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From Myocarditis to Cardiomyopathy: Mechanisms of Inflammation and Cell Death : Learning From the Past for the Future -- Kawai 99 (8): 1091 -- Circulation
(Circulation. 1999;99:1091-1100.)
© 1999 American Heart Association, Inc.
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Presented in part as a State-of-the-Art lecture at the Featured Research Sessions:
Myocarditis—Mechanisms of Inflammation and Cell Death at the 69th Scientific Sessions of the
American Heart Association, New Orleans, La, November 13, 1996.
Chuichi Kawai, MD
From Kyoto University and Kyoto Regional Study Center, University of the Air.
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Cardiovascular Pharmacology
Correspondence to Chuichi Kawai, MD, Nishiiru Karasuma Shimochojamachi-dori, Kamikyoku, Kyoto
602-8002, Japan.
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Heart failure - basic studies
From Myocarditis to Cardiomyopathy: Mechanisms of Inflammation and Cell Death : Learning From the Past for the Future -- Kawai 99 (8): 1091 -- Circulation
Abstract
Top
Abstract—A progression from viral myocarditis to dilated cardiomyopathy has long been
Abstract
hypothesized, but the actual extent of this progression has been uncertain. However, a causal
Introduction
link between viral myocarditis and dilated cardiomyopathy has become more evident than
Host Factors That Influence...
before with the tremendous developments in the molecular analyses of autopsy and
Sequential Pathological Changes...
endomyocardial biopsy specimens, new techniques of viral gene amplification, and modern
Future Therapeutic Implications
immunology. The persistence of viral RNA in the myocardium beyond 90 days after
Future Studies
inoculation, confirmed by the method of polymerase chain reaction, has given us new insights
References
into the pathogenesis of dilated cardiomyopathy. Moreover, new knowledge of T-cell–mediated
immune responses in murine viral myocarditis has contributed a great deal to the understanding of the mechanisms of ongoing disease
processes. Apoptotic cell death may provide the third concept to explain the pathogenesis of dilated cardiomyopathy, in addition to
persistent viral RNA in the heart tissue and an immune system–mediated mechanism. Beneficial effects of 1-adrenergic blocking
agents, carteolol, verapamil, and ACE inhibitors have been shown clinically and experimentally in the treatment of viral myocarditis and
dilated cardiomyopathy. Antiviral agents should be more extensively investigated for clinical use. The rather discouraging results
obtained to date with immunosuppressive agents in the treatment of viral myocarditis indicated the importance of sparing neutralizing
antibody production, which may be controlled by B cells, and raised the possibility of promising developments in immunomodulating
therapy.
Key Words: viruses • myocarditis • cardiomyopathy • immune system • apoptosis
Introduction
Since Gore and Saphir1 demonstrated in 1947 that rheumatic and diphtheritic carditides each constituted only 10% of a series of 1402
cases of myocarditis, increasing attention has been paid to myocarditis occurring in various viral diseases. A number of agents induce
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myocarditis. Among them, viruses are believed to be the most common agents causing
myocarditis in the developed countries. However, direct proof of the presence of a given virus
in the heart is very difficult to obtain in clinical settings.
A 4-fold rise in neutralizing antibody titers to viruses in paired sera over a 2- to 4-week period
has been generally believed to establish a viral pathogenesis in patients with myocarditis. The
persistence of a higher incidence of neutralizing antibodies to coxsackievirus B (CVB) in
patients with cardiomyopathy than in age-, sex-, race-, and living district–matched control
subjects has prompted the theory of a viral cause underlying the pathogenesis of
cardiomyopathy.2 3
Top
Abstract
Introduction
Host Factors That Influence...
Sequential Pathological Changes...
Future Therapeutic Implications
Future Studies
References
The present review summarizes clinical and experimental studies on the viral origin of myocarditis and dilated cardiomyopathy and
suggests directions for future investigations.
Host Factors That Influence Susceptibility to Viral Myocarditis
The virulence of murine viral infection is increased by malnutrition,4 exercise,5 sex and sex
hormones,6 7 8 and age.8 9 10 More importantly, genetic factors, including immune states, which
are heavily involved in the above-mentioned host factors, play a crucial role in susceptibility to
infection.
Top
Abstract
Introduction
Host Factors That Influence...
Sequential Pathological Changes...
Future Therapeutic Implications
Future Studies
References
Ample evidence suggests that the same strain of virus causes different lesions in the heart in
different inbred strains of mice. Severe myocarditis was induced at high frequency in BALB/c,
DBA/2, and C3H/He mice inoculated with EMC virus, but A/J and C57BL/6 mice treated
similarly did not show any cardiac lesions.11 12 Susceptibility to viral infection may be regulated primarily by the major
histocompatibility complexes, or H-2 complexes, in each strain of inbred mice.
