Combination Therapy with Atorvastatin and Amlodipine Suppresses Angiotensin II-Induced Aortic Aneurysm Formation

Background

Abdominal aortic aneurysm (AAA) is a life-threatening vascular disease. It is controversial whether statin and calcium channel blockers (CCBs) has an inhibitory effect on the expansion of AAA. Some studies reported that CCBs have an inhibitory effect on Rho-kinase activity. Rho-kinase plays an important role in the pathogenesis of various cardiovascular diseases. However, there is no study reporting of the association between Rho-kinase and human AAAs.

Methods and Results

Experimental AAA was induced in Apolipoprotein E-deficient (ApoE^-/-) mice infused with angiotensin II (AngII) for 28 days. They were randomly divided into the following 5 groups; saline infusion alone (sham), AngII infusion alone, AngII infusion plus atorvastatin (10 mg/kg/day), AngII infusion plus amlodipine (1 mg/kg/day), and AngII infusion plus combination therapy with atorvastatin (10 mg/kg/day) and amlodipine (1 mg/kg/day). The combination therapy significantly suppressed AngII-induced increase in maximal aortic diameter as compared with sham, whereas each monotherapy had no inhibitory effects. The combination therapy significantly reduced AngII-induced apoptosis and elastin degradation at the AAA lesion, whereas each monotherapy did not. Moreover, Rho-kinase activity, as evaluated by the extent of phosphorylation of myosin-binding subunit (a substrate of Rho-kinase) and matrix metalloproteinase activity were significantly increased in the AngII-induced AAA lesion as compared with sham, both of which were again significantly suppressed by the combination therapy. In human aortic samples, immunohistochemistory revealed that the activity and expression of Rho-kinase was up-regulated in AAA lesion as compared with abdominal aorta from control subjects.

Conclusions

Rho-kinase is up-regulated in the aortic wall of human AAA. The combination therapy with amlodipine and Atorvastatin, but not each monotherapy, suppresses AngII-induced AAA formation in mice in vivo, for which Rho-kinase inhibition may be involved.     

Plasma cathepsin s and cystatin C levels and risk of abdominal aortic aneurysm: a randomized population-based study

Background

Human abdominal aortic aneurysm (AAA) lesions contain high levels of cathepsin S (CatS), but are deficient in its inhibitor, cystatin C. Whether plasma CatS and cystatin C levels are also altered in AAA patients remains unknown.

Methods and Results

Plasma samples were collected from 476 male AAA patients and 200 age–matched male controls to determine CatS and cystatin C levels by ELISA. Student''s t test demonstrated higher plasma levels of total, active, and pro–CatS in AAA patients than in controls (P<0.001). ROC curve analysis confirmed higher plasma total, active, and pro–CatS levels in AAA patients than in controls (P<0.001). Logistic regression suggested that plasma total (odds ratio [OR] = 1.332), active (OR = 1.21), and pro–CatS (OR = 1.25) levels were independent AAA risk factors that associated positively with AAA (P<0.001). Plasma cystatin C levels associated significantly, but negatively, with AAA (OR = 0.356, P<0.001). Univariate correlation demonstrated that plasma total and active CatS levels correlated positively with body–mass index, diastolic blood pressure, and aortic diameter, but negatively with the lowest ankle–brachial index (ABI). Plasma cystatin C levels also correlated negatively with the lowest ABI. Multivariate linear regression showed that plasma total, active, and pro–CatS levels correlated positively with aortic diameter and negatively with the lowest ABI, whereas plasma cystatin C levels correlated negatively with aortic diameter and the lowest ABI, after adjusting for common AAA risk factors.

Conclusions

Correlation of plasma CatS and cystatin C with aortic diameter and the lowest ABI suggest these serological parameters as biomarkers for human peripheral arterial diseases and AAA.     

