Publications by authors named "Andrew D Krahn"

378 Publications

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

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

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

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

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

Europace 2021 May 5. Epub 2021 May 5.

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

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

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

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

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

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

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

Herzschrittmacherther Elektrophysiol 2021 Apr 21. Epub 2021 Apr 21.

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

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

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

Heart Rhythm 2021 Mar 26. Epub 2021 Mar 26.

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

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

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

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

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

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

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

Use of healthcare claims to validate the Prevention of Arrhythmia Device Infection Trial cardiac implantable electronic device infection risk score.

Europace 2021 Mar 23. Epub 2021 Mar 23.

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

Aim: The Prevention of Arrhythmia Device Infection Trial (PADIT) infection risk score, developed based on a large prospectively collected data set, identified five independent predictors of cardiac implantable electronic device (CIED) infection. We performed an independent validation of the risk score in a data set extracted from U.S. healthcare claims.

Methods And Results: Retrospective identification of index CIED procedures among patients aged ≥18 years with at least one record of a CIED procedure between January 2011 and September 2014 in a U.S health claims database. PADIT risk factors and major CIED infections (with system removal, invasive procedure without system removal, or infection-attributable death) were identified through diagnosis and procedure codes. The data set was randomized by PADIT score into Data Set A (60%) and Data Set B (40%). A frailty model allowing multiple procedures per patient was fit using Data Set A, with PADIT score as the only predictor, excluding patients with prior CIED infection. A data set of 54 042 index procedures among 51 623 patients with 574 infections was extracted. Among patients with no history of prior CIED infection, a 1 unit increase in the PADIT score was associated with a relative 28% increase in infection risk. Prior CIED infection was associated with significant incremental predictive value (HR 5.66, P < 0.0001) after adjusting for PADIT score. A Harrell's C-statistic for the PADIT score and history of prior CIED infection was 0.76.

Conclusion: The PADIT risk score predicts increased CIED infection risk, identifying higher risk patients that could potentially benefit from targeted interventions to reduce the risk of CIED infection. Prior CIED infection confers incremental predictive value to the PADIT score.
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http://dx.doi.org/10.1093/europace/euab028DOI Listing
March 2021

Implantable Cardioverter Defibrillator Lead Survival in Athletic Patients.

Circ Arrhythm Electrophysiol 2021 Mar 16;14(3):e009344. Epub 2021 Mar 16.

Yale University School of Medicine, Yale Center of Analytic Sciences, New Haven, CT (F.L., J.D., C. Brandt, C. Barth).

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http://dx.doi.org/10.1161/CIRCEP.120.009344DOI Listing
March 2021

Sex-Related Differences in Cardiac Channelopathies: Implications for Clinical Practice.

Circulation 2021 Feb 15;143(7):739-752. Epub 2021 Feb 15.

Heart Rhythm Services, Division of Cardiology, Department of Medicine, University of British Columbia, Vancouver, Canada (L.Y., A.D.K.).

Sex-related differences in prevalence, clinical presentation, and outcome of cardiac channelopathies are increasingly recognized, despite their autosomal transmission and hence equal genetic predisposition among sexes. In congenital long-QT syndrome, adult women carry a greater risk for Torsades de pointes and sudden cardiac death than do men. In contrast, Brugada syndrome is observed predominantly in adult men, with a considerably higher risk of arrhythmic sudden cardiac death in adult men than in women. In both conditions, the risk for arrhythmias varies with age. Sex-associated differences appear less evident in other cardiac channelopathies, likely a reflection of their rare(r) occurrence and our limited knowledge. In several cardiac channelopathies, sex-specific predictors of outcome have been identified. Together with genetic and environmental factors, sex hormones contribute to the sex-related disparities in cardiac channelopathies through modulation of the expression and function of cardiac ion channels. Despite these insights, essential knowledge gaps exist in the mechanistic understanding of these differences, warranting further investigation. Precise application of the available knowledge may improve the individualized care of patients with cardiac channelopathies. Promoting the reporting of sex-related phenotype and outcome parameters in clinical and experimental studies and advancing research on cardiac channelopathy animal models should translate into improved patient outcomes. This review provides a critical digest of the current evidence for sex-related differences in cardiac channelopathies and emphasizes their clinical implications and remaining gaps requiring further research.
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http://dx.doi.org/10.1161/CIRCULATIONAHA.120.048250DOI Listing
February 2021

Familial Evaluation in Idiopathic Ventricular Fibrillation: Diagnostic Yield and Significance of J Wave Syndromes.

