Early down-regulation of K+ channel genes and currents in the postinfarction heart

Introduction: Down-regulation of key K+ channel subunit gene expression and K+ currents is a universal response to cardiac hypertrophy, whatever the c ause, including the postmyocardial infarction (post-MI) remodeled heart. Methods and Results: We investigated the hypothesis that down-regulation of K+ channel genes and currents post-MI occurs early and before significant remodeled hypertrophy of the noninfarcted myocardium could be detected. We investigated (1) the incidence of induced ventricular tachyarrhythmias (VT) in 3-day post-MI rat heart; (2) action potential (AP) characteristics of i solated left ventricular (LV) myocytes from sham-operated and 3-day post-MI heart; (3) time course of changes in outward K+ currents Ito-fast(f) and I -K in isolated myocytes from 3-day and 4-week post-MI noninfarcted LV and c ompared the changes with sham-operated animals; and (4) changes in the mess enger and protein levels of Kv2.1, Kv4.2, and Kv4.3 in the LV and right ven tricle of 3-day post-MI heart. Sustained VT was induced in 6 of 10 3-day po st-MI rats and in none of 8 sham rats. The membrane capacitance of myocytes isolated from 3-day post-MI noninfarcted LV was not significantly differen t from control, whereas membrane capacitance 4-week post-MI was significant ly higher, reflecting the development of hypertrophy, AP duration was incre ased and the density of Ito-f and I-K were significantly decreased in 3-day post-MI LV myocytes compared with sham, The reduced density of I-to did no t significantly differ in 4-week post-MI LV myocytes, whereas the density o f I-K was decreased further at 4 weeks post-MI. The changes in Ito-f and I- k correlated with decreased messenger and protein levels of Kv4.2/Kv4.3 and Kv2.1, respectively. Conclusion: These results support the hypothesis that down-regulation of K channel gene expression and current in the post-MI LV occurs early and may be dissociated from the slower time course of post-MI remodeled hypertroph y. These changes may contribute to early arrhythmogenesis of the post-MI he art.