RESIDENTS’ CLINIC
40-Year-Old Man With Fatigue, Dyspnea,
and Nausea
Jaime de la Fuente, MD; S. Bradley Hicks, MD; and Nandan S. Anavekar, MB, BCh
A
40-year-old white man with
bipolar I disorder, neuroleptic-
induced parkinsonism, and nonma-
lignant catatonia presented with a 2-day
history of worsening fatigue, dyspnea, and
nausea. He had been admitted to the psychiat-
ric unit 3 weeks previously for catatonia,
where he gradually improved following medi-
cation adjustments. Specifically, risperidone
was tapered off and replaced by clozapine to
minimize extrapyramidal effects. He
continued to improve, showing independence
both in his activities of daily living and other
self-cares. However, amid his progress, he
experienced fatigue, dyspnea, and nausea,
warranting further evaluation. At the time of
the current presentation, he had no known
exposures or sick contacts. He had never
smoked and had no notable family history of
any medical problems.
Vitals were notable for a temperature of
39.5 C, heart rate of 121 beats/min, blood
pressure of 122/73 mm Hg, respiratory rate
of 16 breaths/min, and oxygen saturation of
93% while breathing room air. Physical
examination revealed a flushed, inattentive
man lying in bed. Notably, he was quite
lethargic, which was an acute change
compared to his mental state on the previous
day. Cardiac examination revealed a regular
rhythm with no appreciable jugular venous
distention or lower extremity peripheral
edema. Pulmonary, abdominal, neurologic,
and skin examination findings were within
normal limits. Laboratory evaluation yielded
the following results (reference ranges
provided parenthetically): hemoglobin,
14.4 g/dL (13.2-16.6 g/dL); leukocytes,
13.1  109/L (3.4-9.6  109/L); platelets,
182  109/L (135-317  109/L); sodium,
137 mmol/L (135-145 mmol/L); potassium,
4.3 mmol/L (3.6-5.2 mmol/L); creatinine,
Mayo Clin Proc. n January 2019;94(1):e1-e6 n https://doi.org/10.1016/j.mayocp.2018.04.027
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0.8 mg/dL (0.74-1.35 mg/dL); thyroid- See end of article
stimulating hormone, 0.5 mIU/L (0.3-4.2 for correct answers
mIU/L); and C-reactive protein, 62.1 mg/ to questions.
L (8.0 mg/L). His troponin T level Resident in Internal Medicine,
increased from 0.09 ng/dL (<0.04 ng/mL) Mayo Clinic School of Grad-
at initial measurement to 0.2 ng/dL at 3 uate Medical Education,
Rochester, MN (J.d.l.F., S.B.H.);
hours and 0.33 ng/dL at 6 hours. During Advisor to residents and
this time, he reported no chest pain, pres- Consultant in Cardiovascular
Diseases, Mayo Clinic,
sure, or discomfort. Results of urinalysis
Rochester, MN (N.S.A.).
and blood cultures were unremarkable. Po-
lymerase chain reaction was negative for
influenza A and B and respiratory syncytial
virus.
Chest radiography revealed no consoli-
dation, pleural effusion, cardiomegaly, or
signs of heart failure. Initial electrocardiog-
raphy (ECG) showed only sinus tachycardia
with no ST-T wave abnormalities. Transtho-
racic echocardiography (TTE) was notable
for generalized hypokinesis with a calculated
ejection fraction of 43% and normal right
ventricular size, function, and pulmonary
pressures. No previous echocardiograms
were available because the patient had never
undergone echocardiography.
1. Which one of the following is the most
concerning diagnosis to exclude for this
patient?
a. Acute coronary syndrome (ACS)
b. Stress-induced cardiomyopathy
c. Myopericarditis
d. Pulmonary embolism
e. Myocarditis
The patient’s clinical syndrome, including
fever, dyspnea, fatigue, sinus tachycardia,
elevated troponin and C-reactive protein
levels, and reduced ejection fraction
(w40%), is very nonspecific. Although he
has no chest pain or known coronary artery
disease risk factors, with an increasing
e1

elevated troponin level, the most important
diagnostic consideration is ACS, particularly
a noneST-elevation myocardial infarction.
