Publications by authors named "Peter Leong-Sit"

104 Publications

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

Differences in Healthcare Use Between Patients With Persistent and Paroxysmal Atrial Fibrillation Undergoing Catheter-Based Atrial Fibrillation Ablation: A Population-Based Cohort Study From Ontario, Canada.

J Am Heart Assoc 2021 Jan 31;10(1):e016071. Epub 2020 Dec 31.

Department of Medicine University of Toronto Ontario Canada.

Background Patients with persistent atrial fibrillation (AF) undergoing catheter-based AF ablation have lower success rates than those with paroxysmal AF. We compared healthcare use and clinical outcomes between patients according to their AF subtypes. Methods and Results Consecutive patients undergoing AF ablation were prospectively identified from a population-based registry in Ontario, Canada. Via linkage with administrative databases, we performed a retrospective analysis comparing the following outcomes between patients with persistent and paroxysmal AF: healthcare use (defined as AF-related hospitalizations/emergency room visits), periprocedural complications, and mortality. Multivariable Poisson modeling was performed to compare the rates of AF-related and all-cause hospitalizations/emergency room visits in the year before versus after ablation. Between April 2012 and March 2016, there were 3768 consecutive patients who underwent first-time AF ablation, of whom 1040 (27.6%) had persistent AF. The mean follow-up was 1329 days. Patients with persistent AF had higher risk of AF-related hospitalization/emergency room visits (hazard ratio [HR], 1.21; 95% CI, 1.09-1.34), mortality (HR, 1.74; 95% CI, 1.15-2.63), and periprocedural complications (odds ratio, 1.36; 95% CI, 1.02-1.75) than those with paroxysmal AF. In the overall cohort, there was a 48% reduction in the rate of AF-related hospitalization/emergency room visits in the year after versus before ablation (rate ratio [RR], 0.52; 95% CI, 0.48-0.56). This reduction was observed for patients with paroxysmal (RR, 0.45; 95% CI, 0.41-0.50) and persistent (RR, 0.74; 95% CI, 0.63-0.87) AF. Conclusions Although patients with persistent AF had higher risk of adverse outcomes than those with paroxysmal AF, ablation was associated with a favorable reduction in downstream AF-related healthcare use, irrespective of AF type.
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http://dx.doi.org/10.1161/JAHA.120.016071DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7955473PMC
January 2021

Para-Hisian Pacing During Sinus Rhythm: Establishing Threshold Values to Distinguish Nodal From Septal Pathway Conduction.

JACC Clin Electrophysiol 2020 10 12;6(10):1246-1252. Epub 2020 Aug 12.

London Heart Rhythm Program, Western University, London, Ontario, Canada.

Objectives: This study sought to identify minimum threshold values below which conduction over the atrioventricular (AV) node would be unexpected.

Background: Para-Hisian pacing is used to evaluate for the presence of a septal accessory pathway (AP); however, threshold values to differentiate nodal from AP conduction are unknown.

Methods: The authors performed high- and low-output para-Hisian pacing during sinus rhythm to capture the His and para-Hisian ventricular myocardium (H+V) and para-Hisian ventricular myocardium (V) alone, respectively. The change in stimulation (stim)-to-atrial electrogram interval after loss of His bundle capture in patients with (AP+) and without (AP-) a septal AP was evaluated. Stim-to-proximal coronary sinus (PCS) and stim-to-high right atrium (HRA) intervals were measured and within-patient differences (△) for V and H+V capture were calculated.

Results: A total of 23 AP+ and 45 AP- patients were evaluated. The difference in stimulus to earliest atrial signal in the high right atrial catheter seen with the loss of His bundle capture (△-stim-HRA) (21 ms; interquartile range [IQR]: 3 to 43 ms vs. 64 ms; IQR: 56 to 73 ms; p < 0.001) and difference in stimulus to earliest atrial signal in the proximal coronary sinus catheter seen with the loss of His Bundle capture (△-stim-PCS) (11 ms; IQR: 0 to 30 ms vs. 61 ms; IQR: 52 to 72 ms; p < 0.001) were shorter in AP+ patients. The shortest △-stim-PCS and △-stim-HRA in AP- patients were 37 ms and 32 ms, respectively, whereas the longest corresponding intervals in AP+ patients were 51 ms and 75 ms, respectively.

Conclusions: A △-stim-PCS <37 ms or △-stim-HRA <32 ms confirmed the presence of a septal AP, whereas a value >51 ms for △-stim-PCS or >75 ms for △-stim-HRA excluded it. Alternatively, the minimum △-stim-PCS with loss of His capture compatible with AV nodal conduction in isolation was 37 ms, and a △-stim-PCS >51 ms effectively ruled out the presence of a septal AP.
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http://dx.doi.org/10.1016/j.jacep.2020.05.012DOI Listing
October 2020

A simple maneuver to determine if septal accessory pathway ablation requires a left atrial approach.

J Cardiovasc Electrophysiol 2020 12 24;31(12):3207-3214. Epub 2020 Sep 24.

Division of Cardiology, Schulich School of Medicine and Dentistry, Western University, London, Ontario, Canada.

Introduction: Septal accessory pathway (AP) ablation can be challenging due to the complex anatomy of the septal region. The decision to access the left atrium (LA) is often made after failure of ablation from the right. We sought to establish whether the difference between ventriculo-atrial (VA) time during right ventricular (RV) apical pacing versus the VA during tachycardia would help establish the successful site for ablation of septal APs.

Methods: Intracardiac electrograms of patients with orthodromic reciprocating tachycardia (ORT) using a septal AP with successful catheter ablation were reviewed. The ∆VA was the difference between the VA interval during RV apical pacing and the VA interval during ORT. The difference in the VA interval during right ventricular entrainment and ORT (StimA-VA) was also measured.

Results: The median ∆VA time was significantly less in patients with a septal AP ablated on the right side compared with patients with a septal AP ablated on the left side (12 ± 19 vs. 56 ± 10 ms, p < .001). The StimA-VA was significantly different between the two groups (22 ± 14 vs. 53 ± 9 ms, p < .001). The ∆VA and StimA-VA were always 40 ms in patients with non-decremental septal APs ablated from the right side and always greater than 40 ms in those with septal APs ablated from the left.

