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Novel Molecular Imaging Approaches to Abdominal Aortic Aneurysm Risk Stratification.

ABSTRACT: Selection of patients for abdominal aortic aneurysm repair is currently based on aneurysm size, growth rate, and symptoms. Molecular imaging of biological processes associated with aneurysm growth and rupture, for example, inflammation and matrix remodeling, could improve patient risk stratification and lead to a reduction in abdominal aortic aneurysm morbidity and mortality. (18)F-fluorodeoxyglucose-positron emission tomography and ultrasmall superparamagnetic particles of iron oxide magnetic resonance imaging are 2 novel approaches to abdominal aortic aneurysm imaging evaluated in clinical trials. A variety of other tracers, including those that target inflammatory cells and proteolytic enzymes (eg, integrin ?v?3 and matrix metalloproteinases), have proven effective in preclinical models of abdominal aortic aneurysm and show great potential for clinical translation.

SUBMITTER: Toczek J

PROVIDER: S-EPMC4714781 | biostudies-literature | 2016 Jan

REPOSITORIES: biostudies-literature

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Novel Molecular Imaging Approaches to Abdominal Aortic Aneurysm Risk Stratification.

Toczek Jakub J Meadows Judith L JL Sadeghi Mehran M MM

Circulation. Cardiovascular imaging 20160101 1

Selection of patients for abdominal aortic aneurysm repair is currently based on aneurysm size, growth rate, and symptoms. Molecular imaging of biological processes associated with aneurysm growth and rupture, for example, inflammation and matrix remodeling, could improve patient risk stratification and lead to a reduction in abdominal aortic aneurysm morbidity and mortality. (18)F-fluorodeoxyglucose-positron emission tomography and ultrasmall superparamagnetic particles of iron oxide magnetic r ...[more]

PMID: 26763279

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Project description:ObjectiveFew large-animal models exist for the study of aortic aneurysms. β-Aminopropionitrile (BAPN) is a compound known to cause aortic aneurysms by inhibiting lysyl oxidase, a collagen cross-linking enzyme. It is hypothesized that BAPN plus aneurysm induction surgery would result in significant aneurysm formation in swine with biologic properties similar to human disease.MethodsInitial experiments were performed in uncastrated male swine not treated with BAPN (surgery alone). Subsequently, uncastrated male swine were fed BAPN (0.15 g/kg) for 7 days before undergoing surgery; the infrarenal aorta was circumferentially dissected and measured, balloon dilated, and perfused with elastase (500 units) and type I collagenase (8000 units), with extraluminal elastase application. In the BAPN groups, daily BAPN feedings continued until swine harvest at postoperative days 7, 14, and 28.ResultsSwine undergoing surgery alone (n = 12) had significantly less dilation at 28 days compared with BAPN + surgery swine (51.9% ± 29.2% [0%-100%] vs 113.5% ± 30.2% [52.9%-146.2%]; P < .0003). Mean aortic dilation in animals undergoing treatment with surgery and BAPN was 86.9% ± 47.4% (range, 55.6%-157.1%), 105.4% ± 58.1% (50%-133.3%), and 113.5% ± 30.2% (52.9%-146.2%) at 7, 14, and 28 days, respectively. In the BAPN + surgery group, significant elastolysis was present at all time points, whereas aortic wall collagen content was not significantly different. Smooth muscle cells were significantly depleted at 14 and 28 days, and M1 macrophages were increased at 14 and 28 days (P < .05, all). Matrix metalloproteinase 2 was elevated at 7 days (P < .05). Multiple proinflammatory cytokines were elevated within the aortic wall of BAPN + surgery swine.ConclusionsBAPN plus surgery resulted in significantly larger aortic aneurysms than surgery alone and was critical to aneurysm formation in this novel swine model. Hallmarks of human disease, such as elastin fragmentation, smooth muscle cell depletion, macrophage infiltration, matrix metalloproteinase activation, and proinflammatory cytokine expression, were observed in BAPN-treated swine. This model better parallels many of the characteristics of human AAAs and may be suitable for prehuman drug trials.

Project description:The abdominal aortic aneurysm (AAA) is a silent and often deadly vascular disease caused by the localized weakening of the arterial wall. Previous work has indicated that local changes in wall stiffness can be detected with pulse wave imaging (PWI), which is a non-invasive technique for tracking the propagation of pulse waves along the aorta at high spatial and temporal resolutions. The aim of this study was to assess the capability of PWI to monitor and stage AAA progression in a murine model of the disease. ApoE/TIMP-1 knockout mice (N = 18) were given angiotensin II for 30 days via subcutaneously implanted osmotic pumps. The suprarenal sections of the abdominal aortas were imaged every 2-3 d after implantation using a 30-MHz VisualSonics Vevo 770 with 15-?m lateral resolution. Pulse wave propagation was monitored at an effective frame rate of 8 kHz by using retrospective electrocardiogram gating and by performing 1-D cross-correlation on the radiofrequency signals to obtain the displacements induced by the waves. In normal aortas, the pulse waves propagated at constant velocities (2.8 ± 0.9 m/s, r(2) = 0.89 ± 0.11), indicating that the composition of these vessels was relatively homogeneous. In the mice that developed AAAs (N = 10), the wave speeds in the aneurysm sac were 45% lower (1.6 ± 0.6 m/s) and were more variable (r(2) = 0.66 ± 0.23). Moreover, the wave-induced wall displacements were at least 80% lower within the sacs compared with the surrounding vessel. Finally, in mice that developed fissures (N = 5) or ruptures (N = 3) at the sites of their AAA, higher displacements directed out of the lumen and with no discernible wave pattern (r(2) < 0.20) were observed throughout the cardiac cycle. These findings indicate that PWI can be used to distinguish normal murine aortas from aneurysmal, fissured and ruptured ones. Hence, PWI could potentially be used to monitor and stage human aneurysms by providing information complementary to standard B-mode ultrasound.

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Novel Molecular Imaging Approaches to Abdominal Aortic Aneurysm Risk Stratification.

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Novel Molecular Imaging Approaches to Abdominal Aortic Aneurysm Risk Stratification.

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