Background—Previous studies have shown disappointing results for immunosuppressive treatment in patients with dilated cardiomyopathy. Therefore, we studied the effectiveness of such therapy in patients with HLA upregulation on biopsy. Methods and Results—Of 202 patients with dilated cardiomyopathy, 84 patients with increased HLA expression were randomized to receive either immunosuppression or placebo for 3 months; they were then followed for 2 years. After 2 years, there were no significant differences in the primary end point (a composite of death, heart transplantation, and hospital readmission) between the 2 study groups (22.8% for the immunosuppression group and 20.5% for the placebo). The secondary efficacy end point included changes in ejection fraction, end-diastolic diameter, end-diastolic volume, end-systolic volume and NYHA class; left ventricular ejection fraction increased significantly in the immunosuppression group compared with the placebo group (95% CI, 4.20 to 13.12; P<0.001) after 3 mon...

Randomized, placebo-controlled study for immunosuppressive treatment of inflammatory dilated cardiomyopathy: two-year follow-up results.

Myocarditis is a cardiac disease associated with inflammation and injury of the myocardium. Several viruses have been associated with myocarditis in humans. However, coxsackievirus B3 is still considered the dominant etiological agent. The observed pathology in viral myocarditis is a result of cooperation or teamwork between viral processes and host immune responses at various stages of disease. Both innate and adaptive immune responses are crucial determinants of the severity of myocardial damage, and contribute to the development of chronic myocarditis and dilated cardiomyopathy following acute viral myocarditis. Advances in genomics and proteomics, and in the use of informatics and biostatistics, are allowing unbiased initial evaluations that can be the basis for testable hypotheses about virus pathogenesis and new therapies.

Molecular biology and pathogenesis of viral myocarditis

The World Health Organization/International Society and Federation of Cardiology (WHO/ISFC) task force on the definition and classification of cardiomyopathies recently updated and reclassified heart muscle diseases.1 Myocarditis was defined as “an inflammatory disease of the myocardium . . . diagnosed by established histological, immunological, and immunohistochemical criteria.” Three distinct forms of inflammatory cardiomyopathy (that is, myocarditis associated with cardiac dysfunction) are recognised: idiopathic, autoimmune, and infectious. Various infectious factors may cause myocarditis, but viral agents, especially coxsackie group B viruses, are most commonly associated with this disease.2 

Myocarditis has been recognised for almost two centuries, since Corvisart first described this disease in clinical terms in 1812,3 but in the last three decades there has been renewed interest in the inflammatory process in the myocardium. The reasons for this are multiple: the introduction of endomyocardial biopsy for in vivo diagnosis (the disease was often overdiagnosed in the past on purely clinical grounds)4; related efforts to produce standardised criteria for histological diagnosis (the Dallas criteria; fig 1)5; better understanding of cardiotropic viruses, studied in animal models of myocarditis,6 leading to new insights into the immunological mechanisms of the disease (fig2)7 and potential treatments in humans8; and lastly—and perhaps most interestingly—the finding of a possible causal relation between viral myocarditis and dilated cardiomyopathy,9 a major cause of congestive heart failure in western countries.



Figure 1 
Histological section of active lymphocytic myocarditis according to the Dallas criteria. A dense infiltrate of lymphocytes in close contact with damaged and necrotic myocytes is evident (haematoxylin and eosin × 100).





Figure 2 
CD4RO positive T lymphocytic cellular infiltrates in a diffuse pattern (× 40).



Despite numerous published reports on this disease, the natural history of acute myocarditis is still poorly understood, despite the development of immunological …

https://heart.bmj.com/content/heartjnl/85/5/499.full.pdf

The fate of acute myocarditis between spontaneous improvement and evolution to dilated cardiomyopathy: a review

Background— Maternal anti-Ro and anti-La antibodies are associated with congenital heart block (CHB) Although endocardial fibroelastosis (EFE) has been described in isolated cases of autoantibody-mediated CHB, the natural history and pathogenesis of this disease are poorly understood Methods and Results— We retrospectively reviewed the clinical history, echocardiography, and pathology of fetuses and children with EFE associated with CHB born to mothers positive for anti-Ro or anti-La antibodies at 5 centers Thirteen patients were identified, 6 with a prenatal and 7 with a postnatal diagnosis Six mothers were positive for anti-Ro and anti-La antibodies, and 7 were positive for anti-Ro antibodies only Only 1 mother had autoimmune disease Severe ventricular dysfunction was seen in all fetal and postnatal cases Four fetal and 3 postnatal cases had EFE at initial presentation However, 2 fetal and 4 postnatal cases developed EFE 6 to 12 weeks and 7 months to 5 years from CHB diagnosis, respectively, eve

Maternal Anti-Ro and Anti-La Antibody–Associated Endocardial Fibroelastosis

Endocardial fibroelastosis associated with maternal anti-Ro and anti-La antibodies in the absence of atrioventricular block.