Circ Arrhythm Electrophysiol 2021 Mar 7;14(3):e009089. Epub 2021 Feb 7.

Cardiovascular Clinical Academic Group, Molecular & Clinical Sciences Rsrch Inst, St. George's, University of London and St. George's University Hospitals NHS Foundation Trust, London, United Kingdom (B.E., C.S., E.R.B.).

[Figure: see text].
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http://dx.doi.org/10.1161/CIRCEP.120.009089DOI Listing
March 2021

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

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

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

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

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

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

Paradoxical impact of socioeconomic factors on outcome of atrial fibrillation in Europe: trends in incidence and mortality from atrial fibrillation.

Eur Heart J 2021 Feb;42(8):847-857

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

Aims: The aim of this study was to understand the changing trends in atrial fibrillation (AF) incidence and mortality across Europe from 1990 to 2017, and how socioeconomic factors and sex differences play a role.

Methods And Results: We performed a temporal analysis of data from the 2017 Global Burden of Disease Database for 20 countries across Europe using Joinpoint regression analysis. Age-adjusted incidence, mortality, and mortality-to-incidence ratios (MIRs) to approximate case fatality rate are presented. Incidence and mortality trends were heterogenous throughout Europe, with Austria, Denmark, and Sweden experiencing peaks in incidence in the middle of the study period. Mortality rates were higher in wealthier countries with the highest being Sweden for both men and women (8.83 and 8.88 per 100 000, respectively) in 2017. MIRs were higher in women in all countries studied, with the disparity increasing the most over time in Germany (43.6% higher in women vs. men in 1990 to 74.5% higher in women in 2017).

Conclusion: AF incidence and mortality across Europe did not show a general trend, but unique patterns for some nations were observed. Higher mortality rates were observed in wealthier countries, potentially secondary to a survivor effect where patients survive long enough to suffer from AF and its complications. Outcomes for women with AF were worse than men, represented by higher MIRs. This suggests that there is widespread healthcare inequality between the sexes across Europe, or that there are biological differences between them in terms of their risk of adverse outcomes from AF.
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http://dx.doi.org/10.1093/eurheartj/ehaa1077DOI Listing
February 2021

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

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

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

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

Abstract: Mutations of SCN5Ahave been identified as the genetic substrate of various inherited arrhythmia syndromes, including long-QT-3 and Brugada syndrome. We recently identified a novel SCN5A variant (C683R) in two genetically unrelated families. The index patients of both families experienced adrenaline-triggered ventricular arrhythmia with cardiac arrest but did not show a specific ECG phenotype, raising the hypothesis that SCN5A-C683R might be a susceptibility variant and the genetic substrate of distinct inherited arrhythmia. We conducted functional cellular studies to characterize the electrophysiological properties of Na 1.5/C683R in order to explore the potential pathogenicity of this novel variant. The C683R variant was engineered by site-directed mutagenesis. Na 1.5/wild type (WT) and Na 1.5/C683R were expressed in tsA201 cells. Electrophysiological characterization of C683R was performed using the whole-cell patch-clamp technique. Adrenergic stimulation was mimicked by exposure to the protein kinase A activator 8-CPT-cAMP. The impact of β-blockers was tested by exposing Na 1.5/WT and Na 1.5/C683R currents to propranolol and nadolol. C683R resulted in a co-association of gain-of-function and loss-of-function properties of Na 1.5. Gain-of-function properties were characterized by a significant increase of the maximal Na 1.5 current density compared with Na 1.5/WT (861 ± 309 vs. 627 ± 489 pA/pF; P < 0.05, n ≥ 9) that was potentiated in Na 1.5/C683R with 8-CPT-cAMP stimulation (869 ± 287 vs. 607 ± 320 pA/pF; P < 0.05, n ≥ 12). C683R also resulted in a significant hyperpolarizing shift in the voltage of steady-state activation (-65.4 ± 3.0 vs. -57.2 ± 4.8 mV; P < 0.001), resulting in an increased window current compared with WT. The loss-of-function effect of Na 1.5/C683R was characterized by significantly increased closed-state inactivation compared with Na 1.5/WT (P < 0.05). C683R is a novel SCN5A variant resulting in a co-association of gain-of-function and loss-of-function properties of the cardiac sodium channel Na 1.5. The phenotype is characterized by adrenaline-triggered ventricular arrhythmias. Electrophysiological properties and clinical manifestations are different from long-QT-3 or Brugada syndrome and might represent a distinct inherited arrhythmia syndrome.
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http://dx.doi.org/10.1113/EP089088DOI Listing
March 2021

Brugada syndrome and reduced right ventricular outflow tract conduction reserve: a final common pathway?

