Inflammation and prolonged QT time: Results from the Cardiovascular Disease, Living and Ageing in Halle (CARLA) study

Background: Previous research found an association of CRP with QT time in population based samples. Even more, there is evidence of a substantial involvement of the tumor necrosis factor-alpha system in the pathophysiology of cardiac arrhythmia, while the role of Interleukin 6 remains inconclusive. Objective: To determine the association between inflammation with an abnormally prolonged QT-time (APQT) in men and women of the elderly general population. Methods: Data descend from the baseline examination of the prospective, population-based Cardiovascular Disease, Living and Ageing in Halle (CARLA) Study. After exclusion of subjects with atrial fibrillation and missing ECG recording the final study cohort consisted of 919 men and 797 women. Blood parameters of inflammation were the soluble TNF-Receptor 1 (sTNF-R1), the high-sensitive C-reactive protein (hsCRP), and Interleukin 6 (IL-6). In accordance with major cardiologic societies we defined an APQT above a QT time of 460 ms in women and 450 ms in men. Effect sizes and the corresponding 95% confidence intervals (CI) were estimated by performing multiple linear and logistic regression analyses including the analysis of sex differences by interaction terms. Results: After covariate adjustment we found an odds ratio (OR) of 1.89 (95% CI: 1.13, 3.17) per 1000 pg/mL increase of sTNF-R1 in women, and 0.74 (95% CI: 0.48, 1.15) in men. In the covariate adjusted linear regression sTNF-R1 was again positively associated with QT time in women (5.75 ms per 1000 pg/mL, 95% CI: 1.32, 10.18), but not in men. Taking possible confounders into account IL-6 and hsCRP were not significantly related to APQT in both sexes. Conclusion: Our findings from cross-sectional analyses give evidence for an involvement of TNF-alpha in the pathology of APQT in women

Biological activities of lipopolysaccharides are determined by the shape of their lipid a portion

Lipopolysaccharide (LPS) represents a major virulence factor of Gram-negative bacteria (\u27endotoxin\u27) that can cause septic shock in mammals including man. The lipid anchor of LPS to the outer membrane, lipid A, has a peculiar chemical structure, harbours the \u27endotoxic principle\u27 of LPS and is responsible for the expression of pathophysiological effects. Chemically modified lipid A can be endotoxically inactive, but may express strong antagonistic activity against LPS, a property that can be utilized in antisepsis treatment. We show here that these different biological activities are directly correlated with the molecular shape of lipid A. Only (hexaacyl) lipid A with a conical/concave shape, the cross-section of the hydrophobic region being larger than that of the hydrophilic region, exhibited strong interleukin-6 (IL-6)-inducing capacity. Most strikingly, a correlation between a cylindrical molecular shape of lipid A and antagonistic activity was established: IL-6 induction by enterobacterial LPS was inhibited by cylindrically shaped lipid A except for compounds with reduced headgroup charge. The antagonistic action is interpreted by assuming that lipid A molecules intercalate into the cytoplasmic membrane of mononuclear cells, and subsequently blocking of the putative signaling protein by the lipid A with cylindrical shape

Inflammation and Renal Function after a Four-Year Follow-Up in Subjects with Unimpaired Glomerular Filtration Rate: Results from the Observational, Population-Based CARLA Cohort

<div><p>Background</p><p>There is evidence that chronic inflammation is associated with the progression/development of chronic renal failure; however, relations in subjects with preserved renal function remain insufficiently understood.</p><p>Objective</p><p>To examine the association of inflammation with the development of renal failure in a cohort of the elderly general population.</p><p>Methods</p><p>After excluding subjects with reduced estimated glomerular filtration rate (eGFR<60 mL/min/1.73 m²) and missing data, the cohort incorporated 785 men and 659 women (aged 45–83 years). Follow-up was performed four years after baseline. Covariate adjusted linear and logistic regression models were used to assess the association of plasma/serum concentrations of soluble tumour necrosis factor receptor 1 (sTNF-R1), C-reactive protein (CRP), and interleukin 6 (IL-6) with change in eGFR/creatinine. The areas under the curve (AUCs) from receiver operating characteristics (ROCs) were estimated.</p><p>Results</p><p>In adjusted models sTNF-R1 was distinctively associated with a decline in eGFR in men (0.6 mL/min/1.73 m² per 100 pg/mL sTNF-R1; 95% CI: 0.4–0.8), but not in women. A similar association could not be found for CRP or IL-6. Estimates of sTNF-R1 in the cross-sectional analyses were similar between sexes, while CRP and IL-6 were not relevantly associated with eGFR/creatinine.</p><p>Conclusion</p><p>In the elderly male general population with preserved renal function sTNF-R1 predicts the development of renal failure.</p></div

Inflammation and Prolonged QT Time: Results from the Cardiovascular Disease, Living and Ageing in Halle (CARLA) Study

