Abdominal Aortic Aneurysm Subjects Research Articles

T lymphocyte-derived extracellular vesicles aggravate abdominal aortic aneurysm by promoting macrophage lipid peroxidation and migration via pyruvate kinase muscle isozyme 2

T lymphocyte and macrophage infiltration in the aortic wall is critical for abdominal aortic aneurysm (AAA). However, how T lymphocytes interact with macrophages in the pathogenesis of AAA remains largely uncharacterized. In an elastase-induced murine AAA model, we first found that the expression of pyruvate kinase muscle isozyme 2 (PKM2), the last rate-limiting enzyme in glycolysis, was increased in infiltrated T lymphocytes of vascular lesions. T lymphocyte-specific PKM2 deficiency in mice (LckCrePKM2fl/fl) or intraperitoneal administration of the sphingomyelinase inhibitor GW4869 caused a significant attenuation of the elastase-increased aortic diameter, AAA incidence, elastic fiber disruption, matrix metalloproteinases (MMPs) expression, and macrophage infiltration in the vascular adventitia compared with those in PKM2fl/fl mice. Mechanistically, extracellular vesicles (EVs) derived from PKM2-activated T lymphocytes elevated macrophage iron accumulation, lipid peroxidation, and migration in vitro, while macrophages treated with EVs from PKM2-null T lymphocytes or pretreated with the lipid peroxidation inhibitors ferrostatin-1 (Fer-1), liproxstatin-1 (Lip-1), or the iron chelating agent deferoxamine mesylate (DFOM) reversed these effects. In vascular lesions of elastase-induced LckCrePKM2fl/fl mice with AAA, the oxidant system weakened, with downregulated 4-hydroxynonenal (4-HNE) levels and strengthened antioxidant defense systems with upregulated glutathione peroxidase 4 (GPX4) and cystine/glutamate antiporter solute carrier family 7 member 11 (Slc7a11) expressions in macrophages. High-throughput metabolomics showed that EVs derived from PKM2-activated T lymphocytes contained increased levels of polyunsaturated fatty acid (PUFA)-containing phospholipids, which may provide abundant substrates for lipid peroxidation in target macrophages. More importantly, upregulated T lymphocyte PKM2 expression was also found in clinical AAA subjects, and EVs isolated from AAA patient plasma enhanced macrophage iron accumulation, lipid peroxidation, and migration ex vivo. Therefore, from cell-cell crosstalk and metabolic perspectives, the present study shows that PKM2-activated T lymphocyte-derived EVs may drive AAA progression by promoting macrophage redox imbalance and migration, and targeting the T lymphocyte-EV-macrophage axis may be a potential strategy for early warning and treating AAA.

Imaging Biological Pathways in Abdominal Aortic Aneurysms Using Positron Emission Tomography.

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The interplay between abdominal aortic aneurysm, metabolic syndrome and fatty liver disease: a retrospective case-control study.

BackgroundAbdominal aortic aneurysm (AAA) and fatty liver disease are both associated with the metabolic syndrome (MS); the aim of this study was to investigate whether patients with AAA are also at a higher risk for fatty liver disease.MethodsA case-control retrospective study. Patients diagnosed with AAA were compared with age- and sex-matched controls regarding the prevalence of fatty liver disease. Extracted data include anthropometric parameters, clinical and laboratory data, and liver imaging.Results995 patients were enrolled in the final analysis, 495 patients with AAA and 500 age- and sex-matched controls. The prevalence of fatty liver disease among AAA subjects was 48.9% compared with 21.2% among the controls (P<0.005). After adjusting for age, smoking, body mass index, and MS components, the logistic regression analysis indicates that AAA (men: OR 1.29, 95% CI 1.17, 1.49, P=0.001; women: OR 1.23, 95% CI 1.06, 1.43, P=0.002), obesity (men: OR 1.32, 95% CI 1.17, 1.59, P<0.001; women: OR 1.32, 95% CI 1.07, 1.52, P=0.012), hypertension (men: OR 1.23, 95% CI 1.13, 1.46, P=0.001; women: OR 1.13, 95% CI 1.00, 1.33, P=0.045), MS (men: OR 1.31, 95% CI 1.19, 1.53, P=0.001; women: OR 1.28, 95% CI 1.16, 1.42, P=0.002) were associated with non-alcoholic fatty liver disease/non-alcoholic steatohepatitis (NAFLD/NASH). The prevalence of liver cirrhosis was 1.23%; subjects with obesity, diabetes, hypertension, and AAA had increased risk for cirrhosis (OR 1.89, 95% CI 1.18, 3.22, P=0.014; OR 1.27, 95% CI 1.09, 2.72, P=0.0027; OR 2.08, 95% CI 1.29, 3.42, P=0.004; OR 1.73, 95% CI 1.08, 2.87, P=0.027, respectively).ConclusionAAA patients are at increased risk for NAFLD/NASH, may predict advance liver disease and liver cirrhosis.