Missing this diagnosis is associated with
considerable morbidity and potential mortal-
ity. Stress-induced cardiomyopathy is a
consideration when elevated troponin with
wall motion abnormalities is present, most
commonly in the apical distribution, and a
discordant absence of severe epicardial coro-
nary artery disease is seen on angiography.
Notably, stress cardiomyopathy, in this
context, remains a diagnosis of exclusion.1
Myopericarditis is another consideration in
view of the patient’s elevated troponin level
and depressed left ventricular function. In
this scenario, pericarditis alone would be a
less likely diagnosis because the patient does
not meet 2 of the 4 criteria required for the
clinical diagnosis of pericarditis. These
criteria include pleuritic/sharp chest pain
that typically improves with sitting forward,
ECG changes (diffuse ST elevation and/or
PR depression), detection of a pericardial fric-
tion rub on auscultation, and pericardial effu-
sion on cardiac imaging.2 Myopericarditis
remains a diagnostic possibility once ACS
has reliably been excluded. With an elevated
troponin level and tachycardia, pulmonary
embolism could be considered as well. Using
the Wells criteria for risk stratification,
meeting only one criterion, with tachycardia,
puts the patient at low risk for pulmonary em-
bolism.3 In addition, with troponin elevation,
one may expect to see a more substantial
component of right ventricular strain on
TTE. Myocarditis is a nonspecific entity with
a heterogeneous presentation, typically mani-
festing 1 of 3 clinical patterns: recent-onset
heart failure, arrhythmia, and/or chest pain.4
Diagnostic criteria for myocarditis include
ECG changes, fever, elevation of troponin
level, and unexplained functional and struc-
tural changes in the heart.5 In the absence of
suspected ACS and coronary artery disease,
valve disease, congenital heart disease, hyper-
thyroidism, and hypertensive cardiomyopa-
thy, higher clinical suspicion should be
given to this entity. With the patient present-
ing with new-onset decreased ejection frac-
tion, dyspnea, fever, low suspicion for other
n n
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MAYO CLINIC PROCEEDINGS
cardiac entities, elevated troponin level, and
his echocardiographic findings, myocarditis
was deemed the most likely diagnosis, after
the concern for ACS was ruled out using
noninvasive testing with coronary computed
tomographic (CT) angiography.
The patient was treated conservatively
with acetaminophen, and his fever resolved
in about 24 hours. Coronary computed
tomographic angiography disclosed absence
of obstructive epicardial coronary artery dis-
ease. After cardiology consultation, contin-
uous telemetry was initiated in the setting
of tachycardia, elevated troponin level, and
presumed myocarditis diagnosis. Troponin
T values peaked at 0.57 ng/dL over the
next 24 hours.
2. Which one of the following is the
most likely cause for this patient’s
myocarditis?
a. Coxsackievirus B
b. Adenovirus
c. Parvovirus B19
d. Borrelia burgdorferi
e. Drug induced
All of these etiologies can cause myocar-
ditis. A thorough history and physical exam-
ination can narrow the differential diagnosis.
Unfortunately, the etiology of the myocar-
ditis is often unknown, with the other
typical etiologic distributions being (1) idio-
pathic, (2) infectious (typically viral), (3)
autoimmune, and (4) other.5 Classically in
terms of infection, enteroviruses such as
coxsackievirus B and viruses like adenovirus
are implicated. In recent years, studies using
endomyocardial biopsies along with poly-
merase chain reaction and serologic testing
have found that viruses, such as parvovirus
B19, are becoming much more prevalent.6
In enterovirus infections, patients often pre-
sent with viral symptoms including head-
ache, pharyngitis, gastroenteritis, and
muscle pains. Adenovirus has a very similar
presentation, but with the addition of
conjunctivitis. Parvovirus B19 has many
other unique manifestations including
rashes, arthralgias, and anemia due to a
decrease in erythropoiesis. This patient did
January 2019;94(1):e1-e6 https://doi.org/10.1016/j.mayocp.2018.04.027
www.mayoclinicproceedings.org
RESIDENTS’ CLINIC
not manifest any of these symptoms. Other
infections like B burgdorferi (causative agent
in Lyme disease) have also been reported.
