TAKOTSUBO CARDIOMYOPATHY

​Case 1

BACK TO INDEX

A 43 yo female presents with chest pain. It had occurred following a family tragedy. Her chest pain began whilst she was in ICU visiting her family member. (This case is taken from the literature)(1)
On arrival to the emergency department, her pain was 10/10. She was diaphoretic and vomiting. 
Her vital signs in the emergency department were:
HR      109 bpm
BP       101/78 mmHg
RR       2o breaths/min
O2sat   97% on RA
 
Examination was normal.
 
Her ECG is shown below:

​
, ST Elevation in in I and aVL and V1-V3
 
Cardiac markers were raised.
Cardiac catheterisation showed:

• Normal coronary arteries
• Severe hypokinesis of LV anteroapical wall, with apical ballooning.

This is Takotsubo Cardiomyopathy
 
Below is her ECG at day 1. ​Notice the large T wave inversion in I, II, aVL and V2-V6. There is a prolonged QT.

Case 2

Here is another case
A 64 yo woman is brought to the ED with chest pain. She had been visiting her sick husband on the ward.
Her ECG is shown below.
It looks like a STEMI, but again it's Takotsubo.

Answer

This is Takotsubo Cardiomyopathy: It is a STEMI MIMIC

try quiz 2 then read the text below

NOW LET's GO DEEP

Below is a summary based on the International Expert Consensus Document on Takotsubo Syndrome(1,2)

Epidemiology

Takotsubo Syndrome accounts for up to 3% of all patients presenting with potential STEMI. The incidence is higher in female patients. About 90% of patients are women with a mean age of 67-70 years. However, this is not a disease that only affects adults. It is also described in children.
It can recur in 5% of cases and does so within 3 weeks and 3.8 years.
It was first described in Japan in 1990 and was initially thought to be a disorder that affected only patients of Asian descent. However, we now see it in all parts of the world and in all races. 
 
It’s been called ‘broken heart syndrome’, ‘stress cardiomyopathy’ and ‘apical ballooning syndrome’. The initial name of Takotsubo was a Japanese word for an octopus trap and described the shape of the left ventricle at the end of systole. It is called a syndrome as there are a range of triggers, both emotional and physical that lead to a condition that appears similar to acute coronary syndrome and results in the left ventricular dysfunction.

Diagnostic Criteria

​​Patients present very similarly to those have an acute myocardial infarction (AMI). They can have chest pain, palpitations, dyspnoea and syncope. They can also present with symptoms related to its complications ie., heart failure, stroke, cardiogenic shock and cardiac arrest.
 
Diagnosing Takotsubo can be challenging, given that it presents similarly to AMI, both in terms of ECG changes and elevation of cardiac markers. The only way to reliably diagnose it is to perform coronary angiography and left ventriculography.
A complicating factor is that coronary occlusive lesions can occur concurrently.
 
There is no worldwide consensus on Diagnostic Criteria. There are multiple criteria available including:

• The Mayo Clinic Diagnostic Criteria
• The Japanese Guidelines
• The Gothenburg Criteria
• The Johns Hopkins Criteria
• The Tako-tsubo Italian Network Proposal
• Criteria of Heart Failure Association Taskforce of European Society of Cardiology

 
The InterTAK diagnostic criteria, are as follows:

1. Postmenopausal women are more commonly affected
2. Emotional + physical triggers can precede it, but is not obligatory
3. Significant coronary artery disease is not a contraindication to the syndrome
   1. Concommitant CAD can be present and ranges from 10-29%
4. Neurological disorders (SAH, stroke/TIA or seizures) may be a trigger
5. Pheochromocytoma may be a trigger
6. New ECG abnormalities are present as below, however rarely there may be no ECG changes:
   1. ST segment elevation
   2. T wave inversion
   3. QTc prolongation
7. Cardiac biomarkers are moderately raised

Transient Left Ventricular Dysfunction that presents as apical ballooning or midventricular, basal, or focal wall motion abnormalities.

Pathophysiology
 
Sympathetic Stimulation appears to be the cause of this condition. Triggering by emotional or physical triggers is the main cause, however it is also associated with catecholamine access such as occurs in pheochromocytoma and central nervous system disorders. 
 