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Sequential Pathological Changes in Murine Viral Infection
After inoculation of mice with a virus, 2 principal pathogenic mechanisms, the direct viral and
immunocyte-mediated pathogenic mechanisms, are implicated in the destruction of myocardial
tissue. The outline of temporal changes in the murine myocytes inoculated with virus is
depicted as a flow diagram in Figure 1 .
Top
Abstract
Introduction
Host Factors That Influence...
Sequential Pathological Changes...
Future Therapeutic Implications
Future Studies
References
Figure 1. Flow diagram indicating temporal changes in murine myocytes inoculated with virus
covering days 0 to 90. Large solid arrow indicates beneficial effect; dashed arrow, detrimental
effect; small solid arrow, induced, produced, or activated; and NT, neutralizing antibody titer.
*Detailed changes in this phase are shown in Figure 4 .
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Acute Phase of Viral Myocarditis (Days 0 to 3)
Mice injected intraperitoneally with a cardiotropic virus (eg, encephalomyocarditis virus [EMCV] or CVB) exhibit a direct consequence
of virus-induced cytotoxicity, including focal necrotic myofibers in the absence of an inflammatory cell infiltrate within 3 days after
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infection.13 Cytokine mRNA, such as that of interleukin (IL)-1ß, tumor necrosis factor (TNF)- , and interferon (IFN)- , is already
induced 3 days after inoculation, when few cell infiltrates are seen.14 15
Subacute Phase of Viral Myocarditis (Days 4 to 14)
After viral invasion of the myocardium, the first wave of infiltrating cells in the heart consists mainly of natural killer (NK) cells. Various
cytokines, including IL-1ß, TNF- , IFN- , and IL-2, are produced at this stage and persist as long as 80 days after the inoculation of
EMCV.14 Circulating levels of plasma TNF- , IL-1 , and IL-1ß were also elevated in patients with acute myocarditis, dilated
cardiomyopathy, and other cardiac patients with congestive heart failure.15 16 17 18 It is well known that most cytokines have multiple
biological activities that overlap, and there is considerable redundancy in actions. A given cytokine can activate a variety of cell types.
Such interactions are further amplified by the capacity of some cytokines to act as potent inducers of other cytokines. Thus, most
cytokines exert both beneficial and deleterious effects on myocytes. Nitric oxide (NO) is also generated during this phase in response to
cytokines that are induced by EMCV. Both beneficial and detrimental actions of NO have also been observed.19 20 21 NO is beneficial as
a modulator of immunological self-defense mechanisms, and at the same time, it plays an important role in killing infectious agents.
Conversely, NO is also associated with detrimental effects on the myocardial tissue in autoimmune myocarditis in rats.22
NK Cells, Perforin, and IFN
NK cells, activated by IL-2, have protective effects against viral invasion by limiting virus replication. The hypothesis of the defensive
role of NK cells during viral infection has been supported by the prolonged viral infection or increased viral titers and severe myocarditis
in murine strains with decreased NK-cell responses23 and in NK-cell–deficient mice treated with antiserum against NK cells.24 25 26 In
contrast, NK-like large granular lymphocytes and asialo GM1–positive cells both cause myocardial damage by releasing perforin
molecules, which form circular pore lesions on the membrane surface of the cardiac myocytes in murine CVB3 myocarditis27 and in
patients with acute myocarditis.28 However, there would seem to be no further contribution of NK cells to lesion pathology, because they
interact only with virus-infected myofibers.25
Viral myocarditis can be ameliorated in mice if IFN is administered before, simultaneously with, or within 24 hours of inoculation with
EMCV or CVB3.29 30 31 32 33 NK cells and IFN frequently interact to control virus infection, but CVB-induced "native" IFN does not
appear to be fully protective.20 As shown in the above-mentioned studies, "exogenous" IFN treatment was beneficial in ameliorating
myocarditis only when IFN was administered before or during the very early stages of infection. Thus, it seems reasonable to assume that
IFN evokes other antiviral processes. It is believed that the IFN-mediated induction of NO is important in controlling an enterovirus
infection. "Knockout" mice rapidly succumbed to CVB3 myocarditis compared with normal infected mice carrying the IFN gene.20 As
described previously, the IL-1ß, TNF- , and IFN- produced at this stage each induce inducible NO synthase (iNOS) in cardiac
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myocytes, but only the combination of IL-1ß and IFN- causes contractile dysfunction in the presence of insulin in adult rat ventricular
myocytes.34 IFN- , which by itself does not induce iNOS in cardiac microvascular endothelial cells, potentiates and accelerates iNOS
induction by IL-1. Transforming growth factor-ß (TGF-ß) decreases iNOS activity, protein content, and mRNA in IL-1ß– and IFN–pretreated adult rat cardiac microvascular endothelial cells.35
Viral Titers and Neutralizing Antibody
Viral titers in the myocardium were maximal on day 4 after EMCV inoculation in BALB/c mice.36 Almost no neutralizing antibodies to
