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.
"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). "
[Show abstract][Hide abstract] 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.
Frontiers in Physiology 09/2013; 4:254. DOI:10.3389/fphys.2013.00254 · 3.53 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Cardiovascular research is progressing on many fronts, as highlighted in the collection of Reviews in this issue of the JCI. MicroRNAs that regulate cardiac function have been implicated in cardiac disorders, and efforts to develop therapeutic antagomirs are underway. The genetic bases of several cardiac disorders, including cardiomyopathies that cause heart failure and channelopathies that underlie cardiac arrhythmias, have been elucidated. Genetic testing can identify asymptomatic individuals at risk, potentially leading to effective preventative measures. Growing evidence supports the role of chronic inflammation in atherosclerosis, providing new opportunities for therapeutic intervention. For heart failure, recent work suggests that cardiac regeneration using stem/progenitor cells, gene transfer, new drugs that restore normal Ca2+ cycling, and agents that reduce reperfusion injury following myocardial infarction are all viable new approaches to managing disease. Cumulatively, it seems likely that the clinical advances emerging from ongoing research will, in the foreseeable future, reduce the number of deaths in the industrialized world from cardiovascular disease.
The Journal of clinical investigation 01/2013; 123(1):6-10. DOI:10.1172/JCI67541 · 13.22 Impact Factor
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