International Journal of Cardiology 182 (2015) 381–383
Contents lists available at ScienceDirect
International Journal of Cardiology journal homepage: www.elsevier.com/locate/ijcard
Letter to the Editor
Takotsubo cardiomyopathy, beyond ventriculography and classical bidimensional echocardiography Daniel Caldeira a,b,⁎, Luís R. Lopes a,c, Susana Carmona d, Catarina Gomes a, Inês Cruz a, Joaquim Santos d, Hélder Pereira a, Ana Isabel Santos d a
Cardiology Department, Hospital Garcia de Orta, Almada, Portugal Laboratory of Clinical Pharmacology and Therapeutics, Faculty of Medicine, University of Lisbon, Clinical Pharmacology Unit, Instituto Medicina Molecular, Lisbon, Portugal Centro de Cardiologia da Universidade de Lisboa, Lisbon, Portugal d Nuclear Medicine Department, Hospital Garcia de Orta, Almada, Portugal b c
a r t i c l e
i n f o
Article history: Received 20 December 2014 Accepted 31 December 2014 Available online 3 January 2015 Keywords: MIBG Radionuclide imaging Takotsubo cardiomyopathy Heart/innervations Myocardial strain Nuclear Scintigraphy
Takotsubo cardiomyopathy (TTC) is a non-familial unclassified cardiomyopathy [1]. It was firstly diagnosed in Japan in the early 90s as the classical transient left ventricular dysfunction consisting in systolic apical ballooning — apical akinesia/dyskinesia and hyperkinesia of basal segments [2]. The majority of patients are initially diagnosed as having an acute coronary syndrome, based on the symptoms, ECG and biomarkers, but do not have coronary artery lesions in the coronary angiography that are sufficient to explain the presentation [3]. TTC is a diagnosis of exclusion and usually based on the morphological aspect of left ventricle in systole, using bidimensional echocardiography and/or ventriculography. Functional cardiac sympathetic denervation has been proposed as a pathophysiological mechanism of TTC. Stress-induced high levels of catecholamines, particularly epinephrine (which has higher affinity for β2 adrenergic receptors) are thought to have a paradoxical effect in the myocardial apex, where β2 adrenergic receptors have higher concentrations compared to β1 adrenergic receptors and are more ⁎ Corresponding author at: Serviço de Cardiologia, Hospital Garcia de Orta, Avenida Torrado da Silva, 2805-267 Almada, Portugal. E-mail address: [email protected] (D. Caldeira).
http://dx.doi.org/10.1016/j.ijcard.2014.12.163 0167-5273/© 2015 Elsevier Ireland Ltd. All rights reserved.
sensitive [4–6]. This paradoxical regional effect is likely to be related to exceeding an inotropic threshold at which occurs an intracellular shift from inotropic stimulating protein G (Gs) to non-inotropic inhibitor protein G (Gi), leading to a myocardial unresponsiveness to sympathetic stimuli [7,8]. 123 I-metaiodobenzylguanidine (123I-MIBG) is a norepinephrine analogue and scintigraphy with this radiotracer can be used to evaluate the sympathetic nervous system in dilated cardiomyopathy and heart failure. In TTC, the excess of epinephrine prevents the uptake of norepinephrine from synaptic clefts [9]. Therefore MIBG, as an analogue of norepinephrine is not expected to demonstrate uptake in the affected segments of the myocardium. Here, we describe three cases of patients with suspected TTC where 123 I-MIBG helped to establish a definitive diagnosis. Three consecutive female patients aged between 60 and 85 years old presented with chest pain (Table 1). Diagnostic work-up showed repolarization abnormalities in the ECG and elevated troponin. All patients underwent coronary angiography that did not show significant coronary stenoses. Two of the patients had classical TTC regional wall abnormalities, while one had an inverted pattern. In all the patients, 123 I-MIBG scintigraphy showed a complete absence of myocardial uptake of the radiotracer in the segments where regional wall abnormalities were noticed. Post-discharge 123I-MIBG scintigraphy in the first two cases (1 month for patient 1, and 2 months for patient 2), after recovery of all regional wall motion abnormalities, showed an impaired myocardial uptake of the radiotracer in the segments where regional wall abnormalities were noticed — the apex (Fig. 1). In the third case and remarkably, segmental longitudinal strain at the basal segments remained impaired even after the recovery of wall motion abnormalities (Fig. 2). 