the virus were present until day 4, when the highest viral titer was detected. The neutralizing antibody titers were then elevated rapidly on
days 8 and 10 and reached the highest level on day 14. The viral titers were still elevated on day 8 but rapidly decreased and disappeared
after day 10.36 The appearance of a rising antibody titer is closely related to the elimination of the virus from the heart. The neutralizing
antibody titers in the prednisolone-treated group of mice in that study36 were significantly lower than those in the nonprednisolone group
(Figure 2 ) on days 8 and 10, when the viral titers were still high in the prednisolone-treated group (Figure 3 ). Neutralizing antibodies,
however, do not appear to be exclusively responsible for resistance to CVB infection. Infiltrating mononuclear cells, which appear in the
heart 5 to 10 days after viral infection, play a definite role in suppressing viral infection.4 23 37 Thus, direct virus-mediated damage
occurs primarily at the start of the disease process, but at the same time, NK cells, protective neutralizing antiviral antibodies, and
infiltrating macrophages begin clearing the virus from the myocardium with or without the help of cytokines.
Figure 2. Neutralizing antibody titers between prednisolone-treated and control groups
of BALB/c mice after EMCV inoculation. Antibody titers of prednisolone group on
days 8 and 10 were significantly lower than those of control group (P<0.01 for both).
Each circle represents 1 mouse. Reproduced with permission from Reference 36.
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Figure 3. Myocardial viral titers between prednisolone-treated and control groups of
BALB/c mice after EMCV inoculation. In prednisolone group, viral titers remained
significantly elevated on day 10, whereas only 1 of 5 control mice maintained a
detectable viral titer. TCD50 indicates 50% tissue culture infective dose. Each circle
represents 1 mouse. Reproduced with permission from Reference 36.
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Cell-Mediated Immune Pathogenicity
Infiltrating T lymphocytes are seen in the myocardium as the second wave of cells. The immune T-cell infiltrate peaked on day 7 to 14
after virus inoculation, coinciding with the most severe acute pathological damage in the myocardium.38 In the myocardium of DBA/2
and BALB/c mice, Thy 1.2+ (pan T) cells with Lyt 1+, 23+ (precursor) cells as the largest T-cell subset predominated on days 7 and 14
after an inoculation of EMCV; Lyt 1–positive cells (helper/inducer) were present in the myocardium to the same extent as they were in
the peripheral blood and the spleen. Lyt 2–positive cells (suppressor/cytotoxic) were greatly increased in the myocardium on days 7 and
14, although there were some differences in their respective serial changes of lymphocyte subsets in the myocardium of DBA/2 and
BALB/c mice.39 These infiltrating immune cells also play a critical protective role in limiting viral replication in the heart and in
eliminating infected myocardial cells. The B lymphocytes were 10% to 20% of the infiltrating lymphocytes in the myocardium of DBA/2
and BALB/c mice on days 7 to 14; thereafter, the levels of B cells increased, while those of Thy 1.2 (pan T) cells gradually decreased
over 1 to 3 months. In other words, the B lymphocytes in the myocardium seem to show reciprocal changes of less intensity than those of
the T lymphocytes; peripheral blood and spleen B cells in both strains of mice showed no significant changes throughout the
experimental period.38
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The inflammatory response continues at a lesser intensity at sites surrounding cardiac necrosis after a culturable virus has been
eliminated. The cell-mediated immune mechanisms evoked by these infiltrating immune cells then play a pivotal role in the ongoing
destruction of cardiac tissue. Cytotoxic T lymphocytes [CTLs; Lyt 2–positive cells=(Lyt 1+, 23+)+ (Lyt1-, 23+)] have been shown to be
capable of lysing virus-infected cardiocytes in vitro.39 40 Foreign particles such as viruses are reduced to component peptides in the
target cell cytoplasm, and the peptides are then placed on the surface of the target cell membrane in the groove of major
histocompatibility complex (MHC) molecules for presentation to the T-cell receptors (TCRs), which consist mainly of - and ß-chain
heterodimers (Figure 4 ), designated as V and Vß, respectively. Through their TCRs, CTLs recognize virus-derived peptides presented
by MHC class I antigen, which is strongly induced on cardiac myocytes in murine acute myocarditis caused by CVB3,41 and lead to
further myocardial cell damage.42 A recent study demonstrated that TCR V and Vß gene usage by infiltrating T cells in the murine
heart on day 12 after virus inoculation is restricted, raising the possibility of using anti-TCR antibodies or a vaccination with synthetic
TCR V-region peptides to prevent T-cell–mediated myocardial damage after viral infection.43 44
Figure 4. Proposed mechanism of virus-specific CTL-mediated myocardial injury in subacute
phase of viral myocarditis. Th indicates helper T lymphocyte; LFA-1, lymphocyte
function–associated antigen-1. Reproduced with permission from Seko Y. Shinkin-shogai to
secchaku-bunshi (Myocardial injury and adhesion molecules). Saishin-igaku.
