心力衰竭免疫学机制及治疗的研究进展

心力衰竭作为一种常见病、多发病,越来越受到重视,但其发生、发展的机制仍然不清楚。现有研究表明,心力衰竭的发病与免疫系统的激活有关。免疫激活产生的某些炎症因子能通过促进心肌细胞肥厚、恶化心肌收缩功能以及诱导细胞凋亡,在心力衰竭的发生、发展过程中起重要作用,同时针对心力衰竭的免疫调节治疗有望成为一个潜在的治疗新靶点。     

脂肪因子与心血管疾病的研究进展

1994年瘦素的发现引起了人们对白色脂肪组织的研究兴趣。脂肪组织是代谢活跃的内分泌器官,能产生重要的化学介质即脂肪因子和细胞因子,这些化学介质在炎症、厌食症、新陈代谢和心肌功能中起到重要作用,并为检测它们影响心血管疾病的新研究和理论奠定了基础。脂肪因子对机体内环境稳态有双重性,一方面保护心脏,促进内皮保护功能,血管生成及减少高血压、动脉粥样硬化和炎症的发生;相反也可促进高血压、心力衰竭发生等不利作用。现就脂肪因子与心血管疾病的相关性做一综述。     

心力衰竭合并心房颤动与心房纤维化研究

心房颤动在心力衰竭患者中普遍存在,心力衰竭时通过激活肾素-血管紧张素-醛固酮系统(RASS),促进转化生长因子β1(TGF-β1)和炎症因子的表达,增强氧化应激等加重心房纤维化,促进心房颤动的发生。抑制RASS的过度激活,降低TGF-β1和炎症因子的表达,减轻氧化应激作用将成为预防心力衰竭患者心房颤动发生的治疗靶点。     

信号素4D与心血管疾病的研究进展

信号素4D是Semaphorin分子家族的成员,信号素4D除了参与轴突寻路,作为神经元发育过程中的化学驱动因子外,还参与血脂异常的血小板超敏反应从而促进动脉粥样硬化的发展。炎症反应发生以后,经基质金属蛋白酶切割后产生的可溶性信号素4D参与心肌炎症反应,在心力衰竭的发生发展中起关键一环,现就信号素4D在心血管方面的相关研究进展做一综述。     

心外膜脂肪组织:心血管病防治的新靶点

心外膜脂肪组织(EAT)增加心脏代谢风险。高血压、糖尿病、肥胖等危险因素促进EAT积聚,EAT产生促炎症脂肪因子,损害冠状动脉微循环血管,引起心房和心室心肌纤维化、冠状动脉钙化,从而引发心血管病。心脏磁共振是目前测量EAT厚度的重要手段。通过测量EAT厚度有助于判断心房颤动、冠心病和心力衰竭等心血管病预后。抑制EAT形成的药物可以降低心房颤动和心力衰竭的发生发展。     

脑钠尿肽抗心肌纤维化的研究进展

当心脏持续暴露在各种压力和损伤时,心脏发生重构。心肌纤维化是心脏重构的主要特征。心脏局部的炎症反应和肾素—血管紧张素—醛固酮系统的激活可促进心肌纤维化。在心肌纤维化的过程中,炎症因子如肿瘤坏死因子α、白细胞介素1和白细胞介素6等被激活,且这些炎症因子可加重心肌纤维化。脑钠尿肽是主要由心室分泌的一种由32个氨基酸构成的多肽。心室分泌的脑钠尿肽通过作用于其受体使得环磷酸鸟苷水平升高从而发挥其生物效应。脑钠尿肽具有调节肾血流量、扩张血管、抑制肾素—血管紧张素—醛固酮系统、抗纤维化及抗炎等多种作用。心力衰竭时,脑钠尿肽可以减轻心脏的前后负荷,减轻心脏重塑,而且脑钠尿肽可抑制心脏局部血管紧张素Ⅱ、肿瘤坏死因子α、白细胞介素1和白细胞介素6等引起的心脏纤维化。     

