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beta2 adrenoceptor gene therapy ameliorates left ventricular dysfunction following cardiac surgery
J Mark Jones1, Jason A Petrofski, Katrina H Wilson
1Department of Surgery, Duke University Medical Center, Durham, NC 27710, USA. mark.jones@royalhospitals.n-i.nhs.uk
Summary
Cardiac surgery impairs heart function by reducing beta-adrenoceptor (betaAR) density. Gene transfer of beta2-adrenoceptor (beta2AR) during surgery effectively restored betaAR levels and improved left ventricular function post-operatively.
Area of Science:
- Cardiovascular Science
- Molecular Cardiology
- Gene Therapy
Background:
- Cardiac surgery, particularly cardiopulmonary bypass (CPB) and cardioplegic arrest, leads to myocardial beta-adrenoceptor (betaAR) system impairment and post-operative left ventricular (LV) dysfunction.
- Existing therapies for post-operative ventricular dysfunction are limited, and prolonged inotropic agent use can exacerbate betaAR downregulation.
Purpose of the Study:
- To assess LV dysfunction and myocardial betaAR impairment following CPB and cardioplegic arrest in a neonatal pig model.
- To evaluate the efficacy of human beta2-adrenoceptor transgene (Adeno-beta2AR) transfer as a therapeutic strategy for post-operative cardiac dysfunction.
Main Methods:
- Five groups of six neonatal piglets were studied, including a non-surgical control group.
- Adeno-beta2AR or phosphate-buffered saline (PBS) was administered via the aortic root during cardioplegic arrest.
- Left ventricular pressure recordings and betaAR density measurements were performed at 2 days and 2 weeks post-surgery.
Main Results:
- Cardiac surgery significantly reduced LV betaAR density and beta-agonist-stimulated contractility (LV dP/dtmax).
- Adeno-beta2AR therapy during surgery markedly increased LV betaAR density at both 2 days and 2 weeks post-operatively compared to PBS-treated and non-operated groups.
- Adeno-beta2AR treatment enhanced beta-agonist-stimulated LV dP/dtmax and heart rate, while reducing LV end-diastolic pressure (LVEDP), effectively ameliorating LV dysfunction.
Conclusions:
- CPB and cardioplegic arrest induce significant betaAR downregulation and LV dysfunction.
- Cardiac-selective beta2AR gene transfer during CPB effectively restores betaAR density and ameliorates LV dysfunction post-cardiac surgery.
- This gene transfer technique represents a promising novel approach for post-operative ventricular support.