Abstract
Spatiotemporal gene expression during cardiac development is a highly regulated process. Activation of key signaling pathways involved in electrophysiological programming, such as Notch and Wnt signaling, occurs in early cardiovascular development and these pathways are reactivated during pathologic remodeling. Direct targets of these signaling pathways have also been associated with inherited arrhythmias such as Brugada syndrome and arrhythmogenic cardiomyopathy. In addition, evidence is emerging from animal models that reactivation of Notch and Wnt signaling during cardiac pathology may predispose to acquired arrhythmias, underscoring the importance of elucidating the transcriptional and epigenetic effects on cardiac gene regulation. Here, we highlight specific examples where gene expression dictates electrophysiological properties in both normal and diseased hearts.
Highlights
The human heart starts beating spontaneously about 3 weeks after fertilization [1]
The RV expresses lower levels of cardiac N a+ channels and higher levels of cardiac K + channels when compared with the LV, which contributes to slower conduction in the RV [15]. These differences can provide a critical substrate for developing lifethreatening arrhythmias that originate in the right ventricle including the ventricular outflow tract in disorders such as Brugada syndrome, where inherited mutations of the gene that encodes N a+ channels (SCN5A) or the direct Notch signaling pathway target HEY2 (Hairy/enhancer-of-split related with YRPW motif protein 2), among other mutations, can result in ventricular arrhythmias and sudden cardiac death [16, 17]
We have previously shown that developmental Notch gain of function (GOF) mice have increased action potential duration (APD) in the LV [11]
Summary
The human heart starts beating spontaneously about 3 weeks after fertilization [1]. To reach this remarkable milestone, embryonic cells must differentiate into various cardiac cell types and maintain their identity through regulated spatiotemporal gene expression [2,3,4,5]. These differences can provide a critical substrate for developing lifethreatening arrhythmias that originate in the right ventricle including the ventricular outflow tract in disorders such as Brugada syndrome, where inherited mutations of the gene that encodes N a+ channels (SCN5A) or the direct Notch signaling pathway target HEY2 (Hairy/enhancer-of-split related with YRPW motif protein 2), among other mutations, can result in ventricular arrhythmias and sudden cardiac death [16, 17].
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