Immune mechanisms in pathogenesis of chronic heart failure

In the review the new information about a participation of immune mechanisms in a pathogenesis of a chronic heart failure (CHF) is presented. Significance of a bacterial endotoxin, as inductor of activation of immune system at CHF, and factors of a system inflammation in a pathogenesis of the disease, breaking balance of matrix metalloproteinases and tissue inhibitors of metalloproteinases system, leading to change of structure of an extracellular matrix of a myocardium, are discussed.     

黄连素抑制慢性心衰大鼠心肌炎性反应

 目的 在慢性心衰(CHF)大鼠模型检测Toll样受体4(TLR4)的表达,探讨黄连素在慢性心衰炎性反应干预中可能的作用机制。方法 大鼠每周腹腔注射阿霉素2.8mg/kg共10周建立慢性心衰模型,将其随机分为黄连素组、安慰剂组及对照组,每组10只。黄连素组给予黄连素每天21mg/kg灌胃4周,另两组给予等量生理盐水。用酶联吸附免疫反应法(ELISA)检测大鼠血清中BNP、TNFα、IL-1及IL-6的含量;qRT-PCR法检测大鼠血清诱生型一氧化氮合酶(iNOS)表达;HE染色观察大鼠心肌细胞形态学改变;免疫组织化学观察大鼠心肌TLR4蛋白表达和分布。结果 黄连素组大鼠血清TNFα、IL-1、IL-6及iNOS mRNA水平显著低于安慰剂组(P<0.05);黄连素组及安慰剂组TLR4吸光度值均高于对照组,而黄连素组显著低于安慰剂组(P<0.05)。结论 黄连素可能通过抑制TLR4 信号传导抑制慢性心衰炎性反应。     

Adrenomedullin and endothelin-1 are related to inflammation in chronic heart failure

Background:  Adrenomedullin (ADM) and endothelin-1 (ET-1) are novel promising peptide biomarkers in chronic heart failure (CHF). According to recent studies among their pleiotropic effect they play roles in the regulation of inflammation. The aim of the study was to measure the above mentioned two vasoactive peptides in parallel in a well characterized population of patients with CHF, and study their associations with inflammatory markers. Materials and methods:  A total of 186 patients (138 male, 48 female) with <45% left ventricular ejection fraction (LVEF), and without acute inflammatory disease, were enrolled. Plasma midregional-proADM (MR-proADM) and C-terminal-proET-1 (CT-proET-1) were determined by a novel sandwich immunoluminomertic assay. Results:  Increased MR-proADM and CT-proET-1 plasma levels were measured in patients with severe CHF (NYHA III-IV) as compared to the group of NYHA I-II (p<0.0001). MR-proADM and CT-proET-1 levels showed significant negative correlation with serum albumin and prealbumin levels (p≤0.0001), while positive correlations were found with levels of CRP, TNF-alpha, soluble TNF receptors and IL-6 (p≤0.0001). In multiple linear regression models after adjustments for several potential confounders (disease severity [LV-EF, NYHA classes, NT-proBNP], ion and water homeostasis [sodium and presence of peripheral oedema], renal function [serum creatine]) the relationship between ADM and albumin, CRP, soluble TNF receptors and between ET-1 and CRP, TNF receptors and IL-6 remained significant. Conclusions:  Vasoregulation and inflammation may be connected in heart failure patients independently of the disease severity. The observed link may contribute to the understanding of the complex pathomechanism in CHF. Received 14 August 2008; returned for revision 31 October 2008; received from final revision 9 November 2008; accepted by C. Kasserra 18 November 2008     

Endotoxinemia in the portal and the systemic circulation in obstructive jaundice

Abstract. Endotoxinemia in patients with obstructive jaundice is linked to acute renal failure and sepsis and remains a major cause of complications during postoperative treatment. The current study examines the mechanisms of endotoxinemia in the portal and the systemic circulation in obstructive jaundice. As an experimental model of the disease we used rabbits subjected to sham operation. Serum total bilirubin aminotransferases and endotoxin concentrations were determined at 2, 5, 8, and 13 days after operation. Endotoxin concentrations were estimated by the limulus lysate endotoxin test. A high frequency of portal or systemic endotoxinemia is observed in obstructive jaundice, but no difference between endotoxinemia levels in the portal and systemic circulation was observed.     

