Publications by authors named "Martin Gardner"

74 Publications

Short-coupled ventricular fibrillation represents a distinct phenotype among latent causes of unexplained cardiac arrest: a report from the CASPER registry.

Eur Heart J 2021 May 19. Epub 2021 May 19.

Heart Rhythm Services, Department of Medicine, St-Paul's Hospital, University of British Columbia, Vancouver, BC, Canada.

Aims : The term idiopathic ventricular fibrillation (IVF) describes survivors of unexplained cardiac arrest (UCA) without a specific diagnosis after clinical and genetic testing. Previous reports have described a subset of IVF individuals with ventricular arrhythmia initiated by short-coupled trigger premature ventricular contractions (PVCs) for which the term short-coupled ventricular fibrillation (SCVF) has been proposed. The aim of this article is to establish the phenotype and frequency of SCVF in a large cohort of UCA survivors.

Methods And Results : We performed a multicentre study including consecutive UCA survivors from the CASPER registry. Short-coupled ventricular fibrillation was defined as otherwise unexplained ventricular fibrillation initiated by a trigger PVC with a coupling interval of <350 ms. Among 364 UCA survivors, 24/364 (6.6%) met diagnostic criteria for SCVF. The diagnosis of SCVF was obtained in 19/24 (79%) individuals by documented ventricular fibrillation during follow-up. Ventricular arrhythmia was initiated by a mean PVC coupling interval of 274 ± 32 ms. Electrical storm occurred in 21% of SCVF probands but not in any UCA proband (P < 0.001). The median time to recurrent ventricular arrhythmia in SCVF was 31 months. Recurrent ventricular fibrillation resulted in quinidine administration in 12/24 SCVF (50%) with excellent arrhythmia control.

Conclusion : Short-coupled ventricular fibrillation is a distinct primary arrhythmia syndrome accounting for at least 6.6% of UCA. As documentation of ventricular fibrillation onset is necessary for the diagnosis, most cases are diagnosed at the time of recurrent arrhythmia, thus the true prevalence of SCVF remains still unknown. Quinidine is effective in SCVF and should be considered as first-line treatment for patients with recurrent episodes.
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http://dx.doi.org/10.1093/eurheartj/ehab275DOI Listing
May 2021

Variant Reinterpretation in Survivors of Cardiac Arrest With Preserved Ejection Fraction (the Cardiac Arrest Survivors With Preserved Ejection Fraction Registry) by Clinicians and Clinical Commercial Laboratories.

Circ Genom Precis Med 2021 Jun 7;14(3):e003235. Epub 2021 May 7.

Division of Cardiology, Department of Medicine (B.D., K.B., A.D.K., Z.W.M.L.), The University of British Columbia, Vancouver, Canada.

Background: Following an unexplained cardiac arrest, clinical genetic testing is increasingly becoming standard of care. Periodic review of variant classification is required, as reinterpretation can change the diagnosis, prognosis, and management of patients and their relatives.

Methods: This study aimed to develop and validate a standardized algorithm to facilitate clinical application of the 2015 American College of Medical Genetics and Association for Molecular Pathology guidelines for the interpretation of genetic variants. The algorithm was applied to genetic results in the Cardiac Arrest Survivors With Preserved Ejection Fraction Registry, to assess the rate of variant reclassification over time. Variant classifications were then compared with the classifications of 2 commercial laboratories to determine the rate and identify sources of variant interpretation discordance.

Results: Thirty-one percent of participants (40 of 131) had at least 1 genetic variant with a clinically significant reclassification over time. Variants of uncertain significance were more likely to be downgraded (73%) to benign than upgraded to pathogenic (27%; =0.03). For the second part of the study, 50% (70 of 139) of variants had discrepant interpretations (excluding benign variants), provided by at least 1 team.

Conclusions: Periodic review of genetic variant classification is a key component of follow-up care given rapidly changing information in the field. There is potential for clinical care gaps with discrepant variant interpretations, based on the interpretation and application of current guidelines. The development of gene- and disease-specific guidelines and algorithms may provide an opportunity to further standardize variant interpretation reporting in the future. Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT00292032.
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http://dx.doi.org/10.1161/CIRCGEN.120.003235DOI Listing
June 2021

Potential Role of Life Stress in Unexplained Sudden Cardiac Arrest.

CJC Open 2021 Mar 10;3(3):285-291. Epub 2020 Nov 10.

BC Children's Hospital, Vancouver, British Columbia, Canada.

Background: The etiology of sudden cardiac arrest (SCA) in individuals without known cardiovascular heart disease remains elusive in nearly half of all patients after systematic testing. We investigated the relationship between stressful life events and SCA risk in cases of explained and unexplained SCA (USCA) events.

Methods: Individuals who previously experienced SCA were enrolled prospectively and divided into a USCA or explained SCA (ESCA) subgroup dependent on whether a diagnosis was ascribed after SCA. Participants completed either the 1997 Recent Life Changes Questionnaire, Student Stress Scale, or Social Re-adjustment Rating Scale for Non-Adults recalling events during the year preceding their SCA, depending on age at SCA presentation; all measure stress in life change units (LCUs). SCA group scores were compared with an age- and sex-matched control group.

Results: We compared 36 SCA group participants (22 USCA, 14 ESCA, age 47 ± 15 years, age at SCA 40 ± 14 years, 50% male) with 36 control participants (age 47 ± 15 years, 50% male). There was no significant difference in LCU score between the control group and the SCA group (248 ± 181 LCU vs 252 ± 227 LCU; > .05). The ESCA subgroup had significantly lower mean LCU scores than the USCA subgroup (163 ± 183 LCU vs 308 ± 237 LCU;  = .030).

Conclusions: Stressful life events, especially those producing chronic stress, might predispose otherwise healthy individuals to lethal arrhythmias. Further investigation into the role of stress in SCA precipitation is warranted.
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http://dx.doi.org/10.1016/j.cjco.2020.10.016DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7984995PMC
March 2021

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

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

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

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

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

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

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

The effect of revascularization on mortality and risk of ventricular arrhythmia in patients with ischemic cardiomyopathy.

BMC Cardiovasc Disord 2020 10 21;20(1):455. Epub 2020 Oct 21.

Queen Elizabeth II Health Sciences Center, HI Site, 1796 Summer Street, Room 2501D, Halifax, Nova Scotia, Canada.

Background: There is clear evidence that patients with prior myocardial infarction and a reduced ejection fraction benefit from implantation of a cardioverter-defibrillator (ICD). It is unclear whether this benefit is altered by whether or not revascularization is performed prior to ICD implantation.

Methods: This was a retrospective cohort study following patients who underwent ICD implantation from 2002 to 2014. Patients with ischemic cardiomyopathy and either primary or secondary prevention ICDs were selected for inclusion. Using the electronic medical record, cardiac catheterization data, revascularization status (percutaneous coronary intervention or coronary bypass surgery) were recorded. The outcomes were mortality and ventricular arrhythmia.

Results: There were 606 patients included in the analysis. The mean age was 66.3 ± 10.1 years, 11.9% were women, and the mean LVEF was 30.5 ± 12.0, 58.9% had a primary indication for ICD, 82.0% of the cohort had undergone coronary catheterization prior to ICD implantation. In the overall cohort, there were fewer mortality and ventricular arrhythmia events in patients who had undergone prior revascularization. In patients who had an ICD for secondary prevention, revascularization was associated with a decrease in mortality (HR 0.46, 95% CI (0.24, 0.85) p = 0.015), and a trend towards fewer ventricular arrhythmia (HR 0.62, 95% CI (0.38, 1.00) p = 0.051). There was no association between death or ventricular arrhythmia with revascularization in patients with primary prevention ICDs.

