CLINICAL STUDIES
Antimyosin autoantibodies are associated with deterioration of systolic and diastolic left ventricular function in patients with chronic myocarditis
Bernward Lauer, MD*,
Mira Schannwell, MD ,
Uwe Kühl, MD ,
Bodo-Eckhard Strauer, MD and
Heinz-Peter Schultheiss, MD
* Klinik für Innere Medizin/Kardiologie, Universität Leipzig-Herzzentrum, Leipzig, Germany
Medizinische Klinik und Poliklinik B, Heinrich-Heine-Universität, Düsseldorf, Germany
Abteilung für Kardiologie, Pneumologie und Angiologie, Universitätsklinikum Benjamin Franklin, Berlin, Germany
Manuscript received January 8, 1999;
revised manuscript received September 3, 1999,
accepted September 13, 1999.
Reprint requests and correspondence: Dr. Bernward Lauer, Klinik für Innere Medizin/Kardiologie, Universität Leipzig—Herzzentrum GmbH, Russenstr. 19, D-04289 Leipzig, Germany
laub{at}server3.medizin.uni-leipzig.de
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Abstract
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OBJECTIVES
The study evaluates the clinical course and the development of systolic and diastolic left ventricular function in patients with chronic myocarditis with or without autoantibodies against cardiac myosin.
BACKGROUND
Patients with myocarditis often show autoantibodies against cardiac myosin. The clinical and pathophysiologic significance of these antimyosin autoantibodies (AMAAB) is yet unknown. The results from studies comparing the clinical course and the development of left ventricular function in patients with chronic myocarditis with or without AMAAB are not yet available.
METHODS
Thirty-three patients with biopsy proven chronic myocarditis underwent analysis of AMAAB, right and left heart catheterization and left ventriculography at baseline and after six months. Left ventricular volumes and ejection fraction as well as the time constant of left ventricular relaxation "tau" and the constant of myocardial stiffness "b" were determined at baseline and at follow-up.
RESULTS
In 17 (52%) patients, AMAAB could be detected at baseline. After six months, AMAAB were still found in 13 (76%) initially antibody-positive patients. No initially antibody-negative (n = 16) patient developed AMAAB during follow-up. Clinical symptoms improved slightly in antibody-negative patients and remained stable in antibody-positive patients. Left ventricular ejection fraction developed significantly better in antibody-negative patients (+8.9 ± 10.1%) compared with antibody-positive patients (–0.1 ± 9.4%) (p < 0.012). Stroke volume (SV) and stroke volume index (SVI) also improved in antibody-negative patients (SV: +20 ± 31 ml; SVI: +10 ± 17 ml) compared with antibody-positive patients (SV: –14 ± 43 ml; SVI: –8 ± 22 ml) (SV: p < 0.015; SVI: p < 0.016). Left ventricular end-diastolic and end-systolic volumes and the time constant of left ventricular relaxation "tau" did not change significantly different in antibody-positive and antibody-negative patients. The constant of myocardial stiffness "b" improved significantly in antibody-negative patients (–6.1 ± 10.8) compared with antibody-positive patients (+7.3 ± 22.6) (p < 0.040). Analyzing only the persistently antibody-positive patients yielded essentially the same results.
CONCLUSIONS
Antimyosin autoantibodies are associated with worse development of left ventricular systolic function and diastolic stiffness in patients with chronic myocarditis.
