International Journal of Cardiology xxx (2012) xxx–xxx

IJCA-15293; No of Pages 3

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International Journal of Cardiology

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Letter to the Editor

Takotsubo and Takotsubo-like syndrome: A common neurogenic myocardialstunning pathway?

Nidaa Mikail a,⁎, Sébastien Hess b, Laurence Jesel b, Soraya El Ghannudi a,b, Ziad El Husseini c, Annie Trinh b,Patrick Ohlmann b, Olivier Morel b, Alessio Imperiale a,d

a Service de Biophysique et de Médecine nucléaire, Hôpitaux Universitaires de Strasbourg, Hôpital de Hautepierre, Franceb Pôle d'activité médico-chirurgicale des Hôpitaux Universitaires de Strasbourg, Nouvel Hôpital Civil, Francec Hôpital Sainte-Thérèse IFAC, Bastogne, Belgiqued Université de Strasbourg, CNRS LINC FRE 3289, Strasbourg, France

⁎ Corresponding author.E-mail address: mnidaa@yahoo.fr (N. Mikail).

0167-5273/$ – see front matter © 2012 Elsevier Irelandhttp://dx.doi.org/10.1016/j.ijcard.2012.09.116

Please cite this article as: Mikail N, et al, TaInt J Cardiol (2012), http://dx.doi.org/10.10

a r t i c l e i n f o

Article history:

Received 24 July 2012Accepted 16 September 2012Available online xxxx

Keywords:Stress cardiomyopathyTakotsuboTakotsubo-likePheochromocytomaScintigraphyMIBG

criteria could be further discussed, both entities being mergedinto one category, i.e. catecholamine-induced TLVDS.

We report here the case of a patient presenting with apheochromocytoma-associated TTL, whose pathophysiologic basiswere explored through nuclear medicine imaging.

A 52-year-old man presented to the emergency department withabrupt nausea, sweating and headache, concomitant with chest pain.No onset of emotionally stressful event was reported. Initial emergencyroom examination revealed blood pressure of 200/100 mm Hg, pulse81 beats/min, and palpitations. Electrocardiogram showed alternatingtachycardia-bradycardia with negative T waves in leads V1-V6 andD1-D2-aVL (Fig. 1A).

Takotsubo diagnosis is currently established according to thewidespread Mayo Clinic criteria [1], which excluded in its originalversion patients with concomitant intracranial haemorrhage orpheochromocytoma. Yet, a quite similar cardiomyopathy, definedas “neurocardiogenic stunning”, has been described in associationwith intracranial bleeding. Though originally considered a distinctentity, the updated version of theMayo Clinic criteria integrate cerebralbleeding as a potential cause of Takotsubo Cardiomyopathy (TTC). Onthe other hand, pheochromocytoma remains an exclusion criterion forTTC diagnosis. However, growing data report transient left ventriculardysfunction syndromes (TLVDS) concurrent with catecholamine excessstate, either exogenous, such as iatrogenic epinephrin-induced cardio-genic stunning [2], or endogenous, such as in pheochromocytoma. Sim-ilarity in clinical presentation and evolution between typical TTC andintracranial haemorrhage-related or pheochromocytoma-related stresscardiomyopathies led the Takotsubo Cardiomyopathy Study Group [3] toconsider them as Takotsubo-like (TTL) syndromes. More broadly speak-ing, TTC and TTL may be considered a common subgroup ofcatecholamine-linked TLVDS. Blurred boundary between them il-

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kotsubo and Takotsubo-like16/j.ijcard.2012.09.116

lustrates TTC is a still being defined disease, which diagnostic

Initial laboratory work-up revealed elevated troponin I concentration1 ng/mL (nlb0.1), CPK 917 IU/L (nlb190). Echocardiography displayedsegmental antero-apical hypokinesis.

