Publications by authors named "Lorne J Gula"

159 Publications

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

Europace 2021 Jun;23(6):844-850

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
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8184224PMC
June 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

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

2020 Canadian Cardiovascular Society/Canadian Heart Rhythm Society Position Statement on the Management of Ventricular Tachycardia and Fibrillation in Patients With Structural Heart Disease.

Can J Cardiol 2020 06;36(6):822-836

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

This Canadian Cardiovascular Society position statement is focused on the management of sustained ventricular tachycardia (VT) and ventricular fibrillation (VF) that occurs in patients with structural heart disease (SHD), including previous myocardial infarction, dilated cardiomyopathy, and other forms of nonischemic cardiomyopathy. This patient population is rapidly increasing because of advances in care and improved overall survival of patients with all forms of SHD. In this position statement, the acute and long-term management of VT/VF are outlined, and the many unique aspects of care in this population are emphasized. The initial evaluation, acute therapy, indications for chronic suppressive therapy, choices of chronic suppressive therapy, implantable cardioverter-defibrillator programming, alternative therapies, and psychosocial care are reviewed and recommendations for optimal care are provided. The target audience for this statement includes all health professionals involved in the continuum of care of patients with SHD and VT/VF.
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http://dx.doi.org/10.1016/j.cjca.2020.04.004DOI 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

Is atrial flutter ablation a stop along the road to atrial fibrillation?

Authors:
Lorne J Gula

Int J Cardiol 2020 01 7;298:52-53. Epub 2019 Sep 7.

London Heart Rhythm Program, Western University, London, Ontario, Canada. Electronic address:

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http://dx.doi.org/10.1016/j.ijcard.2019.09.002DOI Listing
January 2020

QT-Interval Assessment in Left Bundle Branch Block: Deciphering Normal Within Abnormal.

Can J Cardiol 2019 07 19;35(7):802-804. Epub 2019 Mar 19.

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

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http://dx.doi.org/10.1016/j.cjca.2019.03.004DOI Listing
July 2019

Incremental Value of Implantable Cardiac Device Diagnostic Variables Over Clinical Parameters to Predict Mortality in Patients With Mild to Moderate Heart Failure.

J Am Heart Assoc 2019 07 11;8(14):e010998. Epub 2019 Jul 11.

1 Western University London Ontario Canada.

Background Heart failure remains a leading cause of morbidity and mortality. Clinical prediction models provide suboptimal estimates of mortality in this population. We sought to determine the incremental value of implantable device diagnostics over clinical prediction models for mortality. Methods and Results RAFT (Resynchronization/Defibrillation for Ambulatory Heart Failure Trial) patients with implanted devices capable of device diagnostic monitoring were included, and demographic and clinical parameters were used to compute Meta-Analysis Global Group in Chronic Heart Failure (MAGGIC) heart failure risk scores. Patients were classified according to MAGGIC score into low (0-16), intermediate (17-24), or high (>24) risk groups. Mortality was evaluated from 6 months postimplant in accordance with the RAFT protocol. In a subset of 1036 patients, multivariable analysis revealed that intermediate and high MAGGIC scores, fluid index, atrial fibrillation, and low activity flags were independent predictors of mortality. A device-integrated diagnostic parameter that included a fluid index flag and either a positive atrial fibrillation flag or a positive activity flag was able to significantly differentiate higher from lower risk for mortality in the intermediate MAGGIC cohort. The effect was more pronounced in the high-risk MAGGIC cohort, in which device-integrated diagnostic-positive patients had a shorter time to death than those who were device-integrated diagnostic negative. Conclusions Device diagnostics using a combination of fluid index trends, atrial fibrillation burden, and patient activity provide significant incremental prognostic value over clinical heart failure prediction scores in higher-risk patients. This suggests that combining clinical and device diagnostic parameters may lead to models with better predictive power. Whether this risk is modifiable with early medical intervention would warrant further studies. Clinical Trial Registration URL : http://www.clinicaltrials.gov . Unique identifier: NCT00251251.
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http://dx.doi.org/10.1161/JAHA.118.010998DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6662119PMC
July 2019

Challenge and Impact of Quinidine Access in Sudden Death Syndromes: A National Experience.

