Fine particulate matter (PM2.5) inhalation-induced alterations in the plasma lipidome as promoters of vascular inflammation and insulin resistance.

Fine particulate matter (PM2.5) air pollution exposure increases the risk of developing cardiovascular disease (CVD). Although the precise mechanisms by which air pollution exposure increases CVD risk remain uncertain, research indicates that PM2.5-induced endothelial dysfunction contributes to CVD risk. Previous studies demonstrate that concentrated ambient PM2.5 (CAP) exposure induces vascular inflammation and impairs insulin and vascular endothelial growth factor (VEGF) signaling dependent on pulmonary oxidative stress. To assess whether CAP exposure induces these vascular effects via plasmatic factors, we incubated aortas from naïve mice with plasma isolated from mice exposed to HEPA-filtered air or CAP (9 days) and examined vascular inflammation and insulin and VEGF signaling. We found that treatment of naïve aortas with plasma from CAP-exposed mice activates NF-κBα and induces insulin and VEGF resistance, indicating transmission by plasmatic factor(s). To identify putative factors, we exposed lung-specific ecSOD-transgenic (ecSOD-Tg) mice and wild-type (WT) littermates to CAP at concentrations of either ∼60 µg/m3 (CAP60) or ∼100 µg/m3 (CAP100) and measured the abundance of plasma metabolites by mass spectrometry. In WT mice, both CAP concentrations increased levels of fatty acids such as palmitate, myristate, and palmitoleate and decreased numerous phospholipid species; however, these CAP-induced changes in the plasma lipidome were prevented in ecSOD-Tg mice. Consistent with the literature, we found that fatty acids such as palmitate are sufficient to promote endothelial inflammation. Collectively, our findings suggest that PM2.5 exposure, by inducing pulmonary oxidative stress, promotes unique lipidomic changes characterized by high levels of circulating fatty acids, which are sufficient to trigger vascular pathology.NEW & NOTEWORTHY We found that circulating plasma constituents are responsible for air pollution-induced vascular pathologies. Inhalation of fine particulate matter (≤PM2.5) promotes a unique form of dyslipidemia that manifests in a manner dependent upon pulmonary oxidative stress. The air pollution-engendered dyslipidemic phenotype is characterized by elevated free fatty acid species and diminished phospholipid species, which could contribute to vascular inflammation and loss of insulin sensitivity.

Sustained Focal Vascular Inflammation Accelerates Atherosclerosis in Remote Arteries.

OBJECTIVE: Evidence from preclinical and clinical studies has demonstrated that myocardial infarction promotes atherosclerosis progression. The impact of focal vascular inflammation on the progression and phenotype of remote atherosclerosis remains unknown. Approach and Results: We used a novel ApoE-/- knockout mouse model of sustained arterial inflammation, initiated by mechanical injury in the abdominal aorta. Using serial in vivo molecular MRI and ex vivo histology and flow cytometry, we demonstrate that focal arterial inflammation triggered by aortic injury, accelerates atherosclerosis in the remote brachiocephalic artery. The brachiocephalic artery atheroma had distinct histological features including increased plaque size, plaque permeability, necrotic core to collagen ratio, infiltration of more inflammatory monocyte subsets, and reduced collagen content. We also found that arterial inflammation following focal vascular injury evoked a prolonged systemic inflammatory response manifested as a persistent increase in serum IL-6 (interleukin 6). Finally, we demonstrate that 2 therapeutic interventions-pravastatin and minocycline-had distinct anti-inflammatory effects at the plaque and systemic level. CONCLUSIONS: We show for the first time that focal arterial inflammation in response to vascular injury enhances systemic vascular inflammation, accelerates remote atheroma progression and induces plaques more inflamed, lipid-rich, and collagen-poor in the absence of ischemic myocardial injury. This inflammatory cascade is modulated by pravastatin and minocycline treatments, which have anti-inflammatory effects at both plaque and systemic levels that mitigate atheroma progression.

Renal cystic disease in the Fbn1C1039G/+ Marfan mouse is associated with enhanced aortic aneurysm formation.