This overall presentation alongwith a past medical history of hyper-tension, type 2 diabetes and smoking, suggested the diagnosis of acutemyocardial infarction (AMI). The patient thus underwent emergent car-diac catheterization, which showed no significant coronary artery ab-normalities (Fig. 1B). Therefore, initial diagnosis was corrected to highblood pressure-linked AMI, with no coronary artery stenosis.

Because of the association of headache, sweating and nausea(Menard's triad), pheochromocytoma was suspected and a 24-hoururine collection of catecholamines analyzed, detecting catecholaminehypersecretion, with epinephrine 1700 nmol (nlb164), norepineph-rine 3928 nmol (nlb414) and dopamine 8682 nmol (nl 652–3260).An abdomen computed tomography (CT) scan displayed a 10 cmnon enhanced right adrenal mass, with a hypodense necrotic centralarea, initially considered to be a hematoma.

Despite the CT-scan result, the clinical and biological presentationjustified metaiodobenzylguanidine scintigraphy (MIBG-I131) scintigra-phy, which was performed 2 weeks after the onset of symptoms.

Whole-body planar acquisition, followed by single-photon emissioncomputed tomography/CT (SPECT/CT), showed a focal intense traceruptake with a central photopenic area, corresponding to the previouslydescribed right adrenal lesion. No extra-adrenal scintigraphic abnormal-ity was observed.

In view of the patient's recent cardiovascular history, thoracicSPECT/CT was performed to assess possible cardiac sympathetic

syndrome: A common neurogenic myocardial stunning pathway?...,

Fig. 1. Repolarizationdisturbance in antero-lateral and inferior leads (A). Emergent angiography showedno significant coronary stenosis (B). Apical and infero-lateral sympathetic denervation(yellow arrow) assessed by 123I-MIBG (C). Rest perfusion appears normal (red arrow) in this region, as assessed by delayed 99mTc-Tetrofosmin myocardial perfusion imaging (D). (For inter-pretation of the references to colour in this figure legend, the reader is referred to the web version of this article.)

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innervation abnormalities, in the hypothesis of TTL. MIBG SPECT actu-ally revealed severe apical and infero-lateral left ventricle uptakedefect (Fig. 1C). 99mTc-tetrofosmin rest myocardial perfusion wasperformed within one day, showing normal LV perfusion and wall kinet-ics (Fig. 1D), excluding myocardial necrosis. Mismatch between normalperfusion and regional altered sympathetic innervation was suggestiveof stress cardiomyopathy. Hence, initial diagnosis was corrected to apheochromocytoma-linked TTL. Adrenal tumour was surgically removed5 weeks later. Finally, pheochromocytomawas confirmedbypathologicalexamination.

According to our experience [2,4], this case could suggest the exis-tence of a common sympathetic pathway to typical TTC and TTL, bothbeing a unique entity, a possibility already considered by some authors.

In a review study by Agarwal et al. [5], when compared to TTC,TTL mainly differ in that they affect relatively younger patients(50.3 years vs 68.4 years), with a less marked feminine prevalence(71,1% vs 88,8%) and with significantly less stressor antecedents,and constantly elevated catecholamines (100% vs 74,3%). TTL alsodiffer by more frequent complications, such as cardiogenic shock(34,2% vs 4,2%), heart failure (46,7% vs 17,7%) and lower meanLV ejection fraction at presentation (28,7% vs 41%). However, bothTTC and TTL share overall similar features: chest pain mimicking AMI,similar EKG findings, transient LV regional dysfunction, mild increasein troponin and no significant coronary artery stenosis.

Likewise, evidence for histological similarity between TTC and TTLhave been reported by Nef et al. [6], showing neutrophilic infiltrationand diffuse contraction-band necrosis in a patient presenting withTTL and pheochromocytoma, a commonly described pattern in typical

Please cite this article as: Mikail N, et al, Takotsubo and Takotsubo-likeInt J Cardiol (2012), http://dx.doi.org/10.1016/j.ijcard.2012.09.116

Takotsubo [7]. Therefore, could TLVDS be used as a generic term, in-cluding all of typical TTC and TTL?

