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Eur J Cardiothorac Surg 2004;26:1161-1168
© 2004 Elsevier Science NL

ß₂ Adrenoceptor gene therapy ameliorates left ventricular dysfunction following cardiac surgery

^a Department of Surgery, Duke University Medical Center, Durham, NC 27710, USA
^b Department of Biochemistry, Duke University Medical Center, Durham, NC 27710, USA
^c Department of Pathology, Duke University Medical Center, Durham, NC 27710, USA

Received 21 June 2004; received in revised form 2 August 2004; accepted 10 August 2004.

^* Corresponding author. Present address: Department of Cardiac Surgery, Royal Victoria Hospital, Grosvenor Road, Belfast BT12 6BA, UK. Tel.: +44 289 0633 500; fax: +44 289 0312 907. (E-mail: mark.jones{at}royalhospitals.n-i.nhs.uk).

Objective: Heart surgery is associated with impairment of the myocardial ß-adrenoceptor (ßAR) system. Effective therapies for post-operative ventricular dysfunction are limited. Prolonged inotrope exposure is associated with further ßAR down-regulation. Left ventricular (LV) dysfunction and myocardial ßAR impairment were assessed following cardiopulmonary bypass (CPB) and cardioplegic arrest in a pig model. Transfer of the human ß₂-adrenoceptor transgene (Adeno-ß₂AR) 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-ß₂AR or phosphate buffered saline (PBS) were delivered via the aortic root during cardioplegic arrest. Groups B (PBS) and C (Adeno-ß₂AR) were assessed at 2 days while Groups D (PBS) and E (Adeno-ß₂AR) were assessed at 2 weeks from the time of surgery. An LV micromanometer was inserted under sedation to obtain pressure recordings following surgery. ßAR density was measured subsequently. Results: Following cardiac surgery LV ßAR density was reduced (104±5.7 vs 135±6.1fmol/mg membrane protein; P=0.007), and, in response to ß agonist stimulation, LV dP/dt_max was reduced (4337±405 vs 5328±194mmHg/s; P<0.05) compared to animals which did not undergo surgery. Adeno-ß₂AR therapy during cardiac surgery resulted in elevated LV ßAR density (520±250.9fmol/mg) 2 days post-operatively compared to PBS (104±5.7fmol/mg; P=0.002) and compared to the no surgery group (135±6.1fmol/mg; P=0.002). Elevated LV ßAR density was also present at 2 weeks (315±74.1 vs 119±7.1fmol/mg; P=0.002). In addition, Adeno-ß₂AR therapy enhanced ß agonist stimulated LV dP/dt_max (5348±121 vs 4337±405mmHg/s; P<0.05) and heart rate (209±6.9 vs 173±11.0bpm; P<0.05), and reduced LVEDP (2.1±0.4 vs 6.4±1.8mmHg; P<0.05) compared to PBS treatment. Interestingly, gene delivery was cardiac-selective and beneficial effects on function persisted for 2 weeks. Moreover, ß₂AR gene transfer ameliorated LV dysfunction following surgery such that there were no significant differences between non-operated controls and animals treated with Adeno-ß₂AR during CPB and cardioplegic arrest. Conclusions: Reduced ßAR density and impaired LV function were present following CPB and cardioplegic arrest. Cardiac-selective ß₂AR 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.