PHILIP J. ROBINSON, M.D.
Royal Children’s Hospital, Melbourne Melbourne, Australia Murdoch Childrens Research Institute Melbourne, Australia and University of Melbourne Melbourne, Australia
References
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3. Stuart-Andrews CR, Kelly VJ, Sands SA, Lewis AJ, Ellis MJ, Thompson BR. Automated detection of the phase III slope during inert gas washout testing. J Appl Physiol 2012;112:1073-1081.
4. King L, Welsh L, Soto-Martinez M, Jiminez G, Oliver M, Catto-Smith A, Tomai M, Robinson P. Functional respiratory abnormalities in chil- dren and adolescents with active Crohn’s disease: a pilot study [ab- stract]. Respirology 2010;15:25.
5. Bonniere P, Wallaert B, Cortot A, Marchandise X, Riou Y, Tonnel AB, Colombel JF, Voisin C, Paris JC. Latent pulmonary involvement in Crohn’s disease: biological, functional, bronchoalveolar lavage and scintigraphic studies. Gut 1986;27:919-925.
6. Wallaert B, Colombel JF, Tonnel AB, Bonniere P, Cortot A, Paris JC, Voisin C. Evidence of lymphocyte alveolitis in Crohn’s disease. Chest 1985;87:363-367.
7. Munck A, Murciano D, Pariente R, Cezard JP, Navarro J. Latent pul- monary function abnormalities in children with Crohn’s disease. Eur Respir J 1995;8:377-380.
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Copyright @ 2012 by the American Thoracic Society
Takotsubo Syndrome Secondary to Adrenal Adenocarcinoma: Cortisol as a Possible Culprit
To the Editor:
Takotsubo syndrome, first described by Satoh and colleagues (1) in 1990, is a reversible left ventricular apical wall motion abnormality associated with electrocardiogramanges and minor myocardial enzymatic release; it mimics acute coronary syndrome.
A 47-year-old healthy patient was admitted to the intensive care unit for a cardiogenic shock with ST elevation in I, aVL, and V2- V6 on electrocardiogramtricular dysfunction
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(left ventricular ejection fraction 15-20%) with global hypokinesia in the apical region with a typical apical ballooning was revealed by echocardiography (Figure 1). Troponin and creatinine kinase were increased to 1.5 U/L (normal range < 0.09 U/L) and 254 U/L (normal range 47-222 U/L), respectively. The coronarography excluded any coronary artery stenosis. Within 48 hours after ad- mission, with intraaortic balloon pump and an initial catechol- amine support until the diagnosis of Takotsubo, the patient recovered a left ventricular ejection fraction of 45-50%, allowing the weaning of all cardiac support. The patient subsequently de- veloped a severe and refractory hypertension requiring several antihypertensive medications. A pheochromocytoma and a Cush- ing syndrome were evoked. The computed tomography scan showed a voluminous necrotic nodular left adrenal tumor with multiple hepatic, pulmonary, and bone metastatic lesions (Figure 2). The endocrinal assessment revealed a high 24-hour urine cor- tisol level (11,000 nmol/24 h; normal range 30-220 nmol/24 h). After surgical excision, pathology and immunohistochemical tests confirmed a corticoadrenal adenocarcinoma, with positive ex- pression of synaptophysin, neuron-specific enolase, inhibin, and Melan-A without secretion of adrenocorticotropic hormone; tests were also negative for chromogranin and positive for keratin, thereby excluding pheochromocytoma. The patient died from extensive metastasization of the tumor within 3 months. This case report illuminates a potential new mechanism for Takotsubo syn- drome. So far, although it has been intensely discussed by dif- ferent research groups, the myocardial damage induced by catecholamine is suggested to be the main cause of Takotsubo cardiomyopathy. Epinephrine binds to ß1-adrenoreceptors (B1ARs) and preferentially to ß2-adrenoreceptors (B2ARs), couples to proteins of the Gs family, and activates the adenyl cyclase-protein kinase A pathway generating positive inotropic and lusitropic responses (2). At “supraphysiological” concentra- tions, epinephrine has a negative inotropic effect due to a switch in the ß2AR coupling from Gs protein to Gi protein signaling (3, 4) in human atrial (5) and ventricular (6) muscles. This change might have a protective role (2). Norepinephrine, how- ever, preferentially binds ß1ARs and has the same positive ino- tropic effect on myocyte contraction (2). Although the ratio of
C.T. was supported by the Swiss National Science Foundation (SCORE grant 3232230-126233).
