Molecular and genetic basis of sudden cardiac death

The Journal of clinical investigation (Impact Factor: 13.22). 01/2013; 123(1):75-83. DOI: 10.1172/JCI62928
Source: PubMed


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.

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    • "Ventricular fibrillation (VF), manifesting as chaotic unsynchronized electrical activity in the heart, is known to cause sudden cardiac death (SCD). SCD is one of the largest natural causes of death, killing more than 300,000 people annually in the United States [1] [2]. Alternans, which is a beat-to-beat alternation in the action potential duration (APD), has been implicated as being proarrhythmic and a potential source of cardiac instability [3] [4] [5] [6]. "
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    ABSTRACT: Sudden cardiac death instigated by ventricular fibrillation (VF) is the largest cause of natural death in the USA. Alternans, a beat-to-beat alternation in the action potential duration, has been implicated as being proarrhythmic. The onset of alternans is mediated via a bifurcation, which may occur through either a smooth or a border-collision mechanism. The objective of this study was to characterize the mechanism of bifurcation to alternans based on experiments in isolated whole rabbit hearts. High resolution optical mapping was performed and the electrical activity was recorded from the left ventricle (LV) epicardial surface of the heart. Each heart was paced using an “alternate pacing protocol,” where the basic cycle length (BCL) was alternatively perturbed by ± δ . Local onset of alternans in the heart, BCL start , was measured in the absence of perturbations ( δ = 0 ) and was defined as the BCL at which 10% of LV exhibited alternans. The influences of perturbation size were investigated at two BCLs: one prior to BCL start ( BCL prior = BCL start + 2 0 ms) and one preceding BCL prior ( BCL far = BCL start + 40 ms). Our results demonstrate significant spatial correlation of the region exhibiting alternans with smooth bifurcation characteristics, indicating that transition to alternans in isolated rabbit hearts occurs predominantly through smooth bifurcation.
    Full-text · Article · Nov 2015
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    • "Because most of the 25 genes linked to SCD also serve roles outside the heart, the possibility arises that even monogenic forms of SCD may involve complex, multisystem disease pathogenesis not confined to direct dysfunction of cardiac myocyte electrical activity. Many SCD-linked genes encode ion channel pore-forming (α) subunits , but the rest encode proteins that regulate them [2]. KCNE2 (which we originally named MiRP1) is a relatively promiscuous, single-transmembrane span ion channel β subunit best known for its ability to co-assemble with and alter the trafficking and functional properties of voltage-gated potassium (Kv) channels [3]. "
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    ABSTRACT: Coronary artery disease (CAD) is the leading cause of death worldwide. An estimated half of cases involve genetic predisposition. Sequence variants in human KCNE2, which encodes a cardiac and epithelial K(+) channel β subunit, cause inherited cardiac arrhythmias. Unexpectedly, human KCNE2 polymorphisms also associate with predisposition to atherosclerosis, with unestablished causality or mechanisms. Here, we report that germline Kcne2 deletion promotes atherosclerosis in mice, overcoming the relative resistance of this species to plaque deposition. In female western diet-fed mice, Kcne2 deletion increased plaque deposition >6-fold and also caused premature ventricular complexes and sudden death. The data establish causality for the first example of ion channel-linked atherosclerosis, and demonstrate that the severity of Kcne2-linked cardiac arrhythmias is strongly diet-dependent. Copyright © 2015. Published by Elsevier Ltd.
    Full-text · Article · Aug 2015 · Journal of Molecular and Cellular Cardiology
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    • "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). "
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    ABSTRACT: Researchers and clinicians have discovered several important concepts regarding the mechanisms responsible for increased risk of arrhythmias, heart failure, and sudden cardiac death. 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 and sudden cardiac death by changing channel-gating characteristics. Indeed, mutations in several genes encoding ion channels, such as SCN5A, which encodes the major cardiac Na(+) channel, have emerged as the basis for a variety of inherited cardiac arrhythmias such as long QT syndrome, Brugada syndrome, progressive cardiac conduction disorder, sinus node dysfunction, or sudden infant death syndrome. In addition, genes encoding ion channel accessory proteins, like anchoring or chaperone proteins, which modify the expression, the regulation of endocytosis, and the degradation of ion channel a-subunits have also been reported as susceptibility genes for arrhythmic syndromes. The regulation of ion channel protein expression also depends on a fine-tuned balance among different other mechanisms, such as gene transcription, RNA processing, post-transcriptional control of gene expression by miRNA, protein synthesis, assembly and post-translational modification and trafficking. The aim of this review is to inventory, through the description of few representative examples, the role of these different biogenic mechanisms in arrhythmogenesis, HF and SCD in order to help the researcher to identify all the processes that could lead to arrhythmias. Identification of novel targets for drug intervention should result from further understanding of these fundamental mechanisms.
    Full-text · Article · Sep 2013 · Frontiers in Physiology
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