Search

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.

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.

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

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.

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.

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.

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 Trials 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. immunostimulatory 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.

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.

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 cardiovirulent (able to cause disease). Here, we present preliminary data mapping the site in a coxsackievirus B3 genome which determines a cardiovirulent phenotype.

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 histocompatibility complex and of the Il2 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 Il2 receptor on interstitial cells as a specific marker of cell activation was only seen in acute rejection and in some cases of myocarditis.