerable sheaths on multiple contact force parameters during atrial fibrillation (AF) ablation. Steerable sheaths are commonly used during AF ablation, at an additional cost to standard fixed-curve sheaths. However, there is little data on their incremental value in the era of contact force-guided radiofrequency ablation.

Methods: This multi-center cohort study included consecutive patients undergoing index pulmonary vein (PV) isolation with a force-sensing catheter. Operators employed either only steerable or only fixed-curve sheaths. Operators targeted a force of 10-40 g for each ablation lesion. Automated ablation lesion assessment software with standardized settings was employed.

Results: Of 85 subjects, 52 and 33 underwent ablation with steerable and fixed-curve sheaths, respectively. The steerable sheath group showed significantly higher average and maximum forces, but predominantly for the right PVs. The proportion of lesions with ≥ 10% of time with less than 10 g of force was lower in the steerable sheath group (adjusted odds ratio 0.56, steerable vs. fixed; 95% confidence interval 0.35, 0.89, p = 0.01). Improved stability was seen in the posterior aspect of both PV pairs. The proportion of RF time-in-target (the proportion of RF time meeting lesion criteria) was not different between the two groups (p = 0.176).

Conclusions: Even with contemporary contact force targets, steerable sheath use in AF ablation is associated with better average and maximum contact force and increased stability in comparison to fixed-curve sheaths.
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http://dx.doi.org/10.1007/s10840-019-00514-1DOI Listing
April 2020