1995;50:1597–1603. (In Japanese). See details in text.
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Perforin particles expressed on virus-specific CTLs also cause myocardial injury. At the same time, virus-specific CTLs play an
important role in the pathogenic immune mechanism in viral myocarditis and dilated cardiomyopathy. It is believed that cell-cell contact
and adhesion are required in such immune responses. Intercellular adhesion molecule-1 (ICAM-1) expressed on the infected myocytes
induced by IFN- and TNF- plays a crucial role in the interaction with CTLs as the ligand of lymphocyte function–associated antigen-1
expressed on the lymphocytes. The enhanced expressions of HLA class I and ICAM-1 and the infiltration of perforin-expressing killer
cells were demonstrated in the hearts of patients with acute myocarditis and dilated cardiomyopathy45 and in murine hearts with viral
myocarditis.46 In addition, recent studies47 48 demonstrated that the adhesion molecules B7-1 (B7, CD80), B7-2 (B70, CD86), and
CD40, expressed in some infected myocytes, bind to a counterreceptor, CD28 and CD40L (ligand, gp39), expressed on T lymphocytes,
and play a role in the costimulation of T cells in a primary immune response through TCR.
Myocardial Injury in T-Cell–Depleted Mice
A marked reduction in myocardial damage was noted in T-cell–depleted mice inoculated with CVB3 pretreated with antithymocyte
serum, in TXBM mice (thymectomized, irradiated, and reconstituted with bone marrow cells), and in mice treated with monoclonal
antibody against total T cells.49 50 The reduction in myocardial damage in the mice was independent of myocardial CVB3 virus
replications, because the viral titers were similar in the T-cell–depleted and intact mice.
Pathological changes in the myocardium were less prominent in T-cell–depleted nude mice (BALB/c-nu/nu) inoculated with EMCV.38
There was a mild mononuclear cell infiltration in the right and left ventricular myocardium; no cavity enlargement was visible (Figure 5
). Myocardial damage in BALB/c-nu/+ mice inoculated with EMCV was markedly severe, demonstrating prominent mononuclear cell
infiltration in the myocardium and cavity enlargement of both ventricles (Figure 6 ). Severe myocarditis was also found in BALB/c-nu/
nu mice injected with spleen cells from BALB/c-nu/+ mice (Figure 7 ). The survival rate of the nude mice inoculated with EMCV on
days 10 to 15 was significantly higher than that of nu/+ mice and nude mice injected with spleen cells from nu/+ mice. There were no
significant differences in virus titrations of the heart and serum neutralizing antibody titers among the 3 varieties of mice. These results
indicated that viral clearance from the myocardium is controlled by B lymphocytes, which are involved mainly in humoral immunity, and
occurs independently of T-cell function in murine viral myocarditis. These studies and others4 40 51 support the view that the severity and
development of myocarditis are mediated by T lymphocytes, which control cell-mediated immunity.
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Figure 5. Hematoxylin-eosin stains of hearts obtained 16 days after inoculation with
EMCV in BALB/c-nu/nu mice. There was neither cavity dilatation nor a decrease in
wall thickness in right (RV) and left (LV) ventricles (top, magnification x12).
Myocardial necrosis and cellular infiltration were minimal (RV, lower left,
magnification x180; LV, lower right, magnification x370). Modified with permission
from Reference 38.
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Figure 6. Hematoxylin and eosin stains of hearts obtained 16 days after inoculation with
EMCV in BALB/c-nu/+ mice. There was obvious cavity dilatation and a decrease in wall
thickness in right (RV) and left (LV) ventricles (top, magnification x12). Marked
myocardial necrosis and cellular infiltration were evident (LV wall, lower left,
magnification x180; inner layer of LV, lower right, magnification x370). Modified with
permission from Reference 38.
