1) Takotsubo syndrome is a cardiac condition triggered by stressful events where the left ventricle temporarily takes on a distinctive "Takotsubo" shape. 2) It is thought to be caused by very high levels of stress hormones like adrenaline activating negative inotropic pathways in the heart through beta-2 adrenergic receptors, particularly in the left ventricular apex. 3) This leads to left ventricular dysfunction and heart failure symptoms, but the heart typically recovers its normal function within weeks as the stress response subsides. However, the full pathophysiology and long term effects are still being uncovered.

1. Cardiomyopathies: what are the mechanisms?
Takotsubo Syndrome
Dr. Alexander Lyon
Senior Lecturer and Consultant Cardiologist
Royal Brompton Hospital and Imperial College, London

3. 25 years since original description of
Takotsubo Syndrome by Hiraku Sato
Sato H, Tateishi H, Uchida T, Dote K, Ishihara M. Tako-tsubo-like left ventricular dysfunction due to multivessel
coronary spasm. In: Kodama K, Haze K, Hori M, editors. Clinical aspect of myocardial injury: from ischemia to heart
failure. Tokyo: Kagakuhyoronsha Publishing Co.; 1990. p. 56–64. (in Japanese)
Figure 2. The left ventriculography of Case 1 at admission (left) and a week later (right)
The left ventricle had a unique “Takotsubo shape” and it disappeared after a week.
Thanks to Birke Schneider

4. Takotsubo Syndrome: Pathophysiology
Overview
• Clinical Syndrome
• Pathophysiology hypotheses
• Not acute myocardial infarction
• Central role of catecholamines
– β2AR Hypothesis
– Metabolic effects
– Haemodynamics
– Nitrosative stress
– Inflammation
– Longterm abnormalities
• What we have to learn

5. Physiology of Stress

6. Primary Takotsubo Syndrome
Classical Clinical Presentation
• Stressful trigger
• Chest Pain, Dyspnoea
• ECG Repolarisation changes
– ST↑, QT↑, T↓
– Arrhythmias
• Cardiac Enzyme rise
– >95% cases troponin +ve
• Acute Heart Failure
– 20-40% cases
• Serum catecholamines
30x normal

7. Primary Takotsubo Syndrome
Classical Clinical Presentation
Enter PPCI protocol
• Normal Coronary Angiography
*no culprit coronary disease
*no coronary intervention
• Apical and usually mid left ventricular
wall motion abnormality
– >1 coronary territory
• Preserved basal LV contraction
• Left ventricular dysfunction recovers
over days – weeks
= Myocardial Stunning
• Post menopausal women ~90% cases

8. Why?
• Acute Multivessel Coronary Spasm
• Acute Coronary Microvascular Dysfunction
• Acute Endothelial Dysfunction
• Aborted Myocardial Infarction
– Spontaneous recanalisation
– ‘Wrap around LAD’
• Acute LVOTO
• Direct Catecholamine-Mediated Myocardial Stunning

9. Multivessel Vasospasm
• Spontaneous multivessel vasospasm reported
• Provocation-induced vasospasm was present
in 34 of 123 patients studied (27.6%)
Pilgrim et al IJC 2008 124: 283-292

10. Haghi et al Clinical Cardiology 2010 (May 20) 33 307 - 310
Aborted Myocardial Infarction?

11. Takotsubo Syndrome
1. Why negative inotropic response?
2. Why full recovery?
3. Why regional effect - apical and mid LV
suppression with basal sparing?

12. Central Role of Catecholamines
• Supraphysiological serum levels
• Iatrogenic cases
– Dobutamine
– Adrenaline
• Phaeochromocytoma
• Subarachnoid haemorrhage/head injury
• I131-MIBG Myocardial Scintigraphy
• Myocardial Histopathology
– Endomyocardial Biopsies from Takotsubo pts
– Subarachnoid Haemorrhage +
Phaeochromocytoma

13. Takotsubo Syndrome and the β2AR Hypothesis
2008 5 (Jan) pp1-8

14. β Adrenergic Receptor Signalling Pathways in
Ventricular Cardiomyocytes
1
1 AR 2
AR
AC
cAMP
ATP
PKA
Arrhythmias
Cell death
(necrosis, apoptosis)
Increased rate
Increased force
Accelerated relaxation
Gsα Gsα
+
++
 
-
Anti-apoptotic
Pathways e.g.
p38MAPK,
PI3K + Akt
Giα
-

Decreased rate
Decreased force
Prolonged relaxation
Pi
_
_ _
+
PTX
GRK5

15. Transgenic Mouse Model
Overexpresses Human β2 AR
Negative inotropic effect of high dose
adrenaline via human β2 adrenoceptor
coupled to Gi protein
Gi protein inhibition by PTX
Heubach et al Molecular Pharmacology 2004 65: 1313-1322

16. Adrenaline-Induced Negative Inotropism
• High adrenaline concentrations
• Mediated via the β2AR switch to the Gi pathway
(stimulus trafficking = biased agonism)
• Fully reversible
– washout during in vitro studies
– β2AR dephosphorylation
– β2AR internalisation and degradation
• Several β2AR blockers mediate negative inotropism
via this mechanism e.g. propranolol

