Gene transfection of hepatocyte growth factor attenuates cardiac remodeling in the canine heart: A novel gene therapy for cardiomyopathy.
OBJECTIVE
Hepatocyte growth factor, a potent angiogenic agent, is unique in having the effects of antiapoptosis and antifibrosis. In the present study we used the rapid pacing-induced heart failure canine model to investigate the effect of gene transfection of hepatocyte growth factor on the failing heart.


METHODS
Four weeks after onset of rapid pacing, either the human hepatocyte growth factor gene (160 microg; hepatocyte growth factor group, n = 7) or empty vector (control group, n = 7) was directly injected into the left ventricular myocardium by means of the hemagglutinating virus of Japan liposome method.


RESULTS
At 4 weeks after gene transfection, the left ventricular global function, assessed by means of pressure-volume loop analysis, was improved in the hepatocyte growth factor group as preload-recruitable stroke work (percentage of baseline: 80% +/- 20% from 38% +/- 15% before gene transfection, P =.005), whereas it was not changed in the control group (50% +/- 18% from 50% +/- 18%). Weekly echocardiography showed that this improvement began in the week after gene transfer. The hearts in the hepatocyte growth factor group had a large wall thickness, large myocyte diameter, high capillary density, low fibrotic area fraction, and low density of apoptotic nuclei revealed by means of histologic analysis compared with that in the control group. Myocardial perfusion flow, assessed with color microspheres, was increased in the hepatocyte growth factor group (percentage of baseline: 79% +/- 16% from 48% +/- 14%, P =.010), whereas it was reduced in the control group (30% +/- 12% from 45% +/- 17%).


CONCLUSIONS
Gene transfection of hepatocyte growth factor promoted angiogenesis, improved perfusion, decreased fibrosis and apoptosis, promoted recovery from myocyte atrophy, and thereby attenuated cardiac remodeling and improved myocardial function in the failing heart. It is a novel gene therapy for human heart failure.
Ahmet
Ismayil
I
First Department of Surgery, Osaka University Medical School, Osaka, Japan.
Sawa
Yoshiki
Y
Iwata
Keiji
K
Matsuda
Hikaru
H
D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000235:genetics; D001284:Atrophy / Q000235:genetics / Q000628:therapy; D002311:Cardiomyopathy, Dilated / Q000235:genetics / Q000628:therapy; D004195:Disease Models, Animal; D004285:Dogs; D004452:Echocardiography; D005260:Female; D005355:Fibrosis / Q000235:genetics; D015316:Genetic Therapy; D006352:Heart Ventricles / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D017228:Hepatocyte Growth Factor / Q000235:genetics* / Q000627:therapeutic use*; D008955:Models, Cardiovascular; D009200:Myocardial Contraction / Q000187:drug effects / Q000235:genetics; D009206:Myocardium / Q000378:metabolism / Q000473:pathology; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000473:pathology; D018919:Neovascularization, Physiologic / Q000187:drug effects / Q000235:genetics; D012333:RNA, Messenger / Q000187:drug effects / Q000235:genetics / Q000378:metabolism; D013318:Stroke Volume / Q000187:drug effects / Q000235:genetics; D014162:Transfection; D016896:Treatment Outcome; D016277:Ventricular Function, Left / Q000187:drug effects / Q000235:genetics
D012333:RNA, Messenger; D017228:Hepatocyte Growth Factor