Heart and Vessels

, Volume 28, Issue 2, pp 255–263

Endomyocardial biopsy in a patient with hemorrhagic pheochromocytoma presenting as inverted Takotsubo cardiomyopathy


    • Department of CardiologyAizawa Hospital
    • Department of OrthopedicsHirosaki University School of Medicine
  • Shunpei Sakurai
    • Department of CardiologyAizawa Hospital
  • Tamon Kato
    • Department of CardiologyAizawa Hospital
  • Shigeki Nishiyama
    • Department of CardiologyAizawa Hospital
  • Takeki Hata
    • Department of CardiologyAizawa Hospital
  • Eiichiro Mawatari
    • Department of CardiologyAizawa Hospital
  • Chihiro Suzuki
    • Department of CardiologyAizawa Hospital
  • Kazuhiro Takekoshi
    • Department of Laboratory Medicine, Graduate School of Comprehensive Human SciencesUniversity of Tsukuba
  • Kayoko Higuchi
    • Department of PathologyAizawa Hospital
  • Toru Aizawa
    • Diabetes Center, Aizawa Hospital
  • Uichi Ikeda
    • Department of CardiologyShinshu University School of Medicine
Case Report

DOI: 10.1007/s00380-012-0247-4

Cite this article as:
Iio, K., Sakurai, S., Kato, T. et al. Heart Vessels (2013) 28: 255. doi:10.1007/s00380-012-0247-4


A 29-year-old female patient presented with shock and dyspnea due to heart failure and pulmonary edema. Echocardiography indicated excessive contraction limited to the left ventricular apex and akinesis of the basal and middle ventricle, which were confirmed by emergency left ventriculography. The finding was diagnostic of inverted Takotsubo cardiomyopathy. An abdominal computed tomography scan showed a tumor in the left adrenal gland with a central low-density area, and the plasma and urinary catecholamines were strikingly elevated. Taken together, these findings suggested the presence of a hemorrhagic pheochromocytoma. A myocardial biopsy in the very acute stage on the day of admission revealed neutrophilic infiltration and contraction-band necrosis, which was indistinguishable from the previously reported pathology in the acute phase of idiopathic Takotsubo cardiomyopathy without pheochromocytoma. The diagnosis of pheochromocytoma in this case was confirmed 7 weeks later by surgical removal of the left adrenal gland with massive hemorrhage at the center of the pheochromocytoma. The marked similarity of the endomyocardial pathology between this case and cases with idiopathic Takotsubo cardiomyopathy strongly points to catecholamine excess as a common causality for Takotsubo cardiomyopathy with or without pheochromocytoma.


PheochromocytomaTakotsubo cardiomyopathyEndomyocardial biopsyShock


Pheochromocytoma is a rare but clinically important tumor composed of chromaffin cells that produce, store, and release catecholamines, with potentially life-threatening complications. While the classic triad of pheochromocytoma is an episodic headache, diaphoresis, and palpitations [1, 2], unusual presentations including hypotension, acute cardiogenic shock, pulmonary edema, and sudden death have also been reported [2, 3]. In addition, cardiomyopathy characterized by transient hypokinesis of the basal and mid-ventricular segments with sparing of the apical contraction, i.e., so-called inverted Takotsubo cardiomyopathy [48], a variant of Takotsubo cardiomyopathy [913], have been reported in patients with pheochromocytoma. Takotsubo cardiomyopathy per se is a potentially fatal condition, which can even cause ventricular septal perforation and septal dissection [14]. We report here the case of a young woman with a pheochromocytoma presenting with shock and severe pulmonary edema with inverted Takotsubo cardiomyopathy. Pathological findings in the myocardium in this patient in the very acute phase were indistinguishable from those reported in idiopathic Takotsubo cardiomyopathy.

