Search

Background. Automated peritoneal dialysis (APD) has been increasingly used in recent years. Our purpose was to investigate whether the good preservation of residual renal function (RRF) that has been reported in patients on continuous ambulatory peritoneal dialysis (CAPD) is also observed in APD. [ABSTRACT FROM PUBLISHER]

This overview examines the immunological rationale for immunosuppressive and immunomodulating therapy in man and experimental animals. The controversy of whether immunosuppressive treatment is beneficial in myocarditis will continue even after the Myocarditis Treatment Trial has been published. It is known that in viral heart disease immunosuppressive drugs should be avoided, but in autoreactive forms of myocarditis with proven humoral and cellular effector mechanisms they may be used in controlled randomized trials to validate or refute their benefit. Immunomodulating factors, e.g. immuno-stimulatory or antiviral substances such as ribaverin, the interleukins and interferons have demonstrated some effect in experimental animal myocarditis but proof of their benefit in man is still lacking. Hyperimmunoglobulin therapy appears to be of particular interest because it incurs few side effects and has positive results in cytomegalovirus-associated myopericarditis in man and suspected myocarditis in children. [ABSTRACT FROM PUBLISHER]

Pericardioscopy is a new diagnostic tool for macroscopic visualization of alterations in both the epicardium and pericardium. We report on 35 patients with pericardial effusion due to inflammatory perimyocardial disease.After puncture of the pericardial effusion, an 8F sheath was introduced over a guidewire under X-ray control. The pericardial pressures were measured; the fluid was removed by aspiration and exchanged with 100 ml of body-warm saline until the pericardial fluid was clear. To visualize the peri- and epicardium, for video- and photo documentation, two sorts of 8F endoscope were used, either a flexible fibreglass version or a rigid 110° one—both made by Storz. Cytology of the fluid and optically guided and controlled epicardial and pericardial biopsies were performed to classify the form of pericarditis. A specific diagnosis of viral pericarditis could thus be established in seven cases—by in situ hybridization for cytomegalovirus (n = 3) and by microneutralization test for enteroviruses and /or coxsackievirus B4 isolation (n = 4); of lymphocytic perimyocarditis in 16; of bacterial pericarditis in seven and antibody-mediated autoreactive pericarditis in five cases. [ABSTRACT FROM PUBLISHER]

Inflammation of the heart muscle is caused either by infection (i.e. coxsackie virus) resulting in myocarditis or by rejection following heart transplantation. These processes induce activation of the immune system. We examined endomyocardial biopsies from patients with myocarditis, perimyocarditis and rejection following heart transplantation and compared these to biopsies from patients with coronary artery disease. The biopsies were examined immunohistologically with specific monoclonal antibodies against class I and class II molecules of the major histocompatibility complex (MHC). MHC class I antigens on the normally negative myocytes were evident in myocarditis (38%) and in rejection after heart transplantation (68%). In the interstitium there was an increase of both MHC class I and class II antigens. MHC class II antigens, however, were never seen on myocytes. MHC class I antigens are required for the action of CD 8 positive cytotoxic T cells. Therefore myocytes which express MHC class I antigens are susceptible to cytotoxic effects of the immune system. MHC class II antigens are essential to T helper cells. By cytokine release, activated T helper cells play a central role in the initiation, regulation and mediation of an immune response in myocarditis and rejection following heart transplantation. [ABSTRACT FROM PUBLISHER]

In this study from two specialized centres 85 patients with histologically proven myocarditis(n = 10) and clinically ascertained perimyocarditis (pericardial effusion and cardiomegaly or segmental wall motion abnormality; n = 75) were followed up for 4·5+1·9 years. Immunosuppressive treatment was not applied.After a mean follow-up period of 4·5 years 55% of patients had improved clinically and 35 % of patients were completely free of symptoms. Relapses had occurred up to three times. Chronic forms were found in 20% of patients, mostly in those with pericarditis and effusions. Eighteen percent of the patients deteriorated gradually. In 20% of the chronic or deteriorating patients congestive heart failure developed (postmyocarditic heart muscle disease). Fifteen percent of the patients died, mainly from bacterial perimyocarditis and to a lesser extent from inflammatory heart disease from enteroviruses. Patients who succumbed after more than 6 months died either suddenly or from progressive heart failure. A favourable outcome was often accompanied by a decrease in titre, but this decrease was less impressive in those who had antimyolemmal and antisarcolemmal antibodies. The persistence of these antibodies in high titres predominated in patients with poor prognosis and postmyocarditic dilated heart muscle disease, as did cytolytic serum activity. [ABSTRACT FROM PUBLISHER]

In myocarditis and dilated cardiomyopathy a secondary immunopathogenesis is likely, since alterations to the humoral and cellular immune system have been repeatedly demonstrated. In rejection after heart transplantation activation of the immune system has been clearly seen. This may be comparable to myocarditis and thus could be a model for inflammatory heart disease. This study was set up to investigate whether an increased expression of antigens of the major histocombatibility complex and of the 112 receptor in endomyocardial biopsies of patients after cardiac transplantation, myocarditis and dilated cardiomyopathy takes place. Cryostat sections were investigated immunohistologically by the immunoperoxidase test. There was an expression of class II antigens (HLA-DR, HLA-DP, HLA-DQ) in acute rejection and in myocarditis and in some patients with dilated cardiomyopathy on endothelial cells, interstitial cells but not on the myocytes. The results for class I (HLA-A, B, C) are similar, but in addition an expression on myocytes was observed in myocarditis and rejection. A second immunopathogenesis is most likely in some patients with dilated cardiomyopathy. The expression of the I12 receptor on interstitial cells as a specific marker of cell activation was only seen in acute rejection and in some cases of myocarditis. [ABSTRACT FROM PUBLISHER]

Endomyocardial biopsy in this study of 1250 biopsied patients (mean of five samples/patient) proved to be a remarkably safe technique with no lethal complications. It may help to detect the underlying cause of heart failure but is handicapped by sampling error in focal disease processes (such as myocarditis and sarcoid heart disease) when conventional light and electron microscopy are used. In this biopsy series 123 patients (9.8%) suffered from severe heart failure; lymphocytic infiltrates were found in only 10 (8%). Immunohistological data suggested a secondary humoral immunopathogenesis in all patients with myocarditis and perimyocarditis, in 75% of patients with postmyocarditic heart muscle disease and in 48% of patients with primary dilated cardiomyopathy. There may thus be a need for a new classification of heart muscle diseases that includes immunological parameters of humoral and cellular autoreactivity. [ABSTRACT FROM PUBLISHER]

