心肌组织柯萨奇毒-腺病毒受体表达与病毒持续感染的关系

目的探讨心肌组织中柯萨奇病毒-腺病毒受体(CAR)表达与病毒性心肌病发病的关系。方法应用免疫组化技术检测慢性心肌炎和扩张型心肌病(DCM)心肌组织中CAR的表达;应用巢式聚合酶链反应检测相应心肌组织中柯萨奇B组病毒(CVB)RNA和腺病毒(AV)DNA,并以冠心病和先心病等非感染性心脏疾病心肌组织及意外事故死亡者正常心肌标本为对照组。结果26例心肌炎和39例DCM心肌组织中均检测到较高水平CAR表达(0.011 6±0.003 6),而对照组仅有较低表达(0.004 0±0.0025),两组比较差异有非常显著意义(P< 0.001)。心肌炎和DCM患者心肌中CVB RNA 阳性率分别为42%和35.9%(平均38.5%),AV DNA阳性率分别为15.4%和10.3%(平均12.3%),对照组14例均为阴性。心肌组织病毒核酸阳性者CAR免疫组化面积积分(0.013 1±0.003 4)较阴性者(0.010 1±0.003 0)明显增高(P< 0.001)。结论CAR在慢性心肌炎和DCM心肌组织中表达明显增高,心肌组织中CVB和AV感染与CAR表达上调相关,在慢性心肌炎和DCM的发病过程中可能起重要作用。     

Relevance of cardiac parvovirus B19 in myocarditis and dilated cardiomyopathy: review of the literature

Over the last decade, parvovirus B19 (B19V) has frequently been linked to the pathogenesis of myocarditis (MC) and its progression towards dilated cardiomyopathy (DCM). The exact role of the presence of B19V and its load remains controversial, as this virus is also found in the heart of healthy subjects. Moreover, the prognostic relevance of B19V prevalence in endomyocardial biopsies still remains unclear. As a result, it is unclear whether the presence of B19V should be treated. This review provides an overview of recent literature investigating the presence of B19V and its pathophysiological relevance in MC and DCM, as well as in normal hearts. In brief, no difference in B19V prevalence is observed between MC/DCM and healthy control hearts. Therefore, the question remains open whether and how cardiac B19V may be of pathogenetic importance. Findings suggest that B19V is aetiologically relevant either in the presence of other cardiotropic viruses, or when B19V load is high and/or actively replicating, which both may maintain myocardial (low‐grade) inflammation. Therefore, future studies should focus on the prognostic relevance of the viral load, replicative status and virus co‐infections. In addition, the immunogenetic background of MC/DCM patients that makes them susceptible to develop heart failure upon presence of B19V should be more thoroughly investigated.     

抗柯注射液对柯萨奇B病毒性心肌炎和扩张型心肌病持续感染干预的实验研究

目的 :研究柯萨奇B病毒性心肌炎 (VMC)、扩张型心肌病 (DCM )中病毒持续感染与中药干预作用。方法 :①通过急慢性VMC动物模型 ,用定量多聚酶链反应测脾脏白细胞 (WBC)中以及心肌匀浆中的柯萨奇B病毒核糖核酸 (CBV RNA) ,观察其病毒持续状态 ,以明确病毒持续感染与DCM的意义 ;②观察苦参中抗柯萨奇B病毒的有效成分 (SFA)干预价值。结果 :在急性VMC模型中 ,10mg·kg-1·d-1、15mg·kg-1·d-1、2 0mg·kg-1·d-1SFA分别能清除CBV RNA达 6 7.5 8%、77.0 0 %及 92 .88%。在慢性 (2 70d)VMC动物模型脾脏WBC及心肌匀浆中定量检测的结果均证明有持续感染的存在。用 2 0mg·kg-1·d-1SFA治疗后 ,在心肌匀浆中CBV RNA的清除率为 92 .77% ,脾脏中CBV RNA的清除率为 89.0 4 %。结论 :DCM与病毒持续感染有关 ,SFA能清除CBV RNA ,其清除率与剂量有关 ,并见明显减少病变心肌的病理变化。     

