Evolution of a genetic diagnosis.

Understanding the relationship between genotype and phenotype has become an integral part of the diagnosis and management of patients with inherited arrhythmias and cardiomyopathies. Given the existence of background noise, the majority of genetic testing results should be incorporated into clinical decision making as probabilistic, rather than deterministic, in the diagnosis and management of inherited arrhythmias. This case report captures multiple snapshots of clinical care in the evolution of a diagnosis of a single patient, highlighting the need for repeated phenotypic and genotypic assessment for both the patient and their family.

Randomized assessment of syncope trial: conventional diagnostic testing versus a prolonged monitoring strategy.

BACKGROUND: Establishing a diagnosis in patients with unexplained syncope is complicated by infrequent and unpredictable events. Prolonged monitoring may be an alternative strategy to conventional testing with short-term monitoring and provocative tilt and electrophysiological testing. METHODS AND RESULTS: Sixty patients (aged 66+/-14 years, 33 male) with unexplained syncope were randomized to "conventional" testing with an external loop recorder and tilt and electrophysiological testing or to prolonged monitoring with an implantable loop recorder with 1 year of monitoring. If patients remained undiagnosed after their assigned strategy, they were offered crossover to the alternate strategy. A diagnosis was obtained in 14 of 27 patients randomized to prolonged monitoring compared with 6 of 30 patients undergoing conventional testing (52% versus 20%, P=0.012). Crossover was associated with a diagnosis in 1 of 6 patients undergoing conventional testing compared with 8 of 13 patients who completed monitoring (17% versus 62%, P=0.069). Overall, prolonged monitoring was more likely to result in a diagnosis than was conventional testing (55% versus 19%, P=0.0014). Bradycardia was detected in 14 patients undergoing monitoring compared with 3 patients undergoing conventional testing (40% versus 8%, P=0.005). CONCLUSIONS: A prolonged monitoring strategy is more likely to provide a diagnosis than conventional testing in patients with unexplained syncope. Consideration should be given to earlier implementation of a monitoring strategy.

Cryothermal ablation of the slow pathway for the elimination of atrioventricular nodal reentrant tachycardia.

BACKGROUND: We report the first successful slow pathway ablation using a novel catheter-based cryothermal technology for the elimination of atrioventricular nodal reentrant tachycardia (AVNRT). METHODS AND RESULTS: Eighteen patients with typical AVNRT underwent cryoablation. Reversible loss of slow pathway (SP) conduction during cryothermy (ice mapping) was demonstrated in 11 of 12 patients. Because of time constraints, only 2 sites were ice mapped in 1 patient. Seventeen of 18 patients had successful cryoablation of the SP. One patient had successful ice mapping of the SP, but inability to cool beyond -38 degrees C prevented successful cryoablation. A single radiofrequency lesion at this site eliminated SP conduction. No patient has had recurrent AVNRT over 4.9+/-1.7 months of follow-up. During cryoablation, accelerated junctional tachycardia was not seen and was therefore not available to guide lesion delivery. Adherence of the catheter tip during cryothermy (cryoadherence) allowed atrial pacing to test for SP conduction. Cryoablation in the anterior septum produced inadvertent transient PR prolongation consistent with loss of fast pathway conduction in 1 patient and transient (6.5 seconds) 2:1 AV block in another. On rewarming, the PR interval returned to normal, and the AV nodal effective refractory period was unchanged in both. Accelerated junctional tachycardia was seen on rewarming in both but not during cryothermy. CONCLUSIONS: Cryothermal ablation of the SP was achieved in patients with this novel technique. Successful ice mapping of both the SP and fast pathway was demonstrated. The ability to test the functionality of specific ablation sites before production of a permanent lesion may eliminate inadvertent AV block.

Progression to chronic atrial fibrillation after pacing: the Canadian Trial of Physiologic Pacing. CTOPP Investigators.

