Voltage-gated sodium channels drive the initial depolarization phase of the cardiac action potential and therefore critically determine conduction of excitation through the heart. In patients, deletions or loss-of-function mutations of the cardiac sodium channel gene, SCN5A, have been associated with a wide range of arrhythmias including bradycardia (heart rate slowing), atrioventricular conduction delay, and ventricular fibrillation. The pathophysiological basis of these clinical conditions is unresolved. Here we show that disruption of the mouse cardiac sodium channel gene, Scn5a, causes intrauterine lethality in homozygotes with severe defects in ventricular morphogenesis whereas heterozygotes show normal survival. Whole-cell patch clamp analyses of isolated ventricular myocytes from adult Scn5a ؉/؊ mice demonstrate a Ϸ50% reduction in sodium conductance. Scn5a ؉/؊ hearts have several defects including impaired atrioventricular conduction, delayed intramyocardial conduction, increased ventricular refractoriness, and ventricular tachycardia with characteristics of reentrant excitation. These findings reconcile reduced activity of the cardiac sodium channel leading to slowed conduction with several apparently diverse clinical phenotypes, providing a model for the detailed analysis of the pathophysiology of arrhythmias. Cardiac arrhythmias, manifest clinically by symptoms of extra, slow, or rapid heart beats, form one of the most common groups of diseases (1). The detailed understanding of the pathophysiology of these conditions now seems possible (2), having been advanced by the identification of ion channel mutations in patients with these conditions (3-5). What has become clear is that the functional consequences of such mutations can be complex, resolved only by combining appropriate clinical, experimental, and theoretical approaches (2). Accordingly, the consequences of gainof-function mutations in the cardiac sodium channel gene, SCN5A, in patients with long-QT syndrome (LQT3) (6, 7), have been investigated by studies of clinical genotype-phenotype relationships (3)(4)(5)8) and their cellular electrophysiology (9, 10) by using computer models (11,12) and the construction of a transgenic mouse (13). The results of these various investigations have allowed a clearer picture to emerge of the pathophysiology of LQT3 (7).In addition to the descriptions of long-QT syndrome-associated mutations, loss-of-function mutations in SCN5A (14, 15) have been described in patients with phenotypic characteristics of bradycardia (16, 17), atrioventricular block (16, 18), and ventricular fibrillation (18)(19)(20)(21)(22). These observations suggest a central role for the sodium channel in the maintenance of the normal heart beat (23-25). The mechanism of arrhythmias in these conditions, however, remains unresolved, although fibrillation could result from delayed conduction, unidirectional block, and reentrant excitation (3, 4). We have used homologous recombination in embryonic stem cells to establish mice with a null mutatio...

Objective: To report the timing of presentation and clinical profile of a cohort of fetuses with normal main cardiac connections but fetal echocardiographic signs suggestive of coarctation of the aorta. Design: Retrospective observational study. Setting: Tertiary fetal and paediatric cardiology centre. Patients: Between 1 January 1998 and 31 December 2002, 174 fetuses were studied, of whom 144 infants were born alive. Main outcome measures: Of the 144 liveborn infants, 43 had coarctation of the aorta, four had interruption of the aortic arch, and one was managed as having hypoplastic left heart syndrome. Hemianomalous pulmonary venous drainage was diagnosed in two infants. Three infants with coarctation presented late at 7-13 weeks of age, 6-12 weeks after closure of the arterial duct. Fetuses with cardiac asymmetry had a higher incidence of left superior vena cava than a control group. For fetuses with cardiac asymmetry, the incidence of left superior vena cava and ventricular septal defects was similar in infants who proved to have coarctation postnatally and in those who did not. The 30 day and one year surgical mortality of infants having repair of coarctation of the aorta was two of 41 (4.9%, 95% confidence interval (CI) 0.6 to 16.0). All cause mortality of liveborn infants with any abnormality of the aortic arch was five of 48 (10.4%, 95% CI 3.5 to 22.7) at 30 days and one year, which was heavily influenced by prematurity and extracardiac abnormalities. Conclusions: Precise diagnosis of coarctation of the aorta during fetal life remains difficult. Coarctation of the aorta may present several weeks after closure of the arterial duct and sequential echocardiography is recommended.

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Beta-adrenoreceptor blockade does not confer an antiarrhythmic effect and may even enhance arrhythmogenesis by increasing reentrant substrate in Scn5a+/Delta hearts while mexiletine protects against VT without modifying conduction characteristics. Together these findings permit a scheme where VT in LQT3 is initiated by triggered mechanisms but propagated by reentry.

Atrial septal defects (ASDs) are among the most common of congenital heart defects and are frequently associated with atrial arrhythmias. Atrial and ventricular geometrical remodelling secondary to the intracardiac shunt promotes evolution of the electrical substrate, predisposing the patient to atrial fibrillation and other arrhythmias. Closure of an ASD reduces the immediate and long-term prevalence of atrial arrhythmias, but the evidence suggests that patients remain at an increased long-term risk in comparison with the normal population. The closure technique itself and its timing impacts future arrhythmia risk profile while subsequent transseptal access following surgical or device closure is complicated. Newer techniques combined with increased experience will help to alleviate some of the difficulties associated with optimal management of arrhythmias in these patients.