扩张型心肌病HLA－DRB_1基因多态性的研究

借助聚合酶链反应（ＰＣＲ）／序列特异性引物（ＳＳＰ）技术对４２例扩张型心肌病（ＤＣＭ）患者和１６８例正常对照者进行人类白细胞抗原（ＨＬＡ）－ＤＲＢ１基因型分析。结果发现ＤＣＭ组ＨＬＡ－ＤＲＢ１＊１１基因频率与对照组比较明显增高（２６．１９％对１３．１％，Ｐ＜０．０５），其ＲＲ＝２．３６。其他等位基因频率在ＤＣＭ组与对照组间差异无显著性。提示ＨＬＡ－ＤＲＢ１＊１１基因可能与ＤＣＭ有关联。     

卡维地洛治疗扩张型心肌病心力衰竭耐受性分析

目的 :评价卡维地洛治疗国人扩张型心肌病 (DCM )心力衰竭的耐受性。方法 :对NYHAⅡ～Ⅳ级DCM患者在常规治疗 (强心、利尿、扩血管 )基础上加用卡维地洛 ,起始剂量 5mg/d ,如能耐受则逐渐滴定到最大耐受量 ,通过临床监测及调查表随访观察其不良事件。结果 :① 34例正式应用卡维地洛治疗的DCM患者至随访结束后平均卡维地洛用量为 (2 9.0 6± 6 .5 4 )mg/d ,临床疗效好 ;②卡维地洛大剂量 (≥ 35mg/d ,n =17)者舒张压、收缩压明显高于卡维地洛小剂量者 (≤ 30mg/d ,n =17) ,P <0 .0 5 ;前者年龄明显低于后者 (P <0 .0 5 ) ,但两组间心率、心功能、左室射血分数、短轴缩短率、6 0min步行距离差异无显著性意义 (P >0 .0 5 ) ;③不良事件共4 4次 ,主要包括 :乏力、腹胀、头昏等 ;④不良事件主要发生在 5mg/d及 10mg/d时的初始期及 30～ 4 0mg/d的耐受量期 ,与剂量无显著关系。结论 :我国DCM患者对第三代 β受体阻滞剂卡维地洛的耐受性好 ,不良事件少 ,安全性高     

Epidemiology of dilated cardiomyopathy: A prospective post-mortem study of 5252 necropsies

Dilated cardiomyopathy is a heart muscle disease of unknownaetiology, characterized by left ventricular dilatation andimpaired systolic function. Data on the incidence and prevalenceof the disease is ambiguous, due to geographic variations, patientselection and the diagnostic criteria adopted. Methods All the post-mortem and clinical cases observed in aconsecutive series of 5252 patients resident in Trieste duringthe period November 1987–November 1989 were studied. Results Incidence of the disease discovered at autopsy was estimatedat 4·5/100 000/year (24 cases), while clinical incidencein the same period was 2·45/100 000/year (13 cases).This is a total incidence of 6·95/100 000 new cases ayear. A possible family history of heart muscle disease wasfound in three patients (12·5%). In 15 patients (62·5%)deaths were due to cardiological complications. Endocardialthickening (P=0·03), fatty infiltration (P=0·01)and arterial involvement (P=0·04) were found more frequentlyin older patients (>65 years). Conclusions The study confirms that dilated cardiomyopathy inEurope has a higher incidence than previously suggested andemphasizes the need for greater diagnostic sensitivity, particularlysince pharmacological treatment is now so effective.     

扩张型心肌病发病机理及治疗进展

扩张型心肌病(DCM)以左心室或双心室扩张及收缩功能受损为特征,其发病机理主要与病毒感染后的自身免疫反应有关。80年代以后,遗传因素与DCM的关系逐渐受到重视。DCM的基本治疗是纠正心力衰竭,心律失常及预防血栓栓塞等并发症。针对免疫介导的心肌损伤的早期干预已成为DCM的主要治疗方法。在DCM早期应用地尔硫和β-受体阻滞剂治疗,可以阻止免疫介导的心肌损害,改善患者预后。     

Parvovirus B19 in Endomyocardial Biopsy of Patients With Idiopathic Dilated Cardiomyopathy: Foe or Bystander?