OBJECTIVES: This study examined the effect of physiologic pacing on the development of chronic atrial fibrillation (CAF) in the Canadian Trial Of Physiologic Pacing (CTOPP). BACKGROUND: The role of physiologic pacing to prevent CAF remains unclear. Small randomized studies have suggested a benefit for patients with sick sinus syndrome. No data from a large randomized trial are available. METHODS: The CTOPP randomized patients undergoing first pacemaker implant to ventricular-based or physiologic pacing (AAI or DDD). Patients who were prospectively found to have persistent atrial fibrillation (AF) lasting greater than or equal to one week were defined as having CAF. Kaplan-Meier plots for the development of CAF were compared by log-rank test. The effect of baseline variables on the benefit of physiologic pacing was evaluated by Cox proportional hazards modeling. RESULTS: Physiologic pacing reduced the development of CAF by 27.1%, from 3.84% per year to 2.8% per year (p = 0.016). Three clinical factors predicted the development of CAF: age > or =74 years (p = 0.057), sinoatrial (SA) node disease (p < 0.001) and prior AF (p < 0.001). Subgroup analysis demonstrated a trend for patients with no history of myocardial infarction or coronary disease (p = 0.09) as well as apparently normal left ventricular function (p = 0.11) to derive greatest benefit. CONCLUSIONS: Physiologic pacing reduces the annual rate of development of chronic AF in patients undergoing first pacemaker implant. Age > or =74 years, SA node disease and prior AF predicted the development of CAF. Patients with structurally normal hearts appear to derive greatest benefits.

Dynamics of wavelets and their role in atrial fibrillation in the isolated sheep heart.

BACKGROUND: The multiple wavelet hypothesis is the most commonly accepted mechanism underlying atrial fibrillation (AF). However, high frequency periodic activity has recently been suggested to underlie atrial fibrillation in the isolated sheep heart. We hypothesized that in this model, multiple wavelets during AF are generated by fibrillatory conduction away from periodic sources and by themselves may not be essential for AF maintenance. METHODS AND RESULTS: We have used a new method of phase mapping that enables identification of phase singularities (PSs), which flank individual wavelets during sustained AF. The approach enabled characterization of the initiation, termination, and lifespan of wavelets formed as a result of wavebreaks, which are created by the interaction of wave fronts with functional and anatomical obstacles in their path. AF was induced in six Langendorff-perfused sheep hearts in the presence of acetylcholine. High resolution video imaging was utilized in the presence of a voltage sensitive dye; two-dimensional phase maps were constructed from optical recordings. The major results were as follows: (1) the critical inter-PS/wavelet distance for the formation of rotors was 4 mm, (2) the spatial distribution of wavelets/PSs was non-random. (3) the lifespan of PSs/wavelets was short; 98% of PSs/wavelets existed for < 1 rotation, and (4) the mean number of waves that entered our mapping field (15.7 +/- 1.6) exceeded the mean number of waves that exited it (9.7 +/- 1.5; P < 0.001). CONCLUSIONS: Our results strongly suggest that multiple wavelets may result from breakup of high frequency organized waves in the isolated Langendorff-perfused sheep heart, and as such are not a robust mechanism for the maintenance of AF in our model.

The 2020 Canadian Cardiovascular Society/Canadian Heart Rhythm Society Comprehensive guidelines for the management of Atrial Fibrillation

The Canadian Cardiovascular Society (CCS) atrial fibrillation (AF) guidelines program was developed to aid clinicians in the management of these complex patients, as well as to provide direction to policy makers and health care systems regarding related issues. The most recent comprehensive CCS AF guidelines update was published in 2010. Since then, periodic updates were published dealing with rapidly changing areas. However, since 2010 a large number of developments had accumulated in a wide range of areas, motivating the committee to complete a thorough guideline review. The 2020 iteration of the CCS AF guidelines represents a comprehensive renewal that integrates, updates, and replaces the past decade of guidelines, recommendations, and practical tips. It is intended to be used by practicing clinicians across all disciplines who care for patients with AF. The Grading of Recommendations, Assessment, Development and Evaluations (GRADE) system was used to evaluate recommendation strength and the quality of evidence. Areas of focus include: AF classification and definitions, epidemiology, pathophysiology, clinical evaluation, screening and opportunistic AF detection, detection and management of modifiable risk factors, integrated approach to AF management, stroke prevention, arrhythmia management, sex differences, and AF in special populations. Extensive use is made of tables and figures to synthesize important material and present key concepts. This document should be an important aid for knowledge translation and a tool to help improve clinical management of this important and challenging arrhythmia.

