Pheochromocytoma-Induced Acute Myocarditis

Chih-Chung Hsiao,1 Cheng-Ting Tsai,1 Yih-Jer Wu,1,2 Hung-I Yeh,1,3

Charles Jia-Yin Hou1,3 and Cheng-Ho Tsai1,3

Pheochromocytoma is a neuroendocrine tumor, characterized by an excess of catecholamine production, which

results in paroxysmal or sustained hypertension, even hypertensive crisis. The classic triad of pheochromocytoma is

paroxysmal headache, sweating and palpitation. Myocarditis is a rare manifestation of pheochromocytoma. We

report 2 middle-aged women with a long history of hypertension and headache, presenting initial symptoms

mimicking acute coronary syndrome and finally developing heart failure and unstable hemodynamics. The

characteristic fluctuation of blood pressure and hypertensive crisis prompted us to further survey and diagnose this

rare pheochromocytoma-related myocarditis.

Key Words: Catecholamine � Myocarditis � Pheochromocytoma

INTRODUCTION

Pheochromocytoma is a rare catecholamine-produc-

ing tumor that arises from chromaffin cells of the adre-

nal medulla or the sympathetic ganglia, accounting for

less than 0.2% of overall hypertension.1 Although the

spells of the typical triad of pheochromocytoma are

headache, sweating and palpitation, paroxysmal hyper-

tension or hypertensive crisis is also suggestive of the

disease. Acute myocarditis is a rare complication of

pheochromocytoma. We report 2 cases with pheochro-

mocytoma-induced myocarditis. Both patients mani-

fested blood pressure fluctuation, and one of them pre-

sented cardiogenic shock requiring mechanical circula-

tory support.

CASE REPORTS

Case 1

A 41-year-old woman, who had 7 years of regularly

treated hypertension and chronic headache, presented

hemoptysis, short of breath, dyspnea on exertion, and

vomiting one day prior to admission. She visited our

outpatient clinic on the day of admission, and her chest

roentgenogram showed acute pulmonary edema. She de-

nied any flu-like symptoms prior to admission. En-

gorged jugular vein, breathing sound with diffuse crackles,

and a heart sound with S3 gallop were found on physical

examination. Acute respiratory failure together with pro-

found shock developed a few hours after admission. The

patient’s blood pressure was 62/50 mmHg, with a body

temperature of 37.5 �C, a heart rate of 130 beats per

minute and a respiratory rate approaching 40 per minute.

The electrocardiogram demonstrated sinus tachycardia

and ST segment depression in precordial leads V4-V6

(Figure 1A). The cardiac markers were elevated (tro-

ponin I > 100 ng/ml, creatine phosphokinase-MB 60.3

U/L and creatine phosphokinase 2006 IU/L), with the

other hemodynamic data obtained from pulmonary ar-

tery catheter consistent with a cardiogenic shock. To ex-

clude the possibility of acute coronary syndrome, The

patient underwent emergency coronary angiography,

229 Acta Cardiol Sin 2009;25:229�33

Pheochromocytoma-Induced Acute MyocarditisCase Report Acta Cardiol Sin 2009;25:229�33

Received: January 5, 2009 Accepted: March 11, 20091Cardiovascular Medicine, Department of Internal Medicine, Mackay

Memorial Hospital; 2Institute of Traditional Medicine, National

Yang-Ming University; 3Mackay Medicine, Nursing and Manage-

ment College and Taipei Medical University, Taipei, Taiwan.