Conclusion: Revascularization may be beneficial in preventing recurrent ventricular arrhythmia, and should be considered as adjunctive therapy to ICD implantation to improve cardiovascular outcomes.
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http://dx.doi.org/10.1186/s12872-020-01726-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7576697PMC
October 2020

Prospective Assessment of an Automated Intraprocedural 12-Lead ECG-Based System for Localization of Early Left Ventricular Activation.

Circ Arrhythm Electrophysiol 2020 07 15;13(7):e008262. Epub 2020 Jun 15.

Heart Rhythm Service, Cardiology Division, Department of Medicine, Queen Elizabeth II Health Sciences Centre, Halifax, NS, Canada (S.Z., A.A., J.S.D., I.E., D.C.L., C.J.M., R.P., C.J.G., M.J.G., C.M., R.C., J.L.S.).

Background: To facilitate ablation of ventricular tachycardia (VT), an automated localization system to identify the site of origin of left ventricular activation in real time using the 12-lead ECG was developed. The objective of this study was to prospectively assess its accuracy.

Methods: The automated site of origin localization system consists of 3 steps: (1) localization of ventricular segment based on population templates, (2) population-based localization within a segment, and (3) patient-specific site localization. Localization error was assessed by the distance between the known reference site and the estimated site.

Results: In 19 patients undergoing 21 catheter ablation procedures of scar-related VT, site of origin localization accuracy was estimated using 552 left ventricular endocardial pacing sites pooled together and 25 VT-exit sites identified by contact mapping. For the 25 VT-exit sites, localization error of the population-based localization steps was within 10 mm. Patient-specific site localization achieved accuracy of within 3.5 mm after including up to 11 pacing (training) sites. Using 3 remotes (67.8±17.0 mm from the reference VT-exit site), and then 5 close pacing sites, resulted in localization error of 7.2±4.1 mm for the 25 identified VT-exit sites. In 2 emulated clinical procedure with 2 induced VTs, the site of origin localization system achieved accuracy within 4 mm.

Conclusions: In this prospective validation study, the automated localization system achieved estimated accuracy within 10 mm and could thus provide clinical utility.
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http://dx.doi.org/10.1161/CIRCEP.119.008262DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7375941PMC
July 2020

Mortality Risk Increases With Clustered Ventricular Arrhythmias in Patients With Implantable Cardioverter-Defibrillators.

JACC Clin Electrophysiol 2020 03 29;6(3):327-337. Epub 2020 Jan 29.

Division of Cardiology, Queen Elizabeth II Health Sciences Centre, Halifax, Nova Scotia, Canada.

Objectives: This study sought to examine the adverse prognosis associated with ventricular arrhythmia clusters that falls outside the current electrical storm definition.

Background: Electrical storm is most frequently defined as a cluster of ≥3 episodes of ventricular arrhythmia (VA) in a 24-h period. This definition has been associated with adverse cardiovascular outcomes and mortality, but the effect of lesser and greater clustering of arrhythmias has not been described.

Methods: Among all patients in the Resynchronization in Ambulatory Heart Failure trial, 14,515 implantable cardioverter-defibrillator-detected events with data available were rigorously adjudicated in blinded fashion. Arrhythmia incidence was examined for clustering, defined as 2 or more VA events occurring within 3 months. The prognostic importance of clustering was analyzed by varying the cluster length and number of events used to define a cluster. Mortality rates of groups with clustered arrhythmias were compared to patients with no arrhythmia or with unclustered arrhythmia.

Results: The trial included 1,764 patients, among whom 465 patients had two or more VA episodes within 3 months, whereas 406 had unclustered arrhythmias. Compared to patients with no arrhythmia, patients experiencing unclustered VA had increased risk of death (hazard ratio [HR]: 1.45; 95% confidence interval [CI]: 1.09 to 1.93; p = 0.011), whereas the risk was even higher in patients with clustered arrhythmia (HR: 2.68; 95% CI: 2.13 to 3.36; p < 0.0001). Mortality risk increased with higher VA burden (number of VAs in a cluster) and shorter cluster length. This was observed in all groups tested, including the cluster with the least VA burden in the longest cluster length tested (2 VA episodes occurring within 3 months) (mortality HR: 2.85; 95% CI: 1.95 to 4.17; p < 0.0001). Although clustered arrhythmias terminated with antitachycardia pacing were associated with increased mortality, clusters terminated with implantable cardioverter-defibrillator shocks were associated with still higher mortality risk.

Conclusions: Significant adverse prognostic association of clustered VAs is observable with even 2 VA events within 3 months and increases with higher cluster density.
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http://dx.doi.org/10.1016/j.jacep.2019.11.012DOI Listing
March 2020

The Effect of Shock Burden on Heart Failure and Mortality.

CJC Open 2019 Jul 7;1(4):161-167. Epub 2019 Jun 7.

Department of Medicine, Division of Cardiology, QEII Health Sciences Centre, Halifax, Nova Scotia, Canada.

Background: Prior studies have demonstrated an association between appropriate implantable cardioverter defibrillator (ICD) shocks and mortality in clinical trials. The effect of shock burden on heart failure and mortality has not been previously studied in a large population-based cohort.

Methods: The cohort was derived using a comprehensive prospective ICD registry in the province of Nova Scotia with a mean follow-up of 4 ± 2.3 years. With the use of time-varying analysis, the relationship among shock burden, mortality, and heart failure hospitalization was determined.

Results: A total of 776 patients (mean age of 64.8 years) were included in the study, of whom 37% received appropriate therapy during follow-up. A single ICD shock did not confer an increased mortality risk compared with no therapy (hazard ratio [HR], 1.23; 95% confidence interval [CI], 0.84-1.79; 0.3), but mortality risk was significantly increased with ≥ 2 shocks (HR, 3.23; 95% CI, 2.04-5.09; 0.0001). There was a significant increase in heart failure hospitalization associated with receiving 1 ICD shock (HR, 2.05; 95% CI, 1.46-2.89; 0.0001) or more than 1 ICD shock (HR, 4.36; CI, 2.53-7.52; 0.0001) compared with patients receiving no ICD therapy. Patients who received antitachycardia pacing alone showed no difference in heart failure hospitalization (HR, 0.93; CI, 0.67-1.29; 0.7) and improved survival (HR, 0.69; CI, 0.5-0.96; 0.03) compared with those receiving no ICD therapy.

Conclusion: Ventricular arrhythmia treated with appropriate ICD shocks is associated with an increased risk of heart failure hospitalization, whereas recurrent episodes of ventricular arrhythmia requiring shocks are associated with both higher mortality and higher heart failure hospitalization rates.
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http://dx.doi.org/10.1016/j.cjco.2019.04.003DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7063602PMC
July 2019

Mortality and Heart Failure After Upgrade to Cardiac Resynchronization Therapy.

CJC Open 2019 Mar 6;1(2):93-99. Epub 2019 Mar 6.

Division of Cardiology, Department of Medicine, Queen Elizabeth II Health Centre, Halifax, Nova Scotia, Canada.

Background: Cardiac resynchronization therapy (CRT) is effective in treating advanced heart failure (HF), but data describing benefits and long-term outcomes for upgrades from a preexisting device are limited. This study sought to compare long-term outcomes in de novo CRT implants with those eligible for CRT with a prior device.

