Takotsubo syndrome diagnostic criteria. position papers :Mayo clnic ,HFA and InterTAK Diagnostic Criteria.Takotsubo Syndrome and COVID-19.Noninvasive Multimodality Imaging in the Diagnosis and Management of Patients with Takotsubo Syndrome

1. A fresh look at
Takotsubo Syndrome
Magdy El-Masry
Prof. of Cardiology
Tanta University
CardioEgypt 2021
15th - 18th February 2021
Cairo - Egypt.

2. Today’s talk will include:
How to see the big picture
is not
as easy as you would think
 Historical Perspective & Nomenclature
 Definition & Diagnostic Criteria
 Risk Factors & Triggers
 Pathophysiology
 Clinical presentation & initial workup
 Diagnostic Studies { Cardiac Imaging }
 Differential Diagnosis
 Does Biological Sex Matter?
 Complications
 Outcome
 Treatment

3. Historical Perspective
& Nomenclature

4. It is now 30 years since Japanese
investigators first described Takotsubo
Syndrome as a disorder occurring
mainly in ageing women, ascribing it to
the impact of multivessel coronary
artery spasm.

5. The LV apical ballooning seen in Takotsubo cardiomyopathy
resembles a traditional Japanese octopus trap.
Journal of the American Academy of PAs33(3):24-29, March 2020.
Japanese octopus trap and Takotsubo cardiomyopathy

6. Reversible LV Dysfunction
Takotsubo Cardiomyopathy
Broken Heart Syndrome
Stress Cardiomyopathy
Apical Ballooning Syndrome
Reverse Takotsubo and
Midventricular Takotsubo Cardiomyopathy
Focal Takotsubo Cardiomyopathy
Takotsubo Syndrome
1990
2020
The table shows the most frequently used names
that have been used for TS.

7. Takotsubo Cardiomyopathy
Broken Heart Syndrome
Takotsubo Syndrome
‘Broken heart syndrome’ is easy to remember and has more appeal for the general
community compared with the name ‘Takotsubo syndrome’.
Thus, it is a popular term used in the media for Takotsubo syndrome , but it is a misnomer.
Valentine’s Day and the Broken Heart Syndrome
( February 14 )

8. Definition &
Diagnostic Criteria

9. Year Publication Criteria
2003 Abe et al. Abe criteria
2004 Bybee et al. Mayo Clinic Diagnostic Criteria
2007 Kawai et al. Japanese diagnosis guidelines
2008 Prasad et al. Mayo Clinic Diagnostic Criteria, revised
2011 Omerovic Gothenburg criteria
2012 Wittstein Johns Hopkins criteria
2013 Redfors et al. Gothenburg criteria, revised
2014 Parodi et al. Takotsubo-Italian Network Proposal
2014 Madias Madias criteria
2014 Redfors et al. Gothenburg criteria, proposed new criteria
2016 Lyon et al. ESC Heart Failure Association Taskforce Criteria
2018 Ghadri et al. InterTAK Criteria
Takotsubo syndrome diagnostic criteria

10. Mayo clinic criteria
New ECG
abnormalities * Absence of
obstructive
CAD
Transient LV
apical akinesis/
dyskinesis
*Without concurrent conditions; head injury/intracranial bleed/
pheochromocytoma/myocarditis/hypertrophic cardiomyopathy
In 2004, the Mayo Clinic group published their diagnostic criteria ,
which are still widely used today
Ann Intern Med 2004; 141: 858.

11. The definition of TS according to the two most recent position papers involves several diagnostic
criteria , most of which are common and include transient RWMAs of the LV and/or RV after a stressful
trigger (emotional, physical, or combined, neurologic disorders, or pheochromocytoma), RWMAs extend
beyond the distribution of a single coronary artery, new and reversible ECG abnormalities, elevated
serum NPs, and relatively small Tp elevation.
Similarities and differences between HFA and InterTAK Diagnostic Criteria.

12. Diagnostic Criteria
Mayo Clinic,
2004
ESC HFA Taskforce,
2016
InterTak
Registry,2018
Transient wall motion
abnormalities
√ √ √
Stress as trigger √ √ √
Neurological trigger √
Coronary artery Absence of atherosclerosis Absence of atherosclerosis Atherosclerosis can coexist
New ECG abnormalities √ √
* √
*
Cardiac biomarkers Troponin √ ** √**
Recovery √
No evidence of myocarditis √ √
No evidence of
phaeochromocytoma
√
Postmenopausal women √
*Also includes QTc prolongation. ** ↑ Troponin ↑ ↑ ↑ NT-proBNP
Importantly, InterTAK criteria describe that the presence of pheochromocytoma and significant CAD are not contradictory to the diagnosis of TTS.
The most widely used diagnostic
criteria are HFA/ESC diagnostic
criteria, which have revised the
earlier Mayo Clinic Criteria .
Recently, the InterTAK Diagnostic
Criteria have been proposed
ECR 2019,14(3) 191-6

