Diagnosis

Proposed diagnostic criteria

2004    The Mayo Criteria1
2007    Japanese Takotsubo Cardiomyopathy Group2
2008    The modified Mayo Criteria3
2012     Johns Hopkins criteria4
2013     Gothenburg Group5
2014     Takotsubo Italian Network6
2014     Madias-proposed criteria7
2015     European Society of Cardiology (Heart Failure Association)8
2018     International Takotsubo Diagnostic Criteria (InterTAK Diagnostic Criteria)9

There are now several publications that propose diagnostic criteria and diagnostic algorithms for Takotsubo syndrome (TTS) with subsequent modifications as knowledge about TTS has evolved.  Some of these have been proposed by individual experts and institutional research groups. Others have been proposed by organisational working groups with international membership or panels of experts that include experts from around the world. Reassuringly, these proposed diagnostic criteria and algorithms differ mainly in format and the amount of detail included, and generally have the same (or similar) content, with some minor points of difference.   The Mayo criteria (with the 2008 modifications) were used for several years. The most recent diagnostic criteria from the European Society of Cardiology and the InterTAK are shown below. They do not differ from each other in the core criteria but each has some added criteria. It is likely that these will continue to be revised as understanding of TTS evolves.

Box 1. Heart Failure Association Diagnostic Criteria

  1. Transient regional wall motion abnormalities of LV or RV myocardium which are frequently, but not always, preceded by a stressful trigger (emotional or physical).
  2. The regional wall motion abnormalities usuallya extend beyond a single epicardial vascular distribution, and often result in circumferential dysfunction of the ventricular segments involved.
  3. The absence of culprit atherosclerotic coronary artery disease including acute plaque rupture, thrombus formation, and coronary dissection or other pathological conditions to explain the pattern of temporary LV dysfunction observed (e.g. hypertrophic cardiomyopathy, viral myocarditis).
  4. New and reversible electrocardiography (ECG) abnormalities (ST-segment elevation, ST depression, LBBBb, T-wave inversion, and/or QTc prolongation) during the acute phase (3 months).
  5. Significantly elevated serum natriuretic peptide (BNP or NT-proBNP) during the acute phase.
  6. Positive but relatively small elevation in cardiac troponin measured with a conventional assay (i.e. disparity between the troponin level and the amount of dysfunctional myocardium present).c
  7. Recovery of ventricular systolic function on cardiac imaging at follow-up (3–6 months).d

aAcute, reversible dysfunction of a single coronary territory has been reported.
bLeft bundle branch block may be permanent after Takotsubo syndrome, but should also alert clinicians to exclude other cardiomyopathies. T-wave  changes and QTc prolongation may take many weeks to months to normalize after recovery of LV function.
cTroponin-negative cases have been reported, but are atypical.
dSmall apical infarcts have been reported. Bystander subendocardial infarcts have been reported, involving a small proportion of acutely dysfunctional myocardium. These infarcts are insufficient to explain the acute regional wall motion abnormality observed.

© 2015 Lyon et al. European Journal of Heart Failure © 2015 European Society of Cardiology

Box 2. InterTAK Diagnostic Criteria

  1. Patients show transienta left ventricular dysfunction (hypokinesia, akinesia, or dyskinesia) presenting as apical ballooning or midventricular, basal, or focal wall motion abnormalities. Right ventricular involvement can be present. Besides these regional wall motion patterns, transitions between all types can exist. The regional wall motion abnormality usually extends beyond a single epicardial vascular distribution; however, rare cases can exist where the regional wall motion abnormality is present in the subtended myocardial territory of a single coronary artery (focal TTS).b
  2. An emotional, physical, or combined trigger can precede the takotsubo syndrome event, but this is not obligatory.
  3. Neurologic disorders (e.g. subarachnoid haemorrhage, stroke/transient ischaemic attack, or seizures) as well as pheochromocytoma may serve as triggers for takotsubo syndrome.
  4. New ECG abnormalities are present (ST-segment elevation, ST-segment depression, T-wave inversion, and QTc prolongation); however, rare cases exist without any ECG changes.
  5. Levels of cardiac biomarkers (troponin and creatine kinase) are moderately elevated in most cases; significant elevation of brain natriuretic peptide is common.
  6. Significant coronary artery disease is not a contradiction in takotsubo syndrome.
  7. Patients have no evidence of infectious myocarditis.b
  8. Postmenopausal women are predominantly affected.

aWall motion abnormalities may remain for a prolonged period of time or documentation of recovery may not be possible. For example, death before evidence of recovery is captured.
bCardiac magnetic resonance imaging is recommended to exclude infectious myocarditis and diagnosis confirmation of takotsubo syndrome.

