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INFLAMMATORY CARDIOMYOPATHY
LIFE-THREATENING COMPLICATIONS OF AUTOIMMUNE DISEASE
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INFLAMMATORY CARDIOMYOPATHY The Controversy of Diagnosis and Management Karen B. James, MD, Norman Ratliff, MD, Randall Starling, MD, and James B. Young, MD
Myocarditis and dilated cardiomyopathy can occur as isolated entities or in association with systemic inflammatory diseases. The. catastrophic results of a damaged myocardium include congestive heart failure, cardiogenic shock, and sudden arrhythmogenic death. Congestive heart failure remains one of the most prevalent and costly health problems in the United States. Over 3 million people in the United States are affected, with an estimated $8 billion per year spent in the treatment of heart failure.43It has become clear that determining heart failure etiology is extraordinarily important because many diseases can be effectively treated or, at least, ameliorated, with ensuing reduction in morbidity and mortality. Considerable controversy exists regarding lymphocytic myocarditis, including its etiology, immunology, diagnostic approach, and relationship to dilated cardiomyopathy. Often a diagnosis of myocarditis is rendered when patients present with cryptogenic heart failure and a peri-presentation "viral" syndrome. This observation raises the controversy of the relationship between inflammatory heart disease and heart failure. Etiology, diagnosis, and treatment options for this devastating illness and the surrounding debates are addressed. Lymphocytic myocarditis as an isolated disease is reviewed first, followed by myocarditis associated with systematic inflammatory illnesses.
From the Department of Cardiology (KBJ, RS, JBY), and Department of Pathology (NR), Cleveland Clinic Foundation, Cleveland, Ohio
RHEUMATIC DISEASE CLINICS OF NORTH AMERICA VOLUME 23 NUMBER 2 * MAY 1997
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LYMPHOCYTIC MYOCARDITIS Etiology and Immunology
Lymphocytic myocarditis, histologically, is characterized by infiltration of the myocardium by lymphocytes and macrophages adjacent to myocyte injury or necrosis. It is intuitive that these inflammatory cells are the culprits in causing cardiac cell injury that leads to necrosis. Clinically, left ventricular systolic function may remain normal or, more frequently, may be subclinically impaired, with subsequent development of symptoms of heart failure or arrhythmias. In acute myocarditis, myocardial edema and inflammation may alter the diastolic function as well.25Indeed, lymphocytic myocarditis has been shown to be a cause of restrictive cardiomyopathy by echocardiographic diastolic In 50% of myocarditis cases, a viral infection, usually upper respiratory or gastrointestinal, precedes symptomatic heart failure by 1 to 4 weeks.53Although a virus is rarely demonstrated in myocardium, there is indirect evidence implicating viral presence. Acute and convalescent antiviral titers may suggest antecedent viral infection.6 Furthermore, genes and proteins of many viruses have been demonstrated in myocytes. The most common viruses implicated in lymphocytic myocarditis include Coxsackie A and B, echo, influenza, polio, mumps, reovirus, adenovirus, Epstein-Barr, cytomegalovirus, and the HIV-1 virus.I8 It has been hypothesized that viral infection triggers an anticardiac immunologic response. Seko et a1 theorize that viral infection and subsequent host cytokine response elicit enhanced expression of HLA (human leukocyte antigen) and ICAM-1 (intercellular adhesion molecule-1) on m y o ~ y t e sT. ~cells ~ recognize virus-derived antigens and damaged virus-infected myocytes. Later, after viral genomes have dissipated, T cells recognize a different autoantigen and can cause ongoing myocyte damage. It appears that the pathogenic T-cell clones in early myocarditis are different from. those in the later stages.5O Research using the murine myocarditis model has paved a cornerstone in our understanding of this disease.l9*30, 40, 41 Susceptible strains of mice were infected with Coxsackie B virus. Two populations of antibodies developed in the mice. One population reacted with both skeletal and cardiac myosin, whereas the other population was specific for only the cardiac isoform. Immunization in uninfected mice with skeletal myosin failed to produce myocarditis, whereas immunization with cardiac myosin alone induced myo~arditis.'~, 30, 40, 41 Genetic susceptibility plays an important role in experimental myocarditis. Rose et a1 show that both major histocompatibility complex (MHC) genes and background non-MHC genes play a role in the susceptibility of different strains of mice to Coxsackie B %induced my0carditis.4~Other factors affecting susceptibility include age, gender, nutritional status, exercise-induced stress, drugs such as adriamycin, the occurrence of sequential viral infections, and pregnancy.38,48 Humoral
There is evidence implicating participation of both the humoral and cellular aspects of the immune system in lymphocytic myocarditis following the initial viral or other insult. Cross-reaction of antibodies to viral proteins with various microstructures of the myocyte has been reported.I8 Specific autoantigens described include sarcolemma, myosin, adenine nucleotide translocator (ANT), calcium channel, p-adrenoreceptor, intermediate filaments, matrix (collagen,
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laminin), branched chain alpha ketoacid dehydrogenase (BCKD) complex, and recently, heat shock (HSP)-60 molecule.'8,29 These antibodies are characterized according to IgM, IgG, or IgA isotypes.'8 Because most of the autoantigens reported are intracellular, it is difficult to envision how antibodies lead to myocyte damage. There are two possible explanations: (1) following initiation of the autoimmune response, antibodies to intracellular antigens cross-react with membrane cardiac proteins; (2) Alternately, following the initial insult, myocytes may present self-peptides, complexed with MHC molecules, that are then presented to T cell^.'^ Cellular
The response of T lymphocytes in myocarditis has been a subject of intense study as well. In acute myocarditis, the number of activated T lymphocytes has been found to be increased.18 Natural killer activity is reduced. Non-MHC restricted T-lymphocyte activity to the heart muscle is elevated. Response of suppressor T lymphocytes remains Cytokines have been shown to play a role in damaging the myocardium. Treatment of Coxsackie-infected mice with tumor necrosis factor-alpha or interleukin-1 beta has been shown to markedly exaggerate myocyte injury.28Blocking the effects of cytokines may pose one exciting future avenue for controlling the ravages of myocarditis. Dilated Cardiomyopathy
It remains unclear how often dilated cardiomyopathy is a sequela of lymphocytic myocarditis. Interestingly, Kandolf et a1 found that 8 of 47 (17%) patients with dilated cardiomyopathy showed positive in situ hybridization with a group-specific enterovirus probe.23On the other hand, Ansari et a1 reported an autoimmune response in a large proportion of dilated cardiomyopathy patients by measuring antibodies to ANT, BCKD, mitochondria1 antigen, myosin, and the P-adrenergic receptor.' Other investigators also have detected autoantibodies to the PI-adrenoreceptorin the sera of patients with dilated cardiomyopathy.= Furthermore, they found that these autoantibodies exert a positive chronotropic effect on isolated myocytes.= This finding adds to the understanding of the role beta-blockers play in dilated cardiomyopathy and may explain otherwise unexplained tachycardia in some patients without demonstrable systolic dysfunction. Dilated cardiomyopathy is familial in roughly 20% of casesz5Caforio et a1 conducted an interesting study on autoimmunity in dilated cardiomyopathy using familial studies? He measured organ-specific antibodies (to atria and ventricles) in 342 asymptomatic relatives of cardiomyopathy patients. He found a much higher frequency of cardiac autoantibodies in relatives of cardiomyopathy patients than controls (20% versus 3.5%0,p = 0.0001). Interestingly, the antibody-positive relatives also had significantly larger ventricular end-systolic dimensions and lower fractional shortening as compared with antibody-negative relatives5 A number of parallels were drawn between dilated cardiomyopathy and another immunologic disorder, juvenile-onset diabetes mellitus. Both diseases share a male preponderance, HLA-DR4 association, a familial pattern in 15% to 20%, and end-organ-specific antibodies5 The absence of antibodies in many cardiomyopathy patients may indicate that this is an early marker that becomes indetectible as the disease progresses, similar to juvenile-onset diabetes.
