Subchronic exposure of cardiomyocytes to low concentrations of tumor necrosis factor α attenuates the positive inotropic response not only to catecholamines but also to cardiac glycosides and high calcium concentrations

The study investigated the changes in individual molecular species in PE and the effects of a variety of dietary fats with varying proportions of saturated and unsaturated fatty acids on membrane composition, eicosanoid production and cytokine production in thioglycollate-elicited rat macrophages.The data obtained indicates that the greatest degree of modulation by dietary fats on cytokine production was observed after 8 weeks feeding and at this time, the total diacyl species containing linoleic acid (18:2 n-6) and arachidonic acid (20:4 n-6) at the sn-2 position related in a curvilinear fashion to total 18:2 n-6 intake and that IL1 and IL6 production related in a curvilinear fashion to the total diacyl species with 20:4 and 18:2 at the sn-2 position.After 4 weeks of feeding, fish and olive oils enhanced production of IL6 and LTB₄, however, while IL1 production, after 8 weeks of dietary treatment, was greatest from macrophages of animals fed corn and olive oils, PGE₂ production was greatest in the former group and LTB₄ production in the latter. Thus an eicosanoid effect may explain the modulatory influence of olive oil and IL1 production but, cannot explain the effect of corn oil on production of the cytokine. The data from the present study provides some insight into how dietary fats could provide therapy for conditions in which inflammatory cytokines are implicated.     

Genetic impact of TNF-beta on risk factors for coronary atherosclerosis

BACKGROUND: Inflammatory processes are considered to play an important role in the development of coronary atherosclerosis. The proinflammatory cytokine, tumor necrosis factor beta (TNF-beta), is thought to contribute to the pathogenesis of atherosclerosis. STUDY DESIGN: In this clinical study, the influence of genetic variants of TNF-beta (c.7G>A, IVS1+90G>A, C13R, T60N) on major coronary risk factors, including gender, smoking, history of cardiovascular diseases, biochemical data (inflammatory markers, factors of lipid metabolism, coagulation/fibrinolysis balance), and angiographically-proven coronary state, was investigated in 176 European Caucasian probands (130 males, mean age: 51.9 +/- 8.9 y). RESULTS: The most frequent combinations of the polymorphisms investigated were significantly associated with four of the coronary risk factors evaluated: hypertension, body mass index, the common inflammatory marker TNF-alpha (mRNA expression), and fibrinogen (p < 0.05). However, on testing the impact of the genetic background on the incidence of coronary stenosis in this sample of European Caucasians, no significant influence of these polymorphisms (stepwise binary logistic regression analysis) could be proven. These findings emphasise a distinct influence of TNF-beta polymorphisms on important modulators of the development of coronary atherosclerosis, but exclude its genetic background, investigated in this study as an independent coronary risk factor.     

Cytokines in chronic heart failure: possible interaction in the neurohormonal and the cytokine system at the cAMP level?

In recent years, the pathophysiological concept of chronic heart failure (CHF) has changed from an isolated hemodynamic view to a more complex concept involving neuroendocrine and inflammatory pathways. New therapeutic strategies, such as beta-blocker therapy, are based on these new concepts and provide clinical evidence for a clinical benefit in patients with CHF. The survival benefit of beta-blocker therapy in CHF has been related to neurohumoral regulation. Thus, evidence evolved showing that following beta-blocker therapy cytokine levels in CHF patients are altered. We have shown that the levels of soluble TNF receptor type 2 correlated well with cAMP in leukocytes. Data from clinical studies in adult and infant CHF patients have demonstrated that beta-blocker therapy is accompanied by altered cytokine, cytokine antagonist, and/or soluble cytokine receptor levels. These alterations may result from a dysregulated interaction of beta-adrenergic pathways and the cytokine system, and are possibly related to cAMP-dependent regulation of the release or shedding of these mediators.     

Stimulatory (insulin-mimetic) and inhibitory (ouabain-like) action of vanadate on potassium uptake and cellular sodium and potassium in heart cells in culture

