99mTc-Annexin A5 for noninvasive characterization of atherosclerotic lesions: imaging and histological studies in myocardial infarction-prone Watanabe heritable hyperlipidemic rabbits | springermedicine.com

Springer Medicine

Top

European Journal of Nuclear Medicine and Molecular Imaging

Published in:

01-06-2007 | Original Article

^99mTc-Annexin A5 for noninvasive characterization of atherosclerotic lesions: imaging and histological studies in myocardial infarction-prone Watanabe heritable hyperlipidemic rabbits

Authors: Seigo Ishino, Yuji Kuge, Nozomi Takai, Nagara Tamaki, H. William Strauss, Francis G. Blankenberg, Masashi Shiomi, Hideo Saji

Published in: European Journal of Nuclear Medicine and Molecular Imaging | Issue 6/2007

Login to get access

Abstract

Purpose

Apoptosis is commonly observed in advanced atherosclerotic lesions. ^99mTc-annexin A5 (^99mTc-annexin V) has been proposed as a potential tracer for imaging apoptosis in atherosclerotic plaques. Accordingly, we determined the usefulness of ^99mTc-annexin A5 as an atherosclerosis imaging tracer in a rabbit model (myocardial infarction-prone Watanabe heritable hyperlipidemic rabbits; WHHLMI rabbits) of spontaneous atherosclerosis.

Methods

The WHHLMI and control rabbits were injected intravenously with ^99mTc-annexin A5. After in vivo planar imaging, the radioactivity in the aorta was measured. Autoradiography, TUNEL staining, Azan-Mallory staining and immunohistological studies were performed serially throughout the aorta.

Results

^99mTc-Annexin A5 accumulation in the aorta of the WHHLMI rabbits was 5.6-fold higher than in that of control rabbits. Autoradiography showed heterogeneous multifocal accumulation of ^99mTc-annexin A5 in WHHLMI rabbits. ^99mTc-Annexin A5 accumulation was highest in the atheromatous lesions (6.2 ± 2.5, %ID × BW/mm² × 10³), followed in decreasing order by neointimal (4.9 ± 1.3), fibroatheromatous (4.5 ± 1.9), and collagen-rich lesions (3.3 ± 1.4). The regional ^99mTc-annexin A5 accumulation was significantly correlated with the TUNEL-positive cell density, macrophage density and “vulnerability index,” an index of the morphological destabilized characteristics. The in vivo imaging clearly visualized the atherosclerotic lesions in WHHLMI rabbits.

Conclusion

The present study in WHHLMI rabbits showed higher ^99mTc-annexin A5 accumulation in grade IV atheroma than in other more stable lesions. ^99mTc-Annexin A5 may be useful in identifying atheroma that is at higher risk for rupture and possibly in assessing the response to anti-atherosclerotic therapy.

1.

Lendon C, Born GV, Davies MJ, Richardson PD. Plaque fissure: the link between atherosclerosis and thrombosis. Nouv Rev Fr Hematol 1992;34:27–9.PubMed

2.

Bjorkerud S, Bjorkerud B. Apoptosis is abundant in human atherosclerotic lesions, especially in inflammatory cells (macrophages and T cells), and may contribute to the accumulation of gruel and plaque instability. Am J Pathol 1996;149:367–80.PubMed

3.

Geng YJ, Henderson LE, Levesque EB, Muszynski M, Libby P. Fas is expressed in human atherosclerotic intima and promotes apoptosis of cytokine-primed human vascular smooth muscle cells. Arterioscler Thromb Vasc Biol 1997;17:2200–8.PubMed

4.

Thiagarajan P, Tait JF. Binding of annexin A5/placental anticoagulant protein I to platelets. Evidence for phosphatidylserine exposure in the procoagulant response of activated platelets. J Biol Chem 1990;265:17420–3.PubMed

5.

Blankenberg FG, Katsikis PD, Tait JF, Davis RE, Naumovski L, Ohtsuki K, et al. In vivo detection and imaging of phosphatidylserine expression during programmed cell death. Proc Natl Acad Sci USA 1998;95:6349–54.PubMedCrossRef

6.

Mochizuki T, Kuge Y, Zhao S, Tsukamoto E, Hosokawa M, Strauss HW, et al. Detection of apoptotic tumor response in vivo after a single dose of chemotherapy with ^99mTc-annexin V. J Nucl Med 2003;44:92–7.PubMed

7.

Blankenberg FG, Strauss HW. Nuclear medicine applications in molecular imaging. J Magn Reson Imaging 2002;16:352–61.PubMedCrossRef

8.

Belhocine T, Steinmetz N, Green A, Rigo P. In vivo imaging of chemotherapy-induced apoptosis in human cancers. Ann N Y Acad Sci 2003;1010:525–9.PubMedCrossRef

9.

Blankenberg FG, Strauss HW. Will imaging of apoptosis play a role in clinical care? A tale of mice and men. Apoptosis 2001;6:117–23.PubMedCrossRef

10.

Narula J, Hofstra L. Imaging myocardial nearosis and apoptosis. In: Dilsizian V, Narula J, editors. Atlas of nuclear cardiology. Philadelphia: Current Medicine; 2003. p. 197–216.

