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(Circulation. 2003;108:II-230.)
© 2003 American Heart Association, Inc.

Cardiac Transplantation and Surgery for Congestive Heart Failure

Gene Transfer of Hepatocyte Growth Factor Attenuates Postinfarction Heart Failure

Vasant Jayasankar, MD; Y. Joseph Woo, MD; Lawrence T. Bish, BA; Timothy J. Pirolli; Subhasis Chatterjee, MD; Mark F. Berry, MD; Jeffrey Burdick, BS; Timothy J. Gardner, MD; H. Lee Sweeney, PhD

From the Departments of Cardiothoracic Surgery and Physiology, University of Pennsylvania School of Medicine, Pliladelphia, PA

Correspondence to Y. Joseph Woo MD, Division of Cardiothoracic Surgery, University of Pennsylvania School of Medicine, 6 Silverstein Pavilion, 3400 Spruce St., Philadelphia, PA 19104. Phone: 215-662-2956; Fax: 215-349-5798; E-mail: wooy{at}uphs.upenn.edu

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 descending coronary artery with direct intramyocardial injection of replication-deficient recombinant adenovirus encoding HGF (n=10) or empty null virus as control (n=9), 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 (79±5 versus 56±4 mm Hg, P<0.001) and maximum dP/dt (2890±326 versus 1622±159 mm Hg/sec, P<0.01). Significant preservation of LV geometry was associated with HGF treatment (LV Diameter HGF 13.1±0.54 versus Null 14.4±0.15 mm P<0.01; LV wall thickness 1.73±0.10 versus 1.28±0.07 mm P<0.01). 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 (3.42±0.83% versus 8.36±1.16%, P<0.01), 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.

Key Words: angiogenesis • heart failure • gene therapy • apoptosis