A Moreo

A Prasad

A Sato

AA Elesber

AJ Scholte

Berthe L. F. van Eck-Smit

Dirk J. van der Heijden

E Alexanderson

G. Aernout Somsen

GA Somsen

Hein J. Verberne

IS Wittstein

K Ito

K Obunai

KA Bybee

M Feola

PA Milliano de

RJ Lefkowitz

S Cimarelli

SW Sharkey

English

PubMed

Verberne, H.J.

van der Heijden, D.J.

van Eck-Smit, B.L.F.

Somsen, G.A.

UvA-DARE

Persisting myocardial sympathetic dysfunction in takotsubo cardiomyopathy

Verberne, Hein J.

van der Heijden, Dirk J.

van Eck-Smit, Berthe L. F.

Aernout Somsen, G.

NARCIS 

Springer - Publisher Connector

NUCLEAR CARDIOLOGY BULLET
Persisting myocardial sympathetic dysfunction
in takotsubo cardiomyopathy
Hein J. Verberne, MD, PhD,a Dirk J. van der Heijden, MD,b Berthe L. F.
van Eck-Smit, MD, PhD,a and G. Aernout Somsen, MD, PhDc
A 73-year-old woman without a cardiovascular
history was admitted with chest discomfort, dizziness,
and nausea after an emotional meeting with the staff of a
nursing home. She experienced the same complaints
some years before when her father died.
On admission the patient was in cardiogenic shock.
Auscultation of the heart revealed a grade 3/6 systolic
murmur radiating to the left axilla. The electrocardio-
graphy (ECG) showed an acute anterior wall infarction
(Figure 1). Acute coronary angiography was performed
but no significant coronary artery disease was found.
Left ventricular (LV) angiography showed severe mitral
regurgitation and apical ballooning (Figure 2). An
intraventricular gradient of 100 mmHg was measured.
Echocardiography showed apical akinesia and basal
hyperkinesia resulting in severe mitral regurgitation due
to systolic anterior movement of the anterior mitral
valve leaflet. Troponin T (1.73 ng/L) and CK-MB
(22 lg/L) were slightly increased. Based on these find-
ings, the diagnosis of a takotsubo cardiomyopathy (TC)
was made. Shortly after treatment with intravenous
inotropics, and ACE inhibition the patient became
hemodynamically stable and metoprolol was added.
Cardiac MRI did not show late contrast enhance-
ment which excludes myocardial fibrosis and myocardial
infarction as the cause of the hemodynamic instability.
Myocardial 123I-metaiodobenzylguanidine (123I-MIBG,
a radiolabelled noradrenalin analog) scintigraphy, per-
formed 4 days after admission, showed diffuse reduced
myocardial uptake and increased washout of 123I-MIBG
which reflects impaired sympathetic neuronal function
and increased sympathetic activity, respectively (Fig-
ure 3A). Cardiac ultrasound was repeated at 3 and
7 months and showed no mitral regurgitation and a
normalized LV function. However, cardiac sympathetic
neuronal function and activity remained abnormal as was
shown by 123I-MIBG scintigraphy at 3 and 7 months
(Figure 3B and C, respectively).
The diagnosis of a stress-induced cardiomyopathy,
apical ballooning syndrome or TC was based on the
presence of the typical symptoms and signs of an ante-
rior wall infarction after a highly stressful moment
(a lifetime crisis), combined with normal coronary
angiography, LV apical ballooning, no signs of late
contrast enhancement on MRI scanning, and rapid
recovery of LV function.1
The name Takotsubo is related to the morphology
of the left ventricle, which shows resemblance to a
Japanese round-bottomed narrow-necked fishing pot
used for trapping octopus. Postmenopausal women seem
to be most at risk for developing this syndrome, espe-
cially after an episode of acute emotional stress. In a
systematic review, women accounted for 82-100% of
patients with an average age of 62-75 years, although
cases have been described in individuals aged
10-91 years.2 Formal diagnostic criteria have yet to be
established. Bybee et al have suggested diagnostic cri-
teria for TC, requiring the following: (1) transient LV
wall motion abnormalities involving the apical and/or
midventricular myocardial segments with wall motion
abnormalities extending beyond a single epicardial
coronary distribution; (2) absence of obstructive epi-
cardial CAD or angiographic evidence of acute plaque
rupture that could be responsible for the observed wall
motion abnormality; and (3) new ECG abnormalities
such as transient ST-segment elevation and/or diffuse
T-wave inversions or Troponin T elevation.2-4
Although the exact pathophysiology of TC is
unknown, it has been suggested that catecholamine-
mediated cardiac toxicity is related to the pathophysio-
logical basis of TC. In these patients, increased
myocardial sympathetic activity is caused by increased
presynaptic release and reduced re-uptake of noradren-
alin. This leads to down regulation and desensitization
of the postsynaptic cardiac b-adrenoreceptors, leading to
From Department of Nuclear Medicine,a Academic Medical Center,
University of Amsterdam, Amsterdam 1100 DE, The Netherlands
and Department of Cardiology,b Rijnland Ziekenhuis, Leiderdorp,
The Netherlands and Department of Cardiology,c Onze Lieve
Vrouwe Gasthuis, Amsterdam, The Netherlands.
Reprint requests: Hein J. Verberne, MD, PhD, Department of Nuclear
Medicine, Academic Medical Center, University of Amsterdam,
P.O. Box 22700, Amsterdam 1100 DE, The Netherlands; h.j.verberne@
amc.uva.nl.
J Nucl Cardiol 2009;16:321–4.
1071-3581/$34.00
Copyright  2008 The Author(s). This article is published with open
access at Springerlink.com.
doi:10.1007/s12350-008-9017-1
321
a further decline of the LV function.5 The changes in the
presynaptic myocardial sympathetic activity can be
assessed with the radio-labeled noradrenalin analog
123I-MIBG.6 However, it has been shown that some
b-adrenoreceptor-blockers may influence myocardial
123I-MIBG uptake. This has also been suggested for
ACE-inhibitors. This may explain in part the initial
scintigraphic findings. However, in the case report of
Moreo et al 123I-MIBG myocardial uptake increased,
after a 2-month treatment with carvedilol.6 Moreover, in
patients with heart failure b-adrenoreceptor-blockers
and ACE inhibitors are associated with an increase in
123I-MIBG uptake and reduced washout.7,8 In our patient
ACE inhibition was discontinued after the acute phase
and the b-adrenoreceptor-blocker was continued.
Another possible confounding factor of persisting
abnormal 123I-MIBG scintigraphic findings is denerva-
tion due to a previous myocardial infarction. However,
MRI showed no signs of a previous myocardial infarc-
tion. Taken together it is likely that the scintigraphic
images, at presentation and during follow-up, reflect true
persisting increased myocardial sympathetic activity.
Another possible pathophysiological mechanism for
the development of TC might be related to stress-induced
coronary epicardial spasm or endothelial dysfunction
resulting in myocardial stunning. In a recent study, Sato
et al evaluated coronary artery endothelial dysfunction in
35 patients with TC.9 In 54% of patients with TC, diffuse
coronary vasoconstriction occurred after intracoronary
acetylcholine provocation. In the acute phase, myocardial
perfusion and myocardial fatty acid metabolism scintig-
raphy (123I-BMIPP) were impaired. During follow-up
myocardial perfusion and myocardial fatty acid metabo-
lism improved to normal in association with improvement
of LV function. Myocardial stunning due to stress-
induced coronary epicardial spasm or endothelial dys-
function might therefore be a likely explanation for TC.
Figure 1. ECG at admission suggestive for an acute anterior
wall infarction: sinus-rhythm with 58 beats per minute, 1st
degree AV block, ST segment elevation in leads V1-V4, and
