Clinical Summary - Case A
A 54-year-old female dentist had a 5-day history of 'flu-like' symptoms (including cough, fatigue,
shortness of breath chills and malaise). On admission to a local hospital for shortness of breath and
inability to sleep, she was found to have left ventricular failure, cardiogenic shock and marked
hypoxemia. She then developed uncontrollable cardiac arrhythmias and later that day, was transferred to
St. Paul's Hospital for further care. The differential diagnosis was viral myocarditis, acute coronary
syndrome, and / or sepsis. Investigations for pulmonary embolus and cardiac tamponade were negative.
She was transferred to the intensive care unit, intubated, and given oxygen and inotropic support. She
became profoundly hypotensive with severe arrhythmias, terminating in ventricular tachycardia on the same
This patient had hypothyroidism, treated effectively with Synthroid.
Autopsy examination of the heart revealed fulminant lymphocyte-predominant myocarditis.
Slide 4 - Hematoxylin and eosin stained slide from the lateral left ventricular free wall which exemplifies the heavy infiltrates and damage seen throughout the myocardium (X125).
Slide 5 - Higher power of the same area showing myocyte necrosis and a cellular infiltrate (X250).
Slide 6 - Immunohistochemical stain for muscle-specific actin showing widespread myocyte loss (X250).
Clinical Summary - Case B
A 27-year-old female admitted to hospital with a 5 day history of exertional chest pain and dyspnea.
Her presumptive diagnosis was acute myocardial infarction with NYHA Class IV heart failure. No prior
cardiac disease or significant coronary risk factors were known. Her initial ECG demonstrated ST
elevation in the anteroseptal leads, ST depression laterally, complete atrioventricular block and
frequent ventricular premature complexes. Troponin I was markedly elevated at 41.7 ug/L . She was
transferred to St. Paul's Hospital where cardiac catheterization revealed normal coronaries with mildly
depressed LVEF of 54% and hypokinesis of anterior and posterior LV wall. Endomyocardial biopsy revealed
active lymphocyte predominant myocarditis. Viral serology was positive for Cytomegalovirus, Herpes
simplex and Varicella Zoster virus. She clinically deteriorated during the first 48 hours with
hypotension and worsening heart failure requiring inotropic support and intubation. Drug therapies
resulted in improvement of the patient's condition 6 days after initial presentation. A repeat
endomyocardial biopsy 5 weeks after presentation showed late-healing myocarditis. Her heart
function-related symptoms improved to NYHA Class I and a repeat echocardiogram showed an LVEF of 50%.
Slide 7 - Hematoxylin and eosin stained slide showing features of a widespread cellular infiltrate with myocyte loss and degeneration (X500).
Slide 8 - Another biopsy fragment from this patient showing features as above (X500).
Definition of Myocarditis
According to the Dallas Criteria, myocarditis is a non-ischemic primary inflammatory disease of the
myocardium. The diagnostic hallmarks of myocarditis are inflammatory infiltration and myocyte necrosis
in endomyocardial biopsy (EMBx) specimens. The causes of inflammation may or may not be known.
Causes of Myocarditis
Myocarditis is commonly caused by infection by viruses, bacteria, rickettsia and fungi, as well as
toxic and allergic effects, hypersensitivity responses, and endocrine and immune disorders. Due to the
possibility that drug hypersensitivity and direct toxicity may cause myocarditis, a complete clinical
history including medications should be obtained with each biopsy. The most common viruses associated
with myocarditis include picornaviruses, influenza viruses, human immunodeficiency virus (HIV),
herpesviruses such as Epstein Barr Virus and cytomegalovirus, and adenoviruses. Among the most prevalent
enteroviruses in the picornavirus family that cause myocarditis coxsackieviruses groups B and echoviruses
Clinically, myocarditis may present with diverse, nonspecific and variable manifestations including
shortness of breath, chest pain, life-threatening arrhythmias and sudden heart failure. Particularly if
viral in origin, patients may also have severe flu-like symptoms. However, acute myocardial infarction,
dilated cardiomyopathy, valvular heart disease, sepsis, and hematological malignancy may mimic
myocarditis. Microscopically, infarcted myocardium exhibits primarily coagulation necrosis, whereas
myocyte injury associated with myocarditis is characterized by sarcoplasmic vacuolization as well as
coagulative effacement and contraction band formative disruption. Idiopathic dilated cardiomyopathy is
commonly associated with myocyte hypertrophy and heterogeneity, and interstitial fibrosis, although focal
mononuclear inflammation may also occur.
How Does One Really Make the Diagnosis?
Clinical diagnostic approaches include peripheral blood leukocyte count, chest radiography,
electrocardiogram, echocardiography, serum creatine kinase and troponin, viral serology, and fecal
isolation of virus or genome (Figure). Endomyocardial biopsy (EMBx) of the right ventricle is the gold
standard for the diagnosis of myocarditis in the pathology laboratory. For suspected myocarditis, it is
recommended that 5-10 biopsy samples be examined at multiple levels. The first EMBx will distinguish
myocarditis, borderline myocarditis and no myocarditis based on degree of inflammation and myocyte
injury. Lymphocytic and phagocytic infiltration, and associated myocyte death that is discrete and
multifocal or diffuse and abundant are clearly abnormal. However, there still exists some debate about
the diagnostic meaning of infiltrates that are diffuse and sparse. The presence or absence of fibrosis
must also be considered. Fibrosis should be designated according to localization (endocardial versus
interstitial), extent (mild, moderate or severe), and type (perivascular, pericellular and replacement).
