HF-1 b, an SP1 -related transcription factor, is preferentially expressed in the cardiac conduction system and ventricular myocytes in the heart. Mice deficient for HF-1 b survive to term and exhibit normal cardiac structure and function but display sudden cardiac death and a complete penetrance of conduction system defects, including spontaneous ventricular tachycardia and a high incidence of AV block. Continuous electrocardiographic recordings clearly documented cardiac arrhythmogenesis as the cause of death. Single-cell analysis revealed an anatomic substrate for arrhythmogenesis, including a decrease and mislocalization of connexins and a marked increase in action potential heterogeneity. Two independent markers reveal defects in the formation of ventricular Purkinje fibers. These studies identify a novel genetic pathway for sudden cardiac death via defects in the transition between ventricular and conduction system cell lineages.

Slow conduction in the TV-IVC isthmus may be mechanistically important for the development of human type I atrial flutter.

Background-Stimulation of 5-HT 4 receptors increases atrial chronotropic and inotropic responses. Whether other electrophysiological effects are produced is unknown. In humans and swine, 5-HT 4 receptors are present only in atrium. Therefore, the effects of a novel 5-HT 4 receptor antagonist, RS-100302, and the partial agonist cisapride on atrial flutter and fibrillation induced in swine were studied to delineate the role of the 5-HT 4 receptor in modulating atrial electrophysiological properties and the antiarrhythmic potential of RS-100302. Methods and Results-In 17 anesthetized, open-chest, juvenile pigs, atrial flutter or fibrillation was induced by rapid right atrial pacing with or without a right atrial free wall crush injury, respectively. Atrial effective refractory period (ERP), conduction velocity, wavelength, and dispersion of refractoriness were determined during programmed stimulation via a 56-electrode mapping plaque sutured to the right atrial free wall. Ventricular electrophysiological parameters were also measured. All electrophysiological parameters were measured at baseline and after infusion of RS-100302 and cisapride.In the atrium, RS-100302 prolonged mean ERP (115Ϯ8 versus 146Ϯ7 ms, PϽ0.01) and wavelength (8.3Ϯ0.9 versus 9.9Ϯ0.8 cm, PϽ0.01), reduced dispersion of ERP (15Ϯ5 versus 8Ϯ1 ms, PϽ0.01), and minimally slowed conduction velocity (72Ϯ4 versus 67Ϯ5 cm/s, PϽ0.01). These effects were all partially reversed by cisapride. RS-100302 produced no ventricular electrophysiological effects. RS-100302 terminated atrial flutter in 6 of 8 animals and atrial fibrillation in 8 of 9 animals and prevented reinduction of sustained tachycardia in all animals. Conclusions-The electrophysiological profile of RS-100302 suggests that it may have atrial antiarrhythmic potential without producing ventricular proarrhythmic effects.

The electrophysiologic profile of KCB-328 in this canine model of AFL, particularly its lack of reverse use-dependent effect on atrial refractoriness, suggests that it may have significant antiarrhythmic potential in treatment of atrial arrhythmias.

BACKGROUND: The electrophysiologic mechanisms of the persistence of atrial fibrillation (AF) after its initiation are not well understood. Therefore, the electrophysiologic characteristics of the right atrium were evaluated in an acute, pacing-induced model of AF in the pig in order to identify parameters associated with persistence of AF. METHODS AND RESULTS: AF was induced by rapid atrial pacing in 30 anesthetized, open-chest, juvenile pigs. Sustained (S) AF was defined as that lasting >10 minutes, nonsustained (NS) AF <10 minutes but >30 seconds, and no (N) AF <30 seconds. Activation mapping and programmed stimulation (S1S1 = 200 ms) was performed at 56 electrodes on the right atrial free wall, to determine ERP (mean and minimum), dispersion of refractoriness (ERPdisp, ELEdisp), conduction velocity (CV), wavelength, AF cycle length (mean of 10 beats), and AF cycle length/time (electrical remodeling). SAF was induced in 10 pigs, NSAF in 9, and NAF in 11. AF cycle length was shorter in SAF and/vs NS vs NAF (P <.001). Mean ERP (107 +/- 9 and/vs 122 +/- 5 vs 142 +/- 9, p <.001) and wavelength (7 +/- 1 and/vs 9 +/- 1 vs 11 +/- 1, P <.001) were shorter in SAF and/vs NSAF vs NAF. Minimum ERP was shorter in SAF and NSAF vs NAF (P <.001). CV at cycle lengths of 200 and 150 msec was not different between groups. Dispersion of ERP was greater in SAF and/vs NSAF vs NAF (8 +/- 1 and/vs 11 +/- 1 vs 19 +/- 4, P <.001). CONCLUSIONS: Persistence of AF correlated with shorter ERP and wavelength, and greater dispersion of ERP and electrical remodeling. There was no correlation with CV.