A number of Phase I trials have looked
at different mediators and delivery systems in myocardial
therapeutic angiogenesis, essentially bypassing
obstructive coronary artery disease (CAD). Several
trials have shows that VEGF121 and VEGF165 and fibroblast
growth factor (FGF) are angiogenic mediators. Mediators
have been delivered in protein solution or via microcapsules
or in a gene therapy form (plasmid, adenovirus).
The two routes of delivery have been intracoronary/intravenous
or intramyocardial (epicardial).
Schumacher showed angiographic improvement
at 3 months in patients who received fibroblast
growth factor-1 (FGF-1). In this placebo-controlled,
randomized, adjunct to coronary artery bypass trial,
FGF-1 or inactivated FGF was injected into the territory
of the LAD (20 patients per group). At 3 months,
gray-scale analysis of angiography showed the FGF-1
patients had a higher lateral score compared to
the control patients (59 vs 20, respectively).
A Phase I study of intracoronary recombinant
human VEGF (rhVEGF165), by Henry consisted of two
studies. In Study I, the dose escalation study,
two 10-minute intracoronary infusions were delivered.
In Study II a 20-minute intracoronary infusion,
supplemented by three 4-hr intravenous infusions
on days 3, 6 and 9 were delivered. In Study I, on
SPECT analysis 7 of the 15 patients (47%) showed
improvement, and on angiogram 5 of 7 (71%) showed
improvement. However, in the Phase II study, no
clinical benefit was seen as evidenced by no improvement
in either angina class or exercise tolerance test.
In a study by Losordo in 16 patients,
plasmid VEGF165 (125 mcg) was delivered into the
anterolateral left ventricle via mini-thoracotomy
by direct intramyocardial injection (4 injections,
each 2 ml). In 66% of patients, there was complete
resolution of angina. Weekly anginal episodes were
reduced from 50.1 to 3 and weekly nitroglycerin
use reduced from 60.7 to 2.5. Improvement in the
ischemic territory was shown by dobutamine SPECT
estimated scans and other analyses. Normally perfused
segments increased from 6.9 to 8.9, and irreversibly
ischemic segments reduced from 2.4 to 1.2. The stress
perfusion ischemia score was reduced from 21 to
16.8 and the real perfusion ischemia score from
18.3 to 12.4.
Laham used basic FGF (FGF-3) in a
randomized, double blind, placebo-controlled trial
as an adjunct to bypass surgery. Heparin alginate
microcapsules carrying FGF-2 (10 mcg and 100 mcg
doses) were delivered to the non-revascularized
territory. At 3 months, the incidence of recurrent
angina was significantly decreased to zero in the
100 mcg FGF-3 group (n=3, to 13% in the 10 mcg FGF-3
group (n=3), and 39% in the control group.
Commentary
FGF appears to be a potent angiogenic,
however there is at least a theoretical risk of
potential promiscuity as it can also induce smooth
muscle cell hyperplasia and fibrosis.
VEGF has multiple isoforms (206, 189,
165, 121) but it is presently unclear whether any
will have a superior therapeutic effect.
VEGF has an advantage due to its high specificity,
theoretically minimizing the concern of smooth muscle
cell hyperplasia and fibrosis.
The intramyocardial route was a more
efficient delivery route than the intracoronary
route and significantly more efficient that the
intravenous route to deliver high levels of VEGF
expression localized to the heart, versus systemic
effects. The epicardial route was more efficacious
than the endocardial route in these early studies.
Protein versus gene therapy-based
strategies is an area of great debate. Gene therapy
represents an alternative delivery system. However,
the adenovirus is interesting because 1) it has
high levels of expression, 2) it mediates expression
in 1-2 weeks, which appears to be ideal for inducing
angiogenesis, 3) direct administration to an organ
yields local expression only, and 4) similar vectors
have been safely used in humans.