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Therapeutic Angiogenesis for Patients with Limb
Ischemia |
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Nicholas
Kipshidze, M.D, Ph.D. 1, Kote Kipiani, M.D., Ph.D. 2,
Nutsa Beridze, M.D. 2, Gary Roubin, M.D., Ph.D 1.,
Mykola Tsapenko, M.D., Ph.D. 1 , Muhammad Z Shehzad, M.D 1,
Sriram Iyer, M.D.1, Jeffrey Moses, M.D.,1
Nodar N. Kipshidze, M.D., Ph.D. 3 Key words: fibrin, angiogenesis, chronic limb ischemia. |
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Introduction. According
to the Second European Consensus Document on chronic critical leg
ischemia, this pathology develops in approximately 500 to 1000 people per
million per year.1,34 This disease may be life or limb
threatening especially in patients with diabetes and very often causes
permanent disability.2,3 Due
to the anatomic extent and distribution of arterial occlusive disease,
direct revascularization through bypass or angioplasty may be unsuccessful
in most of these cases.3-4. No pharmacologic treatment has been
proven to stop the aggressive nature of the chronic critical leg ischemia.4
Most often these patients require amputation of the limb with extremely
high consecutive morbidity and mortality. 5, 6 For these severe cases, alternative treatment modalities including angiogenesis are clearly needed to avoid amputation or at least decrease the severity of ischemia, which could limit the extent of amputation and its related complications. 6-9 Inspired
by seminal observations of Folkman [2] many experimental studies have
demonstrated that receptors of ischemic endothelial cells (EC) accept
endogenous and exogenous growth factors (GFs) or their DNA-constructs . It
has been considered as a primary mechanism for the intrinsic process of
compensatory neovascularization. Among the growth factors involving in
blood vessel growth and development, vascular endothelial growth factors (VEGFs)
and fibroblast growth factors (FGFs)
have been most extensively studied. A large number of preclinical
studies have shown proof of principle and demonstrated that angiogenic
growth factors are effective in different experimental treatment models of
myocardial ischemia 10-12 and hind-limb ischemia. 13-15
Moreover, providing further support for the concept, VEGF was used
clinically to treat critical limb ischemia 16-19 and advanced
coronary artery disease. 21
Recent
trials using VEGF, recombinant fibroblast growth factor-2 (FGF-2), and
basic fibroblast growth factor (bFGF) demonstrate minimal or no
improvement of myocardial perfusion following angiogenic procedures. 14,20,
21 In summary, although
safe, the clinical trials
with growth factors therapy failed to demonstrate measurable therapeutic
efficacy and significantly dampened the original enthusiasm for this new
therapy.
Our
previous studies 40-42 as
well as data from several other laboratories 25-26,43,46
showed that fibrin can be used as an angiogenic substance or carrier for
the application of angiogenic growth factors.
A fibrin network is critical for effective wound healing, and it is
biodegradable through ro‑utine tissue fibrinolysis. Since fibrin
sealant is lysed slowly, it can serve as a vehicle to deliver various
therapeutic agents that may help in wound healing 25,39,43,48-50 ,
promotion of new vessel growth 27,43 and possibly enhancement of growth factor production.45
We investigated the deferoxamine in our experimental series, and
after that added it to our conventional composition of fibrin meshwork. Indeed
we reported that the enhanced angiogenesis was induced by intramuscular
injection of vascular endothelial growth factor and deferoxamine added to
the fibrin platform in a rabbit hind-limb ischemia model.
Based on experimental findings we conducted a pilot clinical trial
in humans. The study has been performed to evaluate efficacy and clinical
feasibility of intramuscular injections of fibrin with and without
additives (VEGF165 and deferoxamine) in inducing neovascularization. Materials
and Methods. The study design was
double-blinded and randomized (Figure 1).
Patients were qualified for entering the study if they had chronic
critical limb ischemia, including rest pain and/or pain-free walking time
(PFWT) of less then 1 min., non-healing ulcers and referred for below the
knee amputations. All patients had to have at least two infrageniculate
arterial stenoses or occlusions and deemed candidates for amputation and
not surgical or catheter revascularization because of poor distal
targets.
We excluded patients with advanced diabetes, retinopathy and
evidence of malignancy during past three years.
