1. Stress Cardiomyopathy
K V Patil

2. History Takotsubo cardiomyopathy –
(Apical Ballooning Syndrome, Gebrochenes-Herz-Syndrome, Broken heart syndrome, Stress cardiomyopathy)
‘Takotsubo’ = ‘octopus pot’
Described in Japan by Hikaru Sato et al. in 1990

3. First reported case 64-year-old female
Acute chest pain consistent with acute myocardial infarction
Typical electrocardiographic (ECG) changes
Normal coronary arteries
Unusual appearance of the left ventricle (LV)
a narrow neck and apical ballooning during systole.
Abnormalities on left ventriculography disappeared after 2 weeks

5. Dote K, Sato H, Tateishi H & Uchida T & Ishihara M
Dote K, Sato H, Tateishi H & Uchida T & Ishihara M. Myocardial stunning due to simultaneous multivessel coronary spasms: A review of 5 cases. Journal of cardiology
415 consecutive AMI patients examined invasively
Prevalence 1.2%
ECG: ST elevations - 4 patients, R waves decreased transiently – 1 patient, Q waves - 1 patient
Typical left ventriculogram (LVG): akinesis in the apical, diaphragmatic and/or anterolateral segments, but hyperkinesis in the basal segments ---- resolved in 7 days
CAG: diffuse multi-vessel spasms in 2 patients,

6. Described before 1990 and outside Japan - Broken heart syndrome

7. After the first year of bereavement mortality rates fell off sharply
Survey of the death rate among 903 relatives of patients dying in a semirural area of Wales
4.8% of bereaved close relatives died within a year of bereavement compared with 0.68% of a non-bereaved control group
Among widows and widowers, mortality rate being 10 times greater than matched controls
After the first year of bereavement mortality rates fell off sharply
Parkes et al. followed 4486 widowers (1969) – similar results
Sir Albert Morton

8. autopsy in 11 out of 15 such victims of homicidal assaults showed cardiac myofibrillar degenerative changes ----consistent with stress cardiomyopathy

9. Pavin et al. 1997 - two cases of ‘reversible LV dysfunction precipitated by acute emotional stress.’

10. 19 patients who presented with left ventricular dysfunction after sudden emotional stress
underwent coronary angiography and serial echocardiography
five underwent endomyocardial biopsy
Plasma catecholamine levels in 13 patients with stress-related myocardial dysfunction compared with those in 7 patients with Killip class III myocardial infarction

11. Diffuse T-wave inversion and a prolonged QT interval in most patients
Mildly elevated serum troponin I levels in 17. Undetectable in 2.
Median ejection fraction, 0.20; rapidly resolved in all patients.
Endomyocardial biopsy - mononuclear infiltrates and contraction- band necrosis
Plasma catecholamine levels at presentation - markedly higher with stress induced cardiomyopathy than with Killip class III myocardial infarction

12. DEFINITION
acute and transient (<21 days) left ventricular (LV) systolic (and diastolic) dysfunction - often related to an emotional or physical stressful event, most often identified in the preceding days (1 to 5 days)
LV regional wall motion abnormalities extending beyond a single epicardial coronary artery distribution
apical hypokinesia/ akinesia/dis-kinesia (apical ballooning) with basal hyperkinesis
Other forms- localized to the base or the midventricular regions

13. clinical context, electrocardiographic (ECG) abnormalities, mild elevation of serum cardiac troponin, significant elevation in serum natriuretic peptide levels (BNP or NT-proBNP), and noninvasive cardiovascular imaging
Coronary angiography usually performed to exclude an acute obstruction in an epicardial coronary artery
bystander CAD- regional wall motion abnormalities that extend beyond a single epicardial vascular distribution, usually in a circumferential distribution, coexist with CAD

14. Acute reversible heart failure syndrome
A form of neurocardiogenic myocardial stunning
initially believed to represent a benign condition due to its self-limiting clinical course.
while the link between the brain and the heart is established, the exact pathophysiological
mechanisms remain unclear
Due to an increased awareness and recognition, the incidence of stress cardiomyopathy has been rising (15-30 cases per 100,000 per year), although the
true incidence is unknown as the condition is likely underdiagnosed

15. Epidemiology 15-30 cases per 100,000 per year
1 - 3% of all and 5–6% of female patients with suspected STEMI
0.02% of hospitalizations in the United States
Recurrence rate - 1.8% per-patient year
true incidence is likely higher, if one
considers that milder forms may not receive medical
attention

