title: Spontaneous initiation of premature ventricular complexes and arrhythmias in type 2 long QT syndrome.
abstract: The occurrence of early afterdepolarizations (EADs) and increased dispersion of repolarization are two known factors for arrhythmogenesis in long QT syndrome. However, increased dispersion of repolarization tends to suppress EADs due to the source-sink effect, and thus how the two competing factors cause initiation of arrhythmias remains incompletely understood. Here we used optical mapping and computer simulation to investigate the mechanisms underlying spontaneous initiation of arrhythmias in type 2 long QT (LQT2) syndrome. In optical mapping experiments of transgenic LQT2 rabbit hearts under isoproterenol, premature ventricular complexes (PVCs) were observed to originate from the steep spatial repolarization gradient (RG) regions and propagated unidirectionally. The same PVC behaviors were demonstrated in computer simulations of tissue models of rabbits. Depending on the heterogeneities, these PVCs could lead to either repetitive focal excitations or reentry without requiring an additional vulnerable substrate. Systematic simulations showed that cellular phase 2 EADs were either suppressed or confined to the long action potential region due to the source-sink effect. Tissue-scale phase 3 EADs and PVCs occurred due to tissue-scale dynamical instabilities caused by RG and enhanced L-type calcium current (ICa,L), occurring under both large and small RG. Presence of cellular EADs was not required but potentiated PVCs when RG was small. We also investigated how other factors affect the dynamical instabilities causing PVCs. Our main conclusion is that tissue-scale dynamical instabilities caused by RG and enhanced ICa,Lgive rise to both the trigger and the vulnerable substrate simultaneously for spontaneous initiation of arrhythmias in LQT2 syndrome.
authors.affiliation: Department of Medicine (Cardiology), David Geffen School of Medicine, University of California, Los Angeles, California.|Department of Physics, South China University of Technology, Guangzhou, China; and.
authors.forename: Xiaodong
authors.initials: X
authors.lastname: Huang
authors.affiliation: Division of Cardiology, Cardiovascular Research Center, Rhode Island Hospital, Warren Alpert Medical School of Brown University, Providence, Rhode Island.
authors.forename: Tae Yun
authors.initials: TY
authors.lastname: Kim
authors.affiliation: Division of Cardiology, Cardiovascular Research Center, Rhode Island Hospital, Warren Alpert Medical School of Brown University, Providence, Rhode Island.
authors.forename: Gideon
authors.initials: G
authors.lastname: Koren
authors.affiliation: Division of Cardiology, Cardiovascular Research Center, Rhode Island Hospital, Warren Alpert Medical School of Brown University, Providence, Rhode Island.
authors.forename: Bum-Rak
authors.initials: BR
authors.lastname: Choi
authors.affiliation: Department of Medicine (Cardiology), David Geffen School of Medicine, University of California, Los Angeles, California; zqu@mednet.ucla.edu.|Department of Biomathematics, David Geffen School of Medicine, University of California, Los Angeles, California.
authors.forename: Zhilin
authors.initials: Z
authors.lastname: Qu
mesh_terms: D000318:Adrenergic beta-Agonists / Q000633:toxicity; D000818:Animals; D030801:Animals, Genetically Modified; D001145:Arrhythmias, Cardiac / Q000139:chemically induced / Q000378:metabolism / Q000503:physiopathology; D002118:Calcium / Q000378:metabolism; D003198:Computer Simulation; D006329:Heart Conduction System / Q000378:metabolism / Q000503:physiopathology*; D007545:Isoproterenol / Q000633:toxicity; D008133:Long QT Syndrome / Q000378:metabolism / Q000503:physiopathology*; D009206:Myocardium / Q000378:metabolism; D011817:Rabbits; D018879:Ventricular Premature Complexes / Q000139:chemically induced / Q000378:metabolism / Q000503:physiopathology*
chemical_list: D000318:Adrenergic beta-Agonists; D007545:Isoproterenol; D002118:Calcium
keywords: early afterdepolarization; initiation of arrhythmias; premature ventricular complex; repolarization gradient