Methods: This is a retrospective cohort study using data from a provincial registry (2002-2015). Patients were included if they had mild-moderate HF, left ventricular ejection fraction ≤ 35%, and QRS duration ≥ 130 ms. Patients were classified as de novo CRT or upgraded to CRT from a prior device. Outcomes were mortality and composite mortality and HF hospitalization.

Results: There were 342 patients included in the study. In a multivariate model, patients in the upgraded cohort (n = 233) had a higher 5-year mortality rate (adjusted hazard ratio, 2.86; 95% confidence interval, 1.59-5.15;  = 0.0005) compared with the de novo cohort (n = 109) and higher composite mortality and HF hospitalization (adjusted hazard ratio, 2.60; 95% confidence interval, 1.54-4.37;  = 0.0003).

Conclusions: Implantation of de novo CRTs was associated with lower mortality and HF hospitalization compared with upgraded CRTs from preexisting devices. It is unknown whether these differences are due to the timing of CRT implementation or other clinical factors. Further work in this area may be helpful to determine how to improve outcomes for these patients.
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http://dx.doi.org/10.1016/j.cjco.2019.02.002DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7063653PMC
March 2019

Haptoglobin Phenotype Modifies the Influence of Intensive Glycemic Control on Cardiovascular Outcomes.

J Am Coll Cardiol 2020 02;75(5):512-521

Department of Medicine, Dalhousie University, Halifax, Nova Scotia, Canada; Queen Elizabeth II Health Sciences Centre, Nova Scotia Health Authority, Halifax, Nova Scotia, Canada; Department of Nutrition, Harvard T.H. Chan School of Public Health, Boston, Massachusetts. Electronic address:

Background: Whereas there exists a direct relationship between glycated hemoglobin and cardiovascular disease (CVD), clinical trials targeting glycated hemoglobin to near-normal levels using intensive therapy have failed to prevent CVD and have even increased mortality, making clinical decision making difficult. A common polymorphism at the haptoglobin (Hp) genetic locus is associated with CVD, especially coronary heart disease, in the setting of hyperglycemia.

Objectives: This study sought to determine whether the treatment difference of intensive versus standard glucose-lowering therapy on risk of CVD events in the ACCORD (Action to Control Cardiovascular Risk in Diabetes) study depended on Hp phenotype.

Methods: Hp phenotype was measured within 5,806 non-Hispanic white ACCORD participants using a validated assay. Adjusted hazard ratios (aHR) with 95% confidence intervals (CI) estimated from stratified Cox regression models were used to quantify the association between intensive therapy and incident CVD for the 2 different Hp phenotype groups (Hp2-2, Hp1 carriers).

Results: Compared with standard therapy, intensive therapy was associated with a lower risk of incident coronary heart disease among participants with the Hp2-2 phenotype (n = 2,133; aHR: 0.71; 95% CI: 0.55 to 0.91; p = 0.006), but not among the other 2 phenotypes (Hp1 allele carriers) (n = 3,673; aHR: 0.95; 95% CI: 0.79 to 1.13; p = 0.550). The same pattern was observed for CVD. Conversely, intensive therapy was associated with an increased risk of fatal CVD (aHR: 1.50; 95% CI: 1.00 to 2.25; p = 0.049) and total mortality (aHR: 1.40; 95% CI: 1.08 to 1.81; p = 0.011) among the Hp1 carriers, whereas this risk was not increased in the Hp2-2 phenotype (fatal CVD: aHR: 1.02; 95% CI: 0.59 to 1.77; p = 0.931; total mortality: aHR: 0.98; 95% CI: 0.68 to 1.41; p = 0.908).

Conclusions: Intensive glucose-lowering therapy was effective at preventing incident coronary heart disease and CVD events in ACCORD study participants with the Hp2-2 phenotype but not in Hp1 carriers, who had increased mortality risk from intensive therapy.
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http://dx.doi.org/10.1016/j.jacc.2019.11.051DOI Listing
February 2020

Automated intraprocedural localization of origin of ventricular activation using patient-specific computed tomographic imaging.

Heart Rhythm 2020 04 25;17(4):567-575. Epub 2019 Oct 25.

Cardiology Division, Department of Medicine, Queen Elizabeth II Health Sciences Centre, Halifax, Canada.

Background: To facilitate catheter ablation of ventricular tachycardia (VT), we previously developed an automated method to identify sources of left ventricular (LV) activation in real time using 12-lead electrocardiography (ECG), the accuracy of which depends on acquisition of a complete electroanatomic (EA) map.

Objective: The purpose of this study was to assess the feasibility of using a registered cardiac computed tomogram (CT) rather than an EA map to permit real-time localization and avoid errors introduced by incomplete maps.

Methods: Before LV VT ablation, 10 patients underwent CT imaging and 3-dimensional reconstruction of the cardiac surface to create a triangle mesh surface, which was registered to the EA map during the procedure and imported into custom localization software. The software uses QRS integrals from leads III, V, and V; derives personalized regression coefficients from pacing at ≥5 sites with known locations; and estimates the location of unknown activation sites on the 3-dimensional patient-specific LV endocardial surface. Localization accuracy was quantified for VT exit sites in millimeters by comparing the calculated against the known locations.

Results: The VT exit site was identified for 20 VTs using activation and entrainment mapping, supplemented by pace-mapping at the scar margin. The automated localization software achieved incremental accuracy with additional pacing sites and had a mean localization error of 6.9 ± 5.7 mm for the 20 VTs.

Conclusion: Patient-specific CT geometry is feasible for use in real-time automated localization of ventricular activation and may avoid reliance on a complete EA map.
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http://dx.doi.org/10.1016/j.hrthm.2019.10.025DOI Listing
April 2020

Integrated Management Approach to Atrial Fibrillation Care: A Cost Utility Analysis.

Can J Cardiol 2019 09 23;35(9):1142-1148. Epub 2019 Apr 23.

Department of Medicine, QEII Health Sciences Center, Halifax, Nova Scotia, Canada. Electronic address:

Background: Atrial fibrillation (AF) is a substantial burden on health care. Combined specialist and nurse-based AF clinics are associated with improved outcomes. However, Canadian data on the cost-effectiveness of this integrated management approach to AF care are lacking.

Methods: We evaluated health care costs and outcomes of 413 patients with newly-diagnosed AF in 3 emergency departments in Nova Scotia between January 1, 2011 and January 31, 2014. Using a before-after study design, patients were divided into usual care (228 patients) and intervention (185 patients) groups. The intervention was a nurse-run, physician-supervised AF clinic. Costs and quality-adjusted life years (QALYs) were compared between usual care and intervention. Costs were those incurred because of the clinical outcome, bleeding events, medications, and cardiovascular-related procedures. Probabilistic analysis was conducted to assess uncertainty.

Results: The AF clinic was associated with an average cost reduction of CAD$210.83 and an average improvement in QALY of 0.0007 per patient. The AF clinic was dominant over usual care despite higher operational and medication costs over 1 year. It provided greater cost-saving in approximately 66% of probabilistic analysis simulations and generated more QALYs in approximately 92% of simulations. An incremental cost-effectiveness ratio < $50,000 was found in 68% of simulations.

