Vascular Remodeling and Immune Cell Infiltration in Splenic Artery Aneurysms.

Rupture of splenic artery aneurysms (SAAs) is associated with a high mortality rate. The aim of this study was to identify the features of SAAs. Tissue sections from SAAs were compared to nonaneurysmal splenic arteries using various stains. The presence of intraluminal thrombus (ILT), vascular smooth muscle cells (VSMCs), cluster of differentiation (CD)-68+ phagocytes, myeloperoxidase+ neutrophils, CD3+, and CD20+ adaptive immune cells were studied using immunofluorescence microscopy. Analysis of SAAs revealed the presence of atherosclerotic lesions, calcifications, and ILT. Splenic artery aneurysms were characterized by a profound vascular remodeling with a dramatic loss of VSMCs, elastin degradation, adventitial fibrosis associated with enhanced apoptosis, and increased matrix metalloproteinase 9 expression. We observed an infiltration of immune cells comprising macrophages, neutrophils, T, and B cells. The T and B cells were found in the adventitial layer of SAAs, but their organization into tertiary lymphoid organs was halted. We failed to detect germinal centers even in the most organized T/B cell follicles and these lymphoid clusters lacked lymphoid stromal cells. This detailed histopathological characterization of the vascular remodeling during SAA showed that lymphoid neogenesis was incomplete, suggesting that critical mediators of their development must be missing.

Superior vena caval obstruction: a rare presentation of Behcet's disease.

A 25-year-old Indian man presented with low-grade fever followed by gradually increasing swelling of neck and face. Physical examination showed bilateral neck swelling, facial swelling and dilated veins in the upper chest. Superior vena cava (SVC) obstruction due to an underlying malignancy was suspected. CT thorax showed large saccular aneurysm with thrombosis of bilateral subclavian arteries of which the right one caused external compression of right innominate vein draining into the SVC. A history of recurrent oral and scrotal ulcers was obtained following which skin pathergy test was done, which was suggestive of a diagnosis of Behcet's disease (BD). He responded to treatment with steroids and azathioprine. This report illustrates that rare nonmalignant cause such as BD could also present with SVC obstruction.

Plasmablastic lymphoma presenting as a brachial artery aneurysm associated with haemodialysis arteriovenous access ligation in a renal transplant patient.

INTRODUCTION: Plasmablastic lymphoma is a rare and aggressive neoplasm, generally associated with immunodeficiencies and related to latent Epstein-Barr virus infection. This case is the first reported case of plasmablastic lymphoma relapse in aneurysmatic brachial artery wall. CASE DESCRIPTION: We describe the case of male patient who underwent cadaveric donor kidney transplant when he was 61 years old and radio-cephalic distal arteriovenous fistula ligation 8 months later. After 8 years, he developed gingival plasmablastic lymphoma treated with cyclophosphamide, hydroxydaunorubicin, oncovin and prednisone regimen with subsequent remission. During follow-up, a mid-forearm vascular access was created because of the worsening of renal function. Twenty-two months later, the patient showed a symptomatic 20 mm brachial artery aneurysm with radiological signs of imminent rupture, for which he was surgically treated. The histological evaluation of the brachial artery specimen revealed a relapse of plasmablastic lymphoma in the arterial wall and in an adjacent lymph node. CONCLUSION: Brachial artery aneurysms are a rare complication in kidney transplant recipients after ligation of arteriovenous access for haemodialysis. Here, we report a case in which this condition is associated with an even rarer plasmablastic lymphoma. A common aetiology, due to immunosuppressive therapy, is postulated for the two coexisting diseases.

Giant brachial artery aneurysm as a rare complication of a dialysis shunt.

Our patient exhibited a large tumor on his right upper arm where his former dialysis access site had been. X-ray, Doppler ultrasound, and magnetic resonance imaging scan could not fully reveal the nature of that tumor. Eventually, a surgical approach showed a giant aneurysm of the inflowing brachial artery to a partially obliterated arteriovenous fistula. This case highlights the importance of ongoing care for patients with arteriovenous shunts. Even arteriovenous fistulas, that are obliterated or no longer in use, can, especially when immunosuppressant therapy and other vascular risk factors are added to the overall cardiovascular risk, transform and endanger the health of our patients.

Occlusive vasculopathy in human immunodeficiency virus (HIV)-associated vasculitis: unusual clinical and imaging course.

