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Takotsubo syndrome (TTS), an acute and usually reversible condition, is associated with both tachy- and bradyarrhythmias. Such arrhythmias can be life-threatening, e.g. ventricular tachycardia and fibrillation, and associated with cardiac arrest. Others, such as atrioventricular block, persist and require long-term device therapy. In this narrative review, we aim to provide a summary of the current literature on arrhythmias in TTS and their clinical sequelae.
Methods
PubMed and Medline databases were searched with various permutations of TTS, arrhythmias and beta-adrenoceptors. After application of exclusion criteria and review, 84 articles were included.
Results
Although there are no specific electrocardiograph (ECG) findings in TTS to differentiate it from ST-elevation myocardial infarction, suggestive patterns include small QRS amplitude, ST segment elevation without reciprocal ST depression and prolonged QT interval. Atrial tachyarrhythmias (incidence of 5–15%) are associated with a more unwell patient cohort. Ventricular arrhythmias (incidence 4–14%) are often associated with prolonged QT interval and are a cause of sudden death in TTS. Bradyarrhythmias are less common (incidence 1.3–2.5%), but have been reported with TTS, and usually persist beyond the acute phase.
Conclusions
Takotsubo syndrome, though considered primarily a disease of the myocardium, carries multiple arrhythmic manifestations that affect short- and long-term prognosis. The management of such arrhythmias represents a constantly evolving area of research.
Takotsubo syndrome (TTS) is an acutely reversible form of heart failure, traditionally associated with catecholamine release in both physically and emotionally stressful states [
] are used for the diagnosis of this condition; all specify the transient nature of left ventricular mid to apical segment hypokinesis, akinesis or dyskinesis and the absence of obstructive coronary artery disease. The International Takotsubo (InterTAK) registry working group have attempted to address multiple exceptions to the rule in recent guidelines, which now includes cases without an obvious trigger, and even cases with significant coronary artery disease [
]. Life-threatening arrhythmias commonly occur in the setting of a prolonged QT interval, with Torsades de Pointes (TdP) being the most well-known association [
In this narrative review, we aim to synthesise a comprehensive summary of the current literature on the role of electrophysiological disturbances in TTS, including typical electrocardiographic (ECG) changes, atrial and ventricular arrhythmias, sudden arrhythmic death and device therapy, and hypothesised mechanisms of arrhythmia.
Methods
Search Strategy
Relevant journal articles were identified using PubMed and OvidMedline databases. Search terms used included “Takotsubo”, “apical ballooning syndrome”, “transient left ventricular dysfunction”, “broken heart” AND “ECG” OR “beta receptors” OR “arrhythmias” OR “sudden death” OR “pathophysiology”. In addition, reference lists of articles were hand-searched for relevant sources of information.
Inclusion and Exclusion Criteria
Article types included cohort studies, case series, and basic science studies. Case reports and small case series <10 individuals were excluded, unless they represented unique phenomena not reported elsewhere. Cohort studies and reviews were excluded if there was no sub-section devoted to arrhythmia diagnosis and management, or if they represented the smallest cohort in several articles reporting similar findings. After study selection (Figure 1), 85 studies were identified for review.
Figure 1Flowchart depicting strategy for article inclusion.