© Ghadri et al. 2018. Published by Oxford University Press on behalf of the European Society of Cardiology.

Differential diagnoses

Differential diagnoses for TTS include ACS, myocarditis and spontaneous coronary artery dissection (SCAD). Click on the table below for more information.

 

For information on TTS clinical presentation CLICK HERE

For information on TTS associated triggers CLICK HERE

Diagnostic tests

The electrocardiogram (ECG)

The ECG at TTS onset is like that of ACS in that it may show ST-segment elevation, T wave inversion, non-specific abnormalities, or no detectable abnormalities.

Key point  Absence of ST-segment elevation or other ECG abnormalities at presentation does not rule out TTS.

  • Isolated ST-segment depression is rarely seen in TTS, particularity in the inferior leads. ST-segment depression is present in less than 10% of patients with TTS.  As ST-segment depression is seen in over 30% of ACS patients, the presence of ST-segment depression may be more suggestive of ACS.1  The presence of ST‐depression in inferior leads in STEMI suggests left anterior descending coronary artery occlusion proximal to the first septal branch.3
  • ST -segment elevation is seen in just under 50% of patients with TTS.  ST-segment elevation in TTS involving the mid and apical segments of the left ventricle often resembles that seen in anterior ST-segment elevation myocardial infarction (precordial leads V1–V4 and limb leads I and aVL). As yet there is no absolutely reliable way to distinguish between TTS and STEMI on the ECG; thus urgent coronary angiography is required.1  ST-segment elevation that persists for more than 48 hours after TTS presentation is an independent predictor of longer hospitalisation, a higher rate in-hospital complications, and greater incidence of major cardiac adverse events at follow-up.10
  • Q-waves or poor R-wave progression are sometimes seen in the anterior leads in TTS but R waves often reappear within a few hours.11
  • As in ACS, the ECG in TTS undergoes temporal changes. Within 24 – 48 hours following onset of TTS, widespread T-wave inversion and QTc-interval prolongation is commonly seen on the ECG.  If these abnormalities are present on the first ECG at patient presentation, it is suggestive of a delayed presentation.12   T-wave inversion may persist for several months.13

Figure 1. ECG at 48 hours after onset of symptoms in Takotsubo syndrome in a 62-year-old female with apical ballooning

Image by Dr. Stephen Smith, http://hqmededecg.blogspot.com/2010/12/takostubo-stress-cardiomyopathy-with.html.

At a minimum, an ECG should be obtained at admission, 24 hours, and 48 hours following a suspected diagnosis of TTS, and with any change in the patient’s condition. In cases where there is QTc-interval prolongation, an ECG should be obtained daily during hospital admission or until the QTc-interval returns to normal.
Key point  New and progressive T- wave inversion and QTc-prolongation in a patient who has  a primary medical illness or in whom TTS not been diagnosed may indicate a need for further investigation.

Biomarkers

Troponin and creatine kinase (CK)

Troponin values are almost always elevated in TTS but the rise in serum troponin or creatine kinase (CK) is disproportionately low relative to the extent of regional wall motion abnormality and cardiac dysfunction.8  Peak troponin and CK values are usually lower than those typically found in ACS.   High admission troponin levels in TTS predict worse in-hospital outcome.14

B-type natriuretic peptide (BNP) and N-terminal prohormone of  BNP (NT-proBNP)

Plasma levels of B-type natriuretic peptide (BNP) and N-terminal prohormone of brain natriuretic peptide (NT-proBNP) are almost always elevated in TTS, often to extremely high levels.  NT-proBNP/BNP increase significantly during the first 24 hours after the onset of symptoms with slow and incomplete resolution during the 3 months thereafter.15 NT-proBNP/BNP levels correlate more closely with the degree of ventricular wall motion abnormality and therefore may be more useful diagnostically than troponin in TTS.8  NT-proBNP is a valuable marker of myocardial deterioration and recovery. Low NT-proBNP at admission may reliably indicate a favourable prognosis8 while higher NT-proBNP/BNP levels are associated with adverse outcomes in TTS.16 It should be noted that angiotensin receptor-neprilysin inhibitor (ARNI) medications may falsely elevate BNP but  does not affect NT-proBNP.  A high BNP in patients taking ARNI medications does not necessarily mean a worse prognosis or outcome.

