It has been estimated that 1–2% of patients with suspected acute coronary syndrome (ACS) are found to have Takotsubo syndrome (TTS),1,2 but if only women are considered, this may be as high as 10%. It is probable that the incidence of TTS is underestimated.3 A more recent study conducted in a large urban hospital in the USA found that the ratio of non-ST-segment-elevation myocardial infarction (NSTEMI) to TTS was 24:1 (4.2%).4 With increasing awareness, TTS is becoming more frequently recognised, but there are still some subgroups of people in whom TTS is likely under-diagnosed such as those with pre-hospital sudden cardiac death,3 obstetric, surgical, anaesthetised and critically ill patients. TTS occurs in a variety of settings and contexts and can be classified as primary or secondary TTS.
Primary Takotsubo syndrome Acute cardiac symptoms are the main reason for seeking care in primary TTS. The first point of medical contact is usually from emergency medical services (ambulance and emergency departments), acute cardiac services, or the primary care physician. A stressful trigger may or may not be identifiable in primary TTS. A co‐existing medical condition may be present but it is not the primary cause of the catecholamine rise.3
Secondary Takotsubo syndrome TTS can be precipitated by an existing medical, surgical, anaesthetic, obstetric, or psychiatric condition that causes sudden activation of the sympathetic nervous system or a rise in catecholamines. TTS occurs as a complication of the primary condition or its treatment, and thus is known as secondary TTS.3
90% of reported cases of TTS are in women with a mean age of 67–70 years, but TTS can also occur in younger women, men, children and neonates. TTS cases may be classified as primary or secondary TTS. TTS is most commonly found in women, but a diagnosis of TTS should not be excluded based on gender. With increased awareness of TTS, reported cases in men are increasing. Emotional stress or the absence of identifiable triggers are more common in women. Conversely, a physical triggering event is more common in males. Mortality is higher in males than in females perhaps reflecting the higher frequency of underlying severe critical illness and secondary TTS in males.3
90% of reported cases of TTS are women with a mean age of 67–70 years,5 but a diagnosis of TTS cannot be excluded on the basis of age. There have been published case reports of TTS in neonates,6,7 children,8-14 and younger men and women.15
Key point The index of suspicion for TTS may be higher in post-menopausal females, but TTS cannot be excluded on the basis of age or gender.
Pre-existing mental health disorders
There have been several studies linking mental health disorders and TTS.16 The International Takotsubo Registry reported significantly higher rates of affective disorders and anxiety in people with TTS compared to controls.17 A large observational study with over 24,000 patients from the National Inpatient Sample also found higher prevalence of anxiety and mood disorders in patients with TTS compared to controls.18 There are, however, some limitations in reporting psychiatric diagnoses obtained from the medical record without real-time assessment of
each patient for consistency with Diagnostic and Statistical Manual of Mental Disorders (DSM) criteria that may lead to under-, over-, or misdiagnosis of psychiatric disorders in such studies.16 Explanations of the aetiology behind the association of TTS and mental health disorders is speculative in nature, but patients with pre-existing psychiatric illness may be at increased risk of TTS due to disproportionately high catecholaminergic responses and increased cardiac sympathetic sensitivity.16
Acute exacerbation of psychiatric illness19 and changes in psychotropic medications including up-titration and overdose of serotonin-norepinephrine reuptake inhibitors (SNRIs)20 have been shown to trigger TTS.
The most common symptoms of TTS are chest pain and/or dyspnoea. As with ACS, angina in women may not fit a typical pattern. Less commonly, the presenting symptoms may result from complications of TTS and include heart failure, cardiogenic shock, syncope or cardiac arrest.1 Cardiac arrest as the presenting feature appears to be more common in younger women.16
With the exception of mental health conditions including stress and anxiety, traditional risk factors for coronary heart disease do not appear to be associated with the development of TTS.
