Heart Failure in Chronic Myocarditis: A Role for microRNAs?

Myocarditis is an inflammatory disease of the heart, which can persist over a long time. During this time, known as the chronic phase of myocarditis, ongoing inflammation damages the cardiomyocytes. The loss of cardiac cells culminates in the development of dilated cardiomyopathy, often followed by non-ischemic heart failure due to diminished cardiac function. During the course of the disease, expression levels of non-coding small RNAs, called microRNAs (miRNAs), change. Although mainly studied in the acute setting, some of these changes in expression level appear to persist in the chronic phase. In addition to being a much-needed diagnostic tool, these miRNA could provide new treatment options. miRNA-based intervention strategies already showed promising results in the treatment of ischemic cardiovascular diseases in preclinical animal models. By implementing more knowledge on the role of miRNAs in the progression towards heart failure, this can potentially be used in the development of miRNA-based therapeutic interventions in the treatment of myocarditis and thereby preventing the progression towards heart failure. The first part of this review will focus on the natural course of myocarditis and the progression towards heart failure. Secondly, we will discuss the current knowledge on alterations of miRNA expression patterns, and suggest some possible future interventions.     

临床死亡川金丝猴心肌炎病例的诊断及病因分析

对临床送检的急性死亡川金丝猴进行解剖,观察各组织脏器的大体病理变化并对其进行中性甲醛固定、石蜡包埋切片和病理组织学分析;无菌操作进行肉汤法分离培养细菌和细胞培养法分离病毒,通过形态学、动物回归试验和RT-PCR 方法对分离的病原进行培养、鉴定。结果,眼观心肌呈局灶性坏死,镜下心肌纤维断裂、崩解,肌间有大量炎性细胞浸润,呈典型的病毒性心肌炎变化;从肺脏中分离获得大肠杆菌;电镜负染可见心肌组织匀浆液和心包积液以及其Vero 细胞培养物中均有直径在20 ～ 25 nm,形似小RNA 病毒的粒子存在;RTPCR检测结果说明所分离病毒为柯萨奇B 型病毒;动物回归试验证实,分离的大肠杆菌对昆明种小鼠无致病性,而分离的病毒对小鼠有致病性,且病理组织学变化与金丝猴相似。根据临床症状、病理剖检和病理组织学变化特征,结合病原分离结果综合分析,推测该金丝猴死亡的原因可能与该病毒感染有关。      

Regulatory effects of IL-18 on cytokine profiles and development of myocarditis during Trypanosoma cruzi infection

Chagas disease, caused by Trypanosoma cruzi (Tc), is an important cause of heart disease. Resistance to Tc infection is multifactorial and associated with Th1 response. IL-18 plays an important role in regulation of IFN-γ production/development of Th1 response. However, the role of IL-18 in the setting of Tc infection remains unclear. Therefore, we investigated the role of IL-18 in the modulation of immune response and myocarditis in Tc infection. C57BL/6 and IL-18 KO mice were infected with Tc (Y or Colombian strain) and parasitemia, immune response and pathology were evaluated. Y strain infection of IL-18 KO did not alter any parameters when compared with C57BL/6 mice. However, during the acute phase (20 and 40 days post infection-dpi), Colombian strain infected-IL-18 KO mice displayed higher serum levels of IL-12 and IFN-γ, respectively, and at the chronic phase (100 dpi) an increase in splenic IFN-γ-producing CD4⁺ and CD8⁺ T memory cells. There was an IL-10, FOXP3 and CD4⁺CD25⁺ cells reduction during acute infection in spleen. Additionally, there was a significant reduction in leukocyte infiltration and parasite load in myocardium of chronically infected IL-18 KO mice. Collectively, these data indicate that IL-18 contributes to the pathogenesis of Tc-induced myocarditis when infected with Colombian but not Y strain. These observations also underscore that parasite and host strain differences are important in evaluation of experimental Tc infection pathogenesis.     