JACC Clin Electrophysiol 2019 03 28;5(3):376-382. Epub 2018 Nov 28.

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

Objectives: This study sought to determine the nature of quinidine use and accessibility in a national network of inherited arrhythmia clinics.

Background: Quinidine is an antiarrhythmic medication that has been shown to be beneficial in select patients with Brugada syndrome, early repolarization syndrome, and idiopathic ventricular fibrillation. Because of the low prevalence of these conditions and restricted access to quinidine through a single regulatory process, quinidine use is rare in Canada.

Methods: Subjects prescribed quinidine were identified through the Hearts in Rhythm Organization that connects the network of inherited arrhythmia clinics across Canada. Cases were retrospectively reviewed for patient characteristics, indications for quinidine use, rate of recurrent ventricular arrhythmia, and issues with quinidine accessibility.

Results: In a population of 36 million, 46 patients are currently prescribed quinidine (0.0000013%, age 48.1 ± 16.1 years, 25 are male). Brugada syndrome, early repolarization syndrome, and idiopathic ventricular fibrillation constituted a diagnosis in 13 subjects (28%), 6 (13%), and 21 (46%), respectively. Overall, 37 subjects (81%) had cardiac arrest as an index event. After initial presentation, subjects experienced 7.47 ± 12.3 implantable cardioverter-defibrillator shocks prior to quinidine use over 34.3 ± 45.9 months, versus 0.86 ± 1.69 implantable cardioverter-defibrillator shocks in 43.8 ± 41.8 months while on quinidine (risk ratio: 8.7, p < 0.001). Twenty-two patients access quinidine through routes external to Health Canada's Special Access Program.

Conclusions: Quinidine use is rare in Canada, but it is associated with a reduction in recurrent ventricular arrhythmias in patients with Brugada syndrome, early repolarization syndrome, and idiopathic ventricular fibrillation, with minimal toxicity necessitating discontinuation. Drug interruption is associated with frequent breakthrough events. Access to quinidine is important to deliver this potentially lifesaving therapy.
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http://dx.doi.org/10.1016/j.jacep.2018.10.007DOI Listing
March 2019

Early Repolarization in Long QT Syndrome: Modifier of Arrhythmic Risk or Benign Incidental Finding?

JACC Clin Electrophysiol 2018 09;4(9):1245-1247

Heart Rhythm Program, London Health Sciences Centre, Western University, London, Ontario, Canada.

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http://dx.doi.org/10.1016/j.jacep.2018.07.003DOI 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

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

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

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

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

Cost Analysis of Patients Referred for Inherited Heart Rhythm Disorder Evaluation.

Can J Cardiol 2017 06 20;33(6):814-821. Epub 2016 Dec 20.

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

Background: Inherited heart rhythm disorders (IHRDs) are complex and uncommon arrhythmogenic conditions that can lead to sudden unexpected death in seemingly healthy individuals. Multidisciplinary programs can assist in the diagnostic testing of potentially affected individuals and their family members.

Methods: Patients evaluated in a specialized adult and pediatric IHRD clinic between April 2013 and February 2015 were characterized. The total costs per evaluation and diagnosis were calculated. Patients were divided according to referral indication (primary referral or family member).

Results: A total of 618 patients were evaluated (age 36 ± 21 years; 52% male), of which 274 (44%) were primary referrals and 344 (56%) were family members referred for cascade screening. Overall, 47% had at least 1 follow-up visit. Patients had a median of 3 tests; primary referrals required more tests (4 vs 2; P < 0.01). The median cost per patient was $1340 CAD. Evaluation of the primary referrals was costlier than family members ($3096 vs $983; P < 0.01). A definite or probable diagnosis was determined in 464 patients (77%), with no difference according to patient type (P = 0.18). The total cost per diagnosis was $4021 in primary referrals compared with $1277 in family members (P < 0.01).

Conclusions: Clinical evaluation of patients with suspected IHRD results in a high diagnostic yield and costs aligned with other complex disorders involving multidisciplinary clinics. Evaluation costs are expectedly higher in primary referrals compared with targeted family screening.
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http://dx.doi.org/10.1016/j.cjca.2016.12.009DOI Listing
June 2017

Arrhythmia Management in the Elderly-Implanted Cardioverter Defibrillators and Prevention of Sudden Death.