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Prognosis
Spontaneous improvement has been described in up to 48% of patients with lymphocytic myocarditis.22Grogan et a1 compared the outcome of biopsy-proven myocarditis patients with biopsy-negative dilated cardiomyopathy patients.16 Five-year survival in the myocarditis group (56%)was not significantly different from the cardiomyopathy group (54%). It was concluded, therefore, that outcome is poor in either group. On an encouraging note, however, a recent study by Stephenson et a1 compared 1-year mortality in heart failure patients in the years 1986 through 1990 with the years after 1990.51The 1-year mortality rate dropped from 33% before 1989 to 16% after 1990 ( p = O.OOOl), with a similar fall in sudden death from 20% to 8% ( p = 0.0006). They attributed these improvements to the impact of therapeutic advances, including drugs such as captopril and amiodarone. Of note, this study included patients with heart failure and ejection fractions less than 40% due to all causes, not just dilated cardiomy~pathy.~~ Diagnosis of Lymphocytic Myocarditis
There are no typical electrocardiographic findings in myocarditis. Often, cardiac enzymes are normal in more chronic cases. Endomyocardial biopsy remains the technique of choice for diagnosing myocarditis, although it is fraught with shortcomings. Obtaining biopsy specimens is invasive and costly. The major complication is perforation-tamponade, with an incidence of 0.82Y~.~~ Myocarditis may be missed due to a sampling error if the inflammation is sparse or focal. The myocardial biopsy may already be negative for myocarditis if it is performed later than 3 to 4 weeks after symptom onset.= Importantly, the Myocarditis Treatment Trial (see later discussion) showed no benefit in treating biopsy-proven myocarditis with immunos~ppression.~~ Owing to the lack of proven therapy, therefore, endomyocardial biopsy is currently not clinically advocated in patients with presumed myocarditis. The exceptions, however, are patients with either suspected giant cell myocarditis, which mandates urgent immunosuppression and transplantation, and acute, fulminant inflammatory heart disease in the setting of cardiogenic The clinical presentation that would suggest either of these entities would be rapidly progressive heart failure, shock, or arrhythmias. The histologic criteria for myocarditis have been contentious, with a lack of consensus on the best criteria. With hematoxylin-eosin staining, there can be difficulty differentiating noninflammatory cells from infiltrating T lymphocyte^.^^ Kuhl et a1 compared the accuracy of light microscopy with immunohistology in detecting myocarditis in cardiomyopathy patients.27The Dallas criteria, which were developed for the Myocarditis Treatment Trial, were utilized in this study for light microscopic diagnosis. The Dallas criteria for myocarditis are "a process characterized by an inflammatory infiltrate of the myocardium with necrosis and/or degeneration of adjacent myocytes not typical of the ischemic damage associated with coronary artery disease"2 (Fig. 1).By the alternate immunohistologic criteria, the number of T lymphocytes in the entire biopsy specimen was counted under high power, with myocarditis defined as the mean number of lymphocytes (CD2, CD3) greater than 2.0 per high power field (6.0 per mm2).In their study, Kuhl et a1 diagnosed myocarditis in 5% of the cardiomyopathy patients using Dallas criteria; however, by immunohistology, myocarditis was found in 37% of the patients, indicating increased sensitivity of this technique in evaluating biopsy specimen^.^'
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Figure 1. Marked inflammatory myocardial cellular infiltration of lymphocytic myocarditis (hematoxylin-eosin,original magnification x 400).
Noninvasive techniques of diagnosing myocarditis remain under active investigation, with many failing to gain popularity due to low sensitivity or specificity. One of the more promising modalities in use is indium-lllantimyosin scanning. Carrio et a1 reported abnormal antimyosin scans in 11 of 16 patients with suspected myocarditis, with positive biopsies in only 4.7 Of note, there was considerable discordance between positive scans and negative biopsies; however, the usefulness of the scan may ultimately be as a screening test because normal scans were associated with a low rate of positive biopsies7 Treatment of Myocarditis
The landmark clinical trial in assessing the role of immunosuppression in myocarditis was recently reported by Mason et a1.36 In this study, 111 patients with biopsy-proven myocarditis were selected at random to undergo either conventional therapy alone or immunosuppression with prednisone plus either cyclosporine or azathioprine. At the 28-week follow-up, there was no significant difference in ejection fraction or survival between the two groups, arguing against the efficacy of immunosuppression in myocarditis. In view of the various stages of myocarditis, it seems prudent to tailor treatment to the underlying etiology in each stage. Specifically,immunosuppression may cause more harm than good during viral presence; however, it may be effective during the autoimmune phase of myocarditis. There is growing evidence in support of this In Coxsackie B-infected mice, mortality from myocardial lesions has been shown to increase due to FK506 but decrease due to antiviral treatment with gamma-interferon (IFN-gamma).47Similarly, other studies using the murine model substantiate the efficacy of antiviral therapy with ribavirin or interferon as long as the virus is
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Use of T-cell directed monoclonal antibodies is effective in preventing Coxsackie myocarditis in mice. This therapy does not suppress the neutralizing antibody formation that protects the host from virus entrance.Z2Conversely, prednisone or cyclosporine may cause the myocarditis to worsen in the viral stage due to inhibition of the neutralizing antibody. Clinically, diagnosing the specific stage of myocarditis (viral versus autoimmune) remains an enigma; however, there are many promising therapies on the horizon for the autoimmune stageA8 These include antigen-specific immunosuppression, blockade of antigen presentation at the level of class I1 MHC expression, and the development of "vaccines" specific for a particular T-cell receptor. It is possible that some day class I1 haplotype determination will be available to prognosticate which patients with viral myocarditis are at greatest risk for autoimmune seq ~ e l a eLastly, . ~ ~ interruption of the effector arm by use of monoclonal antibodies to cytokines is another area of research that shows great promise for the future in this devastating When myocarditis results in severe persistent or hemodynamically unstable heart failure, cardiac transplantation remains an option. Whether patients with myocarditis before transplantation have more rejection episodes than those without pretransplant myocarditis is still an unsettled issue. CARDIOMYOPATHIES ASSOCIATED WITH SYSTEMIC INFLAMMATORY DISEASES Systemic Lupus Erythematosus
Cardiac involvement has been reported in 18% to 38% of cases of systemic lupus erythematosus (SLE).31Cardiovascular involvement is the third leading cause of death in SLE.33Pericarditis is the most common manifestation, found ~ arteritis and occlusions are in 20% to 30% of patients with l u p ~ s . 3Coronary rare. Libman-Sacks endocarditis is reported in 13% to 74Yi3 Myocarditis is also infrequent; it is reported in less than 10% of the cases? Domenech et a1 reported that cardiomyopathy is more frequently found in lupus patients over 50 years 31 of age than in younger patients (13% versus 2%, respe~tively).'~~ There are isolated reports in patients with lupus of unusual causes of myocardial dysfunction as well. Dickens et a1 reported a fatal case of acute hemorrhagic myocarditis that resembled allograft hyperacute rejection.Iz Histologic sections of the heart revealed florid extravasation of erythrocytes into the interstitium separating the myocytes. The postulated etiology was thrombocytopenia and an immune-mediated angiopathic process. Another unusual presentation reported was calciphylaxis-induced cardiomyopathy in a lupus patient with chronic renal failure and secondary hyperparathyroidi~m.~~ Endomyocardial biopsy revealed intra- and extracellular myocardial calcification. It was believed that the patient's glucocorticoids may have served as promotors of the calciphylaxis. There are case reports of the usefulness of indium-111-antimyosin imaging to detect myocardial involvement in patients with This technique, however, is not without its limitations (as discussed earlier); the diagnosis is established by endomyocardial biopsy. Owing to the infrequency of myocarditis in individuals with lupus, reports on treatment are generally anecdotal. Disla et a1 described a poor response to steroids or cyclophosphamide in a patient who later recovered after immunoglobulin was added.13 There are other isolated, reports of favorable responses to steroids in SLE my0carditis.3~Overall, there is