16. Women older than 55 years - a five-fold
90% patients - women - mean age of 67–70 years; 80% older than 50 years
Women older than 55 years - a five-fold
greater risk of developing TTS than women younger than 55 years and a 10-fold greater risk than men
emotional stress or the absence of identifiable triggers more common in women
Postmenopausal women have an increased sympathetic drive and endothelial dysfunction, predisposing to microvascular dysfunction.
More markers of oxidative stress, greater anxiety, depression, and sleep disturbances, increase in NPY with menopause
With growing awareness of TTS, male patients are diagnosed more often

17. Templin et al. NEJM 2015.

18. Also described in children
Youngest reported TTS patient - a premature neonate born in the 28th gestational week
Rozema et al., Takotsubo cardiomyopathy: a case report and literature review. Cardiology in the Young (2016), 26, 406–409
4. Deshmukh A, Kumar G, Pant S, Rihal C, Murugiah K, Mehta JL. Prevalence
of Takotsubo cardiomyopathy in the United States. Am Heart J 2012;164:
66–71 e1

19. Racial data lacking and inconsistent
Uncommon in African–Americans and Hispanics
African-Americans - more in-hospital complications (respiratory failure - mechanical ventilation, stroke)
African- Americans - QT prolongation, T-wave inversion more common
Japanese – Relatively higher incidence in men

20. Symptoms
Acute or subacute chest pain (>75%), dyspnea (approximately 50%), dizziness (>25%), syncope (5% to 10%) – indistinguishable from AMI
History of emotional/physical stress
Emotional stress factors - chest pain and palpitations common
Other triggers - manifestation of the underlying acute illness e.g., stroke, seizures
Symptoms arising from complications - heart failure, pulmonary oedema, stroke, cardiogenic shock or cardiac arrest

21. Signs
Respiratory distress, tachycardia, hypotension, S3 gallop, jugular vein distention, rales at the bases
Narrow pulse pressure
Systolic ejection murmur (due to LVOTO and MR)
Rarely, lower extremity edema

22. Diagnostic criteria
Coronary angiography with left ventriculography - gold standard to exclude or confirm TTS

23. Transient LV apical ballooning
ST-T segment change in several leads in electrocardiogram
No history of old myocardial infarction, valvular heart disease, subarachnoid hemorrhage, or pheochromocytoma
Investigated 17 patients - 14 women
Technetium-99m tetrofosmin - decreased uptake at the apex in 11 patients (85%) that later returned to uniform
No significant coronary stenosis
mechanism of uptake of TF by myocytes was reported as via a metabolism-dependent process, and subcellular localization was in the mitochondria (19). Thus, it was suggested that the scintigraphic abnormality was caused by the abnormalities in the mitochondria. Two patients were without scintigraphic abnormality.

24. Prolonged QTc interval observed in all patients
ST-segment elevations in several leads during the acute phase in 14 patients (82%) - became negative T waves at a median of 4 days
Prolonged QTc interval observed in all patients
ECG returned to normal between 97 and 191 days after the onset.
other three patients (18%) revealed inverted T waves in several leads during the acute phase.

25. Mayo criteria 2004

26. Based on 7 case series

27. Concomitant CAD is reported with a prevalence ranging from 10–29%
TTS may co-exist with ACS46 and it has been reported that ACS itself may trigger TTS

28. Modified Mayo Criteria 2008

29. “In the current version, we no longer exclude patients who develop typical ballooning in the setting of intracranial bleeding, including those with subarachnoid hemorrhage. Neurogenic stunning in this situation has the same features as ABS”
Ventriculography findings and anatomical subtypes
Apical sparing
Invetred
Right ventricular – approx. 30% patients - sicker

30. Other criteria/guidelines
Japanese Guidelines, 2007
Gothenburg criteria – Sweden, 2012
Johns Hopkins criteria, 2012
Tako-tsubo Italian Network proposal, 2014
Madias, 2014
Heart Failure Association of the European Society of Cardiology diagnostic criteria for Takotsubo Syndrome, 2016

31. Japanese guidelines 2007

32. Gothenburg criteria – Sweden 2012

33. Johns Hopkins criteria 2012

34. Tako-tsubo Italian Network 2014

35. Madias 2014

36. Heart Failure Association of the European Society of Cardiology diagnostic criteria for Takotsubo Syndrome 2016
Pheochromocytoma included as secondary cause

