炙甘草汤对实验性自身免疫性心肌炎的治疗作用及机制研究

目的 探讨炙甘草汤对实验性自身免疫性心肌炎的疗效及可能的作用机制.方法 40只BALB/c鼠随机分成空白对照组、实验性自身免疫性心肌炎(EAM)组、炙甘草汤组及强的松组各10只.采用重组α肌球蛋白重链多肽(MyHC-α)诱导小鼠制备实验性自身免疫性心肌炎(EAM)模型.将弗氏佐剂与MyHC-α等体积混合,分别在第0 d...     

Blockade of macrophage migration inhibitory factor ameliorates experimental autoimmune myocarditis

Macrophage migration inhibitory factor (MIF) is a cytokine that plays a critical role in the regulation of macrophage effector functions and T-cell activation. However, its role in the pathogenesis of experimental autoimmune myocarditis (EAM) has remained unresolved. In this study, we studied the role of the MIF in EAM. We investigated the expression of MIF in EAM using enzyme-linked immunosorbent assay, Northern blotting, and immunohistochemistry. Moreover, a neutralizing antibody (Ab) to MIF was injected intraperitoneally from day 0 to 20 (experiment 1), or from day 13 to 19 (experiment 2), after the immunization. Disease severity was estimated by the macroscopic and microscopic findings for the heart, heart weight to body weight ratio, and cellular and humoral immune responses on day 21. Enhanced MIF protein and mRNA expression in the heart tissue and an elevated serum MIF concentration were confirmed in EAM. In experiment 1, the anti-MIF Ab treatment markedly inhibited the onset of EAM. Moreover, a significant reduction in disease severity was also achieved even after the delayed anti-MIF Ab treatment in experiment 2. Furthermore, we demonstrated that MIF blockade decreased the expression of VCAM-1, TNF-alpha, and IL-1beta and the migration of T-cells and macrophages in the EAM heart. These results demonstrate an important role of MIF in the pathogenesis of EAM and suggest that MIF blockade may be a promising new strategy for the treatment of myocarditis.     

Increased expression of CCR5 in experimental autoimmune myocarditis and reduced severity induced by anti-CCR5 monoclonal antibody

Experimental autoimmune myocarditis (EAM) is a T-cell-mediated autoimmune disease. CCR5, which is expressed mostly on activated T cells and monocytes/macrophages, are potent chemotactic factors for autoimmune myocarditis. We investigated the role of CCR5 in the formation of experimental autoimmune myocarditis. Expression of CCR5 and its cognate ligands was assessed by RT-PCR and immunohistochemical analysis. Single-cell suspension of splenocytes and whole blood specimens from EAM mice were subjected to flow-cytometry analysis. We investigated the critical role of CCR5 in EAM mice by adoptively transferring CCR5-positive/negative T cells to mice and by neutralizing CCR5 with monoclonal antibody to observe the influence on the severity and prevalence of myocarditis. In this report, we found that CCR5-positive cells predominate in infiltrated inflammatory cells in cardiac tissue of EAM mice and CCR5-positive T cells in peripheral blood increased markedly in EAM mice compared with controls. Moreover, we demonstrated that the severity of myocarditis was significantly reduced when CCR5-negative T cells from EAM mice were adoptively transferred. When administrated with CCR5-positive T cells, the myocarditis was significantly aggravated. We also demonstrated that blockade of CCR5 with monoclonal antibodies significantly reduced severity of myocarditis in EAM mice. Overall, these findings indicate that CCR5 is important in the induction of EAM and inhibition of CCR5 with monoclonal antibody significantly reduces the severity of myocarditis. CCR5 may have the potential to become a new therapy target against autoimmune myocarditis.     

实验性自身免疫性心肌炎小鼠体内一氧化氮的变化

目的:研究实验性自身免疫性心肌炎(experimental autoimmune myocarditis,EAM)小鼠体内一氧化氮(nitric oxide,NO)含量的变化。方法:以20只小鼠建立EAM小鼠模型(EAM组),以同数量的小鼠作为对照组。于初次免疫后21 d,观察心脏大体和组织学变化,同时提取心肌蛋白进行western blot检测。分离小鼠脾脏细胞检测巨噬细胞含量变化及细胞内NO含量,并且利用化学试剂盒对小鼠血清和心肌组织中NO含量进行分析。结果:成功建立了EAM小鼠模型。流式细胞术分析显示,EAM组小鼠脾脏中CD11b+F4/80+巨噬细胞的比率显著升高(P0.05);但NO荧光探针检测显示,单个细胞内NO的含量明显减少(P0.05)。与对照组相比,EAM组小鼠血清中NO的含量未见明显变化;但心脏中NO的含量显著升高(P0.05)。Western blot的结果表明,EAM组小鼠心脏中内皮型NOS(e NOS)和诱导型NOS(i NOS)的含量均有所升高(P0.05)。结论:NO可能是参与自身免疫性心肌炎疾病发生发展过程的一种调控物质。     

