# 30 - 268 Acute and Chronic Myocarditis

### 268 Acute and Chronic Myocarditis

Neal K. Lakdawala, 

Lynne Warner Stevenson, Joseph Loscalzo

Acute and Chronic 

Myocarditis
Myocarditis is defined as inflammation of the heart muscle, which 
may present acutely, subacutely, or insidiously. Outcomes can include 
resolution, relapsing course, or progression to chronic cardiomyopathy. 
Myocarditis is generally considered acute when presenting with less 
than a month of symptoms, often only a few days. The profile of acute 
myocarditis is changing as the use of sensitive troponin assays and car­
diac magnetic resonance imaging (MRI) are increasing recognition of 
mild cases with good outcomes. Acute myocarditis is most often attrib­
uted to active infection but can be caused by multiple types of nonin­
fectious inflammation, such as sarcoidosis, giant cell and eosinophilic 
myocarditis, and systemic autoimmune disease or immunotherapies. It 
is uncertain as to how often chronic myocardial inflammation contrib­
utes to dilated cardiomyopathy. As with other cardiomyopathies, there 
is increasing implication of genetic predisposition to inflammatory 
responses and of independent pathogenic variants as primary cause of 
myocyte pathology, with almost one in five patients with inflamma­
tory myocarditis harboring genetic variants considered pathogenic for 
cardiomyopathy.
MODELS OF INFECTIOUS MYOCARDITIS
Infectious agents can injure the myocardium through direct invasion 
with disruption of normal cellular processes and through activation 
of different phases of immune responses with or without persistent 
infection. Although myocarditis has been reported with most types of 
infectious agents, it is most often associated with viruses and the pro­
tozoal disease Trypanosoma cruzi (Chagas’ disease). The pathogenesis 
of viral myocarditis has been traditionally portrayed in three phases, 
arising from extensive study in murine models of enteroviruses, with 
much less known about human infection. As defined by infection 
with coxsackie B virus, phase I includes direct invasion of the myocar­
dium. Cellular entry may be enhanced by some genetic variants of the 
coxsackie/adenovirus receptors. The enteroviral protease A degrades 
the myocyte structural protein dystrophin and interacts with other 
proteins to induce apoptosis and interfere with autophagy. Direct 
myocardial invasion with entry of the viral genome has been shown to 
occur with the enteroviruses, HIV, and dengue virus. However, most 
common viruses do not appear to inflict cardiac damage directly. Early 
cardiac effects may result primarily from cytokine storm and other 
nonspecific immune responses leading to myocardial depression. This 
initial immune response appears to be crucial to recovery, as early 
immunosuppression increased viral replication and worsened cardiac 
injury in animal models.
The second phase is host response to infection in recognition of 
common antigenic patterns, triggering macrophage activation and 
expansion of specific T- and B-cell populations. Myocarditis due to 
this phase of immune response without direct viral-mediated injury is 
considered to be virally “triggered” myocarditis, implicated with respi­
ratory viruses including adenovirus, influenza, and COVID-19. Molec­
ular mimicry between viral and cardiac antigens may be the cause of 
some cases of myocardial injury caused by autoreactive T cells in the 
absence of ongoing viral infection. There is increasing study of the 
role of viral “hijacking” of cellular machinery to produce extracellular 
vesicles containing viral RNA that may then gain protected entry into 
other cells. A third phase of progression to chronic cardiomyopathy 
has been demonstrated in animal models of enteroviruses. However, 
myocarditis is rarely due to enteroviruses in adults. There are limited 
data providing direct links between chronic cardiomyopathy and previous 
viral infection (see “Chronic Myocarditis and Cardiomyopathy” below). 
The MRI pattern of intramyocardial late gadolinium enhancement 

in chronic cardiomyopathy was previously considered as evidence of 
prior viral myocarditis, but this pattern is now recognized to be com­
mon in genetic cardiomyopathy as well.