Twenty-seven patients with bronchopulmonary or generalised sarcoidosis were classified with a clinical score as certain, probable, possible or no cardiac sarcoidosis. Certain cardiac involvement was assumed only when endomyocardial biopsy or necropsy showed a granuloma of the heart (N = I); it was probable (N = 14) when a resting or an exercise-induced defect in the thallium scan was found and severe arrhythmia (Lown III-V), A–V block (2nd or 3rd degree), cardiomegaly, pericardial effusion or segmental wall motion abnormality was detected in addition; it was considered possible (N = 7) when only one of the above-mentioned criteria (rhythm disturbances, cardiomegaly/pericardial effusion, exercise-induced defect in the thallium scan) was positive.With thallium-201 scintigraphy a defect at rest was found in nine, on exercise in six, at rest and on exercise in six, and no defects were found in six cases. Determination of antimyocardial antibodies with adult human and rat cardiocytes and with cryostat sections, and of circulating immune complexes, showed differences from non-cardiac controls but not from patients with sarcoidosis and a negative score for cardiac manifestations. Antimyolemmal antibodies of the IgG class were found in all patients, and of the IgM class in 30–50% of all patients irrespective of cardiac involvement. Only complement fixation to the myolemma was cardiospecific. Cytolytic serum activity, NK cell activity, antibody-dependent (ADCC) and -independent lymphocytotoxicity against vital heart cells could not be detected in any group of patients. [ABSTRACT FROM PUBLISHER]

Diagnosis of myocarditis has improved with the application of new techniques such as immunohistochemistry, polymerase chain reaction, in situ hybridization and Southern blot in endomyocardial biopsies. Treatment of inflammatory heart disease is still difficult and not yet validated by a study with patient numbers sufficient to allow statistical analysis. The European Study of Epidemiology and Treatment of Cardiac Inflammatory Disease (ESETCID) addresses problems of aetiology, pathogenesis and specific treatment of myocarditis. It is the first multicentre, double-blind placebo-controlled randomized study, apart from the Myocarditis Treatment Trial, to discriminate between different forms of myocarditis. Patients with cytomegalovirus-induced myocarditis are treated by hyperimmunoglobulin compared to placebo. Patients with enterovirus-positive myocarditis will receive interferon alpha vs placebo. Patients with virus-negative myocarditis, which is considered autoimmune, will be treated with immunosuppression compared to placebo. The primary endpoint of this study is an improvement in ejection fraction of more than 5%. This trial may give a better understanding of the course of myocarditis, leading to more specific treatment which may in turn reduce the number of patients with post-myocardial heart muscle disease who require heart transplantation as a final therapeutic remedy [ABSTRACT FROM PUBLISHER]

The human enteroviruses, especially the coxsackie B viruses, have been established as aetiologic agents of human inflammatory heart disease, a condition which may lead to dilated cardiomyopathy and heart failure. It is clear from murine models of coxsackievirus B3-induced inflammatory heart disease that not all strains of the virus are cardiovindent (able to cause disease). Here, we present preliminary data mapping the site in a coxsackievirus B3 genome which determines a cardiovindent phenotype. [ABSTRACT FROM PUBLISHER]

The most extensively studied animal model of coxsackievirus B3 (CVB3) -induced inflammatory heart muscle disease is the murine model. In the acute and chronic phase of the disease, it has been suggested that autoimmune mechanisms play a major role in the pathogenesis of the disease. In this study, C3H mice without functional T- and B-lymphocytes (C3H SCID) were inoculated either with a cardiovindent (CVB3/20) or a non-cardiovirulent (CVB3/0) strain of coxsackievirus B3. Both viruses caused myocarditis in SCID mice. Furthermore, it could be demonstrated, that CVB3/0 had mutated to a cardio-virulent phenotype, able to cause myocarditis in immunocompetent mice. [ABSTRACT FROM PUBLISHER]

The toxicity, volatility and persistence of the obsolete organochlorine pesticide hexachlorocyclohexane (HCH), makes reclamation of contaminated areas a priority for the health and welfare of neighboring human communities. Microbial diversity and functions and their relation to spontaneous vegetation in post-excavation situations, are essential indicators to consider in bioaugmentation or microbe-assisted phytoremediation strategies at field scale. Our study aimed to evaluate the effects of long-term HCH contamination on soil and plant-associated microbial communities, and whether contaminated soil has the potential to act as a bacterial inoculum in post-excavation bioremediation strategies. To scrutinize the role of vegetation, the potential nitrogen fixation of free-living and symbiotic diazotrophs of the legume Lotus tenuis was assessed as a measure of nutrient cycling functions in soil under HCH contamination. Potential nitrogen fixation was generally not affected by HCH, with the exception of lower nifH gene counts in excavated contaminated rhizospheres, most probably a short-term HCH effect on early bacterial succession in this compartment. HCH shaped microbial communities in long-term contaminated bulk soil, where we identified possible HCH tolerants such as Sphingomonas and Altererythrobacter. In L. tenuis rhizosphere, microbial community composition was additionally influenced by plant growth stage. Sphingobium and Massilia were the bacterial genera characteristic for HCH contaminated rhizospheres. Long-term HCH contamination negatively affected L. tenuis growth and development. However, root-associated bacterial community composition was driven solely by plant age, with negligible HCH effect. Results showed that L. tenuis acquired possible HCH tolerant bacteria such as the Allorhizobium-Neorhizobium-Pararhizobium-Rhizobium clade, Sphingomonas, Massilia or Pantoea which could simultaneously offer plant growth promoting (PGP) benefits for the host. Finally, we identified an inoculum with possibly HCH tolerant, PGP bacteria transferred from the contaminated bulk soil to L. tenuis roots through the rhizosphere compartment, consisting of Mesorhizobium loti, Neorhizobium galegae, Novosphingobium lindaniclasticum, Pantoea agglomerans and Lysobacter bugurensis., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2021 Elsevier B.V. All rights reserved.)

The presence of a biofilm within the peritoneal dialysis catheter where bacteria are encapsulated, protected from the action of antibiotics and insidiously liberated within the dialysate, best explains the relapse of the infectious peritonitis, when antibiotics are withdrawn. We here report a serie of four clinical cases in whom the administration of urokinase within the peritoneal catheter in addition to the current antibiotherapy, has cured relapsing peritonitis due to Staphylococcus epidermidis in two cases, Acinetobacterjohnsonii in one case and Staphylococcus haemolyticus in one case, respectively. This approach, safe and easy, allowed the infection eradication and did prevent a catheter removal and a potential transfer of the patients to hemodialysis., (Copyright © 2020 Société francophone de néphrologie, dialyse et transplantation. Published by Elsevier Masson SAS. All rights reserved.)

