[show abstract][hide abstract] ABSTRACT: Fibroblasts are widely distributed cells and are responsible for the deposition of extracellular matrix (ECM) components but also secrete ECM-degrading matrix metalloproteases. A finely balanced equilibrium between deposition and degradation of ECM is essential for structural integrity of tissues. In the past, fibroblasts have typically been understood as a uniform cell population with comparable functions regardless of their origin. Here, we determined growth curves of fibroblasts derived from heart, skin, and lung and clearly show the lowest proliferation rate for cardiac fibroblasts. Furthermore, we examined basal expression levels of collagen and different MMPs in these three types of fibroblasts and compared these concerning their site of origin. Interestingly, we found major differences in basal mRNA expression especially for MMP1 and MMP3. Moreover, we treated fibroblasts with TNF-α and observed different alterations under these proinflammatory conditions. In conclusion, fibroblasts show different properties in proliferation and MMP expression regarding their originated tissue.
Biochemistry research international. 01/2012; 2012:875742.
[show abstract][hide abstract] ABSTRACT: Aims. Several mechanisms can be involved in the development of exercise intolerance in patients with heart failure despite normal left ventricular ejection fraction (HFNEF) and may include impairment of left ventricular (LV) stiffness. We therefore investigated the influence of LV stiffness, determined by pressure-volume loop analysis obtained by conductance catheterization, on exercise capacity in HFNEF. Methods and Results. 27 HFNEF patients who showed LV diastolic dysfunction in pressure-volume (PV) loop analysis performed symptom-limited cardiopulmonary exercise testing (CPET) and were compared with 12 patients who did not show diastolic dysfunction in PV loop analysis. HFNEF patients revealed a lower peak performance (P = .046), breathing reserve (P = .006), and ventilation equivalent for carbon dioxide production at rest (P = .002). LV stiffness correlated with peak oxygen uptake (r = -0.636, P < .001), peak oxygen uptake at ventilatory threshold (r = -0.500, P = .009), and ventilation equivalent for carbon dioxide production at ventilatory threshold (r = 0.529, P = .005). Conclusions. CPET parameters such as peak oxygen uptake, peak oxygen uptake at ventilatory threshold, and ventilation equivalent for carbon dioxide production at ventilatory threshold correlate with LV stiffness. Increased LV stiffness impairs exercise capacity in HFNEF.
Cardiology research and practice. 01/2011; 2011:692862.
[show abstract][hide abstract] ABSTRACT: Non-small cell lung cancer (NSCLC) comprises of 75% of all lung cancers. Human full length tissue factor (flHTF), the physiological initiator of blood coagulation, is aberrantly expressed in certain solid tumors. FlHTF and its soluble isoform, alternatively spliced human tissue factor (asHTF), have been shown to contribute to thrombogenicity of the blood of healthy individuals. The aim of this study was to quantify flHTF and asHTF on mRNA and protein levels (using immunohistochemistry, immunoblotting, and ELISA) on a panel of human NSCLC tissue and plasma specimens. The tissue factor (TF) expression of 21 pulmonary adenomatous (AC) and 12 normal healthy tissues was assessed by real-time qRT-PCR. The TF protein concentration was quantified by ELISA in a subset of 11 AC and 9 normal tissue specimens as well as in the plasma of 13 lung cancer patients and 15 healthy controls. We found a significant increase in the ratio of flHTF/HGAPDH mRNA in AC (0.24+/-0.06 vs. 0.07+/-0.01; p=0.02 vs. controls) and in asHTF/HGAPDH mRNA (0.027+/-0.01 vs. 0.004+/-0.001; p=0.03 AC vs. controls). AsHTF mRNA expression was significantly lower in patients with stage IA disease compared to patients with higher grade stages, pointing to TF as being a marker of malignancy and metastases. TF protein of lung tumors was significantly increased in AC (p=0.004 vs. controls). TF in plasma was up-regulated in lung cancer patients (334.9+/-95.4 vs. 124.1+/-14.8 pg/ml; p=0.02 vs. controls). Immunohistochemical and immunoblotting data are in line with the increased TF expression, showing elevated blood thrombogenicity of NSCLC patients. The up-regulation of flHTF and, especially, asHTF in AC suggests not only a raised risk of thrombosis, but also of tumor progression, thereby, indicating a poor prognosis in these patients.