Homocysteine Level and Risk of Abdominal Aortic Aneurysm: A Meta-Analysis

Objectives

Previous studies have reported inconsistent findings regarding the association between elevated plasma homocysteine (Hcy) levels and abdominal aortic aneurysm (AAA). We investigated this association between Hcy levels in patients with AAA and unaffected controls by conducting a meta-analysis and systematic review.

Methods

We conducted a systematic literature search (up to August 2013) of the PubMed database and Embase. We selected observational studies that evaluated Hcy levels in subjects with AAA compared to unaffected controls. Criteria for inclusion were the assessment of baseline Hcy and risk of AAA as an outcome. The results were presented as odd ratio (OR) and corresponding 95% confidence intervals (CI) comparing AAA patients to the control subjects.

Results

7 studies with 6,445 participants were identified and analyzed. Overall, elevated plasma Hcy was associated with an increased risk of AAA (3.29; 95% CI 1.66–6.51). The pooled adjusted OR from a random effect model of only men participants in the AAA compared with the control group was 2.36 (95% CI 0.63–8.82).

Conclusion

This meta-analysis and systematic review suggested that Hcy significantly increased the risk of AAA.     

In vivo imaging of macrophages during the early-stages of abdominal aortic aneurysm using high resolution MRI in ApoE mice

Background

Angiotensin II (ANG II) promotes vascular inflammation and induces abdominal aortic aneurysm (AAA) in hyperlipidemic apolipoprotein E knock-out (apoE^−/−) mice. The aim of the present study was to detect macrophage activities in an ANG II-induced early-stage AAA model using superparamagnetic iron oxide (SPIO) as a marker.

Methodology/Principal Findings

Twenty-six male apoE^−/− mice received saline or ANG II (1000 or 500 ng/kg/min) infusion for 14 days. All animals underwent MRI scanning following administration of SPIO with the exception of three mice in the 1000 ng ANG II group, which were scanned without SPIO administration. MR imaging was performed using black-blood T2 to proton density -weighted multi-spin multi-echo sequence. In vivo MRI measurement of SPIO uptake and abdominal aortic diameter were obtained. Prussian blue, CD68,α-SMC and MAC3 immunohistological stains were used for the detection of SPIO, macrophages and smooth muscle cells. ANG II infusion with 1000 ng/kg/min induced AAA in all of the apoE^−/− mice. ANG II infusion exhibited significantly higher degrees of SPIO uptake, which was detected using MRI as a distinct loss of signal intensity. The contrast-to-noise ratio value decreased in proportion to an increase in the number of iron-laden macrophages in the aneurysm. The aneurysmal vessel wall in both groups of ANG II treated mice contained more iron-positive macrophages than saline-treated mice. However, the presence of cells capable of phagocytosing haemosiderin in mural thrombi also induced low-signal-intensities via MRI imaging.

Conclusions/Significance

SPIO is taken up by macrophages in the shoulder and the outer layer of AAA. This alters the MRI signaling properties and can be used in imaging inflammation associated with AAA. It is important to compare images of the aorta before and after SPIO injection.     

Reported High Salt Intake Is Associated with Increased Prevalence of Abdominal Aortic Aneurysm and Larger Aortic Diameter in Older Men

Background

Salt intake has been implicated in the pathogenesis of abdominal aortic aneurysm (AAA) through studies in rodent models but not previously studied in humans. The aim of this study was to examine the association between reported addition of salt to food and the prevalence of AAA.

Methods

A risk factor questionnaire which contained a question about salt intake was included as part of a population screening study for AAA in 11742 older men. AAA presence was assessed by abdominal ultrasound imaging using a reproducible protocol.

Results

The prevalence of AAA was 6.9, 8.5 and 8.6% in men who reported adding salt to food never, sometimes and always, respectively, p = 0.005. Addition of salt to food sometimes (odds ratio [OR]: 1.22, 95% confidence interval [CI]: 1.03–1.44) or always (OR: 1.23, 95% CI 1.04–1.47) was independently associated with AAA after adjustment for other risk factors including age, waist-hip ratio, blood pressure, history of hypertension, high cholesterol, angina, diabetes, myocardial infarction and stroke. Salt intake was also independently associated with aortic diameter (beta 0.023, p = 0.012). In men with no prior history of hypertension, high cholesterol, angina, myocardial infarction or stroke (n = 4185), the association between addition of salt to food sometimes (OR: 1.41, 95% CI 0.96–2.08) or always (OR: 1.52, 95% CI 1.04–2.22) and AAA remained evident.