Background: We report our findings on a hospital-based retrospective pilot cohort with case-controls study, which we carried out to examine genetic, environmental, and occupational risk factors in men with breast cancer., Methods: 86 men with breast cancer were diagnosed in eight VA medical centers that agreed to collaborate on this project. A case-control analysis was conducted on a subset of the male breast cancer cases (n = 44) and age- and ethnicity-matched controls (n = 77). We compared host characteristics, comorbidities, and medications intake between cases and controls by using Chi-square analysis and Fisher's exact test., Results: The descriptive analysis showed that the majority of veterans with male breast cancer were non-Hispanic white (60%), older than 65 years at diagnosis (56%), and more likely estrogen receptor positive (45%). World War II veterans represented the largest group (22%), followed by the Vietnam era veterans (10%). Thirty-three percent reported a positive family history of cancer, while 18% had another primary cancer diagnosis. Prior alcohol (43%) and tobacco use (56%) was substantial among these patients. Twenty percent of patients were overweight or obese and 55% had comorbid diseases with heart disease being the most prevalent, followed by diabetes mellitus. The case-control analysis yielded a significantly greater proportion of cases with gynecomastia (p < 0.0001), a positive family history of cancer (p = 0.0028), history of antibiotic use (p = 0.0112), and history of tobacco use (p = 0.0143) compared to controls., Conclusion: The findings of this hospital-based pilot study indicate case-control differences in gynecomastia and family history of cancer. The pilot study lacked sufficient power to determine a true association between the variables of interest and warrants a large-scale collaborative study between the VA medical centers.

Outpatient hemodialysis therapy (HD) can be associated with hemodynamic compromise. Bioreactance has recently been shown to provide accurate, noninvasive, continuous, measurements of cardiac output (CO) and thoracic impedance (Zo) from which thoracic fluid content (TFC) can be derived assuming TFC=1000/Zo. This study was designed to evaluate the changes in TFC in comparison with the traditional indices of fluid removal (FR) and to understand the trends in CO changes in HD patients. Minute-by-minute changes in TFC and CO were prospectively collected using the bioreactance system (NICOM) in HD patients of a single unit. Changes in body weight (DeltaW), hematocrit (DeltaHct), and amount of FR were also measured. Twenty-five patients (age 77 +/- 11 years) were included. The TFC decreased in all patients by an average of 5.4 +/- 7.9 kohm(-1), weight decreased by 1.48 +/- 0.98 kg, and FR averaged 2.07 +/- 1.93 L over a 3- to 4-hour HD session. There were good correlations between DeltaTFC and DeltaW (R=0.80, P<0.0001) and FR (R=0.85, P<0.0001). DeltaHct (4.13 +/- 3.42%) was poorly correlated with DeltaTFC (R=0.35, P=0.12) and FR (R=0.40, P=0.07). The regression line between FR and TFC yielded FR=1.0024-0.1985TFC; thus, a 1 kohm(-1) change of Zo correlates with an approximately 200 mL change in total body water. The change in CO (-0.52 +/- 0.49 L/min m(2)) during HD did not correlate with FR (R=0.15, P=NS). Changes in TFC represented the monitored variable most closely related to FR. CO remained fairly constant in this stable patient cohort. Further studies in high-risk patients are warranted to understand whether TFC and CO monitoring can improve HD session management.

Objectives: Treatment objectives in inflammatory dilated cardiomyopathy (DCMi), myocarditis (M) and peri(myo)carditis are 1) the elimination of inflammatory cells from the myocardium and pericardium, 2) the elimination or (second best) mitigation of B-cell products such as antibodies and immuncomplexes directed against cardiac epitopes such as sarcolemmal, fibrillary and mitochondrial epitopes, and 3) the eradication of the causative viral or microbial agent, if present., Antiphlogistic Treatment: A "non-specific" anti-inflammatory treatment in peri(myo)carditis can be carried out with antiphlogistics (NSAIDs preferably colchicine 1-3 mg/d) independent from the presence of the infective agent. In larger virus and bacteria negative effusions we recommend intrapericardial instillation of cristalloid triamcinolon (Volon A) at a dose of 500 mg/m(2), which should be left in place to have a sustained effect over at least 4 weeks. This will effectively prevent recurrences particularly when colchicine is added over a period of at least 3-6 months. Taking into account the 2004 ESC task force recommendations on the management of pericardial diseases the treatment recommendation for NSAIDs and colchicine can be classified as level of evidence A, indication class I, for intrapericardial triamcinolon instillation as level of evidence B, indication class IIa., Immunosuppression: In (immuno)histologically validated autoreactive (virus negative) myocarditis and DCMi double-blind randomized trials are lacking to demonstrate the superiority of immunosuppression over conventional heart failure management. The only published randomized and double-blind immunosuppression treatment trial (American Myocarditis Treatment Trial) was underpowered and did not distinguish viral from non-viral disease. It showed neither benefit nor harm of a combination of cyclosporin and prednisone. A number of retrospective analyses of immunosuppression in myocarditis showed some benefit of surrogate parameters (ejection fraction, exercise tolerance) but improvement under conventional heart failure treatment cannot be ruled out completely as the main cause for amelioration. ESETCID (European Study on the Epidemiology and Treatment of Cardiac Inflammatory Disease) is a double-blind, randomized, placebo-controled three-armed trial with prednisolone and azathioprine for autoreactive (virus negative) DCMi, interferon alpha for enterovirus positive DCMi, high-dose immunoglobulin for cytomegalovirus and intermediate dose for adeno- and Parvo B19 DCMi. It has now randomized more than 120 patients to the different treatment arms. Its final result has still to be awaited.-Patients not willing to randomize in the trial were included in a registry follow-up, which shows improvement of hemodynamic parameters and elimination of the inflammation in the majority of patients. This is in concordance with several non-randomized trials. Since evidence is conflicting (level of evidence C, indication class IIb; if negative viral etiology is taken into consideration class IIa) treatment with immunosuppression cannot be generally recommended but should be further evaluated in doubleblind randomized clinical trials or at least in controlled trials and registries. This also applies to treatment with interferon for enteroviral or other viral infections in the heart., Immunoadsorption: : The elimination of anticardiac antibodies, which have been associated with DCMi, is a currently discussed concept, which is supported by published registry data and a few very small controlled investigations but not by a randomized double-blind trial with clinical endpoints of relevance. In some studies immunoglobulins have been substituted, so that an additional immunomodulatory effect has to be taken into account. The current proof of concept can be ranked level of evidence C, indication class IIa only. An even more challenging and still more attractive hypothesis is that cardiac inflammation caused by specific circulating beta-adrenoceptor antibodies can be eradicated with the elimination of the beta-receptor antibody thus healing dilated cardiomyopathy. Application of this approach can be ranked level of evidence C, indication class IIb at present only. Therefore these two pathophysiologically attractive concepts have to await further validation by a double-blind, randomized clinical endpoint trial., Immunoglobulin Treatment: It has been shown that immunoglobulins have both an antiviral and an anti-inflammatory effect. They may suppress proinflammatory cytokines and reduce oxidative stress. HIGH-DOSE I.V., Immunoglobulins (ivig): In biopsy proven CMVmyocarditis a controlled trial demonstrated eradication of inflammation and of the virus (level of evidence B, indication class IIa), which is in accordance with registry data and case reports. In suspected myocarditis (not biopsy proven, no viral etiology established or excluded) conflicting data exist with respect to the improvement of surrogate markers such as the ejection fraction under high-dose immunoglobulins. More evidence can be weighted in favour of a positive treatment effect (level of evidence B, indication class IIb). Importantly there were no detrimental effects of the ivIG reported in these trials. One has to consider the high costs of this treatment, however. A trial taking into account the different etiologies (different viruses assessed separately vs. non-viral/autoreactive vs. placebo) is still lacking. MODERATE-DOSE I.V., Immunoglobulins: Registry data support a positive effect of 20 g i.v. pentaglobin (IgG and IgM) in adenovirus positive myocarditis for clinical improvement, eradication of both the inflammation and the virus. In Parvo B19 myocarditis our own registry data indicate that clinical improvement can be noted, but only inflammation is successfully eliminated, whereas Parvo B19 persistence remains a problem in the majority of patients. In Parvo B19 associated DCMi therefore dose finding studies and randomized trials are needed.

