?2 Adrenoceptor gene therapy ameliorates left ventricular dysfunction following cardiac surgery

Abstract

Heart surgery is associated with impairment of the myocardial beta-adrenoceptor (betaAR) system. Effective therapies for post-operative ventricular dysfunction are limited. Prolonged inotrope exposure is associated with further betaAR down-regulation. Left ventricular (LV) dysfunction and myocardial betaAR impairment were assessed following cardiopulmonary bypass (CPB) and cardioplegic arrest in a pig model. Transfer of the human beta2-adrenoceptor transgene (Adeno-beta2AR) during cardioplegic arrest was then tested as a potential therapy. Five groups of six neonatal piglets were studied. One group did not undergo surgery (Group A). Adeno-beta2AR or phosphate buffered saline (PBS) were delivered via the aortic root during cardioplegic arrest. Groups B (PBS) and C (Adeno-beta2AR) were assessed at 2 days while Groups D (PBS) and E (Adeno-beta2AR) were assessed at 2 weeks from the time of surgery. An LV micromanometer was inserted under sedation to obtain pressure recordings following surgery. betaAR density was measured subsequently. Following cardiac surgery LV betaAR density was reduced (104+/-5.7 vs 135+/-6.1 fmol/mg membrane protein; P=0.007), and, in response to beta agonist stimulation, LV dP/dtmax was reduced (4337+/-405 vs 5328+/-194 mmHg/s; P<0.05) compared to animals which did not undergo surgery. Adeno-beta2AR therapy during cardiac surgery resulted in elevated LV betaAR density (520+/-250.9 fmol/mg) 2 days post-operatively compared to PBS (104+/-5.7 fmol/mg; P=0.002) and compared to the no surgery group (135+/-6.1 fmol/mg; P=0.002). Elevated LV betaAR density was also present at 2 weeks (315+/-74.1 vs 119+/-7.1 fmol/mg; P=0.002). In addition, Adeno-beta2AR therapy enhanced beta agonist stimulated LV dP/dtmax (5348+/-121 vs 4337+/-405 mmHg/s; P<0.05) and heart rate (209+/-6.9 vs 173+/-11.0 bpm; P<0.05), and reduced LVEDP (2.1+/-0.4 vs 6.4+/-1.8 mmHg; P<0.05) compared to PBS treatment. Interestingly, gene delivery was cardiac-selective and beneficial effects on function persisted for 2 weeks. Moreover, beta2AR gene transfer ameliorated LV dysfunction following surgery such that there were no significant differences between non-operated controls and animals treated with Adeno-beta2AR during CPB and cardioplegic arrest. Reduced betaAR density and impaired LV function were present following CPB and cardioplegic arrest. Cardiac-selective beta2AR gene transfer during CPB resulted in amelioration of LV dysfunction after cardiac surgery. Such a technique may offer a new approach to post-operative ventricular support.