pathological Q waves in V2 and V3.
Figure 2. Left ventricular (LV) angiography showing severe
mitral regurgitation and apical ballooning.
322 Verberne et al Journal of Nuclear Cardiology
123I-MIBG and takotsubo cardiomyopathy March/April 2009
Figure 3. 123I-MIBG scintigraphy: images on the left were made 15 min postinjection (p.i.) of
123I-MIBG (early) and the images on the right were made 4 h p.i. (late). Upper left panel shows the
regions of interest over the myocardium and mediastinum for the calculation of the semiquan-
titative parameters of 123I-MIBG myocardial uptake and washout. 123I-MIBG images 4 days after
hospital admission, show severely reduced myocardial uptake (A). Semiquantitative analysis of the
myocardial uptake confirmed the visual interpretation (early heart/mediastinal (H/M) ratio: 1.54,
late H/M: 1.26 and myocardial washout of 123I-MIBG: 18%). Three (B) and seven months (C) after
hospital admission 123I-MIBG myocardial uptake and washout remained abnormal. The
semiquantitative parameters remained abnormal after 3 months (early H/M: 1.78, late H/M: 1.33,
and myocardial washout of 123I-MIBG: 25%) and after 7 months (early H/M: 1.66, late H/M: 1.13,
and myocardial washout of 123I-MIBG: 32%). Due to the diffuse reduced myocardial 123I-MIBG
uptake SPECT images could not reliably be reconstructed.
Journal of Nuclear Cardiology Verberne et al 323
Volume 16, Number 2;321–4 123I-MIBG and takotsubo cardiomyopathy
Assessment of myocardial perfusion with SPECT
and PET tracers and assessment of glucose metabolism
with 18F-FDG have been used to evaluate TC
patients.10-15 Typically in the early/acute phase of TC
myocardial perfusion can be (regionally, i.e., apex)
disturbed and shows an impaired (regional, i.e., apex)
coronary flow reserve (CFR) and a more pronounced
impairment of (regional, i.e., apex) myocardial glucose
metabolism. In general, the regional reduction of per-
fusion and impairment of glucose metabolism have the
tendency to resolve completely 3 months after the early/
acute phase.
In our patient, myocardial sympathetic activity was
increased in the early phase of TC. Although LV function
was completely normalized, increased myocardial sym-
pathetic activity persisted. Normalization of myocardial
123I-MIBG uptake has been described in several case
reports.6,16 This is the first report showing persisting
sympathetic dysfunction in a patient with TC after com-
plete normalization of the LV function and no signs of late
enhancement on MRI. The recurrence of TC is rare and is
estimated at 2.9% per year and the overall cardiovascular
survival is not different from age- and gender-matched
controls.17 Echocardiographic follow-up of TC patients
has never been performed in a consistent way. This may
implicate that the recurrence rate of TC is underestimated.
In the present case, the patient experienced the same
symptoms after an emotional event several years earlier
which may have been an earlier episode of TC.
Predictors of TC recurrence are not known. As
TC is associated with a hyperadrenergic state, the per-
sisting increased myocardial sympathetic activity may
have prognostic implications.18 Therefore, myocardial
123I-MIBG scintigraphy may identify patients at risk for
the recurrence of TC. These findings may warrant
extensive pharmacological therapy and follow-up in TC
patients. Theoretically, recurrence rates may be lower in
those who are maintained on adrenergic blockade
assuming that catecholamines play a central role in the
pathogenesis of the syndrome.
Open Access
This article is distributed under the terms of the Creative
Commons Attribution Noncommercial License which permits
any noncommercial use, distribution, and reproduction in any
medium, provided the original author(s) and source are
credited.
References
1. Sharkey SW, Lesser JR, Zenovich AG, Maron MS, Lindberg J,
Longe TF, et al. Acute and reversible cardiomyopathy provoked
by stress in women from the United States. Circulation 2005;
111:472-9.
2. Bybee KA, Kara T, Prasad A, Lerman A, Barsness GW, Wright
RS, et al. Systematic review: Transient left ventricular apical
ballooning: A syndrome that mimics ST-segment elevation myo-
cardial infarction. Ann Intern Med 2004;141:858-65.
3. Bybee KA, Prasad A. Stress-related cardiomyopathy syndromes.
Circulation 2008;118:397-409.
4. Prasad A. Apical ballooning syndrome: An important differential
diagnosis of acute myocardial infarction. Circulation 2007;115:
e56-9.
5. Lefkowitz RJ, Caron MG, Stiles GL. Mechanisms of membrane-
receptor regulation. Biochemical, physiological, and clinical
insights derived from studies of the adrenergic receptors. N Engl J
Med. 1984;310:1570-9.
6. Moreo A, De Chiara B, Possa M, Sara R, Bossi I, Orrego PS, et al.
Functional derangement and cardiac innervation in the apical bal-
looning syndrome: a 123I-meta-iodobenzylguanidine scintigraphic
and dobutamine stress echocardiographic study. J Cardiovasc Med
2007;8:205-9.
7. de Milliano PA, de Groot AC, Tijssen JG, van Eck Smit BL, van
Zwieten PA, Lie KI. Beneficial effects of metoprolol on myo-
cardial sympathetic function: Evidence from a randomized,
placebo-controlled study in patients with congestive heart failure.
Am Heart J 2002;144:E3.
8. Somsen GA, van Vlies B, de Milliano PA, Borm JJ, van Royen
EA, Endert E, et al. Increased myocardial [123I]-metaiodobenzyl-
guanidine uptake after enalapril treatment in patients with chronic
heart failure. Heart 1996;76:218-22.
9. Sato A, Aonuma K, Nozato T, Sekiguchi Y, Okazaki O, Kubota K,
et al. Stunned myocardium in transient left ventricular apical
ballooning: A serial study of dual I-123 BMIPP and Tl-201
SPECT. J Nucl Cardiol 2008;15:671-9.
10. Feola M, Chauvie S, Rosso GL, Biggi A, Ribichini F, Bobbio M.
Reversible impairment of coronary flow reserve in takotsubo
cardiomyopathy: A myocardial PET study. J Nucl Cardiol 2008;
15(6):811-17.
11. Cimarelli S, Imperiale A, Ben-Sellem D, Rischner J, Detour J,
Morel O, et al. Nuclear medicine imaging of takotsubo cardio-
myopathy: Typical form and midventricular ballooning syndrome.
J Nucl Cardiol 2008;15:137-41.
12. Alexanderson E, Cruz P, Talayero JA, Damas F, Zeron J, Meave
A. Transient perfusion and motion abnormalities in takotsubo
cardiomyopathy. J Nucl Cardiol 2007;14:129-33.
13. Bybee KA, Murphy J, Prasad A, Wright RS, Lerman A, Rihal CS,
et al. Acute impairment of regional myocardial glucose uptake in
the apical ballooning (takotsubo) syndrome. J Nucl Cardiol
2006;13:244-50.
14. Scholte AJ, Bax JJ, Stokkel MP, Plokker T, Kaandorp TA, Lamb
HJ, et al. Multimodality imaging to diagnose takotsubo cardio-
myopathy. J Nucl Cardiol 2006;13:123-6.
15. Obunai K, Misra D, Van Tosh A, Bergmann SR. Metabolic evidence
of myocardial stunning in takotsubo cardiomyopathy: A positron
emission tomography study. J Nucl Cardiol 2005;12:742-4.
16. Ito K, Sugihara H, Kinoshita N, Azuma A, Matsubara H.
Assessment of Takotsubo cardiomyopathy (transient left ven-
tricular apical ballooning) using 99mTc-tetrofosmin, 123I-BMIPP,
123I-MIBG and 99mTc-PYP myocardial SPECT. Ann Nucl Med
2005;19:435-45.
17. Elesber AA, Prasad A, Lennon RJ, Wright RS, Lerman A, Rihal
CS. Four-year recurrence rate and prognosis of the apical bal-
looning syndrome. J Am Coll Cardiol 2007;50:448-52.
18. Wittstein IS, Thiemann DR, Lima JAC, Baughman KL, Schulman
SP, Gerstenblith G, et al. Neurohumoral features of myocardial
stunning due to sudden emotional stress. N Engl J Med 2005;352:
539-48.
324 Verberne et al Journal of Nuclear Cardiology
123I-MIBG and takotsubo cardiomyopathy March/April 2009