CHAPTER 268
ACUTE MYOCARDITIS
■
■PRESENTATION AND DIAGNOSIS
Acute myocarditis in adults typically occurs between 30 and 45 years 
and is more common in men than women, who tend to present at 
over 45 years of age. Prodromal symptoms typical of influenza, gas­
troenteritis, or upper respiratory infection may have occurred days to 
a few weeks earlier. Fever is present in over half of cases. Chest pain 
is the most common symptom of acute myocarditis, occurring in 
>80% of patients, who also often present with dyspnea or arrhythmias. 
Arrhythmias can manifest as palpitations or syncope but can also cause 
sudden cardiac death, as in an autopsy series in which inflammatory 
myocarditis was diagnosed 3–10% of previously healthy young adults. 
At presentation, about one-fourth of acute myocarditis cases include 
left ventricular ejection fraction (LVEF) <0.50, ventricular arrhyth­
mias, or clinical shock, which is reported in ~3–9% of cases and termed 
fulminant myocarditis.
Acute and Chronic Myocarditis 
Viral titers are not often helpful to guide initial therapy of acute 
myocarditis. Respiratory viral panels can confirm recent infection 
with influenza and adenovirus, most implicated in acute myocarditis 
in adults with a viral prodrome. Finding of COVID-19 may alert 
to extracardiac involvement. Specific infectious serologies for HIV, 
Chagas’ disease, cytomegalovirus, dengue fever, and Lyme disease and 
serologies for systemic autoimmune disease should be sent in selected 
patients. Eosinophil counts should be routinely checked because hype­
reosinophilia is present in most cases of eosinophilic myocarditis.
The common definition for “probable myocarditis” includes new 
appearance of least one symptom listed above and at least one sup­
porting finding, which can be elevated troponin levels, consistent 
ECG findings, or imaging findings of decreased LVEF or obvious wall 
motion abnormality. Other laboratory findings may include elevated 
creatine phosphokinase levels, indicating cardiac or skeletal muscle 
involvement, and elevated C-reactive protein levels. The most com­
mon electrocardiogram (ECG) findings are ST elevation suggesting 
infarction, but also include conduction block, tachyarrhythmias, and 
nonspecific ST-T changes. Because the combination of chest pain, ECG 
changes, and elevated troponin is typical of both acute myocarditis 
and myocardial infarction, the first step in the differential diagnosis is 
often coronary artery imaging. Subsequent diagnosis of acute myocar­
ditis has been reported in up to one-third of patients with myocardial 
infarction and nonobstructed coronary arteries (MINOCA).
“Definite myocarditis” previously required positive biopsy findings 
of typical inflammatory lymphocytic infiltrate on myocardial biopsy 
(Fig. 268-1).
Newer techniques of immunohistochemistry may increase sensitiv­
ity of biopsies and advance our understanding of the inflammatory cell 
populations. However, the diagnosis can now be confirmed noninva­
sively when typical symptomatic presentation is accompanied by com­
bination of elevated troponin levels and consistent findings on MRI, 
which include evidence of both myocardial edema and nonischemic 
myocardial injury in the absence of other known cause (Fig. 268-2).
Although cardiac MRI may often be sufficient to diagnose acute 
myocarditis, endomyocardial biopsy should be performed when ven­
tricular arrhythmias, conduction block, elevated eosinophil count, 
or evidence of systemic autoimmune disease suggests causes of acute 
myocarditis with specific implications for therapy and prognosis, as 
discussed below in “Noninfective Inflammatory Myocarditis.”
■
■THERAPY AND OUTCOMES
The prognosis is good for “uncomplicated” acute myocarditis, present­
ing with LVEF ≥0.50 without ventricular arrhythmias or circulatory 
shock. In the largest series, this low-risk group accounted for about 
three-fourths of patients with acute myocarditis, in which spontaneous 
recovery was common without specific therapies other than diuretics 
and nonsteroidal analgesics for chest pain. Almost all of these patients