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Figure 7. Hematoxylin-eosin stains of hearts obtained 16 days after inoculation with
EMCV in BALB/c-nu/nu* mice (BALB/c-nu/nu mice injected with spleen cells from
nu/+ mice). There was obvious cavity dilatation and a decrease in wall thickness in
right (RV) and left (LV) ventricles as in Figure 6 (top, magnification x12). Marked
myocardial necrosis and cellular infiltration were also evident (RV free wall, lower left,
magnification x180; LV wall, lower right, magnification x370). Modified with
permission from Reference 38.
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Chronic Phase of Viral Myocarditis (Days 15 to 90)
From day 15 after viral inoculation, after the culturable virus had been eliminated, myocardial damage persists insidiously. In the DBA/2
mice surviving 90 days after acute EMCV myocarditis, both the heart weight and the heart weight/body weight ratio were significantly
larger than those of control mice. The cavity dimensions of the left ventricle were enlarged. Myocardial fibrosis was prominent,
particularly in the inner two thirds of the left ventricular free wall. There was no longer any inflammatory cell infiltration at this stage,
thus resulting in cardiac lesions that resembled human dilated cardiomyopathy in mice 3 months after viral infection.11 IL-1 is said to be
correlated with the increased heart weight/body weight ratio and the extent of fibrotic lesions in the chronic phase.15
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The pathogenic mechanisms involved in the transition from viral myocarditis to dilated cardiomyopathy have been a challenging puzzle.
Because of the absence of culturable virus and viral capsid proteins after the initial phase of myocarditis, it has been suggested that a cellmediated autoimmune mechanism(s) possibly triggered by virus infection may play a role in the pathogenesis of dilated cardiomyopathy.
Persisting Viral RNA
Recent evidence suggests that a viral mechanism contributes not only to the acute phase of myocarditis but also to the evolution of
ongoing heart disease. With currently available molecular techniques, the role of persisting virus has been rediscovered in its interaction
with the immune system to provide clinical and experimental evidence on the viral pathogenesis of myocarditis and dilated
cardiomyopathy.52 In EMCV-infected mice, viral RNA was detected in the heart for 3 weeks and in the brain for 4 weeks by in situ
hybridization.53 There is a hypothesis that in the chronic phase, the T lymphocytes infiltrate the myocardium in response to viral RNA in
myocytes. This hypothesis is supported by the observation that 3 different strains of immunocompetent inbred mice in which viral RNA
(detected by in situ hybridization) persists progressed to chronic heart disease. In contrast, DBA/1 J mice, which are capable of
terminating the inflammatory processes by eliminating the virus from the heart, showed no evidence of viral RNA persisting in the
myocardium.54 Because viral RNA diminishes during the chronic phase of the disease, its detection by in situ hybridization becomes
progressively more difficult. Alternatively, polymerase chain reaction (PCR) provides a more sensitive method for the detection of viral
RNA by a rapid amplification of specific DNA sequences, although a wide discrepancy exists in the reported results, probably because of
the use of different procedures by different investigators.55 56 Using PCR in our laboratory, we were able to demonstrate that EMCV
RNA persists in the absence of infectious virus beyond 90 days after inoculation,57 when cardiac lesions resembling human dilated
cardiomyopathy in mice have been developed in the same animal model.11 Another group58 used PCR and showed that EMCV RNA
signals were detectable in the myocardium up to day 42 after infection, at which point most of the inflammatory response had subsided in
the murine model of viral myocarditis.
The levels of positive detection of enteroviruses by PCR are still low in myocardial biopsy specimens from patients with myocarditis and
dilated cardiomyopathy.59 60 With the current technique, EMCV RNA was detected only in 2 of 7 mice 90 days after inoculation,57 even
under excellent experimental conditions within inbred animals.
Some evidence suggests that the persisting viral RNA appears to be capable of replication.54 However, in the absence of detectable virus
titers, it seems likely that the replication is done in a restricted or altered manner.54 Even such replication could produce new antigenic
noninfectious or defective interfering viral particles, enough to cause ongoing myocardial injury.
Carrier state infections are an alternative mechanism to explain the virus-induced ongoing heart disease. These infections may occur in
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murine CVB heart disease, particularly under conditions in which the host defense mechanisms are depressed.4 Persistent viral infection
has been observed in the spleen and lymph nodes,54 liver, and pancreas61 as extracardiac reservoirs of virus during the chronic phase of
the disease.
