Biomedical Engineering Reference
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models subjected to left circumflex arterial constriction, VEGF treatment improved
coronary flow and preserved regional hemodynamics [ 35 ]. Intracoronary treatment
with VEGF, either by single intracoronary bolus or local delivery, stimulated
significant angiogenesis in pigs [ 36 ]. In canine models subjected to left circumflex
arterial occlusion, intracoronary VEGF infusion at the occlusion site was associated
with a 40 % increase in collateral blood flow [ 37 ].
The safety of intracoronary infusion of recombinant human VEGF was assessed
in a phase I clinical trial; the trial included 7 patients with coronary artery disease
whose coronary anatomy was suboptimal for percutaneous or surgical revasculari-
zation [ 38 ]. Coronary infusion of VEGF was tolerated up to a maximal dose of
0.050 mg/kg/min; beyond this dose, patients experienced hypotension. VEGF gene
transfer has also been attempted in phase I clinical trials. In one study of 5 patients
who had failed conventional therapy for myocardial ischemia, naked plasmid DNA
was injected directly into ischemic myocardium. The technique was safe, and there
was objective evidence of reduced ischemia in all patients [ 39 ]. Direct myocardial
injection of naked plasmid DNA encoding VEGF was subsequently shown to be safe
in additional phase I trials [ 40 , 41 ]. Further, the direct myocardial injection of an
adenoviral vector expressing VEGF cDNA has demonstrated safety, in a phase I
clinical trial of 21 patients with severe coronary artery disease [ 42 ].
Unfortunately, the successes of therapeutic angiogenesis with VEGF in
pre-clinical and phase I clinical trials have not been reproduced in large phase II
trials. In the VIVA (Vascular Endothelial Growth Factor in Ischemia for Vas-
cular Angiogenesis) trial, a total of 178 patients with myocardial ischemia who
were unsuitable for mechanical revascularization were randomized to receive
placebo, low dose recombinant human VEGF, or high dose recombinant human
VEGF [ 43 ]. Patients received an initial dose via intracoronary infusion on day 0,
followed by peripheral infusions on days 3, 6, and 9. While the VEGF therapy
was safe, the trial failed to meet its primary endpoint: VEGF offered no
improvement beyond placebo in exercise treadmill time (the primary endpoint)
at day 60. Direct myocardial injection of VEGF-encoding plasmid DNA has also
been attempted in a randomized, double-blind placebo-controlled phase II study.
In the Euroinject One trial, 80 ''no-option'' patients with severe stable coronary
artery disease were randomized to receive either placebo or VEGF gene transfer
[ 44 ]. This trial also failed to meet its primary endpoint: after 3 months, VEGF
gene transfer did not significantly improve myocardial perfusion defects, though
VEGF treatment was associated with improvements in local wall motion.
Finally, the Kuopio Angiogenesis Trial assessed the efficacy of VEGF gene
transfer during angioplasty and stenting [ 45 ]. This randomized, double-blind
placebo-controlled phase II study involved 103 patients with coronary artery
disease who were undergoing angioplasty. Patients were randomized to receive
placebo, VEGF adenovirus, or VEGF plasmid liposome. Again, this trial did not
meet its primary endpoint: after 6 months, there were no significant differences
between study groups in clinical restenosis rates or minimal lumen diameter,
though
patients
receiving
VEGF
adenovirus
did
demonstrate
a
significant
increase in myocardial perfusion.
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