[show abstract][hide abstract] ABSTRACT: To explore the role of angiotensin II, we assessed hemodynamics and cardiac function in angiotensinogen-deficient mice in comparison to wild-type animals. Left ventricular end-diastolic diameter and wall thickness were evaluated by echocardiography and systolic and diastolic left ventricular function by pressure-volume relations using a micro-conductance catheter. Compared to wild-type animals, the angiotensinogen-deficient mice were hypotensive and showed impaired systolic function. The hearts were dilated, demonstrated by echocardiography and by a right-ward shift of the pressure-volume loops, but end-diastolic pressure, isovolumic relaxation (tau) and diastolic stiffness were unchanged. Afterload, however, was reduced leading to maintained cardiac output. Although a blockade of the renin-angiotensin system via angiotensin converting enzyme inhibitors or angiotensin AT1 receptor antagonist is beneficial after cardiac failure, the absence of angiotensin peptides during the ontogenesis leads to dilated cardiomyopathy.
European Journal of Pharmacology 07/2004; 493(1-3):161-5. · 2.59 Impact Factor
[show abstract][hide abstract] ABSTRACT: Several lines of evidence suggest a viral infection as the initiating event for the development of myocarditis (MC). Especially enteroviruses like coxsackie B3 virus have been shown to induce MC in humans and strains of MC-prone mice after an infection. The further course of the disease is, however, determined not only by the viral infection but also by the host's immune system. Both the humoral and the cellular immune system can modify the extent of the damage caused by the disease. The humoral immune system mounts an anti-viral immune response immediately after the infection; however, during the course of the disease, autoantibodies against a variety of different autoantigens emerge. The epitopes recognized by the anti-viral antibodies and those of several autoantibodies have been identified using synthetic peptides. The human disease could be transferred into SCID mice using peripheral blood leukocytes of patients, suggesting a pathophysiological significance of the autoimmune reaction. However, the significance of the humoral immune responses needs to be tested in randomized, prospective studies using immunoadsorption of autoantibodies in patients with inflammatory cardiomyopathy.
Medical Microbiology and Immunology 06/2004; 193(2-3):115-9. · 3.55 Impact Factor
[show abstract][hide abstract] ABSTRACT: Diabetes mellitus impairs the cardiac kallikrein-kinin system by reducing cardiac kallikrein (KLK) and kininogen levels, a mechanism that may contribute to the deleterious outcome of cardiac ischemia in this disease. We studied left ventricular (LV) function and bradykinin (BK) coronary outflow in buffer-perfused, isolated working hearts (n = 7) of controls and streptozotocin (STZ)-induced diabetic rats before and after global ischemia. With the use of selective kininase inhibitors, the activities of angiotensin I-converting enzyme, aminopeptidase P, and neutral endopeptidase were determined by analyzing the degradation kinetics of exogenously administered BK during sequential coronary passages. Basal LV function and coronary flow were impaired in STZ-induced diabetic rats. Neither basal nor postischemic coronary BK outflow differed between control and diabetic hearts. Reperfusion after 15 min of ischemia induced a peak in coronary BK outflow that was of the same extent and duration in both groups. In diabetic hearts, total cardiac kininase activity was reduced by 41.4% with an unchanged relative kininase contribution compared with controls. In conclusion, despite reduced cardiac KLK synthesis, STZ-induced diabetic hearts are able to maintain kinin liberation under basal and ischemic conditions because of a primary impairment or a secondary downregulation of kinin-degrading enzymes.
