Adenylylcyclase Gene Transfer Increases Function of the Failing Heart

San Diego Veterans Healthcare System, and Department of Medicine, University of California, San Diego 92093, USA.
Human Gene Therapy (Impact Factor: 3.76). 10/2006; 17(10):1043-8. DOI: 10.1089/hum.2006.17.1043
Source: PubMed


A persistent question in cardiovascular gene transfer concerns whether an exogenously delivered gene can increase function of the failing heart. Here we test the hypothesis that intracoronary delivery of adenovirus encoding adenylylcyclase type VI (Ad.ACVI) in the setting of active heart failure will increase function of the failing heart. As a model of heart failure, we used transgenic mice with dilated and poorly functioning hearts resulting from cardiac-directed expression of Galphaq.Galphaq mice with equivalent pretreatment impairment in left ventricular (LV) function (echocardiography) received 2.5x1010 viral particles of Ad.ACVI or Ad.EGFP (enhanced green fluorescent protein), or saline, by indirect intracoronary delivery. Serial echocardiograms obtained before and 14 days after gene transfer showed that Ad.ACVI increased LV ejection fraction (p<0.01) and velocity of circumferential fiber shortening (p<0.03). Detailed measurements in isolated hearts showed that ACVI gene transfer increased LV positive dP/dt (p=0.02) and LV negative dP/dt (p=0.01). Gene transfer was confirmed by polymerase chain reaction. These data show that, in an animal model that mimics key aspects of clinical congestive heart failure, cardiac gene transfer of ACVI increases function of the failing heart.

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    • "When this protein was overexpressed in mice with cardiomyopathy-induced by overexpression of Ga-q enhancement of cyclase increased survival, possibly by a mechanism that involves enhanced response to catecholamines (Roth et al. 1999, Rebolledo et al. 2006). However, transgenic expression of the same gene did not cause significant effects on heart rate or basal function (Roth et al. 2003), although it did improve survival in a coronary artery ligation model (Takahashi et al. 2006). "
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    • "Exogenous gene transfer will be required if AC6 is ever to be applied in the treatment of clinical heart failure. Mice with Gaq cardiomyopathy received indirect intracoronary delivery of an adenovirus vector encoding AC6, and LV systolic and diastolic function were increased fourteen days after delivery (Rebolledo et al., 2006). However, this study used thoracotomy and aortic and pulmonary artery cross clamping to deliver the adenovirus vector, a technique that will not be applicable to patients with severe CHF. "
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