Patient
Population Twenty-three
patients (males, ages 37-62) with critical limb ischemia and referred for
below the knee amputations were randomized for treatment. Patients were
divided into three groups: group 1: seven patients received only a saline
injection; group 2: nine
received intramuscular injection of fibrin (Baxter, Hyland Immuno) and group 3: seven received the fibrin composition with
deferoxamine and added endothelial growth factor (VEGF165)).
The fibrin meshwork was introduced into the popliteal area of the diseased
limbs using a dual syringe system (one contained thrombin solution [1mg,
5000U] and one contained fibrinogen [1 mg, Baxter Hyland Immuno]
solution). In group 3, Deferoxamine (100 µg) and 500 µg of VEGF165
was added to the fibrinogen solution. Along with this treatment all patients also received conventional therapy for peripheral vascular disease (PVD). In addition to PVD, hyperlipidemia was present in 67% of patients, 34% had previous myocardial infarction, 70% had hypertension and 80% had a history of smoking. Procedure The fibrin was introduced into the popliteal areas of the diseased limbs using a dual syringe system (one contained thrombin solution [1-2 mg, 5000U] and one contained fibrinogen [1-2 mg, Baxter Hyland Immuno] solution). In the 3 group of patients Deferoxamine (100 µg) and 500 µg of VEGF165 were added to the fibrinogen solution. Intramuscular
administration of fibrin with or without VEGF was well tolerated.
There were no signs of systemic or local inflammatory reaction or
reported complications or serious adverse events related to the drug
administration. End
Points Primary
end points were the safety and efficacy of the treatment defined as
reducing the need for amputation or the extent of amputation, increase in
ABI, transcutaneous oxygen pressure( TcO2), rest pain and
improvement of claudication (pain-free walking time (PFWT)).
We
continuously followed up patients up to 3 years post treatment.
To measure ABI, we established Doppler-derived arterial segmental
pressures on the ankle and brachium with a standard adult cuff and indexed
ankle systolic pressure against brachial one (normal range >1.0).
PFWT was determined on a treadmill at 3 km/h with no incline. We judged an increase in PFWT of more then 1 minute, as well
as decrease in demand for pain medication for rest pain as an improvement.
TcO2 was measured with an oxymonitor and recorded in mm Hg (normal
range > 60 mm Hg). Angiograms also were performed before and after the
treatment. Statistical
analysis Values
are expressed as mean+SEM. The significance of differences was determined
with the Student’s t-test. Statistical significance was established as p
less then 0.05. ResultsIntramuscular
administration of fibrin with or without VEGF was well tolerated.
There were no signs of systemic or local inflammatory reaction or
reported complications or serious adverse events related to the drug
administration. The ankle-brachial index (Figure 2) in the control group was 0.46 ± 0.12 before beginning the clinical trial and was 0.41 ± 0.16 at the 3 month follow-up. (The follow-up period was different for the control group because amputations were performed during this period in four of seven patients). The ankle-brachial index in patients treated with fibrin increased from 0.43 ± 0.20 to 0.73 ± 0.12 at six months follow-up (p<0.05 vs. baseline data and vs. control group). When VEGF was added to the fibrin-deferoxamine compound, the ankle-brachial index of patients increased from 0.49 ± 0.12 to 0.78 ± 0.19 (no differences between the fibrin treated groups). Transcutaneous oxygen pressure (Tc02) increased in both fibrin treated groups from 21 ± 4 mmHg to 45 ± 7 mmHg as compared to 19 ± 3 mmHg in the control groups of patients (Figure 3) . In the control group (saline injection only) there has been no improvement and as a result five patients had undergone below the knee amputation by the 3-6 month follow-up. In contrast clinical improvement (increase in PFWT for more then 1 min. or/and decrease of rest pain) (Table 1) was noted in eight of nine patients following fibrin treatment alone, and in all seven patients injected with the fibrin meshwork, deferoxamine and VEGF combination . This was observed in the course of 3 months post therapy in 3 patients; 6 months post therapy in 5 patients, and by a year post treatment in 7 patients. At one year, clinical improvement was sustained in all patients from the fibrin, deferoxamine and VEGF combination treated group. Only one patient from fibrin alone treated group had below the knee amputation six months following fibrin administration. There were 6 patients with three-year follow-up. All represent both fibrin treated groups. Four sustained clinical improvement, however, pain-free walking time remained significantly deceased and one patient underwent below the knee amputation. DiscussionAlthough
treatment of critical, life threatening peripheral vascular disease (PVD)
has greatly improved over recent decades by surgical and interventional
techniques, it remains limited by vascular proliferative lesions and by
our inability to modulate it. In most cases, the extent and distribution
of advanced PVD precludes any operative or percutaneous revascularization
and an inexorable downhill course follows. 3
Attempts at direct revascularization in patients who have severe
chronic limb-threatening ischemia may fail because: 1) there is no
adequate conduit for arterial reconstruction; 2) the disease is diffuse
and progressive; 3) there is small vessel disease as a result of diabetes
or other co-morbidities; or 4) advanced age poses higher risk of surgery.