Conclusion: ΔVA and StimA-VA values identified with RV apical pacing in the setting of ORT involving a septal AP predict when left atrial access will be necessary for successful ablation.
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http://dx.doi.org/10.1111/jce.14745DOI Listing
December 2020

Quality of Life and Health Care Utilization in the CIRCA-DOSE Study.

JACC Clin Electrophysiol 2020 08;6(8):935-944

Montreal Heart Institute, Department of Medicine, Université de Montréal, Montreal, Quebec, Canada; Montreal Health Innovations Coordinating Centre, Montreal, Québec, Canada.

Objectives: This study evaluated the impact of contact force-guided radiofrequency ablation versus cryoballoon ablation on quality of life and health care utilization.

Background: Traditional outcome parameters, such as arrhythmia-free survival, are insufficient to evaluate the clinical impact of atrial fibrillation (AF), as it fails to the capture patient- and health system-level differences in treatment approaches.

Methods: The CIRCA-DOSE (Cryoballoon Vs. Contact-Force Atrial Fibrillation Ablation) study randomly assigned 346 patients with drug-refractory paroxysmal AF to contact force-guided radiofrequency or cryoballoon ablation. Health-related quality-of-life (HRQOL) was assessed at baseline, and at 6 and 12 months post-ablation using a disease-specific and generic HRQOL instruments. Health care utilization (hospitalization, emergency department visits, and cardioversion) and antiarrhythmic drug use for the 12 months preceding ablation was compared with the 12 months following ablation.

Results: Disease-specific and generic HRQOL was moderately to severely impaired at baseline and improved significantly at 6 and 12 months of follow-up (median improvement in AFEQT [Atrial Fibrillation Effect on QualiTy of Life] score 32.4 [interquartile range: 17.7 to 48.9]). When compared with the 12 months pre-ablation, the proportion and absolute number of cardioversions decreased significantly (41.1% vs. 10.1% of patients, 137 vs. 35 events; p < 0.0001). Similar significant reductions in emergency department visits (66.7% vs. 25.1% of patients, 224 vs. 87 events; p < 0.0001), and hospitalizations (25.5% vs. 14.5% of patients, 86 vs. 50 events; p < 0.001) were observed. There were no significant differences between randomized groups.

Conclusions: In this multicenter randomized trial, catheter ablation with advanced-generation technologies resulted in a significant improvement in HRQOL and a significant reduction in health care utilization in the year following AF ablation. (Cryoballoon vs. Irrigated Radiofrequency Catheter Ablation [CIRCA-DOSE]; NCT01913522).
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http://dx.doi.org/10.1016/j.jacep.2020.04.017DOI Listing
August 2020

Repeat Atrial Fibrillation Ablation Procedures in the CIRCA-DOSE Study.

Circ Arrhythm Electrophysiol 2020 09 23;13(9):e008480. Epub 2020 Jul 23.

Department of Medicine, University of British Columbia, Vancouver, Canada (C.C.C., M.W.D., J.G.A.).

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http://dx.doi.org/10.1161/CIRCEP.120.008480DOI Listing
September 2020

Impact of Left Common Pulmonary Veins in the Contact-Force vs. Cryoballoon Atrial Fibrillation Ablation (CIRCA-DOSE) Study.

J Cardiovasc Electrophysiol 2020 Jul 6. Epub 2020 Jul 6.

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

Background: Concerns remain regarding the effectiveness of PVI using the fixed diameter non-compliant cryoballoon in the presence of a left common pulmonary vein (LCPV). We sought to evaluate the effectiveness of PVI performed by contact-force guided radiofrequency (CF-RF) versus second-generation cryoballoon-based ablation in patients with LCPV.

Methods And Results: We enrolled 346 patients with paroxysmal AF and randomized them to CF-RF or cryoballoon ablation. PV anatomy was not assessed prior to enrolment, and there were no exclusions based on PV anatomy. All patients received an implantable cardiac monitor. LCPV was observed in 13.6% of patients (47/346). Left atrial time and fluoroscopy time did not differ between those with and without LCPV (P=0.58 and P=0.06, respectively). Freedom from any atrial tachyarrhythmia at one year was observed in 46.8% with LCPV and 54.5% without LCPV (P=0.06). In those with LCPV the freedom from any atrial tachyarrhythmia did not differ between those randomized to CF-RF or cryoballoon ablation (HR for recurrence 1.19, 95% CI 0.53-2.65, P=0.69). In those with LCPV the AF burden was reduced to a similar extent with CF-RF and cryoballoon ablation (99.7% vs. 99.5%, respectively; P=0.97).

Conclusions: In this randomized clinical trial, the presence of a LCPV was associated with a trend towards higher rates of arrhythmia recurrence following PVI. No significant difference in arrhythmia recurrence was observed between patients with LCPV randomized to cryoballoon ablation or contact-force guided RF ablation, suggesting that either ablation modality is suitable in this population. (Cryoballoon vs. Irrigated Radiofrequency Catheter Ablation [CIRCA-DOSE], NCT01913522) This article is protected by copyright. All rights reserved.
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http://dx.doi.org/10.1111/jce.14652DOI Listing
July 2020

Association of Atrial Fibrillation Episode Duration With Arrhythmia Recurrence Following Ablation: A Secondary Analysis of a Randomized Clinical Trial.

JAMA Netw Open 2020 07 1;3(7):e208748. Epub 2020 Jul 1.

Montreal Heart Institute, Department of Medicine, Université de Montréal, Montréal, Quebec, Canada.

Importance: Contemporary guidelines recommend that atrial fibrillation (AF) be classified based on episode duration, with these categories forming the basis of therapeutic recommendations. While pragmatic, these classifications are not based on pathophysiologic processes and may not reflect clinical outcomes.

Objective: To evaluate the association of baseline AF episode duration with post-AF ablation arrhythmia outcomes.

Design, Setting, And Participants: The current study is a secondary analysis of a prospective, parallel-group, multicenter, single-masked randomized clinical trial (the Cryoballoon vs Irrigated Radiofrequency Catheter Ablation: Double Short vs Standard Exposure Duration [CIRCA-DOSE] study), which took place at 8 Canadian centers. Between September 2014 and July 2017, 346 patients older than 18 years with symptomatic AF referred for first catheter ablation were enrolled. All patients received an implantable cardiac monitor at least 30 days before ablation. Data analysis was performed in September 2019.

Exposure: Before ablation, patients were classified based on their longest AF episode. Ablation consisted of circumferential pulmonary vein isolation using standard techniques.

