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
Isao Kondo, MD, PhD*,
Koji Ohmori, MD, PhD*,*,
Akira Oshita, MD, PhD*,
Hiroto Takeuchi, MD, PhD*,
Sachiko Fuke, DVM, MCs*,
Kaori Shinomiya, MD, PhD*,
Takahisa Noma, MD, PhD*,
Tsunetatsu Namba, MD, PhD* and
Masakazu Kohno, MD, PhD*
* Second Department of Internal Medicine, Kagawa University School of Medicine, Kagawa, Japan
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Figure 1 Protocol of this study. Various treatments following myocardial contrast echocardiography (MCE) were performed within 2 h after the onset of myocardial infarction (MI). Half of the rats in each group were killed on day 7 for myocardial hepatocyte growth factor (HGF) immunostain. The rest of the rats underwent serial echocardiography until week 3, when they were subjected to cardiac catheterization and were killed for histopathologic assessments.
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Figure 2 (A) Representative recordings of intermittent short-axis images during myocardial contrast echocardiography after coronary occlusion at pulsing interval (PI) of every cardiac cycle (PI = 1) and of every 4th end systole (PI = 4). Arrows denote the risk area. (B) The first frame of the three-frame burst during hepatocyte growth factor gene transfer with ultrasonic microbubble destruction is shown (top) with an illustration (bottom).
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Figure 3 Immunohistology for hepatocyte growth factor (HGF) at x400 magnification. (A) Sections obtained from the anterior region adjacent to the scar (top) and that obtained from the remote control posterior region (bottom) were shown. Naked HGF plasmid infusion with ultrasound-mediated microbubble destruction (US/MB) (HGF-US/MB) exhibited positive staining of HGF in both regions. Hepatocyte growth factor stain was negative in control plasmid infusion with US/MB (pVax1-US/MB) and was limited to perivascular regions in naked plasmid HGF infusion during insonation (HGF-US) and naked HGF plasmid infusion without US/MB (HGF-alone) in both regions. Bar graphs compare the score of the magnitude of HGF expression among the groups for the regions adjacent to the scar (B) and for the remote non-infarcted regions (C). *p < 0.05 versus pVax1-US/MB, HGF-US, and HGF-alone.
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Figure 4 Representative recordings of left ventricular (LV) two-dimensional (top) and M-mode (bottom) echocardiography at three weeks after the treatments. Left ventricular remodeling was almost completely inhibited in a rat form naked plasmid hepatocyte growth factor (HGF) infusion with ultrasound-mediated microbubble destruction (US/MB) (HGF-US/MB) group, while the intraventricular septum was thinned and LV chamber was dilated in the other groups. Other abbreviations as in Figure 3.
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Figure 5 Azan-Mallory stain (x100 magnification). Scar corresponding to the infarction was small in a rat from HGF-US/MB (A) compared with those from pVax1-US/MB (B), HGF-US (C), and from HGF-alone (D). Abbreviations as in Figure 3.
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Figure 6 Endothelial alkaline phosphatase stain (x400 magnification). (A) In the regions adjacent to the scar, capillary density was significantly higher in a rat from HGF-US/MB than those from other groups (top). No significant differences were noted among the groups in the capillary density in the remote non-infarcted regions (bottom). Bar graphs compare the vessel count per high-power field (HPF) among the groups for the regions adjacent to the scar (B) and for the remote non-infarcted regions (C). *p < 0.05 versus pVax1-US/MB, HGF-US, and HGF-alone. Abbreviations as in Figure 3.
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Figure 7 Anti- -smooth muscle actin immuno-stain (x100 magnification). (A) In the regions adjacent to the scar, significant increase in arterial density was demonstrated only in a rat from HGF-US/MB but not in the other groups (top). These groups showed similar vascular density in the remote non-infarcted regions (bottom). Bar graphs compare the count of vessels per high-power field (HPF) among the groups for the regions adjacent to the infarction scar (B) and for the remote non-infarcted regions (C). *p < 0.05 versus pVax1-US/MB, HGF-US, and HGF-alone. Abbreviations as in Figure 3.
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