Pathophysiologic quantities of endotoxin-induced tumor necrosis factor-alpha release in whole blood from patients with chronic heart failure

Bacterial endotoxin activity is elevated in patients with decompensated chronic heart failure (HF) and acts as a potent stimulus for immune activation. We sought to determine whether endotoxin, at an activity level seen in vivo (around 0.6 EU/ml), is sufficient to stimulate the secretion of tumor necrosis factor-alpha (TNF-alpha) and TNF-alpha soluble receptor (sTNFR2) in ex vivo whole blood from patients with HF. We studied 15 patients with HF (aged 65 +/- 1.9 years, New York Heart Association class 2.1 +/- 0.3, left ventricular ejection fraction 31 +/- 5%; mean +/- SEM), of whom 5 had cardiac cachexia, and 7 healthy control subjects (59 +/- 5 years, p = NS). Reference endotoxin was added to venous blood at concentrations of 0.6, 1.0, and 3.0 EU/ml, and was incubated for 6 hours. Endotoxin induced a dose-dependent increase in TNF-alpha release (p <0.05 in all groups). Patients with noncachectic HF produced significantly more TNF-alpha compared with controls after stimulation with 0.6, 1.0, and 3.0 EU/ml of endotoxin (113 +/- 46 vs 22 +/- 4 [p = 0.009], 149 +/- 48 vs 34 +/- 4 [p = 0.002], and 328 +/- 88 vs 89 +/- 16 pg/ml [p = 0.002], respectively; mean +/- SEM). Patients with cardiac cachexia produced significantly less TNF-alpha compared with patients without cardiac cachexia for all given concentrations (all p <0.05, analysis of variance p = 0.02). Production of sTNFR2 was greater at all concentrations of endotoxin versus controls (all p <0.05, analysis of variance p = 0.002). Plasma endotoxin levels were higher in patients with cardiac cachexia (4.3 times higher than in control subjects, p <0.005). Thus, low endotoxin activity, at levels seen in vivo in patients with HF, induces significant TNF-alpha and sTNFR2 production ex vivo. These results suggest that elevated plasma endotoxin activity observed in patients with HF is of pathophysiologic relevance.     

Physical training modulates proinflammatory cytokines and the soluble Fas/soluble Fas ligand system in patients with chronic heart failure

OBJECTIVES: We sought to investigate the effects of physical training on circulating proinflammatory cytokines and the soluble apoptosis mediators Fas (sFas) and Fas ligand (sFasL) in patients with chronic heart failure (CHF). BACKGROUND: Recent investigations have shown an overexpression of circulating proinflammatory cytokines and soluble apoptosis mediators in patients with CHF, which may be related to their exercise intolerance and clinical deterioration. METHODS: Plasma levels of tumor necrosis factor-alpha (TNF-alpha), soluble TNF receptors I and II (sTNF-RI and sTNF-RII, respectively), interleukin-6 (IL-6), soluble IL-6 receptor (sIL-6R), sFas and sFasL were measured in 24 patients with stable CHF (New York Heart Association functional class II/III; left ventricular ejection fraction 23.2 +/- 1.3%) and in 20 normal control subjects before and after a 12-week program of physical training in a randomized, crossover design. Functional status of patients with CHF was evaluated by using a cardiorespiratory exercise test to measure peak oxygen consumption (VO2max). RESULTS: Physical training produced a significant reduction in plasma levels of TNF-alpha (7.5 +/- 1.0 pg/ml vs. 4.6 +/- 0.7 pg/ml, p < 0.001), sTNF-RI (3.3 +/- 0.2 ng/ml vs. 2.7 +/- 0.2 ng/ml, p < 0.005), sTNF-RII (2.6 +/- 0.2 ng/ml vs. 2.3 +/- 0.2 ng/ml, p = 0.06), IL-6 (8.3 +/- 1.2 pg/ml vs. 5.9 +/- 0.8 pg/ml, p < 0.005), sIL-6R (34.0 +/- 3.0 ng/ml vs. 29.2 +/- 3.0 ng/ml, p < 0.01), sFas (5.5 +/- 0.7 ng/ml vs. 4.5 +/- 0.8 ng/ml, p = 0.05) and sFasL (34.9 +/- 5.0 pg/ml vs. 25.2 +/- 4.0 pg/ml, p < 0.05), as well as a significant increase in VO2max (16.3 +/- 0.7 ml/kg per min vs. 18.7 +/- 0.8 ml/kg per min, p < 0.001). Good correlations were found between a training-induced increase in VO2max and a training-induced reduction in levels of the proinflammatory cytokine TNF-alpha (r = -0.54, p < 0.01) and the apoptosis inducer sFasL (r = -0.57, p < 0.005) in patients with CHF. In contrast, no significant difference in circulating cytokines and apoptotic markers was found with physical training in normal subjects. CONCLUSIONS: Physical training reduces plasma levels of proinflammatory cytokines and the sFas/sFasL system in patients with CHF. These immunomodulatory effects may be related to the training-induced improvement in functional status of patients with CHF.     