Le programme de lignes directrices de la Société canadienne de cardiologie (SCC) en matière de fibrillation auriculaire (FA) a été élaboré pour aider les cliniciens à prendre en charge ces patients complexes, ainsi que pour orienter les décideurs politiques et les systèmes de soins de santé sur des questions connexes. La dernière édition complète des lignes directrices de la SCC en matière de FA a été publiée en 2010. Depuis lors, des mises à jour périodiques ont été publiées, traitant de domaines en évolution rapide. Cependant, en 2020, un grand nombre de développements s'y étaient ajoutés, couvrant un large éventail de domaines, ce qui a motivé le comité à créer une refonte complète des lignes directrices. L'édition 2020 des lignes directrices de la SCC en matière de FA représente un renouvellement complet qui intègre, met à jour et remplace les lignes directrices, les recommandations et les conseils pratiques des dix dernières années. Elle est destinée à être utilisée par les cliniciens praticiens de toutes les disciplines qui s'occupent de patients souffrant de FA. L'approche GRADE (Gradation des Recommandations, de l'Appréciation, du Développement et des Évaluations) a été utilisée pour évaluer la pertinence des recommandations et la qualité des résultats. Les domaines d'intérêt incluent : la classification et les définitions de la FA, son épidémiologie, sa physiopathologie, l'évaluation clinique, le dépistage de la FA, la détection et la gestion des facteurs de risque modifiables, l'approche intégrée de la gestion de la FA, la prévention des accidents vasculaires cérébraux, la gestion de l'arythmie, les différences entre les sexes et la FA dans des populations particulières. Des tableaux et figures ont été largement utilisés pour synthétiser les éléments importants et présenter les concepts clés. Ce document devrait représenter une aide importante pour l'intégration des connaissances et un outil pour aider à améliorer la gestion clinique de cette arythmie importante et difficile à traiter.

Supraventricular tachycardia.

Supraventricular tachycardias (SVT) comprise those tachycardias that originate above the bifurcation of the bundle of His. They can be classified broadly as AV node dependent and AV node independent. The mechanism and clinical manifestation of SVTs, which is essential to their correct diagnosis, is reviewed. The therapeutic management of SVTs, including acute and chronic drug therapy and catheter ablation, is discussed also.

Recurrent seizure diagnosed by the insertable loop recorder.

INTRODUCTION: The Insertable Loop Recorder (ILR) has emerged as an important new tool in the diagnostic armamentarium for patients with syncope. METHODS AND RESULTS: A case report illustrates how the ILR unexpectedly led to the diagnosis of seizure as the explanation for a man's recurrent, but infrequent episodes of sudden loss of consciousness. CONCLUSIONS: This case raises the possibility that the development of implantable recording devices which monitor physiologic parameters other than cardiac rhythm (eg. brain, nerve or muscle activity) may provide the long-term monitoring capability needed to improve the diagnostic yield for conditions, such as seizures, which occur infrequently.

What have clinical trials taught us about proarrhythmia?

Proarrhythmia is defined as the developmental of a new arrhythmia, or the worsening of a preexisting arrhythmia, following the institution of anti-arrhythmic therapy. The most important manifestation of proarrhythmia is sudden arrhythmic death. Possible mechanisms of proarrhythmia include early afterdepolarizations, dispersion of repolarization, a conduction-slowing effect that promotes reentry, and the interaction of arrhythmic drugs with ischemia. Recent trials of arrhythmic drugs have focused attention on the increase in mortality due to some of these drugs. In many studies, the effect of placebo has been compared with that of antiarrhythmic drugs on mortality in high-risk patients following myocardial infarction (MI). In most of these trials, anti-arrhythmic drugs were associated with an increase in mortality has been most clearly shown with encainide, flecainide, moricizine and d-sotalol. In addition, increased mortality has been suggested in patients treated with antiarrhythmics for atrial fibrillation especially in the presence of structural heart disease. In contrast, several post-MI benefit. This suggests that amiodarone may be safe for the treatment of arrhythmias in the post-MI patient. Further evidence will come from two majors studies (CAMIAT and EMIAT) which should be available by early 1996.