Besides the vascular theories, and though not exclusive of them [8],emerges an overwhelming neurohumoral-based demonstration, takinginto account the frequent stress trigger and the associated rise inserum catecholamine level [9]. Indeed, catecholamine-mediated neuro-genicmyocardial stunning seems to be a centralmechanismof TTC [2,4].In the absence of any documented spasmor perfusion abnormalities, thedefective uptake of 123I-MIBG in the hypocontractile LV segmentssuggests that epinephrine-induced stunned myocardium is themain mechanism of LV systolic dysfunction. Cimarelli et al. demon-strated that this kinetical and morphological apical injury matchedwith glucidic hypometabolism topographically concordant with asympathetic hypoinnervation area, rest perfusion being preservedin the sub-acute phase. According to the theory developed byLyon et al. [10], it is likely that the release of epinephrine by adrenal me-dulla could trigger a switch in intracellular trafficking in cardiomyocytesfrom Gs protein to Gi protein signalling via the β2 receptor, which isnegatively inotropic. This switch to β2 receptors-Gi protein could beviewed as beneficial by protecting against the proapoptotic effects of in-tense activation of β1-adrenoreceptors.

In our patient with pheochromocytoma, a regional denervated/normoperfused LV aspect was found. We previously described thesame pattern in patients with TTC [4] as well as exogenousepinephrine-induced stunned myocardium [2], tightening the hy-pothesis of a common neurogenic myocardial stunning pathway.This report is to be added to the series of cases linking TTL andTTC to a unique TLVDS entity.

syndrome: A common neurogenic myocardial stunning pathway?...,

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In conclusion, TTC and TTL could be merged as a common clinicalentity, i.e. TLVDS, presenting with a constant core of hallmark tran-sient regional LV dysfunction, triggered by a catecholamine excessstate, and manifesting with various patterns and causes.

The authors of this manuscript have certified that they complywith the principles of ethical publishing in the International Journalof Cardiology [11].

References

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[2] Morel O, Jesel L, Morel N, et al. Transient left ventricular dysfunction syndromeduring anaphylactic shock: vasospasm, Kounis syndrome or epinephrine-inducedstunned myocardium? Int J Cardiol 2010;145(3):501-3.

[3] Kawai S, Kitabatake A, Hitonobu T. Guidelines for diagnosis of Takotsubo (Ampulla)cardiomyopathy. Circ J 2007;71:990-2.

Please cite this article as: Mikail N, et al, Takotsubo and Takotsubo-likeInt J Cardiol (2012), http://dx.doi.org/10.1016/j.ijcard.2012.09.116

[4] Cimarelli S, Sauer F, Morel O, Ohlmann P, Constantinesco A, Imperiale A. Transientleft ventricular dysfunction syndrome: patho-physiological bases through nuclearmedicine imaging. Int J Cardiol 2010;144(2):212-8.

[5] Agarwal V, Kant G, Hanz N, Messerli F. Takotsubo-like cardiomyopathy in pheo-chromocytoma. Int J Cardiol 2011:241-8.

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[7] Pilgrim TM, Wyss TR. Takotsubo cardiomyopathy or transient left ventricular api-cal ballooning syndrome: a systematic review. Int J Cardiol 2008;124:283-92.

[8] Lindsay J, Paixao A, Chao T, Pichard AD. Pathogenesis of the Takotsubo syndrome:a unifying hypothesis. Am J Cardiol 2010;106:1360-3.

[9] Wittstein IS, Thiemann DR, Lima JAC, et al. Neurohumoral features of myocardialstunning due to sudden emotional stress. N Engl J Med 2005;352:539-48.

[10] Lyon AR, Rees PS, Prasad S, Poole-Wilson PA, Harding SE. Stress (Takotsubo)cardiomyopathy: a novel pathophysiological hypothesis to explain catecholamine-induced acute myocardial stunning. Nat Clin Pract Cardiovasc Med 2008;5:22-9.

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syndrome: A common neurogenic myocardial stunning pathway?...,