Connection between Telomerase Activity in PBMC and Markers of Inflammation and Endothelial Dysfunction in Patients with Metabolic Syndrome

Metabolic syndrome (MS) is a constellation of metabolic derangements associated with vascular endothelial dysfunction and oxidative stress and is widely regarded as an inflammatory condition, accompanied by an increased risk for cardiovascular disease. The present study tried to investigate the implications of telomerase activity with inflammation and impaired endothelial function in patients with metabolic syndrome. Telomerase activity in circulating peripheral blood mononuclear cells (PBMC), TNF-α, IL-6 and ADMA were monitored in 39 patients with MS and 20 age and sex-matched healthy volunteers. Telomerase activity in PBMC, TNF-α, IL-6 and ADMA were all significantly elevated in patients with MS compared to healthy volunteers. PBMC telomerase was negatively correlated with HDL and positively correlated with ADMA, while no association between TNF-α and IL-6 was observed. IL-6 was increasing with increasing systolic pressure both in the patients with MS and in the healthy volunteers, while smoking and diabetes were positively correlated with IL-6 only in the patients' group. In conclusion, in patients with MS characterised by a strong dyslipidemic profile and low diabetes prevalence, significant telomerase activity was detected in circulating PBMC, along with elevated markers of inflammation and endothelial dysfunction. These findings suggest a prolonged activity of inflammatory cells in the studied state of this metabolic disorder that could represent a contributory pathway in the pathogenesis of atherosclerosis

Leukocyte Telomere Length in Major Depression: Correlations with Chronicity, Inflammation and Oxidative Stress - Preliminary Findings

Depression is associated with an unusually high rate of aging-related illnesses and early mortality. One aspect of “accelerated aging” in depression may be shortened leukocyte telomeres. When telomeres critically shorten, as often occurs with repeated mitoses or in response to oxidation and inflammation, cells may die. Indeed, leukocyte telomere shortening predicts early mortality and medical illnesses in non-depressed populations. We sought to determine if leukocyte telomeres are shortened in Major Depressive Disorder (MDD), whether this is a function of lifetime depression exposure and whether this is related to putative mediators, oxidation and inflammation.Leukocyte telomere length was compared between 18 unmedicated MDD subjects and 17 controls and was correlated with lifetime depression chronicity and peripheral markers of oxidation (F2-isoprostane/Vitamin C ratio) and inflammation (IL-6). Analyses were controlled for age and sex.The depressed group, as a whole, did not differ from the controls in telomere length. However, telomere length was significantly inversely correlated with lifetime depression exposure, even after controlling for age (p<0.05). Average telomere length in the depressed subjects who were above the median of lifetime depression exposure (≥9.2 years' cumulative duration) was 281 base pairs shorter than that in controls (p<0.05), corresponding to approximately seven years of “accelerated cell aging.” Telomere length was inversely correlated with oxidative stress in the depressed subjects (p<0.01) and in the controls (p<0.05) and with inflammation in the depressed subjects (p<0.05).These preliminary data indicate that accelerated aging at the level of leukocyte telomeres is proportional to lifetime exposure to MDD. This might be related to cumulative exposure to oxidative stress and inflammation in MDD. This suggest that telomere shortening does not antedate depression and is not an intrinsic feature. Rather, telomere shortening may progress in proportion to lifetime depression exposure

Genetic Basis of Myocarditis: Myth or Reality?

