(Circulation. 1997;95:1979-1980.)
© 1997 American Heart Association, Inc.
Articles |
Cardiac Autoantibodies in Dilated Cardiomyopathy
A Pathogenetic Role?
From the Onassis Cardiac Surgery Center, Athens, Greece.
Correspondence to Constantinos J. Limas, MD, Department of Cardiology, Onassis Cardiac Surgery Center, 356 Syngrou Ave, 176 74 Athens, Greece.
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Introduction |
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 Top Introduction References |
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Disturbances in both humoral and cellular immunity have been described in patients with dilated cardiomyopathy and have been implicated in the initiation and progression of this disease entity. In particular, a variety of autoantibodies against cardiac cellular proteins have been identified in dilated cardiomyopathy,1 2 3 4 5 6 7 and the list includes G-protein–linked receptors (such as the ß1-adrenergic and muscarinic cholinergic receptors), myosin, mitochondrial proteins (such as the adenine nucleotide translocator and keto-
-acid dehydrogenase),
actin, tubulin, heat shock proteins, and the sarcoplasmic reticulum
ATPase. The list is likely to expand as more putative autoantigens are
tested. The pathophysiological relevance of these
autoantibodies, however, is far from clear. After all, low titers of
autoantibodies are found in normal subjects and are part of the
immunologic repertoire. Interpretation of the findings is further
complicated by the fact that dilated cardiomyopathy
is most likely nosologically heterogeneous, and immune
mechanisms may be important in only a subset of patients with this
disease. Furthermore, observations are routinely made in patients with
established disease, and inferences about the mechanisms by which
myocardial injury was initiated must, by necessity, be based on
indirect and circumstantial evidence. These reservations
notwithstanding, three possible mechanisms through which autoantibodies
can participate in the pathophysiology of dilated
cardiomyopathy may be distinguished. 1. Initiation of cardiac injury. Evidence that autoantibodies can directly damage the myocardium and initiate the sequence of events that lead to dilated cardiomyopathy comes exclusively from experimental models. For example, in genetically susceptible strains of mice, injection of anti-myosin antibodies leads to autoimmune myocarditis morphologically similar to that induced by myosin injections.8 It should be noted, however, that autoimmune myocarditis associated with high titers of anti-myosin antibodies can also be induced by injection of cardiac myosin, although this experimental model is thought to be mediated by T lymphocytes and not by the anti-myosin antibodies.9 It is probable that development of autoantibodies is, by itself, insufficient to cause disease unless other, as yet undetermined, genetically based changes also take place. Two recent studies suggest that administration in rabbits of two other putative autoantigens, the muscarinic cholinergic10 and the ß1-adrenergic receptors,11 can lead to functional and morphological changes resembling cardiomyopathy. Although these are provocative findings, there is no corresponding evidence that autoantibodies can play an initiating role in human dilated cardiomyopathy.
2. Induction of myocardial dysfunction. By virtue of their interaction with key cell constituents, autoantibodies have the potential to influence cardiac metabolism and contractility. For example, interruption of ß-adrenergic pathways could affect both force development and relaxation; inhibition of sarcoplasmic reticulum Ca2+ ATPase or the Ca2+ channels (with which anti–adenine nucleotide translocator antibodies cross-react) likewise disrupts Ca2+ cycling, and anti-mitochondrial antibodies have been shown to impair energy metabolism in the heart. These functional abnormalities induced by cardiac autoantibodies mirror the changes observed in dilated cardiomyopathy patients and therefore support a role for these autoantibodies in sustaining myocardial injury and contributing to the progression of disease. In addition, there is some evidence that patients with autoantibodies have clinically and hemodynamically more severe disease, as would be expected if they were pathogenetically relevant.2 However, it is not known whether this correlation reflects a direct effect of antibodies on greater disease severity (mediated through cellular mechanisms), with autoantibodies being an epiphenomenon.
3. Markers of autoimmunity. Dilated
cardiomyopathy has a strong genetic background, and
20% of first-degree relatives of patients with dilated
cardiomyopathy have asymptomatic
disease.12 Furthermore, the prevalence of autoantibodies
is as high in familial as in sporadic cases of
cardiomyopathy.13 More importantly,
two studies14 15 suggest that autoantibodies can be
frequent in first-degree relatives who have either no clinical disease
or only asymptomatic left ventricular
dysfunction. This may be analogous to observations in insulin-dependent
diabetes mellitus, in which the appearance of anti-islet antibodies
precedes the onset of clinical disease by several years.16
In addition, a recent study suggests that the prevalence of
autoantibodies in dilated cardiomyopathy declines
with time,1 supporting the view that development of
autoantibodies is an early event in the course of the disease. These
observations are consistent with the concept that
autoantibodies occur in individuals genetically susceptible to
cardiomyopathy but that (in agreement with data
from experimental models of myocarditis) additional events are required
before clinical disease develops. It is also likely that in patients
with clinically manifest dilated cardiomyopathy,
autoantibodies reflect the presence of an active inflammatory
(myocarditic) process.
If cardiac autoantibodies do play a role either in initiating dilated cardiomyopathy or in contributing to the progressive functional deterioration of the myocardium, their removal would be expected to lead to disease stabilization or improvement. Conversely, if they only serve as markers of the underlying autoimmune process, efforts to remove them would not lead to any clinical improvement. It is in the context of these considerations that the report by Dörffel et al17 in this issue of Circulation is of special interest. In this preliminary report, the authors demonstrate clinical and hemodynamic improvement after a short course of immunoadsorption that led to a decline in immunoglobulin levels as well as titers of anti–ß-receptor antibodies. If this report is confirmed by a more extensive and prolonged study, it would add considerable support to the proposal that autoantibodies play an active role in the pathogenesis of dilated cardiomyopathy.
Several caveats, however, are in order. First, the number of patients studied is too small, and in any case the conclusions will not apply to cases of dilated cardiomyopathy in which immunologic disturbances do not participate in the pathogenesis of the disease. Patients with high autoantibody titers would most probably be the best candidates for immunoadsorption only. Second, it is not certain that the improvement noted is attributable to the removal of autoantibodies. The hemodynamic pattern of the response to immunoadsorption includes a decline in systemic vascular resistance with a concomitant fall in left ventricular filling pressures without a change in ejection fraction. It is possible that the fall in systemic vascular resistance was the primary event leading to the decline in left ventricular filling pressures and that this fall may be unrelated to the removal of autoantibodies. The case for a pathogenetic role of putative autoantibodies would have been strengthened by the demonstration that functional consequences of antigen-antibody interactions (eg, impairment of ß-adrenergic responsiveness in response to anti–ß-receptor antibodies) were indeed reversed by immunoadsorption. Also, as the authors correctly point out, it is difficult to exclude an anti-idiotypic effect of the infused immunoglobulin. Finally, one should consider that activation of T lymphocytes (and macrophages) also occurs in dilated cardiomyopathy,18 19 as in experimental models of autoimmune myocarditis, and may not be influenced by immunoadsorption. Full benefit from immunomodulation probably requires modification of both humoral and cellular immunity, the relative contributions of which may vary in individual patients or at different stages in the evolution of the disease. Despite these shortcomings, the report by Dörffel et al17 sets the conceptual framework for the design of further studies in the pathogenesis of dilated cardiomyopathy as well as for novel therapeutic approaches that would benefit a substantial number of patients with this disease.
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Footnotes |
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The opinions expressed in this editorial are not necessarily those of the editors or of the American Heart Association.
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References |
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TopIntroductionReferences |
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