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Prof. Skaia Nikol
Therapeutic angiogenesis describes an emerging field of cardiovascular medicine whereby new blood vessels are induced to grow to supply oxygen and nutrients to cardiac muscle tha has mostly been rendered ischaemic as a result of progressive atherosclerosis.
Myocardial ischemia is one of the most promising targets of gene therapy, particularly, in the case of refractory angina.
As life expectancy is increasing, patients with angina pectoris refractory to conventional antianginal therapeutics are a challenging problem. Therapeutic angiogenesis may be one way to approach this problem.
The following review concentrates on data generated in the phase II and phase III clinical trials for angiogenic protein and gene therapy strategies for their use in coronary artery disease.
Most of the early angiogenesis trials employed recombinant protein formulations of VEGF-A or members of the FGF family rather than gene constructs. Among those were two large trials, FIRST and VIVA.
The FGF Initiating RevaScularization Trial (FIRST) evaluated the efficacy and safety of recombinant fibroblast factor 2 (rFGF2) in a multicenter, randomised, double-blind, placebo-controlled trial of a single intracoronary infusion of rFGF2 at 0, 0.3, 3, or 30 ?g/kg (n=337 patients) (Simons et al. 2002). Single intracoronary infusion of rFGF2 did not improve exercise tolerance, myocardial perfusion or angina symptoms at 180 days significantly, due to continued improvement also seen in the placebo group. Adverse events were similar across all groups, except for hypotension, which occurred with higher frequency in the high-dose 30-?g/kg rFGF2 group.
The VIVA (Vascular endothelial growth factor in Ischemia for Vascular Angiogenesis) trial was a double-blind, placebo-controlled trial designed to evaluate the safety and efficacy of intracoronary and intravenous infusions of the recombinant vascular endothelial growth factor (rhVEGF) in 178 patients with stable exertional angina unsuitable for standard revascularisation (Henry et al. 2003). Intracoronary infusions of rhVEGF (17 or 50 ng • kg-1 • min-1) were followed by intravenous infusions on days 3, 6, and 9. RhVEGF seemed to be safe and well tolerated. By day 120, only high-dose rhVEGF resulted in significant improvement in angina and favorable trends in exercise tolerance time and angina frequency.
Overall, such protein trials have not shown durable efficacy.
One unexpected and underestimated problem in those first angiogenic trials was the extent of improvement in the placebo group preventing those trials from turning out positive. It is well known that good standard care including optimal medication and lifestyle changes - in particularly exercise - increases may induce the formation of collaterals via release of growth factors and progenitor cells. Such improvement of the placebo group may require much higher numbers of randomised patients to demonstrate significant differences. Safety observations in some of the smaller trials and preclinical work have revealed dose-related proteinuria and transient hypotension, presumed to be due to activation of endothelial nitric oxide synthase (eNOS) and subsequent nitric oxide release.
Another more specific problem of protein therapy is the short half-life and residence time of most recombinant protein formulations, - probably too short considering that effective angiogenesis and arteriogenesis takes several months. Targeted delivery to ischaemic zones of delayed release preparations of angiogenic peptides may yet prove efficacious. Clinical studies using this method of delivery are now in preclinical development. This problem can also be circumvented by the use of gene therapy allowing for long-term over-expression of the target gene. Consequently, most remaining and ongoing angiogenic therapy trials for coronary heart disease have been or are conducted with genes, either using plasmid or an adenoviral vector.
The randomized double-blind Angiogenic GENe Therapy AGENT (AGENT) study was among the first published viral gene therapy studies.
One of the objectives of the AGENT trial were to evaluate the safety and anti-ischaemic effects of 5 ascending doses of intra-coronary pro-angiogenic FGF4 delivered in a replication defective serotype 5 adenoviral vector (Ad5-FGF4) to 79 patients with stable mild to moderate angina and no clinically significant heart failure.
Another objective was to select potentially safe and effective doses for subsequent study (Grines et al. 2002; Grines et al. 2003). The Ad5-FGF4 was administered by percutaneous intracoronary infusion of the reagent into the LAD, CX, and RCA distributions (and/or bypass graft where applicable). Fever of <1-day duration occurred in 3 patients in the highest-dose group. Transient, asymptomatic elevations in liver enzymes occurred in 2 patients in lower-dose groups that returned to the normal range within 4 weeks. This was possibly related to the adenovirus tendency to a natural tropism for liver and spleen.
The limitation of this trial is, that only one dose group showed positive results. Thus, there was overall no significant difference in clinical efficacy between the treated and placebo patients in the time of onset of angina, although a post-hoc analysis suggested that patients who received active treatment improved more than placebo patients in treadmill walking times.
AGENT-2 was a randomised, double-blind study that compared Ad5-FGF4 at a single dose of 1x1010 vp in 25 patients to placebo in 17 patients, delivered via selective intracoronary infusion to a region of cardiac muscle with reversible ischaemia (Grines et al. 2003). In this study, transient elevation of liver enzymes were observed in both placebo and actively treated groups to a similar degree. Actively treated patients had a lower incidence of subsequent interventional procedures for worsening of anginal symptoms than placebo patients (6% versus 18%). This study did not meet its prespecified endpoint, a decline in reversible perfusion defect size, a result attributed to a 50% improvement in a single placebo patient.
