TY - JOUR
T1 - β 2 Adrenoceptor gene therapy ameliorates left ventricular dysfunction following cardiac surgery
AU - Jones, J. Mark
AU - Petrofski, Jason A.
AU - Wilson, Katrina H.
AU - Steenbergen, Charles
AU - Koch, Walter J.
AU - Milano, Carmelo A.
N1 - Funding Information:
The authors thank Robert J. Lefkowitz for helpful discussions throughout these studies. George Quick, Ronnie Johnston and Kurt Campbell provided technical assistance. This work was supported in part by National Institutes of Health grants HL 56205 (W.J.K.) and HL 59533 (W.J.K.), and the American Heart Association Grant-in-aid (C.A.M.).
PY - 2004/12
Y1 - 2004/12
N2 - 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 β 2-adrenoceptor transgene (Adeno-β 2AR) 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-β 2AR or phosphate buffered saline (PBS) were delivered via the aortic root during cardioplegic arrest. Groups B (PBS) and C (Adeno-β 2AR) were assessed at 2 days while Groups D (PBS) and E (Adeno-β 2AR) 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-β 2AR 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-β 2AR 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, β 2AR gene transfer ameliorated LV dysfunction following surgery such that there were no significant differences between non-operated controls and animals treated with Adeno-β 2AR during CPB and cardioplegic arrest. Conclusions: Reduced βAR density and impaired LV function were present following CPB and cardioplegic arrest. Cardiac-selective β 2AR 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.
AB - 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 β 2-adrenoceptor transgene (Adeno-β 2AR) 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-β 2AR or phosphate buffered saline (PBS) were delivered via the aortic root during cardioplegic arrest. Groups B (PBS) and C (Adeno-β 2AR) were assessed at 2 days while Groups D (PBS) and E (Adeno-β 2AR) 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-β 2AR 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-β 2AR 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, β 2AR gene transfer ameliorated LV dysfunction following surgery such that there were no significant differences between non-operated controls and animals treated with Adeno-β 2AR during CPB and cardioplegic arrest. Conclusions: Reduced βAR density and impaired LV function were present following CPB and cardioplegic arrest. Cardiac-selective β 2AR 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.
KW - Animal model
KW - Cardiopulmonary bypass
KW - Circulatory assistance
KW - Gene therapy
KW - Receptors
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U2 - 10.1016/j.ejcts.2004.08.028
DO - 10.1016/j.ejcts.2004.08.028
M3 - Article
C2 - 15541978
AN - SCOPUS:8444245517
SN - 1010-7940
VL - 26
SP - 1161
EP - 1168
JO - European Journal of Cardio-thoracic Surgery
JF - European Journal of Cardio-thoracic Surgery
IS - 6
ER -