37. May 2018

38. Rationale fot InterTAK
Concomitant CAD is reported with a prevalence ranging from 10– 29%
TTS may co-exist with ACS - ACS itself may trigger TTS
Rare cases - regional wall motion abnormality may correspond to distribution of a single coronary artery --- Role of CMR
As in HF association of ESC criteria – Pheochromocytoma included
‘catecholamine storm’ with LV dysfunction, ECG abnormalities, and increased biomarkers as well as hypercontraction of sarcomeres and contraction band necrosis indistinguishable from TTS
differentiation of TTS, ACS, or myocarditis requires cardiac magnetic resonance imaging demonstrating myocardial oedema rather than late gadolinium enhancement in case of TTS

39. STEMI versus STE-TTC (106 vs 111)
2016
Twelve-lead admission ECGs of consecutive 200 TTC and 200 MI patients were compared
7 cardiovascular centers of 4 countries (Austria, Germany, Poland, and Switzerland)
Dichotomised groups
STEMI versus STE-TTC (106 vs 111)
Non-ST elevation MI versus non ST elevation-TTC
4 countries (Austria, Germany,Poland, and Switzerland) (Data S1) participating in the International Takotsubo Registry

43. STEMI vs STE-TTC

46. Pathophysiology

47. Sympathetic stimulation
Associated with conditions of catecholamine excess (e.g. pheochromocytoma, central nervous systemdisorders) and activated specific cerebral regions
Intravenous administration of catecholamines and beta-agonists
Abraham J, Mudd JO, Kapur NK, Klein K, Champion HC, Wittstein IS. Stress cardiomyopathy after intravenous administration of catecholamines and betareceptor agonists. J Am Coll Cardiol 2009;53:1320–1325
Markedly elevated levels of catecholamines compared to patients with Killip Class III myocardial infarction

48. Elevated norepinephrine levels in the coronary sinus
Microneurographic studies and myocardial scintigraphy using 123I- metaiodobenzylguanidine - increased muscle sympathetic nerve activity
Abnormalities in myocardial sympathetic function persist for months after recovery of LV systolic function
In rats, LV apical ballooning attenuated by alpha- and beta-receptor blockade

49. All catecholamines induced takotsubo-like cardiac dysfunction
Isoprenaline – low blood pressure and predominantly apical dysfunction
Other catecholamines - high blood pressure and basal dysfunction
Hydralazine or nitroprusside to rats receiving epinephrine or norepinephrine (to maintain systolic BP <120 mm Hg) - akinesia of the apex instead of the base
Phenylephrine to maintain blood pressure >120 mm Hg after isoprenaline administration - prevented apical TCM-like dysfunction
2014 International Journal of Cardiology
Conclusions: Catecholamine-induced takotsubo-like cardiac dysfunction appears to be afterload dependent rather
than depend on stimulation of a specific adrenergic receptor subtype.

50. Plaque rupture hypothesis
Various hypotheses
Plaque rupture hypothesis
Transient ischaemia induced by plaque rupture followed by rapid lysis may cause myocardial stunning
Intravascular ultrasound and optical coherence tomography have failed to identify ruptured plaques
mechanism by which catecholamine excess precipitates myocardial dysfunction is unknown
apical ballooning phenotype is known to occur in the absence of a wraparound LAD and this coronary anatomical variant is notmore prevalent in TTS than in the control group

51. Multi-vessel epicardial spasm
Sympathetically mediated epicardial vessel spasm
TTS associated with endothelial dysfunction (migraine or Raynaud’s phenomenon common)
Marked impairment in brachial artery flow-mediated dilation, at presentation
Yet, vast majority of patients - no evidence of epicardial spasm even with use of provocative agents
Oxidative stress due to endothelial dysfunction
5. Zhang et al. found that hydrogen sulfide relieved cardiac dysfunction in animal models by
decreasing oxidative stress

52. Microcirculatory dysfunction
Catecholamines and endothelin predominate
Microvascular flow and coronary flow reserve decrease in acute phase
Increased thrombolysis in myocardial infarction (TIMI) frame counts and abnormal grades of TIMI myocardial perfusion
Intravenous administration of adenosine - transiently improve myocardial perfusion, wall motion score index and left ventricular ejection fraction (LVEF)
3. (normal = 1, hypokinesis = 2, akinesis = 3). The index (WMSI) is calculated by dividing the total of the wall motion scores of each segment by 16

53. Endomyocardial biopsies - apoptosis of microvascular endothelial cells
Cold pressor testing 1–3 years after the acute episode - elevation of catecholamines and transient apical and mid-LV wall motion abnormalities
Coronary vasomotion to acetylcholine is impaired
4. Impaired microvascular endothelial function was observed in virtually all patientswith TTS.