<div><p>Background</p><p>Previous research found an association of CRP with QT time in population based samples. Even more, there is evidence of a substantial involvement of the tumor necrosis factor-alpha system in the pathophysiology of cardiac arrhythmia, while the role of Interleukin 6 remains inconclusive.</p><p>Objective</p><p>To determine the association between inflammation with an abnormally prolonged QT-time (APQT) in men and women of the elderly general population.</p><p>Methods</p><p>Data descend from the baseline examination of the prospective, population-based Cardiovascular Disease, Living and Ageing in Halle (CARLA) Study. After exclusion of subjects with atrial fibrillation and missing ECG recording the final study cohort consisted of 919 men and 797 women. Blood parameters of inflammation were the soluble TNF-Receptor 1 (sTNF-R1), the high-sensitive C-reactive protein (hsCRP), and Interleukin 6 (IL-6). In accordance with major cardiologic societies we defined an APQT above a QT time of 460 ms in women and 450 ms in men. Effect sizes and the corresponding 95% confidence intervals (CI) were estimated by performing multiple linear and logistic regression analyses including the analysis of sex differences by interaction terms.</p><p>Results</p><p>After covariate adjustment we found an odds ratio (OR) of 1.89 (95% CI: 1.13, 3.17) per 1000 pg/mL increase of sTNF-R1 in women, and 0.74 (95% CI: 0.48, 1.15) in men. In the covariate adjusted linear regression sTNF-R1 was again positively associated with QT time in women (5.75 ms per 1000 pg/mL, 95% CI: 1.32, 10.18), but not in men. Taking possible confounders into account IL-6 and hsCRP were not significantly related to APQT in both sexes.</p><p>Conclusion</p><p>Our findings from cross-sectional analyses give evidence for an involvement of TNF-alpha in the pathology of APQT in women.</p></div

Subject characteristics.

<p>Baseline and follow-up means, displayed as geometric means with respective 95% confidence limits.</p><p>Abbreviations: sTNF-R1: Soluble tumour necrosis factor-α receptor 1; hsCRP: High-sensitivity C-reactive protein; IL-6: Interleukin 6; eGFR: estimated glomerular filtration rate; BMI: Body mass index; Dia. BP: Diastolic blood pressure; Sys. BP: Systolic blood pressure; LDL: Low-density lipoprotein; HDL: High-density lipoprotein; PAD: Peripheral arterial disease.</p>†<p>p-values for mean differences between men and women (using T-test) or differences in numbers between men and women (using Fisher’s exact test); ** indicates p-values <0.0001 for baseline to follow-up change; * indicates p-values <0.05 for baseline to follow-up change.</p><p>Subject characteristics.</p

Cross-sectional and longitudinal regression analyses in women: association of inflammation parameters with GFR/creatinine.

<p>unadj. = unadjusted estimates; CI = confidence limit; adj. = estimates adjusted for age, body mass index (BMI), HbA1c, low-density lipoprotein (LDL), high-density lipoprotein (HDL), baseline diastolic and systolic blood pressure and baseline to follow-up change in the longitudinal analyses, number of cigarettes/cigars/pipes smoked, presence of cardio-vascular diseases, regular intake of anti-diabetic (Anatomical Therapeutic Chemical Classification [ATC]: A10) and anti-hypertensive medication (ATC: C02/C03/C07/C08/C09); users coded as “1”, non-users coded as “0”. GFR estimated by means of CKD-EPI formula¹⁰. Effect estimates with 95% confidence intervals are displayed.</p><p>*Effect estimates refer to an increase of one standard deviation in the log-transformed inflammation parameter.</p><p>Abbreviations: sTNF-R1: Soluble tumour necrosis factor-α receptor 1; hsCRP: High-sensitivity C-reactive protein; IL-6: Interleukin 6; eGFR: estimated glomerular filtration rate.</p><p>Cross-sectional and longitudinal regression analyses in women: association of inflammation parameters with GFR/creatinine.</p

ROC curves and respective AUCs [95% confidence intervals].

<p>Abbreviations: sTNF-R1: Soluble tumour necrosis factor-α receptor 1; hsCRP: High- sensitivity C-reactive protein; IL-6: Interleukin 6; CI: confidence interval.</p

Linear regression of QTc, QT time and heart rate (HR) on sTNF-R1 in men and women (estimates with 95% confidence interval).

<p>Estimates refer to a 1,000 pg/mL increase in sTNF-R1, a 10 pg/mL increase in IL-6, and a 10 mg/L increase in hsCRP.</p><p>*unadjusted values; ** covariate adjusted values: models were adjusted age, anti-arrhythmic (ATC code: C01B) and anti-phlogistic medication (ATC code: A07), current smoking status, high density lipoprotein (HDL), cholesterol, glucose blood level, alcohol intake, body mass index, thyroid stimulating hormone (TSH), systolic blood pressure and potentially QT prolonging drugs (see <a href="http://www.qtdrugs.org" target="_blank">www.qtdrugs.org</a>).</p><p>OR refers to a 1,000 pg/mL increase in sTNF-R1, a 10 pg/mL increase in IL-6, and a 10 mg/L increase in hsCRP.</p