Crossref

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UvA-DARE is a service provided by the library of the University of Amsterdam (https://dare.uva.nl)UvA-DARE (Digital Academic Repository)Persisting myocardial sympathetic dysfunction in takotsubo cardiomyopathyVerberne, H.J.; van der Heijden, D.J.; van Eck-Smit, B.L.F.; Somsen, G.A.DOI10.1007/s12350-008-9017-1Publication date2009Document VersionFinal published versionPublished inJournal of nuclear cardiologyLink to publicationCitation for published version (APA):Verberne, H. J., van der Heijden, D. J., van Eck-Smit, B. L. F., & Somsen, G. A. (2009).Persisting myocardial sympathetic dysfunction in takotsubo cardiomyopathy. Journal ofnuclear cardiology, 16(2), 321-324. https://doi.org/10.1007/s12350-008-9017-1General rightsIt is not permitted to download or to forward/distribute the text or part of it without the consent of the author(s)and/or copyright holder(s), other than for strictly personal, individual use, unless the work is under an opencontent license (like Creative Commons).Disclaimer/Complaints regulationsIf you believe that digital publication of certain material infringes any of your rights or (privacy) interests, pleaselet the Library know, stating your reasons. In case of a legitimate complaint, the Library will make the materialinaccessible and/or remove it from the website. Please Ask the Library: https://uba.uva.nl/en/contact, or a letterto: Library of the University of Amsterdam, Secretariat, Singel 425, 1012 WP Amsterdam, The Netherlands. Youwill be contacted as soon as possible.Download date:10 Nov 2022NUCLEAR CARDIOLOGY BULLETPersisting myocardial sympathetic dysfunctionin takotsubo cardiomyopathyHein J. Verberne, MD, PhD,a Dirk J. van der Heijden, MD,b Berthe L. F.van Eck-Smit, MD, PhD,a and G. Aernout Somsen, MD, PhDcA 73-year-old woman without a cardiovascularhistory was admitted with chest discomfort, dizziness,and nausea after an emotional meeting with the staff of anursing home. She experienced the same complaintssome years before when her father died.On admission the patient was in cardiogenic shock.Auscultation of the heart revealed a grade 3/6 systolicmurmur radiating to the left axilla. The electrocardio-graphy (ECG) showed an acute anterior wall infarction(Figure 1). Acute coronary angiography was performedbut no significant coronary artery disease was found.Left ventricular (LV) angiography showed severe mitralregurgitation and apical ballooning (Figure 2). Anintraventricular gradient of 100 mmHg was measured.Echocardiography showed apical akinesia and basalhyperkinesia resulting in severe mitral regurgitation dueto systolic anterior movement of the anterior mitralvalve leaflet. Troponin T (1.73 ng/L) and CK-MB(22 lg/L) were slightly increased. Based on these find-ings, the diagnosis of a takotsubo cardiomyopathy (TC)was made. Shortly after treatment with intravenousinotropics, and ACE inhibition the patient becamehemodynamically stable and metoprolol was added.Cardiac MRI did not show late contrast enhance-ment which excludes myocardial fibrosis and myocardialinfarction as the cause of the hemodynamic instability.Myocardial 123I-metaiodobenzylguanidine (123I-MIBG,a radiolabelled noradrenalin analog) scintigraphy, per-formed 4 days after admission, showed diffuse reducedmyocardial uptake and increased washout of 123I-MIBGwhich reflects impaired sympathetic neuronal functionand increased sympathetic activity, respectively (Fig-ure 3A). Cardiac ultrasound was repeated at 3 and7 months and showed no mitral regurgitation and anormalized LV function. However, cardiac sympatheticneuronal function and activity remained abnormal as wasshown by 123I-MIBG scintigraphy at 3 and 7 months(Figure 3B and C, respectively).The diagnosis of a stress-induced cardiomyopathy,apical ballooning syndrome or TC was based on thepresence of the typical symptoms and signs of an ante-rior wall infarction after a highly stressful moment(a lifetime crisis), combined with normal coronaryangiography, LV apical ballooning, no signs of latecontrast enhancement on MRI scanning, and rapidrecovery of LV function.1The name Takotsubo is related to the morphologyof the left ventricle, which shows resemblance to aJapanese round-bottomed narrow-necked fishing potused for trapping octopus. Postmenopausal women seemto be most at risk for developing this syndrome, espe-cially after an episode of acute emotional stress. In asystematic review, women accounted for 82-100% ofpatients with an average age of 62-75 years, althoughcases have been described in individuals aged10-91 years.2 Formal diagnostic criteria have yet to beestablished. Bybee et al have suggested diagnostic cri-teria for TC, requiring the following: (1) transient LVwall motion abnormalities involving the apical and/ormidventricular myocardial segments with wall motionabnormalities extending beyond a single epicardialcoronary distribution; (2) absence of obstructive epi-cardial CAD or angiographic evidence of acute plaquerupture that could be responsible for the observed wallmotion abnormality; and (3) new ECG abnormalitiessuch as transient ST-segment elevation and/or diffuseT-wave inversions or Troponin T elevation.2-4Although the exact pathophysiology of TC isunknown, it has been suggested