Human immunodeficiency virus (HIV)-associated vasculitis is a rare secondary systemic vasculitis involving small and medium arteries. We report a 42-year-old man with uncontrolled HIV infection presenting with long-lasting abdominal pain. An abdominal CT angiography revealed multiple microaneurysms and stenoses in intrarenal arteries, with involvement of mesenteric and hepatic arteries. HIV-associated vasculitis was diagnosed and glucocorticoids and raltegravir-based antiretroviral therapy were administered with good initial clinical and virological response. Several episodes of acute intestinal ischaemia were later developed requiring bowel resections of which histological examination showed vascular occlusive fibrotic changes without active vasculitic lesions. Vasculitis persisted in remission and intrarenal microaneurysms disappeared.

Optical imaging of MMP-12 active form in inflammation and aneurysm.

Matrix metalloproteinase (MMP)-12 plays a key role in the development of aneurysm. Like other members of MMP family, MMP-12 is produced as a proenzyme, mainly by macrophages, and undergoes proteolytic activation to generate an active form. Accordingly, molecular imaging of the MMP-12 active form can inform of the pathogenic process in aneurysm. Here, we developed a novel family of fluorescent probes based on a selective MMP-12 inhibitor, RXP470.1 to target the active form of MMP-12. These probes were stable in complex media and retained the high affinity and selectivity of RXP470.1 for MMP-12. Amongst these, probe 3 containing a zwitterionic fluorophore, ZW800-1, combined a favorable affinity profile toward MMP-12 and faster blood clearance. In vivo binding of probe 3 was observed in murine models of sterile inflammation and carotid aneurysm. Binding specificity was demonstrated using a non-binding homolog. Co-immunostaining localized MMP-12 probe binding to MMP-12 positive areas and F4/80 positive macrophages in aneurysm. In conclusion, the active form of MMP-12 can be detected by optical imaging using RXP470.1-based probes. This is a valuable adjunct for pathophysiology research, drug development, and potentially clinical applications.

Cryopreserved Arterial Allografts and ABO and Rhesus Compatibility.

BACKGROUND: Arterial cryopreserved allografts are conduit of choice for arterial bypass in case of infection. They are sometimes submitted to accelerated degeneration: stenosis, thrombosis, or aneurysmal evolution. We hypothesized that ABO group and Rhesus compatibility could play a role in arterial cryopreserved allograft complications. METHODS: Patients who benefit from allograft bypass from 2006 to 2011 were retrospectively compared, regarding ABO or rhesus compatibility and irregular agglutinins. RESULTS: Seventy-two patients were included. Regarding ABO mismatch, there was no difference in terms of death (51% vs. 43%, P = 0.820), thrombosis (25% vs. 32%, P = 0.78), rupture (9% vs. 0%, P = 0.247), stenosis (3% vs. 12%, P = 0.331), aneurysmal degeneration (16% vs. 12%, P = 1), and 5 years of secondary patency rate (34% vs. 39%, P = 0.141). There was also no difference regarding Rhesus mismatch. CONCLUSIONS: Allograft degeneration does not seem to be related to ABO mismatch. This degeneration could be related to another way of immunogenicity, particularly Human Leukocyte Antigen mismatch, and needs further exploration.

Popliteal artery aneurysms differ from abdominal aortic aneurysms in cellular topography and inflammatory markers.

OBJECTIVE: Popliteal artery aneurysms (PAAs) and abdominal aortic aneurysms (AAAs) frequently coincide; however, symptoms differ. We systematically assessed aneurysm cellular wall composition and inflammatory markers to compare both anatomic locations. METHODS: Aneurysmal walls of 38 PAAs and 198 AAAs were harvested from patients undergoing elective open surgical repair. Elastin, collagen, smooth muscle cells, iron, and inflammatory cells were quantified by immunohistochemistry. In addition, protease and cytokine levels were measured. RESULTS: Aneurysmal degradation resulted in similarly degraded media. The location of inflammation differed: the focus for T and B lymphocytes and plasma cells was the intima in PAAs (all P < .001) and the adventitia for AAAs (all P < .001). Iron was more often observed in PAAs than in AAAs (68% vs 1%; P < .001), indicating more previous intramural hemorrhages. Matrix metalloproteinase 2 activity was higher in PAAs than in AAAs (median [interquartile range], 0.363 [0.174-0.556] vs 0.187 [0.100-0.391]; P = .008), whereas matrix metalloproteinase 9 showed no difference. Walls of AAAs were richer in tested cytokine levels than were walls of PAAs. CONCLUSIONS: PAAs showed more signs of previous intramural hemorrhages compared with AAAs. In addition, inflammation in PAAs is mainly located in the intima, whereas its focus in AAAs is the adventitia. These results suggest important differences in the pathophysiologic mechanism of aneurysm formation between these locations and might explain the differences in presentation on diagnosis.

