Proposed scheme of events leading to DADs and triggered tachyarrhythmia. (A) Congenital (e.g., ankyrin-B mutation) and/or acquired factors (e.g., ischemia, hypertrophy, increased sympathetic tone) will cause a diastolic Ca²⁺ leak through RyR2, resulting in localized and transient increases in [Ca²⁺]_i in cardiomyocytes. (B) Representative series of images showing changes in [Ca²⁺]_i during a Ca²⁺ wave in a single cardiomyocyte loaded with a Ca²⁺-sensitive fluorescent dye. Images were obtained at 117-ms intervals. Focally elevated Ca²⁺ (ii) diffuses to adjacent junctional SR, where it initiates more Ca²⁺ release events, resulting in a propagating Ca²⁺ wave (iii–viii). Reproduced with permission from Biophysical Journal (85). (C) The Ca²⁺ wave, through activation of Ca²⁺-sensitive inward currents, will depolarize the cardiomyocyte (DAD). In cardiomyocytes, the inward I_Na/Ca is the major candidate for the transient inward current underlying DADs, although the role of the Ca²⁺-activated Cl^– current [I_Cl(Ca)] and a Ca²⁺-sensitive nonspecific cation current [I_NS(Ca)] cannot be excluded. If of sufficient magnitude, the DAD will depolarize the cardiomyocyte above threshold resulting in a single or repetitive premature heartbeat (red arrows), which can trigger an arrhythmia. Downregulation of the inward rectifier potassium current (I_K1), upregulation of I_Na/Ca, or a slight increase in intercellular electrical resistance can promote the generation of DAD-triggered action potentials. S, stimulus. Modified with permission from Circulation Research (26) and Nature (12).