A (patho)physiological study of CVB3 infection and HCN4 in a human iPSC-based pacemaker system

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The technology to reprogram human somatic cells back to pluripotency enables virtually unlimited access to human induced pluripotent stem cells (hiPSC). In basic experimental cardiology, hiPSC-transdifferentiated cells provide subtype-specific cardiomyocytes allowing for studies of (patho)physiological cellular functionalities. The proposed work plan aims at establishing a comprehensive mechanistic understanding of the normal and disease-impacted human pacemaker system. An improved iPSC pacemaker system will be established. iPSC pacemaker cells generated by a novel methodology will be evaluated in detail and compared with cells from the human sinus node. In these cells, the impact of cardiomyopathy causing Coxsackie virus B3 expression on electrical rhythmicity and cell structure will be studied. Further, the impact of the clinically relevant HCN4 mutation HCN4-G482R on electrical rhythmicity and cell structure will be analysed. Specific biophysical features of HCN4-G482R will also be studied in more detail. We expect that the novel iPSC-System will allow for new insights of viral myocarditis and a channelopathy.