Chapter 70

Myocarditis and Dilated Cardiomyopathy

Noel R. Rose1 and Ziya Kaya2
1
Department of Pathology and W. Harry Feinstone Department of Molecular Microbiology and Immunology, The Johns Hopkins University Medical
Institutions, Baltimore, MD, USA, 2Department of Cardiology, University of Heidelberg, Heidelberg, Germany

Chapter Outline
Historical Background 1033 Immunologic Assessment of Biopsies 1038
Clinical, Pathologic, and Epidemiologic Features 1033 Genetic Features 1039
Myocarditis 1033 Environmental Features 1039
Dilated Cardiomyopathy 1035 Animal Models and Pathogenic Mechanisms 1040
Autoimmune Features and Immunologic Markers 1037 Treatment and Outcome 1043
Circulating Antibodies 1037 Personal Thoughts 1044
Immunofluorescence 1037 Acknowledgments 1044
Western Immunoblot 1038 References 1044
Immunoassay with Defined Antigens 1038

HISTORICAL BACKGROUND because of the availability of better antemortem diagnos-

The role of autoimmunity in cardiovascular disease has
long been a topic of investigation in the clinic and the lab-
oratory. Years of research effort were devoted to establish-
ing a link between streptococcal infection and rheumatic
heart disease on the basis of an autoimmune response (see
Chapter 69). Chagas’ disease is still believed to be based
on a cross-reaction of antibodies to Trypanosoma cruzi
with myocardial or cardiac conductive tissue (Coura and
Borges-Pereira, 2012). Finally, post-pericardiotomy syn-
drome and post-myocardial infarction syndrome are some-
times cited as instances of an autoimmune response
instigated by damaged or necrotic tissue (Maisch et al.,
1979). This chapter reviews the evidence linking autoim-
munity with two important forms of heart disease, myo-
carditis and dilated cardiomyopathy (DCM). It must be
stated, ab initio, that immunologic testing has so far not
been effective in allowing a clear distinction between
autoimmune and other etiologies of these diseases.
The classic description of myocarditis was given by
Corvisart in 1812 (referenced in Gravanis and Sternby,
1991), but for many years progress in studying the disease
was impeded by the uncertainties of clinical diagnosis.
Definitive diagnosis was dependent upon autopsy exami-
nation. Interest in the disease increased in recent years
tic tools, especially the endomyocardial biopsy, greater
understanding of the role of cardiotropic viruses, and the
potential of new modalities of therapy.
CLINICAL, PATHOLOGIC, AND
EPIDEMIOLOGIC FEATURES
Myocarditis
While myocarditis may be asymptomatic, the major fea-
tures include arrhythmias (palpitations, dizziness, syncope,
or sudden cardiac death), embolic events, congestive heart
failure, or cardiogenic shock. These clinical findings can
be supported by electrocardiographic changes, such as
nonspecific ST-T wave abnormalities and atrial or ventric-
ular arrhythmias. Two-dimensional echocardiography, a
noninvasive way of evaluating heart size and function,
may show normal ventricular size with thick walls and
decreased contractility early in the illness or progressive
heart enlargement with thinning of the muscle in chronic
cases. Biventricular enlargement is seen in chronic cases.
A pericardial rub may be detected, indicating pericardial
irritation with or without a pericardial effusion. As the dis-
ease progresses, gallop rhythms and signs of congestive

N. Rose & I. Mackay (Eds): The Autoimmune Diseases, Fifth edition. DOI: http://dx.doi.org/10.1016/B978-0-12-384929-8.00070-8
© 2014 Elsevier Inc. All rights reserved. 1033
1034 PART | 14 Cardiovascular System and Lungs

heart failure appear. The patient may recall a recent

viral illness with symptoms of malaise, chills and TABLE 70.1 An Exemplary Classification Scheme for
fever, upper respiratory or gastrointestinal symptoms, Myocarditis (Modified from Sagar et al., 2011)
myalgia, and chest pain. The majority of cases, however, Etiologic Histologic Clinicopathologic
cannot be traced back to an obvious preceding illness.
Viral, such as enteroviruses Eosinophilic Fulminant
Most patients with myocarditis present with either left
(e.g., Coxsackie B),
ventricular failure or arrhythmias as their only clinical Erythroviruses (eg, Giant cell Acute
signs. Parvovirus B19),
Studies of the occurrence of myocarditis in North adenoviruses, and Herpes
America, Europe, and Japan have suggested that the inci- viruses
Bacterial, such as Granulomatous Chronic active
dence varies widely in different areas (Jacobson et al.,
Corynebacterium diphtheria,
1997). Prevalence figures of 1.06, 3.5, 5.4, and as high as Staphylococcus aureus,
10 have been reported in different series (Gravanis and Borrelia burgdorferi, and
Sternby, 1991). The reasons for these wide differences are Ehrlichia species
not known, but may be related to the differing diagnostic Protozoal, such as Babesia Lymphocytic Chronic persistent
Trypanosomal, such as
criteria used or may reflect exposures to different
Trypanosoma cruzi
types and strains of cardiotropic viruses, as well as Toxic: alcohol, radiation,
genetic differences in the host populations. The 5-year chemicals (hydrocarbons
survival of biopsy-proven acute or chronic myocarditis in and Arsenic), and drugs,
adults is only 56% (Grogan et al., 1995). In pediatric including doxorubicin
Hypersensitivity:
populations, the prevalence and mortality are even
sulfonamides and penicillins
higher. Noren et al. (1976) described histologic evidence
of latent myocarditis in 4.2% of accidental deaths of
children and 16.7% of unexplained, unexpected deaths,
suggesting that unsuspected myocarditis may be a signifi-
cant cause of unexpected death in children (Liberthson,
1996). Fabre et al. describe myocarditis in up to 12% of 2 3 years (Lieberman et al., 1991). Patients with giant
cases of sudden death in young adults (Fabre and cell or necrotizing eosinophilic myocarditis (Sagar et al.,
Sheppard, 2006). Prospective studies have also revealed a 2012) develop rapidly progressive mildly dilated but
grave prognosis for myocarditis patients, with a 5- to severely hypofunctional cardiomyopathy and have a life
10-year survival rate of 25 46%, mostly due to manifes- expectancy, without vigorous treatment, that is measured
tations of DCM and sudden cardiac death (Dec et al., in months.