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no consensus as to the best treatment of lupus myocarditis because. of its infrequency, but immunosuppression appears reasonable given the autoimmune nature of the underlying disease. Antiphospholipid Syndrome
Autoantibodies that react with phospholipids were initially reported in those with lupus but have subsequently been reported in other rheumatic disorders, malignancies, and viral infections, although they are more commonly found in otherwise healthy patients.z4These antibodies may be of the IgG, IgM, or IgA isotypes and include the lupus anticoagulant, anticardiolipin antibodies, and the biologic false-positive test for syphilis. Some of these antibodies are associated with an increased risk of venous or arterial thrombosis. Cardiomyopathies resulting from diffuse intramyocardial arteriolar occlusions have been reported in antiphospholipid syndr0me.2~Various mechanisms for the thrombotic events have been proposed, including blockade of prostacyclin by the antiphospholipid antibodies, direct activation of platelet membranes, inhibition of antithrombin I11 activity, and interference with protein C or S functi0n.2~Treatment includes administration of anticoagulants unless limited by severe thrombocytopenia. For those patients in whom thrombosis continues despite anticoagulation, immunosuppression can be considered in an attempt to suppress antiphospholipid antibody production, although there is no conclusive evidence for the efficacy of this approach. Systemic Sclerosis
Cardiac manifestations of progressive systemic sclerosis include myocardial disease, pulmonary hypertension, and pericardial disease. Myocardial fibrosis is present in the majority of patients at autopsy, but global systolic ventricular dysfunction with clinical symptoms is often absent? Advanced myocardial fibrosis has been found to cause diastolic restriction in some patients, confirmed by right heart catheterizati~n.~~ Myocardial contraction band necrosis occurs in nearly one third of patients with systemic sclerosis, perhaps due to ischemia from vasospasm followed by reperfusion? Arrhythmias also occur in systemic sclerosis and are related to fibrotic involvement of the conducting system and myocardium? Myocarditis is rare in systemic sclerosis and only sporadically reported. It is often associated with peripheral myositis and is usually seen early in the clinical course. Endomyocardial biopsy is needed to establish the diagnosis. Improvement in ventricular function has been reported following pulsed methylprednisolone. Still's Disease
Goldenberg et a1 reported a series of 172 patients with Still's disease.15 Symptomatic cardiac involvement occurred in 13 (7.6%) of the patients. Pericarditis was seen in 7 patients, perimyocarditis in 4, and myocarditis alone in 2. In the series, 5 of 172 children died. Four belonged to the group with cardiac manifestations, indicating poor prognosis in this subset. Empiric use of steroids for at least 3 months has been recommended.
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Polymyositis
Polymyositis is an inflammatory disease of unknown etiology involving skeletal muscles. Histologically it presents with muscle fiber necrosis, endomysial inflammatory infiltrates, and perivascular Antibodies to Cell-mediated myoglobin have been reported in this disease in 70% of immunity plays an important role in polymyositis, as evidenced through histologic studies showing macrophages and lymphocytes in perivascular areas and between muscle fibersz0 The myocardium is occasionally involved in polymyositis with symptoms of congestive heart failure. In a necropsy series by Denbow et al, 6 of 20 polymyositis patients exhibited active myocarditis, and 4 of these also had fibrosis." In this study, steroid treatment did not appear to influence the histopathology of myocarditis. Whipple's Disease
Whipple's disease is a rare systemic disorder caused by a recently identified intracellular bacillus, Tropkeyrna wkippelii. Lymphocytic myocarditis in this entity has been reported only twice." Of these, one patient died suddenly of an arrhythmia. An autopsy of the heart revealed compatibility with lymphocytic myocarditis owing to dense infiltration of the myocardial interstitium with lymphocytes mixed with some eosinophils. Giant Cell Myocarditis
Giant cell myocarditis was first described in 1905 by Saltikow as a myocarditis of unknown etiology characterized by widespread degeneration of myocardial fibers and the presence of multinucleated giant cells.37As compared with sarcoidosis, granulomata are not present, but eosinophils are commonly seen. It rarely has been recognized ante mortem in the past and requires endomyocardial biopsy for diagnosis. A wide variety of systemic diseases have been associated with giant cell myocarditis, including sarcoidosis, endocarditis, rheumatoid arthritis, Wegener's granulomatosis, Takayasu's arteritis, fungal infections, tuberculosis, syphilis, foreign body reaction, and drug hypersensitivity.'" An idiopathic form of giant cell myocarditis has been described that often coexists with autoimmune diseases and is rapidly fatal. Davidoff et a1 retrospectively compared the clinical course in 10 giant cell myocarditis patients (group I) with 36 lymphocytic myocarditis patients (group II).]" Four of the 10 patients with giant cell myocarditis had clinical findings consistent with sarcoidosis and a fifth had evidence of widespread Whipple's disease. Age, gender, and hemodynamics did not differ significantly between the two groups; however, ventricular tachycardia occurred in 90% of group I patients and only 25% of those in group I1 ( p = 0.007). Atrioventricular block requiring a pacemaker was also more common in group I than in group I1 (60% versus 8.3%, respectively). Left ventricular function declined in group I but improved in group 11. A greater proportion of patients in group I died or required transplantation (7 of 10 versus 11 of 36, p = 0.03). In the same study, 9 of the 10 patients with giant cell myocarditis received corticosteroid-based immunosuppression. There was a lack of clinical improvement, however, in 8
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of the 9 treated patients despite histologic evidence of partial or complete resolution. Cooper et a1 similarly described a small series of 5 patients with giant cell myocarditis? Despite immunosuppressive therapy with prednisone and azathioprine in all 5, progressive heart failure and ventricular arrhythmias developed in all. Three died rapidly while the surviving 2 underwent orthotopic heart transplantation. These two series underscore the malignant course in this disease, with its high frequency of arrhythmias and heart failure. Obtaining a biopsy specimen is essential to establish the diagnosis, with adequate sampling to avoid missing focal involvement. Given the dismal clinical course despite immunosuppression, urgent heart transplantation is the current treatment of choice. Of note, patients did not receive cyclosporine in Cooper’s series; it is possible that the addition of cyclosporine may be beneficial, as suggested by 0thers.4~
CONCLUSION In the past decade, advances in immunology have greatly added to our understanding of myocarditis. Therapy with empiric steroids has been categorically futile. Hopefully, more selective immunosuppressive therapies will yield better outcomes. Further research in basic immunology and molecular biology will likely lead to exciting future therapies targeted at the cellular level.
