Introduction: The extracellular potential (Ve) has been used frequently to detect the time of electrical activation in cardiac tissue. Previous computational studies demonstrated that the moment of the minimum time derivative (dVe/dtmin) coincides with the moment of the maximum rate of increase of sodium current (INa) and sodium channel conductivity (gNa). However, researchers have given little attention to the magnitude of dVe/dtmin and its potential use as a marker of ischemia. Also, the relationship between |dVe/dtmin| and ischemia mechanisms has not been well established. This computational simulation study examined effects of individual major mechanisms of ischemia on |dVe/dtmin|.

Methods: We used a three-dimensional bidomain model to simulate major mechanisms of acute ischemia and their effects on propagation, i.e. elevated extracellular potassium concentration [K]o, acidosis, anoxia and reduced intra- and extracellular conductivity. Acidosis was implemented by reduced maximum conductance of both sodium and calcium channels and shift of the sodium channel current-voltage curves. The ratio of intracellular ATP and ADP concentration was decreased for the hypoxic condition.

Results: [K]o elevation from 4 to 12 mM resulted in 68% decrease of |dVe/dtmin|. The decrease was explained by depolarized resting transmembrane voltage, which caused inactivation of sodium channels. Acidosis caused less than 15% decrease of |dVe/dtmin| . Hypoxia showed negligible effect. The maximum upstroke of transmembrane voltage dVm/dtmax showed a similar decrease as |dVe/dtmin| with incidence of hyperkalemia and acidosis. However, extra- and intracellular conductivities caused opposite results between |dVe/dtmin| and dVm/dtmax. Decreased extracellular conductivity resulted in increased |dVe/dtmin| and decreased dVm/dtmax, while decreased intercellular conductivity caused decreased |dVe/dtmin| and increased dVm/dtmax.

Conclusions: Reduction of |dVe/dtmin| during ischemia was caused mostly by elevated [K]o. Minor |dVe/dtmin| reductions were associated with acidosis and attenuation of intracellular conductivity.

Acknowledgements: This work has been supported by the Richard A. and Nora Eccles Fund for Cardiovascular Research and awards from the Nora Eccles Treadwell Foundation.