Can J Cardiol 2016 09 24;32(9):1117-23. Epub 2016 Mar 24.

London Heart Rhythm Program, Western University, London, Ontario, Canada. Electronic address:

We present an overview of arrhythmia management in elderly patients as it pertains to implantable cardioverter defibrillator (ICD) therapy and prevention of sudden death. Treatment of arrhythmia in elderly patients is fraught with challenges pertaining to goals of care and patient frailty. With an ever increasing amount of technology available, realistic expectations of therapy need to balance quality and quantity of life. The ICD is an important treatment option for selected patients at risk of ventricular arrhythmia and sudden cardiac death. However, the incidence of sudden death as a percentage of all-cause mortality decreases with age. Studies have reported that 20% of elderly patients might die within 1 year of an episode of life-threatening ventricular arrhythmia, but most because of nonarrhythmic causes. This illustrates the 'sudden cardiac death paradox,' with a great proportion of death in elderly patients, even those at risk for ventricular arrhythmias, attributable to medical conditions that cannot be addressed by an ICD. We discuss current practices in ICD therapy in elderly patients, existing evidence from registries and clinical trials, approaches to risk stratification, and important ethical considerations. Although the decision on whether ICD insertion is appropriate in the elderly population remains an area of uncertainty from an evidence-based and ethical perspective, we offer insight on potential clinical and research strategies for this growing population.
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http://dx.doi.org/10.1016/j.cjca.2016.03.009DOI Listing
September 2016

Risk of Ventricular Arrhythmia with Citalopram and Escitalopram: A Population-Based Study.

PLoS One 2016 11;11(8):e0160768. Epub 2016 Aug 11.

Division of Nephrology, Department of Medicine, Western University, London, Ontario, Canada.

Background: The risk of ventricular arrhythmia with citalopram and escitalopram is controversial. In this study we investigated the association between these two drugs and the risk of ventricular arrhythmia.

Methods: We conducted a population-based retrospective cohort study of older adults (mean age 76 years) from 2002 to 2012 in Ontario, Canada, newly prescribed citalopram (n = 137 701) or escitalopram (n = 38 436), compared to those prescribed referent antidepressants sertraline or paroxetine (n = 96 620). After inverse probability of treatment weighting using a propensity score, the baseline characteristics of the comparison groups were similar. The primary outcome was a hospital encounter with ventricular arrhythmia within 90 days of a new prescription, assessed using hospital diagnostic codes. The secondary outcome was all-cause mortality within 90 days.

Results: Citalopram was associated with a higher risk of a hospital encounter with ventricular arrhythmia compared with referent antidepressants (0.06% vs. 0.04%, relative risk [RR] 1.53, 95% confidence intervals [CI]1.03 to 2.29), and a higher risk of mortality (3.49% vs. 3.12%, RR 1.12, 95% CI 1.06 to 1.18). Escitalopram was not associated with a higher risk of ventricular arrhythmia compared with the referent antidepressants (0.03% vs. 0.04%, RR 0.84, 95% CI 0.42 to 1.68), but was associated with a higher risk of mortality (2.86% vs. 2.63%, RR 1.09, 95% CI 1.01 to 1.18).

Conclusion: Among older adults, initiation of citalopram compared to two referent antidepressants was associated with a small but statistically significant increase in the 90-day risk of a hospital encounter for ventricular arrhythmia.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0160768PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4981428PMC
July 2017

Effect of Left Atrial Wall Thickness on Radiofrequency Ablation Success.

J Cardiovasc Electrophysiol 2016 Nov 16;27(11):1298-1303. Epub 2016 Sep 16.

Robarts Research Institute, The University of Western Ontario, London, Ontario, Canada.

Introduction: Radiofrequency (RF) ablation in thicker regions of the left atrium (LA) may require increased ablation energy in order to achieve effective transmural lesions. Consequently, many cases of recurrent atrial fibrillation (AF) postablation may be due to thicker-than-normal atrial tissue. The aim of this study was to test the hypotheses that patients with recurrent AF have thicker tissue overall and that electrical reconnection is more likely in regions of thicker tissue.

