The n e w e ng l a n d j o u r na l of m e dic i n e

Case Records of the Massachusetts General Hospital

Founded by Richard C. Cabot

Eric S. Rosenberg, M.D., Editor
Virginia M. Pierce, M.D., David M. Dudzinski, M.D., Meridale V. Baggett, M.D.,
Dennis C. Sgroi, M.D., Jo‑Anne O. Shepard, M.D., Associate Editors
Allison R. Bond, M.D., Case Records Editorial Fellow
Emily K. McDonald, Sally H. Ebeling, Production Editors

Case 8-2018: A 55-Year-Old Woman

with Shock and Labile Blood Pressure
Joseph Loscalzo, M.D., Ph.D., Nathalie Roy, M.D., Ravi V. Shah, M.D.,
Joy N. Tsai, M.D., Alexis M. Cahalane, M.D., Johannes Steiner, M.D.,
and James R. Stone, M.D., Ph.D.​​

Pr e sen tat ion of C a se

Dr. Nathalie Roy: A 55-year-old woman was transferred to this hospital for evalua- From the Department of Medicine,
tion and treatment of cardiogenic shock. Brigham and Women’s Hospital (J.L.),
the Departments of Surgery (N.R.), Med‑
Approximately 4 months before presentation, the patient was admitted to a icine (R.V.S., J.N.T., J.S.), Radiology
hospital in her home state for “pounding” in her chest, nausea, and diaphoresis (A.M.C.), and Pathology (J.R.S.), Massa‑
that persisted for 40 minutes after a routine jog. The heart rate was 65 beats per chusetts General Hospital, and the De‑
partments of Medicine (J.L., R.V.S.,
minute, and the blood pressure 138/72 mm Hg; the remainder of the examination J.N.T., J.S.), Surgery (N.R.), Radiology
was normal. Four serial electrocardiograms were reportedly normal, but the tro- (A.M.C.), and Pathology (J.R.S.), Harvard
ponin I level was elevated, at 0.055 ng per milliliter, and 11 hours later, it had Medical School — all in Boston.

risen to 0.415 ng per milliliter (normal range, 0 to 0.045). Transthoracic echocar- N Engl J Med 2018;378:1043-53.
diography revealed normal biventricular function. Coronary angiography revealed DOI: 10.1056/NEJMcpc1712225
Copyright © 2018 Massachusetts Medical Society.
no evidence of obstructive coronary artery disease; the left ventricular end-diastolic
pressure was 5 mm Hg. After discharge (4 days after admission), cardiac mag-
netic resonance imaging (MRI) revealed normal biventricular function and size,
with no evidence of myocardial edema or fibrosis. Aspirin and a beta blocker were
prescribed for presumed exercise-related supraventricular tachycardia.
The symptoms did not recur, and the patient returned to jogging and stopped
taking the beta blocker. On the day before her transfer to this hospital, she was
on a downhill-skiing trip in Vermont. In the morning, she felt fatigued. In the
afternoon, palpitations, dyspnea, and weakness developed while she was at the top
of a mountain; the ski patrol took her down the mountain, and the symptoms
abated. In the evening, while she was at dinner, she had acute nausea and emesis
followed by chest pain and dyspnea. She was taken to a local emergency depart-
ment. The heart rate was 111 beats per minute, the blood pressure 115/81 mm Hg,
the respiratory rate 28 breaths per minute, and the oxygen saturation 84% while
she was breathing ambient air. Auscultation revealed diffuse crackles in the lungs.
The troponin I level was 11.000 ng per milliliter (normal range, 0 to 0.045), the
N-terminal pro–B-type natriuretic peptide (NT-proBNP) level 15,159 pg per milli-