54. Catecholamine toxicity on cardiomyocytes
Endomyocardial biopsies - occasional contraction band necrosis
Seen in extreme catecholamine production such as pheochromocytoma or subarachnoid haemorrhage
Hypercontracted sarcomeres, dense eosinophilic transverse bands, and interstitial mononuclear inflammation
catecholamines from either sympathetic nerves, the adrenal medulla, or as drug therapy

55. calstabin 2, inhibits RyR2 and thereby the release of Ca2+ from the SR
calcium sparks - Ca2+ is released from the SR through a Ca2+ release channel, a cardiac isoform of the ryanodine receptor (RyR2)
calstabin 2, inhibits RyR2 and thereby the release of Ca2+ from the SR
PKA dissociates calstabin from the RyR2
Catecholamines 
cAMP mediated Ca overload
Depleted SR Ca stores and thereby impairs cardiac contraction
SERCA2a gene expression is downregulated and that of sarcolipin upregulated
End. SR Ca2+ ATPase (SERCA2A), reaccumulates Ca2+ against a concentration gradient, and the Ca2+ is stored in the SR by its attachment to a protein, calsequestrin
Sarcolipin : small transmembrane proteolipid that regulates several sarcoplasmic reticulum Ca2+-ATPases by reducing the accumulation of Ca2+ in the sarcoplasmic reticulum without affecting the rate of ATP hydrolysis

56. Phospholamban is dephosphorylated
Increased (dephosphorylated)phospholamban/SERCA2a ratio
Intense G-protein stimulated b1-adrenergic receptor signaling - modulates gene expression via the cAMP responsive element binding protein-1  activated T-cells signalling pathways
PKA phosphorylates the SR protein phospholamban; the latter, in turn, permits activation of the Ca2+ pump, thereby increasing the uptake of Ca2+ by the SR, accelerating the rate of relaxation, and providing larger quantities of Ca2+ in the SR for release by subsequent depolarization, thereby stimulating contraction

57. More sensitive to high levels of catecholamines
Mammalian LV apex
beta adrenergic receptor density is highest; sympathetic innervation is the lowest
More sensitive to high levels of catecholamines
High catecholamines  reduced coronary blood flow, paradoxical negative inotropic effects
Gi activation  stimulation of endothelial nitric oxide (NO) synthase  peroxynitrate
molecular switch’ of the b2-adrenergic receptor from the positive inotropic Gs to the negatively inotropic Gi pathway
TTS patients have been found to have markers of increased NO signallin

58. Peroxynitrate
Nitrosative stress
Activation of poly(ADP-ribose)-transferase-1  myocardial energetic impairment

59. Activation of myocardial survival pathways
Two different mechanisms
Adrenoceptor-related protective mechanisms
Supra-physiological levels of epinephrine  b2-adrenoceptor switch from Gs to Gi coupling  negative inotropic response - limits the degree of acute myocardial injury
Phosphoinositide 3-kinase/protein kinase B (AKT) survival pathway

60. AKT
Critical for postnatal cardiac growth and coronary angiogenesis
Downstream targets - mechanistic target of rapamycin and glycogen synthase kinase 3 (GSK3) [regulators of metabolism, proliferation, and cell survival]
Direct inhibition of apoptosis
Inhibition of proapoptotic transcriptional factors
Enhancement of anti-apoptotic transcriptional factors
Enhancement of cell metabolism by inhibition of the GSK3

61. Predisposition and risk factors
Hormonal factors
Declining oestrogen levels
Oestrogens
Influence vasomotor tone via up-regulation of endothelial NO synthase
Attenuate catecholamine-mediated vasoconstriction
Decrease the sympathetic response to mental stress in perimenopausal women

62. Women with subarachnoid haemorrhage - low levels of oestradiol associated with an increased risk of LV wall motion abnormalities
Ovariectomized rats – Immobilization stress -- ECG and contractile abnormalities -- attenuated with oestrogen supplementation