Marfan syndrome (MFS) is a connective tissue disorder caused by mutations in the fibrillin-1 gene (FBN1), resulting in aortic aneurysm formation and dissections. Interestingly, variable aortopathy is observed even within MFS families with the same mutation. Thus, additional risk factors determine disease severity. Here, we describe a case of a 2-month-old Fbn1C1039G/+ MFS mouse with extreme aortic dilatation and increased vascular inflammation, when compared to MFS siblings, which coincided with unilateral renal cystic disease. In addition, this mouse presented with increased serum levels of creatinine, angiotensin-converting enzyme, corticosterone, macrophage chemoattractant protein-1, and interleukin-6, which may have contributed to the vascular pathology. Possibly, cystic kidney disease is associated with aneurysm progression in MFS patients. Therefore, we propose that close monitoring of the presence of renal cysts in MFS patients, during regular vascular imaging of the whole aorta trajectory, may provide insight in the frequency of cystic kidney disease and its potential as a novel indicator of aneurysm progression in MFS patients.

The many faces of IgG4-related disease: report of a case with inaugural recurrent aortic aneurism ruptures and literature review.

Vascular involvement in IgG4-related disease (IgG4-RD), is a well-recognized feature and large vessel commitment, especially the aorta, can be the only manifestation of the disease. Being a newly recognized disease, its diagnosis and workup still represents a challenge in clinical practice. A 47-year-old-man with two aortic aneurysms ruptures, one at abdominal and the other at thoracic level, was referred to our rheumatology department. The initial analysis of the surgical specimen obtained 3 years earlier revealed a nonspecific aortitis. Re-evaluation of the biopsy with immunohistology now demonstrated the presence of IgG4 deposits. Evidence-based recommendations regarding diagnosis, treatment and follow-up of IgG4-related large-vessel involvement are lacking. In this particular case, histopathology were crucial. The authors review and discuss vascular involvement in IgG4-RD and respective treatment options.

[IgG4-related disease, the new "great mimicker": report of one case]. / Enfermedad relacionada a IgG4, el nuevo "gran simulador": caso clínico.

Due to its multisystem involvement, IgG4 -related disease should be considered in the differential diagnosis of medical conditions such as lymphadenopathies, aortitis, serositis and retroperitoneal fibrosis. It shares features with other entities historically described as "great mimickers" such as syphilis, tuberculosis, sarcoidosis, and systemic lupus erythematosus. We report a 40 year-old male with recurrent effusive - constrictive pericarditis, lymphadenopathy and aortitis. The study revealed an inactive tuberculosis with negative cultures for acid fast bacilli. The patient had high serum levels of IgG4 and a mediastinal lymph node biopsy was consistent with IgG4 -related disease. The patient was treated with prednisone 40 mg/day with an excellent response.

Enfermedad relacionada a IgG4, el nuevo "gran simulador": caso clínico / IgG4-related disease, the new "great mimicker": Report of one case

Due to its multisystem involvement, IgG4 -related disease should be considered in the differential diagnosis of medical conditions such as lymphadenopathies, aortitis, serositis and retroperitoneal fibrosis. It shares features with other entities historically described as "great mimickers" such as syphilis, tuberculosis, sarcoidosis, and systemic lupus erythematosus. We report a 40 year-old male with recurrent effusive - constrictive pericarditis, lymphadenopathy and aortitis. The study revealed an inactive tuberculosis with negative cultures for acid fast bacilli. The patient had high serum levels of IgG4 and a mediastinal lymph node biopsy was consistent with IgG4 -related disease. The patient was treated with prednisone 40 mg/day with an excellent response.

Inflammatory thoracic aortic aneurysm (lymphoplasmacytic thoracic aortitis): a 13-year-experience at a German Heart Center with emphasis on possible role of IgG4.

