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(Circulation. 2004;110:3435-3443.)
© 2004 American Heart Association, Inc.

Genetics

In Vivo Cardiac Gene Transfer of Kv4.3 Abrogates the Hypertrophic Response in Rats After Aortic Stenosis

Djamel Lebeche, PhD^*; Roger Kaprielian, PhD^*; Federica del Monte, MD, PhD; Gordon Tomaselli, MD; Judith K. Gwathmey, VMD, PhD; Arnold Schwartz, MD; Roger J. Hajjar, MD

From the Cardiovascular Research Center (D.L., R.K., F.d.M., R.J.H.), Massachusetts General Hospital, Harvard Medical School, Charlestown, Mass; the Institute of Molecular Pharmacology and Biophysics (D.L., A.S.), University of Cincinnati Medical Center, Cincinnati, Ohio; the Johns Hopkins University School of Medicine (G.T.), Baltimore, Md; and Boston University School of Medicine (J.K.G.), Boston, Mass.

Correspondence to Roger J. Hajjar, MD, Cardiovascular Research Center, Massachusetts General Hospital, 149 13th St, CNY-4, Charlestown, MA 02129. E-mail hajjar{at}cvrc.mgh.harvard.edu

Received June 29, 2004; revision received August 10, 2004; accepted August 17, 2004.

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 ß-galactosidase gene (Ad.ß-gal). I_to density was reduced and APD₅₀ 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.ß-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.ß-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 APD₅₀ 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.

Key Words: hypertrophy • gene therapy • ion channels • potassium • stenosis

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