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BACKGROUND Empiric anticoagulation is not routinely indicated in patients with cryptogenic stroke without documentation of atrial fibrillation (AF). Therefore, identification of patients at increased risk of AF from this vulnerable group is vital. OBJECTIVES To identify electrocardiographic (ECG) predictors of AF in patients with cryptogenic stroke or transient ischemic attack (TIA) undergoing insertion of an implantable cardiac monitor (ICM). METHODS In this single-center study, 48 patients with cryptogenic stroke or TIA had an ICM implanted for detection of AF between January 2013 and September 2019. Patients with and without AF were compared in terms of p-wave duration and a novel index (MVP score). RESULTS During a mean follow-up of 16±14 months, AF was detected in 7 patients (15%). Diagnosis of AF was made after a mean of 10 ± 14 months, with time to first AF detection ranging between 1 and 40 months. Patients with AF had a longer p-wave duration (136±9 ms vs 116±10 ms; p = 0.0001) and a higher MVP score (4.5±1.2 vs 2.0±0.9, p = 0.0001) than those without AF. Advanced interatrial block was observed in 43% of patients with ICM evidence of AF and 0% of those without AF (p = 0.002). Age, LA size or LVEF were not predictors of AF. CONCLUSION An increased p-wave duration, advanced interatrial block and high MVP score are associated with AF occurrence in patients with cryptogenic stroke. Identifying patients with these markers may be helpful as they may benefit from more exhaustive and prolonged monitoring. This article is protected by copyright. All rights reserved.

Background The conduction delay and block that compose the critical isthmus of macroreentrant ventricular tachycardia (VT) is partly “functional” in that they only occur at faster cycle lengths. Close-coupled pacing stresses the myocardium's conduction capacity and may reveal late potentials (LPs) and fractionation. Interest has emerged in targeting this functional substrate. Objective The purpose of this study was to assess the feasibility and efficacy of a functional substrate VT ablation strategy. Methods Patients with scar-related VT undergoing their first ablation were recruited. A closely coupled extrastimulus (ventricular effective refractory period + 30 ms) was delivered at the right ventricular apex while mapping with a high-density catheter. Sites of functional impaired conduction exhibited increased electrogram duration due to LPs/fractionation. The time to last deflection was annotated on an electroanatomic map, readily identifying ablation targets. Results A total of 40 patients were recruited (34 [85%] ischemic). Median procedure duration was 330 minutes (interquartile range [IQR] 300–369), and ablation time was 49.4 minutes (IQR 33.8–48.3). Median functional substrate area was 41.9 cm2 (IQR 22.1–73.9). It was similarly distributed across bipolar voltage zones. Noninducibility was achieved in 34 of 40 patients (85%). Median follow-up was 711 days (IQR 255.5–972.8), during which 35 of 39 patients (89.7%) did not have VT recurrence, and 3 of 39 (7.5%) died. Antiarrhythmic drugs were continued in 53.8% (21/39). Conclusion Functional substrate ablation resulted in high rates of noninducibility and freedom from VT. Mapping times were increased considerably. Our findings add to the encouraging trend reported by related techniques. Randomized multicenter trials are warranted to assess this next phase of VT ablation.

The presence of carotid arterial plaque by ultrasound enhances cardiovascular risk stratification beyond traditional risk factors. However, plaque quantification techniques require further outcomes-based investigation. The purpose of this study was to evaluate the utility of a focused carotid ultrasound protocol and novel plaque grading system developed by the American Society of Echocardiography (ASE). A retrospective analysis of 514 outpatients who were referred for coronary angiography between 2011 and 2014 was performed using a province-sponsored health database. All participants prospectively received a focused carotid ultrasound. Maximum plaque height (MPH) of arterial carotid plaque was quantified, using the Grade II–III plaque definition of MPH ≥ 1.5 mm for stratification, according to recent ASE recommendations. Participants were followed for 1.33–5.11 years (average follow-up = 3.60 ± 1.65 years) to identify the occurrence of cardiovascular events. Major events (death, myocardial infarction [MI], stroke, and transient ischemic attack [TIA]) were correlated to MPH. Participants with MPH ≥ 1.5 mm were more likely to experience stable angina, coronary artery bypass grafting, and stress testing at both 1-year and total follow-up. After adjusting for cardiac risk factors, increased MPH was shown to be predictive for TIA (odds ratio [OR] = 1.33, 95% confidence interval (CI) = 1.01–1.75); p = 0.04), whereas the odds of non-ST-elevation MI (OR = 1.55, 95% CI = 0.99–2.43; p = 0.06) approached significance. Using Kaplan–Meier survival analysis, MPH ≥ 1.5 mm demonstrated good separation for the composite outcome of death, MI, stroke, and TIA over total follow-up (p = 0.02). This rapid, office-based quantification of MPH in carotid ultrasound may serve as a stratification tool for predicting major cardiovascular events.

Background Drivers at risk of sudden incapacitation from syncope pose a potential threat to themselves and to society. The purpose of this systematic review is to synthesize the risk of motor vehicle collisions (MVCs) for patients with a history of syncope. Methods We systematically searched Medline (1946-2019) as well as Cinahl, Embase, Psychinfo, and the Transportation Research Information Documentation (1806-2017) for articles on MVCs and drivers with vasovagal syncope (VVS), arrhythmic syncope, or syncope not yet diagnosed (NYD). Quality ratings were assigned by team consensus. Results Eleven studies of moderate quality were included (n = 42,972). Compared with the general populations of Canada, the United States, and the United Kingdom (0.49%-2.29% per driver-year), the prospective MVC risk was lower for VVS (0.0%-0.31% per driver-year; 3 studies; n = 782) and higher for arrhythmic syncope (1.9%-3.4% per driver-year; 2 studies; n = 730). The results were more variable for syncope NYD (0.0%-6.9% per driver-year prospectively; 6 studies; n = 41,460). Patients with syncope NYD had an almost 2-fold increased MVC risk in the largest study, although the smaller studies showed contradictory findings. Conclusions VVS patients appear to be at very low risk for MVCs, supporting current guidelines which do not recommend driving suspension for these patients in most cases. Although the data for other forms of syncope are too limited for definitive conclusions and must be improved, arrhythmic syncope appears to be associated with nontrivial risk.