References 1. Ansari AA, Neckelmann B, Wang YC, et al: Immunologic dialogue between myocardial myocytes, endothelial cells, and mononuclear cells. Clin Immunol Immunopathol 68:208-214, 1993 2. Aretz HT, Billingham ME, Edwards WD, et al: Myocarditis: A histopathological definition and classification. Am J Cardiovasc Pathol 1 3 1 4 , 1987 3. Asherson RA, Ames D, Coltart J, et al: Hypertrophic cardiomyopathy in systemic lupus erythematosus and ”lupus-like” disease. J Rheumatol 19:1973-1977, 1992 4. Bulkley BH, Ridolfi RL, Salyer WR: Myocardial lesions of progressive systemic sclerosis: A cause of cardiac dysfunction. Circulation 53:483490, 1976 5. Caforio ALP, Keeling PJ, Zachara E, et al: Evidence from family studies for autoimmunity in dilated cardiomyopathy. Lancet 344:773-777, 1994 6. Cambridge G, MacArthur CGC, Waterson AP, et al: Antibodies to Coxsackie B viruses in congestive cardiomyopathy. Br Heart J 41:692496, 1979 7. Carrio I, Berna L, Ballester M, et al: Indium-111-antimyosin scintigraphy to assess myocardial damage in patients with suspected myocarditis and cardiac rejection. J Nucl Med 29:1893-1900, 1988 8. Clemson BS, Miller WR, Luck JC, et al: Acute myocarditis in fulminant systemic sclerosis. Chest 101:872-874, 1992 9. Cooper LT, Berry GJ, Rizeq M, et al: Giant cell myocarditis. J Heart Lung Transplant 14:394401, 1995 10. Davidoff R, Palacios I, Southern J, et al: Giant cell versus lymphocytic myocarditis: A comparison of their clinical features and long-term outcomes. Circulation 83:953-961, 1991 11. Denbow CE, Lie JT, Tancked RG: Cardiac involvement in polymyositis. Arthritis Rheum 221088-1092, 1979 12. Dickens P, Nicholls J, Lav C: Acute hemorrhagic myocarditis in systemic lupus erythematosus. Heart Vessels 7104-106. 1992
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13. Disla E, Rhim HR, Reddy A, et al: Reversible cardiogenic shock in a patient with lupus myocarditis. J Rheumatol202174, 1993 14. Domenech I, Aydintug 0, Cervera R, et a1 Systemic lupus erythematosus in 50-yearolds. Postgrad Med J 68:44044, 1992 15. Goldenberg J, Ferraz MB, Pessoa AP, et al: Symptomatic cardiac involvement in juvenile rheumatoid arthritis. Intern Jour Cardiol 3457-62, 1992 16. Grogan M, Redfield M, Bailey KR, et al: Long-term outcome of patients with biopsyproven myocarditis: Comparison with idiopathic dilated cardiomyopathy. J Am Coll Cardiol 26:80-84, 1995 17. Herskowitz A, Neumann DA, Ansari AA: Concepts of autoimmunity applied to idiopathic dilated cardiomyopathy. J Am Coll Cardiol 22:1385-1388, 1993 18. Herzum M, Maisch 8: Humoral and cellular immune reactions to the myocardium in myocarditis. Herz 17:91-96, 1992 19. Huber SA, Lodge PA: Coxsackie B-3 myocarditis in B alb/c mice: Evidence for autoimmunity to myocyte antigens. Am J Pathol 116:21-30, 1984 20. Hughes JT, Esiri MM: Ultrastructural studies in human polymyositis. J Neurol 5ci 25:347-357, 1975 21. James KB, Lee I, Thomas JD, et a1 Left ventricular diastolic dysfunction in lymphocytic myocarditis as assessed by Doppler echocardiography. Am J Cardiol 73:282-285, 1994 22. Jett GK, Miller A, Savino D, et al: Reversal of acute fulminant myocarditis with combined technology of OKT3 monoclonal antibody and mechanical circulatory support. J Heart Lung Transplant 11:73%738, 1992 23. Kandolf R, Klingel K, Zell R, et al: Molecular mechanisms in the pathogenesis of enteroviral heart disease: Acute and persistent infections. Clin Immunol Immunopathol 68:153-158, 1993 24. Kaplan SD, Chartash EK, Pizzarello RA, et al: Cardiac manifestations of the antiphospholipid syndrome. Am Heart J 1241331-1338, 1992 25. Karjalainen J: Clinical diagnoses of myocarditis and dilated cardiomyopathy. Scand J Infect Dis Suppl8833-43, 1993 26. Kishimoto C, Crumpacker CS, Abelmann WH: Ribavirin treatment of murine coxsackievirus B3 myocarditis with analyses of lymphocyte subsets. J Am Coll Cardiol12:13341341, 1988 27. Kiihl V, Seeberg B, Schultheiss HP, et a1 Immunohistological characterization of infiltrating lymphocytes in biopsies of patients with clinically suspected dilated cardiomyopathy. Eur Heart J 15:62-67, 1994 28. Lane JR, Neumann DA, Lafond-Walker A, et al: Interleukin 1 or tumor necrosis factor can promote coxsackie virus B-3-induced myocarditis in resistant B10 mice. J Exp Med 175:112%1129, 1992 29. Latif N, Baker CS, DUM MJ, et al: Frequency and specificity of antiheart antibodies in patients with dilated cardiomyopathy using SDS-PAGE and Western blotting. J Am Coll Cardiol 22:137&1384, 1993 30. Lodge PA, Herzum M, Huber SA. Coxsackie B-3 Acute and chronic forms of the disease by different immunopathogenic mechanisms. Am J Pathol 128:455-463, 1987 31. Logar D, Kveder T, Rozman B, et al: Possible association between anti-Ro antibodies and myocarditis or cardiac conduction defects in adults with systemic lupus erythematosus. Ann Rheum Dis 49:627-629, 1990 32. Maclean C, Brahn E Systemic lupus erythematosus: Calciphylaxis induced cardiomyopathy. J Rheumatol 22:177-179, 1995 33. Macro M, LeGangneux E, Gallet E, et al: Severe lupus with infectious thyroiditis and lethal cardiomyopathy. Clin Exp Rheumatol 13:99-102, 1995 34. Magnusson Y, Wallukat G, Waagstein F, et al: Autoimmunity in idiopathic dilated cardiomyopathy. Circulation 8932760-2767, 1994 35. Mason JW,OConnell J B Clinical merit of endomyocardial biopsy. Circulation 79:971979, 1989 36. Mason JW,OConnell JB, Herskowitz A, et al: A clinical trial of immunosuppressive therapy for myocarditis. N Engl J Med 333:269-275, 1995 37. McFalls EO, Hosenpud JD, McAnulty JR, et al: Granulomatous myocarditis: Diagnosis
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by endomyocardial biopsy and response to corticosteroids in 2 patients. Chest 89:509511, 1986 38. Mide MG, DeMert SH, Feldman A M Peripartum myocarditis and cardiomyopathy. Circulation 81:922-928, 1990 39. Morguet AJ, Sandrock D, Stille-Siegener M, et al: Indium-111-antimyosin Fab imaging to demonstrate myocardial involvement in systemic lupus erythematosus. J Nucl Med 361432-1435, 1995 40. Neu N, Rose NR, Beisel KW, et al: Cardiac myosin induces myocarditis in genetically predisposed mice. J Immunol 139:3630-3636, 1987 41. Neu N, Beisel KW, Traystman MD, et al: Autoantibodies specific for the cardiac myosin isoform are found in mice susceptible to Coxsackie 83 induced myocarditis. J Immun01 138:2488-2492, 1987 42. Nishikai M, Homma M. Circulating autoantibodies against human myoglobin in polymyositis. JAMA 2371842-1844, 1977 43. OConnell JB, Bristow MR Economic impact of heart failure in the United States: Time for a different approach. J Heart Lung Transplant 13:S107-S112,1993 44. Pelech T, Fric P, Huslarovk A, et al: Interstitial lymphocytic myocarditis in Whipple’s disease. Lancet 337553-554, 1991 45. Ren H, Poston RS, Hruban RH, et al: Long survival with giant cell myocarditis: Mod Pathol 6:402407,1993 46. Roelofs RI: Pathology of polymyositis/dermatomyositis.Mt Sinai J Med 55:453-458, 1988 47. Rose NR, Neumann DA, Herskowitz A Autoimmune myocarditis: Concepts and questions. Immunol Today 12253-255,1991 48. Rose NR, Herskowitz A, Neumann DA: Autoimmunity in myocarditis and cardiomyopathy: Models and mechanisms. Clin Immunol Immunopathol 68:95-99, 1993 49. Rose NR, Herskowitz A, Neuman DA, et al: Autoimmune myocarditis: A paradigm of post-infection autoimmune disease. Immunol Today 9:117-119, 1988 50. Seko Y, Ishiyama S, Nishikawa T, et al: Y: Restricted usage of T-cell receptor Va-VP genes in infiltrating cells in the hearts of patients with acute myocarditis and dilated cardiomyopathy. J Clin Invest 961035-1041,1995 51. Stevenson WG, Stevenson LW, Middlekauff HR, et al: Improving survival for patients with advanced heart failure: A study of 737 consecutive patients. J Am Coll Cardiol 26:1417-1423, 1995 52. Todesco S, Gatta A, Glorioso S Cardiac involvement in progressive systemic sclerosis. Acta Cardiol N311-322, 1979 53. Tracy S, Wiegand V, McManus B, et a1 Molecular approaches to enteroviral diagnosis in idiopathic cardiomyopathy and myocarditis. J Am Coll Cardiol 15:1688-1694, 1990
Address reprint requests to Karen B. James, MD Cleveland Clinic Foundation 9500 Euclid Avenue, F25 Cleveland, OH 44195
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INFLAMMATORY CARDIOMYOPATHY The Controversy of Diagnosis and Management Karen B. James, MD, Norman Ratliff, MD, Randall Starling, MD, and James B. Young, MD