11.

Kolodgie FD, Petrov A, Virmani R, Narula N, Verjans JW, Weber DK, et al. Targeting of apoptotic macrophages and experimental atheroma with radiolabeled annexin A5: a technique with potential for noninvasive imaging of vulnerable plaque. Circulation 2003;108:3134–9.PubMedCrossRef

12.

Watanabe Y. Serial inbreeding of rabbits with hereditary hyperlipidemia (WHHL-rabbit). Atherosclerosis 1980;36:261–8.PubMedCrossRef

13.

Shiomi M, Ito T, Shiraishi M, Watanabe Y. Inheritability of atherosclerosis and the role of lipoproteins as risk factors in the development of atherosclerosis in WHHL rabbits: risk factors related to coronary atherosclerosis are different from those related to aortic atherosclerosis. Atherosclerosis 1992;96:43–52.PubMedCrossRef

14.

Buja LM, Kita T, Goldstein JL, Watanabe Y and Brown MS. Cellular pathology of progressive atherosclerosis in the WHHL rabbit. An animal model of familial hypercholesterolemia. Arteriosclerosis 1983;3:87–101.PubMed

15.

Shiomi M, Ito T, Tsukada T, Yata T, Ueda M. Cell compositions of coronary and aortic atherosclerotic lesions in WHHL rabbits differ. An immunohistochemical study. Arterioscler Thromb 1994;14:931–7.PubMed

16.

Shiomi M, Ito T, Yamada S, Kawashima S, Fan J. Development of an animal model for spontaneous myocardial infarction (WHHLMI rabbit). Arterioscler Thromb Vasc Biol 2003;23:1239–44.PubMedCrossRef

17.

Stary HC, Chandler AB, Glagov S, Guyton JR, Insull W Jr, Rosenfeld ME, et al. A definition of initial, fatty streak, and intermediate lesions of atherosclerosis. A report from the Committee on Vascular Lesions of the Council on Arteriosclerosis, American Heart Association. Circulation 1994;89:2462–78.PubMed

18.

Stary HC, Chandler AB, Dinsmore RE, Fuster V, Glagov S, Insull W Jr, et al. A definition of advanced types of atherosclerotic lesions and a histological classification of atherosclerosis. A report from the Committee on Vascular Lesions of the Council on Arteriosclerosis, American Heart Association. Circulation 1995;92:1355–74.PubMed

19.

Kobayashi S, Inoue N, Ohashi Y, Terashima M, Matsui K, Mori T, et al. Interaction of oxidative stress and inflammatory response in coronary plaque instability: important role of C-reactive protein. Arterioscler Thromb Vasc Biol 2003;23:1398–404.PubMedCrossRef

20.

Shiomi M, Ito T, Hirouchi Y, Enomoto M. Stability of atheromatous plaque affected by lesional composition: study of WHHL rabbits treated with statins. Ann N Y Acad Sci 2001;947:419–23.PubMedCrossRef

21.

Mann JM, Davies MJ. Vulnerable plaque. Relation of characteristics to degree of stenosis in human coronary arteries. Circulation 1996;94:928–31.PubMed

22.

Falk E, Shah PK, Fuster V. Coronary plaque disruption. Circulation 1995;92:657–71.PubMed

23.

Shiomi M, Ito T, Hirouchi Y, Enomoto M. Fibromuscular cap composition is important for the stability of established atherosclerotic plaques in mature WHHL rabbits treated with statins. Atherosclerosis 2001;157:75–84.PubMedCrossRef

24.

Suzuki H, Kobayashi H, Sato F, Yonemitsu Y, Nakashima Y, Sueishi K. Plaque-stabilizing effect of pitavastatin in Watanabe heritable hyperlipidemic (WHHL) rabbits. J Atheroscler Thromb 2003;10:109–16.PubMed

25.

Fayad ZA, Fuster V. Clinical imaging of the high-risk or vulnerable ahteroscelrosis. Circ Res 2001;89:305–16.PubMed

26.

Mollet NR, Cademartiri F, Nieman K, Saia F, Lemos PA, McFadden EP, et al. Multislice spiral computed tomography coronary angiography in patients with stable angina pectoris. J Am Coll Cardiol 2004;43:2265–70.PubMedCrossRef

27.

Jaffer FA, Libby P, Weissleder R. Molecular and cellular imaging of atherosclerosis. J Am Coll Cardiol 2006;47:1328–38.PubMedCrossRef

28.

Rudd JH, Warburton EA, Fryer TD, Jones HA, Clark JC, Antoun N, et al. Imaging atherosclerotic plaque inflammation with [¹⁸F]-fluorodeoxyglucose positron emission tomography. Circulation 2002;105:2708–11.PubMedCrossRef

29.

Kietselaer BL, Reutelingsperger CP, Heidendal GA, Daemen MJ, Mess WH, Hofstra L, et al. Noninvasive detection of plaque instability with use of radiolabeled annexin A5 in patients with carotid-artery atherosclerosis. N Engl J Med 2004;350:1472–3.PubMedCrossRef

30.

