Effect of Terplex/VEGF-165 gene therapy on left ventricular function and structure following myocardial infarction. VEGF gene therapy for myocardial infarction.
BACKGROUND
We used a novel lipopolymeric gene delivery system, TeplexDNA, to transfect myocardium with plasmid vascular endothelial growth factor-165 (pVEGF) and evaluated the ability of pVEGF to preserve left ventricular function and structure after coronary ligation in a rabbit model.


METHODS
New Zealand white rabbits underwent circumflex coronary ligation after direct intramyocardial injection of either Terplex alone or Terplex + 50 microg pVEGF-165. Serial echocardiography and histologic studies were performed (n = 12/group). Mortality did not differ between groups. The data is reported as the mean +/- standard deviation.


RESULTS
Over the 21 days following coronary ligation, pVEGF-165-treated animals demonstrated significant improvement in fractional shortening (20-25%, p = 0.02), long axis two-dimensional ejection fraction (42-51%, p=0.02) and short axis m-mode ejection fraction (46-54%, p = 0.02). No significant improvements were noted in the control group. VEGF-treated animals had a 50% increase in peri-infarct vessel density and a trend towards a smaller infarct size (20% vs. 29%, p = 0.10). In animals receiving pVEGF-165, the diastolic ventricular area increased from 1.87 +/- 0.24 cm2 prior to ligation to 2.19 +/- 0.23 cm2 at 21 days following ligation, compared to an increase from 1.84 +/- 0.38 to 2.54 +/- 0.55 cm2 over the same period in control animals (p = 0.03). Similarly, the systolic ventricular area in VEGF-165 animals increased from 1.06 +/- 0.26 cm2 prior to ligation to 1.50 +/- 0.29 cm2 at 21 days following ligation, compared to an increase from 1.16 +/- 0.30 to 1.86 +/- 0.43 cm2 over the same period in the control animals (p = 0.04).


CONCLUSIONS
TerplexDNA mediated delivery of plasmid VEGF administered at the time of coronary occlusion improves left ventricular function and reduces left ventricular dilation following myocardial infarction.
Bull
David A
DA
Division of Cardiothoracic Surgery, University of Utah Health Sciences Center, Salt Lake City, UT 84132, USA. david.bull@hsc.utah.edu
Bailey
Stephen H
SH
Rentz
Jeffrey J
JJ
Zebrack
James S
JS
Lee
Minhyung
M
Litwin
Sheldon E
SE
Kim
Sun Wan
SW
D000818:Animals; D003327:Coronary Disease / Q000150:complications / Q000188:drug therapy / Q000503:physiopathology; D003331:Coronary Vessels / Q000293:injuries / Q000503:physiopathology; D004247:DNA / Q000008:administration & dosage / Q000235:genetics* / Q000493:pharmacokinetics; D004353:Drug Evaluation, Preclinical; D004452:Echocardiography; D015316:Genetic Therapy / Q000379:methods*; D005822:Genetic Vectors / Q000008:administration & dosage / Q000493:pharmacokinetics; D006352:Heart Ventricles / Q000033:anatomy & histology / Q000187:drug effects*; D008055:Lipids / Q000008:administration & dosage / Q000737:chemistry / Q000493:pharmacokinetics; D008077:Lipoproteins, LDL / Q000008:administration & dosage / Q000235:genetics / Q000493:pharmacokinetics; D009203:Myocardial Infarction / Q000401:mortality / Q000503:physiopathology / Q000628:therapy*; D010957:Plasmids / Q000008:administration & dosage / Q000235:genetics / Q000493:pharmacokinetics; D011107:Polylysine / Q000008:administration & dosage / Q000235:genetics / Q000493:pharmacokinetics; D011108:Polymers / Q000008:administration & dosage / Q000737:chemistry / Q000493:pharmacokinetics; D011817:Rabbits; D013228:Stearates / Q000008:administration & dosage / Q000493:pharmacokinetics; D013318:Stroke Volume / Q000187:drug effects / Q000502:physiology; D013997:Time Factors; D042461:Vascular Endothelial Growth Factor A / Q000008:administration & dosage / Q000235:genetics* / Q000493:pharmacokinetics; D042442:Vascular Endothelial Growth Factors / Q000008:administration & dosage / Q000235:genetics* / Q000493:pharmacokinetics*; D016276:Ventricular Function; D016277:Ventricular Function, Left / Q000187:drug effects / Q000502:physiology
D008055:Lipids; D008077:Lipoproteins, LDL; D011108:Polymers; D013228:Stearates; C467484:VEGFA protein, human; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors; C115579:stearyl-poly(lysine); D011107:Polylysine; D004247:DNA