that catecholamine-mediated cardiac toxicity is related to the pathophysio-logical basis of TC. In these patients, increasedmyocardial sympathetic activity is caused by increasedpresynaptic release and reduced re-uptake of noradren-alin. This leads to down regulation and desensitizationof the postsynaptic cardiac b-adrenoreceptors, leading toFrom Department of Nuclear Medicine,a Academic Medical Center,University of Amsterdam, Amsterdam 1100 DE, The Netherlandsand Department of Cardiology,b Rijnland Ziekenhuis, Leiderdorp,The Netherlands and Department of Cardiology,c Onze LieveVrouwe Gasthuis, Amsterdam, The Netherlands.Reprint requests: Hein J. Verberne, MD, PhD, Department of NuclearMedicine, Academic Medical Center, University of Amsterdam,P.O. Box 22700, Amsterdam 1100 DE, The Netherlands; h.j.verberne@amc.uva.nl.J Nucl Cardiol 2009;16:321–4.1071-3581/$34.00Copyright  2008 The Author(s). This article is published with openaccess at Springerlink.com.doi:10.1007/s12350-008-9017-1321a further decline of the LV function.5 The changes in thepresynaptic myocardial sympathetic activity can beassessed with the radio-labeled noradrenalin analog123I-MIBG.6 However, it has been shown that someb-adrenoreceptor-blockers may influence myocardial123I-MIBG uptake. This has also been suggested forACE-inhibitors. This may explain in part the initialscintigraphic findings. However, in the case report ofMoreo et al 123I-MIBG myocardial uptake increased,after a 2-month treatment with carvedilol.6 Moreover, inpatients with heart failure b-adrenoreceptor-blockersand ACE inhibitors are associated with an increase in123I-MIBG uptake and reduced washout.7,8 In our patientACE inhibition was discontinued after the acute phaseand the b-adrenoreceptor-blocker was continued.Another possible confounding factor of persistingabnormal 123I-MIBG scintigraphic findings is denerva-tion due to a previous myocardial infarction. However,MRI showed no signs of a previous myocardial infarc-tion. Taken together it is likely that the scintigraphicimages, at presentation and during follow-up, reflect truepersisting increased myocardial sympathetic activity.Another possible pathophysiological mechanism forthe development of TC might be related to stress-inducedcoronary epicardial spasm or endothelial dysfunctionresulting in myocardial stunning. In a recent study, Satoet al evaluated coronary artery endothelial dysfunction in35 patients with TC.9 In 54% of patients with TC, diffusecoronary vasoconstriction occurred after intracoronaryacetylcholine provocation. In the acute phase, myocardialperfusion and myocardial fatty acid metabolism scintig-raphy (123I-BMIPP) were impaired. During follow-upmyocardial perfusion and myocardial fatty acid metabo-lism improved to normal in association with improvementof LV function. Myocardial stunning due to stress-induced coronary epicardial spasm or endothelial dys-function might therefore be a likely explanation for TC.Figure 1. ECG at admission suggestive for an acute anteriorwall infarction: sinus-rhythm with 58 beats per minute, 1stdegree AV block, ST segment elevation in leads V1-V4, andpathological Q waves in V2 and V3.Figure 2. Left ventricular (LV) angiography showing severemitral regurgitation and apical ballooning.322 Verberne et al Journal of Nuclear Cardiology123I-MIBG and takotsubo cardiomyopathy March/April 2009Figure 3. 123I-MIBG scintigraphy: images on the left were made 15 min postinjection (p.i.) of123I-MIBG (early) and the images on the right were made 4 h p.i. (late). Upper left panel shows theregions of interest over the myocardium and mediastinum for the calculation of the semiquan-titative parameters of 123I-MIBG myocardial uptake and washout. 123I-MIBG images 4 days afterhospital admission, show severely reduced myocardial uptake (A). Semiquantitative analysis of themyocardial uptake confirmed the visual interpretation (early heart/mediastinal (H/M) ratio: 1.54,late H/M: 1.26 and myocardial washout of 123I-MIBG: 18%). Three (B) and seven months (C) afterhospital admission 123I-MIBG myocardial uptake and washout remained abnormal. Thesemiquantitative parameters remained abnormal after 3 months (early H/M: 1.78, late H/M: 1.33,and myocardial washout of 123I-MIBG: 25%) and after 7 months (early H/M: 1.66, late H/M: 1.13,and myocardial washout of 123I-MIBG: 32%). Due to the diffuse reduced myocardial 123I-MIBGuptake SPECT images could not reliably be reconstructed.Journal of Nuclear Cardiology Verberne et al 323Volume 16, Number 2;321–4 123I-MIBG and takotsubo cardiomyopathyAssessment of myocardial perfusion with SPECTand PET tracers and assessment of glucose metabolismwith 18F-FDG have been used to evaluate TCpatients.10-15 Typically in the early/acute phase of TCmyocardial perfusion can be (regionally, i.e., apex)disturbed and shows an impaired (regional, i.e., apex)coronary flow reserve (CFR) and a more pronouncedimpairment of (regional, i.e., apex) myocardial glucosemetabolism. In general, the regional reduction of per-fusion and impairment of glucose metabolism have thetendency to resolve completely 3 months after the early/acute phase.In our patient, myocardial sympathetic activity wasincreased in the early phase of TC. Although LV functionwas completely normalized, increased