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Abbreviations and Acronyms
| | AMAAB | = antimyosin autoantibodies | | AMAAB(+) | = antimyosin autoantibody-positive | | AMAAB(–) | = antimyosin autoantibody-negative | | EDV | = end-diastolic volume | | EDVI | = end-diastolic volume index | | EF | = ejection fraction | | ELISA | = enzyme-linked immunosorbent assay | | ESV | = end-systolic volume | | ESVI | = end-systolic volume index | | LVEDP | = left ventricular end diastolic pressure | | MHC | = major histocompatibility antigens | | NYHA | = New York Heart Association | | RNA | = ribonucleic acid | | SV | = stroke volume | | SVI | = stroke volume index |
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Currently, most cases of human myocarditis are thought to be of viral origin (1–5). Viral ribonucleic acid (RNA) has been detected in the myocardium of patients with myocarditis and dilated cardiomyopathy (6–8). Although the exact pathogenetic mechanisms are only vaguely understood, an increasing body of evidence suggests that in the course of myocarditis, autoimmunological mechanisms may play an important role (9). Several autoantibodies against human cardiac antigens have been identified in patients with myocarditis and dilated cardiomyopathy (10–14), including cardiac myosin (15,16). In vitro studies disclosed several possible pathogenetic mechanisms by which autoantibodies against cardiac antigens may influence cardiac function (17), but only a few clinical studies have investigated the impact of anticardiac autoantibodies on clinical course and functional parameters of the patients (18,19). In patients with dilated cardiomyopathy, antimyosin autoantibodies (AMAAB) become undetectable in about 50% of the patients after one year (18). In this study, persistence of AMAAB was associated with stable clinical conditions. To our knowledge, no studies are available that have investigated the impact of AMAAB on clinical outcome and changes of left ventricular function in patients with myocarditis.
Therefore, this study investigates the association of AMAAB with the clinical course and changes in left ventricular systolic and diastolic function in patients with chronic myocarditis.
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Methods
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Patients.
Thirty-three patients with chronic myocarditis (20 men, 13 women, 47.4 ± 12.7 years) were included in the study. Clinical symptoms of the patients at the time of presentation were systolic left ventricular dysfunction in 23 patients, angina pectoris in 7 patients, new rhythm disturbances in 6 patients and signs of congestive heart failure with preserved systolic left ventricular function suggesting diastolic dysfunction in 2 patients. All patients presented initially within six months of onset of symptoms. Eleven patients reported the presence of symptoms of upper respiratory tract infections or gastrointestinal symptoms before clinical presentation.
All patients underwent right and left heart catheterization including left ventriculography and right ventricular endomyocardial biopsy. Coronary artery disease was excluded in all patients by coronary angiography. Sera of all patients were analyzed for the presence of AMAABs. Myocarditis was diagnosed by histological and immunohistological analysis of endomyocardial biopsy specimen. Nineteen (58%) patients were treated with angiotensin-converting enzyme inhibitors, 21 (64%) patients with diuretics, 16 patients (45%) with digitalis, 8 (24%) patients with beta-adrenergic blocking agents, 16 (45%) patients with anticoagulants and 7 (21%) with antiarrythmic agents. No patient did receive specific, i.e., immunosuppressive, therapy. The diagnosis of chronic myocarditis was established in all patients by histologic or immunohistologic criteria in a second endomyocardial biopsy after six months, when right and left heart catheterization, left ventriculography and assessment of AMAAB were repeated.
Analysis of endomyocardial biopsy specimen.
Endomyocardial biopsies were taken transvenously via the femoral approach from the right heart side of the interventricular septum. The endomyocardial biopsies were examined histologically according to the "Dallas Criteria" (20). The histological sections were analyzed by light microscopy for evidence of myocardial necrosis, interstitial fibrosis and for the presence of lymphocytic infiltrates. Because the histological evaluation of myocardial biopsies is known to be difficult and affected by many problems (21,22) including high interobserver variability (23) and sampling error (24), this technique is regarded as rather insensitive for the diagnosis of myocarditis (25). Therefore, the biopsy specimens were examined additionally with immunohistological techniques. Monoclonal antibodies directed against surface antigens of human lymphocytes (CD3, CD4, CD8) were used to detect and quantitate lymphocytic infiltrates in the myocardium (26–29). Additionally, using antibodies against the major histocompatibility antigens (MHC), the expression of MHC I and II antigens was analyzed. With these techniques, the diagnostic accuracy in the biopsies could be increased (30) and the interobserver variability could be minimized (31,32).
The biopsy specimens were classified as "acute myocarditis" when histological sections of endomyocardial biopsies revealed lymphocytic infiltrates in the neighborhood of myocardial necrosis (20). "Borderline myocarditis" was diagnosed when lymphocytic infiltrates were present in histological sections without myocyte necrosis (20) (Fig. 1A). When the immunohistological analysis revealed pathologically increased lymphocytic infiltrates (>2.0 lymphocytes/high power field [32]) and an increased expression of MHC I and II antigens, the biopsy was classified as "lymphocytic myocarditis" (Fig. 1B).