Conclusions: The present study provides guidance regarding the cost-effectiveness of an integrated management approach compared with usual specialty care of AF in a Canadian setting. We recommend further study be undertaken that prospectively plans for economic evaluation before definitive assessments of cost-effectiveness can be made.
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http://dx.doi.org/10.1016/j.cjca.2019.04.016DOI Listing
September 2019

Ankyrin-B dysfunction predisposes to arrhythmogenic cardiomyopathy and is amenable to therapy.

J Clin Invest 2019 07 2;129(8):3171-3184. Epub 2019 Jul 2.

Division of Cardiology, Department of Medicine, Johns Hopkins University, Baltimore, Maryland, USA.

Arrhythmogenic cardiomyopathy (ACM) is an inherited arrhythmia syndrome characterized by severe structural and electrical cardiac phenotypes, including myocardial fibrofatty replacement and sudden cardiac death. Clinical management of ACM is largely palliative, owing to an absence of therapies that target its underlying pathophysiology, which stems partially from our limited insight into the condition. Following identification of deceased ACM probands possessing ANK2 rare variants and evidence of ankyrin-B loss of function on cardiac tissue analysis, an ANK2 mouse model was found to develop dramatic structural abnormalities reflective of human ACM, including biventricular dilation, reduced ejection fraction, cardiac fibrosis, and premature death. Desmosomal structure and function appeared preserved in diseased human and murine specimens in the presence of markedly abnormal β-catenin expression and patterning, leading to identification of a previously unknown interaction between ankyrin-B and β-catenin. A pharmacological activator of the WNT/β-catenin pathway, SB-216763, successfully prevented and partially reversed the murine ACM phenotypes. Our findings introduce what we believe to be a new pathway for ACM, a role of ankyrin-B in cardiac structure and signaling, a molecular link between ankyrin-B and β-catenin, and evidence for targeted activation of the WNT/β-catenin pathway as a potential treatment for this disease.
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http://dx.doi.org/10.1172/JCI125538DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6668697PMC
July 2019

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

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

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

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

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

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

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

Conclusions: The outcome of SCB challenge was significantly affected by the drug used, with ajmaline more likely to provoke a type 1 Brugada electrocardiographic pattern compared with procainamide. Patients undergoing SCB challenge may have contrasting results depending on the drug used, with potential clinical, psychosocial, and socioeconomic implications.
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http://dx.doi.org/10.1016/j.jacep.2019.01.026DOI Listing
April 2019

The Effect of Cardiac Rehabilitation and a Specialized Clinic on Outcomes of Patients With Atrial Fibrillation.

Can J Cardiol 2019 04 14;35(4):382-388. Epub 2018 Dec 14.

Queen Elizabeth II Health Sciences Centre, Halifax, Nova Scotia, Canada. Electronic address:

Background: Cardiac rehabilitation (CR) intervention programs are currently not part of management in patients with atrial fibrillation (AF). We sought to determine the effect of CR compared with a specialized AF clinic (AFC) and usual care on outcomes in patients with AF.

Methods: This was a single-centre retrospective cohort study that was carried out using 3 databases: the Hearts in Motion database (2010-2014), prospectively collected data in an AFC (2011-2014), and a retrospective chart review for patients in usual care (2009-2012). Three care pathways were compared: (1) CR; (2) AFC; and (3) usual specialist-based care. The main outcome was AF-related emergency department visits and cardiovascular hospitalizations.

Results: Of 566 patients with newly diagnosed AF, 133 (23.5%) patients underwent CR, 197 patients (34.8%) attended the AFC, whereas the remaining 236 (41.7%) were followed in a usual specialist-based care clinic. At 1 year, AF-related emergency department visits and cardiovascular hospitalization rates occurred in 7.5% in the CR group, 16.8% in the AFC group, and 29.2% in usual care. After a propensity matched analysis, usual care was associated with the highest rate of the main outcome (odds ratio, 4.91; 95% confidence interval, 2.09-11.53) compared with CR, as did the AFC compared with CR (odds ratio, 2.75; 95% confidence interval, 1.14-6.6).

Conclusions: Among patients with AF, CR was associated with a lower risk of AF-related outcomes. These findings support further study of the use of CR in the management of these patients to determine the optimal model of care for AF patients.
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http://dx.doi.org/10.1016/j.cjca.2018.12.013DOI Listing
April 2019

Use of Administrative Data to Monitor Cardiac Implantable Electronic Device Complications.

Can J Cardiol 2019 01 13;35(1):100-103. Epub 2018 Nov 13.

Division of Cardiology, QEII Health Sciences Centre, Halifax, Nova Scotia, Canada.

Cardiac implantable electronic devices (CIEDs) are increasingly used in the Canadian population, because of expanding indications and an aging population. Device-related complications are a source of morbidity and mortality. There is currently no comprehensive monitoring strategy of CIED-related complications in Canada. The objective of this study was to determine the utility of administrative data in tracking CIED complications. This was a retrospective observational study in patients with newly implanted pacemakers, pacemaker system revisions, and implantable cardioverter defibrillators (ICDs) from 2011 to 2014. The study was performed at a single academic centre in Nova Scotia. A comprehensive chart review was used as the gold standard for device-related complications. This was compared with the reporting of complications identified in the Canadian Institute for Health Information Discharge Abstract Database and the National Ambulatory Care Reporting System Database (NACRS). Sensitivity and specificity of Canadian Institute for Health Information/NACRS was reported. There were 1327 patients included in the study (742 pacemakers, 585 ICDs). The rate of complications in the pacemaker population was 8.0%; the sensitivity of Discharge Abstract Database/NACRS for detection of these was 83.1%, and specificity 100%. The rate of complications in the ICD population was 12.0%, with a sensitivity of 92.1%, and specificity 100%. Thirty-day mortality was 1.8% in the pacemaker population, and 0.3% in the ICD population. This study provides feasibility for use of administrative data for detection of device-related complications, showing reasonable sensitivity and excellent specificity. Further work to determine generalizability of these data across Canada is required to ensure accurate monitoring of device-related complications.
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http://dx.doi.org/10.1016/j.cjca.2018.10.018DOI Listing
January 2019

Early Repolarization Pattern Inheritance in the Cardiac Arrest Survivors With Preserved Ejection Fraction Registry (CASPER).

JACC Clin Electrophysiol 2018 11 29;4(11):1473-1479. Epub 2018 Aug 29.

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

Objectives: This study explored early repolarization (ER) pattern inheritance between survivors of unexplained cardiac arrest (UCA) and their first-degree relatives.

Background: ER is considered a factor that confers an increased risk of sudden death. A monogenic explanation for ER is seldom evident after cascade screening.

Methods: UCA survivors and their first-degree relatives enrolled in the CASPER (Cardiac Arrest Survivors With Preserved Ejection Fraction Registry) were included in the study. ER was defined and characterized according to accepted criteria. Logistic regression was performed to explore the association between ER status in the UCA survivor and first-degree relative groups based on the presence of an ER pattern in their related family members after adjusting for age, sex, and ethnicity.

Results: A total of 289 patients from 14 Canadian sites were studied (age: 43.0 ± 15.9 years; 148 women), and 945 electrocardiograms were analyzed. Seventy-five patients had the ER pattern. There was a significantly higher prevalence of the ER pattern in UCA survivors who had first-degree relatives with the ER pattern (adjusted odds ratio: 5.79; 95% confidence intervals [CIs]: 1.79 to 18.7). There was also a nonsignificant higher prevalence of the ER pattern in first-degree relatives of UCA survivors with the ER pattern (OR: 2.43; 95% CI: 0.70 to 8.43). The highest prevalence of the ER pattern was seen in first-degree relatives of UCA survivors with ER syndrome (29%).