Background

Parvovirus B19 (PVB19) has emerged as one of the viruses possibly inducing chronic myocarditis and subsequent idiopathic dilated cardiomyopathy (IDCM). The aim of this work was to investigate the presence and long-term consequences of PVB19-DNA within myocardial biopsies from patients with IDCM and to compare the findings with those from donor hearts (control group).

Autoantigen estimation and simple screening assay against cardiodepressant autoantibodies in patients with dilated cardiomyopathy

The objective of this study was to identify the cardiodepressant autoantibodies that could directly influence left ventricular ejection fraction (LVEF) in patients with dilated cardiomyopathy (DCM), as well as to establish a simple screening method for these antibodies. Not only acute hemodynamic but also chronic prognosis improvements were reported with immunoadsorption in some patients with DCM. Various antibodies determined by immunohistochemistry, immunoblotting, and enzyme-linked immunosorbent assay (beta1-adrenergic [beta1-] receptors, muscarinic M2-acetylcholine [M2-] receptors, troponin I, or Na-K-ATPase) were measured in 104 patients with DCM. Cardiodepressant antibodies were also determined by ultrasonic echocardiography (UCG) of 18 day old chick embryos after adding the patients' purified immunoglobulin G, and the following clinical features were compared: age, gender, New York Heart Association class, LVEF, neurohumoral factors, arrhythmias, and other antibodies. We also checked the in vitro immunoadsorption effect against these cardiodepressant antibodies. Cardiodepressant antibodies were found in 63% of 104 patients with DCM and had no relation to other clinical parameters, except for some antibodies such as anti-beta1-receptor antibodies (81% vs. 52%, P < 0.01), anti-M2-receptor antibodies (83% vs. 48%, P < 0.01), or anti-Na-K-ATPase antibodies (85% vs. 55%, P < 0.01). However, cardiodepressant antibodies were similarly found in patients with and without antibodies against troponin I (56% vs. 64%). The LVEF of chick embryos measured by UCG in the presence of patient serum was improved after in vitro immunoadsorption. The ex vivo system using chick embryos was able to determine cardiodepressant antibodies. By multivariate analysis, antibodies against beta1- or M2-receptors was a predictor of these autoantibodies.     

MolecularphenotypesofhumanparvovirusB19inpatientswithmyocarditis Bock CT,Düchting A,Utta F,Brunner E,Sy BT,Klingel K,Lang F,Gawaz M,Felix SB,

