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. Author manuscript; available in PMC: 2014 Nov 1.
Published in final edited form as: Circ Cardiovasc Imaging. 2013 Aug 30;6(6):950–956. doi: 10.1161/CIRCIMAGING.113.000234

Integrin-Targeted Molecular Imaging of Experimental Abdominal Aortic Aneurysms by 18F-FPPRGD2 Positron Emission Tomography

Toshiro Kitagawa 1,4,5, Hisanori Kosuge 1,4, Edwin Chang 2, Michelle L James 2, Tomoaki Yamamoto 1,4, Bin Shen 2, Frederick T Chin 2, Sanjiv S Gambhir 2,4, Ronald L Dalman 3,4, Michael V McConnell 1,4
PMCID: PMC3909706  NIHMSID: NIHMS542958  PMID: 23995363

Abstract

Background

Both inflammation and neoangiogenesis contribute to abdominal aortic aneurysm (AAA) disease. Arg-Gly-Asp (RGD)-based molecular imaging has been shown to detect the integrin αvβ3. We studied a clinical dimeric18F-labeled RGD positron emission tomography (PET) agent (18F-FPPRGD2) for molecular imaging of experimental AAAs.

Methods and Results

Murine AAAs were induced in Apo-E deficient mice by angiotensin II infusion, with monitoring of aortic diameter on ultrasound. AAA (n=10) and saline-infused control mice (n=7) were injected intravenously with 18F-FPPRGD2, as well as an intravascular computed tomography (CT) contrast agent, then scanned using a small-animal PET/CT scanner. Aortic uptake of 18F-FPPRGD2 was quantified by percent-injected dose per gram (%ID/g) and target-to-background ratio (TBR). Focal increased PET signal was found in AAA lesions, but not in normal control aortae, confirmed by quantitative analysis (median %ID/g [interquartile range]: 2.05 [1.05–2.85] vs. 0.63 [0.43–0.83], p=0.003; median TBR [interquartile range]: 2.72 [2.31–3.49] vs. 1.44 [1.10–1.52], p=0.0008). Ex vivo autoradiography demonstrated high uptake of 18F-FPPRGD2 into the AAA wall, with immunohistochemistry showing substantial CD-11b+ macrophages and CD-31+ neovessels. TBR of AAAs on PET did not correlate with AAA diameter (r=−0.29, p=0.41), but did strongly correlate with both mural macrophage density (r=0.79, p=0.007) and neovessel counts (r=0.87, p=0.001) on immunohistochemistry.

Conclusions

PET imaging of experimental AAAs using 18F-FPPRGD2 detects biologically active disease, correlating to the degree of vascular inflammation and neoangiogenesis. This may provide a clinically translatable molecular imaging approach to characterize AAA biology in order to predict risk beyond size alone.

Keywords: aneurysm, RGD, positron emission tomography, macrophage, angiogenesis

Abdominal aortic aneurysm (AAA) disease is a common and highly lethal age-associated vascular degenerative disease, which affects 6% of men and 1% of women over the age of 60.1 Characteristic pathological features present in both clinical and experimental aneurysms include marked elastin degradation and reduced medial vascular smooth muscle cells. While much emphasis has been placed on medial smooth muscle cell loss and matrix degeneration during aneurysm pathogenesis, the contribution of vascular inflammation and angiogenesis to AAA progression increasingly appears significant. Macrophages play a key role in vascular inflammation, producing proteases such as matrix metalloproteinases that can degrade the extracellular matrix of the vessel wall, contributing to the development and rupture of AAAs.2, 3 We and others have shown that vascular angiogenesis is present in animal models of AAA and is associated with AAA progression.4–6 Clinical studies also demonstrate that AAA tissue has increased mural neovascularization compared to non-aneurysmal aorta,7 and that rupture foci show increased neovascularity compared to intact aneurysm segments.8 Therefore, both vascular inflammation and angiogenesis have the potential to be major biological markers for targeted imaging and therapy of AAA disease.

The integrin αvβ3, a cell surface glycoprotein receptor, has been well validated as an indicator of angiogenesis because of its upregulation on vascular endothelial cells in angiogenesis.8, 9 It has also been shown that vascular macrophages express high levels of αvβ3.10 Arg-Gly-Asp (RGD) is an extensively studied short amino acid sequence binder to αvβ3. Radiolabeled RGD peptides have been developed for clinical αvβ3-targeted tumor imaging using single photon emission computed tomography (SPECT) and positron emission tomography (PET).11, 12

We have previously developed the dimeric RGD PET tracer 18F-FPPRGD2,13, 14 which has enhanced target-tissue binding and reduced background signal for tumor imaging15 and is undergoing initial human testing.16, 17 In the current study, we evaluated 18F-FPPRGD2 for αvβ3-targeted PET imaging of experimental AAA disease.