Conclusion

Reported salt intake is associated with AAA in older men. Additional studies are needed to determine whether reducing salt intake would protect against AAA.     

Endothelial and smooth muscle cells from abdominal aortic aneurysm have increased oxidative stress and telomere attrition

Background

Abdominal aortic aneurysm (AAA) is a complex multi-factorial disease with life-threatening complications. AAA is typically asymptomatic and its rupture is associated with high mortality rate. Both environmental and genetic risk factors are involved in AAA pathogenesis. Aim of this study was to investigate telomere length (TL) and oxidative DNA damage in paired blood lymphocytes, aortic endothelial cells (EC), vascular smooth muscle cells (VSMC), and epidermal cells from patients with AAA in comparison with matched controls.

Methods

TL was assessed using a modification of quantitative (Q)-FISH in combination with immunofluorescence for CD31 or α-smooth muscle actin to detect EC and VSMC, respectively. Oxidative DNA damage was investigated by immunofluorescence staining for 7, 8-dihydro-8-oxo-2′-deoxyguanosine (8-oxo-dG).

Results and Conclusions

Telomeres were found to be significantly shortened in EC, VSMC, keratinocytes and blood lymphocytes from AAA patients compared to matched controls. 8-oxo-dG immunoreactivity, indicative of oxidative DNA damage, was detected at higher levels in all of the above cell types from AAA patients compared to matched controls. Increased DNA double strand breaks were detected in AAA patients vs controls by nuclear staining for γ-H2AX histone. There was statistically significant inverse correlation between TL and accumulation of oxidative DNA damage in blood lymphocytes from AAA patients. This study shows for the first time that EC and VSMC from AAA have shortened telomeres and oxidative DNA damage. Similar findings were obtained with circulating lymphocytes and keratinocytes, indicating the systemic nature of the disease. Potential translational implications of these findings are discussed.     

Neural Substrates of Cognitive Subtypes in Parkinson's Disease: A 3-Year Longitudinal Study

Background

The neuropsychological features and neuropathological progression patterns associated with rapidly evolving cognitive decline or dementia in Parkinson''s disease (PD) remain to be elucidated.

Methods

Fifty-three PD patients without dementia were recruited to participate in a 3-year longitudinal cohort study. The patients were grouped according to the Clinical Dementia Rating (CDR). Group-wise comparisons were made with regard to demographic characteristics, motor symptoms, neuropsychological performances and 18F-fluorodeoxyglucose positron emission tomography.

Results

Patients who had memory-plus cognitive impairment (patients whose CDR was 0 at baseline and 0.5 in memory and other domains at follow-up, and those whose baseline CDR was 0.5 in memory and other domains) exhibited higher age at onset, visuoperceptual impairment, non-tremor-dominant motor disturbance, rapid symptomatic progression and posterior neocortical hypometabolism. In patients who were cognitively unimpaired and those who had memory-dominant cognitive impairment (patients whose CDR was 0 at baseline and 0.5 only in memory domain at follow-up, and those whose baseline CDR was 0.5 only in memory domain), the posterior neocortex was relatively unaffected until a later stage of the disease.

Conclusions

These results suggest that visuoperceptual impairment and the early involvement of the posterior neocortex may be risk factors for rapid symptomatic progression and dementia in PD.     

Short-Term Curative Effect of Endovascular Stent-Graft Treatment for Aortic Diseases in China: A Systematic Review

Introduction

We analyzed the short-term efficacy of endovascular treatment for aortic diseases by summarizing all available published data on endovascular stent-graft treatment for abdominal aortic aneurysm (AAA), thoracic aortic aneurysm (TAA), type A aortic dissection (type A AD) and type B aortic dissection (type B AD) in China.