Vascular aneurysms: a perspective.

Aneurysms develop as a result of chronic inflammation of vascular bed, where progressive destruction of structural proteins, especially elastin and collagen of smooth muscle cells has been shown to manifest. The underlying mechanisms are an increase in local production of proinflammatory cytokines and subsequent increase in proteases, especially matrix metalloproteinases (MMPs) that degrade the structural proteins. The plasminogen system: urokinase-type PA (u-PA), tissue-type PA (t-PA) and plasminogen activator inhibitor-1 (PAI-1) and the MMPs system-MMPs and TIMPs contribute to the progression and development of aneurysms. Recent studies suggest that aneurysms may be genetically determined. To date, most observable candidate genes for aneurysm (elastin, collagen, fibrillin, MMPs and TIMPs) have been explored with little substantiation of the underlying cause and effect. Recently, overexpression of the MMP-2 gene has been suggested as an important phenomenon for aneurysm formation. Along with MMPs, matrix formation also depends on JNK (c-Jun N-terminal kinase) as its activation plays important role in downregulating several genes of matrix production. Under stress, activation of JNK by various stimuli, such as angiotensin II, tumor necrosis factor-α and interleukin-1ß has been noted significantly in vascular smooth muscle cells. Several therapeutic indications corroborate that inhibition of MMP-2 and JNK is useful in preventing progression of vascular aneurysms. This review deals with the role of proteases in the progression of vascular aneurysm.

The role of prostaglandin E2 in human vascular inflammation.

Prostaglandins (PG) are the product of a cascade of enzymes such as cyclooxygenases and PG synthases. Among PG, PGE2 is produced by 3 isoforms of PGE synthase (PGES) and through activation of its cognate receptors (EP1-4), this PG is involved in the pathophysiology of vascular diseases. Some anti-inflammatory drugs (e.g. glucocorticoids, nonsteroidal anti-inflammatory drugs) interfere with its metabolism or effects. Vascular cells can initiate many of the responses associated with inflammation. In human vascular tissue, PGE2 is involved in many physiological processes, such as increasing vascular permeability, cell proliferation, cell migration and control of vascular smooth muscle tone. PGE2 has been shown to contribute to the pathogenesis of atherosclerosis, abdominal aortic aneurysm but also in physiologic/adaptive processes such as angiogenesis. Understanding the roles of PGE2 and its cognate receptors in vascular diseases could help to identify diagnostic and prognostic biomarkers. In addition, from these recent studies new promising therapeutic approaches like mPGES-1 inhibition and/or EP4-antagonism should be investigated.

Pathogenic arterial remodeling: the good and bad of microRNAs.

A number of cardiovascular diseases, such as restenosis, aneurysm, and atherosclerosis, lead to vascular remodeling associated with complex adaptive reactions of different cell populations. These reactions include growth of smooth muscle cells, proliferation of endothelial cells, and the inflammatory response of macrophages. MicroRNAs (miRNAs), a class of short RNAs, play key roles in various biological processes and in the development of human disease by post-transcriptional regulation of gene expression. Here, we review the molecular mechanisms of a subset of miRNAs involved in vascular remodeling, including miR-143/145, miR-221/222, miR-126, miR-21, and miR-155. Some of these miRNAs, such as miR-143/145 and miR-126, have been shown to be protective during vascular remodeling, whereas others, such as miR-21, may promote the cellular response that leads to neointima formation. The increasing knowledge regarding the roles of miRNAs in vascular remodeling opens novel avenues for the treatment of various cardiovascular diseases. However, more in vivo studies on the functional roles of these miRNAs are required in the future.

A clinicopathologic study of immunoglobulin G4-related disease of the femoral and popliteal arteries in the spectrum of immunoglobulin G4-related periarteritis.

