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In a 66-year-old woman with unstable angina, treated with 20,000 IU heparin daily for 6 days, platelet count fell dramatically from 310,000 to 1000/microliters 8 hours after injection of 90 ml of contrast medium (Iopromide) during coronary angiography. In addition to a marked tendency towards spontaneous bleeding she developed a large haematoma at the site of the arterial puncture, with a fall in haemoglobin to 9 g/dl, and acute renal failure.Red blood cell and platelet infusions were given, together with cortisone, 1000 mg, and immunoglobulins. Platelet count returned to within normal limits after 8 days. Two haemodialyses initiated polyuria, followed by rapid normalization of kidney function. No antibodies against iopromide, iopamidol, heparin or heparinoids were found. At an emergency coronary balloon angioplasty 3 weeks later iopamidol was injected (45 ml). Again there was a profound fall in platelets to 1000/microliters, associated with acute renal failure. Treatment identical to that after the first episode brought about complete normalization.The reported reactions were most likely due to immune thrombocytopenia after administration of contrast medium.

Five thousand consecutive percutaneous transluminal coronary angioplasties (PTCA) were electively performed between January 1988 and June 1993. They were analysed for the incidence of acute coronary occlusion, its acute treatment and subsequent course. In 133 patients (2.7%) the occlusion persisted. Recanalization by repeat PTCA was attempted in all of them, but succeeded in only 68 (51%). In 65 patients recanalization was impossible. In 25 of the latter--patients with a small infarct vessel and infarction having already occurred in the vessel's supply area while the haemodynamics remained stable--conservative treatment was practised. Acute surgical revascularization was undertaken in 30 patients (23%) with a large area and/or haemodynamic instability. In all, 14 patients died (overall death rate 0.28%, death rate of patients with occlusion 11%), ten of them before operative intervention was possible.--Not all coronary artery occlusions can be treated nonsurgically. Consequently, availability of surgical intervention at the place of elective PTCA is mandatory.

Rapid reperfusion of the occluded coronary artery is essential for the reduction of mortality and complications of acute myocardial infarctions. Intravenous thrombolytic therapy using various thrombolytic substances has proven to be effective and easy to perform and has gained widespread acceptance for treatment of acute myocardial infarction. Because of several contraindications, as well as failure to achieve patency of the infarcted vessel in 25-30% of patients, severe bleeding complications, a time interval of 6 or more hours after suspected onset of myocardial infarction, and a high rate of recurrent ischemia, this treatment is currently limited to a small percentage of patients with acute myocardial infarction. Immediate percutaneous transluminal coronary angioplasty (PTCA) can be applied to nearly every patient presenting with acute myocardial infarction. Therefore, we offer immediate PTCA as the primary treatment to all of our patients presenting with acute myocardial infarction. Between January 1987 and December 1991, immediate PTCA was performed in 785 of 903 (87%) consecutive patients (aged 23-86 years, mean 61 +/- 10). 82% (640/785) of the patients were men. Anterior myocardial infarction was present in 372 patients (47%), inferior infarction in 413 patients (53%). 245 patients (31%) had 1-vessel disease, 221 patients (28%) two-vessel disease and 319 patients (41%) had three-vessel disease. 97 patients (12%) were in cardiogenic shock. In 675/785 patients (86%) the infarct related vessel was occluded (TIMIor = 1). 86% of patients had a patent infarct related vessel (TIMIor = 2) leaving the catheterization laboratory. The overall in-hospital mortality was 6.9% (54/785 patients), after exclusion of high-risk patients (age75 years, cardiogenic shock, PTCA under cardiopulmonary resuscitation) mortality decreased to 2.5%. Recurrent ischemia necessitated immediate repeat PTCA in 4.4% of the patients, in 8.1% of patients another elective PTCA was performed during hospitalization and 9.7% of patients were sent to surgery (4.0% on an emergency basis). 87% of all patients presenting with acute myocardial infarction could be treated successfully with immediate PTCA. With respect to the severely ill group of patients the primary success rate is high, the rate of reocclusion is low, and the overall mortality is extremely low. From our data, it is obvious that immediate PTCA compared to thrombolytic therapy is the superior treatment of myocardial infarction.

