C protein-induced myocarditis and subsequent dilated cardiomyopathy: rescue from death and prevention of dilated cardiomyopathy by chemokine receptor DNA therapy

Severe experimental autoimmune myocarditis and subsequent dilated cardiomyopathy (DCM) were successfully produced in Lewis rats by immunization with recombinant cardiac C protein. Seventy-five percent of immunized rats died between days 15 and 49 postimmunization, and all of the survived rats showed typical DCM characterized by the presence of ventricular dilatation and extensive fibrosis. Immunopathological and chemokine analysis during the acute phase revealed that there were marked macrophage infiltration with myocyte necrosis and up-regulation of MCP-1 and IFN-gamma-inducible protein-10 (IP-10). Based on these findings, we prepared plasmid DNAs encoding the binding site of CCR2 and CXCR3, which are receptors for MCP-1 and IP-10, respectively. The culture supernatant of cells transfected with these DNAs inhibited the migration of T cells and macrophages induced by MCP-1 and IP-10. Remarkably, administration of the DNAs to C protein-immunized rats prevented the disease progression and rescued animals from death. The present study has demonstrated for the first time that gene therapy targeting the chemokine receptor could be a powerful tool for the control of experimental autoimmune myocarditis and DCM.     

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.     

Quinapril inhibits progression of heart failure and fibrosis in rats with dilated cardiomyopathy after myocarditis

The cardioprotective properties of quinapril, an angiotensin-converting enzyme inhibitor, were studied in a rat model of dilated cardiomyopathy. Twenty-eight days after immunization of pig cardiac myosin, four groups rats were given 0.2 mg/kg (Q0.2, n = 11), 2 mg/kg (Q2, n = 11) or 20 mg/kg (Q20, n = 11) of quinapril or vehicle (V, n = 15) orally once a day. After 1 month, left ventricular end-diastolic pressure (LVEDP), ±dP/dt, area of myocardial fibrosis, and myocardial mRNA expression of transforming growth factor (TGF)-1, collagen-III and fibronectin were measured. Four of 15 (27%) rats in V and two of 11 (18%) in Q0.2 died. None of the animals in Q2 or Q20 died. The LVEDP was higher and ±dP/dt was lower in V (14.1 ± 2.0 mmHg and +2409 ± 150/–2318 ± 235 mmHg/sec) than in age-matched normal rats (5.0 ± 0.6 mmHg and +6173 ± 191/–7120 ± 74 mmHg/sec; all p < 0.01). After quinapril treatment, LVEDP was decreased and ±dP/dt was increased in a dose-dependent manner (10.8 ± 1.8 mmHg and +3211 ± 307/–2928 ± 390 mmHg/sec in Q0.2, 9.4 ± 1.5 mmHg and +2871 ± 270/–2966 ± 366 mmHg/sec in Q2, and 6.6 ± 1.5 mmHg, and +3569 ± 169/–3960 ± 203 mmHg/sec in Q20). Increased expression levels of TGF-1, collagen-III and fibronectin mRNA in V were reduced in Q20. Quinapril improved survival rate and cardiac function in rats with dilated cardiomyopathy after myocarditis. Furthermore, myocardial fibrosis was regressed and myocardial structure returned to nearly normal in animals treated with quinapril.     

Identification of dilated cardiomyopathy signature genes through gene expression and network data integration

Dilated cardiomyopathy (DCM) is a leading cause of heart failure (HF) and cardiac transplantations in Western countries. Single-source gene expression analysis studies have identified potential disease biomarkers and drug targets. However, because of the diversity of experimental settings and relative lack of data, concerns have been raised about the robustness and reproducibility of the predictions. This study presents the identification of robust and reproducible DCM signature genes based on the integration of several independent data sets and functional network information. Gene expression profiles from three public data sets containing DCM and non-DCM samples were integrated and analyzed, which allowed the implementation of clinical diagnostic models. Differentially expressed genes were evaluated in the context of a global protein–protein interaction network, constructed as part of this study. Potential associations with HF were identified by searching the scientific literature. From these analyses, classification models were built and their effectiveness in differentiating between DCM and non-DCM samples was estimated. The main outcome was a set of integrated, potentially novel DCM signature genes, which may be used as reliable disease biomarkers. An empirical demonstration of the power of the integrative classification models against single-source models is also given.     

An analytical comparison of cobalt cardiomyopathy and idiopathic dilated cardiomyopathy

Toxic cardiomyopathy (TC) has a rapid clinical course and morphologically resembles idiopathic dilated cardiomyopathy (IDC). To further characterize TC, we used light microscopy to compare lesions caused by cobalt (Co) to those of IDC. Cobalt levels were also measured as a chemical marker to differentiate TC from IDC. We reviewed cases with TC and IDC and excluded all cases with chemotherapy-induced myopathy and catecholamine toxicity as well as cases with possible infectious, ischemic, or hypersensitivity-induced myopathies. We compared the light microscopic findings of 12 TC cases to 12 cases of IDC, and measured trace Co levels on digested heart tissue samples. The TC cases had prominent myofibrillar loss and atrophy; no cases had neutrophil infiltration or frank myocyte necrosis. In contrast, IDC had minimal myofibril loss and atrophy. Cobalt levels in the range of 0.6 to 5.45 μg/g of dry tissue were obtained for the TC cases, while IDC demonstrated Co levels of 0.01–0.2 μg/g. Distinction between TC and IDC is predominantly a function of myocyte change, with TC showing myofibrillar loss and atrophy in the absence of inflammatory infiltrates and fibrosis; IDC is predominantly associated with myocyte hypertrophy, atrophy, and fibrosis. The opinions or assertions expressed herein are the private views of the authors and are not to be construed as official or as representing the views of the Armed Forces Institute of Pathology, the Department of the Army or the Department of Defense.     

