What new approaches are there to prevent restenosis following PTCA?

Percutaneous transluminal coronary angioplasty (PTCA) is a well-established treatment for patients with coronary artery disease. However, the excellent initial procedural outcome is limited by the late development of restenosis occurring in approximately 30% of cases between 3 and 6 months. The introduction of intracoronary stents, which now account for more than 70% of all interventional procedures has had only a modest effect on restenosis rates. There were over 20,000 angioplasty or related procedures in the UK in 1996 and it is easy to appreciate the clinical and economic burden of restenosis.

Pharmacological approaches
To date no pharmacological agent has had a significant effect on reducing the incidence of restenosis. There are a number of reasons for this including the lack of correlation between animal models and the situation in man, the drug doses used or the power of some of the trials. Recent interest has focused on the use of antiproliferative agents such as paclitaxel and tranilast.

The antioxidant Probucol has been shown to be effective in limiting restenosis after balloon angioplasty. However, lack of licensing in some countries, limited data on the clinical impact of treatment, and the fact that pre-treatment for 4 weeks is required, may all be factors in limiting its use.

Gene therapy involves the transfer of DNA into host cells with the aim of inducing specific biological effects. Vectors for gene delivery include plasmid DNA-liposome complexes and viral vectors such as the replication deficient recombinant adenovirus. Design of appropriate delivery devices has taken a number of directions including double balloon catheters and perforated balloons allowing high pressure injection through radial pores. Various approaches have been used to limit experimental
restenosis by inducing cell death (e.g. fas ligand gene to induce apoptosis), inhibiting smooth muscle cell migration (e.g. overexpression of TIMP-1 and eNOS) or by inhibiting cell cycle regulators of smooth muscle cell proliferation (e.g. antisense c-myc or c-myb oligonucleotides). There is a vast amount of experimental data, with early results from gene therapy trials for angiogenesis, but clinical trials for restenosis are awaited.

Brachytherapy
Over the last few years there has been considerable interest in intravascular brachytherapy (radiation therapy). The ability of ionising radiation to halt cell growth by damaging the DNA of dividing cells, and the view that neointimal hyperplasia represented a benign proliferative condition led to its application in vascular disease. A variety of catheter based delivery systems and radioactive stents are available using either beta (e.g. 32P) or gamma (e.g. 192Ir) sources. A number of studies have shown
impressive results on reducing restenosis rates and many more are underway but enthusiasm for the technique should be tempered because there are concerns about long term safety. Indeed there are very recent reports of unexpected late thrombotic occlusion.

Photodynamic therapy (PTD) involves the local activation of a systemically administered photosensitising agent by nonionising radiation in the form of non-thermal laser light. Many of the sensitising agents that have been studied have been products of porphyrin metabolism such as 5-aminolaevulinic acid. Much of the work in this field to date has been in the treatment of cancer but there is an accumulation of small and large animal data showing a reduction in neointimal hyperplasia after balloon injury. Favourable vessel wall remodelling has also been observed in a pig model of balloon coronary and iliac angioplasty. Reports of the clinical application of photodynamic therapy are
limited but a clinical pilot study of adjuvant PDT in superficial femoral angioplasty showed it to be a safe and effective technique. Further work needs to be done to establish its role in coronary disease.