Methods

Radiotracer preparation

Clinical-grade 18F-FPPRGD2 was synthesized as previously described.15, 17, 18 In brief, the dimeric RGD peptide precursor PEG3-c(RGDyK)2 was purchased from Peptides International (Louisville, KY) and coupled to 4-nitrophenyl-2-18F-fluoropropionate (18F-NPE). No-carrier-added 18F-fluoride ion was prepared on a PETtrace cyclotron (GE Medical Systems, Waukesha, WI, USA) via the 18O(p,n)18F nuclear reaction by irradiating 18O-enriched water (1.6 ml, >95% isotopic enrichment, Rotem Industries Ltd, Beer Sheva, Israel) with 16 MeV protons. Crude radiolabeled products were purified and analyzed via reversed phase high-performance liquid chromatography.15, 17, 18 Quality control was performed based on the criteria set for human clinical use.

Experimental AAAs

Murine AAAs were induced in apolipoprotein E-deficient (apo-E−/−) mice, as described previously.4–6, 19 A total of 17 male mice, 17–20 weeks of age, 31±1g, were studied after continuous angiotensin II infusion via subcutaneous implanted osmotic mini-pumps (n=10) or after receiving mini-pumps loaded with saline (n=7). Transabdominal 40 MHz B-mode ultrasound (US) imaging (Vevo 770 Imaging System and RMV 704 microvisualization scan head, Visualsonics Inc, Toronto, Canada) was performed to monitor aortic diameter in vivo (in the longitudinal and transverse scan plane) for up to 28 days, as previously described, 5 with >25% diameter increase from baseline (1.0–1.2 mm) defined as AAA.

The Administrative Panel on Laboratory Animal Care (APLAC) at Stanford University approved all animal procedures. All animals were anesthetized with inhaled 2% isoflurane for surgical and imaging procedures and recovered with free access to food and water.

Small animal PET/CT

At 21–28 days after mini-pump implantation, 10 AAA and 7 control mice were imaged with an Inveon small animal PET/computed tomography (CT) scanner (Siemens, Knoxville, TN) Approximately 60 min after a tail vein injection of 18F-FPPRGD2 (174±3 µCi [6.4±0.1 MBq], range 155–205 µCi [5.7–7.6 MBq]) in 120 µL of phosphate buffered saline (PBS), a 5-min prone PET acquisition scan followed by a 10-min CT scan was performed without moving the animal. To obtain vascular CT contrast, 0.3–0.4ml of the iodine-based intravascular contrast agent Fenestra (ART, Advanced Research Technologies, Montreal, Canada) was injected. CT acquisition consisted of 120 projections acquired with exposure time of 240 ms, x-ray voltage of 80 keV and anode current of 500 µA.

PET images were reconstructed with the ordered-subsets expectation-maximization (OSEM) algorithm using 16 subsets and 4 iterations. No corrections were made for attenuation, as an attenuation-corrected cylinder phantom study and an attenuation-correction scan performed with the body outline of a mouse using uniform attenuation both showed very little change in the activity profile across the mouse.20 The resulting near-isotropic voxel size was 861x861x796 µm with a total of 128x128x159 voxels. CT images were reconstructed using a filtered back-projection algorithm, with an isotropic resolution of 200x200x200 µm.

The PET and CT images were fused and analyzed using the Inveon Research Workplace software (Siemens). Image registration was performed using automatic-weighted, mutual-information algorithm and confirmed visually on the basis of anatomic landmarks showing physiological accumulation of the tracer, such as kidneys and bladder. The angiotensin II-induced murine AAA lesions are typically suprarenal. Therefore, for measurement of tracer uptake, three-dimensional volumes of interest were drawn in the most aneurysmal segment of the suprarenal aorta as well as the non-aneurysmal remote aortic segment and blood pool (left ventricle), as seen on the CT images, avoiding adjacent organs. The mean activities were corrected for injected dose to calculate the percentage of injected dose per gram (%ID/g) and the target-to-background ratio (TBR) of aorta activity to blood pool. Analysis was also performed by a second observer to provide interobserver variability data.

