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J Am Coll Cardiol, 2004; 44:644-653, doi:10.1016/j.jacc.2004.04.042 © 2004 by the American College of Cardiology Foundation |
* Second Department of Internal Medicine, Kagawa University School of Medicine, Kagawa, Japan
Manuscript received December 25, 2002; revised manuscript received April 12, 2004, accepted April 20, 2004.
* Reprint requests and correspondence: Dr. Koji Ohmori, The Second Department of Internal Medicine, Kagawa University School of Medicine, 1750-1, Ikenobe, Miki-cho, Kita-gun, Kagawa 761-0793 Japan.
komori{at}kms.ac.jp
OBJECTIVES: We examined whether ultrasonic microbubble destruction (US/MB) enables therapeutic myocardial gene transfer of hepatocyte growth factor (HGF) for acute myocardial infarction (MI).
BACKGROUND: Hepatocyte growth factor gene transfer provides cardioprotective effects in MI, which requires direct intramyocardial injection or special vectors. Although US/MB was used in myocardial gene transfer, its feasibility in transfer of a therapeutic gene with non-viral vector remains unknown.
METHODS: In a rat model of acute MI, naked plasmid (pVax1) encoding human HGF (1,500 µg) was infused into the left ventricular (LV) chamber during US/MB (HGF-US/MB) or insonation only (HGF-US) or alone (HGF-alone), while control MI rats received empty pVax1 during US/MB (pVax1-US/MB). For US/MB, transthoracic intermittent insonation with a diagnostic transducer (1.3 MHz) was performed for 2 min at a peak negative pressure of –2,160 kPa during intravenous 20% Optison.
RESULTS: Baseline risk area was comparable among the groups. Immunohistology seven days after treatment revealed significant myocardial expression of HGF protein only in HGF-US/MB. At three weeks, LV weight in HGF-US/MB (0.89 ± 0.03 g) was significantly lower than those in HGF-alone (1.09 ± 0.08 g), HGF-US (1.04 ± 0.07 g), and pVax1-US/MB (1.04 ± 0.05 g). Moreover, scar size was significantly smaller (16 ± 6% vs. 39 ± 5%, 41 ± 6%, and 40 ± 4% of total myocardial circumferential length, respectively), while capillary density (49 ± 8 vs. 34 ± 5, 37 ± 6, and 36 ± 4 capillaries/high-power field, respectively) and arterial density (37 ± 7 vs. 15 ± 9, 18 ± 4, and 14 ± 11 arterioles/high-power field, respectively) in the risk area were higher in HGF-US/MB than the other groups.
CONCLUSIONS: Ultrasound-mediated microbubble destruction may enable myocardial HGF gene transfer with systemic administration of naked plasmid, which enhances angiogenesis, limits infarction size, and prevents LV remodeling after MI.
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