CCR2 Positron Emission Tomography for the Assessment of Abdominal Aortic Aneurysm Inflammation and Rupture Prediction.

BACKGROUND: The monocyte chemoattractant protein-1/CCR2 (chemokine receptor 2) axis plays an important role in abdominal aortic aneurysm (AAA) pathogenesis, with effects on disease progression and anatomic stability. We assessed the expression of CCR2 in a rodent model and human tissues, using a targeted positron emission tomography radiotracer (64Cu-DOTA-ECL1i). METHODS: AAAs were generated in Sprague-Dawley rats by exposing the infrarenal, intraluminal aorta to PPE (porcine pancreatic elastase) under pressure to induce aneurysmal degeneration. Heat-inactivated PPE was used to generate a sham operative control. Rat AAA rupture was stimulated by the administration of ß-aminopropionitrile, a lysyl oxidase inhibitor. Biodistribution was performed in wild-type rats at 1 hour post tail vein injection of 64Cu-DOTA-ECL1i. Dynamic positron emission tomography/computed tomography imaging was performed in rats to determine the in vivo distribution of radiotracer. RESULTS: Biodistribution showed fast renal clearance. The localization of radiotracer uptake in AAA was verified with high-resolution computed tomography. At day 7 post-AAA induction, the radiotracer uptake (standardized uptake value [SUV]=0.91±0.25) was approximately twice that of sham-controls (SUV=0.47±0.10; P<0.01). At 14 days post-AAA induction, radiotracer uptake by either group did not significantly change (AAA SUV=0.86±0.17 and sham-control SUV=0.46±0.10), independent of variations in aortic diameter. Competitive CCR2 receptor blocking significantly decreased AAA uptake (SUV=0.42±0.09). Tracer uptake in AAAs that subsequently ruptured (SUV=1.31±0.14; P<0.005) demonstrated uptake nearly twice that of nonruptured AAAs (SUV=0.73±0.11). Histopathologic characterization of rat and human AAA tissues obtained from surgery revealed increased expression of CCR2 that was co-localized with CD68+ macrophages. Ex vivo autoradiography demonstrated specific binding of 64Cu-DOTA-ECL1i to CCR2 in both rat and human aortic tissues. CONCLUSIONS: CCR2 positron emission tomography is a promising new biomarker for the noninvasive assessment of AAA inflammation that may aid in associated rupture prediction.

Familial clustering of ruptured intracranial aneurysms in autosomal dominant polycystic kidney disease.

Ruptured intracranial aneurysm (RICA) is a life-threatening complication of autosomal dominant polycystic kidney disease (ADPKD). A family history of RICA may be a risk factor for RICA. Six hundred eight adult members of 199 ADPKD families were interviewed, and family pedigrees were constructed. Individuals were classified as having definite, probable, or possible RICAs from evidence and history obtained in interviews. Central nervous system (CNS) events not consistent with RICA were classified as other CNS events. Seventy-seven CNS events occurred in 906 subjects with ADPKD (8.5%) versus 13 events in 823 subjects without ADPKD (1.6%; P < 0.0001). No event in subjects without ADPKD was consistent with an RICA. Twenty-seven other (non-RICA) CNS events occurred in subjects with ADPKD (3%) versus 13 events in subjects without ADPKD (1.6%; P = 0.05). The frequency of RICA was increased in subjects with ADPKD: 21 definite RICAs in subjects with ADPKD (2%) versus none in subjects without ADPKD (P < 0.001); 28 definite and probable RICAs in subjects with ADPKD (3%) versus none in subjects without ADPKD (P < 0.001); and 50 definite, probable, and possible RICAs in subjects with ADPKD (5.5%) versus none in subjects without ADPKD (P < 0.001). The null hypothesis that RICAs are randomly distributed among subjects with ADPKD was tested for definite RICAs (n = 21), definite and probable RICAs (n = 28), and definite, probable, and possible RICAs (n = 50). In the three categories, the null hypothesis was rejected at P less than 0.05, P less than 0.05, and P less than 0.005, respectively. Vascular CNS events occurred more frequently in ADPKD than non-ADPKD family members, and clustering of RICAs occurred in families with ADPKD.

Should we screen for familial intracranial aneurysm?

BACKGROUND AND PURPOSE: The purpose of this study was to establish whether individuals with a family history of >/=2 first-degree relatives with intracranial aneurysm should be offered screening for aneurysm. METHODS: We derived 3 theoretical models and calculated the outcomes of screening with magnetic resonance angiography (MRA) followed by digital subtraction angiography (DSA) if MRA was positive (model 1), screening with DSA alone (model 2), and not screening (model 3). Screening was repeated at intervals of 10 years, and aneurysms detected were treated surgically. We assumed a prevalence of aneurysm of 9.8% (95% CI, 8.9% to 10.6%) in the population screened, an annual rupture rate of asymptomatic aneurysm of 0.8% (95% CI, 0.4% to 1.5%), and a 75% chance of poor outcome from rupture. We assumed the sensitivity and specificity of MRA were each 90% and the risk of DSA was 0.1%. The risk of surgery was taken as 5.1%. RESULTS: Screening 1000 individuals on 3 occasions with MRA and DSA or with DSA alone followed by surgery resulted in poor outcome in 14 and 18 individuals, respectively, over 30 years. Without screening, poor outcome occurred in 15 individuals over the same period of time. CONCLUSIONS: Screening is not an effective way of reducing morbidity and mortality from ruptured intracranial aneurysm in individuals with a history of >/=2 affected first-degree relatives with ruptured intracranial aneurysm unless the expected incidence of asymptomatic aneurysm is considerably >10%.