1985; McCarthy et al., 2000; Magnani et al., 2006; The so-called Dallas criteria, the consensus of a group
Caforio et al., 2007). of cardiovascular pathologists, led to better standardiza-
The clinical diagnosis of myocarditis remains a chal- tion of the histopathologic examination (Aretz et al.,
lenge (Schultheiss and Kuhl, 2011). Myocarditis can be 1986). Active myocarditis requires the presence of mono-
classified by etiology, histology, immunohistology, clini- nuclear inflammation associated with adjacent myocyte
cal pathologic, or clinical criteria (Table 70.1). Felker damage (Figure 70.1). Myocyte damage can take the form
et al. (2000) and McCarthy et al. (2000) have demon- of necrosis or myocyte vacuolization. The term borderline
strated that the prognosis of cardiomyopathy in patients myocarditis is applied when an unequivocal diagnosis of
with myocarditis is dependent on the clinical pathologic myocarditis cannot be made either because the inflamma-
classification of their initial disorder. Patients with fulmi- tory infiltrate is too sparse or because the damage to the
nant myocarditis, who do not die within the first 2 weeks, myocyte is not clearly demonstrable (Figure 70.2). The
have a survival rate which is virtually identical to that of terminology used for subsequent biopsies is ongoing,
age-matched controls. Patients with subacute myocarditis resolving, or resolved myocarditis. Ongoing myocarditis
who develop persistent left ventricular dysfunction indicates persistent myocardial inflammation associated
have an outcome that is virtually identical to that of with myocyte damage. Resolving myocarditis resembles
patients with idiopathic DCM. Patients with chronic per- borderline myocarditis, but reparative fibrosis is evident.
sistent myocarditis, while they continue to have myocar- Resolved or healed myocarditis is diagnosed if no inflam-
dial inflammation, have no deterioration in ventricular matory infiltrate is seen. The Dallas criteria also require
function and usually have a normal survival. Patients that myocarditis be distinguished from the histologic
with chronic active myocarditis and who have ongoing pattern of myocardial injury evident in ischemic heart dis-
inflammation and fibrosis develop a restrictive cardiomy- ease. The inflammatory infiltrate in myocarditis is com-
opathy severe enough to require transplantation within posed primarily of mononuclear cells, although in the
Chapter | 70 Myocarditis and Dilated Cardiomyopathy
FIGURE 70.1 Lymphocytic myocarditis. There is a heavy infiltrate
of large activated lymphocytes throughout the myocardium. Myocyte
necrosis is noted in the middle of this image. Fibrosis is present on the
right side of the image. (H&E 4003)
more acute phases polymorphonuclear cell infiltration is
common. Giant cells and prominent eosinophilia are seen
in some cases of myocarditis and often indicate a dire
outcome.
The Dallas criteria, which have been used extensively
for clinical trials, may be too insensitive to diagnose many
patients with inflammatory heart disease. In one trial, only
9.6% of 2233 patients with a clinical diagnosis of myocar-
ditis were positive by the rigid Dallas criteria (Mason and
O’Connell, 1989). Utilizing the Dallas criteria even in
patients who have died of myocarditis, and with five tissue
samples, it is only possible to establish a histologic diagno-
sis of myocarditis in 54% of patients (Chow et al., 1989;
Hauck et al., 1989). Additionally, in Towbin et al.’s (1994)
study of children with suspected clinical myocarditis (67%
of these patients had adenoviral infection), 13 of the 26
patients positive for viral nucleic acid by the polymerase
chain reaction (PCR) did not display the histopathologic
features that would allow the diagnosis of myocarditis to
be established. The standard Dallas criteria are further lim-
ited by variability in interpretation as well as low sensitiv-
ity. These limitations have led to alternative pathological
classifications. Wojnicz et al. (2001) and Frustaci et al.
(2003), utilizing upregulation of HLA by endomyocardial
biopsy or the presence of antiheart antibodies as markers of
an autoimmune response, identified patients with suspected
myocarditis who appeared to respond to immunosuppres-
sive therapy.
Additional criteria rely on cell-specific immunoperoxi-
dase stains for surface antigens, such as anti-CD3, anti-
CD4, anti-CD20, anti-CD68, and anti-human leukocyte
antigen (HLA) (Herskowitz et al., 1990; Maisch et al.,
2000). Criteria that are based on immunoperoxidase stain-
ing have greater sensitivity and may have prognostic value.
1035
Nevertheless there is the diagnostic lack due to sampling
error. Noninvasive cardiac magnetic resonance imaging
(MRI) may provide additional diagnostic value (Jesirich
et al., 2010). With the unique potential for tissue characteri-
zation using T1- and T2-weighted images, cardiac MRI can
evaluate three important markers of tissue injury: (1) intra-
cellular and interstitial edema; (2) hyperemia and capillary
leakage; and (3) necrosis and fibrosis (Mahrholdt et al.,
2004; Abdel-Aty et al., 2005; Gutberlet et al., 2008;
Friedrich et al., 2009). In practice, although the number of
medical centers performing endomyocardial biopsy has
been increased, it is still not routinely performed in all
patients and all centers.
There are several distinct histologic forms of myocarditis
(Basso et al., 2012). Drug- or allergy-mediated myocarditis
is characterized by an eosinophilic infiltrate. Fulminant myo-
carditis demonstrates intense infiltration in virtually all sec-
tions with marked myocyte necrosis (Figure 70.3). Chronic
active myocarditis reveals ongoing myocardial inflammation
associated with fibrosis and occasional giant cells
(Lieberman et al., 1993). Giant-cell myocarditis is a rare but
frequently fatal form of myocarditis (Figure 70.4) (Elamm,
et al., 2012). The victims are primarily young, healthy adults
who die suddenly of heart failure or ventricular arrhythmia.
Although cardiac transplantation may be curative, several
instances of recurrent disease in the transplanted heart have
been reported. Histologic findings in giant-cell myocarditis
are diffuse myocardial necrosis with numerous multinucle-
ated giant cells and a mixed inflammatory infiltrate of lym-
phocytes and macrophages. Collections of eosinophils are
seen in some of these patients.
Dilated Cardiomyopathy
Dilated cardiomyopathy (DCM) is a chronic form of heart
disease characterized by left and right ventricular dilata-
tion and impaired contraction (Gravanis and Ansari,
1987). The clinical spectrum is broad, ranging from indi-
viduals with asymptomatic cardiomegaly to patients who
present with severe congestive heart failure. Patients may
also display symptoms or signs of arrhythmia or systemic
embolization with or without congestive heart failure.
