Gene therapy with iNOS enhances regional contractility and reduces delayed contrast enhancement in a model of postischemic congestive heart failure.
OBJECTIVE
The purpose of this study was to evaluate the effect of transient local myocardial gene transfer of iNOS on cardiac function in a large mammal animal model of heart failure induced by chronic ischemia.


METHODS
Chronic myocardial ischemia was induced using a minimally invasive model in 16 landrace pigs. Upon demonstration of heart failure, eight animals were treated with liposome-mediated iNOS-gene-transfer by local intramyocardial injection; eight animals received a sham procedure to serve as control.


RESULTS
The transmurality of late enhancement (control: 46.4%, iNOS: 35.9%; p < 0.05) was significantly decreased in the ischemic area in the iNOS-treated group. Wall thickness at end-systole (6.8 mm vs. 5.9 mm, p < 0.001) and at end-diastole (5.4 mm vs. 4.2 mm, p < 0.001) were significantly higher in the therapy group. Additionally, the regional wall motion at the level of the ischemic region was 3.5 mm in the therapy group while it was significantly less (3.0 mm, p < 0.001) in the control group.


CONCLUSIONS
Our findings demonstrate that transient iNOS overexpression potentially leads to a significant decrease of regional late enhancement with a positive effect on regional cardiac function in the ischemic area in a large animal model of postischemic heart failure.
Department of Medicine II, Johannes Gutenberg-University Mainz, Mainz, Germany. nico@uni-mainz.de
Nico
N
Abegunewardene
Kai-Helge
KH
Schmidt
Markus
M
Vosseler
Karl-Friedrich
KF
Kreitner
Laura M
LM
Schreiber
Hans-Anton
HA
Lehr
Tommaso
T
Gori
Thomas
T
Münzel
Georg
G
Horstick
D000818:Animals; D000925:Anticoagulants / Q000627:therapeutic use; D001241:Aspirin / Q000627:therapeutic use; D000077144:Clopidogrel; D003287:Contrast Media; D017023:Coronary Angiography; D023921:Coronary Stenosis / Q000209:etiology / Q000503:physiopathology; D004195:Disease Models, Animal; D004337:Drug Carriers; D005260:Female; D005355:Fibrosis; D005682:Gadolinium; D017930:Genes, Reporter; D005813:Genes, Synthetic; D015316:Genetic Therapy; D006333:Heart Failure / Q000209:etiology / Q000628:therapy*; D008081:Liposomes; D008279:Magnetic Resonance Imaging; D008297:Male; D009200:Myocardial Contraction; D017202:Myocardial Ischemia / Q000473:pathology / Q000503:physiopathology*; D052247:Nitric Oxide Synthase Type II / Q000235:genetics / Q000627:therapeutic use*; D011897:Random Allocation; D015607:Stents / Q000009:adverse effects; D034421:Sus scrofa; D013552:Swine; D013988:Ticlopidine / Q000031:analogs & derivatives / Q000627:therapeutic use; D018487:Ventricular Dysfunction, Left / Q000209:etiology / Q000473:pathology / Q000503:physiopathology / Q000628:therapy
D000925:Anticoagulants; D003287:Contrast Media; D004337:Drug Carriers; D008081:Liposomes; D000077144:Clopidogrel; D005682:Gadolinium; C496319:NOS2 protein, human; D052247:Nitric Oxide Synthase Type II; D013988:Ticlopidine; D001241:Aspirin