Methods

We performed a systematic analysis of 935 published series on retrograde endovascular treatment for aortic diseases in China from January 1996 to November 2010. Based on the inclusion criteria, 159 studies, involving a total of 5531 patients, were included.

Results

There were no significant differences in procedural success among the studies (P>0.05). The rates of overall neurologic complications and stroke were significantly different in all two-group comparisons (P<0.01). The type A AD patients had the highest rates of neurologic complications (both 6.67±0.00%), and the AAA patients had the lowest rates (0.31±0.04% and 0.11±0.02%). Significant differences were noted in the rates of cardiac, renal, pulmonary and visceral complications, which were all higher in the type A AD patients than in the other three groups (P<0.01). The endoleak rate was highest in the TAA patients (19.27±5.74%) and was similar in the type A AD patients (P>0.05). A significant difference was noted between the 30-day mortality rate of the type A AD patients and the AAA or type B AD patients (P<0.05).

Conclusion

Endovascular stent-graft is a feasible and safe treatment for aortic diseases, with high procedural success and low incidences of post-procedural complications and short-term mortality. Endovascular treatment for AAA and type B AD is more efficient than for type A AD and TAA.     

Quantitative mass spectrometry analysis using PAcIFIC for the identification of plasma diagnostic biomarkers for abdominal aortic aneurysm

Background

Abdominal aortic aneurysm (AAA) is characterized by increased aortic vessel wall diameter (>1.5 times normal) and loss of parallelism. This disease is responsible for 1–4% mortality occurring on rupture in males older than 65 years. Due to its asymptomatic nature, proteomic techniques were used to search for diagnostic biomarkers that might allow surgical intervention under nonlife threatening conditions.

Methodology/Principal Findings

Pooled human plasma samples of 17 AAA and 17 control patients were depleted of the most abundant proteins and compared using a data-independent shotgun proteomic strategy, Precursor Acquisition Independent From Ion Count (PAcIFIC), combined with spectral counting and isobaric tandem mass tags. Both quantitative methods collectively identified 80 proteins as statistically differentially abundant between AAA and control patients. Among differentially abundant proteins, a subgroup of 19 was selected according to Gene Ontology classification and implication in AAA for verification by Western blot (WB) in the same 34 individual plasma samples that comprised the pools. From the 19 proteins, 12 were detected by WB. Five of them were verified to be differentially up-regulated in individual plasma of AAA patients: adiponectin, extracellular superoxide dismutase, protein AMBP, kallistatin and carboxypeptidase B2.

Conclusions/Significance

Plasma depletion of high abundance proteins combined with quantitative PAcIFIC analysis offered an efficient and sensitive tool for the screening of new potential biomarkers of AAA. However, WB analysis to verify the 19 PAcIFIC identified proteins of interest proved inconclusive save for five proteins. We discuss these five in terms of their potential relevance as biological markers for use in AAA screening of population at risk.     

Efficacy and Mechanism of Angiotensin II Receptor Blocker Treatment in Experimental Abdominal Aortic Aneurysms

Background

Despite the importance of the renin-angiotensin (Ang) system in abdominal aortic aneurysm (AAA) pathogenesis, strategies targeting this system to prevent clinical aneurysm progression remain controversial and unproven. We compared the relative efficacy of two Ang II type 1 receptor blockers, telmisartan and irbesartan, in limiting experimental AAAs in distinct mouse models of aneurysm disease.

