心力衰竭患者血清炎症因子变化与心功能的关系

目的 探讨中老年心力衰竭患者血清肿瘤坏死因子α(TNF-α)、可溶性肿瘤坏死因子受体I(sTNFRI)、IL-6和IL-10水平变化及其与心功能之间的关系.方法 应用ELISA法测定60例中老年心力衰竭患者及30例健康中老年人的血清TNF-α、IL-6、sTNFRI、IL-10水平,同时采用超声心动图测定左心室舒张末期内径(LVEDD)和左心室射血分数(LVEF).结果 与健康者相比,心力衰竭患者血清TNF-α、IL-6、sTNFRI、IL-10水平及TNF-α/sTNFRI、IL-6/IL-10明显升高,且随着心功能的恶化逐渐升高(P＜0.05或＜0.01);心力衰竭患者血清TNF-α和IL-6水平与LVEF呈负相关,与LVEDD呈显著正相关(P均＜0.05).结论 在中老年心力衰竭患者中,促炎症细胞因子与抗炎症细胞因子的平衡偏移于炎症方向,两者的改变能够反映心功能的变化,促炎症性细胞因子与心功能状态密切相关.     

TGF-β1和TNF-α及IL-6与酒精性肝病的关系

目的 探讨转化生长因子β1( TGF-β1 ) 、肿瘤坏死因子α( TNF-α) 及白细胞介素6( IL- 6 )在酒精性肝病中的作用.方法 用ELISA方法检测63 例酒精性肝病患者血清TGF-β1 、TNF-α及IL- 6、HPCIII、HA、IV-C及LN水平,观察它们在酒精性肝病各期的水平变化,推测细胞因子在酒精性肝病中的作用.20例健康者作为对照组.结果 (1)酒精性肝病患者血清TGF-β1 、TNF-α及IL- 6水平显著高于正常组,差异有统计学意义(P<0.0 1).(2)酒精性肝病患者血清TGF-β1 、TNF-α及IL- 6水平与肝纤维化指标HPCIII、HA、IV-C及LN水平呈正相关.(3)TGF-β1 、TNF-α及IL- 6水平之间呈中度正相关.结论 血清TGF-β1 、TNF-α及IL- 6 这三种细胞因子参与了酒精性肝病的形成和发展,联合检测对综合判断ALD炎性反应和纤维化程度有一定的参考价值.     

慢性心力衰竭病人TNF-α、IL-1β水平及相关性研究

目的 研究慢性心力衰竭(CHF)病人循环中肿瘤坏死因子-α(TNF-α)、白细胞介素-1β(IL-1β)水平间的相关性.方法 60例CHF病人按心功能及病因不同分组,分别与对照组比较TNF-α、IL-1β的水平变化及其与左室射血分数(LVEF)、左室舒张末内径(LVEDd)的相关关系.结果 CHF病人循环中TNF-α、IL-1β水平较对照组增高(P<0.001),两者与病因无关,只与心功能相关.CHF病人血清TNF-α与LVEF呈负相关、与LVEDd呈正相关;IL-1β与TNF-α、LVEDd呈正相关,与LVEF呈负相关.结论 CHF病人循环中TNF-α、IL-1β水平的特征性变化及其彼此间的相关关系,充分体现了失衡的细胞因子网络在CHF的发生和发展中的重要作用.     

细胞因子与冠状动脉狭窄程度的相关性研究

目的 探讨细胞因子白细胞介素1β(IL-1β)、白细胞介素6(IL-6)、肿瘤坏死因子α(TNF-α)和γ干扰素(IFN-γ)在冠状动脉病变中的作用。方法 将93例冠心病患者根据冠状动脉狭窄程度分成三组：轻度组，34例；中度组，33例；重度组，26例。采用酶联免疫吸附法检测外周血各炎症细胞因子水平，并与30例年龄和性别相当的健康体检者进行比较。结果冠心病组外周血IL-1β、IL-6、TNF-α和IFN-γ水平均显著高于对照组各项指标，而且增高程度与冠状动脉狭窄程度一致，血管重度狭窄组细胞因子增高尤为明显。结论 研究显示：细胞因子IL-1β、IL-6、TNF-α和IFN-γ与冠状动脉狭窄呈显著正相关，提示细胞因子可能损伤血管内皮细胞，使血管内皮功能失调，导致冠状动状血管狭窄。同时也为判断冠状动脉狭窄病变程度指标而提供了一条线索。     

