Recent Developments

1 It is now recognized that the severity of symptoms in PAD and treatment outcomes are related to the degree of occlusive arterial disease and to the extent of collateral vessel formation. Therapeutic angiogenesis4 by local administration of angiogenic growth factors, such as vascular endothelial growth factor (VEGF), in the form of gene transfer using viral or plasmid vectors or recombinant protein delivery, may stimulate collateral circulation through growth and proliferation of new blood vessels. Gene transfer allows prolonged expression of the protein, reduced systemic exposure to growth factors and ease of delivery to peripheral tissues, which may be advantageous. Although pre-clinical studies of VEGF delivered via gene transfer have been able to induce collateral blood flow and arteriogenesis, results from phase 1 and phase II 'proof of concept' clinical studies have been inconsistent. These inconsistencies may be explained by differences in VEGF isoforms (e.g. VEGF121 and VEGF165), utilization of nonoptimal doses and duration of VEGF expression, as well as uncertainties about the efficiency of gene transfer in adult skeletal muscles due to low concentrations of adenoviral receptors and physical barriers to transfection.

2 Advances in the understanding of the pathophysiology of glycaemic vascular injury have also identified pathways which have potential for therapeutic modulation.5 These include: (1) increased oxidative stress and free radical-mediated damage; (2) formation of advanced glycosylation end-products; (3) diversion of glucose into the aldose reductase pathway; and (4) activation of one or more isozymes of protein kinase C. Experimental studies in targeting these pathways have focused on developing agents to restore normal vasorelaxation, stabilize plaques, reduce intercellular adhesion and enable regression of inflammatory mediators. In addition, further understanding of anti-atherosclerotic properties of currently available agents has also widened the scope of use of these agents. For example, recent ultrasonography evidence has shown that angiotensin-converting enzyme inhibitor may retard the progression of atherosclerosis as demonstrated by carotid intima-media thickness; statins improve endothelial function independent of their lipid-lowering effects, whilst cilostazol inhibits neo-intimal hyperplasia and increases VEGF-mediated collateral vessel formation.

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