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PRE-CLINICAL RESEARCH

Molecular Imaging of Interstitial Alterations in Remodeling Myocardium After Myocardial Infarction

Susanne W.M. van den Borne, MD^_*,, Satoshi Isobe, MD, PhD^_*, Johan W. Verjans, MD^_*, Artiom Petrov, PhD^_*, Dagfinn Lovhaug, MSc, Peng Li, MD, PhD^_*, H. Reinier Zandbergen, MD^_*, Youping Ni, MD, PhD^_*, Peter Frederik, PhD, Jun Zhou, MD^_*, Bente Arbo, PhD, Astri Rogstad, PhD, Alan Cuthbertson, PhD, Salah Chettibi, PhD, Chris Reutelingsperger, PhD, W. Matthijs Blankesteijn, PhD, Jos F.M. Smits, PhD, Mat J.A.P. Daemen, MD, PhD, Faiez Zannad, MD, PhD, FACC, Mani A. Vannan, MD, FACC^_*, Navneet Narula, MD^_*, Bertram Pitt, MD, FACC^||, Leonard Hofstra, MD, PhD and Jagat Narula, MD, PhD, FACC^_*,_*

^_* University of California, Irvine School of Medicine, Irvine, California
Cardiovascular Research Institute Maastricht, Maastricht University, Maastricht, the Netherlands
GE Healthcare, AS, Oslo, Norway
University Henri Poincaré, Nancy, France
^|| University of Michigan, Ann Arbor, Michigan

Manuscript received April 30, 2008; revised manuscript received July 31, 2008, accepted July 31, 2008.

^_* Reprint requests and correspondence: Dr. Jagat Narula, Division of Cardiology, University of California, Irvine School of Medicine, 101 The City Drive, Building 53, Mail Route 81, Orange, California 92868-4080 (Email: narula{at}uci.edu).

Objectives: The purpose of this study was to evaluate interstitial alterations in myocardial remodeling using a radiolabeled Cy5.5-RGD imaging peptide (CRIP) that targets myofibroblasts.

Background: Collagen deposition and interstitial fibrosis contribute to cardiac remodeling and heart failure after myocardial infarction (MI). Evaluation of myofibroblastic proliferation should provide indirect evidence of the extent of fibrosis.

Methods: Of 46 Swiss-Webster mice, MI was induced in 41 by coronary artery occlusion, and 5 were unmanipulated. Of the 41 mice, 6, 6, and 5 received intravenous technitium-99m labeled CRIP for micro–single-photon emission computed tomography imaging 2, 4, and 12 weeks after MI, respectively; 8 received captopril or captopril with losartan up to 4 weeks after MI. Scrambled CRIP was used 4 weeks after MI in 6 mice; the remaining 10 of 46 mice received unradiolabeled CRIP for histologic characterization.

Results: Maximum CRIP uptake was observed in the infarct area; quantitative uptake (percent injected dose/g) was highest at 2 weeks (2.75 ± 0.46%), followed by 4 (2.26 ± 0.09%) and 12 (1.74 ± 0.24%) weeks compared with that in unmanipulated mice (0.59 ± 0.19%). Uptake was higher at 12 weeks in the remote areas. CRIP uptake was histologically traced to myofibroblasts. Captopril alone (1.78 ± 0.31%) and with losartan (1.13 ± 0.28%) significantly reduced tracer uptake; scrambled CRIP uptake in infarct area (0.74 ± 0.17%) was similar to CRIP uptake in normal myocardium.

Conclusions: Radiolabeled CRIP allows for noninvasive visualization of interstitial alterations during cardiac remodeling, and is responsive to antiangiotensin treatment. If proven clinically feasible, such a strategy would help identify post-MI patients likely to develop heart failure.

Key Words: myofibroblasts • integrins • interstitial fibrosis • radionuclide imaging • heart failure • coronary artery disease

Abbreviations and Acronyms   ASMA = alpha smooth muscle actin   CRIP = Cy5.5-RGD imaging peptide   CT = computed tomography   HF = heart failure   LV = left ventricle/ventricular   MI = myocardial infarction   PBS = phosphate-buffered saline   RGD = arginine-glycine-aspartate   SPECT = single-photon emission computed tomography   Tc = technetium

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