Methodology/Principal Findings

AAAs were induced using either 1) Ang II subcutaneous infusion (1000 ng/kg/min) for 28 days in male ApoE^−/− mice, or 2) transient intra-aortic porcine pancreatic elastase infusion in male C57BL/6 mice. One week prior to AAA creation, mice started to daily receive irbesartan (50 mg/kg), telmisartan (10 mg/kg), fluvastatin (40 mg/kg), bosentan (100 mg/kg), doxycycline (100 mg/kg) or vehicle alone. Efficacy was determined via serial in vivo aortic diameter measurements, histopathology and gene expression analysis at sacrifice. Aortic aneurysms developed in 67% of Ang II-infused ApoE^−/− mice fed with standard chow and water alone (n = 15), and 40% died of rupture. Strikingly, no telmisartan-treated mouse developed an AAA (n = 14). Both telmisartan and irbesartan limited aneurysm enlargement, medial elastolysis, smooth muscle attenuation, macrophage infiltration, adventitial neocapillary formation, and the expression of proteinases and proinflammatory mediators. Doxycycline, fluvastatin and bosentan did not influence aneurysm progression. Telmisartan was also highly effective in intra-aortic porcine pancreatic elastase infusion-induced AAAs, a second AAA model that did not require exogenous Ang II infusion.

Conclusion/Significance

Telmisartan suppresses experimental aneurysms in a model-independent manner and may prove valuable in limiting clinical disease progression.     

Absence of p55 TNF Receptor Reduces Atherosclerosis,but Has No Major Effect on Angiotensin II Induced Aneurysms in LDL Receptor Deficient Mice

Background

The aim of the current study was to investigate the role of p55 TNF Receptor (p55 TNFR), the main signaling receptor for the pro-inflammatory cytokine tumor necrosis factor (TNF), in the development of two vascular disorders: atherosclerosis and angiotensin (Ang) II-induced abdominal aortic aneurysms (AAA).

Methodology/Principal Findings

p55 TNFR deficient mice were crossed to an LDL receptor deficient background and were induced for the development of either atherosclerosis or AngII-induced AAA, and compared to littermate controls, wild-type for p55 TNFR expression. p55 TNFR deficient mice developed 43% smaller atherosclerotic lesions in the aortic sinuses compared to controls. Moreover, expression of CD68, a macrophage specific marker, exhibited a 50% reduction in the aortic arches. Decreased atherosclerosis correlated with a strong down-regulation in the expression of adhesion molecules, such as VCAM-1 and ICAM-1, by p55 TNFR deficient endothelium. In addition, expression levels of the pro-inflammatory cytokines and chemokines TNF, IL-6, MCP-1 and RANTES were significantly reduced in aortas of p55 TNFR deficient mice. In contrast, in the AngII-induced model of AAA, p55 TNFR deficiency correlated with a slight trend towards increased aneurismal lethality, but the incidence of aortic rupture due to a dissecting aneurysm, and the expansion of the suprarenal aorta were not significantly different compared to controls.

Conclusion/Significance

We found that p55 TNFR expression promotes atherosclerosis, among other mechanisms, by enhancing expression of endothelial adhesion molecules, while it seems to have no major role in the development of AngII-induced AAA.     

Adipose Stem Cells Promote Smooth Muscle Cells to Secrete Elastin in Rat Abdominal Aortic Aneurysm

Background

Abdominal aortic aneurysm (AAA) is a life-threatening disease and its prevalence rate increases with social aging. The degradation of elastic is an important factor in the formation of AAA.

Methods

Adipose derived stem cells (ADSCs) and bone marrow mesenchymal stem cells (BMSCs) were isolated from rats, and identified by Oil red O and alizarin red staining after adipogenesis and osteogenesis induction. In addition, ADSCs were also identified by flow cytometry with CD markers. AAA model in rats was established, and smooth muscle cells (SMCs) were isolated from AAA aortic wall and identified by immunohistochemistry. ADSCs or BMSCs were co-cultured with AAA aortic wall for in vitro experiment, and ADSCs were injected into AAA model for in vivo test. Then orcein staining was used for observing the morphology of elastic fiber, Western blot and real-time PCR were used respectively to detect the protein and gene expression of elastin, gelatinases spectrum analysis was used to detect the activity of matrix metalloproteinase-2 (MMP-2) and MMP-9.