Release of proinflammatory cytokines by mitogen-stimulated peripheral blood mononuclear cells from critically ill multiple-trauma victims

This study investigated the alterations in circulating proinflammatory cytokines and cytokine production by peripheral blood mononuclear cells (PBMCs) in response to lipopolysaccharide (LPS) or phytohemagglutinin (PHA) after severe trauma. Plasma and PBMCs were collected from 17 severely injured trauma patients and 10 healthy subjects. Plasma was stored at -80 degrees C and analyzed for cytokines. Isolated PBMCs from each subject were stimulated with LPS or PHA and incubated at 5% CO2 for 24 hours. Supernatants were collected and analyzed for cytokines. There was no significant change in the plasma concentration of free TNF-alpha and IL-1beta between healthy subjects and trauma patients. Plasma IL-6, total TNF-alpha, and total IL-1beta were significantly increased in severely traumatized patients compared with healthy control subjects. PBMCs from trauma patients produced higher levels of TNF-alpha in response to LPS but it showed no significant change in IL-1beta and IL-6 production in response to PHA or LPS in comparison to PBMCs from control subjects. We conclude that severe trauma results in a significant increase in plasma proinflammatory cytokine IL-6. Free TNF-alpha and IL-1beta in plasma remain at levels comparable to those in uninjured controls, while plasma free IL-6 levels in trauma patients remain high. Serious injury is associated with an enhanced production of TNF-alpha by PBMCs stimulated with LPS.     

Effects of carvedilol on plasma levels of interleukin-6 and tumor necrosis factor-alpha in nine patients with dilated cardiomyopathy

OBJECTIVES: Whether beta-blocker therapy changes the circulating levels of cytokines as congestive heart failure improves remains uncertain. METHODS: Nine patients with idiopathic dilated cardiomyopathy, who had previously received conventional treatment and were classified as New York Heart Association (NYHA) functional class II, received carvedilol by stepwise dose increase up to 20 mg daily, and the plasma interleukin-6 (IL-6) and tumor necrosis factor-alpha (TNF-alpha) levels were measured. RESULTS: IL-6 was significantly reduced from 0.80 +/- 0.49 pg/ml before therapy to 0.21 +/- 0.08 pg/ml after carvedilol was increased to 20 mg daily (p < 0.05). Moreover, IL-6 level had already decreased significantly compared to the baseline when the dose of carvedilol had reached 10 mg daily (0.28 +/- 0.12 pg/ml, p < 0.05). TNF-alpha levels did not change significantly. CONCLUSIONS: These results demonstrate that IL-6 concentration is significantly decreased by beta-blocker therapy. The efficacy for heart failure may be related to the change of IL-6 concentration.     

