A quest for novel players in cardiac electrical function

Coordinated contraction and pumping of the heart critically depends on its electrical function. Disturbances of cardiac electrical activity may result in arrhythmias, which significantly contribute to morbidity and mortality. The identification of novel regulators of cardiac electrical function is crucial for future development of preventive and therapeutic strategies. The work, presented in this thesis, identifies several (candidate) modulators of cardiac electrical function using various approaches and provided insight into underlying molecular mechanisms. An overview is presented on previous studies employing quantitative trait locus (QTL) mapping and systems genetics approaches to identify novel genetic factors modulating cardiovascular traits. Through a murine mutagenesis study, we provide evidence that impaired branched chain amino acid (BCAA) metabolism is associated with increased risk of cardiac arrhythmias and sudden death. In addition, we identify a new ultra-rare genetic variant (c.2302G>A, p.Glu768Lys) in the TNNI3K gene in three independent multigenerational families exhibiting supraventricular tachycardias with or without conduction abnormalities and cardiomyopathy. Moreover, we uncover a role for the HEY2 gene in the maintenance of cardiac electrical patterning across the ventricular wall and implicate this gene in the pathophysiology of Brugada syndrome. Additionally, applying an unbiased proteomics screen, we identify several novel candidate interacting partners of the cardiac sodium channel Na_V1.5. Lastly, we show that the microtubule-associated EB1-CLASP2 protein complex modulates Na_V1.5 preferentially at the intercalated disc. The knowledge acquired from this thesis may inform the development of novel treatments for cardiac arrhythmias and facilitate improvements in risk stratification approaches.