TRANSCRIPTIONAL REGULATION OF THE CARDIAC CONDUCTION SYSTEM

Abstract

The cardiac conduction system (VCS) is essential for normal myocardial excitation and contraction. Heritable and acquired syndromes perturbing conduction system formation or function are responsible for a substantial burden of cardiovascular disease, including heart block, triggered and reentrant arrhythmias, sudden cardiac death, myocardial dyssynchrony, and progression of heart failure. Our laboratory has employed stem cell models, genetically encoded conduction system reporter mice, comparative transcriptional profiling, and a battery of functional assays to elucidate the molecular determinants of conduction system development, physiology, and disease pathogenesis. Through these strategies, we have uncovered a diversity of novel conduction system-enriched genes, including transcription factors, receptors, and signaling molecules that modulate conduction system physiology. Our long-term goals are to leverage these discoveries for therapeutic impact and to diminish the burden of diseases resulting from abnormal cardiac rhythmicity.

Fig. 1.

Sodium nitroprusside enhances generation of cardiac conduction system cells. A. Flow cytometry analysis of Cntn2-EGFP expression. Murine ESC-derived cardiomyocytes were treated for five days with either DMSO or sodium nitroprusside (SN) and harvested at Day 25 of differentiation. Quantification of Cntn2-EGFP expression is shown in the right panel. B. Comparison of action potential duration, quantified by APD(50) and APD(90) between GFP− (black bars) presumptive ventricular cardiomyocytes and GFP⁺ presumptive Purkinje-like myocytes (gray bars). Adapted from (16).

Fig. 2.

Abnormal conduction system structure and function in Etv1 mutant mice. A. Appearance of the ventricular conduction system as visualized by the Cntn2-EGFP reporter gene in postnatal Day 18 wildtype (WT) and ETV1 knockout (KO) mice. B. Representative electrocardiograms in postnatal Day 18 WT and KO mice, showing prolonged P, PR, and QRS intervals in the KO mice. Adapted from (15).