Coxsackie B viruses are thought to be involved in the induction of myocarditis. However, the diagnosis of acute infections by serology even today is practically impossible. The major problem is that no antigenic determinants of coxsackie B viruses have been identified or characterized which could be used as antigens in a rapid routine antibody screening test. Therefore, we synthesized overlapping peptides according to the sequence of the capsid protein VP1 of coxsackie B3 (CB3) virus in order to identify antigenic determinants located on VP1. Using sera raised against CB3 in mice, we were able to identify several antigenic determinants of CB3. Here we present a characterization of three epitopes found. We also tested the type-specificity of these antigenic determinants by using rabbit antisera against coxsackie viruses B1-B6. One antigenic determinant, peptide VP1-1, representing residues 1-15 of VP1, reacted highly type-specific for CB3. A second antigenic determinant (peptide VP1-3, residues 21-35 of VP1) reacted as well with the anti-CB3 sera as with the anti-CB4 sera. Therefore, the peptide VP1-3 seems to represent a non-type-specific antigenic determinant of coxsackie B viruses. Peptide VP1-24 (residues 229-243 of VP1) showed broad cross-reaction with anti-CB sera except with the anti-CB1 sera. This identification of type-specific and non-type-specific epitopes of coxsackie B viruses may provide the basis for the establishment of an effective and fast antibody screening test for coxsackie B viruses in patients with clinically suspected myocarditis.

Bei erworbenen Herzklappenfehlern mit erhohtem Risiko intrakardialer Thrombenbildung und konsekutiver Embolien besteht aufgrund empirischer Erfahrung Konsens uber den Nutzen einer oralen Dauerantikoagulanzienbehandlung. Hierzu zahlen Mitralstenosen oder kombinierte Mitralklappenfehler mit uberwiegender Stenosekomponente, wenn Vorhofflimmern oder ein instabiler Sinusrhythmus vorliegen. Bei Mitralinsuffizienzen gilt die Indikation als gegeben, wenn neben Vorhofflimmern mindestens ein thromboembolisches Ereignis eingetreten ist. Gleiches gilt fur Aortenklappenfehler. Die Intensitat der Antikoagulation, die heute sinnvollerweise mittels der Internationalen Normalisierten Ratio (INR) gemessen wird, richtet sich nach dem vermutlichen Thromboembolierisiko. Die Zielbereiche konnen zwischen INR 2,0 und 4,0 schwanken. Ein besonders hohes Risiko intrakardialer Thrombenbildungen und konsekutiver Embolisationen besteht fur Kunstklappentrager. Obwohl bislang keine prospektiven Dosisfindungsstudien durchgefuhrt wurden, ist fur diese Patienten bislang eine Antikoagulation mit einer Intensitat von INR 3,0–4,5 angestrebt worden. Jungste Untersuchungen zum Management der oralen Antikoagulation nach Implantation von Kunstklappen belegen eine gegenuber der ersten und zweiten Generation von Ersatzklappen deutlich niedrigere Thrombogenitat der heute verwandten Prothesen sowie die Notwendigkeit einer individuellen Antikoagulation, die die Koagulabilitat, die kardiale Morphologie und Physiologie des Patienten berucksichtigt. Besondere Richtlinien fur eine gerinnungshemmende Therapie bestehen fur Patienten mit Mitralklappenprolaps, angeborenen zyanotischen Herzfehlern, infektioser Endokarditis und in der Schwangerschaft.

The aetiology of dilated cardiomyopathy is unknown. Recent clinical and experimental data have suggested a temporal relationship with viral myocarditis. The clinical diagnosis, however, is non-specific. The evaluation of endomyocardial biopsies by light microscopy and their histological classification according to the Dallas criteria is limited by the difficulty in differentiating and quantifying infiltrating inflammatory lymphocytes from non-inflammatory interstitial cells. Using immunohistological methods that allow better identification and quantification of infiltrating lymphocytes and that also provide evidence for an activated immunological process within the myocardium, myocarditis was diagnosed on endomyocardial biopsy in 48 of 130 patients (37%). On the basis of both haemodynamic and immunohistological findings, 31 of these patients were selected for immunosuppressive treatment. After a 6-month treatment period with 6-methylprednisolone, 23 patients showed an improvement according to the NYHA classification. Lymphocytic infiltrates were abolished in 24 patients. Left ventricular systolic function was improved in 20 patients (64%) as indicated by an increased ejection fraction and stroke volume with a concomitant decrease of left ventricular end diastolic pressure. The three patients with severely impaired left ventricular function did not improve either clinically or histologically, whilst in four patients the clinical findings remained unchanged in spite of histological resolution of the inflammatory infiltrate in the myocardium. Our study suggests that immunosuppressive treatment in a subgroup of patients with dilated cardiomyopathy who have a continuing active immunohistologically proven inflammatory process results in a clinical haemodynamic and immunohistological improvement in 60-70% of the patients.

