Zachary W.M. Laksman

Making better scar: Emerging approaches for modifying mechanical and electrical properties following infarction and ablation.

Following myocardial infarction (MI), damaged myocytes are replaced by collagenous scar tissue, which serves an important mechanical function - maintaining integrity of the heart wall against enormous mechanical forces - but also disrupts electrical function as structural and electrical remodeling in the infarct and borderzone predispose to re-entry and ventricular tachycardia. Novel emerging regenerative approaches aim to replace this scar tissue with viable myocytes. Yet an alternative strategy of therapeutically modifying selected scar properties may also prove important, and in some cases may offer similar benefits with lower risk or regulatory complexity. Here, we review potential goals for such modifications as well as recent proof-of-concept studies employing specific modifications, including gene therapy to locally increase conduction velocity or prolong the refractory period in and around the infarct scar, and modification of scar anisotropy to improve regional mechanics and pump function. Another advantage of scar modification techniques is that they have applications well beyond MI. In particular, ablation treats electrical abnormalities of the heart by intentionally generating scar to block aberrant conduction pathways. Yet in diseases such as atrial fibrillation (AF) where ablation can be extensive, treating the electrical disorder can significantly impair mechanical function. Creating smaller, denser scars that more effectively block conduction, and choosing the location of those lesions by balancing their electrical and mechanical impacts, could significantly improve outcomes for AF patients. We review some recent advances in this area, including the use of computational models to predict the mechanical effects of specific lesion sets and gene therapy for functional ablation. Overall, emerging techniques for modifying scar properties represents a potentially important set of tools for improving patient outcomes across a range of heart diseases, whether used in place of or as an adjunct to regenerative approaches.

Exercise and Inherited Arrhythmias

Sudden cardiac death (SCD) in an apparently healthy individual is a tragedy that prompts a series of investigations to identify the cause of death and to prevent SCD in potentially at-risk family members. Several inherited channelopathies and cardiomyopathies, including long QT syndrome (LQTS), catecholaminergic polymorphic ventricular cardiomyopathy (CPVT), hypertrophic cardiomyopathy (HCM), and arrhythmogenic right ventricular cardiomyopathy (ARVC) are associated with exercise-related SCD. Exercise restriction has been a historical mainstay of therapy for these conditions. Syncope and cardiac arrest occur during exercise in LQTS and CPVT because of ventricular arrhythmias, which are managed with β-blockade and exercise restriction. Exercise may provoke hemodynamic or ischemic changes in HCM, leading to ventricular arrhythmias. ARVC is a disease of the desmosome, whose underlying disease process is accelerated by exercise. On this basis, expert consensus has erred on the side of caution, recommending rigorous exercise restriction for all inherited arrhythmias. With time, as familiarity with inherited arrhythmia conditions has increased and patients with milder forms of disease are diagnosed, practitioners have questioned the historical rigorous restrictions advocated for all. This change has been driven by the fact that these are often children and young adults who wish to lead active lives. Recent evidence suggests a lower risk of exercise-related arrhythmias in treated patients than was previously assumed, including those with previous symptoms managed with an implantable cardioverter-defibrillator. In this review, we emphasize shared decision making, monitored medical therapy, individual and team awareness of precautions and emergency response measures, and a more permissive approach to recreational and competitive exercise.

Modeling Atrial Fibrillation using Human Embryonic Stem Cell-Derived Atrial Tissue

Since current experimental models of Atrial Fibrillation (AF) have significant limitations, we used human embryonic stem cells (hESCs) to generate an atrial-specific tissue model of AF for pharmacologic testing. We generated atrial-like cardiomyocytes (CMs) from hESCs which preferentially expressed atrial-specific genes, and had shorter action potential (AP) durations compared to ventricular-like CMs. We then generated confluent atrial-like CM sheets and interrogated them using optical mapping techniques. Atrial-like CM sheets (~1 cm in diameter) showed uniform AP propagation, and rapid re-entrant rotor patterns, as seen in AF could be induced. Anti-arrhythmic drugs were tested on single atrial-like CMs and cell sheets. Flecainide profoundly slowed upstroke velocity without affecting AP duration, leading to reduced conduction velocities (CVs), curvatures and cycle lengths of rotors, consistent with increased rotor organization and expansion. By contrast, consistent with block of rapid delayed rectifier K+ currents (Ikr) and AP prolongation in isolated atrial-like CMs, dofetilide prolonged APs and reduced cycle lengths of rotors in cell sheets without affecting CV. In conclusion, using our hESC-derived atrial CM preparations, we demonstrate that flecainide and dofetilide modulate reentrant arrhythmogenic rotor activation patterns in a manner that helps explain their efficacy in treating and preventing AF.