Impaired HDL (High-Density Lipoprotein)-Mediated Macrophage Cholesterol Efflux in Patients With Abdominal Aortic Aneurysm-Brief Report.

Objective- The ability of HDL (high-density lipoprotein) to promote macrophage cholesterol efflux is considered the main HDL cardioprotective function. Abdominal aortic aneurysm (AAA) is usually characterized by cholesterol accumulation and macrophage infiltration in the aortic wall. Here, we aim to evaluate the composition of circulating HDL particles and their potential for promoting macrophage cholesterol efflux in AAA subjects. Approach and Results- First, we randomly selected AAA and control subjects from Spain. The AAA patients in the Spanish cohort showed lower plasma apoA-I levels concomitantly associated with low levels of plasma HDL cholesterol and the amount of preβ-HDL particles. We determined macrophage cholesterol efflux to apoB-depleted plasma, which contains mature HDL, preβ-HDL particles and HDL regulatory proteins. ApoB-depleted plasma from AAA patients displayed an impaired ability to promote macrophage cholesterol efflux. Next, we replicated the experiments with AAA and control subjects derived from Danish cohort. Danish AAA patients also showed lower apoA-I levels and a defective HDL-mediated macrophage cholesterol efflux. Conclusions- AAA patients show impaired HDL-facilitated cholesterol removal from macrophages, which could be mechanistically linked to AAA.

Monocyte count-to-high-density lipoprotein-cholesterol ratio is associated with abdominal aortic aneurysm size.

To determine the association of monocyte count-to-high-density lipoprotein (HDL)-cholesterol ratio, a recently emerged inflammatory marker, with abdominal aortic aneurysm (AAA) size. A total of 120 asymptomatic AAA subjects (99 male, mean age: 67.1 ± 10.2 years) were enrolled into the study. All data were compared between patients with low and high admission monocyte/HDL ratio. Multivariate linear regression analysis was performed to study the relationship between different variables and AAA size. Compared to patients with below-median monocyte/HDL ratio, aneurysm diameter was significantly higher in above-median monocyte/HDL ratio group (54.3 ± 10.6 mm vs 62.0 ± 12.4 mm, p < 0.001, respectively). Hypertension, coronary artery disease, monocyte/HDL ratio and C-reactive protein were independently associated with AAA diameter. Monocyte/HDL ratio is independently associated with AAA size.

Abstract 256: Decreased Serum MiR-155 Expression is Associated with Increased Tumor Necrosis Factor-Alpha Levels in Patients with Abdominal Aortic Aneurysm

Introduction: The inflammatory response plays a crucial role in abdominal aortic aneurysm (AAA) pathogenesis and expansion. The cytokine tumor necrosis factor-alpha (TNF-α) and MicroRNA-155 (miR-155) are implicated in inflammatory diseases. Previous studies have found miR-155 regulates TNF-α expression in cardiovascular disease. However, the relationship between TNF-α expression and miR-155 in AAA disease is not fully understood. This study examines the relationship between serum TNF-α levels and miR-155 expression in AAA patients. Methods: MicroRNA’s were isolated from patient serum and quantified using Agilent BioAnalyzer 2100. MiR-155 levels were assessed using qPCR with Exiqon LNA primers and normalized using the 2-ΔΔCT method. Media was collected from the co-culture of control or AAA monocytes with endothelial cells. The supernatant was analyzed for the presence of TNF-α via Luminex ® 200 TM analyzer. AAA is defined as ≥3.0 cm in maximum aortic diameter and measurement was obtained from abdominal ultrasound. Student’s t-test was used to compare AAA and control groups for statistical analysis. Results: Average aortic diameter for AAA group was 5.1±0.7 cm and 2.4±0.4 cm for controls. Q-PCR results showed miR-155 was significantly down-regulated in serum (p=0.03) in AAA subjects (n=5) versus non-AAA controls (n=4) (Figure 1A). Serum TNF-α levels from Luminex assays trended towards greater levels in AAA patients (n=4) vs. controls (n=3) (920.1±591.1 vs. 294.8±102.2 pg/mL, p=0.14) (Figure 1B). Conclusion: Patients with AAA may have more unregulated TNF-α activity due to decreased miR-155 expression compared to controls. Serum miR-155 may serve as a potential biomarker for patients at risk for aortic expansion leading to AAA disease.