17. Why regional effect?
Typical anatomical variant
Apical and mid LV suppression
with basal sparing?

18. Apical-Basal Physiological Gradients
1. Sympathetic Innervation

19. Apical-Basal Gradients
2. β Adrenoceptor Density
Dog Cat

20. β2
β2
β2
β2
β2
β2
β1 β1
β1 β1
β1
β1
β1
Adrenaline – β2 – Gi signalling
NEGATIVELY INOTROPIC
ANTIAPOPTOTIC
Noradrenaline – β1 – Gs signalling
POSITIVELY INOTROPIC
PROAPOPTOTIC
= sympathetic nerve
Takotsubo Syndrome and the β2AR Hypothesis
Lyon AR et al Nat Clin Pract Cardiovasc Med 2008 5 (1): 22-29.

21. B 10 20 30 40 50 60
-40
-20
0
20
40
Apex
Adrenaline
Noradrenaline
A
%ΔFS
B 10 20 30 40 50 60
-40
-20
0
20
40
B
Mid LV
%ΔFS
Time post-catecholamine injection
(mins)
C
Base
B 10 20 30 40 50 60
-40
-20
0
20
40
%ΔFS
Time post-catecholamine injection
(mins)
Time post-catecholamine injection
(mins)
Rat Takotsubo Syndrome Model
2 Way ANOVA: A vs NA
Apex p<0.001 MLV p<0.001 Base p=ns
Paur et al Circulation 2012 126: 697-706

22. Human Biopsy data
?Cardioprotective
Nef H et al EJHF 2009 11:758-64.Nef H et al EHJ 2007 28:2456-64.

23. Nitrosative stress in Takotsubo Syndrome

24. Abnormal Myocardial Metabolism
Fat droplet accumulation
Mouse Model
Human TTS Biopsies
Acute and Recovery
Shao et al IJC 2013 168:1943–1950Shao et al EJHF 2013 15(1):9-22.

25. Haemodynamics
Redfors et al 2014 IJC 174:330-336

26. Sal E NE E+PTX Sal E NE E+PTX
A B
C D
0
50
100
150
200
250
*
*
*
PeakSBP(mmHg)
0
25
50
75
100
125
* **
PeakDBP(mmHg)
PRESSURE(mmHg)
0
50
100
150
200
Epinephrine
0 1 2 3 4 5 6
Time from Epinephrine Injection (min)
7
PRESSURE(mmHg)
0
50
100
150
200
0 10 20 30 40
Time from Epinephrine Injection (s)
Baseline
HR:
361
Immediate
Vagal HR:
227
Delayed
Vagal HR:
320
Hypertensive Phase
Onset of LVF
Acute Haemodynamic Responses

27. Cardioprotective effects of Estrogen
Protection against acute Takotsubo syndrome
Total=9
VF
Pump Failure
0 20 40 60
0.6
0.8
1.0
1.2
1.4
Time (mins)
FSFoldChange
Female Apex
Female Base
No TTS in females
Female Ovariectomised
0
20
40
60
80
Mortality(%)
Ovariectomy increased mortality
OVX mortality was both pump death and VF
%Mortality
M
ale
Fem
ale
O
VX
O
VX-E
O
VX-V
0
20
40
60
80
**
*** **
Estrogen reduced mortality
Matthew Tranter

29. Whole-slice T2-weighted signal intensity (T2-w SI) data from normal
controls (A) and patients with acute Takotsubo syndrome (B).
Christopher Neil et al. Heart 2012;98:1278-1284
Does the heart fully recover following acute
Takotsubo syndrome?
Abnormal myocardial oedema persists at 3 months
Acute 3 months Control

30. Altered Cortical-Hypothalamic-Pituitary-Adrenal
axis response to stress?
• 4 TTS vs 8 healthy matched controls
• fMRI analysis
– a significant variation of the blood
oxygen level dependent signal triggered
by the Valsalva manoeuvre
– in specific areas of the brain involved in
the cortical control of the autonomic
system
– significant differences in the pattern of
activation of the insular cortex,
amygdala and the right hippocampus

31. Pathophysiology
What we have to learn?
• How to integrate molecular, cellular and systemic
physiology
– Cardiac
– Vascular
– Peripheral nerves, adrenal, cognitive responses and
CNS
• Temporal phases
• Spontaneous cases
• Anatomical variants
• Influence of genetics, sex hormones

32. Pathophysiology
What we have to learn?
• Diagnosis
– Grey cases
– Missed cases
• Treatment
– Severe cases with cardiogenic shock
– Prevention in recurrent cases
– Refractory symptoms

33. Conclusions
• Complicated systemic biology
– Not myocardial infarction/plaque rupture
• Cardiac perspective
– High afterload and intracavity pressure acutely
– Negative inotropic pathway activation
• β2AR may play a role in some cases
• Cardioprotective
– Metabolic changes
– Vasospasm → ischaemia in subset
– Inflammation
• Systemic vascular responses
– Initially high followed by ‘dysregulation’
• Central HPA axis – level of gain
• Lots still to learn….

34. Thank you