Preceding physical or emotional stressor
Typically there is a history of an acute physical or emotional stressor within the preceding hours/few days that triggers TTS, but approximately one third of people have no identifiable trigger at the time of presentation. Emotional triggers vary in nature, ranging from what may be perceived by others to be a trivial event (loss of a personal item) to a life-changing event (death of a loved one). TTS can also be triggered by positive emotional events such as winning a prize, or happiness at a celebration of a birthday, wedding or family reunion). The magnitude of the event does not appear to be the determinant of TTS occurrence. Any event that causes acute emotional stress in a susceptible individual can trigger TTS. Physical stressors, usually in the form of acute illness, trigger around 40% of TTS cases. As with emotional stressors, there is a wide range of physical stressors that have been associated with TTS. When TTS occurs secondary to physical illness (particularly in critically ill patients), or those undergoing surgery and/or anaesthesia, patients may not experience chest pain or dyspnoea. Alternately, symptoms may be attributed to the pre-existing physical illness or surgery.
Key point The index of suspicion for TTS may be higher when the patient identifies a physical or emotional stress that precedes symptoms, but TTS cannot be excluded in the absence of an identifiable stressor.
Key point TTS should be considered as a possible cause of sudden unexpected or unexplained haemodynamic or respiratory deterioration17, and impaired consciousness or neurologic complications1 in patients with impaired ability to communicate due to illness or medical/surgical intervention. TTS should be considered in the setting of new troponin elevation and/or ECG changes in critically ill and surgical patients.
See the Takotsubo Wall for causes of TTS listed by people with TTS. This is frequently updated.
Adrenalin (epinephrine), noradrenalin (norepinephrine), isoprenaline (isoproteranol), dopamine, and phenylephrine have all been used successfully to induce TTC-like changes in rat models.21
Adrenaline (epinephrine) and noradrenaline (norepinephrine)
Catecholamines have a central role in the development of TTS, and there are many case reports linking exogenous catecholamines to the development of TTS. Reviews suggest that adrenaline, also called epinephrine, is the most commonly used drug to cause TTS.22 Reports of TTS related to adrenaline use show that the population affected are generally younger than what is commonly reported in large registry databases.23,24 Women were still the dominant gender affected, but one study found that this was in a significantly lower percentage than general TTS population reports.24 Some of the common indications for adrenaline use are cardiac arrest, cardiogenic shock, hypotension, anaphylaxis (life threatening allergic reactions), control of superficial bleeding in dental or surgical some procedures. Routes of administration for adrenalin are inhalation, intra-ocular, topical, local irrigation, and subcutaneous, submucosal, intramuscular and intravenous injection. Multiple cases of TTS associated with uses of adrenaline and noradrenaline (norepinephrine) have been reported in various medical conditions. Some examples of these are listed below:
Clinicians should be aware of the potential for development of TTS related to these drugs. Adrenalin and noradrenaline are drugs that are often crucial in resuscitation, managing hypotension and treating anaphylaxis. Use of these drugs may be unavoidable, but clinicians should explore other options and use these drugs judiciously where circumstances mandate their use.
Dobutamine and dopamine
Dobutamine is the second-most commonly reported drug to cause TTS. Dobutamine is a synthetic catecholamine that increases contractility of the heart. It is used as an intravenous infusion for the short term treatment of patients with depressed myocardial contractility. There are few reports of dobutamine being associated with TTS in this context,66 but it is possible that TTS could be masked or signs and symptoms mistaken for the underlying illness. However, there are numerous reports of dobutamine triggering TTS when used in cardiac investigations.67-82 These have predominantly occurred in the context of pharmacological stress testing when the patient is unable to exercise on a treadmill.
Dopamine is one of the catecholamine neurotransmitters in the brain and like dobutamine has been used to support blood pressure in cases of severe hypotension. There are rare reports83,84 of association of dopamine with TTS in the context of managing hypotension, but as with dobutamine, it is possible TTS is masked or mistaken for the underlying illness.
