Sudden cardiac death and inherited channelopathy: the basic electrophysiology of the myocyte and myocardium in ion channel disease

Abstract

Mutations involving cardiac ion channels result in abnormal action potential formation or propagation, leading to cardiac arrhythmias. Despite the large impact on society of sudden cardiac death resulting from such arrhythmias, understanding of the underlying cellular mechanism is poor and clinical risk stratification and treatment consequently limited. Basic research using molecular techniques, as well as animal models, has proved extremely useful in improving our knowledge of inherited arrhythmogenic syndromes. This offers the practitioner tools to accurately diagnose rare disorders and provides novel markers for risk assessment and a basis for new strategies of treatment.

Pluripotent Stem Cell Models of Human Heart Disease

“…Several chromosomal abnormalities, rare DNA variants, or common DNA variants have been associated with congenital heart disease in newborns (Bruneau 2008), and many mutations in genes encoding cardiac ion channels and sarcomeric proteins have been identified in several electrophysiological cardiac disorders (channelopathies) and cardiomyopathies (Jacoby and McKenna 2012;Martin et al 2012). With the advent of new techniques for efficient genetic manipulation through homologous recombination, introduction of targeted mutations into hESCs is becoming a very attractive tool for generating hESC-based models of monogenic cardiac diseases.…”

Identifying potential functional impact of mutations and polymorphisms: linking heart failure, increased risk of arrhythmias and sudden cardiac death

“…These arrhythmias can be the result of a variety of structural changes of the heart or ion channel dysfunctions sometimes through an altered expression. During the last decade, researchers and clinicians have discovered important concepts by elucidating the mechanisms responsible for rare monogenic arrhythmic disorders, so called channelopathies (Martin et al, 2012; George, 2013). Indeed, one major step in defining the molecular basis of normal and abnormal cardiac electrical behavior has been the identification of single mutations that greatly increase the risk for arrhythmias, cardiomyopathies, and SCD (for review see Basso et al, 2011; McNally et al, 2013).…”

The Use of Implantable Cardioverter-defibrillators in the Prevention of Sudden Cardiac Death: A Focus on Congenital Heart Disease and Inherited Arrhythmia Syndromes

“…42 Clinical manifestations can range from asymptomatic carriers to malignant VAs and SCD. 43 This heterogeneity of disease expression poses significant challenges to appropriate risk stratifications for SCD and patient selection for ICD use. Current disease-specific recommendations are largely based on expert opinion and small observational studies.…”