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In Vivo Serial Assessment of Aortic Aneurysm Formation in Apolipoprotein E–Deficient Mice via MRI

From the Cardiovascular and Urogenital Center of Excellence for Drug Discovery (G.H.T., A.R.O., R.E.B., K.A., H.W.K., R.N.W., P.J.G., B.M.J.), and Safety Assessment (R.C.M.), GlaxoSmithKline, King of Prussia, Pa.

Correspondence to Beat M. Jucker, PhD, GlaxoSmithKline, 709 Swedeland Rd, King of Prussia, PA 19406. E-mail beat.m.jucker{at}gsk.com

Received April 22, 2008; accepted September 5, 2008.

Background— Hyperlipidimic mice administered angiotensin II have been used for the study of abdominal aortic aneurysms (AAAs). The purpose of this study was to examine the use of MRI for studying AAA development and for examining the effects of pharmacological intervention on AAA development in the apolipoprotein E–deficient mouse.

Methods and Results— Suprarenal aortic aneurysms were generated in apolipoprotein E–deficient mice administered angiotensin II (1000 ng/kg per min) for up to 28 days. In vivo MRI was performed serially (once weekly) to assess AAA development and rupture. Comparison of AAA size as measured by in vivo and ex vivo MRI resulted in excellent agreement (r=0.96, P<0.0001). In addition, MRI correlated with histology-derived AAA area assessment (in vivo versus histology: r=0.84, P<0.0001; ex vivo versus histology: r=0.89, P<0.0001). In a separate study, angiotensin II–administered apolipoprotein E–deficient mice were treated with doxycycline (broad-based matrix metalloproteinase inhibitor; 30 mg/kg per day for 28 days). MRI was able to noninvasively assess a reduced rate of AAA development (46% versus 71%, P<0.05), a decreased AAA area (2.56 versus 4.02 mm², P<0.01), and decreased incidence of rupture (43% versus 100%) in treated versus control animals. Inhibition of aorta matrix metalloproteinase 2/9 activity was observed in the treated animals.

Conclusions— These results demonstrate the use of MRI to noninvasively and temporally assess AAA development on pharmacological intervention in this preclinical cardiovascular disease model.

Key Words: abdominal aortic aneurysms • imaging • MRI • doxycycline • MMP