柯萨奇病毒B组3型基因疫苗预防实验性心肌炎的研究

目的：以构建的柯萨奇病毒B组3型（CV3）VP1基因的真核表达系统pCEP4-CVB3VP1作为基因疫苗,评价其对CVB3实验性心肌炎的预防作用。方法：大量制备pCEP4-CVB3VP1,提纯后将其接种BALB／C小鼠,取血清进行ELISA,病毒中和试验和病毒攻击保护实验,结果：ELISA证明pCEP4-CVB3VP1表达产物可刺激机体产生抗CVB3的的特异性IgM,病毒中和试验证明其可诱导机体产生中和抗体。中和CVB3毒力,病毒攻击保护实验证明其可保护接种小鼠抵抗CVB3攻击,结论：pCEP4-CVB3VP1能诱导机产生免疫应答,可作为基因疫苗预防CVB3心肌炎。     

Blockade of T cell costimulatory signals using adenovirus vectors prevents both the induction and the progression of experimental autoimmune myocarditis

Experimental autoimmune myocarditis (EAM) has been used as a model for human myocarditis in relation to the autoimmune mechanism and proved to be a T cell-mediated autoimmune disease. Interactions of T cell surface receptors CD28 and CD40L with their ligands B7 and CD40, respectively, on APCs are critical for antigen-specific T cell activation under physiological and pathological conditions. To achieve effective inhibition of these interactions, we have constructed adenovirus vectors containing CTLA4Ig (AdexCTLA4Ig) and CD40Ig (AdexCD40Ig) and examined the effects of these adenovirus vectors in preventing EAM. AdexLacZ as a control, or AdexCTLA4Ig and/or AdexCD40Ig were injected intravenously into rats on day 0 or 14 after immunization to study the preventive effects on EAM in the T cell activation phase or inflammatory phase. Disease severity was estimated by the macroscopic and microscopic findings of the heart, heart weight to body weight ratios, and cellular and humoral immune responses on day 21. The onset of EAM after AdexCTLA4Ig or AdexCD40Ig treatment on day 0 was completely inhibited and antigen-specific lymphocyte proliferation was significantly reduced in those adenovirus-treatment groups, suggesting that those therapies induce antigen-specific T cell anergy. Moreover, significant reduction in disease severity was achieved after the adenovirus vector treatment even on day 14 compared with EAM rats. This study indicates the therapeutic potential of costimulatory pathway blockade by gene-transfer in myocarditis.     

Acute hemorrhagic myocarditis in systemic lupus erythematosus

We report a 46-year-old patient with longstanding systemic lupus erythematosus (SLE) who developed rapidly progressive heart failure and died. At postmortem, there was a unique picture of hemorrhage and mild inflammation present in the myocardium causing the heart failure. As far as we are aware, this picture has not been described before in SLE and is similar to that seen in the cardiac allograft hyperacute rejection.     

Successful treatment of fulminant myocarditis with biventricular mechanical circulatory support: A two-year follow-up

Fulminant myocarditis (FM) is an inflammation of the myocardium characterized by progressive acute heart failure leading to cardiogenic shock that develops over several hours. In this article, we present a case of a female patient with acute fulminant lymphocytic myocarditis who was successfully treated with biventricular MCS.     

细菌脂多糖促进克氏锥虫抗原诱导的自身免疫性心肌炎

目的观察细菌脂多糖（LPS）对克氏锥虫抗原诱导自身免疫性心肌炎的影响。方法克氏锥虫抗原辅以完全弗氏佐剂免疫A／J小鼠，LPS经腹腔接种方式给药，其后加强免疫2次，28d后，测定心肌肌球蛋白特异的迟发型超敏反应（DTH）及自身抗体，并取鼠心脏观察心肌炎症情况。结果LPS提高锥虫抗原诱导的心肌肌球蛋白特异性DTH及自身抗体。并且25μg LPS与锥虫抗原免疫的小鼠可见明显的心肌炎。结论LPS能够促进心肌肌球蛋白特异的自身免疫反应及锥虫抗原诱导的自身免疫性心肌炎。     