Although enteroviruses have long been considered the most common cause of inflammatory heart muscle diseases, parvovirus B19 (PVB19) is emerging as a new and important candidate for myocarditis and dilated cardiomyopathy with inflammation (DCMi) and without inflammation (DCM). We investigated left ventricular endomyocardial biopsy specimens from 110 patients with suspected inflammatory heart disease for the presence of PVB19, Coxsackie virus (CVB), and adenovirus (Ad2) genome by polymerase chain reaction. Diagnosis of myocarditis (36 patients), DCM (18 patients), DCMi (13 patients), and perimyocarditis (12 patients) was made by immunohistochemical and histopathological investigation of endomyocardial biopsy specimens. A control group consisting of patients with arterial hypertension was also investigated. Prevalence of the PVB19 genome in endomyocardial biopsy specimens was highest in patients with DCMi (3 of 13) and patients with myocarditis (7 of 36); in patients with DCM and perimyocarditis, prevalence was 3 of 13 and 2 of 12, respectively. In patients with resolved myocarditis, no PVB19 DNA was detected; in patients with no inflammation and controls, prevalence was only 4% and 7%, respectively. CVB-RNA was detected in endomyocardial biopsy specimens from 3 of 37 patients with myocarditis; Ad2-DNA was found in 1 patient with DCM and 1 patient with perimyocarditis. These findings suggest an association of the PVB19 genome in endomyocardial biopsy specimens of adults with the development of DCM, DCMi, and chronic myocarditis more frequently than previously expected. PVB19 should therefore be recognized as a potential cardiotropic pathogen in patients of all ages.

Unlabelled: Renal dysfunction is a frequent and severe complication after conventional hypothermic cardiac surgery. Little is known about this complication when cardiopulmonary bypass (CPB) is performed under normothermic conditions (e.g., more than 36 degrees C). Thus, we prospectively studied 649 consecutive patients undergoing coronary artery bypass surgery or valve surgery with normothermic CPB. The association between renal dysfunction (defined as a > or =30% preoperative-to-maximum postoperative increase in serum creatinine level) and perioperative variables was studied by univariate and multivariate analysis. Renal dysfunction occurred in 17% of the patients. Twenty-one (3.2%) patients required dialysis. Independent preoperative predictors of this complication were: advanced age, ASA class >3, active infective endocarditis, radiocontrast agent administration <48 h before surgery, and combined surgery. When all the variables were entered, active infective endocarditis, radiocontrast agent administration, postoperative low cardiac output, and postoperative bleeding were independently associated with renal dysfunction. The in-hospital mortality rate was 27.5% when this complication occurred (versus 1.6%; P < 0.0001). Furthermore, postoperative renal dysfunction was independently associated with in-hospital mortality (odds ratio, 4.1 [95% confidence interval, 1.3-12.8]). We conclude that advanced age, active endocarditis, and recent (within 48 h) radiocontrast agent administration, as well as postoperative hemodynamic dysfunction, are more consistently predictive of postoperative renal dysfunction than CPB factors., Implications: We found that postoperative renal dysfunction was a frequent and severe complication after normothermic cardiac surgery, independently associated with poor outcome. Independent predictors of this complication were advanced age, active endocarditis, and recent (within 48 h) radiocontrast agent administration (the only preoperative modifiable factor), as well as postoperative hemodynamic dysfunction.

Definition and Classification: Cardiomyopathies are disorders affecting the heart muscle that frequently result in congestive heart failure. Five major forms are recognized: dilated, hypertrophic, restrictive, right ventricular, and nonclassifiable cardiomyopathies with distinct hemodynamic properties. Furthermore, the new WHO/WHF definition also comprises inflammatory cardiomyopathy, defined as myocarditis in association with cardiac dysfunction. Idiopathic, autoimmune, and infectious forms of inflammatory cardiomyopathy were recognized. Viral cardiomyopathy is defined as viral persistence in a dilated heart. It may be accompanied by myocardial inflammation and then termed inflammatory viral cardiomyopathy (or viral myocarditis with cardiomegaly). If no inflammation is observed in the biopsy of a dilated heart (< 14 lymphocytes and macrophages/mm2), the term viral cardiomyopathy or viral persistence in dilated cardiomyopathy should be applied., Diagnosis and Treatment: In recent years, there have been breakthroughs in understanding the molecular and genetic mechanisms involved in this group of conditions, enabling improvement of diagnostic strategies and introduction of new therapies. Ongoing evaluation of antiviral, immunoglobulin, and immunosuppressive therapies including the European Study of Epidemiology and Treatment of Cardiac Inflammatory Diseases (ESETCID), removal of antibodies by immunoadsorption, anticytokine and gene therapy, as well as the mechanical support devices may provide new treatment options.

The pathophysiology of viral myocarditis is still a matter of debate. Humoral autoimmunity in postviral heart disease remains an attractive but complex hypothesis. Antigenic mimicry with or without cytolytic antibody properties has been shown to play a role in the immunopathogenesis of myocarditis with respect to sarcolemmal/myolemmal epitopes (including the beta-receptor), myosin and some mitochondrial proteins including the antinucleotide translocator (ANT)-carrier and dihydrolipoamid dehydrogenase. Today, refined two-dimensional Western blots are able to identify receptors and enzymes that are target of a humoral immune response or the consequence of an "immunization process." A humoral immune response to an invading agent will most likely lead to immunodestruction first. After conversion to IgG, the continuing antibody response may indicate the healing or healed process and last for many years or life-long. This paper reviews our present knowledge on the humoral immune response in myocarditis and its interplay with the viral agents and the other components of the immune system.