After the identification and immunochemical characterization of the ADP/ATP carrier of the inner mitochondrial membrane as an organ- and a conformation-specific autoantigen in myocarditis and dilated cardiomyopathy, we investigated whether an immunoreaction against the ADP/ATP carrier leads to a disturbance of cellular energy metabolism and consequently of myocardial function.Either immunization of guinea pigs with the isolated carrier protein or infection of A/J mice with coxsackievirus B3 induced heart reactive antibodies against the ADP/ATP carrier and led to a disturbance of the cellular energy metabolism: delta Gcyt-mit: 4.9 +/- 0.6 kJ/mol ATP (controls) to 2.3 +/- 1.1 kJ/mol ATP (immunized animals). In the isolated, perfused working heart preparation, the hemodynamic results of these hearts showed a50% reduction in external heart work. Because the amount of the decrease of external heart work and the magnitude of the reduction of delta Gcyt-mit showed a very close correlation, it must be suspected that the imbalance of the myocardial energy metabolism is responsible for the impairment of cardiac function.These data suggest that virus infection of the myocardium as shown for viral myocarditis and dilated cardiomyopathy may lead to a disturbed function of the ADP/ATP carrier and, thus, may be the cause of impaired myocardial function.

Clinical and experimental data suggest that autoimmunological mechanisms may play an important role in the pathogenesis of postmyocarditic cardiomyopathy. This may be due to the viral infection itself, or may be induced by persistence of the virus. Apart from the clinical signs of myocarditis, which are usually not specific, the diagnosis of acute myocarditis should be enabled by the histological examination of endomyocardial biopsies. In accordance with the Dallas criteria the histological diagnosis of acute myocarditis is defined by the presence of inflammatory cells in the myocardium associated with myocyte necrosis and degeneration of adjacent myocytes. This morphology, however, is only seen within the first 7 to 10 days of the acute stage of the disease. Later, most cases of clinically suspected acute myocarditis are histopathologically consistent with the diagnosis of "borderline myocarditis". Although endomyocardial biopsies have markedly improved diagnostic possibilities, the diagnosis of myocarditis by light microscopy has its limitations. Mainly the differentiation of infiltrating mononuclear cells from interstitial fibroblasts or pericytes is visually difficult. New immunohistochemical methods were therefore introduced to improve the specificity and sensitivity of the diagnosis. Using monoclonal antibodies against cell surface markers from lymphocytes (CD3, CD4, CD8) the identification, characterization and quantification of lymphocytic infiltrates in the myocardium is improved very significantly. Furthermore, the use of monoclonal antibodies against MHC-class-I and class-II-antigens provides further information about the immunological status of the myocardium. In conclusion, the use of these new immunohistological methods offers the possibility of establishing immunological criteria in addition to histological parameters.(ABSTRACT TRUNCATED AT 250 WORDS)

Current concepts of autoimmunity emphasise the role of antibodies in the development and maintenance of autoimmune disorders. The problem con­cerning the role of autoantibodies in mediating disease is to show that a given autoantibody is an essential component of a pathological mechanism which leads to tissue damage and organ dysfunction. As well as contributing to an under­standing of the pathogenesis, the precise characterisation of the antibodies involved in an autoimmune process may have diagnostic and prognostic value.

Clinical and experimental data suggest that autoimmunological mechanisms may play an important role in the pathogenesis of postmyocardial cardiomyopathy. This may be due to the viral infection itself, or may be induced by persistence of the virus. On this basis immunosuppressive therapy aimed at preventing the progression of myocarditis to dilated cardiomyopathy is discussed. Apart from the clinical signs of myocarditis, which are usually not specific, the diagnosis of acute myocarditis should be enabled by the histological examination of endomyocardial biopsies. In accordance with the Dallas criteria the histological diagnosis of acute myocarditis is defined by the presence of inflammatory cells in the myocardium associated with myocyte necrosis and degeneration of adjacent myocytes. This morphology, however, is only seen within the first seven to ten days of the acute stage of the disease. Later, most cases of clinically suspected acute myocarditis are histopathologically consistent with the diagnosis of "borderline myocarditis" 1 h according to the Dallas classification. Although endomyocardial biopsies have markedly improved diagnostic possibilities, the diagnosis of myocarditis by light microscopy has its limitations. Thus, interobserver variability in the interpretation of biopsy samples remains high, and divergent frequencies of reported positive biopsies have continued to be published. Mainly the differentiation of infiltrating mononuclear cells from interstitial fibroblasts or pericytes is visually difficult. New immunohistochemical methods were therefore introduced to improve the specificity and sensitivity of the histological diagnosis. Using monoclonal antibodies against cell surface markers from lymphocytes (CD3, CD4, CD8) the identification, characterization and quantification of lymphocytic infiltrates in the myocardium was improved very significantly. Furthermore, the use of monoclonal antibodies against MHC-class-I and class-II-antigens provides further information about the immunological status of the myocardium. In conclusion, the use of these new immunohistological methods offers the possibility of establishing immunological criteria in addition to histological parameters permit a more accurate diagnosis and a better understanding of immune mechanisms possibly involved in the pathogenesis of myocarditis and dilated cardiomyopathy. Since the introduction of endomyocardial biopsies in the diagnosis of myocarditis several papers have reported trials of immunosuppressive therapy in histologically-proven myocarditis. However, none of these studies were randomised, and only a limited number of patients were treated. Neither the primary diagnosis of myocarditis nor the histology, evaluating the course of the disease was well defined, and therefore different from one study to another. Moreover, the regimens so far used for immunosuppressive therapy were not standardized, making it impossible to compare the various studies.(ABSTRACT TRUNCATED AT 400 WORDS)