63. Genetic factors
Report of five cases of familial TTS, two in mother-daughter pairs
Genetic predisposition (if present) may interact with environmental factors, polygenic aetiology and/or recessive susceptibility alleles
?Polymorphisms in adrenergic genes
affect receptor function and downstream signaling
b1-adrenergic receptor (389 Gly) and b2-adrenergic receptor (27 Glu) variants - greater release of troponin I
a2-adrenergic receptor (del322–325) – reduced LVEF
Higher frequency of rs polymorphism in the GRK5 gene found in TTS patients

64. Genetic studies – conflicting results
But, similar genetic polymorphisms in the b1-adrenergic receptor and the b2-adrenergic receptor in TTS and controls
Genetic studies – conflicting results
Published studies conducted in small cohorts
Borchert et al. : ‘takotsubo in a dish’ model – overactive b- adrenergic pathway and higher sensitivity of catecholamines
induced pluripotent stem cell-derived cardiomyocytes (iPSCCMs)

65. Psychiatric and neurologic disorders
High prevalence reported
27% history of neurologic disorders, 42% psychiatric diagnosis – half depression
Templin et al., Clinical features and outcomes of takotsubo (stress) cardiomyopathy. N Engl J Med 2015;373:929–938
Depression and anxiety 78%, much higher than in patients with ACS
Summers MR, Lennon RJ, Prasad A. Pre-morbid psychiatric and cardiovascular diseases in apical ballooning syndrome (tako-tsubo/stress-induced cardiomyopathy): potential pre-disposing factors? J Am Coll Cardiol 2010;55:700–701
High prevalence of type-D-personality - negative emotions and social inhibition

66. miRNAs - miR-16 and miR-26a – associated with neuropsychiatric conditions : significantly upregulated in TTS
Depressed patients exaggerated norepinephrine response to emotional stress - increased spillover and decreased reuptake
Substantial structural differences between TTS and healthy controls in the limbic network
2. SNRIs may facilitate myocardial stunning
3. insula, amygdala, cingulate cortex, and hippocampus

67. Link between the brain and heart noticed since long time
Acute stroke of the basal ganglia or the brain stem, electroconvulsive therapy and seizures  transient cardiac dysfunction and injury, dynamic ECG changes, increased risk of arrhythmias
neurogenic stunning myocardium
Acute phases of stress cardiomyopathy  increase in cerebral blood flow in the hippocampus, brainstem, basal ganglia -- with a return to normal when the syndrome resolved

68. exact pathophysiology remains elusive
Stress  activation of brainstem noradrenergic neurons and stress- related neuropeptides (NPY produced by the arcuate nucleus in the hypothalamus)  complex neocortical and limbic integration
Stress 
Norepinephrine and NPY (stored in the presynaptic terminations of the post- ganglionic sympathetic system) --- spillover at myocardial level 
direct toxic effect and/or epicardial and microvascular dysfunction OR
impaired microvascular perfusion leading to a demand-supply mismatch and an ischemic stunning
exact pathophysiology remains elusive

69. Triggers Most reported – Emotional – bereavement
Men – Physical stressor - in-hospital TTS common - higher prevalence of in-hospital death ……(preceded mainly by chronic comorbidities or acute medical illnesses)
Women – Emotional stressor
One-third of patients without evidence of an identifiable stressful event
combination of emotional and physical issues16 (e.g. panic attack during a medical procedure), as well as environmental triggers such as long-term exposure to aircraft noise

73. Types of takotsubo syndrome
CLINICAL SUBTYPES
Primary: primary reason of care-seeking
Secondary : patient already in health care setting during evaluation or treatment of another critical illness
Different characteristics and clinical outcomes

74. ANATOMICAL SUBTYPES

76. Diagnosis

77. definite diagnosis cannot be established at presentation because of the need to demonstrate the reversible nature of the condition

78. ECG InterTAK Registry ST-segment elevation 44%
ST-segment depression 8%
T-wave inversion 41%
Left bundle branch block 5%
Temporal evolution : initial ST-segment elevation (if present)  progressive T-wave inversion and QT interval prolongation  gradual resolution of T-wave inversion and QT interval prolongation
5. ECG findings are influenced by several variables, including the geographic pattern of left ventricular (LV) ballooning, presence or absence of right ventricular (RV) ballooning, time from symptom onset to presentation, presence of myocardial oedema, and recovery rate of myocardial cellular function