卡维地洛对心力衰竭患者外周血单个核细胞分泌细胞因子的影响

目的观察卡维地洛对充血性心力衰竭(CHF)患者外周血单个核细胞分泌炎症性细胞因子[白细胞介素(IL)-1β、IL-6、肿瘤坏死因子(TNF-α)]的影响。方法选取心功能Ⅲ、Ⅳ级CHF患者25例,分离外周血单个核细胞,加入脂多糖(lipopolysaccharide,LPS)和不同浓度的卡维地洛0(单纯LPS刺激组,D组)、2.5(A组)、5.0(B组)、10.0(C组)μmol/L,经体外培养24h后,采用放射免疫法检测培养上清液中TNF-α、IL-6和IL-1β水平。结果卡维地洛对A、B、C组CHF患者IL-1β、IL-6和TNF-α的水平均有抑制作用。与D组的TNF-α比较,均有统计学意义(P<0.05),C组与A组的TNF-α比较差异亦有统计学意义(P<0.05);B、C组与D组的IL-1β、IL-6水平相比均有显著性下降(P<0.05),C组与A组之间也有显著差异(P<0.05)。结论卡维地洛具有剂量依赖性抑制炎症性细胞因子分泌的作用,这可能是其降低CHF死亡率的机制之一。     

中晚期单纯性肝癌疼痛诱导的肿瘤微环境因子及相关受体的变化

目的观察和分析中晚期单纯性肝癌疼痛诱导的肿瘤微环境因子及相关受体的变化。方法收集2014年7月至2017年1月在我院收治的中晚期单纯性肝癌患者110例,疼痛评分NRS3的患者归入肝癌无痛组(B组)58例,6≤NRS≤8的患者归入肝癌合并疼痛组(C组)52例,同期健康体检者55名为对照组(A组)。B+C组接受经肝动脉化疗栓塞术,C组还接受WHO三阶梯治疗方案。检测治疗前后外周血和肝脏的转化生长因子-β(transforming growth factor-β,TGF-β)、肿瘤坏死因子(tumor necrosis factor alpha,TNF-α),白介素-1(interleukin-1,IL-1)、白介素-6(interleukin-6,IL-6)、内皮素-1(endothelin-1,ET-1)和前列腺素E-2(prostaglandin E2,PGE-2)及肝脏相应受体。结果外周血中TGF-β1、TNF-α、IL-1、IL-6、ET-1和PGE-2呈A组、B组和C组的顺序增高,且组间差异有统计学意义(P0.05)。与治疗前比,治疗后C组外周血TGF-β1、TNF-α、IL-1、IL-6、ET-1和PGE-2呈不同程度降低,且与B组比降低明显(P0.05)。与治疗前比,治疗后C组肝脏TGF-β1、TNF-α、IL-1、IL-6、ET-1和PGE-2及对应受体呈不同程度降低,与B组比降低明显(P0.05),B组肝脏的TGF-β1、IL-1、PGE-2和ET-1R有不同程度地增高(P0.05)。结论在疼痛的持续刺激下,肿瘤生长的微环境发生了利于肿瘤细胞生长的变化,TGF-β1、TNF-α、IL-1、IL-6、ET-1和PGE-2等因子和/或相关受体在血液和/或肝脏组织表达增高,给予系统抗痛治疗,可明显降低上述因子及受体。     