Eur Heart J 2021 Mar;42(11):1073-1081

European Reference Network for Rare and Low Prevalence Complex Diseases of the Heart: ERN GUARD-Heart (ERN GUARDHEART http://guardheart.ern-net.eu).

Brugada syndrome (BrS) was first described as a primary electrical disorder predisposing to the risk of sudden cardiac death and characterized by right precordial lead ST elevation. Early description of right ventricular structural abnormalities and of right ventricular outflow tract (RVOT) conduction delay in BrS patients set the stage for the current controversy over the pathophysiology underlying the syndrome: channelopathy or cardiomyopathy; repolarization or depolarization. This review examines the current understanding of the BrS substrate, its genetic and non-genetic basis, theories of pathophysiology, and the clinical implications thereof. We propose that the final common pathway for BrS could be viewed as a disease of 'reduced RVOT conduction reserve'.
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http://dx.doi.org/10.1093/eurheartj/ehaa1051DOI Listing
March 2021

Post-operative pain following cardiac implantable electronic device implantation: insights from the BRUISE CONTROL trials.

Europace 2020 Dec 28. Epub 2020 Dec 28.

Division of Cardiology, Department of Medicine, University of Calgary, Libin Cardiovascular Institute, Calgary, AB, Canada.

Aims : Post-operative pain following cardiac implantable electronic device (CIED) insertion is associated with patient dissatisfaction, emotional distress, and emergency department visits. We sought to identify factors associated with post-operative pain and develop a prediction score for post-operative pain.

Methods And Results : All patients from the BRUISE CONTROL-1 and 2 trials were included in this analysis. A validated Visual Analogue Scale (VAS) was used to assess the severity of pain related to CIED implant procedures. Patients were asked to grade the most severe post-operative pain, average post-operative pain, and pain on the day of the first post-operative clinic. Multivariable regression analyses were performed to identify predictors of significant post-operative pain and to develop a pain-prediction score. A total of 1308 patients were included. Multivariable regression analysis found that the presence of post-operative clinically significant haematoma {CSH; P value < 0.001; odds ratio (OR) 3.82 [95% confidence interval (CI): 2.37-6.16]}, de novo CIED implantation [P value < 0.001; OR 1.90 (95% CI: 1.47-2.46)], female sex [P value < 0.001; OR 1.61 (95% CI: 1.22-2.12)], younger age [<65 years; P value < 0.001; OR 1.54 (95% CI: 1.14-2.10)], and lower body mass index [<20 kg/m2; P value < 0.05; OR 2.05 (95% CI: 0.98-4.28)] demonstrated strong and independent associations with increased post-operative pain. An 11-point post-operative pain prediction score was developed using the data.

Conclusion : Our study has identified multiple predictors of post-operative pain after CIED insertion. We have developed a prediction score for post-operative pain that can be used to identify individuals at risk of experiencing significant post-operative pain.
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http://dx.doi.org/10.1093/europace/euaa349DOI Listing
December 2020

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

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

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

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

Cardiovascular Care Delivery During the Second Wave of COVID-19 in Canada.

Can J Cardiol 2021 05 9;37(5):790-793. Epub 2020 Dec 9.

Mazankowski Alberta Hearth Institute, University of Alberta, Edmonton, Alberta, Canada.