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. Résumé: Contexte: La Hearts in Rhythm Organization (HiRO) est une équipe d’experts canadiens en matière de rythmes cardiaques et de cardiomyopathies héréditaires, de conseillers en génétique, d’infirmières, de chercheurs, de patients et de familles qui se consacrent à la détection des arythmies et des cardiomyopathies héréditaires, à la mise en place des meilleures thérapies et à la protection contre la tragédie que représente une mort subite d’origine cardiaque. Méthodes: Récemment, les registres existants relatifs à des maladies spécifiques ont été fusionnés en un registre national élargi de l’HiRO, créant ainsi un ensemble de données commun unique à destination des patients et leurs familles, atteints de maladies héréditaires, qui sont à risque de mort subite au Canada. Les patients admissibles sont invités à s’associer au registre et à la biobanque facultative regroupant 20 cliniques spécialisées en cardiogénétique au Canada. Résultats: Actuellement, 4 700 participants sont inscrits au registre national de l’HiRO, avec une moyenne de 593 participants inscrits chaque année au cours des cinq dernières années. La capacité à favoriser l’application des connaissances issues de la recherche fait partie de la structure organisationnelle de l’HiRO, avec trois groupes de travail supplémentaires (comité des soins cliniques de l’HiRO, comité des communautés cctives de l’HiRO et comité du symposium annuel de l’HiRO), soutenant les objectifs et les priorités actuels de l’organisation tels qu’ils ont été fixés en partenariat avec les patients. Conclusion: Le registre national de l’HiRO vise à devenir une plateforme de recherche intégrée au sein de laquelle les chercheurs peuvent exposer des questions de recherche inédites permettant de mieux comprendre, détecter et soigner les personnes atteintes de troubles du rythme cardiaque et de cardiomyopathie héréditaires et, à terme, de prévenir la mort subite d’origine cardiaque.

Aims Genetic testing is recommended in specific inherited heart diseases but its role remains unclear and it is not currently recommended in unexplained cardiac arrest (UCA). We sought to assess the yield and clinical utility of genetic testing in UCA using whole-exome sequencing (WES). Methods and results Survivors of UCA requiring external defibrillation were included from the Cardiac Arrest Survivor with Preserved Ejection fraction Registry. Whole-exome sequencing was performed, followed by assessment of rare variants in previously reported cardiovascular disease genes. A total of 228 UCA survivors (mean age at arrest 39 ± 13 years) were included. The majority were males (66%) and of European ancestry (81%). Following advanced clinical testing at baseline, the likely aetiology of cardiac arrest was determined in 21/228 (9%) cases. Whole-exome sequencing identified a pathogenic or likely pathogenic (P/LP) variant in 23/228 (10%) of UCA survivors overall, increasing the proportion of ‘explained’ cases from 9% only following phenotyping to 18% when combining phenotyping with WES. Notably, 13 (57%) of the 23 P/LP variants identified were located in genes associated with cardiomyopathy, in the absence of a diagnosis of cardiomyopathy at the time of arrest. Conclusions Genetic testing identifies a disease-causing variant in 10% of apparent UCA survivors. The majority of disease-causing variants was located in cardiomyopathy-associated genes, highlighting the arrhythmogenic potential of such variants in the absence of an overt cardiomyopathy diagnosis. The present study supports the use of genetic testing including assessment of arrhythmia and cardiomyopathy genes in survivors of UCA.

Lyme disease is the most reported tick-borne illness in North America. Lyme carditis (LC) is an early-disseminated manifestation of Lyme disease, most commonly presenting as symptomatic high-degree atrioventricular block (AVB) which resolves with appropriate antibiotic therapy. However, long-term outcomes of treated LC have not previously been described. We present a series of 7 patients (median 28 years, 6 male) with serologically confirmed LC treated with a standard protocol developed at our center including antibiotics and pre-discharge stress test to assess AV node stability. At a mean follow-up of 20.8 months, all patients were asymptomatic, had resumed normal activities, and were free of conduction abnormalities. None required permanent pacing. Our study supports avoidance of permanent pacing for LC if conduction is stable at discharge.

Research teams developing biobanks and/or genomic databases must develop policies for the disclosure and reporting of potentially actionable genomic results to research participants. Currently, a broad range of approaches to the return of results exist, with some studies opting for non-disclosure of research results while others follow clinical guidelines for the return of potentially actionable findings from sequencing. In this review, we describe current practices and highlight decisions a research team must make when designing a return of results policy, from informed consent to disclosure practices and clinical validation options. The unique challenges of returning incidental findings in cardiac genes, including reduced penetrance and the lack of clinical screening standards for phenotype-negative individuals are discussed. Lastly, the National Hearts in Rhythm Organization (HiRO) Registry approach is described to provide a rationale for the selective return of field-specific variants to those participating in disease-specific research. Our goal is to provide researchers with a resource when developing a return of results policy tailored for their research program, based on unique factors related to study design, research team composition and availability of clinical resources.