Sudden cardiac death: A reappraisal

Sudden cardiac death (SCD) is still among the leading causes of death in women and men, accounting for over 50% of all fatal cardiovascular events in the United States. Two arrhythmia mechanisms of SCD can be distinguished as follows: shockable rhythms (ventricular fibrillation and pulseless ventricular tachycardia) and non-shockable rhythms including asystole or pulseless electrical activity. The overall prognosis of cardiac arrest due to shockable rhythms is significantly better. While the majority of SCDs is attributed to coronary artery disease or other structural heart disease, no obvious cause can be identified in 5% of all events, and those events are labeled as sudden unexplained deaths (SUD). Those unexplained events are typically caused by rare hereditary electrical disorders or arrhythmogenic cardiomyopathies. A systematic approach to the diagnosis of cardiac arrest followed by tailored therapy based on etiology has emerged in the last 10-15 years, with significant changes of medical practice and risk management of cardiac arrest victims. The aim of this review is to summarize our contemporary understanding of SCD/SUD in adults and to discuss current concepts of management and secondary prevention in cardiac arrest victims. A full discussion of the topic of primary prevention of SCD is beyond the scope of this article.

Beyond the Electrocardiogram: Mutations in Cardiac Ion Channel Genes Underlie Nonarrhythmic Phenotypes:

Cardiac ion channelopathies are an important cause of sudden death in the young and include long QT syndrome, Brugada syndrome, catecholaminergic polymorphic ventricular tachycardia, idiopathic ventricular fibrillation, and short QT syndrome. Genes that encode ion channels have been implicated in all of these conditions, leading to the widespread implementation of genetic testing for suspected channelopathies. Over the past half-century, researchers have also identified systemic pathologies that extend beyond the arrhythmic phenotype in patients with ion channel gene mutations, including deafness, epilepsy, cardiomyopathy, periodic paralysis, and congenital heart disease. A coexisting phenotype, such as cardiomyopathy, can influence evaluation and management. However, prior to recent molecular advances, our understanding and recognition of these overlapping phenotypes were poor. This review highlights the systemic and structural heart manifestations of the cardiac ion channelopathies, including their phenotypic spectrum and molecular basis.

Genetic Testing in the Evaluation of Unexplained Cardiac ArrestCLINICAL PERSPECTIVE: From the CASPER (Cardiac Arrest Survivors With Preserved Ejection Fraction Registry)

Background— Unexplained cardiac arrest may be because of an inherited arrhythmia syndrome. The role of genetic testing in cardiac arrest survivors without a definite clinical phenotype is unclear. Methods and Results— The CASPER (Cardiac Arrest Survivors with Preserved Ejection Fraction Registry) is a large registry of cardiac arrest survivors where initial assessment reveals normal coronary arteries, left ventricular function, and resting ECG. Of 375 cardiac arrest survivors in CASPER from 2006 to 2015, 174 underwent genetic testing. Patients were classified as phenotype-positive (n=72) or phenotype-negative (n=102). Genetic testing was performed at treating physicians’ discretion in line with contemporary guidelines and availability. All genetic variants identified from original laboratory reports were reassessed by the investigators in line with modern criteria. Pathogenic variants were identified in 29 (17%) patients (60% channelopathy-associated and 40% cardiomyopathy-associated genes) and 70 variants of unknown significance were identified in 32 (18%) patients. Prior syncope (odds ratio, 4.0; 95% confidence interval, 1.6–9.7) and a family history of sudden death (odds ratio, 3.2; 95% confidence interval, 1.1–9.4) were independently associated with the presence of a pathogenic variant. In phenotype-negative patients, broad multiphenotype genetic testing led to higher yields (21% versus 8%; P=0.04) but was associated with more variants of unknown significance (55% versus 5%; P<0.01). Conclusions— Genetic testing identifies a pathogenic variant in a significant proportion of unexplained cardiac arrest survivors. Prior syncope and family history of sudden death are predictors of a positive genetic test. Both arrhythmia and cardiomyopathy genes are implicated. Broad, multiphenotype testing revealed the highest frequency of pathogenic variants in phenotype-negative patients. Clinical Trial Registration— https://www.clinicaltrials.gov. Unique Identifier: NCT00292032