13. Risk Factors
& Triggers

14. The Many Triggers of TS
Emotional and
physical stress factors
precipitating TS
TS can be caused by a
variety of stressors, and
some of them may
surprise you.
Eur Hear J, 39 (2018), pp. 2032-2046

15. A Few Words About Takotsubo Syndrome and COVID-19
Covidsubo ?????!!!!!
Octopus
COVID-19

16. Takotsubo Rising During COVID-19?
Stress, Viral Triggers Need Attention
Stress or Virus?
What’s not clear is the extent to which the telltale
characteristics of Takotsubo are directly related to the viral
infection or are caused by stress secondary to the pandemic
and its economic and social effects.
The two distress situations
empower each other, the
COVID and Takotsubo.
Covidsubo
If we have a patient who might be
more emotional, pay attention:
psychological support is very
important to them.

17. Pathophysiology

18. This figure draws attention to potential pathophysiological mechanisms for the observed reversible
myocardial dysfunction such as sympathetic overdrive-mediated multi-vessel epicardial spasms,
microvascular dysfunction, the direct toxicity of catecholamines, lipotoxicity, and inflammation.
Clin. Med. 2021, 10(3), 479
The exact
pathophysiology
of the TS is
not known

19. Clinical presentation
& initial workup

20. Clinical presentation
 Chest pain, dyspnea, syncope, palpitations,
cardiac arrest.
 Usually in postmenopausal female and often
preceded by an emotional or physical stress
ECG
 ST-segment elevation ,ST-segment depression
T-waves inversion
 QTc prolongation
Cannot distinguish between Takotsubo and
STEMI at presentation!!!

21. Biomarkers in Takotsubo cardiomyopathy and AMI. Journal of the American Academy of PAs33(3):24-29, March 2020
Labs “Biomarkers”:
↑ troponin & higher NT-proBNP/troponin ratio than in STEMI
{ TS : NT- proBNP/TnI ratio is 2235 .The troponin level is
lower than in patients with STEMI . AMI : NTproBNP/TnI ratio is 82 }

22. Diagnostic
Studies
{Cardiac Imaging}

23. Apical, midventricular, basal (inverted) or focal
hypo/akinesia.
Echocardiography
Absence of culprit obstructive CAD.
Ventriculography identifies the anatomical
variant.
No signs of acute plaque destabilization at
intravascular imaging.
Coronary
angiography and
ventriculography
Edema: transmural edema in the areas of
ventricular dysfunction
Cine: regional wall motion abnormalities
without coronary distribution
LGE: absent (cut-off>5 SD).
Cardiac MRI
Cardiac Imaging in TS
July 2020 Future Cardiology 17(7)

24. TS - Transthoracic four-chamber view showing the hypercontractile
basal segment and the ballooning apical segment
Indian J Anaesth 2017;61:728-35

25. Schematic representation of takotsubo cardiomyopathy. A takotsubo is a pot used to catch an octopus. A A takotsubo is
tied to a rope and submerged in the sea; it is retrieved after an octopus has entered the pot. B The shape of the
takotsubo resembles the configuration of the left ventricle during systole on imaging, such as left ventriculography.
Journal of Nuclear Cardiology volume 26, pages1602–1616(2019)

26. White lesions are the territory of a transient abnormality in LV wall motion. Apical type which
is the so-called takotsubo is most frequent. Some of the other variations are reported such as
mid-ventricular, basal, and focal type. Journal of Nuclear Cardiology volume 26, pages1602–1616(2019
Variation of TS.
There are other variants of TS for which the prevalence is unknown. This may be because they are rare, or alternately,
they may be poorly recognised. These variants include: 1 right ventricular involvement. 2 apical tip sparing variant.
3 biventricular apical dysfunction. 4 isolated RV involvement 5 global dysfunction.

