(Circulation. 1999;99:1091-1100.)
© 1999 American Heart Association, Inc.
Current Perspective |
From Myocarditis to Cardiomyopathy: Mechanisms of Inflammation and Cell Death
Learning From the Past for the Future
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.
From Kyoto University and Kyoto Regional Study Center, University of the Air.
Correspondence to Chuichi Kawai, MD, Nishiiru Karasuma Shimochojamachi-dori, Kamikyoku, Kyoto 602-8002, Japan.
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Abstract |
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Abstract—A progression from viral myocarditis to dilated cardiomyopathy has long been hypothesized, but the actual extent of this progression has been uncertain. However, a causal link between viral myocarditis and dilated cardiomyopathy has become more evident than before with the tremendous developments in the molecular analyses of autopsy and endomyocardial biopsy specimens, new techniques of viral gene amplification, and modern immunology. The persistence of viral RNA in the myocardium beyond 90 days after inoculation, confirmed by the method of polymerase chain reaction, has given us new insights 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
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Introduction |
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TopAbstractIntroductionHost Factors That Influence...Sequential Pathological Changes...Future Therapeutic ImplicationsFuture StudiesReferences |
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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 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
The present review summarizes clinical and experimental studies on the viral origin of myocarditis and dilated cardiomyopathy and suggests directions for future investigations.
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Host Factors That Influence Susceptibility to Viral Myocarditis |
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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.
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 |
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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
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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 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
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.
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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
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
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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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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
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 cell-mediated 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 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 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.
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Future Therapeutic Implications |
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TopAbstractIntroductionHost Factors That Influence...Sequential Pathological Changes...Future Therapeutic ImplicationsFuture StudiesReferences |
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1- and ß-Adrenergic Blockers, Calcium Channel
Blockers, ACE Inhibitors, and AmiodaroneThe 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.
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 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
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 cyclosporine-treated 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 T- and 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
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 anti-inflammatory
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 anti-CD40L monoclonal antibody suppressed myocardial injuries, which in contrast were exacerbated by anti-B7-2 monoclonal antibody administration in murine viral myocarditis.107
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Future Studies |
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TopAbstractIntroductionHost Factors That Influence...Sequential Pathological Changes...Future Therapeutic ImplicationsFuture StudiesReferences |
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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, B7-2, 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. 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.
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References |
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P. E. F. Daubeney, A. W. Nugent, P. Chondros, J. B. Carlin, S. D. Colan, M. Cheung, A. M. Davis, C.W. Chow, R. G. Weintraub, and on behalf of the National Australian Childhood Car Clinical Features and Outcomes of Childhood Dilated Cardiomyopathy: Results From a National Population-Based Study Circulation, December 12, 2006; 114(24): 2671 - 2678. [Abstract] [Full Text] [PDF]