Conclusions: The ER pattern appeared to be more common among UCA survivors and first-degree relatives whose related family members had similar changes on electrocardiography, which suggested that genetically complex factors contribute to electrocardiographic patterns that predispose to cardiac arrest.
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http://dx.doi.org/10.1016/j.jacep.2018.07.001DOI Listing
November 2018

Role of contact force in ischemic scar-related ventricular tachycardia ablation; optimal force required and impact of left ventricular access route.

J Interv Card Electrophysiol 2018 Dec 26;53(3):323-331. Epub 2018 Jun 26.

Queen Elizabeth II Health Sciences Centre, 1796 Summer street, Room 2501, Halifax, Nova Scotia, B3H 3A7, Canada.

Background: Contact force-sensing technology has become a widely used addition to catheter ablation procedures. Neither the optimal contact force required to achieve adequate lesion formation in the ventricle, nor the impact of left ventricular access route on contact force has been fully clarified.

Patients And Methods: Consecutive patients (n = 24) with ischemic cardiomyopathy who underwent ablation for scar-related ventricular tachycardia were included in the study. All ablations (n = 25) were performed using irrigated contact force-sensing catheters (Smart Touch, Biosense Webster). Effective lesion formation was defined as electrical unexcitability post ablation at sites which were electrically excitable prior to ablation (unipolar pacing at 10 mA, 2 ms pulse width). We explored the contact force which achieved effective lesion formation and the impact of left ventricular access route (retrograde aortic or transseptal) on the contact force achieved in various segments of the left ventricle. Scar zone was defined as bipolar signal amplitude < 0.5 mV.

Results: Among 427 ablation points, effective lesion formation was achieved at 201 points (47.1%). Contact force did not predict effective lesion formation in the overall group. However, within the scar zone, mean contact force ≥ 10 g was significantly associated with effective lesion formation [OR 3.21 (1.43, 7.19) P = 0.005]. In the 12-segment model of the left ventricle, the retrograde approach was associated with higher median contact force in the apical anterior segment (31 vs 19 g; P = 0.045) while transseptal approach had higher median force in the basal inferior segment (25 vs 15 g; P = 0.021). In the 4-segment model, the retrograde approach had higher force in the anterior wall (28 vs 16 g; P = 0.004) while the transseptal approach had higher force in the lateral wall (21 vs 18 g; P = 0.032). There was a trend towards higher force in the inferior wall with the transseptal approach, but this was not statistically significant (20 vs 15 g; P = 0.063).

Conclusions: In patients with ischemic cardiomyopathy, a mean contact force of 10 g or more within the scar zone had the best correlation with electrical unexcitability post ablation in our study. The retrograde aortic approach was associated with better contact force over the anterior wall while use of a transseptal approach had better contact force over the lateral wall.
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http://dx.doi.org/10.1007/s10840-018-0396-1DOI Listing
December 2018

Cost Effectiveness of Ventricular Tachycardia Ablation Versus Escalation of Antiarrhythmic Drug Therapy: The VANISH Trial.

JACC Clin Electrophysiol 2018 05 28;4(5):660-668. Epub 2018 Mar 28.

Department of Medicine, Queen Elizabeth II Health Sciences Centre, Dalhousie University, Halifax, Canada. Electronic address:

Objectives: This analysis uses the data from the randomized controlled trial to assess the cost effectiveness of catheter ablation (n = 132) versus escalated antiarrhythmic therapy (n = 127).

Background: For survivors of myocardial infarction with implantable cardioverter-defibrillator shocks despite antiarrhythmic drugs, the VANISH (Ventricular Tachycardia Ablation Versus Escalated Antiarrhythmic Drug Therapy in Ischemic Heart Disease) trial demonstrated improved clinical outcomes with catheter ablation compared with more aggressive antiarrhythmic pharmacotherapy.

Methods: Health care resource use and quality-of-life data were used to determine the cost effectiveness of catheter ablation. Published references were used to estimate costs (in 2015 Canadian dollars). The analysis was over 3 years, with a 5% discount rate. Adjustment was made for censoring and baseline utilities.

Results: Ablation resulted in greater quality-adjusted life-years (QALYs) than escalated drug therapy did (1.63 vs. 1.49; difference: 0.14; 95% confidence interval [CI]: -0.20 to 0.46) and higher cost ($65,126 vs. $60,269; difference: $4,857; 95% CI: -$19,757 to $27,106); with an incremental cost per QALY gained for ablation versus escalated drug therapy of $34,057 primarily due to the initial costs of ablation, which were partially offset by the costs of subsequent ablations and adverse outcomes in the escalated drug therapy arm. For patients with amiodarone-refractory ventricular tachycardia, ablation dominated escalated drug therapy, with greater QALYs (1.48 vs. 1.26; difference: 0.22; 95% CI: -0.19 to 0.59) and lower costs ($67,614 vs. $68,383; difference: -$769; 95% CI: -$35,330 to $27,092). For those with sotalol-refractory ventricular tachycardia, ablation resulted in similar QALYs (1.90 vs. 1.90; difference: -0.00; 95% CI: -0.59 to 0.62) and higher costs ($60,455 vs. $45,033; difference: $15,422; 95% CI: -$10,968 to $48,555).

Conclusions: For the total trial population, results are suggestive that ablation is cost effective compared with escalation of drug therapy. This result was only manifest for the subgroup of patients whose qualifying arrhythmia occurred despite amiodarone.
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http://dx.doi.org/10.1016/j.jacep.2018.01.007DOI Listing
May 2018

Benefit of Implantable Cardioverter-Defibrillator Generator Replacement in a Primary Prevention Population-Based Cohort.

JACC Clin Electrophysiol 2017 10 31;3(10):1180-1189. Epub 2017 May 31.

Division of Cardiology, QEII Health Sciences Center, Halifax, Nova Scotia, Canada. Electronic address:

Objectives: This study investigated the benefit of an implantable cardioverter-defibrillator (ICD) generator replacement in patients who did not have an ongoing theoretical indication for ICD therapy at time of replacement.

Background: Primary prevention ICD therapy is known to reduce mortality in patients with cardiomyopathy and reduced left ventricular systolic function. The data describing outcomes after generator replacement are limited.

Methods: This was a retrospective cohort study following patients implanted with primary prevention ICD therapy from 2002 until 2015 who subsequently received a generator replacement. Patients with an ongoing theoretical indication for ICD therapy were defined as either left ventricular ejection fraction ≤35% or having had prior appropriate ICD therapy. Outcomes were mortality, appropriate ICD therapy and shock, inappropriate shock, and device and lead complications.

Results: A total of 614 patients were identified; 173 (28.2%) underwent a generator replacement and were followed for a mean of 2.9 years after replacement; 144 (83.2%) had an ongoing theoretical indication. Patients with no ongoing theoretical indication (n = 29, 16.7%) had lower mortality (hazard ratio [HR]: 0.39, 95% confidence interval [CI]: 0.15-1.00; p = 0.0495), appropriate shock rate (HR: 0.29, 95% CI: 0.09 to 0.96; p = 0.04), and appropriate ICD therapy rate (HR: 0.30, 95% CI: 0.12 to 0.77; p = 0.012) when compared with patients with ongoing theoretical indication. In the entire cohort, there were low rates of inappropriate shock (4.0%), device complication (5.1%), and lead complication (2.3%).