Experimental and clinical data suggest a relationship between myocarditis and dilated cardiomyopathy. One postulated pathomechanism is a viral infection triggering a host response with autoimmune features directed against the heart, resulting in an initial myocarditis which is followed by a dilated cardiomyopathy. Until now, the importance of an undetected myocarditis as an etiological factor in the pathogenesis of idiopathic cardiomyopathy is unknown. This investigation was undertaken to determine the frequency of lymphocytic infiltrations in endomyocardial biopsies of patients with dilated cardiomyopathy by immunohistological methods and to analyze T lymphocytic subsets and other immunological features in order to search for possible relationships between immunohistological-documented myocarditis and dilated cardiomyopathy. In our study, 48 of 130 biopsies (37%) from patients with clinically proven dilated cardiomyopathy contained lymphocytic infiltrates when stained by the immunoperoxidase method with lymphocyte surface markers (Table 1). 23% (n = 30) of these biopsies contained more than 2.0 (range: 2.0 to 13.8) T lymphocytes per high power light microscopy field (x 400), in 14% (n = 18) 1.5 to 2.0 cells/HPH were seen (Table 2). 82 biopsies (63%) with less than 0.8 cells/HPF were regarded as negative (dilated cardiomyopathy). By histological analysis, only seven cases (5%) were classified as borderline myocarditis by conventional histological evaluation according to the Dallas classification. In the other patients, our results were consistent with the clinical diagnosis of dilated cardiomyopathy (Table 1). 71% of biopsies with lymphocytic infiltrates contained activated T cells when analysed with activation markers in serial sections (Table 2). Activated macrophages were seen in 52% of biopsies with T cell infiltrations, but only in 31% of tissues containing normal numbers of lymphocytes (Table 2). In biopsy specimens with lymphocytic infiltrates HLA-class I and II antigen expression was increased. An enhanced HLA-DR antigen staining was seen in 80% on interstitial cells and vascular endothelium while HLA class I was found at an increased level in 67% (Table 3). In negative biopsies, an enhanced class I staining was seen in only 14%, class II in 30%. Because of the specific identification of lymphocytes by immunocytochemical methods, lymphocytic infiltrates are easily detected, even if the infiltrate is sparse or focal (Figure 1). The considerable interobserver variability in the quantitation of lymphocyte counts, which is a main problem in hematoxylin and eosin stained sections is negligible when lymphocyte quantitation is performed by immunoperoxidase staining. Thus, our data indicate that in about 37% of patients with clinical suspected idiopathic cardiomyopathy an ongoing or reactivated myocarditic process is involved.(ABSTRACT TRUNCATED AT 400 WORDS)

The adenine nucleotide translocator (ADP/ATP carrier) plays a key role in nucleotide transport across the mitochondrial membrane. The quantity and function of this transport protein were investigated in myocardium from hearts with endstage failing dilated and ischemic cardiomyopathy, and were compared to measurements in nonfailing myocardium. In addition, lactate dehydrogenase (LDH) isoenzymes were determined. The concentration of the ADP/ATP carrier was significantly increased by 48% in myocardium from dilated cardiomyopathic hearts compared to control myocardium. The concentration of the carrier in explanted hearts with ischemic cardiomyopathy did not differ from values in the normal human hearts. Analysis of carrier function revealed similar nucleotide exchange rates in control hearts and hearts with ischemic cardiomyopathy, whereas carrier function was reduced in most hearts with dilated cardiomyopathy. Compared to control hearts, in hearts with dilated cardiomyopathy and decreased nucleotide exchange rate, the carrier content was significantly higher, whereas the carrier content was only slightly increased compared to control in cardiomyopathy hearts with unchanged transport activity. Compared to hearts, in dilated cardiomyopathy there was a significant increase in LDH5 and a decrease in LDH1 isoforms, indicating more anaerobic metabolism in failing dilated cardiomyopathic hearts. In summary, in hearts with dilated cardiomyopathy disturbed function of the ADP/ATP-carrier may result in altered myocardial energy metabolism and, thus, may be the cause of impaired myocardial function.

