Long QT syndrome - a genetic cardiac channelopathy.

INTRODUCTION Long QT-syndrome (LQTS) is a genetic cardiac channelopathy characterised by a prolonged QT interval on a surface electrocardiogram (ECG), syncope, T-wave abnormalities, ventricular tachycardia of the torsades de pointes (TdPVT) type (Fig. 1) and an increased risk of sudden death [1]. LQTS has variable clinical presentation and is genetically characterised by incomplete penetrance, as seen in many other cardiac genetic conditions [2]. Historically, LQTS is divided into a congenital and an acquired form. Four clinical types of congenital LQTS (cLQTS) have been defined. The commonest is the Romano-Ward syndrome (RWS), with autosomal dominant inheritance and a prevalence of approximately 1 in 2,500 [1]. The other three variants known are much rarer. These are: Jervell-Lange Nielsen syndrome (JLNS), wherein LQTS is associated with congenital deafness and the pattern of inheritance is autosomal recessive; Andersen syndrome (AS), where LQTS is variably present together with other arrhythmias, periodic paralysis and malformations; and the very rare Timothy syndrome (TS), characterised by a more malignant form of LQTS, cardiac and other somatic malformations, and autism [3, 4]. The acquired form of LQTS (aLQTS) presents itself with a normal QT-interval on the ECG under normal conditions, but a prolonged interval under the influence of drug-intake or structural heart disease [5]. The aLQTS occurs much more frequently than cLQTS, and (interestingly) may have a genetic element that makes the individual more susceptible to certain drugs. The clinical diagnosis of LQTS is made using the diagnostic criteria given in Table 1 [6]. As seen, it comprises ECG findings, a clinical history of syncope and a family history of LQTS or sudden cardiac death. Importantly, the QT interval increases with decreasing heart rate, making it necessary to use a rate-corrected QT interval termed QTc (QTc = QT/÷RR) when assessing whether the interval is prolonged or normal [7]. Presently, the diagnostic criteria do not involve the results from genetic testing, but such testing is necessary to identify asymptomatic carriers and relatives of affected individuals who may otherwise present clinically with sudden death as the first symptom [8]. As beta-adrenergic blockade or the application of an ICD unit may dramatically reduce the risk of cardiac events, there exists a real treatment option in LQTS [9]. The aim of this review is to give an update on the expanding number of genes known to be associated with LQTS and their pathophysiological mechanisms.