BACKGROUND: Immunoglobulin (Ig) G4-related disease has recently been recognized to occur in the cardiovascular system in the aorta and main branching arteries, often manifesting as aneurysms and arteritis/periarteritis. Peripheral arteries (the femoral and popliteal arteries) are frequent sites of arteriosclerosis obliterans (ASO) and occasionally show aneurysms or arteritis. This study re-examined peripheral arterial lesions from the standpoint of IgG4-related disease. METHODS: The study comprised 104 patients who underwent surgical treatment of peripheral arterial lesions, including 30 patients with peripheral arterial aneurysms (PAAs) and 74 with ASO. IgG4-related disease was identified on the basis of diffuse infiltration of numerous IgG4-positive plasmacytes as revealed by immunohistochemical examination. Clinicopathologic features were compared between IgG4-related and IgG4-unrelated lesions. RESULTS: IgG4-related disease was found in four of the 30 patients with PAAs (13.3%; two in the deep femoral artery, two in the popliteal artery) but not in any patients with ASO. IgG4-related PAA displayed clinicopathologic features resembling those of other IgG4-related diseases and a characteristic saccular appearance (P = .002). CONCLUSIONS: IgG4-related disease was detected in PAA patients but not in ASO patients. IgG4-related disease thus represents one potential etiology of aneurysm in the peripheral arteries.

Circulating interferon-γ-inducible Cys-X-Cys chemokine receptor 3 ligands are elevated in humans with aortic aneurysms and Cys-X-Cys chemokine receptor 3 is necessary for aneurysm formation in mice.

OBJECTIVE: Inflammation is associated with the formation of aortic aneurysm. This study investigates the role of inducible Cys-X-Cys chemokine receptor 3 and its ligands in the pathogenesis of arterial aneurysms. METHODS: Plasma samples from patients with or without a diagnosis of thoracic aortic aneurysms were analyzed by enzyme-linked immunosorbent assay for the T-helper 1 cytokine interferon-γ and the interferon-γ-inducible chemokine receptor 3 ligands: interferon-inducible protein-10, interferon-inducible T-cell alpha chemoattractant, and monokine induced by interferon gamma. Patient charts were reviewed for demographics, initial aortic diameter, and growth rates. Aneurysm diameter and growth rates were correlated with plasma cytokine and chemokine levels using linear regression analysis. We used an animal model of aneurysm formation, where calcium chloride is applied topically to the carotid arteries of wild-type and Cys-X-Cys chemokine receptor 3(-/-) mice. After 10 weeks, the arteries were harvested and analyzed by histology and immunohistochemistry. RESULTS: Patients with thoracic aortic aneurysms had significant elevations in circulating interferon-γ, interferon-inducible protein-10, interferon-inducible T-cell alpha chemoattractant, and monokine induced by interferon gamma compared with referent patients (P < .001). Cytokine and chemokine plasma levels did not correlate with aneurysm size or growth rates. Cys-X-Cys chemokine receptor 3(-/-) mice were protected from aneurysm formation and showed decreased vascular infiltration by CD45(+) leukocytes. CONCLUSIONS: Elevated plasma levels of interferon-γ and Cys-X-Cys chemokine receptor 3-binding chemokines are present in patients with thoracic aortic aneurysms. The Cys-X-Cys chemokine receptor 3 receptor is necessary for vascular inflammation and the formation of arterial aneurysms in mice.

Inflammatory popliteal aneurysm.

A 67-year-old man was referred to our department because of fever, right lower thigh swelling, and redness with pain. Laboratory tests showed slightly elevated leukocytes and markedly elevated C-reactive protein levels. Computed tomography confirmed a popliteal aneurysm with wall thickening, so-called mantle sign. Aneurysmorrhaphy with a reversed autologous saphenous vein reconstruction was performed. Aneurysm sac and perianeurysm tissue cultures were negative for aerobic and anaerobic bacteria. The microscopic appearance of the aneurysm showed thickening of the adventitia and infiltration of inflammatory cells. This report presents, for the first time, findings suggestive of an inflammatory aneurysm of the popliteal artery.

Differential expression of YAMA/CPP-32 by T lymphocytes in popliteal artery aneurysm.