Case report

A 29-year-old woman presented at the emergency department with shock and severe dyspnea. She gave a history of occasional palpitations while walking for the past 2 years. Approximately 1 year previously, she had experienced palpitations lasting as long as 30 min. Her electrocardiogram (ECG) showed normal sinus rhythm with a heart rate of 73 beats/min and transient ST depression on II, III, aVF, V3 through V6. Her palpitations progressed, occurring even at rest, to several times a week. An hour before her arrival at the hospital, she collapsed after having a sudden onset of palpitations, nausea, vomiting, dyspnea, dizziness, and high-left backache. She looked pale and severely dyspneic, and was assessed as a 10 on the Glasgow Coma Scale 10 (E2V3M5). Her blood pressure was 122/91 mmHg, heart rate 129 beats/min with a body temperature of 35.4 °C, respiratory rate 52 breaths/min, and oxygen saturation 66 % on 3 l oxygen by nasal cannula. Copious amounts of pink foamy secretion were present, resulting in her being intubated.

The ECG showed sinus tachycardia, 133 beats/min (Fig. 1), without significant ST–T change. Her chest X-ray showed severe bilateral pulmonary edema (Fig. 2a), while the cardiothoracic ratio showed no increase (46 %).
Fig. 1

Electrocardiogram on admission. Sinus tachycardia without significant ST-segment change or T-wave abnormality

Fig. 2

Chest X-ray. On admission (a), diffuse bilateral opacity, suggesting severe bilateral pulmonary edema, was found. Note that the cardiothoracic ratio was not increased (46 %). On day 4 (b), lung edema was relieved

The plasma concentration of the N-terminal fragment of proBNP1-76 (NT-proBNP) measured with a fully automated “sandwich” electrochemiluminescence method [15] was 97.58 pg/ml, which was within the normal range (≤125 pg/ml). A low platelet count (118 000/μl) and elevation of alanine aminotransferase (575 U/l) were also noted. Other data including electrolytes and creatine kinase were within the normal range, but the troponin T semi-quantitative test (TROP T® Sensitive Rapid Assay, Roche) was positive, indicating myocardial damage. Arterial blood gas revealed severe metabolic acidosis, with a pH of 7.090. A computed tomography (CT) scan revealed diffuse, severe pulmonary edema. A 26-mm left adrenal tumor with possible central hemorrhage (Fig. 3) [16] was also found on CT. Ninety minutes later, her blood pressure suddenly dropped to 74/52 mmHg and echocardiography demonstrated diffuse akinesis of the basal and middle segment of the left ventricle, while the ventricular apex contracted excessively (Fig. 4). The left ventricular ejection fraction (LVEF) was as low as 15 %. At this stage, left ventricular end-diastolic pressure was 18 mmHg, pulmonary capillary wedge pressure 14 mmHg, and cardiac output 3.27 l/min.
Fig. 3

Abdominal CT scan. Arrows indicate a heterogeneous left adrenal mass without enhancement (a), with area of central low density after contrast enhancement (b). The finding suggested adrenal tumor with central hemorrhage or necrosis

Fig. 4

Echocardiogram (apical two-chamber view). a Systolic phase; b diastolic phase. Akinesis of the basal and middle segments of left ventricle and apical hypercontraction were observed

Intravenous administration of dopamine hydrochloride (DOA), 250 μg/min and dobutamine (DOB), 150 μg/min (3.75 μg/kg/min) was started, and intra-aortic balloon pumping (IABP) support was given to maintain hemodynamic conditions.

Emergency coronary angiography was performed, and no coronary artery stenosis was found. The left ventriculography showed discriminating motion of the ventricle, i.e., akinesis of the basal and middle segments of the left ventricle and excessive apical contraction were observed (Fig. 5). The LVEF was 24.8 %. To rule out viral myocarditis, an endomyocardial biopsy of the ventricular septum was performed from the right ventricular side. This revealed mild neutrophilic infiltration and diffuse contraction-band necrosis (Fig. 6a, b) [17]. After being stained by immunohistochemistry against CD-15 antibody (DAKO, Glostrup, Denmark) (Fig. 6c), the infiltrated cells were found to be nonlymphoid.
Fig. 5

Left ventriculography on the 1st day during the acute phase. Discriminating motion of the ventricle is shown. Akinesis of the basal and middle segments of left ventricle and excessive apical contraction (arrows) were apparent. a Right anterior oblique (RAO) view during diastole; b left anterior oblique (LAO) view during diastole; c RAO during systole; d LAO during systole. The LVEF was 24.8 %

Fig. 6

Endomyocardial biopsy. Mild neutrophilic infiltration and diffuse contraction band necrosis were found. a Hematoxylin–eosin (H&E) stain (×10); b H&E stain (×40); c immunohistochemical staining with anti-CD15 antibody (×20)