BACKGROUND & AIM: Aortic aneurysms represent one of the major causes of cardiovascular surgery. Their etiology varies greatly based on patient's age and other clinicopathologic determinants. In addition to common atherosclerotic vascular diseases, an inflammatory etiology, in particular IgG4-related disease (IgG4-RD) has increasingly emerged as a cause of dissecting inflammatory aortic aneurysms (IAA). METHODS: To assess the frequency and types of IAA, we reviewed all cases of aortic aneurysms resected at our Erlangen Heart Center during 2000-2013. RESULTS: 376 patients underwent resection of aortic aneurysms in the study period. These are further categorized as ascending aortic aneurysms (45%), aortic arch aneurysm (2%), descending aortic aneurysm (3%), type A dissection (46%) and type B dissection (4%). Fifteen cases (4%) showed variable lymphoplasmacytic inflammation thus qualifying as IAA. Affected were 9 females and 6 males (female to male ratio = 1.5:1; age range: 52-80 yrs; mean: 70 yrs; median: 72 yrs). None was known to have IgG4-RD and serum IgG4 and/or IgG levels (known in 6 cases) were normal. Variable sclerosing lymphoplasmacytic inflammation was seen either confined to the adventitia (periaortitis; mainly in males) or extending through all layers (mainly in females). A wide range of IgG4 plasma cells (range: 3-182/HPF; mean: 51/HPF) and IgG4: IgG ratios (range: 0.02 to 0.91; mean: 0.37) were detected. All but one of the cases with at least focally transmural inflammation showed a higher IgG4: IgG ratios in excess of 0.3 (range, 0.32-0.91; median, 0.62). Lymphoid follicle and variable fibrosis were common but obliterative phlebitis was not seen. CONCLUSION: IgG4-rich sclerosing lymphoplasmacytic thoracic aortitis is a constant histological feature of thoracic IAA. Normal serum IgG4 in most patients, predilection for women and absence of other features of IgG4-RD all suggest a tissue-specific localized autoimmunological process and argue against a systemic disorder. The relationship (if any) of IgG4-rich lymphoplasmacytic thoracic aortitis in those patients with IAA lacking other organ manifestations or an elevated serum IgG4 level to systemic IgG4-RD remains unclear and merit further studies.

Local inflammation is associated with aortic thrombus formation in abdominal aortic aneurysms. Relationship to clinical risk factors.

Intraluminal thrombus formation in aortic abdominal aneurysms (AAA) is associated with adverse clinical prognosis. Interplay between coagulation and inflammation, characterised by leukocyte infiltration and cytokine production, has been implicated in AAA thrombus formation. We studied leukocyte (CD45+) content by flow cytometry in AAA thrombi from 27 patients undergoing surgical repair. Luminal parts of thrombi were leukocyte-rich, while abluminal segments showed low leukocyte content. CD66b+ granulocytes were the most prevalent, but their content was similar to blood. Monocytes (CD14+) and T cells (CD3+) were also abundant, while content of B lymphocytes (CD19+) and NK cells (CD56+CD16+) were low. Thrombi showed comparable content of CD14highCD16- monocytes and lower CD14highCD16+ and CD14dimCD16+, than blood. Monocytes were activated with high CD11b, CD11c and HLA-DR expression. Total T cell content was decreased in AAA thrombus compared to peripheral blood but CD8 and CD3+CD4-CD8- (double negative T cell) contents were increased in thrombi. CD4+ cells were lower but highly activated (high CD69, CD25 and HLA-DR). No differences in T regulatory (CD4+CD25+FoxP3+) cell or pro-atherogenic CD4+CD28null lymphocyte content were observed between thrombi and blood. Thrombus T cells expressed high levels of CCR5 receptor for chemokine RANTES, commonly released from activated platelets. Leukocyte or T cell content in thrombi was not correlated with aneurysm size. However, CD3+ content was significantly associated with smoking in multivariate analysis taking into account major risk factors for atherosclerosis. In conclusion, intraluminal AAA thrombi are highly inflamed, predominantly with granulocytes, CD14highCD16- monocytes and activated T lymphocytes. Smoking is associated with T cell infiltration in AAA intraluminal thrombi.

Investigation and treatment of a complicated inflammatory aortoiliac aneurysm.

