A Model of Canine Purkinje Cell Electrophysiology and Ca 2+ Cycling

Abstract

Purkinje cells (Pcell) are characterized by different electrophysiological properties and Ca 2+ cycling processes than ventricular myocytes (Vcell) and are frequently involved in ventricular arrhythmias. Yet, the mechanistic basis for their arrhythmic vulnerability is not completely understood. The objectives were to: (1) characterize Pcell electrophysiology, Ca 2+ cycling, and their rate dependence; (2) investigate mechanisms underlying Pcell arrhythmogenicity; and compare Pcell and Vcell electrophysiology, Ca 2+ cycling, and arrhythmic properties. We developed a new mathematical model of Pcell. The Ca 2+ subsystem includes spatial organization and receptors distribution unique to Pcell. Results were: (1) in Pcell and Vcell, Na + accumulation via its augmentation of repolarizing I NaK dominates action potential duration adaptation and, in Pcell, I NaL contributes additional action potential duration shortening at short cycle length; (2) steep Pcell restitution is attributable to slow recovery of I NaL ; (3) biphasic Ca 2+ transients of Pcell reflect the delay between Ca 2+ release from junctional sarcoplasmic reticulum and corbular sarcoplasmic reticulum; (4) Pcell Ca 2+ alternans, unlike Vcell, can develop without inducing action potential alternans; (5) Pcell action potential alternans develops at a shorter cycle length than Vcell, with increased subcellular heterogeneity of Ca 2+ cycling attributable to refractoriness of Ca 2+ release from corbular sarcoplasmic reticulum and junctional sarcoplasmic reticulum; (6) greater Pcell vulnerability to delayed afterdepolarizations is attributable to higher sarcoplasmic reticulum Ca 2+ content and ionic currents that reduce excitation threshold and promote triggered activity; and (7) early after depolarizations generation in Pcell is mostly attributable to reactivation of I NaL2 , whereas I CaL plays this role in Vcell. Steeper rate dependence of action potential and Ca 2+ transients, central peripheral heterogeneity of Ca 2+ cycling, and distinct ion channel profile underlie greater arrhythmic vulnerability of Pcell compared to Vcell.