takotsubo cardiomyopathy machanism
TRANSCRIPT
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