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TWA and TWL in patients tend to occur at normal heart rates and are usually potentiated by bradycardia. Whether or how TWA and TWL at normal or slow heart rates are causally linked to arrhythmogenesis remains unknown. In the present study, we used computer simulations and experiments of a transgenic rabbit model of long QT syndrome to investigate the underlying mechanisms. Computer simulations showed that APD prolongation and slowed heart rates caused early afterdepolarization\u2010mediated APD alternans and chaos, manifesting as TWA and TWL, respectively. Regional APD alternans and chaos exacerbated pre\u2010existing APD dispersion and, in addition, APD chaos could also induce APD dispersion <jats:italic>de novo<\/jats:italic> via chaos desynchronization. Increased APD dispersion, combined with substantially enhanced <jats:italic>I<\/jats:italic><jats:sub>Ca,L<\/jats:sub>, resulted in a tissue\u2010scale dynamical instability that gave rise to the spontaneous occurrence of unidirectionally propagating premature ventricular complexes (PVCs) originating from the APD gradient region. These PVCs could directly degenerate into re\u2010entrant arrhythmias without the need for an additional tissue substrate or could block the following sinus beat to result in a longer RR interval, which further exacerbated the APD dispersion giving rise to the spontaneous occurrence of ventricular arrhythmias. Slow heart rate\u2010induced PVC alternans was observed in experiments of transgenic LQT2 rabbits under isoproterenol, which was associated with increased APD dispersion and spontaneous occurrence of ventricular arrhythmias, in agreement with the theoretical predictions.<\/jats:p><\/jats:sec>","DOI":"10.1113\/jp275492","type":"journal-article","created":{"date-parts":[[2018,1,29]],"date-time":"2018-01-29T22:02:39Z","timestamp":1517263359000},"page":"1341-1355","source":"Crossref","is-referenced-by-count":52,"title":["Mechanisms linking T\u2010wave alternans to spontaneous initiation of ventricular arrhythmias in rabbit models of long QT syndrome"],"prefix":"10.1113","volume":"596","author":[{"given":"Weiqing","family":"Liu","sequence":"first","affiliation":[{"name":"Department of Medicine University of California  Los Angeles California USA"},{"name":"School of Science Jiangxi University of Science and Technology  Ganzhou 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