1. Takotsubo Cardiomyopathy
Blake Wachter, Spring 2009 蛸壺

2. Case Presentation
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.

4. Labs CBC - normal Chem 14 – normal except glucose of 203
Troponin I in ER 0.9
CK-MB 6.7

5. 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 …

6. Differential Diagnosis
Coronary artery disease with acute plaque rupture
Coronary artery spasm
Microvascular disease of the coronaries
Drugs (Cocaine)
Takotsubo cardiomyopathy
Our patient is back

9. Parasternal long axis view

10. Call it what you like… Takotsubo cardiomyopathy
Transient apical ballooning
Apical ballooning cardiomyopathy
Stress-induced cardiomyopathy
Broken heart syndrome

11. Outline History of Takotsubo cardiomyopathy Diagnostic criteria
Clinical presentation
Pathophysiology
Management
Prognosis

12. Significance
Takotsubo cardiomyopathy is thought to account for 0.5-2% of all suspected acute myocardial infarction

13. Takotsubo Cardiomyopathy History
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)

15. Left ventriculogram of the patient during systole showing mid, distal and apical left ventricular ballooning, with vigorous contraction of the basal segment
Rao projection of the LVgram

16. Tako Tsubo Tako Tsubo Tako-tsubo Octopus
Medieval Japanese ceramic jar shaped with a wide body and narrow mouth
Originally used to store seeds
Tako-tsubo
Japanese octopus trap

17. 蛸壺

19. Why haven’t I heard of this?
Many of you may be unfamiliar with this condition and has only recently been described.

20. A search of the literature shows that there is increasing interest in this condition. A search on takotsubo cardiomyopathy returned 325 citations published in 2008.
This growing interest begs to question: Is the prevelence increasing or was it misdianosing in the past.

21. Case descriptions
Review articles
Retrospective studies
Prospective studies

22. Diagnostic Criteria
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

23. Describe the neurohumoral features
Source publications
Year
Author
Country #
Time
Type
Focus
2001
Tsuchihashi
Japan 88
9 yrs
Retro
Descriptive
2002
Kurisu 30
18 yrs
2005
Witstein US 19
4 yrs
Pro
Describe the neurohumoral features
Inoue 18
5 yrs
Compare to LAD STEMI
2006
Sato 16
Stress as a precursor
2007
Kurowski
Germany 35
2 yrs
These are 6 key source publications which I reviewed. These publications are primarily grouped case description which focused on defining the takotsubo syndrome and Pathophysiology. In the next couple of slides I will review the clinical features compiled from these studies.

24. Clinical Features Predominantly women (80-100%)
Post menopausal (Mean age: )
Identifiable preceding stressor (14-100%)
Chest pain (54-100%)
ECG changes (56-100%)
Elevated cardiac enzymes (56-100%)
Normal coronaries (83-100%)

25. Clinical features Long QTc (mean 501 – 542ms)
Reduced EF at presentation (mean LVEF 29-49%)
Recovered EF at discharge (mean LVEF 63-76%)
Pulmonary edema (0-44%)
Intraaortic balloon pump (0-18%)
Inducible multivessel spasm (0-43%)
Death(4 deaths)
Severe sepsis, PE

26. Figure 2. Serial Echocardiographic Assessment of the Ejection Fraction in 19 Patients with Stress Cardiomyopathy.
Echocardiography was performed on admission; on hospital day 3, 4, 5, 6, or 7 (median, day 4); and at outpatient follow-up (a median of 21 days after the onset of symptoms). Gray lines illustrate values for individual patients. The black bar represents the median ejection fraction at each time; error bars show the interquartile range. P<0.001 for the comparison between admission and inpatient values, and P<0.001 for the comparisons between admission and outpatient values and between inpatient and outpatient values
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):

27. Stress?

28. Takotsubo cardiomyopathy: A Stress-induced cardiomyopathy
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

29. Other stressors 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!)

31. Pathophysiology

32. Cardiac biopsy
Interstitial infiltrates of mononuclear lymphocytes, leukocytes, macrophages
Myocardial fibrosis
Contraction bands with or without overt myocyte necrosis
The inflammation and contraction bands are what distingish takostubo’s from necrosis from an occulded coronary artery

33. Acute MI
Takotsubo
Figure 4. A toluidine blue–stained 1-µm-thick plastic-embedded section of myocardium from one of the study patients. Marked contraction band formation is noted. Magnification x400.
Can also be seen in pheo and subarachnoid hemorrhage
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):

34. Mild mononuclear cell infiltration
Fig. 6. Endomyocardial biopsy specimen from the left ventricle of case 8. Mild mononuclear cell infiltration are present. A, Original magnification ×100. B, Original magnification ×200.
Acute MI usually show polymorphonuclear cell infiltrates
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):

35. Theories to explain the unique wall motion abnormalities of takotsubo cardiomyopathy
Multivessel Epicardial Coronary Artery Spasm
Coronary microvascular impairment
Catecholamine cardiotoxicity
Neurogenic stunned myocardium

