Israel Medical Association Journal

Background: Interleukin-10 is an anti-inflammatory cytokine and consequently is considered by many to have a protective role in heart failure, as opposed to the notorious tumor necrosis factor-alpha.

Objectives: To test the hypothesis of the possible beneficial impact of IL-10[1] on mortality in systolic heart failure patients in relation to their circulating TNFα[2] levels.

Methods: We measured circulating levels of IL-10 and TNFα in 67 ambulatory systolic heart failure patients (age 65 ± 13 years).

Results: Mortality was or tended to be higher in patients with higher levels (above median level) of circulating TNFα (9/23, 39% vs. 6/44, 14%; P = 0.02) or IL-10 (10/34, 30% vs. 5/33, 15%; P = 0.10). However, mortality was highest in the subset of patients with elevation of both markers above median (7/16, 44% vs. 8/51, 16%; P = 0.019). Elevation of both markers was associated with more than a threefold hazard ratio for mortality (HR[3] 3.67, 95% confidence interval 1.14–11.78).

Conclusions: Elevated circulating IL-10 levels in systolic heart failure patients do not have a protective counterbalance effect on mortality. Moreover, patients with elevated IL-10 and TNFα had significantly higher mortality, suggesting that the possible interaction in the complex inflammatory and anti-inflammatory network may need further study.

Background: Fat tissue mediates the production of inflammatory cytokines and oxidative products, which are key steps in the development of type 2 diabetes and atherosclerosis. Antioxidant-rich diets protect against chronic diseases, but antioxidants may interfere with pro-inflammatory signals.

Objectives: To investigate the effect of the potent tomato-derived antioxidant carotenoid, lycopene, on plasma antioxidants (carotenoids and vitamin E), inflammatory markers (C-reactive protein, interleukin-6, tumor necrosis factor-alpha), and oxidation products (conjugated dienes).

Methods: Eight obese patients (body mass index 37.5 ± 2.5 kg/m²) were compared with a control group of eight lean, age and gender-matched subjects (BMI[1] 21.6 ±  0.6 kg/m²), before and after 4 weeks of lycopene supplementation (tomato-derived Lyc-O-Mato) (30 mg daily).

Results: Plasma carotenoids were significantly reduced in the obese compared to control subjects (0.54 ± 0.06 vs. 0.87 ± 0.08 mg/ml, P < 0.01). CRP[2] levels were significantly higher (6.5 vs. 1.1 mg/L, P = 0.04) in obese vs. controls, as were IL-6[3] and conjugated dienes (3.6 and 7.9-fold, respectively). CRP, IL-6 and conjugated dienes correlated with BMI, while IL-6 and conjugated dienes correlated inversely with carotenoids (P < 0.05). Following lycopene treatment, a significant elevation of plasma carotenoids (1.79 vs. 0.54 ug/ml) and specifically lycopene (1.15 vs 0.23 ug/ml) (P < 0.001) occurred in the treatment vs. placebo group, respectively. Markers of inflammation and oxidation products were not altered by lycopene.
Conclusions: Obese patients showed abnormally higher markers of inflammation and oxidation products and lower plasma carotenoids. The lack of reduction of pro-inflammatory markers could be attributed to the short period of the study and the small number of participants. More studies are needed on the protective qualities of natural antioxidant-rich diets against obesity-related co-morbidities.

Background: High sensitivity C-reactive protein, a marker of inflammation, has been proposed to stratify coronary artery disease risk and is lowered by HMG-CoA reductase (statin) therapy. However, the reproducibility of persistently elevated hs-CRP[1] levels and association with other markers of inflammation in patients with stable CAD[2] on aggressive statin therapy is unknown.

Objectives: To determine the reproducibility of hs-CRP levels measured within 2 weeks in patients with documented CAD with stable symptoms and to identify associations with other markers of inflammation.

Methods: Levels of hs-CRP were measured twice within 14 days (7 ± 4) in 23 patients (22 males and 1 female, average age 66 ± 10 years) with stable CAD and hs-CRP ≥ 2.0 mg/L but ≤ 10 mg/L at visit 1. All patients had received statins for cholesterol management (low density lipoprotein-cholesterol 84 ± 25 mg/dl) with no dose change for > 3 months. None had a history or evidence of malignancy, chronic infection or inflammation, or recent trauma. There was no change in medications between visits 1 and 2, and no patient reported a change in symptoms or general health during this interval. White blood cell count and pro- and anti-inflammatory cytokines were measured at both visits.