PART 6
Disorders of the Cardiovascular System
FIGURE 268-1  Acute myocarditis. Microscopic image of an endomyocardial biopsy 
showing massive infiltration with mononuclear cells and occasional eosinophils 
associated with clear myocyte damage. The myocyte nuclei are enlarged and 
reactive. Such extensive involvement of the myocardium would lead to extensive 
replacement fibrosis even if the inflammatory response could be suppressed. 
Hematoxylin and eosin–stained section, 200× original magnification. (Image 
courtesy of Robert Padera, MD, PhD, Department of Pathology, Brigham and 
Women’s Hospital, Boston.)
still had LVEF ≥0.50 on follow-up imaging and survived without trans­
plantation at 5 years of follow-up. In the one-fourth of patients with 
complicated presentations, ~18% died or underwent heart transplanta­
tion in the next 5 years. Patients with reduced LVEF are generally dis­
charged on the recommended therapies for heart failure with reduced 
ejection fraction (HFrEF). There are no data supporting routine immu­
nosuppression in patients with acute myocarditis with presumed viral 
etiology. Fulminant myocarditis requiring high-dose inotropic therapy 
or mechanical circulatory support occurs in 3–9% of acute myocarditis, 
with early outcomes of refractory cardiogenic shock but recovery to 
near-normal LVEF in >50% of affected patients.
CHRONIC MYOCARDITIS AND 
CARDIOMYOPATHY
Patients with reduced LVEF at the time of presentation with acute 
myocarditis are at higher risk of developing chronic cardiomyopathy. 
When the LVEF does not resolve in the initial months after diagnosis, 
FIGURE 268-2  Magnetic resonance image of myocarditis showing the typical midwall location (arrow) for late gadolinium enhancement from cardiac inflammation 
and scarring. (Image courtesy of Ron Blankstein, MD, and Marcelo Di Carli, MD, 
Division of Nuclear Medicine, Brigham and Women’s Hospital, Boston.)

particularly with persistent elevation of troponin, cardiac magnetic 
resonance imaging (CMRi) or endomyocardial biopsy may reveal 
ongoing inflammation and developing fibrosis. Evaluation should 
again be considered for specific etiologies of myocarditis including 
noninfectious causes of inflammatory disease and for other causes of 
dilated cardiomyopathy (Chap. 266, Table 266-2).
Evidence of chronic inflammatory disease may also be found 
in some patients presenting with gradual onset of dilated cardio­
myopathy without prior acute myocarditis. Immunosuppression 
for nonspecific lymphocytic myocarditis in the chronic setting has 
been tried in multiple series but has not demonstrated convinc­
ing benefit. Additional findings of anticardiac antibodies and viral 
genome fragments are of uncertain significance, as they could be 
either causes of ongoing cardiac injury or neutral bystanders. Assay 
for anticardiac antibodies and viral genome analysis in chronic 
cardiomyopathy continue to be investigated but are not in routine 
clinical use.
In the past, dilated cardiomyopathy without other cause was gener­
ally assumed to result from previously unrecognized viral myocarditis, 
in part because CMRi patterns of fibrosis suggested prior inflamma­
tion. However very similar patterns are typical of genetic cardiomy­
opathies. The expanding access to genetic testing reveals that 20–40% 
of patients with dilated cardiomyopathy have pathogenic variants suf­
ficient to cause their cardiomyopathy, and the prevalence and nature 
of these variants are similar in acute myocarditis. Mapping of the 
interconnections between genetic predisposition, inflammation, and 
cardiomyopathy is evolving rapidly.
■
■SPECIFIC CAUSES OF INFECTIOUS MYOCARDITIS
The first viruses implicated in infectious myocarditis were the picor­
navirus family of RNA viruses, principally the enteroviruses, coxsackie 
virus, echovirus, and poliovirus. Influenza, another RNA virus, is 
implicated with varying frequency every winter and spring as epitopes 
change. Of the DNA viruses, adenovirus, vaccinia, and the herpes­
viruses (varicella-zoster virus, cytomegalovirus, Epstein-Barr virus, 
and human herpesvirus 6 [HHV6]) can cause myocarditis but also 
occur commonly in the healthy population. Polymerase chain reaction 
(PCR) detects viral genomes in some patients with dilated cardio­
myopathy and persistent lymphocytic infiltrates defined as “chronic 
myocarditis,” such as the DNA viruses parvovirus B19 and HHV6, but 
these are also found in normal “control” hearts, so their contribution 
to chronic cardiomyopathy is uncertain.
COVID-19 is an RNA virus for which infection was associated with 
substantial rates of cardiac involvement in patients hospitalized with 
severe disease, including acute coronary syndrome, thromboemboli, 
pericarditis, and myocarditis, for which the diagnosis was limited to 
clinical findings and elevated enzymes rather than demonstration of 
lymphocytic infiltrates, as biopsies were rarely performed. From broad 
population data, the rate of myocarditis during the pandemic was 
estimated at 150/100,000 people, a 15-fold increase over pre-COVID 
incidence. As for most causes of viral myocarditis, the most common 
adult patients are young men under the age of 40. As for other viruses, 
there are multiple potential mechanisms of cardiac injury. Viral par­
ticles were identified by PCR in myocardial samples but in low levels 
at which pathogenicity was uncertain. Other mechanisms include 
cytokine storm, activated T cells and macrophages, and potential 
molecular mimicry by which autoimmune reactions may be triggered, 
as for some animal models of myocarditis with other viruses. As with 
multiple other viruses, extracellular vesicles containing viral RNA have 
been identified in myocardium during COVID infection, potentially 
promoting protected entry into other cells for further injury. In addi­
tion, the endothelium is also vulnerable, leading to prothrombotic 
endotheliopathy that may contribute to myocardial ischemia and 
stroke, along with the systemic coagulopathy.
HIV was associated with a dilated cardiomyopathy incidence of 
1–2%, but this is declining with the availability of highly active anti­
retroviral therapy. Cardiomyopathy in HIV may also result from other 
associated viruses, such as cytomegalovirus and hepatitis C. Antiviral 
drugs to treat chronic HIV can cause cardiomyopathy, both directly