]; therefore, there has been considerable interest in utilising the ECG to distinguish these two clinical entities, although the final diagnosis usually mandates exclusion of coronary artery disease by cardiac catheterisation [
Interestingly, basal-variant TTS encompasses a wide range of ST segment and T wave changes, such as those limited to a single vascular territory, minimal T wave changes or no changes at all [
]. Focal TTS variants frequently involve the interventricular septum, with ECG changes that reflect the involved territory, with or without reciprocal changes [
]. Takotsubo syndrome is also associated with a longer PR interval in the setting of life-threatening arrhythmia (185±51 ms in those with vs 162±30 ms in those without) [
Q waves may represent established myocardial necrosis or a variant of normal conduction. In one study, they always appeared at 48 hours post presentation with ST-elevation myocardial infarction (STEMI), but not in TTS [
]. However, evidence suggests that Q waves can appear transiently in the first 24 hours of a TTS presentation and remain present in up to 10% of cases [
Per Madias and Guerra, patients with TTS often have low QRS voltages in the acute phase, with recovery of QRS amplitude associated with improvement in left ventricular systolic function and reduction in cardiac enzymes [
]. Less common changes include QRS prolongation (117±33 ms vs 95±18 ms), which has been described in association with life-threatening arrhythmia in TTS groups with and without such arrhythmias [
]. However, a study with 12-month follow-up of TTS patients with and without left bundle branch block showed no difference in long-term mortality once comorbidities were accounted for [
]. This may relate to the fact that lead aVR records electric potentials at the base of the heart, showing reciprocal changes relative to injury-related ST-elevation at the cardiac apex (Figure 2). Based on an InterTAK study, ST elevation in aVR alone is 43% sensitive and 95% specific for TTS. This has decreased sensitivity when combined with inferior ST elevation (sensitivity 12%, specificity 98%), but increased specificity with anteroseptal ST elevation (sensitivity 12%, specificity 100%) [
Note the position of recording potential in lead aVR relative to the cardiac apex. Figure available under Creative Commons Attribution-Non-commercial-No Derivative Works 3.0 Licence, from Rezaie [
Specific findings of the standard 12-lead ECG in patients with 'Takotsubo' cardiomyopathy: comparison with the findings of acute anterior myocardial infarction.
ST depression in leads V2–4 is 100% specific for STEMI, and 99% specific for non-ST elevation acute coronary syndrome (NSTEACS), which was not a finding in ECGs of patients with TTS [
Specific findings of the standard 12-lead ECG in patients with 'Takotsubo' cardiomyopathy: comparison with the findings of acute anterior myocardial infarction.
In TTS, T wave inversion (TWI) progresses and reaches maximal depth at approximately 3 days. TWI is frequently seen in leads V2–6 and does not necessarily require preceding ST changes [
In STEMI, hyperacute T waves are followed by the development of Q waves, ST elevation and T wave inversion. T wave inversion may regress, leaving Q waves long-term. In Takostubo syndrome, changes are less well-defined, however Q waves, ST elevation and QT prolongation can develop within 24 hours, with development of deep T wave inversion after 24 hours. These changes are likely to resolve after the acute admission.
Abbreviations: STEMI, ST elevation myocardial infarction; ECG, electrocardiograph.
ECG of the “spiked helmet sign”, named after its resemblance to the German pickelhaube (pickaxe bonnet). Dome-shaped, upsloping ST elevation preceding the QRS complex is characteristic. Figure from Littmann et al. [
The criteria of TWI ≥6 leads and peak TWI ≥ 3 mm have sensitivities of 74.1% and 75.9% in distinguishing TTS without ST elevation from NSTEACS. TWI lead number has a relatively higher specificity compared to the depth of TWI—91.9% vs 79.0% [
The corrected QT (QTc) interval in TTS is often dynamic throughout hospitalisation. QT interval length increases with increasing T wave amplitude and shortens with decreasing amplitude [
]. Significant variability in the R-R interval (mean of 30 ms vs 14 ms) may reflect changing QT intervals and alter the timing of ventricular repolarisation, leading to TdP [
]. Cardiac magnetic resonance work has shown that the development of an apico-basal oedema gradient, rather than late gadolinium enhancement, is correlated with QTc prolongation and deep TWI [
There has also been interest in the relatively rare ‘spiked helmet sign’ (SHS) (Figure 3). It is dome-shaped ST-segment elevation accompanied by an upward shift of the baseline before the QRS complex, first described in patients with acute abdominal pathology and often regarded as a sign of critical illness [
]. Several investigators have postulated that the baseline shift represents prolonged repolarisation in the form of prolonged QT (or QU) or T (or U) wave from the previous beat [
]. This draws together the concepts of QT-prolongation and T wave inversion seen in TTS, alongside the frequent physical stressors of TTS including critical illness.