myocardial sym-pathetic activity persisted. Normalization of myocardial123I-MIBG uptake has been described in several casereports.6,16 This is the first report showing persistingsympathetic dysfunction in a patient with TC after com-plete normalization of the LV function and no signs of lateenhancement on MRI. The recurrence of TC is rare and isestimated at 2.9% per year and the overall cardiovascularsurvival is not different from age- and gender-matchedcontrols.17 Echocardiographic follow-up of TC patientshas never been performed in a consistent way. This mayimplicate that the recurrence rate of TC is underestimated.In the present case, the patient experienced the samesymptoms after an emotional event several years earlierwhich may have been an earlier episode of TC.Predictors of TC recurrence are not known. AsTC is associated with a hyperadrenergic state, the per-sisting increased myocardial sympathetic activity mayhave prognostic implications.18 Therefore, myocardial123I-MIBG scintigraphy may identify patients at risk forthe recurrence of TC. These findings may warrantextensive pharmacological therapy and follow-up in TCpatients. Theoretically, recurrence rates may be lower inthose who are maintained on adrenergic blockadeassuming that catecholamines play a central role in thepathogenesis of the syndrome.Open AccessThis article is distributed under the terms of the CreativeCommons Attribution Noncommercial License which permitsany noncommercial use, distribution, and reproduction in anymedium, provided the original author(s) and source arecredited.References1. Sharkey SW, Lesser JR, Zenovich AG, Maron MS, Lindberg J,Longe TF, et al. Acute and reversible cardiomyopathy provokedby stress in women from the United States. Circulation 2005;111:472-9.2. Bybee KA, Kara T, Prasad A, Lerman A, Barsness GW, WrightRS, et al. Systematic review: Transient left ventricular apicalballooning: A syndrome that mimics ST-segment elevation myo-cardial infarction. Ann Intern Med 2004;141:858-65.3. Bybee KA, Prasad A. Stress-related cardiomyopathy syndromes.Circulation 2008;118:397-409.4. Prasad A. Apical ballooning syndrome: An important differentialdiagnosis of acute myocardial infarction. Circulation 2007;115:e56-9.5. Lefkowitz RJ, Caron MG, Stiles GL. Mechanisms of membrane-receptor regulation. Biochemical, physiological, and clinicalinsights derived from studies of the adrenergic receptors. N Engl JMed. 1984;310:1570-9.6. Moreo A, De Chiara B, Possa M, Sara R, Bossi I, Orrego PS, et al.Functional derangement and cardiac innervation in the apical bal-looning syndrome: a 123I-meta-iodobenzylguanidine scintigraphicand dobutamine stress echocardiographic study. J Cardiovasc Med2007;8:205-9.7. de Milliano PA, de Groot AC, Tijssen JG, van Eck Smit BL, vanZwieten PA, Lie KI. Beneficial effects of metoprolol on myo-cardial sympathetic function: Evidence from a randomized,placebo-controlled study in patients with congestive heart failure.Am Heart J 2002;144:E3.8. Somsen GA, van Vlies B, de Milliano PA, Borm JJ, van RoyenEA, Endert E, et al. Increased myocardial [123I]-metaiodobenzyl-guanidine uptake after enalapril treatment in patients with chronicheart failure. Heart 1996;76:218-22.9. Sato A, Aonuma K, Nozato T, Sekiguchi Y, Okazaki O, Kubota K,et al. Stunned myocardium in transient left ventricular apicalballooning: A serial study of dual I-123 BMIPP and Tl-201SPECT. J Nucl Cardiol 2008;15:671-9.10. Feola M, Chauvie S, Rosso GL, Biggi A, Ribichini F, Bobbio M.Reversible impairment of coronary flow reserve in takotsubocardiomyopathy: A myocardial PET study. J Nucl Cardiol 2008;15(6):811-17.11. Cimarelli S, Imperiale A, Ben-Sellem D, Rischner J, Detour J,Morel O, et al. Nuclear medicine imaging of takotsubo cardio-myopathy: Typical form and midventricular ballooning syndrome.J Nucl Cardiol 2008;15:137-41.12. Alexanderson E, Cruz P, Talayero JA, Damas F, Zeron J, MeaveA. Transient perfusion and motion abnormalities in takotsubocardiomyopathy. J Nucl Cardiol 2007;14:129-33.13. Bybee KA, Murphy J, Prasad A, Wright RS, Lerman A, Rihal CS,et al. Acute impairment of regional myocardial glucose uptake inthe apical ballooning (takotsubo) syndrome. J Nucl Cardiol2006;13:244-50.14. Scholte AJ, Bax JJ, Stokkel MP, Plokker T, Kaandorp TA, LambHJ, et al. Multimodality imaging to diagnose takotsubo cardio-myopathy. J Nucl Cardiol 2006;13:123-6.15. Obunai K, Misra D, Van Tosh A, Bergmann SR. Metabolic evidenceof myocardial stunning in takotsubo cardiomyopathy: A positronemission tomography study. J Nucl Cardiol 2005;12:742-4.16. Ito K, Sugihara H, Kinoshita N, Azuma A, Matsubara H.Assessment of Takotsubo cardiomyopathy (transient left ven-tricular apical ballooning) using 99mTc-tetrofosmin, 123I-BMIPP,123I-MIBG and 99mTc-PYP myocardial SPECT. Ann Nucl Med2005;19:435-45.17. Elesber AA, Prasad A, Lennon RJ, Wright RS, Lerman A, RihalCS. Four-year recurrence rate and prognosis of the apical bal-looning syndrome. J Am Coll Cardiol 2007;50:448-52.18. Wittstein IS, Thiemann DR, Lima JAC, Baughman KL, SchulmanSP, Gerstenblith G, et al. Neurohumoral features of myocardialstunning due to sudden emotional stress. N Engl J Med 2005;352:539-48.324 Verberne et al Journal of Nuclear Cardiology123I-MIBG and takotsubo cardiomyopathy March/April 2009