Other cardiotonic drugs associated with cases of TTS include dipyridamole,85 isoprenaline (isoproteranol),86 terlipressin.87
Phenylephrine, a synthetic sympathomimetic amine that acts predominantly on α-adrenergic receptors, is mainly used to treat nasal congestion, but may also be used in treating hypotension and shock and hypotension during spinal anaesthesia. It has been associated with cases of TTC in obstetrics in the setting caesarean section for anaesthetic induction-related hypotension or perioperative hypotension,88-90 but in this context, it is usually not the only drug used that has the propensity to cause TTC. Use of phenylephrine alone has been reported in cases of TTC81,82 but is often used in combination with other drugs.52,83,84 Phenylephrine is likely to have triggered TTS in several cases.85-88
Serotonin norepinephrine reuptake inhibitors (SNRIs)
Serotonin norepinephrine re-uptake inhibitors (SNRIs) are monoamine re-uptake inhibitors and their action is to inhibit the re-uptake of serotonin and norepinephrine. SNRIs are primarily used to treat depression, anxiety, and chronic pain disorders. Although SNRIs are often referred to as “dual action agents” the degree to which re-uptake of serotonin and norepinephrine is inhibited depends upon their affinity for the serotonin transporter and norepinephrine transporter and the dose administered.89 Desvenlafaxine, duloxetine, and venlafaxine are more potent inhibitors of serotonin re-uptake than norepinephrine re-uptake, whereas levomilnacipran preferentially blocks re-uptake of norepinephrine. Cases of TTS have been reported in association with desvenlafaxine (Pristiq),90,91duloxetine (Cymbalta),92-94milnacipran (Ixel, Savella, Dalcipran, Toledomin),95 and venlafaxine (Effexor).96-100
Other medications used to treat mental health conditions that have been suggested to possibly have had an association with the development of TTS include:
Recent studies have described an increasing trend in the incidence of TTS among adult patients receiving chemotherapy and significantly higher mortality for cancer patients with TTS compared with those with no TTS.106-108 Several chemotherapeutic agents, monoclonal antibodies, and tyrosine kinase inhibitors have been identified as possible sole culprits of TTS.107 The most common chemotherapy drugs associated with TTS are 5-fluorouracil (5-FU)109-127 and its oral pro-drug capecitabine.128-134
Other drugs used in the treatment of cancer that have been associated with TTS are:
Cases of TTS have been reported in the obstetric setting and is a serious complication that is associated with acute pulmonary oedema,156-164 cardiogenic shock,165 cardiac arrest,166-170 and death. TTS can happen throughout pregnancy or later in the peripartum period, but the risk is greatest in during or soon after birthing. Peripartum TTS appears to be more common in women with pre-existing maternal high-risk features including age >35 years, multiple gestations, preterm birth (<37 weeks), and almost all reported cases are associated with caesarean delivery. There are also reported cases associated with preeclampsia and HELLP syndrome (haemolysis, elevated liver enzyme levels, and low platelet levels) and vaginal delivery.156,171-173
The development of TTS within 24 hours of delivery may be multifactorial. In cases of hypotension induced by spinal anaesthesia, the drugs given to counteract the hypotension are the likely trigger for TTS. These include adrenaline,167 noradrenaline,160,163,167 dopamine,156,170 dobutamine,157, 160,163,174 phenylephrine,161,175,176 ephedrine.161,176 Most of these are given in combination so it is difficult to know whether it is one of these drugs alone or the combination of drugs, but all of these have a propensity to trigger TTS alone. Similarly, in the setting of peripartum haemorrhage (PPH), drugs used to reduce the risk of PPH or control haemorrhage may have triggered TTS. Uterotonics that have been linked with the development of TTS include oxytocin,157,159,162,167 ergot alkaloids,157,159,162,177 and prostaglandins (PGE2160,162 and PGF2α).174
Ritodrine, used as a tocolytic, has also been reported as a possible trigger for TTS cases.163,178
TTS should be considered as a possible diagnosis if symptoms of chest pain, shortness of breath and signs of haemodynamic compromise occur, particularly during or soon after birthing.
Chronic obstructive pulmonary disease, asthma, pulmonary embolism, and malignancies have been described as potential physical triggers for TTS. Exacerbation of asthma and status asthmaticus have been associated with TTS. β2 adrenergic receptor agonists including albuterol (salbutamol),179-185 terbutaline186 and salmeterol187) likely have a role, but in at least some cases appears to be due to higher than recommended doses, suggesting that medical review of unstable asthma should be sought sooner rather than taking excessive doses of β2 adrenergic receptor agonists.
Adrenaline (epinephrine) as a treatment for asthma can also trigger TTS.52,188
Cocaine,189-192 methamphetamines,193-195 and cannabis196-197 are known to trigger TTS.
TTS can be triggered by withdrawal from alcohol,198-200 methadone,201-202 opioids,203-204 baclofen, 205-206 and buprenorphine.207 TTS has also been associated with abrupt beta blocker withdrawal.208-209
Other drugs that have possibly been associated with TTS are