Increased production of inflammatory cytokines in mild cognitive impairment

Recent studies indicate that chronic inflammation plays a pathogenic role in both the central nervous system (CNS) and periphery in Alzheimer's disease (AD). We have screened for cytokines differentially produced by peripheral blood mononuclear cells (PBMCs) isolated from subjects with mild cognitive impairment (MCI) and mild AD subjects who had progressed from MCI using a commercially available cytokine array. Following determination of expressed cytokines, we quantified levels of the proinflammatory cytokines TNF-alpha, IL-6, and IL-8, and the anti-inflammatory cytokine IL-10 using flow cytometry. We have found a significant increase in the levels of IL-6, IL-8, and IL-10 produced by PBMCs stimulated for 24 h with phytohemagglutinin (PHA) in MCI subjects compared to healthy elderly controls. However, in PBMCs stimulated for 48 h with lipopolysaccharide (LPS), lower TNF-alpha/IL-10, IL-6/IL-10, and IL-8/IL-10 ratios were seen in MCI subjects. There were no differences in plasma levels of IL-8 between aged controls, MCI, and mild AD, and the levels of circulating IL-6 and IL-10 were below detection limits. Our data indicate that changes in cytokine production by PBMCs may be detected early in MCI, and an alteration of the immune response may precede clinical AD.     

Whole blood endotoxin responsiveness in patients with chronic heart failure: the importance of serum lipoproteins

BACKGROUND: Endotoxin [lipopolysaccharide (LPS)] may be an important stimulus for cytokine release in patients with chronic heart failure (CHF). We sought to investigate the relationship between whole blood endotoxin responsiveness and serum lipoprotein concentrations. It is not known if low-dose LPS is sufficient to stimulate immune activation. METHODS AND RESULTS: Whole blood from 32 CHF patients (mean age 66+/-2 years, NYHA class 2.7+/-0.2, five female) and 11 healthy control subjects (mean age 47+/-4 years, six female) was stimulated with LPS at nine different concentrations (0.001 to 10 ng/mL), and tumor necrosis factor (TNF-alpha) release was quantified. Reference standard endotoxin at concentrations of 0, 0.6, 1, and 3 EU/ml was added to whole blood from nine CHF patients (age 64+/-9.1 years, all NYHA class II, eight male) and incubated for 6 h, the TNF-alpha production being measured. Serum lipoproteins were quantified using standard techniques. In CHF patients, there was an inverse relationship between whole blood TNF-alpha release and serum cholesterol which was strongest at 0.6 ng/mL of LPS (r=-0.53, p=0.002). A similar although weaker relationship was found for serum HDL. No such correlation was found in healthy subjects or with serum LDL (all r(2)<0.1). Low concentrations of LPS induced a stepwise increase in TNF-alpha release from whole blood to concentrations well above those seen in CHF. CONCLUSIONS: Serum lipoproteins may play an important role in regulating LPS bioactivity in CHF. Very low LPS activity, at levels seen in vivo in CHF, can induce significant TNF-alpha production ex vivo.     

The relationship between age and production of tumour necrosis factor-alpha in healthy volunteers and patients with chronic heart failure

BACKGROUND: Ageing is associated with an altered immune response. Elevated plasma levels of tumour necrosis factor-alpha (TNF-alpha) are present in patients with advanced chronic heart failure (CHF). However, the relationship between age and the immune response in CHF is unknown. METHODS: We investigated the relationship between age and the TNF-alpha generating capacity of lipopolysaccharide (LPS) stimulated peripheral blood mononuclear cells (PBMC) in nine healthy control subjects (mean age 51.6+/-3.6 years, age range 39-75 years) and 22 stable patients with CHF (mean age 68.3+/-1.5 years, age range 52-78 years, NYHA class 3.0+/-0.2). We also tested the TNF-alpha generating capacity of all control subjects and 18 CHF patients in whole blood cultures. RESULTS: Subjects were subgrouped according to baseline TNF-alpha secretion in PBMC cultures into low- and high-responders, with the latter producing TNF-alpha even without LPS stimulation. High-responders produced more TNF-alpha than low-responders at all LPS doses (0.001-10 ng/ml, P<0.0001, repeated measures ANOVA), and high-responders were significantly older than low-responders (controls: 65.8+/-9.2 vs. 47.5+/-2.5 years; patients: 71.9+/-1.9 vs. 65.9+/-1.9 years, both P<0.05). Age correlated with TNF-alpha production in both patients and controls. This effect was independent of NYHA class. CONCLUSIONS: LPS-responsiveness appears to relate to age in both healthy controls and CHF patients. When assessing the immune status of CHF patients, age should therefore be considered an important confounding factor. In whole blood these findings could only be confirmed at the highest LPS concentration used, thus suggesting that certain factors in the blood may be able to abolish LPS activity at lower concentrations.     