Acute hemodynamic and coronary effects of captopril in chronic cardiac failure

The acute effects of captopril on haemodynamics, coronary flow and myocardial metabolism were studied in 12 patients with chronic severe cardiac failure (primary cardiomyopathy: 10 cases; ischaemic: 2 cases) in functional Classes III or IV of the NYHA. All patients were male and their average age was 51.3 +/- 14.1 years (range 27 to 68 years). Measurements were carried out under basal conditions and 90 minutes after a single dose of 50 mg (5 cases) or 100 mg (7 cases) of captopril. Captopril administration leads to an increase in cardiac index from 2.05 +/- 0.32 to 2.34 +/- 0.35 l/min/m2 (p less than 0.05) and a greater increase in systolic index from 23.9 +/- 6.7 to 29.8 +/- 6.9 ml/syst/m2 (p less than 0.01), because the heart rate decreased slightly (p less than 0.05). These changes were the result of a decrease in afterload: mean aortic pressure fell from 85 +/- 11.8 to 68 +/- 19.6 mmHg (p less than 0.01) and systemic arterial resistance fell from 2 886 +/- 745 to 2 010 +/- 610 dynes/cm-5/sec/m-2 (p less than 0.01). Captopril also led to a fall in venous tone, i.e. pre-load: left ventricular end diastolic pressure fell from 26.9 +/- 6.1 to 20.8 +/- 6.6 mmHg: p less than 0.01. There was no change in contractility as shown by the absence of variation of the V.max (0.92 +/- 0.18 under basal conditions, and 0.90 +/- 0.15 after 90 minutes).(ABSTRACT TRUNCATED AT 250 WORDS)     

Acute hemodynamic effects of coronary artery ligation in conscious rats

Summary Because of the growing interest in the use of coronary artery ligation (CAL) in rats as a model for studies on heart failure, we have investigated the acute hemodynamic changes following CAL in conscious rats.Animals were equipped for measurement of cardiac output (CO), arterial pressure (MAP), and central venous pressure (CVP). These parameters were measured before CAL, immediately after, and 24 h after. Furthermore, peak CO, obtained by rapid infusion of 12 ml Ringer's solution (in 1 min) was measured 2 days before and 1 day after CAL.CAL resulted in immediate reduction of CO, because of reduced stroke volume (SV). CO as well as SV were inversely correlated with infarct size as determined 24h after CAL. Heart rate (HR) and MAP did not change. Twenty-four hours later, CO was still reduced. MAP was now reduced, possibly as a result from resetting of nervous reflex mechanisms.Before CAL, peak CO and SV were similar in CAL and sham animals. At 24 h after CAL, these parameters were greatly reduced in CAL rats. Peak values were strongly correlated to infarct size.Results indicate that CAL in rats leads to hemodynamic changes similar to the ones observed following myocardial infarction in man. Cardiac function is related to infarct size and is altered both at rest and during maximal stimulation.J. F. M. Smits is an Established Investigator for the Netherlands Heart Foundation     

冠状动脉循环时间与心肌缺血关系的初步研究

目的:初步研究冠状动脉循环时间(CCT)与心肌缺血之间的关系及其临床应用。方法:将84例患者分成无心肌缺血(C组,26例)和心肌缺血组(58例),应用数字减影血管造影术分别测定C组和心肌缺血患者的CCT,比较C组及心肌缺血组内各亚组间CCT(A组:CAG阳性组,39例;B组:CAG阴性组,19例)。结果:C组CCT为(4.4168±0.7782)s,B组CCT为(5.3453±0.6901)s,A组CCT为(5.4190±1.0061)s。C组较心肌缺血组CCT短,两者之间有显著性差异(P<0.01);A、B组间CCT的差异无显著性(P>0.05)。C组CCT的95％CI:4.0418～4.7919s。如果以CCT≥5.00s为心肌缺血,其诊断敏感性为65.5％,特异性为65.4％,准确性为65.5％。结论:CCT可以作为判断心肌缺血的一个指标。     

Acute hemodynamic effects of single-dose nicorandil in coronary artery disease

Fifteen patients undergoing routine cardiac catheterization for investigation of chest pain were given a single dose of 40 mg of nicorandil either sublingually (8 patients) or orally (7 patients). Fourteen patients had angina (11 effort, 3 atypical) and 1 had palpitations but all had normal left ventricular (LV) function (mean LV end-diastolic pressure 7.4 mm Hg). Hemodynamic evaluations and plasma drug concentrations were performed at baseline and 5, 15, 30, 45 and 60 minutes after dosing. In addition, venous compliance was determined at baseline, 15 and 45 minutes using forearm venous occlusion plethysmography. Significant (p <0.05) central and peripheral hemodynamic changes occurred within 15 minutes. A reduction in preload was apparent from a decrease in LV end-diastolic pressure (from 7.4 ± 1.7 to −2.6 ±1.5 mm Hg [p <0.05]) and a simultaneous decrease in mean pulmonary artery pressure (from 10.8 ± 0.7 to 5.1 ± 0.6 mm Hg [p <0.05]) at 60 minutes after dosing. This reduction in preload may reflect the venous vasodilatory activity of the drug as indicated by significant (p <0.05) increases in venous capacitance at 15 and 45 minutes. Total peripheral resistance decreased to a maximum of 19% (p <0.05) at 30 minutes and then began to return toward baseline. This effect in reducing afterload led to a substantial decrease (p <0.05) in systolic and diastolic aortic blood pressures, which was maximal at 45 minutes (34 and 21%, respectively). Transient increases in heart rate (p <0.05) and cardiac contractility indexes (p >0.05) were also observed. In addition, there was a gradual decrease in cardiac output that became significant (p <0.05) at 60 minutes. Severe hypotension that necessitated withdrawal from the study was observed in 2 patients and lower doses should be used for future investigation.     

