Her blood pressure on admission was145/90mmHg. Blood tests showed the following: leucocytosis; mildly increased CRP (14mg/L); mild increase of Troponin I (0.04 ng/ml); and normal CK (135U/I). ECG showed ventricular bigeminy. A chest radiograph demonstrated small bilateral pleural effusions. Echocardiography demonstrated a mildly dilated left ventricle with an ejection fraction of 25% and a pericardial effusion. She was initially treated with furosemide, ASA, enoxaparin, levofloxacin, and pantoprazol and was transferred for further evaluation.
Physical examination revealed the following: weight 59 kg; height 165 cm; absence of dysmorphic facial features; BP 130/80 mmHg; HR 72 bpm; 2/6 systolic murmur at the apex. Blood tests were all normal, except for NT proBNP 1366 pg/ml and CRP 8.4 mg/dl. Her electrocardiogram showed sinus rhythm, PR 120 msec, left atrial anomalies; left axis deviation and repolarisation anomalies. Echocardiography demonstrated: left ventricular dilatation (58 mm) with global left ventricular hypokinesia (EF 35%); mild left atrial enlargement (42 mm; 30ml/m2); type I diastolic dysfunction; E/Ea 9; normal right ventricular dimensions (27mm) and contractility (TAPSE: 20mm); small pericardial effusion. A cardiac MRI showed no oedema, mild LV dilation (56mm), EF 35%, absence of myocardial fibrotic scars (Figure 1 A and B).
Figure 1 (A and B). Cardiac magnetic resonance imaging (cMRI) with late gadolinium enhancement (LGE), showing a dilated left ventricle, without evidence of tissue abnormalities (scars, patchy fibrosis).
During her hospital stay, she was treated with bisoprolol (progressively increased to 10mg), ramipril (progressively increased to 10mg), spironolactone (25mg), furosemide (25mg), and pantoprazol (40mg). She complained of nausea and dyspepsia and ASA (600mg x 3) was discontinued. Her six minute walking test was 360 meters. An ambulatory electrocardiogram demonstrated sinus rhythm (mean 89; range 49-160), 8865 ventricular ectopic beats, frequent ventricular bigeminy, 353 polymorphic ventricular couplets, and a 4 beat polymorphic run of ventricular tachycardia (160 bpm); a second ECG Holter (after bisoprolol increase to 10mg) demonstrated frequent AV-node (junctional) rhythm with episodes of AV dissociation. Serum antibodies and a nasopharyngeal swab (to analyse DNA/RNA by PCR amplification) were obtained for Influenza A and B, parainfluenza, respiratory syncitial virus, parvovirus, adenovirus, HIV, HCV, HBV, CMV, EBV, Toxoplasma, Mycoplasma, Chlamydia, Legionella, Rickettsia, Bartonella and Borrelia. ANA, ANCA, antiDNA, ENA, Vidal-Wright, VDRL, and Tine test were also performed. The patient had a mild serological positivity for Rickettsia (ELISA) and was commenced on doxycyclin 50mg x2/die.
What is the differential diagnosis in this patient ?
What further investigations (if any) would you perform?
Should any additional therapy be started?
Polymerase chain reaction (PCR) analysis on the nasopharyngeal swab failed to detect rickettsial DNA. Doxycyclin therapy was then stopped. The patient complained of migraine and increasing dyspepsia and nausea, with sweating and vomiting, associated with palpitations and elevated BP (max 170/100mmHg). A 24 hour BP Holter monitoring (on top of therapy with bisoprolol 10mg; ramipril 10mg; furosemide 25mg; spironolactone 37mg), showed elevated mean systolic and diastolic blood pressure (150/90mmHg), with marked circadian rhythm alteration. Increased 24 hours urine catecholamines (>2 fold) were found. She underwent a CT scan revealing an inhomogeneous right adrenal mass (6.5x 5.cm), with central necrosis, suggesting a malignant pheocromocytoma (Figure 2A and B).
Bisoprolol was stopped, and she was commenced on carvedilol (up to 25mg 2 times a day: 50mg) and doxazosin 2mg (progressively increased to 4mg). A new 24 hour BP Holter revealed an improved BP profile, with persistent circadian rhythm alteration (particularly, diastolic BP values). After three weeks, she underwent laparoscopic resection of the right adrenal mass. Pathology examination confirmed the diagnosis of pheochromocytoma (Figure 3A and 3B).
