Rafik Tadros

Sex Differences in Cardiac Electrophysiology and Clinical Arrhythmias: Epidemiology, Therapeutics, and Mechanisms

Sex differences in cardiac electrophysiological properties and arrhythmias are evident in epidemiologic and investigative studies as well as in daily patient care. At the supraventricular level, women are at increased risk of sick sinus syndrome and atrioventricular (AV) node re-entrant tachycardia, whereas men manifest more AV block and accessory pathway-mediated arrhythmias. At the ventricular level, women are generally at higher risk of long QT-associated arrhythmias, whereas men are more likely to present with early repolarization, idiopathic ventricular fibrillation, and Brugada syndromes. Great advances have been made in unraveling the fundamental mechanisms underlying sex differences in ventricular arrhythmias, particularly those associated with abnormal repolarization. Conversely, the basis for male-predominant arrhythmia risk in structural heart disease and differences in supraventricular arrhythmia susceptibility are poorly understood. Beyond biological differences, arrhythmia occurrence and patient care decisions are also influenced by gender-related factors. This article reviews the current knowledge regarding the nature and underlying mechanisms of sex differences in basic cardiac electrophysiology and clinical arrhythmias.

Predictors of Ventricular Arrhythmias and Sudden Death in a Québec Cohort With Brugada Syndrome

BACKGROUNDnPatients with Brugada syndrome (BrS) are at risk for ventricular arrhythmias (VAs) and sudden death. Identification of high-risk individuals beyond those with syncope or resuscitated sudden death remains a major challenge.nnnMETHODSnWe assessed the value of clinical, electrophysiological, and electrocardiographic (ECG) features, including depolarization and repolarization metrics, in predicting arrhythmic events and sudden death in consecutive patients with BrS diagnosed between 2002 and 2013 in Quebec, Canada. Qualifying electrocardiograms with the highest type 1 ST-segment elevations were reviewed and analyzed by 2 electrophysiologists who were blinded to clinical history. Survival analyses were adjusted for Firth bias correction and left truncation.nnnRESULTSnA total of 105 patients, 79.8% of whom were men, were diagnosed with BrS at a mean age of 46.2 ± 13.3 years and were followed for 59.6 ± 16.4 months. Ten (9.5%) had a history of cardiac arrest, 37 (35.2%) had syncope, and 7 (6.7%) experienced 20 arrhythmic events during follow-up, all consisting of appropriate ICD therapy (7 antitachycardia pacing; 13 shocks). In multivariate Cox regression analyses, a spontaneous type 1 electrocardiographic (ECG) pattern (hazard ratio [HR], 10.80; 95% confidence interval [CI], 1.03-113.87; Pxa0= 0.0476), maximal T peak-end (Tp-e) duration ≥ 100 ms (HR, 29.73; 95% CI, 1.33-666.37; Pxa0= 0.0325), and QRS duration in lead V6 > 110 ms (HR, 15.27; 95% CI, 1.07-217.42; Pxa0= 0.0443) were independently associated with VAs or aborted sudden cardiac death.nnnCONCLUSIONSnIn a multicentre cohort with BrS from Quebec, Canada, VAs and sudden death were independently associated with standard 12-lead ECG features, including a spontaneous type 1 pattern, depolarization (QRS in lead V6), and repolarization (maximal Tp-e duration) criteria.

Risk stratification for sudden death in arrhythmogenic right ventricular cardiomyopathy

Arrhythmogenic right ventricular cardiomyopathy/dysplasia (ARVC) is an uncommon but increasingly recognized inherited cardiomyopathy that is associated with malignant ventricular arrhythmias and sudden cardiac death, particularly in young individuals. The implantable cardioverter-defibrillator (ICD) is widely regarded as the only treatment modality with evidence to support improved survival in patients with ARVC and secondary prevention indications. In contrast, there is no universally accepted risk stratification scheme to guide ICD therapy for primary prevention against sudden cardiac death. Potential benefits must be weighed against the considerable risks of complications and inappropriate shocks in this young patient population. This article tackles the challenges of risk stratification for sudden cardiac death in ARVC and critically appraises available evidence for various proposed risk factors. The authors’ over-arching objective is to provide the clinician with evidence-based guidance to inform decisions regarding the selection of appropriate candidates with ARVC for ICD therapy.