苦参碱注射液对急性病毒性心肌炎的治疗作用

目的：观察苦参碱注射液治疗急性病毒性心肌炎（AVM）的临床疗效。方法：将AVM患者120例随机分为治疗组63例及对照组57例,对照组采用常规疗法,治疗组在对照组基础上给予苦参碱注射液治疗,连用2周。观察临床疗效。结果：治疗组总有效率90.5%,对照组总有效率73.7%,两组比较有显著性差异。治疗组治疗后血清肌酸磷酸激酶（CPK）、天冬氨酸转氨酶（AST）及血清乳酸脱氢酶（LDH）较对照组治疗后明显降低,差异有统计学意义（P〈0.05）。结论：苦参碱对急性心肌炎有良好疗效。     

苦参碱注射液对急性病毒性心肌炎的治疗作用

目的:观察苦参碱注射液治疗急性病毒性心肌炎(AVM)的临床疗效.方法:将AVM患者120例随机分为治疗组63例及对照组57例,对照组采用常规疗法,治疗组在对照组基础上给予苦参碱注射液治疗,连用2周.观察临床疗效.结果:治疗组总有效率90.5%,对照组总有效率73.7%,两组比较有显著性差异.治疗组治疗后血清肌酸磷酸激酶(CPK)、天冬氨酸转氨酶(AST)及血清乳酸脱氢酶(LDH)较对照组治疗后明显降低,差异有统计学意义(P＜0.05).结论:苦参碱对急性心肌炎有良好疗效.     

Long-term follow-up of patients with myocarditis and idiopathic dilated cardiomyopathy after immunomodulatory therapy

Abstract The randomized clinical trial with interferon-α (IFN) or thymic hormones versus conventional therapy was conducted in patients with myocarditis and idiopathic dilated cardiomyopathy (IDC). We enrolled 180 patients to receive IFN (3–5 million units per day) for 3 months, thymomodulin (10 mg three times per week) for 2 months, or conventional therapy alone. Patients were followed-up for 7 years after the end of treatment. Left ventricular function, exercise tolerance and survival rate were significantly better at long-term follow-up in patients treated with IFN or thymomodulin, than in conventionally treated patients. These results implicate that immune modulating therapy might represent important contribution in the treatment of myocarditis and IDC.     

Genetic control of autoimmune myocarditis mediated by myosin-specific antibodies

 Autoimmune disease involves both the development of autoreactivity and the expression of organ damage, and susceptibility is genetically complex. We recently reported that in autoimmune myocarditis susceptibility to antibody-mediated cardiac injury is strain specific. DBA/2 mice develop myocarditis following administration of myosin-specific antibody, while BALB/c mice do not. This susceptibility appears to be controlled by expression of myosin in the myocardial extracellular matrix. CByD2F1 mice are both resistant to induction of myocarditis and do not demonstrate extracellular myosin, indicating a recessive genetic component to these traits. A backcross analysis of susceptibility using DBA/2×CByD2F1 mice revealed a locus on chromosome 12 that is strongly linked with myocarditis. In male mice there was a second region on chromosome 1 that also contributes to disease susceptibility. However, genetic susceptibility in both female and male mice was genetically complex. This study demonstrates that the genetic basis of tissue injury can be analyzed separately from the genetic basis of autoreactivity. Future studies will determine whether the genetic factors identified in this study are also involved in susceptibility to rheumatic fever. Received: 18 May 1998 / Revised: 3 July 1998     

Scintigraphie myocardique et séquelles de myocardite : présentation d’un cas clinique

Acute and subacute myocarditis are well-defined pathological entities but it is often difficult to identify them because their clinical expression is variable and the diagnosis is histological showing myocardial inflammation associated with degeneration and/or necrosis. Often symptoms are similar to those of acute pericarditis with “chest-crushing” pain that mimics myocardial infarction and prompts practitioners to request angiography, especially when there are cardiovascular risk factors. We report the case of a 61-year-old patient with neither cardiac history nor cardiovascular risk factor who consulted for a long and self-limited atypical chest pain with normal clinical examination and electrocardiogram. Myocardial perfusion scintigraphy showed a non-reversible photopenic area suspected of being a nontransmural necrosis or an artifact. The discovery of inferolateral hypokinesis of left ventricle on echocardiography led to perform a coronary angiography which was finally normal. Cardiac MRI allowed to diagnose scars of a previous episode of myocarditis.