白细胞介素与心肌纤维化关系研究进展

心血管疾病已成为全球关注的健康问题,其发病率和病死率呈逐年上升趋势,而心血管疾病导致的心力衰竭与心肌纤维化有着密切的联系。因此,研究心肌纤维化的发病机制有助于预防心血管疾病的发生、发展。心肌纤维化发病机制比较复杂,其中氧化应激和炎症发挥重要作用,作为炎症因子之一的白细胞介素可通过多方面影响心肌纤维化,本文将重点介绍白细胞介素与心肌纤维化关系的研究进展。     

心力衰竭标记物的研究进展

心力衰竭是一种常见的综合征,虽然近年来它的发病机制和治疗研究已取得了很大进展,但是病死率仍较高.最近的研究提示脑利钠肽、炎症因子、心肌损伤标记物、内皮素、基质金属蛋白酶、脂联素等,与心力衰竭的发生、发展以及预后密切相关.这些标记物为心力衰竭的诊疗提供了新的方向.     

半乳糖凝集素-3致心肌纤维化机制的研究进展

半乳糖凝集素-3(Gal-3)是一种通过识别β-糖苷介导多种细胞间相互作用的凝集素,参与纤维化、炎症、自身免疫反应、肿瘤等病理过程。Gal-3与心肌纤维化的发生发展密切相关,可以作为心力衰竭的独立预测因子。本文主要对Gal-3致心肌纤维化机制的最新研究进展进行综述,同时进一步讨论Gal-3作为抗心肌纤维化治疗新靶点的可能性。     

组织因子和组织因子途径抑制物与心肌无复流

组织因子(TF)是凝血途径的启动因子,与动脉粥样硬化的病理生理过程及临床并发症密切相关.凝血和炎症共同作用导致动脉粥样硬化,二者也是心肌无复流的发生发展基础,TF将凝血和炎症紧密联系,使二者相互作用.近些年发现心肌缺血再灌注损伤的动物模型中,缺血心肌TF表达增高,应用抑制TF的单抗可使心肌梗死面积减少,实验动物输注TF可促进心肌无复流的发生.急性冠状动脉无复流的患者TF水平也升高.TF可作为心肌无复流的预测指标.组织因子途径抑制物(TFPI)是TF的生理抑制剂,动物实验表明TFPI有抗血栓、抗炎症、抗增殖作用,输注TFPI可减轻心肌无复流的程度,为治疗心肌无复流开辟了新领域.     

细胞因子与心力衰竭关系的研究进展

心力衰竭是各种心脏疾病发生发展过程中的严重阶段。目前,大量研究提示免疫激活及细胞因子可以调节心血管系统的状态,在心力衰竭病理生理过程中发挥重要作用。循环中细胞因子的水平与心力衰竭心功能分级、预后、危险分层等密切相关,针对炎症免疫激活的治疗亦存在重要的应用潜能。本文就细胞因子与心力衰竭关系的研究进展进行综述。     

A glossary of circulating cytokines in chronic heart failure

Recent studies have emphasized the importance of biologically active molecules, termed cytokines, in the development and progression of the syndrome of chronic heart failure. This article summarizes a glossary of major cytokines and other cytokine-related inflammatory factors implicated in the pathophysiology of chronic heart failure, describing the source of their synthesis and factors regulating their secretion and analyzing their biologic effects on the cardiovascular system.     

Cytokines and anti-cytokine therapeutic approaches to chronic heart failure

Recent investigations have shown that, in addition to neurohormonal system overactivation, another class of biologically active molecules, termed cytokines, is also overexpressed in the setting of chronic heart failure and participates actively in the progression of the syndrome. In this article, we present recent experimental and clinical data describing the pathophysiological role of cytokines in left ventricular remodeling, endothelial dysfunction, and peripheral myopathy characterizing the progression of chronic heart failure, as well as novel therapeutic approaches aimed at attenuating the deleterious effects of cytokines on the cardiovascular system.     