123I-MIBG scintigraphy one week after the onset and after recovery of wall motion abnormalities has shown a dramatic and complete absence of myocardial uptake of the radiotracer (Fig. 3). Our nuclear cardiology data are supportive of the sympathetic denervation theory in TTC. 123I-MIBG scintigraphy is extremely useful to establish a definitive diagnosis. Recent workflows suggest the use of a multi-imaging approach, and start considering nuclear cardiology as
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D. Caldeira et al. / International Journal of Cardiology 182 (2015) 381–383
Table 1 Characteristics of patients with Takotsubo cardiomyopathy. Patient Age Symptom and and signs gender
ECG
Echocardiogram
Biomarkers
Past medical history
Type
#1
60 Y; F
Chest pain and dyspnoea
SR, T wave inversion V3–6
Transient hypokinesia of apical and mid-segments with left ventricular dysfunction
High sensitivity troponin T elevation: 990
Dyslipidemia, depressive disorder
Classical TTC
#2
85 Y; F
Chest pain
AF, Q waves in precordial leads and inverted T waves V3–6
Transient hypokinesia of apical and mid-segments with left ventricular dysfunction
Permanent AF, hypertension
Classical TTC
#3
67 Y; F
Chest pain and dyspnoea
SR, T waves flattened in precordial leads
Transient hypokinesia of all basal and mid segments with left ventricular dysfunction, more pronounced in the anterior and inferior walls
Hypertension, dyslipidemia, DM2, depressive disorder. Classical TTC 7 years before
Inverted TTC
ng/L High sensitivity troponin T elevation: 196 ng/L High sensitivity troponin T elevation: 385 ng/L
AF: Atrial fibrillation; ECG: Electrocardiogram; SR: Sinus rhythm; TTC: Takotsubo cardiomyopathy; and Y: Years.
Fig. 1. 123I-MIBG scintigraphies of patients with classical TTC, showing a decreased radiotracer uptake in the apical segments.
Fig. 2. A) 2D echocardiography for patient 3 in the acute phase showing akinesia/hypokinesia of the basal segments in end-diastolic and B) end-systolic frame (blue arrows showing apical contractility; white arrows basal akinesia). C) Bull's eye representation of longitudinal strain for patient 3. Impairment of longitudinal strain at the basal compared to mid-apical segments, after recovery of the 2D echo wall motion abnormalities, before discharge. (For interpretation of the references to color in this figure legend, the reader is referred to the web version of this article.)
D. Caldeira et al. / International Journal of Cardiology 182 (2015) 381–383
383
Fig. 3. 123I-MIBG scintigraphy with complete absence of myocardial uptake as depicted in the axial planes. There is only liver uptake of 123I-MIBG.
a step in the establishment of a definitive diagnosis [10]. The utility of strain echocardiography in this context seems promising and should be further explored and established. Conflict of interest The authors do not have any competing interests to disclose. References [1] P. Elliott, B. Andersson, E. Arbustini, Z. Bilinska, F. Cecchi, P. Charron, O. Dubourg, U. Kühl, B. Maisch, W.J. McKenna, L. Monserrat, S. Pankuweit, C. Rapezzi, P. Seferovic, L. Tavazzi, A. Keren, Classification of the cardiomyopathies: a position statement from the European Society Of Cardiology Working Group on Myocardial and Pericardial Diseases, Eur. Heart J. 29 (2) (Jan 2008) 270–276. [2] H. Sato, H. Tateishi, T. Uchida, Takotsubo-type cardiomyopathy due to multivessel spasm, in: K. Kodama, K. Haze, M. Hon (Eds.), Clinical aspect of myocardial injury: from ischemia to heart failure, Kagakuhyouronsha, Tokyo, Japan, 1990, pp. 56–64. [3] J.R. Ghadri, F. Ruschitzka, T.F. Lüscher, C. Templin, Takotsubo cardiomyopathy: still much more to learn, Heart (Apr 7 2014). http://dx.doi.org/10.1136/heartjnl-2013304691. [4] A.R. Lyon, P.S. Rees, S. Prasad, P.A. Poole-Wilson, S.E. Harding, Stress (takotsubo) cardiomyopathy—a novel pathophysiological hypothesis to explain catecholamine-induced acute myocardial stunning, Nat. Clin. Pract. Cardiovasc. Med. 5 (2008) 22–29.
