Imaging Vessel Wall Biology to Predict Outcome in Abdominal Aortic Aneurysm

Abstract

Background Abdominal aortic aneurysm (AAA) rupture risk is currently determined based on size and symptoms. This approach does not address the rupture risk associated with small aneurysms. Given the role of matrix metalloproteinases (MMPs) in AAA weakening and rupture, we investigated the potential of MMP-targeted imaging for detection of aneurysm biology and prediction of outcome in a mouse model of AAA with spontaneous rupture. Methods and Results Fifteen week-old mice (n=66) were infused with angiotensin II for four weeks to induce AAA. Saline-infused mice (n=16) served as control. The surviving animals underwent in vivo MMP-targeted microSPECT/CT imaging, using RP805, a 99mTc-labeled MMP-specific tracer, followed by ex vivo planar imaging, morphometry and gene expression analysis. RP805 uptake in suprarenal aorta on microSPECT images was significantly higher in animals with AAA, as compared with angiotensin II-infused animals without AAA or control animals. CD68 expression and MMP activity were increased in AAA and significant correlations were noted between RP805 uptake and CD68 expression or MMP activity, but not aortic diameter. A group of angiotensin II-infused animals (n=24) were imaged at 1 week and were followed for an additional three weeks. RP805 uptake in suprarenal aorta at 1 week was significantly higher in mice that later developed rupture/AAA. Furthermore, tracer uptake at 1 week correlated with aortic diameter at 4 weeks. Conclusions MMP-targeted imaging reflects vessel wall inflammation and can predict future aortic expansion or rupture in murine AAA. If confirmed in humans, this may provide a new paradigm for AAA risk stratification.

Preclinical Evaluation of RYM1, a Matrix Metalloproteinase–Targeted Tracer for Imaging Aneurysm

“…In Vivo Small-Animal SPECT/CT Imaging After 4 wk of Ang II infusion, the surviving apoE 2/2 mice received an intravenous injection of 40 6 7 MBq of 99m Tc-RYM1 and at 1 h after injection underwent small-animal SPECT/CT imaging, as previously described with minor modifications (5). Briefly, the imaging protocol involved 64 circular 30-s projections using a dual-head smallanimal SPECT/CT system with 1-mm pinhole collimators (X-SPECT; g-Medica).…”

“…We have demonstrated the feasibility of MMP-targeted imaging and its predictive value for AAA expansion and rupture in a mouse model of AAA (5). However, the relatively slow blood clearance of 99m Tc-RP805, the tracer used in these studies, which mandates delaying imaging to at least 2 h after injection, is a relative barrier to further development of this agent for clinical applications.…”

Playing slot to hitting the jackpot in molecular imaging: On probability of uncovering subcellular pathogenesis vs achieving clinical applicability

“…In the current study, an MMP targeting probe was evaluated. Besides a role in remodeling, MMP play an important role in various other cardiovascular diseases, including atherosclerosis, [23][24][25][26][27][28][29] calcific aortic valve disease, 30 aortic aneurysm formation, 31 and pulmonary inflammation. 32 Moreover, MMP also play a role in non-cardiac diseases, notably malignancy.…”

Specificity vs versatility: A fine balance for novel targeted molecular imaging radiotracers

“…7 Another emerging biomarker is sphingosine-1 phosphate (S1P), a soluble chemoattractant cytokine involved in postnatal vascular development, immune cell homing, endothelial cell permeability, and vascular smooth muscle migration. In the current issue of the Journal, Jin and colleagues present a preliminary evaluation of the novel sphingosine-1-phosphate receptor 1 (S1P 1 ) ligand 11 C-TZ3321 for molecular PET imaging of vascular injury, specifically targeting neointimal hyperplasia.…”

“…Outcome-based strategies are paramount-the ability to detect a difference in tracer binding between health and disease states is only the first step; rather, it is essential that a candidate tracer determines not only the presence of abnormalities, but also defines the prognostic value or evaluate the resolution of these abnormalities by therapeutic intervention. 2,7,15 It appears that 11 C-TZ3321 can distinguish between mild (wild-type) and more severe (ApoE -/-) neointimal hyperplasia (albeit with limited binding in the mild phenotype), but it will be important to determine whether the tracer has sufficient sensitivity to identify mild vascular smooth muscle proliferation before overt disease. The molecular targeting of the tracer underlies the potential to exceed identification of restenosis by anatomical imaging alone.…”