Response: Adenovirus-Mediated Gene Transfer to the Rat Heart Graft

Abstract

Ogata et al. (1) demonstrate interesting findings regarding the expression of the luciferase gene after adenoviral transfection in rat hearts. The fact that gene expression was detected supports our technique of retrograde aortic injection at the time of donor heart procurement as a method of selective gene manipulation in the perioperative period (2). It is true that adenoviral vectors can cause an inflammatory response that could confound the results of any study using this vector. This is the reason that we selected null adenovirus controls for our experiments. Because of the use of these controls, we believe that the effects we demonstrated on reperfusion injury and graft coronary artery disease were due to the single altered variable, that is, the upregulation of bcl-2. Regarding our use of the syngeneic-allogeneic retransplantation technique, the main purpose of this method is to allow for maximal translation of the bcl-2 gene product at the time of allogeneic transplant reperfusion. As Kita et al. (3) demonstrated, this gene expression occurs at detectable levels over a course of approximately 7 days, and according to our unpublished preliminary data, this expression was optimal at 4 days after the syngeneic transplant. Another way of conceptualizing this double-transplant technique is that the syngeneic recipient essentially acts as a stable environment for bcl-2 gene upregulation, or a relatively inert means by which to house the genetically altered graft until the appropriate time for retransplantation. We did not observe any episodes of cardiac arrest attributed to adenoviral therapy. Regarding the concern that our model is not immediately clinically applicable, we agree. Our purpose was to demonstrate the potential importance of bcl-2 in the short and long-term function of heart allografts, and our model happened to incorporate the use of adenovirus to prove our hypothesis. The issues involved with the use of adenovirus in humans are many, and we do not expect to see adenoviral vectors utilized in the human transplant setting in the near future. However, a variety of pharmacological agents are utilized during the organ procurement process and, considering our data, it would be of interest to see how these agents affect the expression of bcl-2. Douglas N. Miniati Robert C. Robbins Department of Cardiothoracic Surgery Stanford University Stanford, CA