Ex vivo autoradiography

The uptake of 18F-FPPRGD2 in the aortic wall was also studied by digital autoradiography of tissue sections in a subset of 10 mice (AAA, n=6; control, n=4). The aortae were removed approximately 120 min after the tracer injection, frozen in optimum cutting temperature (OCT) compound (Sakura Finetek USA, Inc., Torrance, CA), cut in sequential and transverse 20-µm sections at −20°C, and thaw-mounted onto microscope slides. For measurement of the accumulated 18F activity, the sections were exposed to 18F-sensitive storage phosphor screens (Perkin Elmer, Waltham, MA). After overnight exposure, the imaging plates were scanned with a Typhoon 9410 Variable Mode Imager (GE Healthcare Bio-Sciences, Piscataway, NJ).

The autoradiography images were analyzed with Image J 1.43 software (NIH Image). To quantify the accumulated 18F activity, mean signal intensity per pixel was measured in each section. Regions of interest were traced around the tissue sections of the most aneurysmal segment of suprarenal aorta as well as an unaffected normal infrarenal segment, which allowed normalizing the AAA value to the value of normal aorta.

Histology

The aortae were embedded and frozen in OCT compound, then cut in sequential and transverse 5-µm sections. Aortic tissue sections were stained with hematoxylin & eosin to study histological features corresponding to the autoradiographic images. For immunohistochemistry, the section of the most aneurysmal segment of suprarenal aorta in each mouse was fixed in acetone for 10 minutes, washed in PBS, and then incubated overnight at 4°C with anti-mouse CD-11b antibody to stain for macrophages (BD Biosciences, San Jose, CA) or anti-mouse CD-31 antibody to stain for endothelial cells (BD Biosciences). Sections were then incubated for 30 minutes at room temperature with biotinylated secondary antibodies. Antigen-antibody conjugates were detected with avidin-biotin horseradish peroxidase complex (Vector Laboratories, Burlingame, CA) according to the manufacturer’s instructions. 3-amino-9-ethylcarbazole was used as chromogen. Sections were counterstained with hematoxylin.

Image J 1.43 software was used to quantify the total macrophage-rich (CD-11b+) area per AAA section as a proportion of the medial and adventitial area (mural macrophage density). For mural neovascularization, transverse sections were divided into four quadrants, CD-31+-stained neovessels in each quadrant were counted, and mean numbers of neovessels per section were reported. All sections were analyzed with original magnification 200x.

Statistical analysis

Measured activities of PET and autoradiography were expressed as median value and interquartile range, and other results were expressed as mean±SEM (standard error of the mean). The Mann-Whitney test was used to compare continuous variables between AAA and control mice. The Wilcoxon signed-rank test was used to compare AAA vs. non-aneurysmal remote segments. The Pearson correlation coefficient was used to calculate the correlation among 18F activity on PET (%ID/g, TBR), US-determined aortic diameter, and immunohistochemical measurements (macrophage density, neovessel count). Interobserver variability of measured PET activities was determined by calculating a 95% confidence interval (CI) for mean differences. All analyses were performed using JMP 7.0.1 statistical software (SAS Institute Inc, Cary, NC). A p value of < 0.05 was considered statistically significant.

Results

Radiochemistry

Clinical-grade 18F-FPPRGD2 was achieved within 3.5 h with radiochemical yield of 16.9±2.7% (decay-corrected to end of bombardment EOB) and specific radioactivity of 114±72 GBq/μmol (EOB). Radiochemical purity was >99% and chemical purity was >95%. All the other quality control results met the criteria for human clinical use.

In vivo US and PET/CT with 18F-FPPRGD2

On the US before administration of 18F-FPPRGD2, AAA diameter was 1.52 to 2.66 mm, with a mean of 2.09 mm. The suprarenal aortic diameter of control mice was 1.14±0.02 mm. There was no overlap in aortic diameter between AAA and control mice.