Address correspondence and reprint requests to: Dr. Chih-Chung

Hsiao, Cardiovascular Medicine, Department of Internal Medicine,

Mackay Memorial Hospital, No. 92, Sec. 2, Chung Shan North Road,

Taipei 10449, Taiwan. Tel: 886-2-2543-3535 ext. 2456; Fax: 886-2-

2543-3535 ext. 3238; E-mail: Isuhchen@gmail.com

which demonstrated a substantially normal study. We

placed an intra-aorta balloon pump because of her pro-

found cardiogenic shock. Echocardiography showed a

generalized left ventricular (LV) hypokinesia with an

ejection fraction of 34%. We weaned her off the intra-

aorta balloon pumping 3 days after admission because of

improved hemodynamics. Nevertheless, paroxysmal ele-

vation of blood pressure (220/130 mmHg) occurred on

day 5. Angiotensin-converting enzyme inhibitor, nitrate,

diuretic, �-blocker and calcium channel blocker were

given, and her hypertension and pulmonary edema were

ameliorated after treatment. She was weaned off venti-

lator and extubated successfully after 2 weeks of ad-

mission. However, the hypertensive crisis recurred,

Acta Cardiol Sin 2009;25:229�33 230

Chih-Chung Hsiao et al.

Figure 1. (A) The 12-lead electrocardiogram on admission shows sinus tachycardia, and ST segment depression over inferior and precordial leads.

(B) The abdominal computed tomography reveals one well-defined, ovoid, right adrenal mass, estimated at 2.5 � 3 � 2.5 cm, with inhomogenous

strong enhancement (arrow). (C) Microscopically, the sections of adrenal medullar tumor show the feature of pheochromocytoma. The tumor cells

have copious cytoplasm with dense eosinophilic staining in alveolar and trabecular patterns. Hyaline globules are occasionally seen (haematoxylin

and eosin stain, 200X). (D) The tumor cells are immunoreactive to chromogranin-A staining (200X). (E) The tumor cells are immunoreactive to

synaptophysin staining (200X).

A

B C

D E

which prompted us to consider the possibility of second-

ary hypertension. The laboratory data, including adreno-

corticotropic hormone, aldosterone, plasma renin activ-

ity, cortisol and thyroid profile, were all within normal

limit. Urine catecholamines and metabolites revealed ab-

normally high levels (vanillylmandelic acid [VMA]:

14.5 mg/day [reference 1~7.5]; epinephrine: 311 �g/day

[reference < 22.4]; norepinephrine: 314.4 �g/day [refer-

ence 11~85], dopamine: 215.6 �g/day [reference 50~

450]). Abdominal computed tomography disclosed a 2.5

� 3 � 2.5-cm, well-defined, right adrenal tumor with

inhomogenous strong enhancement (Figure 1B). She un-

derwent right adrenalectomy after a short period of treat-

ment with �-blocker. The histopathology showed the tu-

mor cells were immunoreactive with chromogranin-A,

synaptophysin, neuron-specific enolase, vimentin, and

negative for cytokeratin, supporting the diagnosis of

pheochromocytoma (Figures 1C, D, E). The follow-up

echocardiography showed fair contractility with an EF

of 66% one month after surgery, and the levels of urine

catecholamine had returned to normal (VMA: 3.4

mg/day; epinephrine: 4.6 �g/day; norepinephrine: 45.2

�g/day; dopamine: 248 �g/day).

Case 2

A 56-year-old woman, who had had paroxysmal hy-

pertension with palpitation and headache for 2 years,

was incidentally found to have an adrenal tumor by ab-

dominal sonography. All checkups for the secondary hy-

pertension appeared normal except for abnormal 24-hour

urine catecholamines and metabolites (VMA: 11 mg/

day; epinephrine: 36 �g/day; norepinephrine: 36.5 �g/

day; dopamine: 127 �g/day). The abdominal computed

tomography demonstrated a big left adrenal tumor 3 �

3.5 � 5 cm in size with eccentric necrosis (Figure 2A).

I-131 MIBG adrenal scan was scheduled to further con-

firm the diagnosis and elucidate if there was extra-adre-

nal tumor. However, the patient came to our emergency

231 Acta Cardiol Sin 2009;25:229�33

Pheochromocytoma-Induced Acute Myocarditis

Figure 2. (A) The abdominal computed tomography shows one big ovoid left adrenal mass, estimated to be 3 � 3.5 � 5 cm in size, with central

tumor necrosis or cystic change (arrow). (B) The 12-lead electrocardiogram on admission shows sinus tachycardia, limb lead low voltage and ST

segment depression in precordial leads V4-V6.