肺结核患者支气管肺泡灌洗液中某些细胞因子与受体的检测及其临床意义

目的 研究肺结核患者支气管肺泡灌洗液(BALF)中TNF-α及受体、IL-1β及受体的特征及其临床意义,并探讨其在结核病免疫发病中的作用.方法 采用双抗体夹心ABC-ELISA法检测46例活动性肺结核患者、21例非活动性肺结核患者BALF及血清和20例健康者血清TNF-α、可溶性TNF受体(sTNF-R)Ⅰ、IL-1β、IL-1受体水平,对其中19例活动性肺结核患者抗结核治疗后的上述细胞因子水平进行随访.组间比较采用t检验.结果 活动性肺结核组BALF中TNF-α、sTNF-R Ⅰ、IL-1β、IL-1受体水平及TNF-α/sTNF-R Ⅰ比值分别为(286.2±96.3)、(2 431.5±1 124.6)、(58.6±3.2)、(162.4±17.1)pg/L和0.06±0.01,显著高于非活动性肺结核组(t值分别为3.36、3.25、2.95、2.27和3.12,均P<0.05).空洞组BALF中TNF-α、sTNF-R Ⅰ、IL-1β、IL-1受体水平及TNF-α/sTNF-R Ⅰ比值分别为(381.4±106.4)、(2 824.7±1 318.5)、(66.4±4.6)、(176.4±18.7)pg/L和0.07±0.01,均显著高于无空洞组(t值分别为3.46、2.37、3.19、2.99和3.22,均P<0.05).抗结核治疗2个月末,19例患者中有16例患者BALF中TNF-α、sTNF-RI、IL-1β、IL-1受体水平及TNF-α/sTNF-R Ⅰ比值较治疗前明显降低(t值分别为3.26、3.17、3.28、2.92和3.12,均P<0.01),且上述患者临床症状改善,痰菌阴转,胸部X线片病灶吸收、空洞缩小或闭合.结论 TNF-α、sTNF-R Ⅰ、IL-1β、IL-1受体等均参与结核病免疫发病过程.肺结核患者BALF中TNF-α、sTNF-R Ⅰ、IL-1β、IL-1受体水平的检测可作为了解疾病活动性、判断病情及预后、监测抗结核疗效的参考.     

急性胰腺炎患者致炎与抗炎因子的变化及生长抑素的调节作用

目的:探讨急性胰腺炎患者血浆中致炎因子肿瘤坏死因子-α(TNF-α)、白介素-6(IL-6)和抗炎因子转化细胞生长因子-β(TGF-β)、白介素-10(IL-10)的变化、意义及生长抑素的调节作用。方法:急性胰腺炎48例,随机分成生长抑素治疗组和常规治疗组,分别在治疗前(入院时)、治疗后8 h和第2、3、4 d清晨空腹抽肘静脉血3 ml,测定TNF-α、IL-6、TGF-β和IL-10,并设对照组。结果:TNF-α和IL-6各监测点均比对照组显著升高(P<0.05,P<0.01),高峰在入院时。TGF-β和IL-10入院后8 h以后各监测点均比对照组显著升高(P<0.05,P<0.01);第2天达高峰。生长素抑素治疗组TNT-α、IL-6、和TGF-β、IL-10含量治疗后8 h明显低于常规治疗组。治疗后各观察点持续降低(P<0.05,P<0.01)。结论:急性胰腺炎患者血中致炎因子与抗炎因子均升高,机体免疫功能紊乱。生长抑素对致炎因子与抗炎因子的升高有抑制作用。     

雷米普利对老年心力衰竭患者血清细胞因子的影响

目的研究老年心力衰竭患者血清细胞因子水平与心功能的关系以及雷米普利对血清细胞因子的影响.方法将76例老年心力衰竭患者随机分为雷米普利治疗组(36例)和常规治疗组(40例),另设年龄、性别与之匹配的健康老年人作为对照组(30例).应用双抗夹心ELISA法检测各组受试者血清肿瘤坏死因子α(TNF-α)、可溶性肿瘤坏死因子受体(STNFRI)、白细胞介素6(IL-6)、白细胞介素10(IL-10)和转化生长因子β1(TGF-β1)水平.常规治疗组和雷米普利组在治疗2周后复查上述指标.结果(1)血清TNF-α、STNFRI、IL-6、IL-10和TGF-βI水平与老年心力衰竭患者的基础心脏病无关(P＜0.05);上述血清细胞因子水平随心功能的恶化而升高(P＜0.05或P＜0.01).(2)与治疗前比较,雷米普利治疗组治疗前后血清TNF-α[(20.9±8.2)μg/L比(13.2±8.4)μg/L]、sTNFRI[(2.7±0.9)μg/L比(1.9±0.4)μg/L]、IL-6[(29.2±6.8)ng/L比(20.5±6.0)ng/L]、IL-10[(22.1±6.4)ng/L比(13.8±5.7)ng/L]及TGF-β1[(2144.1±597.9)ng/L比(1348.8±342.4)ng/L]水平均下降(分别为P＜0.05或P＜0.01),雷米普利治疗组比常规治疗组下降明显(P＜0.01).结论老年心力衰竭患者血清细胞因子与心功能密切相关,能够反映心力衰竭的程度;雷米普利能明显改善老年心力衰竭患者细胞因子的异常.     

