Sudden cardiac death; KCNQ1; Long QT syndrome; Autoantibody
Maguy Ange, Tardif Jean-Claude, Busseuil David, Ribi Camillo, Li Jin (2020), Autoantibody Signature in Cardiac Arrest, in Circulation
, 141(22), 1764-1774.
Maguy Ange, Kucera Jan P., Wepfer Jonas P., Forest Virginie, Charpentier Flavien, Li Jin (2020), KCNQ1 Antibodies for Immunotherapy of Long QT Syndrome Type 2, in Journal of the American College of Cardiology
, 75(17), 2140-2152.
Cardiac arrhythmias are the main contributors to cardiovascular mortality. Structural heart diseases and inherited channelopathies predispose patients to potentially life-threatening arrhythmias. Despite many advances in diagnostic tools, nearly half of the cases of sudden cardiac death (SCD) remain unexplained. Recent studies suggest the involvement of autoantibodies in the pathogenesis of heart rhythm disorders. A variety of autoantibodies recognizing cardiac antigens such as cardiac myosin, Na+/K+-ATPase, b1-adrenergic or muscarinic cholinergic type 2 (M2)-receptors have been detected in patients and were found to promote cardiac arrhythmias. However, data on potentially arrhythmogenic autoantibodies targeting cardiac ion channels are still scarce and therefore constitute the primary focus of the present research project. Within the scope of a clinical study, SCD victims will be screened for the presence of arrhythmogenic autoantibodies directed against cardiac ion channels. The establishment of an autoantibody profile in patients will undoubtedly improve the diagnostic approach to cardiac arrhythmias and provide further valuable information ensuring a personalized and optimal therapeutic management.Furthermore, a subgroup of SCD victims are affected by the long QT syndrome, a disease typically characterized by an abnormally prolonged repolarization of the heart. We have previously shown that antibodies targeting the cardiac voltage-gated KCNQ1 potassium channel are associated with a shortened QT interval in patients. These findings were reproduced in an own KCNQ1-immunized rabbit model, where isolated cardiomyocytes exhibited shortened action potentials due to enhanced repolarizing IKs currents. The question whether circulating KCNQ1 antibodies are the main effectors of IKs increase and the associated mechanisms remains unclear. To address these issues, we will purify KCNQ1 antibodies and study the antibody-ion channel interaction. After the functional characterization, the effect of KCNQ1 antibodies on the whole-heart will be examined. Finally, the therapeutic potential of purified KCNQ1 antibodies will be studied in a transgenic rabbit model of the long QT syndrome. Identifying an activating antibody would not only be unique as such but may open novel avenues to treat patients with the long QT syndrome resistant to standard therapy.