Takotsubo Syndrome: Basic Science
Understanding TTS begins with understanding of the effects of catecholamines such as adrenaline and noradrenaline, which bind to both beta-1 and beta-2 adrenoceptors (β1AR and β2AR) on the myocardium. These receptors couple to the G alpha subunit of a G protein complex, which stimulates dissociation of the G protein into two subunits, each of which can affect adenylyl cyclase in a different way (stimulatory or inhibitory). Both β1AR and β2AR couple to the stimulatory G protein subunit (Gαs), but β2AR additionally couples to the inhibitory G protein subunit (Gαi) [
]. An adrenaline surge switches internal adrenoceptor signalling from the Gs to Gi protein at the apex. This switch protects against apoptosis, but also results in negative inotropy [
High levels of circulating epinephrine trigger apical cardiodepression in a β2-adrenergic receptor/Gi-dependent manner: a new model of Takotsubo cardiomyopathy.
Catecholamine-induced hyper-phosphorylation of the RyR2 (ryanodine receptor 2) in animal models has been shown to result in cellular calcium leak and myocyte death [
]. Work in induced human pluripotent stem cells from TTS patients demonstrates certain groups of cardiomyocytes that show increased rather than decreased beating frequency with administration of low-dose isoprenaline [
], and displayed increased transient calcium currents, which may play a part both in arrhythmogenesis and reduced contractility.
Catecholamines also contribute to the downstream effects of myocardial oedema and cell death in TTS. Detailed human endomyocardial biopsy work by Nef et al. [
] shows the role of inflammation with a greater presence of macrophage and T lymphocytes in the acute phase compared to biopsy samples taken from the same patients after functional recovery. Histological findings of increased extracellular matrix and disorganised contractile protein structure likely indicate the presence of myocardial oedema.
The classic pathological finding in animal neurogenic cardiac lesions (also suspected to occur in humans), is coagulative myocytolysis/myofibrillar degeneration [
]. This is characterised by early calcification and development of contraction band necrosis in cardiac myocytes. The diffuse subendocardial nature of this lesion and proximity of cardiac nerve terminals to necrotic areas on histology point to the possibility of arrhythmia generation by an autonomic surge [
], and are more likely related to genes involved in energy production. Human endomyocardial biopsy work has shown upregulation of oxidative stress triggered-induced genes and protein biosynthesis genes in the acute phase, and downregulation of glycogen metabolism genes [
]. Sympathetic stimulation affects diastolic ryanodine receptor calcium leak and reduces calcium uptake into the sarcoplasmic reticulum, resulting in early afterdepolarisations that lead to triggered atrial activity [
]. Additionally, left atrial strain has been shown to be impaired in parallel with the left ventricle, reflecting possible mechanical atrial dysfunction by alteration of atrial reservoir function [
The left atrial function is transiently impaired in Tako-tsubo cardiomyopathy and associated to in-hospital complications: a prospective study using two-dimensional strain.
Clinical impact of atrial fibrillation on short-term outcomes and in-hospital mortality in patients with Takotsubo syndrome: a propensity-matched national study.
Left ventricular thrombi in Takotsubo syndrome: incidence, predictors, and management: results from the GEIST (German Italian Stress Cardiomyopathy) Registry.
]. However, it is reasonable to assume that AF might further increase stroke risk independent of left ventricular thrombus.
Beta blockade for both TTS and atrial arrhythmias can be difficult to tolerate in the setting of acute left ventricular impairment, and vasodilation in those without acute left ventricular dysfunction [
]. As such, there is a lack of guidance for the treatment of atrial arrhythmias in TTS, but this may entail use of rhythm control agents (e.g., digoxin or amiodarone) in preference to beta blockade. Like other cases of acute, potentially reversible triggers of atrial dysrhythmias, initiation and continuation of anticoagulation for TTS-induced atrial fibrillation/flutter is currently individualised due to a lack of clinical consensus. However, patients may receive anticoagulation for mural thrombus related to ventricular dysfunction [
]. These mainly consist of ventricular tachycardia (VT), including TdP, and ventricular fibrillation (VF). About a third of ventricular arrhythmias (VAs) are sustained or non-sustained ventricular tachycardia (VT), which can be monomorphic [
]. However, T2-weighted CMR sequences frequently reveal extensive myocardial oedema, and it is conceivable that such areas lead to functional, rather than anatomical block, within the myocardium [
Electrocardiogram mimics of acute ST-segment elevation myocardial infarction: insights from cardiac magnetic resonance imaging in patients with tako-tsubo (stress) cardiomyopathy.