慢性乙型肝炎病人血清及外周血单个核细胞培养上清液白细胞介？…

目的 探讨慢性乙型肝炎（ＣＨＢ）病人血清及外周血单个核细胞（ＰＢＭＣ）培养上清液白细胞介素－１０（ＩＬ－１０）检测的临床意义。方法 分离１５例ＣＨＢ病人及６名正常人血清及ＰＢＭＣ。ＰＢＭＣ体外单独或与金黄色葡萄球菌肠毒素Ｂ（ＳＥＢ）或重组ＨＢｃＡｇ（ｒＨＢｃＡｇ）共培养４８小时后。用双抗体夹心ＥＬＩＳＡ方法检测血清及ＰＢＭＣ培养上清液ＩＬ－Ｈ１０水平。结果 ＣＨＢ病人血清ＩＬ－１０水平为（１２３．     

Ongoing myocardial damage in chronic heart failure is related to activated tumor necrosis factor and Fas/Fas ligand system.

BACKGROUND: Elevated concentrations of cardiac troponin T and heart-type fatty acid-binding protein (H-FABP) identify patients with chronic heart failure (CHF) and ongoing myocardial damage (OMD) who are at increased risk for future cardiac events. Cardiomyocyte necrosis and/or apoptosis via activated tumor necrosis factor (TNF) and the Fas/Fas ligand (FasL) system may be related to the development of OMD. METHODS AND RESULTS: The serum concentrations of H-FABP, a sensitive marker of membrane damage of cardiomyocytes, soluble Fas (sFas) and TNF-alpha were measured in 38 patients with CHF. The concentrations of H-FABP, TNF-alpha and s-Fas in patients with New York Heart Association (NYHA) III + IV were all significantly higher than in those patients in NYHA II (H-FABP; III + IV 9.3+/-5.9 vs II 5.1+/-1.8 ng/ml, p=0.003, TNF-alpha; III + IV 10.5+/-3.8 vs II 8.0+/-2.7 pg/ml, p=0.02, sFas; III + IV 3.36+/-1.37 vs II 2.58 +/-0.84 ng/ml, p=0.03). Increased concentrations of H-FABP significantly correlated with the concentrations of TNF- alpha (r=0.57, p=0.0001) and sFas (r=0.69, p<0.0001), independent of renal function. CONCLUSION: OMD detected by H-FABP, a marker of membrane damage, is related to activated TNF and the Fas/FasL system, which suggests a pathophysiological role of cardiomyocyte necrosis and/or apoptosis in patients with worsening heart failure.     

Relation between CD4+ T-cell activation and severity of chronic heart failure secondary to ischemic or idiopathic dilated cardiomyopathy

The percentage of CD4(+) T cells in blood is correlated with left ventricular dysfunction and decreased ejection fraction in heart disease. The aim of this study was to determine the relation between activation of CD4(+) T cells and New York Heart Association functional classes in chronic heart failure (HF) and differences in inflammatory activation between ischemic cardiomyopathy (IC) and idiopathic dilated cardiomyopathy (IDC). Blood samples were obtained from 47 patients with HF and 20 controls. Percentages of interferon-gamma-positive CD4(+) T cells (representative type 1 T-helper cells) and interleukin-4-positive CD4(+) T cells (representative type 2 T-helper cells) were analyzed using 3-color flow cytometry. The proportion of interferon-gamma-positive CD4(+) T cells was higher in patients with HF (28.96 +/- 12.90%) than in controls (18.12 +/- 5.28, p = 0.0006), but there was no difference in percentage of interleukin-4-positive CD4(+) T cells between the 2 groups. The proportion of interferon-gamma-positive CD4(+) T cells and plasma B-type natriuretic peptide levels increased with worsening of New York Heart Association functional class in the IC and IDC groups. The proportion of interferon-gamma-positive CD4(+) T cells in the IC group (33.88 +/- 13.33%) was higher than in the IDC group (22.33 +/- 8.88%, p = 0.002); however, plasma B-type natriuretic peptide levels were higher in the IDC group (358.0 pg/ml, 327.5 to 1,325.7) than in the IC group (82.7 pg/ml, 34.7 to 252.9, p = 0.019). In conclusion, we demonstrated pronounced type 1 T-helper cell activation in patients with HF in proportion to severity of HF and that the specificity of T-cell activation differs between patients with IC and those with IDC.     