Torsade de pointes with amiodarone in a patient with previous torsade during beta-receptor blockade.

Torsade de pointes is a potentially lethal ventricular arrhythmia that is associated with prolonged QT intervals and is often caused by drugs that prolong repolarization. Among the most common drugs that may cause torsade de pointes are antiarrhythmic drugs including quinidine, procainamide, sotalol and newer class III antiarrhythmic agents. The incidence of torsade de pointes associated with amiodarone, however, is reported to be much lower. A case is reported of amiodarone-induced torsade de pointes following the development of the same arrhythmia during beta-blocker use. This case illustrates that although the reported incidence of torsade de pointes during amiodarone therapy is low, patients with bradycardia-induced torsade de pointes may be a subgroup of patients who are at increased risk of this arrhythmia with amiodarone.

A cost effective approach to the investigation of syncope: relative merit of different diagnostic strategies.

OBJECTIVE: To compare the cost effectiveness of a conventional diagnostic work-up with that of several different diagnostic cascades for the investigation of undifferentiated syncope. DESIGN: A MEDLINE search established a weighted estimate of diagnostic yield for several diagnostic investigations. 'High-end' and 'low-end' cost estimates were calculated for these investigations based on figures from four representative Canadian tertiary care centres in four different provinces. Several diagnostic models were applied to a hypothetical cohort of 100 patients with undifferentiated syncope. RESULTS: The conventional diagnostic cascade resulted in a diagnosis in 85% of patients, at a cost per diagnosis of $467 to $959. The optimal model increased the diagnostic yield to 98.9%, at a cost of $460 to $1043 per diagnosed patient. CONCLUSION: A combination of new technology and selective use of investigations has the potential to raise diagnostic yield without appreciably increasing cost per diagnosis.

Impact of a mandatory physician reporting system for cardiac patients potentially unfit to drive.

CONTEXT: Sudden cardiac incapacitation of a driver may lead to the death or serious injury of passengers or bystanders. This has raised public safety concerns and has led to the creation of legislation to protect the public. Some jurisdictions in Canada and the United States have introduced mandatory physician reporting of patients who may be unfit to drive for medical reasons. The impact on motor vehicle accident (MVA)-related morbidity and mortality of mandatory physician reporting for at-risk cardiac patients is unknown. OBJECTIVE: To determine the impact of mandatory physician reporting legislation (for cardiac patients) in Ontario (population 10.3 million) on MVA-related morbidity and mortality. DATA SOURCES: Reporting data were obtained from the Ontario Ministry of Transportation. Incidence and prevalence data were taken from Ontario Ministry of Health sources and from the literature (MEDLINE). Data for modelling were taken from the literature (MEDLINE) and from the Canadian Cardiovascular Society's Consensus Conference document on cardiac illness and fitness to drive. DATA EXTRACTION: Licence suspension data (correlated with medical illness) were taken directly from government documents. These were then applied to a 'risk of harm' formula used to calculate the risk posed to bystanders and passengers by the suspended patients if they had continued to drive. Canadian licence suspension guidelines were then reviewed in conjunction with cardiac disease incidence and prevalence data to arrive at the number of patients who should have been suspended. Physician compliance with the legislation was then calculated, along with the potential impact on MVA-related morbidity and mortality in the scenario of 100% physician compliance. STUDY SELECTION: All Ontario drivers who had licence suspensions in 1996 for reasons of cardiac disease were included in the analysis. DATA SYNTHESIS: Nine hundred and ninety-four licences were suspended for cardiac reasons in 1996, compared with an estimated 72,407 that should have been suspended if Canadian guidelines had been followed (1.4%). Less than one death or serious injury was avoided as a result of the legislation (from the 'risk of harm' formula). If all drivers with cardiac illness had been suspended from driving, up to 29.2 such events could potentially have been avoided. However, only 13 of 929 (1.4%) road fatalities in Ontario in 1996 were attributed to a driver with a medical illness. CONCLUSIONS: Mandatory physician reporting of patients with cardiac illness has a negligible impact on MVA-related morbidity and mortality.