Main Outcomes And Measures: Time to first recurrence of symptomatic or asymptomatic atrial tachyarrhythmia (AF, atrial flutter, or atrial tachycardia) following ablation and AF burden (percentage of time in AF) on preablation and postablation continuous rhythm monitoring.

Results: The study included 346 patients (mean [SD] age, 59 [10] years; 231 [67.7%] men). Overall, 263 patients (76.0%) had AF episode duration of less than 24 hours; 25 (7.2%), 24 to 48 hours; 40 (11.7%), 2 to 7 days; and 18 (5.2%), more than 7 days. Documented recurrence of any atrial tachyarrhythmia following ablation was significantly lower in patients with baseline AF episode duration of less than 24 continuous hours compared with those with longer AF episodes (24 hours vs 24-48 hours: hazard ratio [HR], 0.41; 95% CI, 0.21-0.80; P = .009; 24 hours vs 2-7 days: HR, 0.25; 95% CI, 0.14-0.45; P < .001; 24 hours vs >7 days: HR, 0.23; 95% CI, 0.09-0.55; P < .001). Patients with preablation AF episodes limited to less than 24 continuous hours had a significantly lower median (interquartile range) postablation AF burden (0% [0%-0.1%]) compared with those with AF preablation episodes lasting 2-7 days (0.1% [0%-1.0%]; P = .003) and those with AF preablation episodes lasting more than 7 days (1.0% [0%-5.4%]; P = .008). There was no significant difference in arrhythmia recurrence or AF burden between the 3 groups with a baseline AF episode duration of longer than 24 hours.

Conclusions And Relevance: In this study, patients with AF episodes limited to less than 24 continuous hours had a significantly lower incidence of arrhythmia recurrence following AF ablation. This suggests that current guidelines for classification of AF may not reflect clinical outcomes.

Trial Registration: ClinicalTrials.gov Identifier: NCT01913522.
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http://dx.doi.org/10.1001/jamanetworkopen.2020.8748DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7333024PMC
July 2020

Relationship between quality of life and burden of recurrent atrial fibrillation following ablation: CAPCOST multicentre cohort study.

Europace 2020 07;22(7):1017-1025

Southlake Regional Health Centre, 602-581 Davis Drive, Newmarket, ON L3Y 2P6, Canada.

Aims: Atrial fibrillation (AF) significantly impairs patients' quality of life (QOL). We performed this study to investigate the effect of AF-ablation success and atrial fibrillation burden (AFB) on QOL measures.

Methods And Results: Overall, 230 patients with paroxysmal AF refractory to antiarrhythmic drugs were enrolled and underwent ablation in a multicentre, prospective cohort. Electrocardiogram, 48-h Holter, Canadian Cardiovascular Society Severity of Atrial Fibrillation (CCS-SAF), short form-12 (SF-12), and Atrial Fibrillation Effect on Quality of life (AFEQT) scales were used to assess patients. Atrial fibrillation burden was defined as total duration of AF during the month prior to each visit (h/month). The change in AFB was calculated as the difference between the month prior to the 12-month post-ablation and the baseline pre-ablation. The Minimal Clinically Important Difference (MCID) was considered as a 19-point change for AFEQT and 3-5-point change for SF-12 scores. There was significant rise in the AFEQT and SF12 and decrease in CCS-SAF score post-AF ablation; however, the magnitude of these changes was greater in patients without AF recurrence (P < 0.05). The QOL score that best differentiated patients with and without recurrence was AFEQT, while, CCS-SAF was the most specific score. Patients with AFB decrease >19 h/month had significantly greater change in QOL scores. Atrial fibrillation burden < 24 h/month at 12-months post-ablation was associated with significant changes in QOL and CCS-SAF when adjusting for baseline scores and other covariates. These changes were consistent with the MCID of these measures.

Conclusion: Patients experience significant improvements in QOL post-ablation, which correlate with a decrease in AFB despite ongoing brief recurrences of AF.

Clinical Trial Registration: NCT01562912. https://www.clinicaltrials.gov/ct2/show/NCT01562912? term=capcost&rank=1.
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http://dx.doi.org/10.1093/europace/euaa066DOI Listing
July 2020

Canada-wide mixed methods analysis evaluating the reasons for inappropriate emergency department presentation in patients with a history of atrial fibrillation: the multicentre AF-ED trial.

BMJ Open 2020 04 16;10(4):e033482. Epub 2020 Apr 16.

Department of Cardiology, Sunnybrook Health Sciences Centre, Toronto, Ontario, Canada

Objectives: The primary objective of this study was to ascertain the reasons for emergency department (ED) attendance among patients with a history of atrial fibrillation (AF).

Design: Appropriate ED attendance was defined by the requirement for an electrical or chemical cardioversion and/or an attendance resulting in hospitalisation or administration of intravenous medications for ventricular rate control. Quantitative and qualitative responses were recorded and analysed using descriptive statistics and content analysis, respectively. Random effects logistic regression was performed to estimate the OR of inappropriate ED attendance based on clinically relevant patient characteristics.

Participants: Participants ≥18 years with a documented history of AF were approached in one of eight centres partaking in the study across Canada (Ontario, Nova Scotia, Alberta and British Columbia).

Results: Of the 356 patients enrolled (67±13, 45% female), the majority (271/356, 76%) had inappropriate reasons for presentation and did not require urgent ED treatment. Approximately 50% of patients(172/356, 48%) were driven to the ED due to symptoms, while the remainder presented on the basis of general fear or anxiety (67/356, 19%) or prior medical advice (117/356, 33%). Random effects logistic regression analysis showed that patients with a history of congestive heart failure were significantly more likely to seek urgent care for appropriate reasons (p=0.03). Likewise, symptom-related concerns for ED presentation were significantly less likely to result in inappropriate visitation (p=0.02). When patients were surveyed on alternatives to ED care, the highest proportion of responses among both groups was in favour of specialised rapid assessment outpatient clinics (186/356, 52%). Qualitative content analysis confirmed these results.

Conclusions: Improved education focused on symptom management and alleviating disease-related anxiety as well as the institution of rapid access arrhythmias clinics may reduce the need for unnecessary healthcare utilisation in the ED and subsequent hospitalisation.