 

Key Point NT-proBNP are more useful diagnostic biomarkers than troponin, and it is recommended that they be measured in all suspected cases of TTS if the assay is available.

Coronary angiography and ventriculography

Coronary angiography is required to secure the diagnosis of TTS and exclude obstructive coronary artery disease as the cause of symptoms.  Coronary angiography in TTS typically shows normal coronary arteries or mild to moderate coronary artery disease (CAD).   Approximately 15% of patients with TTS will have significant CAD14 and biplane ventriculography in similar views is mandatory in these patients to detect perfusion-contraction mismatch.17,18
Venticulography in TTS will  show regional wall motion abnormalities (hypokinesis, akinesis, or dyskinesis) in one of the following characteristic patterns:

Apical Takotsubo is the most commonly recognised form of TTS and accounts for around 80% of cases in the InterTAK Registry.14 Systolic apical ballooning of the left ventricle is present with depressed function of the mid and apical segments. Hyperkineses of the basal walls is often present. Around one-third of patients with the apical ballooning form of TS have a small zone of preserved contractility in the most distal portion of the apex.  This has been described as the 'apical nipple sign'. which is described as the ‘apical nipple sign’.19
Mid-ventricular Takotsubo  is restricted to the mid-ventriclular hypokinesis with relative sparing of the apex.
Basal  (reverse or inverted Takotsubo)  is associated with basal hypokinesis and sparing of the mid-ventricle and apex
Focal Takotsubo is characterised by dysfunction of an isolated segment (most commonly the anterolateral segment) of the LV. This is a relatively recently recognised form of Takotsubo and is likely under-recognised as a form of TTS.
Global Takotsubo is reportedly rare, but as with the focal type of Takotsubo, may be under-recognised as a form of TTS.

Four types of takotsubo (stress) cardiomyopathy — apical, midventricular, basal, and focal — are shown in videos of left ventricular angiography.
NEJM Video
Sept 3, 2015.

Echocardiogram

Echocardiography plays a very important role in the assessment of heart function in TTS since it is easily available and has virtually no contraindications it is usually the first step in assessing pump function.

Transthoracic echocardiography (TTE) with colour and tissue Doppler should be the first non-invasive imaging technique to verify a suspected diagnosis of TTS. In addition to assessing LV morphology and function, TTE can identify anatomic variants, detect potential complications including left ventricular outflow obstruction (LVOTO), mitral regurgitation, right ventricular involvement, thrombus formation, and cardiac rupture. It is also used to monitor recovery.8

Accurate echocardiographic estimation of global left ventricular (LV) function can be subjective and for that reason, over the past few years, strain echocardiography has emerged as an important and accurate method of assessing LV function with the advantage of revealing myocardial dysfunction even before significant changes in ejection fraction have occurred.

This technique can be also used for monitoring recovery or early changes in LV function if new symptoms arise or recovery is taking longer than expected.

 

Cardiac magnetic resonance imaging

If available, cardiac magnetic resonance imaging (CMR) should be considered in all patients with suspected TTS in the acute phase (within 7 days). It is also useful to confirm recovery of ventricular function on follow-up.8

CMR is useful in distinguishing TTS from other diseases, acute myocardial infarction (MI) and myocarditis.  During the acute phase of TTS, T2-weighted CMR shows oedema of the left ventricular (LV) myocardium as high signal intensity, with a diffuse or transmural distribution consistent with the wall motion abnormality. Typically, late gadolinium enhancement (LGE) is absent in TTS distinguishing it from MI.  There is some controversy about whether minor LGE may be present during the acute phase of TTS but absent at follow up in some patients.  Atypical cases with small areas of persistent apical transmural LGE have been reported.(Lyon) .

