Background— Angiogenic gene therapy is a promising treatment paradigm for patients with ischemic heart disease. In this study, we used micro-positron emission tomography (microPET) to monitor the transgene expression, function, and effects in a whole-body system. Methods and Results— Adenovirus with cytomegalovirus promoter driving an angiogenic gene (vascular endothelial growth factor [VEGF]) linked to a PET reporter gene (herpes simplex virus type 1 mutant thymidine kinase; Ad-CMV-VEGF 121 -CMV-HSV1-sr39tk) was used to transfect rat embryonic cardiomyoblasts in vitro. Expression of both genes correlated strongly ( r =0.98; P <0.001). Afterward, rats underwent ligation of the left anterior descending artery followed by injection of 1×10 10 pfu of Ad-CMV-VEGF 121 -CMV-HSV1-sr39tk (study; n=35) or Ad-null (control; n=15) at the peri-infarct region. Noninvasive microPET imaging was used to assess the uptake of 9-(4-[ 18 F]-fluoro-hydroxymethylbutyl)guanine ([ 18 F]-FHBG) PET reporter probe by cells expressing the HSV1-sr39tk PET reporter gene. Cardiac transgene expression peaked at day 1 and declined over the next 2 weeks. Repeat adenoviral injections at day 60 yielded no detectable signal. The in vivo reporter gene expression (% injected dose/g of [ 18 F]-FHBG) correlated well with ex vivo gamma counting ( r =0.92), myocardial tissue HSV1-sr39TK enzyme activity ( r =0.95), and myocardial tissue VEGF level ( r =0.94; P <0.001 for all). The VEGF 121 isoform induced significant increases in capillaries and small blood vessels. However, the level of neovasculature did not translate into significant improvements in functional parameters such as myocardial contractility by echocardiography, perfusion by nitrogen-13 ammonia imaging, and metabolism by [ 18 F]-fluorodeoxyglucose imaging. Conclusions— Taken together, these findings establish the feasibility of molecular imaging for monitoring angiogenic gene expression with a PET reporter gene and probe noninvasively, quantitatively, and repetitively. The principles demonstrated here can be used to evaluate other therapeutic genes of interest in animal models before future clinical trials are initiated.

The introduction of percutaneous transluminal coronary angioplasty has revolutionized the field of cardiology by providing patients with coronary artery disease immediate and effective therapy. Overshadowing the early success of angioplasty was the high rate of angiographic restenosis and recurrent symptoms at 6 months. The use of stents reduced the incidence of restenosis; however, the rise in the number of patients undergoing percutaneous interventions produced a new problem of restenosis occurring within the stent: in-stent restenosis (ISR). Mechanical approaches, including directional and rotational atherectomy and systemic pharmacotherapy, have failed to demonstrate a reduction in ISR in randomized clinical trials. Intravascular brachytherapy is currently the only approved therapy for ISR, although this treatment has numerous unresolved questions and is not effective in a large percent of patients. Drug-eluting stents have reduced the incidence of restenosis by providing localized therapy to the targeted lesion without systemic toxicity. The purpose of this review is to synthesize data from major clinical trials involving the 2 most successful agents used in the prevention of restenosis: sirolimus and paclitaxel. The cellular and molecular mechanisms of both ISR and restenosis postangioplasty derived from animal models will be introduced. Second, an overview of 3 alternate interventions that attempt to reduce the rates of restenosis is presented. Finally, the major randomized, controlled trials involving sirolimus and paclitaxel are described, and their clinical implications and use as a possible solution in the prevention of restenosis is discussed.

Background:The belief that vascular remodeling and intimal hyperplasia are causes of luminal narrowing in cardiac allograft vasculopathy (CAV) is controversial. This study evaluated the relationship of vascular remodeling and intimal hyperplasia to luminal narrowing 1 year after orthotopic heart transplantation. Methods:Intravascular ultrasound imaging was performed on 190 cardiac transplant recipients at baseline and again 1 year after transplantation as part of a randomized trial of mycophenolate mofetil (MMF) and azathioprine (Aza). Studies 1 year apart were matched at 625 sites. All sites were classified into positive, non-significant and negative remodeling patterns, depending on a change of Ϯ10% in external elastic membrane area. Of the 190 patients, 99 were randomized to receive MMF, and 91 to receive Aza. Results:A total of 625 sites were observed. Of these, 52% had no remodeling, 25%

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