79. ST-segment elevation
Location and extent of ST-segment elevation in TTS corresponds to the anatomic location of myocardial injury – resembling LAD STEMI
-aVR (inverse of aVR) representing +30 in the frontal plane is generally aligned with the LV apex
TTS centred on precordial leads V2–V5 and limb leads II and aVR
STEMI centred on precordial leads V1–V4 and limb leads I and aVL
Lead V1 : ST-segment elevation less pronounced in TTS than in anterior STEMI
ST-segment elevation limited to the inferior leads (II, III, aVF) uncommon in TTS
1. precordial, lateral, and apical ECG leads

80. T-wave inversion and QT interval prolongation
Geographic distribution of T-wave inversion closely parallels that of ST-segment elevation
T-wave inversion is often more prominent and more broadly distributed than in ACS
T-wave inversion is associated with presence of myocardial oedema - may persist for several months even after LV contractile recovery
Electrophysiological footprint
QT interval prolongation - a substrate for torsades de pointes

81. Other electrocardiogram findings
Anterior Q-waves (or poor R-wave progression) without accompanying ST-segment elevation or T-wave inversion - ‘anterior infarction, age indeterminate’ pattern
Pathologic Q-waves less frequently encountered in TTS than anterior STEMI (15% vs. 69%)
J-wave and/or fragmented QRS complexes
Low QRS voltage - myocardial oedema
ST-segment depression - uncommon, fewer than 10% of TTS
J waves - associated with death from cardiac causes and/or ventricular tachyarrhythmia

82. InterTAK Diagnostic Score

83. Biomarkers Markers of myocardial necrosis Cardiac troponin T or I
elevated in >90% of patients
peak troponin levels generally <10 ng/ml
CK-MB) also only mildly elevated
Discrepancy between the minimal elevation in biomarkers compared with extensive wall motion abnormalities
measured by conventional assays (not high sensitivity)

84. BNP and NT pro-BNP almost always elevated
higher levels correlating with the degree of ventricular wall motion abnormalities
Usually greater than those observed with ACS
peak occurs at 48 h, elevation up to 3 months
BNP/troponin and BNP/CK-MB ratios

85. Other potential biomarkers
Interleukin (IL)-6 less elevated, IL-7 more elevated in TTS compared with AMI
miR-133a more elevated in STEMI
miR-1, miR-16, miR-26a and miR-133a
Eur Heart J 2014
stress-responsive cytokine growth differentiation factor-15 – biventricular involvement.

86. Imaging Coronary angiography and ventriculography
CAG and biplane ventriculography in similar views for a perfusion- contraction mismatch
‘apical nipple sign’ - one-third of patients with classical apical ballooning - small zone with preserved contractility in the most distal portion of the apex

87. Echocardiography
AWMSI >_1.75 with more than four dysfunctional segments identifies TTS with 83% sensitivity and 100% specificity
Doppler estimation of coronary artery flow
Adenosine - dramatic improvements of global and regional LV function
Intravenous ultrasound contrast agents - wall motion assessment especially at the apex
Coronary flow reserve - reduced to 1.6–2.6 at the levels of the right and left coronary arteries
4. useful method especially in patients in whom CAG is not performed, mainly due to active bleeding or other comorbid conditions that may imbalance the risk-benefit ratio of CAG. Myocardial opacification is reduced within dysfunctional segments

88. Mitral regurgitation with SAM (14–25% of TTS)
Detection of dynamic LVOTO – in patients with pre-existing septal bulge - reduces stroke volume
Mitral regurgitation with SAM (14–25% of TTS)
Covered rupture of the LV free wall
LV apical thrombus
1. Echo may help in detecting complications of TTS like….

89. Cardiac computed tomography angiography
Useful in cases where invasive CAG may pose a considerable risk for complications
In stable patients with low suspicion of ACS, suspected recurrent TTS
Provides information on both - coronary artery anatomy and regional LV contraction
Terminal malignancy, intracranial bleeding, advanced age with frailty and bleeding diathesis
3. Assessment of LV contraction by CCTA requires image acquisition throughout the cardiac cycle and thus higher radiation exposure

90. Cardiac magnetic resonance imaging
Useful in the subacute phase
Identification of typical RWMAs
Quantification of RV and LV function
Assessment of additional abnormalities/complications (pericardial and/or pleural effusion, LV and RV thrombi)
Characterization of myocardial tissue (i.e. oedema, inflammation, necrosis/fibrosis)