重症狼疮肾炎患者血清TNF-α与sTNF-R水平及甲泼尼龙与环磷酰胺双冲击治疗对其的影响

目的探讨重症狼疮肾炎(SLN)患者血清肿瘤坏死因子!(TNF-!)、可溶性肿瘤坏死因子受体(sTNF-R)的水平、sTNF-R/TNF-!比值及甲泼尼龙(MP)与环磷酰胺(CTX)双冲击治疗对其的影响。方法采用双抗体夹心酶联免疫吸附试验(ELISA)检测35名健康人(正常对照组)和38例SLN患者经MP与CTX双冲击治疗前后血清TNF-!、sTNF-RⅠ、sTNF-RⅡ的水平;抗双链DNA抗体采用ELISA法测定;抗核抗体采用间接免疫荧光法检测;补体C3、C4含量采用速率散射比浊法测定。结果SLN患者血清中TNF-!、sTNF-RⅠ、sTNF-RⅡ水平及TNF-!/sTNF-RⅠ、TNF-!/sTNF-RⅡ比值均显著高于正常对照组(P<0.01),且sTNF-RⅡ增高幅度明显高于sTNF-RⅠ(P<0.01),TNF-!、sTNF-RⅠ、sTNF-RⅡ水平与系统性红斑狼疮疾病活动指数(SLEDAI)评分、抗核抗体、抗双链DNA抗体、血沉、24h尿蛋白定量、血尿素氮(BUN)、血肌酐(Scr)呈显著正相关(P<0.05或P<0.01),与补体C3、C4、内生肌酐清除率(Ccr)呈显著负相关(P<0.05或P<0.01);sTNF-RⅠ与sTNF-RⅡ之间呈显著正相关(P<0.01)。MP与CTX双冲击治疗能显著降低SLN患者血清TNF-!、sTNF-RⅠ、sTNF-RⅡ水平及sTNF-RⅠ/TNF-!、sTNF-RⅡ/TNF-!比值(P<0.01)。结论TNF-!、sTNF-R参与了SLN的发病过程,血清TNF-!、sTNF-RⅠ、sTNF-RⅡ在一定程度上可反映SLN患者肾脏损害程度、病情轻重。动态观察血清TNF-!、sTNF-RⅠ、sTNF-RⅡ水平及sTNF-R/TNF-!比值,有助于判断SLN的狼疮活动、治疗效果及预后。MP与CTX双冲击疗法可能通过抑制SLN患者单核/巨噬细胞、T细胞产生TNF-!而发挥治疗作用。     

Cytokine network in congestive heart failure secondary to ischemic or idiopathic dilated cardiomyopathy

Inflammatory cytokines may play a pathogenic role in the development of congestive heart failure (CHF). Elevated circulating levels of inflammatory cytokines have been reported in CHF, but most studies have focused on only a few cytokine parameters. However, the activity of these cytokines are modulated by soluble cytokine receptors and cytokines with anti-inflammatory activities, and in the present study several of these interacting factors were examined simultaneously in 38 CHF patients with various degrees of heart failure and in 21 healthy controls. Patients with CHF had increased plasma concentrations of tumor necrosis factor (TNF)alpha, interleukin-6, soluble TNF receptors and the soluble interleukin-6 receptor, glycoprotein (gp)130. They also had elevated ratios of TNFalpha/soluble TNF receptors and interleukin-6/soluble gp130 as well as enhanced interleukin-6 bioactivity in serum, suggesting inflammatory net effects. In addition to raised circulating levels of inflammatory cytokines, CHF patients with severe heart failure also had abnormalities in the levels of anti-inflammatory cytokines, with decreased levels of transforming growth factor beta1 and inadequately raised interleukin-10 in relation to the elevated TNFalpha concentrations. This dysbalance between inflammatory and anti-inflammatory cytokines was also found in monocyte supernatants from CHF patients. The abnormalities in the cytokine network were most pronounced in patients with the most severe heart failure, and several of the immunologic parameters, in particular soluble gp130, were correlated with variables reflecting deranged hemodynamic status. The present study analyzing the complexity of the cytokine network in CHF, demonstrates profound disturbances in the levels of both inflammatory and anti-inflammatory mediators with a marked dysbalance favoring inflammatory effects.     