Results

Lots of red lipid droplets were visible by Oil red O staining after adipogenesis induction, and black calcium nodules appeared by alizarin red staining after osteogenesis induction. The results of flow cytometry showed that ADSCs expressed CD44 and CD105, but exhibited negligible expression of CD31 and CD45. SMCs exhibited spindle-like morphology and α-actin protein was positive in cytoplasm. After co-cultured with ADSCs or BMSCs, the elastic fiber recovered normal winding shape, both the gene and protein expression of elastin increased, and the activity of MMP-2 decreased. The in vivo result was similar to that of in vitro.

Conclusions

ADSCs promote the expression of elastin in SMCs and contribute to the reconstruction of elastic fiber, which may provide new ideas for treating AAA.     

Development of a Novel Rabbit Model of Abdominal Aortic Aneurysm via a Combination of Periaortic Calcium Chloride and Elastase Incubation

Background

The purpose of this study was to introduce a novel, simple and effective technique for creating a reliable rabbit model of abdominal aortic aneurysm (AAA) via a combination of periaortic calcium chloride (CaCl₂) and elastase incubation.

Methods

Forty-eight New Zealand white rabbits were divided into four groups. The AAA model was developed via a 20-minute periaortic incubation of CaCl₂ (0.5 mol/L) and elastase (1 Unit/µL) in a 1.5-cm aortic segment (Group CE). A single incubation of CaCl₂ (Group C) or elastase (Group E) and a sham operation group (Sham Group) were used for the controls. Diameter was measured by serial digital subtraction angiography imaging on days 5, 15 and 30. Animals were sacrificed on day 5 and day 30 for histopathological and immunohistochemical studies.

Results

All animals in Group CE developed aneurysm, with an average dilation ratio of 65.3%±8.9% on day 5, 86.5%±28.7% on day 15 and 203.6%±39.1% on day 30. No aneurysm was found in Group C, and only one aneurysm was seen on day 5 in Group E. Group CE exhibited less intima-media thickness, endothelial recovery, elastin and smooth muscle cell (SMC) content, but stronger expression of matrix metalloproteinase-2, matrix metalloproteinase-9 and RAM11 compared to the controls.

Conclusions

The novel rabbit model of AAA created by using a combination of periaortic CaCl₂ and elastase incubation is simple and effective to perform and is valuable for elucidating AAA mechanisms and therapeutic interventions in experimental studies.     

Prevalence and Trends of the Abdominal Aortic Aneurysms Epidemic in General Population - A Meta-Analysis

Objective

To conduct a meta-analysis assessing the prevalence and trends of the abdominal aortic aneurysms (AAA) epidemic in general population.

Method

Studies that reported prevalence rates of AAA from the general population were identified through MEDLINE, EMBASE, Web of Science, and reference lists for the period between 1988 and 2013. Studies were included if they reported prevalence rates of AAA in general population from the community. In stratified analyses possible sources of bias, including areas difference, age, gender and diameter of aneurysms were examined. Publication bias was assessed with Egger''s test method.

Results

56 studies were identified. The overall pooled prevalence of AAA was 4.8% (4.3%, 5.3%). Stratified analyses showed the following results, areas difference: America 2.2% (2.2%, 2.2%), Europe 2.5% (2.4%, 2.5%), Australia 6.7% (6.5%, 7.0%), Asia 0.5% (0.3%, 0.7%); gender difference: male 6.0% (5.3%, 6.7%), female 1.6% (1.2%, 1.9%); age difference: 55–64years 1.3% (1.2%, 1.5%), 65–74 years 2.8% (2.7%, 2.9%), 75–84 years1.2%(1.1%, 1.3%), ≥85years0.6% (0.4%, 0.7%); aortic diameters difference: 30–39 mm, 3.3% (2.8%, 3.9%), 40–49 mm,0.7% (0.4%,1.0%), ≥50 mm, 0.4% (0.3%, 0.5%). The prevalence of AAA has decreased in Europe from 1988 to 2013. Hypertension, smoking, coronary artery disease, dyslipidemia, respiratory disease, cerebrovascular disease, claudication and renal insufficiency were risk factors for AAA in Europe.

