Figure 3.

Physiological influences on the determinants of θ. Three diagrams illustrating the mechanisms by which (a) membrane excitability, (b) cell coupling and (c) fibrotic change influence current. Transmembrane current (dark blue arrow) enters through open Na_v1.5 (green rectangle) and intercellular current (light blue arrow) passes through open Cxs (green ladder). (A) Abnormal membrane excitability results from reductions in either (i) Na_v1.5 function through increases in extracellular [K⁺] and pH and by increases in [Ca²⁺]_i and phosphorylation, or (ii) Na_v1.5 expression by mutations in SCN5A (Brugada syndrome) and through Ca²⁺ mediated down regulation of the channel. (B) Abnormal cell coupling results from reductions in either (i) Cx function through increases in [Ca²⁺]_i and dephosphorylation or (ii) Cx expression by mutations in either CJA1 or CJA5 (idiopathic AF). (C) Abnormal fibrosis produces either (i) increased myocyte-myocyte decoupling, resulting in increased r_a,. or (ii) Cx-mediated myocyte-fibroblast coupling, resulting in increased c_m.