Experimental data on the mechanism of development of alcoholic cardiomyopathy

A study was made of histo- and ultrastructure and of some electron-histochemical characteristics of the myocardium and liver of alcoholic rats. Experimental animals manifested alterations in the myocardium which were similar to those seen in alcoholic cardiomyopathy in humans. In controls, such alterations were either lacking or occurred in rare cases. Rats which received ethanol showed fatty dystrophy of the liver. The experimental animals differed from controls in some morphometric parameters (body and heart weight, diameter of cardiomyocytes) as well.     

Sarcoplasmic reticulum Ca-ATPase-phospholamban interactions and dilated cardiomyopathy

Dilated cardiomyopathy is a disease of the heart muscle resulting from a diverse array of conditions that damages the heart and impairs myocardial function. Heart failure occurs when the heart is unable to pump blood at a rate which can accommodate the heart muscle's metabolic requirements. Several signaling pathways have been shown to be involved in the induction of cardiac disease and heart failure. Many of these pathways are linked to cardiac sarcoplasmic reticulum (SR) Ca cycling directly or indirectly. A large body of evidence points to the central role of abnormal Ca handling by SR proteins, Ca-ATPase pump (SERCA2a) and phospholamban (PLN), in pathophysiological heart conditions, compromising the contractile state of the cardiomyocytes. This review summarizes studies which highlight the key role of these two SR proteins in the regulation of cardiac function, the significance of SERCA2a-PLN interactions using transgenic approaches, and the recent discoveries of human PLN mutations leading to disease states. Finally, we will discuss extrapolation of experimental paradigms generated in animal models to the human condition.     

Adaptations of cytoarchitecture in human dilated cardiomyopathy

Hypertrophic cardiomyopathy is characterised by a histological phenotype of myocyte disarray, but heart tissue samples from patients with dilated cardiomyopathy (DCM) often look comparatively similar to those from healthy individuals apart from conspicuous regions of fibrosis and necrosis. We have previously investigated subcellular alterations in the cytoarchitecture of mouse models of dilated cardiomyopathy and found that both the organisation and composition of the intercalated disc, i.e. the specialised type of cell–cell contact in the heart, is altered. There is also is a change in the composition of the M-band of the sarcomere due to an expression shift towards the more extensible embryonic heart (EH)-myomesin isoform. Analysis of human samples from the Sydney Human Heart Tissue Bank have revealed similar structural findings and also provided evidence for a dramatic change in overall cardiomyocyte size control, which has also been seen in the mouse. Together these changes in cytoarchitecture probably contribute to the decreased functional output that is seen in DCM.     

病毒性心肌炎患者的临床分析

目的:探讨病毒性心肌炎的临床特点,提高对病毒性心肌炎的认识。方法:通过对38例病毒性心肌炎患者临床资料分析,并结合相关文献,总结出病毒性心肌炎的诊断治疗特点。结果:经规范检查、治疗,38例确诊,37例治疗有效。结论:病毒性心肌炎是一种可防、可治的常见疾病。     

Pathogenic roles of cardiac autoantibodies in dilated cardiomyopathy

Whether autoimmunity could cause dilated cardiomyopathy (DCM) was disputed for more than half a century. Autoantibodies against various cardiac antigens have been found in the sera of patients with DCM but none of these autoantibodies has been shown to have a substantial role in the development of DCM. It was recently reported that the injection of autoantibodies against cardiac troponin I (cTnI) can induce DCM in normal mice. This observation showed that autoantibodies can cause DCM and put an end to the controversy. Clinical trials of immunoglobulin-adsorption therapy for DCM have already started in Germany and the results seem promising. Here, we discuss the recent findings and possibilities of immunoglobulin-adsorption therapy for this deadly disease.     

Afterload and blood pressure amplitude in dilated cardiomyopathy]

The beat-to-beat variability of the diastolic blood pressure induces small variations in the afterload of the left ventricle. These variations influence myocardial contractility, and thus blood pressure amplitude. We assessed the interdependence of blood pressure and changes in the afterload. We continuously recorded blood pressure (duration 200 s, at rest) in 20 patients with dilated cardiomyopathy (ejection fraction 32 +/- 13%, left ventricular diameter 67 +/- 8 mm) and in 20 healthy volunteers. Interbeat intervals, diastolic pressures, systolic pressure amplitudes and mean slopes of systolic pressure amplitudes were measured. Correlation coefficients (r) were calculated to assess the interdependence of blood pressure amplitudes/mean systolic slopes and the preceding diastolic pressures/interbeat intervals, respectively. In healthy volunteers we found a strong interdependence between blood pressure amplitude and the preceding diastolic pressures (r = 0.62 +/- 0.21 and 0.47 +/- 0.22). Higher diastolic pressures were followed by higher blood pressure amplitudes, and by steeper slopes of the systolic peaks. In patients with dilated cardiomyopathy, such interdependence was significantly lower (r = 0.33 +/- 22 and r = 0.28 +/- 0.35), and in patients with severely reduced left ventricular function (ejection fraction < 32%) was only marginal (r = 0.23 +/- 0.27 and 0.21 +/- 0.44, respectively). The forces of the isovolumetric contraction necessary to initiate the ejection phase of the left ventricle depend on the afterload, i.e. on the diastolic pressure. The responses of amplitude and slope of the systolic blood pressure to small changes in the afterload make it possible to assess left ventricular contractility. The latter is impaired in dilated cardiomyopathy.