Conclusions: In patients with primary prevention ICD therapy who underwent generator replacement, improved left ventricular ejection fraction and lack of prior appropriate ICD therapy at time of replacement were associated with a lower risk of mortality and incident ventricular arrhythmia.
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http://dx.doi.org/10.1016/j.jacep.2017.03.004DOI Listing
October 2017

Effect of coronary revascularization on long-term clinical outcomes in patients with ischemic cardiomyopathy and recurrent ventricular arrhythmia.

Pacing Clin Electrophysiol 2018 07 4;41(7):775-779. Epub 2018 Jun 4.

Queen Elizabeth II Health Sciences Centre, Halifax, NS, Canada.

Background: Patients with ventricular tachycardia (VT) postmyocardial infarction (MI) are a higher risk group with significant morbidity and mortality. We examined the impact of prior coronary revascularization on clinical outcomes in patients with ischemic cardiomyopathy and VT.

Methods: The VANISH trial randomized 259 patients with prior MI and antiarrhythmic drug-refractory VT to receive escalated medical therapy or catheter ablation. Clinical outcomes were compared according to whether patients have undergone prior revascularization procedures. The primary outcome was a composite of death, appropriate implantable cardiac defibrillator (ICD) shock, or VT storm. The secondary outcomes included elements of the primary outcome, hospitalization, and any ventricular arrhythmia.

Results: 190 patients (73%) had prior coronary revascularization. Revascularization group had more men (97% vs 83%; P  =  0.0003) and patients in that group were older (mean age 69.3 ± 7.6 vs 66.7 ± 9.2; P  =  0.04), had more renal insufficiency (22.6% vs 8.7%; P  =  0.01), and were more likely to have an implanted cardiac resynchronization device (23% vs 10%, P  =  0.03) as compared with the nonrevascularized patients. There were no significant differences in baseline medication use. There was a trend toward fewer hospitalizations in the revascularization group (64% vs 77%; P  =  0.07); there were no differences in the individual outcomes of mortality, VT storm, ICD shocks, recurrent MI, or cardiac failure.

Conclusions: In this cohort of patients with an ischemic cause for VT, a history of prior coronary revascularization was not associated with a reduction in ventricular arrhythmia or mortality.
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http://dx.doi.org/10.1111/pace.13375DOI Listing
July 2018

Differentiating Ventricular From Supraventricular Arrhythmias Using the Postpacing Interval After Failed Antitachycardia Pacing.

Circ Arrhythm Electrophysiol 2018 04;11(4):e005921

Heart Rhythm Service, University of British Columbia, Vancouver, Canada (M.T.B., J.G.A., A.D.K.); University of Toronto, Ontario, Canada (N.L.); Queen Elizabeth II Health Sciences Center, Halifax, Nova Scotia, Canada (J.S., R.P., M.G.); Hamilton Health Sciences Center, Ontario, Canada (J.S.H.); Montreal Heart Institute, Quebec, Canada (B.T.); Royal Jubilee Hospital, Victoria, British Columbia, Canada (L.S.); McGill, Montreal, Quebec, Canada (V.E.); University of Ottawa, Ontario, Canada (D.B., P.N.); University of Alberta, Edmonton, Canada (S.S.); University of Western Ontario, London, Ontario, Canada (A.T.).

Background: Implantable cardioverter defibrillator arrhythmia discrimination algorithms often are unable to discriminate ventricular from supraventricular arrhythmias. We sought to evaluate whether the response to antitachycardia pacing (ATP) in patients with an implantable cardioverter defibrillator could further discriminate ventricular from supraventricular arrhythmias in patients receiving ATP.

Methods And Results: All episodes of ventricular or supraventricular tachycardia where ATP was delivered in patients enrolled in RAFT (Cardiac-Resynchronization Therapy for Mild-to-Moderate Heart Failure Trial) were included. RAFT randomized 1798 patients with New York Heart Association class II/III heart failure, left ventricular ejection fraction ≤30%, and QRS duration of ≥120 ms to a implantable cardioverter defibrillator±cardiac resynchronization therapy. The tachycardia cycle lengths (TCLs) before and after the delivery of ATP and the postpacing intervals were assessed. Overall, 10 916 ATP attempts were reviewed for 8150 tachycardia episodes in 924 patients. After excluding tachycardias where ATP terminated the episode or where the specific mechanism of the tachycardia was uncertain, we analyzed 3676 ATP attempts delivered for 2046 tachycardia episodes in 541 patients. A shorter difference between postpacing interval and TCL (PPI-TCL) was more likely to be associated with ventricular tachycardia than with supraventricular tachyarrhythmia (138.1±104.2 versus 277.4±126.9 ms; <0.001). Analysis of the receiver operator curve for the PPI-TCL revealed an area under the curve of 0.803 (<0.001; 95% confidence interval, 0.784-0.822). The majority of tachycardias with a PPI-TCL >360 ms were supraventricular with a PPI-TCL value of ≤360 ms having a sensitivity of 97.4% and specificity of 28.3% for ventricular tachycardia.

Conclusions: The ATP response, specifically the PPI-TCL, can further discriminate ventricular from supraventricular arrhythmias in patients with implantable cardioverter defibrillators when the currently available discriminators fail.

Clinical Trial Registration: URL: https://www.clinicaltrials.gov. Unique identifier: NCT00251251.
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http://dx.doi.org/10.1161/CIRCEP.117.005921DOI Listing
April 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

Ventricular tachycardia ablation in arrhythmogenic right ventricular cardiomyopathy patients with TMEM43 gene mutations.

J Cardiovasc Electrophysiol 2018 01 26;29(1):90-97. Epub 2017 Oct 26.

Heart Rhythm Service, Cardiology Division, QE II Health Sciences Centre, Nova Scotia Health Authority and Dalhousie University, Halifax, NS, Canada.

Introduction: Catheter ablation of VT in patients with arrhythmogenic right ventricular cardiomyopathy (ARVC) is often challenging, frequently requiring multiple or epicardial ablation procedures; TMEM43 gene mutations typically cause aggressive disease. We sought to compare VT ablation outcomes for ARVC patients with and without TMEM43 mutations.

Methods: Patients with prior ablation for ARVC-related VT were reviewed. Demographic, procedural, and follow-up data were reviewed retrospectively. Patients with confirmed TMEM43 gene mutations were compared to those with other known mutations or who had no known mutations.

Results: Thirteen patients (10 male, mean age 49 ± 14 years) underwent 29 ablation procedures (median 2 procedures/patient, range 1-6) with a median of 4 targeted VTs/patient (range 1-9). They were followed for a mean duration of 7.3 ± 4.2 years. Gene mutations included TMEM43 (n = 5), PKP2 (n = 2), DSG2 (n = 2), unidentifiable (n = 4). TMEM patients showed more biventricular involvement compared to non-TMEM patients (80% vs. 12.5%, P = 0.032), more inducible VTs during their ablation procedures (mean VTs/patient: 5.8 ± 3 vs. 2.6 ± 1, P = 0.021). Acute and long-term procedural outcomes did not show a significant difference between the two groups, however TMEM patients had worse composite endpoint of death or transplantation (60% vs. 0, P = 0.035; log-rank P = 0.013).

Conclusions: TMEM43 mutation patients were more likely to have biventricular arrhythmogenic substrate and more inducible VTs at EP study. Despite comparable acute VT ablation outcomes, long-term prognosis is unfavorable.
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http://dx.doi.org/10.1111/jce.13353DOI Listing
January 2018

The influence of sex and age on ventricular arrhythmia in a population-based registry.