[show abstract][hide abstract] ABSTRACT: Severe combined immune deficiency (SCID) mice have been used as an animal model to study both the direct cytopathic effect of enteroviruses on the heart in the absence of an effective immune system and to investigate the role of immune mediated processes in the pathogenesis of human myocarditis. The infection of SCID mice with coxsackievirus B3 resulted in severe myocarditis with very high titers of the virus in the myocardium and severe necrosis of myocytes. This direct cytopathic effect caused an impairment of the myocardial function and resulted in a high mortality rate of the infected animals. For the study of the immune mechanisms in human myocarditis, peripheral blood leukocytes of patients with myocarditis, having an impaired left ventricular function without viral persistence in the myocardium, were transferred into SCID mice. As controls peripheral blood leukocytes of normal donors were used. At 60 days after transfer, human immunoglobulines could be demonstrated in the peripheral blood of the SCID mice, however, human autoantibodies against the adenine nucleotide translocator, a myocardial autoantigen, were only present in the animals receiving peripheral blood leukocytes from patients with myocarditis. Cellular infiltrates of human leukocytes in the myocardium and an impaired left ventricular function were also only observed in animals reconstituted with peripheral blood leukocytes from patients. These effects were T cell dependent as shown by differential transfer. These results are of interest for the treatment of human myocarditis, suggesting the avoidance of an immunosuppressive therapy in acute or chronic myocarditis with viral persistence to prevent a direct cytopathic effect in the absence of an effective immune system. However, in the setting of a chronic, (auto-)immunological myocarditis with the proven absence of entero- or adenoviral sequences an immunomodulatory therapy seems to be effective and safe.
[show abstract][hide abstract] ABSTRACT: Severe combined immune deficiency (SCID) mice have been used as an animal model to study both the direct cytopathic effect of enteroviruses on the heart in the absence of an effective immune system and to investigate the role of immune mediated processes in the pathogenesis of human myocarditis. The infection of SCID mice with coxsackievirus B3 resulted in severe myocarditis with very high titers of the virus in the myocardium and severe necrosis of myocytes. This direct cytopathic effect caused an impairment of the myocardial function and resulted in a high mortality rate of the infected animals. For the study of the immune mechanisms in human myocarditis, peripheral blood leukocytes of patients with myocarditis, having an impaired left ventricular function without viral persistence in the myocardium, were transferred into SCID mice. As controls peripherals blood leukocytes of normal donors were used. At 60 days after transfer, human immunoglobulines could be demonstrated in the peripheral blood of the SCID mice, however, human autoantibodies against the adenine nucleotide translocator, a myocardial autoantigen, were only present in the animals receiving peripheral blood leukocytes from patients with myocarditis. Cellular infiltrates of human leukocytes in the myocardium and an impaired left ventricular function were also only observed in animals reconstituted with peripheral blood leukocytes from patients. These effects were T cell dependent as shown by differential transfer. These results are of interest for the treatment of human myocarditis, suggesting the avoidance of an immunosuppressive therapy in acute or chronic myocarditis with viral persistence to prevent a direct cytophatic effect in the absence of an effective immune system. However, in the setting of a chronic, (auto-)immunological myocarditis with the proven absence of entero- or adneoviral sequences an immunomodulatory therapy seems to be effective and safe. Zusammenfassung Die Bedeutung einer enteroviralen Infektion sowie einer resultierenden Immunreaktion ist immer noch Gegenstand der Forschung in der Pathogenese der humanen Myokarditis. Muse mit einer kombinierten Immundefizienz ("severe combined immundeficiency", SCID-Muse), die keinen eigenen funktionstchtigen peripheren B- und T-Lymphozyten besitzen, wurden im Tiermodell verwendet, um den direkten zytopathischen Effekt von Enteroviren auf Herzmuskelzellen in der Abwesenheit eines effektiven Immunsystems zu untersuchen. Auerdem kann dieses Tiermodell verwendet werden, um die Rolle von immunologischen und autoimmunologischen Prozessen in der Pathogenese der humanen Myokarditis zu analysieren. Die Infektion