Inflammatory abdominal aortic aneurysms (IAAAs) account for 5% to 10% of all abdominal aortic aneurysms, occurring primarily in males. Their true etiology is unknown. Symptoms and signs of IAAA are so variable that they present to a wide range of specialties. There is debate in the literature whether IAAA is a manifestation of systemic autoimmune disease. We describe the case of a young female patient with complicated inflammatory aortoiliac aneurysmal disease, illustrating diagnostic and treatment challenges that remain. Our patient had a positive autoantibody screen, raised erythrocyte sedimentation rate, positive enzyme-linked immunosorbent spot test, and saccular aneurysms, including infective and inflammatory etiologies in her differential diagnosis. Early diagnosis is crucial to limit disease progression, morbidity, and mortality. Medical management is important to address the underlying disease process, but a combination of endovascular and open surgical intervention is often necessary for definitive treatment. Available evidence offers plausibility for benefit of endovascular intervention over open repair.

[Effects of pulse-therapy on natural anticoagulant system of the endothelium in nonspecific aortoarteritis]. / Vliianie pul's-terapii na estestvennuiu antikoaguliantnuiu sistemu éndoteliia pri nespetsificheskom aortoarterite.

AIM: To investigate the influence of pulse-therapy on anticoagulant system of the endothelium in patients with nonspecific aortoarteritis. MATERIAL AND METHODS: Eleven patients (9 females and 2 males, mean age 33.4 +/- 8.8 years, the disease duration 5.8 +/- 5.7 years) with nonspecific aortoarteritis were examined. 9 patients had the third anatomic type of the disease with affection of the aortic arch and abdominal aorta vessels, 2 patients had the first anatomic type with isolated affection of the aortic arch. The patients received a standard three day course of pulse-therapy (PT) with glucocorticosteroids (GCS) (metipred in a dose 1000 mg/day or dexametasone in a dose 2 mg/kg/day) with a single dose of cytostatic (CS) (cyclophosphamide in a dose 10 mg/kg b.w.) during the first infusion. Further PT consisted of monthly single infusion of GCS and CS in the above doses for 9 to 12 months. Examination of the patients was carried out before the treatment and on the treatment day 4 and 20 and follow-up month 3, 6 and 12. Estimation of clinical activity was carried out according to BVAS. Levels of protein C, S, antithrombin III were measured by ELISA in plasma. Activities of protein C, antithrombin III and plasminogen were determined by the optical assay with chromogenic substrates. RESULTS: Before the start of the treatment BVAS was 6.8 +/- 4.3. During the follow-up mean scores of BVAS were significantly lower than before the pulse-therapy (2.7 +/- 2.2; 2.5 +/- 3.9; 3.1 +/- 5.1; 1.8 +/- 2.6 and 1.7 +/- 1.7, respectively; p < 0.05). Prior to the treatment, a mean level of protein C was 86.6 +/- 37.5% and range of its activity 175.2 +/- 112.9%. On the fourth day after pulse-therapy a mean concentration of protein C increased (128.8 +/- 29.0%; p < 0.05) while activity of protein C tended to a decrease on the 20th day (99.2 +/- 17.6; p > 0.05). There were no significant differences in the levels of protein S, antithrombin III and its activity, activity of plasminogen in the course of PT. CONCLUSION: PT has a good anti-inflammatory effect in the absence of unfavorable influence on anticoagulant system of the endothelium in patients with nonspecific aortoarteritis.

Residual inflammatory process after aortoiliac reconstructive surgery.