The adenine nucleotide translocator (ADP/ATP carrier) plays a key role in nucleotide transport across the mitochondrial membrane. The quantity and function of this transport protein were investigated in myocardium from hearts with endstage failing dilated and ischemic cardiomyopathy, and were compared to measurements in nonfailing myocardium. In addition, lactate dehydrogenase (LDH) isoenzymes were determined. The concentration of the ADP/ATP carrier was significantly increased by 48% in myocardium from dilated cardiomyopathic hearts compared to control myocardium. The concentration of the carrier in explaitted hearts with ischemic cardiomyopathy did not differ from values in the normal human hearts. Analysis of carrier function revealed similar nucleotide exchange rates in control hearts and hearts with ischemic cardiomyopathy, whereas carrier function was reduced in most hearts with dilated cardiomyopathy. Compared to control hearts, in hearts with dilated cardiomyopathy and decreased nucleotide exchange rate, the carrier content was significantly higher, whereas the carrier content was only slightly increased compared to control in cardiomyopathic hearts with unchanged transport activity. Compared to control hearts, in dilated cardiomyopathy there was a significant increase in LDH5 and a decrease in LDH1 isoforms, indicating more anaerobic metabolism in failing dilated cardiomyopathic hearts.

We recently described autoantibodies to the ADP/ATP carrier of the inner mitochondrial membrane as an organ specific autoantigen found in high frequencies in sera of patients with myocarditis and dilated cardiomyopathy. These antibodies not only showed an intracellular binding at the mitochondrial membrane, but also crossreact with antigenic determinants at the cardiac myocyte plasma membrane. They therefore may account, at least in part, for the so-called sarcolemmal-bound IgG of heart-reactive autoantibodies found to be associated with these diseases. Heart muscle diseases are associated with electrocardiographic abnormalities such as complex ventricular arrhythmias and disturbed ventricular function. Our data indicate that abnormalities in current spread and impaired heart contractility might also be caused by an antibody mediated disturbance of calcium channel gating leading to prolongation of the action potential and potentiation of tension. The enhanced calcium permeability of the cell may moreover cause calcium overload and cell death. The calcium channel complex plays a central role in cardiac contractility. Disturbing calcium channel gating by antibodies might therefore contribute to the pathogenesis of these diseases.

The adenine nucleotide translocator (ANT) and myosin have been shown to be major autoantigens in myocarditis and dilated cardiomyopathy. We studied the use of synthetic peptides, with sequences derived from ANT and myosin, as antigens in screening tests for autoantibodies in myocarditis (MC) and dilated cardiomyopathy (DCM) and as absorbants for specific elimination of autoantibodies from the sera of patients. Using computer prediction of the secondary structure of the ANT and myosin we identified two sequences of the ANT and three sequences of myosin as possible main antigenic determinants. Using overlapping synthetic peptides and antibodies against them, the antigenicity of the selected determinants was shown. Of 72 sera from patients with MC or DCM 45 (62·5%) bound to the peptides derived from ANT, 32 (44·4%) reacted with the sequences from myosin, in contrast to healthy controls. Using the peptides from the ANT or myosin immobilized on thiopropyl-sepharose, more than 95% of the autoantibodies could be removed specifically from the positive sera. The results demonstrate the usefulness of synthetic peptides as antigens in antibody screening tests in MC and DCM and offers a new approach to the therapy of inflammatory heart disease by specific elimination of autoantibodies.

Despite all our efforts, the clinical diagnosis viral myocarditis is usually only a tentative one. This diagnosis can be established with a high degree of probability only on the basis of a combination of virological, histological and immunohistological findings in myocardial biopsies. The use of highly specific monoclonal antibodies against lymphocyte subpopulations and histocompatibility antigens makes possible a differentiated consideration of the diagnosis, severity and course of the disease. Although the etiopathogenesis, the natural course and the destructive mechanisms of the viral heart disease have not yet been finally clarified, numerous clinical and experimental findings indicate that underlying the viral myocarditis or the resulting dilatative cardiomyopathy is a viral infection-induced loss of self-tolerance with subsequent autoaggression against myocardial structures.