An 83 year old lady was highly symptomatic from paroxysmal Atrial Fibrillation (AF) despite numerous antiarrhythmic and rate-limiting medications. Given her preserved left ventricular function, a pace and ablate strategy was pursued. Ablation of the AV node proved challenging requiring 2 procedures with apparently stable AV block and regular escape at 40bpm after the first sitting. Persistent Right Bundle Branch Block (RBBB) was created prior to AV node block at the first sitting. Two irrigated-tip ablation catheters (Coolflex, medium curve, St Jude’s Medical, MN, USA) were placed on either side of the interventricular septum but with the intention to ablate the AV node from the left. Identification of the His bundle from the left proved difficult as the patient was now in AF. Instead the left bundle was targeted and complete AV block achieved by combined Right Bundle Branch (RBB) and Left Bundle Branch (LBB) ablation.

Objectives: This study sought to determine the nature of quinidine use and accessibility in a national network of inherited arrhythmia clinics.Background: Quinidine is an antiarrhythmic med...

As cardiovascular implantable electronic devices (CIEDs) are increasingly indicated in older patients, and the burden of cancer is rising with the aging population, the management of patients with CIEDs who require radiotherapy (RT) is a timely concern. The objective of the study was to evaluate the management of, and malfunctions in, patients with CIEDs undergoing RT. A retrospective study of patients with CIEDs receiving RT at Kingston Health Sciences Center from March 2007–April 2018 was conducted. Data on demographics, RT, devices, and management were compared for the primary outcome of device malfunction. Of the 189 patients with CIEDs receiving a total of 297 courses of RT, 4 patients (2.1%) experienced device malfunctions. Higher beam energy was associated with a malfunction (p

Atrial fibrillation (AF) is a risk factor for ischemic stroke and reported to be associated with severe obstructive sleep apnea (OSA). The aim of this study was to determine the occurrence of newly detected AF in patients with severe OSA and no previous history of AF. Prospective observational study included patients with severe OSA (Apnea-Hypopnea Index [AHI] ≥ 30) and no history of AF. Primary outcome was detection of AF lasting ≥10 seconds. Patients were subjected to 2 24-hour Holter monitors, and if no AF was detected, implanted with a Medtronic Reveal XT implantable loop recorder. Follow-up was done every 6 months for a total of 3years. Implantable loop recorder was explanted if the primary outcome was detected (AF) or the battery was exhausted. Of the 31 patients enrolled, 6 withdrew participation in the study before implantation. Mean age was 57 ± 10years, mean body mass index was 35 ± 6; 52% male patients. Hypertension 56% and coronary artery disease 24%. Mean AHI was 55 ± 18. AF was detected in 5 patients (20%). AF mean duration was 4.8hours (range 20 seconds to 15.3 hours). Mean time to diagnosis was 11 ± 7 months. Male gender was predictive for AF detection (p = 0.04). Continuous positive airway pressure therapy was used by 96% of patients with 68% total adherence. Mean follow-up was 27 months. In conclusion, extended cardiac monitoring of patients with severe OSA may facilitate the identification of newly detected AF.

Background The novel SARS-CoV-2 (COVID-19) pandemic has dramatically altered the delivery of healthcare services, resulting in significant referral pattern changes, delayed presentations, and procedural delays. Our objective was to determine the effect of the COVID-19 pandemic on all-cause mortality in patients awaiting commonly performed cardiac procedures. Methods Clinical and administrative data sets were linked to identify all adults referred for: (1) percutaneous coronary intervention; (2) coronary artery bypass grafting; (3) valve surgery; and (4) transcatheter aortic valve implantation, from January 2014 to September 2020 in Ontario, Canada. Piece-wise regression models were used to determine the effect of the COVID-19 pandemic on referrals and procedural volume. Multivariable Cox proportional hazards models were used to determine the effect of the pandemic on waitlist mortality for the 4 procedures. Results We included 584,341 patients who were first-time referrals for 1 of the 4 procedures, of whom 37,718 (6.4%) were referred during the pandemic. The pandemic period was associated with a significant decline in the number of referrals and procedures completed compared with the prepandemic period. Referral during the pandemic period was a significant predictor for increased all-cause mortality for the percutaneous coronary intervention (hazard ratio, 1.83; 95% confidence interval, 1.47-2.27) and coronary artery bypass grafting (hazard ratio, 1.96; 95% confidence interval, 1.28-3.01), but not for surgical valve or transcatheter aortic valve implantation referrals. Procedural wait times were shorter during the pandemic period compared with the prepandemic period. Conclusions There was a significant decrease in referrals and procedures completed for cardiac procedures during the pandemic period. Referral during the pandemic was associated with increased all-cause mortality while awaiting coronary revascularization.

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%; P =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.

BACKGROUND Lyme disease (LD) is a tick-born bacterial infection caused by Borrelia burgdorferi. Lyme carditis (LC) is an early-disseminated manifestation of LD, commonly manifesting as high-degree atrioventricular block (AVB) that fluctuates rapidly over minutes to days. Most conduction abnormalities caused by LC resolves with appropriate antibiotic therapy. However, the long-term outcomes of treated LC are not known. In this case series, we describe and characterize the long-term outcomes of patients treated with LC. METHODS AND RESULTS Prospective study of patients with serologically-confirmed LC. All were treated with the standard protocol designed at our center including 10 days of intravenous ceftriaxone followed by oral antibiotics for a total course of 3 weeks. All patients performed a stress test at discharge with 1:1 AV conduction above 120 bpm. Seven patients (mean age 31.3 years, 86% male) with LC presented with second-degree type I/II or third-degree AVB to our center. Presenting symptoms included malaise (71%), presyncope (43%), syncope (29%), palpitations (57%), and dyspnea (43%). 2 patients required temporary pacing for symptomatic bradycardia. Mean follow-up was 20.8 months, at which time all patients were asymptomatic and resumed usual physical activities. All were in sinus rhythm without any repolarization abnormalities. None required permanent pacing. A summary of short- and long-term outcomes is shown in Table 1. The progression of atrioventricular block at admission, discharge, and long-term follow-up is shown in Figure 1. CONCLUSION To our knowledge, this is the first prospective study characterizing long-term LC follow-up. All patients in this study were asymptomatic, in sinus rhythm, and had no conduction abnormalities in long-term follow-up. Given the lack of literature on long-term outcomes of LC, further prospective studies are necessary to develop evidence-based guidelines.