(1) The influence of vanadate (Na3VO4) on sodium and potassium uptake as well as on cellular ion contents of sodium and potassium has been studied in heart muscle and non-muscle cells obtained from various species. An ouabain-like inhibition of potassium uptake (up to 50%), combined with a decrease of cellular potassium (up to 20%) has been observed by vanadate (10(-4)-10(-3) M) in heart non-muscle cells obtained from neonatal guinea pigs and chick embryos. In heart muscle and non-muscle cells prepared from neonatal rats, as well as in Girardi human heart cells, a vanadate-induced stimulation of potassium uptake (up to 100%), combined with a rise in cellular potassium (up to 20%) and without significant alteration of cellular sodium, has been found. A slight increase of 22Na+ influx can be measured in rat heart muscle cells and in Girardi human heart cells in the presence of vanadate (10(-4)--10(-3) M). (2) In beating rat heart muscle cells in culture, detrimental effects of serum deprivation--concerning beating properties, potassium uptake and cellular potassium--can at least in part be overcome by addition of vanadate. Furthermore, this compound prevents ouabain-induced signs of toxicity (contractures) in these cells. (3) The stimulatory effects of vanadate on potassium can be mimicked by insulin (1-10 mU/ml). Furthermore, vanadate produces an insulin-like stimulation of 2-deoxy-D-glucose uptake in rat heart muscle and non-muscle cells as well as in Girardi human heart cells. (4) The experimental data demonstrate an ouabain-like inhibition as well as an insulin-mimetic stimulation of potassium-uptake in various heart cells. The reason for this antagonistic mode of action may be due to the different capabilities of the heart cell types to reduce vanadium in the V-valence state of vanadium in the IV-valence state, thereby favouring either ouabain-like inhibition (vanadium V) or insulin-mimetic stimulation (vanadium IV) of potassium transport.     

Aging in vitro and D-glucose uptake kinetics of diploid human fibroblasts

By use of a rapid technique, initial rates of D-glucose transport were obtained during the lifespan in vitro of a commercially available strain of human embryo lung fibroblasts (Flow 2000). The apparent Km of the D-glucose carrier did not change during senescence in vitro: x̄ = 1.8 mM (range 1.3–2.3) in phase II, x̄ = 1.8 mM (range 1.5–2.2) in phase III. Transport rates remained constant in stationary phase II cultures, which had completed between 30% and 80% of their replicative lifespan. A wide variation, however, was observed in terminally differentiated cells (phase III), which showed a two- to threefold increase in average cell size and protein content. In some senescent cultures, glucose transport calculated on a per cell basis was also two-to threefold increased, while it was strongly decreased (-75%) in others. When calculated per unit of cell water, protein, and surface area, respectively, transport rates in phase III cultures ranged from values established for stationary phase II cultures down to very low values. Detaching cells flushed off from senescent cultures did not show measurable rates of glucose transport into the inulin impermeable cell space. Present evidence argues against the idea that an impairment of D-glucose transport might precede loss of replicative potential in aging human fibroblasts. Instead our data indicate that the transport capacity of cell membrane finally decreases during postreplicative senescence in terminally differentiated cells.     

Prevalence of Symptomatic Heart Failure with Reduced and with Normal Ejection Fraction in an Elderly General Population–The CARLA Study

Background/Objectives

Chronic heart failure (CHF) is one of the most important public health concerns in the industrialized world having increasing incidence and prevalence. Although there are several studies describing the prevalence of heart failure with reduced ejection fraction (HFREF) and heart failure with normal ejection fraction (HFNEF) in selected populations, there are few data regarding the prevalence and the determinants of symptomatic heart failure in the general population.

Methods

Cross-sectional data of a population-based German sample (1,779 subjects aged 45–83 years) were analyzed to determine the prevalence and determinants of chronic SHF and HFNEF defined according to the European Society of Cardiology using symptoms, echocardiography and serum NT-proBNP. Prevalence was age-standardized to the German population as of December 31st, 2005.

Results

The overall age-standardized prevalence of symptomatic CHF was 7.7% (95%CI 6.0–9.8) for men and 9.0% (95%CI 7.0–11.5) for women. The prevalence of CHF strongly increased with age from 3.0% among 45–54- year-old subjects to 22.0% among 75–83- year-old subjects. Symptomatic HFREF could be shown in 48% (n = 78), symptomatic HFNEF in 52% (n = 85) of subjects with CHF. The age-standardized prevalence of HFREF was 3.8 % (95%CI 2.4–5.8) for women and 4.6 % (95%CI 3.6–6.3) for men. The age-standardized prevalence of HFNEF for women and men was 5.1 % (95%CI 3.8–7.0) and 3.0 % (95%CI 2.1–4.5), respectively. Persons with CHF were more likely to have hypertension (PR = 3.4; 95%CI 1.6–7.3) or to have had a previous myocardial infarction (PR = 2.5, 95%CI 1.8–3.5).

Conclusion

The prevalence of symptomatic CHF appears high in this population compared with other studies. While more women were affected by HFNEF than men, more male subjects suffered from HFREF. The high prevalence of symptomatic CHF seems likely to be mainly due to the high prevalence of cardiovascular risk factors in this population.     

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

Background

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.

Objective

To examine the association of inflammation with the development of renal failure in a cohort of the elderly general population.

Methods

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.

Results

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.

Conclusion

In the elderly male general population with preserved renal function sTNF-R1 predicts the development of renal failure.