27. Four Types of Takotsubo
Cardiomyopathy.
Among the 1750 study patients, the most
common type of takotsubo (stress)
cardiomyopathy was the apical type
(in 81.7% of patients) (Panels A and B),
followed by the midventricular type (in 14.6%
of patients) (Panels C and D), the basal type (in
2.2% of patients) (Panels E and F), and the
focal type (in 1.5% of patients) (Panels G and
H).
All left ventricular angiograms were obtained in the
right anterior oblique view (30 degrees) during
diastole (left column) and systole (middle column).
In the far right column, the wall-motion
abnormality that was observed
with each type of the disorder is shown, with
red indicating diastole, white indicating
systole, and the dashed line indicating the
location of the wall-motion abnormality.
n engl j med 373;10 nejm.org
September 3, 2015

28. CMR imaging of takotsubo cardiomyopathy.
A Wall motion abnormalities at the mid-ventricular to apical anterior segments with cine imaging as apical ballooning. High signal
intensity with fat-saturated T2-weighted images (fsT2WI) (yellow arrows) due to the myocardial edema (B), but the absence of the late
gadolinium enhancement (LGE) (C) are shown. Journal of Nuclear Cardiology volume 26, pages1602–1616(2019

29. The Importance of
Noninvasive Multimodality Imaging
in the Diagnosis and Management
of Patients with Takotsubo Syndrome
Echocardiography
Cardiac Magnetic Resonance Imaging
Computed Tomography Imaging
Nuclear Imaging

30. Strengths and weaknesses of non-invasive multimodality imaging in TS.
Journal of Echocardiography (2020) 18:199–224
Echocardiography CMR CTA Nuclear imaging
Accessibility ++++ ++ +++ ++
Cost + +++ ++ ++
Radiation risk – – ++ ++++
LV morphology and
function
+++ ++++ ++ +++
RV function ++ ++++ ++ –
MR quantification +++ +++ – –
LVOTO ++++ ++ – –
LV/RV thromb ++ ++++ +++ –
Tissue
characterization
+ ++++ ++ +
Coronary artery
imaging
+ ++ ++++ –
Differential diagnosis
a
:
CAD ++ ++++ ++++ +++
MINOCA + ++++ +++ ++
Myocarditis ++ ++++ ++ +
Usefulness in FU +++ +++ – ++
aCTA can be useful to exclude pulmonary embolism and aortic dissection.
+, low; ++, medium; +++, high; ++++, excellent, – = none.

31. Differential
Diagnosis
TS Mimicking an
Acute Myocardial
Infarction

32. ECG of onset, coronary angiography, and ventriculogram of a patient with typical form of
Takotsubo syndrome.

33. TS diagnosis
during the
evaluation
Of ACS
Cureus. 2020 Jan; 12(1)

34. Because clinical presentation of TTS mimics ACS , the differential
diagnosis between the two syndromes is challenging.
To differentiate TS and ACS , the InterTAK Diagnostic Score has been proposed.
If 50 or more points were present, the specificity of TS was 95%.
If score was 31 or less, the specificity of ACS was also 95%.
Eur J Heart Fail. 2017;19(8):1036.

35. The differential diagnosis of patients with Takotsubo Syndrome (TS), Acute Myocardial Infarction (AMI).
Current Cardiology Reviews, 2020, Vol. 16, No. 0 3

36. In STEMI patients with MINOCA
{ MI With Non-Obstructive Coronary Artery Presenting With STEMI }

37. The differential diagnosis of patients with Takotsubo Syndrome (TS), Acute Myocardial Infarction
(AMI) and Myocardial Infarction with Nonobstructive Coronary Arteries (MINOCA). Current
Cardiology Reviews, 2020, Vol. 16, No. 0 3

38. European Cardiology Review 2020;15:e20.
CMR imaging is a key investigation in identifying the underlying cause
Differential can include Takotsubo
cardiomyopathy ,plaque erosion ,
myocarditis)

39. Does Biological
Sex Matter?

40. Worldwide , 90% of patients with TS are post-menopausal women
Women > Men

41. Biological sex influences health and disease “from womb to tomb”.
The spectrum of acute coronary syndromes :
Compared to men, women present more often NSTEMI , endothelial
erosion is more common in younger female smokers, and Takotsubo
syndrome and spontaneous coronary dissection are typical female
presentations of ACSs

42. The spectrum of ACSs is indeed different between the sexes
Typical female presentations of ACSs

43. Complications

44. Different complications that can occur in Takotsubo syndrome.
Complications are divided into heart failure and functional complications as well as mechanical,
arrhythmic and thromboembolic. Swiss Med Wkly. 2017;147:w14490

45. Overview of in-hospital complications according to their prevalence.
AV, atrioventricular block; LV, left ventricle; LVOTO, left ventricular outflow tract obstruction.
Eur Hear J, 39 (2018), pp. 2047-2062