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H. Mahrholdt, A. Wagner, C. C. Deluigi, E. Kispert, S. Hager, G. Meinhardt, H. Vogelsberg, P. Fritz, J. Dippon, C. -T. Bock, et al. Presentation, Patterns of Myocardial Damage, and Clinical Course of Viral Myocarditis Circulation, October 10, 2006; 114(15): 1581 - 1590. [Abstract] [Full Text] [PDF]
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Developed in Collaboration With the European Heart, D. P. Zipes, A. J. Camm, M. Borggrefe, A. E. Buxton, B. Chaitman, M. Fromer, G. Gregoratos, G. Klein, A. J. Moss, et al. ACC/AHA/ESC 2006 Guidelines for Management of Patients With Ventricular Arrhythmias and the Prevention of Sudden Cardiac Death--Executive Summary: A Report of the American College of Cardiology/American Heart Association Task Force and the European Society of Cardiology Committee for Practice Guidelines (Writing Committee to Develop Guidelines for Management of Patients With Ventricular Arrhythmias and the Prevention of Sudden Cardiac Death) J. Am. Coll. Cardiol., September 5, 2006; 48(5): 1064 - 1108. [Full Text] [PDF]
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Developed in Collaboration With the European Heart, D. P. Zipes, A. J. Camm, M. Borggrefe, A. E. Buxton, B. Chaitman, M. Fromer, G. Gregoratos, G. Klein, A. J. Moss, et al. ACC/AHA/ESC 2006 Guidelines for Management of Patients With Ventricular Arrhythmias and the Prevention of Sudden Cardiac Death: A Report of the American College of Cardiology/American Heart Association Task Force and the European Society of Cardiology Committee for Practice Guidelines (Writing Committee to Develop Guidelines for Management of Patients With Ventricular Arrhythmias and the Prevention of Sudden Cardiac Death) J. Am. Coll. Cardiol., September 5, 2006; 48(5): e247 - e346. [Full Text] [PDF]
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J. W. Magnani and G. W. Dec Myocarditis: Current Trends in Diagnosis and Treatment Circulation, February 14, 2006; 113(6): 876 - 890. [Full Text] [PDF]
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Z. Yuan, M. Nimata, T.-a. Okabe, K. Shioji, K. Hasegawa, T. Kita, and C. Kishimoto Olmesartan, a novel AT1 antagonist, suppresses cytotoxic myocardial injury in autoimmune heart failure Am J Physiol Heart Circ Physiol, September 1, 2005; 289(3): H1147 - H1152. [Abstract] [Full Text] [PDF]
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H. Mahrholdt, A. Wagner, R. M. Judd, U. Sechtem, and R. J. Kim Delayed enhancement cardiovascular magnetic resonance assessment of non-ischaemic cardiomyopathies Eur. Heart J., August 1, 2005; 26(15): 1461 - 1474. [Abstract] [Full Text] [PDF]
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R. W. Azuma, J.-i. Suzuki, M. Ogawa, H. Futamatsu, N. Koga, Y. Onai, H. Kosuge, and M. Isobe HMG-CoA reductase inhibitor attenuates experimental autoimmune myocarditis through inhibition of T cell activation Cardiovasc Res, December 1, 2004; 64(3): 412 - 420. [Abstract] [Full Text] [PDF]
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R. L. DeBiasi, B. A. Robinson, B. Sherry, R. Bouchard, R. D. Brown, M. Rizeq, C. Long, and K. L. Tyler Caspase Inhibition Protects against Reovirus-Induced Myocardial Injury In Vitro and In Vivo J. Virol., October 15, 2004; 78(20): 11040 - 11050. [Abstract] [Full Text] [PDF]
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H. Mahrholdt, C. Goedecke, A. Wagner, G. Meinhardt, A. Athanasiadis, H. Vogelsberg, P. Fritz, K. Klingel, R. Kandolf, and U. Sechtem Cardiovascular Magnetic Resonance Assessment of Human Myocarditis: A Comparison to Histology and Molecular Pathology Circulation, March 16, 2004; 109(10): 1250 - 1258. [Abstract] [Full Text] [PDF]
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M. Afanasyeva, D. Georgakopoulos, D. F. Belardi, A. C. Ramsundar, J. G. Barin, D. A. Kass, and N. R. Rose Quantitative Analysis of Myocardial Inflammation by Flow Cytometry in Murine Autoimmune Myocarditis: Correlation with Cardiac Function Am. J. Pathol., March 1, 2004; 164(3): 807 - 815. [Abstract] [Full Text] [PDF]
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Z. Yuan, K. Shioji, Y. Kihara, H. Takenaka, Y. Onozawa, and C. Kishimoto Cardioprotective effects of carvedilol on acute autoimmune myocarditis: anti-inflammatory effects associated with antioxidant property Am J Physiol Heart Circ Physiol, January 1, 2004; 286(1): H83 - H90. [Abstract] [Full Text] [PDF]
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Z. Yuan, Y. Liu, Y. Liu, J. Zhang, C. Kishimoto, Y. Wang, A. Ma, and Z. Liu Peroxisome proliferation-activated receptor-{gamma} ligands ameliorate experimental autoimmune myocarditis Cardiovasc Res, September 1, 2003; 59(3): 685 - 694. [Abstract] [Full Text] [PDF]
