Brugada Syndrome.

Brugada syndrome (BrS) is an "inherited" condition characterized by predisposition to syncope and cardiac arrest, predominantly during sleep. The prevalence is ∼1:2,000, and is more commonly diagnosed in young to middle-aged males, although patient sex does not appear to impact prognosis. Despite the perception of BrS being an inherited arrhythmia syndrome, most cases are not associated with a single causative gene variant. Electrocardiogram (ECG) findings support variable extent of depolarization and repolarization changes, with coved ST-segment elevation ≥2 mm and a negative T-wave in the right precordial leads. These ECG changes are often intermittent, and may be provoked by fever or sodium channel blocker challenge. Growing evidence from cardiac imaging, epicardial ablation, and pathology studies suggests the presence of an epicardial arrhythmic substrate within the right ventricular outflow tract. Risk stratification aims to identify those who are at increased risk of sudden cardiac death, with well-established factors being the presence of spontaneous ECG changes and a history of cardiac arrest or cardiogenic syncope. Current management involves conservative measures in asymptomatic patients, including fever management and drug avoidance. Symptomatic patients typically undergo implantable cardioverter defibrillator insertion, with quinidine and epicardial ablation used for patients with recurrent arrhythmia. This review summarizes our current understanding of BrS and provides clinicians with a practical approach to diagnosis and management

Canadian Cardiovascular Society Clinical Practice Update on Contemporary Management of the Patient with Hypertrophic Cardiomyopathy

Numerous guidelines on the diagnosis and management of hypertrophic cardiomyopathy (HCM) have been published, by learned societies, over the last decade. While helpful they are often long and less adapted to non-experts. This writing panel was challenged to produce a document that grew as much from years of practical experience as it did from the peer-reviewed literature. As such, rather than produce yet another set of guidelines, we aim here to deliver a concentrate of our own experiential learning and distil for the reader the essence of effective and appropriate HCM care. This Clinical Practice Update on HCM is therefore aimed at general cardiologists and other cardiovascular practitioners rather than for HCM specialists. We set the stage with a description of the condition and its clinical presentation; discuss the central importance of 'obstruction' and how to look for it; review the role of cardiac magnetic resonance imaging; reflect on the appropriate use of genetic testing; review the treatment options for symptomatic HCM - crucially including cardiac myosin inhibitors; and deal concisely with practical issues surrounding risk assessment for sudden cardiac death, and management of the end-stage HCM patient. Uniquely, we have captured the pediatric experience on our panel to discuss appropriate differences in the management of younger patients with HCM. We ask the reader to remember that this document represents expert consensus opinion rather than dogma and to use their best judgement when dealing with the HCM patient in front of them

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

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

Isolating Nuclei From Frozen Human Heart Tissue for Single-Nucleus RNA Sequencing

Version of Record online: 11 July 2022Heart disease is the leading cause of global morbidity and mortality. This is in part because, despite an abundance of animal and in vitro models, it has been a challenge to date to study human heart tissue with sufficient depth and resolution to develop disease-modifying therapies for common cardiac conditions. Single-nucleus RNA sequencing (snRNA-seq) has emerged as a powerful tool capable of analyzing cellular function and signaling in health and disease, and has already contributed to significant advances in areas such as oncology and hematology. Employing snRNA-seq technology on flash-frozen human tissue has the potential to unlock novel disease mechanisms and pathways in any organ. Studying the human heart using snRNA-seq is a key priority for the field of cardiovascular sciences; however, progress to date has been slowed by numerous barriers. One key challenge is the fact that the human heart is very resistant to shearing and stress, making tissue dissociation and nuclear isolation difficult. Here, we describe a tissue dissociation method allowing the efficient and cost-effective isolation of high-quality nuclei from flash-frozen human heart tissue collected in surgical operating rooms. Our protocol addresses the challenge of nuclear isolation from human hearts, enables snRNA-seq of the human heart, and paves the way for an improved understanding of the human heart in health and disease. Ultimately, this will be key to uncovering signaling pathways and networks amenable to therapeutic intervention and the development of novel biomarkers and disease-modifying therapies.Sina Safabakhsh, Funda Sar, Luciano Martelotto, Anne Haegert, Gurpreet Singhera, Paul Hanson, Jeremy Parker, Colin Collins, Leili Rohani, Zachary Laksma

Personalized Medicine: Understanding Probabilities and Managing Expectations

Personalized medicine promises to represent a transformation in clinical care that will be ushered in by the unprecedented growth and development in the field of human genetics. Further examination of the scientific foundations of this new hope reveals a great number of challenges that lie ahead. While basic science research feverishly races to produce solutions, we continue to wait for the translation of deliverables. Products that have and will come to market may leave our clinical communities and systems exposed and unprepared. At each step, from basic science research to infrastructure development, a great deal of creativity and investment are required before the arsenal of more personalized tools can be assimilated into our current models of health care. This commentary seeks to share perspectives on the current status of personalized medicine from the vantage point of several potential investors, and integrate them into a common set of goals and understanding. We conclude that the stylized model of personalized medicine is more akin to a marketing tool than a literal prediction of the future

Type 8 long QT syndrome: pathogenic variants in CACNA1C-encoded Cav1.2 cluster in STAC protein binding site.

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