Trial Registration Number: NCT03127085.
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http://dx.doi.org/10.1136/bmjopen-2019-033482DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7201301PMC
April 2020

Prevalence and clinical impact of spontaneous and adenosine-induced pulmonary vein reconduction in the Contact-Force vs. Cryoballoon Atrial Fibrillation Ablation (CIRCA-DOSE) study.

Heart Rhythm 2020 06 21;17(6):897-904. Epub 2020 Jan 21.

Montreal Heart Institute, Department of Medicine, Université de Montréal, Montreal, Canada.

Background: Use of intraprocedural observation and pharmacologic challenges have been proposed as means to differentiate permanent pulmonary vein (PV)-left atrial conduction block from inadequate ablation lesions.

Objective: The purpose of this study was to determine the prevalence and clinical impact of spontaneous and adenosine-provoked reconnection using contemporary atrial fibrillation (AF) ablation technologies.

Methods: The CIRCA-DOSE (Cryoballoon vs. Irrigated Radiofrequency Catheter Ablation: Double Short vs. Standard Exposure Duration) study enrolled 346 patients with paroxysmal AF and randomized them to contact force-guided radiofrequency ablation (CF-RF) or cryoballoon ablation. Patients underwent provocative testing with adenosine after a 20-minute observation period. All patients received an implantable cardiac monitor for arrhythmia monitoring.

Results: Spontaneous reconnection was observed in 5.4% of PVs (71/1318) during the 20-minute postprocedure observation period, and dormant conduction was elicited in 5.7% of PVs (75/1318). Both spontaneous reconnection and dormant conduction were more common after CF-RF compared to cryoballoon ablation (P = .03 and P <.0001, respectively). Acute PV reconnection (spontaneous or adenosine-provoked) was associated with a significantly higher incidence of recurrent atrial tachyarrhythmia in the cryoballoon group (hazard ratio [HR] 2.39; 95% confidence interval [CI] 1.44-3.96; P = .0007) but not in the CF-RF group (HR 1.47; 95% CI 0.84-2.58; P = .16). In the absence of acute reconnection, the freedom from recurrent arrhythmia did not differ between groups (HR 0.95; 95% CI 0.6057-1.495; P = .83).

Conclusion: Patients without spontaneous or adenosine-provoked reconnection had better outcomes compared to those with acute PV reconnection, suggesting that efforts should be directed toward ensuring an ideal ablation lesion at the first attempt in order to achieve durable PV isolation.
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http://dx.doi.org/10.1016/j.hrthm.2020.01.017DOI Listing
June 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

Cryoballoon or Radiofrequency Ablation for Atrial Fibrillation Assessed by Continuous Monitoring: A Randomized Clinical Trial.

Circulation 2019 11 21;140(22):1779-1788. Epub 2019 Oct 21.

Montreal Heart Institute, Department of Medicine, Université de Montréal, Montreal, Canada (J.G.A., M.D., L.M., P.K.).

Background: Advanced generation ablation technologies have been developed to achieve more effective pulmonary vein isolation (PVI) and minimize arrhythmia recurrence after atrial fibrillation (AF) ablation.

Methods: We randomly assigned 346 patients with drug-refractory paroxysmal AF to contact force-guided radiofrequency ablation (CF-RF; n=115), 4-minute cryoballoon ablation (Cryo-4; n=115), or 2-minute cryoballoon ablation (Cryo-2; n=116). Follow-up was 12 months. The primary outcome was time to first documented recurrence of symptomatic or asymptomatic atrial tachyarrhythmia (AF, atrial flutter, or atrial tachycardia) between days 91 and 365 after ablation or a repeat ablation procedure at any time. Secondary end points included freedom from symptomatic arrhythmia and AF burden. All patients received an implantable loop recorder.

Results: One-year freedom from atrial tachyarrhythmia defined by continuous rhythm monitoring was 53.9%, 52.2%, and 51.7% with CF-RF, Cryo-4, and Cryo-2, respectively (=0.87). One-year freedom from symptomatic atrial tachyarrhythmia defined by continuous rhythm monitoring was 79.1%, 78.2%, and 73.3% with CF-RF, Cryo-4, and Cryo-2, respectively (=0.26). Compared with the monitoring period before ablation, AF burden was reduced by a median of 99.3% (interquartile range, 67.8%-100.0%) with CF-RF, 99.9% (interquartile range, 65.3%-100.0%) with Cryo-4, and 98.4% (interquartile range, 56.2%-100.0%) with Cryo-2 (=0.36). Serious adverse events occurred in 3 patients (2.6%) in the CF-RF group, 6 patients (5.3%) in the Cryo-4 group, and 7 patients (6.0%) in the Cryo-2 group, with no significant difference between groups (=0.24). The CF-RF group had a significantly longer procedure duration but significantly shorter fluoroscopy exposure (<0.001 vs cryoballoon groups).

Conclusions: In this multicenter, randomized, single-blinded trial, CF-RF and 2 different regimens of cryoballoon ablation resulted in no difference in 1-year efficacy, which was 53% by time to first recurrence but >98% burden reduction as assessed by continuous cardiac rhythm monitoring.

Clinical Trial Registration: URL: https://www.clinicaltrials.gov. Unique identifier: NCT01913522.
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http://dx.doi.org/10.1161/CIRCULATIONAHA.119.042622DOI Listing
November 2019

Comparison of efficacy of phased multipolar versus traditional radiofrequency ablation: A prospective, multicenter study (CAPCOST).

Pacing Clin Electrophysiol 2019 07 14;42(7):942-950. Epub 2019 Jun 14.

Southlake Regional Health Centre, Newmarket, Ontario, Canada.

Background: Multipolar phased pulmonary vein ablation catheter (PVAC), specifically its second-generation (PVAC-Gold), has been associated with reduced procedural time for atrial fibrillation (AF) ablation compared to traditional catheters. We performed this study to compare the efficacy of PVAC with point-by-point radiofrequency (RF) ablation.

Methods: This is a multicenter-cohort study (2012-2017), involving patients with symptomatic, paroxysmal AF refractory to at least one antiarrhythmic medication. Overall, 230 patients were enrolled to (A) PVAC and (B) control groups. Subanalyses were done for ablations performed with PVAC-Gold, and for ablations performed without left atrial (LA) ablation in addition to pulmonary vein isolation. Electrocardiogram and 48-h Holter monitoring were used to assess patients at 3, 6, 9, and 12 months postablation. Recurrence was defined as any atrial arrhythmia >30 s excluding an initial 3-month blanking period.