Interleukin-2-induced tumor necrosis factor-alpha (TNF-alpha) gene expression in human alveolar macrophages and blood monocytes

Recent investigations have demonstrated interleukin-2 receptor (IL-2R) expression on both human alveolar macrophages (AM phi) and blood monocytes (PBM), but the function of these receptors has not been fully elucidated. In this study, we demonstrate that human AM phi, as well as PBM, can be induced to express biologically active TNF-alpha after challenge with interleukin-2 (IL-2). Furthermore, we examined the expression of TNF-alpha at the mRNA level via Northern blot and in situ hybridization analysis. Normal AM phi, obtained by bronchoalveolar lavage, and PBM were stimulated with either IL-2 (2,000 U/ml) or lipopolysaccharide (LPS) (10 micrograms/ml) for 18 h. Specificity was demonstrated by neutralizing TNF-alpha activity with a polyclonal rabbit anti-human TNF-alpha antibody. PBM TNF-alpha biologic activity from 11 subjects challenged with either IL-2 or LPS was 19 +/- 6 and 85 +/- 15 U/ml/10(6) cells, respectively, which represented 5-fold and 21-fold increases over control values. AM phi TNF-alpha biologic activity from nine subjects was 110 +/- 28 (IL-2-mediated) and 304 +/- 69 (LPS-mediated) U/ml/10(6) cells, which represented 2- and 6-fold increases over controls. AM phi exhibited statistically greater (p less than 0.05) TNF production in response to both IL-2 and LPS as compared to PBM. IL-2 challenge resulted in an induction of TNF-alpha mRNA accumulation, as demonstrated by Northern blot and in situ hybridization analyses. TNF-alpha mRNA was quantitated by laser densitometry for Northern blots or by counting the number of silver grains/mononuclear phagocytic cell in the in situ hybridization analysis.(ABSTRACT TRUNCATED AT 250 WORDS)     

Activation of the cytokine network in familial Mediterranean fever

OBJECTIVE: To elucidate the role of cytokines in the pathogenesis of familial Mediterranean fever (FMF), an inherited disease characterized by attacks of serosal membrane inflammation. METHODS: Blood samples were obtained from patients with FMF during attacks and remission. The cytokine concentrations in plasma and in supernatants from whole blood stimulated by bacterial lipopolysaccharide (LPS) were determined. RESULTS: There were 27 patients with FMF, of whom 8 were studied during attacks, 9 during remission and 10 during both attack and remission. FMF attacks did not affect levels of plasma tumor necrosis factor-alpha (TNF-alpha) or interleukin 1beta (IL-1beta). In contrast, compared to remission, FMF attacks were associated with significantly higher mean levels of plasma IL-6 [8.4 pg/ml, 95% confidence interval (CI) 7.8-8.9 in remission vs 59 pg/ml, CI 21.4-96.7 during attacks; p=0.0005], sTNFr p55 (1.3 ng/ml, CI 1.2-1.4, vs 1.98 ng/ml, CI 1.6-2.3; p=0.005), and sTNFr p75 (2.9 ng/ml, CI 2.5-3.3, vs 4.09 ng/ml, CI 3.2-4.9; p=0.0249). The TNF-alpha, IL-1beta, and IL-6 content in supernatants derived from LPS stimulated blood cells was not modified by the attacks of FMF. Significant lower TNF-alpha release in LPS stimulated whole blood was detected in patients who were sampled in a later stage of the attacks (r=-0.54, p=0.047). CONCLUSION: Our results suggest that the cytokine network is activated during attacks of FMF. IL-6 appears to play an important role in the evolution of FMF attacks. Whether TNF-alpha or IL-1beta has a function in initiating the attacks remains to be established.     