Int J Cardiol 2017 Oct 13;244:169-174. Epub 2017 Jun 13.

Department of Medicine, QE, II Health Sciences Centre, Halifax, Canada. Electronic address:

Background: Post-hoc analyses of clinical trials and population-based studies have shown no difference in mortality between men and women, but often show that men are more likely to receive appropriate ICD therapy. We utilized a population-based registry to investigate the interaction of sex and age and the occurrence of ventricular arrhythmia in an ICD population.

Methods And Results: A total of 776 consecutive patients receiving an ICD for primary or secondary prevention in a provincial ICD registry were studied. No significant mortality difference was found between men and women (27.5% versus 23.7%, p=0.39). Overall, men were more likely to receive appropriate ICD therapy compared to women (39.3% versus 26.7%, p=0.006). The hazard ratio for appropriate therapy in men vs. women <60years of age was 3.22, CI 95% (1.56-6.65), p=0.002, and the same comparison in men vs. women over the age of 60 showed no significant difference (HR 1.11, CI 95% [0.74-1.65], p=0.61). This interaction between age and sex remained significant when adjusted for New York Heart Associated Class, ejection fraction, coronary artery disease and indication for ICD (p=0.02).

Conclusions: This study demonstrates that the risk of appropriate ICD therapy increases as women are older, reaching similar risk as men in that age group. Further study of the mechanism of the interaction of age and sex as they modulate the occurrence of ventricular arrhythmia may be warranted.
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http://dx.doi.org/10.1016/j.ijcard.2017.06.041DOI Listing
October 2017

Genetic Testing in the Evaluation of Unexplained Cardiac Arrest: From the CASPER (Cardiac Arrest Survivors With Preserved Ejection Fraction Registry).

Circ Cardiovasc Genet 2017 Jun;10(3)

Background: Unexplained cardiac arrest may be because of an inherited arrhythmia syndrome. The role of genetic testing in cardiac arrest survivors without a definite clinical phenotype is unclear.

Methods And Results: The CASPER (Cardiac Arrest Survivors with Preserved Ejection Fraction Registry) is a large registry of cardiac arrest survivors where initial assessment reveals normal coronary arteries, left ventricular function, and resting ECG. Of 375 cardiac arrest survivors in CASPER from 2006 to 2015, 174 underwent genetic testing. Patients were classified as phenotype-positive (n=72) or phenotype-negative (n=102). Genetic testing was performed at treating physicians' discretion in line with contemporary guidelines and availability. All genetic variants identified from original laboratory reports were reassessed by the investigators in line with modern criteria. Pathogenic variants were identified in 29 (17%) patients (60% channelopathy-associated and 40% cardiomyopathy-associated genes) and 70 variants of unknown significance were identified in 32 (18%) patients. Prior syncope (odds ratio, 4.0; 95% confidence interval, 1.6-9.7) and a family history of sudden death (odds ratio, 3.2; 95% confidence interval, 1.1-9.4) were independently associated with the presence of a pathogenic variant. In phenotype-negative patients, broad multiphenotype genetic testing led to higher yields (21% versus 8%; =0.04) but was associated with more variants of unknown significance (55% versus 5%; <0.01).

Conclusions: Genetic testing identifies a pathogenic variant in a significant proportion of unexplained cardiac arrest survivors. Prior syncope and family history of sudden death are predictors of a positive genetic test. Both arrhythmia and cardiomyopathy genes are implicated. Broad, multiphenotype testing revealed the highest frequency of pathogenic variants in phenotype-negative patients.

Clinical Trial Registration: https://www.clinicaltrials.gov. Unique Identifier: NCT00292032.
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http://dx.doi.org/10.1161/CIRCGENETICS.116.001686DOI Listing
June 2017

Cardiac Resynchronization Therapy Reduces Ventricular Arrhythmias in Primary but Not Secondary Prophylactic Implantable Cardioverter Defibrillator Patients: Insight From the Resynchronization in Ambulatory Heart Failure Trial.

Circ Arrhythm Electrophysiol 2017 Mar;10(3)

From the Department of Medicine, Division of Cardiology, Dalhousie University, Halifax, NS, Canada (J.L.S., R.P., M.J.G.); Department of Medicine (G.A.W.), Cardiovascular Research Methods Centre (E.Y.), and Department of Medicine, Division of Cardiology (D.B., P.B.N.), University of Ottawa Heart Institute, ON, Canada; Department of Medicine, Division of Cardiology, Population Health Research Institute, Hamilton, ON, Canada (J.S.H.); Department of Medicine, Montreal Heart Institute, QC, Canada (B.T.); Department of Medicine, Division of Cardiology, Royal Jubilee Hospital, Victoria, BC, Canada (L.D.S.); Department of Medicine, Division of Cardiology, University of Alberta, Edmonton, Canada (S.S.); Department of Medicine, Division of Cardiology, McGill University Health Centre and Hopital Sacre Coeur de Montreal, Quebec, Canada (V.E.); Department of Medicine, Division of Cardiology, University of Toronto, ON, Canada (P.D.); and Division of Cardiology, Department of Medicine, Western University, London, Canada (A.S.L.T.).

Background: The RAFT (Resynchronization in Ambulatory Heart Failure Trial) demonstrated that cardiac resynchronization therapy (CRT) reduced both mortality and heart failure hospitalizations in patients with functional class II or III heart failure and widened QRS. We examined the influence of CRT on ventricular arrhythmias in patients with primary versus secondary prophylaxis defibrillator indications.

Methods And Results: All ventricular arrhythmias among RAFT study participants were downloaded and adjudicated by 2 blinded reviewers with an overreader for disagreements and committee review for remaining discrepancies. Incidence of ventricular arrhythmias among patients randomized to CRT-D versus implantable cardioverter defibrillator (ICD) were compared within the groups of patients treated for primary prophylaxis and for secondary prophylaxis. Of 1798 enrolled patients, 1764 had data available for adjudication and were included. Of these, 1531 patients were implanted for primary prophylaxis, while 233 patients were implanted for secondary prophylaxis; 884 patients were randomized to ICD and 880 to CRT-D. During 5953.6 patient-years of follow-up, there were 11 278 appropriate ICD detections of ventricular arrhythmias. In the primary prophylaxis group, CRT-D significantly reduced incidence ventricular arrhythmias in comparison to ICD (hazard ratio, 0.86; 95% confidence interval, 0.74-0.99; =0.044). This effect was not seen in the secondary prophylaxis group (hazard ratio, 1.14; 95% confidence interval, 0.82-1.58; =0.45). CRT-D was not associated with significant differences in overall ventricular arrhythmia burden in either group.

Conclusions: CRT reduced the rate of onset of new ventricular arrhythmias detected by ICDs in patients without a history of prior ventricular arrhythmias. This effect was not observed among patients who had prior ventricular arrhythmias.

Clinical Trial Registration: URL: http://www.clinicaltrials.gov. Unique identifier: NCT00251251.
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http://dx.doi.org/10.1161/CIRCEP.116.004875DOI Listing
March 2017

Effect of Aggressive Blood Pressure Control on the Recurrence of Atrial Fibrillation After Catheter Ablation: A Randomized, Open-Label Clinical Trial (SMAC-AF [Substrate Modification With Aggressive Blood Pressure Control]).

