Differential Wnt-mediated programming and arrhythmogenesis in right versus left ventricles.

Several inherited arrhythmias, including Brugada syndrome and arrhythmogenic cardiomyopathy, primarily affect the right ventricle and can lead to sudden cardiac death. Among many differences, right and left ventricular cardiomyocytes derive from distinct progenitors, prompting us to investigate how embryonic programming may contribute to chamber-specific conduction and arrhythmia susceptibility. Here, we show that developmental perturbation of Wnt signaling leads to chamber-specific transcriptional regulation of genes important in cardiac conduction that persists into adulthood.

Multi-Scale Assessments of Cardiac Electrophysiology Reveal Regional Heterogeneity in Health and Disease.

The left and right ventricles of the four-chambered heart have distinct developmental origins and functions. Chamber-specific developmental programming underlies the differential gene expression of ion channel subunits regulating cardiac electrophysiology that persists into adulthood. Here, we discuss regional specific electrical responses to genetic mutations and cardiac stressors, their clinical correlations, and describe many of the multi-scale techniques commonly used to analyze electrophysiological regional heterogeneity.

Transient Notch Activation Induces Long-Term Gene Expression Changes Leading to Sick Sinus Syndrome in Mice.

Rationale: Notch signaling programs cardiac conduction during development, and in the adult ventricle, injury-induced Notch reactivation initiates global transcriptional and epigenetic changes.

Objective: To determine whether Notch reactivation may stably alter atrial ion channel gene expression and arrhythmia inducibility.

Methods And Results: To model an injury response and determine the effects of Notch signaling on atrial electrophysiology, we transiently activate Notch signaling within adult myocardium using a doxycycline-inducible genetic system (inducible Notch intracellular domain [iNICD]).

Notch-Mediated Epigenetic Regulation of Voltage-Gated Potassium Currents.

Rationale: Ventricular arrhythmias often arise from the Purkinje-myocyte junction and are a leading cause of sudden cardiac death. Notch activation reprograms cardiac myocytes to an induced Purkinje-like state characterized by prolonged action potential duration and expression of Purkinje-enriched genes.

Objective: To understand the mechanism by which canonical Notch signaling causes action potential prolongation.