Myocarditis and dilated cardiomyopathy can occur as isolated entities or in association with systemic inflammatory diseases. The. catastrophic results of a damaged myocardium include congestive heart failure, cardiogenic shock, and sudden arrhythmogenic death. Congestive heart failure remains one of the most prevalent and costly health problems in the United States. Over 3 million people in the United States are affected, with an estimated $8 billion per year spent in the treatment of heart failure.43It has become clear that determining heart failure etiology is extraordinarily important because many diseases can be effectively treated or, at least, ameliorated, with ensuing reduction in morbidity and mortality. Considerable controversy exists regarding lymphocytic myocarditis, including its etiology, immunology, diagnostic approach, and relationship to dilated cardiomyopathy. Often a diagnosis of myocarditis is rendered when patients present with cryptogenic heart failure and a peri-presentation "viral" syndrome. This observation raises the controversy of the relationship between inflammatory heart disease and heart failure. Etiology, diagnosis, and treatment options for this devastating illness and the surrounding debates are addressed. Lymphocytic myocarditis as an isolated disease is reviewed first, followed by myocarditis associated with systematic inflammatory illnesses.
From the Department of Cardiology (KBJ, RS, JBY), and Department of Pathology (NR), Cleveland Clinic Foundation, Cleveland, Ohio
RHEUMATIC DISEASE CLINICS OF NORTH AMERICA VOLUME 23 NUMBER 2 * MAY 1997
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LYMPHOCYTIC MYOCARDITIS Etiology and Immunology
Lymphocytic myocarditis, histologically, is characterized by infiltration of the myocardium by lymphocytes and macrophages adjacent to myocyte injury or necrosis. It is intuitive that these inflammatory cells are the culprits in causing cardiac cell injury that leads to necrosis. Clinically, left ventricular systolic function may remain normal or, more frequently, may be subclinically impaired, with subsequent development of symptoms of heart failure or arrhythmias. In acute myocarditis, myocardial edema and inflammation may alter the diastolic function as well.25Indeed, lymphocytic myocarditis has been shown to be a cause of restrictive cardiomyopathy by echocardiographic diastolic In 50% of myocarditis cases, a viral infection, usually upper respiratory or gastrointestinal, precedes symptomatic heart failure by 1 to 4 weeks.53Although a virus is rarely demonstrated in myocardium, there is indirect evidence implicating viral presence. Acute and convalescent antiviral titers may suggest antecedent viral infection.6 Furthermore, genes and proteins of many viruses have been demonstrated in myocytes. The most common viruses implicated in lymphocytic myocarditis include Coxsackie A and B, echo, influenza, polio, mumps, reovirus, adenovirus, Epstein-Barr, cytomegalovirus, and the HIV-1 virus.I8 It has been hypothesized that viral infection triggers an anticardiac immunologic response. Seko et a1 theorize that viral infection and subsequent host cytokine response elicit enhanced expression of HLA (human leukocyte antigen) and ICAM-1 (intercellular adhesion molecule-1) on m y o ~ y t e sT. ~cells ~ recognize virus-derived antigens and damaged virus-infected myocytes. Later, after viral genomes have dissipated, T cells recognize a different autoantigen and can cause ongoing myocyte damage. It appears that the pathogenic T-cell clones in early myocarditis are different from. those in the later stages.5O Research using the murine myocarditis model has paved a cornerstone in our understanding of this disease.l9*30, 40, 41 Susceptible strains of mice were infected with Coxsackie B virus. Two populations of antibodies developed in the mice. One population reacted with both skeletal and cardiac myosin, whereas the other population was specific for only the cardiac isoform. Immunization in uninfected mice with skeletal myosin failed to produce myocarditis, whereas immunization with cardiac myosin alone induced myo~arditis.'~, 30, 40, 41 Genetic susceptibility plays an important role in experimental myocarditis. Rose et a1 show that both major histocompatibility complex (MHC) genes and background non-MHC genes play a role in the susceptibility of different strains of mice to Coxsackie B %induced my0carditis.4~Other factors affecting susceptibility include age, gender, nutritional status, exercise-induced stress, drugs such as adriamycin, the occurrence of sequential viral infections, and pregnancy.38,48 Humoral
There is evidence implicating participation of both the humoral and cellular aspects of the immune system in lymphocytic myocarditis following the initial viral or other insult. Cross-reaction of antibodies to viral proteins with various microstructures of the myocyte has been reported.I8 Specific autoantigens described include sarcolemma, myosin, adenine nucleotide translocator (ANT), calcium channel, p-adrenoreceptor, intermediate filaments, matrix (collagen,
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laminin), branched chain alpha ketoacid dehydrogenase (BCKD) complex, and recently, heat shock (HSP)-60 molecule.'8,29 These antibodies are characterized according to IgM, IgG, or IgA isotypes.'8 Because most of the autoantigens reported are intracellular, it is difficult to envision how antibodies lead to myocyte damage. There are two possible explanations: (1) following initiation of the autoimmune response, antibodies to intracellular antigens cross-react with membrane cardiac proteins; (2) Alternately, following the initial insult, myocytes may present self-peptides, complexed with MHC molecules, that are then presented to T cell^.'^ Cellular
The response of T lymphocytes in myocarditis has been a subject of intense study as well. In acute myocarditis, the number of activated T lymphocytes has been found to be increased.18 Natural killer activity is reduced. Non-MHC restricted T-lymphocyte activity to the heart muscle is elevated. Response of suppressor T lymphocytes remains Cytokines have been shown to play a role in damaging the myocardium. Treatment of Coxsackie-infected mice with tumor necrosis factor-alpha or interleukin-1 beta has been shown to markedly exaggerate myocyte injury.28Blocking the effects of cytokines may pose one exciting future avenue for controlling the ravages of myocarditis. Dilated Cardiomyopathy
It remains unclear how often dilated cardiomyopathy is a sequela of lymphocytic myocarditis. Interestingly, Kandolf et a1 found that 8 of 47 (17%) patients with dilated cardiomyopathy showed positive in situ hybridization with a group-specific enterovirus probe.23On the other hand, Ansari et a1 reported an autoimmune response in a large proportion of dilated cardiomyopathy patients by measuring antibodies to ANT, BCKD, mitochondria1 antigen, myosin, and the P-adrenergic receptor.' Other investigators also have detected autoantibodies to the PI-adrenoreceptorin the sera of patients with dilated cardiomyopathy.= Furthermore, they found that these autoantibodies exert a positive chronotropic effect on isolated myocytes.= This finding adds to the understanding of the role beta-blockers play in dilated cardiomyopathy and may explain otherwise unexplained tachycardia in some patients without demonstrable systolic dysfunction. Dilated cardiomyopathy is familial in roughly 20% of casesz5Caforio et a1 conducted an interesting study on autoimmunity in dilated cardiomyopathy using familial studies? He measured organ-specific antibodies (to atria and ventricles) in 342 asymptomatic relatives of cardiomyopathy patients. He found a much higher frequency of cardiac autoantibodies in relatives of cardiomyopathy patients than controls (20% versus 3.5%0,p = 0.0001). Interestingly, the antibody-positive relatives also had significantly larger ventricular end-systolic dimensions and lower fractional shortening as compared with antibody-negative relatives5 A number of parallels were drawn between dilated cardiomyopathy and another immunologic disorder, juvenile-onset diabetes mellitus. Both diseases share a male preponderance, HLA-DR4 association, a familial pattern in 15% to 20%, and end-organ-specific antibodies5 The absence of antibodies in many cardiomyopathy patients may indicate that this is an early marker that becomes indetectible as the disease progresses, similar to juvenile-onset diabetes.