A

B

department before the time of the scheduled scan with a

chief complaint of chest tightness, palpitation, dizziness

and nausea. She denied any flu-like symptoms before the

admission. The vital signs on admission were blood

pressure 162/107 mmHg, heart rate 111 beats/minute,

and respiratory rate 18 /minute. The chest film exhibited

pulmonary congestion, and her electrocardiogram re-

vealed sinus tachycardia and ST depression in precordial

leads V4-V6 (Figure 2B). Cardiac markers were elevated

(troponin I: > 100 ng/ml; creatine phosphokinase-MB:

78 U/L; creatine phosphokinase: 2205 IU/L). The physi-

cal examination was unremarkable except for tachycar-

dia. The bedside echocardiography showed mild but

generalized LV hypokinesia, with an ejection fraction of

~ 45-50%. Emergency coronary angiography was done

to exclude the possibility of acute myocardial infarction,

but coronary arteries were found normal. The patient’s

blood pressure levels fluctuated between 150/70 and

70/40 after admission. We followed up urine catechol-

amines, and the readings were even higher than before

(VMA: 16.4 mg/day; epinephrine 83 �g/day; norepine-

phrine: 108.8 �g/day; dopamine: 102.8 �g/day). The pa-

tient’s blood pressure was maintained by �-blocker. Al-

though surgery was highly recommended, she hesitated

and was discharged one week after admission.

DISCUSSION

Pheochromocytoma is a rare catecholamine-produc-

ing tumor. The vast majority of patients manifest the

classical triad: headache (~90%), sweating (60~70%),

and palpitation in symptomatic individuals.2,3 Other less

common associated symptoms include chest pain, pallor,

nausea, vomiting, dyspnea, weight loss, general weak-

ness and visual blurring. The most common sign in clini-

cal practice is sustained or paroxysmal hypertension

with occasional orthostatic hypotension, which results

from episodic excess catecholamine release (mostly

norepinephrine though some are epinephrine).4 Physi-

cians usually suspect the disease because of clinical

symptoms and histories, such as refractory hypertension,

recurrent hypertensive crisis, family history of multiple

endocrine tumor syndrome or onset at young age.

In our cases, both patients presented clinical symp-

toms and signs mimicking acute coronary syndrome.

Acute coronary syndrome is a common but serious dis-

ease, and thus should be considered first and excluded

immediately. Normal coronary angiography, together

with elevation of cardiac makers and abnormal LV wall

motion in our patients, suggested acute myocarditis

rather than myocardial infarction. Both of our patients

denied flu-like symptoms prior to the occurrence of

myocarditis, and no known etiology of myocarditis

could be identified, suggesting pheochromocytoma was

the most likely underlying cause of the myocarditis.

The first case demonstrated a fulminant cardiac pre-

sentation (pulmonary edema, cardiogenic shock, hyper-

tensive crisis) as a serious complication of pheochro-

mocytoma. The pathophysiology for catecholamines in

the occurrence of acute myocarditis is complex and not

well understood. Several mechanisms have been pro-

posed.4,5 For example, increased left ventricular work

and hypertrophy contribute to vasoconstriction and hy-

pertension; excess catecholamines could induce direct

toxic effect and free radical production, which in turn

impair cardiomyocyte structure and contractility. Cate-

cholamine could also cause coronary thickening and

spasm, tachycardia or arrhythmia. Finally, chronic myo-

cardial ischemia could result in left ventricular dysfunc-

tion and cardiomyopathy. Our two patients didn’t show

coronary spasm in angiography, but both of them de-

monstrated poor LV contractility. Singal et al. reported

that catecholamine may inhibit viability of myocytes via

cyclic AMP-mediated calcium overload.6 Van Vliet et al.

documented l6 instances of catecholamine-induced

myocarditis in 26 necropsy cases with pheochromo-

cytoma,7 suggesting that pheochromocytoma-induced

myocarditis could be a more common phenomenon than

we actually encounter in the clinical setting.