Methods And Results: Retrospective analysis was performed on 86 CT images acquired preoperatively from a cohort of 119 patients who had undergone RF ablation for AF. Of these, 33 patients experienced recurrence of AF within 1 year of initial treatment and 29 returned for a repeat ablation. For each patient, LA wall thickness (LAWT) was measured from the images in 12 anatomical regions using custom software. Patients with recurrent AF had larger LAWT compared to successfully treated patients (1.6 ± 0.6 mm vs. 1.5 ± 0.5 mm, P < 0.001) and reconnection was found to be at regions of thicker tissue (1.6 ± 0.6 mm, P = 0.038) compared to nonreconnected regions (1.5 ± 0.5 mm). The superior right posterior wall of the LA was significantly related to both recurrence (P = 0.048) and reconnection (P = 0.014).

Conclusion: Increased LAWT has a small but significant effect on postablation recurrence and reconnection. Measures of LAWT may facilitate appropriate dosing of RF energy, but other factors will be critical in transmural lesion formation and ablation success.
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http://dx.doi.org/10.1111/jce.13065DOI Listing
November 2016

A mutation in the atrial-specific myosin light chain gene (MYL4) causes familial atrial fibrillation.

Nat Commun 2016 Apr 12;7:11303. Epub 2016 Apr 12.

Toronto General Research Institute, University Health Network, Toronto, Ontario, Canada M5G 2C4.

Atrial fibrillation (AF), the most common arrhythmia, is a growing epidemic with substantial morbidity and economic burden. Mechanisms underlying vulnerability to AF remain poorly understood, which contributes to the current lack of highly effective therapies. Recognizing mechanistic subtypes of AF may guide an individualized approach to patient management. Here, we describe a family with a previously unreported syndrome characterized by early-onset AF (age <35 years), conduction disease and signs of a primary atrial myopathy. Phenotypic penetrance was complete in all mutation carriers, although complete disease expressivity appears to be age-dependent. We show that this syndrome is caused by a novel, heterozygous p.Glu11Lys mutation in the atrial-specific myosin light chain gene MYL4. In zebrafish, mutant MYL4 leads to disruption of sarcomeric structure, atrial enlargement and electrical abnormalities associated with human AF. These findings describe the cause of a rare subtype of AF due to a primary, atrial-specific sarcomeric defect.
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http://dx.doi.org/10.1038/ncomms11303DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4832069PMC
April 2016

Aerobic Fitness and Risk of Ventricular Arrhythmia Following Physical Exertion.

Can J Cardiol 2016 Apr 28;32(4):533-8. Epub 2015 Dec 28.

Department of Epidemiology and Biostatistics, Schulich Medicine and Dentistry, Western University, London, Ontario, Canada; Division of Cardiology, Western University, London, Ontario, Canada. Electronic address:

Background: Brief episodes of physical exertion are associated with an immediately greater risk of cardiovascular events. Previous studies on the risk of ventricular arrhythmia (VA) shortly after exertion have not assessed if this risk differs according to the level of aerobic fitness or sedentary behaviour. Therefore, we conducted a prospective cohort study of patients with implantable cardioverter-defibrillators (ICDs) with a nested case-crossover analysis to examine the risk of VA shortly after exertion and whether this risk is modified by aerobic fitness and sedentary behaviour.

Methods: Ninety-seven consecutive patients were recruited at the time of ICD implantation and 30 confirmed events occurred among patients who completed interviews about physical exertion preceding ICD therapy. We compared the frequency of exertion within an hour of ICD discharge to each patient's usual frequency of exertion reported at the time of ICD implantation.

Results: Within an hour of episodes of exertion, the risk of VA was 5.3 (95% confidence interval [CI], 2.7-10.6) times greater compared with periods of rest. The association was higher among patients with aerobic fitness below the median (relative risk [RR] = 17.5; 95% CI, 5.2-58.5) than for patients with aerobic fitness above the median (RR, 1.2; 95% CI, 0.4-4.2; P homogeneity = 0.002) and higher among patients who were sedentary (RR, 52.8; 95% CI, 10.1-277) compared with individuals who were not sedentary (RR, 3.2; 95% CI, 1.3-7.6; P homogeneity = 0.0002).