Plasma and urine catecholamine levels were markedly elevated (approximately fivefold) on the 2nd hospital day (Table 1). Although the patient was receiving 7 μg/kg/min DOA and 7 μg/kg/min DOB at the time of blood sampling, plasma epinephrine and norepinephrine levels were remarkably high compared with the reported values in normal subjects receiving 5 μg/kg/min [18] or 7 μg/kg/min [19] DOA. Regarding other catecholamine values, the reference range during DOA infusion is unknown, so that abnormal elevation, if any, was not firmly established.
Table 1

Plasma and urinary catecholamine levels



Normal range

Day 2a

Day 10





<100 pg/ml




100–450 pg/ml




<20 pg/ml

 Vanillylmandelic acid



3.3–8.6 ng/ml





3.4–26.9 μg/day




48.6–168.4 μg/day




365.0–961.5 μg/day

 Vanillylmandelic acid



1.5–4.3 mg/day




0.04–0.19 mg/day




0.09–0.33 mg/day

aThe patient was receiving 7 μg/kg/min dopamine and 7 μg/kg/min dobutamine

On the 4th day after admission, echocardiography showed improvement in abnormal contraction in the basal and middle segments of the left ventricle. The LVEF improved to 35.8 % and the lung edema was cleared (Fig. 2b). The IABP support was withdrawn. Dopamine hydrochloride and DOB were tapered, and discontinued on the 10th hospital day. Viral antibodies against adenovirus, coxsackievirus A16, B1, B2, B3, B4, B5, and B6, echovirus 6 and 8, and cytomegalovirus were all negative. With an oral α1-blocker, doxazosin, 1.5 mg/day, the patient recovered uneventfully during her month-long hospital stay.

A cardiac magnetic resonance image (MRI) taken on the 25th day showed no morphological abnormality with normal contraction of the left ventricle. Gadolinium enhancement showed no delayed enhancement in the ventricular wall (Fig. 7). An abdominal MRI depicted the tumor with its core as high intensity on a T2-weighted image and low intensity on a T1-weighted image, and the rim of the tumor was of low intensity on both the T1- and T2-weighted images, which strongly suggested previous hemorrhage at the center of the tumor (Fig. 8). 131I-metaiodobenzylguanidine scintigraphy revealed a definitive accumulation at the left adrenal gland (Fig. 9). The tumor was surgically removed 7 weeks later, with a pathological diagnosis of pheochromocytoma with a central hemorrhagic necrosis (Fig. 10a, b). As expected, the tumor cells were positively stained for chromogranin (Fig. 10c). Although the family history was negative for both multiple endocrine neoplasia and pheochromocytoma, an investigation was conducted to determine whether a germline mutation might have affected the tumor-suppressor gene VHL (associated with von Hippel–Lindau disease), succinate dehydrogenase subunit D, or succinate dehydrogenase subunit B [20, 21], but no mutations were found.
Fig. 7

Cardiac magnetic resonance imaging (MRI) with gadolinium enhancement. No morphological abnormality and no delayed enhancement in ventricular wall were apparent. Note that the image was taken on day 25. a Four-chamber view; b long-axis view; c short-axis view

Fig. 8

Abdominal MRI. The adrenal tumor per se was high intensity on fat-suppressed T2-weighted imaging (a, thick arrow) and low intensity on fat-suppressed T1-weighted imaging (b). The central portion of the tumor was high intensity on in-phase T1-weighted imaging (c), and surrounded by a rim-like low-intensity structure on the T2-weighted image (a, thin arrow). The findings strongly suggested previous hemorrhage into the center of the adrenal tumor

Fig. 9

131I-Metaiodobenzylguanidine scan. a Anterior view; b posterior view. Accumulation at the left adrenal gland is indicated by the arrow

Fig. 10

Macroscopic and microscopic appearance of the adrenal tumor. a A midline section showing the central hemorrhage. b H&E staining (×20). c Immunohistochemical staining with antichromogranin antibody (×20)


