The pathophysiology of peripheral arterial disease: rational targets for drug intervention.

The most common cause of peripheral arterial disease (PAD) is atherosclerosis, which begins with an alteration in endothelial biology due to hypercholesterolemia, diabetes mellitus, hypertension, tobacco use, elevated levels of lipoprotein(a) or homocystinemia. With chronic and severe arterial disease, changes begin to occur in the microcirculation, including obstruction at the microvascular level and tissue injury. Based on insights into the vascular biology of PAD, new therapies have been developed and are at various stages of clinical trials. Future pharmacotherapy for PAD will include agents that have one or more of the following attributes; (1) reduce, or even reverse, the progression of atherosclerosis; (2) inhibit plaque rupture; (3) inhibit thrombosis by a novel mechanism; (4) induce angiogenesis; (5) reverse microvascular derangements; (6) affect blood rheology; and (7) enhance skeletal muscle's ability to use available nutrients.