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(Circulation. 2005;111:173-178.)
© 2005 American Heart Association, Inc.

Heart Failure

Annexin A5 Scintigraphy of Forearm as a Novel In Vivo Model of Skeletal Muscle Preconditioning in Humans

Gerard A. Rongen, MD, PhD; Wim J.G. Oyen, MD, PhD; Bart P. Ramakers, MSc; Niels P. Riksen, MD; Otto C. Boerman, PhD; Neil Steinmetz, MD; Paul Smits, MD, PhD

From the Departments of Pharmacology-Toxicology (G.A.R., B.P.R., N.P.R., P.S.), Nuclear Medicine (W.J.G.O., O.C.B.), and Internal Medicine (G.A.R., N.P.R., P.S.), Radboud University Nijmegen Medical Center, Nijmegen, the Netherlands, and Theseus Imaging Corporation (N.S.), Boston, Mass.

Correspondence to G.A. Rongen, MD, PhD, Department of Pharmacology-Toxicology, Radboud University Nijmegen Medical Center, Nijmegen, Geert Grooteplein 21, PO Box 9101, 6500 HB Nijmegen, The Netherlands. E-mail G.Rongen{at}pharmtox.umcn.nl

Received July 19, 2004; revision received August 31, 2004; accepted September 14, 2004.

Background— Nonlethal ischemia and reperfusion reduce ischemia-reperfusion-induced cell death, a phenomenon called ischemic preconditioning. In animal models, this potent endogenous protection is mimicked in vivo by administration of adenosine. In humans, exploitation of ischemic preconditioning is hindered by the lack of an appropriate in vivo model to study this phenomenon. To solve this problem, we aimed to set up an easy-to-use human in vivo model to study ischemic or pharmacological preconditioning.

Methods and Results— Healthy male volunteers performed unilateral ischemic handgrip. At reperfusion, we intravenously injected technetium-99m-labeled Annexin A5, a presumed marker of ischemic injury, and we imaged both forearms and hands simultaneously with a gamma camera. Region of interest analysis (counts per pixel) and subsequent calculation of the percentage difference in radioactivity between experimental and control hands (thenar muscle; mean±SE) revealed significant uptake to the ischemically exercised tissue (26±3% at 4 hours after reperfusion; P<0.05). This selective localization of Annexin A5 was reduced by ischemic preconditioning (10 minutes of ischemia plus reperfusion before ischemic exercise) or by infusion of adenosine into the brachial artery to 6±1% and 10±3%, respectively (P<0.05 versus ischemic exercise alone), resembling observations in animal models with infarct size as an end point. Appropriate control experiments supported our conclusion.

Conclusions— Annexin A5 scintigraphy can be applied to test pharmacological or physiological interventions for their ability to prevent ischemia-reperfusion injury.

Key Words: adenosine • exercise • ischemia • scintigraphy

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