Other signs include systemic or pulmonary venous con-
gestion, cardiomegaly, gallop rhythms, and mitral or tri-
cuspid regurgitation. The diagnosis requires exclusion of
heart failure due to other causes, such as coronary artery
disease, toxic exposure, drug allergy, medication (adria-
mycin) effect, or physical agent injury. Once heart failure
is established in a patient with DCM, the expected out-
come is poor, with a 5-year mortality of 46% (Grogan
et al., 1995). D’Ambrosio et al. describe in long-term fol-
low-up studies in patients with acute myocarditis the
development of DCM in 21% of patients over a mean
follow-up period of 3 years (D’Ambrosio et al., 2001).
1036
(A)
FIGURE 70.2 Borderline myocarditis. (A) A single cluster of perivascular lymphocytes is present. No myocardial damage is identified. (H&E
400 3 ). (B) A CD8 immunohistochemical stain highlights the infiltrating T lymphocytes. (H&E 4003)
FIGURE 70.3 Fulminant myocarditis. The myocardium is replaced
by a marked polymorphous inflammatory infiltrate composed predomi-
nantly of lymphocytes and macrophages with rarer eosinophils and neu-
trophils. Global myocyte injury and loss is noted. No giant cells are
present. (H&E 100 3)
Several studies have investigated the frequency of
familial dilated cardiomyopathy. Petretta et al. report in
their meta-analysis an estimated clinically confirmed
FDC of 23% (95% confidence interval 0.17 to 0.31) was
found (Petretta et al., 2011). Furthermore, a large number
of other etiologic agents have been associated with DCM
(Felker et al., 2000), including infections and metabolic,
endocrinologic, and nutritional disturbances, as well as
toxins and drugs. However, in approximately 50% of
patients, no specific etiology can be identified. The same
pathologic process probably results from a number of dif-
ferent etiologies.
Evidence for pathophysiologic relevance of autoim-
munity in DCM has substantially increased over the past
PART | 14 Cardiovascular System and Lungs
(B)
years. Several circulating autoantibodies, some of them
heart specific, have been described in animal experiments
and first clinical pilot studies suggest that antibodies,
including antibodies to the β1-adrenoceptor, play a crucial
role in the induction and progression of heart failure. But
the precise mechanisms on how these autoantibodies per-
petuate or even induce an organ-specific autoimmune
response are not yet fully understood (Leuschner et al.,
2008; Deubner et al., 2010; Kaya et al., 2010, 2012).
Clinical observations on prognostic relevance of autoanti-
bodies have the prompted therapeutic trials focused on
nonspecific removal of autoantibodies from the circula-
tion via immunoadsorption. There are early reports on a
beneficial outcome in patients treated by immunoadsorp-
tion (Felix and Staudt, 2006).
To address cardiac autoimmunity the prospective
Etiology, Titer-Course, and effect on Survival (ETiCS) of
cardiac autoantibodies has been initiated. It is the largest
European clinical diagnostic study initiated so far in the
field of cardiac autoimmunity. ETiCS will enhance cur-
rent knowledge on autoimmunity in human heart disease
and promote endeavors to develop novel therapies target-
ing cardiac autoantibodies (Deubner et al., 2010).
In 1985, the prevalence of DCM in Olmsted County,
Minnesota, was 36.5 in 100,000. African American race
and male gender were associated with increased risk
(Cetta and Michels, 1995). The incidence of DCM in
Malmö, Sweden, was reported to be 10 in 100,000 per
year (Torp, 1981), and estimated in Great Britain at
0.7 7.5 in 100,000 per year, with a prevalence in 1985
of 8.3 cases in 100,000 (Williams and Olsen, 1985). In a
nationwide study in Finland, the incidence of DCM
among children and adolescents was 0.34 in 100,000 per
Chapter | 70 Myocarditis and Dilated Cardiomyopathy
FIGURE 70.4 Giant cell myocarditis. The myocardium is infiltrated
by a patchy and diffuse inflammatory infiltrate composed primarily of
lymphocytes and macrophages. Multiple collections of giant cells are
seen within the infiltrate along with eosinophils. There is significant
injury and loss of myocytes in areas of inflammation, while adjacent
myocardium is relatively uninvolved. (H&E 503).
year, with a prevalence in 1991 of 2.6 in 100,000. In chil-
dren, the incidence is higher in boys than girls, and higher
in babies younger than 1 year than in older children
(Jefferies and Towbin, 2010). Although the male predom-
inance in this disease is not great, it stands in contrast to
most autoimmune disorders that occur more frequently in
females. The basis of the male predominance is still not
clearly understood, but appears to be related to sex-based
differences in cytokine formation. The number of new
cases increased each year over the 10-year study period
(Arola et al., 1997). Since a number of these patients uti-
lize significant medical resources in their care or eventu-
ally require cardiac transplantation, there is a great need
for early and definitive diagnosis.
Cases representing progression from myocarditis to
DCM can be termed inflammatory DCM (Maisch et al.,
2000); Kline and Saphir (1960) documented progressive
myocardial failure and death in a series of patients within
months to years after acute myocarditis. Miklozek et al.
(1986) found that 12 of 16 patients diagnosed as having
viral myocarditis had continued cardiac functional
abnormalities. Abelmann (1984) reported that half of
16 patients had cardiac symptoms or physical evidence of
persistent cardiac dysfunction after recovery from acute
myocarditis. Most symptomatic relatives of DCM patients
with left ventricular dysfunction have evidence of
myocardial inflammation consistent with early or mild
myocarditis (Mahon et al., 2002).
Like myocarditis, DCM may be associated with
Coxsackievirus infection. In 50 infants and children with
DCM, Ayuthya et al. (1974) found significantly increased
titers of neutralizing antibody to Coxsackieviruses B3.
1037
Initially, Bowles et al. (1986) and Kandolf et al. (1987)
demonstrated Coxsackievirus B-specific nucleic acid
sequences in heart tissue of a small number of patients
with DCM. Since then molecular testing has become
increasingly sophisticated. Towbin et al. (1994) demon-
strated that children with suspected myocarditis were
PCR positive for viral etiologies on endomyocardial
biopsy (26 of 38 samples from 34 patients). Additionally,
the viral sequences demonstrated were more frequently
adenoviral (15) than enteroviral (8).
In cases of DCM, the heart assumes a globular shape
due to enlargement of all of the chambers, especially the
left ventricle (Gravanis and Ansari, 1987). The histologic
findings are generally nonspecific, and include myocar-
dial cell hypertrophy and an increase in interstitial fibrous
connective tissue. In areas of degeneration of the myocar-
dial fibers, small clusters of lymphocytes may be seen.
This finding may blur the distinction of DCM from
myocarditis.