Effects of amiodarone on tumor necrosis factor-alpha levels in congestive heart failure secondary to ischemic or idiopathic dilated cardiomyopathy

Tumor necrosis factor-alpha (TNF-alpha) has been implicated in the pathogenesis of congestive heart failure and may be associated with an increase in mortality. A recent in vitro study showed that amiodarone decreases TNF-alpha production by human blood mononuclear cells in response to lipopolysaccharide. However, no previous clinical studies have determined the effect of chronic amiodarone therapy on TNF-alpha levels. Thus, the purpose of this study was to determine whether amiodarone affects TNF-alpha levels in patients with ischemic and nonischemic cardiomyopathy. TNF-alpha levels were analyzed by an enzyme-linked immunoassay using plasma samples at baseline, 1, and 2 years of follow-up in New York Heart Association class III patients (n = 40 in each of the placebo and amiodarone groups, mean ejection fraction 0.25+/-0.09) who were randomized in the Congestive Heart Failure-Survival Trial of Antiarrhythmic Therapy, a multicenter, double-blind, placebo-controlled study in which the effect of amiodarone on survival was investigated. TNF-alpha levels were elevated in both groups of patients at baseline, 6.6+/-3.1 and 7.7+/-5.3 pg/ml in the amiodarone and placebo groups, respectively (p = 0.3). There were no significant differences in demographic or clinical variables between the 2 groups. Amiodarone treatment was associated with a significant increase in TNF-alpha levels in patients with ischemic cardiomyopathy, 12.7+/-12.5 and 6.8+/-3.7 pg/ml in the amiodarone and placebo groups, respectively (p = 0.03) at 1 year. No change in TNF-alpha levels was observed in patients with nonischemic cardiomyopathy. In contrast to the in vitro data, amiodarone treatment is associated with an increase in TNF-alpha levels in patients with ischemic cardiomyopathy. This increase is not associated with an adverse effect on survival.     

Usefulness of preimplantation B-type natriuretic peptide level for predicting response to cardiac resynchronization therapy

Nearly 1/3 of patients with heart failure (HF) fail to respond to cardiac resynchronization therapy (CRT). The purpose of this study was to evaluate the value of preimplantation brain natriuretic peptide (BNP) in predicting the clinical response to CRT. We retrospectively analyzed 164 patients who underwent CRT. Patients with New York Heart Association functional class III or IV HF symptoms despite maximal medical therapy, who were not on inotropic medications, had left ventricular ejection fraction < or =35%, and QRS duration >130 ms were included in the study. CRT response in patients who survived at 6-month follow-up was defined as no HF hospitalization and improvement of > or =1 grades in the New York Heart Association classification. BNP assays were performed before implantation and at 6-month follow-up. Patients had ischemic (47%) or nonischemic (53%) cardiopathy. Responders (n = 107) and nonresponders (n = 57) had similar baseline characteristics. Cardiac death and hospitalization for HF occurred in 5 (4.7%) and 18 (31.6%) patients, respectively. CRT responders compared with nonresponders exhibited higher preimplantation BNP levels (800 +/- 823 vs 335 +/- 348 pg/ml, p = 0.0002) and a significant reduction in the QRS duration after implantation (-6 +/- 34 vs +7 +/- 32 ms, p = 0.048). The preimplantation BNP was the only independent predictor of the CRT response (p = 0.001). A BNP value > or =447 pg/ml demonstrated a sensitivity of 62% and specificity of 79% in identifying CRT response. In a subgroup of 41 patients who underwent Doppler tissue imaging analysis, the preimplantation BNP was higher in patients presenting with intraventricular dyssynchrony (845 +/- 779 vs 248 +/- 290 pg/ml, p = 0.04). In conclusion, the preimplantation BNP value independently predicts CRT response and was superior to QRS duration reduction in identifying CRT responders.     

