Figure 3.

Channel-dependent and channel-independent mechanisms at different stages of disease. The principal mechanisms of arrhythmias in HCM are divided depending on the disease stage (early and advanced) and on the nature of such mechanisms (whether they depend or not on changes of ion currents). While the increase of I_NaL and I_CaL occur early in the pathogenesis of HCM, being the consequence of post-translational channel modifications (e.g., increased phosphorylation by CaMKII), the decrease of K currents occurs later, as it follows a profound change of cardiomyocyte gene expression profile, with reduced transcription of K current genes. Myofilament Ca sensitization may determine arrhythmias even in the absence of ion current changes, due to a combination of functional mechanisms that are detailed in the text. Finally, at later stages of the disease, replacement fibrosis, as well as local ischemia due to microvascular dysfunction, facilitate the formation of stable reentry circuits and underlie sustained arrhythmias. Traces modified from Knollman et al. [37], Coppini et al. [26] and, Coppini et al. [56].