The treatment of viral myocarditis continues to present problems. To date, no specific therapy has become available. Relevant studies performed so far have been open, uncontrolled or randomized, the numbers of patients small, and the patient groups highly inhomogeneous. Furthermore, diagnostic and evolution criteria have differed considerably. Since the results of these studies are inconsistent, and it has so far not proved possible to demonstrate a positive long-term effect of immunosuppressive treatment, general use of immunosuppressive therapy cannot at present be recommended. Before the final word can be spoken on this, we shall have to await the results of numerous ongoing therapeutic studies.

Nach einer 1980 von der WHO-ISFC vorgenommenen Klassifikation [43] (s. Ubersicht 1) unterscheidet man heute 2 grose Gruppen von Herzmuskelerkrankungen: Kardiomyopathien (= Herzmuskelerkrankungen unbekannter Genese), spezifische Herzmuskelerkrankungen (= Herzmuskelerkrankungen mit bekannter Ursache).

Based on circumstantial evidence from clinical, serological, epidemiological, and histological studies, a causal relationship between myocarditis and dilated cardiomyopathy (DCM) has long been suspected [1–5]. The basis of this association were observations during epidemics of Coxsackie B virus infection. Although the majority of affected individuals recovered without evidence of subsequent myocardial dysfunction, a few of these patients subsequently developed DCM. Similarly, serological studies of patients with DCM implicated a viral infection in the etiology of DCM. This has been confirmed by recent findings of Bowles and Kandolf and their coworkers demonstrating the presence of enteroviral RNA in the myocardium of patients with myocarditis and DCM [6–9]. These findings suggest the possibility that Coxsackie B virus persists in the myocardium of patients with myocarditis and may in some way be responsible for the subsequent development of DCM. Thus, the viral infection may act as a trigger initiating the autoimmunological process by altering the host’s immune system, by causing the release or expression of sequestered antigens or through antigenic determinants shared by the virus and the host cell [10,11].

With the use of the enzyme-linked immunosorbent assay technique and indirect immunofluorescence, we determined the frequency of antibodies to laminin (a noncollagenous protein of basement membrane) and their influence on endomyocardial laminin distribution in 132 patients suffering from dilated cardiomyopathy and myocarditis. Seventy-eight percent of 91 patients with dilated cardiomyopathy and 73% of 41 patients with myocarditis exhibited significantly elevated anti-laminin antibody levels compared with 68 apparently healthy persons. A positive correlation was found between hemodynamic data and irregular myocardial immunofluorescence laminin staining patterns in dilated cardiomyopathy and myocarditis. With regard to recent studies, these data suggest that antibodies to laminin in dilated cardiomyopathy and myocarditis enhance clusters of cell-surface laminin, inducing an alteration of the cytoskeleton, which may account for functional abnormalities in dilated cardiomyopathy and myocarditis. Considering the fact that optical microscopy is unable to resolve sarcolemmal structures proper from the basement membranes, the high prevalence of laminin autoantibodies in dilated cardiomyopathy and myocarditis raises doubts as to the diagnostic value of direct immunofluorescence findings.

In an effort to determine the effect of chronic ethanol ingestion on myocardial oligomycin sensitive ATPase, guinea pigs were fed 15% ethanol instead of drinking water for 34 weeks. Mg2+-ATPase activity of isolated mitochondria was determined in control and alcohol fed guinea pigs at 16, 20, 24 and 34 weeks. To prove a possible higher fragility of the mitochondria from alcohol fed animals, the ATPase activity was also determined in the supernatant after the isolation of mitochondria "100 000 g fraction". Mg2+-ATPase activity of the isolated mitochondria was time dependent reduced to 56% of the value obtained in the control animals. In the "100 000 g fraction" the ATPase activity, however, started to increase after 8 weeks and after 34 weeks it was about twice as high than in the control group. The findings of this study document a decrease in oligomycin sensitive ATPase activity and an increase in mitochondrial fragility after chronic ethanol ingestion. It supports in the thesis that chronic alcohol intake affects the activity of the intrinsic membrane enzymes by structural derangements of mitochondrial membrane. The changes may play a role in the development of alcoholic cardiomyopathy.