Lyme myocarditis is less likely in this
patient, especially considering the absence
of any woodland exposure, tick bites, rashes
concerning for erythema migrans, and ECG
abnormalities.7 Drug-induced myocarditis is
another well-described cause of myocarditis
with varying pathophysiologic mechanisms
ranging from toxic effects of the drugs them-
selves to a hypersensitivity reaction to the
medication.5 Following initiation of a new
medicine, clinicians should always be cogni-
zant of potential adverse effects. Clozapine’s
adverse effect of agranulocytosis is well
known, but its cardiotoxicity leading to
myocarditis is less familiar, although still
described in the literature. It has been sug-
gested that approximately 1% of patients
that begin taking clozapine experience
myocarditis, especially within the first few
months of commencing the medication.8 In
this particular patient, in the absence of
any specific infectious symptoms, no known
sick contacts, and high suspicion for a
known drug effect, clozapine was deemed
the likely offending agent causing his
myocarditis.
Following diagnosis, clozapine was
promptly withheld. The psychiatric service
was consulted for input of alternative
therapy.
3. Which one of the following is the best
treatment for this patient?
a. Prednisone and azathioprine
b. High-dose intravenous immunoglobulin
(IVIG)
c. Guideline-directed medical heart failure
therapy
d. Placement of an implantable cardioverter-
defibrillator (ICD)
e. Low-dose daily aspirin
Although pharmacological therapy is
often initiated for its clinical benefits, there
is almost always the potential for unwanted
adverse effects that contradict therapeutic in-
tentions. The clinical features of our patient
Mayo Clin Proc. n January 2019;94(1):e1-e6 n https://doi.org/10.1016/j.mayocp.2018.04.027
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scenario are consistent with toxic myocar-
ditis secondary to clozapine. Considering
this probability, it is imperative to tailor
further therapy to the suspected cause in or-
der to alleviate symptoms. Treatment with
prednisone and azathioprine has shown
some efficacy in randomized controlled trials
but has not been validated in multicenter
studies and is not the first-line therapy for
nonautoimmune myocarditis.5 High-dose
IVIG functions on the presumption that it
suppresses inflammation; however, no cur-
rent evidence supports its use in myocar-
ditis. In addition to exercise restriction for
at least 2 years, heart failure therapy is the
mainstay of therapy for acute myocar-
ditis.9,10 Its benefits have been well docu-
mented in myocarditis, especially in
patients with left ventricular dysfunction,
as seen with our patient. This therapy in-
cludes angiotensin-converting enzyme in-
hibitors or angiotensin receptor blockers,
b-blockers, diuretics as needed, and poten-
tially aldosterone antagonists. In the setting
of arrhythmias, placement of an ICD in pa-
tients with acute myocarditis is controversial
because the myocarditis may completely
heal.5 Temporary pacing can be used if life-
threatening arrhythmias such as third-
degree heart block are present. Because the
patient did not have any evidence of arrhyth-
mias, ICD placement was not warranted.
Lastly, there is no role for aspirin, or any
nonsteroidal anti-inflammatory drugs, in
the current standard of care for myocarditis.
Based on consultative recommendations,
our patient was treated conservatively for his
clinical syndrome of heart failure. We initi-
ated treatment with low-dose carvedilol
twice daily and low-dose lisinopril daily.
These medications were up-titrated slowly
as patient’s heart rate and blood pressure
would allow.