BACKGROUND Following an unexplained cardiac arrest, patients and family members typically undergo a comprehensive series of investigations to identify the underlying cause of arrest, with a diagnosis identified in more than half of cardiac arrest survivors. However, the long-term arrhythmic outcomes among cardiac arrest survivors remains unclear. METHODS AND RESULTS The Cardiac Arrest Survivors with Preserved Ejection Fraction Registry (CASPER) prospectively enrolls cardiac arrest survivors and their first-degree relatives (FDR) across 16 Canadian centers. Patient demographics, cardiac investigations, working diagnoses, and follow-up events are recorded. Those with a history of significant coronary artery disease or manifest cause of cardiac arrest are excluded. Arrhythmic events, including implantable cardioverter-defibrillator (ICD) shock or anti-tachycardia pacing (ATP) are recorded. Patients with at least one follow-up visit were included. Hazard ratios for arrhythmic events were calculated using Cox proportional hazards models. 741 patients were enrolled, with a median age of 42 years (interquartile range [IQR] 29-53), 56% being male, and mostly Caucasian (82%). Patients included cardiac arrest suvivors/probands (n=480, 66%) and first-degree relatives (n=243, 34%). In addition to baseline investigations, patients undertook signal-averaged ECG (56%), exercise testing (70%), extended monitoring (50%), cardiac MRI (62%), and provocative testing with procainamide (39%), adrenaline (31%) or an electrophysiologic study (14%). After excluding 18 patients with ongoing diagnosis adjudication, the working diagnoses of probands and FDRs are reported in the Table. Working diagnoses among probands were divided into three categories, including unexplained/idiopathic (after comprehensive investigations, n=351), structural/cardiomyopathy (including arrhythmogenic right ventricular cardiomyopathy and others, n=64), and electrical/channelopathy (including Long QT Syndrome, Brugada Syndrome, and others, n=65). During a median follow-up of 3.3 years (IQR 1.7-5.9), 69 patients (9%) suffered an ICD shock or ATP with a median time-to-event of 1.0 years (IQR 0.5-2.8). Probands had a significantly higher rate of events (hazard ratio [HR] 16.9, 95% confidence interval [CI] 4.1-69.0, p CONCLUSION In a cohort of unexplained cardiac arrest survivors and first-degree relatives, probands had a significant rate of recurrent events. Probands with structural/cardiomyopathy diagnoses had twice the risk of arrhythmia recurrence. Patients with structural diagnoses may be more likely to have arrhythmic events in follow-up, potentially due to a progressive disease process compared to other diagnoses.

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 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.

Background The risk of typical atrial flutter (AFL) is increased by factors that increase right atrial (RA) size or cause scarring to reduce conduction velocity. These characteristics ensure the macro re-entrant wave front does not meet its refractory tail. The time taken to traverse the circuit would take account of both of these characteristics (being equal to distance divided by velocity), and may provide a superior marker of propensity to develop AFL. Purpose To investigate right atrial collision time (RACT) as a marker of typical AFL. Methods This single centre, prospective study recruited consecutive typical AFL ablation cases that were in sinus rhythm. Controls were consecutive cases other than atrial fibrillation and >50 years of age. Exclusion criteria for both groups were a prior ablation in the RA and class I and III antiarrhythmics. While pacing the coronary sinus ostium at 600 ms, a local activation time map was created to locate the latest collision point on the anterolateral wall, excluding the RA appendage (Figure 1). This RACT approximates half a revolution. Results The AFL group's (n=34) mean RACT was 132.5±15.06 vs 98.7±12.23ms in the controls (n=40) (p Conclusion RACT is a novel and promising marker of propensity for typical AFL. The ability to predict AFL would be of significant clinical value given the risk of stroke and frequent need for ablation. Funding Acknowledgement Type of funding source: None

The presence of carotid arterial plaque by ultrasound enhances cardiovascular risk stratification beyond traditional risk factors. However, plaque quantification techniques require further outcomes-based investigation. The purpose of this study was to evaluate the utility of a focused carotid ultrasound protocol and novel plaque grading system developed by the American Society of Echocardiography (ASE). A retrospective analysis of 514 outpatients who were referred for coronary angiography between 2011 and 2014 was performed using a province-sponsored health database. All participants prospectively received a focused carotid ultrasound. Maximum plaque height (MPH) of arterial carotid plaque was quantified, using the Grade II-III plaque definition of MPH ≥ 1.5 mm for stratification, according to recent ASE recommendations. Participants were followed for 1.33-5.11 years (average follow-up = 3.60 ± 1.65 years) to identify the occurrence of cardiovascular events. Major events (death, myocardial infarction [MI], stroke, and transient ischemic attack [TIA]) were correlated to MPH. Participants with MPH ≥ 1.5 mm were more likely to experience stable angina, coronary artery bypass grafting, and stress testing at both 1-year and total follow-up. After adjusting for cardiac risk factors, increased MPH was shown to be predictive for TIA (odds ratio [OR] = 1.33, 95% confidence interval (CI) = 1.01-1.75); p = 0.04), whereas the odds of non-ST-elevation MI (OR = 1.55, 95% CI = 0.99-2.43; p = 0.06) approached significance. Using Kaplan-Meier survival analysis, MPH ≥ 1.5 mm demonstrated good separation for the composite outcome of death, MI, stroke, and TIA over total follow-up (p = 0.02). This rapid, office-based quantification of MPH in carotid ultrasound may serve as a stratification tool for predicting major cardiovascular events.