Dimmeler S, Haendeler J, Zeiher AM. Regulation of endothelial cell apoptosis in atherothrombosis. Curr Opin Lipidol 2002;13:531–6.PubMedCrossRef

31.

Littlewood TD, Bennett MR. Apoptotic cell death in atherosclerosis. Curr Opin Lipidol 2003;14:469–75.PubMedCrossRef

32.

Libby P, Geng YJ, Aikawa M, Schoenbeck U, Mach F, Clinton SK, et al. Macrophages and atherosclerotic plaque stability. Curr Opin Lipidol 1996;7:330–5.PubMedCrossRef

33.

Virmani R, Burke AP, Kolodgie FD, Farb A. Vulnerable plaque: the pathology of unstable coronary lesions. J Interv Cardiol 2002;15:439–46.PubMed

34.

Santoliquido A, Di Campli C, Miele L, Gabrieli ML, Forgione A, Zocco MA, et al. Hepatic steatosis and vascular disease. Eur Rev Med Pharmacol Sci 2005;9:269–71.PubMed

35.

Campean V, Neureiter D, Varga I, Runk F, Reiman A, Garlichs C, et al. Atherosclerosis and vascular calcification in chronic renal failure. Kidney Blood Press Res 2005;28:280–9.PubMedCrossRef

36.

Hartung D, Sarai M, Petrov A, Kolodgie F, Narula N, Verjans J, et al. Resolution of apoptosis in atherosclerotic plaque by dietary modification and statin therapy. J Nucl Med 2005;46:2051–6.PubMed

37.

Wilensky RL, Song HK, Ferrari VA. Role of magnetic resonance and intravascular magnetic resonance in the detection of vulnerable plaques. J Am Coll Cardiol 2006;47 Suppl 8:C48–56.PubMedCrossRef

38.

Kooi ME, Cappendijk VC, Cleutjens KB, Kessels AG, Kitslaar PJ, Borgers M, et al. Accumulation of ultrasmall superparamagnetic particles of iron oxide in human atherosclerotic plaques can be detected by in vivo magnetic resonance imaging. Circulation 2003;107:2453–8.PubMedCrossRef

39.

Nissen SE, Yock P. Intravascular ultrasound: novel pathophysiological insights and current clinical applications. Circulation 2001;103:604–16.PubMed

40.

Ogawa M, Ishino S, Mukai T, Asano D, Teramoto N, Watabe H, et al. ¹⁸F-FDG accumulation in atherosclerotic plaques: immunohistochemical and PET imaging study. J Nucl Med 2004;45:1245–50.PubMed

41.

Mari C, Blankenberg FG, Narula Z, Narula J, Ghazarossian V, Tait J, et al. ^99mTc-annexin V versus ¹⁸F-FDG in the identification of atherosclerotic plaques in ApoE−/− mice. J Nucl Med 2002;43 Suppl:1–2P.

42.

Zhao Y, Kuge Y, Zhao S, Inubushi M, Morita K, Strauss HW, et al. Comparison of ^99mTc-annexin A5 with ¹⁸F-FDG for detection of atherosclerosis in ApoE−/− mice. J Nucl Med 2006;47 Suppl:1 30–1P.

43.

Johnson LL, Schofield L, Donahay T, Narula N, Narula J. ^99mTc-annexin V imaging for in vivo detection of atherosclerotic lesions in porcine coronary arteries. J Nucl Med 2005;46:1186–93.PubMed

44.

Okane K, Ibaraki M, Toyoshima H, Sugawara S, Takahashi K, Miura S, et al. ¹⁸F-FDG accumulation in atherosclerosis: use of CT and MR co-registration of thoracic and carotid arteries. Eur J Nucl Med Mol Imaging 2006;33:589–94.PubMedCrossRef

45.

Ben-Haim S, Israel O. PET/CT for atherosclerotic plaque imaging. Q J Nucl Med Mol Imaging 2006;50:53–60.PubMed

46.

Shiomi M, Ito T, Yamada S, Kawashima S, Fan J. Correlation of vulnerable coronary plaques to sudden cardiac events. Lessons from a myocardial infarction-prone animal model (the WHHLMI rabbit). J Atheroscler Thromb 2004;11:184–9.PubMed

Title: 99mTc-Annexin A5 for noninvasive characterization of atherosclerotic lesions: imaging and histological studies in myocardial infarction-prone Watanabe heritable hyperlipidemic rabbits
Authors: Seigo Ishino
Yuji Kuge
Nozomi Takai
Nagara Tamaki
H. William Strauss
Francis G. Blankenberg
Masashi Shiomi
Hideo Saji
Publication date: 01-06-2007
Publisher: Springer-Verlag
Published in: European Journal of Nuclear Medicine and Molecular Imaging / Issue 6/2007
Print ISSN: 1619-7070
Electronic ISSN: 1619-7089
DOI: https://doi.org/10.1007/s00259-006-0289-x

Home
Congress Coverage
Clinical Collections
- Advances in Alzheimer’s
About Springer Medicine
Key Specialties