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Prognosis
Spontaneous improvement has been described in up to 48% of patients with lymphocytic myocarditis.22Grogan et a1 compared the outcome of biopsy-proven myocarditis patients with biopsy-negative dilated cardiomyopathy patients.16 Five-year survival in the myocarditis group (56%)was not significantly different from the cardiomyopathy group (54%). It was concluded, therefore, that outcome is poor in either group. On an encouraging note, however, a recent study by Stephenson et a1 compared 1-year mortality in heart failure patients in the years 1986 through 1990 with the years after 1990.51The 1-year mortality rate dropped from 33% before 1989 to 16% after 1990 ( p = O.OOOl), with a similar fall in sudden death from 20% to 8% ( p = 0.0006). They attributed these improvements to the impact of therapeutic advances, including drugs such as captopril and amiodarone. Of note, this study included patients with heart failure and ejection fractions less than 40% due to all causes, not just dilated cardiomy~pathy.~~ Diagnosis of Lymphocytic Myocarditis
There are no typical electrocardiographic findings in myocarditis. Often, cardiac enzymes are normal in more chronic cases. Endomyocardial biopsy remains the technique of choice for diagnosing myocarditis, although it is fraught with shortcomings. Obtaining biopsy specimens is invasive and costly. The major complication is perforation-tamponade, with an incidence of 0.82Y~.~~ Myocarditis may be missed due to a sampling error if the inflammation is sparse or focal. The myocardial biopsy may already be negative for myocarditis if it is performed later than 3 to 4 weeks after symptom onset.= Importantly, the Myocarditis Treatment Trial (see later discussion) showed no benefit in treating biopsy-proven myocarditis with immunos~ppression.~~ Owing to the lack of proven therapy, therefore, endomyocardial biopsy is currently not clinically advocated in patients with presumed myocarditis. The exceptions, however, are patients with either suspected giant cell myocarditis, which mandates urgent immunosuppression and transplantation, and acute, fulminant inflammatory heart disease in the setting of cardiogenic The clinical presentation that would suggest either of these entities would be rapidly progressive heart failure, shock, or arrhythmias. The histologic criteria for myocarditis have been contentious, with a lack of consensus on the best criteria. With hematoxylin-eosin staining, there can be difficulty differentiating noninflammatory cells from infiltrating T lymphocyte^.^^ Kuhl et a1 compared the accuracy of light microscopy with immunohistology in detecting myocarditis in cardiomyopathy patients.27The Dallas criteria, which were developed for the Myocarditis Treatment Trial, were utilized in this study for light microscopic diagnosis. The Dallas criteria for myocarditis are "a process characterized by an inflammatory infiltrate of the myocardium with necrosis and/or degeneration of adjacent myocytes not typical of the ischemic damage associated with coronary artery disease"2 (Fig. 1).By the alternate immunohistologic criteria, the number of T lymphocytes in the entire biopsy specimen was counted under high power, with myocarditis defined as the mean number of lymphocytes (CD2, CD3) greater than 2.0 per high power field (6.0 per mm2).In their study, Kuhl et a1 diagnosed myocarditis in 5% of the cardiomyopathy patients using Dallas criteria; however, by immunohistology, myocarditis was found in 37% of the patients, indicating increased sensitivity of this technique in evaluating biopsy specimen^.^'
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Figure 1. Marked inflammatory myocardial cellular infiltration of lymphocytic myocarditis (hematoxylin-eosin,original magnification x 400).
Noninvasive techniques of diagnosing myocarditis remain under active investigation, with many failing to gain popularity due to low sensitivity or specificity. One of the more promising modalities in use is indium-lllantimyosin scanning. Carrio et a1 reported abnormal antimyosin scans in 11 of 16 patients with suspected myocarditis, with positive biopsies in only 4.7 Of note, there was considerable discordance between positive scans and negative biopsies; however, the usefulness of the scan may ultimately be as a screening test because normal scans were associated with a low rate of positive biopsies7 Treatment of Myocarditis
The landmark clinical trial in assessing the role of immunosuppression in myocarditis was recently reported by Mason et a1.36 In this study, 111 patients with biopsy-proven myocarditis were selected at random to undergo either conventional therapy alone or immunosuppression with prednisone plus either cyclosporine or azathioprine. At the 28-week follow-up, there was no significant difference in ejection fraction or survival between the two groups, arguing against the efficacy of immunosuppression in myocarditis. In view of the various stages of myocarditis, it seems prudent to tailor treatment to the underlying etiology in each stage. Specifically,immunosuppression may cause more harm than good during viral presence; however, it may be effective during the autoimmune phase of myocarditis. There is growing evidence in support of this In Coxsackie B-infected mice, mortality from myocardial lesions has been shown to increase due to FK506 but decrease due to antiviral treatment with gamma-interferon (IFN-gamma).47Similarly, other studies using the murine model substantiate the efficacy of antiviral therapy with ribavirin or interferon as long as the virus is
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Use of T-cell directed monoclonal antibodies is effective in preventing Coxsackie myocarditis in mice. This therapy does not suppress the neutralizing antibody formation that protects the host from virus entrance.Z2Conversely, prednisone or cyclosporine may cause the myocarditis to worsen in the viral stage due to inhibition of the neutralizing antibody. Clinically, diagnosing the specific stage of myocarditis (viral versus autoimmune) remains an enigma; however, there are many promising therapies on the horizon for the autoimmune stageA8 These include antigen-specific immunosuppression, blockade of antigen presentation at the level of class I1 MHC expression, and the development of "vaccines" specific for a particular T-cell receptor. It is possible that some day class I1 haplotype determination will be available to prognosticate which patients with viral myocarditis are at greatest risk for autoimmune seq ~ e l a eLastly, . ~ ~ interruption of the effector arm by use of monoclonal antibodies to cytokines is another area of research that shows great promise for the future in this devastating When myocarditis results in severe persistent or hemodynamically unstable heart failure, cardiac transplantation remains an option. Whether patients with myocarditis before transplantation have more rejection episodes than those without pretransplant myocarditis is still an unsettled issue. CARDIOMYOPATHIES ASSOCIATED WITH SYSTEMIC INFLAMMATORY DISEASES Systemic Lupus Erythematosus
Cardiac involvement has been reported in 18% to 38% of cases of systemic lupus erythematosus (SLE).31Cardiovascular involvement is the third leading cause of death in SLE.33Pericarditis is the most common manifestation, found ~ arteritis and occlusions are in 20% to 30% of patients with l u p ~ s . 3Coronary rare. Libman-Sacks endocarditis is reported in 13% to 74Yi3 Myocarditis is also infrequent; it is reported in less than 10% of the cases? Domenech et a1 reported that cardiomyopathy is more frequently found in lupus patients over 50 years 31 of age than in younger patients (13% versus 2%, respe~tively).'~~ There are isolated reports in patients with lupus of unusual causes of myocardial dysfunction as well. Dickens et a1 reported a fatal case of acute hemorrhagic myocarditis that resembled allograft hyperacute rejection.Iz Histologic sections of the heart revealed florid extravasation of erythrocytes into the interstitium separating the myocytes. The postulated etiology was thrombocytopenia and an immune-mediated angiopathic process. Another unusual presentation reported was calciphylaxis-induced cardiomyopathy in a lupus patient with chronic renal failure and secondary hyperparathyroidi~m.~~ Endomyocardial biopsy revealed intra- and extracellular myocardial calcification. It was believed that the patient's glucocorticoids may have served as promotors of the calciphylaxis. There are case reports of the usefulness of indium-111-antimyosin imaging to detect myocardial involvement in patients with This technique, however, is not without its limitations (as discussed earlier); the diagnosis is established by endomyocardial biopsy. Owing to the infrequency of myocarditis in individuals with lupus, reports on treatment are generally anecdotal. Disla et a1 described a poor response to steroids or cyclophosphamide in a patient who later recovered after immunoglobulin was added.13 There are other isolated, reports of favorable responses to steroids in SLE my0carditis.3~Overall, there is