From tissue iron retention to low systemic haemoglobin levels, new pathophysiological biomarkers of human abdominal aortic aneurysm

Iron deposits are observed in tissue of abdominal aortic aneurysm (AAA) patients, although the underlying mechanisms are not completely elucidated. Therefore we explored circulating markers of iron metabolism in AAA patients, and tested if they could serve as biomarkers of AAA. Increased red blood cell (RBC)-borne iron retention and transferrin, transferrin receptor and ferritin expression was observed in AAA tissue compared to control aorta (immunohistochemistry and western blot). In contrast, decreased circulating iron, transferrin, mean corpuscular haemoglobin concentration (MCHC) and haemoglobin concentration, along with circulating RBC count, were observed in AAA patients (aortic diameter >3 cm, n=114) compared to controls (aortic diameter <3 cm, n=88) (ELISA), whereas hepcidin concentrations were increased in AAA subjects (MS/MS assay). Moreover, iron, transferrin and haemoglobin levels were negatively, and hepcidin positively, correlated with aortic diameter in AAA patients. The association of low haemoglobin with AAA presence or aortic diameter was independent of specific risk factors. Moreover, MCHC negatively correlated with thrombus area in another cohort of AAA patients (aortic diameter 3-5 cm, n=357). We found that anaemia was significantly more prevalent in AAA patients (aortic diameter >5 cm, n=8,912) compared to those in patients with atherosclerotic aorto-iliac occlusive disease (n=17,737) [adjusted odds ratio=1.77 (95% confidence interval: 1.61;1.93)]. Finally, the mortality risk among AAA patients with anaemia was increased by almost 30% [adjusted hazard ratio: 1.29 (95% confidence interval: 1.16;1.44)] as compared to AAA subjects without anaemia. In conclusion, local iron retention and altered iron recycling associated to high hepcidin and low transferrin systemic concentrations could lead to reduced circulating haemoglobin levels in AAA patients. Low haemoglobin levels are independently associated to AAA presence and clinical outcome.

Pulse wave imaging in normal, hypertensive and aneurysmal human aortas in vivo: a feasibility study

Arterial stiffness is a well-established biomarker for cardiovascular risk, especially in the case of hypertension. The progressive stages of an abdominal aortic aneurysm (AAA) have also been associated with varying arterial stiffness. Pulse wave imaging (PWI) is a noninvasive, ultrasound imaging-based technique that uses the pulse wave-induced arterial wall motion to map the propagation of the pulse wave and measure the regional pulse wave velocity (PWV) as an index of arterial stiffness. In this study, the clinical feasibility of PWI was evaluated in normal, hypertensive, and aneurysmal human aortas. Radiofrequency-based speckle tracking was used to estimate the pulse wave-induced displacements in the abdominal aortic walls of normal (N = 15, mean age 32.5 ± 10.2 years), hypertensive (N = 13, mean age 60.8 ± 15.8 years), and aneurysmal (N = 5, mean age 71.6 ± 11.8 years) human subjects. Linear regression of the spatio-temporal variation of the displacement waveform in the anterior aortic wall over a single cardiac cycle yielded the slope as the PWV and the coefficient of determination r2 as an approximate measure of the pulse wave propagation uniformity. The aortic PWV measurements in all normal, hypertensive, and AAA subjects were 6.03 ± 1.68, 6.69 ± 2.80, and 10.54 ± 6.52 m s−1, respectively. There was no significant difference (p = 0.15) between the PWVs of the normal and hypertensive subjects while the PWVs of the AAA subjects were significantly higher (p < 0.001) compared to those of the other two groups. Also, the average r2 in the AAA subjects was significantly lower (p < 0.001) than that in the normal and hypertensive subjects. These preliminary results suggest that the regional PWV and the pulse wave propagation uniformity (r2) obtained using PWI, in addition to the PWI images and spatio-temporal maps that provide qualitative visualization of the pulse wave, may potentially provide valuable information for the clinical characterization of aneurysms and other vascular pathologies that regionally alter the arterial wall mechanics.