Amputation, despite its associated morbidity, mortality, and
functional implications, is still often recommended at this stage of limb
ischemia. 24,29,30,36
Therapeutic options are so limited for patients who have lower
extremity vascular obstructive disease 4,11, because typically
neither conservative measures nor drug therapy is effective.
Several studies have shown that neovascularization by utilizing of
angiogenic growth factors are effective in experimental models of
myocardial ischemia 10-12 and hind-limb ischemia. 13-15 Moreover,
VEGF was used clinically to treat critical limb ischemia
16-19 and advanced coronary artery disease.21 Providing
further support for the concept, Isner and colleagues 17
reported improvement of peripheral arterial ischemia after they used a
hydrogel-coated balloon catheter to transfect the peripheral arteries with
cDNA encoded VEGF. Subsequently, the same group initiated intramuscular
injection of VEGF165-encoding naked human plasmid cDNA in nine
patients (10 ischemic limbs). 16 In this initial series of intramuscular (rather than
intra-arterial) injections of an angiogenic gene, blood flow improved in
eight of ten limbs, as demonstrated by magnetic resonance angiography, and
there was an overall increase of 30% in ABI, a key measure of improved
limb blood supply. Isner’s
group 37 also injected naked plasmid DNA directly into the
myocardium through a minimally invasive incision in the chest wall. They
concluded that the procedure is safe and may lead to reduced symptoms and
improved myocardial perfusion in selected patients with chronic myocardial
ischemia. Despite
this very encouraging early experience, it is not known whether new
collaterals will have hemodynamic significance.
Recent trials using VEGF, recombinant fibroblast growth factor-2
(FGF-2), and basic fibroblast growth factor (bFGF) demonstrate minimal or
no improvement of myocardial perfusion following angiogenic procedures. 14,
20, 21, 38 Another
burgeoning area of research involves the utilization of bone marrow cells
and/or endothelial precursor cells. Indeed recent controlled studies
demonstrated very intriguing results.2.
They showed an increase in ABI, Tco2 and PFWT, and concluded that
autologous implantation of bone marrow mononuclear cells (BM-MNC) could be
safe and effective for the achievement of therapeutic angiogenesis because
of the natural ability of BM-MNC
to supply endothelial progenitor cells and to secrete various angiogenic
factors and cytokines.22 Recently conducted TRAFFIC (Therapeutic
angiogenesis with recombinant fibroblast growth factor
-2 for intermittent claudication) study investigated the
safety and effectiveness of intra-arterial infusion of single and double
doses of rFGF-2 39 190
patients with intermittent claudication were randomly assigned to
treatments or placebo. The primary endpoint was a 90 day change in peak
walking time (PWT). Secondary outcomes included ankle –brachial pressure
index (ABI) and safety. Intra-arterial
rFGF-2 resulted in a statistically significant increase in peak walking
time at 90 minutes; however repeat infusion was no better then a single
infusion. Although the increase in PWT and ABI were modest, there was no
significant difference in claudication onset time or quality of life
between treatment groups. This
study clearly provided evidence of angiogenesis induced by infusion of the
growth factor.
Although some of the studies of
peripheral angiogenesis 17,18,20,28,37 showed good clinical
results, they did not reveal
neovascularization by angiography .