[5] H. Mori, S. Ishikawa, S. Kojima, J. Hayashi, Y. Watanabe, J.I. Hoffman, H. Okino, Increased responsiveness of left ventricular apical myocardium to adrenergic stimuli, Cardiovasc. Res. 27 (2) (Feb 1993) 192–198. [6] D.O. Verschure, G.A. Somsen, B.L. van Eck-Smit, R.J. Knol, J. Booij, H.J. Verberne, Tako-tsubo cardiomyopathy: how to understand possible pathophysiological mechanism and the role of (123)I-MIBG imaging, J. Nucl. Cardiol. 21 (4) (Aug 2014) 730–738. [7] J.F. Heubach, U. Ravens, A.J. Kaumann, Epinephrine activates both Gs and Gi pathways, but norepinephrine activates only the Gs pathway through human beta2-adrenoceptors overexpressed in mouse heart, Mol. Pharmacol. 65 (5) (May 2004) 1313–1322. [8] H. Paur, P.T. Wright, M.B. Sikkel, M.H. Tranter, C. Mansfield, P. O'Gara, D.J. Stuckey, V.O. Nikolaev, I. Diakonov, L. Pannell, H. Gong, H. Sun, N.S. Peters, M. Petrou, Z. Zheng, J. Gorelik, A.R. Lyon, S.E. Harding, High levels of circulating epinephrine trigger apical cardiodepression in a β2-adrenergic receptor/Gi-dependent manner: a new model of takotsubo cardiomyopathy, Circulation 126 (6) (Aug 7 2012) 697–706. [9] P. Merlet, H. Valette, J.L. Dubois-Randé, D. Moyse, D. Duboc, P. Dove, M.H. Bourguignon, C. Benvenuti, A.M. Duval, D. Agostini, et al., Prognostic value of cardiac metaiodobenzylguanidine imaging in patients with heart failure, J. Nucl. Med. 33 (4) (Apr 1992) 471–477. [10] E. Bossone, A. Lyon, R. Citro, A. Athanasiadis, P. Meimoun, G. Parodi, S. Cimarelli, E. Omerovic, F. Ferrara, G. Limongelli, A. Cittadini, J.A. Salerno-Uriarte, P. Perrone Filardi, B. Schneider, U. Sechtem, R. Erbel, Takotsubo cardiomyopathy: an integrated multi-imaging approach, Eur. Heart J. Cardiovasc. Imaging 15 (4) (Apr 2014) 366–377.
Contents lists available at ScienceDirect
International Journal of Cardiology journal homepage: www.elsevier.com/locate/ijcard
Letter to the Editor
Takotsubo cardiomyopathy, beyond ventriculography and classical bidimensional echocardiography Daniel Caldeira a,b,⁎, Luís R. Lopes a,c, Susana Carmona d, Catarina Gomes a, Inês Cruz a, Joaquim Santos d, Hélder Pereira a, Ana Isabel Santos d a
Cardiology Department, Hospital Garcia de Orta, Almada, Portugal Laboratory of Clinical Pharmacology and Therapeutics, Faculty of Medicine, University of Lisbon, Clinical Pharmacology Unit, Instituto Medicina Molecular, Lisbon, Portugal Centro de Cardiologia da Universidade de Lisboa, Lisbon, Portugal d Nuclear Medicine Department, Hospital Garcia de Orta, Almada, Portugal b c
a r t i c l e
i n f o
Article history: Received 20 December 2014 Accepted 31 December 2014 Available online 3 January 2015 Keywords: MIBG Radionuclide imaging Takotsubo cardiomyopathy Heart/innervations Myocardial strain Nuclear Scintigraphy
Takotsubo cardiomyopathy (TTC) is a non-familial unclassified cardiomyopathy [1]. It was firstly diagnosed in Japan in the early 90s as the classical transient left ventricular dysfunction consisting in systolic apical ballooning — apical akinesia/dyskinesia and hyperkinesia of basal segments [2]. The majority of patients are initially diagnosed as having an acute coronary syndrome, based on the symptoms, ECG and biomarkers, but do not have coronary artery lesions in the coronary angiography that are sufficient to explain the presentation [3]. TTC is a diagnosis of exclusion and usually based on the morphological aspect of left ventricle in systole, using bidimensional echocardiography and/or ventriculography. Functional cardiac sympathetic denervation has been proposed as a pathophysiological mechanism of TTC. Stress-induced high levels of catecholamines, particularly epinephrine (which has higher affinity for β2 adrenergic receptors) are thought to have a paradoxical effect in the myocardial apex, where β2 adrenergic receptors have higher concentrations compared to β1 adrenergic receptors and are more ⁎ Corresponding author at: Serviço de Cardiologia, Hospital Garcia de Orta, Avenida Torrado da Silva, 2805-267 Almada, Portugal. E-mail address: [email protected] (D. Caldeira).