Experimental rat model representing both acute and chronic heart failure related to autoimmune myocarditis

Summary The most important clinical manifestation of myocarditis is congestive heart failure. The precise mechanisms of heart failure during myocarditis have not been elucidated because no animal model that would permit in vivo study of hemodynamics in severe active myocarditis has been available. We monitored hemodynamics and left ventricular function in a rat model of experimental autoimmune myocarditis to determine if this model could be useful for the study of in vivo hemodynamics in severe active myocarditis. Lewis rats were immunized with human cardiac myosin suspended in complete Freund's adjuvant. Baseline hemodynamics were measured using an ultraminiature catheter pressure transducer via the right internal carotid artery, 4 weeks after immunization in one group of rats (acute phase) and 3 months after immunization in another group (chronic phase). Untreated rats served as the control group. Hemodynamic measurements were also obtained after infusion of dobutamine in the acute-phase and chronic-phase groups. The heart weight-to-body weight ratios were significantly higher in both the acute-phase group and the chronic-phase group compared with normal control rats. The baseline left ventricular systolic pressure was significantly lower in the chronic phase group than in the control group. Peak dP/dt and peak -dP/dt were significantly lower in both the acute-phase group and the chronic-phase group compared with the control group. Dobutamine significantly increased left ventricular systolic pressure, peak dP/dt, and peak -dP/dt in the chronic-phase group but caused only minor changes in hemodynamic variables in the acute-phase group. In vivo measurements of hemodynamic variables indicated the presence of left ventricular dysfunction in rats with experimental autoimmune myocarditis. This animal model may be useful for the study of both acute heart failure related to acute myocarditis and chronic heart failure due to diffuse myocardial fibrosis.     

Acute myocarditis associated with transient marked myocardial thickening and complete atrioventricular block

A 17-day-old male infant with acute myocarditis developed complete heart block and cardiogenic shock. In addition, extensive concentric thickening of the left ventricular walls and diminution of the ventricular cavity were demonstrated by serial echocar-diography. The echocardiographic findings mimicked a nonobstructive hypertrophic cardiomyopathy. However, the wall thickness gradually returned to normal, coincident with clinical improvement. This unusual myocardial thickening may have resulted from myocardial edema or cellular infiltration. Its relationship to high-dose steroid therapy is unclear.     

Acute myocarditis with thrombus near left ventricular outflow tract

A young woman presented with fulminant heart failure. Transthoracic echocardiography revealed severe left ventricular dysfunction with a mass adjacent to the basal anterior wall, near the left ventricular outflow tract (LVOT). The cause of the acute heart failure and mass was unclear. Transesophageal echocardiography, with contrast, and cardiac magnetic resonance imaging findings were consistent with thrombus near the LVOT. Cardiac biopsy suggested giant cell myocarditis. The patient was treated with anticoagulation, steroids, and heart failure medications with resolution of the thrombus. This case was remarkable for the location of thrombus at the base of the ventricle.     

Postpartum onset of acute heart failure possibly due to postpartum autoimmune myocarditis. A report of three cases

Autoimmune diseases, especially autoimmune thyroid disease, frequently develop after delivery due to the immune rebound mechanism. Most cases have transient dysfunction of affected organs. Cardiac dysfunction developed after delivery is called postpartum or peripartum cardiomyopathy. However, the aetiology of the disease is not clarified yet. Here we report three cases that developed acute heart failure in the postpartum period. One was complicated with an atrioventricular block and postpartum autoimmune thyroiditis. All patients recovered to normal cardiac function or pre-attack condition after 1 month of therapy with conventional drugs and bed rest. All three had positive antiheart antibody detected by indirect immunofluorescence assay, and one had antibody to heart myosin detected by enzyme-linked immunosorbent assay. Moreover, one of two patients examined revealed lymphocytic infiltration by endomyocardial biopsy. Antibodies to 26 viruses were not elevated significantly during the first 2 weeks after admission in any case. It is strongly suggested that heart failure is induced by postpartum autoimmune myocarditis, and thus clinicians should be aware of this disease.