The idea to use fibrin as an
angiogenesis substance alone or with the addition of proteins was
introduced by Fasol et al 43 who demonstrated that a modified
fibrin glue implant containing the angiogenic growth factors bFGF-I
induced significant site-directed formation of new blood vessel structures
in a rat model. Later
Laube et al 44 used human recombinant basic fibroblast growth
factor in a fibrin matrix applied directly to the epicardium in 8 patients
with diffuse coronary artery disease during conventional bypass grafting.
This study demonstrated induction of a collateral network of capillaries
visualized by coronary angiography and thallium scans.
Pre-operative borderline ischemic myocardium had recovered almost
to near normal perfusion.
The expected – but not yet
proven – slow release and longer availability of the growth factors may
enhance and sustain angiogenesis, and thus improve oxygen supply in
ischemic tissue. Without
growth factors, fibrin glue applied subcutaneously has been shown to
stimulate angiogenesis. 42
Moreover, in our
previous experimental study, high dose fibrin applications demonstrated
significantly higher induced
angiogenesis and increased blood flow than in the low
dose group, showing its dose dependent effect. We also believe that
fibrin glue enhances the effect of VEGF.
Our, and other experiments demonstrate that the fibrin glue becomes
vascularized 41,42 indicating that plasma proteins alone are
able to perform some of the functions of the extra cellular matrix
involved in anchoring EC to the vessel wall. As described above applied to
ischemic tissue, the fibrin glue serves as a temporary matrix for gradual
development of granulation tissue that is characterized by a high degree
of vascularity. Because it is well known that ischemia interrupts local
circuit neurons, previous studies showing that fibrin can also enhance
nerve regeneration. 45,47
Intramuscular administration of
growth factors without fibrin glue can stimulate angiogenesis in some
animal models 13,15,31
but not in others 33, which
further supports the value of adding the fibrin.
We suggested that vascular
endothelial growth factor (VEGF) supplemented in a fibrin carrier will
stimulate angiogenesis in severe ischemic tissue. However, our hypothesis
was that it is necessary to use both administration of exogenous VEGF and
stimulate the production of the body’s own endogenous VEGF from
endothelial cells. Since iron chelators have been reported to interfere
with inflammatory cells 23 and possibly enhance vascular growth
factor production 24 we investigated the deferoxamine in our
experimental series, and after that added it to our conventional
composition of fibrin meshwork.
Previously we have demonstrated in
a patient with bilateral ischemic gangrene of the feet, that VEGF and
fibrin accelerated the wound healing process.
Unfortunately, however, the patient required bilateral below the
knee amputation, but less extensive and severe than anticipated before the
protocol40. Soon
after that we showed the efficacy of this approach in another patient with
chronic leg ischemia induced by intramuscular injection of VEGF165 and
deferoxamine added to the fibrin platform.
In
the cases reported here, it is clear that there was substantial
improvement in blood flow of the ischemic extremities, which consequently
improved symptoms and the patient’s quality of life. We have objectively
demonstrated by angiography the growth of new blood vessels after
treatment with VEGF and fibrin. The fibrin glue aids in the slow release
of the growth factor and thus prolongs its availability, sustaining
angiogenesis and improving oxygen supply. This demonstrates again and
confirms that fibrin glue alone, applied directly, can stimulate
angiogenesis. Theoretical
risks of therapeutic angiogenesis include non-target organ
neovascularization, acceleration of atherosclerosis, or spread of
undetected malignancy. We saw
no evidence of such toxic effect during the follow up. ConclusionIn summary, our clinical study
demonstrated significant reduction in the rate of amputation, healing of
ulcers, substantial improvement in symptoms (rest pain, pain-free walking
time) and, consequently, in the patient’s quality of life after
treatment. We have also demonstrated sustained effect of treatment at
3-year follow-up after local application of Fibrin+VEGF and/or fibrin
alone. We propose that this strategy can be used as a possible therapeutic
intervention in the management of limb ischemia by enhancing growth of new
blood vessels. A larger clinical study is underway at the
Lenox Hill Heart and Vascular Institute
of New York to
establish efficacy of fibrin therapy in the treatment of critical limb
ischemia.
ACKNOWLEDGMENTS The authors wish to thank Cathy Kennedy, project editor, for copyediting and other editorial assistance.
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