Hemodynamic Changes Quantified in Abdominal Aortic Aneurysms with Increasing Exercise Intensity Using MR Exercise Imaging and Image-Based Computational Fluid Dynamics

Abdominal aortic aneurysm (AAA) is a vascular disease resulting in a permanent, localized enlargement of the abdominal aorta. We previously hypothesized that the progression of AAA may be slowed by altering the hemodynamics in the abdominal aorta through exercise [Dalman, R. L., M. M. Tedesco, J. Myers, and C. A. Taylor. Ann. N.Y. Acad. Sci. 1085:92-109, 2006]. To quantify the effect of exercise intensity on hemodynamic conditions in 10 AAA subjects at rest and during mild and moderate intensities of lower-limb exercise (defined as 33±10% and 63±18% increase above resting heart rate, respectively), we used magnetic resonance imaging and computational fluid dynamics techniques. Subject-specific models were constructed from magnetic resonance angiography data and physiologic boundary conditions were derived from measurements made during dynamic exercise. We measured the abdominal aortic blood flow at rest and during exercise, and quantified mean wall shear stress (MWSS), oscillatory shear index (OSI), and particle residence time (PRT). We observed that an increase in the level of activity correlated with an increase of MWSS and a decrease of OSI at three locations in the abdominal aorta, and these changes were most significant below the renal arteries. As the level of activity increased, PRT in the aneurysm was significantly decreased: 50% of particles were cleared out of AAAs within 1.36±0.43, 0.34±0.10, and 0.22±0.06s at rest, mild exercise, and moderate exercise levels, respectively. Most of the reduction of PRT occurred from rest to the mild exercise level, suggesting that mild exercise may be sufficient to reduce flow stasis in AAAs.

Cardiopulmonary exercise testing in small abdominal aortic aneurysm: profile, safety, and mortality estimates

Few data are available regarding exercise testing in patients with abdominal aortic aneurysm (AAA) disease. The purpose of this study was to evaluate safety and to characterize the hemodynamic and cardiopulmonary (CPX) response to exercise in a large group of patients with AAA. Three hundred and six patients with AAA ≥3.0 to ≤5.0 cm (mean 72 ± 8 years) underwent CPX as part of a randomized trial of exercise training. CPX and hemodynamic responses, ischemic events, rhythm disturbances, and risk estimates based on treadmill scores were quantified and compared to an age-matched group of 2155 veterans referred for exercise testing for clinical reasons. Peak VO(2) was similar between patients with AAA and the referral group (20.0 ± 6 ml/kg/min; 77 percent of age-predicted and 20.3 ± 7 ml/kg/min; 80 percent of age-predicted, respectively). The incidence of exercise-induced hypotension and hypertension was higher in AAA patients versus the referral group (2.9 and 3.6 percent vs <1.0 percent, p < 0.001), but there were no occurrences of ventricular tachycardia (≥3 beats) or other serious events in the AAA subjects. The Duke Treadmill Score and VA Treadmill Scores, which estimate annual cardiovascular events and all-cause mortality, respectively, were similar between groups. Patients with AAA have a slightly higher incidence of hyper- and hypotensive responses to exercise than age-matched referrals, but no serious events related to CPX occurred. AAA patients can undergo maximal CPX safely and have risk scores based on treadmill test results that are similar to age-matched referral subjects. These findings extend recent studies using sub-maximal evaluations to stratify risk in patients considered for surgery, and support the routine use of exercise testing for risk evaluation and the functional assessment of patients with AAA.

Effects of Exercise Training in Patients With Abdominal Aortic Aneurysm

No effective medical therapy exists for early abdominal aortic aneurysm (AAA) disease. Lower extremity exercise improves aortic hemodynamics and reduces inflammation, but the safety and efficacy of exercise training in AAA disease is unknown. As an interim analysis of our prospective, randomized, longitudinal trial of exercise for AAA suppression, we investigated whether subjects with early disease could safely achieve target metabolic and hemodynamic goals. One hundred eight participants were randomized to exercise training (EX) or usual care (UC). EX subjects participated in a combination of in-house and home exercise training, with efforts directed toward moderate daily exercise participation. Comparisons were made between EX and UC subjects who completed 1 year of follow-up (n = 26 and 31, respectively, mean age 72 ± 8 years). EX and UC groups were compared for safety, cardiopulmonary exercise test responses, weekly energy expenditure, and biometric indices. No paradoxical increase in AAA growth rate or adverse clinical events occurred as a consequence of exercise training. EX participants expended an average of 2269 ± 1207 kcal/wk and increased exercise capacity (42% increase in treadmill time, 24% increase in estimated metabolic equivalents, P = .01 and .08 between groups, respectively). EX participants demonstrated a significant reduction in C-reactive protein and tended to reduce waist circumference and waist-to-hip ratio (P = .06 and .07, respectively). Preliminary analyses suggest that exercise training is well tolerated and sustainable in small AAA subjects over 1 year. Despite age and comorbidities, exercising AAA subjects achieve meaningful exercise targets and significantly modify activity-dependent variables.