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 The n e w e ng l a n d j o u r na l
liter (normal range, 0 to 125), the lactate level
4.6 mmol per liter (41.0 mg per deciliter; normal
range, 0.5 to 2.0 mmol per liter [4.5 to 18.0 mg
per deciliter]), the venous blood pH 7.22 (normal
range, 7.38 to 7.46), and the white-cell count
36,100 per cubic millimeter (normal range, 4500
to 11,000). Bedside cardiac ultrasonography re-
vealed severe left ventricular dysfunction with
apical ballooning. Intravenous infusions of hep-
arin and furosemide were administered, and the
patient was transferred by helicopter to a nearby
tertiary care center for treatment of suspected
cardiogenic shock.
On the patient’s arrival at the tertiary care
center, the temperature was 37.2°C, the heart
rate 143 beats per minute, the blood pressure
96/72 mm Hg, the respiratory rate 26 breaths per
minute, and the oxygen saturation 84% while
she was breathing ambient air and 88 to 94%
while she was receiving oxygen through a non-
rebreather face mask. On physical examination,
she appeared fatigued and had jugular venous
distention, diffuse crackles in the lungs, and
cold arms and legs. The troponin I level was
4.790 ng per milliliter (normal range, <0.034),
the white-cell count 30,240 per cubic millimeter
(normal range, 4500 to 11,000), the arterial
blood pH 7.08 (normal range, 7.35 to 7.45), the
lactate level 5.9 mmol per liter (53 mg per deci-
liter; normal range, <2.0 mmol per liter [<18 mg
per deciliter]), the NT-proBNP level 24,900 pg per
milliliter (normal range, <300), and the creati-
nine level 1.41 mg per deciliter (125 μmol per
liter; normal range for women, 0.52 to 1.04 mg
per deciliter [46 to 92 μmol per liter]).
Chest radiography revealed diffuse pulmo-
nary edema. Electrocardiography showed sinus
tachycardia and T-wave inversions in leads V4
through V6. The trachea was intubated, and me-
chanical ventilation was initiated for respiratory
failure. Transthoracic echocardiography revealed
a left ventricular ejection fraction of 15% and
left ventricular apical akinesis, as well as severe
right ventricular apical dysfunction. Infusions of
norepinephrine, dobutamine, epinephrine, amio-
darone, propofol, midazolam, fentanyl, and so-
dium bicarbonate were administered. Empirical
methylprednisolone was administered for pre-
sumed myocarditis. Coronary angiography re-
vealed normal coronary arteries; the left ven-
tricular end-diastolic pressure was 38 mm Hg.
A percutaneous transaortic left ventricular assist
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of m e dic i n e
device was placed. After the institution of me-
chanical circulatory support, the intravenous
doses of norepinephrine, dobutamine, and epi-
nephrine were tapered and eventually stopped.
Hematuria developed, and the urine output de-
clined. The blood pressure was labile, ranging
from 60/40 to 140/110 mm Hg, and an infusion
of sodium nitroprusside was administered for
control of elevated blood pressure. The patient
was transferred by helicopter to this hospital.
On the patient’s arrival at this hospital, addi-
tional history was obtained from her husband.
She had a history of thyroid cancer (unknown
pathologic subtype) that had been treated with
thyroidectomy and radioactive iodine ablation.
Medications included levothyroxine and a calcium
supplement. The use of cefadroxil had caused the
Stevens–Johnson syndrome. She did not smoke
cigarettes, drink alcohol, or use illicit drugs. She
was employed in health care, was married, and
had one healthy daughter. Her maternal grand-
father had died from myocardial infarction at
60 years of age, her father had had an aortic-
valve replacement, and her mother had had lung
cancer.
On examination, the temperature was 36.9°C,
the heart rate 132 beats per minute, the blood
pressure 105/72 mm Hg, and the oxygen satura-
tion 96% while the patient was receiving oxygen
through a mechanical ventilator (positive end-
expiratory pressure, 12; tidal volume, 400 ml;
fraction of inspired oxygen, 1.0; respiratory rate,
16 breaths per minute). The pupils were reactive
to light in a symmetric but slightly sluggish
manner. The patient was able to follow simple
commands. She had no masses in the neck or
exophthalmos. The jugular veins appeared dis-
tended. Auscultation of the chest revealed the
hum of the ventricular assist device, distant
tachycardic heart sounds, and scattered crackles
in the lungs. The ventricular assist device had
been secured in place by way of the left groin.
She had 1+ pedal edema bilaterally and no rash
or lymphadenopathy. A small amount of reddish
brown urine was noted.
Levels of thyrotropin, bilirubin, and alkaline
phosphatase were normal; other test results are
shown in Table 1. Urinalysis revealed 3+ blood.
Tests of a nasopharyngeal swab for nucleic
­acids of influenza A and B and respiratory syn-
cytial virus and for metapneumovirus antigens
were negative, as was combination testing for
 Case Records of the Massachuset ts Gener al Hospital

