Published Online
on June 17, 2002

A more recent version of this article appeared on July 2, 2002

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Submitted on February 18, 2002
Revised on April 17, 2002
Accepted on April 17, 2002

Myocardial Gene Transfer and Overexpression of ß₂-Adrenergic Receptors Potentiates the Functional Recovery of Unloaded Failing Hearts

Hendrik T. Tevaearai MD, Andrea D. Eckhart PhD, G. Brant Walton BS, Janelle R. Keys PhD, Katrina Wilson BS, and Walter J. Koch PhD^*

From the Departments of Surgery (H.T.T., A.D.E., G.B.W., W.J.K.) and Medicine (K.W.), Duke University Medical Center, Durham, NC. Dr Tevaearai is now at the Department of Cardiovascular Surgery, Centre Hospitalier Universitaire Vaudois, Lausanne, Switzerland.

^* To whom correspondence should be addressed. E-mail: koch0002{at}mc.duke.edu.

Background—Mechanical assistance of the failing left ventricle (LV) can lead to functional recovery after a period of unloading, including restoration of ß-adrenergic receptor (ßAR) inotropic reserve. We tested whether prolonged LV unloading of failing rabbit hearts by use of a heterotopic transplantation technique could lead to recovery and whether adenoviral gene transfer of a ß₂AR transgene (Adv-ß₂AR) could alter this process.

Methods and Results—Heart failure was induced by coronary artery ligation in adult New Zealand White rabbits. After 4 weeks, failing hearts were heterotopically transplanted into recipient rabbits, allowing normal coronary perfusion but complete LV unloading. We also placed an LV latex balloon for remote access and in vivo physiological analysis. We found that there was reversal of signaling and functional abnormalities after 30 days of unloading. In another set of failing hearts, we randomly delivered, at the time of transplantation, either 2x10¹¹ viral particles of Adv-ß₂AR or saline via the coronary arteries. Sham-operated animals with nonfailing hearts served as controls. After 5 days of unloading, in vivo LV contractility (LV dP/dt_max) and relaxation (LV dP/dt_min) were significantly decreased in saline-treated failing hearts compared with control nonfailing hearts (P<0.05). In failing hearts treated with Adv-ß₂AR, however, LV dP/dt_max and LV dP/dt_min were improved in response to higher preloads (P<0.05) and ßAR stimulation (P<0.01).

Conclusions—Heterotopic transplantation in the rabbit does allow recovery of the failing heart, and ß₂AR overexpression acutely enhances this functional improvement. Accordingly, genetic manipulation of ßAR signaling may represent a novel molecular adjunct to mechanical assistance to facilitate functional myocardial recovery.

Key words: heart failure • receptors, adrenergic, beta • remodeling • heart-assist device • gene therapy

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