Tumor necrosis factor receptors sTNF-RI and sTNF-RII in advanced chronic heart failure

The inflammatory process in chronic heart failure (CHF) is the result of dysbalance between the function of inflammatory and natural antiinflammatory mediators. Tumor necrosis factor alpha (TNF-alpha) is increased in patients with severe CHF. Two soluble proteins, the extracellular domains of the TNF receptors (sTNF-RI and sTNF-RII) inhibit the TNF-alpha biological effect. The aim of the study was to examine the plasma levels of sTNF-RI and sTNF-RII in patients with CHF and its relation to clinical, biochemical parameters of CHF severity. 41 patients with CHF (NYHA III and NYHA IV) and 18 control subjects were enrolled in this study. Plasma levels of sTNF-RI and sTNF-RII were analyzed by immunosorbent assay (ELISA) kits R&D (Research and Diagnostics Systems) (pg/ml). RESULTS: CHF patients had significantly increased receptor plasma levels compared to controls (p < 0.001). Soluble sTNF-RI and sTNF-RII receptors levels were similar in class NYHA III and NYHA IV. Receptor sTNF-RII correlated negatively with sodium plasma levels (p < 0.001), and sTNF-RI positively correlated with urice acid plasma level (p < 0.05). No statistically significant correlations were found between those receptors and age and gender etiology and severity of CHF, body weight (BMI) or other examined parameters (clinical, hemodynamic, echocardiographic, holter). CONCLUSIONS: Plasma level of sTNF-RI and sTNF-RII are increased in patients with CHF.     

Interleukin-6 and tumor necrosis factor-alpha levels increase in response to maximal exercise in patients with chronic heart failure

Chronic heart failure (CHF) is characterized by the activation of neurohormones and cytokines. Strenuous exercise causes activation of both systems but the effect of acute bouts of exercise on cytokines is not known in patients with CHF. This study determined whether maximal exercise induces activation of cytokines in CHF. Plasma interleukin-6 (IL-6), tumor necrosis factor (TNF)-alpha, epinephrine, norepinephrine, and atrial and brain natriuretic peptides (ANP and BNP) were determined before and after symptom-limited cardiopulmonary exercise testing in 80 patients with CHF (LVEF=38+/-1%, peak VO(2)=18.8+/-0.5 ml/min/kg) and age-matched 33 controls. Resting IL-6 (Controls vs. CHF: 1.3+/-0.2 vs. 2.5+/-0.3 pg/ml, P<0.001) and TNF-alpha (2.7+/-0.2 vs. 3.8+/-0.2 pg/ml, P<0.01) were elevated in CHF. LogIL-6 and logTNF-alpha were positively correlated (r=0.34 and r=0.35, respectively) with logplasma norepinephrine, and were negatively correlated (r=-0.39 and r=-0.32, respectively) with peak VO(2). Maximal exercise increased IL-6 and TNF-alpha both in controls and CHF (all P<0.01). Changes in IL-6 (DeltaIL-6) correlated with Deltaepinephrine (r=0.63, P<0.0001) and Deltanorepinephrine (r=0.57, P=0.0006) in controls, but not in CHF. DeltaTNF-alpha correlated with DeltaANP (r=0.28, P=0.01) only in CHF. In summary, cytokine activation at rest was associated with high plasma norepinephrine and exercise intolerance. Maximal exercise caused increases in IL-6 and TNF-alpha concentrations. Sympathetic activation seems to be important for the IL-6 increase during exercise in controls. In CHF, changes in ANP during exercise were associated with the exercise-induced increase in TNF-alpha, but still unknown mechanisms are involved for the cytokine activation during exercise.     

The oxygen stress index and levels of circulating interleukin-10 and interleukin-6 in patients with chronic heart failure

OBJECTIVES: We sought to study circulating levels of pro- and anti-inflammatory cytokines together with the oxygen stress index in patients with chronic heart failure (CHF). BACKGROUND: Patients with CHF exhibit elevated levels of inflammatory and anti-inflammatory cytokines but the relative level of these cytokines with the oxygen stress index have not been reported. METHODS: Twenty-two patients with CHF and 10 control subjects were studied. Plasma levels of IL-6 and IL-10 were determined and the oxygen stress index was evaluated by urine 8-iso-PGF2alpha estimations. RESULTS: Plasma levels of IL-6 and IL-10 in CHF patients were significantly higher than those observed in the control subjects. Patients with more advanced disease (higher NYHA class) showed higher concentrations of IL-10 and IL-6 than those with less serious disease. 8-iso-PGF2alpha urine concentration (and therefore the oxygen stress index) was significantly higher in patients with CHF in comparison with control subjects. IL-6 plasma levels, but not IL-10 concentrations, correlated significantly with 8-iso-PGF2alpha levels in urine. CONCLUSIONS: Inflammatory and anti-inflammatory cytokine levels, as well as the oxidative stress index, are increased in patients with chronic heart failure. Inflammatory cytokine IL-6, but not anti-inflammatory cytokine Il-10, levels correlated significantly with the oxygen stress index.     