46. Outcome
Recovery
&
Recurrence

47. Variables Predicting Outcome
Eur Cardiol. 2019 Dec; 14(3): 191–196.

48. Clinical presentation and subsequent course
Early (first 5 days) outcome Late outcome
Hypotension±shock Prolonged impairment of quality of life a
Respiratory failure, usually secondary to
non-cardiogenic pulmonary oedema
Recurrence of TTS
Ventricular tachyarrhythmias Death, predominantly of cardiovascular
origin
Bradycardia/heart block
Left ventricular (LV) mural
thrombus±systemic embolisation
Death, predominantly from shock
a Reflecting impaired myocardial energetics, ongoing inflammation and variable fibrosis.
Heart,Lung and Circulation (2021) 30,36-44

49.  Clinical progress after the first 48 hours generally includes
substantial recovery, as measured by resolution of regional LV
hypokinesis on echo , and also of hypotension.
 However, most patients continue to feel lethargic for at least 3
months post onset of symptoms , and many complain of
exertional dyspnoea.
Recovering from takotsubo : Will it happen again?
 Recurrence of TS is a relatively rare problem, with a risk of
approximately 1–2% per annum .
 Most importantly, it has progressively emerged that the long-
term mortality risk after attacks of TS is similar to that after
acute MI , and that a substantial proportion of these deaths is
of cardiovascular origin.

50. TS can either be benign or a life-threating condition depending on the inciting stress factor.
Overall, TS patients had long-term outcomes comparable to age- and sex-matched ACS patients.
TS patients related to physical stress showed higher mortality rates than ACS patients during long-
term follow-up, whereas patients related to emotional stress had better outcomes compared with
ACS patients.
Based on the type of
triggering event

51. Treatment

55. Proposal of acute complications management during Takotsubo syndrome (TTS).
Legend: AV = atrioventricular, BP = blood pressure, CPAP = Continuous positive airway pressure, LVOTO = left ventricular outflow tract
obstruction, LVEF = left ventricular ejection fraction, MCS = mechanical circulatory support, NIV = non-invasive ventilation OAC = oral
anticoagulation, PMK = pacemaker. J.Clin.Med.2021,10, 648
Acute treatment in TS

56. Current literature on long-term management of Takotsubo syndrome patients.
First column shows all potential drugs in TS patients, second one potential benefits, third one current evidence in
literature. Legend: CS = cardiogenic shock, LV = left ventricle, LVOTO = left outflow tract obstruction, MACE= mayor cardiac events,
OAC = oral anticoagulation, TTS = takotsubo syndrome. J.Clin.Med.2021,10, 648
Chronic treatment in TS

57. Appendix Slides

58. Key References
R.Elias et al :Current Knowledge and Future Challenges in Takotsubo Syndrome:
Part 1—Pathophysiology and Diagnosis.J. Clin. Med. 2021, 10(3), 479
S.Francesco et al :Current Knowledge and Future Challenges in Takotsubo Syndrome:
Part 2—Treatment and Prognosis.J. Clin. Med. 2021, 10(3), 468
A.R. Lyon et al : 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.Eur J Heart Fail, 18 (2016), pp. 8-27
J.R. Ghadri et al: International expert consensus document on takotsubo syndrome
(part I): clinical characteristics, diagnostic criteria, and pathophysiology.- Eur Hear J, 39 (2018),
pp. 2032-2046
J.R. Ghadri et al : International expert consensus document on takotsubo syndrome
(part II): diagnostic workup, outcome and management.Eur Hear J, 39 (2018), pp. 2047-2062
K. A .Bybee et al : "Systematic review: transient left ventricular apical ballooning: a syndrome that
mimics ST-segment elevation myocardial infarction". Ann Intern Med 2004; 141: 858.
Medina de Chazal et al :Stress Cardiomyopathy Diagnosis and Treatment : JACC State-of-the-Art
Review JACC 2018 ; 72( 16):1955

60. Drugs recommended to treat takotsubo syndrome (TTS).
Drugs Main indication
Levosimendan
Ejection fraction <55% ( & absence of LVOTO )
With systolic BP >90 mmHg
Beta-blockers LVOTO . QTc <500 msec
ACE inhibitors/ARBs To reduce the rate of recurrence
Diuretics To reduce edema
Nitrates No if LVOTO
BioMed Research International / Volume 2019 |Article ID 6571045

61. Direct and indirect mechanisms leading to myocardial and microvascular injury in SARS-CoV-2 infection

62. Dynamic left ventricular outflow tract obstruction in apical ballooning syndrome
(Takotsubo cardiomyopathy)
Abstract
Patients with apical ballooning syndrome may develop dynamic left ventricular
outflow obstruction due to systolic anterior motion of the mitral valve leaflet and
secondary functional mitral regurgitation, causing decreased cardiac output and
hypotension.
If suspected, bedside echocardiography will quickly confirm this complication.
Positive inotropic/chronotropic agents should be avoided as they may exacerbate
outflow tract obstruction, resulting in further hemodynamic compromise.