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no consensus as to the best treatment of lupus myocarditis because. of its infrequency, but immunosuppression appears reasonable given the autoimmune nature of the underlying disease. Antiphospholipid Syndrome
Autoantibodies that react with phospholipids were initially reported in those with lupus but have subsequently been reported in other rheumatic disorders, malignancies, and viral infections, although they are more commonly found in otherwise healthy patients.z4These antibodies may be of the IgG, IgM, or IgA isotypes and include the lupus anticoagulant, anticardiolipin antibodies, and the biologic false-positive test for syphilis. Some of these antibodies are associated with an increased risk of venous or arterial thrombosis. Cardiomyopathies resulting from diffuse intramyocardial arteriolar occlusions have been reported in antiphospholipid syndr0me.2~Various mechanisms for the thrombotic events have been proposed, including blockade of prostacyclin by the antiphospholipid antibodies, direct activation of platelet membranes, inhibition of antithrombin I11 activity, and interference with protein C or S functi0n.2~Treatment includes administration of anticoagulants unless limited by severe thrombocytopenia. For those patients in whom thrombosis continues despite anticoagulation, immunosuppression can be considered in an attempt to suppress antiphospholipid antibody production, although there is no conclusive evidence for the efficacy of this approach. Systemic Sclerosis
Cardiac manifestations of progressive systemic sclerosis include myocardial disease, pulmonary hypertension, and pericardial disease. Myocardial fibrosis is present in the majority of patients at autopsy, but global systolic ventricular dysfunction with clinical symptoms is often absent? Advanced myocardial fibrosis has been found to cause diastolic restriction in some patients, confirmed by right heart catheterizati~n.~~ Myocardial contraction band necrosis occurs in nearly one third of patients with systemic sclerosis, perhaps due to ischemia from vasospasm followed by reperfusion? Arrhythmias also occur in systemic sclerosis and are related to fibrotic involvement of the conducting system and myocardium? Myocarditis is rare in systemic sclerosis and only sporadically reported. It is often associated with peripheral myositis and is usually seen early in the clinical course. Endomyocardial biopsy is needed to establish the diagnosis. Improvement in ventricular function has been reported following pulsed methylprednisolone. Still's Disease
Goldenberg et a1 reported a series of 172 patients with Still's disease.15 Symptomatic cardiac involvement occurred in 13 (7.6%) of the patients. Pericarditis was seen in 7 patients, perimyocarditis in 4, and myocarditis alone in 2. In the series, 5 of 172 children died. Four belonged to the group with cardiac manifestations, indicating poor prognosis in this subset. Empiric use of steroids for at least 3 months has been recommended.
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Polymyositis
Polymyositis is an inflammatory disease of unknown etiology involving skeletal muscles. Histologically it presents with muscle fiber necrosis, endomysial inflammatory infiltrates, and perivascular Antibodies to Cell-mediated myoglobin have been reported in this disease in 70% of immunity plays an important role in polymyositis, as evidenced through histologic studies showing macrophages and lymphocytes in perivascular areas and between muscle fibersz0 The myocardium is occasionally involved in polymyositis with symptoms of congestive heart failure. In a necropsy series by Denbow et al, 6 of 20 polymyositis patients exhibited active myocarditis, and 4 of these also had fibrosis." In this study, steroid treatment did not appear to influence the histopathology of myocarditis. Whipple's Disease
Whipple's disease is a rare systemic disorder caused by a recently identified intracellular bacillus, Tropkeyrna wkippelii. Lymphocytic myocarditis in this entity has been reported only twice." Of these, one patient died suddenly of an arrhythmia. An autopsy of the heart revealed compatibility with lymphocytic myocarditis owing to dense infiltration of the myocardial interstitium with lymphocytes mixed with some eosinophils. Giant Cell Myocarditis
Giant cell myocarditis was first described in 1905 by Saltikow as a myocarditis of unknown etiology characterized by widespread degeneration of myocardial fibers and the presence of multinucleated giant cells.37As compared with sarcoidosis, granulomata are not present, but eosinophils are commonly seen. It rarely has been recognized ante mortem in the past and requires endomyocardial biopsy for diagnosis. A wide variety of systemic diseases have been associated with giant cell myocarditis, including sarcoidosis, endocarditis, rheumatoid arthritis, Wegener's granulomatosis, Takayasu's arteritis, fungal infections, tuberculosis, syphilis, foreign body reaction, and drug hypersensitivity.'" An idiopathic form of giant cell myocarditis has been described that often coexists with autoimmune diseases and is rapidly fatal. Davidoff et a1 retrospectively compared the clinical course in 10 giant cell myocarditis patients (group I) with 36 lymphocytic myocarditis patients (group II).]" Four of the 10 patients with giant cell myocarditis had clinical findings consistent with sarcoidosis and a fifth had evidence of widespread Whipple's disease. Age, gender, and hemodynamics did not differ significantly between the two groups; however, ventricular tachycardia occurred in 90% of group I patients and only 25% of those in group I1 ( p = 0.007). Atrioventricular block requiring a pacemaker was also more common in group I than in group I1 (60% versus 8.3%, respectively). Left ventricular function declined in group I but improved in group 11. A greater proportion of patients in group I died or required transplantation (7 of 10 versus 11 of 36, p = 0.03). In the same study, 9 of the 10 patients with giant cell myocarditis received corticosteroid-based immunosuppression. There was a lack of clinical improvement, however, in 8
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of the 9 treated patients despite histologic evidence of partial or complete resolution. Cooper et a1 similarly described a small series of 5 patients with giant cell myocarditis? Despite immunosuppressive therapy with prednisone and azathioprine in all 5, progressive heart failure and ventricular arrhythmias developed in all. Three died rapidly while the surviving 2 underwent orthotopic heart transplantation. These two series underscore the malignant course in this disease, with its high frequency of arrhythmias and heart failure. Obtaining a biopsy specimen is essential to establish the diagnosis, with adequate sampling to avoid missing focal involvement. Given the dismal clinical course despite immunosuppression, urgent heart transplantation is the current treatment of choice. Of note, patients did not receive cyclosporine in Cooper’s series; it is possible that the addition of cyclosporine may be beneficial, as suggested by 0thers.4~
CONCLUSION In the past decade, advances in immunology have greatly added to our understanding of myocarditis. Therapy with empiric steroids has been categorically futile. Hopefully, more selective immunosuppressive therapies will yield better outcomes. Further research in basic immunology and molecular biology will likely lead to exciting future therapies targeted at the cellular level.