The release of catecholamines in some patients with increased susceptibility of coronary microcirculation and cardiac myocytes, can lead to LV dysfunction and secondary myocardial inflammation. 
Hypotheses for how this occurs include:

• Plaque Rupture: In this theory plaque rupture causes ischaemia, which is then followed by lysis and myocardial stunning. Although not a likely theory as wall abnormalities are often expressed beyond single vessel territory.
• Multivessel epicardial spasm: Epicardial coronary vasoconstriction may contribute to Taketsubo in some patients
• Microcirculatory Dysfunction: This may be due to catecholamines and endothelin exerting their effects in the coronary vasculature.
• Catecholamine Toxicity on Cardiomyocytes: Catecholamines could directly affect cardiomyocytes, resulting in contraction band necrosis.

What are the Triggers?
Triggers can be both emotional or physical, or a combination of the two. Males are more often affected by physical stressors and women by emotional stressors.
 
Emotional triggers don’t have to be negative. Positive emotional triggers can also produce the syndrome, giving rise to the description ‘Happy Heart Syndrome’.
 
Physical stressors can be related to physical activities such as sports, to medical conditions, procedures or traumatic injury.

What Predisposes patients to Takotsubo Syndrome?
 
Hormonal Factors
Women older than 55 years of age have 5 times the risk than those less than 55 years of age.
Given the significant number of post-menopausal women that are susceptible to this syndrome, it is thought that declining oestrogen levels increase susceptibility. Oestrogen can decrease the sympathetic response to stress. 
 
Genetic Factors
Familial cases of Takotsubo have been reported raising the likelihood that there is a genetic predisposition.
 
Psychiatric and Neurological Disorders
Rates of psychiatric and neurological disorders was much higher in Takotsubo patients. Studies have shown that depression and anxiety is much higher in these patients.
Patients with depression have an exaggerated noradrenaline response to stress and may have a decrease noradrenaline reuptake.
 
It can also occur following a stroke or a subarachnoid haemorrhage or a seizure.




​The following are independent predictors of death:

• LVEF <45%
• Atrial fibrillation
• Neurological disorders

Types of Takotsubo Syndrome

​There are 4 types based on the distribution of regional wall abnormalities. These are:

1. Apical Ballooning: This occurs in the majority of cases and is the typical pattern
2. Midventricular
3. Basal
   1. ​Phenotype is associated with:
      1. Pheochromocytoma
      2. Adrenaline induced Takotsubo
      3. Subarachnoid haemorrhage
4. Focal Wall Motion patterns

The one-year mortality is higher in the typical types. Beyond one year, mortality is similar for typical and atypical.

Investigations

​ECG
The initial ECG is abnormal in most patients. Specifically, there is ST elevation and T wave inversion, or both. There is a progression with ST elevation, followed by T wave inversion and QT interval prolongation, over several days. This is followed by resolution of over days or weeks.
 
ST Elevation
It is usually in the:

• Precordial
• Lateral and 
• Apical leads

It mimics a left anterior descending coronary artery occlusion.

T wave inversion 
These are progressive changes. However, in the patient who presents late, they may be the only changes to find, given that ST elevation may no longer be present.. T wave inversion may represent myocardial stunning. It is usually more prominent than in ACS. It may persist for several months as it is associated with myocardial oedema.
 
QT interval prolongation
This may predispose patients to developing torsades de pointes and is a prognostic marker for sudden cardiac death.
 
Anterior Q waves
These represent poor R wave progression  and occur frequently.
 
Low QRS voltage
This occurs frequently and is due to myocardial oedema

​Can we use ECG criteria to distinguish between Takotsubo and a STEMI?

​
The following criteria have a high sensitivity and specificity for Takotsubo and assist in distinguishing it from anterior STEMI, however there is considerable overlap. 
​
The criteria are:

• ST elevation in V1 is lesser than in STEMI
• Strict inferior lead ST elevation is uncommon in Takotsubo
• ST segment depression is uncommon and more likely suggests ACS.

BIOMARKERS
Cardiac Markers
Cardiac troponin is raised equally to that of ACS
 
B-type natriuretic peptide and N-terminal prohormone of brain natriuretic peptide.
Takotsubo is associated with a large increase in these two markers.
The degree of rise of NT-proBNP is related to:

• Degree of sympathetic overactivation
• Peak -reactive activation
• Systolic LV dysfunction

IMAGING
​Coronary angiography and ventriculography
Angiography is performed in the setting of ST elevation. If there is coexisting coronary artery disease ventriculography is used to perfusion-contraction mismatch.
 