von SCID-Musen mit Coxsackie-B3-Viren fhrt zu einer ausgeprgten Myokarditis bei sehr hohen Virustitern im Myokardgewebe und schweren Myokardzellnekrosen. Dieser direkte zytopathische Effekt verursacht eine Einschrnkung der myokardialen Pumpfunktion und fhrte zu einer hohen Mortalittsrate in den infizierten Tieren, whrend immunkompetente Muse praktisch keine Mortalitt aufweisen. Zur Untersuchung der Immunmechanismen bei der humanen Myokarditis wurden periphere Blutleukozyten von Patienten mit Myokarditis, die eine eingeschrnkte linksventrikulre Funktion, jedoch keine Viruspersistenz im Myokard aufwiesen, auf SCID-Muse bertragen. Als Kontrollen dienten die peripheren Blutleukozyten von gesunden Personen. 60 Tage nach dem Transfer fanden sich humane Immungloboline im peripheren Blut der SCID-Muse. Humane Autoantikrper gegen den Adenin-Nukleotid-Translokator, ein myokardiales Autoantigen, fanden sich hingegen nur bei den Tieren, die periphere Blutleukozyten von Patienten mit Myokarditis erhalten hatten. Zellulre Infiltrate von humanen Leukozyten im Myokard und eine Einschrnkung der linksventrikulren Funktion (verminderte Druckanstiegsgeschwindigkeit) lagen ebenso nur bei den SCID-Musen vor, die periphere Blutleukozyten von Patienten mit Myokarditis erhalten hatten. Die Tiere wiesen jedoch keinen Anhalt fr eine Graft-versus-Host-Reaktion auf, wie die Untersuchung von verschiedenen anderen Geweben ergab. Der Transfer der humanen Myokarditis in SCID-Musen ist ein T-Zell-abhngiger Prozess, wie ein entsprechender differenzieller Transfer von nur CD4-positiven oder CD4-depletierten peripheren Blutleukozyten zeigte. Diese Untersuchungen drften fr die Therapie der humanen Myokarditis von Bedeutung sein. Diese Experimente legen nahe, dass im Rahmen der Myokarditis des Menschen vor allem im Stadium der akuten Erkrankung auf eine immunsuppressive Therapie verzichtet werden sollte, um eine Schwchung des Immunsystems und damit eine erhhte Virmie und somit auch eine Verstrkung des direkten zytopathischen Effektes auf die Herzmuskelzellen zu verhindern. Aber auch im chronischen Stadium der Erkrankung sollte eine Viruspersistenz durch Entnahme von Myokardbiopsien mit entsprechender molekularbiologischer Analyse (Polymerasekettenreaktion und/oder In-situ-Hybridisierung fr Entero- bzw. Adenoviren) untersucht werden, bevor eine immunsuppressive Therapie erwogen wird. In diesem Stadium der Erkrankung sollte bei nachgewiesener Viruspersistenz vielmehr mglicherweise eine Therapie mit subkutanen Gaben von Interferon initiiert werden, wie Untersuchungen unserer eigenen Arbeitsgruppe zwischenzeitlich nahelegen. Zum anderen sprechen die Befunde dieses Tiermodells auch dafr, dass es sich bei der Myokarditis des Menschen im chronischen Stadium der Erkrankung bei Ausschluss einer Viruspersistenz um einen chronischen autoimmunologischen Prozess handelt, der einer immunmodulatorischen Therapie zugefhrt werden sollte. Nur durch eine differenzierte histologische, immunhistologische und molekularbiologische Diagnostik ist es jedoch mglich, eine Differenzierung des akuten virologischen Stadiums der Erkrankung von einem chronischen, immunologisch bedingten Stadium vorzunehmen und dementsprechend eine sinnvolle kausale Therapie durchzufhren.
[show abstract][hide abstract] ABSTRACT: The adenine nucleotide translocator (ANT) of the inner mitochondrial membrane is an autoantigen in myocarditis and in dilated cardiomyopathy. Clinical and experimental studies showed that specific autoantibodies inhibit the transmembrane nucleotide transport. In isolated hearts of guinea pigs immunized with the ANT, energy metabolism is disturbed. This metabolic disorder is related to functionally active specific antibodies and to a reduced heart function. This study tests whether similar immunological, metabolical and functional responses also occur in experimental virus myocarditis.
Experimental virus myocarditis was induced in A.SW/SnJ-mice by Coxsackie B3 virus infection. Specific antibodies against the ANT were detected by Western Blot in 14 out of 19 infected animals. In the isolated perfused hearts of five of these 14 mice cytosolic and mitochondrial ATP/ADP-ratios, determined by nonaqueous fractionation, were significantly altered, signalling a reduced ANT function [cytosolic ATP/ADP: 59 +/- 18 vs. 136 +/- 20 (controls), mitochondrial ATP/ADP: 4.2 +/- 1.0 vs. 1.1 +/- 0.3], all P < 0.05. Also, left ventricular pressure [43 +/- 9 vs. 78 +/- 6 mmHg (noninfected controls)], rate-pressure product (15.8 +/- 3.2 vs. 30.5 +/- 3.0 mmHg/min/1000), dp/dt (2410 +/- 222 vs. 3250 +/- 118 mmHg/s), and oxygen consumption (4.7 +/- 0.9 vs. 7.3 +/- 0.7 mumol/g/min), all P < 0.05, were lowered.