However, a recent study62 demonstrated that enterovirus is not a primary cause of dilated cardiomyopathy. A significantly high
frequency of the presence of anti–hepatitis C antibody associated with hepatitis C virus RNA in the sera was found in patients with
dilated cardiomyopathy.63 Both positive- and negative-strand RNA of hepatitis C virus was present in myocardial and liver tissue
samples at necropsy in 3 patients with chronic active myocarditis.64 Further studies of the increasing number of myocarditis patients with
appropriate control subjects may establish whether these findings simply represent a coincidence and/or the uptake of viral material from
the neighboring infected cells or plasma.
Animal models in which myocarditis is inducible by purified cardiac myosin have been established and serve as an exclusively virus-free
system for investigations of the pathological mechanisms acting in autoimmune heart disease.65 66 Murine strains susceptible to chronic
CVB-induced myocarditis developed myocarditis when cardiac myosin was injected. There are many other circulating heart-specific
autoantibodies, including antisarcolemma antibodies.67 Some of them exhibit cross-reactivity to CVB3 capsid proteins. The
immunological similarity between myosin and CVB3 capsid proteins could reflect the fact that they both share 40% identity in the
amino acid sequence.68 Thus, some heart-specific autoantibodies that react with CVB3 and cardiac myosin demonstrate cell lysis
capabilities and induce myocardial lesions when they are injected into mice.69 Although their origin and pathogenic role seem to depend
on the experimental system used, further investigations of these cross-reacting autoantibodies through molecular mimicry may be
important for understanding autoimmune mechanisms in viral heart disease and dilated cardiomyopathy. However, it has been reported
that the myocardiogenic epitopes are located in the cardiac myosin rod in one study70 and in the head portion in another study.71 The
identification of pathogenic epitopes on the cardiac myosin is important because of the future application of the peptide therapy.
Apoptosis
Thus far, the discussion in this review has been focused on virus- and immunocyte-mediated pathogenic mechanisms in the development
of dilated cardiomyopathy from viral myocarditis. The cell death dealt with here, as James72 describes in his excellent review, "has
almost universally been considered synonymous with necrosis, and necrosis was generally regarded as an abnormal or pathological
condition." In contrast to necrosis, apoptotic cell death demonstrates distinctive morphological characteristics that consist of the
shrinkage instead of swelling of cells, early disintegration of the nucleolus with a typical form of cleavage into 2 pieces of the entire
nucleus forming apoptotic bodies, and rapid phagocytosis by local macrophages or even neighboring cells such as cardiac myocytes, with
a total absence of inflammation. Very few reports had been published on the recognition of apoptosis in the human heart until James et
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al72 73 74 called attention to the significant participation of apoptosis in the postnatal morphogenesis of the human cardiac conduction
system, arrhythmias including sudden unexpected death, cardiomyopathy, arrhythmogenic right ventricular dysplasia, Uhl's anomaly, and
complete heart block. Although electron microscopic examination of apoptotic bodies is the most reliable and direct diagnostic method
for recognition of an apoptotic cell, indirect evidence of the presence of apoptosis has accumulated in necropsied ventricular myocytes of
patients with myocardial infarction, by the expression of bcl-2 at the acute stage and the overexpression of Bax at the late stage75; in
human vascular pathology, including restenotic lesions and primary atherosclerotic lesions, by terminal deoxynucleotidyl
transferase–mediated dUTP-biotin nick-end labeling (TUNEL) staining76; and in hypoxic cultured neonatal rat cardiomyocytes by DNA
fragmentation, TUNEL staining, and the enhanced expression of Fas antigen messenger RNA.77 It is now known that in the absence of
culturable viruses and with a characteristic avoidance of inflammatory changes, cardiac injuries persist and cardiac lesions resembling
human dilated cardiomyopathy develop after murine viral myocarditis. A new and intriguing hypothesis is that apoptotic cell death is at
least in part responsible for the disease process from acute viral myocarditis to dilated cardiomyopathy. Moreover, some reports indicate
that several different viruses act as triggers of apoptosis.78 79 80 Apoptotic cell death may provide the third mechanism, in addition to an
immune-mediated mechanism initiated by viral infection and persistent viral RNA in the myocardium, to explain the development of
dilated cardiomyopathy.