Conclusion

AAA is common in general population. The prevalence of AAA is higher in Australia than America and Europe. The pooled prevalence in western countries is higher than the Asia. Future research requires a larger database on the epidemiology of AAA in general population.     

ACE Inhibitors Potently Reduce Vascular Inflammation,Results of an Open Proof-Of-Concept Study in the Abdominal Aortic Aneurysm

Background

Independent of their blood pressure lowering effect, ACE inhibitors are thought to reduce vascular inflammation. The clinical relevance of this effect is unclear with the current knowledge. Abdominal aortic aneurysms (AAA) are characterized by a broad, non-specific inflammatory response, and thus provide a clinical platform to evaluate the anti-inflammatory potential of ACE inhibitors.

Methods and Results

Eleven patients scheduled for open AAA repair received ramipril (5 mg/day) during 2–4 weeks preceding surgery. Aortic wall samples were collected during surgery, and compared to matched samples obtained from a biobank. An anti-inflammatory potential was evaluated in a comprehensive analysis that included immunohistochemistry, mRNA and protein analysis. A putative effect of ACE inhibitors on AAA growth was tested separately by comparing 18-month growth rate of patients on ACE inhibitors (n = 82) and those not taking ACE inhibitors (n = 204). Ramipril reduces mRNA expression of multiple pro-inflammatory cytokines such as IL-1β, IL-6, IL-8, TNF -α, Interferon-, and MCP-1, as well as aortic wall IL-8 and MCP-1 (P = 0.017 and 0.008, respectively) protein content. The is followed by clear effects on cell activation that included a shift towards anti-inflammatory macrophage (M2) subtype. Evaluation of data from the PHAST cohort did not indicate an effect of ACE inhibitors on 18-month aneurysm progression (mean difference at 18 months: −0.24 mm (95% CI: −0.90–0.45, P = NS).

Conclusions

ACE inhibition quenches multiple aspects of vascular inflammation in AAA. However, this does not translate into reduced aneurysm growth.

Trial Registration

Nederlands Trial Register 1345.     

Homocysteine, grey matter and cognitive function in adults with cardiovascular disease

Background

Elevated total plasma homocysteine (tHcy) has been associated with cognitive impairment, vascular disease and brain atrophy.

Methods

We investigated 150 volunteers to determine if the association between high tHcy and cerebral grey matter volume and cognitive function is independent of cardiovascular disease.

Results

Participants with high tHcy (≥15 µmol/L) showed a widespread relative loss of grey matter compared with people with normal tHcy, although differences between the groups were minimal once the analyses were adjusted for age, gender, diabetes, hypertension, smoking and prevalent cardiovascular disease. Individuals with high tHcy had worse cognitive scores across a range of domains and less total grey matter volume, although these differences were not significant in the adjusted models.

Conclusions

Our results suggest that the association between high tHcy and loss of cerebral grey matter volume and decline in cognitive function is largely explained by increasing age and cardiovascular diseases and indicate that the relationship is not causal.     

Angiotensin-Induced Abdominal Aortic Aneurysms in Hypercholesterolemic Mice: Role of Serum Cholesterol and Temporal Effects of Exposure

Objective

Understanding variations in size and pattern of development of angiotensin II (Ang II)-induced abdominal aortic aneurysms (AAA) may inform translational research strategies. Thus, we sought insight into the temporal evolution of AAA in apolipoprotein (apo)E^−/− mice.

Approach

A cohort of mice underwent a 4-week pump-mediated infusion of saline (n = 23) or 1500 ng/kg/min of Ang II (n = 85) and AAA development was tracked via in vivo ultrasound imaging. We adjusted for hemodynamic covariates in the regression models for AAA occurrence in relation to time.