The data support the hypothesis that a virus infection alters cardiac energy metabolism and function by an antibody-mediated modulation of the function of the ANT.
Cardiovascular Research 10/1999; 44(1):91-100. · 5.94 Impact Factor
[show abstract][hide abstract] ABSTRACT: Experimental and clinical studies have detected an impaired respiratory function of cardiomyocyte mitochondria in heart failure. Since the reasons for heart failure are manifold, so is mitochondrial involvement. Characteristics of mitochondrial participation in heart failure are as follows: (1) Inherited or acquired mutations of the mitochondrial or nuclear genome cause defects in different mitochondrial components, eventually resulting in cardiomyopathy. (2a) Oxidative stress depresses mitochondrial function. This occurs slowly and inevitably in the ''physiological'' process of ageing, but rapidly in pathophysiologic conditions such as post-ischemic reperfusion. (2b) Free radicals damage mitochondrial DNA, proteins, and membrane lipids. Interactions between altered membrane lipids, respiratory chain components, and carrier proteins further enhance mitochondrial dysfunction. (3) Mitochondrial energy transfer via the adenine nucleotide translocator (ANT) and the mitochondrial creatine kinase is disturbed in heart failure. Especially an altered expression and a functional impairment of the ANT seems to be involved in the disturbed energy metabolism of dilated and inflammatory cardiomyopathy. (4) Mitochondria are mainly involved in the initiation and modulation of the process of programmed cell death (apoptosis). (5) Triggered by a variety of conditions during cellular dysfunction mitochondrial membrane permeability suddenly increases, followed by the collapse of the membrane potential, thus abolishing energy production and further aggravating cellular damage. (6a) Increased levels of cytokines, in particular TNF-, in heart failure and cardiomyopathy modulate mitochondrial function. (6b) Cytokines activate the generation of nitric oxide and heat shock proteins, thus further depressing or preserving mitochondrial activity.These main mechanisms of active and passive participation of mitochondria in heart failure are reviewed in this article. At present, most of them are not completely resolved and some are still hypothetical.
[show abstract][hide abstract] ABSTRACT: The adenine nucleotide translocator (ANT) is an autoantigen in myocarditis and dilated cardiomyopathy. Carrier-specific antibodies impair myocardial energy metabolism and heart function. They cross-react with a myolemmal calcium channel and alter calcium fluxes in isolated myocytes. To test whether antibodies against the ANT can alter calcium homeostasis in intact hearts, guinea pigs were immunized with the carrier protein and their isolated hearts loaded with the intracellular calcium indicator INDO-1. The diastolic and systolic ratios of fluorescence signals at 410 nm and 510 nm (emission wavelengths of the calcium-bound and calcium-free indicator), 'd-s410/510', were measured by excitation at 364 nm. This index of the transient calcium concentration associated with the contraction cycle correlated with the external heart work (EHW) in non-immunized controls. EHW of immunized animals was lower (76 +/- 62 vs 153 +/- 47 mJ/g/min in controls, p < 0.005) and the amplitude of d-s410/510 was elevated (27.6 +/- 4.1% of the average ratio of the whole heart cycle vs 21.7 +/- 1.2% in controls, p < 0.005) and essentially independent of EHW. Isoproterenol stimulation increased EHW in all hearts but d-s410/510 was hightened in control hearts, only. Thus, a disorder between cytosolic calcium transients and work was recorded in hearts from guinea pigs immunized with the ANT. It may contribute to an immunopathic mechanism of heart failure subsequent to myocarditis.
[show abstract][hide abstract] ABSTRACT: Two days before admission a 22-year-old woman developed general fatigue, nausea, headache and retrosternal pain. Physical examination was unremarkable.