Patients with polycystic kidney disease would benefit from routine magnetic resonance angiographic screening for intracerebral aneurysms: a decision analysis.

Autosomal dominant polycystic kidney disease (ADPKD) is associated with increased prevalence of cerebral aneurysms and increased risk of subarachnoid hemorrhage. A decision analysis by Levey et al. in 1983 demonstrated that patients with ADPKD would not significantly benefit from routine arteriographic screening for cerebral aneurysms. We reexamined this conclusion in light of new clinical data and the introduction of magnetic resonance imaging (MRI) as a screening method. We compared an MRI screening strategy with a nonscreening strategy. The screening strategy specified MRI screening and then neurosurgical management of detected aneurysms. The nonscreening strategy specified cerebrovascular care only in the event of subarachnoid hemorrhage. The decision tree incorporated estimates derived from the clinical literature for the prevalence of asymptomatic aneurysms in patients with ADPKD (15%), the annual incidence of aneurysmal rupture (1.6%), the morbidity and mortality rates associated with subarachnoid hemorrhage (70 and 56%, respectively), the risk of transfemoral arteriography (0.2%), the sensitivity and specificity of MRI, the morbidity and mortality rates associated with surgical treatment of an unruptured aneurysm (4.1 and 1.0%, respectively), and the life expectancy of patients with ADPKD. The model predicted that the screening strategy would provide 1.0 additional year of life without neurological disability to a 20-year-old patient with ADPKD. A sensitivity analysis showed that the model was most sensitive to estimates of the prevalence of aneurysms in ADPKD, the annual incidence of rupture, and the morbidity and mortality rates associated with rupture. A financial analysis showed that a screening strategy is likely to cost less than a nonscreening strategy. The model predicts that an MRI screening strategy would increase the life expectancy of young patients with ADPKD and reduce the financial impact on society of ADPKD.

Angiographic screening and elective surgery of familial cerebral aneurysms: a decision analysis.

Up to 6% of cerebral aneurysms may be familial. Because the pattern of inheritance and the prevalence of aneurysms within families are unknown, the management of family members at risk of harboring a cerebral aneurysm is currently empirical. We established the prevalence of aneurysms in the second generation of individuals with familial cerebral aneurysms and determined the possible benefit of angiographic screening and elective surgery of such individuals by using a simple decision analysis model. Four consecutive families were identified in whom the mother and a child had a ruptured cerebral aneurysm. A total of 19 siblings at risk in the second generation were identified. Fifteen underwent elective cerebral angiography: one had a cerebral aneurysm and two had an infundibulum at the origin of the posterior communicating artery. Including the previously known aneurysms, the prevalence of aneurysms in the second generation was thus established at 29.4%. A decision analysis was performed with 2% as the annual risk of rupture, 72.7% as the risk of death or disability with rupture, 0.1% as the risk of angiography, and 6.5% as the risk of surgery. The benefit in years of survival free of sequelae resulting from angiographic screening and elective surgery (intervention) over natural history was computed for life expectancy corresponding to each quinquennial age group from age 15 to 100 years. Intervention equaled natural history, in terms of years of survival expected with each choice, at a life expectancy of 10.6 years, corresponding to age 76.5 years for men and 80 years for women, and produced a net gain of at least 1 year for patients whose life expectancy was 32 years or more, corresponding to age 53.5 years for women and 49 years for men. Greater benefit was achieved with increasing life expectancy (younger age). The prevalence of aneurysms in the second generation when a mother and child have an aneurysm is 29.4%. Intervention produces a benefit of at least 1 year of survival free of sequelae over natural history in such individuals if their life expectancy is 32 years or more.

Screening for unruptured familial intracranial aneurysms. A decision analysis.

Decision analysis is used to assess the decision to screen for unruptured intracranial aneurysms (IAs) in two affected families, and to formulate guide-lines for similar decisions. Four strategies are compared: "no screening", "screening directly", "screening twice", and "screening later". Intravenous and intra-arterial digital subtraction angiography techniques (iv-DSA, ia-DSA) are considered. Life years lived with and without disability are computed for each strategy. Loss of life expectancy with and without discounting and quality correction is used as an outcome measure. "No screening" is the preferred strategy when population based estimates of the prevalence of IAs are used. Thus, the results of this analysis provide no justification for screening patients without a familial history. But a physician who thinks that the risk of an IA is increased may rightly decide for screening, especially when the patient is aged 40 to 60. Ia-DSA is preferable over iv-DSA. A scenario analysis suggests that screening with magnetic resonance angiography is only slightly better than with ia-DSA, because the complication rate of screening plays a minor role in the analysis.