Notice of Retraction: Ahimastos AA, et al. Effect of Ramipril on Walking Times and Quality of Life Among Patients With Peripheral Artery Disease and Intermittent Claudication: A Randomized Controlled Trial. JAMA. 2013;309(5):453-460.

InReplyWeagreewithDrsRedingtonandCaldarone thatmany animal andhumanstudieshave shownthat a singleor few (≤5) short episodes of remote ischemic preconditioning (typically 5minutes of limb ischemia followed by 5minutes of reperfusion)areprotective formanyorgans (including theheart, brain, and kidney) with few reported adverse effects. However, few studies have examined the long-term effects of repeated episodes of remote ischemic preconditioning, and this iswhatwe referred to in our Editorial that the effectsofmultiple episodesof remote ischemicpreconditioning, which patientsmay be exposed to if remote ischemic preconditioning is widely used, are unclear. For example, the study byMeng et al1 used remote ischemic preconditioning twice daily during 300 consecutive days to reduce stroke, but did not examinemolecularmechanisms of brain protection or cardiovascular adverse effects. Similarly, a study by Shaked et al2 that used intermittent cycles of remote ischemic preconditioning as adjunctive therapy for treatment of diabetic foot ulcers did not examine cardiovascular effects. Redington appeared to agree with our point of view as the coauthor of a review article,3 which cautioned that “hyperconditioning (ie, an as-yet undefined, excessive number of conditioning episodes) may be deleterious.” Another recent review article by Whittaker and Przyklenk4 suggested that in addition to tachyphylaxis (ie, increased tolerance to the effect of an intervention), repeated episodes of limb ischemia may have unfavorable consequences for collagen and systemic effects mediated via matrix metalloproteinases. The authors concluded that the benefits of protection against ischemia may be found at low doses (ie, low number andduration of preconditioning episodes), but these benefits may be lost and adverse effects may occur (collagen damage) at high doses. In addition, remote ischemic preconditioning may have limited utility for cardioprotection in 2 large populations (elderly patients and those with diabetes) at high risk for cardiovascular diseases,5 and may be associated with higher risk for atrial fibrillation, even when used at the conventional dose (5-minute episodes of ischemia/reperfusion repeated 5 times) before coronary artery bypass graft surgery.6 Therefore, even thoughwe share the enthusiasm of Redington andCaldarone for thepromise of remote ischemic preconditioning for organ protection, investigators in the field should examine potential long-term harmful effects to various organs, including the heart, particularly when hyperconditioning is used.