AUTOIMMUNE FEATURES AND
IMMUNOLOGIC MARKERS
Circulating Antibodies
The ambiguities in diagnosing inflammatory disease of
the heart muscle are evident. Although the availability of
endomyocardial biopsy has helped to clarify the situation,
many cases are still inconclusive. There is, at present, a
need for noninvasive, inexpensive diagnostic procedures
to distinguish autoimmune from other forms of inflamma-
tory heart disease. Much evidence points to a significant
role of autoimmunity in some animal models of heart
muscle disease. It is logical, therefore, to propose that
serologic tests, based on the demonstration of circulating
autoantibodies to cardiac antigens, might be useful in the
identification of autoimmune forms of myocarditis and
DCM in humans. The literature has been reviewed by
Caforio et al. (2002), Cihakova and Rose (2008), and,
most recently, Kaya et al. (2012).
Immunofluorescence
Immunofluorescence tests utilize cardiac tissue of rat or
human origin. Both frozen sections and isolated myocytes
have been employed. Antibody generally localizes at the
surface of the myocyte, giving a sarcolemmal or myolem-
mal pattern, or on the striations, producing a fibrillar pat-
tern. Whether these two immunofluorescent patterns
represent antibodies of different specificities is unclear,
because both patterns can be seen in sera from mice
immunized with purified cardiac myosin. A major prob-
lem in the interpretation of indirect immunofluorescence
is the high prevalence of reactions obtained with sera
1038
from healthy control subjects. Maisch (1987) found that
91% of patients with myocarditis gave positive reactions
with human or rat cardiocytes, but 31 35% of healthy
controls showed similar reactions, although generally at
lower levels. Neumann et al. (1990) used more conserva-
tive criteria, 59% of patients with biopsy-proven myocar-
ditis being positive, as were 20% of patients with DCM.
In contrast, none of the healthy controls and only 4% of
patients with ischemic heart disease were positive in this
test under the conditions used.
Western Immunoblot
The Western immunoblot is potentially more sensitive
than immunofluorescence and is capable of identifying
particular antigens recognized by heart-reactive antibo-
dies. Neumann et al. (1990) detected heart-reactive anti-
bodies in 48 of 103 samples from biopsy-proven
myocarditis or DCM patients by immunofluorescence,
whereas 97 of the 103 samples exhibited reactivity by
Western immunoblotting. No single pattern of antigen
reactivity was unique to patients with myocarditis or
DCM, but myocarditis sera showed an elevated preva-
lence of antibody against myosin heavy chain, whereas
cardiomyopathy sera exhibited a greater prevalence of
reactivity against cardiac muscle actin. Many normal sera
reacted with the same antigen, but generally in lower
titers. A quantitative immunoassay, such as an enzyme-
linked immunosorbent assay (ELISA) using purified
human cardiac myosin heavy chain, therefore, is needed
for clinical evaluation of these antibodies.
Immunoassay with Defined Antigens
Among the well-characterized antigens used for the study
by immunoassay of antibodies in sera of patients with
myocarditis and DCM are myosin (Neumann et al., 1990;
Caforio et al., 1992), laminin (Wolff et al., 1989), β1-
adrenergic receptors (Limas et al., 1989), and the mito-
chondrial components, adenine nucleotide translocator
(ANT) protein (Schultheiss et al., 1986) and branched-
chain ketodehydrogenase (BCKD) (Ansari et al., 1988).
These results show that many patients with myocardi-
tis and DCM develop autoantibodies to a number of car-
diac constituents. Large-scale evaluation is necessary
before it can be concluded that detection of any single
antibody, or group of antibodies, is sufficiently sensitive
and specific to replace the endomyocardial biopsy as a
primary diagnostic tool. It does seem, even at this early
stage of investigation, that a decline in some antibody
titers during treatment may predict a favorable therapeutic
response (Müller et al., 2000).
None of these antibodies to cardiac antigens is known
to play a direct pathogenic role in the disease. However,
PART | 14 Cardiovascular System and Lungs
the presence of antibodies to β1-adrenergic receptors in
DCM is highly suggestive of a direct pathogenic effect,
since the antigen is accessible on the surface of the myo-
cardiocyte. β1-Adrenergic receptor antibodies can induce
apoptosis in isolated adult cardiomyocytes (Staudt et al.,
2003) and antibodies activating the receptors are associ-
ated with reduced cardiac function in chronic heart failure
(Jahns et al., 2010).
While the pathogenic importance of antibodies is still
controversial, the finding that reduction of immunoglo-
bulins in plasma by an immunoadsorption column bene-
fits cardiomyopathy patients provides strong evidence of
their involvement (Winters, 2012). Although immunoad-
sorption does not establish the specificity of the autoan-
tibodies that are depleted, reduction of certain
immunoglobulin subclasses (IgG3) may be especially
beneficial (Nagatomo et al., 2011). In a preliminary
study, absorption columns using β1-adrenergic receptors
benefited patients with the corresponding antibody
(Dandel et al., 2012).
Although the role of T cells in the pathogenesis of
myocarditis has been difficult to study in humans, animal
models have proved to be invaluable in discovering their
pathogenic mechanisms. Findings in mice indicate that
they play a key role in inducing myocarditis (Smith and
Allen, 1991).
Immunologic Assessment of Biopsies
In addition to studies of circulating antibody, immuno-
logic methods can contribute to the diagnosis of heart dis-
ease by the identification of immunoglobulin and
complement in biopsy specimens. Hammond et al. (1988)
found that 55% of patients with active myocarditis had
deposits of IgG and complement component C3 in their
biopsies. Thirty-nine percent of borderline myocarditis
(inflammation without myocyte necrosis) cases and 6% of
DCM cases were also positive. Patients with other auto-
immune diseases, such as systemic lupus erythematosus
and scleroderma, sometimes showed deposits of IgG and
C3 in their heart tissue, but these usually were coarse,
granular deposits in the interstitial spaces of the myocar-
dium or endocardium, probably representing immune
complexes.
Immunofluorescence with defined antisera has been
used to identify infiltrating cells in cardiac biopsies. Luppi
et al. (2003) found that the myocardium of myocarditis and
DCM patients was infiltrated by macrophages and CD41
and CD81 T lymphocytes. In the majority of patients, the T
cell receptor (TCR) repertoire was restricted with a poly-
clonal expansion of the Vb7 gene family. Evidence of
Coxsackievirus infection was also found.
The expression of MHC class I and class II antigens
in biopsy specimens was evaluated by Herskowitz et al.
Chapter | 70 Myocarditis and Dilated Cardiomyopathy
(1990). In control samples, only low levels of MHC class
I molecules were expressed on interstitial cells and vascu-
lar epithelium, while MHC class II could not be demon-
strated immunohistologically. Increased myocardial
expression of MHC class I and de novo expression of
class II antigens were found in 85% of the myocarditis
patients and 33% of the DCM patients.
