Around 20% of patients with coronary artery disease (CAD) have run out of options. These are patients who, despite being on maximal medical therapy, are still experiencing angina and are unsuitable for revascularisation due to diffuse CAD with poor targets and no useable conduits.
In addition, new therapies need to be developed for critical limb ischaemia (CLI), a condition affecting 1.5 million patients in the USA and Europe, where no pharmaceutical treatments have proven effective.
Initial approaches for inducing angiogenesis have involved delivery of single angiogenic growth factors, or of genes encoding that factor, in the form of injected plasmids or viral vectors. So far, the angiogenic factors used have been primarily members of the vascular endothelial growth factor (VEGF) family or the fibroblast growth factor (FGF) family.
Each mode of delivery has pros and cons. Imo Hoefer (UMC Utrecht, The Netherlands) explained: “The major advantage of viral transfection is that it leads to prolonged production of the protein the virus encodes for, ensuring longer-term delivery of the factor. While protein delivery has limited duration of action, its advantage is you know the dosage applied, and can deliver more than one factor simultaneously.”
Studies have shown that delivery of VEGF and FGF increased the vascularity of skeletal and cardiac muscle in rodents, rabbits, dogs, and pigs. More recently, clinical trials for CAD and CLI have provided more mixed results.
Researchers are not surprised at the difficulties in translating animal studies into clinical trials. Eric Van Belle (Cardiology Hospital, University of Lille, France) explained: “In animal models you know exactly where to apply growth factors, whereas the clinical situation is more complex.”
Matt Springer (University of California, San Francisco, USA) said that another important distinction between people and small animals was that the cardiac muscle to be revascularised was much larger in humans, so the dynamics of tissue diffusion were different. Since doses of VEGF and FGF could not exceed those determined to cause hypotension, it was debatable whether sufficient levels could be achieved in humans.
The VIVA phase II trial tested the efficacy of VEGF in CAD (Circulation. 2003; 107:1359- 65). In the study, 178 patients with stable exertional angina, unsuitable for standard revascularisation, were randomly assigned to receive placebo, low-dose or high-dose single intracoronary bolus infusions of VEGF on day one, followed by intravenous infusions on the third, sixth and ninth days.
Although initial 60-day results proved disappointing, with no significant differences in the primary endpoint of treadmill exercise time, a statistically significant difference in angina frequency between the high-dose VEGF and placebo groups emerged at 120 days. However, there were no objective measurements for myocardial perfusion and ventricular ejection fractions.
The AGENT study, the first randomised trial using gene therapy to test the angiogenic potential of FGF-4, proved more positive (Circulation. 2002; 105:1291-7). Seventynine patients with chronic stable angina were randomly assigned in a double blind procedure to placebo (n=19) or adenovirus type 5 (ad5-FGF-4) (n=60).
Results showed that patients receiving Ad5-FGF-4 tended to have greater improvements in exercise time at four weeks (1.3 versus 0.7 minutes, P=NS). A protocolspecified, sub-group analysis showed the greatest improvement in patients with baseline ETT <10 minutes (1.6 versus 0.6 minutes, P=0.01, n=50).
Trials in PAD are proving more promising. Van Belle said: “It’s obviously easier to inject directly into the leg than the heart.” He added that, for the present, he believed it sensible to concentrate efforts on PAD. “Once we have demonstrated proof of concept here, we can devote more time and money to the myocardium.”
Noteworthy is the TRAFFIC study – the first trial showing a positive effect for treatment with fibroblast growth factor (FGF-2) in 180 patients with CLI (The Lancet. 2002; 359:2053-2058). patients were randomly assigned to bilateral intra-arterial infusions of placebo on days one and 30, FGF-2 on day one and placebo on day 30 (single dose), or FGF- 2 on both days one and 30 (double dose). Results indicated significant increases in peak walking time at 90 days for patients receiving the active treatment; but repeat infusions at 30 days proved no better than one infusion.
One year results from the TALISMAN 201 study in 107 patients, presented by Sigrid Nikol (University Hospital of Munster, Germany) at the American College of Cardiology meeting this year, showed NV1FGF gene therapy significantly reduced the risk of amputation (15.7% for NV1FGF therapy vs 33.9% for those receiving placebo, p= 0.02) and might lead to lower mortality (11.8% vs 23.2%, p=0.11).
Other research suggests stem cell therapy may also work by stimulating angiogenesis. In the TOPCARE-AMI study, 60 patients with acute myocardial infarction (MI) were randomised to receive either bone marrow–derived mononuclear cells or endothelial progenitor cells (Circulation. 2002; 106:r23-61). In addition to improving the ejection fraction, cell therapy increased coronary flow reserve, indicating an enhancement of neovascularisation.
Ian Zachary (London, UK) said such studies pointed to a future where stem cell therapy would be combined with different angiogenic factors. Rather than simply delivering one angiogenic factor, a more viable approach was likely to involve tightly regulated gene expression of angiogenic factors, targeting different stages of angiogenesis. Ultimately, endothelial progenitor cells might be transfected with angiogenic cytokines.
Springer concluded: “Although progress toward the achievement of clinical therapeutic angiogenesis has been slower than hoped, the basic premise is still sound. However, a method whereby stable vessels can be grown when and where they’re required, for functional benefit, has yet to be attained clinically.”