- Diversity and complexity of cardiac sodium channel (dys)function
- Relevance for arrhythmias in inherited and acquired diseases
- Award date
- 31 May 2018
- Number of pages
- Document type
- PhD thesis
- Faculty of Medicine (AMC-UvA)
The cardiac sodium channel NaV1.5 plays a major role in the initiation of the cardiac action potential and propagation of the electrical impulse in the heart. Dysfunction of NaV1.5, caused by inherited mutations in SCN5A (the gene encoding NaV1.5), or acquired diseases (such as myocardial ischemia and heart failure), is associated with a diversity of cardiac electrical disorders and sudden cardiac death. In the past decades, genetic, electrophysiological and molecular studies have significantly advanced our understanding of NaV1.5 (dys)function and its role in cardiac electrophysiology and arrhythmogenesis. However, the diverse and heterogeneous clinical phenotypes associated with NaV1.5 (dys)function remain incompletely understood, which hampers identification of patients at risk for sudden cardiac death and their clinical management. The work presented in this thesis is centered on the hypothesis that sodium channel functions are diverse and extend beyond the generation of an action potential. We thus studied the consequences of inherited sodium channel (dys)function on sodium and calcium homeostasis, the modulatory effect of hypertension on arrhythmia susceptibility, sudden cardiac death and (atrio-)ventricular conduction in inherited sodium channelopathy and the microdomain-specific remodeling of NaV1.5 in heart failure. Novel insight presented in this thesis will facilitate future development of new risk stratification and therapeutic strategies for patients with sodium channel disease.
Thesis (complete) (Embargo up to and including 31 May 2020)
Chapter 1: Introduction and scope of the thesis (Embargo up to and including 31 May 2020)
Chapter 2: Multifunctionality of the cardiac sodium channel NaV1.5: From ionic to non-ionic function (Embargo up to and including 31 May 2020)
Chapter 5: Modulation of atrio-ventricular conduction by enhanced late sodium current and calcium-dependent signaling in Scn5a1798insD/+ mice (Embargo up to and including 31 May 2020)
Chapter 8: General discussion and future perspectives (Embargo up to and including 31 May 2020)
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