Noninvasive imaging of angiotensin receptors after myocardial infarction.
OBJECTIVE
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.
Verjans
Johan W H
JW
Department of Cardiology, University of California at Irvine, School of Medicine, 101 The City Drive, Orange, CA 92868-4080, USA.
Lovhaug
Dagfinn
D
Narula
Navneet
N
Petrov
Artiom D
AD
Indrevoll
Bård
B
Bjurgert
Emma
E
Krasieva
Tatiana B
TB
Petersen
Lizette B
LB
Kindberg
Grete M
GM
Solbakken
Magne
M
Cuthbertson
Alan
A
Vannan
Mani A
MA
Reutelingsperger
Chris P M
CP
Tromberg
Bruce J
BJ
Hofstra
Leonard
L
Narula
Jagat
J
D000804:Angiotensin II / Q000031:analogs & derivatives / Q000378:metabolism; D047228:Angiotensin II Type 1 Receptor Blockers / Q000378:metabolism; D000818:Animals; D001665:Binding Sites; D015415:Biomarkers / Q000378:metabolism; D004195:Disease Models, Animal; D005240:Feasibility Studies; D005456:Fluorescent Dyes / Q000378:metabolism; D006333:Heart Failure / Q000000981:diagnostic imaging / Q000209:etiology / Q000378:metabolism* / Q000503:physiopathology; D019808:Losartan / Q000378:metabolism; D008297:Male; D051379:Mice; D018613:Microscopy, Confocal; D008856:Microscopy, Fluorescence / Q000379:methods; D036641:Microscopy, Fluorescence, Multiphoton; D018715:Microscopy, Video; D009203:Myocardial Infarction / Q000150:complications* / Q000000981:diagnostic imaging / Q000378:metabolism / Q000503:physiopathology; D009206:Myocardium / Q000378:metabolism* / Q000473:pathology; D019275:Radiopharmaceuticals / Q000378:metabolism; D011945:Receptors, Angiotensin / Q000378:metabolism*; D013667:Technetium; D013997:Time Factors; D015899:Tomography, Emission-Computed, Single-Photon / Q000379:methods; D020257:Ventricular Remodeling; D055114:X-Ray Microtomography
D047228:Angiotensin II Type 1 Receptor Blockers; D015415:Biomarkers; D005456:Fluorescent Dyes; D019275:Radiopharmaceuticals; D011945:Receptors, Angiotensin; D000804:Angiotensin II; D013667:Technetium; D019808:Losartan