Use of the implantable loop recorder in patients with unexplained syncope.

Syncope is a complex clinical syndrome with multiple etiologies that can be very difficult to diagnose. The major obstacles to diagnosis are the periodic and unpredictable nature of events and the high spontaneous remission rate. Conventional testing is often unproductive in patients when initial non-invasive testing is negative, particularly when a paroxysmal ar-rhythmia is suspected. Holter monitoring is often employed initially, with limited utility. Holter monitoring provides a rhythm profile, but rarely achieves the gold standard of a symptom rhythm correlation. The external loop re-corder extends the period of monitoring, enhancing the diagnostic yield to as high as 60% in patients with symptoms likely to recur during a month of device use. Finally, implantable loop recorders further extend the ability to monitor cardiac patients, enhancing the diagnostic yield to as high as 85% in difficult to diagnose syncope. Several recent studies suggest that prolonged monitoring with an implantable loop recorder has a role in patients with syncope and conduction disturbances, negative tilt testing, unexplained seizures and may be superior to conventional testing with tilt and electrophysiologic studies in select patients.

Use of medications in Wolff-Parkinson-White syndrome.

The diagnosis of Wolff-Parkinson-White syndrome is generally straightforward; however, the management may not be, and requires an understanding of the competing risks of various treatment options and that of the clinical setting in which the diagnosis is made. The symptomatic patient with Wolff-Parkinson-White has an increased risk of atrial fibrillation and a small but significant risk of sudden cardiac death. Therapy is based on reduction in symptom burden and attenuation of the risk of pre-excited atrial fibrillation. Catheter ablation is the most effective means of achieving this goal with abolition of symptoms and risk of pre-excited atrial fibrillation. Medication is often employed in the acute setting to terminate paroxysms of arrhythmia associated with the accessory pathway and reduce the subsequent burden of symptoms until ablation can be performed. An overview of the agents commonly used is provided together with recommendations.

Ventriculophasic modulation of atrioventricular nodal conduction in humans.

BACKGROUND: Baroreceptor-mediated phasic changes in vagal tone have been hypothesized to cause ventriculophasic sinus arrhythmia (VPSA). The objectives of this study were to demonstrate ventriculophasic modulation of AV nodal conduction and to substantiate the role of the baroreflex on ventriculophasic AV nodal conduction (VPAVN) by pharmacological perturbation of parasympathetic tone. METHODS AND RESULTS: Twelve patients with infra-Hisian second-degree heart block and VPSA were studied. Incremental atrial pacing was performed until AV nodal Wenckebach block at baseline, after phenylephrine infusion, and after atropine. AV nodal conduction curves were constructed for each phase and compared. At baseline, VPAVN was present in 9 of 12 patients on the steep portion of the AV nodal conduction curves. Phenylephrine increased systolic blood pressure from 149+/-33 to 177+/-22 mmHg (P<0.001) and sinus cycle length from 844+/-169 to 1010+/-190 ms (P<0.001) and shifted the AV nodal conduction curves up and to the right. Phenylephrine induced VPAVN in 2 of 3 patients in whom it was not present at baseline and in 11 of 12 total. Atropine abolished both VPSA and VPAVN in all patients. CONCLUSIONS: VPAVN was demonstrated in patients with infra-Hisian second-degree AV block. It was accentuated by phenylephrine and abolished by atropine, suggesting a baroreflex mechanism for VPSA and VPAVN.

Predictive value of presyncope in patients monitored for assessment of syncope.