抗炎症细胞因子在心力衰竭中的治疗进展

充血性心力衰竭是多种心血管疾病所致的一种临床综合征,近年来愈来愈多的研究证实,炎症细胞因子介导的免疫应答在心力衰竭的病理生理过程中起到了重要致病作用.干预此过程已经成为近年来研究的热点.本文总结了目前心力衰竭中抗炎症细胞因子治疗的现状,探讨通过此途径治疗心力衰竭的效果.     

白介素-18与心血管疾病

心血管疾病在现代社会中严重威胁人类健康,死亡率高。近年来,随着基因组学、蛋白质学和生物学的研究发展,确定心血管疾病的生物学标志物已经成为一种迫切需要,因为其能够客观反映生物学进程、发病机制和药理学改变,并可能成为可测定或评估的特征性指标。白介素-18(interleukin-18,IL-18)是近年来发现的具有多种生物学特性的炎性细胞因子,其作为细胞因子的重要成员在炎症过程中起重要作用。越来越多的实验和临床证据表明,IL-18在心血管疾病的发生、发展、预后及并发症中扮演着重要的角色。本文就IL-18与冠心病、高血压病、心力衰竭、房颤的关系作简要综述。     

Natural variability of circulating levels of cytokines and cytokine receptors in patients with heart failure: implications for clinical trials

OBJECTIVES

The purpose of this study was to examine the variability in cytokines and cytokine receptors in patients with heart failure in comparison with a group of healthy control subjects who were free of cardiovascular disease.

BACKGROUND

Despite increasing interest in cytokines as mediators of disease progression in heart failure and the recent interest in suppressing cytokines in clinical studies, the extent of variability in cytokines and cytokine receptors is largely unknown. This information is important for interpreting the results of studies in which changes in cytokine levels are measured in response to a specific form of therapy.

METHODS

Circulating levels of tumor necrosis factor-alpha (TNF-), and soluble TNF receptors (types 1 and 2), as well as interleukin (IL)-6 and IL-6 receptor were measured on a daily, weekly and monthly basis in heart failure patients (New York Heart Association class IIIa and IIIb; n = 10) and healthy volunteer subjects (n = 10). Measurements of cytokines and cytokine receptors were performed on plasma samples by enzyme-linked immunoassay. The daily, weekly and monthly degree of variability in cytokine and cytokine receptor levels was assessed by determining the coefficient of variation each point in time.

RESULTS

The coefficient of variation for TNF- and IL-6 levels increased over time in patients with heart failure; moreover, the coefficient of variation in heart failure subjects was significantly greater for IL-6 than for TNF-. The coefficient of variation in cytokine receptor levels was minimal, and did not differ significantly between heart failure and control subjects.

CONCLUSIONS

In patients with heart failure the degree of natural variability in circulating cytokine levels increases with time, and is greater for IL-6 than for TNF-. Accordingly, the results of the present study suggest that the sample size needed to show a statistically significant change in the circulating level of a given cytokine will vary depending on the specific cytokine that is being measured, as well as the time period over which that cytokine is being assayed.     

HMGB1在缺血性心衰中作用的研究进展

HMGB1是一种DNA结合蛋白,主要起维持核小体结构、调节基因转录、复制、DNA修复等作用。最近,针对HMGB1功能的研究主要着重于其对细胞的细胞外调节作用,HMGB1除在细胞核内存有活性外,它更有着细胞因子的功能。近年来在发展中国家,心血管疾病越来越被视为发病和死亡的一个重要原因,而慢性心力衰竭作为各种心脏病发展的严重阶段,正成为本世纪最重要的心血管疾病。随着流行病学的变迁和社会经济的发展,冠心病作为心衰的主要病因之一在我国显得越来越突出,越来越多的研究显示HMGB1在缺血性心衰发生及发展中起着多种重要作用。     