Table 1. Laboratory Data.*

Reference Range, This Hospital, This Hospital,

Variable Adults† on Arrival Day 3‡
Hemoglobin (g/dl) 12.0–16.0 15.3 8.6
Free hemoglobin (g/dl) 0–15.2 121.1
Hematocrit (%) 36.0–46.0 44.7 24.8
White-cell count (per mm3) 4500–11,000 35,440 21,390
Platelet count (per mm3) 150,000–400,000 482,000 138,000
Sodium (mmol/liter) 135–145 146 138
Potassium (mmol/liter) 3.4–5.0 3.8 4.2
Chloride (mmol/liter) 98–108 105 102
Carbon dioxide (mmol/liter) 23–32 23 20
Urea nitrogen (mg/dl) 8–25 33 30
Creatinine (mg/dl) 0.60–1.50 1.64 1.84
Glucose (mg/dl) 70–110 189 148
Central venous oxygen saturation (%) 70–80 80.4 73.2
Phosphorus (mg/dl) 2.6–4.5 5.1 3.6
Calcium (mg/dl) 8.5–10.5 6.0 9.3
Ionized calcium (mmol/liter) 1.14–1.30 0.84 1.21
Magnesium (mg/dl) 1.7–2.4 1.6 2.7
Protein (g/dl)
Total 6.0–8.3 5.3 4.9
Albumin 3.3–5.0 2.9 3.5
Globulin 1.9–4.1 2.4 1.4
Lactic acid (mmol/liter) 0.5–2.2 5.0 1.5
Lactate dehydrogenase (U/liter) 110–210 890 519
Aspartate aminotransferase (U/liter) 9–32 136 64
Alanine aminotransferase (U/liter) 7–33 42 14
Troponin T (ng/ml) <0.03 1.93 0.67
Creatine kinase (U/liter) 40–150 749 333
Creatine kinase MB isoenzyme (U/liter) 0–6.9 29.0 12.5
Erythrocyte sedimentation rate (mm/hr) 0–20 13
Prothrombin time (sec) 11.5–15.4 17.0 14.8
International normalized ratio 0.9–1.1 1.4 1.2
Partial-thromboplastin time (sec) 22.0–35.0 >150.0 40.8
Fibrinogen (mg/dl) 150–400 463
Arterial blood gas
Fraction of inspired oxygen 1.0 0.35
pH 7.35–7.45 7.24 7.37
Partial pressure of carbon dioxide (mm Hg) 35–42 58 38
Partial pressure of oxygen (mm Hg) 80–100 101 143

* To convert the values for urea nitrogen to millimoles per liter, multiply by 0.357. To convert the values for creatinine to
micromoles per liter, multiply by 88.4. To convert the values for glucose to millimoles per liter, multiply by 0.05551. To
convert the values for phosphorus to millimoles per liter, multiply by 0.3229. To convert the values for calcium to milli‑
moles per liter, multiply by 0.250. To convert the values for ionized calcium to milligrams per deciliter, divide by 0.250.
To convert the values for magnesium to millimoles per liter, multiply by 0.4114. To convert the values for lactic acid to
milligrams per deciliter, divide by 0.1110.
† Reference values are affected by many variables, including the patient population and the laboratory methods used. The
ranges used at Massachusetts General Hospital are for adults who are not pregnant and do not have medical conditions
that could affect the results. They may therefore not be appropriate for all patients.
‡ These data were obtained at the time of decannulation of extracorporeal life support.

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 The n e w e ng l a n d j o u r na l of m e dic i n e

I aVR V1 V4

II aVL V2 V5

III aVF V3 V6

V1

Figure 1. Electrocardiogram.
An electrocardiogram obtained on the day of admission shows sinus tachycardia, poor R-wave progression, T-wave
inversions in leads V3 through V6 and in inferior leads, low QRS voltage, and a prolonged corrected QT interval.