http://dx.doi.org/10.1016/j.ijcard.2014.12.163 0167-5273/© 2015 Elsevier Ireland Ltd. All rights reserved.
sensitive [4–6]. This paradoxical regional effect is likely to be related to exceeding an inotropic threshold at which occurs an intracellular shift from inotropic stimulating protein G (Gs) to non-inotropic inhibitor protein G (Gi), leading to a myocardial unresponsiveness to sympathetic stimuli [7,8]. 123 I-metaiodobenzylguanidine (123I-MIBG) is a norepinephrine analogue and scintigraphy with this radiotracer can be used to evaluate the sympathetic nervous system in dilated cardiomyopathy and heart failure. In TTC, the excess of epinephrine prevents the uptake of norepinephrine from synaptic clefts [9]. Therefore MIBG, as an analogue of norepinephrine is not expected to demonstrate uptake in the affected segments of the myocardium. Here, we describe three cases of patients with suspected TTC where 123 I-MIBG helped to establish a definitive diagnosis. Three consecutive female patients aged between 60 and 85 years old presented with chest pain (Table 1). Diagnostic work-up showed repolarization abnormalities in the ECG and elevated troponin. All patients underwent coronary angiography that did not show significant coronary stenoses. Two of the patients had classical TTC regional wall abnormalities, while one had an inverted pattern. In all the patients, 123 I-MIBG scintigraphy showed a complete absence of myocardial uptake of the radiotracer in the segments where regional wall abnormalities were noticed. Post-discharge 123I-MIBG scintigraphy in the first two cases (1 month for patient 1, and 2 months for patient 2), after recovery of all regional wall motion abnormalities, showed an impaired myocardial uptake of the radiotracer in the segments where regional wall abnormalities were noticed — the apex (Fig. 1). In the third case and remarkably, segmental longitudinal strain at the basal segments remained impaired even after the recovery of wall motion abnormalities (Fig. 2). 123I-MIBG scintigraphy one week after the onset and after recovery of wall motion abnormalities has shown a dramatic and complete absence of myocardial uptake of the radiotracer (Fig. 3). Our nuclear cardiology data are supportive of the sympathetic denervation theory in TTC. 123I-MIBG scintigraphy is extremely useful to establish a definitive diagnosis. Recent workflows suggest the use of a multi-imaging approach, and start considering nuclear cardiology as
382
D. Caldeira et al. / International Journal of Cardiology 182 (2015) 381–383
Table 1 Characteristics of patients with Takotsubo cardiomyopathy. Patient Age Symptom and and signs gender
ECG
Echocardiogram
Biomarkers
Past medical history
Type
#1
60 Y; F
Chest pain and dyspnoea
SR, T wave inversion V3–6
Transient hypokinesia of apical and mid-segments with left ventricular dysfunction
High sensitivity troponin T elevation: 990
Dyslipidemia, depressive disorder
Classical TTC
#2
85 Y; F
Chest pain
AF, Q waves in precordial leads and inverted T waves V3–6
Transient hypokinesia of apical and mid-segments with left ventricular dysfunction
Permanent AF, hypertension
Classical TTC
#3
67 Y; F
Chest pain and dyspnoea
SR, T waves flattened in precordial leads
Transient hypokinesia of all basal and mid segments with left ventricular dysfunction, more pronounced in the anterior and inferior walls
Hypertension, dyslipidemia, DM2, depressive disorder. Classical TTC 7 years before
Inverted TTC
ng/L High sensitivity troponin T elevation: 196 ng/L High sensitivity troponin T elevation: 385 ng/L
AF: Atrial fibrillation; ECG: Electrocardiogram; SR: Sinus rhythm; TTC: Takotsubo cardiomyopathy; and Y: Years.
Fig. 1. 123I-MIBG scintigraphies of patients with classical TTC, showing a decreased radiotracer uptake in the apical segments.
Fig. 2. A) 2D echocardiography for patient 3 in the acute phase showing akinesia/hypokinesia of the basal segments in end-diastolic and B) end-systolic frame (blue arrows showing apical contractility; white arrows basal akinesia). C) Bull's eye representation of longitudinal strain for patient 3. Impairment of longitudinal strain at the basal compared to mid-apical segments, after recovery of the 2D echo wall motion abnormalities, before discharge. (For interpretation of the references to color in this figure legend, the reader is referred to the web version of this article.)