The PET images post administration of 18F-FPPRGD2 showed focal increased signal in the AAA, but not in normal control aorta (Figure 1A). Note also the uptake in the kidneys, consistent with the predominant renal clearance of 18F-FPPRGD2 (Figure 1A).15 Quantitative analysis confirmed significantly higher PET activities in AAAs than in control aortae (%ID/g: 2.05 [1.05–2.85] vs. 0.63 [0.43–0.83], p=0.003; TBR: 2.72 [2.31–3.49] vs. 1.44 [1.10–1.52], p=0.0008; Figure 1B). The non-aneurysmal remote aortic segments in AAA mice showed minimal PET activity (%ID/g: 0.004 [0.002–0.04], p=0.008 vs. AAAs; TBR: 0.008 [0.004–0.07], p=0.008 vs. AAAs). There was excellent interobserver agreement for both %ID/g (mean difference −0.03, 95% CI −0.24–0.17) and TBR (mean difference −0.07, 95% CI −0.54–0.39).

Figure 1. In vivo 18F-FPPRGD2 PET imaging of abdominal aortic aneurysm (AAA) and normal control aorta.

Figure 1

Figure 1

Figure 1

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(A) AAA mouse with aortic diameter of 1.89 mm on ultrasound (US) showed focal increase in 18F-FPPRGD2 signal of the AAA lesion (yellow arrows), while control mouse with aortic diameter 1.09 mm on US showed no significant aortic signal. Both mice showed high signal from the kidneys (K), but very little from liver (L), spleen (S), and remote aortic segments (A). Scale bars, 0.5 cm. (B) By quantitative analysis, both the percent injected dose per gram (%ID/g) and target-to-background ratio (TBR) were significantly higher in AAAs than in normal control aortae.

* p=0.003 vs. Control, † p=0.0008 vs. Control

Additionally, we examined whether PET activity simply corresponded to aortic diameter. When combining AAA and control mice, 18F-FPPRGD2 activity showed a positive moderate correlation with aortic diameter (%ID/g: r=0.52, p=0.03; TBR: r=0.56, p=0.02; Figure 2). However, within the AAA mice only, there was no significant correlation between PET activity and AAA diameter (%ID/g: r=−0.18, p=0.62; TBR: r=−0.29, p=0.41; Figure 2). Note that between AAA and control mice there was some overlap in %ID/g, but no overlap in TBR (Figure 2).

Figure 2. Correlation between aortic diameter on ultrasound (US) and 18F-FPPRGD2 PET activity.

Figure 2

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Combining data from abdominal aortic aneurysm (AAA) mice (n = 10, filled circles) and control mice (n=7, open circles), both the %ID/g (r=0.52, p=0.03) and TBR (r=0.56, p=0.02) were positively and moderately correlated with US-determined aortic diameter. In just the AAA mice, there was no significant correlation between PET activity and AAA diameter (%ID/g: r=−0.18, p=0.62, TBR: r=−0.29, p=0.41). Note that there is no overlap in aortic diameter and TBR between AAA and control mice, with some overlap in %ID/g.

Validation with ex vivo autoradiography and histology

The ex vivo autoradiography showed high uptake of 18F-FPPRGD2 into the AAA wall, compared with minimal uptake into normal control aortae (Figure 3A). Quantitative analysis confirmed significantly higher signal in AAA sections than in control aorta sections (normalized mean signal intensity per pixel 2.32 [2.01–3.92] vs. 1.14 [0.85–1.35], p=0.01; Figure 3B). Histological correlates of 18F-FPPRGD2 uptake were studied in serial tissue sections stained with hematoxylin & eosin and immunohistochemistry, as shown in Figure 3. Immunohistochemical staining with CD-11b and CD-31 demonstrated substantial macrophage infiltration and neovascularization colocalizing with high 18F-FPPRGD2 signal intensity area of the AAA wall (Figure 3C).

Figure 3. Ex vivo autoradiography and histology of abdominal aortic aneurysm (AAA) and normal control aorta.

Figure 3

Figure 3

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(A) Autoradiography demonstrated high uptake of 18F-FPPRGD2 corresponding to the AAA wall of tissue sections stained with hematoxylin and eosin. Normal control aorta showed minimal uptake of 18F-FPPRGD2. Dotted lines in autoradiography images indicate the contour of the aortic tissue section. Scale bars in autoradiography images, 500 µm. (B) By quantitative analysis of autoradiography images, normalized mean signal intensity per pixel was significantly higher in AAAs than in normal control aortae. (C) Immunohistochemical staining of the region with highest 18F-FPPRGD2 signal intensity (outlined in the AAA hematoxylin and eosin staining) showed substantial macrophages stained with CD-11b and neovessels stained with CD-31.

