QRS interval on the electrocardiogram reflects ventricular depolarization and conduction time, and is a risk factor for mortality, sudden death, and heart failure. We performed a genome-wide association meta-analysis in 40,407 European-descent individuals from 14 studies, with further genotyping in 7170 additional Europeans, and identified 22 loci associated with QRS duration (P < 5 × 10−8). These loci map in or near genes in pathways with established roles in ventricular conduction such as sodium channels, transcription factors, and calcium-handling proteins, but also point to novel biologic processes, such as kinase inhibitors and genes related to tumorigenesis. We demonstrate that SCN10A, a gene at our most significant locus, is expressed in the mouse ventricular conduction system, and treatment with a selective SCN10A blocker prolongs QRS duration. These findings extend our current knowledge of ventricular depolarization and conduction.

Background-Purkinje cells (PCs) comprise the most distal component of the cardiac conduction system, and their unique electrophysiological properties and the anatomic complexity of the Purkinje fiber network may account for the prominent role these cells play in the genesis of various arrhythmic syndromes. Methods and Results-Differential transcriptional profiling of murine Purkinje fibers and working ventricular myocytes was performed to identify novel genes expressed in PCs. The most highly enriched transcript in Purkinje fibers encoded Contactin-2 (Cntn2), a cell adhesion molecule critical for neuronal patterning and ion channel clustering. Endogenous expression of Cntn2 in the murine ventricle was restricted to a subendocardial network of myocytes that also express ␤-galactosidase in CCS-lacZ transgenic mice and the connexin40 gap junction protein. Key Words: cell adhesion molecules Ⅲ electrophysiology Ⅲ genetics Ⅲ Purkinje fiber P urkinje fibers (PFs) are the most distal component of the cardiac conduction system (CCS), first described by Purkinje in 1839 as gray, flat, gelatin-like ramifications, running under the endocardium. 1 Some 70 years later, Tawara 2 more fully characterized the Purkinje system, identifying the left (anterior, septal, and posterior) and right fascicular strands, which served to connect the distal PFs to the bundle branches proper. Tawara was also the first to correctly suggest the functional role of the Purkinje system in rapidly transmitting the electric wave of excitation to the ventricular muscle. Clinical Perspective on p 194PFs appear to play a prominent role in the genesis of ventricular arrhythmias, (reviewed in Reference 3). 3 PF and anterior or posterior left fascicular triggers have been implicated in the initiation of monomorphic ventricular tachycardia in post-myocardial infarction patients, as demonstrated by cure after focal ablation of Purkinje fiber or fascicular potentials. 4 -6 PF-based triggers have also been described in patients with ventricular tachycardia associated with dilated forms of cardiomyopathy, 7 as well as idiopathic ventricular fibrillation (VF), in which ablation of premature beats arising from the PF network resulted in significant reductions in the recurrence of VF. 8 PF-dependent triggering of arrhythmias has also been proposed in inherited syndromes including catecholaminergic polymorphic VT, 9 Brugada syndrome, and long-QT syndrome. 10 Despite growing evidence implicating PFs in ventricular arrhythmogenesis, our understanding of the cellular mechanisms underlying PF-dependent diseases is hampered by the lack of knowledge of the developmental biology of individual Purkinje cells (PCs), their patterning into a network of highly coupled cells, and their adaptive and maladaptive responses to pathological stimuli. To some extent, this gap in knowledge reflects the anatomic complexity of the PF network, which includes branching cells that couple not only with neighboring PCs but also with working myocytes at Purkinje- In recent years, a number of "...

Rationale Post-translational phosphorylation of connexin43 (Cx43) has been proposed as a key regulatory event in normal cardiac gap junction expression and pathologic gap junction remodeling. Nonetheless, the role of Cx43 phosphorylation in the context of the intact organism is poorly understood. Objective To establish whether specific connexin43 phosphorylation events influence gap junction expression and pathologic remodeling. Methods and Results We generated Cx43 germline knock-in mice in which serines 325/328/330 were replaced with phosphomimetic glutamic acids (S3E) or non-phosphorylatable alanines (S3A). The S3E mice were resistant to acute and chronic pathologic gap junction remodeling (GJR) and displayed diminished susceptibility to the induction of ventricular arrhythmias. Conversely, the S3A mice showed deleterious effects on cardiac gap junction formation and function, developed electrical remodeling and were highly susceptible to inducible arrhythmias. Conclusions These data demonstrate a mechanistic link between post-translational phosphorylation of Cx43 and gap junction formation, remodeling and arrhythmic susceptibility.

Rationale: The Purkinje fiber network has been proposed as the source of arrhythmogenic Ca 2؉ release events in catecholaminergic polymorphic ventricular tachycardia (CPVT), yet evidence supporting this mechanism at the cellular level is lacking.