Chromogranin-A is a protein that is stored and se-

creted along with the catecholamines from the adrenal

medulla and the sympathetic nervous system. It may be

detected in more than 80 percent of patients with pheo-

chromocytoma but is not a pheochromocytoma-specific

protein.8 Synaptophysin, a synaptic vesicle glycoprotein,

presents in the membrane of neuronal presynaptic vesi-

cles in the brain, spinal cord, retina, vesicles of the adre-

nal medulla, neuromuscular junctions, and endocrine

cells. It usually acts as a marker for neuroendocrine tu-

mors. Neuron-specific enolase (NSE) is the isoform of

enolase, a glycolytic enzyme found in the neural tissue

Acta Cardiol Sin 2009;25:229�33 232

Chih-Chung Hsiao et al.

and neuroendocrine system. Cytokeratins and vimentin

are intermediate filaments. The former is found in the

intracytoplasmic cytoskeleton of epithelial tissue and the

latter attaches to the nucleus, endoplasmic reticulum,

and mitochondria. Both were detectable in 29% and 24%

of studied pheochromocytomas, respectively.9 In our

case 1, the immunostains were positive for chromo-

granin-A, synaptophysin, neuron-specific enolase and

vimentin, but negative for cytokeratin, a picture compat-

ible with the diagnosis of pheochromocytoma.

Surgical resection is still the treatment of choice to

eliminate the malignant myocardial effects from cate-

cholamines secreted by pheochromocytoma. �-blockade

is given preoperatively to control the norepinephrine-

mediated hypertension. �-blockade combination therapy

can be prescribed but never initiated before �-blockade

because an unopposed � stimulation may trigger another

hypertensive storm. Plouin et al. conducted a study of

the largest series of 147 patients with pheochromo-

cytoma undergoing surgery and showed overall mortal-

ity and morbidity of 2.4% and 24%, respectively.10

In summary, we have presented here two rare cases

with pheochromocytoma-induced myocarditis. These

case reports remind us that pheochromocytoma is one of

the causes of acute myocarditis, especially for those who

have a simultaneous blood pressure fluctuation or hyper-

tensive crisis.

REFERENCES

1. Young WF Jr. Adrenal causes of hypertension: pheochromo-

cytoma and primary aldosteronism. Rev Endocr Metab Disord

2007;8:309.

2. Manger WM, Gifford RW. Pheochromocytoma. J Clin Hypertens

(Greenwich) 2002;4:62.

3. Bravo EL, Gifford RW Jr. Pheochromocytoma. Endocrinol

Metab Clin North Am 1993;22:329.

4. Klein I. Endocrine disorders and cardiovascular disease. In:

Libby P, Ed. Braunwald’s Heart Disease: A Textbook of Cardio-

vascular Medicine. 8th ed. Philadelphia: Saunders, 2008:2045.

5. Wittstein IS, Thiemann DR, Lima JA, et al. Neurohumoral fea-

tures of myocardial stunning due to sudden emotional stress. N

Engl J Med 2005;352:539-48.

6. Singal PK, Kapur N, Dhillon KS, et al. Role of free radicals in

catecholamine-induced cardiomyopathy. Can J Physiol Pharmacol

1982;60:1390-7.

7. Van Vliet PD, Burchell HB, Titus JL. Focal myocarditis associ-

ated with pheochromocytoma. N Eng J Med 1966;274:1102-8.

8. Hsiao RJ, Parmer RJ, Takiyyuddin MM, et al. Chromogranin-A

storage and secretion: sensitivity and specificity for the diagnosis

of pheochromocytoma Medicine (Baltimore) 1991;70:33-45.

9. Kimura N, Nakazato Y, Nagura H, et al. Expression of inter-

mediate filaments in neuroendocrine tumors. Arch Pathol Lab

Med. 1990;114:506-10.

10. Plouin PF, Duclos JM, Soppelsa F, et al. Factors associated with

perioperative morbidity and mortality in patients with pheo-

chromocytoma: analysis of 165 operations at a single center. J

Clin Endocrinol Metab 2001;86:1480.

233 Acta Cardiol Sin 2009;25:229�33

Pheochromocytoma-Induced Acute Myocarditis