antibodies to human immunodeficiency virus
types 1 and 2 and p24 antigen.
Dr. Ravi V. Shah: Electrocardiography showed
sinus tachycardia, poor R-wave progression, T-wave
inversions in leads V3 through V6 and in inferior
leads, low QRS voltage, and a prolonged correct­
ed QT (QTc) interval (Fig. 1). Chest radiography
revealed diffuse interstitial infiltrates, small bi-
lateral pleural effusions, and the tip of the ven-
tricular assist device projecting over the left ven-
tricle. Transthoracic echocardiography revealed
severe left ventricular systolic dysfunction, with
an estimated ejection fraction of 20% and severe
mid-to-apical hypokinesis, as well as right ven-
tricular free-wall and apical dysfunction, no clini-
cally significant valvular disease, and a small
Videos showing pericardial effusion (see Video 1, available with
cardiac studies the full text of this article at NEJM.org). On
are available at
echocardiography, the tip of the ventricular as-
NEJM.org
sist device was in the appropriate position in the
left ventricle.
Dr. Roy: Shortly after the patient’s arrival at
this hospital, hypotension again developed, and
infusions of milrinone, epinephrine, and norepi-
nephrine were administered. Femoral venoarte-
rial extracorporeal life support was initiated to
facilitate sufficient cardiac output, since the per-
cutaneous ventricular assist device had provided
insufficient support and caused increasing he-
molysis.1 Continuous venovenous hemofiltration
was initiated for anuria, fluid overload, and acido-
sis in the context of acute kidney injury. Methyl-
prednisolone was administered intravenously.
During the first 3 hospital days, the blood
pressure remained labile, with the systolic blood
pressure ranging from 65 to 205 mm Hg, despite
stable levels of sedation and extracorporeal life
support. The patient intermittently received an
infusion of nitroprusside for hypertension and
received infusions of norepinephrine and vaso-
pressin during episodes of hypotension.
On the third hospital day, transesophageal
echocardiography revealed slight improvement in
global ventricular function. Extracorporeal life
support was discontinued, and milrinone ther-
apy was continued. While the patient was in the
operating room for decannulation of extracorpo-
real life support and removal of the ventricular
assist device, a left ventricular endomyocardial
biopsy was performed.
Dr. James R. Stone: The biopsy specimen was
evaluated with the use of routine, special, and
immunohistochemical stains.2 Examination of
the specimen revealed acute and healing myo-
cardial injury (Fig. 2). There were focal necrotic
myocytes, which were C4d+ on immunohisto-

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 Case Records of the Massachuset ts Gener al Hospital

A B

C D

Figure 2. Endomyocardial-Biopsy Specimens.

An endomyocardial biopsy was performed on the third hospital day. Hematoxylin and eosin staining of the biopsy
specimens shows focal areas of myocardial injury with a mild inflammatory infiltrate (Panel A, arrow). Immunohisto‑
chemical staining shows C4d+ necrotic cells (Panel B, arrow); the cells in the inflammatory infiltrate are primarily
CD68+ macrophages (Panel C, arrows), with rare CD3+ T lymphocytes (Panel D, arrow). Trichrome staining shows
scarring (fibrosis) in blue (Panel E, arrows).

chemical staining. There was a reparative inflam-
matory infiltrate that was composed primarily
of CD68+ macrophages, with rare CD3+ T lym-
phocytes. There was focal fibrosis, which sug-
gested that the disorder had been present for at
least 4 weeks. The cardiomyocytes showed hyper-
trophy, a nonspecific phenomenon that is con-
sistent with an injury response.3,4 There were no
histologic features of active myocarditis or fea-
tures of a storage or deposition disorder. The

