Transmyocardial laser revascularization combined with vascular endothelial growth factor 121 (VEGF121) gene therapy for chronic myocardial ischemia--do the effects really add up?
OBJECTIVE
Different therapy strategies for coronary disease in conventionally untreatable patients have been developed, among them transmyocardial laser revascularization (TMLR) and the application of growth factors. The objective of our study was to determine whether a combined therapy of TMLR with a vascular endothelial growth factor(121) (VEGF(121)) plasmid is able to stimulate the development of sufficient collateral circulation and hereby to preserve cardiac function.


METHODS
A severe stenosis of the left anterior descending artery was created in healthy pigs. After 1 week, perfusion and regional contractility were assessed at baseline. Afterwards, the ischemic area was treated with TMLR (n=8), intramyocardial injection of naked plasmid DNA encoding VEGF(121) (n=7), or both (n=7). Control animals were left untreated (n=8). After 3 months, the animals were re-examined and underwent immunohistological analysis.


RESULTS
The number of capillaries increased only after injection of VEGF(121) plasmid alone compared to untreated ischemia and to the other therapy groups, whereas the number of arterioles was higher following TMLR treatment alone or in combination with VEGF(121) than it was in the case in untreated ischemic animals. However, only combined VEGF(121)+TLMR therapy resulted in an improvement in regional myocardial blood flow in comparison with 1 week ischemia, indicating the efficient development of collateral circulation. In contrast, better regional contractility compared to the 1-week baseline, as well as restoration of the pre-ischemic values, were achieved by both VEGF(121) and combined VEGF(121)+TLMR therapies.


CONCLUSIONS
This study of chronic myocardial ischemia with a porcine model indicates a synergistic action of TMLR and VEGF(121) gene therapy. Combined treatment alone achieved an increase of regional myocardial perfusion, which accompanied arteriogenesis and corresponded with the restoration of regional function.
Heilmann
Claudia A U
CA
Department of Cardiovascular Surgery, Albert-Ludwigs-University Freiburg, Hugstetter Strasse 55, 79106 Freiburg, Germany.
Attmann
Tim
T
von Samson
Patrick
P
Göbel
Heike
H
Marmé
Dieter
D
Beyersdorf
Friedhelm
F
Lutter
Georg
G
D000818:Animals; D002908:Chronic Disease; D003097:Collateral Circulation; D003131:Combined Modality Therapy; D004247:DNA / Q000008:administration & dosage; D016228:Endothelial Growth Factors / Q000008:administration & dosage* / Q000235:genetics; D015316:Genetic Therapy / Q000379:methods*; D007267:Injections; D036341:Intercellular Signaling Peptides and Proteins / Q000008:administration & dosage* / Q000235:genetics; D053685:Laser Therapy / Q000379:methods*; D008222:Lymphokines / Q000008:administration & dosage* / Q000235:genetics; D017202:Myocardial Ischemia / Q000601:surgery* / Q000628:therapy; D009204:Myocardial Revascularization / Q000379:methods*; D018919:Neovascularization, Physiologic; D013552:Swine; D014162:Transfection / Q000379:methods; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors
D016228:Endothelial Growth Factors; D036341:Intercellular Signaling Peptides and Proteins; D008222:Lymphokines; C467484:VEGFA protein, human; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors; D004247:DNA