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Figure 1 Representative histologic and immunohistologic pictures of biopsy specimen from patients with myocarditis. A: histology (borderline myocarditis). B: immunohistology (lymphocytic myocarditis).
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The diagnosis of "chronic myocarditis" was based on the histological or immunohistological detection of lymphocytic infiltrates in the myocardium in the second biopsy six months after the initial evaluation.
Analysis of antimyosin autoantibodies.
Sera of patients with myocarditis were analyzed for the presence of AMAAB as previously described (15). Sera were taken on admission of the patients and immediately stored at –70°C. Analysis of AMAAB was done in batches. Human cardiac myosin was prepared according to Offer et al. (33) and modified after Lompré et al. (34). Serum samples of patients were incubated on enzyme-linked immunosorbent assay (ELISA) microtiter plates with human cardiac myosin as antigen. After removal of the serum, bound antibodies were visualized with peroxidase-labeled goat antihuman IgG (Fa. Sigma, St. Louis, Missouri). Extinction was read at 492 nm in an automated ELISA reader. Specificity of the antibody binding to human cardiac myosin was checked by Western-blot analysis.
Hemodynamic measurements.
Left ventricular function was measured by biplane left ventriculography in 30° right anterior oblique and 60° left anterior oblique projections and left ventricular pressures were recorded simultaneously by use of a micromanometer in the left ventricle. Left ventriculograms were recorded at 25 frames/s. Each left ventricular frame was digitized by use of an electronic "digitizer" (Numonics Corp., Montgomeryville, Pennsylvania) and corrected for magnification by use of a reference grid. Left ventricular volumes were calculated using the "area-length-method" (35). Left ventricular pressures were plotted on a Versatec Printer-Plotter in 5 ms intervals with a paper speed of 100 mm/s. The time constant of diastolic relaxation tau was measured according to Raff and Glantz (36). The constant of diastolic stiffness was calculated using a monoexponential model with variable asymptote (37–39).
Statistical analysis.
Variables were analyzed by Mann-Whitney U test (two-sided). P values <0.05 were considered to indicate statistical significance.
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Results
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Histological and immunohistological analysis of endomyocardial biopsies in patients with chronic myocarditis.
The findings in the endomyocardial biopsies are shown in Figure 2. At baseline, no patient showed histological evidence of myocytolysis. "Borderline myocarditis" was diagnosed at baseline in six patients, additional immunohistological analysis demonstrated "lymphocytic myocarditis" in all 33 patients. Evidence of interstitial fibrosis was present in eight patients; the degree of fibrosis was not quantitated in the small biopsy specimen.
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Figure 2 Histological and immunohistological analysis of the endomyocardial biopsies in 33 patients with chronic myocarditis at baseline and at follow-up (six months). Acute MC = acute myocarditis (histology); bord MC = borderline myocarditis (histology); lymph MC = lymphocytic myocarditis (immunohistology); no MC = no myocarditis (histology or immunohistology).
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After six months, the endomyocardial biopsy disclosed evidence of chronic myocarditis in all patients. Histologically, no patient had "acute myocarditis"; "borderline myocarditis" was diagnosed in 10 patients and "lymphocytic myocarditis" was demonstrated immunohistologically in 31 patients. Evidence of fibrosis was detected in 10 patients; in 3 of these patients, it was already present at baseline, and in 7 patients fibrosis was not detectable at baseline.
AMAAB in patients with chronic myocarditis.
At baseline, AMAAB were found in 17 (52%) patients (Fig. 3). After six months AMAAB were still detectable in 13/17 (76%) initially antimyosin-autoantibody positive (AMAAB[+]) patients. In 4/17 (24%) initially AMAAB(+) patients, no AMAAB could be detected after six months. Sixteen (48%) patients were initially antimyosin-autoantibody negative (AMAAB[–]). After six months, all 16 patients had remained AMAAB(–); no patient had developed AMAAB.
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Figure 3 Antimyosin autoantibodies in patients with chronic myocarditis at baseline and at follow-up (six months). AMAAB = antimyosin autoantibodies.
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Impact of AMAAB at baseline on clinical symptoms and changes of systolic and diastolic left ventricular function.
