Long-term effects of hepatocyte growth factor gene therapy in rat myocardial infarct model

Abstract

We investigated the long-term effects of human hepatocyte growth factor (HGF) gene therapy in a rat myocardial infarct model. Treatment adenovirus coexpressing the HGF therapeutic gene and the human sodium/iodide symporter (NIS) reporter gene or control adenovirus expressing the NIS gene alone were injected directly into the infarct border zone immediately after permanent coronary ligation in rats (n=6 each). A uniform disease state was confirmed in the acute phase in terms of impaired left ventricular (LV) function by cine magnetic resonance imaging (MRI), large infarct extent by (99m)Tc-tetrofosmin single-photon emission computed tomography (SPECT) and successful gene transfer and expression by (99m)TcO(4)(-) SPECT. After a 10-week follow-up, repeated cine MRI demonstrated no significant difference in the LV ejection fraction between the time points or groups, but a significantly increased end-diastolic volume from the acute to the chronic phase without a significant difference between the groups. Capillary density was significantly higher in the treatment group, whereas arteriole density remained unchanged. Two-photon excitation fluorescence microscopy revealed extremely thin capillaries (2-5 μm), and their irregular networks increased in the infarct border zone of the treated myocardium. Our results indicated that single HGF gene therapy alone induced an immature and irregular microvasculature.