AIM: To investigate molecular phenotypes of myocardial B19V-infection to determine the role of B19V in myocarditis and dilated cardiomyopathy (DCM).METHODS: Endomyocardial biopsies (EMBs) from 498 B19V-positive patients with myocarditis and DCM were analyzed using molecular methods and functional experiments. EMBs were obtained from the University Hospitals of Greifswald and Tuebingen and additionally from 36 German cardiology centers. Control tissues were obtained at autopsy from 34 victims of accidents, crime or suicide. Identification of mononuclear cell infiltrates in EMBs was performed using immunohistological staining. Anti-B19V-IgM and anti-B19V-IgG were analyzed by enzyme-linked immunosorbent assay (ELISA). B19V viral loads were determined using in-house quantitative real-time polymerase chain reaction (PCR). For B19V-genotyping a new B19V-genotype-specific restriction fragment length polymorphism (RFLP)-PCR was established. B19V-genotyping was verified by direct DNA-sequencing and sequences were aligned using BLAST and BioEdit software. B19V P6-promoter and HHV6-U94-transactivator constructs were generated for cell culture experiments. Transfection experiments were conducted using human endothelial cells 1. Luciferase reporter assays were performed to determine B19V-replication activity. Statistical analysis and graphical representation were calculated using SPSS and Prism5 software.RESULTS: The prevalence of B19V was significantly more likely to be associated with inflammatory cardiomyopathy (iCMP) compared to uninflamed DCM (59.6% vs 35.3%) (P < 0.0001). The detection of B19V-mRNA replication intermediates proved that replication of B19V was present. RFLP-PCR assays showed that B19V-genotype 1 (57.4%) and B19V-genotype 2 (36.7%) were the most prevalent viral genotypes. B19V-genotype 2 was observed more frequently in EMBs with iCMP (65.0%) compared to DCM (35%) (P = 0.049). Although there was no significant difference in gender-specific B19V-loads, women were more frequently infected with B19V-genotype 2 (44.6%) than men (36.0%) (P = 0.0448). Coinfection with B19V and other cardiotropic viruses was found in 19.2% of tissue samples and was associated with higher B19V viral load compared to B19V-monoinfected tissue (P = 0.0012). The most frequent coinfecting virus was human herpes virus 6 (HHV6, 16.5%). B19V-coinfection with HHV6 showed higher B19V-loads compared to B19V-monoinfected EMBs (P = 0.0033), suggesting that HHV6 had transactivated B19V. In vitro experiments confirmed a 2.4-fold increased B19V P6-promoter activity by the HHV6 U94-transactivator.CONCLUSION: The finding of significantly increased B19V loads in patients with histologically proven cardiac inflammation suggests a crucial role of B19V-genotypes and reactivation of B19V-infection by HHV6-coinfection in B19V-associated iCMP. Our findings suggest that B19V-infection of the human heart can be a causative event for the development of an endothelial cell-mediated inflammatory disease and that this is related to both viral load and genotype.     

Prognostic value of posterior wall thickness in childhood dilated cardiomyopathy and myocarditis

M-mode indices of left ventricular dimension and posterior wallthickness were derived from echocardiograms of children presentingwith dilated cardiomyopathy/myocarditis and were related tooutcome. Echocardiograms from 16 of 18 children were manuallydigitized to obtain changes of left ventricular dimension andposterior wall thickness throughout the cardiac cycle. Indicesof ventricular function and the ratio of end-diastolic posteriorwall thickness to cavity dimensions were obtained. Patients were divided into group I (alive, n=7), and group II(died, n=6 or heart transplantation, n=3) at median follow-upof 25 months. No significant difference was seen for the shorteningfraction, the percentage of posterior wall thickening or thenormalized peak rate of left ventricular filling. The normalizedpeak rate of posterior wall thinning was greater in group II.The posterior wall thickness to cavity dimension ratio was higherin group I (median=0·19) than group II (median=0·13)(P<0·005). Five of six survivors, whose ventricularfunction improved, had ratios >0·17. All but one witha ratio 0·16 remained with a dilated heart, died or requiredtransplantation (P=<0·01). A relatively thicker posterior wall (ratio >0·17)was associated with better prognosis and recovery. This indexshould be taken into account in decision-making regarding timingfor cardiac transplantation.     

曲美他嗪治疗扩张型心肌病的Meta分析

目的评价联用曲美他嗪治疗扩张型心肌病的疗效及安全性。方法计算机检索Cochrane图书馆临床对照试验库、PubMed、EBSCO、万方数据库、中国学术期刊全文数据库、中国生物医学文献数据库、维普数据库,收集曲美他嗪治疗扩张型心肌病的随机对照试验,按纳人和排除标准由2名评价者独立选择文献、提取资料,交叉核对并进行方法学质量评估,使用RevMan5．0软件进行Meta分析。结果共纳入11项研究,644例患者。Meta分析结果显示：与常规治疗比较,联用曲美他嗪明显增加左室射血分数（WMD=4．14,95％Ch3．16—5．12,P〈0．01）,减少左室舒张末期内径（WMD=-4．12,95％Ch-4．88-3．36,P〈0．01）,减少左室收缩末期内径（WMD=-3．83,95％CI：-6．16-1．5,P〈0．01）,增加6分钟步行距离（WMD=38．95,95％CI：29．85—48．06,P〈0．01）,并减少再入院率。结论现有的证据提示联用曲美他嗪可改善患者心功能指标,减少患者再住院率。但受纳入文献质量的限制,其治疗扩张性心肌病的疗效的评价期待更多高质量的随机对照双盲研究,以做进一步的评价。     