Future Therapeutic Implications
1-
and ß-Adrenergic Blockers, Calcium Channel Blockers, ACE Inhibitors, and
Amiodarone
The administration of prazosin or doxazosin,81 82 carteolol,83 verapamil,84 and captopril85 86
has been shown to be effective in the treatment of viral myocarditis and dilated
cardiomyopathy, both clinically and experimentally. These results raise the possibility that
microvascular spasm81 87 may underlie the evolution of viral myocarditis to dilated
cardiomyopathy; these agents are effective in reducing myocardial injury at least in part by
abolishing microvascular spasm.
Top
Abstract
Introduction
Host Factors That Influence...
Sequential Pathological Changes...
Future Therapeutic Implications
Future Studies
References
In addition, some dihydropyridine calcium channel blockers, amlodipine in particular, prolonged survival and reduced myocardial
damage without significant effect on viral replication in the murine heart; these beneficial effects of amlodipine may be due to altered
inflammatory responses or immunomodulating effect by inhibiting NO production.15 Amlodipine improved survival of patients with
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heart failure due to nonischemic dilated cardiomyopathy.88
A recent study also demonstrated that amiodarone, a well-known antiarrhythmic drug to prevent fatal arrhythmia in patients with heart
failure, may contribute its beneficial effects through inhibition of TNF- and IL-6 production. Modulation of IL-1ß production by
amiodarone was biphasic.89
Antiviral Agents
If viral myocarditis is a precursor of dilated cardiomyopathy, antiviral agents may be crucial in preventing the development of the
disease.
Ribavirin (Virazole, 1-ß-D-ribofuranosyl-1,2,4-triazole-3-carboxamide), a synthetic nucleoside analogue, has a broad antiviral activity
against RNA and DNA viruses. The early administration of ribavirin after virus infection reduced EMCV replication in FL (human
amnion) cells in vitro and inhibited virus replication in the heart, reduced myocardial damage, and decreased the mortality of treated
mice.90
Recombinant human leukocyte IFN- A/D, when administered before or simultaneously with the virus inoculation, inhibited virus
replication and reduced the inflammatory response and myocardial damage in DBA/2 mice inoculated with EMCV91 and C3H/He mice
inoculated with CVB3.31
The combined use of ribavirin and IFN- A/D showed a synergistic effect on the inhibition of myocardial virus replication and enhanced
the survival of infected mice with the lower dose of each agent, which had no suppressive effect in a single use.31 Thus, this combination
may be able to reduce the frequency of unfavorable effects of ribavirin and IFN by lowering the effective dose of both agents in future
clinical use.
Immunosuppressive Agents
A wide variety of immunosuppressive agents have been used in both animal models and humans with no clear favorable effects.
Prednisolone given in the early stage aggravated the course of acute viral murine myocarditis with the increased viral titers because of its
inhibition of the synthesis of neutralizing antibody.36 However, extrapolation of these results in mice to humans should be done with
caution, because there are distinctive differences in susceptibility to steroids between mice, a steroid-sensitive species, and humans, a
steroid-resistant species.92
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Cyclosporine, which preferentially inhibits helper T-cell functions, probably through the inhibition of IL-2 production, caused greater
mortality when administered early in the illness and greater myocardial failure without an evident reduction of myocardial pathology
when administered later during the early recovery phase in murine EMCV93 and CVB394 myocarditis models. Decreases in Thy 1.2+
(pan T) and L3T4+ (activated helper T) cells in the peripheral blood and thymus may account for the higher mortality in the cyclosporinetreated mice, in which the serum neutralizing antibody titers showed no reduction due to an incomplete depletion of the T- and B-cell
zones in the spleen.94
FK-506, a novel potent immunosuppressant at least 10-fold stronger than cyclosporine in vivo, induced an almost total depletion of Tand B-cell functions in mice inoculated with CVB3, resulting in lower titers of serum neutralizing antibody, higher virus titers in the
heart, and a higher mortality rate, notwithstanding an apparent reduction of myocardial cellular infiltration compared with control
subjects.95
Cyclophosphamide suppressed mainly the B-cell region in lymphoid organs at a low dose (30 mg · kg-1 · d-1); a high dose (300 mg · kg-1
· d-1) caused total cellular depletion of the B-cell as well as T-cell regions.96 The treatment of CVB3 murine myocarditis with high-dose
(100 mg · kg-1 · d-1) cyclophosphamide in the early stage resulted in an increased mortality rate, probably due to the total depression of
T- and B-cell functions or the subsequent decreased neutralizing antibody associated with an increase in virus titers, despite less severe
myocardial cellular infiltration and necrosis. Treatment in the late stage had no effect.97
The above results of immunosuppressant therapy indicated the importance of sparing the neutralizing antibody production in the host for
the treatment of viral myocarditis. It has been reported that the serum neutralizing antibody production in experimental CVB3 virus
infection in mice was not affected by the absence of T cells; it may thus be controlled only by B cells.4 38 98
A recent multicenter clinical trial of immunosuppressive therapy for biopsy-proven myocarditis, consisting of prednisone with either
cyclosporine or azathioprine, revealed no distinct benefit for patients with myocarditis.99
Immunomodulating Therapy
It was reported that the administration of rat anti-mouse monoclonal antibodies against total T cells, Lyt 1 plus Lyt 2, during the viremic
stage resulted in decreased mortality with less myocardial cellular infiltration and necrosis in mice with CVB3 myocarditis.50 The serum
neutralizing antibody titers and virus replications showed no significant changes.50
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These results indicate that the inhibition of deleterious heightened T-cell activity without any effect on B cells by appropriately timed
immunosuppressive treatment, if such an agent becomes available, would be helpful in ameliorating myocarditis. High-dose
immunoglobulin treatment suppressed CVB3 murine myocarditis through the transfer of an antiviral antibody and by exerting an antiinflammatory effect.100 High-dose intravenous -globulin has been effective in the treatment of patients with myocarditis101 and with
myocarditis secondary to Kawasaki disease.102 In view of the absence of a general consensus on the effective treatment of myocarditis,
high-dose immunoglobulin could be a candidate for the future treatment for myocarditis.
