Myocardial gene transfer and overexpression of β2-adrenergic receptors potentiates the functional recovery of unloaded failing hearts

Abstract

Background - Mechanical assistance of the failing left ventricle (LV) can lead to functional recovery after a period of unloading, including restoration of β-adrenergic receptor (βAR) 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 β2AR transgene (Adv-β2AR) 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 2×1011 viral particles of Adv-β2AR 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/dtmax) and relaxation (LV dP/dtmin) were significantly decreased in saline-treated failing hearts compared with control nonfailing hearts (P<0.05). In failing hearts treated with Adv-β2AR, however, LV dP/dtmax and LV dP/dtmin were improved in response to higher preloads (P<0.05) and βAR stimulation (P<0.01). Conclusions - Heterotopic transplantation in the rabbit does allow recovery of the failing heart, and β2AR overexpression acutely enhances this functional improvement. Accordingly, genetic manipulation of βAR signaling may represent a novel molecular adjunct to mechanical assistance to facilitate functional myocardial recovery.