CMR is useful in assessment of regional wall motion abnormalities (RWMAs) in both the left and right ventricles and often provides more complete views of the right ventricle than echocardiography. TTS involves the right ventricle in up to one-third of patients..
Patients with extensive akinesia may benefit from CMR as CMR is superior to echocardiography in detecting apical LV thrombi.

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Eitel et al 2011. Cardiovascular Magnetic Resonance (CMR) Images of 4 Distinct Ballooning Patterns in Stress Cardiomyopathy and at 3-Month Follow-up

Diagnostic algorithms

Takotsubo diagnostic algorithm (Heart Failure Association of the European Society of Cardiology)

Click on the image to enlarge

 

 

 

 

 

 

 

 

© 2015 Lyon et al. European Journal of Heart Failure

Diagnostic algorithm of Takotsubo
(InterTAK)

Click on the image to enlarge

 

 

 

 

 

 

 

© 2015 Ghadri et al. European Heart Journal

 

 

 

 

 

References

1Bybee, K.A., Kara, T., Prasad, A., Lerman, A., Barsness, G.W., Wright, R.S. and Rihal, C.S., 2004. Systematic review: transient left ventricular apical ballooning: a syndrome that mimics ST-segment elevation myocardial infarction. Annals of Internal Medicine, 141(11), pp.858-865.
2Kawai, S., Kitabatake, A., Tomoike, H. and Takotsubo Cardiomyopathy Study Group, 2007. Guidelines for diagnosis of takotsubo (ampulla) cardiomyopathy. Circulation Journal, 71(6), pp.990-992. https://doi.org/10.1253/circj.71.990
3Prasad, A., Lerman, A. and Rihal, C.S., 2008. Apical ballooning syndrome (Tako-Tsubo or stress cardiomyopathy): a mimic of acute myocardial infarction. American Heart Journal, 155(3), pp.408-417. https://doi.org/10.1016/j.ahj.2007.11.008
4Wittstein, I.S., 2012. Stress cardiomyopathy: a syndrome of catecholamine-mediated myocardial stunning?. Cellular and Molecular Neurobiology, 32(5), pp.847-857. https://doi.org/10.1007/s10571-012-9804-8
5Schultz, T., Shao, Y., Redfors, B., Sverrisdóttir, Y.B., Råmunddal, T., Albertsson, P., Matejka, G. and Omerovic, E., 2012. Stress-induced cardiomyopathy in Sweden: evidence for different ethnic predisposition and altered cardio-circulatory status. Cardiology, 122(3), pp.180-186. https://doi.og/10.1159/000338814
6Parodi, G., Citro, R., Bellandi, B., Provenza, G., Marrani, M. and Bossone, E., 2014. Revised clinical diagnostic criteria for Tako-tsubo syndrome: the Tako-tsubo Italian Network proposal. International Journal of Cardiology, 172(1), pp.282-283. https://doi.org/10.1016/j.ijcard.2013.12.239
7Madias, J.E., 2014. Why the current diagnostic criteria of Takotsubo syndrome are outmoded: a proposal for new criteria. International Journal of Cardiology, 174(3),p.468-470. https://doi.org/10.1016/j.ijcard.2014.04.241
8Lyon, A.R., Bossone, E., Schneider, B., Sechtem, U., Citro, R., Underwood, S.R., Sheppard, M.N., Figtree, G.A., Parodi, G., Akashi, Y.J. and Ruschitzka, F., 2016. Current state of knowledge on Takotsubo syndrome: a Position Statement from the Taskforce on Takotsubo Syndrome of the Heart Failure Association of the European Society of Cardiology. European Journal of Heart Failure, 18(1), pp.8-27.
https://doi.org/10.1002/ejhf.424
9Ghadri, J.R., Wittstein, I.S., Prasad, A., Sharkey, S., Dote, K., Akashi, Y.J., Cammann, V.L., Crea, F., Galiuto, L., Desmet, W. and Yoshida, T., 2018. International expert consensus document on takotsubo syndrome (part I): clinical characteristics, diagnostic criteria, and pathophysiology. European Heart Journal, 39(22), pp.2032-2046. https://doi.org/10.1093/eurheartj/ehy076