GENETIC FEATURES
Because of the possible autoimmune origin of myocarditis
and DCM in humans, and the well-documented associa-
tion of experimental myocarditis with the major histocom-
patibility complex (MHC) in mice (Rose et al., 1988), a
number of studies to determine the relationship with the
human MHC (HLA) have been carried out. Anderson
et al. (1984) reported that DCM patients had an increased
frequency of HLA-DR4 and a decreased frequency of
HLA-DR6. These findings were corroborated by Limas
et al. (1990), who also demonstrated an increased fre-
quency of HLA-DR4 in DCM patients. A genetic
predisposition toward cardiac autoimmunity was demon-
strated, in that 72% of HLA-DR41 patients had anti-β1-
adrenergic receptor antibodies compared with 21% of
HLA-DR42 patients. In the largest study to date,
Carlquist et al. (1991) reconfirmed these findings and also
found that the DR4-DQw4 haplotype conferred height-
ened risk of disease. In a meta-analysis of five studies,
they confirmed that the DR4 association with myocarditis
was sustained among different patient populations. No dif-
ferences in disease phenotypes have been reported.
A predominance of myocarditis in males has been
reported in a number of studies. The proportion of male
patients is about 60% (Lieberman et al., 1991; et al.,
1995). In this respect, myocarditis differs from most
autoimmune diseases, which predominantly affect
females.
ENVIRONMENTAL FEATURES
Myocarditis has both infectious and noninfectious causes.
As noninfectious agents of myocarditis, a number of
drugs have been implicated, acting either directly as toxic
agents or as triggers of an allergic response. This section
deals with infectious myocarditis; there is less informa-
tion on cardiac autoimmunity in other forms (see
Table 70.1).
Acute myocarditis is associated with infections of
many types, including bacterial, rickettsial, viral, mycotic,
protozoan, and helminthic. Several viruses have been
implicated in this disease and, in some cases, multiple
viruses may be detected in the heart. In Europe and North
America, among the most common agents are the entero-
viruses and the adenoviruses. Grist and Bell (1974)
1039
reported that Coxsackievirus group B infections were
associated with at least half of the acute cases of myocar-
ditis. By immunofluorescence, Burch et al. (1968) found
Coxsackievirus B antigen in the myocardium of 30.9% of
routine autopsy specimens of myocarditis. Serotype B3 is
identified most frequently. Other studies have suggested
that adenoviruses are more prevalent in pediatric patients
(Bowles et al., 2003).
By using molecular genetic methods, enteroviral and
adenoviral genomes were detected in 10 35% of endo-
myocardial biopsies from patients with myocarditis or
DCM (Baboonian and McKenna, 2003; Pauschinger
et al., 2004). In a study in Europe, 32.6% of biopsies in
the study group contained enteroviral RNA, 8.1% adeno-
virus DNA, 36.6% parvovirus B19 DNA, and 10.5%
human herpesvirus type 6 DNA. In 12.2% of the samples,
dual infection with PVB19 and herpesvirus was present
(Kuhl et al., 2003). A study carried out in the United
States identified parvovirus DNA in 12% of samples, but
its presence did not correlate with clinical presentation
(Stewart et al., 2011).
Like other enteroviruses, Coxsackieviruses enter the
alimentary tract and are acid stable. They multiply in the
small intestine. Following replication, viremia develops,
seeding the infectious agents in selected tissues. As an
obligatory intracellular parasite, the virus must enter a
cell through receptor-mediated endocytosis. The virus
receptor determines the tropism of the virus. Cardiotropic
CB3 employs myocyte surface molecules as receptors,
whereas hepatotropic or diabetogenic virus strains utilize
receptors on hepatocytes or pancreatic islet cells, respec-
tively. The infection may cause cell death directly, or act
indirectly to stimulate an immunopathic host response
(Huber, 1997). Coxsackievirus B3 RNA can persist in the
myocardium for many days after infectious virus is no
longer demonstrable (Klingel et al., 1992) and may, even
without the ability to multiply, cause ventricular compro-
mise in the face of a stimulated immune system (Wessely
et al., 1998; Esfandiarei and McManus, 2008).
The CB3 genome is a single molecule of positive-
sense RNA of approximately 7400 nucleotides in length.
The genome codes for four capsid proteins as well as for
the nonstructural proteins necessary for viral replication.
A comparison of cloned cDNA from cardiovirulent and
noncardiovirulent strains showed that sites within a non-
translated region and in the capsid protein affect virulence
(Tracy et al., 1996).
Nutrition also plays a role in determining susceptibil-
ity to viral myocarditis. Beck et al. (1995) demonstrated
that mice fed a diet deficient in selenium and infected
with a noncardiovirulent strain of CB3 developed severe
myocardial damage. Virus isolated from the hearts was
fully virulent; six point mutations distinguished the viru-
lent strains. The accumulation of these multiple mutations
1040
may be the result of greater viral replication in the hearts
of selenium-deficient mice and may be attributable to
decreased immune responses compared to selenium-
adequate mice (Levander and Beck, 1997). These results
may shed light on the etiology of an endemic form of car-
diomyopathy known as Keshan disease, seen primarily in
selenium-deficient regions of China (Abelmann, 1984).
Chagas’ disease is a major cause of heart muscle dis-
ease in Latin America, responsible for 8 to 9 million
cases annually (Hashimoto and Yoshioka, 2012). It is
caused by the hemoflagellate Trypanosoma cruzi, which
is transmitted to humans via the bite of the reduviid
triatomine bug. Most patients initially have only mild,
influenza-like symptoms, but 10 30% of infected indi-
viduals develop fulminant myocarditis. Chronic
Chagas’ disease may present with arrhythmias, throm-
boembolic events, and congestive heart failure. It repre-
sents a particularly lethal form of cardiomyopathy, as
survival after presentation is two- to four-fold shorter
than that of patients with other forms of DCM (Cunha-
Neto et al., 2004).
Antibodies to a number of cardiac antigens, including
fibronectin, laminin, and myosin, are found in many
patients with chronic Chagas’ disease, as well as with
other forms of DCM (Ballinas-Vedugo et al., 2003).
Molecular mimicry between T. cruzi and heart disease
has been cited as a mechanism to explain the production
of autoantibodies during infection (Kalil and Cunha-
Neto, 1996). A number of candidate antigens have been
described, including a heart-specific epitope of cardiac
myosin heavy chain and a 12-amino acid peptide of
Fl160, a 160-kDa protein on the surface of T. cruzi that
mimics a similar protein found on mammalian axonal
and myenteric plexus cells (Van Voorhis et al., 1991).