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 The n e w e ng l a n d j o u r na l
differential diagnosis for the myocardial injury
includes ischemia, myocardial toxicity, mechani-
cal stress, and treated myocarditis.3,5
Dr. Roy: The next day, marked hypertension
developed, and intravenous hydralazine was ad-
ministered. The blood pressure remained very
labile during the next 4 days; therefore, intermit-
tent infusions of sodium nitroprusside and ther­
apy with carvedilol, oral hydralazine, and cloni-
dine were administered. The patient continued
to receive renal-replacement therapy, but sponta-
neous urine output resumed. Blood tests for anti-
nuclear antibodies and antibodies to adenovirus,
coxsackievirus, and parvovirus were negative, as
was a test for adenovirus DNA. Serum protein
electrophoresis revealed low levels of IgG and
IgA. Cultures of the blood and urine were sterile.
On the seventh hospital day, the blood pressure
stabilized and cardiac MRI could be performed.
Dr. Shah: Cardiac MRI, performed without the
administration of gadolinium, revealed a mildly
reduced left ventricular ejection fraction of 49%
and left ventricular mid-to-apical hypokinesis, with
relative sparing of the base (see Video 2). Right
ventricular function was normal. T2-weighted
imaging did not reveal any clear evidence of
clinically significant myocardial edema. Because
gadolinium was not administered, patterns sug-
gestive of myocarditis or a myocardial scar could
not be detected. Given the normal results of
coronary angiography and the low level of suspi-
cion for an acute coronary syndrome, the find-
ings in this patient would be consistent with
takotsubo (stress) cardiomyopathy.
Dr. Roy: A diagnosis was made.
Differ en t i a l Di agnosis
Dr. Joseph Loscalzo: This 55-year-old woman pre-
sented with pulmonary edema, severe left ven-
tricular dysfunction, and apical ballooning that
developed during a skiing trip. The finding of
ventricular apical ballooning in the absence of
atherothrombotic coronary artery disease has a
limited differential diagnosis. Key considerations
include recurrent apical ballooning syndrome
(perhaps due to exercise-induced hypertension),
takotsubo cardiomyopathy, acute myocarditis,
coronary vasospasm, cocaine-induced coronary
vasoconstriction, and thrombosis with endog-
enous fibrinolysis before angiography.
Recurrent apical ballooning syndrome and
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of m e dic i n e
takotsubo cardiomyopathy reflect a similar patho-
physiology that is caused by catecholamine-­
induced ventricular dysfunction. Recurrent apical
ballooning syndrome has been associated with a
transient hypertensive response during exercise,
which suggests a hypersympathetic mechanism.6,7
Because the pathophysiology of these disorders
is similar (if not identical) and takotsubo cardio-
myopathy can be recurrent, the difference between
these two conditions may be only nominal.
Since takotsubo cardiomyopathy was initially
described, it has been increasingly recognized as
a cause of acute, nonischemic cardiomyopathy.8
In a review of cases in which patients were ad-
mitted with chest-pain syndromes,9 takotsubo
cardiomyopathy was diagnosed on the basis of
findings of apical ballooning and normal coro-
nary arteries in 7.5% of patients. Among those
patients, catecholamine-associated triggers were
emotional trauma (in 72.5%), surgical stress (in
12.5%), adrenergic intoxication (in 7.5%), and
catecholamine-producing tumor (in 7.5%); 20%
presented in cardiogenic shock.
The other leading diagnosis in this case is
acute myocarditis. Patients with either takotsubo
cardiomyopathy or acute myocarditis can present
with cardiovascular collapse, but patients with
acute myocarditis generally have the following
features: signs or symptoms of infection, ST-
segment elevation or depression, a substantially
elevated troponin level, localized or diffuse left
ventricular wall-motion abnormalities, the pres-
ence of many inflammatory cells and interstitial
edema on examination of an endomyocardial-
biopsy specimen, evidence of a viral infection on
laboratory testing, and a gadolinium-enhancement
pattern on cardiac MRI that is nonischemic in
distribution, commonly affects the epicardial
zone, and occurs long after disease onset.
This patient did not have many of these fea-
tures. Instead, she presented with a condition
associated with a stressor or trigger that was
presumably related to exercise, T-wave inversions
with a prolonged QTc interval, an elevated tro-
ponin level that was discordant with the extent
of ventricular dysfunction, and apical ballooning
with right ventricular involvement. Therefore, this
patient is more likely to have takotsubo cardio-
myopathy than acute myocarditis, although the