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.     

Soluble TNF-alpha and interleukin-6 receptors in the urine of heart failure patients. Their clinical value and relationship with plasma levels

BACKGROUND: Proinflammatory cytokines are important mediators in heart failure (HF). Recently, urinary levels of tumor necrosis factor-alpha (TNF-alpha) and interleukin-6 (IL-6) have been determined. AIMS: The purpose of this study was to measure the urinary levels of TNF-alpha and IL-6 receptors, sTNF-RI, sTNF-RII, sIL-6R, and the relationship with plasma levels and NYHA classes in HF. METHODS: Plasma and urine were collected from 114 HF patients and sTNF-RI, sTNF-RII and sIL-6R (ng/ml) were analyzed. RESULTS: For the whole population, plasma levels of sTNF-RI were 2.1+/-0.1, of sTNF-RII were 5.0+/-0.3 and of sIL-6R were 49.8+/-2.5. Urinary levels were: sTNF-RI, 2.8+/-0.5, r=0.5, p<0.001; sTNF-RII, 12.6+/-2.1, r=0.4, p<0.001; and sIL-6R, 4.2+/-0.4, NS. In NYHA III subjects, we found sTNF-RI, r=0.6, p<0.01, sTNF-RII, r=0.5, p<0.05, and sILR-6, r=0.5, p<0.05. Both plasma TNF receptors and urinary levels of sTNF-RII were higher in patients in a more severe NYHA class (p<0.05). CONCLUSIONS: Urine is a good environment to study sTNF-RI and sTNF-RII, and this fact has diagnostic and prognostic implications. Plasma and urinary levels of TNF receptors showed a fair correlation, which was increased in higher NYHA classes. Plasma and urinary levels of sIL6R showed a good correlation in NYHA III. The TNF receptor levels in urine increased in patients with more severe HF.     

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)     

慢性心力衰竭患者炎性细胞因子的变化及作用

目的探讨致炎细胞因子白细胞介素1(IL-1)、白细胞介素6(IL-6)、肿瘤坏死因子α(TNF-α)、γ干扰素(IFN-γ)和抗炎细胞因子白细胞介素10(IL-10)在慢性心力衰竭发生发展中的变化及作用。方法入选心力衰竭患者150例和健康对照50名,采用酶联免疫吸附法检测血清IL-1、IL-6、IL-10、TNF-α和IFN-γ的水平。结果心力衰竭组患者血清IL-1、IL-6、IL-10、TNF-α和IFN-γ的水平显著高于对照组(P<0.05或P<0.01),且随着纽约心功能分级(NYHA)的增加而升高,并与左心室射血分数(LVEF)呈负相关(r=-0.586、-0.454、-0.521、-0.514、-0.502,均为P<0.01),与左心室舒张末容积(LVEDV)呈正相关(r=0.603、0.45、0.542、0.519、0.438,均为P<0.01);IL-1、IL-6、TNF-α、IFN-γ总和与IL-10的比值:NYHAⅢ级和Ⅳ级患者高于对照组(P<0.05或P<0.01),NYHAⅣ级患者高于Ⅲ级和Ⅱ级患者(P<0.05),NYHAⅢ级患者高于Ⅱ级患者(P<0.05),但NYHAⅡ级患者与对照组间差异无统计学意义(P>0.05);冠心病心力衰竭和扩张型心肌病心力衰竭患者的IL-1、IL-6、IL-10、TNF-α和IFN-γ水平比较,差异无统计学意义(P>0.05)。结论心力衰竭患者致炎细胞因子和抗炎细胞因子均增高,但抗炎因子增加相对不足,炎症反应随着心力衰竭程度加重而加重,与心功能状态有相关性,与病因无显著相关性,细胞因子在心力衰竭的发生发展中起着重要的作用。     