Background: There is limited data on the safety and efficacy of a novel high-definition mapping catheter with 16 equidistant electrodes (Advisor HD Grid). We describe procedural details for the treatment of complex atrial arrhythmias and associated outcomes using this novel catheter design. Methods and Results: The HD Grid was employed for patients with clinically relevant arrhythmia using the EnSite Precision™ electroanatomic mapping system. AVRT and typical flutter cases were excluded. Major procedural complications were defined as bleeding, stroke or TIA, sepsis, and death from any cause, whereas minor complications were defined as no changes to the length of hospital stay or to the expected management of the patient. Recurrence was defined as sustained tachycardia after 3 months post-procedure. Consecutive patients attending for the treatment of paroxysmal atrial fibrillation (66), persistent atrial fibrillation (38), atrial tachycardia (29), and atypical flutter (18) were included, resulting in a final inclusion of 142 patients and 151 procedures. Eighty-four patients (55.3%) received general anesthetic and intracardiac echocardiography was used in 23 (15.1%). Long term follow-up was available in 150/151 procedures, mean 185.2±134.3 days; 32 patients (21.3%) documented recurrence. Three (2.0%) patients experienced complications within 30-days of the procedure including acute tamponade (1), TIA (1) and stroke (1) and 1 (0.7%) died from complications of septic arthritis 183 days post-procedure. Conclusion: The novel HD Grid differs significantly in design and handling compared to the traditional multielectrode catheters. Our data report procedural outcomes in line with contemporary clinical expectations with low complication and recurrence rates.

Background: Insight into type 5 long QT syndrome (LQT5) has been limited to case reports and small family series. Improved understanding of the clinical phenotype and genetic features associated with rare KCNE1 variants implicated in LQT5 was sought through an international multicenter collaboration. Methods: Patients with either presumed autosomal dominant LQT5 (N = 229) or the recessive Type 2 Jervell and Lange-Nielsen syndrome (N = 19) were enrolled from 22 genetic arrhythmia clinics and 4 registries from 9 countries. KCNE1 variants were evaluated for ECG penetrance (defined as QTc >460 ms on presenting ECG) and genotype-phenotype segregation. Multivariable Cox regression was used to compare the associations between clinical and genetic variables with a composite primary outcome of definite arrhythmic events, including appropriate implantable cardioverter-defibrillator shocks, aborted cardiac arrest, and sudden cardiac death. Results: A total of 32 distinct KCNE1 rare variants were identified in 89 probands and 140 genotype positive family members with presumed LQT5 and an additional 19 Type 2 Jervell and Lange-Nielsen syndrome patients. Among presumed LQT5 patients, the mean QTc on presenting ECG was significantly longer in probands (476.9±38.6 ms) compared with genotype positive family members (441.8±30.9 ms, P P =0.001). Event incidence did not differ significantly for Type 2 Jervell and Lange-Nielsen syndrome patients relative to the overall heterozygous cohort (10.5% [2/19]; HR 1.7 [95% CI, 0.3–10.8], P =0.590). The cumulative prevalence of the 32 KCNE1 variants in the Genome Aggregation Database, which is a human database of exome and genome sequencing data from now over 140 000 individuals, was 238-fold greater than the anticipated prevalence of all LQT5 combined (0.238% vs 0.001%). Conclusions: The present study suggests that putative/confirmed loss-of-function KCNE1 variants predispose to QT prolongation, however, the low ECG penetrance observed suggests they do not manifest clinically in the majority of individuals, aligning with the mild phenotype observed for Type 2 Jervell and Lange-Nielsen syndrome patients.

Background: Current algorithms and device morphology templates have been proposed in current Implantable Cardioverter-Defibrillators (ICDs) to minimize inappropriate therapies (ITS), but this has not been completely successful. Aim: Assess the impact of a deliberate strategy of using an atrial lead implant with standardized parameters; based on all current ICD discriminators and technologies, on the burden of ITS. Method: A retrospective single-centre analysis of 250 patients with either dual chamber (DR) ICDs or biventricular ICDs (CRTDs) over a (41.9 ± 27.3) month period was performed. The incidence of ITS on all ICD and CRTD patients was chronicled after the implementation of standardized programming. Results: 39 events of anti-tachycardial pacing (ATP) and/or shocks were identified in 20 patients (8% incidence rate among patients). The total number of individual therapies was 120, of which 34% were inappropriate ATP, and 36% were inappropriate shocks. 11 patients of the 250 patients received ITS (4.4%). Of the 20 patients, four had ICDs for primary prevention and 16 for a secondary prevention. All the episodes in the primary indication group were inappropriate, while seven patients (43%) of the secondary indication group experienced inappropriate therapies. Conclusions: The burden of ITS in the population of patients receiving ICDs was 4.4% in the presence of atrial leads. The proposed rationalized programming criteria seems an effective strategy to minimize the burden of inappropriate therapies and will require further validation. Keywords: Implantable cardioverter-defibrillator (ICDs), Inappropriate therapies, Standardized programming