4. Which one of the following diagnostic
tests is the most appropriate to confirm
this patient’s myocarditis?
a. Endomyocardial biopsy
b. Cardiac magnetic resonance imaging
(MRI)
e3

c. Cardiac catheterization
d. Cardiac CT angiography
e. Exercise echocardiography
To definitively diagnose myocarditis, the
gold standard is endomyocardial biopsy.
Unfortunately, this test is invasive and is
best utilized only under certain clinical sce-
nariosdin particular, new-onset fulminant
heart failure with hemodynamic compro-
mise in which the cause cannot be explained
or heart failure that is not appropriately
responding to usual therapy11 and suspicion
for giant cell myocarditis is present. Given
the lack of clinical suspicion for giant cell
myocarditis and the absence of hemody-
namic comprise, biopsy was not pursued.
In clinical practice, and when available, car-
diac MRI is the test of choice for the diag-
nosis of myocarditis, with both T1- and
T2-weighted changes increasing the speci-
ficity of the test for myocardial inflamma-
tion. Cardiac catheterization and cardiac
CT angiography are useful to exclude severe
coronary artery disease but are not specific
to the diagnosis of myocardial disease. Exer-
cise echocardiography in this patient would
provide insight into exercise hemodynamics
but would not be diagnostic and may in fact
be harmful if a clinical suspicion for active
myocarditis exists.
Cardiac MRI revealed abnormal delayed
enhancement involving the right ventricular
outflow tract and the right ventricular free
wall, as well as patchy involvement of the
epicardium and mid myocardium of the
lateral left ventricular wall. After excluding
other causes of myocarditis and considering
the temporal relationship of symptoms to
medication changes, the consensus was
that the new myocardial disease was second-
ary to clozapine-induced myocarditis.
5. Which one of the following would be the
best proposal for the scheduled surveil-
lance of this patient’s myocarditis?
a. One month, 6 months, 2 years
b. Three months, 6 months, 12 months,
then yearly
c. Three weeks, 3 months, 6 months, 12
months, then yearly
n n
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MAYO CLINIC PROCEEDINGS
d. One-time follow-up in 1 month
e. No follow-up is required
At this time, no definitive guidelines for
scheduled outpatient surveillance in patients
with myocarditis have been published. This
lack of guidelines is largely due to the variable
natural history of myocarditis, complete reso-
lution in some patients, and sudden cardiac
death in others. Specific recommendations
for surveillance have been proposed. They
were developed on the basis of the clinical
manifestations of the individual patient’s
myocarditis and predicted prognosis, in part
based on left ventricular predictors of recov-
ery in myocarditis including use of heart
failure therapy, less late gadolinium enhance-
ment on MRI, and higher baseline left ventric-
ular function at the time of myocarditis
diagnosis.10 In high-risk patients, including
those with acute hemodynamic compromise,
conduction abnormalities, and extensive left
ventricular derangements seen on MRI, it is
recommended that the patient should initially
follow up in less than a month, then at least 2
more times by the 12-month mark, followed
by annual visits for life. Low-risk patients,
including those solely presenting with chest
pain, normal left ventricular function, and
no arrhythmias, can be followed up in 1
months’ time to assure stability of disease,
with expected completion of follow-up in 2
years’ time. Individuals in between these 2 cat-
egories, like our patient, should plan to follow
up in 3 months, then at 6 and 12 months, and
eventually annually thereafter (unless a sud-
den change in their clinical status develops,
necessitating closer surveillance).
The cardiology service recommended
continuation of carvedilol, lisinopril, and ex-
ercise restriction. Additionally, they arranged
for follow-up in 3 months, with plans for an
MRI and measurement of inflammatory
markers before the appointment. Repeat
TTE obtained several weeks after dismissal
revealed recovered left ventricular function
with an estimated ejection fraction of 55%.