The isoenzyme pattern of the lactate-dehydrogenase (LDH) in different parts of the heart was measured by micro-isoelectric focusing. Samples were taken from the right and left auricle, the outer, middle and inner layer of the myocardial wall of both ventricles and from the papillary muscle of the left ventricle. The results show that the activity of LDH total and the isoenzyme pattern are different in the various parts of the heart. In both auricles the isoenzymes LDH 3,4,5 were mostly found, whereas in the ventricles a significant increase of LDH 1,2 could be seen. Additionally, there was a shift in the isoenzyme pattern from the outside to the inner part of the myocardium wall with a significant increase of LDH1.

Endomyocardial biopsy samples from patients suffering from congestive cardiomyopathy of unknown etiology (COCM) were analyzed for lactate dehydrogenase (LDH) isoenzyme distribution by microisoelectric focusing. In addition, the concentration of collagen in the biopsy samples was estimated by determination of hydroxyproline and proline. The results were correlated with the clinical and hemodynamic data of the patients. Increased activities of total LDH and LDH5 — the worse the hemodynamic parameters, the higher the concentration of LDH5 — indicate an enhanced anaerobic glycolysis in the myocardium of COCM patients. The close correlation between the hemodynamic data and the LDH isoenzyme pattern suggests an association between severity of COCM and impairment of aerobic metabolism. The results of the alteration in the LDH isoenzyme pattern were not influenced by the collagen content in the myocardial biopsy samples. Varying isoenzyme patterns in the different parts and wall layers of the normal heart show the necessity of analyzing biopsy samples only from comparable localizations.

Antibodies previously described to inhibit specifically nucleotide transport (ADP-ATP carrier) of the inner mitochondrial membrane were found to bind specifically to the sarcolemma of the enzymatically isolated rat ventricular myocytes. In this communication, we report for the first time that a component of these antibodies enhanced the Ca2+ current in isolated cardiac myocytes and potentiated twitch tension in ventricular strips. Prolonged exposure of rat myocytes to large concentrations of antibodies caused spontaneous contractions, progressive cell deterioration, and death. Our results thus show that a component of antibodies against ADP-ATP carrier cross-reacts with cardiac sarcolemmal proteins enhancing the Ca2+ channel.

Abnormalities in Ca2+ metabolism of myocardium and coronary vessels are thought to be involved in genesis of cardiac myopathies [11]. In Syrian hamster (Bio 14.6), Ca2+ influx was enhanced and Dihydropytidine (DHP) binding sites increased in early stages of cardiac myopathy [4, 10, 12]. Prolongation of action potential reported in cardiomyopathic hamsters [9] is also consistent with possible enhancement of Ca2+ current. Abnormalities in Ca2+ metabolism may also result from heart reactive antibodies. Such antibodies have been identified in myocarditis and cardiac myopathies [1, 3]. Antibodies previously described as inhibiting the adenosine diphosphate (ADP)/adenosine triphosphate (ATP) carrier of the inner mitochondrial membrane [8] have been found in myocarditis and dilated cardiomyopathy [7]. Such antibodies were found to bind specifically to the sarcolemma of isolated cardiac myocytes causing oscillating contractions leading to cell death. Cell deterioration, as judged by the number of cells losing their rectangular shape and clear striation, was delayed or prevented by addition of Ca2+ channel blockers to the antibody- containing solutions. These results, consistent with those described in Syrian hamster, suggest that etiology of disease may be related to possible enhancement of the Ca2+ channel, causing subsequent Ca2+ overload. In this report, therefore, we examine the direct effects of antibodies against ADP/ATP carrier and autoantibodies from patients with myocarditis and dilated cardiomyopathies on the Ca2+ current recorded in isolated mammalian and amphibian ventricular myocytes.

To obtain further knowledge of the antigen-antibody system, immunochemical characterization of the adenine nucleotide translocator was achieved by crossed immunoelectrophoresis, immunoreplica technique, radioimmunoassay, immunoabsorption studies, and nucleotide-transport measurements. Sera of 18 patients with proven congestive cardiomyopathy (CCM) were tested. On the adenine nucleotide translocator (ANT) from heart, kidney, and liver, organ-specific antigenic determinants were demonstrable, although a partial cross-reactivity existed. Conformation specificity was also confirmed by experimental studies. Of the patients studied, 17 of 18 with CCM showed a significant binding to the heart ANT, while no or a lower binding was seen on the kidney/liver ANT. In CCM, a correlation exists between the ejection fraction and the anti-ANT titer. These results give new evidence for autoimmunological events in MC and CCM and indicate a possible causal relationship between these two diseases.