and through drug hypersensitivity. The clinical picture may be com­
plicated by pericardial effusions and pulmonary hypertension. There is 
an increased frequency of lymphocytic myocarditis found at autopsy; 
HIV viral particles have been demonstrated in the myocardium in 
some cases.
For any serious infection, the systemic inflammatory response can 
cause nonspecific depression of cardiac function, which is generally 
reversible if the patient survives. Other viruses implicated specifically 
in myocarditis include mumps, respiratory syncytial virus, the arbovi­
ruses (dengue fever and yellow fever), and arenaviruses (Lassa fever).
■
■OTHER INFECTIOUS CAUSES
Parasitic Myocarditis 
Chagas’ disease is the third most com­
mon parasitic infection in the world and the most common infective 
cause of cardiomyopathy. The protozoan T. cruzi is transmitted by 
the bite of the reduviid bug, endemic in the rural areas of South and 
Central America. Transmission can also occur through blood transfu­
sion, organ donation, from mother to fetus, and occasionally orally. 
Programs to eradicate the insect vector have decreased the global 
prevalence from about 18 million in 1990 to 6 million, with the highest 
number of cases in Brazil and Argentina and increased prevalence also 
in Spain. It is estimated that >300,000 residents in the United States 
are infected with Chagas’ disease, a minority of whom have acquired 
it locally.
Initial infection with T. cruzi is usually silent but, in 5–10% of 
cases, can present with systemic illness and acute myocarditis with 
systemic dense parasitic infiltration in the myocardium forming 
pseudocysts that rupture and lead to diffuse myocyte necrosis. After 
initial infection, patients enter an “indeterminate phase,” which can 
last for decades. The silent progression during this phase was at one 
time attributed to secondary immune activation, but a degree of per­
sistent parasitemia can now be detected and is recognized as the major 
determinant of ongoing inflammation and progression to chronic 
heart failure. Depopulation of parasympathetic neurons in the heart 
and gastrointestinal tract likely contributes to clinical disease. Under­
standing of the disease patterns has improved in part from the ability 
to test blood donors for infection. Better detection of the organism 
has revealed that both the prevalence and survival of patients in the 
indeterminate phase are higher than previously recognized, with over 
half of patients remaining asymptomatic.
T. cruzi infection should be considered during evaluation of acute 
myocarditis or cardiomyopathy in all patients from endemic regions 
and for other patients with suggestive features. These include sinus 
and atrioventricular node conduction system disease and right bundle 
branch block, with frequent atrial and ventricular arrhythmias, some 
of which may cause sudden death before symptomatic disease. The 
dilated ventricles are thrombogenic and sometimes have aneurysms. 
For acute myocarditis, PCR is the most sensitive test and trypomasti­
gotes may also be detected in blood when parasite levels are high. In 
the chronic phase with low parasite burden, multiple serologic tests 
may be necessary for diagnosis, but their sensitivity and specificity are 
improving.
Antiparasitic treatment with nifurtimox or benznidazole is recom­
mended for acute myocarditis with Chagas’ cardiomyopathy. During 
the indeterminate phase prior to clinical symptoms, therapy is widely 
recommended for children. For the indeterminate phase, there is 
controversy over the routine use of antiparasitic treatment, which is 
associated with significant toxicity. Therapy is more often advocated 
for patients <50 years old, who are more likely to tolerate chronic 
suppressive therapy. Treatment is recommended for premenopausal 
women and for patients on immunosuppression, such as after cardiac 
transplantation. A large multinational trial showed no benefit for 
benznidazole given to patients with chronic heart failure from Chagas’ 
cardiomyopathy. In these patients, general therapy is as indicated for 
other HFrEF, with increased indications for anticoagulation and for 
pacemaker defibrillators. Improvement of LVEF is uncommon and 
survival is lower than for other cardiomyopathies after the onset of 
overt clinical heart failure.