Results: Freedom from any atrial arrhythmia at 12 months postablation was 35.70% and 52.80% in groups A and B, respectively (P = .01). Freedom from atrial arrhythmia was not significantly different when limiting the PVAC cohort to PVAC-Gold and excluding patients with additional LA ablation (A: 44.30%; B: 44.30%, P = .80). Procedural and ablation time was significantly lower in group A than B. Multivariate regression model showed female gender (odds ratio [OR] = 2.90) and recurrence during blanking period (OR = 6.60) as significant predictors of recurrence.

Conclusion: This study suggests that PVAC may achieve less freedom from AF than point-by-point RF; however, efficacy is similar when comparing PVAC-Gold and point-by-point stand-alone PV isolation. PVAC is associated with significantly reduced procedural times for AF ablation.
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http://dx.doi.org/10.1111/pace.13737DOI Listing
July 2019

Prevention of venous thrombosis after electrophysiology procedures: a survey of national practice.

J Interv Card Electrophysiol 2018 Dec 8;53(3):357-363. Epub 2018 Oct 8.

McGill University Health Centre, 1001 Decarie Blvd, Montreal, QC, H4A 3J1, Canada.

Purpose: Femoral venous access is required for most electrophysiology procedures. Limited data are available regarding post-procedure venous thromboembolism (VTE), specifically deep vein thrombosis (DVT) and pulmonary embolism (PE). Potential preventative strategies are unclear. We aimed to survey Canadian centers regarding incidence of VTE and strategies for prevention of VTE after procedures that do not require post-procedure anticoagulation.

Methods: An online survey was distributed to electrophysiologists representing major Canadian EP centers. Participants responded regarding procedural volume, incidence of VTE post-procedure, and their practice regarding pharmacological and non-pharmacological peri-procedural VTE prophylaxis.

Results: The survey included 17 centers that performed a total of 6062 procedures in 2016. Ten patients (0.16%) had VTE (including 9 DVTs and 6 PEs) after diagnostic electrophysiology studies and right-sided ablation procedures excluding atrial flutter. Five centers (41.6%) administered systemic intravenous heparin during both diagnostic electrophysiology studies and right-sided ablation procedures. For patients taking oral anticoagulants, 10 centers (58.8%) suspend therapy prior to the procedure. Two centers (11.8%) routinely prescribed post-procedure pharmacologic prophylaxis for VTE. Four centers (23.5%) used compression dressings post-procedure and all prescribed bed rest for a maximum of 6 h. Of the variables collected in the survey, none were found to be predictive of VTE.

Conclusions: VTE is not a common complication of EP procedures. There is significant variability in the strategies used to prevent VTE events. Future research is required to evaluate strategies to reduce the risk of VTE that may be incorporated into EP practice guidelines.
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http://dx.doi.org/10.1007/s10840-018-0461-9DOI Listing
December 2018

Cardiac resynchronization is pro-arrhythmic in the absence of reverse ventricular remodelling: a systematic review and meta-analysis.

Cardiovasc Res 2018 09;114(11):1435-1444

Division of Cardiology, Department of Medicine, Western University, 339 Windermere Road, London, Ontario, Canada.

Aims: Cardiac resynchronization therapy (CRT) has been shown to reduce mortality and heart failure (HF) hospitalization but its effects on the rate of ventricular arrhythmias (VAs) appears to be neutral. We hypothesize that CRT with LV epicardial stimulation is inherently pro-arrhythmic and increases VA rates in the absence of reverse ventricular remodelling while conferring an anti-arrhythmic effect in mechanical responders.

Methods And Results: In this systematic review and meta-analysis, we considered retrospective cohort, prospective cohort, and randomized controlled trials comparing VA rates between cardiac resynchronization therapy-defibrillator (CRT-D) non-responders, CRT-D responders and those with implantable cardioverter-defibrillator (ICD) only. Studies were eligible if they defined CRT-D responders using a discrete left ventricular volumetric value as assessed by any imaging modality. Studies were identified through searching electronic databases from their inception to July 2017. We identified 2579 citations, of which 23 full-text articles were eligible for final analysis. Our results demonstrated that CRT-D responders were less likely to experience VA than CRT-D non-responders, relative risk (RR) 0.49 [95% confidence interval (CI) 0.41-0.58, P < 0.01] and also less than patients with ICD only: RR 0.59 (95% CI 0.50-0.69, P < 0.01). However, CRT-D mechanical non-responders had a greater likelihood of VA compared with ICD only, RR 0.76 (95% CI 0.63-0.92, P = 0.004).

Conclusion: CRT-D non-responders experienced more VA than CRT-D responders and also more than those with ICD only, suggesting that CRT with LV epicardial stimulation may be inherently pro-arrhythmic in the absence of reverse remodelling.
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http://dx.doi.org/10.1093/cvr/cvy182DOI Listing
September 2018

Elevated Incidence of Atrial Fibrillation and Stroke in Patients With Atrial Flutter-A Population-Based Study.

Can J Cardiol 2018 06 6;34(6):774-783. Epub 2018 Jan 6.

Institute for Clinical Evaluative Sciences, Western University, London, Ontario, Canada.

Background: The risk of stroke from atrial flutter and its relationship with progression to atrial fibrillation (AF) is unclear. This study describes the incidence of AF and stroke in patients with atrial flutter, and whether atrial flutter ablation attenuates the incidence of AF and stroke.

Methods: We performed a population-based retrospective cohort study of adults with typical atrial flutter with no AF history. Using linked health administrative databases we defined 3 cohorts: (1) adult patients diagnosed with new isolated atrial flutter; (2) a contemporary, 1-to-1 matched cohort from the Ontario population; and (3) patients with isolated atrial flutter who underwent atrial flutter ablation.

Results: A total of 9339 new typical atrial flutter patients were identified and 7248 were matched to general population subjects. Over the 3-year follow-up, AF occurred in 40.4% of patients with atrial flutter, and 3.3% of the matched general population (rate ratio, 12.2; P < 0.001). Stroke occurred in 4.1% of patients with atrial flutter and 1.2% of the general population cohort (rate ratio, 3.4; P < 0.001). Among 218 patients who had an atrial flutter ablation, AF occurred in 47 (21.6%) over the following 3 years, and incidence of stroke was between 0 and 2.3%.

