Michael B Liu1, Enno de Lange2, Alan Garfinkel3, James N Weiss4, Zhilin Qu5. 1. UCLA Cardiovascular Research Laboratory; Department of Medicine (Cardiology), David Geffen School of Medicine, University of California, Los Angeles, California. 2. UCLA Cardiovascular Research Laboratory; Department of Knowledge Engineering, Maastricht University, Maastricht, The Netherlands. 3. UCLA Cardiovascular Research Laboratory; Department of Medicine (Cardiology), David Geffen School of Medicine, University of California, Los Angeles, California; Department of Integrative Biology and Physiology, University of California, Los Angeles, California. 4. UCLA Cardiovascular Research Laboratory; Department of Medicine (Cardiology), David Geffen School of Medicine, University of California, Los Angeles, California; Department of Integrative Biology and Physiology, University of California, Los Angeles, California; Department of Physiology, David Geffen School of Medicine, University of California, Los Angeles, California. 5. UCLA Cardiovascular Research Laboratory; Department of Medicine (Cardiology), David Geffen School of Medicine, University of California, Los Angeles, California. Electronic address: zqu@mednet.ucla.edu.
Abstract
BACKGROUND: Delayed afterdepolarizations (DADs) have been well characterized as arrhythmia triggers, but their role in generating a tissue substrate vulnerable to reentry is not well understood. OBJECTIVE: The purpose of this study was to test the hypothesis that random DADs can self-organize to generate both an arrhythmia trigger and a vulnerable substrate simultaneously in cardiac tissue as a result of gap junction coupling. METHODS: Computer simulations in 1-dimensional cable and 2-dimensional tissue models were performed. The cellular DAD amplitude was varied by changing the strength of sarcoplasmic reticulum calcium release. Random DAD latency and amplitude in different cells were simulated using gaussian distributions. RESULTS: Depending on the strength of spontaneous sarcoplasmic reticulum calcium release and other conditions, random DADs in cardiac tissue resulted in the following behaviors: (1) triggered activity (TA); (2) a vulnerable tissue substrate causing unidirectional conduction block and reentry by inactivating sodium channels; (3) both triggers and a vulnerable substrate simultaneously by generating TA in regions next to regions with subthreshold DADs susceptible to unidirectional conduction block and reentry. The probability of the latter 2 behaviors was enhanced by reduced sodium channel availability, reduced gap junction coupling, increased tissue heterogeneity, and less synchronous DAD latency. CONCLUSION: DADs can self-organize in tissue to generate arrhythmia triggers, a vulnerable tissue substrate, and both simultaneously. Reduced sodium channel availability and gap junction coupling potentiate this mechanism of arrhythmias, which are relevant to a variety of heart disease conditions.
BACKGROUND: Delayed afterdepolarizations (DADs) have been well characterized as arrhythmia triggers, but their role in generating a tissue substrate vulnerable to reentry is not well understood. OBJECTIVE: The purpose of this study was to test the hypothesis that random DADs can self-organize to generate both an arrhythmia trigger and a vulnerable substrate simultaneously in cardiac tissue as a result of gap junction coupling. METHODS: Computer simulations in 1-dimensional cable and 2-dimensional tissue models were performed. The cellular DAD amplitude was varied by changing the strength of sarcoplasmic reticulum calcium release. Random DAD latency and amplitude in different cells were simulated using gaussian distributions. RESULTS: Depending on the strength of spontaneous sarcoplasmic reticulum calcium release and other conditions, random DADs in cardiac tissue resulted in the following behaviors: (1) triggered activity (TA); (2) a vulnerable tissue substrate causing unidirectional conduction block and reentry by inactivating sodium channels; (3) both triggers and a vulnerable substrate simultaneously by generating TA in regions next to regions with subthreshold DADs susceptible to unidirectional conduction block and reentry. The probability of the latter 2 behaviors was enhanced by reduced sodium channel availability, reduced gap junction coupling, increased tissue heterogeneity, and less synchronous DAD latency. CONCLUSION:DADs can self-organize in tissue to generate arrhythmia triggers, a vulnerable tissue substrate, and both simultaneously. Reduced sodium channel availability and gap junction coupling potentiate this mechanism of arrhythmias, which are relevant to a variety of heart disease conditions.
Authors: Sung-Jin Park; Donghui Zhang; Yan Qi; Yifei Li; Keel Yong Lee; Vassilios J Bezzerides; Pengcheng Yang; Shutao Xia; Sean L Kim; Xujie Liu; Fujian Lu; Francesco S Pasqualini; Patrick H Campbell; Judith Geva; Amy E Roberts; Andre G Kleber; Dominic J Abrams; William T Pu; Kevin Kit Parker Journal: Circulation Date: 2019-07-17 Impact factor: 29.690
Authors: Jordi Heijman; Vincent Algalarrondo; Niels Voigt; Jonathan Melka; Xander H T Wehrens; Dobromir Dobrev; Stanley Nattel Journal: Cardiovasc Res Date: 2015-12-23 Impact factor: 10.787