Background Direct oral anticoagulants (DOACs) have expanded the armamentarium for antithrombotic therapy. Although DOAC-related major bleeding was associated with favorable outcomes compared with warfarin in clinical trials, warfarin effects were reversed in Methods Consecutive patients ≥ 66 years presented to five tertiary care hospitals across three cities in Ontario, Canada from October 2010 to March 2015 with diagnoses that included hemorrhage. Charts were screened for association with DOAC or warfarin use; eligible cases were abstracted and linked to administrative databases. Results Among 19,061 records screened, 2,002 (460 receiving DOAC, 1,542 receiving warfarin) were eligible. Reversal agents (72.9% vitamin K, 40.7% prothrombin complex concentrates) were frequently used in warfarin bleeding events. Red blood cell transfusions occurred more often in DOAC bleeding events than in warfarin events (52.0% vs 39.5%; adjusted relative risk [aRR], 1.32; 95% CI, 1.19-2.47). However, units of blood products transfused were not different between the two groups. Thirty-four DOAC cases (7.4%) received activated prothrombin complex concentrates or recombinant factor VIIa. In-hospital mortality was lower following DOAC bleeding events (9.8% vs 15.2%; aRR, 0.66; 95% CI, 0.49-0.89), although differences in 30-day mortality did not reach statistical significance (12.6% vs 16.3%; aRR, 0.79; 95% CI, 0.61-1.03). Conclusions In this unselected cohort of patients with oral anticoagulant-related hemorrhage with high rates of warfarin reversal, in-hospital mortality was lower among DOAC-associated bleeding events. These findings support the safety of DOACs in routine care and present useful baseline measures for evaluations of DOAC-specific reversal agents.

The application of optimum contact force (CF) can be used to improve ablation procedure success and safety. The lesion size index (LSI) is a novel dimensionless contact force parameter that allows for an accurate estimation of lesion volume in real time by integrating contact force (grams), duration (seconds) and power (watts). The aim was to correlate LSI values with current contact force parameters to achieve successful and safe bidirectional block of the cavotricuspid isthmus (CTI) using a maximum voltage-guided (MVG) ablation strategy. Fifteen consecutive patients (age 69 ± 7.9 years, nine males) with symptomatic atrial flutter (AFL) were evaluated and compared with 23 control (age 66.3 ± 10.4 years, 16 males) non-contact force-guided ablation cases. Irrigated-tip force-sensing ablation catheters (TactiCath Quartz™, St. Jude Medical, St. Paul, MN, USA) were used in the CF group to achieve the primary endpoint of complete bidirectional block of the isthmus. In the CF group, a total of 233 radiofrequency (RF) applications were examined. A mean LSI of 6.4 ±1.0 correlated with a force-time integral (FTI) of 581.2 ±230.9 g/s and an average CF of 13.9 ±4.9 g concurrently. Intraprocedural, fluoroscopy time and RF time demonstrated lower trends in the CF group, but no significance with respect to these trends was observed. The secondary endpoint of no reconnection within 20 min after the procedure was equally attained in both groups, and, likewise, the level of safety was comparable. An LSI value of >5 represents a new effective parameter in MVG ablation for the cavotricuspid region that demonstrates a safe profile. Guidance of CTI ablation using LSI and other contact force parameters of CF 13.9 ±4.9 g and FTI 581.2 ±230.9 g/s demonstrated highly effective and safe outcomes.

Objectives This study evaluated the incidence of ventricular arrhythmia and implantable cardioverter-defibrillator (ICD) therapies in patients with a diagnosis of cancer. Background Cardiac disease and cancer are prevalent conditions and share common predisposing factors. No studies have assessed the impact of cancer on the burden of ventricular arrhythmia in patients with cancer and ICDs. Methods Retrospective study of patients with an ICD and cancer who were followed from January 2007 to June 2015. Rates of ventricular tachycardia (VT) and ventricular fibrillation (VF) before and after patients’ cancers were diagnosed were evaluated by searching device data collection systems. Rates were adjusted for length of follow-up and compared using the Wilcoxon test, and times to first therapy following diagnosis (stages I to III vs. IV) were compared using Kaplan-Meier curves and log-rank test. Results Among 1,598 patients with an ICD, 209 patients (13.1%) had a pathological diagnosis of malignancy; and in 102 patients (6.4%), malignancy was diagnosed following device insertion. After the diagnosis of cancer, 32% of patients experienced VT/VF over 23.2 ± 23.6 months, and the frequency of arrhythmic events was significantly increased after the diagnosis (1.19 ± 0.32 vs. 0.12 ± 0.21 episodes per month, respectively; p = 0.03). The incidence of VT/VF was markedly higher in patients with stage IV cancer than in those with earlier stages (p = 0.03). In this group, the incidence of VT/VF was 41.2%, with an average of 7.2 ± 18.5 events per patient, all of whom received ICD shocks. The rate of ICD deactivation in stage IV patients was 35.3%. Inappropriate therapies occurred in 13.7%, and atrial fibrillation was the most frequent cause. Conclusions One-third of patients who had received ICDs developed ventricular arrhythmia after a diagnosis of cancer. The incidence was significantly higher in those with advanced metastatic disease. Findings underscore the need to discuss ICD management as part of end-of-life care.

Twiddler's syndrome is caused by patient manipulation of the cardiac implantable device (CID) around its central axis within the pocket, resulting in retraction and dislocation of the electrodes. There are, however, some reports that Twiddler's syndrome may occur spontaneously without the patient's manipulation. This remains contentious as it may be argued that patients may not want to admit to manipulating the CID or may have been unaware of their actions. Recently, we have observed three very similar cases with a "spontaneous" Twiddler's syndrome resulting in lead displacement. All of the three patients denied device manipulation and were not prone to somnambulism or repetitive involuntary motor behaviors. It, therefore, seems highly unlikely that all patients could have manipulated the device in exactly the same way to result in the same postrotational position within the implant pocket. The fact is that the same device was implicated in all these cases in a relatively similar time sequence from implant to recognition of the implantable cardiac defibrillator rotation. We postulate that the unique elongated decision of the Fortify Assura (St. Jude Medical, Minneapolis, MN, USA) ICD makes this device prone to spontaneous rotation as is exemplified by our case series.

