Figure 6. Improvement of mammalian AP conduction by BacNa_v in modeled pathological conditions.

(a) Schematic depicting direct expression of BacNa_v in mammalian excitable tissues containing endogenous Na_v1.5, to enhance conduction and prevent conduction block in simulated pathological conditions. (b) Steady-state inactivation (h_∞) of Na_vSheP D60A is more depolarized compared with that of Na_v1.5 (n=5). (c,d) Conduction failure due to inactivation of Na_v1.5 by membrane depolarization with elevated extracellular K⁺ (c, n=6) or blocking of intercellular coupling by PA (d, n=12–18) in Ex293 monolayers (black squares) is rescued by co-expression of Na_vSheP D60A (white circles). (e) Schematic depicting exogenous expression of BacNa_v in neonatal rat CMs to increase resistance to conduction block in ischaemic conditions. Black dashed circle denotes position of glass coverslip used to induce regional ischaemia in CM monolayer. (f) Progressive conduction slowing until block with time of ischaemia in control (CM) and Na_vSheP D60A transduced (CM+D60A) monolayers (n=6). (g,h) Representative isochrones maps of a CM monolayer showing conduction slowing after 6 min (g) and complete block after 11 min of ischaemia (h). Pulse signs indicate location of stimulating electrode. Circles denote 504 recording sites. (i) Under ischaemic condition, CMs transduced with Na_vSheP D60A lentivirus (white) resisted conduction block longer than control CMs (black) (n=6, #P<0.01). Error bars indicate s.e.m; statistical significance was determined by an unpaired Student's t-test to calculate P-value.