Background: Dialysis is becoming increasingly frequent in patients over 75 years of age. Age is a superimposed comorbid factor commonly associated with poor prognosis in these patients., Objective: To analyze the survival of 292 patients aged over 75 years on initiation of peritoneal dialysis (PD) from September 1982 to September 1999., Design: Retrospective study., Setting: Nephrology department in a University Hospital., Results: Mean age was 81.5 years (range 75-92 years); 178 patients were over 80 years and 60 patients were over 85 years. Sex ratio was 136F/156M. Ninety-day mortality rate was 12%. Excluding the first 3 months, median patient survival was 21.6 months; 226 patients died on PD and 24 were shifted to hemodialysis. Survival was inversely correlated with the Charlson combined comorbidity index (CCI), but independent of predialysis hemoglobin and serum albumin levels. Over three selected periods, 1982-1989, 1989-1995, and 1995-1999, an increase was found in mean age (79.7 +/- 3.3, 82.6 +/- 3.9, and 81.8 +/- 4.4 years; p < 0.001), CCI (7.6 +/- 1.59, 8.0 +/- 1.52, and 8.5 +/- 1.63; p = 0.01), and predialysis creatinine clearance (6.2 +/- 2.3, 6.4 +/- 2.4, and 9.8 +/- 3.8 mL/minute; p < 0.001). Median survival was similar in the various selected periods (21.0, 21.5, and 25.4 months). The incidence of peritonitis decreased from 0.63 to 0.21 episodes per patient year., Conclusion: From 1982 to 1999, mean age and comorbidity increased on initiation of dialysis in elderly patients, with no increase in mortality. Survival in elderly patients on PD was related to the age-comorbidity index.

The six serotypes of the group B coxsackieviruses (CVB) are common human enteroviruses linked etiologically to inflammatory cardiomyopathies. This has been demonstrated by molecular detection of enteroviral RNA in human heart tissue, serologic associations with disease, and virus isolation from cases of fulminant myocarditis. The murine model of CVB-associated myocarditis has demonstrated that CVB can be attenuated through mutations at different genomic sites. Human CVB3 isolates demonstrate varying degrees of cardiovirulence in the murine model; one site of virulence determination has been mapped to domain II of the 5' non-translated region. The interplay of CVB replication and the immune response to that replication in the heart is a complex interaction determining the extent to which the virus replication is limited and the degree to which a pathogenic inflammation of cardiac muscle occurs. Studies of CVB3-induced myocarditis in murine strains lacking subsets of the immune system or genes regulating the immune response have demonstrated a pivotal role of the T cell response to the generation of myocarditis. While CVB are associated with 20-25% of cases of myocarditis or cardiomyopathy, the severity of the disease and the existence of attenuated strains shown to generate protective immunity in animal models indicates that vaccination against the CVBs would be valuable., (Copyright 2001 John Wiley & Sons, Ltd.)

Background: Atrial fibrillation is the most frequent arrhythmia. It can impair quality of life considerably. Due to thromboembolic complications it contributes to the patients' morbidity and mortality and to the costs for their medical treatment., Prevention: In chronic atrial fibrillation there is a need for adequate anticoagulation and heart rate control. In paroxysmal and intermittent atrial fibrillation it should be sought to prevent its progression to chronic atrial fibrillation. Since atrial fibrillation initiates negative processes of remodeling within the atrial myocardium, it has the tendency to perpetuate itself. From a theoretical point of view, it can be expected that all means which prevent episodes of atrial fibrillation or which terminate it immediately after its onset, are able to prevent or at least to delay the progression to chronic atrial fibrillation. Pharmacologic treatment is usually used to prevent recurrences of atrial fibrillation. Based on the actual data it can also be expected that pacemakers with special preventive pacing algorithms are able to reduce the atrial arrhythmic burden. Besides consequent overdrive pacing, more sophisticated algorithms like "suppression of premature atrial contractions", "post exercise response", "automatic rest rate" or "post mode-switch pacing" have been developed. They can be applied either alone or in combination with special lead positions (interatrial septal pacing or pacing of the triangle of Koch) or special stimulation configurations like dual site right atrial pacing or biatrial pacing. These pacing strategies cover the most relevant onset mechanisms of atrial fibrillation. Furthermore, there are algorithms to treat atrial tachyarrhythmias actively by antitachycardia pacing (ATP). First clinical results have shown that about 2/3 of the diagnosed atrial tachyarrhythmias could be terminated by these means immediately after their onset., Ongoing Trials: This article gives an overview over the principles of pacing in the management of atrial arrhythmias and ongoing clinical trials in this field. Before a definite judgement on the clinical relevance of these new preventive and therapeutic pacing strategies can be given, the results of these ongoing controlled clinical studies have to be analyzed.

The case presented in this study illustrates the peritoneal changes observed in long-term peritoneal dialysis (PD) patients. This male patient was on peritoneal dialysis (CAPD) for seven months before and 86 months after renal transplantation. Two episodes of peritonitis occurred during that time. The patient developed symptoms (ascites, gastro-intestinal disturbances, deteriorating general condition, inflammatory syndrome) four months after starting hemodialysis, one month after ablation of the PD catheter. Other potential causes (infection, malignancy, hepatitis, etc.) of these symptoms were ruled out following an exhaustive etiological work-up. A final diagnosis of sclerosing peritonitis was made, and the patient was started on corticosteroid therapy. Both morphological and functional alterations of the peritoneal membrane associated with long term PD and the detection of such alterations in everyday practice are reviewed here, along with possible etiological factors and therapeutic measures discussed in the literature. A better understanding of the pathophysiological mecHanisms underlying these alterations would make it possible to develop preventive measures, such as more biocompatible dialysates.

There are many causes of pericardial effusion and it is useful to classify them etiologically, since this disorder is the most common pathologic process involving the pericardium. This report details our experience with pericardioscopy and epicardial biopsy in 101 patients with pericardial effusions in whom pericardioscopy was performed. By means of clinical data and polymerase chain reaction we tried to elucidate the etiology of the pericardial effusion which were classified as follows: we found 41 effusions to be induced by primary malignant tumors or tumors metastatic to the pericardium. Specific diagnosis of viral and bacterial pericarditis was established in 17 patients by examination of the pericardial effusion with PCR, where we found 3 patients positive for adenovirus, 5 patients positive for cytomegalovirus, 2 patients positive for enterovirus-RNA and 5 patients positive for borrelia Burgdorferi-DNA. Additionally, idiopathic effusions (lymphocytic and autoreactive) were seen in 35 patients. In summary immunological and molecular biology investigations seem to provide an additional tool in the diagnostic of pericardial effusion with unknown etiology. If we focus on the ELISA results, there is some evidence, that the demonstration [table: see text] of activation markers and soluble mediators of inflammation such as Il-6, Il-8 and IFN-gamma in pericardial effusion and the simultaneously lack of these mediators in sera of the patients first may be helpful in the discrimination of autoreactive and lymphocytic effusion. Second, this cytokine pattern or distribution indicates a possible local inflammatory process, where these cytokines were all released from activated T lymphocytes present in lymphocytic effusion. In the future, this may have therapeutic implications.