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13. Disla E, Rhim HR, Reddy A, et al: Reversible cardiogenic shock in a patient with lupus myocarditis. J Rheumatol202174, 1993 14. Domenech I, Aydintug 0, Cervera R, et a1 Systemic lupus erythematosus in 50-yearolds. Postgrad Med J 68:44044, 1992 15. Goldenberg J, Ferraz MB, Pessoa AP, et al: Symptomatic cardiac involvement in juvenile rheumatoid arthritis. Intern Jour Cardiol 3457-62, 1992 16. Grogan M, Redfield M, Bailey KR, et al: Long-term outcome of patients with biopsyproven myocarditis: Comparison with idiopathic dilated cardiomyopathy. J Am Coll Cardiol 26:80-84, 1995 17. Herskowitz A, Neumann DA, Ansari AA: Concepts of autoimmunity applied to idiopathic dilated cardiomyopathy. J Am Coll Cardiol 22:1385-1388, 1993 18. Herzum M, Maisch 8: Humoral and cellular immune reactions to the myocardium in myocarditis. Herz 17:91-96, 1992 19. Huber SA, Lodge PA: Coxsackie B-3 myocarditis in B alb/c mice: Evidence for autoimmunity to myocyte antigens. Am J Pathol 116:21-30, 1984 20. Hughes JT, Esiri MM: Ultrastructural studies in human polymyositis. J Neurol 5ci 25:347-357, 1975 21. James KB, Lee I, Thomas JD, et a1 Left ventricular diastolic dysfunction in lymphocytic myocarditis as assessed by Doppler echocardiography. Am J Cardiol 73:282-285, 1994 22. Jett GK, Miller A, Savino D, et al: Reversal of acute fulminant myocarditis with combined technology of OKT3 monoclonal antibody and mechanical circulatory support. J Heart Lung Transplant 11:73%738, 1992 23. Kandolf R, Klingel K, Zell R, et al: Molecular mechanisms in the pathogenesis of enteroviral heart disease: Acute and persistent infections. Clin Immunol Immunopathol 68:153-158, 1993 24. Kaplan SD, Chartash EK, Pizzarello RA, et al: Cardiac manifestations of the antiphospholipid syndrome. Am Heart J 1241331-1338, 1992 25. Karjalainen J: Clinical diagnoses of myocarditis and dilated cardiomyopathy. Scand J Infect Dis Suppl8833-43, 1993 26. Kishimoto C, Crumpacker CS, Abelmann WH: Ribavirin treatment of murine coxsackievirus B3 myocarditis with analyses of lymphocyte subsets. J Am Coll Cardiol12:13341341, 1988 27. Kiihl V, Seeberg B, Schultheiss HP, et a1 Immunohistological characterization of infiltrating lymphocytes in biopsies of patients with clinically suspected dilated cardiomyopathy. Eur Heart J 15:62-67, 1994 28. Lane JR, Neumann DA, Lafond-Walker A, et al: Interleukin 1 or tumor necrosis factor can promote coxsackie virus B-3-induced myocarditis in resistant B10 mice. J Exp Med 175:112%1129, 1992 29. Latif N, Baker CS, DUM MJ, et al: Frequency and specificity of antiheart antibodies in patients with dilated cardiomyopathy using SDS-PAGE and Western blotting. J Am Coll Cardiol 22:137&1384, 1993 30. Lodge PA, Herzum M, Huber SA. Coxsackie B-3 Acute and chronic forms of the disease by different immunopathogenic mechanisms. Am J Pathol 128:455-463, 1987 31. Logar D, Kveder T, Rozman B, et al: Possible association between anti-Ro antibodies and myocarditis or cardiac conduction defects in adults with systemic lupus erythematosus. Ann Rheum Dis 49:627-629, 1990 32. Maclean C, Brahn E Systemic lupus erythematosus: Calciphylaxis induced cardiomyopathy. J Rheumatol 22:177-179, 1995 33. Macro M, LeGangneux E, Gallet E, et al: Severe lupus with infectious thyroiditis and lethal cardiomyopathy. Clin Exp Rheumatol 13:99-102, 1995 34. Magnusson Y, Wallukat G, Waagstein F, et al: Autoimmunity in idiopathic dilated cardiomyopathy. Circulation 8932760-2767, 1994 35. Mason JW,OConnell J B Clinical merit of endomyocardial biopsy. Circulation 79:971979, 1989 36. Mason JW,OConnell JB, Herskowitz A, et al: A clinical trial of immunosuppressive therapy for myocarditis. N Engl J Med 333:269-275, 1995 37. McFalls EO, Hosenpud JD, McAnulty JR, et al: Granulomatous myocarditis: Diagnosis
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by endomyocardial biopsy and response to corticosteroids in 2 patients. Chest 89:509511, 1986 38. Mide MG, DeMert SH, Feldman A M Peripartum myocarditis and cardiomyopathy. Circulation 81:922-928, 1990 39. Morguet AJ, Sandrock D, Stille-Siegener M, et al: Indium-111-antimyosin Fab imaging to demonstrate myocardial involvement in systemic lupus erythematosus. J Nucl Med 361432-1435, 1995 40. Neu N, Rose NR, Beisel KW, et al: Cardiac myosin induces myocarditis in genetically predisposed mice. J Immunol 139:3630-3636, 1987 41. Neu N, Beisel KW, Traystman MD, et al: Autoantibodies specific for the cardiac myosin isoform are found in mice susceptible to Coxsackie 83 induced myocarditis. J Immun01 138:2488-2492, 1987 42. Nishikai M, Homma M. Circulating autoantibodies against human myoglobin in polymyositis. JAMA 2371842-1844, 1977 43. OConnell JB, Bristow MR Economic impact of heart failure in the United States: Time for a different approach. J Heart Lung Transplant 13:S107-S112,1993 44. Pelech T, Fric P, Huslarovk A, et al: Interstitial lymphocytic myocarditis in Whipple’s disease. Lancet 337553-554, 1991 45. Ren H, Poston RS, Hruban RH, et al: Long survival with giant cell myocarditis: Mod Pathol 6:402407,1993 46. Roelofs RI: Pathology of polymyositis/dermatomyositis.Mt Sinai J Med 55:453-458, 1988 47. Rose NR, Neumann DA, Herskowitz A Autoimmune myocarditis: Concepts and questions. Immunol Today 12253-255,1991 48. Rose NR, Herskowitz A, Neumann DA: Autoimmunity in myocarditis and cardiomyopathy: Models and mechanisms. Clin Immunol Immunopathol 68:95-99, 1993 49. Rose NR, Herskowitz A, Neuman DA, et al: Autoimmune myocarditis: A paradigm of post-infection autoimmune disease. Immunol Today 9:117-119, 1988 50. Seko Y, Ishiyama S, Nishikawa T, et al: Y: Restricted usage of T-cell receptor Va-VP genes in infiltrating cells in the hearts of patients with acute myocarditis and dilated cardiomyopathy. J Clin Invest 961035-1041,1995 51. Stevenson WG, Stevenson LW, Middlekauff HR, et al: Improving survival for patients with advanced heart failure: A study of 737 consecutive patients. J Am Coll Cardiol 26:1417-1423, 1995 52. Todesco S, Gatta A, Glorioso S Cardiac involvement in progressive systemic sclerosis. Acta Cardiol N311-322, 1979 53. Tracy S, Wiegand V, McManus B, et a1 Molecular approaches to enteroviral diagnosis in idiopathic cardiomyopathy and myocarditis. J Am Coll Cardiol 15:1688-1694, 1990
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