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UvA-DARE is a service provided by the library of the University of Amsterdam (https://dare.uva.nl)UvA-DARE (Digital Academic Repository)Persisting myocardial sympathetic dysfunction in takotsubo cardiomyopathyVerberne, H.J.; van der Heijden, D.J.; van Eck-Smit, B.L.F.; Somsen, G.A.DOI10.1007/s12350-008-9017-1Publication date2009Document VersionFinal published versionPublished inJournal of nuclear cardiologyLink to publicationCitation for published version (APA):Verberne, H. J., van der Heijden, D. J., van Eck-Smit, B. L. F., & Somsen, G. A. (2009).Persisting myocardial sympathetic dysfunction in takotsubo cardiomyopathy. Journal ofnuclear cardiology, 16(2), 321-324. https://doi.org/10.1007/s12350-008-9017-1General rightsIt is not permitted to download or to forward/distribute the text or part of it without the consent of the author(s)and/or copyright holder(s), other than for strictly personal, individual use, unless the work is under an opencontent license (like Creative Commons).Disclaimer/Complaints regulationsIf you believe that digital publication of certain material infringes any of your rights or (privacy) interests, pleaselet the Library know, stating your reasons. In case of a legitimate complaint, the Library will make the materialinaccessible and/or remove it from the website. Please Ask the Library: https://uba.uva.nl/en/contact, or a letterto: Library of the University of Amsterdam, Secretariat, Singel 425, 1012 WP Amsterdam, The Netherlands. Youwill be contacted as soon as possible.Download date:09 Mar 2023NUCLEAR CARDIOLOGY BULLETPersisting myocardial sympathetic dysfunctionin takotsubo cardiomyopathyHein J. Verberne, MD, PhD,a Dirk J. van der Heijden, MD,b Berthe L. F.van Eck-Smit, MD, PhD,a and G. Aernout Somsen, MD, PhDcA 73-year-old woman without a cardiovascularhistory was admitted with chest discomfort, dizziness,and nausea after an emotional meeting with the staff of anursing home. She experienced the same complaintssome years before when her father died.On admission the patient was in cardiogenic shock.Auscultation of the heart revealed a grade 3/6 systolicmurmur radiating to the left axilla. The electrocardio-graphy (ECG) showed an acute anterior wall infarction(Figure 1). Acute coronary angiography was performedbut no significant coronary artery disease was found.Left ventricular (LV) angiography showed severe mitralregurgitation and apical ballooning (Figure 2). Anintraventricular gradient of 100 mmHg was measured.Echocardiography showed apical akinesia and basalhyperkinesia resulting in severe mitral regurgitation dueto systolic anterior movement of the anterior mitralvalve leaflet. Troponin T (1.73 ng/L) and CK-MB(22 lg/L) were slightly increased. Based on these find-ings, the diagnosis of a takotsubo cardiomyopathy (TC)was made. Shortly after treatment with intravenousinotropics, and ACE inhibition the patient becamehemodynamically stable and metoprolol was added.Cardiac MRI did not show late contrast enhance-ment which excludes myocardial fibrosis and myocardialinfarction as the cause of the hemodynamic instability.Myocardial 123I-metaiodobenzylguanidine (123I-MIBG,a radiolabelled noradrenalin analog) scintigraphy, per-formed 4 days after admission, showed diffuse reducedmyocardial uptake and increased washout of 123I-MIBGwhich reflects impaired sympathetic neuronal functionand increased sympathetic activity, respectively (Fig-ure 3A). Cardiac ultrasound was repeated at 3 and7 months and showed no mitral regurgitation and anormalized LV function. However, cardiac sympatheticneuronal function and activity remained abnormal as wasshown by 123I-MIBG scintigraphy at 3 and 7 months(Figure 3B and C, respectively).The diagnosis of a stress-induced cardiomyopathy,apical ballooning syndrome or TC was based on thepresence of the typical symptoms and signs of an ante-rior wall infarction after a highly stressful moment(a lifetime crisis), combined with normal coronaryangiography, LV apical ballooning, no signs of latecontrast enhancement on MRI scanning, and rapidrecovery of LV function.1The name Takotsubo is related to the morphologyof the left ventricle, which shows resemblance to aJapanese round-bottomed narrow-necked fishing potused for trapping octopus. Postmenopausal women seemto be most at risk for developing this syndrome, espe-cially after an episode of acute emotional stress. In asystematic review, women accounted for 82-100% ofpatients with an average age of 62-75 years, althoughcases have been described in individuals aged10-91 years.2 Formal diagnostic criteria have yet to beestablished. Bybee et al have suggested diagnostic cri-teria for TC, requiring the following: (1) transient LVwall motion abnormalities involving the apical and/ormidventricular myocardial segments with wall motionabnormalities extending beyond a single epicardialcoronary distribution; (2) absence of obstructive epi-cardial CAD or angiographic evidence of acute plaquerupture that could be responsible for the observed wallmotion abnormality; and (3) new ECG abnormalitiessuch as transient ST-segment elevation and/or diffuseT-wave inversions or Troponin T elevation.2-4Although the exact pathophysiology of TC isunknown, it has been suggested that catecholamine-mediated cardiac toxicity is related to the pathophysio-logical basis of TC. In these patients, increasedmyocardial sympathetic activity is caused by increasedpresynaptic release and reduced re-uptake of noradren-alin. This leads to down regulation and desensitizationof the postsynaptic cardiac b-adrenoreceptors, leading toFrom Department of Nuclear Medicine,a Academic Medical Center,University of Amsterdam, Amsterdam 1100 DE, The Netherlandsand Department of Cardiology,b Rijnland Ziekenhuis, Leiderdorp,The Netherlands and Department of Cardiology,c Onze LieveVrouwe Gasthuis, Amsterdam, The Netherlands.Reprint requests: Hein J. Verberne, MD, PhD, Department of NuclearMedicine, Academic Medical Center, University of Amsterdam,P.O. Box 22700, Amsterdam 1100 DE, The Netherlands; h.j.verberne@amc.uva.nl.J Nucl Cardiol 2009;16:321–4.1071-3581/$34.00Copyright  2008 The Author(s). This article is published with openaccess at Springerlink.com.doi:10.1007/s12350-008-9017-1321a further decline of the LV function.5 The changes in thepresynaptic myocardial sympathetic activity can beassessed with the radio-labeled noradrenalin analog123I-MIBG.6 However, it has been shown that someb-adrenoreceptor-blockers may influence myocardial123I-MIBG uptake. This has also been suggested forACE-inhibitors. This may explain in part the initialscintigraphic findings. However, in the case report ofMoreo et al 123I-MIBG myocardial uptake increased,after a 2-month treatment with carvedilol.6 Moreover, inpatients with heart failure b-adrenoreceptor-blockersand ACE inhibitors are associated with an increase in123I-MIBG uptake and reduced washout.7,8 In our patientACE inhibition was discontinued after the acute phaseand the b-adrenoreceptor-blocker was continued.Another possible confounding factor of persistingabnormal 123I-MIBG scintigraphic findings is denerva-tion due to a previous myocardial infarction. However,MRI showed no signs of a previous myocardial infarc-tion. Taken together it is likely that the scintigraphicimages, at presentation and during follow-up, reflect truepersisting increased myocardial sympathetic activity.Another possible pathophysiological mechanism forthe development of TC might be related to stress-inducedcoronary epicardial spasm or endothelial dysfunctionresulting in myocardial stunning. In a recent study, Satoet al evaluated coronary artery endothelial dysfunction in35 patients with TC.9 In 54% of patients with TC, diffusecoronary vasoconstriction occurred after intracoronaryacetylcholine provocation. In the acute phase, myocardialperfusion and myocardial fatty acid metabolism scintig-raphy (123I-BMIPP) were impaired. During follow-upmyocardial perfusion and myocardial fatty acid metabo-lism improved to normal in association with improvementof LV function. Myocardial stunning due to stress-induced coronary epicardial spasm or endothelial dys-function might therefore be a likely explanation for TC.Figure 1. ECG at admission suggestive for an acute anteriorwall infarction: sinus-rhythm with 58 beats per minute, 1stdegree AV block, ST segment elevation in leads V1-V4, andpathological Q waves in V2 and V3.Figure 2. Left ventricular (LV) angiography showing severemitral regurgitation and apical ballooning.322 Verberne et al Journal of Nuclear Cardiology123I-MIBG and takotsubo cardiomyopathy March/April 2009Figure 3. 