Hongliang Li1, Ling Zhang1, Bing Huang1, Vineet Veitla1, Benjamin J Scherlag1, Madeleine W Cunningham2, Christopher E Aston3, David C Kem1, Xichun Yu4,5. 1. Heart Rhythm Institute and Department of Medicine, University of Oklahoma Health Sciences Center and Veterans Affairs Medical Center, Oklahoma City, OK, USA. 2. Department of Microbiology and Immunology, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA. 3. Department of Pediatrics, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA. 4. Heart Rhythm Institute and Department of Medicine, University of Oklahoma Health Sciences Center and Veterans Affairs Medical Center, Oklahoma City, OK, USA. xichun-yu@ouhsc.edu. 5. Heart Rhythm Institute, University of Oklahoma Health Sciences Center, TCH 6E103, 1200 Everett Drive, Oklahoma City, OK, 73104, USA. xichun-yu@ouhsc.edu.
Abstract
PURPOSE: Previous studies demonstrated that burst pacing and subthreshold infusion of acetylcholine in β1-adrenergic receptor (β1AR)-immunized rabbits induced sustained sinus tachycardia. The aim of this study was to examine the anti-arrhythmogenic effect of a newly designed retro-inverso (RI) peptidomimetic inhibitor that specifically targets the β1AR antibodies in the rabbit. METHODS: Six New Zealand white rabbits were immunized with a β1AR second extracellular loop peptide to produce sympathomimetic β1AR antibodies. A catheter-based electrophysiological study was performed on anesthetized rabbits before and after immunization and subsequent treatment with the RI peptide inhibitor. Each rabbit served as its own control. RESULTS: No sustained arrhythmias were induced at preimmune baseline. At 6 weeks after immunization, there was a marked increase in induced sustained tachyarrhythmias, predominantly sinus tachycardia, which was largely suppressed by the RI peptide. The atrial effective refractory period was shortened significantly in immunized rabbits compared to their preimmune state. The RI peptide reversed and prolonged this shortening. β1AR antibody levels were negatively correlated with the atrial effective refractory period. Postimmune sera-induced β1AR activation in transfected cells in vitro was also blocked by the RI peptide. CONCLUSIONS: β1AR-activating autoantibodies are associated with reduction of the atrial effective refractory period and facilitate arrhythmia induction in this model. The RI peptide reversal may have important therapeutic implications in subjects who harbor these autoantibodies.
PURPOSE: Previous studies demonstrated that burst pacing and subthreshold infusion of acetylcholine in β1-adrenergic receptor (β1AR)-immunized rabbits induced sustained sinus tachycardia. The aim of this study was to examine the anti-arrhythmogenic effect of a newly designed retro-inverso (RI) peptidomimetic inhibitor that specifically targets the β1AR antibodies in the rabbit. METHODS: Six New Zealand white rabbits were immunized with a β1AR second extracellular loop peptide to produce sympathomimetic β1AR antibodies. A catheter-based electrophysiological study was performed on anesthetized rabbits before and after immunization and subsequent treatment with the RI peptide inhibitor. Each rabbit served as its own control. RESULTS: No sustained arrhythmias were induced at preimmune baseline. At 6 weeks after immunization, there was a marked increase in induced sustained tachyarrhythmias, predominantly sinus tachycardia, which was largely suppressed by the RI peptide. The atrial effective refractory period was shortened significantly in immunized rabbits compared to their preimmune state. The RI peptide reversed and prolonged this shortening. β1AR antibody levels were negatively correlated with the atrial effective refractory period. Postimmune sera-induced β1AR activation in transfected cells in vitro was also blocked by the RI peptide. CONCLUSIONS: β1AR-activating autoantibodies are associated with reduction of the atrial effective refractory period and facilitate arrhythmia induction in this model. The RI peptide reversal may have important therapeutic implications in subjects who harbor these autoantibodies.
Authors: Hongliang Li; Benjamin J Scherlag; David C Kem; Caitlin Zillner; Shailesh Male; Sorkko Thirunavukkarasu; Xiaohua Shen; Jan V Pitha; Madeleine W Cunningham; Ralph Lazzara; Xichun Yu Journal: Heart Rhythm Date: 2012-11-23 Impact factor: 6.343
Authors: Sanjay R Kharche; Tomas Stary; Michael A Colman; Irina V Biktasheva; Antony J Workman; Andrew C Rankin; Arun V Holden; Henggui Zhang Journal: Europace Date: 2014-08-01 Impact factor: 5.214
Authors: Katrin Wenzel; Sarah Schulze-Rothe; Johannes Müller; Gerd Wallukat; Annekathrin Haberland Journal: PLoS One Date: 2018-02-09 Impact factor: 3.240
Authors: Hongliang Li; Gege Zhang; Liping Zhou; Zachary Nuss; Marci Beel; Brendon Hines; Taylor Murphy; Jonathan Liles; Ling Zhang; David C Kem; Xichun Yu Journal: J Am Heart Assoc Date: 2019-09-24 Impact factor: 5.501