The heartbeat is organized by the cardiac conduction system (CCS), a specialized network of cardiomyocytes. Patterning of the CCS into atrial node versus ventricular conduction system (VCS) components with distinct physiology is essential for the regular heartbeat.

Distinct node versus VCS physiology has been recognized for more than a century, but this regional patterning’s molecular basis is not well understood. This study aimed to determine the genetic and genomic mechanisms underlying node versus VCS distinction and investigate rhythm consequences of failed VCS patterning. Action potentials of Tbx5-deficient VCS myocytes adopted nodal-specific characteristics, including increased action potential duration and cellular automaticity. TBX5 bound and directly activated cis-regulatory elements at fast conduction channel genes required for the VCS action potential’s fast physiological characteristics, defining the identity of the adult VCS. Further studies are necessary to investigate the genomic establishment of the slow versus fast GRNs to explain how two states, slow versus fast, are observed in the conduction system with no intermediate phenotypes. Incomplete removal of the fast network, by decreased but not eliminated expression of Tbx5 or its targets, are associated with arrhythmia risk in mice and men.

In conclusion, the degree to which these perturbations afford uncovering underlying nodal potential as an arrhythmia risk factor remains to be determined. The patterning model for the CCS provides a model for the homeostatic control of the cardiac contraction cycle.