presence of a focal macrophage-rich inflamma-
tory infiltrate is somewhat unexpected.10
Another feature of this patient’s presenta-
 Case Records of the Massachuset ts Gener al Hospital
tion that is not commonly noted in patients with
takotsubo cardiomyopathy is the low QRS volt-
age on electrocardiography, although attenua-
tion of the QRS voltage has been described with
takotsubo cardiomyopathy and attributed to myo-
cardial edema.11,12 Despite the low QRS voltage
on electrocardiography, there was no evidence of
interstitial edema on cardiac MRI. This inconsis-
tency may reflect the rapid progression of this
patient’s clinical condition; it is possible that the
interval between the two cardiac studies was too
long, given that her ventricular function was
changing rather dramatically. This explanation
is supported by the fact that electrocardiograms
obtained later in the patient’s course (not shown)
showed recovery of the QRS voltage.
In addition, the presence of perivascular mac-
rophages but no other inflammatory cells is
somewhat unexpected. Patients with takotsubo
cardiomyopathy typically have inflammatory infil-
trates,10,13 although these are present primarily
during the acute phase. The presence of extracel-
lular clusters of macrophages both in areas of
acute myocardial injury and in areas without ap-
parent acute injury, which may reflect the clear-
ance of necrotic myocytes and cellular debris, has
been described with takotsubo cardiomyopathy.13
Takotsubo cardiomyopathy may be primary
or secondary. In general, patients with primary
takotsubo cardiomyopathy are more likely to
present with a chest-pain syndrome, whereas
patients with secondary takotsubo cardiomyopa-
thy are more likely to present with heart failure
or cardiogenic shock, with correspondingly worse
prognoses.14 Although this patient had a brief
episode of chest pain, the most prominent fea-
ture of her presentation was cardiogenic shock,
which suggests that she had an underlying cause
of the cardiomyopathy.
There are many possible underlying causes of
takotsubo cardiomyopathy,15 with the majority
falling into four categories: endocrinologic con-
ditions (e.g., thyrotoxicosis, pheochromocytoma,
or adrenal crisis), neurologic conditions (e.g.,
stroke or subarachnoid hemorrhage), induction
of general anesthesia, and use of medications
(epinephrine, nortriptyline, or venlafaxine) or il-
licit drugs (cocaine). On the basis of this patient’s
history and clinical presentation, we can rule out
neurologic conditions, induction of general anes-
thesia, and use of medications or illicit drugs as
the cause.
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In considering endocrinologic causes of sec-
ondary takotsubo cardiomyopathy, three other
features of this patient’s presentation warrant
consideration. These are the relationship of her
symptomatic episodes to exercise, the extremely
labile blood pressure, and the presence of car-
diomyocyte hypertrophy on examination of an
endomyocardial-biopsy specimen in the absence
of a history of hypertension.
Pheochromocytoma
Could pheochromocytoma be the underlying
cause of this patient’s cardiomyopathy? The rela-
tionship between pheochromocytoma and cate-
cholamine-induced shock has been recognized
for more than 40 years,16,17 but the link between
the ventricular apical ballooning typically seen
in patients with takotsubo cardiomyopathy and
a pheochromocytoma-related crisis leading to
acute heart failure or shock was not recognized
until more recently.18,19 Triggers for these severe
pheochromocytoma-related crises include use of
high-dose glucocorticoids20 (which the patient
had received on admission), spontaneous hemor-
rhage into the tumor,21 and use of imipramine.22
An association between pheochromocytoma and
recurrent takotsubo cardiomyopathy (which must
be presumed in this patient, owing to the ab-
sence of characteristic findings on echocardiog-
raphy at the first presentation) has been de-
scribed.23 The electrocardiographic abnormalities
of low QRS voltage and a prolonged QTc interval
have been described in patients with pheochro-
mocytoma who do not have cardiogenic shock.24,25
Left ventricular hypertrophy is more commonly
seen in patients with takotsubo cardiomyopathy
who have pheochromocytoma than in those with
takotsubo cardiomyopathy that is not associated
with pheochromocytoma.24
Although pheochromocytoma appears to fit
well with this patient’s presentation, we also
need to consider her previous diagnosis of thy-
roid cancer and its potential relationship to
pheochromocytoma. Although we do not know
the type of thyroid cancer, it is tempting to
speculate that she may have had a medullary
carcinoma of the thyroid as part of multiple
endocrine neoplasia type 2A. However, the thy-