Background Ablation of scar related ventricular tachycardia (VT) has been shown to be superior to escalation of drug therapy. However, the incremental benefit remains modest, with 42% experiencing recurrent shocks and 64% appropriate anti-tachycardia pacing (ATP) in the VANISH study. Improved ablation strategies are needed. Paced electrogram feature analysis (PEFA) is a novel substrate based ablation technique. Purpose To investigate the effectiveness of the PEFA based VT ablation technique. Methods A single centre, prospective study. Consecutive cases of scar related VT that had an implantable cardiac defibrillator (ICD) and no prior ablations were recruited. Close coupled pacing was performed at the right ventricular apex and the VT isthmus(es) identified on high density mapping catheters by increased electrogram (EGM) duration and latency. A algorithm was developed to identify the latest EGM component after the S2 pacing artefact,. This millisecond value was displayed on the geometry as a colour (PEFA map) (St Jude Ensite Precision Electroanatomic Mapping). PEFA identified VT isthmus sites were targeted for ablation (Figure 1). Follow up ICD interrogation data was utilized to assess for VT recurrence. Results A total of 20 patients were recruited. These comprised ischaemic cardiomyopathy (CM) (17/20), dilated CM (2/20), and arrhythmogenic CM (1/20), male (18/20), and endocardial only approach (19/20). Mean age was 64.3±11.3 years, ejection fraction 24.4% ± 14.4, and ablation time was 1989.9±1078.1 seconds. Non-inducibility was demonstrated at the end of the case in 18/20. A class I or III anti-arrhythmic drug was continued in 50%. VT recurred in three cases (Day 28,30,55). One death occurred following a stroke on day 181. Mean follow up was 437.5±231.7 days. Figure 1 Conclusion This is the largest study to date on PEFA based VT ablation, the first to include non-ischaemic aetiologies, and reports a longer mean follow up. A high proportion of cases were non-inducible, and low VT recurrence rates were observed. PEFA appears to be a promising tool to guide VT ablation targets. Acknowledgement/Funding This research was funded in part by the Canadian Institute for Health Research (139080) and a grant from St. Jude Medical.

Background: Oral anticoagulant use is common among patients undergoing pacemaker or defibrillator surgery. BRUISE CONTROL (Bridge or Continue Coumadin for Device Surgery Randomized Controlled Trial; NCT00800137) demonstrated that perioperative warfarin continuation reduced clinically significant hematomas (CSH) by 80% compared with heparin bridging (3.5% versus 16%). BRUISE-CONTROL-2 (NCT01675076) observed a similarly low risk of CSH when comparing continued versus interrupted direct oral anticoagulant (2.1% in both groups). Using patient level data from both trials, the current study aims to: (1) evaluate the effect of concomitant antiplatelet therapy on CSH, and (2) understand the relative risk of CSH in patients treated with direct oral anticoagulant versus continued warfarin. Methods: We analyzed 1343 patients included in BRUISE-CONTROL-1 and BRUISE-CONTROL-2. The primary outcome for both trials was CSH. There were 408 patients identified as having continued either a single or dual antiplatelet agent at the time of device surgery. Results: Antiplatelet use (versus nonuse) was associated with CSH in 9.8% versus 4.3% of patients ( P P =0.0071). In multivariable analysis, adjusting for antiplatelet use, there was no significant difference in CSH observed between direct oral anticoagulant use compared with continued warfarin (odds ratio, 0.858; 95% CI, 0.375–1.963; P =0.717). Conclusions: Concomitant antiplatelet therapy doubled the risk of CSH during device surgery. No difference in CSH was found between direct oral anticoagulant versus continued warfarin. In anticoagulated patients undergoing elective or semi-urgent device surgery, the patient specific benefit/risk of holding an antiplatelet should be carefully considered. Clinical Trial Registration: URL: https://www.clinicaltrials.gov . Unique identifiers: NCT00800137, NCT01675076.

Background Ablation of scar related ventricular tachycardia (VT) has been shown to be superior to escalation of drug therapy. However, the incremental benefit remains modest, with 42% experiencing recurrent shocks and 64% appropriate anti-tachycardia pacing (ATP) in the VANISH study. Furthermore, VT induction to allow activation mapping and entrainment is not tolerated in 70% of cases. Improved substrate based ablation strategies are needed. Paced electrogram feature analysis (PEFA) is a novel and promising technique. This method utilizes close coupled extra-stimuli to reveal latency and increased electrogram (EGM) duration (figure 1) that is evident at critical VT isthmus(es) (figure 2). Purpose To investigate the effectiveness of PEFA based VT ablation. Methods A single centre, prospective study. Consecutive cases of scar related VT that had an implantable cardiac defibrillator (ICD) and no prior ablations were recruited. Close coupled pacing was performed at the right ventricular apex (VERP + 50 ms) and the VT isthmus(es) identified on high density mapping catheters (HD Grid™ or Reflexion™, St Jude) by increased electrogram (EGM) duration and latency (figure 1). An algorithm was developed to identify the latest EGM component after the S2 pacing artefact (St Jude EnSite Precision Electroanatomic Mapping). The amplitude sensitivity was set at 0.05 mV and manual assessment was used to correct the automated annotation when visibly inaccurate. This millisecond value was displayed on the geometry as a colour (PEFA map) (figure 2). PEFA identified VT isthmus sites were targeted for ablation (figure 1). The PEFA map was repeated to ensure comprehensive abolition. VT stim protocol with three extra-stimuli was performed at the end of each case. Follow up ICD interrogation data was utilized to assess for VT recurrence and mortality. Results A total of 23 cases were recruited. table 1 provides an overview of baseline characteristics. table 2 includes procedure details and outcomes. Conclusion PEFA based VT ablation is feasible and effective. A high proportion of cases were non-inducible, with low VT recurrence rates. This is the largest dataset to date on PEFA based VT ablation, the first to include non-ischaemic aetiologies, and reports a longer mean follow up. PEFA appears to be a promising substrate based VT ablation strategy.