The latter antibody is of special interest because of the
occurrence of megacolon, megaesophagus, and other
neuropathies during chronic Chagas’ disease. Among the
other antigens described as possible initiators of cross-
reactive responses are a peptide of the second extracellu-
lar loop of the β1-adrenergic receptor (Ferrari et al.,
1995), a T. cruzi ribosomal protein R13 (Motran et al.,
2000), a ribosomal P protein (Kaplan et al., 1997), and
Cha. The latter antigen is recognized by T cells of
patients as well as antibodies (Girones et al., 2001). An
early decision about the course of immunity is made dur-
ing the early innate response determined by activation of
Toll-like receptors and macrophage development. The
subsequent adaptive immunity may be protective or path-
ogenic (Pellegrini et al 2012).
Kawasaki syndrome is an acute febrile disease of
infants and young children that is often associated with
myocarditis (see Chapter 72). In addition to prolonged
fever lasting more than 5 days, the principal signs are dif-
fuse mucosal inflammation, bilateral nonpurulent
PART | 14 Cardiovascular System and Lungs
conjunctivitis, dysmorphic skin rashes, indurative angioede-
ma of hands and feet, and cervical lymphadenopathy (Kuo
et al., 2012). Although the etiology is uncertain, available
evidence implicates bacterial infection. Cunningham et al.
(1999) showed that sera from five of 13 patients with
Kawasaki syndrome recognized peptides from the light
meromysin region of human cardiac myosin and had a dif-
ferent pattern of reactivity from acute rheumatic fever sera.
ANIMAL MODELS AND PATHOGENIC
MECHANISMS
Since enteroviruses are most often implicated in human
myocarditis and DCM, these agents have been widely used
to investigate the pathogenic mechanisms of these diseases.
Although infections by CB3 are relatively common, the
development of clinically significant, ongoing myocardial
disease in humans is relatively uncommon, suggesting that
differences in host response play a critical role in disease
susceptibility. These differences are likely to be genetically
determined and may relate to the expression of virus-
specific receptor on heart tissue or to the immune response
of the host. Because it is difficult to examine the role that
genetic polymorphisms play in humans, investigators have
developed models of Coxsackievirus-induced myocarditis
in mice, for which a large number of genetically different,
inbred strains are available.
A model of the timecourse of viral myocarditis is illus-
trated in Figure 70.5. All strains of mice tested developed
acute myocarditis starting 2 or 3 days after CB3 infection.
The disease reached its peak on day 7 and gradually
resolved so that by day 21 the heart was histologically nor-
mal. No infectious virus was found after day 9. In a few
strains of mice, however, the myocarditis persisted (Rose
et al., 1987; Cihakova and Rose, 2008), but the histologic
picture shifted. The first phase was characterized by focal
necrosis of myocytes and accompanying a focal acute
inflammatory response with a mixed cell infiltrate consist-
ing of polymorphonuclear and mononuclear cells. In those
mice that developed the second phase of disease, the
inflammatory process was diffuse rather than focal and
consisted mainly of mononuclear interstitial infiltrates,
including both T and B lymphocytes and little or no myo-
cyte necrosis. In the mice that developed the second phase
of disease, heart-reactive autoantibodies were present and
shown to be specific for the cardiac isoform of myosin
(Neu et al., 1987a). This finding suggested that the second
phase represented an autoimmune response initiated by the
viral infection. Direct evidence to support this hypothesis
was produced by immunizing the susceptible strains of
mice with purified cardiac myosin and showing that they
developed a very similar histologic picture of myocarditis
(Neu et al., 1987b). No heart disease was found in animals
Chapter | 70 Myocarditis and Dilated Cardiomyopathy
FIGURE 70.5 Schematic of the pathogenesis of viral myocarditis.
that received skeletal myosin and none appeared in the
strains of mice that were not genetically susceptible to the
second phase. They found evidence that this form of
inflammatory heart disease was due to an immune
response to cardiac myosin, assembled by inducing spe-
cific tolerance to cardiac myosin (Wang et al., 2000;
Fousteri et al., 2011). This finding suggested that the sec-
ond phase represents an autoimmune response initiated by
molecular mimicry between the virus and heart antigens
(Cunningham, 2004). On the other hand, available evi-
dence suggests that the autoimmune response depends
upon virus-induced damage to the heart since Horwitz
et al. (2000) found that transgenic mice expressing inter-
feron gamma (IFN-γ) in their pancreatic cells failed to
produce CB3-induced myocarditis, even though the virus
proliferated great in other sites. These findings suggest
that the virus infection may serve as an adjuvant for car-
diac antigens that have been expressed or liberated during
the viral infection of the heart (Rose, 2000). Of importance
is the finding that a number of other viruses unrelated to
Coxsackieviruses such as cytomegalovirus produce a simi-
lar autoimmune myocarditis following infection. The
experiments showing that myocarditis can be produced by
immunization with cardiac myosin in animals that have
not undergone viral infection demonstrate that the disease
does not depend upon persisting virus even though it is
possible to demonstrate traces of viral RNA in the heart of
Coxsackievirus B3 infected animals.
Unless subjected to exercise stress, most mice survived
the autoimmune phase of myocarditis whether induced by
viruses, infection, or by immunization with cardiac myo-
sin. Gradually the disease waned in severity (Rose and
Hill, 1996; Cihakova and Rose, 2008). Under some condi-
tions, however, the histologic picture changed again to
1041
produce a mainly fibrotic disease. As the process contin-
ued, there was a thinning of the ventricular cell walls and
a large increase in size of the left ventricle. By day 35,
after infection or immunization there were definite signs
of cardiac insufficiency and by day 60, most of the ani-
mals with these changes died of heart failure. This form
of the disease, whether induced by viral infection or myo-
sin autoimmunity, replicated the major characteristics of
dilated cardiomyopathy, suggesting that DCM can repre-
sent an end stage of autoimmune myocarditis in some
instances.
The striking finding from the investigations described
above was that strains of mice highly susceptible to the
autoimmune myocarditis following viral infection were
also the strains most susceptible to the myosin-induced
disease. On the other hand, other strains were relatively
resistant to both forms of myocarditis. These observations
indicated that the disease susceptibility was under a large
measure of genetic control. As in most autoimmune dis-
eases, genes of the major histocompatibility complex
have an important influence on the development and
course of autoimmune disease (Li et al., 2008a). Thus, in
both the viral and myosin-induced models, the H-2s,
H-2a, and H-2b alleles were associated with increased
morbidity of autoimmune myocarditis, whereas the H-2b
allele is associated with a relatively low susceptibility.