63. RV involvement
Reverse McConnell sign
(biventricular
ballooning)
Am J of Cardiology 111,8,1232-1235,2013
In patients with TC, the motion of the basilar and middle segments of the RV free wall is
often hyperkinetic.
However, the motion of the apical segment of the RV free wall is usually hypokinetic,
in the same manner as LV apical motion .
Interestingly, this distinct imaging feature is exactly opposite the classic echo appearance in
patients with acute and massive pulmonary embolism, McConnell's sign, which is defined as
hyperkinesis of the RV apex and hypokinesis of the remaining segments of the RV free wall.

64. Graphic representation of focal TTS’ main characteristics.Heart Failure Reviews (2020)

65. Therapeutic algorithm proposal for oral anticoagulation (OAC) management during the
acute phase of Takotsubo syndrome. Santoro et al. Journal of the American Heart Association, 2017;6: e006990

66. Principal conditions to consider in the differential diagnosis of patients with MINOCA
and clues into differential diagnosis. July 2020 Future Cardiology 17(7)
Clinical presentation Clinical presentation ECG Echocardiography Coronary angiography Cardiac MRI
MINOCA
‘Epicardial pattern’: epicardial
spasm; plaque disruption;
nonangiographically
obstructive SCAD
‘Microvascular pattern’:
unstable microvascular
dysfunction,
nonangiographically
obstructive coronary
embolism/thrombosis
Chest pain, dyspnea,
arrhythmias.
Less often heart
failure/cardiogenic shock,
cardiac arrest.
Compared with those patients
with MI-CAD are more
commonly younger and
women.
ST-segment elevation or ST-
segment depression and/or T
waves inversion.
Regional wall motion
abnormalities according with
epicardial coronary artery
distribution (epicardial pattern)
or extended beyond a single
epicardial coronary artery
territory (microvascular
pattern)
Contrast echo (transthoracic or
transesophageal) to search the
source of embolization
Absence of angiographic
obstructive CAD:
– FFR: may be considered in
selected patients with
borderline stenosis.
– Intravascular imaging (IVUS
and OCT): to assess the
presence of coronary plaque
disruption/erosion or SCAD
– Provocative tests
(intracoronary acetylcholine):
to assess the presence of
coronary epicardial or
microvascular vasospasm.
Edema: At sites of wall motion
abnormalities
Cine: Regional wall motion
abnormalities according with
epicardial coronary artery
distribution (epicardial pattern)
or extended beyond a single
epicardial coronary artery
territory (microvascular
pattern)
LGE: At sites of wall motion
abnormalities.
Takotsubo syndrome Chest pain, dyspnea, syncope,
palpitations, cardiac arrest.
Usually in postmenopausal
female and often precepted by
an emotional or physical stress.
ST-segment elevation, T waves
inversion, QTc prolongation
Apical, midventricular, basal
(inverted) or focal
hypo/akinesia.
Absence of culprit obstructive
CAD. Ventriculography
identifies the anatomical
variant.
No signs of acute plaque
destabilization at intravascular
imaging.
Edema: transmural edema in
the areas of ventricular
dysfunction
Cine: regional wall motion
abnormalities without coronary
distribution
LGE: absent (cut-off>5 SD).
MI (with obstructive CAD) Chest pain, dyspnea,
arrhythmias, heart
failure/cardiogenic shock, SCD.
ST-segment elevation (STEMI),
ST-segment depression and/or
T waves inversion (NSTEMI).
Regional wall motion
abnormalities according with
epicardial coronary artery
distribution.
Coronary artery disease with
acute plaque rupture and
thrombus formation.
Edema: Subendocardial or
transmural at sites of wall
motion abnormalities.
Cine: Regional wall motion
abnormalities matching
epicardial coronary artery
distribution
LGE: Bright LGE, typically
subendocardial or transmural
matching epicardial coronary
artery distribution
Myocarditis Chest pain, dyspnea, heart
failure/shock, cardiac arrest.
Often preceded by an infection
ST and/or T wave changes. Global or regional systolic
dysfunction Pericardial
involvement may be also
present.
Absence of obstructive CAD Edema: Subepicardial, basal
and lateral
Cine: Global, or regional
contractile dysfunction.
LGE: Low intensity or bright;
typically focal, ‘patchy’,
subepicardial or midventricular
with a noncoronary
distribution