Myocardial gene transfer and overexpression of beta2-adrenergic receptors potentiates the functional recovery of unloaded failing hearts.

Abstract

Mechanical assistance of the failing left ventricle (LV) can lead to functional recovery after a period of unloading, including restoration of beta-adrenergic receptor (betaAR) 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 beta2AR transgene (Adv-beta2AR) could alter this process. 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 2x10(11) viral particles of Adv-beta2AR 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-beta2AR, however, LV dP/dt(max) and LV dP/dt(min) were improved in response to higher preloads (P<0.05) and betaAR stimulation (P<0.01). Heterotopic transplantation in the rabbit does allow recovery of the failing heart, and beta2AR overexpression acutely enhances this functional improvement. Accordingly, genetic manipulation of betaAR signaling may represent a novel molecular adjunct to mechanical assistance to facilitate functional myocardial recovery.