A novel genetic pathway for sudden cardiac death via defects in the transition between ventricular and conduction system cell lineages

HF-1b, an SP1-related transcription factor, is preferentially expressed in the cardiac conduction system and ventricular myocytes in the heart. Mice d eficient for HF-1b survive to term and exhibit normal cardiac structure and function but display sudden cardiac death and a complete penetrance of con duction system defects, including spontaneous ventricular tachycardia and a high incidence of AV block. Continuous electrocardiographic recordings cle arly 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 p otential heterogeneity. Two independent markers reveal defects in the forma tion of ventricular Purkinje fibers. These studies identify a novel genetic pathway for sudden cardiac death via defects in the transition between ven tricular and conduction system cell lineages.