Hospitals and ambulatory facilities significantly reduced cardiac care delivery in response to the first wave of the COVID-19 pandemic. The deferral of elective cardiovascular procedures led to a marked reduction in health care delivery with a significant impact on optimal cardiovascular care. International and Canadian data have reported dramatically increased wait times for diagnostic tests and cardiovascular procedures, as well as associated increased cardiovascular morbidity and mortality. In the wake of the demonstrated ability to rapidly create critical care and hospital ward capacity, we advocate a different approach during the second and possible subsequent COVID-19 pandemic waves. We suggest an approach, informed by local data and experience, that balances the need for an expected rise in demand for health care resources to ensure appropriate COVID-19 surge capacity with continued delivery of essential cardiovascular care. Incorporating cardiovascular care leaders into pandemic planning and operations will help health care systems minimise cardiac care delivery disruptions while maintaining critical care and hospital ward surge capacity and continuing measures to reduce transmission risk in health care settings. Specific recommendations targeting the main pillars of cardiovascular care are presented: ambulatory, inpatient, procedural, diagnostic, surgical, and rehabilitation.
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http://dx.doi.org/10.1016/j.cjca.2020.11.016DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7836859PMC
May 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

Sudden Cardiac Death Prediction in Arrhythmogenic Right Ventricular Cardiomyopathy: A Multinational Collaboration.

Circ Arrhythm Electrophysiol 2021 Jan 9;14(1):e008509. Epub 2020 Dec 9.

Department of Medicine, Division of Cardiology (J.C.-T., W.W., A.B., C.T., B.M., S.C., J.E.C., D.P.J., H.T., H.C., C.A.J.), Johns Hopkins Hospital, Baltimore, MD.

Background: Arrhythmogenic right ventricular cardiomyopathy (ARVC) is associated with ventricular arrhythmias (VA) and sudden cardiac death (SCD). A model was recently developed to predict incident sustained VA in patients with ARVC. However, since this outcome may overestimate the risk for SCD, we aimed to specifically predict life-threatening VA (LTVA) as a closer surrogate for SCD.

Methods: We assembled a retrospective cohort of definite ARVC cases from 15 centers in North America and Europe. Association of 8 prespecified clinical predictors with LTVA (SCD, aborted SCD, sustained, or implantable cardioverter-defibrillator treated ventricular tachycardia >250 beats per minute) in follow-up was assessed by Cox regression with backward selection. Candidate variables included age, sex, prior sustained VA (≥30s, hemodynamically unstable, or implantable cardioverter-defibrillator treated ventricular tachycardia; or aborted SCD), syncope, 24-hour premature ventricular complexes count, the number of anterior and inferior leads with T-wave inversion, left and right ventricular ejection fraction. The resulting model was internally validated using bootstrapping.

Results: A total of 864 patients with definite ARVC (40±16 years; 53% male) were included. Over 5.75 years (interquartile range, 2.77-10.58) of follow-up, 93 (10.8%) patients experienced LTVA including 15 with SCD/aborted SCD (1.7%). Of the 8 prespecified clinical predictors, only 4 (younger age, male sex, premature ventricular complex count, and number of leads with T-wave inversion) were associated with LTVA. Notably, prior sustained VA did not predict subsequent LTVA (=0.850). A model including only these 4 predictors had an optimism-corrected C-index of 0.74 (95% CI, 0.69-0.80) and calibration slope of 0.95 (95% CI, 0.94-0.98) indicating minimal over-optimism.

Conclusions: LTVA events in patients with ARVC can be predicted by a novel simple prediction model using only 4 clinical predictors. Prior sustained VA and the extent of functional heart disease are not associated with subsequent LTVA events.
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http://dx.doi.org/10.1161/CIRCEP.120.008509DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7834666PMC
January 2021

2020 APHRS/HRS expert consensus statement on the investigation of decedents with sudden unexplained death and patients with sudden cardiac arrest, and of their families.

Heart Rhythm 2021 Jan 19;18(1):e1-e50. Epub 2020 Oct 19.

The First Affiliated Hospital of Nanjing Medical University, Nanjing, China.