BACKGROUND: The purpose of this study was to assess the diagnostic value of recording the cardiac rhythm during presyncope in patients undergoing monitoring for undiagnosed syncope. METHODS AND RESULTS: Eighty-five patients (age, 59 +/- 18 years; 44 men, 41 women) with recurrent unexplained syncope underwent prolonged monitoring with an implantable loop recorder. Patients were examined for syncope, which was either recurrent or associated with at least 2 presyncopal episodes. Patients had a mean of 5.1 +/- 5.5 syncopal episodes in the previous 12 months, and 70% of patients had symptoms for >2 years. Sixty-two (73%) patients had recurrent symptoms during a 12-month follow-up period. Of 150 recurrent events captured by the implantable loop recorder, there were 38 (25%) episodes of syncope and 112 (75%) episodes of presyncope. Syncope alone recurred in 12 patients, presyncope in 25, and both in 16. An arrhythmia was present in 64% of syncopal events (bradycardia in 16, tachycardia in 2) versus 25% for presyncopal events (bradycardia in 7, tachycardia in 3, P =.001). An arrhythmia was detected in 9 (56%) of the 16 patients with both syncope and presyncope, which was present in all recorded episodes of syncope compared with 6 of 9 presyncopal episodes. Patient-related failure to freeze the device after symptoms occurred in 21 (36%) of 59 syncopal events compared with 15 (12%) of 127 presyncopal events (P =.0001). CONCLUSIONS: Syncope is more likely to be associated with an arrhythmia than is presyncope in patients undergoing extended monitoring. Presyncope is a nonspecific end point that is frequently associated with sinus rhythm. Patients undergoing extended monitoring for syncope should continue to be monitored after an episode of presyncope unless an arrhythmia is detected.

Spatio-temporal patterns of atrial fibrillation: role of the subendocardial structure.

Despite many years of research and speculation, the precise mechanisms underlying atrial fibrillation remain elusive. Prevalent understanding relies on assumptions, which are based on two-dimensional numerical simulations and on the idea that atrial fibrillation is the result of total disorganization of electrical activity, with multiple wavelets wandering randomly throughout the atria. However, recent studies both clinical and basic, have suggested that focal mechanisms, either re-entrant or automatic, may explain fibrillatory activity in some cases. Here we review the major hypotheses that have prevailed at one time or another to explain this complex arrhythmia and discuss some recent experimental results that strongly suggest that, whatever the electrophysiological basis of atrial fibrillation may be, it must involve complex patterns of propagation through the intricate multidimensional anatomical structure of the atria.

Effects of postshock atrial pacing on atrial defibrillation outcome in the isolated sheep heart.

BACKGROUND: Failed atrial defibrillation shocks are associated with organization of postshock activity and a substantial postshock electrical quiescence. We investigated the ability of a train of pacing stimuli to capture or locally entrain atrial myocardium during the quiescent period after low-energy shocks and to alter defibrillation outcome. METHODS AND RESULTS: High-resolution video imaging of near-defibrillation-threshold atrial shocks was performed in 12 Langendorff-perfused sheep hearts. A train of 10 pacing stimuli (10-ms pulse width, 200-ms cycle length) was coupled to the shock at various delays in 7 hearts. Coupling intervals of 40 to 130 ms were investigated for feasibility of capture of the first pacing stimulus. The success rate of capture was 0, 0.08+/-0.08, 0.43+/-0.13, 0.73+/-0.13, and 0.11+/-0.1 for 40-, 60-, 80-, 100-, and 120-ms coupling intervals, respectively (P<0.001). In 5 experiments, the coupling interval was fixed at 100 ms (highest success, see above), and the pacing stimulus amplitude was varied between 1.0, 2.0, and 4.0 V. Successful capture rates were 0.38+/-0.08, 0.75+/-0.08, and 0.64+/-0.08, respectively (P<0.003 for 1.0 versus 2.0 V, P=0.2 for 2.0 versus 4.0 V). Rates of successful defibrillation for the groups without and with pacing were 0.56+/-0.07 and 0.64+/-0.04, respectively (P=0.3). With capture of the first pacing stimulus, the rate of successful defibrillation rose to 0.75+/-0.05 (P<0.01); it remained unchanged without capture (0.48+/-0.07 versus 0.56+/-0.07 for no pacing). CONCLUSIONS: Pacing during the quiescent period that follows defibrillation shocks is feasible. A pacing train whose first pacing stimulus successfully captures during the quiescent period of near-defibrillation-threshold shocks appears to alter the outcome.