Transcript Takotsubo - S. Blake Wachter, MD, PhD Advanced Heart Failure

蛸壺

57 year old women presenting to the ED
with complaint of 2 hours of crushing
pressure-like chest pain, non radiating. She
says she feels short of breath and
diaphoretic but denies nausea and
vomiting. She does not have a family or
personal history of heart disease. She
denies a life long history of smoking. Her
past medical history is significant for obesity,
DM II, OA. She takes metformin and occ
NSAIDS.
CBC - normal
 Chem 14 – normal except glucose of 203
 Troponin I in ER 0.9
 CK-MB 6.7


Our patient’s pain is now controlled with
the nitro and morphine she got in the ER.
We have talked with the interventional
cardiologist and she will be going to the
cath lab now.

Meanwhile …
Coronary artery disease with acute
plaque rupture
 Coronary artery spasm
 Microvascular disease of the coronaries
 Drugs (Cocaine)
 Takotsubo cardiomyopathy


Our patient is back
Takotsubo cardiomyopathy
 Transient apical ballooning
 Apical ballooning cardiomyopathy
 Stress-induced cardiomyopathy
 Broken heart syndrome

History of Takotsubo cardiomyopathy
 Diagnostic criteria
 Clinical presentation
 Pathophysiology
 Management
 Prognosis


Takotsubo cardiomyopathy is thought to
account for 0.5-2% of all suspected
acute myocardial infarction
1970’s researchers and physicians first
described reversible toxic effects of
catecholamines on the heart
 1990, Sato et al first described a
reversible tako-tusbo like left ventricular
dysfunction (Kagakuhyouronsha;
1990:56-64)


Tako
› Octopus

Tsubo
› Medieval Japanese ceramic jar shaped with
a wide body and narrow mouth
› Originally used to store seeds

Tako-tsubo
› Japanese octopus trap
蛸壺
Pubmed Search of “Takotsubo
Cardiomyopathy”
350
300
250
200
150
100
50
0
2000 2001 2002 2003 2004 2005 2006 2007 2008
Case descriptions
 Review articles
 Retrospective studies
 Prospective studies

Transient wall motion abnormalities that extend
beyond a single vascular distribution
 ECG changes
 Modest elevation in cardiac enzymes
 Frequently but not always, a stressful trigger
 Exclusion criteria:

› Absence of obstructive coronary disease or angiographic
evidence of acute plaque rupture
› The absence of pheochromocytoma, subarachnoid
hemorrhage, and myocarditis
Year
Author
Country
#
Time Type
Focus
2001 Tsuchihashi Japan
88 9 yrs Retro
Descriptive
2002
30 18 yrs Retro
Descriptive
Kurisu
2005 Witstein
Japan
US
19 4 yrs
Pro
Describe the neurohumoral features
2005
Inoue
Japan
18 5 yrs Retro
Compare to LAD STEMI
2006
Sato
Japan
16 4 yrs Retro
Stress as a precursor
2007 Kurowski Germany 35 2 yrs
Pro
Compare to LAD STEMI
Predominantly women (80-100%)
 Post menopausal (Mean age: 61-76)
 Identifiable preceding stressor (14-100%)
 Chest pain (54-100%)
 ECG changes (56-100%)
 Elevated cardiac enzymes (56-100%)
 Normal coronaries (83-100%)








Long QTc (mean 501 – 542ms)
Reduced EF at presentation (mean LVEF 2949%)
Recovered EF at discharge (mean LVEF 6376%)
Pulmonary edema (0-44%)
Intraaortic balloon pump (0-18%)
Inducible multivessel spasm (0-43%)
Death(4 deaths)
› Severe sepsis, PE
Wittstein, I. S., D. R. Thiemann, et al. (2005). "Neurohumoral features of myocardial stunning due to sudden emotional stress." N Engl J Med 352(6): 539-48.
Niigata was shaken by a series of three
earthquakes on 23 October 2004 and 90
aftershocks during the following week
 25 cases of Takotsubo’s cardiomyopathy
in the 4 weeks following the earthquake
compared to 1 case in the 4 weeks prior
none in 2003 and one in 2002
 All recovered within several weeks
following the improvement of apical
dysfunction












Status asthmaticus
Child birth (C-Section)
Strenuous exercise (cardiac stress test)
Sick child
Mopping the floor
Argument with supervisor
Watching/Attending the World Cup Soccer
Sexual intercourse
Fixing a neighbor’s car
Severe illness
Public speaking (beware seniors!)
Interstitial infiltrates of mononuclear
lymphocytes, leukocytes, macrophages
 Myocardial fibrosis
 Contraction bands with or without overt
myocyte necrosis