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Detection of Chlamydia pneumoniae in peripheral blood mononuclear cells: correlation with inflammation and atherosclerosis in haemodialysis patients

Background. Chlamydia pneumoniae has been implicated as an inflammatory agent in atherosclerosis. Clinical studies in this field have yielded conflicting results, which may have resulted from a lack of standardization for C. pneumoniae detection. We attempted to accurately estimate C. pneumoniae prevalence and to examine whether C. pneumoniae is associated with atherosclerosis and inflammation in haemodialysis (HD) patients. To do this, we assessed C. pneumoniae presence by a combination of methods and correlated its levels with inflammatory and atherosclerotic indexes in these patients. Methods. Chlamydia pneumoniae was identified by polymerase chain reaction (PCR) in DNA extracted from cell cultures inoculated with patient buffy coats and by serum IgG antibodies against C. pneumoniae (IgGCp). Inflammation was assessed by C-reactive protein and serum amyloid A and atherosclerosis was evaluated from clinical and laboratory data. Results. Of the 130 patients, only nine had viable C. pneumoniae in peripheral blood mononuclear cells (PBMCs) while 64 had serum IgGCp. Although patients with viable C. pneumoniae had higher atherosclerotic scores, seropositive and negative patients showed similar scores. Patients with atherosclerosis exhibited higher inflammatory indexes. Neither patients with detectable C. pneumoniae in PBMCs nor seropositive subjects had higher inflammation than negative patients. Conclusions. We found that viable C. pneumoniae in PBMCs, assessed by cell culture and PCR, was present in a small percentage of HD patients and was correlated with atherosclerosis. Seropositivity was much higher in HD patients but was not associated with viable C. pneumoniae or with atherosclerosis. Further studies in HD patients using high sensitivity and specificity methods in larger populations will be necessary to clarify the relationship between C. pneumoniae and atherosclerosis

Serum and peripheral blood mononuclear cells infectious burden: Correlation to inflammation and atherosclerosis in haemodialysis patients

Background: Infectious agents may be implicated in the inflammatory atherosclerotic process. Not only specific microorganisms but also the infectious burden, defined as the number of pathogens to which a patient is exposed, has been associated with atherosclerosis. In the present study, the infectious burden, determined directly (by identification of viable pathogens in peripheral blood mononuclear cells (PBMC)) and indirectly (by serum antibodies detection) is correlated to the inflammatory and atherosclerotic status in haemodialysis (HD) patients, a population at high risk for cardiovascular disease. Methods: The viable forms of four microorganisms (Chlamydia pneumoniae, herpes virus 1 and 2 and cytomegalovirus) were identified in patients PBMC by cell cultures and subsequent polymerase chain reaction. Serum IgG against the above pathogens and Helicobacter pylori were also determined. Inflammation was assessed by measurement of C-reactive protein (CRP), serum amyloid A (SAA), three pro- and one anti-inflammatory cytokines and four adhesion molecules. Atherosclerosis was defined by a scoring system using medical history data. Results: The number of viable pathogens identified in PBMC in the 122 HD patients included in the study were zero in 22.1% of them, one in 33.6%, two in 43.4% and three in one patient. The number of IgG antibodies determined was one in 6.6% of patients, two in 32%, three in 48.4% and four in 13.1%. Seropositivity was not significantly different between patients with or without the respective viable pathogen identified in PBMC. Atherosclerosis was present in 40.2% of patients, and CRP, SAA and interleukin-6 were all increased in these patients. Neither inflammatory indexes nor atherosclerosis were significantly different in patients with a higher number of viable pathogens detected in PBMC or in those with a higher antibodies number. Conclusions: The direct infectious burden determination (the number of viable pathogens in PBMC) does not coincide with the serum (by IgG detection) infectious burden. Although inflammation correlates to atherosclerosis, neither PBMC nor the serum infectious burden is associated with these two entities in the inflamed and atherosclerotic HD patients

Treatment with fluvastatin rapidly modulates, via different pathways, and in dependence on the baseline level, inflammation in hemodialysis patients

