Mechanisms of hypokalemia-induced ventricular arrhythmogenicity

Hypokalemia is a common biochemical finding in cardiac patients and may represent a side effect of diuretic therapy or result from endogenous activation of renin-angiotensin system and high adrenergic tone. Hypokalemia is independent risk factor contributing to reduced survival of cardiac patients and increased incidence of arrhythmic death. Animal studies demonstrate that hypokalemia-induced arrhythmogenicity is attributed to prolonged ventricular repolarization, slowed conduction, and abnormal pacemaker activity. The prolongation of ventricular repolarization in hypokalemic setting is caused by inhibition of outward potassium currents and often associated with increased propensity for early afterdepolarizations. Slowed conduction is attributed to membrane hyperpolarization and increased excitation threshold. Abnormal pacemaker activity is attributed to increased slope of diastolic depolarization in Purkinje fibers, as well as delayed afterdepolarizations caused by Ca2+ overload secondary to inhibition of Na+--K+ pump and stimulation of the reverse mode of the Na+--Ca2+ exchange. Hypokalemia effect on repolarization is not uniform at distinct ventricular sites thereby contributing to amplified spatial repolarization gradients which promote unidirectional conduction block. In hypokalemic heart preparations, the prolongation of action potential may be associated with shortening of effective refractory period, thus increasing the propensity for ventricular re-excitation over late phase of repolarization. Shortened refractoriness and slowed conduction contribute to reduced excitation wavelength thereby facilitating re-entry. The interplay of triggering factors (early and delayed afterdepolarizations, oscillatory prepotentials in Purkinje fibers) and a favorable electrophysiological substrate (unidirectional conduction block, reduced excitation wavelength, increased critical interval for ventricular re-excitation) may account for the mechanism of life-threatening tachyarrhythmias in hypokalemic patients.