Histology confirmed confluent tissue necrosis and cellular atypia (Figure 3C and 3D).
Immunoreactivity for chromogranin A (CgA), a major constituent of the matrix of catecholamine-containing secretory granules, representing the most specific and reliable generic neuroendocrine marker currently used in pathology practice, was evidenced (Figure 3 E).
Also, Ki-67 immunoreactivity, a marker of tumour malignancy, was positive (Figure 3 F).
The blood pressure became stable after the resection. She remained asymptomatic for dyspnoea and palpitations. Nevertheless, repeated echocardiographic examinations (1,3,6 months) showed persistent left ventricular systolic dysfunction (EF 35%).
Pheocromocytoma and catecholamine-related myocardial diseases
Acute cardiac failure due to highly elevated catecholamines is a rare entity. In vitro and in vivo animal experiments have confirmed that chronic exposure to catecholamines is toxic to cardiac myocytes . Catecholamine over-production (“catecholamine toxicity”) can occur in different conditions, including:
-central nervous system trauma (catecholamine dump); 
-neuroendocrine tumors in the adrenal medulla (pheochromocytoma);
-genetic disorders, such as monoamine oxidase A deficiency (one of the enzymes responsible for degradation of cathecolamines); 
-cocaine abuse. 
Catecholamine toxicity has been also advocated as possible mechanism of myocardial damage in scorpion envenomation (“adrenergic myocarditis”)  and transient basal left ventricular ballooning syndrome (“Takotsubo cardiomyopathy”) .
Pheochromocytomas are rare neuroectodermal catecholamine-secreting tumors commonly found in the adrenal medulla.  Adrenal pheochromocytomas secrete both epinephrine and norepinephrine, unlike the extra-adrenal tumors (functional paragangliomas), which lack phenylethanolamine-N-methyl transferase and secrete only norepinephrine. They are often referred to as the “10% tumour” (10% bilateral, 10% malignant, 10% familial, 10% paediatric, 10% extra adrenal, and 10% inherited). They show no gender partiality and can occur at any age, although they are most common in the fourth and fifth decades of life. Although approximately 10% of all pheochromocytomas are inherited, they are relatively rare in the general population with a prevalence of 0.3% to 1.9%. Pheochromocytomas are more frequent in patients with a history of von Recklinghausen disease, Von Hippel-Lindau disease, multiple endocrine neoplasia type IIA and IIB, and neuroectodermal disorders including Sturge-Weber syndrome and tuberous sclerosis. Up to 25% of pheochromocytomas may be familial. Mutations of the genes VHL, RET, NF1, SDHB and SDHD are all known to cause familial pheochromocytomas/extra-adrenal paragangliomas.
The clinical diagnosis is difficult
Especially when few or none of the other classic signs or symptoms are present (i.e., the classic triad of palpitations, diaphoresis, and headache; hypertension; chest pain; shortness of breath; flushing; anxiety). They can be found in about 0.1% to 0.2% of hypertensive patients, and although hypertension is the most commonly noted clinical sign among other possible symptomatology, it may be paroxysmal in nature and not always evident.  Although it is rare, myocardial involvement, from a pheochromocytoma can include angina pectoris, acute heart failure and cardiogenic shock, acute myocarditis/dilated cardiomyopathy, myocardial infarction, and arrhythmias.
The acute onset of severe congestive heart failure secondary to catecholamine overproduction from a pheochromocytoma is a rare entity, and the diagnosis is difficult in absence of a classic clinical picture. Nevertheless, a misdiagnosis may often lead to inappropriate treatment with a very poor outcome.
Diagnosis and screening for a suspected pheochromocytoma consists of obtaining 24-hour urinary catecholamine levels (epinephrine, norepinephrine, and dopamine), including their metabolites (metanephrine, normetanephrine, and vanillyl mandelic acid), or measurement of plasma fractionated metanephrine and normetanephrine levels.  Urinary metanephrines (metanephrine and normetanephrine) are highly sensitive and specific for diagnosing pheochromocytomas, although new research is showing plasma metanephrines to be the most consistent with nearly 100% sensitivity.