Acute MI
Takotsubo
M., R. J. Wiechmann, et al. (1995). "Cardiac beta-adrenergic neuroeffector
systems in acute myocardial dysfunction related to brain injury. Evidence for
catecholamine-mediated myocardial damage." Circulation 92(8): 2183-9.
1.Kurisu, S., H. Sato, et al. (2002). "Tako-tsubo-like left ventricular dysfunction with ST-segment elevation: a novel cardiac syndrome mimicking acute myocardial
infarction." Am Heart J 143(3): 448-55.
Multivessel Epicardial Coronary Artery
Spasm
 Coronary microvascular impairment
 Catecholamine cardiotoxicity
 Neurogenic stunned myocardium

Regionally stunned myocardium results
from coronary artery spasm
 If no observed spontaneous spasm then
impaired blood flow is caused by a
vulnerable plaque rupture

Discrepancy between severe apical
ventricular dysfunction and slightly
increased cardiac enzymes
 Plaque rupture would not be expected to
extend beyond the perfusion territory
supplied by the artery
 Ischemic stunning does not produce the
histological changes
 Spasms of vessels are not consistently seen
in takotsubo cardiomyopathy

Wittstein, I. S., D. R. Thiemann, et al. (2005). "Neurohumoral features of myocardial stunning due to sudden emotional stress." N Engl J Med 352(6): 539-48.
In the setting of a normal coronary cath,
microvascular disturbances could
explain the expanded area of
distribution
 Impaired perfusion on thallium stress and
PET
 Correlation between microvascular
dysfunction and severity of myonecrosis
and ECG abnormalities

1.Tsuchihashi, K., K. Ueshima, et al. (2001). "Transient left ventricular apical ballooning without coronary artery stenosis: a novel heart syndrome mimicking acute
myocardial infarction. Angina Pectoris-Myocardial Infarction Investigations in Japan." J Am Coll Cardiol 38(1): 11-8.
DDT: Deceleration time of diastolic velocity
1.Kume, T., T. Akasaka, et al. (2005). "Assessment of coronary microcirculation in patients with takotsubo-like left ventricular dysfunction." Circ J 69(8): 934-9.

Which came first?
› Microvascular abnormalities resulting from
the mechanical wall stress
› Microvascular abnormalities causing the
mechanical wall stress
Patients with pheochromocytoma are
known to have reversible
cardiomyopathy
 Circulating serum catecholamines cause
a direct myocyte injury
 Takotsubo cardiomyopathy and
catecholamine cardiotoxicity have
common histological changes

Plasma Catecholamine Levels
2500
2000
1500
Epinephrine
Norephinephrine
1000
500
0
Da1 Day 4Day 8
Takotsubo
Day 1Day 4Day 8
Acute MI
Wittstein, I. S., D. R. Thiemann, et al. (2005). "Neurohumoral features of myocardial stunning due to sudden emotional stress." N Engl J Med 352(6): 539-48.
http://www.cvpharmacology.com/cardioinhibitory/beta-blockers.htm

Norepinephrine:
› Beta 1 adrenoceptors
 Myocardium
 G-s protein  positive inotropic responses

Epinephrine:
› Beta 2 adrenoceptors
 Smooth muscles
 G-s protein vasodilatation
 Myocardium
 G-s protein  positive inotropic responses
› Beta 1 adrenoceptors
 Myocardium
 G-s protein  positive inotropic responses

Beta 2 adrenoceptors found on apex of left
ventricle
› 4:1 (B1:B2)

Epinephrine surges
› Beta 2-Gs protein coupling switches to a Beta 2-Gi protein
coupling

Beta 2-Gi pathway
› Negative inotropic responses

Epinephrine levels decrease
› Beta 2-Gi protein coupling switches back or is degraded

Protective
› High levels PKA of the Beta 1-Gs and Beta 2-Gs pathway
causes apoptosis
1.Lyon, A. R., P. S. Rees, et al. (2008). "Stress (Takotsubo) cardiomyopathy--a novel pathophysiological hypothesis to explain catecholamine-induced acute
myocardial stunning." Nat Clin Pract Cardiovasc Med 5(1): 22-9.

Not all patients diagnosed with
takotsubo cardiomyopathy have
elevated catecholamines
Stroke and subarachnoid hemorrhages are
known to cause cardiac stunning
 Sympathetic activation on the heart results
in a local norepinephrine surge
 Sympathectomy has been shown to
prevent brain-mediated cardiac injury
 Evidence that apical myocardium has
enhanced responsiveness to sympathetic
stimulation which may cause the
characteristic apical ballooning

NET/Uptake-1
Basal segment of the left ventricle has
greater density of sympathetic nerves
 High levels of catecholamines can interfere
with the uptake of Norepinephrine via a
presynaptic Norepi transporter/ uptake-1
 Left ventricular apex has greater # of Beta 1
adrenoceptors compared to the base
 With high catecholamines

› Decreased number of beta receptors
› Decrease responsiveness of beta receptors

MEN
› Higher levels of basal sympathetic activity
› Higher catecholamine levels in response to
emotional stress
› More susceptible to catecholamine
vasoconstriction

Women
› More vulnerable to sympathetic mediated
myocardial stunning thought secondary to the
catecholamine surge
› Role of Estrogen?