Results

The overall effect of time was statistically significant (p<0.001). Compared to day 7 of AngII infusion, there was no decrease in the log odds of AAA occurrence by day 14 (−0.234, p = 0.65), but compared to day 21 and 28, the log odds decreased by 9.07 (p<0.001) and 2.35 (p = 0.04), respectively. Hemodynamic parameters were not predictive of change in aortic diameter (Δ) (SBP, p = 0.66; DBP, p = 0.66). Mean total cholesterol (TC) was higher among mice with large versus small AAA (601 vs. 422 mg/ml, p<0.0001), and the difference was due to LDL. AngII exposure was associated with 0.43 mm (95% CI, 0.27 to 0.61, p<0.0001) increase in aortic diameter; and a 100 mg/dl increase in mean final cholesterol level was associated with a 12% (95% CI, 5.68 to 18.23, p<0.0001) increase in aortic diameter. Baseline cholesterol was not associated with change in aortic diameter (p = 0.86).

Conclusions

These are the first formal estimates of a consistent pattern of Ang II-induced AAA development. The odds of AAA occurrence diminish after the second week of Ang II infusion, and TC is independently associated with AAA size.     

Establishment of a New Murine Elastase-Induced Aneurysm Model Combined with Transplantation

Introduction

The aim of our study was to develop a reproducible murine model of elastase-induced aneurysm formation combined with aortic transplantation.

Methods

Adult male mice (n = 6–9 per group) underwent infrarenal, orthotopic transplantation of the aorta treated with elastase or left untreated. Subsequently, both groups of mice were monitored by ultrasound until 7 weeks after grafting.

Results

Mice receiving an elastase-pretreated aorta developed aneurysms and exhibited a significantly increased diastolic vessel diameter compared to control grafted mice at 7 week after surgery (1.11±0.10 mm vs. 0.75±0.03 mm; p≤0,001). Histopathological examination revealed disruption of medial elastin, an increase in collagen content and smooth muscle cells, and neointima formation in aneurysm grafts.

Conclusions

We developed a reproducible murine model of elastase-induced aneurysm combined with aortic transplantation. This model may be suitable to investigate aneurysm-specific inflammatory processes and for use in gene-targeted animals.     

Suitability of Pharmacokinetic Models for Dynamic Contrast-Enhanced MRI of Abdominal Aortic Aneurysm Vessel Wall: A Comparison

Purpose

Increased microvascularization of the abdominal aortic aneurysm (AAA) vessel wall has been related to AAA progression and rupture. The aim of this study was to compare the suitability of three pharmacokinetic models to describe AAA vessel wall enhancement using dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI).

Materials and Methods

Patients with AAA underwent DCE-MRI at 1.5 Tesla. The volume transfer constant (K^trans), which reflects microvascular flow, permeability and surface area, was calculated by fitting the blood and aneurysm vessel wall gadolinium concentration curves. The relative fit errors, parameter uncertainties and parameter reproducibilities for the Patlak, Tofts and Extended Tofts model were compared to find the most suitable model. Scan-rescan reproducibility was assessed using the interclass correlation coefficient and coefficient of variation (CV). Further, the relationship between K^trans and AAA size was investigated.

Results

DCE-MRI examinations from thirty-nine patients (mean age±SD: 72±6 years; M/F: 35/4) with an mean AAA maximal diameter of 49±6 mm could be included for pharmacokinetic analysis. Relative fit uncertainties for K^trans based on the Patlak model (17%) were significantly lower compared to the Tofts (37%) and Extended Tofts model (42%) (p<0.001). K^trans scan-rescan reproducibility for the Patlak model (ICC = 0.61 and CV = 22%) was comparable with the Tofts (ICC = 0.61, CV = 23%) and Extended Tofts model (ICC = 0.76, CV = 22%). K^trans was positively correlated with maximal AAA diameter (Spearman’s ρ = 0.38, p = 0.02) using the Patlak model.

Conclusion

Using the presented imaging protocol, the Patlak model is most suited to describe DCE-MRI data of the AAA vessel wall with good K^trans scan-rescan reproducibility.