Significance of the antioxidant factor,thioredoxin, in heart failure

OBJECTIVES: Increases in oxidative stress may be involved in the progression of heart diseases. However, the serum levels of thioredoxin, a redox regulating protein, have been poorly investigated in patients with heart diseases. This study evaluated the clinical significance of the serum thioredoxin levels in patients with heart failure. METHODS: The serum thioredoxin levels were determined with a sandwich enzyme-linked immunosorbent assay in a total of 34 patients with dilated cardiomyopathy (n = 5), acute coronary syndrome (n = 7), and stable angina (n = 18), including effort angina (n = 7) and vasospastic angina (n = 11), and control subjects (n = 4). RESULTS: The serum thioredoxin levels were significantly elevated in patients with acute coronary syndrome (30.6 +/- 4.9 ng/ml, p < 0.001) and dilated cardiomyopathy (36.9 +/- 8.6 ng/ml, p < 0.001), but not in patients with stable angina (16.8 +/- 5.7 ng/ml, p = 0.27) compared with the control subjects (n = 4, 13.0 +/- 4.9 ng/ml). The serum thioredoxin level in patients with III and IV functional classes of the New York Heart Association (n = 8, 33.3 +/- 8.6 ng/ml, p < 0.001) was significantly higher than in the control subjects. In addition, the serum thioredoxin levels were negatively correlated with left ventricular ejection fractions of the patients (r = 0.59, p < 0.001). CONCLUSIONS: These results indicate a possible association between thioredoxin and the severity of heart failure.     

Clinical and neurohumoral consequences of diuretic withdrawal in patients with chronic, stabilized heart failure and systolic dysfunction

BACKGROUND: Loop diuretics are beneficial in heart failure in the short term because they eliminate fluid retention, but in the long-term, they could adversely influence prognosis due to activation of neurohumoral mechanisms. AIMS: To explore the changes induced by diuretic withdrawal in chronic nonadvanced heart failure. METHODS: Diuretics were withdrawn in 26 stabilized heart failure patients with systolic dysfunction (ejection fraction [EF]<45%). Clinical status was evaluated by physical exam, exercise capacity (corridor test) and New York Heart Association (NYHA) class. Biochemical and neurohumoral determinations were performed at baseline and at 3 months. RESULTS: At 3 months, 17 out of 26 patients (65%) were able to tolerate diuretic interruption without a deterioration in exercise capacity or New York Heart Association functional class. Renal function parameters improved (baseline urea 46.2+/-10.8 to 39.2+/-10.1 mg/dl at 3 months, p=0.014; creatinine 1.1+/-0.23 to 0.98+/-0.2 mg/dl, p=0.013). Glucose metabolism also improved (fasting glucose 151+/-91 to 122+/-14 mg/dl, p=0.035). Heart rate and systolic blood pressure did not significantly change, while diastolic blood pressure increased (from 80+/-10 to 87+/-13 mm Hg, p=0.006). Neurohumoral determinations showed a decrease in plasma renin activity (4.19+/-5.96 to 2.88+/-4.98 ng/ml, p=0.026), with no changes in aldosterone, arginine-vasopressin, endothelin-1 and norepinephrine. In contrast, atrial natriuretic peptide significantly increased (115+/-87 to 168+/-155 pg/ml, p=0.004). CONCLUSION: Diuretic withdrawal in stabilized heart failure with systolic dysfunction is associated with an improvement in renal function parameters, glucose metabolism and some neurohumoral parameters, such as plasma renin activity; however, atrial natriuretic peptide levels increased.     

慢性阻塞性肺疾病患者炎症细胞因子与肺通气功能的相关研究

目的　探讨慢性阻塞性肺疾病 (COPD)患者肺通气功能改变与炎症因子变化之间的关系。方法　稳定期COPD和慢性支气管炎 (简称慢支 )患者各 8例 ,,另有 8名健康者作为对照 ,进行肺功能检查 ,并经支气管肺泡灌洗获取肺泡巨噬细胞进行培养 ,采用酶联免疫吸附 (ELISA)方法测定大肠杆菌内毒素 (LPS)刺激后上清液中白细胞介素 8(IL 8)、IL 1β、IL 6和肿瘤坏死因子α(TNF α)的浓度 ,细胞因子之间相关性采用Pearson相关阵分析 ,肺功能值与细胞因子相关性采用多元后退回归法分析。结果　 (1)肺泡巨噬细胞释放IL 8:加入LPS后COPD组为 [(43± 2 7) μg/L和 (5 7± 41) μg/L],与正常对照组 [(13± 10 ) μg/L和 (2 0± 13 ) μg/L) ]比较差异有显著性 (P <0 .0 5 ) ;与慢支组 [(2 9± 2 1)μg/L和 (3 2± 2 3 ) μg/L]比较差异有显著性 (P >0 .0 5 )。 (2 )加入LPS前、后 ,COPD组、慢支组和正常对照组肺泡巨噬细胞释放IL 1β分别为 [(5 0± 41)ng/L、(94± 5 9)ng/L、(3 7± 3 2 )ng/L、(2 2 5± 10 8)ng/L、(15 3± 175 )ng/L、(70± 3 7)ng/L],与IL 8的释放呈正相关 (P <0 .0 5 ) ;三组肺泡巨噬细胞在LPS刺激后释放TNF α分别为 [(12 3 8± 679)ng/L、(3 0 88± 2 879)ng/L、(13 3 2± 1846)ng/L],与IL 1β呈正相     