It is still controversial whether the arrhythmias in acute pericarditis are of myocardial or pericardial origin. The aim of the present study was to investigate the occurrence of arrhythmias and conduction disorders in patients with acute pericarditis with no endomyocardial biopsy evidence of myocarditis (group 1: 40 patients, 65% males, mean age 45.6 +/- 15.7 years, mean heart rate [HR] 98.7 +/- 22.2 beats per minute) in comparison to endomyocardial biopsy proven acute myocarditis/perimyocarditis (group 2: 10 patients, 3/10 with perimyocarditis, 70% males, mean age 46.1 +/- 15.8 years, mean heart rate 76.7 +/- 33.1 beats per minute). At the initial assessment all patients underwent comprehensive clinical work-up including echocardiography, cardiac catheterization, and endomyocardial biopsy. In all patients biventricular endomyocardial biopsy was performed using standard femoral approach and Schikumed 7 F or 8 F bioptomes. Tissue samples were stained by H & E, v. Gieson and independently reviewed by two cardiac pathologists. In addition immunohistochemistry and immunocytochemistry were performed, and only patients fulfilling Dallas and World Heart Federation criteria were selected for group 2. Comparative analysis of electrocardiograms and 24-hour Holter recordings at initial presentation revealed in group 1 vs group 2 significantly less frequent paroxysmal supraventricular tachyarrhythmias (5% vs 40%), and ventricular fibrillation (0 vs 20%), in contrast to atrial fibrillation that occurred more often (20% vs 0) (all p < 0.05). Furthermore, in the group 2 one patient died due to VF and two patients underwent ICD implantation. Low voltage (40% vs 30%) and ST/T wave changes (47.5% vs 30%), as well as the incidence of the II degree AV block (5% vs 0) and complete AV block (2.5% vs 10%) were not significantly different between the groups. In conclusion, patients with pericarditis and no endomyocardial biopsy indications of myocarditis had significantly less often life threatening rhythm disorders in contrast to patients with endomyocardial biopsy proven acute myocarditis/perimyocarditis. On the contrary, incidence of transitory atrial fibrillation was higher in acute pericarditis, than in myocarditis.

Background: To date, considerable controversy exists regarding noninvasive arrhythmia risk stratification in idiopathic dilated cardiomyopathy (IDC). Methods and Results Between 1992 and 1997, 202 patients with IDC without a history of sustained ventricular tachycardia (VT) underwent echocardiography, signal-averaged electrocardiogram (ECG), and 24-hour Holter ECG in the absence of antiarrhythmic drugs. During 32 +/- 15 months of prospective follow-up, major arrhythmic events, including sustained VT, ventricular fibrillation, or sudden death, occurred in 32 (16%) of 202 patients. After adjusting for baseline medical therapy and antiarrhythmic therapy during follow-up, multivariate Cox regression analysis identified a left ventricular (LV) end-diastolic diameter >/=70 mm and nonsustained VT on Holter as the only independent arrhythmia risk predictors. The combination of an LV end-diastolic diameter >/=70 mm and nonsustained VT was associated with a 14. 3-fold risk for future arrhythmic events (95% confidence interval 2. 3-90). To further elucidate the prognostic value of LV ejection fraction, multivariate Cox analysis was repeated with ejection fraction forced to remain in the model. In the latter model, an ejection fraction /=70 mm and nonsustained VT on Holter, and the combination of LV ejection fraction

By including immunohistochemical parameters the WHF Task Force for the Definition of Acute and Chronic Myocarditis expanded the light microscopical Dallas criteria of myocarditis. The rapid development of new molecular biological techniques such as polymerase chain reaction (PCR) and in-situ hybridization has improved our understanding of the underlying etiological and pathophysiological mechanisms in inflammatory heart disease. Treatment of dilated cardiomyopathy with inflammation is still controversial, however. The American Myocarditis Treatment Trial could not demonstrate a significant difference in the improvement of ejection fraction between patients with active myocarditis in the cyclosporine/prednisolone treated group when compared to placebo. In the European Study of Epidemiology and Treatment of Inflammatory Heart Disease (ESETCID) patients with acute or chronic myocarditis are treated specifically according to the etiology of the disease. Patients are screened not only for infiltrating cells, but also for the presence of persisting viral genome (enterovirus, cytomegalovirus and adenovirus). By investigating endomyocardial biopsies of 3,055 patients ongoing inflammatory processes in the heart could be found in 17.2%. Only 182 showed a reduced ejection fraction below 45% fulfilling the entrance criteria for the ESETCID trial. These data imply that in symptomatic patients inflammatory heart muscle disease has to be considered regardless of left ventricular function and that endomyocardial biopsy can be an important tool for diagnosis. Virus could be detected in 11.8% (enterovirus 2.2%, cytomegalovirus 5.4%, adenovirus 4.2%). These first epidemiological results of this prospective randomized study demonstrate that viral persistence may contribute to the pathogenesis of inflammatory heart muscle disease, and that in chronic myocarditis viral persistence occurs in a smaller percentage of patients compared to previously published studies which were performed on highly selected patients.

This article reviews the current state of consensus reached for the diagnosis of myocarditis and dilated cardiomyopathy on the basis of conventional histopathological and immunohistochemical methods for inflammatory infiltrates in addition to molecular biological methods for persistence of viral genome in endomyocardial biopsies. Additionally, a brief overview is presented stating the current knowledge on effector mechanisms of the immune system in myocarditis and dilated cardiomyopathy.

In the report of the 1995 World Health Federation/International Society and Federation of Cardiology (WHF/ISFC) Task Force on the Definition and Classification of Cardiomyopathies, the definition of heart muscle diseases was updated. Idiopathic, autoimmune, and infectious forms of inflammatory cardiomyopathy are now recognized in this definition. Enteroviruses, adenoviruses and cytomegaloviruses are considered as main etiopathological factors in the pathogenesis of inflammatory heart disease. A wide range of different assays have been and are currently being used, either alone or in combination, to assay for the presence of enteroviral RNA and/or DNA of cytomegalo- and adenoviruses in endomyocardial biopsy and explanted heart samples. The prevalence of cardiotropic viruses in endomyocardial biopsies of patients with clinically suspected inflammatory cardiomyopathy varies widely: enteroviral genome was detected in endomyocardial biopsies of 3 to 53% of patients, cytomegaloviral DNA was detected in 3 to 40% of patients with inflammatory heart disease and adenoviruses in 3 to 23% of the patients. This report summarizes the methods that have been used and the results of molecular biological investigation with polymerase chain reaction, which were reported by several groups over the last years. Taking this together it seems to be clear that the improvement of molecular biological techniques and the experience of people working with these methods will lead to more reliable results on prevalence, persistence and the diagnostic value of these investigations. These findings have to be taken into account in future diagnostic and therapeutic studies in the field of cardiomyopathies.

