Intermittent claudication: new targets for drug development

Peripheral artery disease (PAD) is the result of extensive atherosclerosis in the arterial supply to the lower extremities. PAD is associated with increased systemic cardiovascular morbidity and mortality as well as substantial disability due to walking impairment. Claudication is the classic symptom of leg pain with walking that is relieved by rest, but patients with PAD without typical claudication also have a walking limitation. Treatment of the patient with PAD is directed towards reducing cardiovascular risk and improving exercise capacity. The pathophysiology of the physical impairment is complex as changes in the muscle distal to the arterial stenoses contribute to the limitations. Current treatment options to improve exercise performance have limitations emphasizing the need for new pharmacotherapies for this highly prevalent condition. The multifactorial contributors to the exercise impairment in PAD suggest potential targets for novel drug therapies. Advances in understanding angiogenesis make pharmacologic revascularization possible. However, ensuring that new blood vessels develop in a distribution relevant to the clinical impairment remains a challenge. Skeletal muscle metabolism and its regulation are altered in patients with PAD and strategies to improve the efficient oxidation of fuel substrates may improve muscle function. PAD is associated with increased oxidative stress which may result in injury to the muscle microvasculature and myocyte. Minimizing this oxidative stress by enhancing cellular defense mechanisms, administration of anti-inflammatory agents or by providing antioxidants, could prevent oxidative injury. Given the central role of atherosclerosis in the flow limitation, therapies to induce regression of atherosclerotic lesions could result in improved blood flow and oxygen delivery. Drugs targeting the distribution of blood flow in the microcirculatory environment of the muscle have the potential to better match oxygen delivery with working myocytes. The physical disability and flow limitations contribute to a loss of leg muscle mass in patients with PAD. Drugs to increase muscle mass and strength could enhance walking ability in these patients. Pharmacotherapies that recapitulate the muscle adaptations induced by preconditioning may result in improved physical performance in patients with PAD. Adjunctive therapies combined with exercise training or revascularization may be important given the complexity of integrative muscle function and the multiple pathologic changes induced by PAD. New research into the pathophysiology of the physical impairment associated with PAD has identified potential new targets for drug therapy, and will likely continue to do so in the years to come. Translation of these opportunities into effective therapeutics will be important as the already high prevalence of PAD is expected to increase as the population ages.