Exploring autoimmunity in the pathogenesis of abdominal aortic aneurysms

Chang, Tiffany Wen-Zone; Gracon, Adam; Murphy, Michael P.; Wilkes, David S.

doi:10.1152/ajpheart.00273.2015

Cited by 34 publications

(42 citation statements)

References 97 publications

(120 reference statements)

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“…Several cytokines have been linked to the muscle wasting seen in cancer cachexia including tumor necrosis factor-alpha (TNF-), interleukin (IL)-1, IL-6, and interferon-gamma (IFN-) (32)(33)(34)(35)(36)(37)(38). TNF-, IL-1, IL-6, and IFN- are produced by AAA (39,40). Patients with AAA have also been shown to have elevated circulatory serum levels of TNF-, IL-1, IL-6 and these cytokines have been implicated in the pathogenesis of AAA (17,39).…”

Section: Discussionmentioning

confidence: 99%

“…TNF-, IL-1, IL-6, and IFN- are produced by AAA (39,40). Patients with AAA have also been shown to have elevated circulatory serum levels of TNF-, IL-1, IL-6 and these cytokines have been implicated in the pathogenesis of AAA (17,39). During repair the aneurysmal tissue is not excised, and like cancer, may act as a non-healing wound, continuing to drive inflammation and production of cachexiaassociated cytokines.…”

Section: Discussionmentioning

confidence: 99%

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Sarcopenia is a Significant Predictor of Mortality After Abdominal Aortic Aneurysm Repair

Kays

Liang

Zimmers

et al. 2018

JCSM Clinical Reports

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Aims Repair of abdominal aortic aneurysms (AAA) decreases the incidence of rupture and death. In cancer patients, sarcopenia has been associated with increased surgical complications and mortality. The impact of sarcopenia on survival after AAA repair has yet to be described. Methods and ResultsPatient demographic, laboratory, body composition measurements and survival data were obtained from patients undergoing AAA repair at the Indiana University medical campus over a 5-year period. Univariate and multivariate analyses were performed to identify factors associated with overall survival. Overall, 58.2% presented with sarcopenia. Sarcopenic patients were older (71.88.3 versus 66.88.1 years; p<0.001), had lower body mass index (BMI) (26.35.2 versus 31.55.9 kg/m 2 ; p<0.001), higher rates of myosteatosis (84.4% versus 52.%; p<0.001), greater AAA diameter (60.614.0 versus 57.811.7 mm; p=0.016), higher Charlson Comorbidity Index (CCI) (32.3% versus 25.1% 6; p=0.034), and increased rates of rupture (8.2% versus 3.8%; p=0.047). Sarcopenic and nonsarcopenic patients had no difference in 30-day morbidity (8.5% versus 8.5%; p=0.991) or mortality (3.7% versus 0.9%; p=0.07). Univariate analysis demonstrated age, sarcopenia, myosteatosis, CCI, and BMI to be associated with long-term survival. There was no correlation between BMI and sarcopenia. Both sarcopenia and myosteatosis resulted in decreased one-, three-, and five-year survivals compared to their counterparts. On multivariate analysis sarcopenia is independently associated with survival, conferring a 1.6-fold increase in death (p=0.04). The combination of sarcopenia plus myosteatosis doubled the risk of death compared to sarcopenia alone.Conclusions This is the first study to demonstrate that over half of all patients undergoing AAA repair are sarcopenic, a condition associated with increased mortality. Sarcopenia with myosteatosis is associated with double the mortality of sarcopenia alone. CT scan, but not BMI, accurately identifies sarcopenia and myosteatosis. Defining the mechanisms through which sarcopenia contributes to late death after AAA repair is critical to developing novel interventions that may improve survival in this high risk population.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Sarcopenia is a Significant Predictor of Mortality After Abdominal Aortic Aneurysm Repair

Kays

Liang

Zimmers

et al. 2018

JCSM Clinical Reports

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“…Of note, concentrations of CD4 + T cells have been recently discovered in the periadventitial vascular-associated lymphatic tissue expressing identical T cell receptors, against a currently unknown antigen, and therefore clonally expanded, providing crucial evidence for AAA as an autoimmune disease. 1 Moreover, interleukin (IL)-17, a cytokine elaborated from the antigen-specific Th17 lymphocyte and overexpressed in autoimmune disorders, is highly expressed in the AAA condition. Abrogation of this cytokine, in animal models, has demonstrated efficacy in decreasing aneurysm diameter growth.…”

