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(Circulation. 2007;116:I-71 – I-76.)
© 2007 American Heart Association, Inc.

Cell Transplantation and Tissue Regeneration

Intracoronary Administration of AdvFGF-5 (Fibroblast Growth Factor-5) Ameliorates Left Ventricular Dysfunction and Prevents Myocyte Loss in Swine With Developing Collaterals and Ischemic Cardiomyopathy

Petra Lynch, MD; Te-Chung Lee, PhD; James A. Fallavollita, MD; John M. Canty, Jr, MD; Gen Suzuki, MD, PhD

From the VA WNY Health Care System (J.A.F., J.M.C.), the Departments of Medicine (J.A.F., J.M.C., G.S.), Biochemistry (T.-C.L.), Physiology & Biophysics (J.M.C.), and the Center for Research in Cardiovascular Medicine (P.L., T.-C.L., J.A.F., J.M.C., G.S.) at the University at Buffalo, NY.

Correspondence to Gen Suzuki, MD, PhD, Division of Cardiolovascular Medicine, University at Buffalo, Biomedical Research Building, Room 347, 3435 Main Street, Buffalo, NY 14214. E-mail gsuzuki{at}buffalo.edu

Background— Fibroblast growth factor (AdvFGF-5) improves regional function by stimulating myocyte hypertrophy without increasing myocardial perfusion in swine with hibernating myocardium. We performed the present study to determine whether AdvFGF-5 could prevent the progression of LV dysfunction in swine with ischemic cardiomyopathy.

Methods and Results— Swine were chronically instrumented with LAD and LCX stenoses to produce viable dysfunctional myocardium and studied 1 month after instrumentation in the closed-chest sedated state. Flow and regional function before and 30 days after intracoronary AdvFGF-5 (2x10¹² vp, n=9) were compared with animals receiving intracoronary AdvEGFP (2x10¹² vp, n=6). Histological analysis was performed to quantify myocyte size, myocyte nuclear density, apoptosis (TUNEL), and the frequency of myocytes in the proliferative phase of the cell cycle (Ki-67 staining). LAD wall-thickening (27±3 to 46±6%, P<0.05) and EF (39±4 to 56±3%, P<0.05) increased after AdvFGF-5. AdvFGF-5 increased maximal perfusion during adenosine vasodilation despite no differences in baseline flow or stenosis severity. After AdvFGF-5, TUNEL-positive myocytes decreased 6-fold and Ki-67 positive myocyte nuclei increased 2-fold. As a result, AdvFGF-5 produced a marked increase in myocyte nuclear density (957±54 to 1447±40 nuclei/mm², P<0.05).

Conclusion— These data indicate that AdvFGF-5 increases regional function and maximal perfusion distal to stenotic arteries when administered before the development of collaterals. This was associated with a reduction in myocyte apoptosis, an increase in Ki-67–positive myocytes, and an increase in myocyte number. Thus, AdvFGF-5 offers a potential therapeutic approach to prevent the progression of ischemic cardiomyopathy and heart failure.

Key Words: ischemia • cardiomyopathy • growth substances • gene therapy