Conclusions: Patients with isolated atrial flutter develop AF and stroke at a higher rate than the general population. Catheter ablation reduces but does not eliminate future AF incidence and stroke risk and continued anticoagulation after successful atrial flutter ablation might therefore be warranted.
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http://dx.doi.org/10.1016/j.cjca.2018.01.001DOI Listing
June 2018

Mexiletine or catheter ablation after amiodarone failure in the VANISH trial.

J Cardiovasc Electrophysiol 2018 04 1;29(4):603-608. Epub 2018 Feb 1.

Department of Medicine, QEII Health Sciences Centre and Dalhousie University, Halifax, Nova Scotia, Canada.

Introduction: In patients with ischemic heart disease and ventricular tachycardia (VT) refractory to high dose amiodarone, the two most common therapeutic options are adjunctive mexiletine therapy or catheter ablation. There are little existing data on the efficacy of these strategies. We examined the relative efficacy of adjunctive mexiletine and catheter ablation among patients enrolled in the VANISH trial.

Methods: All subjects enrolled in the VANISH trial who had VT refractory to high dose (≥ 300 mg daily) amiodarone at baseline were included. Per protocol, subjects randomized to escalated drug therapy received adjunctive mexiletine.

Results: Nineteen of the 259 patients were receiving high-dose amiodarone at baseline and 11 were randomized to escalated therapy with mexiletine and 8 to ablation. The adjunctive mexiletine group had a higher rate of the primary composite outcome (death, VT storm, or appropriate shock) in comparison to catheter ablation (HR 6.87 [2.08-22.8]). Over 90% of the patients in the adjunctive mexiletine/group experienced a primary endpoint during a median 9.2 months' follow-up. There was no difference in the rate of adverse events between the two groups.

Conclusions: Mexiletine has limited efficacy in the treatment of recurrent VT despite high-dose amiodarone therapy, in patients with ischemic heart disease. Catheter ablation is a superior strategy in this population.
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http://dx.doi.org/10.1111/jce.13431DOI Listing
April 2018

Quality of life with ablation or medical therapy for ventricular arrhythmias: A substudy of VANISH.

J Cardiovasc Electrophysiol 2018 03 30;29(3):421-434. Epub 2018 Jan 30.

Department of Medicine, QEII Health Sciences Centre and Dalhousie University, Halifax, Nova Scotia, Canada.

Background/objective: We compared health-related quality of life (HRQoL) in patients randomized to escalated therapy and those randomized to ablation for ventricular tachycardia in the VANISH trial.

Methods: HRQoL was assessed among VANISH patients at baseline and 3-, 6-, and 12-month follow-up visits. Four validated instruments were used: the SF-36, the implanted cardioverter defibrillator (ICD) Concerns questionnaire (ICDC), the Hospital Anxiety and Depression Scale (HADS), and the EuroQol five dimensions questionnaire (EQ-5D). Linear mixed-effects modeling was used for repeated measures with SF-36, HADS, ICDC, and EQ-5D as dependent variables. In a second model, treatment was subdivided by amiodarone use prior to enrollment.

Results: HRQoL did not differ significantly between those randomized to ablation or escalated therapy. On subgroup analysis, improvement in SF-36 measures was seen at 6 months in the ablation group for social functioning (63.5-69.3, P = 0.03) and energy/fatigue (43.0-47.9, P = 0.01). ICDC measures showed a reduction in ICD concern in the ablation group at 6 months (10.4-8.7, P = 0.01) and a reduction in ICD concern in the escalated therapy group at 6 months (10.9-9.4, P = 0.04). EQ-5D measures showed a significant improvement in overall health in ablation patients at 6 months (63.4-67.3, P = 0.04).

Conclusion: Patients in the VANISH study randomized to ablation did not have a significant change in quality of life outcomes compared to those randomized to escalated therapy. Some subgroup findings were significant, as those randomized to ablation showed persistent improvement in SF-36 energy/fatigue and ICD concern, and transient improvement in SF-36 social functioning and EQ-5D overall health.
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http://dx.doi.org/10.1111/jce.13419DOI Listing
March 2018

Feasibility of extravascular pacing with a novel substernal electrode configuration: The Substernal Pacing Acute Clinical Evaluation study.

Heart Rhythm 2018 04 2;15(4):536-542. Epub 2017 Dec 2.

Institut Universitaire de Cardiologie et de Pneumologie de Québec, Quebec City, Quebec, Canada.

Background: Subcutaneous implantable cardioverter-defibrillators provide an alternative to transvenous defibrillation but require higher shock outputs and offer no antitachycardia pacing. The Substernal Pacing Acute Clinical Evaluation (SPACE) study evaluated the feasibility of pacing from an extravascular substernal location.

Objectives: The primary purpose of the SPACE study was to characterize pacing from the substernal space. Secondary objectives included evaluating extracardiac stimulation and recording electrograms.

Methods: The SPACE study prospectively evaluated the feasibility of pacing with a commercially available electrophysiology catheter acutely implanted in the substernal space via minimally invasive subxiphoid access. Pacing data were collected in ≥7 vectors using constant current stimulation up to 20 mA and pulse width up to 10 ms.

Results: Catheter placement was successful in all 26 patients who underwent the procedure, with a mean placement time of 11.7 ± 10.1 minutes. Eighteen patients (69%) had successful ventricular capture in ≥1 tested vector. The mean pacing threshold at a pulse width of 10 ms was 7.3 ± 4.2 mA across all vectors (5.8 ± 4.4 V). Failed capture was generally associated with suboptimal catheter placement or presumed air ingression. A low level of extracardiac stimulation was observed in 1 patient. The mean R-wave amplitude ranged from 2.98 to 4.11 mV in the unipolar configuration and from 0.83 to 3.95 mV in the bipolar configuration.

Conclusion: The data from the SPACE study demonstrate that pacing is feasible from the extravascular substernal location. A substernal electrode configuration has the potential to provide pacing in a future extravascular device without need for intracardiac hardware placement.
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http://dx.doi.org/10.1016/j.hrthm.2017.11.030DOI Listing
April 2018

Measuring the Impact of Guideline Concordance: The More Things Change, the More They Stay the Same.

Circ Arrhythm Electrophysiol 2017 11;10(11)

From the London Heart Rhythm Program, Division of Cardiology, Department of Medicine, Western University, London, Ontario, Canada.