Cardiopulmonary exercise testing and cytokines in chronic heart failure. Comparison of patients with ischaemic and with dilated cardiomyopathy

Heart failure (HF) is a complex clinical syndrome due to ischaemic heart disease, idiopathic cardiomyopathy, hypertension, valve heart disease and others. It is not clear if the etiology of HF influences decreased in this syndrome exercise tolerance. Controversial is also dependence of cytokine levels on etiology of HF. The aim of the study was to compare exercise capacity and cytokines levels in pts with ischaemic and dilated cardiomyopathy. We analyzed circulating levels of TNF-alpha and its soluble receptors sTNF-RI and sTNF-RII, and interleukin-1beta (IL-1beta), and interleukin-6 (IL-6) in 41 pts with CHF, functional class NYHA I-IV, mean EF--25.2 +/- 7.1%. For determination of cytokines level (using R & D System tests) venous blood was withdrawn after 30 minutes of supine rest. All underwent echocardiography and cardiopulmonary exercise stress testing. Dilated cardiomyopathy (DCM) was diagnosed in 21 pts, ischaemic (ICM) in 20 pts. Pts with DCM were younger then with ICM (48 +/- 6.6 vs 56 +/- 6.6 yrs; p = 0.001). There were no significant differences between groups concerning BMI and EF. There were no significant differences in the level of TNF-alpha and sTNF-RI between groups. There was a trend of increased sTNF-RII in pts with ICM (3179.7 +/- 832.7 vs 2699 +/- 680.1 pg/ml; p = 0,07), IL-1beta (2.55 +/- 2.41 vs 1.49 +/- 1.68 pg/ml; p = 0.087) and IL-6 (6.25 +/- 2.21 vs 4.98 +/- 3.64 pg/ml; p = 0.065), and significant increased ESR (11.2 +/- 9.5 vs 5.5 +/- 4.7 mm/h; p = 0.04). Peak VO2 was reduced in pts with ICM group as compared to those with DCM (14.1 +/- 3.7 vs 18.1 +/- 4.8 ml/kg/min; p = 0.0069). In chronic heart failure circulating levels of cytokines tended to be higher in pts with ischaemic origin of the syndrome. The exercise capacity is lower in ischaemic cardiomyopathy.     

Cytokines and heart rate variability in patients with chronic heart failure

INTRODUCTION: Heart rate variability (HRV) analysis is a non-invasive method of assessment of the autonomic nervous system's effects on heart function. In chronic heart failure (CHF), decreased HRV correlates with the progression of the disease. It is also known that in CHF increased levels of proinflammatory cytokines are present. Because these molecules are believed to influence the nervous system at both the central and peripheral levels, their potential role in HRV reduction in the course of CHF has been proposed. AIM: The study was designed to verify potential relations between cytokines and HRV parameters in CHF patients. The concept of the study was driven by the recognition of controversies in this field and the paucity of published reports. METHODS: Forty-four patients with CHF and stable NYHA class I-IV symptoms and 15 healthy controls were enrolled in the study. Time-domain HRV analysis was performed based on of 24-hour Holter ECG monitoring. Plasma concentrations of soluble TNFalpha receptors sTNF-RI and sTNF-RII and interleukin 6 (IL-6) were measured using commercially available ELISA kits (Quantikine, RD Systems). RESULTS: In patients with CHF, HRV indices included in the analysis were significantly decreased, and the levels of cytokines increased in comparison with the control group. In the whole study population, both in the CHF patients and the control group, significant negative correlations were observed between sTNF-RI level and long-term HRV indices such as SDNN (r=-0.44; p=0.0006), SDANN (r=-0.44; p=0.0005) and short-time index SDNNI (r=-0.37; p=0.004). Similar negative correlations were found between sTNF-RII level and SDNN (r=-0.35; p=0.007), SDANN (r=-0.34; p=0.01), and SDNNI (r=-0.31; p=0.02), as well as between IL-6 level and SDNN (r=-0.41; p=0.001), SDANN (r=-0.44; p=0.0005) and SDNNI (r=-0.34; p=0.009). CONCLUSIONS: Significant negative correlations between TNF-alpha soluble receptors sTNF-RI, sTNF-RII and IL-6 levels and time-domain HRV parameters were observed in the study. Because the results of investigations conducted so far do not elucidate the cause-effect relationship, further studies are needed to clarify the mechanisms of HRV depression in CHF and the role of cytokines in this severe clinical condition.