Am J Physiol Heart Circ Physiol. 2026 May 15. doi: 10.1152/ajpheart.00093.2026. Online ahead of print.
ABSTRACT
Different modes of onset of ventricular arrhythmias (VA), preceded by characteristic electrocardiogram patterns, have been observed in patients with J-wave syndromes (JWS), including Brugada syndrome, early repolarization syndrome, and idiopathic ventricular fibrillation. However, the underlying mechanisms remain unclear. The goal of this study is to use computational modeling to elucidate the mechanisms for spontaneous initiation of VA in JWS, particularly the characteristic modes of onset shown in clinical settings. Phase-2 reentry (P2R) was induced by transient outward potassium currents (I) or loss of function sodium channel (I) mutations in heterogeneous tissue. The computational models replicated the characteristic electrocardiogram patterns and modes of VA onset observed in human patients, including: 1) fast heart rate-dependent or "short-long-normal-short" sequence to VA; 2) pause-dependent or "short-long-short" sequence to VA; and 3) sudden onset of VA. Fast heart rate-dependent arrhythmogenesis was driven by either fast I or I mutations induced P2R with the rate dependence caused by delayed rectifier potassium current recovery. Pause-dependent arrhythmogenesis was driven by slow I or by fast I combined with calcium transient restitution. P2Rs could manifest as short-coupled premature ventricular complexes or degenerate into reentrant arrhythmias, depending on the size of the all-or-none repolarization region caused by the spike-and-dome action potential morphology. In conclusion, VA in JWS can be initiated via P2R following a "short-long-normal-short" sequence, a "short-long-short" sequence, or suddenly. P2R and its rate-dependence via the recovery of slow I, delayed rectifier potassium current, or calcium transient underlie different modes of onset of VA.
PMID:42141763 | DOI:10.1152/ajpheart.00093.2026