Live Observation of Atherosclerotic Plaque Disruption in Apolipoprotein E-Deficient Mouse

Abstract

Aim:

The actual occurrence of spontaneous plaque rupture in mice has been a matter of debate. We report on an in vivo observation of the actual event of possible plaque disruption in a living ApoE^-/- mouse.

Methods and Results:

During live contrast-enhanced ultrasonography of a 50-week-old ApoE^-/- male mouse, symptoms suggesting plaque disruption in the brachiocephalic artery were observed. Histological analysis confirmed the presence of advanced atherosclerotic lesions with dissections and intraplaque hemorrhage in the affected brachiocephalic trunk, pointing towards plaque rupture as the cause of the observed event. However, we did not detect a luminal thrombus or cap rupture, which is a key criterion for plaque rupture in human atherosclerosis.

Conclusion:

This study reports the real-time occurrence of a possible plaque rupture in a living ApoE^-/- mouse.

Key words

ultrasound - microbubbles - plaque rupture - ApoE - atherosclerosis

• References

• 1 Fitzgerald PJ, Ports TA, Yock PG. Contribution of localized calcium deposits dissection after angioplasty an observational study using intravascular ultrasound. Circulation 1992; 86: 64-70
• 2 Falk E, Nakano M, Bentzon JF et al. Update on acute coronary syndromes: the pathologists’ view. European heart journal 2013; 3410: 719-728
• 3 Virmani R, Kolodgie FD, Burke AP et al. Lessons from sudden coronary death: a comprehensive morphological classification scheme for atherosclerotic lesions. Arterioscler Thromb Vasc Biol 2000; 20: 1262-1275
• 4 Stary HC, Chandler AB, Dinsmore RE. 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. Arterioscler Thromb Vasc Biol 1995; 15: 1512-1531
• 5 Glass CK, Witztum JL. Atherosclerosis. The road ahead Cell 2001; 104: 503-516
• 6 Mahoney WM, Schwartz SM. Defining smooth muscle cells and smooth muscle injury. J Clin Invest 2005; 115: 221-224
• 7 Schwartz SM, Galis ZS, Rosenfeld ME et al. Plaque rupture in humans and mice. Arterioscler Thromb Vasc Biol 2007; 27: 705-713
• 8 Jackson CL. Defining and defending murine models of plaque rupture. Arterioscler Thromb Vasc Biol 2007; 27: 973-977
• 9 Hansson GK, Heistad DD. Two views on plaque rupture. Arterioscler Thromb Vasc Biol 2007; 27: 697
• 10 Bentzon JF, Falk E. Atherosclerotic lesions in mouse and man: is it the same disease?. Curr Opin Lipidol 2010; 21: 434-440
• 11 Jawien J. The role of an experimental model of atherosclerosis: apoE-knockout mice in developing new drugs against atherogenesis. Curr Pharm Biotechnol 2012; 13: 2435-2439
• 12 Jin SX, Shen LH, Nie P et al. Endogenous renovascular hypertension combined with low shear stress induces plaque rupture in apolipoprotein E-deficient mice. Arterioscler Thromb Vasc Biol 2012; 32: 2372-2379
• 13 Falk E, Schwartz SM, Galis ZS et al. Putative murine models of plaque rupture. Arterioscler Thromb Vasc Biol 2007; 27: 969-972
• 14 Rosenfeld ME, Polinsky P, Virmani R et al. Advanced atherosclerotic lesions in the innominate artery of the apoE knockout mouse. Arterioscler Thromb Vasc Biol 2000; 20: 2587-2592
• 15 Johnson JL, Jackson CL. The apolipoprotein E knockout mouse: an animal model of atherosclerotic plaque rupture. Atherosclerosis 2001; 154: 399-406
• 16 Calara F, Silvestre M, Casanada F et al. Spontaneous plaque rupture and secondary thrombosis in apolipoprotein E-deficient and LDL receptor-deficient mice. J Pathol 2001; 195: 257-263
• 17 Zhou J, Moller J, Danielsen CC et al. Dietary supplementation with methionine and homocysteine promotes early atherosclerosis but not plaque rupture in ApoE-deficient mice. Arterioscler Thromb Vasc Biol 2001; 21: 1470-1476
• 18 Jackson CL, Bennett MR, Biessen EAB et al. Assessment of unstable therosclerosis in mice. Arterioscler Thromb Vasc Biol 2007; 27: 714-720
• 19 Sasaki T, Kuzuya M, Nakamura K et al. A simple method of plaque rupture induction in apolipoprotein E-deficient mice. Arterioscler Thromb Vasc Biol 2006; 26: 1304-1309
• 20 Bond AR, Jackson CL. The fat-fed apolipoprotein E knockout mouse brachiocephalic artery in the study of atherosclerotic plaque rupture. J Biomed Biotechnol 2011; 379069
• 21 Needles A, Arditi M, Rognin NG et al. Nonlinear contrast imaging with an array based micro-ultrasound system. Ultrasound Med Biol 2010; 36: 2097-2106
• 22 Livingston C. Bancroft’s theory and practice of histological techniques. 2008
• 23 Von der Thusen JH, van Vlijmen BJ, Hoeben RC et al. Induction of atherosclerotic plaque rupture in apolipoprotein E2/2 mice after adenovirus-mediated transfer of p53. Circulation 2002; 105: 2064-2070
• 24 Hansson GK. Inflammation, atherosclerosis, and coronary artery disease. N Engl J Med 2005; 352: 1685-1695
• 25 Ni M, Chen WQ, Zhang Y. Animal models and potential mechanisms of plaque destabilisation and disruption. Heart 2009; 95: 1393-1398
• 26 Skyba DM, Price RJ, Linka AZ et al. Direct in vivo visualization of intravascular destruction of microbubbles by ultrasound and its local effects on tissue. Circulation 1998; 98: 290-293
• 27 Hu X, Kheirolomoom A, Mahakian LM et al. Insonation of targeted microbubbles produces regions of reduced blood flow within tumor vasculature. Invest Radiol 2012; 47: 398-405