roid cancer was effectively treated with resection
and radioactive iodine ablation; therefore, medul-
lary carcinoma of the thyroid would be unlikely
because of its relative resistance to radioactive
1049
 The n e w e ng l a n d j o u r na l
iodine therapy. In addition, the patient had no
evidence of hyperparathyroidism — in fact, she
had transient hypocalcemia. Pheochromocytoma
is associated with hypocalcemia,26,27 especially
during crises, most likely as a result of increased
expression of adrenomedullin.28 Adrenomedullin
not only is a highly potent vasodilator but also
causes proliferation of osteoblasts, promotes
bone growth and mineralization, and can lead
to calcium sequestration and hypocalcemia. Pa-
tients with pheochromocytomas that secrete
epinephrine and adrenomedullin may present
with hemodynamic instability because of the
vasoconstrictor effect of the catecholamine cou-
pled with the profound vasodilator effect of ad-
renomedullin. In this patient, the episodic re-
lease of endogenous vasoactive substances was
most likely further complicated by the adminis-
tration of vasoactive drugs to normalize blood
pressure. For these reasons, I believe that this
patient was more likely to have an isolated pheo-
chromocytoma than multiple endocrine neopla-
sia type 2A and that her tumor most likely se-
creted epinephrine and adrenomedullin.
Another feature of this patient’s presentation
that warrants consideration is the involvement of
the right ventricle. Patients with takotsubo car-
diomyopathy who have right ventricular involve-
ment have a worse prognosis than those who do
not; right ventricular involvement is the only
independent predictor of the combined outcome
of death from any cause, rehospitalization for
heart failure, or recurrent takotsubo cardiomy-
opathy.29
The diagnosis of pheochromocytoma in this
patient would rely on the observation of elevated
catecholamine levels in plasma or urine and ele-
vated 24-hour fractionated urinary metanephrine
and catecholamine levels. It is preferable to ob-
tain the specimens when the patient is not re-
ceiving vasopressor support. The laboratory
studies are usually coupled with imaging studies
to identify a tumor; once a tumor is identified,
surgical resection is essential. Genotyping may
also be useful to rule out multiple endocrine
neoplasia type 2A (due to a mutation in the re­
arranged during transfection proto-oncogene
[RET]), although the pretest probability of this
diagnosis is low.
Dr. David M. Dudzinski (Medicine): Dr. Roy, what
was your impression when you evaluated this
patient?
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of m e dic i n e
Dr. Roy: This patient’s presentation with shock
leading to the use of extracorporeal life support,
as well as the presence of apical ballooning on
echocardiography and the results on examina-
tion of an endomyocardial-biopsy specimen and
on cardiac MRI, led us to a primary diagnosis of
acute takotsubo cardiomyopathy. In the absence
of a precipitating event and in the presence of
extremely labile blood pressure, severe hyperten-
sion that did not respond to clonidine treat-
ment,30 and a history of palpitations, we thought
the most likely cause of her cardiomyopathy was
pheochromocytoma.31 Plasma metanephrine lev-
els were obtained, and the endocrine service was
consulted.
Cl inic a l Di agnosis
Takotsubo cardiomyopathy and catecholamine-
induced crisis due to pheochromocytoma.
Dr . Joseph L osc a l z o’s Di agnose s
Takotsubo cardiomyopathy due to pheochromo-
cytoma.
Catecholamine-induced cardiomyopathy.
Discussion of M a nagemen t
Dr. Joy N. Tsai: I evaluated this patient when the
fractionated plasma metanephrine levels were
obtained. The plasma metanephrine level was
3.2 nmol per liter (normal range, <0.50), and the
plasma normetanephrine level was 21 nmol per
liter (normal range, <0.90). We considered poten-
tial reasons that the elevated fractionated plas-
ma metanephrine levels would be false positive,
since the sensitivity of these levels for pheochro-
mocytoma is 96 to 100% but the specificity is ap-
proximately 85 to 89%.32-34 Although fractionated
plasma metanephrine levels can be up to 2 times
the upper limit of the normal range in renal
failure,35 we were uncertain of the expected de-
gree of elevation in renal failure combined with
cardiomyopathy, another potential cause of false
positive results. We recommended checking the
fractionated urinary metanephrine levels, which
are very sensitive and specific (98% for each),33,36
and thus negative urinary tests would be helpful.
The 24-hour fractionated urinary metanephrine
level was 830 μg (normal range for women, 30 to
180), and the 24-hour fractionated urinary
 Case Records of the Massachuset ts Gener al Hospital