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http://dx.doi.org/10.1161/CIRCEP.117.005838DOI Listing
November 2017

Randomised clinical trial of cryoballoon versus irrigated radio frequency catheter ablation for atrial fibrillation-the effect of double short versus standard exposure cryoablation duration during pulmonary vein isolation (CIRCA-DOSE): methods and rationale.

BMJ Open 2017 Oct 5;7(10):e017970. Epub 2017 Oct 5.

Department of Medicine, Montreal Heart Institute, Université de Montréal, British Columbia, Canada.

Introduction: Pulmonary vein isolation (PVI) is an effective therapy for paroxysmal atrial fibrillation (AF), but it has limitations. The two most significant recent advances have centred on the integration of real-time quantitative assessment of catheter contact force into focal radio frequency (RF) ablation catheters and the development of dedicated ablation tools capable of achieving PVI with a single ablation lesion (Arctic Front cryoballoon, Medtronic, Minneapolis, MN, USA). Although each of these holds promise for improving the clinical success of catheter ablation of AF, there has not been a rigorous comparison of these advanced ablation technologies. Moreover, the optimal duration of cryoablation (freezing time) has not been determined.

Methods And Analysis: Patients undergoing an initial PVI procedure for paroxysmal AF will be recruited. Patients will be randomised 1:1:1 between contact-force irrigated RF ablation, short duration cryoballoon ablation (2 min applications) and standard duration cryoballoon ablation (4 min applications). The primary outcome is time to first documented AF recurrence on implantable loop recorder. With a sample size of 111 per group and a two-sided 0.025 significance level (to account for the two main comparisons), the study will have 80% power (using a log-rank test) to detect a difference of 20% between contact force RF catheter ablation and either of the two cryoballoon ablation groups. Factoring in a 4% loss to follow-up, 116 patients per group should be randomised and followed for a year (total study population of 348).

Ethics And Dissemination: The study was approved by the University of British Columbia Office of Research (Services) Ethics Clinical Research Ethics Board. Results of the study will be submitted for publication in a peer-reviewed journal.

Trial Registration Number: NCT01913522; Pre-results.
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http://dx.doi.org/10.1136/bmjopen-2017-017970DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5639989PMC
October 2017

Loss-of-Function Variants: True Monogenic Culprits of Long-QT Syndrome or Proarrhythmic Variants Requiring Secondary Provocation?

Circ Arrhythm Electrophysiol 2017 Aug;10(8)

For author affiliations, please see the Appendix.

Background: Insight into type 6 long-QT syndrome (LQT6), stemming from mutations in the -encoded voltage-gated channel β-subunit, is limited. We sought to further characterize its clinical phenotype.

Methods And Results: Individuals with reported pathogenic mutations identified during arrhythmia evaluation were collected from inherited arrhythmia clinics and the Rochester long-QT syndrome (LQTS) registry. Previously reported LQT6 cases were identified through a search of the MEDLINE database. Clinical features were assessed, while reported mutations were evaluated for genotype-phenotype segregation and classified according to the contemporary American College of Medical Genetics guidelines. Twenty-seven probands possessed reported pathogenic mutations, while a MEDLINE search identified 17 additional LQT6 cases providing clinical and genetic data. Sixteen probands had normal resting QTc values and only developed QT prolongation and malignant arrhythmias after exposure to QT-prolonging stressors, 10 had other LQTS pathogenic mutations, and 10 did not have an LQTS phenotype. Although the remaining 8 subjects had an LQTS phenotype, evidence suggested that the variant was not the underlying culprit. The collective frequency of variants implicated in LQT6 in the Exome Aggregation Consortium database was 1.4%, in comparison with a 0.0005% estimated clinical prevalence for LQT6.

Conclusions: On the basis of clinical phenotype, the high allelic frequencies of LQT6 mutations in the Exome Aggregation Consortium database, and absence of previous documentation of genotype-phenotype segregation, our findings suggest that many variants, and perhaps all, have been erroneously designated as LQTS-causative mutations. Instead, variants may confer proarrhythmic susceptibility when provoked by additional environmental/acquired or genetic factors, or both.
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http://dx.doi.org/10.1161/CIRCEP.117.005282DOI Listing
August 2017

Subclinical Atrial Fibrillation in Older Patients.

Circulation 2017 Oct 4;136(14):1276-1283. Epub 2017 Aug 4.

From Population Health Research Institute, Hamilton, ON, Canada (J.S.H., J.W., D.L., H.D., K.S., S.R.M., S.J.C.); McMaster University, Hamilton, ON, Canada (J.S.H., J.W., D.L., H.D., W.F.M., S.R.M., A.S.P., S.J.C.); Amphia Ziekenhuis, Breda, the Netherlands (M.A.); WCN-Dutch Network for Cardiovascular Research (M.A.); University of Toronto, ON, Canada (A.H., A.V.); University of Western Ontario, London, Canada (P.L.-S.); University of Ottawa Heart Institute, ON, Canada (D.H.B.); Nij Smellinghe Hospital, Drachten, the Netherlands (J.J.d.G.); Ikazia Ziekenhuis, Rotterdam, the Netherlands (M.F.); Institut Universitaire de Cardiologie et de Pneumologie de Québec, QC, Canada (F.P.); University of Alberta, Edmonton, Canada (W.B.); University of Calgary, AB, Canada (M.D.H.); St. Jude Medical, Sylmar, CA (M.C.); Slingeland Ziekenhuis, Doetinchem, the Netherlands (F.S.); and Cambridge Cardiac Care Centre, ON, Canada (A.S.P.).

Background: Long-term continuous electrocardiographic monitoring shows a substantial prevalence of asymptomatic, subclinical atrial fibrillation (SCAF) in patients with pacemakers and patients with cryptogenic stroke. Whether SCAF is also common in other patients without these conditions is unknown.

Methods: We implanted subcutaneous electrocardiographic monitors (St. Jude CONFIRM-AF) in patients ≥65 years of age attending cardiovascular or neurology outpatient clinics if they had no history of atrial fibrillation but had any of the following: CHADS-VASc score of ≥2, sleep apnea, or body mass index >30 kg/m. Eligibility also required either left atrial enlargement (≥4.4 cm or volume ≥58 mL) or increased (≥290 pg/mL) serum NT-proBNP (N-terminal pro-B-type natriuretic peptide). Patients were monitored for SCAF lasting ≥5 minutes.