The pathogenesis of chronic renal failure

The pathogenesis of terminal renal failure is discussed. The following are distinguished: 1. Renal failure occurring against a background of decompensated benign nephrosclerosis, primary and secondary malignant nephrosclerosis, and stenosis of the renal artery. 2. Renal failure caused by loss of glomeruli. It is pointed out that in most glomerulopathies, including diabetic glomerulopathy and renal amyloidosis, terminal renal failure only develops when accompanying disease of the postglomerular vessels leading to interstitial fibrosis impairs the outflow of blood from the glomerulus to such an extent that no more urine is produced. 3. Renal failure in disease of the tubules themselves. It is emphasized that acute renal failure only becomes chronic when interstitial fibrosis develops from the interstitial edema occurring in the early stage of the disease. 4. Renal failure occurring in primary diseases of the renal cortical interstitium. The chronic sclerosing renal diseases arising from acute interstitial nephritis are dealt with, as also are reflux nephropathy, incomplete obstructive nephropathy, analgesic nephropathy, and chronic interstitial rejection reactions in transplanted kidneys.     

Hemofiltration in chronic heart failure

30 patients with severe congestive heart failure (NYHA IV) unresponsive to medical management were treated by continuous hemofiltration (CHF). 57% of patients received arteriovenous CHF and 43% of patients venovenous, machine assisted CHF over 95 +/- 31 hours. A reduction of body edemas was achieved. The removal of body fluid by CHF between 2 and 40 kg led to a reduction of body edemas and short-term clinical improvement. Furthermore CHF treatment induced hemodynamic improvement with a reduction of central venous pressure (18 +/- 6 cm H2O pre CHF vs 8 +/- 4 cm H2O post CHF p less than 0.01) and a reduction of left ventricular filling pressure (22 +/- 6 mm Hg vs 14 +/- 5 mm Hg, p less than 0.01), while the left ventricular ejection fraction remained unchanged. Patients with low serum sodium levels (less than 132 mval/l) benefited most. While 28/30 of patients has short-term clinical improvement between 2 and 8 weeks, 38% of patients had long-term benefits.     

Morphological aspects of heart remodeling in chronic heart failure

Intraoperative biopsy specimens of the right atrium auricula from patients at different stages of chronic heart failure (CHF) were studied using the methods of light and electron microscopy. Marked heteromorphism of cardiomyocytes (CMC) was demonstrated which was found to be correlated to CHF progression. CMC showing the signs of hypertrophy and organelle hyperplasia, sarcomere discomplexation, myofibril fragmentation were identified, as well as CMC containing numerous pinocytotic vesicles, caveolae, distended T-system tubules. Apoptotic CMC and interstitial cells were also shown. No significant correlation between the myocardial cell apoptosis and CHF stage was established.     

Myocyte loss in chronic heart failure

This study examined whether or not there is progressive loss of individual myocytes in established heart failure, accounting for the progressive left ventricular dysfunction; whether such loss is by necrosis or apoptosis; and whether such loss is more pronounced in ischaemic heart disease or idiopathic dilated cardiomyopathy. Tissue for patients undergoing cardiac transplantation for clinical end-stage heart disease was used. The clinical diagnosis was not known to the observer at the time of analysis. Indices of potential myocyte loss were: detection of apoptotic nuclei in situ, using the TUNEL method, immunohistochemistry for CD120a, CD120b, CD95, perforin and granzyme B; binding of C9 complex; and lipofuscin deposition within macrophages. Interstitial macrophages and T cells and their relationship to myocyte loss were also examined. There is indeed low grade myocyte loss in chronic heart failure, but there was no difference between the disease groups; rather, there was marked patient-to-patient variation within each category. Thus in chronic heart failure myocyte loss does occur, and both necrosis and apoptosis contribute to this loss, irrespective of the underlying nature of the disease. Any mechanism which accounts for myocyte loss must be common to both conditions, rather than specific for a pre-operative diagnosis. Copyright © 1999 John Wiley & Sons, Ltd.     

慢性心力衰竭的药物治疗

本文结合对心力衰竭病理生理机制的认识,复习了慢性心衰的药物治疗方法。在传统治疗的基础上,血管紧张素转换酶抑制和β受体阻滞剂的应用已成为常规,其他针对心衰生物学机制的新型制剂正在不断问世。     

慢性心力衰竭的细胞信号转导机制

慢性心力衰竭（chronicheartfailure,CHF）是指各种原因引起心脏泵功能受损,致使心输出量减少,不能满足机体组织代谢需要,并出现心室充盈压升高、体（肺）循环淤血的临床综合征。近年来随着人口老龄化的出现,以及冠心病急性心肌梗塞死亡率的下降,CHF的发病率呈上升趋势,在美国每年有50万人发生心力衰竭’‘’。CHF严重影响老年人生活质量,是发达国家患病率和死亡率最高的疾病之一。CHF发生与发展过程中,多种基因、生理和环境因素共同作用,造成与心肌收缩蛋白功能和兴奋．收缩耦联相关的分子发生变化,如肌球蛋白头部CaZ”－…     