Results: hs-CRP levels tended to be lower at visit 2 (median 2.4 mg/L, range 0.8–11 mg/L) than at visit 1 (median 3.3 mg/L, range 2.0–9.7 mg/L; P = 0.1793). However, between the two visits hs-CRP levels decreased by more than 1.0 mg/L in 10 patients and increased by more than 1.0 mg/L in 4 patients. Changes in hs-CRP levels were unrelated to changes in levels of white blood cells (P = 0.4353). Of the cytokines tested, only the anti-inflammatory cytokine interleukin-1 receptor antagonist and the pro-inflammatory cytokine interleukin-8 were above lower limits of detection, but there were no correlations between changes in these values and changes in hs-CRP (both P > 0.5).

Conclusions: In stable CAD patients on aggressive statin therapy, hs-CRP levels may fluctuate over brief periods in the absence of changes in health, cardiac symptom status and medications, and without corroboration with other measures of inflammation. Accordingly, elevated hs-CRP levels should be interpreted with caution in this setting.

Background: Myeloperoxidase levels were shown to reflect endothelial dysfunction, inflammation, atherosclerosis and oxidative stress.

Objectives: To examine the role of circulating myeloperoxidase, a leukocyte-derived enzyme, as a predictor of mortality in patients with congestive heart failure.

Methods: Baseline serum MPO[1] levels were measured in 285 consecutive CHF[2] patients and 35 healthy volunteers. N-terminal pro-brain natriuretic peptide and high sensitivity C-reactive protein concentrations were also measured. The primary outcome endpoint was overall mortality.

Results: MPO levels were significantly elevated in patients with CHF compared to healthy volunteers (P = 0.01). During a mean follow-up of 40.9 ± 11.3 months there were 106 deaths. On a univariate Cox regression analysis MPO levels were of marginal value (P = 0.07) whereas NT-proBNP[3] was of considerable value (P < 0.0001) in predicting all-cause mortality. By dividing our cohort according to NT-proBNP levels into high, intermediate and low risk groups a clear difference in mortality was shown. By further dividing the patient cohort according to MPO levels above or below the median (122.5 ng/ml), mortality prediction improved in the patients with intermediate NT-proBNP values.

[1] MPO = myeloperoxidase

[2] CHF = congestive heart failure

[3] NT-proBNP = N-terminal pro-brain natriuretic peptide

Background: Atherosclerosis is a chronic inflammatory process resulting in coronary artery disease.

Objectives: To determine the relationship between inflammatory markers and the angiographic severity of CAD[1].

Methods: We measured inflammatory markers in sequential patients undergoing coronary angiography. This included C-reactive protein, fibrinogen, serum cytokines (interleukin-1 beta, IL-1[2] receptor antagonist, IL-6, IL-8, IL-10) and tumor necrosis factor-alpha), all measured by high sensitivity enzyme-linked immunoabsorbent assay.

Results: There was a significant correlation between TNFα[3] and the severity of CAD as assessed by the number of obstructed coronary vessels and the Gensini severity score, which is based on the proximity and severity of the lesions. Patients had more coronary vessel disease (> 70% stenosis) with increasing tertiles of serum TNFα; the mean number of vessels affected was 1.15, 1.33, and 2.00 respectively (P < 0.001). IL-6 correlated with the Gensini severity score and coronary vessel disease (> 70% stenosis). A weaker correlation was present with IL-1 receptor antagonist. A significant correlation was not found with the other inflammatory markers. After adjustment for major risk factors, multivariate analyses showed that significant independent predictors of CAD vessel disease were TNFα (P < 0.05) and combined levels of TNFα and IL-6 (P < 0.05). IL-6 levels were independently predictive of Gensini coronary score (P < 0.05).

Conclusion: TNFa and IL-6 are significant predictors of the severity of coronary artery disease. This association is likely an indicator of the chronic inflammatory burden and an important marker of increased atherosclerosis risk.

Background: Polymorphonuclear leukocyte priming and low grade inflammation are related to severity of kidney disease. Erythropoietin-receptor is present on PMNLs[1].

Objectives: To evaluate the effect of 20 weeks of EPO[2]-alpha treatment on PMNL characteristics in relation to the rate of kidney function deterioration in patients with chronic kidney disease.

Methods: Forty anemic chronic kidney disease patients, stage 4-5, were assigned to EPO and non-EPO treatment for 20 weeks. A group of 20 healthy controls was also studied. PMNL priming and PMNL-derived low grade inflammation were estimated, in vivo and ex vivo, before and after EPO treatment: The rate of superoxide release, white blood cells and PMNL counts, serum alkaline phosphatase and PMNL viability were measured. EPO-receptor on PMNLs was assayed by flow cytometry. The effect of 20 weeks of EPO treatment on kidney function was related to the estimated glomerular filtration rate.