This international multidisciplinary document intends to provide clinicians with evidence-based practical patient-centered recommendations for evaluating patients and decedents with (aborted) sudden cardiac arrest and their families. The document includes a framework for the investigation of the family allowing steps to be taken, should an inherited condition be found, to minimize further events in affected relatives. Integral to the process is counseling of the patients and families, not only because of the emotionally charged subject, but because finding (or not finding) the cause of the arrest may influence management of family members. The formation of multidisciplinary teams is essential to provide a complete service to the patients and their families, and the varied expertise of the writing committee was formulated to reflect this need. The document sections were divided up and drafted by the writing committee members according to their expertise. The recommendations represent the consensus opinion of the entire writing committee, graded by Class of Recommendation and Level of Evidence. The recommendations were opened for public comment and reviewed by the relevant scientific and clinical document committees of the Asia Pacific Heart Rhythm Society (APHRS) and the Heart Rhythm Society (HRS); the document underwent external review and endorsement by the partner and collaborating societies. While the recommendations are for optimal care, it is recognized that not all resources will be available to all clinicians. Nevertheless, this document articulates the evaluation that the clinician should aspire to provide for patients with sudden cardiac arrest, decedents with sudden unexplained death, and their families.
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http://dx.doi.org/10.1016/j.hrthm.2020.10.010DOI Listing
January 2021

Atrial arrhythmias and thromboembolic complications in adults post Fontan surgery.

Open Heart 2020 10;7(2)

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

Objective: Patients with Fontan surgery experience late complications in adulthood. We studied the factors associated with the development and maintenance of atrial arrhythmias and thromboembolic complications in an adult population with univentricuar physiology post Fontan surgery.

Methods: Single centre retrospective cohort study of patients ≥18 years of age with Fontan circulation followed at our quaternary care centre for more than 1 year were included. Univariate and multivariate regression models were used where applicable to ascertain clinically significant associations between risk factors and complications.

Results: 93 patients were included (age 30.2±8.8 years, 58% men). 28 (30%) had atriopulmonary Fontan connection, 35 (37.6%) had lateral tunnel Fontan and 29 (31.1%) had extracardiac Fontan pathway. After a mean of 7.27±5.1 years, atrial arrhythmia was noted in 37 patients (39.8%), of which 13 developed had atrial fibrillation (14%). The presence of atrial arrhythmia was associated with the number of prior cardiac surgeries/procedures, increasing age and prior atriopulmonary Fontan operation. Thromboembolic events were present in 31 patients (33%); among them 14 had stroke (45%), 3 had transient ischaemic attack (9.7%), 7 had pulmonary embolism (22.6%) and 5 had atrial thrombus with imaging (16.1%). The presence of thromboembolic events was only associated with age and the presence of cirrhosis in multivariate analysis.

Conclusions: Atrial arrhythmias are common in adults with Fontan circulation at an early age, and are associated with prior surgical history and increasing age. Traditional risk factors may not be associated with atrial arrhythmia or thromboembolism in this cohort.
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http://dx.doi.org/10.1136/openhrt-2019-001224DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7566428PMC
October 2020

Cost-Effectiveness of an Antibacterial Envelope for Cardiac Implantable Electronic Device Infection Prevention in the US Healthcare System From the WRAP-IT Trial.

Circ Arrhythm Electrophysiol 2020 10 11;13(10):e008503. Epub 2020 Sep 11.

Cleveland Clinic, OH (B.L.W., K.G.T.).

Background: In the WRAP-IT trial (Worldwide Randomized Antibiotic Envelope Infection Prevention), adjunctive use of an absorbable antibacterial envelope resulted in a 40% reduction of major cardiac implantable electronic device infection without increased risk of complication in 6983 patients undergoing cardiac implantable electronic device revision, replacement, upgrade, or initial cardiac resynchronization therapy defibrillator implant. There is limited information on the cost-effectiveness of this strategy. As a prespecified objective, we evaluated antibacterial envelope cost-effectiveness compared with standard-of-care infection prevention strategies in the US healthcare system.

Methods: A decision tree model was used to compare costs and outcomes of antibacterial envelope (TYRX) use adjunctive to standard-of-care infection prevention versus standard-of-care alone over a lifelong time horizon. The analysis was performed from an integrated payer-provider network perspective. Infection rates, antibacterial envelope effectiveness, infection treatment costs and patterns, infection-related mortality, and utility estimates were obtained from the WRAP-IT trial. Life expectancy and long-term costs associated with device replacement, follow-up, and healthcare utilization were sourced from the literature. Costs and quality-adjusted life years were discounted at 3%. An upper willingness-to-pay threshold of $150 000 per quality-adjusted life year was used to determine cost-effectiveness, in alignment with the American College of Cardiology/American Heart Association practice guidelines and as supported by the World Health Organization and contemporary literature.

