Editorial [ Angiogenesis: A Promising Treatment Option for Peripheral Arterial Disease ]

Peripheral arterial disease (PAD) affects a considerable percentage of the population. A recent large survey including 264,570 patients from 16 countries reported that the prevalence of PAD is 8% (mean age: 54-64 years) [1]. Another population-based study from Sweden including 5,080 subjects aged 60-90 years reported that almost a fifth (18%; 95% confidence interval, 16%-20%) had some form of this disease [2]. PAD is an indicator of systemic atherosclerosis often involving >1 arterial bed (i.e. coronary, cerebrovascular, renal and peripheral arterial systems) [3-6]. Due to the lack of symptoms and physician awareness, PAD often remains undetected and is commonly underdiagnosed [7-9]. The risk factors and medical management of PAD are reviewed elsewhere [10-14]. Among these, smoking deserves special mention because it is the most powerful predictor of PAD [15-17]. Both active [17, 18] and passive [19] cigarette smoking impair flow-mediated endothelium-dependent peripheral arterial vasodilatation (arterial stiffness). Besides PAD, arterial stiffness is also associated with hypertension, obesity, insulin resistance and the metabolic syndrome [20, 21]. Quitting smoking and aggressive risk factor modification (e.g. administering statins, antihypertensive and antiplatelet drugs) can reduce the risk of vascular events and disease progression in patients with PAD [22-26]. Regarding lipids, a recent study on 30,348 elevated-risk primary prevention, coronary heart disease (CHD) and CHD equivalent patients showed that suboptimal lipid levels were associated with up to 45% increased risk for a cardiovascular event (p < 0.05) [27]. However, established and emerging risk factor management, as well as surgical and endovascular procedures are probably still not providing optimal treatment for all patients with PAD [28, 29]. Therefore, new options, like angiogenesis, need to be explored without excluding the established treatment modalities. Furthermore, the interaction between established and novel options need to be identified. Guidelines for the management of PAD were recently published both in Europe [30] and USA [31]. The issue of therapeutic angiogenesis was not addressed as there were not enough evidence-based trials. For patients with critical limb ischemia, there is a growing need for alternative treatment strategies; one option could be angiogenesis by administration of vascular growth factors [32, 33]. Basic fibroblast growth factor (bFGF) levels are elevated in symptomatic PAD patients with critical limb ischemia [34, 35]. This finding, which reflects a physiologic response to limb ischemia, holds implications for the treatment of PAD. The preliminary results from recent animal studies lend further support to this hypothesis [36-38]. In this context, autologous bone marrow mononuclear cells implantation in a PAD patient with critical limb ischemia resulted in an improvement of the ischemic extremity [39]. Bilateral femoral vein plasma concentrations of bFGF and vascular endothelial growth factor (VEGF) were measured before and after the procedure. While plasma VEGF and bFGF concentrations were much greater in the ischemic compared with the non-ischemic leg prior to the implantation, they decreased to the same concentrations as those in the contralateral lower extremity postprocedure [39]. Thus, plasma levels of VEGF and bFGF not only indicate the severity and extent of PAD, but may also predict the effectiveness of the treatment strategy employed for PAD. Positive results for autologous bone marrow mononuclear cells implantation for the treatment of critical limb ischemia have also been reported by other groups [40- 42]. The finding that bone marrow stem cell therapy may induce neovascularization in ischemic myocardium and improve cardiac function further supports this concept [43]. It remains to be determined whether angiogenesis in combination with aggressive risk factor modification offers even better results than either option alone. Current evidence suggests that angiogenesis is a promising additional treatment option for PAD. Future randomised trials may provide more definite results, which will help position angiogenesis in the management of PAD. DECLARATION OF INTEREST This Editorial was written independently; no company or institution supported the authors financially or by providing a professional writer. The authors have given talks, attended conferences and participated in trials and advisory boards sponsored by various pharmaceutical companies.