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U. Kuhl, M. Pauschinger, P. L. Schwimmbeck, B. Seeberg, C. Lober, M. Noutsias, W. Poller, and H.-P. Schultheiss Interferon-{beta} Treatment Eliminates Cardiotropic Viruses and Improves Left Ventricular Function in Patients With Myocardial Persistence of Viral Genomes and Left Ventricular Dysfunction Circulation, June 10, 2003; 107(22): 2793 - 2798. [Abstract] [Full Text] [PDF]
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U. Kuhl, M. Pauschinger, M. Noutsias, J.-F. Kapp, and H.-P. Schultheiss Diagnosis and treatment of patients with virus induced inflammatory cardiomyopathy Eur. Heart J. Suppl., December 1, 2002; 4(suppl_I): I73 - I80. [Abstract] [PDF]
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A. Hjalmarson, M. Fu, and R. Mobini Who are the enemies? Inflammation and autoimmune mechanisms Eur. Heart J. Suppl., November 1, 2002; 4(suppl_G): G27 - G32. [Abstract] [PDF]
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M. Sato, T. Toyozaki, K. Odaka, T. Uehara, Y. Arano, H. Hasegawa, K. Yoshida, K. Imanaka-Yoshida, T. Yoshida, M. Hiroe, et al. Detection of Experimental Autoimmune Myocarditis in Rats by 111In Monoclonal Antibody Specific for Tenascin-C Circulation, September 10, 2002; 106(11): 1397 - 1402. [Abstract] [Full Text] [PDF]
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M. Afanasyeva and N. R. Rose Cardiomyopathy Is Linked to Complement Activation Am. J. Pathol., August 1, 2002; 161(2): 351 - 357. [Full Text] [PDF]
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T. P. Zwaka, D. Manolov, C. Ozdemir, N. Marx, Z. Kaya, M. Kochs, M. Hoher, V. Hombach, and J. Torzewski Complement and Dilated Cardiomyopathy: A Role of Sublytic Terminal Complement Complex-Induced Tumor Necrosis Factor-{alpha} Synthesis in Cardiac Myocytes Am. J. Pathol., August 1, 2002; 161(2): 449 - 457. [Abstract] [Full Text] [PDF]
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B.-K. Lim, S.-C. Choe, J.-O. Shin, S.-H. Ho, J.-M. Kim, S.-S. Yu, S. Kim, and E.-S. Jeon Local Expression of Interleukin-1 Receptor Antagonist by Plasmid DNA Improves Mortality and Decreases Myocardial Inflammation in Experimental Coxsackieviral Myocarditis Circulation, March 19, 2002; 105(11): 1278 - 1281. [Abstract] [Full Text] [PDF]
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J. E. Parrillo Inflammatory Cardiomyopathy (Myocarditis) : Which Patients Should Be Treated With Anti-Inflammatory Therapy? Circulation, July 3, 2001; 104(1): 4 - 6. [Full Text] [PDF]
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R. Wojnicz, E. Nowalany-Kozielska, C. Wojciechowska, G. Glanowska, P. Wilczewski, T. Niklewski, M. Zembala, L. Polonski, M. M. Rozek, and J. Wodniecki Randomized, Placebo-Controlled Study for Immunosuppressive Treatment of Inflammatory Dilated Cardiomyopathy : Two-Year Follow-Up Results Circulation, July 3, 2001; 104(1): 39 - 45. [Abstract] [Full Text] [PDF]
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T. Miyamoto, A. Matsumori, M.-W. Hwang, R. Nishio, H. Ito, and S. Sasayama Therapeutic effects of FTY720, a new immunosuppressive agent, in a murine model of acute viral myocarditis J. Am. Coll. Cardiol., May 1, 2001; 37(6): 1713 - 1718. [Abstract] [Full Text] [PDF]
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R. L. DeBiasi, C. L. Edelstein, B. Sherry, and K. L. Tyler Calpain Inhibition Protects against Virus-Induced Apoptotic Myocardial Injury J. Virol., January 1, 2001; 75(1): 351 - 361. [Abstract] [Full Text]
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K. Shan, R. J. Bick, B. J. Poindexter, S. F. Nagueh, S. Shimoni, M. S. Verani, F. Keng, M. J. Reardon, G. V. Letsou, J. F. Howell, et al. Altered Adrenergic Receptor Density in Myocardial Hibernation in Humans : A Possible Mechanism of Depressed Myocardial Function Circulation, November 21, 2000; 102(21): 2599 - 2606. [Abstract] [Full Text] [PDF]
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C. M Oakley GENERAL CARDIOLOGY: Myocarditis, pericarditis and other pericardial diseases Heart, October 1, 2000; 84(4): 449 - 454. [Full Text]
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G. M. Felker, J. P. Boehmer, R. H. Hruban, G. M. Hutchins, E. K. Kasper, K. L. Baughman, and J. M. Hare Echocardiographic findings in fulminant and acute myocarditis J. Am. Coll. Cardiol., July 1, 2000; 36(1): 227 - 232. [Abstract] [Full Text] [PDF]
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J.-F. Wang, J. Zhang, J.-Y. Min, M. F. Sullivan, C. S. Crumpacker, W. H. Abelmann, and J. P. Morgan Cocaine enhances myocarditis induced by encephalomyocarditis virus in murine model Am J Physiol Heart Circ Physiol, March 1, 2002; 282(3): H956 - H963. [Abstract] [Full Text] [PDF]
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