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...