Arterial Wall Inflammation In Patients Research Articles

Trehalose-induced alterations in serum expression levels of microRNAs associated with vascular inflammation in patients with coronary artery disease - the pilot results from the randomized controlled trial.

IntroductionBackground: This study aimed to investigate the trehalose-induced alterations in serum expression levels of miRNAs associated with vascular inflammation in patients with coronary artery disease (CAD) in order to evaluate the effectiveness of intravenous (IV) trehalose administration in reducing arterial wall inflammation.Material and methodsMethods: This trial enrolled 14 men with a history of myocardial infarction (MI) and systemic inflammation. The patients were randomized in a 2:1 ratio to trehalose (15g/week, IV administration) (N=10) or placebo (equal volume 0.9% normal saline) (N=4) for a period of 12-weeks. The relative serum expression levels of miRNA-126, miRNA-24, miRNA-181b, miRNA-10a and miRNA-92a were assessed.ResultsResults: IV trehalose administration significantly increased the serum level of miRNA-24 (2.473±0.72; P=0.037) compared to the baseline, but did not alter the other miRNA serum levels. However, at the end of the study, miRNA-24 (4.58±0.99; P=0.002), miRNA-181b (4.08±1.75; P=0.009) and miRNA-10a (3.68±0.63; P=0.013) showed notably higher serum levels in the trehalose relative to the placebo group. Furthermore, the reduction (normalized to baseline) in serum levels of miRNA-126 (P=0.042) and miRNA-92a (P=0.001) were reduced in the trehalose versus placebo group, while the serum level of miRNA-24 (P=0.007) was notably higher than that in the placebo group.ConclusionsConclusion: Serum levels of miRNAs associated with vascular inflammation were altered following IV trehalose administration. The alterations in serum miRNAs, especially miRNA-126 and miRNA-24, could be considered as helpful biomarkers for the evaluation of trehalose potency in reducing arterial wall inflammation in patients with CAD.

Potent reduction of plasma lipoprotein (a) with an antisense oligonucleotide in human subjects does not affect ex vivo fibrinolysis

It is postulated that lipoprotein (a) [Lp(a)] inhibits fibrinolysis, but this hypothesis has not been tested in humans due to the lack of specific Lp(a) lowering agents. Patients with elevated Lp(a) were randomized to antisense oligonucleotide [IONIS-APO(a)Rx] directed to apo(a) (n = 7) or placebo (n = 10). Ex vivo plasma lysis times and antigen concentrations of plasminogen, factor XI, plasminogen activator inhibitor 1, thrombin activatable fibrinolysis inhibitor, and fibrinogen at baseline, day 85/92/99 (peak drug effect), and day 190 (3 months off drug) were measured. The mean ± SD baseline Lp(a) levels were 477.3 ± 55.9 nmol/l in IONIS-APO(a)Rx and 362.1 ± 89.9 nmol/l in placebo. The mean± SD percentage change in Lp(a) for IONIS-APO(a)Rx was -69.3 ± 12.2% versus -5.4 ± 6.9% placebo (P < 0.0010) at day 85/92/99 and -15.6 ± 8.9% versus 3.2 ± 12.2% (P = 0.003) at day 190. Clot lysis times and coagulation/fibrinolysis-related biomarkers showed no significant differences between IONIS-APO(a)Rx and placebo at all time points. Clot lysis times were not affected by exogenously added Lp(a) at concentrations up to 200 nmol/l to plasma with very low (12.5 nmol/l) Lp(a) levels, whereas recombinant apo(a) had a potent antifibrinolytic effect. In conclusion, potent reductions of Lp(a) in patients with highly elevated Lp(a) levels do not affect ex vivo measures of fibrinolysis; the relevance of any putative antifibrinolytic effects of Lp(a) in vivo needs further study.

Treatment of Inflammatory Diseases with IL-1 Blockade.

Autoinflammatory diseases are distinct from autoimmune diseases. Whereas autoinflammatory diseases are due to dysfunctional T-cells and B-cells, autoinflammatory diseases are due to overproduction of macrophage cytokines particularly interleukin-1 beta (IL-1β). A causative role for IL-1 in autoinflammatory diseases is derived from clinical studies blocking the IL-1 receptor or neutralizing monoclonal antibodies or soluble receptors. A review was performed of clinical trials in autoinflammatory diseases using the IL-1 receptor antagonist (anakinra), the soluble IL-1 receptor (rilonacept), antibodies to IL-1β (canakinumab, gevokizumab) and anti-IL-1α (xilonix). Anakinra blocks the IL-1 Receptor type 1 (IL-1R1) and therefore blocks the activities of both IL-1α and IL-1β. Off-label use of anakinra is common for a broad spectrum of inflammatory diseases. Neutralization of IL-1β is used to treat hereditary autoinflammatory diseases but also atherosclerosis. Rilonacept reduces arterial wall inflammation in patients with chronic kidney disease. Neutralization of IL-1α has prolonged life in patients with advanced metastatic colorectal cancer. Compared to other cytokine blocking therapies, reducing the activities of IL-1 has an excellent safety record. Blocking IL-1 therapies can be used to treat a wide-spectrum of acute and chronic inflammatory diseases.