BACKGROUND: We have previously demonstrated that programmed cell death, proteolytic activity, and inflammatory infiltrate in the aneurysmal wall may have a role in the pathogenesis of popliteal artery aneurysms (PAA). This investigation examines the expression of a cell death-promoting molecule, a cysteine protease, YAMA/CPP-32 in a series of PAA specimens. METHODS: Twenty PAA specimens were obtained from patients undergoing elective surgical repair. Normal controls were popliteal arteries obtained from patients without PAA who were undergoing infrainguinal bypass surgery (n = 8). Standard histochemistry techniques were used to assess inflammatory infiltrates in PAA. Expression of apoptosis-promoting molecule, CPP-32, vascular smooth muscle cells (VSMC), macrophages, and T lymphocytes was detected by immunohistochemistry. RESULTS: There is a conspicuous disruption and fragmentation of elastic lamellae and increased inflammatory infiltrate in the PAA as compared with normal arteries. As compared with normal popliteal artery tissues, the PAA demonstrated large number of cells immunopositive for CPP-32 (60.45 +/- 4.25% P < 0.05). This study revealed significantly increased expression of CPP-32 in the T-cell population of the PAA as compared with the other cells (P < 0.01). Dual immunolabeling and investigation of serial sections demonstrated that co-expression of CPP-32 was maximum in the CD8+ subset (37 +/- 3.3% of the total CPP-32 immunoreactive cells identified). CONCLUSIONS: The data emphasize that the inflammatory infiltrate in the PAA walls has a significant role in the pathogenesis of this vascular disorder. Cells expressing death-promoting molecules are present in large numbers and are predominantly T lymphocytes in PAA. In addition to compromising the mechanical integrity of the vessel wall, apoptosis in the inflammatory infiltrate may contribute to the production of cytokines, activation of other signaling molecules such as stress proteins that could eventually favor PAA development.

Neutrophil and endothelial cell activation in the vasa vasorum in vasculo-Behçet disease.

AIM: The aim of this study was to analyse the immunopathological mechanisms of vasculo-Behçet disease, which were also compared to cases of Takayasu's arteritis and inflammatory aneurysm to evaluate differences in inflammatory mechanisms. METHOD AND RESULTS: We reviewed six cases of vasculo-Behçet disease, four of Takayasu's arteritis and seven inflammatory aneurysms which underwent surgical repair. Immunohistochemical studies were performed on paraffin-embedded tissue using a labelled streptavidin-biotin method, as was in-situ hybridization for Epstein-Barr virus. Microscopically, neutrophils and lymphocytes accumulated around the vasa vasorum. Neutrophils were prominent as compared to Takayasu's arteritis and inflammatory aneurysm. Elastic fibres were not severely destroyed. Endothelial cells (ECs) of most vasa vasorum expressed HLA-DR. The number of vasa vasorum around which inflammatory infiltrating cells were observed in vasculo-Behçet disease was significantly greater than in inflammatory aneurysms and Takayasu's arteritis (P < 0.001). The cytokines IL-1alpha, TNF-beta and IFN-gamma were expressed in neutrophils and lymphocytes which were distributed around vasa vasorum, as well as neutrophils adherent to HLA-DR positive ECs. CONCLUSION: Our results suggest that vasculo-Behçet disease should be classified as a neutrophilic vasculitis targeting the vasa vasorum. Aneurysm formation may be related to degeneration of arterial wall caused by inflammation of the vasa vasorum.

Histological changes in chronic experimental aneurysms surgically fashioned in sheep.

After experimental venous pouch saccular aneurysms were surgically fashioned on common carotid arteries of sheep, the ensuing long term hemodynamic effects on the vessel walls were examined up to seven years postoperatively. The aneurysms became more spherical rather than remaining elongated, enlarging at variable, individual rates. Venous sac changes were similar to phlebosclerosis in human veins with progression to sclerotic walls and loss of conventional mural architecture at most sites. Lipid accumulation, despite low serum cholesterol levels, calcification, intimal tears of variable depth, mural dissection and secondary mural thrombosis, occurred as in human atherosclerosis and indicated this model's potential for studies of such pathological disorders and the pathological effects of enhanced hemodynamic stress.

Vasculo-Behçet's disease: immunological study of the formation of aneurysm.

We report two patients with vasculo-Behçet's disease who had femoral and popliteal aneurysms. The resected aneurysms and occluded distal arteries were studied clinicopathologically. The most interesting features were prominent fibrosis of the adventitia including the surrounding tissue, venous occlusion, perivasculitis and deposits of C3, C4 and immunoglobulins (IgA, IgG and IgM) in the arterial wall and surrounding tissue. These findings indicate that the formation of aneurysm in vasculo-Behçet's disease is caused by destruction of the intimal and outer side of the arterial wall.