Trichinellosis (trichinosis) is caused by the Trichinella genus of 
nematodes (roundworms). The larvae are ingested with undercooked 
meat, with an initial intestinal phase after which larvae migrate into 
skeletal muscles, causing myalgias, weakness, and fever. Periorbital 
and facial edema and conjunctival and retinal hemorrhage may also 
be seen. Although the larva may occasionally invade the myocardium, 
clinical heart failure is rare and, when observed, attributed to the 
eosinophilic inflammatory response. The diagnosis is made from the 
serologies and is further supported by the presence of eosinophilia. 
Treatment includes anthelminthic drugs and glucocorticoids if inflam­
mation is severe.

CHAPTER 268
Acute and Chronic Myocarditis 
Bacterial Infections 
Most bacterial infections can involve the 
heart occasionally through direct invasion and abscess formation but 
do so rarely. More commonly, systemic inflammatory responses to 
severe infection and sepsis depress myocardial contractility.
Diphtheria is caused by bacillus Corynebacterium diphtheriae, usu­
ally presenting with an upper respiratory illness particularly affecting 
the pharynx, where a pseudomembrane is formed in response to the 
diphtheria toxin. This toxin interferes with protein synthesis in the 
heart and may particularly affect the conduction system. Cardiac 
involvement is the most common cause of death from this infection 
but rarely occurs with the occasional dominant cutaneous presenta­
tion. The prevalence of vaccines has shifted the incidence of diphtheria 
to countries without routine immunization and to older populations 
who have lost their immunity. The diagnosis is made from pharyngeal 
bacterial culture, which requires special culture media and a positive 
assay for the toxin but can be suspected from gram-positive rods on a 
Gram stain. Clinical suspicion is sufficient indication for the specific 
antitoxin, which should be administered as soon as possible, with 
higher priority than antibiotic therapy.
Streptococcal infection with β-hemolytic streptococci is most com­
monly associated with acute rheumatic fever and is characterized by 
inflammation and fibrosis of cardiac valves and systemic connective 
tissue, but it can also lead to a myocarditis with focal or diffuse infil­
trates of mononuclear cells. Other systemic bacterial infections that 
can involve the heart include brucellosis, legionella, meningococcus, 
mycoplasma, psittacosis, and salmonellosis, for which specific treat­
ment is directed at the systemic infection.
Tuberculosis can involve the myocardium directly as well as 
through tuberculous pericarditis but rarely does so when the disease 
is treated with antibiotics. Whipple’s disease is caused by Tropheryma 
whipplei. The usual manifestations are in the gastrointestinal tract, but 
pericarditis, coronary arteritis, valvular lesions, and occasionally clini­
cal heart failure may also occur. Multidrug antituberculous regimens 
are effective, but the disease tends to relapse even with appropriate 
treatment.
Tick-Borne Infections 
Spirochetal myocarditis has been diag­
nosed from myocardial biopsies containing Borrelia burgdorferi, which 
causes Lyme disease. Lyme carditis most often presents with arthritis 
and conduction system disease that resolves within 1–2 weeks of anti­
biotic treatment and is only rarely implicated in chronic heart failure. 
Other borrelia species carried by either ticks or lice can cause relapsing 
fever. Additional tick-borne illnesses associated with febrile illnesses 
and myocarditis include Rocky Mountain spotted fever, Q fever, and 
ehrlichiosis, all of which are treated with doxycycline alone or in com­
bination with other agents.
■
■NONINFECTIVE INFLAMMATORY MYOCARDITIS
Myocardial inflammation can occur in the absence of infectious causes. 
The paradigm of noninfective inflammatory myocarditis is cardiac 
transplant rejection, from which we have learned that myocardial 
depression can develop and reverse quickly, that noncellular mediators 
such as antibodies and cytokines play a major role in addition to lym­
phocytes, and that myocardial antigens are exposed by prior physical 
injury and viral infection. In the largest registry of acute myocarditis, 
chronic systemic inflammatory diseases were implicated in 7% of cases 
and in 15% of those with high-risk features.