Levamisole, a promising immunopotentiating drug, increased the number of myocarditis lesions when it was administered to adolescent
CD-1, ICR, and C57BL/6 mice at the time of or up to 4 days after an inoculation with CVB3.103
Exogenous administration of IL-1 or IL-2 restored myocarditis susceptibility in H310 AI virus–infected mice, which otherwise produce
only minimal myocarditis104; recombinant human TNF caused more severe myocardial changes in EMC viral myocarditis than in the
control mice.105 Severe ventricular dysfunction has been reported in cancer patients treated with high-dose IL-2 immunotherapy.106
Of note is a recent study demonstrating that the in vivo administration of anti-B7-1 monoclonal antibody alone or combined with antiCD40L monoclonal antibody suppressed myocardial injuries, which in contrast were exacerbated by anti-B7-2 monoclonal antibody
administration in murine viral myocarditis.107
Future Studies
1. In the acute stage of viral myocarditis, the roles of NK cells and T-cell–mediated immune
mechanisms should be clearly established. In particular, the contributions of cytokines such as
tumor necrosis factors (TNF- and -ß), ILs, IFNs, NO produced by iNOS, perforins, adhesion
molecules, and ligands such as ICAM-1, lymphocyte function–associated antigen-1, B7-1, B72, CD28, CD40, and gp39 as well as TCR (V and Vß) should be clarified in relation to
potential therapeutic implications. The applications of antiviral agents such as ribavirin and IFN, high-dose immunoglobulin, ACE inhibitors, and ß-blockers are to be further investigated
for clinical use.
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Top
Abstract
Introduction
Host Factors That Influence...
Sequential Pathological Changes...
Future Therapeutic Implications
Future Studies
References
From Myocarditis to Cardiomyopathy: Mechanisms of Inflammation and Cell Death : Learning From the Past for the Future -- Kawai 99 (8): 1091 -- Circulation
2. In the chronic stages of viral myocarditis, it is crucial to determine the significance of persistent enterovirus RNA and other virus
genomes such as hepatitis C virus RNA in the myocardium long after virus infection, in regard to carrier state infections, virus/immune
interactions, and autoimmune mechanisms with or without a triggering by a virus infection to develop dilated cardiomyopathy.
3. In the hypothesis that an underlying viral infection in acute myocarditis progresses to dilated cardiomyopathy in the chronic stage, a
novel concept, apoptosis, has emerged. Although reliable diagnostic criteria for apoptosis remain to be established, this revolutionary
concept may explain the ongoing cardiac damage in the absence of inflammatory responses.
Conclusions
This review summarizes the current status of clinical and experimental studies of the underlying viral pathogenesis of acute myocarditis
that progresses to dilated cardiomyopathy. It should be borne in mind that the evolution of myocardial disease and the development of
dilated cardiomyopathy clearly demarcated into stages in animal models cannot be extrapolated to humans. However, the concepts
derived from the results of the animal experiments described here will no doubt contribute to the establishment of a new paradigm for the
pathogenesis of viral myocarditis and dilated cardiomyopathy and thus to the elucidation of effective treatments for these diseases.
References
Top
Abstract
Introduction
Host Factors That Influence...
Sequential Pathological Changes...
Future Therapeutic Implications
Future Studies
References
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