These MHC polymorphisms were further reflected in the
prevalence and titer of cardiac-specific autoantibodies.
The genetic findings in the mouse can be related to
human myocarditis through experiments by Hayward
et al. (2006) and Taneja and David (2009), who demon-
strated a spontaneous myocarditis model in NOD mice
carrying the transgenically introduced human HLA-DQ8
allele associated with greater susceptibility to human
1042
DCM. Like many autoimmune diseases in animals and
humans, non-MHC genes play a determining role in sus-
ceptibility to myocarditis. To determine the non-MHC
genes that affect susceptibility to myosin-induced myo-
carditis, genome-wide linkage analysis was carried out
and revealed at least two prominent loci that had signifi-
cant effects on susceptibility to autoimmune myocarditis.
A putative susceptibility gene, eam1, was located on the
proximal end of chromosome 1 and eam2 on the distal
region of chromosome 6. Both of these chromosomal seg-
ments bore genes determining susceptibility to a number
of other autoimmune diseases such as autoimmune
encephalomyelitis and autoimmune arthritis as well as
spontaneous diabetes.
In addition to lending themselves to genetic studies,
the experimental models of autoimmune myocarditis
provide the opportunity of following the inflammatory
process from the beginning to the end (Rose, 2011). The
first major question to be considered was the basis of the
susceptibility to autoimmune myocarditis following the
virus infection. Studies show that two critical cytokines,
IL-1β and TNF-α, were both necessary and sufficient for
the progression from viral myocarditis to autoimmune
myocarditis. Blocking either one of these two cytokines
prevented the transition from viral to autoimmune myo-
carditis even in the most highly susceptible strains. Even
more important was the demonstration that providing
either of these two cytokines in recombinant form
allowed normally resistant mice to develop the autoim-
mune form of myocarditis just like their genetically sus-
ceptible counterparts. The earlier signs of susceptibility
to autoimmune myocarditis become evident very early
in the course of viral infection. In fact, significant eleva-
tions of IL-1β were found as early as 8 hours after viral
infection (Fairweather et al., 2004a,b). Thus, the innate
immune response to the virus is the determining factor
in later susceptibility to autoimmune disease. Some evi-
dence points to the mast cell as particularly important in
producing the mediators that determine the course of
innate immunity to the virus. In addition, NK cells
which are also activated during the innate immune
response are responsible for downregulating susceptibil-
ity to the autoimmune response.
An important lesson to be learned from these experi-
ments is that the early steps in innate immunity deter-
mine the later course of adaptive autoimmune diseases.
Adoptive transfer experiments using myosin or myosin
peptide-induced disease have shown that the induction
of autoimmune myocarditis depends upon myosin-
specific CD4 T cells (Smith and Allen, 1991; Li et al.,
2008b; Chen et al., 2012). The course of the inflamma-
tion during autoimmune myocarditis can be traced to the
relative proportions of certain key cytokines. Severe
forms of autoimmune myocarditis are associated with
PART | 14 Cardiovascular System and Lungs
greater production of IL-12 P40 (a Th1 signal), IL-4 (a
Th2 signal), and IL-23 (a signal of the Th17 response)
(Rose, 2011). On the other hand, IFN-γ, a signature of
Th1 responses, definitely retards the development of
autoimmune myocarditis as do two cytokines associated
with Th2 responses, IL-10 and IL-13. These findings are
striking examples of the cytokine “interactome”; they
further suggest a balance of cytokines affects not only
the severity, but the profile of inflammation. For exam-
ple, IL-4 promotes a particularly severe form of eosino-
philic giant-cell myocarditis in A/J mice. IL-17A, a
cytokine associated with neutrophilic inflammation in
some other autoimmune conditions, has little impact on
the severity of inflammation in the myosin-induced auto-
immune disease. It is, however, critical for the later pro-
gression to dilated cardiomyopathy; animals deprived of
IL-17A fail to develop the subsequent fibrotic disease.
The disease can actually be prevented by administering
antibody to IL-17A earlier in the course of inflamma-
tion. This key role of IL-17 may be related to its estab-
lished ability to increase granulocyte proliferation as
well as to activate macrophages. A cytokine acting with
IL-17, i-GM-CSF, stimulates both granulocytes and
monocytes. On the other hand, M-CSF, which acts only
to increase monocytes, retards the development of
dilated cardiomyopathy.
An issue critical to understanding the pathogenesis
of autoimmune myocarditis is the dynamic balance of
mediators tending to favor inflammation and cardio-
myocyte injury with mediators that reduce or retard
inflammation. In contrast to some other experimental
models of autoimmune disease, IFN-γ is downregula-
tory in myocarditis and its deficiency produces a partic-
ularly severe form of the disease. IL-10 and IL-13 are
also downregulatory whereas IL-4 and IL-5 contribute
to severity of the disease. In fact, elevated IL-5 produc-
tion induces a disease with a Th2 phenotype and exten-
sive infiltration by eosinophils, like the disease in
humans, eosinophilic myocarditis in mice tends to be
rapidly fatal.
As mentioned previously, other cardiac-specific anti-
gens can induce autoimmune myocarditis. Goser et al.
(2006) demonstrated the provocation of an autoimmune
response to cardiac troponin I, which induces severe
inflammation in the myocardium of mice followed by
fibrosis and heart failure, with marked mortality. These
investigators identified two sequence motifs of cardiac
troponin I that induced inflammation and fibrosis in the
myocardium (Kaya et al., 2008). Interestingly, these same
animals eventually developed immunity to cardiac myo-
sin following at least 90 days of inflammation. Thus,
autoimmune myocarditis, like most autoimmune diseases,
is characterized by the production of multiple organ-
specific autoantibodies.
Chapter | 70 Myocarditis and Dilated Cardiomyopathy
TREATMENT AND OUTCOME
Until recently, the only treatment for myocarditis and
DCM was supportive therapies, such as bedrest and treat-
ment of heart failure, arrhythmias, and embolic events if
present. In many centers, cardiac transplantation has
become the eventual treatment of choice in patients with
refractory heart failure. In patients whose condition dete-
riorates despite optimal medical management, mechanical
circulatory support, such as ventricular assist devices or
extracorporeal membrane oxygenation, serve as a bridge
to transplantation or recovery.
The role of immunosuppressive therapy in myocarditis
remains controversial (Maisch et al., 2004). Numerous
reported studies on relatively small numbers of patients
have generally found that, while some individuals respond
well to immunosuppression (prednisone and cyclospor-
ine), others fail to respond or even have serious adverse
reactions that preclude continued treatment. The major
problem at present is surely the difficulty in distinguish-
ing immune-mediated cardiac disease from infectious,
genetic, or toxic forms of the disease. Obviously, until
there are reliable biomarkers to distinguish autoimmune
myocarditis/DCM, treatment cannot be rational or capable
of statistical evaluation.
