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Electrophysiological patterning of the heart
Boukens, B.J.D.
Publication date 2012
Link to publication
Citation for published version (APA):
Boukens, B. J. D. (2012). Electrophysiological patterning of the heart.
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Summary of the thesis
Electrophysiological changes in the heart muscle can result in arrhythmias. These changes can be congenital or acquired and are, in some cases, accompanied by structural alterations of the myocardium. The electrophysiological properties of specialized myocardial structures, like the sinus node, atrioventricular (AV) bundle or right ventricular outflow tract (RVOT) are determined by transcription factors that during development guide the spatial and temporal expression of specific ion channels important for electrophysiological function. Genome-wide association have shown that small variations in genetic regions important for the expression of these transcription factors and ion channels modulate the normal electrical function of the heart. Furthermore, mutations in these factors are found in patients with the WPW-syndrome1, 2 or congenital AV block.3-5
In this thesis, we studied transcription factors that generate electrophysiological heterogeneity within heart during development, and investigated their role in the adult heart. Disturbances of the role of these transcription factor cause specific structural cardiac changes that facilitate arrhythmogenesis in the adult. We provide evidence for a potential arrhythmogenic role of these transcription factors in relation to AV node function, arrhythmias based on the presence of accessory pathways, arrhythmias of right ventricular outflow tract origin and of the sinus node. Because mice are often used for the studies as described above, the ECG is an important tool. However, although the interpretation of the human ECG is well validated, that of the mouse is not. Therefore, we have studied the murine ECG in detail in relation to activation and repolarization sequences. We provide evidence that application of human derived ECG criteria may lead to serious misinterpretation. Taken together, the results in this thesis indicates that there is a direct relation between the spatio-temporal activity pattern of particular cardiac transcription factors and the electrophysiological characteristics of myocardial structures. Insight into the mechanisms that regulate the expression of these factors and their target regulatory sequences in ion channel encoding genes, could lead to the identification of new approaches and candidate markers for improved arrhythmogenic risk stratification.
Summary
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Reference List
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