Long QT syndrome (LQTS) is an inherited disorder characterized by a prolonged QT interval in the 12-lead electrocardiogram and increased risk of malignant arrhythmias in patients with a structurally normal heart. Since its first description in the 1950s, advances in molecular genetics have greatly improved our understanding of the cause and mechanisms of this disease. Sixteen genes linked to LQTS have been described and genetic testing had become an integral part of the diagnosis and risk stratification. This article provides an updated review of the genetic basis, diagnosis, and clinical management of LQTS.

Implantable cardioverter defibrillators (ICDs) prevent sudden cardiac death. However, in patients with terminal illnesses, these devices may disrupt the dying process. This study was undertaken to review our current strategies surrounding device deactivation. A retrospective chart review was performed at Kingston Health Sciences Centre of patients with an ICD who died from 2015 to 2018. Data collected included patient demographics, clinical details surrounding device implantation, patient co-morbidities leading to deactivation, time to deactivation, physical place of deactivation, and device programming information. Ethics approval was obtained from the Queen's University Health Sciences Research Ethics Board. A total of 49 patients were included for analysis. Mean age at the time of death was 77.5 years (range: 57 to 94 years) and 12.2% (6/49) were women. The indications for ICD implantation were primary prevention of sudden cardiac death in 69.4% (34/49) and secondary prevention in 30.6% (15/49). Deactivation as part of end-of-life care was performed in 32.7% of patients (16/49). Deactivations occurred in clinic in 6.1% (3/49) of patients, on hospital inpatient wards in 12.2% (6/49) of patients, and in critical care settings in 14.2% (7/49) of patients. The remaining 67.3% (33/49) of patients died with fully functioning devices in place. The most prevalent terminal diagnoses were metastatic cancer (22.4%) and end-stage congestive heart failure (20.4%). On average, patients had their devices deactivated 13 months (range: 0 to 62 months) after their terminal diagnosis was established. Once a patient was documented as Do Not Resuscitate (DNR), deactivation was discussed and carried out within a mean time of 38 days (range: 0 to 400 days). Seven patients had their device active for more than 1 month after being documented as DNR. Ten patients (20.4%) received ICD shocks after their terminal diagnosis, 9 received shocks in the month before death, and 2 received shocks after formal DNR orders were in place. Approximately one-third of patients with ICDs received deactivation of their cardioversion/defibrillation therapies as part of their end-of-life care plan. A relatively high proportion of patients (20%) received an ICD shock in the last month of life. In conclusion, addressing device programming needs, including deactivation of cardioversion/defibrillation therapies, should be considered in the context of a patient's goals of care in every patient with an ICD who has a co-existing life-limiting diagnosis.

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.

Aims Pathogenic gain-of-function variants in CACAN1C cause type-8 long QT syndrome (LQT8). We sought to describe the electrocardiographic features in LQT8 and utilize molecular modelling to gain mechanistic insights into its genetic culprits. Methods and results Rare variants in CACNA1C were identified from genetic testing laboratories. Treating physicians provided clinical information. Variant pathogenicity was independently assessed according to recent guidelines. Pathogenic (P) and likely pathogenic (LP) variants were mapped onto a 3D modelled structure of the Cav1.2 protein. Nine P/LP variants, identified in 23 patients from 19 families with non-syndromic LQTS were identified. Six variants, found in 79% of families, clustered to a 4-residue section in the cytosolic II–III loop region which forms a region capable of binding STAC SH3 domains. Therefore, variants may affect binding of SH3-domain containing proteins. Arrhythmic events occurred in similar proportions of patients with II–III loop variants and with other P/LP variants (53% vs. 48%, P = 0.41) despite shorter QTc intervals (477 ± 31 ms vs. 515 ± 37 ms, P = 0.03). A history of sudden death was reported only in families with II–III loop variants (60% vs. 0%, P = 0.03). The predominant T-wave morphology was a late peaking T wave with a steep descending limb. Exercise testing demonstrated QTc prolongation on standing and at 4 min recovery after exercise. Conclusion The majority of P/LP variants in patients with CACNA1C-mediated LQT8 cluster in an SH3-binding domain of the cytosolic II–III loop. This represents a ‘mutation hotspot’ in LQT8. A late-peaking T wave with a steep descending limb and QT prolongation on exercise are commonly seen.

Background Obstructive sleep apnea (OSA) is strongly associated with atrial fibrillation (AF). Long-term ECG monitoring with implantable loop recorders facilitates the identification of undiagnosed AF in 20% of severe OSA cases. However, ambulatory ECG (AECG) monitoring is less resource intensive, and various parameters have been shown to predict AF. The aim of this study was to assess the efficacy of such AECG-based AF predictors in identifying patients with severe OSA most at risk. Methods Prospective observational study including patients with severe OSA and no history of AF. Patients had two 24-h AECG recordings, and if no AF was detected, implanted with a loop recorder (maximum 3 years). Results Of 25 patients implanted, AF ≥ 10 s was detected in 5 patients. None of the parameters from the AECG recordings were significantly different between patients who did and did not develop AF. Conclusions AECG-based parameters were not effective for the prediction of AF in this severe OSA cohort.