β2 Adrenoceptor gene therapy ameliorates left ventricular dysfunction following cardiac surgery

Objective: Heart surgery is associated with impairment of the myocardial β-adrenoceptor (βAR) system. Effective therapies for post-operative ventricular dysfunction are limited. Prolonged inotrope exposure is associated with further βAR down-regulation. Left ventricular (LV) dysfunction and myocardial βAR impairment were assessed following cardiopulmonary bypass (CPB) and cardioplegic arrest in a pig model. Transfer of the human β₂-adrenoceptor transgene (Adeno-β₂AR) 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-β₂AR or phosphate buffered saline (PBS) were delivered via the aortic root during cardioplegic arrest. Groups B (PBS) and C (Adeno-β₂AR) were assessed at 2 days while Groups D (PBS) and E (Adeno-β₂AR) were assessed at 2 weeks from the time of surgery. An LV micromanometer was inserted under sedation to obtain pressure recordings following surgery. βAR density was measured subsequently. Results: Following cardiac surgery LV βAR density was reduced (104±5.7 vs 135±6.1 fmol/mg membrane protein; P=0.007), and, in response to β agonist stimulation, LV dP/dt_max was reduced (4337±405 vs 5328±194 mmHg/s; P<0.05) compared to animals which did not undergo surgery. Adeno-β₂AR therapy during cardiac surgery resulted in elevated LV βAR 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 βAR density was also present at 2 weeks (315±74.1 vs 119±7.1 fmol/mg; P=0.002). In addition, Adeno-β₂AR therapy enhanced β 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, β₂AR gene transfer ameliorated LV dysfunction following surgery such that there were no significant differences between non-operated controls and animals treated with Adeno-β₂AR during CPB and cardioplegic arrest. Conclusions: Reduced βAR density and impaired LV function were present following CPB and cardioplegic arrest. Cardiac-selective β₂AR 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.