Multimodal clinical imaging to longitudinally assess a nanomedical anti-inflammatory treatment in experimental atherosclerosis.

Atherosclerosis is an inflammatory disease causing great morbidity and mortality in the Western world. To increase the anti-inflammatory action and decrease adverse effects of glucocorticoids (PLP), a nanomedicinal liposomal formulation of this drug (L-PLP) was developed and intravenously applied at a dose of 15 mg/kg PLP to a rabbit model of atherosclerosis. Since atherosclerosis is a systemic disease, emerging imaging modalities for assessing atherosclerotic plaque are being developed. (18)F-Fluoro-deoxy-glucose positron emission tomography and dynamic contrast enhanced magnetic resonance imaging, methods commonly used in oncology, were applied to longitudinally assess therapeutic efficacy. Significant anti-inflammatory effects were observed as early as 2 days that lasted up to at least 7 days after administration of a single dose of L-PLP. No significant changes were found for the free PLP treated animals. These findings were corroborated by immunohistochemical analysis of macrophage density in the vessel wall. In conclusion, this study evaluates a powerful two-pronged strategy for efficient treatment of atherosclerosis that includes nanomedical therapy of atherosclerotic plaques and the application of noninvasive and clinically approved imaging techniques to monitor delivery and therapeutic responses. Importantly, we demonstrate unprecedented rapid anti-inflammatory effects in atherosclerotic lesions after the nanomedical therapy.

Coronary Artery PET/MR Imaging: Feasibility, Limitations, and Solutions.

OBJECTIVES: The aims of this study were to describe the authors' initial experience with combined coronary artery positron emission tomographic (PET) and magnetic resonance (MR) imaging using 18F-fluorodeoxyglucose (18F-FDG) and 18F-sodium fluoride (18F-NaF) radiotracers, describe common problems and their solutions, and demonstrate the feasibility of coronary PET/MR imaging in appropriate patients. BACKGROUND: Recently, PET imaging has been applied to the aortic valve and regions of atherosclerosis. 18F-FDG PET imaging has become established for imaging inflammation in atherosclerosis in the aorta and carotid arteries. Moreover, 18F-NaF has emerged as a novel tracer of active microcalcification in the aortic valve and coronary arteries. Coronary PET imaging remains challenging because of the small caliber of the vessels and their complex motion. Currently, most coronary imaging uses combined PET and computed tomographic imaging, but there is increasing enthusiasm for PET/MR imaging because of its reduced radiation, potential to correct for motion, and the complementary information available from cardiac MR in a single scan. METHODS: Twenty-three patients with diagnosed or documented risk factors for coronary artery disease underwent either 18F-FDG or 18F-NaF PET/MR imaging. Standard breath-held MR-based attenuation correction was compared with a novel free-breathing approach. The impact on PET image artifacts and the interpretation of vascular uptake were evaluated semiquantitatively by expert readers. Moreover, PET reconstructions with more algorithm iterations were compared visually and by target-to-background ratio. RESULTS: Image quality was significantly improved by novel free-breathing attenuation correction. Moreover, conspicuity of coronary uptake was improved by increasing the number of algorithm iterations from 3 to 6. Elevated radiotracer uptake could be localized to individual coronary lesions using both 18F-FDG (n = 1, maximal target-to-background ratio = 1.61) and 18F-NaF (n = 7, maximal target-to-background ratio = 1.55 ± 0.37), including in 1 culprit plaque post-myocardial infarction confirmed by myocardial late gadolinium enhancement. CONCLUSIONS: The authors provide the first demonstration of successful, low-radiation (7.2 mSv) PET/MR imaging of inflammation and microcalcification activity in the coronary arteries. However, this requires specialized approaches tailored to coronary imaging for both attenuation correction and PET reconstruction.

The development of endotension is associated with increased transmission of pressure and serous components in porous expanded polytetrafluoroethylene stent-grafts: characterization using a canine model.