Erythrocyte sedimentation rate was increased to 20/48, C-reactive protein to 3.3 mg/dl, and there was evidence of myocardial damage (creatine kinase 609 U/l, creatine kinase-MB 42 U/l, troponine T 8.39 ng/ml); ST-segment elevations in I, II, III, aVF and V-V6 of the ECG. Echocardiography revealed clearly thickened myocardium, moderate but haemodynamically not significant pericardial effusion, as well as impaired left ventricular function. Antimyosin scintigraphy was very abnormal. Cardiac catheterization confirmed the left ventricular dysfunction, rise of left ventricular enddiastolic pressure to 17 mm Hg, and a markedly reduced cardiac output of 2.4 l/min. Myocardial biopsy showed severe myocarditis with marked myocytolysis and considerable lymphocytic infiltrations. Enteroviral RNA was demonstrated in the myocardium by polymerase chain reaction.
The haemodynamics became normal within only 3 days. Myocardial biopsy after 6 months was unremarkable histologically and immunohistologically, and left ventricular function was also normal. However, while after a further 12 months myocardial biopsy remained normal and no virus was demonstrated, there was definite, though moderate, impairment in left ventricular function, indicating a dilated cardiomyopathy.
Even when histological and immunohistological evidence of healing of an acute viral myocarditis has been achieved, with complete normalization of left ventricular function, a dilated cardiomyopathy may subsequently develop. The pathophysiological mechanism of this occurrence remains unknown.
[show abstract][hide abstract] ABSTRACT: Three adenine nucleotide translocase isoforms (ANT1, ANT2 and ANT3) are coded by different genes. The relative amounts of the three ANT isoform mRNAs were determined in detail in various human tissues. ANT isoforms were co-expressed in all tested tissues revealing tissue-specific transcription patterns. The highest ANT1 mRNA proportions were found in terminally differentiated tissues like skeletal muscle, heart and brain, whereas ANT2 was mainly expressed in tissues capable of proliferation and regeneration as in the kidneys, spleen, liver, fibroblasts and lymphocytes. The ANT3 mRNA proportion was not prominently expressed in any of the tissues tested. In conclusion, tissue-specific expression of ANT isoforms is strongly related to the state of cellular differentiation.
[show abstract][hide abstract] ABSTRACT: Several findings pointed to an insufficient energy supply in heart muscle tissue of patients suffering from dilated cardiomyopathy (DCM). We found a lowered ANT transport capacity of the adenine nucleotide translocator (ANT), the only transport system for ATP and ADP in eucaryotic cells, in explanted hearts of DCM patients. The reduced ANT transport rate was accompanied by a marked elevation in total ANT protein caused by an increase in ANT 1 isoform protein. Simultaneously, a reduction in ANT 2 transcripts and an unchanged ANT 3 expression was observed. In contrast, patients with ischemic or valvular heart disease showed no alteration in ANT function or expression, which indicates the disease-specificity of these findings. With regard to autoimmunological and viral processes, which are thought to play an important role in the pathogenesis of DCM, we could show that the ANT function is reduced in the hearts of A.SW/Sn-J mice infected with the enterovirus Cox-sackie B3, and in those of guinea pigs immunized with purified myocardial ANT. Both treatments led to autoimmunological reactions against the ANT protein, that reduce the myocardial ANT transport capacity, thus disturbing energy metabolism and consequently depressing heart function. In contrast to these animal models, no restriction in ANT capacity was observed in hypoxic hearts of guinea pigs, which corresponds to the findings of unaffected ANT function in ischemic human hearts.
Molecular and Cellular Biochemistry 10/1997; 174(1-2):261-9. · 2.33 Impact Factor
[show abstract][hide abstract] ABSTRACT: There was an unusually high incidence of atypical pneumonias in the catchment area of the Rhine river near the university of Düsseldorf in July 1994 during a long period of hot and dry weather. The 18 patients described in this paper (5 women and 13 men) complained of sudden onset of fever up to over 40 degrees C, often associated with severe headache and dry cough. Almost all of these patients had previously been healthy and active and of young to middle age (average 38 years) without any bronchopulmonary anamnesis. Radiology revealed that all the patients had in most cases defined pulmonary infiltrates without any specific preference for a particular site. Serology was initially negative, but four weeks later the complement fixation reaction titre was positive for Coxiella burnetii antibodies in 14 patients (78%). All patients became symptom-free within a few days'time when treated with a combination of antibiotics which included doxycycline, whereas the infiltrates receded completely only after several weeks. The occurrence of pulmonary Q-fever in a large northern German conurbation had been rare at that time. Such epidemics, however, were also noted in Berlin (1992) and in Dortmund (1993). The epidemic reported in this article probably originated from one of the frequent flocks of sheep grazing along the banks of the Rhine river near Düsseldorf. The infections were probably acquired by inhalation of airborne organisms in infected aerosols derived from infected sheep, promoted by the long-term very hot and dry weather which was at the same time very windy, leading to an unusually extensive spreading of the pathogens throughout a very large infected aerosol area.