BACKGROUND: The aim of the present study was to investigate the inflammatory reaction and its evolution in patients who underwent a prosthetic vascular procedure. Moreover the participation of this chronic process, during the follow-up, as a promoting or a consequence of vascular injury must be discussed. METHODS: Thirty-four patients were enrolled in the study. All patients had an aortic disease and underwent a prosthetic vascular procedure. Preoperative exclusion criteria were an emergency situation, diabetes, infection, chronic inflammatory disease, cancer and hemopathy. Postoperative exclusion criteria were the same together with abdominal complications and additional surgery during the follow-up. The inflammatory process was investigated with the measurement of blood acute phase proteins, haptoglobin, alpha1-glycoprotein acid, C-reactive protein and interleukin-6, before, immediately after surgery and several months after surgery. RESULTS: An increase in acute phase proteins was not observed to the same extent for all the studied patients. Before the surgical procedure, chronic inflammatory process was revealed by an increase in haptoglobin (52.9 p 100) and alpha1 glycoprotein acid (52.9 p 100) whereas increase in C-reactive protein (26.4 p 100) and interleukin-6 (92 p 100) are related to an acute process. Later after surgery, the chronic inflammatory process remained but differed from the observed process before surgery only by haptoglobin (61.7 p 100) and interleukin-6 (47 p 100). CONCLUSIONS: The presented results, observed during the follow-up of vascular surgery focused on persistent inflammatory process and the surgical procedure did not modify the time course of this process. The evolutionary disease could be considered as chronic and independent of the local effect.

Elevated circulating levels of inflammatory cytokines in patients with abdominal aortic aneurysm.

The basic feature in the pathogenesis of abdominal aortic aneurysm (AAA) is the degradation of extracellular matrix components. This process is induced partly by cytokines secreted from inflammatory and mesenchymal cells. Circulating levels of inflammatory cytokines were studied in AAA patients and compared with subjects suffering from atherosclerotic disease only. Furthermore, the predictive value of cytokine concentrations was evaluated for aneurysm expansion rate. Circulating levels of interleukin 1 beta (IL-1 beta), interleukin 6 (IL-6), tumor necrosis factor-alpha (TNF-alpha), and interferon-gamma (IFN-gamma) were measured in 50 AAA patients (40 men, 10 women), 42 patients with coronary heart disease (CHD) (23 men, 19 women), and 38 controls whose angiogram was normal (17 men, 21 women). No differences in cytokine concentrations were found between the CHD patients and the controls. AAA disease was found to be associated with significantly higher IL-1 beta and IL-6 concentrations in both male patients (median concentrations of 19.40 pmol/L and 6.45 pmol/L, respectively) and female patients (19.26 pmol/L and 7.99 pmol/L) than in either the CHD patients or the controls (P < .005). TNF-alpha levels were slightly higher in the AAA patients (1.64 pmol/L in the males and 1.59 pmol/L in the females) than in the other groups (P < .05). IFN-gamma levels were elevated significantly in the female AAA patients (3.75 pmol/L) compared with levels found in the other female (P < .05) or male (P < .01) patient groups. The measured cytokine concentrations were not related to the size of the aneurysm or the maximal thickness of the thrombus within the aneurysm. IFN-gamma concentration showed a significant positive correlation to the aneurysm expansion (R = .37, P < .02) and negative correlation to the concentration of aminoterminal propeptide of type III procollagen during 6-month follow up (R = -.42, P < .005). The results show that circulating levels of inflammatory cytokines are elevated in patients with AAA disease, suggesting that the production of these cytokines is increased in these patients compared with CHD patients and controls. Elevated INF-gamma concentrations seem to predict an increased rate of expansion in AAA.

Elastin degradation in systemic vasculitis.

The elastin peptide level (EP) and elastase-type activity (EA) were investigated in 89 patients with different types of systemic vasculitis (polyarteritis nodosa-14, non-specific aortoarteritis-33, temporal arteritis-23 and thromboangiitis obliterans-18) and compared to the controls: 31 patients with leg atherosclerosis and 12 aged subjects with no evident vascular pathology. EP and EA levels in patients with thromboangiitis obliterans were significantly lower as compared to leg atherosclerosis and the aged control group (p < 0.02 for EA, p < 0.05 for EP). The increase of EP predominated in giant-cell arteritis as compared to the other vasculitic groups (18/56 vs. 5/32, p < 0.05); EA in these patients was the lowest. The activation of elastin degradation after corticosteroid treatment was demonstrated by an increase of EP in temporal arteritis (p < 0.05) and of EA in thromboangiitis obliterans (p < 0.03). We suggest that the determination of the above parameters of elastin degradation may be helpful in the search for differences in mechanisms of vascular damage between atherosclerosis and inflammatory vascular diseases.

Early inflammatory response to gelatin- and collagen-sealed Dacron prostheses.