10Santoro, F., Stiermaier, T., Tarantino, N., Guastafierro, F., Graf, T., Möller, C., ... & Brunetti, N. D. (2018). Impact of persistent ST elevation on outcome in patients with Takotsubo syndrome. Results from the GErman Italian STress Cardiomyopathy (GEIST) registry. International Journal of Cardiology, 255, 140-144. https://doi.org/10.1016/j.ijcard.2017.11.068
11Sclarovsky, S., & Nikus, K. (2010). The electrocardiographic paradox of tako-tsubo cardiomyopathy–comparison with acute ischemic syndromes and consideration of molecular biology and electrophysiology to understand the electrical-mechanical mismatching. Journal of Electrocardiology, 43(2), 173-176. https://doi.org/10.1016/j.jelectrocard.2009.07.015
12Isogai, T., Yoshikawa, T., Yamaguchi, T., Arao, K., Ueda, T., Imori, Y., ... & Takayama, M. (2018). Differences in Initial Electrocardiographic Findings of Apical Takotsubo Syndrome According to the Time from Symptom Onset. The American Journal of Cardiology, 122(10), 1630-1637. https://doi.org/10.1016/j.amjcard.2018.07.042
13Bennett, J., Ferdinande, B., Kayaert, P., Wiyono, S., Goetschalkx, K., Dubois, C., ... & Desmet, W. (2013). Time course of electrocardiographic changes in transient left ventricular ballooning syndrome. International Journal of Cardiology, 169(4), 276-280. https://doi.org/10.1016/j.ijcard.2013.08.126
14Templin, C., Ghadri, J. R., Diekmann, J., Napp, L. C., Bataiosu, D. R., Jaguszewski, M., ... & Seifert, B. (2015). Clinical features and outcomes of Takotsubo (stress) cardiomyopathy. New England Journal of Medicine, 373(10), 929-938.
15Nguyen, T. H., Neil, C. J., Sverdlov, A. L., Mahadavan, G., Chirkov, Y. Y., Kucia, A. M., ... & Struthers, A. D. (2011). N-terminal pro-brain natriuretic protein levels in takotsubo cardiomyopathy. The American journal of cardiology, 108(9), 1316-1321.4Syed, F. F., Asirvatham, S. J., & Francis, J. (2010). Arrhythmia occurrence with takotsubo cardiomyopathy: a literature review. Europace, 13(6), 780-788.
16Murakami, T., Yoshikawa, T., Maekawa, Y., Ueda, T., Isogai, T., Konishi, Y., ... & CCU Network Scientific Committee. (2014). Characterization of predictors of in-hospital cardiac complications of takotsubo cardiomyopathy: multi-center registry from Tokyo CCU Network. Journal of cardiology, 63(4), 269-273.
17 Napp, L. C., Ghadri, J. R., Bauersachs, J., & Templin, C. (2015). Acute coronary syndrome or Takotsubo cardiomyopathy: the suspect may not always be the culprit. International journal of cardiology, 187, 116-119.
18Patel, S. M., Lennon, R. J., & Prasad, A. (2012). Regional wall motion abnormality in apical ballooning syndrome (Takotsubo/stress cardiomyopathy): importance of biplane left ventriculography for differentiating from spontaneously aborted anterior myocardial infarction. The international journal of cardiovascular imaging, 28(4), 687-694.
19Desmet W, Bennett J, Ferdinande B, De Cock D, Adriaenssens T, Coosemans
M, Sinnaeve P, Kayaert P, Dubois C. The apical nipple sign: a useful tool for discriminatingbetween anterior infarction and transient left ventricular ballooning
syndrome. Eur Heart J Acute Cardiovasc Care 2014;3:264–267.
20Eitel, I., von Knobelsdorff-Brenkenhoff, F., Bernhardt, P., Carbone, I., Muellerleile, K., Aldrovandi, A., Francone, M., Desch, S., Gutberlet, M., Strohm, O. and Schuler, G., 2011. Clinical characteristics and cardiovascular magnetic resonance findings in stress (takotsubo) cardiomyopathy. Jama, 306(3), pp.277-286.

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