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Treatment of acute myocardial infarction by hepatocyte growth factor gene transfer

The first demonstration of myocardial transfer of a "functional" gene using ultrasonic microbubble destruction

^* 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.

Abbreviations and Acronyms   HGF = hepatocyte growth factor   LV = left ventricle/ventricular   MB = microbubble   MCE = myocardial contrast echocardiography   MI = myocardial infarction   US = ultrasound   US/MB = ultrasound-mediated microbubble destruction

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