* p=0.01 vs. Control

Immunohistological findings and correlation to aortic diameter and PET data

CD-11b immunohistochemistry showed macrophage infiltration in the media and adventitia of the AAA lesion; CD-31 immunohistochemistry showed neovessel expression within the AAA wall (Figure 4). In contrast, there was minimal CD-11b or CD-31 positivity within the non-aneurysmal remote aortic wall of AAA mouse (Supplemental Figure). Based on the immunohistochemical quantification of AAA sections, there was a significant correlation between mural macrophage density and neovessel counts (r=0.68, p=0.03; Figure 5A).

Figure 4. Examples of abdominal aortic aneurysm (AAA) mice with different aortic diameters, 18F-FPPRGD2 PET activity, and immunohistochemical findings.

Figure 4

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Aortic diameter on ultrasound was smaller in AAA mouse #1 than #2 (1.89 vs. 2.23 mm), but 18F-FPPRGD2 PET activity was greater in #1 than #2 (TBR 4.4 vs. 2.0). Immunohistochemistry showed that both macrophages (mural macrophage density; 24.2 vs. 18.3%) and neovessels (mural neovessels/quadrant; 45 vs. 14) were greater in AAA mouse #1 than #2, in line with the 18F-FPPRGD2 PET activity. Asterisks indicate mural thrombus. Scale bars in PET images, 0.5 cm.

Figure 5. Correlation among abdominal aortic aneurysm (AAA) diameter on ultrasound (US), 18F-FPPRGD2 PET activity, macrophage infiltration, and neovessels.

Figure 5

Figure 5

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The immunohistochemical quantitative analysis of AAA sections showed significant correlation between mural macrophage density and neovessel counts/quadrant (A; r=0.68, p=0.03). AAA diameter on US did not correlate with either mural macrophage density (B; r=−0.08, p=0.83) nor neovessel counts/quadrant (C; r=0.06, p=0.87). 18F-FPPRGD2 PET activity correlated positively and strongly with both mural macrophage density (D; r=0.79, p=0.007) and neovessel counts/quadrant (E; r=0.87, p=0.001). Arrows indicate the data points corresponding to AAA mice #1 and #2 in Figure 4.

Additionally, we examined whether anatomical AAA dilation and 18F-FPPRGD2 PET activity corresponded to the immunohistochemical markers of AAA biological activity. There was no significant correlation between US-determined AAA diameter and mural macrophage density (r=−0.08, p=0.83; Figure 5B) or neovessel counts (r=0.06, p=0.87; Figure 5C). In contrast, the TBR of 18F-FPPRGD2 activity showed a positive strong correlation with both mural macrophage density (r=0.79, p=0.007; Figure 5D) and neovessel counts (r=0.87, p=0.001; Figure 5E). Note that Figure 4 shows two examples of AAA mice representing different levels of anatomical AAA dilation, PET activity, and histological macrophage infiltration and neovessel expression (with corresponding data points highlighted in Figure 5).

Discussion

We demonstrate that PET imaging with the dimeric RGD tracer 18F-FPPRGD2 can assess murine AAAs, with AAA PET activity correlating significantly to vascular inflammation and neoangiogenesis but not to AAA size. To the best of our knowledge, this is the first use of RGD-based PET imaging of AAA disease, and also the first application of 18F-FPPRGD2 to cardiovascular disease. Our results suggest that PET imaging using 18F-FPPRGD2 PET is a potential strategy for in vivo visualization of vascular inflammation and neoangiogenesis in AAAs, with the ultimate goal of detecting high-risk AAA disease more effectively than relying on AAA size alone to guide care.

RGD-based probes have been used previously for in vivo fluorescence, magnetic resonance, and PET imaging in animal models of atherosclerosis,6, 21, 22 which highlights the potential of molecular imaging techniques with the RGD peptide to assess vascular inflammation and angiogenesis. As for AAA disease, we have previously reported the targeting abilities of RGD-conjugated human ferritin nanoparticles toward macrophages and angiogenic endothelial cells in experimental AAA using fluorescence,6 but the penetration depth of fluorescence greatly limits clinical translation for deep structures. In contrast, PET is a highly sensitive noninvasive molecular imaging technique in humans, with many examples of clinical translation, including RGD-based agents.16, 23

