Abstract 3174: Administration of Cyclin A2 by Gene Transfer Improves Cardiac Function in a Porcine Model of Myocardial Infarction
Background: In a rodent model of myocardial infarction, treatment with Cyclin A2 delivered via gene transfer improved myocardial function with a marked increase in the presence of mitotic cells in the periinfarct zone. The purpose of this preclinical study was to determine if gene delivery of Cyclin A2 improved cardiac function in a large animal myocardial infarction model.
Methods: Twenty juvenile swine underwent permanent occlusion of the proximal left anterior descending artery (LAD) with embolic coil placement. One week post-infarction, 1012 replication-deficient adenovirus particles containing Cyclin A2 (n=7) or null content (n=6) were injected directly into the peri-infarct zone via left lateral thoracotomy of surviving animals. Animals were sacrificed six weeks later. Hemodynamic measurements (pulmonary artery catheter and Millar catheter) and imaging (echocardiography, LV angiography, and MRI) were performed at baseline, prior to surgery and at the time of sacrifice.
Results: Myocardial Cyclin A2 expression was confirmed at 2 days, 7 days and 6 weeks after gene transfer and was absent in control animals. By left ventricular angiography, the Cyclin A2 treated animals had improved ejection fraction from the time of gene transfer to sacrifice compared to controls (29.7±19.3% vs. 4.5±8.0%; p=0.01). Three dimensional echocardiography also showed a relative improved ejection fraction in the Cyclin A2 group compared to the control group (30.0±16.9% vs. 8.9±8.5%; p=0.017). MRI quantitated ejection fraction (7 pigs) was improved in the Cyclin A2 group compared to controls at the time of sacrifice (37.0±4.8% vs. 30.0±5.6%; p=0.016), though the relative change from surgery to sacrifice was not statistically superior in the Cyclin A2 group (19.5±8.0% vs −9.2±18.4%; p=0.099). Scar size at the time of sacrifice, as estimated by delayed enhancement MRI, was smaller in the Cyclin A2 group (24.3±6.1% vs. 37.5±0.7%, p=0.02).
Conclusions: Cyclin A2 gene therapy improves cardiac function in a preclinical myocardial infarction model. Histopathological studies will help determine if stimulation of cell division was the mechanism of this improvement.