Local transient myocardial liposomal gene transfer of inducible nitric oxide synthase does not aggravate myocardial function and fibrosis and leads to moderate neovascularization in chronic myocardial ischemia in pigs.
BACKGROUND
This study was designed to explore the effect of transient inducible nitric oxide synthase (iNOS) overexpression via cationic liposome-mediated gene transfer on cardiac function, fibrosis, and microvascular perfusion in a porcine model of chronic ischemia.


RESULTS
Chronic myocardial ischemia was induced using a minimally invasive model in 23 landrace pigs. Upon demonstration of heart failure, 10 animals were treated with liposome-mediated iNOS-gene-transfer by local intramyocardial injection and 13 animals received a sham procedure to serve as control. The efficacy of this iNOS-gene-transfer was demonstrated for up to 7 days by reverse transcriptase-polymerase chain reaction in preliminary studies. Four weeks after iNOS transfer, magnetic resonance imaging showed no effect of iNOS overexpression on cardiac contractility at rest and during dobutamine stress (resting ejection fraction: control 27%, iNOS 26%; P = ns). Late enhancement, infarct size, and the amount of fibrosis were similar between groups. Although perfusion and perfusion reserve in response to adenosine and dobutamine were not significantly modified by iNOS-transfer, both vessel number and diameter were significantly increased in the ischemic area in the iNOS-treated group versus control (point score: control 15.3, iNOS 34.7; P < 0.05).


CONCLUSIONS
Our findings demonstrate that transient iNOS overexpression does not aggravate cardiac dysfunction or postischemic fibrosis, while potentially contributing to neovascularization in the chronically ischemic heart.
2nd Medical Clinic, Johannes Gutenberg University Mainz, Mainz, Germany. nico@uni-mainz.de
Nico
N
Abegunewardene
Kai-Helge
KH
Schmidt
Markus
M
Vosseler
Michael
M
Dreher
Tandis
T
Keller
Nico
N
Hoffmann
Kerstin
K
Veit
Steffen E
SE
Petersen
Hans-Anton
HA
Lehr
Laura M
LM
Schreiber
Tommaso
T
Gori
Georg
G
Horstick
Thomas
T
Münzel
D000818:Animals; D001160:Arterioles / Q000473:pathology / Q000503:physiopathology; D005260:Female; D005355:Fibrosis; D015870:Gene Expression; D018014:Gene Transfer Techniques; D006801:Humans; D008081:Liposomes; D008279:Magnetic Resonance Imaging; D008297:Male; D017202:Myocardial Ischemia / Q000235:genetics / Q000473:pathology* / Q000503:physiopathology*; D009206:Myocardium / Q000378:metabolism* / Q000473:pathology*; D009389:Neovascularization, Pathologic; D009569:Nitric Oxide / Q000096:biosynthesis; D052247:Nitric Oxide Synthase Type II / Q000235:genetics* / Q000378:metabolism*; D011994:Recombinant Proteins / Q000235:genetics / Q000378:metabolism; D034421:Sus scrofa; D016277:Ventricular Function, Left
D008081:Liposomes; D011994:Recombinant Proteins; D009569:Nitric Oxide; D052247:Nitric Oxide Synthase Type II