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
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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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