The rat model
› Immobilization is known to cause stress induced
catecholamine surges resulting in catecholamine
cardiomyopathy

Role of estrogen?
› Reduced estrogen induced a vulnerability to stress
› Estrogen supplementation reduced incidence of
ischemia and arrhythmias
› Estrogen causes an increase in Beta 1 adrenoceptors
› Decrease in estrogen alters the B1:B2 ratio

Species differences?
Emotional or Physical Trigger
Neurohormonal surge of NE
Inhibit the uptake of NE via
NET/uptake – 1 channels
NE acts on B1 receptors
Adrenal catecholamine surge
Epi
Epi acts on B2 receptors
B2/Gs coupling switches to
B2/Gi coupling
B1/Gs pathway creates high
levels of PKA
Apoptosis of cells / decrease
responsiveness
Decrease number of B1
receptors
Decreased
Estrogen?
Decreased inotropic response on left ventricular apex


Supportive
Treat the heart failure
› Diuretics
› Balloon pump if necessary
› Consider LVAD





Avoid catecholamines for BP support
Monitor for arrhythmias associated with long QT
Treat alpha and beta blockers together ?
› Beta blockers can stimulate the switching of B2-Gs
to B2-Gi
High levels of epinephrine can be prothrombolitic
› Controversial to treat with anticoagulation
Estrogen?
Generally very good!
 Few fatalities but most were not
associated with cardiovascular events
 Normalized LV function within weeks
 Normalized ECG within months
 Low recurrence rate of about 2% (so far)

1.
2.
3.
4.
5.
6.
7.
8.
9.
10.
11.
12.
13.
14.
Akashi, Y. J., D. S. Goldstein, et al. (2008). "Takotsubo cardiomyopathy: a new form of acute, reversible heart
failure." Circulation 118(25): 2754-62.
Iga, K., H. Gen, et al. (1989). "Reversible left ventricular wall motion impairment caused by pheochromocytoma-a case report." Jpn Circ J 53(7): 813-8.
Inoue, M., M. Shimizu, et al. (2005). "Differentiation between patients with takotsubo cardiomyopathy and those
with anterior acute myocardial infarction." Circ J 69(1): 89-94.
Jayawardena, S., D. Sooriabalan, et al. (2008). "Takotsubo cardiomyopathy in a 68-year old Russian female."
Cases J 1(1): 64.
Kume, T., T. Akasaka, et al. (2005). "Assessment of coronary microcirculation in patients with takotsubo-like left
ventricular dysfunction." Circ J 69(8): 934-9.
Kurisu, S., H. Sato, et al. (2002). "Tako-tsubo-like left ventricular dysfunction with ST-segment elevation: a novel
cardiac syndrome mimicking acute myocardial infarction." Am Heart J 143(3): 448-55.
Kurowski, V., A. Kaiser, et al. (2007). "Apical and midventricular transient left ventricular dysfunction syndrome
(tako-tsubo cardiomyopathy): frequency, mechanisms, and prognosis." Chest 132(3): 809-16.
Lyon, A. R., P. S. Rees, et al. (2008). "Stress (Takotsubo) cardiomyopathy--a novel pathophysiological hypothesis
to explain catecholamine-induced acute myocardial stunning." Nat Clin Pract Cardiovasc Med 5(1): 22-9.
Sato, M., S. Fujita, et al. (2006). "Increased incidence of transient left ventricular apical ballooning (so-called
'Takotsubo' cardiomyopathy) after the mid-Niigata Prefecture earthquake." Circ J 70(8): 947-53.
Tsuchihashi, K., K. Ueshima, et al. (2001). "Transient left ventricular apical ballooning without coronary artery
stenosis: a novel heart syndrome mimicking acute myocardial infarction. Angina Pectoris-Myocardial Infarction
Investigations in Japan." J Am Coll Cardiol 38(1): 11-8.
M., R. J. Wiechmann, et al. (1995). "Cardiac beta-adrenergic neuroeffector systems in acute myocardial
dysfunction related to brain injury. Evidence for catecholamine-mediated myocardial damage." Circulation
92(8): 2183-9.
Wilbert-Lampen, U., D. Leistner, et al. (2008). "Cardiovascular events during World Cup soccer." N Engl J Med
358(5): 475-83.
Wittstein, I. S., D. R. Thiemann, et al. (2005). "Neurohumoral features of myocardial stunning due to sudden
emotional stress." N Engl J Med 352(6): 539-48.
Yoshida, T., T. Hibino, et al. (2007). "A pathophysiologic study of tako-tsubo cardiomyopathy with F-18
fluorodeoxyglucose positron emission tomography." Eur Heart J 28(21): 2598-604.