Cardiomyopathies: what are the mechanisms? Takotsubo Syndrome

Dr. Alexander LyonSenior Lecturer and Consultant Cardiologist

Royal Brompton Hospital and Imperial College, London

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

Takotsubo Syndrome: PathophysiologyOverview

• 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

Physiology of Stress

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

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

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

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

Haghi et al Clinical Cardiology 2010 (May 20) 33 307 - 310

Aborted Myocardial Infarction?

Takotsubo Syndrome

1. Why negative inotropic response?2. Why full recovery? 3. Why regional effect - apical and mid LV 

suppression with basal sparing?

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

Takotsubo Syndrome and the β2AR Hypothesis

2008 5 (Jan) pp1-8

β Adrenergic Receptor Signalling Pathways in Ventricular Cardiomyocytes

11AR

2AR

AC

cAMP

ATP

PKA

Arrhythmias Cell death(necrosis, apoptosis)

Increased rateIncreased forceAccelerated relaxation

Gsα Gsα+ ++

-

Anti-apoptoticPathways e.g.p38MAPK,PI3K + Akt

Giα

-

Decreased rateDecreased forceProlonged relaxation

Pi

_

_ _

+

PTX

GRK5

Transgenic Mouse ModelOverexpresses 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

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

Why regional effect?

Typical anatomical variant

Apical and mid LV suppression with basal sparing?

Apical-Basal Physiological Gradients1. Sympathetic Innervation

Apical-Basal Gradients2. β Adrenoceptor Density

Dog Cat

β2

β2

β2

β2

β2

β2

β1 β1

β1 β1

β1

β1β1

Adrenaline – β2 – Gi signallingNEGATIVELY INOTROPIC

ANTIAPOPTOTIC

Noradrenaline – β1 – Gs signallingPOSITIVELY INOTROPIC

PROAPOPTOTIC

= sympathetic nerve

Takotsubo Syndrome and the β2AR Hypothesis

Lyon AR et al Nat Clin Pract Cardiovasc Med 2008 5 (1): 22-29.

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

40B

Mid LV

%ΔFS

Time post-catecholamine injection (mins)

CBase

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 NAApex p<0.001 MLV p<0.001 Base p=ns

Paur et al Circulation 2012 126: 697-706

Human Biopsy data?Cardioprotective

Nef H et al EJHF 2009 11:758-64.Nef H et al EHJ 2007 28:2456-64.

Nitrosative stress in Takotsubo Syndrome

Abnormal Myocardial MetabolismFat droplet accumulationMouse Model 

Human TTS BiopsiesAcute and Recovery

Shao et al IJC 2013 168:1943–1950Shao et al EJHF 2013 15(1):9-22.

Haemodynamics

Redfors et al 2014 IJC 174:330-336

Sal E NE E+PTX Sal E NE E+PTX

A B

C D

0

50

100

150

200

250 ***

Peak

SB

P (m

mH

g)

0

25

50

75

100

125* **

Peak

DB

P (m

mH

g)

PR

ES

SU

RE

(mm

Hg)

0

50

100

150

200E

pine

phrin

e

0 1 2 3 4 5 6Time from Epinephrine Injection (min)

7

PR

ES

SU

RE

(mm

Hg)

0

50

100

150

200

0 10 20 30 40Time from Epinephrine Injection (s)

Baseline HR:361

Immediate Vagal HR:

227

Delayed Vagal HR:

320Hypertensive Phase

Onset of LVF

Acute Haemodynamic Responses

Cardioprotective effects of Estrogen Protection against acute Takotsubo syndrome

Total=9

VFPump Failure

0 20 40 60

0.6

0.8

1.0

1.2

1.4

Time (mins)

FS F

old

Cha

nge

Female ApexFemale Base

No TTS in females

Female Ovariectomised0

20

40

60

80

Mo r

tal it

y (%

)

Ovariectomy increased mortality

OVX mortality was both pump death and VF

% M

orta

lity

Male

Female OVX

OVX-E

OVX-V0

20

40

60

80

**

*** **Estrogen reduced mortality

Matthew Tranter

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

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

PathophysiologyWhat 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 

PathophysiologyWhat we have to learn?

• Diagnosis– Grey cases– Missed cases

• Treatment– Severe cases with cardiogenic shock– Prevention in recurrent cases– Refractory symptoms

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….

Thank you