Published Online
on January 10, 2005

A more recent version of this article appeared on January 25, 2005

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Submitted on May 28, 2004
Revised on September 13, 2004
Accepted on October 13, 2004

Targeted Modification of Atrial Electrophysiology by Homogeneous Transmural Atrial Gene Transfer

Kan Kikuchi MD, Amy D. McDonald BS, Tetsuo Sasano MD, PhD, and J. Kevin Donahue MD^*

From the Johns Hopkins University School of Medicine, Baltimore, Md.

^* To whom correspondence should be addressed. E-mail: kdonahue{at}jhmi.edu.

Background--Safe and effective myocardial gene transfer remains elusive. Heterogeneous ventricular gene delivery has been achieved in small mammals but generally with methods not readily transferable to the clinic. Atrium-specific gene transfer has not yet been reported. We hypothesized that homogeneous atrial gene transfer could be achieved by direct application of adenoviral vectors to the epicardial surface, use of poloxamer gel to increase virus contact time, and mild trypsinization to increase virus penetration.

Methods and Results--We "painted" recombinant adenovirus encoding the reporter gene Escherichia coli -galactosidase directly onto porcine atria. Investigational variables included poloxamer use, trypsin concentration, and safety. Using the painting method, we modified the atrial phenotype with an adenovirus expressing HERG-G628S, a long-QT-syndrome mutant. Our results showed that application of virus with poloxamer alone resulted in diffuse epicardial gene transfer with negligible penetration into the myocardium. Dilute trypsin concentrations allowed complete transmural gene transfer. After trypsin exposure, echocardiographic left atrial diameter did not change. Left atrial function decreased on postoperative day 3 but returned to baseline by day 7. Tissue tensile strength was affected only in the 1% trypsin group. HERG-G628S gene transfer prolonged atrial action potential duration and refractory period without affecting ventricular electrophysiology.

Conclusions--We show complete transmural atrial gene transfer by this novel painting method. Adaptation of the method could allow application to other tissue targets. Use with functional proteins in the atria could cure or even prevent diseases such as atrial fibrillation or sinus node dysfunction.

Key words: arrhythmia • gene therapy • electrophysiology • atrium

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