123I-MIBG scintigraphy: images on the left were made 15 min postinjection (p.i.) of123I-MIBG (early) and the images on the right were made 4 h p.i. (late). Upper left panel shows theregions of interest over the myocardium and mediastinum for the calculation of the semiquan-titative parameters of 123I-MIBG myocardial uptake and washout. 123I-MIBG images 4 days afterhospital admission, show severely reduced myocardial uptake (A). Semiquantitative analysis of themyocardial uptake confirmed the visual interpretation (early heart/mediastinal (H/M) ratio: 1.54,late H/M: 1.26 and myocardial washout of 123I-MIBG: 18%). Three (B) and seven months (C) afterhospital admission 123I-MIBG myocardial uptake and washout remained abnormal. Thesemiquantitative parameters remained abnormal after 3 months (early H/M: 1.78, late H/M: 1.33,and myocardial washout of 123I-MIBG: 25%) and after 7 months (early H/M: 1.66, late H/M: 1.13,and myocardial washout of 123I-MIBG: 32%). Due to the diffuse reduced myocardial 123I-MIBGuptake SPECT images could not reliably be reconstructed.Journal of Nuclear Cardiology Verberne et al 323Volume 16, Number 2;321–4 123I-MIBG and takotsubo cardiomyopathyAssessment of myocardial perfusion with SPECTand PET tracers and assessment of glucose metabolismwith 18F-FDG have been used to evaluate TCpatients.10-15 Typically in the early/acute phase of TCmyocardial perfusion can be (regionally, i.e., apex)disturbed and shows an impaired (regional, i.e., apex)coronary flow reserve (CFR) and a more pronouncedimpairment of (regional, i.e., apex) myocardial glucosemetabolism. In general, the regional reduction of per-fusion and impairment of glucose metabolism have thetendency to resolve completely 3 months after the early/acute phase.In our patient, myocardial sympathetic activity wasincreased in the early phase of TC. Although LV functionwas completely normalized, increased myocardial sym-pathetic activity persisted. Normalization of myocardial123I-MIBG uptake has been described in several casereports.6,16 This is the first report showing persistingsympathetic dysfunction in a patient with TC after com-plete normalization of the LV function and no signs of lateenhancement on MRI. The recurrence of TC is rare and isestimated at 2.9% per year and the overall cardiovascularsurvival is not different from age- and gender-matchedcontrols.17 Echocardiographic follow-up of TC patientshas never been performed in a consistent way. This mayimplicate that the recurrence rate of TC is underestimated.In the present case, the patient experienced the samesymptoms after an emotional event several years earlierwhich may have been an earlier episode of TC.Predictors of TC recurrence are not known. AsTC is associated with a hyperadrenergic state, the per-sisting increased myocardial sympathetic activity mayhave prognostic implications.18 Therefore, myocardial123I-MIBG scintigraphy may identify patients at risk forthe recurrence of TC. These findings may warrantextensive pharmacological therapy and follow-up in TCpatients. Theoretically, recurrence rates may be lower inthose who are maintained on adrenergic blockadeassuming that catecholamines play a central role in thepathogenesis of the syndrome.Open AccessThis article is distributed under the terms of the CreativeCommons Attribution Noncommercial License which permitsany noncommercial use, distribution, and reproduction in anymedium, provided the original author(s) and source arecredited.References1. Sharkey SW, Lesser JR, Zenovich AG, Maron MS, Lindberg J,Longe TF, et al. Acute and reversible cardiomyopathy provokedby stress in women from the United States. Circulation 2005;111:472-9.2. Bybee KA, Kara T, Prasad A, Lerman A, Barsness GW, WrightRS, et al. Systematic review: Transient left ventricular apicalballooning: A syndrome that mimics ST-segment elevation myo-cardial infarction. Ann Intern Med 2004;141:858-65.3. Bybee KA, Prasad A. Stress-related cardiomyopathy syndromes.Circulation 2008;118:397-409.4. Prasad A. Apical ballooning syndrome: An important differentialdiagnosis of acute myocardial infarction. Circulation 2007;115:e56-9.5. Lefkowitz RJ, Caron MG, Stiles GL. Mechanisms of membrane-receptor regulation. Biochemical, physiological, and clinicalinsights derived from studies of the adrenergic receptors. N Engl JMed. 1984;310:1570-9.6. Moreo A, De Chiara B, Possa M, Sara R, Bossi I, Orrego PS, et al.Functional derangement and cardiac innervation in the apical bal-looning syndrome: a 123I-meta-iodobenzylguanidine scintigraphicand dobutamine stress echocardiographic study. J Cardiovasc Med2007;8:205-9.7. de Milliano PA, de Groot AC, Tijssen JG, van Eck Smit BL, vanZwieten PA, Lie KI. Beneficial effects of metoprolol on myo-cardial sympathetic function: Evidence from a randomized,placebo-controlled study in patients with congestive heart failure.Am Heart J 2002;144:E3.8. Somsen GA, van Vlies B, de Milliano PA, Borm JJ, van RoyenEA, Endert E, et al. Increased myocardial [123I]-metaiodobenzyl-guanidine uptake after enalapril treatment in patients with chronicheart failure. Heart 1996;76:218-22.9. Sato A, Aonuma K, Nozato T, Sekiguchi Y, Okazaki O, Kubota K,et al. Stunned myocardium in transient left ventricular apicalballooning: A serial study of dual I-123 BMIPP and Tl-201SPECT. J Nucl Cardiol 2008;15:671-9.10. Feola M, Chauvie S, Rosso GL, Biggi A, Ribichini F, Bobbio M.Reversible impairment of coronary flow reserve in takotsubocardiomyopathy: A myocardial PET study. J Nucl Cardiol 2008;15(6):811-17.11. Cimarelli S, Imperiale A, Ben-Sellem D, Rischner J, Detour J,Morel O, et al. Nuclear medicine imaging of takotsubo cardio-myopathy: Typical form and midventricular ballooning syndrome.J Nucl Cardiol 2008;15:137-41.12. Alexanderson E, Cruz P, Talayero JA, Damas F, Zeron J, MeaveA. Transient perfusion and motion abnormalities in takotsubocardiomyopathy. J Nucl Cardiol 2007;14:129-33.13. Bybee KA, Murphy J, Prasad A, Wright RS, Lerman A, Rihal CS,et al. Acute impairment of regional myocardial glucose uptake inthe apical ballooning (takotsubo) syndrome. J Nucl Cardiol2006;13:244-50.14. Scholte AJ, Bax JJ, Stokkel MP, Plokker T, Kaandorp TA, LambHJ, et al. Multimodality imaging to diagnose takotsubo cardio-myopathy. J Nucl Cardiol 2006;13:123-6.15. Obunai K, Misra D, Van Tosh A, Bergmann SR. Metabolic evidenceof myocardial stunning in takotsubo cardiomyopathy: A positronemission tomography study. J Nucl Cardiol 2005;12:742-4.16. Ito K, Sugihara H, Kinoshita N, Azuma A, Matsubara H.Assessment of Takotsubo cardiomyopathy (transient left ven-tricular apical ballooning) using 99mTc-tetrofosmin, 123I-BMIPP,123I-MIBG and 99mTc-PYP myocardial SPECT. Ann Nucl Med2005;19:435-45.17. Elesber AA, Prasad A, Lennon RJ, Wright RS, Lerman A, RihalCS. Four-year recurrence rate and prognosis of the apical bal-looning syndrome. J Am Coll Cardiol 2007;50:448-52.18. Wittstein IS, Thiemann DR, Lima JAC, Baughman KL, SchulmanSP, Gerstenblith G, et al. Neurohumoral features of myocardialstunning due to sudden emotional stress. N Engl J Med 2005;352:539-48.324 Verberne et al Journal of Nuclear Cardiology123I-MIBG and takotsubo cardiomyopathy March/April 2009