Circulating levels of heart-type fatty acid-binding protein and its relation to thallium-201 perfusion defects in patients with hypertrophic cardiomyopathy

Myocyte loss and replacement fibrosis have been observed in patients with hypertrophic cardiomyopathy (HC) with heart failure. This study was designed to elucidate whether heart-type fatty acid-binding protein (H-FABP), a sensitive biochemical marker for myocardial damage, indicates ongoing myocardial damage in patients with HC. We studied 48 patients with HC and 17 control subjects. Patients with HC were divided into 2 groups according to the New York Heart Association (NYHA) functional class: NYHA I + II (n = 40) and NYHA III + IV (n = 8). Serum H-FABP and myoglobin levels were measured, and extent score was used to assess the extent of thallium-201 perfusion defect. Serum H-FABP levels were significantly higher in patients with HC than in control subjects (3.8 +/- 1.6 vs 2.6 +/- 0.7 ng/ml, p = 0.0032). Furthermore, serum H-FABP levels were significantly higher in NYHA III + IV than in NYHA I + II (5.2 +/- 1.3 vs 3.5 +/- 1.5 ng/ml, p = 0.0043). Serum myoglobin levels showed no significant difference among the 3 groups (control, 46.6 +/- 15.0 ng/ml; NYHA I + II, 55.5 +/- 26.4 ng/ml; NYHA III + IV, 65.1 +/- 33.6 ng/ml, p = 0.2115). Extent score correlated positively with serum H-FABP levels (r = 0.420, p = 0.0026) and negatively with fractional shortening (r = -0.542, p <0.0001). Increased H-FABP levels indicate ongoing myocardial damage, which could result in clinical deterioration in patients with HC.     

Role of Cytokines in the Mechanism of Action of Amlodipine: The PRAISE Heart Failure Trial

Objectives. We sought to determine whether the beneficial effects of amlodipine in heart failure may be mediated by a reduction in tumor necrosis factor-alpha (TNF-alpha) and interleukin-6 (IL-6) levels. We postulated that TNF-alpha and IL-6 levels may also have predictive value in patients with congestive heart failure (CHF).Background. The molecular mechanism for progression of CHF may involve cytokine overexpression. The effect of amlodipine on cytokine levels in patients with CHF is unknown.Methods. In the Prospective Randomized Amlodipine Survival Evaluation (PRAISE) trial, we used enzyme-linked immunosorbent assay to measure plasma levels of TNF-alpha in 92 patients and IL-6 in 62 patients in New York Heart Association functional classes III and IV randomized to receive amlodipine (10 mg/day) or placebo. Blood samples were obtained for cytokine measurement at baseline and at 8 and 26 weeks after enrollment.Results. The baseline amlodipine and placebo groups did not differ in demographics and cytokine levels. Mean (±SD) plasma levels of TNF-alpha were 5.69 ± 0.32 pg/ml, and those of IL-6 were 9.23 ± 1.26 pg/ml at baseline. These levels were elevated 6 and 10 times, respectively, compared with those of normal subjects (p < 0.001). Levels of TNF-alpha did not change significantly over the 26-week period (p = 0.69). However, IL-6 levels were significantly lower at 26 weeks in patients treated with amlodipine versus placebo (p = 0.007 by the Wilcoxon signed-rank test). An adverse event—CHF or death—occurred more commonly in patients with higher IL-6 levels.Conclusions. Amlodipine lowers plasma IL-6 levels in patients with CHF. The beneficial effect of amlodipine in CHF may be due to a reduction of cytokines such as IL-6.(J Am Coll Cardiol 1997;30:35–41)