Background-Despite advances in surgical and percutaneous coronary revascularization, ongoing ischemia that is not amenable to standard revascularization techniques is a major cause of morbidity and mortality. Hepatocyte Growth Factor (HGF) has potent angiogenic and anti-apoptotic activities, and this study evaluated the functional and biochemical effects of HGF gene transfer in a rat model of postinfarction heart failure. Methods and Results-Lewis rats underwent ligation of the left anterior

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... cending coronary artery with direct intramyocardial injection of replication-deficient recombinant adenovirus encoding HGF (nϭ10) or empty null virus as control (nϭ9), and animals were analyzed after six weeks. Pressure-volume conductance catheter measurements demonstrated significantly preserved contractile function in the HGF group compared with Null control animals as measured by maximum developed LV pressure (79Ϯ5 versus 56Ϯ4 mm Hg, PϽ0.001) and maximum dP/dt (2890Ϯ326 versus 1622Ϯ159 mm Hg/sec, PϽ0.01). Significant preservation of LV geometry was associated with HGF treatment (LV Diameter HGF 13.1Ϯ0.54 versus Null 14.4Ϯ0.15 mm PϽ0.01; LV wall thickness 1.73Ϯ0.10 versus 1.28Ϯ0.07 mm PϽ0.01). Angiogenesis was significantly enhanced in HGF treated animals as measured by both Von Willebrand's Factor immunohistochemical staining and a microsphere assay. TUNEL analysis revealed a significant reduction in apoptosis in the HGF group (3.42Ϯ0.83% versus 8.36Ϯ1.16%, PϽ0.01), which correlated with increased Bcl-2 and Bcl-x L expression in the HGF animals. Conclusions-Hepatocyte Growth Factor gene transfer following a large myocardial infarction results in significantly preserved myocardial function and geometry, and is associated with significant angiogenesis and a reduction in apoptosis. This therapy may be useful as an adjunct or alternative to standard revascularization techniques in patients with ischemic heart failure. (Circulation. 2003;108[suppl II]:II-230-II-236.)