The most commonly diagnosed noninfective inflammatory process 
affecting the myocardium is sarcoidosis. Sarcoidosis, as discussed in 
Chap. 379, is a multisystem granulomatous disease most commonly 
affecting the lungs, but involving many organs including skin, eyes, 
liver, nervous system, and bones, as well as the heart. The epidemiology 
appears to be changing, now recognized in men and women of all races 
and ethnic groups, typically between 30 and 50 years old but often 
after the age of 50 in women. Sarcoidosis is now understood as a com­
bination of foreign antigen presentation and a dysregulated immune 
response that leads to ongoing inflammation, including activated 
macrophages. Occupational exposures include agriculture, firefight­
ing, metal-working, and construction work, with silica dust, pesticides, 
mold, and other inhaled particles as examples of implicated antigens. 
The occurrence of sarcoidosis is increased in family members, reflect­
ing potential sharing of environments and of genetic variants, which 
have been identified in loci affecting immune responses.

PART 6
Disorders of the Cardiovascular System
Cardiac sarcoidosis often accompanies pulmonary sarcoidosis but 
frequently occurs without detectable lung disease. The time course, 
burden and activity of cardiac granulomata, and the degree of extra­
cardiac involvement are remarkably variable. Patients may present with 
rapid-onset heart failure and ventricular tachyarrhythmias, conduction 
block, chest pain syndromes, or minor cardiac findings in the setting of 
pulmonary sarcoidosis, ocular involvement, an infiltrative skin rash, or 
a nonspecific febrile illness. Chronic sarcoidosis may go unrecognized 
for months or years. When ventricular tachycardia or conduction block 
dominates the initial presentation of heart failure without coronary 
artery disease, suspicion should be high for sarcoidosis as a cause of 
cardiomyopathy. Right bundle branch block should raise suspicion for 
sarcoidosis but is uncommon with other cardiomyopathies, in which 
left bundle branch block is more common.
The pathology of cardiac sarcoidosis often shows a spectrum from 
metabolically active granulomas to bland fibrosis at the sites of previ­
ous inflammation. Regional wall-motion abnormalities are common, 
but global ventricular function may be preserved early during mild 
disease. When left ventricular function is only mildly reduced, ventric­
ular size may be near normal, sometimes described as “nondilated” or 
“minimally dilated cardiomyopathy.” Although occasionally listed with 
restrictive cardiomyopathies, sarcoidosis with a reduced ejection frac­
tion generally has the phenotype of dilated or minimally dilated car­
diomyopathy. There may be a right ventricular predominance of both 
dilation and ventricular arrhythmias, in which case potential diagnoses 
include genetic arrhythmogenic right ventricular cardiomyopathy, with 
which sarcoidosis shares multiple features.
Diagnosis of cardiac sarcoidosis is easiest in the presence of biopsyproven sarcoidosis of other organs. Imaging of the heart can show 
regional wall motion abnormalities or small ventricular aneurysms. 
MRI of the heart can identify late gadolinium enhancement in a pat­
tern of fibrosis not compatible with myocardial infarction. Computed 
tomography of the chest often reveals pulmonary lymphadenopathy 
even in the absence of clinical lung disease. Positron emission tomog­
raphy (PET) of the whole chest can highlight active sarcoid lesions 
that are avid for glucose in heart or lung. When metabolically active 
adenopathy is detected, biopsy is often necessary to rule out malig­
nancy or chronic granulomatous infections such as tuberculosis or his­
toplasmosis before treating with immunosuppression for sarcoidosis. 
The scattered granulomata of sarcoidosis are commonly missed on 
cardiac biopsy (Fig. 268-3).
Immunosuppression for sarcoidosis is generally initiated with 
glucocorticoids. Initial dosing was traditionally high but now is more 
often started at 30–40 mg daily or less, with early addition or substitu­
tion of steroid-sparing agents like methotrexate or mycophenolate. 
Third-line treatment may include tumor necrosis factor-alpha inhibi­
tors or other immunomodulators under investigation. The impact of 
treatment is usually more apparent for suppression of arrhythmias than 
for improvement of markedly impaired left ventricular dysfunction. 
Devices are often indicated for tachyarrhythmias or for conduction 
disease and usually include both pacing and defibrillation capability. 
Patients with sarcoidosis are immunosuppressed, and their manage­
ment should be supervised by an experienced multidisciplinary team. 