OBJECTIVE: This study used a canine model of abdominal aortic aneurysms (AAAs) to compare intra-aneurysmal pressure and thrombus formation after exclusion with Dacron and expanded polytetrafluoroethylene (ePTFE) stent-grafts. METHODS: Prosthetic AAAs with implanted strain-gauge pressure transducers were treated by stent-graft exclusion using Food and Drug Administration-approved devices in 10 mongrel dogs: five Dacron (AneuRx) and five ePTFE (original Excluder). Intra-aneurysmal pressure was measured over 4 weeks after AAA exclusion and indexed to the systemic pressure, represented as a percentage of a simultaneously obtained systemic pressure (value = 1.0). Magnetic resonance imaging (MRI) of the intra-aneurysmal thrombus was performed at 1, 2, and 4 weeks after exclusion and expressed as a signal-to-noise ratio (S:N) to control for background signal intensity. Comparisons of pressures and S:N between the two stent-grafts was analyzed with the Student's t test. Intra-aneurysmal thrombus was characterized histologically. RESULTS: In animals excluded with both Dacron and ePTFE stent-grafts, the intra-aneurysmal pressure was nonpulsatile and reduced to <30% of systemic pressure. Significantly greater pressure transmission was observed after AAA exclusion using ePTFE compared with Dacron stent grafts (systolic pressure: ePTFE, 0.28 +/- 0.12 vs Dacron, 0.11 +/- 0.02, P < .001; mean pressure: ePTFE, 0.16 +/- 0.08 vs Dacron, 0.06 +/- 0.02, P < .001). MRI confirmed the absence of perfusion in all aneurysms. The T1-weighted signal intensity remained persistently elevated (S:N at 1 week, 2.7 +/- 0.4 vs 2 weeks, 4.0 +/- 0.2 vs 4 weeks, 5.4 +/- 1.3) in ePTFE-treated intra-aneurysmal thrombus, suggesting an absence of thrombus organization. In contrast, progressive evolution of T1 signal intensity in aneurysms excluded by Dacron stent-grafts was consistent with maturation from intact red blood cells (S:N at 1 week, 3.3 +/- 0.4) to methemoglobin (S:N at 2 weeks, 6.1 +/- 0.8), and then hemosiderin and ferritin (S:N at 4 weeks, 2.4 +/- 0.5). Histologically, ePTFE-excluded aneurysms contained poorly organized thrombus with red blood cell fragments and haphazardly arranged fibrin deposition indicative of active remodeling and continued influx of transudated serum. In aneurysms excluded by Dacron stent-grafts, dense, mature collagenous connective tissue and organized fibrin were present, indicative of greater thrombus organization. CONCLUSIONS: Stent-graft treatment reduces intra-aneurysmal pressure to <30% of systemic pressure when no endoleak is present; however, significantly greater pressure is present in aneurysms treated with porous ePTFE stent-grafts than Dacron grafts. Histologic and MRI imaging analysis suggest that active transudation of serous blood components may be contributing to this increased intra-aneurysmal pressure.

Treatment of type II endoleaks with a novel polyurethane thrombogenic foam: induction of endoleak thrombosis and elimination of intra-aneurysmal pressure in the canine model.

OBJECTIVE: The clinical significance and treatment of retrograde collateral arterial perfusion of abdominal aortic aneurysms after endovascular repair (type II endoleak) have not been completely characterized. A canine abdominal aortic aneurysm model of type II endoleak with an implanted pressure transducer was used to evaluate the use of polyurethane foam to induce thrombosis of type II endoleaks. The effect on endoleak patency, intra-aneurysmal pressure, and thrombus histology was studied. METHODS: Prosthetic aneurysms with an intraluminal, solid-state, strain-gauge pressure transducer were created in the infrarenal aorta of 14 mongrel dogs. Aneurysm side-branch vessels were reimplanted into the prosthetic aneurysm of 10 animals by using a Carrel patch. Type II (retrograde) endoleaks were created by excluding the aneurysm from antegrade perfusion with an impermeable stent graft. Thrombosis of the type II endoleak was induced by implantation of polyurethane foam into the prosthetic aneurysm sac of four animals. Six animals with type II endoleaks were not treated. In four control animals, no collateral side branches were reimplanted, and therefore no endoleak was created. Intra-aneurysmal and systemic pressures were measured daily for 60 to 90 days after the implantation of the stent graft. Endoleak patency and flow were assessed during surgery and at the time of death by using angiographic imaging and duplex ultrasonography. Histologic analysis of the intra-aneurysmal thrombus was also performed. RESULTS: Intra-aneurysmal pressure values are indexed to systemic pressure and are represented as a percentage of the simultaneously obtained systemic pressure, which has a value of 1.0. All six animals with untreated type II endoleaks maintained patency of the endoleak and side-branch arteries throughout the study period. Compared with control aneurysms that had no endoleak, animals with patent type II endoleaks exhibited significantly higher intra-aneurysmal pressurization (systolic pressure: patent type II endoleak, 0.702 +/- 0.283; control, 0.172 +/- 0.091; P < .001; mean pressure: endoleak, 0.784 +/- 0.229; control, 0.137 +/- 0.102; P < .001; pulse pressure: endoleak, 0.406 +/- 0.248; control, 0.098 +/- 0.077; P < .001; P < .001 for comparison for all groups by analysis of variance). Treatment of the type II endoleak with polyurethane foam induced thrombosis of the endoleak and feeding side-branch arteries in all four animals with type II endoleaks. This resulted in intra-aneurysmal pressures statistically indistinguishable from the controls (systolic pressure, 0.183 +/- 0.08; mean pressure, 0.142 +/- 0.09; pulse pressure, 0.054 +/- 0.04; not significant). Angiography and histology documented persistent patency up to the time of death (mean, 64 days) for untreated type II endoleaks and confirmed thrombosis of polyurethane foam-treated endoleaks in all cases. CONCLUSIONS: Untreated type II endoleaks were associated with intra-aneurysmal pressures that were 70% to 80% of systemic pressure. Treatment with polyurethane foam resulted in a reduction of intra-aneurysmal pressure to a level that was indistinguishable from control aneurysms that had no endoleak. CLINICAL RELEVANCE: Endovascular repair of abdominal aortic aneurysms is dependent on the successful exclusion of the aneurysm from arterial circulation. Type II endoleaks originate from retrograde flow into the aneurysm sac. This study demonstrates the use of polyurethane foam to induce thrombosis in a canine model of a type II endoleak, thereby reducing intra-aneurysmal pressure to levels similar to levels in animals without endoleaks. This approach may be a strategy for future treatment of type II endoleaks.