Background: Our purpose was to evaluate the efficacy and safety of atorvastatin, a potent cholesterol- and triglyceride-lowering agent, in peritoneal dialysis patients with dyslipidaemia., Methods: Peritoneal dialysis patients with hypercholesterolaemia were treated for 4 months with atorvastatin at a starting dose of 10 mg. The dose could be increased to 20 or 40 mg in order to achieve the following targets: plasma LDL-cholesterol of 130 mg/dl for primary prevention of coronary heart disease, plasma LDL cholesterol of 100 mg/dl for secondary prevention, and plasma triglycerides of 200 mg/dl. Plasma lipid profile and liver and muscle enzyme levels were assessed at baseline and then monthly during treatment., Results: Thirty-one patients with hypercholesterolaemia were included (16 males and 15 females; mean age 57+/-16 years; mean duration of peritoneal dialysis 27+/-17 months). Nineteen of the patients also had hypertriglyceridaemia and seven had diabetes. Twenty patients had no coronary history (primary prevention), whereas nine had experienced a coronary event (secondary prevention). In the primary and the secondary prevention patients, mean LDL-cholesterol levels (mg/dl) decreased significantly by 42 and 46% from 204+/-23 to 119+/-27 (P<0. 001) and 198+/-37 to 104+/-21 (P<0.001), and mean triglyceride levels (mg/dl) decreased by 37 and 26% from 289+/-132 to 186+/-92 (P<0.001) and 201+/-62 to 150+/-54 (P<0.001 respectively). Nineteen primary prevention and seven secondary prevention patients achieved the LDL-cholesterol target. The triglyceride target was achieved by 15 of the 19 hypertriglyceridaemic patients. Two patients stopped treatment (one because of gastrointestinal disturbances, the other because of an allergic skin reaction). After 4 months, there were no changes in enzyme levels., Conclusion: Atorvastatin is an effective and safe lipid-lowering agent for peritoneal dialysis patients with mixed dyslipidaemia.

The aim of the present study was to assess the effects of carvedilol therapy in addition to conventional heart failure therapy on heart rate variability (HRV) and on left ventricular function in 14 patients with mild to moderate heart failure due to idiopathic dilated cardiomyopathy (IDC). After a 3- to 4-week titration period, carvedilol was titrated up to 50mg daily, or the highest dose tolerated (at least 25mg daily). Maintenance treatment was then continued for 8 weeks. Digital 24-hour Holter recordings were obtained at baseline and after 8 weeks of carvedilol therapy. HRV for the entire 24-hour period was computed in the time domain using the Oxford Medilog Excel 2 analysis system. Measures of HRV included the mean of all coupling intervals between normal beats (RRm), the standard deviation of all normal RR intervals (SDNN), the square root of the mean of the squared differences between adjacent normal RR intervals (rMSSD), and the proportion of adjacent normal RR intervals differing >50 ms (pNN50). Additional treatment with carvedilol induced a significant increase in HRV: SDNN increased from 77+/-21 ms to 110+/-22 ms (p=0.001), rMSSD from 19+/-7 ms to 26+/-7 ms (p=0.02), and mean pNN50-value increased from 1.7+/-1.3% to 5.5+/-4.5% (p<0.01) under therapy with carvedilol. Mean heart rate on carvedilol calculated over 24 hours was 13 beats less than at baseline (75 bpm versus 88 bpm, p<0.01). After 2 months of additional treatment with carvedilol, both hemodynamic and clinical parameters improved: left ventricular ejection fraction increased from 24+/-7% to 30+/-10% (p<0.05), and New York Heart Association class decreased from 2.5+/-0.8 to 1.8+/-0.7 (p<0.05). In summary, eight weeks of additional carvedilol therapy induced a significant increase in HRV parameters related to parasympathetic activity in patients with IDC. Whether increased vagal tone may contribute to the protective effect of carvedilol has to be evaluated by further studies.

Cell death can be induced by 2 different mechanisms: necrosis and apoptosis. Necrosis, on the one hand, is usually caused by unphysiological stress factors such as hyperthermia or hypoxia, apoptosis, on the other hand, is part of the normal organ development and controls for example immune responses. Morphologically, necrosis is characterized by swelling of cells and their organelles leading to the disruption of the cell membrane, which in turn causes an inflammatory reaction in the surrounding tissue. Morphological and biochemical criteria (Figure 1, Table 1) of apoptosis are the condensation of chromatin leading to the development of apoptotic bodies or membrane-enclosed vesicles containing oligonucleosomal DNA fragments. Important diagnostic tools of cell death (Table 2), such as the TUNEL test (Figure 2) or gel electrophoresis of extracted DNA (Figure 3) are based on the above mentioned biochemical characteristics, but a reliable differentiation of apoptotic versus necrotic processes is not always possible. Experimental studies in animals and studies in various diseases of the cardiovascular system were able to show that apoptosis in myocytes can be induced, an issue that has long been discussed controversially. Ischemia, reperfusion, and myocardial infarction were also shown to lead to apoptosis in cardiomyocytes, whereas cell destruction was caused mainly by necrosis. Several authors (Table 3) demonstrated apoptotic indices in cardiomyocytes of patients with dilatated cardiomyopathy, arrhythmogenic right ventricular cardiomyopathy and patients with acute infarction from 0.25 to 35% by the use of the TUNEL test. Others were able to demonstrate an elevated expression of Fas-receptor in cells of atheroslerotic plaques in patients with atherosclerosis and high indices of apoptotic cardiomyocytes in patients with chronic heart failure. We investigated endomyocardial biopsies of patients with inflammatory cardiomyopathy, DCM without inflammatory reaction but the presence of adenoviral or cytomegaloviral genome and idiopathic DCM using the TUNEL test. The percentage of apoptotic cardiomyocytes in biopsies of patients with DCMi was 1.03 and in biopsies of patients with adenoviral genome 0.25, whereas in all other groups no apoptosis was found. If apoptosis plays a major role in myocardial diseases such as heart failure, arrhythmia and others, blocking this mechanism will have to be considered as a therapeutical strategy. Therefore, studies on the extent of apoptotic processes in diseased versus healthy cardiac tissue are of great importance.

We report a case of severe cutaneous hypersensitivity to icodextrin occurring in a CAPD diabetic patient. Icodextrin withdrawal was necessary to achieve cutaneous recovery. Although rare, this adverse event should be kept in mind.