After six months, two initially AMAAB(+) patients reported moderate clinical improvement of symptoms (New York Heart Association [NYHA] class), two initially AMAAB(+) patients reported moderate deterioration of symptoms (1 NYHA class), whereas six initially AMAAB(–) patients reported moderate improvement of clinical symptoms (1 NYHA class) and no initially AMAAB(–) patient reported clinical deterioration. Severity of myocardial invasion by lymphocytic cells was not different between AMAAB(+) and AMAAB(–) patients [AMAAB(+): 2.6 ± 1.3, lymphocytes/high power field, AMAAB(–): 2.6 ± 1.1 lymphocytes/high power field). Parameters of systolic and diastolic left ventricular function at baseline and after six months of 17 AMAAB(+) and 16 AMAAB(–) patients are shown in Table 1. After six months left ventricular ejection fraction (EF) as well as stroke volume (SV) and stroke volume index (SVI) had significantly improved in AMAAB(–) patients compared with AMAAB(+) patients (EF: p < 0.028, SV: p < 0.019, SVI: p < 0.025). The changes of end-diastolic volume (EDV), end-diastolic volume index (EDVI), end-systolic volume (ESV) and end-systolic volume index (ESVI) were not different between AMAAB(+) and AMAAB(–) patients. Preload (left ventricular end diastolic pressure [LVEDP]) and afterload (systolic arterial pressure) of the left ventricle were not different at baseline between AMAAB(+) and AMAAB(–) patients and did not change during the study in both groups. The development of the constant of diastolic stiffness "b" was better in AMAAB(–) patients compared with AMAAB(+) patients (p < 0.068). The change in the time constant of diastolic relaxation "tau" was not different between AMAAB(+) and AMAAB(–) patients. Right atrial pressure was not different between the study groups throughout the study.
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Table 1 Systolic and Diastolic Left Ventricular Function at Baseline and After Six Months of Initially AMAAB(+) (n = 17) and Initially AMAAB(–) (n = 16) Patients With Chronic Myocarditis
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Seventeen patients had impaired systolic left ventricular function (EF < 50%) at baseline, 8 of these patients were AMAAB(+), 9 patients were AMAAB(–). Severity of myocardial invasion by lymphocytic cells was not different between the two groups (AMAAB[+]: 2.3 ± 1.4 lymphocytes/high power field, AMAAB[–]: 2.6 ± 1.2 lymphocytes/high power field). Parameters of left ventricular systolic and diastolic function of AMAAB(+) and AMAAB(–) patients with impaired left ventricular function at baseline are given in Table 2. Ejection fraction in AMAAB(–) patients with impaired left ventricular function had improved after six months and slightly deteriorated in AMAAB(+) patients with impaired left ventricular function (p < 0.021). The difference in change of SV and SVI did not reach statistical significance. Changes in EDV, EDVI, ESV and ESVI were not different between AMAAB(+) and AMAAB(–) patients. Diastolic stiffness improved significantly in AMAAB(–) patients compared with AMAAB(+) patients (p < 0.036). Changes in "tau" were not different between AMAAB(+) and AMAAB(–) patients.
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Table 2 Systolic and Diastolic Left Ventricular Function at Baseline and After Six Months of Initially AMAAB(+) (n = 8) and Initially AMAAB(–) (n = 9) Patients With Chronic Myocarditis With Impaired Left Ventricular Function at Baseline (EF < 50%)
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Impact of persistence of AMAAB at follow-up (six months) on clinical symptoms and changes of systolic and diastolic left ventricular function.