Conclusions: Within 1 hour of episodes of exertion, there is an increased risk of VA, especially among individuals with lower levels of aerobic fitness and with sedentary behaviour.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5087593PMC
http://dx.doi.org/10.1016/j.cjca.2015.12.026DOI Listing
April 2016

Atrial flutter and atrial fibrillation ablation - sequential or combined? A cost-benefit and risk analysis of primary prevention pulmonary vein ablation.

Heart Rhythm 2016 07 2;13(7):1441-8. Epub 2016 Mar 2.

Arrhythmia Service, University Hospital, Western University, London, Canada.

Background: Recent studies have tested the hypothesis that preventive pulmonary vein isolation (PVI) at time of atrial flutter ablation in patients who have not had atrial fibrillation (AF) will reduce future incidence of AF.

Objective: To model relative procedural costs, risks, and benefits of sequential versus combined ablation strategies.

Methods: The decision model compares a sequential ablation strategy of atrial flutter ablation, followed by future PVI if necessary, with an initial combined flutter and preventive PVI ablation strategy. Assumptions are AF incidence 20% per year, PVI success rate 70%, PVI complication rate 4%, atrial flutter complication rate 1%, and costs $13,056 for PVI and $8,466 for atrial flutter ablation.

Results: The sequential ablation strategy is less expensive, at 1.4 vs 1.6 expected flutter ablation equivalents (FAE) ($11,852 vs $13,545) per patient, and entails less average risk, at 2% vs 4%. A combined ablation strategy is more expensive if the relative cost of PVI is more than 24.6% higher than atrial flutter ablation. A combined ablation strategy has higher total risk if PVI procedural risk is 24.6% more than atrial flutter ablation.

Conclusions: Under base case assumptions of relative cost of PVI to flutter ablation 1.5 and relative risk 4, a sequential ablation approach has less total expected cost and less expected risk. There appears to be no compelling reason to adopt a combined ablation approach into standard practice. Nomograms are presented to allow the reader to assess which strategy is preferred according to local relative costs and risk.
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http://dx.doi.org/10.1016/j.hrthm.2016.02.018DOI Listing
July 2016

Cardiac Sarcoidosis.

Clin Chest Med 2015 Dec 11;36(4):657-68. Epub 2015 Sep 11.

Division of Cardiology, University of Ottawa Heart Institute, 40 Ruskin Street, Ottawa, Ontario K1Y 4 W7, Canada.

Studies suggest clinically manifest cardiac involvement occurs in 5% of patients with pulmonary/systemic sarcoidosis. The principal manifestations of cardiac sarcoidosis (CS) are conduction abnormalities, ventricular arrhythmias, and heart failure. Data indicate that an 20% to 25% of patients with pulmonary/systemic sarcoidosis have asymptomatic (clinically silent) cardiac involvement. An international guideline for the diagnosis and management of CS recommends that patients be screened for cardiac involvement. Most studies suggest a benign prognosis for patients with clinically silent CS. Immunosuppression therapy is advocated for clinically manifest CS. Device therapy, with implantable cardioverter defibrillators, is recommended for some patients.
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http://dx.doi.org/10.1016/j.ccm.2015.08.008DOI Listing
December 2015

Pulmonary Vein Isolation With Incomplete Antral Ablation Lines: Is More Ablation Necessary? Results of a Randomized Trial.

J Cardiovasc Electrophysiol 2016 Mar 18;27(3):298-302. Epub 2015 Dec 18.

Arrhythmia Service, University Hospital, Western University, London, Ontario, Canada.

Background: A full circumferential set of antral lesions is not always required for bidirectional pulmonary vein conduction block. It is unknown whether a partial lesion set that isolates the veins will have clinical success rates similar to a full circumferential lesion set, and if procedural times or procedural risk will be affected.

Methods: We performed a prospective, randomized clinical trial to test the hypothesis that a partial lesion set that isolates the pulmonary veins has comparable clinical success rate and shorter procedure times compared to a strategy of completing the circumferential lesion set once the veins are isolated.