Results: Two hundred fifty-six patients were followed up for 16.3±3.8 months. Baseline age was 74±6 years; mean CHADS-VASc score was 4.1±1.4; left atrial diameter averaged 4.7±0.8 cm; and 48% had a prior stroke, transient ischemic attack, or systemic embolism. SCAF ≥5 minutes was detected in 90 patients (detection rate, 34.4%/y; 95% confidence interval [CI], 27.7-42.3). Baseline predictors of SCAF were increased age (hazard ratio [HR] per decade, 1.55; 95% CI, 1.11-2.15), left atrial dimension (HR per centimeter diameter, 1.43; 95% CI, 1.09-1.86), and blood pressure (HR per 10 mm Hg, 0.87; 95% CI, 0.78-0.98), but not prior stroke. The rate of occurrence of SCAF in those with a history of stroke, systemic embolism, or transient ischemic attack was 39.4%/y versus 30.3%/y without (=0.32). The cumulative SCAF detection rate was higher (51.9%/y) in those with left atrial volume above the median value of 73.5 mL.

Conclusions: SCAF is frequently detected by continuous electrocardiographic monitoring in older patients without a history of atrial fibrillation who are attending outpatient cardiology and neurology clinics. Its clinical significance is unclear.

Clinical Trial Registration: URL: http://www.clinicaltrials.gov. Unique identifier: NCT01694394.
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http://dx.doi.org/10.1161/CIRCULATIONAHA.117.028845DOI Listing
October 2017

Interpatient Variation in Rivaroxaban and Apixaban Plasma Concentrations in Routine Care.

Can J Cardiol 2017 08 24;33(8):1036-1043. Epub 2017 Apr 24.

Division of Clinical Pharmacology, Department of Medicine, London Health Sciences Centre, Western University, London, Ontario, Canada; Department of Physiology and Pharmacology, Western University, London, Ontario, Canada. Electronic address:

Background: Direct-acting oral anticoagulants (DOACs) are widely prescribed for stroke prevention in patients with atrial fibrillation (AF). An important advantage of DOACs is that routine monitoring of an anticoagulation response is not necessary. Nevertheless, because of their mechanism of action, a DOAC anticoagulation effect can be inferred based on the observed plasma concentration. However, there is a paucity of data relating to observed interpatient variation in DOAC plasma concentrations in the postmarket clinical setting.

Methods: We determined rivaroxaban and apixaban plasma concentrations in patients with AF during routine clinic visits.

Results: Among 243 patients (rivaroxaban, n = 94; apixaban, n = 149) enrolled in this study, a 60- and 50-fold interpatient variation in plasma concentration was observed for rivaroxaban and apixaban, respectively. Approximately 12% of patients receiving rivaroxaban and 13% of patients receiving apixaban exceeded the 95th percentile for predicted maximum plasma concentration observed in clinical trials.

Conclusions: In this routine-care setting, rivaroxaban and apixaban plasma concentrations tended to be more variable than those observed in clinical trials. Identification of additional clinical and molecular determinants that more fully predict patients at risk for excessively high or low DOAC concentrations may enable a more precise DOAC dosing regimen for the individual patient.
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http://dx.doi.org/10.1016/j.cjca.2017.04.008DOI Listing
August 2017

Ventricular pacing site separation by cardiac computed tomography: validation for the prediction of clinical response to cardiac resynchronization therapy.

Int J Cardiovasc Imaging 2017 Sep 29;33(9):1433-1442. Epub 2017 Mar 29.

Stephenson Cardiac Imaging Centre, Libin Cardiovascular Institute, Calgary, AB, Canada.

Cardiac Resynchronization Therapy (CRT) fails to provide benefit in up to one-third of patients. Maximizing the geographic separation of right and left ventricular pacing lead sites has been suggested as one way to improve response. Cardiac CT provides an opportunity to explore 3-dimensional inter-lead distance (ILD) measures for the prediction of CRT response. The objective of this study was to investigate associations between standardized measures of ILD by cardiac CT and echocardiographic response to CRT. Forty-two consecutive patients undergoing CRT had serial clinical and echocardiographic evaluations performed in addition to a post-procedural cardiac-gated CT with blinded measurement of direct and circumferential (via the myocardium) ILD measures. Clinical response to CRT, the primary clinical outcome, was defined as a ≥15% reduction in LVESV using echocardiography at 6-months. The mean age and ejection fraction was 63.6 ± 8.9 years and 25.2 ± 7.8%, respectively. The primary outcome occurred in 35 of 42 patients (83%). Both direct and circumferential CT-based ILD measures were associated with the primary outcome by univariate analysis. Receiver Operator Characteristic analysis identified Circumferential ILD to have the strongest predictive accuracy (AUC 0.78). Inter- and intra-observer reproducibility of CT-derived ILD measures was excellent. Circumferential ILD measures on cardiac CT are predictive of clinical response to CRT. Incorporation of these measures into the selection of optimal pacing targets, particularly from pre-procedural CT coronary vein imaging may be of therapeutic benefit and warrants further investigation.
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http://dx.doi.org/10.1007/s10554-017-1120-4DOI Listing
September 2017

Catheter ablation for atrial flutter: a survey by the European Heart Rhythm Association and Canadian Heart Rhythm Society.

Europace 2016 Dec;18(12):1880-1885

Department of Electrophysiology, University Leipzig - Heart Center, Leipzig, Germany.

The purpose of this EP wire survey was to examine current practice in the management of both cavotricuspid isthmus (CTI)-dependent and non-CTI-dependent atrial flutter (AFL) ablation amongst electrophysiologists in European and Canadian centres and to understand how current opinions vary from guidelines. The results of the survey were collected from a detailed questionnaire that was created by the European Heart Rhythm Association Research Network and the Canadian Heart Rhythm Society. Responses were received from 89 centres in 12 countries. The survey highlighted variability within certain aspects of the management of AFL ablation. The variability in opinion regarding other procedural details suggests a need for further research in this area and consideration of the development of guidelines specific to AFL. Overall, there is reasonable consensus regarding oral anticoagulation and the desired endpoints of ablation for patients with CTI-dependent AFL and for non-CTI-dependent AFL.
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http://dx.doi.org/10.1093/europace/euw402DOI Listing
December 2016