Thirteen of 17 initially AMAAB(+) patients demonstrated persistence of AMAAB after six months; all initially AMAAB(–) patients were still AMAAB(–) at follow-up. Two persistently AMAAB(+) patients reported moderate clinical improvement of symptoms (1 NYHA class), two persistently AMAAB(+) patients reported moderate deterioration of symptoms (1 NYHA class). Six persistently AMAAB(–) patients reported moderate improvement of clinical symptoms (1 NYHA class), no persistently AMAAB(–) patient reported clinical deterioration. Severity of myocardial invasion by lymphocytic cells was not different between persistently AMAAB(+) and persistently AMAAB(–) patients (AMAAB[+]: 2.5 ± 1.3 lymphocytes/high power field, AMAAB[–]: 2.6 ± 1.1 lymphocytes/high power field). Parameters of left ventricular systolic and diastolic function of persistently AMAAB(+) or persistently AMAAB(–) patients are shown in Table 3. Ejection fraction had improved significantly after six months in persistently AMAAB(–) patients compared with persistently AMAAB(+) patients (p < 0.028). The difference in change of SV and SVI did not reach statistical significance. Changes of EDV, EDVI, ESV and ESVI were not different between the two groups. The change in diastolic stiffness "b" was significantly better in persistently AMAAB(–) patients than in persistently AMAAB(+) patients (p < 0.017), whereas the change in the time constant of diastolic relaxation tau was not different between the two groups. Seven persistently AMAAB(+) patients and nine persistently AMAAB(–) patients had impaired systolic left ventricular function (EF <50%) at baseline. Severity of myocardial invasion by lymphocytic cells was not different between the two groups (AMAAB[+]: 2.2 ± 1.0 lymphocytes/high power field, AMAAB[–]: 2.6 ± 1.2 lymphocytes/high power field). Parameters of left ventricular systolic and diastolic function in these patients are given in Table 4. Ejection fraction had improved after six months in persistently AMAAB(–) patients with impaired left ventricular function compared with persistently AMAAB(+) patients with impaired left ventricular function (p < 0.042). The difference in change of SV and SVI did not reach statistical significance. Changes in EDV, EDVI, ESV and ESVI were not different between the study groups. Diastolic stiffness improved significantly in AMAAB(–) patients compared with AMAAB(+) patients (p < 0.005). Changes in "tau" were not different between the two groups.
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Table 3 Systolic and Diastolic Left Ventricular Function at Baseline and After Six Months of Persistently AMAAB(+) (n = 13) and Persistently AMAAB(–) (n = 16) Patients With Chronic Myocarditis
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Table 4 Systolic and Diastolic Left Ventricular Function at Baseline and After Six Months of Persistently AMAAB(+) (n = 7) and Persistently AMAAB(–) (n = 9) Patients With Chronic Myocarditis With Impaired Left Ventricular Function at Baseline (EF < 50%)
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Discussion
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Autoantibodies against cardiac myosin have been found in patients with myocarditis (15) and dilated cardiomyopathy (16). These AMAAB are directed against alpha- and beta-cardiac myosin heavy chains (16). At the time of diagnosis, these autoantibodies are not associated with specific clinical or diagnostic features (15,40). In patients with dilated cardiomyopathy, 52% of the patients who showed AMAAB at baseline, became antibody negative after one year and no initially antibody-negative patient became antibody-positive at follow-up (18). This is in concordance with this study where 22% of the initially AMAAB(+) patients with myocarditis had lost their autoantibodies after six months and no initially antibody-negative patient had developed AMAAB at follow-up.
AMAAB and left ventricular function.
This study is the first report that evaluates the time course of systolic and diastolic left ventricular function in patients with myocarditis and autoantibodies against cardiac antigens. In patients with histologically or immunohistologically diagnosed myocarditis, the presence of AMAAB is associated with less favorable development of systolic and diastolic left ventricular function during a six month follow-up period. The change in parameters of systolic left ventricular function (EF, SV, SVI) were significantly better in patients without AMAAB compared with AMAAB(+) patients. This seems not to be due to different preload or afterload of the left ventricle in the two study groups as left ventricular end-diastolic pressure and systolic arterial pressure were not different between the groups at baseline and had not changed at follow-up.
The development of diastolic left ventricular function was also different between AMAAB(+) and AMAAB(–) patients. The constant of diastolic stiffness "b" was higher at follow-up in AMAAB(+) patients compared with baseline, whereas "b" was lower compared with baseline in AMAAB(–) patients, i.e., the left ventricle in AMAAB(+) patients became stiffer and less compliant than it did in AMAAB(–) patients. Left ventricular relaxation did not change throughout the study period in either group.