Skeletal muscle training in chronic heart failure

Patients with heart failure are limited in their ability to tolerate exercise. Recent research has suggested that this limitation cannot be entirely attributed to cardiac or lung impairment but rather that changes in peripheral muscles may play an important role. There are objective similarities between heart failure and muscular deconditioning. Deficiencies in peripheral blood flow and skeletal muscle function, morphology, metabolism and function are present in both conditions. Moreover, an exaggerated activity of the receptors sensitive to exercise‐derived metabolic signals (muscle ergoreceptors and peripheral and central chemoreceptors) leads to early and profound exercise‐induced fatigue and dyspnoea. These muscle afferents contribute to the ventilatory, haemodynamic and autonomic responses to exercise both in physiological and pathological conditions, including chronic heart failure. Against this background, a skeletal muscle origin of symptoms in heart failure has been proposed. The protective effects of physical training have been described in many recent studies: training improves ventilatory control, skeletal muscle metabolism and autonomic nervous system activity. The exercise training appears to induce its beneficial effects on skeletal muscle both directly (on muscle function, histological and biochemical features) and indirectly (by reducing the activation of the muscle afferents). The metabolic mediators of these muscle afferents may become a potential target in the future therapy of heart failure symptoms.     

Central sleep apnea and chronic heart failure

Central sleep apnea with Cheyne-Stokes respiration (CSR) during sleep affects about 40 % of patients with chronic heart failure (CHF). During CSR simultaneous periodic fluctuations in wakefulness and respiration with accompanying changes in blood pressure and heart rate are observed. CSR can be described as an oscillation of the ventilatory feedback loop controlling respiration. The major synergistically acting mechanisms causing this oscillation include reduced body stores of oxygen and carbon dioxide, hyperventilation with concomitant hypocapnia, prolonged circulation time, and a relatively high hypercapnic ventilatory response. The repetitive desaturations and arousals following CSR cause daytime symptoms and an increase in sympathetic activity. In CHF chronically increased sympathetic activity has negative effects on left ventricular function and is associated with reduced exercise tolerance and poor prognosis. Therefore CSR is expected to have an unfavorable influence on the course of CHF. Whether successful treatment of nocturnal CSR has any impact on the high mortality of CHF needs to be resolved in controlled studies with sufficient sample size.     

心肌细胞外基质的改变与心力衰竭

1引言慢性充血性心力衰竭（congestiveheartfailure,CHF）是一组症候群,主要表现在心脏泵功能的进行性减退及心室腔的改建”·‘’。CHF可由多种心血管疾病引起。这些疾病包括缺血性心脏病、心肌肥大、瓣膜性心脏病和自发性心肌病等”－‘’。CHF时,除心肌细胞（mpocardialcells,MC）本身结构、代谢及功能异常外,心脏间质组织也发生异常改变”。上世纪80年代前对CHP的研究多集中在对MC本身的研究上。80年代以后,许多研究结果表明整个心脏泵功能的异常不仅仅取决于MC的改变。例如心肌肥大引起的心功能不全时,单个心肌细胞功能…     

Remodeling myocardium and skeletal muscle in chronic heart failure

The spread and progression of chronic heart failure (CHF) is viewed presently from the standpoint of remodeling the myocardium and skeletal peripheral vessels. However, it is not clear yet, if such remodeling is a common adaptive mechanism in CHF for the myocardium and skeletal muscle. The study aim was to investigate the morphological changes in the myocardium and their interrelations with the skeletal muscle condition in CHF patients. For this purpose the biopsy materials of the left ventricle and pectoral muscles obtained from 36 patients with CHF (functional classes I-IV according to NYHA) of various etiologies as well as biopsy materials of the rectus abdominal muscle obtained from 8 patients without CHF were examined by light and electron microscopy. It was established that the development and progression of CHF is accompanied by similar changes in the morphology of the myocardium and skeletal muscle at the tissue, cellular and subcellular levels. As CHF aggravates, the manifestations of hypertrophy and heteromorphism of tissue fibers equally progress in the myocardium and skeletal muscle. A reliable correlation was detected between changes of cellular-stromal ratio in the myocardium and in the skeletal muscle (r = 0.57; p < 0.05).