Background: Hemodialysis (HD) patients are frequently in an elevated inflammatory state which is correlated to the atherosclerosis-related and overall morbidity and mortality in this population. Statins, beyond their antilipidemic effects, are also considered to have anti-inflammatory, immunomodulating and antioxidant properties. The individual response of HD patients to a short course of fluvastatin, the mechanisms involved in the immunomodulating and anti-inflammatory effects of this drug and the time interval to the appearance of these effects are investigated in this longitudinal study. Methods: In a group of 51 HD patients, fluvastatin 40 mg/day was administered for 4 weeks. Serial measurements of the lipid profile, C-reactive protein (CRP), interleukin-6 (IL-6), soluble IL-6 receptor (sIL-6R), interleukin-10 (IL-10), and serum oxidized LDL (ox-LDL), were performed before, during, and after the treatment period. Results: Total cholesterol was significantly reduced after 14 days of treatment with fluvastatin ( from mean +/- SD 216.7 +/- 34.3 to 179.2 +/- 42.3 mg/dl, p &lt; 0.001). IL-6 and ox-LDL were reduced on day 28 ( p &lt; 0.001 and p &lt; 0.01, respectively) and IL-10 was increased on day 14 ( p = 0.05); CRP did not change significantly during the treatment period while sIL-6R was increased on day 28 of fluvastatin administration ( p &lt; 0.05). In a subgroup of patients with CRP, IL-6, sIL-6R, and ox-LDL baseline serum values 6 the median and IL-10 less than or equal to the median, CRP was reduced on day 28 of fluvastatin treatment ( p &lt; 0.01), IL-6 and ox-LDL were reduced earlier, on day 14 ( p = 0.05 and p &lt; 0.05, respectively) while sIL-6R did not change significantly during the treatment period. Conclusions: Treatment with fluvastatin rapidly modulates inflammation in HD patients. Enhancement of anti-inflammatory mechanisms and attenuation of the inflammatory and oxidative state contribute to this modulation. Patients in an elevated baseline inflammatory state respond more rapidly and effectively to the treatment. This immediate and multi-potent action of the statins could be clinically useful in acute atherosclerosis complications or in the treatment of chronic inflammation in HD patients. Copyright (C) 2004 S. Karger AG, Basel

The effect of viable Chlamydia pneumoniae on serum cytokines and adhesion molecules in hemodialysis patients

Background. Chlamydia pneumoniae (Cp) induces the production of cytokines and adhesion molecules in infected host eukaryotic cells. The causes for pro-inflammatory cytokine and adhesion molecule increase in hemodialysis (HD) patients have not been fully elucidated. The possibility that, in this particularly atherosclerotic population, Cp, a microorganism implicated in the infectious-based inflammatory hypothesis of atherosclerosis’ is also responsible for these molecules’ increase is assessed in this study. Methods. In 130 stable HD patients, serum interleukin-1beta (IL-1), interieukin-6, tumor necrosis factor alpha, interleukin-10, L-selectin, E-selectin, intercellular adhesion molecule-1, and vascular cell adhesion molecule-1 (VCAM-1) levels were determined. Cp presence was identified by inoculation of the patient’s peripheral blood mononuclear cells (PBMCs) in Hep-2 cell lines and subsequent polymerase chain reaction (PCR) in DNA extracted from cell cultures, as well as by determination of serum IgG antibodies against Cp (IgGCp) Results. Patients, positive or negative for IgGCp, had no statistically significant differences in all molecules measured. Patients with viable Cp in PBMCs had higher serum levels of IL-1 and soluble VCAM-I than negative ones for IgGCp (IL-1 6.87 +/- 7.35 vs. 2.34 +/- 1.47 pg/mL; P = 0.0009 and VCAM-1 1647.16 +/- 513.64 vs. 1162.14 +/- 546.83 ng/mL; P = 0.0115, respectively). Viable Cp in PBMCs remained a significant predictor factor for IL-1 and VCAM-1 in statistical analysis, when patients’ characteristics and dialysis conditions were also evaluated. Conclusions. Our results showed that some serum cytokine and adhesion molecule increase in HD patients could be attributed to viable Cp presence in PBMCs. These findings support the Cp-based inflammatory atherogenous hypothesis and add a better understanding of these molecules’ increase in HD patients