A placebo-controlled study of the treatment of idio-
pathic DCM was performed by Parrillo et al. (1989).
The study demonstrated that unselected patients with
DCM overall did not benefit substantially from immu-
nosuppressive therapy, but a small, if transient, benefit
was demonstrated in patients who had histologic evi-
dence of active inflammation by biopsy.
Mason et al. (1995) assigned a series of patients with
a histopathologic diagnosis of myocarditis (based on the
Dallas criteria) and a low left ventricular ejection fraction
to receive conventional therapy, with or without a
24-week course of prednisone plus cyclosporine or azathi-
oprine. The outcome assessed was improvement in the
left ventricular ejection fraction at 28 weeks compared
with a placebo control group. No significant functional
improvement was seen with immunosuppressive therapy.
It should be noted, however, that during the establishment
of the trial as many as 2233 patients with a clinical and
pathologic diagnosis of myocarditis were presented for
entry by their cardiologists, but only 111 met the strict
Dallas criteria; i.e., some 95% of patients with a prelimi-
nary diagnosis of myocarditis failed to fulfill the Dallas
criteria. The patients who would be expected to benefit
most from immunosuppressive treatment are those with
primarily autoimmune rather than viral myocarditis.
This interpretation is favored by the report of Kühl
and Schultheiss (1995), who selected 48 patients present-
ing with mild-to-severe heart failure and immunohistolo-
gic evidence of an active immunologic process on biopsy.
1043
After a 6-month treatment with 6-methylprednisolone, 23
experienced objective improvement in cardiac function.
The suggestion of this study is that in a subgroup of
patients with an active immunopathologic process immu-
nosuppressive treatment will confer clinical benefit.
Wojnicz et al. (2001) evaluated 202 patients with idio-
pathic DCM by endomyocardial biopsy. Eighty-four of
these 202 on biopsy had expression of HLA class II mole-
cules. Those patients were randomized to immunosup-
pressive therapy or placebo. While the major outcome of
the trial (death, transplantation, or hospitalization) was
unchanged by treatment, the ejection fraction in the trea-
ted population rose from 24 to 36%, while it was virtually
unchanged in the placebo group (25 to 27%). In addition,
subjective parameters of improvement were noted at 3
months in 72% of the immunosuppressive therapy
patients compared with only 21% of the control group.
Frustaci et al. (2003) identified 112 of 652 patients with
new-onset left ventricular compromise who had a presen-
tation compatible with myocarditis. Forty-one of the 112
had progressive heart failure despite standard heart failure
management. This patient population was treated with
prednisone and azathioprine. Twenty of the 41 patients
responded while 21 did not. The investigators determined
retrospectively that those who responded had antiheart
antibodies by immunofluorescence, and those who failed
to respond had persistent virus demonstrated by PCR
analysis of the endomyocardial biopsy. Additionally,
Jones et al. (1991) demonstrated that in 20 patients with
Dallas criteria-positive myocarditis, those with borderline
myocarditis had a greater improvement in their ejection
fraction by echocardiography and stroke work index from
right heart catheterization than those with frank myocardi-
tis. These studies suggest that there soon may be more
sensitive and specific biomarkers for immune-mediated
heart disease than are currently available by the Dallas
criteria.
Different myocarditis populations may respond dif-
ferently. Patients with fulminant myocarditis usually
resolve spontaneously and there is suggestive evidence
that immunosuppressive therapy may worsen the out-
come. In contrast, the treatment of giant-cell myocarditis
with immunosuppression may improve the prognosis by
slowing progression of the disease (Cooper, 2002),
suggesting that this form of the disease is an autoim-
mune variant.
Other therapeutic approaches have been based on the
possible pathogenic role of humoral antibodies. As
described above, several investigators reduced the level
of circulating immunoglobulin by means of an immu-
noabsorption column, and showed improvement in car-
diac function. McNamara et al. (2001) demonstrated in
a trial of 72 patients with new onset cardiomyopathy
that 2 g/kg of intravenous immunoglobulin failed to
1044
improve ejection fraction or survival when compared
with placebo-treated patients. Early trials have shown
promising results using extra corporeal immunoadsorp-
tion of antibodies to the p1-adrenoreceptor in the IgG3
subclass (Staudt et al., 2002, 2003; Winters, 2012).
On the premise that many patients with myocarditis or
idiopathic DCM have an undisclosed persistent viral
infection, Miric et al. (1994) treated a series of 180
patients with IFN-α or thymomodulin. Left ventricular
function, exercise tolerance, and survival rate were signif-
icantly improved in patients given the immunomodulatory
therapy. Kühl et al. (2003) treated 22 patients with proven
viral myocarditis with IFN-β. The treatment was well tol-
erated. All patients cleared the viral genome and showed
improved left ventricular function.
The above studies make it obvious that treatment of
myocarditis and DCM is still problematic. As more is
learned about the pathogenic mechanisms in these dis-
eases, treatments can be individualized.
PERSONAL THOUGHTS
The diseases described in this chapter exemplify the
broad range of cardiovascular disorders with which auto-
immune responses have been implicated. Until very
recently the role of autoimmunity in cardiovascular dis-
eases had been rather neglected. Yet, before the early
1960s, rheumatic fever was a major topic of investigation.
Although the decline of rheumatic fever in the 1960s
accounted for a loss of interest in this topic, it must be
recognized that the studies of rheumatic fever were the
stimulus for many current concepts of autoimmunity and
autoimmune disease. A renaissance in cardiovascular
immunology followed efforts to define the role of autoim-
munity in myocarditis and DCM. There is now a substan-
tial challenge in developing reliable and robust in vitro
assays that define autoimmune heart disorders with the
same sensitivity and specificity now available in autoim-
mune disorders affecting other major organs. These stud-
ies will also serve as the impetus to delineate the
contribution of autoimmunity to other enigmatic cardio-
vascular diseases such as atherosclerosis (see Chapter 71).
Further, they provide as a general model for studying the
steps relating infection to the onset of autoimmune dis-
ease (see Chapter 19).
ACKNOWLEDGMENTS
The figures were prepared by Dr. Marc Halushka and Dr. Jobert
Barin, Department of Pathology, Johns Hopkins School of
Medicine. The authors dedicate this chapter to their late colleague,
Kenneth Baughman, a co-author of the original chapter.
PART | 14 Cardiovascular System and Lungs
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