Molecular and genetic basis of sudden cardiac death

Abstract

The abrupt cessation of effective cardiac function due to an aberrant heart rhythm can cause sudden and unexpected death at any age, a syndrome called sudden cardiac death (SCD). Annually, more than 300,000 cases of SCD occur in the United States alone, making this a major public health concern. Our current understanding of the mechanisms responsible for SCD has emerged from decades of basic science investigation into the normal electrophysiology of the heart, the molecular physiology of cardiac ion channels, fundamental cellular and tissue events associated with cardiac arrhythmias, and the molecular genetics of monogenic disorders of heart rhythm. This knowledge has helped shape the current diagnosis and treatment of inherited arrhythmia susceptibility syndromes associated with SCD and has provided a pathophysiological framework for understanding more complex conditions predisposing to this tragic event. This Review presents an overview of the molecular basis of SCD, with a focus on monogenic arrhythmia syndromes.

Muscarinic Receptor Activation Increases hERG Channel Expression through Phosphorylation of Ubiquitin Ligase Nedd4-2

“…There are other potential limitations in the present study. Although we studied the effect of muscarinic receptor activation on various K 1 channels (e.g., hERG, K v 1.5, and EAG) stably expressed in HEK cells and on ERG channels in neonatal rat cardiomyocytes, we did not study the effect of muscarinic receptor activation on sodium and calcium channels, which also play important roles in the cardiac action potential (George, 2013). Thus, extrapolation of our observations to mammalian and human in vivo function must be made with caution.…”

Physiological genomics identifies genetic modifiers of long QT syndrome type 2 severity

“…The cardinal feature of the disease is a prolonged QT interval on surface electrocardiograms that signals elevated risk for a life-threatening cardiac arrhythmia with clinical manifestations including palpitations, syncope, and an increased predisposition for sudden cardiac death (4). Specifically, mutations in KCNH2, which encodes the rapid component (I Kr ) of the delayed rectifier potassium channel (hERG), cause long QT syndrome type 2 (LQT2), which accounts for about 30% of all LQTS diagnoses (5).…”

Cardiovascular science: opportunities for translating research into improved care

“…Genetic abnormalities in cardiac ion channels, commonly referred to as channelopathies, are responsible for the electrophysiologic changes that may cause these serious arrhythmias. George reviews these monogenic disorders and describes recent progress in the understanding of how various mutations affect the proteins that constitute the ion channels (45). The most common and most widely studied of these disorders is congenital long QT syndrome (LQTS), which occurs in 1 of every 2,500 individuals and is characterized by considerable genetic and phenotypic heterogeneity.…”

“…Indeed, guidelines for the application of these tests were recently published (47). Comprehensive genetic testing is recommended for patients with or suspected of having LQTS, catecholaminergic polymorphic ventricular tachycardia, Brugada syndrome, and short QT syndrome, conditions that are discussed by George (45). In addition to aiding in diagnosis, elucidation of the genetic abnormality can also be helpful in estimating prognosis and in the selection of appropriate therapy.…”