91. CMR criteria for TTS - Combination of typical RWMAs, oedema and the absence of evidence of irreversible tissue injury (LGE)
Superior to echocardiography for detection of RV involvement

92. asterisks indicate
pericardial effusion (C.1) and yellow arrows (C.2) shows the region of akinesia
normal signal
intensity of the basal myocardium (3) and global oedema of the mid and apical myocardium

93. Cardiac nuclear imaging
Perfusion imaging
Mild reduction of perfusion in dysfunctional segments (Or Normal perfusion) - ‘myocardial thinning’ in dysfunctional segments may lead to a reduction in isotope counts
Metabolic imaging
Role not defined - Mainly done in TTS for research purpose
SPECT using 123I-b-methyl-iodophenyl pentadecanoic acid (reflects fatty-acid) and PET using 18F-flourodeoxyglucose (glucose utilization) often show reduced metabolic activity and near normal perfusion

95. Sympathetic nervous imaging
123I-metaiodobenzylguanidine (123I-MIBG, imaged with SPECT) - myocardial sympathetic innervation
Reduced for months in dysfunctional segments
ACS - perfusion and innervation are reduced
PET for cardiac innervation - 11C hydroxyephedrine

97. Complications and outcomes
cardiogenic shock and death - comparable to ACS patients treated according to current guidelines
adverse in-hospital events - one-fifth of TTS patients

99. Adverse outcomes
physical trigger
acute neurologic or psychiatric diseases
initial troponin >10 upper reference limit
admission LVEF <45%
high values of BNP and white blood cell counts
age >/=75
moderate to severe MR
High HR, Low BP
RV involvement

100. Typical TTS type - comparable outcome to atypical type
Prognostic role of diabetes mellitus controversial
prevalence
of diabetes mellitus in TTS is lower than expected for an ageand sex-matched population
Some studies : Patients with diabetes mellitus have a more favourable in-hospital and 1-year outcome

102. Arrhythmias Ventricular arrhythmias
Torsades de pointes, VT or VF - 3.0–8.6% patients - frequent cause of death
Most often in subacute phase (i.e. hospital days 2–4)
Coincide with anterolateral T-wave inversion and QT-interval prolongation (QTc >500ms – pause dependent torsades de pointes degenerating into VF)
QTc prolongation at admission in 50% pts
Cardiac magnetic resonance - association between transient myocardial oedema, T inversions and QTc prolongation
Some cases – TTS result of arrhythmias

103. Other cardiac arrhythmias
New-onset paroxysmal or persistent atrial fibrillation occurs 4.7%
Sinus-node dysfunction 1.3%
AV-block 2.9%
Causes - Neuro-autonomic imbalance, catecholamine stress, and increased vagal tone

104. Recurrence Approximately 5% of cases
3weeks to 3.8 years after the first event
triggering event and ballooning pattern may differ

105. Therapeutic management
Guidelines lacking – No prospective randomized clinical trials
Patients should be transferred to a cardiology unit with imaging capabilities and a cardiac catheterization
Guideline based treatment of ACS
Electrocardiogram monitoring – QTc
Prompt evaluation for the presence of LVOTO
Serial Doppler studies during inotrope use – to detect evolving LVOTO

106. Levosimendan can be used safely and effectively
Beta-blockers may improve LVOTO – to be used cautiously
? LVOTO may benefit from the If channel inhibitor – ivabradine
ACEi/ ARB – facilitate recovery
Diuretics – pulmonary edema
Risk of an LV thrombus and subsequent systemic embolism – postdischarge oral anticoagulation or antiplatelet therapy
Excessive prolongation of the QT interval or life threatening ventricular arrhythmias - wearable defibrillator (life vest)
2. due to the potential risk of pause-dependent torsades de pointes, beta-blockers should be used cautiously, especially in patients with bradycardia and QTc >500ms

107. ACEi or ARB – improved 1 year survival, lower recurrence
Long-term treatment
ACEi or ARB – improved 1 year survival, lower recurrence
No evidence for survival benefit or protection from recurrence for beta blockers
? oestrogen supplementation
combined psychocardiologic rehabilitation
? anti-depressants or other psychiatric drugs
3. one-third of patients experienced a TTS recurrence during beta-blockade. Suggesting that other receptors such as alphareceptors, that are more prevalent in the coronary microcirculation, might be involved

109. THANK YOU

114. Heart Failure Association risk stratification in Takotsubo syndrome