The immediate inflammatory response following aortic reconstruction with two types of sealed Dacron grafts was studied in a prospective, randomized manner. C-reactive protein (CRP) levels were measured before surgery and on days 2 and 8 postoperatively. In the collagen-sealed group (n = 10) CRP levels were 10 +/- 9.6, 180.2 +/- 48.3, and 54.3 +/- 34.3 mg/L, respectively. In the gelatin-impregnated group (n = 10) the values were 10.5 +/- 8.7, 200.7 +/- 27.3, and 80.3 +/- 30.2 mg/L, respectively. The slight differences were not significant according to the analysis of variance test for repeated measurements. These findings suggest that implantation of a knitted Dacron graft sealed with collagen does not lead to a higher inflammatory reaction compared with a gelatin-sealed graft.

[Synthesis of cell membrane "signal" ATP in human erythrocyte membranes stimulated by insulin as criteria of the efficacy of therapeutic plasmapheresis]. / Stimuliruemyi insulinom sintez plazmomembrannogo "signal'nogo" ATP v plazmaticheskikh membranakh éritrotsitov cheloveka ka kriterii éffektivnosti lechebnogo plazmafereza.

Insulin-stimulated synthesis of plasma membraneous "signal" ATP (psATP) from ADP and P(i) in oxidation coupled with that of NADH was detected in a preparation of plasma membranes from human erythrocytes; psATP was formed at concentrations of 10(-8)-10(-9) M. Effect of medicinal plasmapheresis on ability of erythrocyte membranes to produce psATP was studied. The rate of psATP biosynthesis was estimated in healthy volunteers and in patients with various diseases: nonspecific aortic arteritis, bronchial asthma, peritonitis, myasthenia before and after plasmapheresis. Distinct values of basal content of ATP (without insulin) and insulin-stimulated biosynthesis of ATP were detected in volunteers. Elevation of ATP biosynthesis, in response to insulin effect, was equal to 8.029 +/- 0.163 nmol/mg of membrane protein per min. Estimation of the psATP biosynthesis rate in patients with various pathological states enabled to detect markedly that psATP content tends to increase after plasmapheresis. Absolute values of psATP content were distinctly lower in these patients than those in healthy volunteers, while after plasmapheresis these parameters approached the normal level. Estimation of the insulin-stimulated synthesis of psATP may serve as a valid criterion of plasmapheresis efficiency.

Inflammatory abdominal aortic aneurysm and the associated T-cell reaction: a case study.

The immune response associated with an inflammatory abdominal aortic aneurysm was studied by determining the phenotypes of lymphocytes in the peripheral blood, the aortic aneurysm wall, and the perianeurysmal tissue. Increased numbers of activated T cells were found in all three areas. After aneurysm repair, peripheral blood analysis demonstrated normalization of the T-cell subsets. These data suggest that inflammatory abdominal aortic aneurysm is associated with a measurable immune response in peripheral blood with elevation of the same subset of inflammatory cells (CD4) as detected in abdominal aortic aneurysm tissue, and the immune response regresses after aneurysm repair.

[Clinical importance of determining Na-Li countertransport in patients with arterial hypertension]. / Klinicheskoe znachenie opredeleniia Na--Li-protivotransporta u bol'nykh arterial'nymi gipertoniiami.

Erythrocyte Na-Li countertransport was assessed in 99 patients with various arterial hypertensions. Mean Na-Li countertransport rate was 476 +/- 43 mumol/l 1 cells/hour in essential hypertension, or nearly twice as high as mean rates for hypertensive chronic diffuse glomerulonephritis, chronic pyelonephritis, renovascular hypertension and nonspecific aortoarteritis, primarily affecting extracranial arteries. In 2 patients, operated on for renal arterial stenosis, Na-Li countertransport was high and the operation had no hypotensive effect, suggesting that renal arterial stenosis was combined with essential hypertension. In 1 patient, the original diagnosis of chronic diffuse glomerulonephritis and aldosteronoma was not confirmed at surgery and renal biopsy, and the diagnosis of essential hypertension was made instead.