In vivo cardiac gene transfer of Kv4.3 abrogates the hypertrophic response in rats after aortic stenosis

Background - Prolongation of the action potential duration (APD) and decreased transient outward K+ current (I-to) have been consistently observed in cardiac hypertrophy. The relation between electrical remodeling and cardiac hypertrophy in vivo is unknown. Methods and Results - We studied rat hearts subjected to pressure overload by surgical ascending aortic stenosis ( AS) and simultaneously infected these hearts with an adenovirus carrying either the Kv4.3 gene ( Ad. Kv4.3) or the beta-galactosidase gene (Ad.beta-gal). I-to density was reduced and APD(50) was prolonged (P < 0.05) in AS rats compared with sham rats. Kv4.2 and Kv4.3 expressions were decreased by 58% and 51%, respectively ( P < 0.05). AS rats infected with Ad.beta-gal developed cardiac hypertrophy compared with sham rats, as assessed by cellular capacitance and heart weight - body weight ratio. Associated with the development of cardiac hypertrophy, the expression of calcineurin and its downstream transcription factor nuclear factor of activated T cells ( NFAT) c1 was persistently increased by 47% and 36%, respectively ( P < 0.05) in AS myocytes infected with Ad. beta-gal compared with sham myocytes. In vivo gene transfer of Kv4.3 in AS rats was shown to increase Kv4.3 expression, increase I-to density, and shorten APD(50) by 1.6-fold, 5.3-fold, and 3.6-fold, respectively ( P < 0.05). Furthermore, AS rats infected with Ad. Kv4.3 showed significant reductions in calcineurin and NFAT expression. ( P < 0.05). Conclusions - Downregulation of I-to, APD prolongation, and cardiac hypertrophy occur early after AS, and in vivo gene transfer of Kv4.3 can restore these electrical parameters and abrogate the hypertrophic response via the calcineurin pathway.