Echocardiography
It is used to assess the changes in left ventricular function. Left ventricular contractility recovers completely in 4-8 weeks.
 
Cardiac computed tomography angiography (CCTA)
This can be performed when comorbid or other conditions do not make angiography an option. It gives information on coronary artery anatomy and regional LV contraction.
 
Cardiac Magnetic Resonance imaging
More for the subacute than the acute phase.
 
Cardiac Nuclear Imaging
SPECT can be used to test perfusion, metabolism and innervation
​

Complications and Outcomes

Takotsubo is often considered a benign reversible disease. However, this is not the case and cardiogenic shock and mortality is similar to those patients with ACS

Complications in Terms of Frequency

• Acute heart failure (12-45%)
• Left Ventricular Outflow Tract Obstruction LVOTO (10-25%)
• Mitral regurgitation (14-25%)
• Cardiogenic Shock (6-20%)
• Atrial fibrillation (5-15%)
• LV Thrombus (2-8%)
• Cardiac Arrest (4-6%)
• AV Block (5%)
  • Occurs due to increased vagal tone
• Tachy/Brady arrhythmias (2-5%)
• Ventricular Arrhythmias
  • Torsades de Pointes (2-5%)
    • These occur in the subacute phase (days 2-4). They coincide with a lengthening of the QT interval and anterolateral T wave inversion.The most malignant episodes are associated wit QTc >500ms.
  • VT/VF (3%)
• Death (1-4.5%)
• Acute ventricular septal defect (<1%)

Treatment is based on expert consensus as no prospective studies exist.

A few words about general medications that may be used:

• Catecholamine drugs in Takotsubo are associated with a 20% mortality
• Beta Blockers may improve LVOTO but are contraindicated in bradycardia and in acute severe heart failure with low LVEF and hypotension
• Angiotensin Converting Enzyme inhibitors and Angiotensin II receptor Blockers may facilitate LV recovery
• Diuretics can be used in Pulmonary oedema
• Nitroglycerin reduces afterload and left and right ventricular filling pressures in heart failure. However, they should be avoided in LVOTO as they worsen the pressure gradient
• Any drugs that prolong QTc should be used with caution as may precipitate Torsades.

​​Treatment of Heart Failure

MILD TAKOTSUBO/NO HEART FAILURE

• Consider ACE inhibitor
• Consider Beta Blocker
• Avoid inotropes such as:
  • Adrenaline / Noradrenaline / Dobutamine / Milrinone / Isoproterenol

HEART FAILURE/PULMONARY OEDEMA

• Consider the following drugs:
  • ACE inhibitor
  • Beta Blocker
  • Diuretics if No LVOTO
  • Nitroglycerin in no LVOTO

CARDIOGENIC SHOCK

In LVOTO

• Consider
  • IV fluid if no heart failure
  • Short acting beta blocker
  • LVAD
• Avoid
  • Diuretics
  • Nitroglycerin
  • IABP

​In Pump Failure

• Consider
  • Levosimendan
  • LVAD
  • VA-ECMO

Treatment of Arrhythmias

Ventricular arrhythmias (VT, VT Torsades de pointes, long QTc) AV Block

• Consider
  • Beta Blocker
  • Temporary RV pacing in AV Block
• Avoid
  • Drugs that prolong QT interval
  • Beta blocker in bradycardia and QTc > 500ms

Treatment of Thrombosis and/or Embolism

• Consider anticoagulation if LVEF < 30% or large LVD

REFERENCES

1. Merchant EE et al. Takotsubo Cardiomyopathy: A Case series and Review of the Literature. West J Emerg Med. 2008 May; 9(2):104-111
2. Ghadri et al. International Expert Consensus Document on Takotsubo Syndrome(part 1): Clinical Characteristics, Diagnostic Criteria and Pathophysiology. European Heart Journal(2018).39, 2032-2046
3. Ghardi et al. International Expert Consensus Document on Takotsubo Syndrome (Part II): Diagnostic Workup, Outcome and Management. European Heart Journal (2018) 39, 2047-2062.
4. Bybee KA et al. Clinical characteristics and thrombolysis in myocardial infarctionfame counts in women with transient left ventricular ballooning syndrome. Am J Cardiol. Aug 1 2004;94(3):343-346
5. Gianni M et al. Apical Ballooning syndrome or takotsubo cardiomyopathy: a systematic review. Eur Heart J July 2006:27(13):1523-29