Metabolic manipulation in dilated cardiomyopathy: Assessing the role of trimetazidine

ObjectivesTo study the role of metabolic modulator (trimetazidine: TMZ) in dilated cardiomyopathy (DCM). Optimizing altered substrate metabolism in heart failure (HF) with metabolic modulators allows more efficacious energy production from glucose than from free fatty acids.Methods100 patients of DCM (47.7 years, NYHA class 2.17, LVEF 27.3%) were randomized to TMZ (20 mg tid, n = 50) vs conventional therapy (n = 50). Functional status, BNP and various echocardiographic parameters were assessed at 3–6 months.ResultsAt 3 months, TMZ group had significantly improved NYHA class (2.25 vs 1.85), 6 min walk test (349.7 vs 402 m), LVD-36 score (25.5 vs 21) and BNP (744.7 vs 248.3 pg/ml), all p 0.001. Significant improvement was also seen in LV end-systolic (LVESV, 87.1 ± 27.5 vs 78.5 ± 24.9 ml/m², p 0.001), LV end-diastolic volumes (LVEDV, 117.6 ± 29.3 vs 110.9 ± 27.4 ml/m², p 0.001), LVEF (27 vs 30.9%, p 0.001) and LV wall stress (90.2 ± 18.9 vs 71.1 ± 13.2 dyn/cm², p 0.0001). The % change in LVESV, LVEDV, LVEF and LV wall stress was −9.5%, −5.4%, +8.4% and −21.8%. Other echo parameters also improved after 3 months of TMZ (E/A ratio 1.9 vs 1.2, p = 0.001, E/A VTI 2.7 vs 1.6, p = 0.001, myocardial performance index, MPI 0.8 vs 0.7, p = 0.0001), Tissue Doppler parameters (E/E′ septal (19.7 vs 12.5, p = 0.001) and E/E′ lateral (13.3 vs 9.4, p = 0.0001)). Patients in control group had no change in NYHA class, LVD-36 scores, LV volumes or LVEF at 3 months although BNP and LV wall stress reduced to a slight extent. Patients on TMZ had further improvement in NYHA class, walk test, BNP levels and echocardiographic parameters at 6 months.ConclusionsMetabolic modulators (TMZ) may help in improving LV function in DCM. In this study, benefit was noted by 3 months with further improvement at 6 months.     

钙网蛋白及基质金属蛋白酶在扩张型心肌病发病机制中的作用

目的 探讨扩张型心肌病与钙网蛋白（Calreticulin）、基质金属蛋白酶（MMPs）家族成员MMP-2和MMP-9之间的关系,为扩张型心肌病的预防和治疗提供理论论据.方法 试验分两组：扩张型心肌病组和对照组.分别收集14例扩张型心肌病患者及14例对照组全血及临床资料（年龄,性别,左房、右房、左室、右室舒张末期内径及左室射血分数等）,提取血浆,通过蛋白免疫印迹法（western blotting）测定血浆钙网蛋白的表达水平,通过明胶酶谱法（Gelatin-PAGE）检测各标本血浆中MMP-2和MMP-9活性.结果 ①扩张型心肌病组与对照组比较,两组间左房、左室舒张末期内径、左室射血分数和MMP-9活性的差异有统计学意义.②在扩张型心肌病组中,MMP-9活性与左室射血分数呈负相关（r＝-0.590,P＜0.05）,与左室舒张末径呈正相关（非正态分布等级相关：r＝0.396,P＜0.05）,但与左房、右房、右室舒张末径和室间隔厚度均无相关关系.对照组中,MMP-9与左房、右房、左室、右室舒张末径和室间隔厚度均无相关关系.③两组比较,MMP-2活性差异无统计学意义,与左房、右房、左室、右室舒张末径,左室射血分数和室间隔厚度之间均无相关关系.④钙网蛋白在扩张型心肌病组的表达升高,但与对照组相比,两者间的表达水平差异无统计学意义（P＞0.05）.结论 ①MMP-9在扩张型心肌病患者左室重构中起重要作用,MMP-9的活性可作为评估心功能情况的参考指标之一.②钙网蛋白在扩张型心肌病病理过程中未直接参与其疾病发展,但未排除通过其他途径作用于该病理过程.     