Heart-reactive antibodies against cell surface and intracellular components have been described in myocarditis [1, 6, 12]. During recent years studies by our group have characterized the adenosine di-/triphosphate (ADP/ATP) carrier of the inner mitochondrial membrane as an autoantigen in myocarditis and dilated cardiomyopathy [14, 15, 18]. The ADP/ATP carrier is a highly specific transport system for the transfer of ATP to the cytosol with its energy-consuming processes and the return of ADP to the inner mitochondrial space for rephosphorylation [7]. Autoantibodies to the ADPI/ATP carrier were shown to be organ specific [15]. They inhibit the nucleotide transport not only in vitro [15, 18], but also in vivo [18, 20] (also Schultheiss et al., this volume).

Current concepts of autoimmunity emphasize the role of antibodies in the development and maintenance of most autoimmune disorders. The problem concerning the role of autoantibodies in mediating disease is to show that a given autoantibody is an essential component of a pathological mechanism which leads to tissue damage and organ dysfunction. Besides the understanding of the pathogenesis, the precise characterization of the antibodies involved in an autoimmune process may have diagnostic and prognostic value.

The etiology of dilated cardiomyopathy (DCM) is unknown [1,2]. There are several possibly associated or conditioning factors [3], but there has lately been renewed interest in the notion that viral myocarditis (MC) may lead to DCM [4]. Clinical and experimental results give good evidence for a causal relation between these two diseases [5–8] and implicate an autoimmunologic process in the pathogenesis of MC and DCM [9–12]. Immunofluorescent methods have revealed an accumulation of gamma globulin bound to different cellular structures in the myocardium [13–15]. On the basis of our own studies we have suggested the existence of antimitochondrial antibodies in patients suffering from MC and DCM.

Enteroviruses of the human Picornaviridae such as the group B coxsackieviruses (types 1 to 5) are generally considered to be the most common agents of viral myocarditis [1, 2, 11, 25, 29, 35]. Other members of the human enteroviruses comprising at present over 70 serotypes (e. g., various coxackie A viruses and echoviruses) have also been associated with human viral heart disease. These agents appear to be capable of producing dilated cardiomyopathy of acute onset or lead to life-threatening arrhythmias. Particularly intriguing is the concept of chronic dilated cardiomyopathy evolving from acute or subacute infections of the human heart.

Seit der Einfuhrung der endomyokardialen Katheterbiopsie [1] besteht die Moglichkeit, biochemische Untersuchungen direkt am Myokardgewebe von Patienten durchzufuhren. Eine biochemische Analyse liegt nahe, da morphologische Untersuchungen bisher keine eindeutigen Kriterien zur weiteren Differenzierung der kongestiven Kardiomyopathien (COCM) erbracht haben [2–4]. Aufgrund von Untersuchungen an kardiomyopathischen Hamstern besteht der Verdacht, das eine Storung der oxydativen Phosphorylierung ursachlich an der Entstehung der COCM beteiligt ist [5–7]. Wir haben daher das Verteilungsmuster und die spezifische Aktivitat der Lactat-Dehydrogenase-Isoenzyme (LDH) bestimmt. Diese spielen wegen der unterschiedlichen physikalischen, chemischen und katalytischen Eigenschaften eine entscheidende Rolle in der Regulation des NADNADH-Gleichgewichtes der Zelle [8, 9]. Somit kann man durch ihre Bestimmung auf den oxydativen Energiestoffwechsel der Zellen im untersuchten Gewebe ruckschliesen.

Considerable progress in the understanding of cardiomyopathies of unknown etiology had been expected by endomyocardial biopsy. The absence of any specific morphological features, however, makes a diagnosis of congestive cardiomyopathy (COCM) unsatisfactory and is of such limited value from the diagnostic standpoint [1, 2, 3], although there is generally a good correlation between the severity of the condition clinically and the extent of the morphological changes [4, 5, 6]. Thus by ultrastructural examination of the biopsy material an assessment of prognosis was attempted [7, 8, 9].

Earlier studies gave an indication for an organ specificity of the ADP ATP carrier. We used a modified charge-shift crossed immunoelectrophoresis for a more precise immunochemical characterization of this detergent-solubilized hydrophobic membrane protein. Immunological differences between the carrier protein from heart, kidney, and liver were demonstrated by a different electrophoretic migration of the three ligand-protein complexes in the first dimension and a distinct staining intensity, sharpness, and shape of the precipitates in the second dimension. However, the antibodies against the heart and kidney protein showed a cross-reactivity between the three antigens. The results are consistent with the view that the ADP ATP carrier has organ-specific antigenic determinants although there is a partial identity between the carrier proteins from heart, kidney, and liver.

New concepts in viral heart disease , New concepts in viral heart disease , کتابخانه دیجیتال جندی شاپور اهواز