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.
OBJECTIVE
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 (pVaxl) encoding human HGF (1,500 microg) 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 pVaxl during US/MB (pVaxl-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 pVaxl-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.
Kondo
Isao
I
Second Department of Internal Medicine, Kagawa University School of Medicine, Kagawa, Japan.
Ohmori
Koji
K
Oshita
Akira
A
Takeuchi
Hiroto
H
Fuke
Sachiko
S
Shinomiya
Kaori
K
Noma
Takahisa
T
Namba
Tsunetatsu
T
Kohno
Masakazu
M
D000818:Animals; D002196:Capillaries; D002921:Cicatrix / Q000517:prevention & control; D004195:Disease Models, Animal; D005786:Gene Expression Regulation; D018014:Gene Transfer Techniques; D015316:Genetic Therapy / Q000379:methods*; D006352:Heart Ventricles; D006439:Hemodynamics / Q000187:drug effects; D017228:Hepatocyte Growth Factor / Q000032:analysis / Q000235:genetics*; D007150:Immunohistochemistry; D007545:Isoproterenol / Q000494:pharmacology; D008297:Male; D045423:Microbubbles; D009203:Myocardial Infarction / Q000235:genetics / Q000473:pathology / Q000628:therapy*; D009206:Myocardium / Q000737:chemistry* / Q000473:pathology*; D010957:Plasmids; D051381:Rats; D017207:Rats, Sprague-Dawley; D014463:Ultrasonography; D020257:Ventricular Remodeling
D017228:Hepatocyte Growth Factor; D007545:Isoproterenol