Circulation 2017 May 22;135(19):1788-1798. Epub 2017 Feb 22.

From Queen Elizabeth II Health Sciences Center and Dalhousie University, Halifax, Nova Scotia, Canada (R.P., J.L.S., C.G., M.G.); University of Ottawa Heart Institute, Ontario, Canada, (G.A.W.); Population Health Research Institute, Hamilton, Ontario, Canada (J.S.H.); Montreal Heart Institute, Quebec, Canada (J.-C.T., L.R.); Centre Hospitalier de L'Universite de Montreal, Quebec, Canada (I.G.); Centre Hospitalier Universitaire de Sherbrooke, Quebec, Canada (J.-F.R.); University of Western Ontario, London, Canada (L.G., A.S.L.T.); Institut Universitaire de Cardiologie et de Pneumologie de Quebec, Canada (I.N.); Royal Jubilee Hospital, Victoria, British Columbia, Canada (P.N.); Ottawa Heart Institute, Ontario, Canada (D.B.); University Health Network, Toronto, Ontario, Canada (A.H.); Libin Cardiovascular Institute of Alberta, Calgary, Canada (S.B.W.); and St. Michael's Hospital, Toronto, Ontario, Canada (I.M.).

Background: Radiofrequency catheter ablation for atrial fibrillation has become an important therapy for AF; however, recurrence rates remain high. We proposed to determine whether aggressive blood pressure (BP) lowering prevents recurrent atrial fibrillation (AF) after catheter ablation in patients with AF and a high symptom burden.

Methods: We randomly assigned 184 patients with AF and a BP >130/80 mm Hg to aggressive BP (target <120/80 mm Hg) or standard BP (target <140/90 mm Hg) treatment before their scheduled AF catheter ablation. The primary outcome was symptomatic recurrence of AF/atrial tachycardia/atrial flutter lasting >30 seconds, determined 3 months beyond catheter ablation by a blinded end-point evaluation.

Results: The median follow-up was 14 months. At 6 months, the mean systolic BP was 123.2±13.2 mm Hg in the aggressive BP treatment group versus 135.4±15.7 mm Hg (<0.001) in the standard treatment group. The primary outcome occurred in 106 patients, 54 (61.4%) in the aggressive BP treatment group compared with 52 (61.2%) in the standard treatment group (hazard ratio=0.94; 95% confidence interval, 0.65-1.38; =0.763). In the prespecified subgroup analysis of the influence of age, patients ≥61 years of age had a lower primary outcome event rate with aggressive BP (hazard ratio=0.58; 95% confidence interval, 0.34-0.97; =0.013). There was a higher rate of hypotension requiring medication adjustment in the aggressive BP group (26% versus 0%).

Conclusions: In this study, this duration of aggressive BP treatment did not reduce atrial arrhythmia recurrence after catheter ablation for AF but resulted in more hypotension.

Clinical Trial Registration: URL: http://www.clinicaltrials.gov. Unique identifier: NCT00438113.
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http://dx.doi.org/10.1161/CIRCULATIONAHA.116.026230DOI Listing
May 2017

Primary Prevention of Sudden Cardiac Death With Device Therapy in Urban and Rural Populations.

Can J Cardiol 2017 04 17;33(4):437-442. Epub 2017 Jan 17.

QE II Health Sciences Centre, Halifax, Nova Scotia, Canada.

Background: Implantable cardioverter defibrillators (ICDs) have shown benefit in reducing mortality in patients with heart failure, after myocardial infarction, and those with reduced ejection fraction. We sought to explore the use of this therapy in specialized heart function clinics, in rural and urban locations.

Methods: This was a retrospective cohort study performed in 3 specialized heart function clinics in Nova Scotia, 2 of which were in rural locations. All patients with an initial left ventricular ejection fraction ≤ 35% were included from 2006 to 2011. Rates of referral, ICD implantation, and mortality were compared between urban and rural groups.

Results: There were 922 patients included in the study; 636 patients in the urban clinic, 286 in the rural locations. Referral rates were higher in the urban clinic compared with the rural locations (80.4% vs 68.3%; P = 0.024). Refusal rates for referral were higher in the rural locations (13.7% vs 2.1%; P < 0.0001). Higher referral rates were associated with urban location (odds ratio [OR], 1.81; 95% confidence interval [CI], 1.01-3.26; P = 0.047), and younger age (OR, 0.96; 95% CI, 0.93-0.99; P = 0.003); lower referral rates for women was observed (OR, 2.29; 95% CI, 1.13-4.63; P = 0.021). Mortality was significantly associated with older age, lack of referral, presence of comorbidities (renal failure, diabetes, peripheral vascular disease) and a rural location.

Conclusions: Specialized heart function clinics have a high rate of appropriate referral for primary prevention ICDs, but referral rates for this life-saving therapy remain lower in rural jurisdictions. This disparity in access to care is associated with increased mortality and might require particular attention to prevent unnecessary deaths.
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http://dx.doi.org/10.1016/j.cjca.2016.10.020DOI Listing
April 2017

Cardiac Abnormalities in First-Degree Relatives of Unexplained Cardiac Arrest Victims: A Report From the Cardiac Arrest Survivors With Preserved Ejection Fraction Registry.

Circ Arrhythm Electrophysiol 2016 09;9(9)

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Background: Unexplained cardiac arrest (UCA) may be explained by inherited arrhythmia syndromes. The Cardiac Arrest Survivors With Preserved Ejection Fraction Registry prospectively assessed first-degree relatives of UCA or sudden unexplained death victims to screen for cardiac abnormalities.

Methods And Results: Around 398 first-degree family members (186 UCA, 212 sudden unexplained death victims' relatives; mean age, 44±17 years) underwent extensive cardiac workup, including ECG, signal averaged ECG, exercise testing, cardiac imaging, Holter-monitoring, and selective provocative drug testing with epinephrine or procainamide. Genetic testing was performed when a mutation was identified in the UCA survivor or when the diagnostic workup revealed a phenotype suggestive of a specific inherited arrhythmia syndrome. The diagnostic strength was classified as definite, probable, or possible based on previously published definitions. Cardiac abnormalities were detected in 120 of 398 patients (30.2%) with 67 of 398 having a definite or probable diagnosis (17%), including Long-QT syndrome (13%), catecholaminergic polymorphic ventricular tachycardia (4%), arrhythmogenic right ventricular cardiomyopathy (4%), and Brugada syndrome (3%). The detection yield was similar for family members of UCA and sudden unexplained death victims (31% versus 27%; P=0.59). Genetic testing was performed more often in family members of UCA patients (29% versus 20%; P=0.03). Disease-causing mutations were identified in 20 of 398 relatives (5%). The most common pathogenic mutations were RyR2 (2%), SCN5A (1%), and KNCQ1 (0.8%).

Conclusions: Cardiac screening revealed abnormalities in 30% of first-degree relatives of UCA or sudden unexplained death victims, with a clear working diagnosis in 17%. Long-QT, arrhythmogenic right ventricular cardiomyopathy, and catecholaminergic polymorphic ventricular tachycardia were the most common diagnoses. Systematic cascade screening and genetic testing in asymptomatic individuals will lead to preventive lifestyle and medical interventions with potential to prevent sudden cardiac death.

Clinical Trial Registration: URL: http://www.clinicaltrials.gov. Unique identifier: NCT00292032.
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http://dx.doi.org/10.1161/CIRCEP.115.004274DOI Listing
September 2016