A spectrum of chronic inflammation is commonly seen in association with advanced human atherosclerosis. This local complication of advanced atherosclerosis is termed '<i>chronic periaortitis</i>'. This may be seen sub-clinically in necropsy samples or may present clinically, in more severe cases, as the conditions previously termed 'idiopathic retroperitoneal fibrosis', 'inflammatory aneurysm' or 'peri-aneurysmal retroperitoneal fibrosis'. The inflammatory cells consist of lymphocytes and plasma cells. Thinning or breaching of the media is common to all forms. A histological survey of necropsy material and surgical material has confirmed the unifying concept of chronic periaortitis. Histochemical, immunohistochemical, immunofluorescence and electron microscopy have been used in this study to examine the nature of the inflammatory response. Locally activated B lymphocytes are stimulated to produce immunoglobulin, predominantly IgG, to oxidised low density lipoprotein (LDL) and ceroid elaborated with human atheroma. T helper lymphocytes and HLA-DR positive cells mediate this response. These findings have been confirmed using <i>in vitro</i> culture of lymphocytes derived from tissue and peripheral blood of patients with chronic periaortitis. Antibodies to oxidized LDL and ceroid have been detected in serum from patients with chronic periaortitis using a modified ELISA technique. This has led to the development of a potential diagnostic test for chronic periaortitis. These results support the hypothesis that chronic periaortitis has an auto-allergic cause and that the allergen is a component of ceroid, likely to be oxidized LDL, elaborated in human atherosclerotic plaques.

Thesis (Ph. D.)--Oregon State University, 2010. / Printout. Includes bibliographical references (leaves 103-119). Also available on the World Wide Web.

Diss. (sammanfattning) Örebro : Örebro universitet, 2006. / Härtill 4 uppsatser.

Systemic inflammatory networks and local signaling cascades trigger culprit pathogenic mechanisms relating clinical cardiovascular disease (CVD) risk factors to atherosclerotic plaque progression and rupture. Imaging vascular inflammation affords a valuable marker of atherosclerotic disease activity to reveal important mechanistic insights for CVD research, to quantify early anti-inflammatory effects of new atherosclerosis drugs, and, ultimately, to help improve CVD risk prediction. While carotid, aortic, and peripheral arterial inflammation can be measured by 18F-fluorodeoxyglucose (FDG) PET-computed tomography (CT), as a glucose analog, high 18F-FDG signal spillover owing to physiological myocardial muscle metabolism prevents reliable coronary interpretation. Lack of cell specificity, and the influence of hypoxia on 18F-FDG uptake within macrophages and other plaque cells, are further limitations that drive the search for an alternative PET tracer for imaging inflammation in atherosclerosis. Up-regulation of the G-protein coupled receptor somatostatin receptor subtype-2 (SST2) occurs on the cell surface of activated macrophages. The central hypothesis tested in this thesis is that vascular SST2 PET imaging using 68Ga-DOTATATE might offer a more accurate marker of macrophage inflammation than 18F-FDG, with superior coronary imaging and therefore better power to discriminate high-risk vs. low-risk atherosclerotic lesions. Comprehensive molecular, histological and clinical evaluation of this experimental CVD imaging biomarker was undertaken, including a prospective clinical study with head-to-head comparison to 18F-FDG in coronary, carotid, and aortic vasculature. In vitro data showed that (i) target SSTR2 gene expression occurred in “pro-inflammatory” M1 macrophages, (ii) specific 68Ga-DOTATATE ligand binding to SST2 receptors occurred in CD68-positive macrophage-rich carotid plaque regions, and (iii) and carotid SSTR2 mRNA was highly correlated with both the pan-macrophage marker CD68 and in vivo 68Ga-DOTATATE PET signals. In clinical imaging, increased 68Ga-DOTATATE inflammatory signals correctly identified culprit vs. non-culprit arteries in patients with acute coronary syndrome and transient ischemic attack/stroke. 68Ga-DOTATATE also demonstrated good diagnostic accuracy for high-risk coronary CT features, and strong correlations with clinical CVD risk factors and 18F-FDG-defined vascular inflammation. While 18F-FDG also differentiated culprit vs. non-culprit carotid and high-risk coronary arteries, myocardial 18F-FDG overspill rendered coronary scans uninterpretable in most patients. In contrast, 68Ga-DOTATATE allowed unimpeded coronary interpretation in all patients. Findings of this thesis provide compelling evidence, from gene, to cell, to plaque, to patient, that SST2 PET imaging using 68Ga-DOTATATE provides a quantifiable marker of macrophage-related atherosclerotic inflammation and disease activity. Further studies are needed to establish whether 68Ga-DOTATATE PET can improve CVD risk prediction when added to current clinical methods, or offer a novel imaging platform to rapidly test the anti-inflammatory capacity of emerging atherosclerosis drugs. Broader translational applications of 68Ga-DOTATATE PET include possible use in diagnosis and therapeutic monitoring of vasculitis, endocarditis, myocarditis, and other manifestations of cardiovascular inflammation.

Thesis (Ph. D.)--University of Virginia, 2008. / Title from title page. Includes bibliographical references. Also available online through Digital Dissertations.

Characterized as a chronic inflammatory disease of the large arteries, atherosclerosis is the primary cause of cardiovascular disease, the leading contributor of morbidity and mortality worldwide. Elevated plasma cholesterol levels and chronic inflammation within the arterial plaque are major mediators of plaque initiation, progression, and instability. In 2003, the protein PCSK9 (proprotein convertase subtilisin/kexin 9) was discovered to play a critical role in cholesterol regulation, thus becoming a key player in the mechanisms behind atherosclerotic plaque development. Emerging evidence suggests that PCSK9 could potentially have effects on atherosclerosis that are independent of cholesterol levels. The objective of this review was to discuss the role on PCSK9 in oxidation, inflammation, and atherosclerosis. This function activates proinflammatory cytokine production and affects oxidative modifications within atherosclerotic lesions, revealing its more significant role in atherosclerosis. Although a variety of evidence demonstrates that PCSK9 plays a role in atherosclerotic inflammation, the direct mechanism of involvement is still unknown, driving a gap in knowledge to such a predominant player in cardiovascular disease. Investigation of proteins structurally related to PCSK9 may interestingly be the link in unveiling the mechanistic role of this protein’s involvement in oxidation and inflammation. Importantly, the unique structure of PCSK9 bears structural homology to a one‐of‐a‐kind domain found in the metabolic protein resistin, which is responsible for many of the same inflammatory outcomes as PCSK9. Closing this gap in knowledge of PCSK9`s role in atherosclerotic oxidation and inflammation will provide fundamental information for understanding, preventing, and treating cardiovascular disease.