β2 Adrenoceptor gene therapy ameliorates left ventricular dysfunction following cardiac surgery

Objective: Heart surgery is associated with impairment of the myocardial beta-adrenoceptor (betaAR) system. Effective therapies for postoperative 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 beta(2)-adrenoceptor transgene (Adeno-beta(2)AR) during cardioplegic arrest was then tested as a potential therapy. Methods: Five groups of six neonatal piglets were studied. One group did not undergo surgery (Group A). Adeno-beta(2)AR or phosphate buffered saline (PBS) were delivered via the aortic root during cardioplegic arrest. Groups B (PBS) and C (Adeno-beta(2)AR) were assessed at 2 days while Groups D (PBS) and E (Adeno-beta(2)AR) 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. Results: 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/dt, a, was reduced (4337 +/- 405 vs 5328 +/- 194 mmHg/s; P < 0.05) compared to animals which did not undergo surgery. Adeno-beta(2)AR 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-beta(2)AR therapy enhanced beta agonist stimulated LV dP/dt(max) (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, betaAR gene transfer ameliorated LV dysfunction following surgery such that there were no significant differences between non-operated controls and animals treated with Adeno-beta(2)AR during CPB and cardioplegic arrest. Conclusions: Reduced OAR density and impaired LV function were present following CPB and cardioplegic arrest. Cardiac-selective beta(2)AR 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. (C) 2004 Elsevier B.V. All rights reserved.