Author Contributions: Conception, design, and writing of the paper: N.W., P.M., and D.P .; drafting the manuscript for important intellectual content: J .- C.P., P .- Y.D., C.T., C.G., and L.B. All authors have made substantive contributions to the study, and all authors endorse the data and the conclusions.
B1ARs to ß2ARs in the human ventricular myocardium is 4:1 (7), the density of ß2ARs is higher (B2 > ß1) in the apical region (8). In response to high catecholamine levels, the ß2AR-Gi sig- naling predominantly located at the apex can lead to the typ- ical ampulla-shaped cardiomyopathy.
In this report, there was no increase of catecholamine levels but a supraphysiological secretion of cortisol. A cardiogenic shock due to a hypertensive crisis related to hypercortisolism does not seem compatible with this typical Takotsubo syndrome-as echocardiographically assessed. Another mechanism can there- fore be hypothesized. High levels of cortisol can enhance the expression of ß2ARs in the ventricles, especially in the apex, and considerably increase the sensitivity to stress. In a rat model, cortisol up-regulated, via a nuclear glucocorticoid recep- tor, by two- to threefold the expression of B-adrenoreceptors (9). Cortisol also increases the sensitivity to ß-agonists and the effects of sympathetic stimulation on the heart (9). The coupling with Gi proteins predominates when the density of receptors is increased and the stimulation is massive (10). In such a situation, small emotional (fright or danger) or physical (activity, infec- tion, or tissue damage) stress could trigger a Takotsubo car- diomyopathy because of synergistic effects of both types of stress hormones, cortisol and catecholamines. Intriguingly, hypocortisolism may also be associated with Takotsubo by a dif- ferent mechanism (11).
The corticoadrenal adenocarcinoma on its own is rare, and its presentation with Takotsubo is to our knowledge the first case described in the literature. This case seems to give a new insight on the mechanism of the Takotsubo syndrome.
Author disclosures are available with the text of this letter at www.atsjournals.org.
NADINE WICKBOLDT, M.D. JEAN-CLAUDE PACHE, M.D. PIERRE-YVES DIETRICH, M.D. CHRISTIAN Toso, M.D. CHRISTOPHE GALLAY, M.D. LAURENT BROCHARD, M.D. PAOLO MERLANI, M.D. DEBORAH PUGIN, M.D. Geneva University Hospitals and the University of Geneva Geneva, Switzerland
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6. Brown LA, Harding SE. The effect of pertussis toxin on beta-adrenoceptor responses in isolated cardiac myocytes from noradrenaline-treated guinea-pigs and patients with cardiac failure. Br J Pharmacol 1992; 106:115-122.
7. Port JD, Bristow MR. Altered beta-adrenergic receptor gene regulation and signaling in chronic heart failure. J Mol Cell Cardiol 2001;33:887-905.
8. Mori H, Ishikawa S, Kojima S, Hayashi J, Watanabe Y, Hoffman JI, Okino H. Increased responsiveness of left ventricular apical myocar- dium to adrenergic stimuli. Cardiovasc Res 1993;27:192-198.
9. Myslivecek J, Ricny J, Kolar F, Tucek S. The effects of hydrocortisone on rat heart muscarinic and adrenergic alpha 1, beta 1 and beta 2 receptors, propranolol-resistant binding sites and on some subsequent steps in intracellular signalling. Naunyn Schmiedebergs Arch Phar- macol 2003;368:366-376.
10. Tucek S, Michal P, Vlachova V. Modelling the consequences of receptor- G-protein promiscuity. Trends Pharmacol Sci 2002;23:171-176.
11. Sakihara S, Kageyama K, Nigawara T, Kidani Y, Suda T. Ampulla (Takotsubo) cardiomyopathy caused by secondary adrenal insuffi- ciency in ACTH isolated deficiency. Endocr J 2007;54:631-636.
Copyright @ 2012 by the American Thoracic Society