A B

*
*

Figure 3. MRI of the Adrenal Glands.

MRI was performed according to an adrenal protocol, without the administration of intravenous contrast material.
Axial T1‑weighted and T2‑weighted images (Panels A and B, respectively) show an ellipsoid mass (asterisks) that is
located anterior to the superior pole of the right kidney (arrows). The mass has an intermediate signal (Panel A) and
mild hyperintensity (Panel B).

normetanephrine level was 1529 μg (normal
range for women 50 to 59 years of age, 128 to
484). However, urinary catecholamine and meta-
nephrine levels are unreliable in patients who
are receiving dialysis,35 and the patient had re-
ceived continuous venovenous hemofiltration as
recently as the day before the urine specimen
was obtained.
Although we typically would not proceed
with tumor localization without a confirmatory
biochemical diagnosis, we had high clinical sus-
picion for a diagnosis of pheochromocytoma on
the basis of the patient’s presentation, and we
knew that confirming this diagnosis would po-
tentially change her hospital care. Because she
was recovering from renal failure and cardiomy-
opathy and the expected degree of elevation in
the plasma or urinary fractionated metaneph-
rine levels was unknown, we recommended pro-
ceeding with imaging studies to identify the
anatomical location of a presumed pheochromo-
cytoma.
Dr. Alexis M. Cahalane: MRI was performed ac-
cording to an adrenal protocol, without the ad-
ministration of intravenous contrast material
(Fig. 3). Axial T1-weighted imaging showed an
ellipsoid mass (3.6 cm by 3.2 cm by 3.6 cm),
with uniform, intermediate signal intensity, that
was located anterior to the superior pole of the
right kidney. Relative to the spleen, the mass
had no signal dropout between in-phase and
out-of-phase images, a finding that suggests the
adrenal mass had no lipid content. On axial T2-
weighted imaging, the mass had mild hyperin-
tensity. The left adrenal gland was normal. For
any adrenal mass lesion, the imaging-based
differential diagnosis includes pheochromocy-
toma, myelolipoma, adenoma, adrenal cortical
carcinoma, and metastatic cancer. The appear-
ance of this lesion is most consistent with pheo-
chromocytoma.37-39
Dr. Johannes Steiner: Once the location of the
presumed pheochromocytoma was identified, the
plan was to proceed with laparoscopic adrenal-
ectomy in 1 month, to ensure alpha-adrenergic
blockade and allow time for recovery from both
catecholamine-induced cardiomyopathy and kid-
ney injury. Renal-replacement therapy was discon-
tinued on day 9. The patient’s hypertension was
treated with phenoxybenzamine for initial blood-
pressure control followed by carvedilol for addi-
tional beta-adrenergic blockade. The patient was
admitted before surgery, and preoperative echo-
cardiography revealed a left ventricular ejection
fraction of 54% and only mild residual left ven-
tricular apical hypokinesis.

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 The n e w e ng l a n d j o u r na l of m e dic i n e

of immunohistochemical staining for subunit B.40

Figure 4. Specimen of the Resected Adrenal Tumor.
On hematoxylin and eosin staining, a specimen of the resected adrenal tu‑
mor is composed of nests of polygonal cells with eosinophilic cytoplasm.
On immunohistochemical staining, the tumor cells show diffuse, strong
staining for the neuroendocrine marker chromogranin A (inset). These
findings are indicative of an adrenal pheochromocytoma.
In this case, staining for succinate dehydroge-
nase subunit B was preserved (not shown),
which suggests that the patient did not have a
mutation in a succinate dehydrogenase gene.
The changes that were seen on examination of
the endomyocardial-biopsy specimen are entirely
consistent with the presence of excess catechol-
amines, which may injure the myocardium by
inducing vasospasm and ischemia or by causing
direct cytotoxic effects.41-45
Dr. Dudzinski: Dr. Steiner, what happened with
this patient?
Dr. Steiner: After the patient underwent laparo-
scopic adrenalectomy, she had an uneventful peri-
operative course. She was discharged on postop-
erative day 3 while she was receiving a low dose
of carvedilol, which was stopped 2 weeks post-
operatively. At her follow-up visit 1 month later,
she did not report any symptoms of heart fail-
ure. Ultimately, laparoscopic adrenalectomy led
to complete recovery of her left ventricular ejec-
tion fraction.

A nat omic a l Di agnosis

Pathol o gic a l Discussion
Catecholamine-induced cardiotoxicity due to pheo­
Dr. Stone: An adrenal tumor (5.5 cm in greatest chromocytoma.
dimension) was resected laparoscopically. The This case was presented at Medical Grand Rounds.
tumor was composed of nests of polygonal cells Dr. Shah reports receiving consulting fees from MyoKardia
and KOL Groups, advisory-board fees from Amgen, and fees for
with a moderate amount of eosinophilic cyto- writing case summaries for Best Doctors, as well as holding a
plasm. Immunohistochemical staining showed pending patent (62/618,349) on extracellular RNA signatures of
that the tumor cells were strongly reactive for the cardiac remodeling; and Dr. Stone, receiving consulting fees
from GlaxoSmithKline, fees for expert testimony from USP Labs,
neuroendocrine marker chromogranin A (Fig. 4). and lecture fees from Alnylam Pharmaceuticals. No other poten-
These pathological features are indicative of tial conflict of interest relevant to this article was reported.
pheochromocytoma. Familial pheochromocytoma Disclosure forms provided by the authors are available with
the full text of this article at NEJM.org.
due to a mutation in a gene encoding a subunit We thank Dr. Danyaal Moin for assistance with preparation of
of succinate dehydrogenase typically shows loss the case narrative.

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