Personalizing therapy for atrial fibrillation: the role of stem cell and in silico disease models

Atrial fibrillation (AF) is the most common cardiac arrhythmia and is associated with substantial morbidity. There is considerable inter-patient variability in the pathologic processes that promote AF, and this variability likely has a significant genetic basis. Clinically this is reflected by the observation that anti-arrhythmic drugs and interventional procedures have highly variable efficacy, and this highlights the need for adopting a more efficacious personalized approach. We explore recent advancements in both in silico and stem cell disease models that set the stage for a personalized approach. Specifically we highlight new mechanistic insights in AF; the future role of computational models in planning personalized ablation strategies; the potential role of stem cell models as a preclinical platform for drug development; and the potential to use gene-editing technology to create patient-specific stem cell models. Finally, we introduce the concept of integrating stem cell models with computational modelling to create a novel pipeline for patient-specific drug discovery and development.

The Canadian Arrhythmogenic Right Ventricular Cardiomyopathy Registry: Rationale, Design, and Preliminary Recruitment

BACKGROUND Arrhythmogenic right ventricular cardiomyopathy (ARVC) is a complex and clinically heterogeneous arrhythmic condition. Incomplete penetrance and variable expressivity are particularly evident in ARVC, making clinical decision-making challenging. METHODS Pediatric and adult cardiologists, geneticists, genetic counsellors, ethicists, nurses, and qualitative researchers are collaborating to create the Canadian ARVC registry using a web-based clinical database. Biological samples will be banked and systematic analysis will be performed to examine potentially causative mutations, variants, and biomarkers. Outcomes will include syncope, ventricular arrhythmias, defibrillator therapies, heart failure, and mortality. RESULTS Preliminary recruitment has enrolled 365 participants (aged 42.7 ± 17.1 years; 50% women), including 129 probands and 236 family members. Previous cardiac arrest occurred in 28 (8%) participants, syncope occurred in 43 (12%) participants, and 46% of probands had a family history of sudden death. Overall yield of genetic testing was 36% for a disease-causing mutation and 20% for a variant of unknown significance. Target enrollment is 1000 affected patients and 500 unaffected family member controls over 7 years. The cross-sectional and longitudinal data collected in this manner will allow a robust assessment of the natural history and clinical course of genetic subtypes. CONCLUSIONS The Canadian ARVC Registry will create a population-based cohort of patients and their families to inform clinical decisions regarding patients with ARVC.

The QT Interval in Anorexia Nervosa: A Meta-Analysis

Anorexia nervosa (AN) affects 1% of the population, with the highest mortality of any eating disorder, in part attributed to ventricular arrhythmia [(1)][1]. The QT interval on the electrocardiogram (ECG), corrected for heart rate (QTc interval), provides a simple and reliable measure of cardiac

Quinidine effective for the management of ventricular and atrial arrhythmias associated with Brugada syndrome

Key Teaching Points • Atrial arrhythmias are common in patients with Brugada syndrome. • Many medications commonly used to treat atrial arrhythmias are contraindicated in patients with Brugada syndrome. • Quinidine has been shown to be an effective antiarrhythmic drug for some patients with Brugada syndrome who suffer from ventricular arrhythmias and may be beneficial to patients with Brugada syndrome who suffer from atrial arrhythmias as well.