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confidence: 99%

Immune Modulation as a Treatment for Abdominal Aortic Aneurysms

Wang

Murphy

2018

Circulation Research

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In the United States, >200 000 new patients are diagnosed with abdominal aortic aneurysm (AAA) each year. Consequently, >40 000 highly morbid aortic reconstructions are performed each year to prevent aneurysm rupture, a catastrophic event associated with near-certain mortality. No pharmaceutical currently exists to slow aneurysm growth, but a 50% reduction in diameter growth per annum could halve the number of aortic reconstructions required. Therefore, successful use of cell therapy to modulate chronic inflammation hallmark to AAA to slow diameter expansion represents a potentially paradigmaltering treatment.There continues to be no US Food and Drug-approved medication to slow or stop AAA growth. This deficit is certainly not because of a lack of effort over the previous decades. Initial investigations focused on the reduction of mechanical stress through decreasing blood pressure and sac pressurization cycles; however, clinical trials investigating drugs, such as, angiotensin II-converting enzyme inhibitors, angiotensin receptor blockers, and β-blockers, all failed to demonstrate a therapeutic reduction of diameter growth compared with placebo. Next, the inhibition of matrix metalloproteinases was trialed with doxycycline, an antibiotic inhibitor of matrix metalloproteinases 2 and 9. Doxycycline also treats species of Chlamydia, which were isolated from the aortic walls of a minority of aneurysmal arteries. Although initial uncontrolled results were promising, therapeutic response was not replicated in large randomized studies. Last, aortic wall inflammation was targeted using statins, a ubiquitous anti-inflammatory, lipid-lowering drug to limited success. The discovery of a nonsurgical treatment for AAA is contingent on the robust understanding of disease pathogenesis, which continues to be nebulous at best.AAA risk factors, such as, tobacco abuse, advancing age, uncontrolled hypertension, male sex, and white ethnicity, have all been well described but fail to provide evidence elucidating pathogenesis. Regardless, existing evidence implicates that disease initiation is multifactorial with a strong genetic element.There has been a focus of late toward the role of autoimmune mechanisms in AAA formation. The characterization of aortic wall inflammation consisting of mononuclear infiltrates, immunoglobulins, cytokines, and proteases implicate both a host innate and adaptive response. Of note, concentrations of CD4 + T cells have been recently discovered in the periadventitial vascular-associated lymphatic tissue expressing identical T cell receptors, against a currently unknown antigen, and therefore clonally expanded, providing crucial evidence for AAA as an autoimmune disease.1 Moreover, interleukin (IL)-17, a cytokine elaborated from the antigen-specific Th17 lymphocyte and overexpressed in autoimmune disorders, is highly expressed in the AAA condition. Abrogation of this cytokine, in animal models, has demonstrated efficacy in decreasing aneurysm diameter growth.2 Although several putative autoantigens have b...

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“…The purpose of this communication is to explain the hypothesis that nitric oxide (NO) in tobacco smoke nitrates a protein related to the fibrinogen superfamily in the aortic adventitia and thus enhances its antigenicity. In particular, I discuss four factors that are often associated with diseases of autoimmunity [7,8]: genetic susceptibility, inflammation, matrix metalloproteinases (MMPs), and antibodies and autoantigens.…”

Section: Introductionmentioning

confidence: 99%

Autoimmunity in the Abdominal Aortic Aneurysm and its Association with Smoking

Tilson

2017

Aorta

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Smoking increases the risk of abdominal aortic aneurysm (AAA) in both humans and mice, although the underlying mechanisms are not completely understood. An adventitial aortic antigen, AAAP-40, has been partially sequenced. It has motifs with similarities to all three fibrinogen chains and appears to be connected in evolution to a large family of proteins called fibrinogen-related proteins. Fibrinogen may undergo non-enzymatic nitration, which may result from exposure to nitric oxide in cigarette smoke. Nitration of proteins renders them more immunogenic. It has recently been reported that anti-fibrinogen antibody promotes AAA development in mice. Also, anti-fibrinogen antibodies are present in patients with AAA. These matters are reviewed in the overall context of autoimmunity in AAA. The evidence suggests that smoking amplifies an auto-immune reaction that is critical to the pathogenesis of AAA.

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Exploring autoimmunity in the pathogenesis of abdominal aortic aneurysms

Cited by 34 publications

References 97 publications

Sarcopenia is a Significant Predictor of Mortality After Abdominal Aortic Aneurysm Repair

Sarcopenia is a Significant Predictor of Mortality After Abdominal Aortic Aneurysm Repair

Immune Modulation as a Treatment for Abdominal Aortic Aneurysms

Autoimmunity in the Abdominal Aortic Aneurysm and its Association with Smoking

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