The pathophysiologic mechanisms responsible for the development of less compliant ventricles in patients with AMAAB are not clear. Patients with myocarditis show various degrees of interstitial fibrosis in the myocardium (41). In patients with presumably chronic myocarditis, massive interstitial fibrosis has been found (42). Therefore, it could be possible that in this study AMAAB(+) patients had developed more fibrosis in six months than AMAAB(–) patients. However, no studies evaluating the time course of the development of interstitial fibrosis in patients with myocarditis are yet available. In this study, interstitial fibrosis could not be evaluated quantitatively in the small biopsy specimen. "Vascular turgor" (43) was not different in the two study groups. Other possible causes for increased chamber stiffness such as amyloidosis or myocardial edema cannot be ruled out in this study; however, they seem unlikely to be responsible for the observed changes in left ventricular stiffness.
AMAAB and clinical course of myocarditis and dilated cardiomyopathy.
In this study, patients with chronic myocarditis and AMAAB reported no change in clinical symptoms after six months; patients without AMAAB reported slight improvement of symptoms. Caforio et al. (18) analyzed AMAAB and the clinical course in patients with dilated cardiomyopathy. Persistence of AMAAB was associated with milder symptoms at presentation and stable disease. In this study, the diagnosis of dilated cardiomyopathy was based only on histological analysis of the endomyocardial biopsy. The histological analysis alone of the endomyocardial biopsy is known to be difficult (21,22) and affected by many problems including high "interobserver-variability" (23) and sampling error (24). Therefore, histological analysis alone is thought to be rather insensitive for the diagnosis of myocarditis (26–29). This study employs both histological and immunohistological analysis of the endomyocardial biopsy specimen. With these techniques, lymphocytic infiltrates could be detected in 48% of patients presenting with the clinical picture of dilated cardiomyopathy, whereas histological analysis alone found myocarditis in only 5% of patients (32). Therefore, it cannot be ruled out that some patients in the study of Caforio et al. (18) probably had lymphocytic myocarditis and that the patients presented in this study may probably not represent a homogeneous group of dilated cardiomyopathy.
Pathophysiologic relevance of AMAAB.
The pathophysiologic significance of AMAAB in patients with myocarditis is poorly understood. In animal studies, autoantibodies against cardiac myosin have been demonstrated in Coxsackie B3 virus induced myocarditis (44,45). Immunization of the animals with cardiac myosin results in histologic and immunohistologic alterations similar to those seen after Coxsackie B3 virus infection (46). These results suggest a pathophysiologic role of AMAAB in the course of myocarditis. One possible explanation could be "molecular mimicry." Schwimmbeck et al. (47) identified regions of high homology between Coxsackie B3 virus and rabbit cardiac myosin heavy chain. However, the AMAAB produced in Coxsackie virus B3-induced murine myocarditis did not cross-react with the virus (48). Another possibility is the exposition of sequestered antigens to the immune system in the course of myocarditis. Intracellular proteins such as myosin are possibly exposed to the immunogenic cells, thus perpetuating the autoimmunologic process.
This study shows that AMAAB are associated with less favorable development of left ventricular systolic and diastolic function in patients with chronic myocarditis. One possible explanation would be that in the two study groups different pathophysiologic mechanisms are responsible for the development of chronic myocarditis. In AMAAB(+) patients, chronic myocarditis may be caused by autoimmunologic mechanisms, probably depending on genetic predisposition (49), whereas in AMAAB(–) patients, other mechanisms like persistence of viral genome in the myocardium (8,50) may be responsible for the development of a chronic disease. In this case, the AMAAB could serve as a marker of an autoimmunologic process in the patients. Another explanation would be that in AMAAB(–) patients, autoantibodies against other cardiac antigens (10–14) may be responsible for the development of chronic myocarditis and that these autoantibodies may have different effects on cardiac function (17,19). However, it cannot be overlooked that the AMAAB themselves may influence cardiac function via a yet unknown mechanism. In patients with myocarditis, in whom myocardial cell damage was studied by antimyosin scintigraphy, the presence of AMAAB seems to prevent the binding of the radioactively labeled AMAAB to the myocardium (51). This suggests that the AMAAB in these patients may bind to epitopes in the heart and consequently may influence cardiac function.
Conclusions.
This study shows that, in patients with chronic myocarditis, the presence of autoantibodies against cardiac myosin is associated with less favorable development of left ventricular systolic function and diastolic stiffness in the course of the disease.
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