36. Theory 1: Multivessel Epicardial Coronary Artery Spasm
Regionally stunned myocardium results from coronary artery spasm
If no observed spontaneous spasm then impaired blood flow is caused by a vulnerable plaque rupture

37. Theory 1: Multivessel Epicardial Coronary Artery Spasm
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

38. Cardiac MRI of myocardial viability
This is a cardiac MRI assessment of myocardial viability. On the left the dark line indicates that the myocardium although ballooned out is still viable. On the right, the white like indicated by the arrow is of ischemic injury 2/2 to an acute infarct. As you can see spasm or plaque rupture of a coronary artery would have a different distribution that what is seen with takotsubos.
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):

39. Theory 2: Coronary microvascular impairment
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

40. Stunned myocardium
This is spectragraph of a patient with takotsubos cardiomyopathy. There is marked perfusion mismatches mainly at the left ventricular apex. However, in the subacute period these perfusion mismatchs decrese correlating with the functional recovery. In the PET, you can see improvement of the coronary flow reserve at the apex at five month follow-up.
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.

41. Coronary flow velocity spectra
Fig 2. Time-course of left ventriculograms (Top) and coronary flow velocity spectra (Bottom) in a patient with takotsubolike
left ventricular (LV) dysfunction. The left ventriculogram shows that the LV wall motion abnormality dramatically
improved within 3 weeks. Deceleration time of diastolic velocity of the left anterior descending coronary artery, left
circumflex artery, and right coronary artery was 312, 198 and 412 ms in the acute phase, and 820, 661 and 603 ms 3 weeks
later, respectively. Coronary flow velocity reserves of the left anterior descending coronary artery, left circumflex artery,
and right coronary artery were 2.0, 2.3 and 1.6 in the acute phase, and 2.8, 4.3 and 1.9 ms 3 weeks later, respectively.
Deceleration time of diastolic velocity and coronary flow velocity reserve of all coronary arteries increased 3 weeks later.
This is a coronary flow velocity spectra of a patient with takotsbuo at admission and 3 weeks later. The decelartion time of the diastolic velocity and the Coronary flow velocity reserves of the shown coronary arteries increase with recovery of the wall motion abnormality 3 weeks later. In other words these slopes are less dramatic on follow up. This is supportive evidence of microvascular involvement.
DDT: Deceleration time of diastolic velocity
Kume, T., T. Akasaka, et al. (2005). "Assessment of coronary microcirculation in patients with takotsubo-like left ventricular dysfunction." Circ J 69(8):

42. Theory 2: Coronary microvascular impairment
Which came first?
Microvascular abnormalities resulting from the mechanical wall stress
Microvascular abnormalities causing the mechanical wall stress

43. Theory 3: Catecholamine cardiotoxicity
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

44. Killip class III
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):

45. Beta receptors

46. Review Norepinephrine: Beta 1 adrenoceptors Epinephrine:
Myocardium
G-s protein  positive inotropic responses
Epinephrine:
Beta 2 adrenoceptors
Smooth muscles
G-s protein vasodilatation

47. Theory 3: Catecholamine cardiotoxicity
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

48. 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.

49. Theory 3: Catecholamine cardiotoxicity
Not all patients diagnosed with takotsubo cardiomyopathy have elevated catecholamines

50. Theory 4: Neurogenic stunned myocardium
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

51. Alpha 2 receptor
NET/Uptake-1

52. Theory 4: Neurogenic stunned myocardium
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

54. Why women? MEN Women 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?

55. Current research The rat model Role of estrogen? Species differences?
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?

56. Emotional or Physical Trigger
Neurohormonal surge of NE
Adrenal catecholamine surge Epi
Inhibit the uptake of NE via NET/uptake – 1 channels
Epi acts on B2 receptors
NE acts on B1 receptors
B2/Gs coupling switches to B2/Gi coupling
B1/Gs pathway creates high levels of PKA
Apoptosis of cells / decrease responsiveness
Decreased Estrogen?
Decrease number of B1 receptors
Decreased inotropic response on left ventricular apex

57. Management 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?

58. Prognosis 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)

59. References
Akashi, Y. J., D. S. Goldstein, et al. (2008). "Takotsubo cardiomyopathy: a new form of acute, reversible heart failure." Circulation 118(25):
Iga, K., H. Gen, et al. (1989). "Reversible left ventricular wall motion impairment caused by pheochromocytoma--a case report." Jpn Circ J 53(7):
Inoue, M., M. Shimizu, et al. (2005). "Differentiation between patients with takotsubo cardiomyopathy and those with anterior acute myocardial infarction." Circ J 69(1):
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):
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):
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):
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):
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):
Wilbert-Lampen, U., D. Leistner, et al. (2008). "Cardiovascular events during World Cup soccer." N Engl J Med 358(5):
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):
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):