Cardiac Gene Delivery With Cardiopulmonary Bypass
It is well recognized that intracoronary injection of an adenoviral vector with the heart beating, leads to rapid washout of the vector and to adherence of the vector to non-target organs such as the liver and lung. With 1-week-old piglets as their model, the authors tested a cardiac-selective gene transfer approach by infusing recombinant replication-deficient adenovirus containing the human b2-adrenergic receptor (b2-AR) after infusion of the cardioplegic solution was completed. After cardioplegic arrest, 1×1011 viral particles were infused into the aortic root and allowed to remain in the myocardium for the 30 minutes of arrest. After weaning from CPB, gene expression was assessed 1 week after the gene substrate was administered. In addition, a subset of animals was studied at 4, 8, 24 hours and at 14 days after gene delivery to determine the time course of gene expression. Heart, liver, and lung samples were studied for gene expression.
Forty-two piglets were studied; 40 survived to time of tissue analysis. Twenty-six had transgene expression studied at 1 week. Eleven piglets receiving adeno-b-gal had transmural staining in all chambers; no b -galactosidase expression was seen in the liver or lung. At 1 week, animals treated with adeno-b2-AR exhibited a left ventricular b2-AR density approximately fourfold higher than controls receiving the marker transgene (P<0.01). The right ventricular b2-AR density was 1.6-fold higher, exhibiting lower but significant transgene expression in that chamber as well (P =0.01). b2-AR density was no different in the liver or lung between adeno-b2-AR and adeno-b-gal-treated animals. Gene expression was studied at varying intervals from time of viral delivery. b-galactosidase expression at 8 hours post delivery was transmural and comparable to expression at either 24 hours or 1 week. This study from Duke University demonstrates the feasibility of selective gene delivery during cold hyperkalemic cardioplegic arrest. It also shows that this therapy appears to limit the risk of gene expression in non-target organs. In fact, the virus is allowed to dwell in the myocardium for the duration of cardioplegic arrest. At the end of cardioplegic arrest, in contrast to simple beating-heart delivery, a higher percentage of viral particles may be taken up by the myocytes or be inactivated by the membrane oxygenator. The authors believe that this approach may have wide applicability in patients having cardiac surgery, particularly those with end-stage heart failure. They further note that this method of transgene delivery may achieve expression during the critical early period after cardiac surgery and indeed continue for 2 to 3 weeks. Comment
The techniques here described is unique and has a potential for exposing the heart alone to the transgene, which would be ideal. Employing a method for transient assist to the heart after cardiac surgery is a very attractive concept that needs to be further explored. Clearly, there are genes that could be used in the setting of heart failure, and the feasibility of cardiac gene administration selectively during cardioplegic arrest is certainly attractive. The authors note the feasibility of retrograde delivery of the transgene along with retrograde cardioplegia; such a concept deserves further investigation.