A prior study by Nahrendorf, et al. used a nanoparticle-based PET agent targeted to macrophages and showed noninvasive imaging of inflammation in experimental AAAs.24 They also showed a modest correlation of PET activity with aortic size when AAA and control animals were combined, but no data on the correlation for AAA mice only were shown. A key finding in our study was the lack of correlation between 18F-FPPRGD2 PET activity and aortic size within the AAA mice, in contrast to the positive and strong correlation of 18F-FPPRGD2 PET with both vascular inflammation (macrophage density) and neoangiogenesis (neovessel counts). These results indicate that size alone is not a reliable indicator of biological activity. While vascular inflammation and neoangiogenesis likely contribute to AAA dilatation, the timing and interrelationship of these factors is not well understood. Serial monitoring of AAA biological activity and AAA growth/rupture would be ideal to understand this complex pathobiology.

The current clinical standard of care for AAA disease is to perform serial noninvasive imaging, predominantly using US, with surgical repair or stent grafting based on AAA size. However, this approach does not eliminate the risk of rupture and typically necessitates operation earlier than may be needed with more precise risk prediction. Thus, assessing AAA biological activity could identify high-risk patients and prompt earlier therapy to prevent rupture while also sparing low-risk patients from expensive and morbid procedures.

Recent clinical studies have reported on the potential of 18F-FDG PET in AAA disease,25, 26 as increased FDG uptake has been shown in vascular inflammation. However, in contrast to the nanoparticle-based PET imaging in experimental AAAs,24 the initial clinical study with 18F-FDG PET showed a negative correlation between PET activity and AAA growth.27 While 18F-FPPRGD2 has been undergoing initial clinical studies in cancer patients,28 it has not been studied in AAA patients to date.

One limitation to the present study is the experimental AAA model. While this murine model has been used extensively in the literature and has biological features found in human AAA, it does involve aortic dissection as part of the AAA expansion process and may not be ideal to study AAA rupture. This complex pathology also makes it challenging to quantify wall thickness/area reliably, so we could not normalize our data to AAA wall area. Plus, murine AAAs develop over weeks, rather than decades, so the model can not fully represent human AAA biology and progression. The use of PET in mice is challenged by spatial resolution, making it difficult to assess different regions within the AAA and to prevent some spillover of adjacent high kidney signal. Also, the mouse tail vein injection is technically challenging and prone to incomplete tracer dose delivery. This may account for some overlap of %ID/g in AAA mice vs. controls. There was no such overlap, however, in TBR, which normalizes by blood pool and appropriately compensates for any incomplete dosing. Additionally, with αvβ3 expressed on both vascular macrophages and neovessels, RGD-based probes cannot distinguish inflammation from angiogenesis. However, both are indicators of AAA biological activity, so RGD offers an approach to detect both processes with a single probe. Clinical studies on the ability of 18F-FPPRGD2 PET to detect AAA and predict AAA growth are needed, including comparisons to 18F-FDG PET, particularly given the mixed clinical results of the latter.

In conclusion, PET imaging with the dimeric 18F-FPPRGD2 can detect experimental AAAs, with activity correlating to the degree of vascular inflammation and neoangiogenesis. 18F-FPPRGD2 PET has potential for clinical molecular imaging of AAA, in order to assess AAA biological activity and perform prospective trials on predicting AAA growth and outcomes beyond AAA size alone.

Supplementary Material

clinical perspective
supplemental figure legend

Acknowledgments

We thank the Stanford Small Animal Imaging Facility for infrastructure support.

Sources of Funding

Younger Fellowship from the Stanford Cardiovascular Institute supported this study. Use of the Small Animal Imaging Core Facility is partially supported by the NIH (P50CA114747).

Footnotes

Disclosures

The Stanford Division of Cardiovascular Medicine has received imaging research equipment support from GE Healthcare. The Stanford Department of Radiology has received imaging research funding from GE Healthcare and Siemens Medical Solutions. The Stanford Division of Vascular Surgery has received educational grants from Cook, W.L. Gore and Associates, and Medtronic, Inc related to AAA disease. Dr. McConnell has received AAA research funding from Tiara Pharmaceuticals. Dr. Dalman has received AAA research funding from Medtronic, Inc. Dr. Chang has received research funding from Bayer Healthcare. Dr. Gambhir has been a scientific advisor for Visualsonics.

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Supplementary Materials

clinical perspective
NIHMS542958-supplement-clinical_perspective.doc (39KB, doc)
supplemental figure legend
NIHMS542958-supplement-supplemental_figure_legend.pdf (46KB, pdf)

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