Characterization of autoantibodies targeting the cardiac repolarizing KCNQ1 potassium channel in a rabbit model.

• Applicant: Dr. Jin Li
• Subject Area: Cardiology, Angiology
• Term: from 2012 to 2013
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 231419723

Heart rhythm disorders contribute significantly to cardiovascular mortality. Myocardial ischemia, cardiomyopathies, electrolyte imbalance and hereditary channelopathies account for the majority of cardiac arrhythmias. However, in a subgroup of cases the cause remains uncertain. Emerging data suggest an important role of the immune system in cardiac arrhythmogenesis. In a pilot study, we provided evidence of autoimmune-mediated QT interval shortening in dilated cardiomyopathy. Patients with autoantibodies targeting the cardiac voltage-gated KCNQ1 potassium channel exhibited shorter QT intervals compared to seronegative patients. At the molecular level, anti-KCNQ1 antibodies increased the repolarizing IKs current in KCNQ1/KCNE1 expressing HEK 293 cells. The present research project investigates the pathophysiological mechanism underlying anti-KCNQ1 antibody-induced modulation of cardiac electrophysiology. An experimental autoimmune rabbit model will be established, and functional and biophysical properties of anti-KCNQ1 autoantibodies will be characterized using in vivo (electrocardiography, electrophysiological study) and in vitro (patch clamp) electrophysiological studies as well as molecular analyses (Western blot, histology, immunohistochemistry). Autoimmune-induced cardiac arrhythmia represents a previously unrecognized pathophysiological concept, and the thorough investigation of autoantibody-mediated modulation of cardiac electrophysiology is expected to impact on patient care.

• DFG Programme: Research Fellowships
• International Connection: Canada
• Host: Professor Dr. Stanley Nattel