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.
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Figure 2 Optical Imaging of AT Receptors
Intravital microscopy images show a 3-week old MI in the murine heart failure model from baseline (A), and 3 min (B), and at 20 min (C) after administration of green fluorescent angiotensin peptide analog (APA), demonstrating gradual increase of the fluorescent APA in infarcted region. Fluorescent uptake was maximized at 20 min after intravenous APA injection. The ex vivo image (D), demonstrates APA uptake in the border zone, as thinned out infarct zone has collapsed and is therefore not visible. Panel E shows APA uptake in smooth muscle cell layer of a small coronary artery (vertical arrows) as well as minimal uptake in thinner veins (diagonal arrows).
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Figure 3 Evolution of APA Uptake After MI
Intravital microscopy images demonstrating uptake of fluorescent APA from 6 groups: no infarction, and 0 day, 1 day, 1 week, 3 weeks and 12 weeks after MI (A). The uptake increases from 1 to 3 weeks, and decreases thereafter. Panel B shows the respective echocardiograms at 1, 3, and 12 weeks, indicating left ventricular dilation and progressive heart failure in these mice with MI.
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Figure 4 Pathologic Characterization APA Localization
The remote zone (A) demonstrates no APA uptake in interstitium (*) or cardiomyocytes (arrows). The cells of nonmyocytic origin demonstrate fluorescent APA uptake in the infarct zone (B), with an enlarged image of cellular uptake (inset). These cells in the infarct region (D, green) also stained positively for smooth muscle actin (SMA) (E, red), showing colocalization (F, yellow), indicating AT receptors (ATR) on myofibroblasts. (C) Ex vivo 2-photon microscopy demonstrated fluorescent APA intracellularly within the myofibroblast (green), with collagen surrounding the myofibroblast using second harmonic generation imaging (blue). Abbreviations as in Figure 1.
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Figure 5 Noninvasive Imaging of AT Receptors With Radiolabeled Losartan
The micro–SPECT and micro-CT images are shown in a control mouse after technetium Tc-99m losartan administration; no uptake in the heart can be seen (A) in the in vivo and ex vivo images. There is only some liver uptake on the bottom left of the SPECT image. (B) In the 3-week post-MI animal, significant radiolabeled losartan uptake is observed in the anterolateral wall (arrows). The infarct uptake on the in vivo image is confirmed in the ex vivo image. The histogram (C) demonstrates significantly (*) higher uptake in the infarcted region (0.524 ± 0.212% ID/g) as compared to control noninfarcted animals (0.215 ± 0.129% ID/g; p < 0.05). ID = injected dose.
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