Results: The base case incremental cost-effectiveness ratio of the antibacterial envelope compared with standard-of-care was $112 603/quality-adjusted life year. The incremental cost-effectiveness ratio remained lower than the willingness-to-pay threshold in 74% of iterations in the probabilistic sensitivity analysis and was most sensitive to the following model inputs: infection-related mortality, life expectancy, and infection cost.

Conclusions: The absorbable antibacterial envelope was associated with a cost-effectiveness ratio below contemporary benchmarks in the WRAP-IT patient population, suggesting that the envelope provides value for the US healthcare system by reducing the incidence of cardiac implantable electronic device infection. Registration: URL: https://www.clinicaltrials.gov. Unique identifier: NCT02277990.
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http://dx.doi.org/10.1161/CIRCEP.120.008503DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7566304PMC
October 2020

Guidance for Rebooting Electrophysiology Through the COVID-19 Pandemic From the Heart Rhythm Society and the American Heart Association Electrocardiography and Arrhythmias Committee of the Council on Clinical Cardiology: Endorsed by the American College of Cardiology.

JACC Clin Electrophysiol 2020 08 12;6(8):1053-1066. Epub 2020 Jun 12.

Cooper Medical School of Rowan University, Camden, New Jersey, USA.

Coronavirus disease 2019 (COVID-19) has presented substantial challenges to patient care and impacted health care delivery, including cardiac electrophysiology practice throughout the globe. Based upon the undetermined course and regional variability of the pandemic, there is uncertainty as to how and when to resume and deliver electrophysiology services for arrhythmia patients. This joint document from representatives of the Heart Rhythm Society, American Heart Association, and American College of Cardiology seeks to provide guidance for clinicians and institutions reestablishing safe electrophysiological care. To achieve this aim, we address regional and local COVID-19 disease status, the role of viral screening and serologic testing, return-to-work considerations for exposed or infected health care workers, risk stratification and management strategies based on COVID-19 disease burden, institutional preparedness for resumption of elective procedures, patient preparation and communication, prioritization of procedures, and development of outpatient and periprocedural care pathways.
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http://dx.doi.org/10.1016/j.jacep.2020.06.004DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7291987PMC
August 2020

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

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

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

Background: Genetic variants in calsequestrin-2 () cause an autosomal recessive form of catecholaminergic polymorphic ventricular tachycardia (CPVT), although isolated reports have identified arrhythmic phenotypes among heterozygotes. Improved insight into the inheritance patterns, arrhythmic risks, and molecular mechanisms of -CPVT was sought through an international multicenter collaboration.

Methods: Genotype-phenotype segregation in -CPVT families was assessed, and the impact of genotype on arrhythmic risk was evaluated using Cox regression models. Putative dominant missense variants and the established recessive CASQ2-p.R33Q variant were evaluated using oligomerization assays and their locations mapped to a recent CASQ2 filament structure.

Results: A total of 112 individuals, including 36 CPVT probands (24 homozygotes/compound heterozygotes and 12 heterozygotes) and 76 family members possessing at least 1 presumed pathogenic variant, were identified. Among homozygotes and compound heterozygotes, clinical penetrance was 97.1% and 26 of 34 (76.5%) individuals had experienced a potentially fatal arrhythmic event with a median age of onset of 7 years (95% CI, 6-11). Fifty-one of 66 heterozygous family members had undergone clinical evaluation, and 17 of 51 (33.3%) met diagnostic criteria for CPVT. Relative to heterozygotes, homozygote/compound heterozygote genotype status in probands was associated with a 3.2-fold (95% CI, 1.3-8.0; =0.013) increased hazard of a composite of cardiac syncope, aborted cardiac arrest, and sudden cardiac death, but a 38.8-fold (95% CI, 5.6-269.1; <0.001) increased hazard in genotype-positive family members. In vitro turbidity assays revealed that p.R33Q and all 6 candidate dominant missense variants evaluated exhibited filamentation defects, but only p.R33Q convincingly failed to dimerize. Structural analysis revealed that 3 of these 6 putative dominant negative missense variants localized to an electronegative pocket considered critical for back-to-back binding of dimers.

