Takotsubo Cardiomyopathy Blake Wachter Spring 2009 Case Presentation

Takotsubo Cardiomyopathy Blake Wachter, Spring 2009 蛸壺

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.

Labs � 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 …

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

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

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

Significance � Takotsubo cardiomyopathy is thought to account for 0. 5 -2% of all suspected acute myocardial infarction

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)

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

Tako Tsubo � 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

Why haven’t I heard of this?

Pubmed Search of “Takotsubo Cardiomyopathy” 350 300 250 200 150 100 50 0 2001 2002 2003 2004 2005 2006 2007 2008

� Case descriptions � Review articles � Retrospective studies � Prospective studies

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

Source publications 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

Clinical Features � 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%)

Clinical features Long QTc (mean 501 – 542 ms) � 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.

Stress?

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

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!)

Pathophysiology

Cardiac biopsy � 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 catecholaminemediated myocardial damage. " Circulation 92(8): 2183 -9.

Mild mononuclear cell infiltration 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.

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

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

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 �

Cardiac MRI of myocardial viability 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.

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

Stunned myocardium 1. Tsuchihashi, 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.

Coronary flow velocity spectra DDT: Deceleration time of diastolic velocity 1. Kume, T. Akasaka, et al. (2005). "Assessment of coronary microcirculation in patients with takotsubo-like left ventricular dysfunction. " Circ J 69(8): 934 -9.

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

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

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.

Beta receptors http: //www. cvpharmacology. com/cardioinhibitory/beta-blockers. htm

Review � 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

Theory 3: Catecholamine cardiotoxicity � Beta 2 adrenoceptors found on apex of left ventricle › 4: 1 (B 1: B 2) � 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.

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

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 �

Alpha 2 receptor NET/Uptake-1

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

Why women? � 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?

Current research � 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 B 1: B 2 ratio � Species differences?

Emotional or Physical Trigger Neurohormonal surge of NE Inhibit the uptake of NE via NET/uptake – 1 channels NE acts on B 1 receptors Adrenal catecholamine surge Epi acts on B 2 receptors B 2/Gs coupling switches to B 2/Gi coupling B 1/Gs pathway creates high levels of PKA Apoptosis of cells / decrease responsiveness Decreased Estrogen? Decrease number of B 1 receptors Decreased inotropic response on left ventricular apex

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 B 2 -Gs to B 2 -Gi High levels of epinephrine can be prothrombolitic › Controversial to treat with anticoagulation Estrogen?

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)

References 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. 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. 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. 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. 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.