应用组织追踪成像评价儿童扩张型心肌病左心功能的探讨

目的:探讨组织追踪技术(TTI)在儿童扩张型心肌病(DCM)左心收缩功能评价中的应用价值.方法:DCM患者14例,NYHA分级分为DCM A组(HYHAⅡ级)和DCM B组(HYHAⅢ一Ⅳ级),健康儿童12例为对照组.用GE Vivid 7彩色多普勒超声显像仪同步获取心尖四腔、左室两腔和左室长轴切面的三平面TTI动态图,分析左室TTI图及心肌收缩期向心尖方向的位移距离(Ds).结果:①DCM组收缩期TTI图色阶较对照组减少.②DCM组左室各节段Ds较对照组显著降低,以DCM B组降低更显著(P＜0.05);DCM B组部分病例Ds呈中间段＞基底段＞瓣环、部分室壁二尖瓣瓣环平均Ds小于基底段及中间段.③DCM组有4例18个心肌节段(25.00%)出现纵向收缩延迟,均来自DCM B组.④对照组、DCM A组及B组二尖瓣瓣环Ds与左室射血分数相关性好(r＝0.74、0.80、0.82,P＜0.01).结论:TTI技术能快速、直观、无创评价局部及整体左心收缩功能,对儿童DCM患者同样适用.     

Frequency and clinical characteristics of dilated cardiomyopathy caused by desmin gene mutation in a Japanese population.

AIMS: Dilated cardiomyopathy is partly caused by a mutation of some cytoskeletal or nuclear envelope proteins. It has been confirmed recently that a missense mutation of the gene encoding desmin, a cytoskeletal protein, can cause dilated cardiomyopathy. This study was aimed at elucidating the frequency and clinical characteristics of dilated cardiomyopathy caused by desmin mutation. METHODS AND RESULTS: We examined 265 Japanese patients with dilated cardiomyopathy (217 sporadic cases and 48 probands of familial dilated cardiomyopathy). The exon 8 of the desmin gene, the critical region for the pathogenesis of dilated cardiomyopathy, was analysed by polymerase chain reaction, single-strand conformation polymorphism and sequencing. The same missense mutation (Ile451Met) as reported previously was detected in three patients (1.1%). All these patients were male and sporadic, and more likely to be accompanied by characteristics such as younger age at diagnosis, lower fractional shortening and ejection fraction than each mean value of sporadic cases. The chronological changes in cardiac function were inconsistent in the three patients. CONCLUSION: The missense mutation (Ile451Met) of the desmin gene can be the genetic cause of dilated cardiomyopathy, although with very low frequency. The ages at diagnosis were younger and the cardiac function had deteriorated further than general cases of sporadic dilated cardiomyopathy.     

人细小病毒B19感染在心肌病发病中的作用

目的 :探讨人细小病毒B19(HPVB19)感染在心肌病发病中的作用。方法 :病理诊断确诊为炎症性心肌病患者 30例 ,扩张型心肌病 (DCM)患者 36例 ,肥厚型心肌病 (HCM)患者 13例 ,无心肌炎、DCM或近期感染者 (对照 ) 36例。所有被研究者均行心肌组织活检 ,用于病理组织学检查和巢式聚合酶链反应 (PCR)检测分析HPVB19 DNA。结果 :炎症性心肌病中有 4例HPVB19 DNA阳性 (占 13.3% ) ,DCM中有 3例HPVB19 DNA阳性 (占 8.3% ) ,HCM中有 2例HPVB19 DNA阳性 (占 15 .4 % ) ,而对照组HPVB19 DNA均为阴性。结论 :心肌病患者中HPVB19感染率较高 ,HPVB19感染可能是心肌病的重要病因之一。