This review examines the immunologic rationale for immunosuppressive and immunomodulating therapy. The controversy as to whether immunosuppressive treatment is beneficial in myocarditis will continue even after the Myocarditis Treatment Trial, which demonstrated that in active myocarditis identified by the Dallas criteria but without taking into account presence or persistence of viral RNA or DNA or signs of autoreactivity, immunosuppression did not influence either central or hemodynamics or prognosis significantly. These findings concur in part with data from experimental mice and also with sporadic human data. In the acute stage of inflammatory viral heart disease, immunosuppressive drugs should be avoided. This recommendation can be upheld even in the light of the Myocarditis Treatment Trial. It is still unresolved, however, whether this also applies in chronic myocarditis with (enteroviral) persistence, in which the residual viral genome may have been rendered noninfective, making it the equivalent of a "scar" or "tombstone" of former infection. Here, demonstration of the viral genome in does not necessarily imply actively replicating virus. Furthermore, evidence is accumulating that the formerly reported incidence of enteroviral persistence in endomyocardial biopsies may have been overestimated. In autoreactive forms of myocarditis with documented humoral and cellular effector mechanisms, studies indicate that immunosuppressive treatment may be useful. However, data from the double-blind, randomized European Study of the Epidemiology and Treatment of Cardiac Inflammatory Disease must be awaited before conclusions can be made. We therefore recommend enrolling virus-negative patients in randomized, controlled treatment trials to validate the benefit of these treatment regimens. In addition, hyperimmunoglobulin therapy appears to be of particular interest because it has shown few side effects but has positive results in cytomegalovirus-associated myopericarditis in humans.

Immunosuppressive and immunomodulatory treatment for myocarditis.

Antisarcolemmal (ASAs) and antimyolemmal antibodies (AMLAs) are serological hallmarks of inflammatory heart muscle disease. They occur in a similar incidence in postcardiac injury syndromes, sarcoid heart disease or in dilated and hypertrophic cardiomyopathy. Rarely but still notably they are found with increasing age or in coronary artery disease. We therefore examined whether they are truly pathogenetic or whether they also possess properties of 'natural antibodies'. AMLAs and ASAs, like natural antibodies, have specificity for preserved structures on the membrane; they possess cross-reactivity and increase with age. In contrast to natural antibodies, however, they occur frequently after viral stimulation or other forms of trauma, are more often of the IgG and IgA than of the IgM isotype and fix complement in the acute stage of the disease. They also possess cytolytic and cytotoxic properties when incubated in vitro with isolated heart muscle cells. Antigenic mimicry has been demonstrated to be operative, since they are cross-reactive to viral proteins.

Cytolytic anticardiac membrane antibodies in the pathogenesis of myopericarditis.

The vascular endothelium plays a key role in immunologic reactions that also involve the heart: Increased expression of class 1 and 2 antigens of the major histocompatibility complex a common finding in acute rejection after heart transplantation whereas in myocarditis this finding is less pronounced. Another form of involvement of the endothelial cells in the secondary immune response has been reported only infrequently; anti-endothelial antibodies, which may be cytolytic to living cultured human endothelial cells, were demonstrated to be bound to the endomyocardial biopsies of patients with different forms of rejection and with biopsy proven myocarditis and circulating in the peripheral blood of the patients as cytolytic autoantibodies.

The vascular endothelium as target of humoral auto-reactivity in myocarditis and rejection.

Dilated cardiomyopathy (DCM) according to the definition of the WHO/ISCF task force as “heart disease of unknown cause” [47] is a feasible working definition for the clinician. On hemodynamic grounds it defines DCM as systolic pump failure, which — as we know better today — may also have features of a diastolic compliance disturbance and severe dysrhythmias. For the cardiologist interested in pathogenetic mechanisms of this form of heart failure and its etiology, it is, however, not a satisfying explanation. Instead, it more likely describes our lack of knowledge than a disease entity. Recent evidence has pointed to viral etiology and the persistence of the enteroviral genome in a proportion of patients. Similary, also the presence of cytomegalovirus DNA in active myocarditis could be ascertained (own unpublished results) in about 15% of patients. In addition, the investigation of immunologic regulator [1, 10, 11, 27, 28, 39, 54, 57], humoral [3, 5, 15, 19, 22–38, 40–47, 49–51, 55, 56], and cellular effector mechanisms in humans [2, 8, 9, 12, 13, 20, 27, 28, 34, 35, 41, 43, 55, 56] has broadened both our understanding of the primary etiology and secondary immunopathogenesis in DCM.

Humoral and Cell-Mediated Immunity: Pathogenetic Mechanisms in Dilated Cardiomyopathy

Immunoserologic and immunohistologic studies of myocarditis and pericarditis

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