Effects of Aging on the Collateral Circulation, and Therapeutic Implications

> That time of year thou mayst in me behold, When yellow leaves, or none, or few, do hang Upon those boughs which shake against the cold, Bare, ruined choirs, where late the sweet birds sang.> > —Shakespeare, Sonnet 73The most important mechanism by which the body compensates for the reduced tissue flow caused by an obstructed artery is through flow supplied by the collateral circulation. Thus, when arterial obstruction occurs, perfusion to the ischemic tissue is provided by collateral vessels—defined as vessels, usually from an adjacent arterial tree, that interconnect the proximal part of an arterial circuit to that part of the artery lying distal to an obstruction.Important as the collateral circulation is, it is often incapable of restoring flow to normal levels at rest, and is usually incapable of delivering the augmented flow required by exercise or increased metabolic demands, as evident by the frequency of patients experiencing either angina or claudication in cohorts with coronary or peripheral vascular disease. The limited capacity to restore full flow at high metabolic demands poses quality-of-life issues to individuals who have chronic arterial obstruction: in the United States alone 300 000 to 900 000 patients have persistent angina despite medical management.1 Additionally, both animal and human studies demonstrate that the clinical outcome of acute arterial obstruction is worse in animals/patients with poor collaterals versus those with a robust collateral circulation.2–5These considerations led to major efforts to develop strategies designed to enhance collateral function, including administration of proteins and genes expressing such proteins, and stem or progenitor cells known to secrete factors that improve collateral function. However, despite proof-of-concept studies in animals, strategies tested to date in patients are inconclusive; some studies have failed to demonstrate clinical improvement, and others reporting positive signals are based on too few patients for …