Results: A total of 119 patients were enrolled, 59 randomized to circumferential ablation, and 60 to segmental. Mean age was 58.3 ± 10.1, 77% male. Mean procedure time was 221.0 ± 46.9 minutes in circumferential and 224.7 ± 51.3 in segmental (P = 0.68). Twelve-month freedom from AF recurrence was 61.3% overall, 64.4% in circumferential, and 58.3% in segmental (P = 0.50). Among 25 segmental patients with AF recurrence, 23 underwent second ablation. Among 33 areas of conduction recovery, 23 (70%) occurred in segments ablated at first procedure and 10 (30%) in segments not previously ablated, suggesting reversible conduction block from edema.

Conclusion: No difference in AF recurrence or procedure time is detectable in a sample of 119 patients randomized to segmental or circumferential antral ablation to achieve pulmonary vein isolation. Second ablation procedures confirmed that some antral sites do not require ablation. A segmental approach results in unacceptably high rates of untargeted or recovered antral sites to make this approach feasible.
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http://dx.doi.org/10.1111/jce.12876DOI Listing
March 2016

A detailed description and assessment of outcomes of patients with hospital recorded QTc prolongation.

Am J Cardiol 2015 Apr 15;115(7):907-11. Epub 2015 Jan 15.

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

Corrected QT (QTc) interval prolongation has been shown to be an independent predictor of mortality in many clinical settings and is a common finding in hospitalized patients. The causes and outcomes of patients with extreme QTc interval prolongation during a hospital admission are poorly described. The aim of this study was to prospectively identify patients with automated readings of QTc intervals >550 ms at 1 academic tertiary hospital. One hundred seventy-two patients with dramatic QTc interval prolongation (574 ± 53 ms) were identified (mean age 67.6 ± 15.1 years, 48% women). Most patients had underlying heart disease (60%), predominantly ischemic cardiomyopathy (43%). At lease 1 credible and presumed reversible cause associated with QTc interval prolongation was identified in 98% of patients. The most common culprits were QTc interval-prolonging medications, which were deemed most responsible in 48% of patients, with 25% of these patients taking ≥2 offending drugs. Two patients were diagnosed with congenital long-QT syndrome. Patients with electrocardiograms available before and after hospital admission demonstrated significantly lower preadmission and postdischarge QTc intervals compared with the QTc intervals recorded in the hospital. In conclusion, in-hospital mortality was high in the study population (29%), with only 4% of patients experiencing arrhythmic deaths, all of which were attributed to secondary causes.
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http://dx.doi.org/10.1016/j.amjcard.2015.01.016DOI Listing
April 2015

A bitter pill to swallow: esophageal lesions after PVI may not be what we expected.

J Cardiovasc Electrophysiol 2015 Feb 14;26(2):127-8. Epub 2015 Jan 14.

Arrhythmia Service, University Hospital, Western University, London, Ontario, Canada.

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http://dx.doi.org/10.1111/jce.12594DOI Listing
February 2015

Reduced Uptake of Family Screening in Genotype-Negative Versus Genotype-Positive Long QT Syndrome.

J Genet Couns 2015 Aug 3;24(4):558-64. Epub 2014 Oct 3.

Division of Cardiology, Grey Nuns Hospital, Edmonton, AB, Canada.

The acceptance and yield of family screening in genotype-negative long QT syndrome (LQTS) remains incompletely characterized. In this study of family screening for phenotype-definite Long QT Syndrome (LQTS, Schwartz score ≥3.5), probands at a regional Inherited Cardiac Arrhythmia clinic were reviewed. All LQTS patients were offered education by a qualified genetic counselor, along with materials for family screening including electronic and paper correspondence to provide to family members. Thirty-eight qualifying probands were identified and 20 of these had family members who participated in cascade screening. The acceptance of screening was found to be lower among families without a known pathogenic mutation (33 vs. 77 %, p = 0.02). A total of 52 relatives were screened; fewer relatives were screened per index case when the proband was genotype-negative (1.7 vs. 3.1, p = 0.02). The clinical yield of screening appeared to be similar irrespective of gene testing results (38 vs. 33 %, p = 0.69). Additional efforts to promote family screening among gene-negative long QT families may be warranted.
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http://dx.doi.org/10.1007/s10897-014-9776-6DOI Listing
August 2015