Nevertheless, based on positive trends observed, AGENT-3 and AGENT-4 were designed to address short and long term safety and efficacy in patients with advanced coronary artery disease. Both studies have recently been stopped at approximately the half-way point in enrollment, apparently due to the absence of identifiable trends in efficacy.
One problem of the AGENT trials may have been the administration via intracoronary infusions with first pass effect and probably only a small amount of active agent reaching the targeted area of the myocardium.
In the randomised, placebo-controlled, double-blind phase II Kuopio Angiogenesis Trial (KAT) 103 patients with CCS class II to III coronary heart disease had PTCA combined with stent implantations in 90% of patients performed, followed by gene transfer with a perfusion-infusion catheter(Hedman et al. 2003). VEGF adenovirus (VEGF-Adv, 2x1010 pfu), was compared to VEGF plasmid liposomes (VEGF-P/L; 2000 ?g of DNA with 2000 ?L of DOTMA:DOPE [1:1 wt/wt]),and controls. After 6 months, myocardial perfusion showed a significant improvement in the VEGF-Adv–treated patients. Some inflammatory responses were transiently present in the VEGF-Adv group, but no increases were detected in the incidences of serious adverse events in any of the study groups.
Preliminary reports have appeared on the REVASC study examining the effects of direct intramyocardial adenoviral delivery of a VEGF-A isoform, VEGF-A121. The effects of 4x1010 pfu Ad-VEGF-A121 were evaluated in no-option patients who had angina that was poorly controlled on standard medical therapy (Stewart 2000). The study, although randomised, was not blinded. It is noteworthy that Ad-VEGF-A121 was delivered by 30 direct injection into the target ischaemic zone of the free wall of the left ventricle via mini-thoracotomy and not by intra-arterial infusion, as had been the case in several negative studies, including the AGENT 3 and 4 studies. There was a difference in the time to 1-mm ST segment depression at 26 weeks. A number of secondary endpoints were also positive, including time to onset of angina, total exercise duration, and improvement of CCS angina class. There were 4 serious adverse events noted due to the mini-thoracotomy/injection procedure in the active treatment group, on the other hand a reduction of cardiac events and surgical revascularisation procedures in the active treatment group.
Other phase II trials conducted in Europe and the Unted States evaluate currently a new target gene, adenoviral hypoxia-inducible factor-1? transription factor (HIF-1?? also using the direct intramyocardial injection as treatment route. This therapeutic gene may have the potential to be more efficacious than any other of the growth factors used before. HIF-1??plays a principal role in the cellular response to changes in oxygen tension. It controls a number of genes including inducible nitric oxide sythase, VEGF and glycolytic enzymes among others and thus potentiates and coordinates adaption to hypoxia. Both trials almost enrolled the targeted total of 32 patients, thus, data will become available soon.
One way to circumvent possible adverse events related to the surgical procedure is the catheter-based intramyocardial injection. Several devices have been developed for such local drug delivery into the myocardium. Among those, the electromechanic mapping and injection catheter NOGA-MyoStar appears as one of the most elegant systems allowing for targeted injections into viable, ischaemic heart tissue.
The Euroinject One randomised double-blind trial assessed therapeutic angiogenesis of percutaneous intramyocardial plasmid gene transfer of 0.5 mg vascular endothelial growth factor (phVEGF-A165) in 80 “no-option” patients with severe stable ischemic heart disease, CCS functional class 3 to 4 (Kastrup et al.).,NOGA procedure-related adverse events occurred in five patients. At 3 months, the VEGF gene transfer did not significantly improve stress-induced myocardial perfusion abnormalities compared with placebo; however, improved regional wall motion, as assessed both by NOGA and by ventriculography, may indicate a favourable anti-ischemic effect.
The latter trial may represent one of those examples where an underestimated improvement of the placebo group did not allow for significant differences due to relatively small and insufficiently selected patient groups. Larger phase II/III trials will be able to clarify this. One such trial may be the NOVA trial currently conducted in 15 study centers in Europe and Israel with 129 preselected randomised patients who will reveive an adenoviral vector for AdGVVEGF121.10NH applied to ischaemic myocardial tissue identified using the NOGA catheter for injection (MyoStar catheter). Unlike the experience with recombinant protein formulations of FGFs or VEGFs, transient hypotension and/or proteinuria have not been consistently observed with either plasmid or viral vector delivery of VEGF or FGF gene therapies.
The content of this article reflects the personal opinion of the author/s and is not necessarily the official position of the European Society of Cardiology.
Although several growth factors and delivery approaches have yielded positive results in preclinical studies, first clinical studies have shown little or no real clinical benefit to the patients. It is likely that less than optimal gene therapy approaches have been used so far, and more thorough preclinical studies are needed in order to establish safe, efficient pro-angiogenic therapy. Growth factor, growth factor combinations, gene transfer vector, delivery method and target microenvironment need to be chosen based on the therapeutic target. Large animal models are necessary in the determination of the optimal therapeutic agent, dose and clinically relevant delivery strategy. Therapeutic angiogenesis in the ischaemic heart is not yet supported by a large body of clinical data and those clinical data available are partially controversial not alone but also due to possible underpowered trials with sub-optimal selection of patients and/or study centers. While some of the important questions remain to be answered in preclinical models, in parallel clinical research more large phase II/III trials are definitely required.
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Prof. S. Nikol Munich, Germany Member of the Nucleus of the ESC Working Group on Interventional Cardiology