Similarly, the inflammatory infiltrate should be described according to extent (mild, moderate and
severe) and type (lymphocytic, eosinophilic, neutrophilic or mixed, granulomatous, giant cell).
However, a temporal analysis of myocarditis would be inappropriate for the first biopsy.
A subsequent biopsy is necessary to establish the status of ongoing, resolving or resolved myocarditis
based on comparisons with the previous biopsy(ies). Ongoing (or persistent) myocarditis indicates that
the inflammatory process is either as extensive, or more so, than in the previous biopsy. Resolving
myocarditis suggests that inflammation and necrosis are still present but are improving. Resolved (or
healed) myocarditis indicates that the inflammation has abated. "Resolving or resolved" is not
restricted to healing by resolution, but also includes healing by organization with fibrosis.
Although the cause of myocarditis is often idiopathic, there are common causes that are associated
with certain types of inflammation. Lymphocytic myocarditis is most often associated with virus
infection, 'autoimmunity', polymyositis, sarcoidosis, Lyme disease and drug toxicity. Eosinophilic
myocarditis is associated with hypereosinophilic syndrome, restrictive cardiomyopathy, asthmatic
bronchitis, parasitic infestations and drug hypersensitivity. Neutrophilic or mixed myocarditis is
associated with general infection, myocardial infarction, bacterial or fungal infections, and drug
toxicity. Giant cell myocarditis is commonly associated with cancers such as thymomas, sarcoidosis,
rheumatic disease, other granulomatoses and drug hypersensitivity.
Figure: Clinical Diagnosis of Myocarditis.
Ish: In-situ Hybridization.
PCR: Polymerase chain reaction. IHC: Immunohistochemistry.
Diagnostic Techniques Aimed at Etiologic Diagnosis
There are several diagnostic techniques that a clinician may use to determine a viral etiology. The
benefits and drawbacks to each assay include sensitivity, specificity, reproducibility, costs,
timeliness, quantitation and localization. Such techniques include RT-PCR, Nested PCR, ISH, IHC and
Plaque Assay. A rough estimate of the value of each technique is portrayed. Ultimately, a definitive
diagnosis will often include use of several of the above techniques depending on the stage of myocarditis
and the patient's clinical course.
| || RT-PCR ||Nested PCR || ISH || IHC ||Plaque Assay|
|Sensitivity || + + || + + + + || + + + || + + + || +|
|Specificity || + + + || + + + + ||+ + + + || + + + || + + +|
|Reproducibility || + + + || + + || + + + || + + || + + +|
|Economy (financial) || + + + || + + || + + || + + || + +|
|Economy (time) ||+ + + + || + + + || + + + || + + || + +|
|Quantitation || + || + || + + + || + || + + +|
|Localization || + || + ||+ + + + ||+ + + + || + +|
|Suggested "ideal" application and value||Detection of acute viral infection||Detection of persistant viral genome||Localization of viral genome and replication in tissues and cells||Localization of viral capsid proteins||Determination of virulence|
Table: Comparative Value of different Methods in
Detection of Cardiotropic
Enterovirus in Fluids, Cells and Tissues.
(+ = perhaps least value, + + + + = most value).
Sources of Error in Biopsy Diagnosis
Myocarditis, by nature, may often be expressed as focal lesions, diffusely scattered. Thus, as eluded
to earlier, the main caveat in using the EMBx for the diagnosis of myocarditis relates to false negative
results due to sampling error. Typically there are false negative results in approximately 50% of
cases. Thus at least five biopsies should be taken. A negative result
should not be used in the "non-diagnosis" of this disease. Although the lesions are focal, they tend to
be spread throughout the myocardium and thus a biopsy of the right ventricle is usually an appropriate
tool for diagnosis. There are myocarditic entities which involve predominantly the base, left
ventricular free wall and subepicardial regions.
As mentioned above, the criteria for diagnosis of myocarditis include myocyte necrosis and
inflammatory infiltration. In some instances, clusters of fibroblastic and myofibroblastic cells or
thickened small vessels may appear to be mononuclear infiltration. Common artifacts in the EMBx include
myocyte contraction bands and small vessel intussusception. Other 'normal' features include right
ventricular adipose tissue and a certain small assembly of sentinel myocardial mononuclear cells, mast
cells and fibroblasts. Myocyte disarray is not uncommon if the EMBx is taken from the junction of the
right ventricular free wall and the septum or at a previous biopsy site. In consideration of such
caveats, it is critical for the pathologist to be aware of all clinical information before making the
There is an approximate 1% complication rate with the use of EMBx including pneumothorax, vasovagal
reaction, transient nerve palsies, infection, atrial arrhythmias, ventricular perforation, air embolism
and embolism of mural thrombotic materials.
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