β 2 Adrenoceptor gene therapy ameliorates left ventricular dysfunction following cardiac surgery

J. Mark Jones, Jason A. Petrofski, Katrina H. Wilson, Charles Jr Steenbergen, Walter J. Koch, Carmelo A. Milano

Research output: Contribution to journalArticle

Abstract

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; P2AR 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; P2AR 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.

Original languageEnglish (US)
Pages (from-to)1161-1168
Number of pages8
JournalEuropean Journal of Cardio-thoracic Surgery
Volume26
Issue number6
DOIs
StatePublished - Dec 2004
Externally publishedYes

Fingerprint

Left Ventricular Dysfunction
Genetic Therapy
Adrenergic Receptors
Thoracic Surgery
Cardiopulmonary Bypass
Phosphates
Ventricular Dysfunction
Therapeutics
Transgenes
Left Ventricular Function
Genes
Membrane Proteins
Swine
Down-Regulation
Pressure

Keywords

  • Animal model
  • Cardiopulmonary bypass
  • Circulatory assistance
  • Gene therapy
  • Receptors

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine
  • Surgery

Cite this

β 2 Adrenoceptor gene therapy ameliorates left ventricular dysfunction following cardiac surgery. / Jones, J. Mark; Petrofski, Jason A.; Wilson, Katrina H.; Steenbergen, Charles Jr; Koch, Walter J.; Milano, Carmelo A.

In: European Journal of Cardio-thoracic Surgery, Vol. 26, No. 6, 12.2004, p. 1161-1168.

Research output: Contribution to journalArticle

Jones, J. Mark ; Petrofski, Jason A. ; Wilson, Katrina H. ; Steenbergen, Charles Jr ; Koch, Walter J. ; Milano, Carmelo A. / β 2 Adrenoceptor gene therapy ameliorates left ventricular dysfunction following cardiac surgery. In: European Journal of Cardio-thoracic Surgery. 2004 ; Vol. 26, No. 6. pp. 1161-1168.
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abstract = "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; P2AR 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; P2AR 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.",
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AU - Jones, J. Mark

AU - Petrofski, Jason A.

AU - Wilson, Katrina H.

AU - Steenbergen, Charles Jr

AU - Koch, Walter J.

AU - Milano, Carmelo A.

PY - 2004/12

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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; P2AR 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; P2AR 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.

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