Results: EPO treatment attenuated superoxide release ex vivo and in vivo and promoted PMNL survival ex vivo. Decreased low grade inflammation was reflected by reduced WBC[3] and PMNL counts and ALP[4] activity following treatment. EPO retarded the deterioration in GFR[5]. The percent of PMNLs expressing EPO-R[6] was higher before EPO treatment and correlated positively with the rate of superoxide release. After 20 weeks of EPO treatment the percent of PMNLs expressing EPO-R was down-regulated.

Conclusions: These non-erythropoietic properties of EPO are mediated by EPO-R on PMNLs, not related to the anemia correction. A new renal protection effect of EPO via attenuation of PMNL priming that decreases systemic low grade inflammation and oxidative stress is suggested.

Background: Based on the outcome of several randomized controlled trials, the orally active leukotriene receptor antagonist montelukast (Singulair®, Merck) has been licensed for treatment of asthma. The drug is favored for treating childhood asthma, where a therapeutic challenge has arisen due to poor compliance with inhalation therapy.

Objectives: To assess the efficiency of and satisfaction with Singulair® in asthmatic children under real-life conditions.

Methods: Montelukast was prescribed for 6 weeks to a cohort of 506 children aged 2 to 18 years with mild to moderate persistent asthma, who were enrolled by 200 primary care pediatricians countrywide. Four clinical correlates of childhood asthma – wheeze, cough, difficulty in breathing, night awakening – were evaluated from patients' diary cards.

Results: Due to under-treatment by their physicians, almost 60% of the children were not receiving controller therapy at baseline. By the end of the study, which consisted of montelukast treatment, a significant improvement over baseline was noted in asthma symptoms and severity, as well as in treatment compliance. The participating pediatricians and parents were highly satisfied with the treatment.

Conclusions: The results of this extensive study show that the use of montelukast as monotherapy in children presenting with persistent asthma resulted in a highly satisfactory outcome for themselves, their parents and their physicians.
 

Management of asthma is currently based on symptoms (in children, usually a second-hand report from parents) and lung function measurements. Inhaled steroids, targeted at controlling airway inflammation, are the mainstay of asthma management. Due to possible side effects they should be used at the lowest possible doses while asthma is adequately controlled. Fractional exhaled nitric oxide is a simple non-invasive method to assess inflammation in asthma and its role in asthma management is increasing in popularity. The present review summarizes recent research on the use of FeNO[1] in monitoring airway inflammation and optimizing asthma management. The addition of FeNO measurements to the conventional assessment of asthma control appears promising. The practicability of including this measuring method into everyday clinical practice is currently being evaluated.

High mobility group box 1 is a nuclear protein participating in chromatin architecture and transcriptional regulation. When released from cells, HMGB1[1] can also act as a pro-inflammatory mediator or alarmin. Upon stimulation with lipopolysaccharides or tumor necrosis factor-alpha, HMGB1 is secreted from certain cells such as monocytes/macrophages and fosters inflammatory responses. In addition, HMGB1 is passively released from necrotic cells and mediates inflammation and immune activation. In contrast, during apoptotic cell death, nuclear HMGB1 gets tightly attached to hypo-acetylated chromatin and is not released into the extracellular milieu, thereby preventing an inflammatory response. There is accumulating evidence that extracellular HMGB1 contributes to the pathogenesis of many inflammatory diseases, including autoimmune diseases. Increased concentrations of HMGB1 have been detected in the synovial fluid of patients with rheumatoid arthritis. In animal models of RA[2], HMGB1 appears to be crucially involved in the pathogenesis of arthritis, since neutralization of HMGB1 significantly ameliorates the disease. Also, in the serum and plasma of patients with systemic lupus erythematosus we detected substantial amounts of HMGB1, which may contribute to the disease process. However, investigations of blood concentrations of HMGB1 and its relevance in human diseases are hindered by the lack of reliable routine test systems.

The most troublesome complication of acute pericarditis is recurrent episodes of pericardial inflammation, which occur in 15–32% of cases. It was recently found that viral infection has a major role, but in many cases the cause is unknown. The optimal method for prevention has not been fully established; accepted modalities include non-steroidal anti-inflammatory drugs, corticosteroids, immunosuppressive agents, and pericardiectomy. Based on the proven efficacy of colchicine in familial Mediterranean fever, several small and large-scale international clinical trials have shown the beneficial effect of colchicine therapy in preventing recurrent pericarditis. Indeed, colchicines-treated patients consistently display significantly fewer recurrences, longer symptom-free periods, and even when attacks occur they are weaker and shorter in nature. It was also found that pretreatment with corticosteroids substantially attenuates the efficacy of colchicine, as evidenced by significantly more recurrences and longer therapy periods. Colchicine is a safe and effective modality for the treatment and prevention of recurrent pericarditis, especially as an adjunct to other modalities, since it provides a sustained benefit superior to all current modalities. The safety profile seems superior to other drugs such as corticosteroids and immunosuppressive drugs.