The myocardium in TTS is vulnerable to early afterdepolarisations with resultant TdP, which can arise from calcium overload in the setting of catecholamine excess [
]. Mechanistic work in human pluripotent stem cells demonstrates enhanced late sodium (INA) and suppressed transient outward potassium (ITO) ion channel function, leading to prolonged action potential duration and increased risk of early afterdepolarisations [
High levels of circulating epinephrine trigger apical cardiodepression in a β2-adrenergic receptor/Gi-dependent manner: a new model of Takotsubo cardiomyopathy.
Despite the high upfront mortality from VA, it is difficult to say if this impact carries through to the longer term, secondary to small sample sizes used in institutional registries and limited follow-up of 1–3 years. VA recurrence rate is as high as 15% in the short term and 5% in the long term [
]; this is based on physiological information from animal studies demonstrating large surges in catecholamines in response to raised intracranial pressure and the subsequent development of ventricular arrhythmias [
] use due to the potential for further QT prolongation. Even though standard heart failure therapy (including beta blockade) shows no efficacy in the treatment of TTS [
], we tend to initiate beta blockade in patients with arrhythmia, based on pathophysiology and the effectiveness of surgical sympatholysis in some cases of non-TTS refractory arrhythmias [
], especially in the absence of life-threatening arrhythmia.
Decisions around device therapy in patients with TTS and life-threatening arrhythmias remain nuanced, largely due to the paucity of studies in this area, and are discussed in detail below.
Sudden Death
There are multiple possible mechanisms for sudden death in TTS; life threatening arrhythmias, cardiogenic shock, heart failure and rarely, rupture of the left ventricular free wall/interventricular septum [
In a large case-control study in TTS, those presenting with cardiac arrest had a presenting rhythm almost evenly split between ventricular fibrillation (VF) (44.0%) and pulselss electrical activity (PEA) (42.9%), with VT (13.1%) making up a smaller proportion of cases. Of those who developed cardiac arrest during the acute admission, PEA arrest dominated (73.7%) versus 15.8% for VF versus 10.5% for VT [
], which may result from the precipitating illnesses of other organ systems.
Patient-level analysis by Singh et al. shows that in the acute phase, hypotension in the setting of TTS was the major cause of arrest (where QTc was normal), while in the 24-to-72-hour period, prolonged QTc-triggered TdP overtook as the major cause. As QTc tends to improve in TTS, TdP occurrence also tends to be confined to the acute phase, in contrast to monomorphic VT, which can result in sudden cardiac death [
Even after the acute admission, the mortality risk in TTS persists in patients who have developed cardiac arrest on presentation or early in their admission, up to a six-fold increase in 60-day and 5-year figures [
The temporal relationship between TTS and arrhythmogenesis can be uncertain, with studies showing that cardiogenic shock is an independent predictor of adverse arrhythmias [
]. It is certainly conceivable that incessant atrial or ventricular arrhythmias from underlying undiagnosed structural heart disease/channelopathies could contribute to myocardial stunning and the TTS phenotype [
] in the setting of diseases such as sepsis, with either the disease, vasopressors or both contributing to TTS and cardiac arrest.