Conclusions: This international multicenter study of -CPVT redefines its heritability and confirms that pathogenic heterozygous variants may manifest with a CPVT phenotype, indicating a need to clinically screen these individuals. A dominant mode of inheritance appears intrinsic to certain missense variants because of their location and function within the CASQ2 filament structure.
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http://dx.doi.org/10.1161/CIRCULATIONAHA.120.045723DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7484339PMC
September 2020

COVID-19 Pandemic: Global Impact and Potential Implications for Cardiovascular Disease in Canada.

CJC Open 2020 Jul 6;2(4):265-272. Epub 2020 Jun 6.

Heart and Stroke Foundation of Canada, Toronto, Ontario, Canada.

Background: The literature indicates that cardiovascular disease (CVD; including stroke), older age, and availability of health care resources affect COVID-19 case fatality rates (CFRs). The cumulative effect of COVID-19 CFRs in global CVD populations and the extrapolated effect on access to health care services in the CVD population in Canada are not fully known. In this study we explored the relationships of factors that might affect COVID-19 CFRs and estimated the potential indirect effects of COVID-19 on Canadian health care resources.

Methods: Country-level epidemiological data were analyzed to study the correlation, main effect, and interaction between COVID-19 CFRs and: (1) the proportion of the population with CVD; (2) the proportion of the population 65 years of age or older; and (3) the availability of essential health services as defined by the World Health Organization Universal Health Coverage index. For indirect implications on health care resources, estimates of the volume of postponed coronary artery bypass grafting, percutaneous coronary intervention, and valve surgeries in Ontario were calculated.

Results: Positive correlations were found between COVID-19 CFRs and: (1) the proportion of the population with CVD (ρ = 0.40;  = 0.001); (2) the proportion of the population 65 years of age or older (ρ = 0.43;  = 0.0005); and (3) Universal Health Coverage index (ρ = 0.27;  = 0.03). For every 1% increase in the proportion of the population 65 years of age or older or proportion of the population with CVD, the COVID-19 CFR was 9% and 19% higher, respectively. Approximately 1252 procedures would be postponed monthly in Ontario because of current public health measures.

Conclusions: Countries with more prevalent CVD reported higher COVID-19 CFRs. Strain on health care resources is likely in Canada.
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http://dx.doi.org/10.1016/j.cjco.2020.06.003DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7275173PMC
July 2020

Canadian Cardiovascular Society Clinical Practice Update on the Assessment and Management of Syncope.

Can J Cardiol 2020 08 2;36(8):1167-1177. Epub 2020 Jul 2.

Department of Emergency Medicine, Queen's University, Kingston, Ontario, Canada.

Syncope is a symptom that occurs in multiple settings and has a variety of underlying causes, ranging from benign to life threatening. Determining the underlying diagnosis and prognosis can be challenging and often results in an unstructured approach to evaluation, which is ineffective and costly. In this first ever document, the Canadian Cardiovascular Society (CCS) provides a clinical practice update on the assessment and management of syncope. It highlights similarities and differences between the 2017 American College of Cardiology/American Heart Association/Heart Rhythm Society and the 2018 European Society of Cardiology guidelines, draws on new data following a thorough review of medical literature, and takes the best available evidence and clinical experience to provide clinical practice tips. Where appropriate, a focus on a Canadian perspective is emphasized in order to illuminate larger international issues. This document represents the consensus of a Canadian panel comprised of multidisciplinary experts on this topic with a mandate to formulate disease-specific advice. The primary writing panel wrote the document, followed by peer review from the secondary writing panel. The CCS Guidelines Committee reviewed and approved the statement. The practice tips represent the consensus opinion of the primary writing panel authors, endorsed by the CCS. The CCS clinical practice update on the assessment and management of syncope focuses on epidemiology, the initial evaluation including risk stratification and disposition from the emergency department, initial diagnostic work-up, management of vasovagal syncope and orthostatic hypotension, and syncope and driving.
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http://dx.doi.org/10.1016/j.cjca.2019.12.023DOI Listing
August 2020

In-hospital and long-term outcomes among patients with spontaneous coronary artery dissection presenting with ventricular tachycardia/fibrillation.

Heart Rhythm 2020 11 24;17(11):1864-1869. Epub 2020 Jun 24.

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

Background: Spontaneous coronary artery dissection (SCAD) is an important cause of myocardial infarction (MI) in young to middle-age women. Ventricular tachycardia/ventricular fibrillation (VT/VF) may complicate acute SCAD presentations, and the long-term outcomes are unknown.