DISCUSSION
Myocarditis is defined as inflammation of the
myocardium. There have been specific ways
January 2019;94(1):e1-e6 https://doi.org/10.1016/j.mayocp.2018.04.027
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RESIDENTS’ CLINIC
to define it in the past using pathologic,
immunologic, and immunohistochemical
criteria.5,9,10 The limitation associated with
this definition is the requirement for an
endomyocardial biopsy, which has gradually
fallen out of favor, unless warranted by
compelling clinical circumstances. Compli-
cating this scenario more is the often hetero-
geneous presentation and clinical course of
myocarditis. Although it typically presents
with acute-onset heart failure symptoms,
arrhythmia, and/or chest pain, myocarditis
should only be suspected after ruling out
other cardiac etiologies, specifically ACS.4
Although some etiologies of myocarditis
remain undiagnosed, a large range of infec-
tious, autoimmune, and toxic causes
currently exist. This case demonstrated a
toxic etiology of myocarditis caused by the
medication clozapine.5 Described in the liter-
ature, the exact mechanism for the cause is
unknown, although it is potentially thought
to be due to an IgE-mediated hypersensitivity
reaction (based on endomyocardial biopsies
showing eosinophilic infiltrate) or elevated
plasma norepinephrine levels (a consistent ef-
fect of clozapine).12 A retrospective review of
the known clozapine myocarditis cases found
that with removal of clozapine and myocar-
ditis treatment, at least 50% of patients
recover from the disease.8 Other drugs
commonly implicated in myocarditis include
illicit medications (amphetamines, cocaine),
antibiotics (penicillin, tetracycline), sulfon-
amides, and antiseizure medications
(phenytoin).
Diagnosis of myocarditis can be defini-
tively established with invasive endomyocar-
dial biopsy.5,9,10 Fortunately, with the
advent of cardiac MRI, biopsy is not required
unless there is no response to treatment or a
more fulminant myocarditis process like
giant cell myocarditis is suspected.10 With
the use of T2-weighted imaging and post-
contrast delayed imaging protocols in car-
diac MRI, myocarditis can be diagnosed
with a sensitivity of 84%, specificity of
74%, and diagnostic accuracy of 79%.13
Unfortunately, because MRI requires a pa-
tient to lay flat for a long period of time, it
may not be easily performed in every patient.
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As previously described, most therapy
for myocarditis, if hemodynamically stable,
should follow the current heart failure
guidelines. In addition, exercise restriction
is recommended for at least 6 months
following the diagnosis. If an offending agent
is suspected, such as in our case, it should be
discontinued. Immunomodulatory therapy,
such as antivirals and IVIG, have no vali-
dated role in therapy as of yet.9,10 New
emerging data show that there may be a
role for the combination of prednisone and
azathioprine, but this hypothesis needs to
be confirmed in multicenter studies.5
Lastly, patients with a confirmed diag-
nosis of myocarditis must be scheduled for
follow-up in the outpatient setting at inter-
vals corresponding to the severity of their
initial presentation and predicted prog-
nosis.10 Initial follow-up should occur
within the first few months, or sooner, and
include at least ECG and TTE at each
appointment, and in some instances cardiac
MRI.5,10
CONCLUSION
Myocarditis is a heterogeneous disease of
exclusion with nonspecific symptoms that
should be considered after other potential
life-threatening etiologies have been ruled
out. Many etiologies of myocarditis exist,
making the diagnosis even more challenging.
Ideally, if MRI can be performed, it can
greatly aid in diagnosis. In hemodynamically
stable patients with reduced left ventricular
function, guideline-directed medical therapy
for heart failure should be administered.
Further outpatient surveillance should then
be performed depending on the initial pre-
sentation of the myocarditis.
Potential Competing Interests: The authors report no
competing interests.
Correspondence: Address to Nandan S. Anavekar, MB,
BCh, Department of Cardiovascular Medicine, Mayo Clinic,
200 First St SW, Rochester, MN 55905 (anavekar.nandan@
mayo.edu).
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 MAYO CLINIC PROCEEDINGS

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CORRECT ANSWERS: 1. a. 2. e. 3. c. 4. b. 5. b.

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