Dronedarone: Basic Pharmacology and Clinical Use

Dronedarone is the newest antiarrhythmic drug approved for the maintenance of sinus rhythm in patients with nonpermanent atrial fibrillation (AF). It is a multi-channel blocker with diverse electrophysiologic properties. Dronedarone decreases the incidence of AF recurrence and the ventricular rate during recurrence. Dronedarone decreases rates of cardiovascular hospitalizations in patients with paroxysmal and persistent AF. Dronedarone increases mortality in patients with permanent AF and those with moderate-severe heart failure, and should thus be avoided in these populations. Dronedarone is less effective than amiodarone but also has less toxicity. Direct comparison with other antiarrhythmic drugs is not available.

SCN5A mutation type and topology are associated with the risk of ventricular arrhythmia by sodium channel blockers

BACKGROUNDnVentricular fibrillation in patients with Brugada syndrome (BrS) is often initiated by premature ventricular contractions (PVCs). Presence of SCN5A mutation increases the risk of PVCs upon exposure to sodium channel blockers (SCB) in patients with baseline type-1 ECG. In patients without baseline type-1 ECG, however, the effect of SCN5A mutation on the risk of SCB-induced arrhythmia is unknown. We aimed to establish whether presence/absence, type, and topology of SCN5A mutation correlates with PVC occurrence during ajmaline infusion.nnnMETHODS AND RESULTSnWe investigated 416 patients without baseline type-1 ECG who underwent ajmaline testing and SCN5A mutation analysis. A SCN5A mutation was identified in 88 patients (S+). Ajmaline-induced PVCs occurred more often in patients with non-missense mutations (Snon-missense) or missense mutations in transmembrane or pore regions of SCN5A-encoded channel protein (Smissense-TP) than patients with missense mutations in intra-/extracellular channel regions (Smissense-IE) and patients without SCN5A mutation (S-) (29%, 24%, 9%, and 3%, respectively; P<0.001). The proportion of patients with ajmaline-induced BrS was similar in different mutation groups but lower in S- (71% Snon-missense, 63% Smissense-TP, 70% Smissense-IE, and 34% S-; P<0.001). Logistic regression indicated Snon-missense and Smissense-TP as predictors of ajmaline-induced PVCs.nnnCONCLUSIONSnSCN5A mutation is associated with an increased risk of drug-induced ventricular arrhythmia in patients without baseline type-1 ECG. In particular, Snon-missense and Smissense-TP are at high risk.

Familial Disease Is Not Always Genetic: A Family With Atrioventricular Block and Mitral Regurgitation

We present a family from a founder population referred for cardiogenetic evaluation for atrioventricular block in 3 siblings. Genetic testing, including whole-exome sequencing, did not identify a disease-causing mutation. After reconsidering the differential diagnosis, a nongenetic cause was identified. This case highlights the importance of a thorough clinical evaluation even when a genetic cause is seemingly obvious.

Pharmacotherapy for inherited arrhythmia syndromes: mechanistic basis, clinical trial evidence and practical application.

In the absence of structural heart disease, sudden cardiac death is frequently caused by inherited arrhythmia syndromes, such as long QT syndrome, Brugada syndrome and catecholaminergic polymorphic ventricular tachycardia. Managing these conditions often requires a combination of lifestyle modification, pharmacotherapy and less frequently, invasive therapy. Over the past decade, patient management has been greatly enhanced by tailored pharmacotherapy as a result of a deeper appreciation for arrhythmia mechanisms and supportive evidence from multicenter cohort studies. This article reviews current knowledge regarding drug therapy for inherited arrhythmias. Anti-arrhythmic mechanisms and available clinical evidence are highlighted while maintaining a practical perspective on patient management.

Atrial fibrillation in young patients

ABSTRACT Introduction: Atrial fibrillation (AF) is the most frequent arrhythmia worldwide. While mostly seen in elderly, it can also affect young adults (≤ 45 years of age), older adolescent, and children. Areas covered: The aim of this review is to provide an overview of the current management of AF in young patients. Specific issues arise over diagnostic workup as well as antiarrhythmic and anticoagulation therapies. The future management and diagnostic strategies are also discussed. Expert commentary: Management of AF in the young adult is largely extrapolated from adult studies and guidelines. In this population, AF could reveal a genetic pathology (e.g. Brugada, Long QT or Short QT syndromes) or be the initial presentation of a cardiomyopathy. Therefore, thorough workup in the young population to eliminate potential malignant pathology