Inflammatory and atherosclerotic interactions in the depleted uremic patient

Despite the improvements in dialysis technology, the cardiovascular mortality rate is still unacceptably high among dialysis patients. It is obvious that traditional risk factors, such as hypertension, chronic heart failure (CHF), dyslipidemia and diabetes mellitus, may account for a large part of the increased cardiovascular mortality rate in these patients. However, based on recent research it could be speculated that other, non-traditional risk factors might also contribute to the high cardiovascular mortality rate in dialysis patients. Chronic inflammation, as evidenced by increased levels of pro-inflammatory cytokines and C-reactive protein (CRP), is a common feature in dialysis patients and is associated with an increased cardiovascular morbidity and mortality. Indeed, elevated levels of pro-inflammatory cytokines (such as TNF-alpha, IL-1 and IL-6) may cause malnutrition and progressive atherosclerotic cardiovascular disease by several pathogenetic mechanisms, which will be discussed in this review. Based on the strong associations observed between malnutrition, inflammation and atherosclerosis in patients with chronic renal failure (CRF) we have proposed that these features constitute a specific syndrome (MIA), which carries a high mortality rate. As elevated levels of pro-inflammatory cytokines may play a central part in the vicious circle of malnutrition, inflammation and atherosclerosis, further research is needed to investigate whether or not different anti-cytokine treatment strategies may improve survival in dialysis patients.     

Heart failure and anti tumor necrosis factor-alpha in systemic chronic inflammatory diseases

Tumor necrosis factor alpha (TNF-alpha) antagonists have emerged as an effective therapy for patients with diseases as Crohn's disease, rheumatoid arthritis, and other chronic systemic inflammatory diseases. In the last years, there has been a growing interest in the role that inflammatory cytokines, which sustain the pathogenesis of these diseases, plays in regulating cardiac structure and function, particularly in the progression of chronic heart failure.In fact there is an increase of anti-TNF alpha levels in advanced heart failure but the treatment with anti-TNF alpha has been shown to worsen the prognosis of heart failure in randomized controlled trials.Patients with rheumatoid arthritis have an increased risk for cardiovascular disease and anti-TNF alpha therapy seems to be beneficial on the risk of cardiovascular disease. In Crohn's disease the increased risk of cardiovascular disease is controversial and therefore it is impossible to demonstrate an effect in reduction of the risk; however, heart failure in patients treated with anti-TNF alpha, despite in a small proportion, has been observed.On the basis of this observation, anti-TNF alpha therapy is contraindicated in patients with Crohn's disease and III–IV New York Heart Association heart failure class.     

The cytokine network in heart failure: pathogenetic importance and potential therapeutic targets

Accumulating evidence indicates that inflammatory mediators are important in the pathogenesis of chronic heart failure. Several studies have shown raised levels of inflammatory cytokines in patients with congestive heart failure (CHF), in both plasma and circulating leukocytes, as well as in the failing myocardium itself. Importantly, many of the inflammatory cytokines (e.g. tumor necrosis factor-a and interleukin-6) have the potential to negatively influence heart contractility, induce hypertrophy, and promote apoptosis or fibrosis, thereby contributing to the continuous remodeling process in CHF. Traditional cardiovascular drugs seem to have little influence on the cytokine network in CHF patients, and immunomodulatory therapy, in addition to 'optimal' cardiovascular treatment regimens, has emerged as an option. Thus, several small studies with therapy targeted against inflammatory mediators have shown promising effects on functional capacity and myocardial performance. These studies suggest a potential for immunomodulating therapy, in addition to optimal conventional cardiovascular-treatment regimens in CHF patients. However, the results in these small studies will have to be confirmed in larger placebo-controlled mortality studies. More importantly, further research in this area will have to precisely identify the most important components in the immunopathogenesis of chronic heart failure, in order to develop more specific immunomodulating agents in this disorder.