[show abstract][hide abstract] ABSTRACT: Enteroviruses like coxsackie are known to cause myocarditis both in animals and humans and enteroviral genom was found in endomyocardial biopsies of patients with myocarditis and dilated cardiomyopathy. However, subsequent to the initial viral infection, immune mechanisms seem to play an important role in the pathogenesis of both diseases. Using synthetic peptides, it was possible to identify T-cell epitopes of coxsackie B3 virus and to test their significance in the pathogenesis of myocarditis in the animal model. The T-cell response against coxsackie virus and autoantigens like the adenine nucleotide translocator is also present in the human disease, since sensitized T-cells can be cultured from about 50% of endomyocardial biopsies of patients with myocarditis and dilated cardiomyopathy. The significance of the cellular immune responses in the human disease can be demonstrated by the transfer of peripheral blood leukocytes of patients with chronic myocarditis into severe combined immune deficiency mice that develop human cellular infiltrates of the myocardium and an impairment of the left ventricular function within 60 days. Thus, these results show the presence and importance of cellular immune responses in the pathogenesis of myocarditis and dilated cardiomyopathy.
International Journal of Cardiology 06/1996; 54(2):117-25. · 5.51 Impact Factor
[show abstract][hide abstract] ABSTRACT: We found recently autoantibodies against the adenine nucleotide translocator (ANT), a carrier in the inner mitochondrial membrane, in sera of patients with myocarditis and dilated cardiomyopathy. To elucidate whether these antibodies are of pathophysiological importance, we investigated the function and expression of the adenine nucleotide translocator (ANT) in the heart muscle tissue of patients suffering from myocarditis and DCM. We found a markedly lowered transport capacity of the translocator accompanied by an elevation in total ANT protein content. The alteration in ANT protein amount is caused by an ANT isoform shift characterized by an increase in ANT 1 isoform protein associated with a decrease in ANT 2 isoform and an unchanged ANT 3 content. It could be shown that the isoform shift is not a progressive process during the disease period but an event in the early period of illness which becomes permanent. Simulating the effect of pathogenetic factors of autoimmunological diseases, we infected A/J mice with the enterovirus Coxsackie B3 and immunized guinea pigs with myocardial ANT protein. Both treatments led to autoimmunological responds and to a lowered myocardial transport capacity of ANT, to a disturbed energy metabolism and consequently to a depression of heart function.
Molecular and Cellular Biochemistry 02/1996; 163-164:319-27. · 2.33 Impact Factor
[show abstract][hide abstract] ABSTRACT: The ADP/ATP carrier is an autoantigen in myocarditis and dilated cardiomyopathy, both of which are diseases related to virus infections. Sera of these patients bear carrier-specific autoantibodies inhibiting transmembrane nucleotide transport on isolated mitochondria. To further assess the role of the ADP/ATP carrier in viral heart disease, guinea pigs were immunized with the isolated ADP/ATP carrier protein and A-strain mice were infected with coxsackie B3 virus. Both species generated specific and carrier-inactivating antibodies after immunization/infection. The transport activity of the ADP/ATP carrier-estimated from the cytosolic-mitochondrial difference of the phosphorylation potential of ATP (delta G[cyt-mit])-markedly declined in guinea pig and mice hearts. A close relationship was observed between the magnitude of reduction of delta G(cyt-mit) and the decrease of cardiac function. Therefore, it seems plausible that carrier dysfunction induced by viral infection creates an imbalance in myocardial energy metabolism, and is responsible for the impairment of cardiac function. The underlying mechanism might be an autoimmune reaction triggered via molecular mimicry or a modulation of the expression of ADP/ATP carrier isoforms changing the overall transport capacity of the cardiac ADP/ATP carrier.