Acute and reversible cardiomyopathy provoked by stress in women from the United States. Circulation

Acute impairment of regional myocardial glucose uptake in the apical ballooning (takotsubo) syndrome.

Apical ballooning syndrome: An important differential diagnosis of acute myocardial infarction.

Assessment of Takotsubo cardiomyopathy (transient left ventricular apical ballooning) using 99mTc-tetrofosmin, 123I-BMIPP, 123I-MIBG and 99mTc-PYP myocardial SPECT.

Beneﬁcial effects of metoprolol on myocardial sympathetic function: Evidence from a randomized, placebo-controlled study in patients with congestive heart failure. Am Heart J

Functional derangement and cardiac innervation in the apical ballooning syndrome: a 123I-meta-iodobenzylguanidine scintigraphic and dobutamine stress echocardiographic study.

Increased myocardial [ 123I]-metaiodobenzylguanidine uptake after enalapril treatment in patients with chronic heart failure.

Mechanisms of membranereceptor regulation. Biochemical, physiological, and clinical insights derived from studies of the adrenergic receptors.

Multimodality imaging to diagnose takotsubo cardiomyopathy.

Neurohumoral features of myocardial stunning due to sudden emotional stress.

Nuclear medicine imaging of takotsubo cardiomyopathy: Typical form and midventricular ballooning syndrome.

ObunaiK,MisraD,VanToshA,BergmannSR.Metabolicevidence of myocardial stunning in takotsubo cardiomyopathy: A positron emission tomography study.

Reversible impairment of coronary ﬂow reserve in takotsubo cardiomyopathy: A myocardial PET study.

Rihal CS. Four-year recurrence rate and prognosis of the apical ballooning syndrome.

Stress-related cardiomyopathy syndromes.

Stunned myocardium in transient left ventricular apical ballooning: A serial study

Systematic review: Transient left ventricular apical ballooning: A syndrome that mimics ST-segment elevation myocardial infarction.

Transient perfusion and motion abnormalities in takotsubo cardiomyopathy.

Persisting myocardial sympathetic dysfunction in takotsubo cardiomyopathy

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