D. Caldeira et al. / International Journal of Cardiology 182 (2015) 381–383
383
Fig. 3. 123I-MIBG scintigraphy with complete absence of myocardial uptake as depicted in the axial planes. There is only liver uptake of 123I-MIBG.
a step in the establishment of a definitive diagnosis [10]. The utility of strain echocardiography in this context seems promising and should be further explored and established. Conflict of interest The authors do not have any competing interests to disclose. References [1] P. Elliott, B. Andersson, E. Arbustini, Z. Bilinska, F. Cecchi, P. Charron, O. Dubourg, U. Kühl, B. Maisch, W.J. McKenna, L. Monserrat, S. Pankuweit, C. Rapezzi, P. Seferovic, L. Tavazzi, A. Keren, Classification of the cardiomyopathies: a position statement from the European Society Of Cardiology Working Group on Myocardial and Pericardial Diseases, Eur. Heart J. 29 (2) (Jan 2008) 270–276. [2] H. Sato, H. Tateishi, T. Uchida, Takotsubo-type cardiomyopathy due to multivessel spasm, in: K. Kodama, K. Haze, M. Hon (Eds.), Clinical aspect of myocardial injury: from ischemia to heart failure, Kagakuhyouronsha, Tokyo, Japan, 1990, pp. 56–64. [3] J.R. Ghadri, F. Ruschitzka, T.F. Lüscher, C. Templin, Takotsubo cardiomyopathy: still much more to learn, Heart (Apr 7 2014). http://dx.doi.org/10.1136/heartjnl-2013304691. [4] A.R. Lyon, P.S. Rees, S. Prasad, P.A. Poole-Wilson, S.E. Harding, Stress (takotsubo) cardiomyopathy—a novel pathophysiological hypothesis to explain catecholamine-induced acute myocardial stunning, Nat. Clin. Pract. Cardiovasc. Med. 5 (2008) 22–29.
[5] H. Mori, S. Ishikawa, S. Kojima, J. Hayashi, Y. Watanabe, J.I. Hoffman, H. Okino, Increased responsiveness of left ventricular apical myocardium to adrenergic stimuli, Cardiovasc. Res. 27 (2) (Feb 1993) 192–198. [6] D.O. Verschure, G.A. Somsen, B.L. van Eck-Smit, R.J. Knol, J. Booij, H.J. Verberne, Tako-tsubo cardiomyopathy: how to understand possible pathophysiological mechanism and the role of (123)I-MIBG imaging, J. Nucl. Cardiol. 21 (4) (Aug 2014) 730–738. [7] J.F. Heubach, U. Ravens, A.J. Kaumann, Epinephrine activates both Gs and Gi pathways, but norepinephrine activates only the Gs pathway through human beta2-adrenoceptors overexpressed in mouse heart, Mol. Pharmacol. 65 (5) (May 2004) 1313–1322. [8] H. Paur, P.T. Wright, M.B. Sikkel, M.H. Tranter, C. Mansfield, P. O'Gara, D.J. Stuckey, V.O. Nikolaev, I. Diakonov, L. Pannell, H. Gong, H. Sun, N.S. Peters, M. Petrou, Z. Zheng, J. Gorelik, A.R. Lyon, S.E. Harding, High levels of circulating epinephrine trigger apical cardiodepression in a β2-adrenergic receptor/Gi-dependent manner: a new model of takotsubo cardiomyopathy, Circulation 126 (6) (Aug 7 2012) 697–706. [9] P. Merlet, H. Valette, J.L. Dubois-Randé, D. Moyse, D. Duboc, P. Dove, M.H. Bourguignon, C. Benvenuti, A.M. Duval, D. Agostini, et al., Prognostic value of cardiac metaiodobenzylguanidine imaging in patients with heart failure, J. Nucl. Med. 33 (4) (Apr 1992) 471–477. [10] E. Bossone, A. Lyon, R. Citro, A. Athanasiadis, P. Meimoun, G. Parodi, S. Cimarelli, E. Omerovic, F. Ferrara, G. Limongelli, A. Cittadini, J.A. Salerno-Uriarte, P. Perrone Filardi, B. Schneider, U. Sechtem, R. Erbel, Takotsubo cardiomyopathy: an integrated multi-imaging approach, Eur. Heart J. Cardiovasc. Imaging 15 (4) (Apr 2014) 366–377.