It is a clinical challenge to correctly diagnose and manage patients with pheochromocytoma in crisis [2]. The clinical presentation, medical history, and discovery of an adrenal tumor on the CT scan together lead us to strongly suspect the presence of pheochromocytoma in our patient. Elevated plasma and urinary catecholamines on the 2nd day, likely due to episodic discharge of the hormones from the tumor, and the accumulation of 131I-metaiodobenzylguanidine in the tumor were compatible with the diagnosis later confirmed by surgical pathology. We believe that the patient’s pulmonary edema was the result of a combination of the abnormally elevated permeability of the pulmonary vascular bed and myocardial damage caused by a catecholamine excess. Hemodynamic data obtained on the day of admission support this hypothesis. The clinical course illustrates the importance of intensive cardiocirculatory support immediately after the crisis onset. Normal plasma concentration of NT-proBNP has been shown to be a predictor of favorable prognosis in idiopathic Takotsubo cardiomyopathy [22], which was also the case in our patient. Although the elevation of serum inflammatory markers was recently found in patients with idiopathic Takotsubo cardiomyopathy [23], such markers were not present in this case.

In the diagnostic guidelines for Takotsubo cardiomyopathy [24, 25], the presence of pheochromocytoma is listed as an exclusion criterion. “Inverted” Takotsubo cardiomyopathy was first described by Ennezat et al. [26] in 2005 as a possible variant form of Takotsubo cardiomyopathy, characterized by excessive contraction of the left ventricular apex and akinesia of the left ventricular base and midportion. The cardiac contour in our case was compatible with the description of inverted Takotsubo cardiomyopathy given as a variant in the guidelines for Takotsubo cardiomyopathy proposed by Prasad et al. [25], although this variant does not feature in the guidelines put forward by Japanese researchers [24]. Catecholamine excess has been recognized as a major underlying mechanism for “idiopathic” Takotsubo cardiomyopathy.

An endomyocardial biopsy in the current case obtained on the day of the attack showed nonlymphocytic infiltration, together with negativity in the viral antibodies, and so excluded the possibility of viral myocarditis. Importantly, the histological evidence for similarity between idiopathic (i.e., without pheochromocytoma) Takotsubo cardiomyopathy and the pheochromocytoma-associated inverted Takotsubo cardiomyopathy was obtained, namely, neutrophilic infiltration and diffuse contraction-band necrosis were present in our patient. Contraction-band necrosis is commonly found in idiopathic Takotsubo cardiomyopathy, especially in the acute phase [27, 28]. As far as we are aware, this is the first report on endomyocardial biopsy findings during the very acute stage of pheochromocytoma-associated Takotsubo cardiomyopathy. Taken together, it is likely that the two conditions, idiopathic Takotsubo cardiomyopathy and pheochromocytoma-associated (inverted) Takotsubo cardiomyopathy, share a virtually indistinguishable pathogenesis. Diagnosis of pheochromocytoma was made early in the course of the disease, which is also an uncommon experience.

The occurrence of a pheochromocytoma crisis with hemorrhaging into the tumor and development of severe pulmonary edema is in line with previous reports [2, 2931]. Although the frequency of germline mutations in apparently sporadic cases with pheochromocytoma is reportedly as high as about 25 % [20], we found no such germline mutation in our patient. The prevalence of genetic mutation in patients with Takotsubo cardiomyopathy or inverted Takotsubo cardiomyopathy associated with pheochromocytoma has never been investigated, and warrants further study.


We reported a case of cardiogenic shock and pulmonary edema due to a pheochromocytoma crisis. The patient survived with intensive cardiopulmonary care. Acute hemorrhage in the tumor with a surge of catecholamines was considered the cause of heart failure and pulmonary edema. At the very acute stage, inverted Takotsubo cardiomyopathy with a pathological finding indistinguishable from that reported in patients with idiopathic Takotsubo cardiomyopathy was present. This is the first such report in a patient with pheochromocytoma-associated Takotsubo cardiomyopathy.


The authors thank Dr Hiroyuki Uchiyama for providing invaluable suggestions during the acute-phase management, Dr Yoshihiko Ikeda for constructive discussion regarding pathology, and Dr Osamu Ishizuka for providing the 131I-metaiodobenzylguanidine scintigraphy image and the photograph of the resected tumor. We are also grateful to Professor Hau C. Kwaan, Northwestern Medical Faculty Foundation, Chicago, and Robert Pastorek for editorial assistance.

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© Springer 2012