Preoperative localisation of pheochromocytomas can be carried out by a variety of radiologic studies, such as CT, magnetic resonance imaging (MRI), and radiolabelled iodine-131 or 123-metaiodobenzylguanidine scintigraphy. CT has a reported sensitivity and specificity of greater than 90% in localising primary adrenal pheochromocytomas; however, it is less accurate in detecting extra-adrenal tumors. A T2-weighted MRI, with 91% to 100% sensitivity and 50% to 97% specificity, provides excellent anatomic detail and is more accurate than CT in localizing paragangliomas. Radiolabelled meta-iodobenzylguanidine (MIBG), which is structurally comparable with norepinephrine, is selectively taken up and concentrated in chromaffin tissue. With a sensitivity of 77% to 91% and specificity of 96% to 100%, it is the test of choice for localizing extra-adrenal neoplasms not appreciated on CT or MRI.
1. Quigg RJ, Om A. Reversal of severe cardiac systolic dysfunction caused by pheochromocytoma in a heart transplant candidate. J Heart Lung Transplant 1994; 13:525–532.
2. Samuels MA. The brain-heart connection. Circulation. 2007;116:77-84.
3. Lenders JW, Eisenhofer G, Mannelli M, Pacak K. Phaeochromocytoma. Lancet 2005; 366: 665–675.Taneja I, Robertson D. Genetic basis of autonomic dysfunction. Semin Neurol. 2003;23:391-7.
4. Nahas GG, Trouvé R, Manger WM. Cocaine, catecholamines and cardiac toxicity. Acta Anaesthesiol Scand Suppl. 1990;94:77-81.
5. Karnad DR. Haemodynamic patterns in patients with scorpion envenomation. Heart. 1998;79:485-9.
6. Di Palma G, Daniele GP, Antonini-Canterin F, Piazza R, Nicolosi GL. Cardiogenic shock with basal transient left ventricular ballooning (Takotsubo-like cardiomyopathy) as first presentation of pheochromocytoma. J Cardiovasc Med (Hagerstown) 2010; Apr 17. [Epub ahead of print].
7. E.L. Bravo, Evolving concepts in the pathophysiology, diagnosis, and treatment of pheochromocytoma, Endocr Rev 1994; 15: 356–368.
8. P.E. Cryer, Pheochromocytoma, Clin Endocrinol Metab 1985; 14: 203–220.
10. W.B. Liao, C.F. Liu, C.W. Chiang, C.T. Kung and C.W. Lee, Cardiovascular manifestations of pheochromocytoma, Am J Emerg Med 2000; 18: 622–625.
11. K. Pacak, W.M. Linehan, G. Eisenhofer, M.M. Walther and D.S. Goldstein, Recent advances in genetics, diagnosis, localization, and treatment of pheochromocytoma, Ann Intern Med 2001; 134: 315–329.
12. J. Lenders, K. Pacak and M. Walther et al., Biochemical diagnosis of pheochromocytoma: which test is best?, J Am Med Assoc 2002; 287: 1427–1434.
13. F. Lumachi, A. Tregnaghi and P. Zucchetta et al., Sensitivity and positive predictive value of CT, MRI and 123I-MIBG scintigraphy in localizing pheochromocytomas: a prospective study, Nucl Med Commun 2006; 27: 583–587.
14. R.R. Perry, H.R. Keiser and J.A. Norton et al., Surgical management of pheochromocytoma with the use of Metyrosine, Ann Surg 1990; 212: 621–628.
15. M.G. Sutton, S.G. Sheps and J.T. Lie, Prevalence of clinically unsuspected pheochromocytoma: Review of a 50-year autopsy series. Mayo Clin Proc 1981; 56. 354–360.
16. R. Humphrey, D. Gray, S. Pautler and W. Davies, Laparoscopic compared with open adrenalectomy for resection of pheochromocytoma: a review of 47 cases. Can J Surg 2008; 51: 276–280.
17. K.A. Gatzoulis, G. Tolis, A. Theopistou, J.H. Gialafos and P.K. Toutouzas, Cardiomyopahty due to a pheochromocytoma: A reversible entity. Acta Cardiol 1998; 53:227–229.
18. Shub C, Cueto-Garcia L, Sheps SG et al. Echocardiographic findings in pheochromocytoma. Am J Cardiol 1986; 57:971–975.
19. Kelley SR, Goel TK, Smith JM. Pheochromocytoma presenting as acute severe congestive heart failure, dilated cardiomyopathy, and severe mitral valvular regurgitation: a case report and review of the literature. J Surg Educ 2009;66:96-101.
European Society of Cardiology
European Heart HouseLes Templiers2035 Route des CollesCS 80179 Biot
06903Sophia Antipolis, FR
Our mission: To reduce the burden of cardiovascular disease
© 2017 European Society of Cardiology. All rights reserved