CCR2 expression on circulating monocytes is associated with arterial wall inflammation assessed by 18F-FDG PET/CT in patients at risk for cardiovascular disease.

Circulating monocytes infiltrate the plaque and differentiate into macrophages, contributing to an inflammatory environment which is associated with higher risk of cardiovascular events. Although the pivotal role of circulating monocytes in plaque inflammation has been firmly established, the search continues to identify specific monocyte subsets that may be especially atherogenic. Therefore, we evaluated the relation between monocyte phenotype, particularly surface receptor expression, and arterial wall inflammation in patients at increased cardiovascular risk. We performed a multivariate linear regression analysis in 79 patients at increased cardiovascular risk who had both an 18F-fluorodeoxyglucose positron emission tomography/computed tomography to assess arterial wall inflammation and extensive monocyte characterization (using flow cytometry). We found that CCR2, a monocyte chemokine receptor essential for transmigration, significantly correlates with arterial wall inflammation. This relationship was independent of traditional cardiovascular risk factors and statin use (β = 0.429, P = 0.015). We found no relation between arterial wall inflammation and monocyte count or monocyte subsets, namely CD14+CD16-, CD14+CD16+, CD14+CD16 ++, CCR5+, CD18+, CD11b+, or CD11c+ monocytes. Monocyte CCR2 expression is associated with arterial wall inflammation in patients at increased cardiovascular risk. Our data warrant further studies to assess if inhibition of CCR2 may attenuate atherosclerotic plaque inflammation.

Increased arterial wall inflammation in patients with familial dysbetalipoproteinemia

Increased arterial wall inflammation in patients with familial dysbetalipoproteinemia

Increased arterial wall inflammation in patients with ankylosing spondylitis is reduced by statin therapy.

Ankylosing spondylitis (AS) is a chronic inflammatory disease with involvement of axial and sacroiliac joints. In addition, patients with AS have increased risk of cardiovascular disease (CVD), which might be attributed to enhanced inflammatory activity of the arterial wall. In the present study, we compared the level of carotid arterial wall inflammation in patients with AS with healthy controls using (18)F-fluorodeoxyglucose ((18)F-FDG) positron emission tomography with CT. As arterial wall inflammation is reduced by statin therapy, we subsequently assessed the effect of 3-month statin therapy on arterial wall inflammation in AS. We included 24 patients with AS (age 44±10, 72% males) without a history of CVD and 20 controls matched for age and gender. Patients with AS had lower high-density lipoprotein cholesterol and increased C reactive protein (CRP) compared with controls. The 10-year CVD risk was 2% in both groups. Notwithstanding, patients with AS had a 20% increase in arterial wall (18)F-FDG uptake compared with controls. Three-month atorvastatin 40 mg daily significantly lowered low-density lipoprotein cholesterol (baseline 3.55±1.15 mmol/L, -53%) and CRP (baseline 5.0 (1.5-9.3) mg/L, -58%) with a concomitant decrease of carotid arterial wall inflammation (maximum target-to-background ratio from 1.90±0.30 to 1.67±0.27; p=0.009). Patients with AS and without other CVD risk factors have increased arterial wall inflammation, which decreases upon statin therapy. These subjects are not identified as being at risk in current cardiovascular prevention guidelines. Our data support the need to revise CV disease management in AS, with perhaps a role for early statin therapy.

Increased arterial wall inflammation in patients with rheumatoid arthritis in remission

Objectives: Patients with rheumatoid arthritis (RA) are characterized by a marked increase in cardiovascular risk, atributed to the systemic pro-inflammatory state. Whereas remission of RA can be achieved in the majority of patients, some require continuous biological therapy, which is potentially mediated by a chronic enhanced cellular drive. It is unclear whether remission in the joint inflammation coincides with attenuation of the inflammatory activity in the arterial wall. We hypothesized that RA patients requiring persistent biological therapy are characterized by a higher inflammatory state.

Quantification of Supra-Aortic Arterial Wall Inflammation in Patients With Arteritis Using High Resolution Dynamic Contrast-Enhanced Magnetic Resonance Imaging