Objective: The purpose of this study was to report the outcomes of SCAD patients presenting with VT/VF.

Methods: We analyzed our prospective Canadian SCAD registries for patients presenting with VT/VF during index hospitalization. Long-term outcomes including VT/VF and cardiac arrest were collected. Univariate and multivariable analyses were performed to identify predictors of VT/VF at follow-up.

Results: Among 1056 consecutive SCAD patients, 84 (8.0%) presented with VT/VF, and 8 underwent implantable cardioverter-defibrillator (ICD) insertion. Patients with VT/VF during index hospitalization were younger (49.3 vs 52.0 years; P = .019) and were more likely to have ST-elevation MI, lower left ventricular ejection fraction (LVEF), and left main dissection (all P <.001). Initial VT/VF was associated with in-hospital events, including recurrent MI, unplanned revascularization, heart failure, ICD insertion, and in-hospital death (all P <.05). At mean follow-up of 4.8 ± 3.3 years, 8 patients suffered VT/VF (time to event 5.2 ± 6.2 years); 5 of 8 patients had VT/VF on initial SCAD presentation, and 1 of 8 had undergone ICD insertion. Predictors of VT/VF during follow-up included LVEF <50%, LVEF <35%, peripartum SCAD, unplanned revascularization, repeat MI, heart failure, and initial VT/VF. Multivariable analysis showed initial VT/VF (odds ratio [OR] 9.5; 95% confidence interval [CI] 2.0-44; P = .004) and LVEF <50% (OR 12.9; 95% CI 1.5-111; P = .019) were independent predictors of VT/VF at follow-up.

Conclusion: SCAD patients presenting with VT/VF were at greater risk for in-hospital events and recurrent VF/VT at follow-up. Both VT/VF and LVEF <50% were independent predictors of subsequent VT/VF.
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http://dx.doi.org/10.1016/j.hrthm.2020.06.019DOI Listing
November 2020

Changes to the electrocardiogram during exercise in anorexia nervosa.

J Electrocardiol 2020 Jul - Aug;61:99-105. Epub 2020 Jun 10.

Hearts in Rhythm Organization, Division of Cardiology, Department of Medicine, University of British Columbia, 220-1033 Davie St., Vancouver V6E 1M7, B.C., Canada. Electronic address:

Background: Anorexia Nervosa (AN) is an eating disorder characterized by low body weight, distorted body image, and an intense fear of gaining weight. Electrocardiogram (ECG) changes, particularly in the QT interval, have been implicated in AN-associated sudden death but not well defined.

Objectives: To characterize QT interval changes during exercise in anorexia nervosa.

Methods: The QT interval was evaluated in a prospective cohort undergoing structured exercise. Patients from the St. Paul's Hospital Provincial Adult Tertiary Eating Disorders Program underwent a 6-minute modified exercise test protocol. A single lead ECG patch recording device was used to record a Lead I equivalent, due to challenges applying standard ECG monitoring in subjects with low body mass. Heart rate (HR) and QT interval were assessed.

Results: Eighteen eating disorder patients (16 female) completed testing (age 31 ± 12 years, BMI 16.5 ± 3.8 kg/m). Patients were compared to age- and sex-matched healthy controls. HR was similar between patients and controls (baseline: 65 (55-70)bpm vs. 69 (53-73)bpm, p = 0.83; maximum: 110 (94-139) bpm vs. 108 (93-141) bpm, p = 0.96; end recovery: 62 (54-68) bpm vs. 66 (55-75) bpm, p = 0.39). QTc intervals were similar between groups at baseline (381 ± 17 ms vs. 381 ± 46 ms, p = 0.93) and end recovery (397 ± 42 ms vs 398 ± 42 ms, p = 0.91). However, AN patients demonstrated QTc prolongation while controls showed QTc shortening at maximum HR (426 ± 70 ms vs. 345 ± 59 ms, p = 0.001).

Conclusion: Low level exercise HR increases are similar between AN patients and controls, but the QTc interval fails to shorten, which may explain the increased arrhythmic risk in AN.
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http://dx.doi.org/10.1016/j.jelectrocard.2020.06.012DOI Listing
June 2020