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

Area of Science:

• Cardiology
• Developmental Biology
• Molecular Biology

Background:

• Inherited arrhythmias like Brugada syndrome often affect the right ventricle, increasing sudden cardiac death risk.
• Distinct embryonic origins of right and left ventricular cardiomyocytes suggest developmental programming influences chamber-specific function and arrhythmia susceptibility.

Purpose of the Study:

• To investigate how embryonic programming, specifically Wnt signaling, contributes to chamber-specific cardiac conduction and arrhythmia susceptibility.
• To determine if developmental Wnt signaling perturbation leads to persistent, chamber-specific electrophysiological differences.

Main Methods:

• Utilized mice models with Wnt transcriptional activity deficiency.
• Performed transcriptional profiling of right and left ventricles.
• Assessed cardiac conduction and excitability through ex vivo and in vivo stimulation.

Main Results:

• Developmental Wnt signaling perturbation induced persistent, chamber-specific transcriptional regulation of cardiac conduction genes (e.g., Gja1, Scn5a).
• Hey2, a Brugada syndrome-associated gene, was identified as a Wnt signaling target exclusively in the right ventricle.
• Wnt-deficient hearts exhibited perturbed right ventricular conduction and excitability, leading to inducible ventricular tachycardia upon right ventricular stimulation.

Conclusions:

• Embryonic Wnt signaling perturbation establishes chamber-specific gene expression patterns that persist into adulthood.
• This developmental programming underlies right ventricular arrhythmia susceptibility by regulating genes involved in cardiac electrophysiology.
• The findings link embryonic Wnt signaling to inherited right ventricular arrhythmias and sudden cardiac death.