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Noninvasive Imaging of Angiotensin Receptors After Myocardial Infarction

Johan W.H. Verjans, MD^_*,||, Dagfinn Lovhaug, PhD, Navneet Narula, MD, Artiom D. Petrov, PhD^_*, Bård Indrevoll, MS, Emma Bjurgert, PhD, Tatiana B. Krasieva, PhD, Lizette B. Petersen, MS, Grete M. Kindberg, PhD, Magne Solbakken, PhD, Alan Cuthbertson, PhD, Mani A. Vannan, MD, FACC^_*, Chris P.M. Reutelingsperger, PhD^||, Bruce J. Tromberg, PhD, Leonard Hofstra, MD, PhD^||, Jagat Narula, MD, PhD, FACC^_*,_*

^_* Department of Cardiology, University of California at Irvine, Irvine, California
Department of Pathology, University of California at Irvine, Irvine, California
Beckman Laser Institute, University of California at Irvine, Irvine, California
GE Healthcare, Oslo, Norway
^|| Cardiovascular Research Institute, Maastricht University, Maastricht, the Netherlands.

^_* Reprint requests and correspondence: Dr. Jagat Narula OR Dr. Leo Hofstra, University of California, Irvine, School of Medicine, 101 The City Drive, Bldg. 53, Mail Route 81, Orange, California 92868-4080. (Email: l.hofstra{at}cardio.unimaas.nl; narula{at}uci.edu).

Objectives: The purpose of this study was to evaluate the feasibility of noninvasive imaging of angiotensin II (AT) receptor upregulation in a mouse model of post-myocardial infarction (MI) heart failure (HF).

Background: Circulating AT levels do not reflect the status of upregulation of renin-angiotensin axis in the myocardium, which plays a central role in ventricular remodeling and evolution of HF after MI. Appropriately labeled AT or AT receptor blocking agents should be able to specifically target AT receptors by molecular imaging techniques.

Methods: AT receptor imaging was performed in 29 mice at various time points after permanent coronary artery ligation or in controls using a fluoresceinated angiotensin peptide analog (APA) and radiolabeled losartan. The APA was used in 19 animals for intravital fluorescence microscopy on a beating mouse heart. Tc-99m losartan was used for in vivo radionuclide imaging and quantitative assessment of AT receptor expression in 10 mice. After imaging, hearts were harvested for pathological characterization using confocal and 2-photon microscopy.

Results: No or little APA uptake was observed in control animals or within infarct regions on days 0 and 1. Distinct uptake occurred in the infarct area at 1 to 12 weeks after MI; the uptake was at maximum at 3 weeks and reduced markedly at 12 weeks after MI. Ultrasonographic examination demonstrated left ventricular remodeling, and pathologic characterization revealed localization of the APA tracer with collagen-producing myofibroblasts. Tc-99m losartan uptake in the infarct region (0.524 ± 0.212% injected dose/g) increased 2.4-fold as compared to uptake in the control animals (0.215 ± 0.129%; p < 0.05).

Conclusions: The present study demonstrates the feasibility of in vivo molecular imaging of AT receptors in the remodeling myocardium. Noninvasive imaging studies aimed at AT receptor expression could play a role in identification of subjects likely to develop heart failure. In addition, such a strategy could allow for optimization of anti-angiotensin therapy in patients after MI.

Abbreviations and Acronyms   ACE = angiotensin-converting enzyme   APA = angiotensin peptide analog   AT = angiotensin II   CT = computed tomography   HF = heart failure   LV = left ventricle   MI = myocardial infarction   SMA = smooth muscle actin   SPECT = single-photon emission computed tomography

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