From a registry of 136 patients undergoing pericardiocentesis, 14 patients with autoimmune and 15 patients with neoplastic effusions were selected. All underwent pericardioscopy, epicardial and pericardial biopsy with histologic, immunohistologic, and polymerase chain reaction/or in situ hybridization analysis for microbial DNAs and RNA. Pericardioscopy identified neoplastic effusions by the high occurrence of protrusions. Fibrin threads and layers and neovascularization were found in both groups. For identification of the inflammatory and neoplastic process, the combined analysis of the cytology of the effusion and epicardial biopsy evaluation proved to be most important. Epicardial biopsy demonstrated a slightly higher sensitivity for identifying neoplastic disorders in the pericardium than cytology alone. Pericardial biopsy was inconclusive. Intrapericardial administration of 1 g of crystalloid triamcinolone in autoreactive pericarditis prevented recurrence in 13 of the 14 cases after 3 months and in 12 of the 14 cases after 1 year. In neoplastic effusion, intrapericardial administration of 50 mg cis-platin for 24 h prevented recurrence of a hemodynamically relevant effusion after 3 months in all, and after 6-12 months in 14 of 15 patients. Mortality in neoplastic effusion due to noncardiac tumor progression was 47 and 80%, respectively, after 3 and 6 months, as can be expected in endstage neoplastic disease. This pilot study demonstrates that local drug application is feasible, life-saving, and well tolerated by the patients. It opens perspectives for local drug application in other cardiac disorders as well.

An increasing number of clinical and experimental studies point to a contribution of various infectious organisms like chlamydia pneumoniae or herpesviruses to atherosclerosis in man. Cytomegalovirus induces atherosclerotic lesions in animals. In vitro studies reveal functional changes of endothelial cells after infection with cytomegalovirus. Infection with this virus renders endothelial cells immunogenic for cellular and humoral immune reactions. In man a significant association of infections with herpesviruses and atherosclerosis could be established in several studies. Cytomegalovirus infection has been incriminated as an independent risk factor in restenosis after coronary angioplasty.

Diagnosis of inflammatory dilated cardiomyopathy relies on the histological and immunohistological examination of endomyocardial biopsies. Only with the demonstration of the etiological agents in the myocardium specific therapy can be attempted. Whereas the spontaneous course of endemic myocarditis with little hemodynamic impairment is fair, the prognosis of symptomatic myocarditis and dilated cardiomyopathy is poor, with complete restitution in 35% and a 10-year survival rate of 30%. Restriction of physical activity is a validated form of therapy with normalization of the heart size in 40 to 60%. Symptomatic medical therapy consists of digitalis, diuretics, ACE-inhibitors and vasodilators and betablocker therapy, where a reduction of mortality was demonstrated in clinical (sub)studies up to 60%. Specific forms of therapy in inflammatory cardiomyopathy rely on the demonstration or lack of viral persistence or signs of autoreactivity in the myocardial tissue. Immunosuppressive therapy in autoimmune forms improved cardiac function in up to 60% of the patients in controlled trials, when compared to controls (40%). The double-blind randomized myocarditis treatment trial, which unfortunately did not distinguish viral from autoimmune myocarditis could not demonstrate such a benefit, however. Depending on the etiology of the disease, immunomodulation with immunoglobulins or interferon or antiviral therapy with hyperimmunoglobulins are presently tested in clinical treatment trials (ESETCID) in patients with enterovirus-positive or cytomegalovirus-positive and adenovirus-positive chronic myocarditis. Specific therapies are aimed to avoid the progression of the disease which may ultimately lead to heart failure with a cardiac assist device or heart transplantation as ultimate therapeutic option.

In the report of the 1995 WHO/ISFC task force on the definition and classification of cardiomyopathies a new entity within the dilated cardiomyopathies was introduced as "inflammatory cardiomyopathy". It is defined as myocarditis associated with cardiac dysfunction. Idiopathic, autoimmune and infectious forms of inflammatory cardiomyopathy are now recognized through this definition. Dilated cardiomyopathy with inflammation (DCMi, chronic myocarditis) was also defined by a recent ISFC task force as > 14 lymphocytes/macrophages/mm3. Enteroviruses, adenoviruses and cytomegaloviruses are considered as main etiopathogenetic factors in the pathogenesis of inflammatory heart disease and have been demonstrated as important trigger for inflammatory cardiac disease. They may also cause dilated cardiomyopathy by viral persistence or secondary immunopathogenesis due to antigenic or molecular mimicry. For the detection of viral persistence the investigation of endomyocardial biopsies in patients with cardiomyopathy by the use of polymerase chain reaction and southern blot analysis is an important step for the standardization of diagnostic criteria on virally induced inflammatory cardiomyopathy. Present studies indicate an incidence of cytomegalovirus-DNA in patients with inflammatory cardiomyopathy in 10%, adenoviral-DNA in 17% and borreliosis only in rare cases (< 1%). In dilated cardiomyopathy without inflammation the respective incidences were for cytomegalovirus 12%, 15% for adenovirus and only 0.5% of cases for borreliosis. In addition the results of immunohistochemical analysis and molecular biological investigations of endomyocardial biopsies may have implications for future therapeutic studies. Depending on the etiology of the disease, immunosuppression may have benefit for patients with virus-negative cardiomyopathy with inflammation in contrast to patients with cytomegalo-, adenovirus-DNA or enteroviral persistence, in whom immunomodulation with hyperimmunoglobulins or immunoglobulins may be a feasible therapeutic option. Patients with a positive PCR for Borrelia burgdorferi should be treated with 3rd generation cephalosporines and/or sublactam.

We report the construction of chimeric coxsackievirus B3 (CVB3) strains in which sequences of an infectious cDNA copy of a noncardiovirulent CVB3 genome were replaced by the homologous sequences from a cardiovirulent CVB3 genome to identify which of 10 predicted genetic sites determine cardiovirulence. Cardiovirulent phenotype expression was consistently linked to nucleotide 234 (U in cardiovirulent CVB3 and C in avirulent CVB3) in the 5' nontranslated region. Reconstructions of the parental noncardiovirulent CVB3 genome from chimeras restored the noncardiovirulent phenotype when tested in mice. Inoculation of severe combined immunodeficient (scid) mice with the noncardiovirulent CVB3 strain resulted in massive cardiomyocyte necrosis in all animals. Sequence analysis of viral genomes isolated from twelve scid mouse hearts showed that only nucleotide position 234 was different (a C-->U transition) from that in the input parental noncardiovirulent CVB3 genome. Higher-order RNA structures predicted by two different algorithms did not demonstrate an obvious local effect caused by the C-->U change at nucleotide 234. Initial studies of parental and chimeric CVB3 replication in primary cultures of fetal murine heart fibroblasts and in adult murine cardiac myocytes demonstrated that viral RNA transcriptional efficiency is approximately 10-fold lower for noncardiovirulent CVB3 than for cardiovirulent CVB3. CVB3 did not shut off protein synthesis in murine cardiac fibroblasts, nor were levels of viral protein synthesis significantly different as a function of viral phenotype. Taken together, these data support a significant role for determination of the CVB3 cardiovirulence phenotype by nucleotide 234 in the 5' nontranslated region, possibly via a transcriptional mechanism.