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Dynamic remodeling of K⁺ and Ca²⁺ currents in cells that survived in the epicardial border zone of canine healed infarcted heart

Department of Pharmacology, Center of Molecular Therapeutics, Columbia University, New York, New York 10032

Submitted 29 January 2004 ; accepted in final form 11 April 2004

Action potentials (APs) of the epicardial border zone (EBZ) cells from the day 5 infarcted heart continue to be altered by day 14 postocclusion, namely, they shortened. However, by 2 mo, EBZ APs appear "normal," yet conduction of wave fronts remains abnormal. We hypothesize that the changes in transmembrane APs are due to a change in the distribution of ion channels in either density or function. Thus we focused on the changes in Ca²⁺ and K⁺ currents in cells isolated from the 14-day (IZ_14d) and 2-mo (IZ_2m) EBZ and compared them with those occurring in cells from the same hearts but remote (Rem) from the EBZ. Whole cell voltage-clamp techniques were used to measure and compare Ca²⁺ and K⁺ currents in cells from the different groups. Ca²⁺ current densities remain reduced in cells of the 14-day and 2-mo infarcted heart and the kinetic changes previously identified in the 5-day heart begin to, but do not recover to, cells from noninfarcted epicardium (NZ) values. Importantly, I_Ca,L in both the EBZ and Rem regions still show a slowed recovery from inactivation. Furthermore, during the remodeling process, there is an increased expression of T-type Ca²⁺ currents, but only regionally, and only within a specific time window postmyocardial infarction (MI). Regional heterogeneity in -adrenergic responsiveness of I_Ca,L exists between EBZ and remote cells of the 14-day hearts, but this regional heterogeneity is gone in the healed infarcted heart. In IZ_14d, the transient outward K⁺ current (I_to) begins to reemerge and is accompanied by an upregulated tetraethylammonium-sensitive outward current. By 2-mo postocclusion, I_to and sustained outward K⁺ current have completed the reverse remodeling process. During the healing process post-MI, canine epicardial cells downregulate the fast I_to but compensate by upregulating a K⁺ current that in normal cells is minimally functional. For recovering I_Ca,L of the 14-day and 2-mo EBZ cells, voltage-dependent processes appear to be reset, such that I_Ca,L "window" current occurs at hyperpolarized potentials. Thus dynamic changes in both Ca²⁺ and K⁺ currents contribute to the altered AP observed in 14-day fibers and may account for return of APs of 2 mo EBZ fibers.

myocardial infarction

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