Bradyarrhythmias
Although often overlooked in due to a focus on life-threatening VA in TTS, conduction disorders can affect the TTS patient more insidiously, and have a higher probability of being the presenting rhythm at hospital admission in comparison to VA [
The mechanism of bradyarrhythmia is unclear, although some authors posit a secondary increase in vagal tone as a compensation for catecholamine surge [
]. This has led to considerable uncertainty around the implantation of cardiac defibrillators, with their long-term risks of pneumothorax, bleeding, and lead/device infections. Some centres have used wearable cardioverter-defibrillators as a temporising measure until the recovery of electrocardiographic changes or left ventricular dysfunction [
]. Interrogation of implanted defibrillators shows that therapies are not utilised after the acute phase, supporting the reversible nature of most VA in TTS [
On the other hand, conduction disturbances can either resolve or persist. In one series, a small number of patients demonstrated recovery of bradyarrhythmia after a period of temporary right ventricular pacing (in some cases pursued to reduce the incidence of bradycardic TdP) [
], and permanent pacemaker interrogation in patients with previous TTS-related bradyarrhythmia frequently reveals a high degree of ventricular pacing, with a relatively smaller requirement for atrial pacing [
]. However, permanent pacemakers have not been observed to reduce sudden death, despite evidence of sudden death occurring in patients with asystole or bradyarrhythmia as their presenting rhythm who did not undergo permanent pacemaker implantation [
Takotsubo syndrome is a unique disease marked by a self-limiting course, with risks of high mortality secondary to acute haemodynamic instability and arrhythmic complications. Acute inflammation and cardiomyocyte disorganisation coupled with catecholamine effects likely contribute to repolarisation abnormalities and electrical instability.
Electrocardiographic changes in TTS can mimic acute myocardial infarction and coronary assessment is required to differentiate these two entities. ST-elevation without reciprocal changes, QT prolongation and giant T wave inversion are commonly recognised ECG findings.
Atrial fibrillation is common in TTS and associated with significant in-hospital mortality, although this is most likely mediated by a shared aetiology of high inflammatory burden in a subset of elderly and co-morbid patients. The ventricular arrhythmias in TTS are mostly, but not always, associated with a prolonged QT interval. Their mechanisms may be understood by increased automaticity, early afterdepolarisations, and regions of functional block from myocardial oedema.
Bradyarrhythmias in TTS often require either temporary or permanent pacing. The role of pacemakers in preventing mortality remains unclear despite evidence of persistence of conduction abnormalities. Decisions regarding device therapy for ventricular arrhythmias should be individualised as rates of recurrence are generally low. A summary of arrhythmias in TTS is provided in Table 1.
Table 1Arrhythmias and their incidence, mechanisms, and treatment in Takotsubo syndrome.
Supportive treatment of underlying sepsis, hypoxia; digoxin, amiodarone Beta blockade if blood pressure allows Anticoagulation based on CHADS2VASc score
Life-threatening ventricular arrhythmia
4-14%
Ventricular tachycardia
∼1-5%
If monomorphic, re-entry around an area of functional block due to myocardial oedema
Magnesium sulfate, consider amiodarone Defibrillation if unstable Consider implantable cardiac defibrillator despite reversible nature of TTS if unstable presentation
Torsades de Pointes and ventricular fibrillation
∼6-10%
Prolonged QT interval due to enhanced late sodium and supressed outward potassium currents → prolonged action potential duration → early afterdepolarisations
Magnesium sulfate Caution with amiodarone and beta blockade (QT interval prolongation) Defibrillation if unstable Consider implantable cardiac defibrillator despite reversible nature of TTS if unstable presentation
Atrioventricular block
0.6-2.9%
Enhanced parasympathetic activity in late phase of autonomic storm. Pause-dependent QT prolongation → risk of early afterdepolarisation and Torsades
Avoid AV-nodal blocking agents e.g., beta blockers, calcium channel blockers, digoxin, amiodarone permanent pacemaker implantation due to high rates of arrhythmia persistence
Specific findings of the standard 12-lead ECG in patients with 'Takotsubo' cardiomyopathy: comparison with the findings of acute anterior myocardial infarction.
High levels of circulating epinephrine trigger apical cardiodepression in a β2-adrenergic receptor/Gi-dependent manner: a new model of Takotsubo cardiomyopathy.
The left atrial function is transiently impaired in Tako-tsubo cardiomyopathy and associated to in-hospital complications: a prospective study using two-dimensional strain.
Clinical impact of atrial fibrillation on short-term outcomes and in-hospital mortality in patients with Takotsubo syndrome: a propensity-matched national study.
Left ventricular thrombi in Takotsubo syndrome: incidence, predictors, and management: results from the GEIST (German Italian Stress Cardiomyopathy) Registry.
Electrocardiogram mimics of acute ST-segment elevation myocardial infarction: insights from cardiac magnetic resonance imaging in patients with tako-tsubo (stress) cardiomyopathy.
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