Identifying Irregular Heartbeat
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Identifying Irregular Heartbeat Genotyping for Diagnosis of Primary Cardiac Arrhythmia1 Executive summary Primary cardiac arrhythmia is an irregular heartbeat resulting from one of several underlying genetic abnormalities known as ‘cardiac ion channelopathies’ – mutations in ion-channel membrane proteins of heart cells. The condition often manifests in clinical events such as fainting and sudden unexpected death due to cardiac arrest. In the last 15 years, the molecular genetics of several cardiac ion channelopathies have been characterized and diagnostic genotyping has become available. The remarkable variability in clinical symptoms (phenotype) arising from a single channelopathy complicates clinical diagnosis and makes genotyping for accurate diagnosis a topic of considerable importance, since effective therapies to prevent sudden death exist. Not surprisingly for such a young and rapidly evolving field, the role of diagnostic genotyping is a work in progress, with no formal guidelines or recommendations currently existing. In the US, genotyping for primary cardiac arrhythmia was performed only in research laboratories until 2004, when Genaissance Pharmaceuticals launched the first commercial diagnostic – the Familion™ test. At present, several laboratories worldwide offer clinical genotyping for the known cardiac ion channelopathies. However, the high rate of false-negatives and occasional false-positives in genotyping of major channelopathies means that interpretation of results in the context of patient phenotype, family history and other clinical features is required for accurate diagnosis. Currently, clinical application of diagnostic genotyping is most clearly established for certain forms of long QT syndrome (LQTS) and Brugada syndrome (BrS). The currently accepted role of genotyping is for diagnosis of individual patients and family members with suspected or known channelopathies, rather than for screening of general at-risk patient groups – although the latter strategy may become feasible in the future. Clinical genotyping to guide therapeutic decisions has limited application at present but will become much more important if genotypespecific therapies are shown to be effective.
An irregular heartbeat due to an underlying genetic abnormality is known medically as a ‘primary cardiac arrhythmia’ or a ‘cardiac ion channelopathy’. The latter name reflects the molecular basis for such a disorder, namely mutation(s) in specific proteins embedded in the membranes of heart cells that act as channels for ions such as potassium and sodium to flow in and out of the cell. These cardiac ion channel proteins control electrical activation and repolarization of the heart, and mutations in them result in abnormal ion flow that leads to cardiac arrhythmias in the absence of any other heart disease or environmental influence. All of the currently known cardiac ion channelopathies (see table I) are associated with arrhythmia, and most with syncope (fainting) or unexpected sudden cardiac death as a consequence of the arrhy
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