: To compare [F]- -fluoro-D-glucose (FDG) positron emission tomography (PET)/computed tomography (CT), used in clinical routine to detect inflamed arteries in patients with arteritis, with high resolution dynamic contrast-enhanced (DCE) magnetic resonance imaging (MRI) in its ability to measure inflammation in carotid and vertebral arteries. : This study was performed with written informed consent, Health Insurance Portability and Accountability Act (HIPAA) compliance, and institutional review board approval. DCE-MRI of the carotid and vertebral arteries of 17 patients with suspected arteritis was acquired at 3T (2D saturation-recovery spoiled gradient echo, in plane resolution 0.625 × 0.625 mm) using a dedicated 4-channel carotid coil. Patients underwent [F] FDG-PET/CT within 1 week of the MRI scan. The blood pool-corrected mean standardized uptake value (mean target-to-background ratio [TBRmean]) was measured on PET/CT images at the identical location as the region-of-interest in the magnetic resonance images. MRI signal intensity data was analyzed to generate estimates of the tissue extraction fraction and interstitial volume using a 2-compartment model. : [F]-FDG PET/CT TBRmean was significantly higher in patients with than without arteritis (1.55 ± 0.34 vs. 1.06 ± 0.14, P = 0.001). Patients diagnosed with arteritis had significantly higher extraction fractions as measured by DCE-MRI than patients without arteritis (8.79% ± 2.19% vs. 5.82% ± 1.13%, P = 0.002). TBRmean correlated significantly with the extraction fraction (r = 0.73, P < 0.001). DCE-MRI and FDG-PET/CT yielded the same sensitivity (86%) and specificity (90%) for the detection of arteritis. Intra- and interreader reproducibility was good with Intraclass Correlation Coefficients of 0.82 and 0.78, respectively. : DCE-MRI is able to measure arterial inflammation reliably and noninvasively with good correlation to [F]-FDG PET/CT in patients suffering from arteritis of the supraaortic arteries.

Detection and Quantification of Large-Vessel Inflammation with 11C-(R)-PK11195 PET/CT

We investigated whether PET/CT angiography using 11C-(R)-PK11195, a selective ligand for the translocator protein (18 kDa) expressed in activated macrophages, could allow imaging and quantification of arterial wall inflammation in patients with large-vessel vasculitis. Seven patients with systemic inflammatory disorders (3 symptomatic patients with clinical suspicion of active vasculitis and 4 asymptomatic patients) underwent PET with 11C-(R)-PK11195 and CT angiography to colocalize arterial wall uptake of 11C-(R)-PK11195. Tissue regions of interest were defined in bone marrow, lung parenchyma, wall of the ascending aorta, aortic arch, and descending aorta. Blood-derived and image-derived input functions (IFs) were generated. A reversible 1-tissue compartment with 2 kinetic rate constants and a fractional blood volume term were used to fit the time-activity curves to calculate total volume of distribution (VT). The correlation between VT and standardized uptake values was assessed. VT was significantly higher in symptomatic than in asymptomatic patients using both image-derived total plasma IF (0.55±0.15 vs. 0.27±0.12, P=0.009) and image-derived parent plasma IF (1.40±0.50 vs. 0.58±0.25, P=0.018). A good correlation was observed between VT and standardized uptake value (R=0.79; P=0.03). 11C-(R)-PK11195 imaging allows visualization of macrophage infiltration in inflamed arterial walls. Tracer uptake can be quantified with image-derived IF without the need for metabolite corrections and evaluated semiquantitatively with standardized uptake values.

Effect of Long-Term Homocysteine Reduction with B Vitamins on Arterial Wall Inflammation Assessed by Fluorodeoxyglucose Positron Emission Tomography: A Randomised Double-Blind, Placebo-Controlled Trial

Background: Homocysteine may promote atherosclerosis by exacerbating inflammatory processes within the arterial wall. B-vitamin supplements reduce total plasma homocysteine concentrations (tHcy), but it is not known whether the treatment also reduces arterial wall inflammation. We used ¹⁸F-fluorodeoxygluose positron emission tomography (¹⁸F-FDG PET) to investigate whether long-term homocysteine-lowering treatment alters arterial wall inflammation in patients with a history of ischemic stroke. Methods: 30 stroke patients were randomly assigned to B-vitamin therapy (folic acid 2 mg, vitamin B₆ 25 mg and vitamin B₁₂ 0.5 mg) or placebo in a double-blind clinical trial. After a mean treatment period of 4.0 ± 0.7 years, all subjects had tHcy, carotid intima-medial thickness (CIMT) and flow-mediated dilation (FMD) of the brachial artery measured and underwent an ¹⁸F-FDG PET scan. Standardised uptake values (SUV) were measured at six sites in the carotid, femoral and aortic arteries. Areas of locally increased tracer uptake in the arterial wall (‘hot spots’) were also identified and counted. Results: Long-term B-vitamin treatment significantly reduced tHcy compared with placebo (8.4 μmol/l, 95% confidence interval, CI, 7.2–9.6 vs. 11.6 μmol/l, 95% CI 10.0–13.4, p = 0.002). The treatment did not affect mean arterial SUV (2.0 ± 0.3 vitamins vs. 2.1 ± 0.3 placebo, p = 0.65) or the number of hot spots (n = 1.1 ± 1.0 vitamins vs. n = 1.2 ± 1.0 placebo, p = 0.65). There was no significant correlation between mean arterial SUV and CIMT or FMD. Conclusions: These results suggest that a long-term Hcy reduction with B vitamins does not affect arterial wall inflammation assessed by ¹⁸F-FDG PET.