beta2 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 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. METHODS: 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. 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/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. CONCLUSIONS: 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.
Jones, JM; Petrofski, JA; Wilson, KH; Steenbergen, C; Koch, WJ; Milano, CA
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