FIGURE 268-3  Sarcoidosis. Microscopic image of an endomyocardial biopsy 
showing a noncaseating granuloma and associated interstitial fibrosis typical of 
sarcoidosis. No microorganisms were present on special stains, and no foreign 
material was identified. Hematoxylin and eosin–stained section, 200× original 
magnification. (Image courtesy of Robert Padera, MD, PhD, Department of 
Pathology, Brigham and Women’s Hospital, Boston.)
Cardiac sarcoidosis may respond to the initial immunosuppression 
course without recurrence, may fluctuate over a chronic course, 
or occasionally may lead to end-stage heart failure requiring heart 
transplantation.
Giant cell myocarditis is less common than sarcoidosis, but accounts 
for 10–20% of biopsy-proven myocarditis, typically presenting acutely 
with rapidly progressive heart failure and tachyarrhythmias. Giant cell 
myocarditis occurs equally in men and women, usually of older age 
than those with acute viral myocarditis, and is more often associated 
with systemic autoimmune disorders. Unlike sarcoidosis, the more dif­
fuse involvement with giant cell myocarditis usually leads to diagnostic 
endomyocardial biopsy, revealing granulomatous lesions surrounded 
by extensive inflammation infiltrate, often with eosinophilic infiltra­
tion. However, the occasional finding of giant cell myocarditis in 
explanted hearts after a previous diagnosis of sarcoidosis suggests that 
they may share the same disease spectrum. Glucocorticoid therapy 
alone is rarely effective, but in combination with other immunosup­
pression therapies similar to those used for severe transplant rejection, 
the rate of death or heart transplantation has decreased for patients 
who are stable at the time of presentation. Most patients presenting 
with cardiogenic shock from giant cell myocarditis progress to need 
urgent mechanical support or transplantation, for which they may 
be rendered ineligible by severe infection resulting from intensive 
immunosuppression.
Eosinophilic myocarditis is one of the causes of fulminant myocarditis 
but may be missed on milder presentation that does not include assess­
ment for hypereosinophilia, which is present in about three-fourths of 
diagnosed cases. Myocardial toxicity of eosinophils may lead to apical 
thrombi on cardiac imaging, and MRI reveals inflammation acutely 
and subendocardial fibrosis in chronic cases. Endomyocardial biopsies 
show infiltration with lymphocytes, neutrophils, and a high proportion 
of eosinophils. Hypersensitivity to chronic medications accounts for up 
to one-third of cases and is often cured by withdrawal of the agent and 
acute steroid therapy. Particularly in Mediterranean and African coun­
tries, hypereosinophilia can result from chronic parasitic infection, for 
which treatment may cure the myocarditis. About 12% of cases are 
due to eosinophilic granulomatosis with polyangiitis (EGPA, formerly 
Churg-Strauss syndrome), which responds to immunosuppression but 
may have a relapsing course. The hypereosinophilic syndrome (HES) 
accounts for 10–15% of cases, resulting from myeloproliferative vari­
ants or overproduction of eosinophil production, for which combined 
immunosuppression may soon include therapies under investigation to 
decrease eosinophil production. About 30% of HES cases are currently