Complete reversal of ischemic wall motion abnormalities by combined use of gene therapy with transmyocardial laser revascularization.
BACKGROUND
Transmyocardial laser revascularization is believed to induce an angiogenic response within ischemic myocardium. We evaluated transgene expression in the setting of transmyocardial laser revascularization and hypothesized that intramyocardial injection of plasmid DNA encoding the gene for vascular endothelial growth factor could enhance the revascularization achieved by transmyocardial laser revascularization, resulting in improved cardiac function.


METHODS
Ten Yorkshire pigs had carbon dioxide-transmyocardial laser revascularization or acupuncture sites with injections of an expression plasmid encoding the gene for beta-galactosidase with or without HVJ-liposomes. Three days after transduction, transgene expression was determined by enzyme-linked immunosorbent assay. Six weeks after placement of a constrictor on the left circumflex artery, 29 pigs were randomized to ischemic controls (n = 5), transmyocardial laser revascularization (n = 4), transmyocardial laser revascularization with expression plasmid beta-galactosidase injections (n = 5), expression plasmid-vascular endothelial growth factor injections (n = 4), or transmyocardial laser revascularization with expression plasmid-vascular endothelial growth factor (n = 5) and harvested 6 weeks after therapy. Six transmyocardial laser revascularization pigs had either expression plasmid beta-galactosidase or expression plasmid-vascular endothelial growth factor injections and were harvested at 2 weeks. Normal pigs (n = 5) were included for comparison. Left ventricular free wall motion was assessed by a cardiologist in a blinded manner.


RESULTS
Transgene expression did not vary significantly with or without HVJ-liposomes in transfected transmyocardial laser revascularization myocardium. However, expression was detected in 56 of 60 (93%) transmyocardial laser revascularization-transfected sites, but in only 10 of 20 (50%) non-transmyocardial laser revascularization sites (P < .001). All (5 of 5 hearts) of the transmyocardial laser revascularization-vascular endothelial growth factor treated hearts displayed no evidence of wall motion abnormalities. Only these hearts had a statistically significantly different rate of wall motion abnormality compared with ischemic controls (P = .004).


CONCLUSIONS
Transfection efficiency was improved with the use of transmyocardial laser revascularization. Wall motion abnormalities were completely reversed within 6 weeks after transmyocardial laser revascularization with the direct injection of an expression plasmid encoding vascular endothelial growth factor.
Sayeed-Shah
U
U
Division of Cardiac Surgery, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA.
Mann
M J
MJ
Martin
J
J
Grachev
S
S
Reimold
S
S
Laurence
R
R
Dzau
V
V
Cohn
L H
LH
D000818:Animals; D003131:Combined Modality Therapy; D017548:Echocardiography, Transesophageal; D004562:Electrocardiography; D016228:Endothelial Growth Factors / Q000235:genetics*; D015870:Gene Expression / Q000502:physiology; D015316:Genetic Therapy; D053685:Laser Therapy; D008222:Lymphokines / Q000235:genetics*; D009200:Myocardial Contraction / Q000502:physiology*; D017202:Myocardial Ischemia / Q000503:physiopathology / Q000628:therapy*; D009204:Myocardial Revascularization; D018919:Neovascularization, Physiologic / Q000235:genetics; D013552:Swine; D019076:Transgenes / Q000235:genetics; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors; D018487:Ventricular Dysfunction, Left / Q000503:physiopathology / Q000628:therapy*; D016277:Ventricular Function, Left / Q000502:physiology
D016228:Endothelial Growth Factors; D008222:Lymphokines; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors