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Heart, Lung and Circulation

Arrhythmias and Their Electrophysiological Mechanisms in Takotsubo Syndrome: A Narrative Review

      Background

      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.

      Keywords

      Introduction

      Takotsubo syndrome (TTS) is an acutely reversible form of heart failure, traditionally associated with catecholamine release in both physically and emotionally stressful states [
      • Medina de Chazal H.
      • Del Buono M.G.
      • Keyser-Marcus L.
      • Ma L.
      • Moeller F.G.
      • Berrocal D.
      • et al.
      Stress cardiomyopathy diagnosis and treatment: JACC state-of-the-art review.
      ]. The apical form is the most common variant (81.7%), followed by mid-ventricular (14.6%), basal (2.2%) and focal (1.5%) forms [
      • Ghadri J.R.
      • Cammann V.L.
      • Napp L.C.
      • Jurisic S.
      • Diekmann J.
      • Bataiosu D.R.
      • et al.
      Differences in the clinical profile and outcomes of typical and atypical takotsubo syndrome: data from the International Takotsubo Registry.
      ].
      Various clinical criteria [
      • Prasad A.
      • Lerman A.
      • Rihal C.S.
      Apical ballooning syndrome (Tako-Tsubo or stress cardiomyopathy): a mimic of acute myocardial infarction.
      ,
      • Kawai S.
      • Kitabatake A.
      • Tomoike H.
      Guidelines for diagnosis of takotsubo (ampulla) cardiomyopathy.
      ] 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 [
      • Ghadri J.-R.
      • Wittstein I.S.
      • Prasad A.
      • Sharkey S.
      • Dote K.
      • Akashi Y.J.
      • et al.
      International Expert Consensus Document on Takotsubo Syndrome (Part I): clinical characteristics, diagnostic criteria, and pathophysiology.
      ] (Supplementary Table 1).
      Although considered a self-limiting condition, TTS carries a significant risk of mortality, with in-hospital mortality as high as 5% [
      • Medina de Chazal H.
      • Del Buono M.G.
      • Keyser-Marcus L.
      • Ma L.
      • Moeller F.G.
      • Berrocal D.
      • et al.
      Stress cardiomyopathy diagnosis and treatment: JACC state-of-the-art review.
      ]. Life-threatening arrhythmias commonly occur in the setting of a prolonged QT interval, with Torsades de Pointes (TdP) being the most well-known association [
      • Medina de Chazal H.
      • Del Buono M.G.
      • Keyser-Marcus L.
      • Ma L.
      • Moeller F.G.
      • Berrocal D.
      • et al.
      Stress cardiomyopathy diagnosis and treatment: JACC state-of-the-art review.
      ]. Cardiac arrest complicates up to 5.9% of cases [
      • Gili S.
      • Cammann V.L.
      • Schlossbauer S.A.
      • Kato K.
      • D'Ascenzo F.
      • Di Vece D.
      • et al.
      Cardiac arrest in takotsubo syndrome: results from the InterTAK Registry.
      ]; as many as 18% of patients with TTS have evidence of significant rhythm disturbance at hospital presentation [
      • El-Battrawy I.
      • Santoro F.
      • Stiermaier T.
      • Möller C.
      • Guastafierro F.
      • Novo G.
      • et al.
      Prevalence, management, and outcome of adverse rhythm disorders in takotsubo syndrome: insights from the international multicenter GEIST registry.
      ].
      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 thumbnail gr1
      Figure 1Flowchart depicting strategy for article inclusion.

      ECG Changes and Evolution

      Clinically and electrocardiographically, TTS can mimic acute anterior myocardial infarction, with ST segment elevation in the praecordial leads [
      • Medina de Chazal H.
      • Del Buono M.G.
      • Keyser-Marcus L.
      • Ma L.
      • Moeller F.G.
      • Berrocal D.
      • et al.
      Stress cardiomyopathy diagnosis and treatment: JACC state-of-the-art review.
      ]; 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 [
      • Medina de Chazal H.
      • Del Buono M.G.
      • Keyser-Marcus L.
      • Ma L.
      • Moeller F.G.
      • Berrocal D.
      • et al.
      Stress cardiomyopathy diagnosis and treatment: JACC state-of-the-art review.
      ].
      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 [
      • Awad H.H.
      • McNeal A.R.
      • Goyal H.
      Reverse Takotsubo cardiomyopathy: a comprehensive review.
      ,
      • Manzanal A.
      • Ruiz L.
      • Madrazo J.
      • Makan M.
      • Perez J.
      Inverted Takotsubo cardiomyopathy and the fundamental diagnostic role of echocardiography.
      ]. Focal TTS variants frequently involve the interventricular septum, with ECG changes that reflect the involved territory, with or without reciprocal changes [
      • Tini G.
      • Limite L.R.
      • Arcari L.
      • Cacciotti L.
      • Russo D.
      • Sclafani M.
      • et al.
      A systematic review on focal takotsubo syndrome: a not-so-small matter.
      ]. The absence of ECG changes is relatively specific for the mid-wall variant of TTS [
      • Hafeez Y.G.K.
      Mid-Ventricular Takotsubo Cardiomyopathy. [Updated 2020 Aug 10]. StatPearls [Internet] [Internet]. 2021.
      ], but T wave inversion without ST elevation has also been described [
      • Weihs V.
      • Szücs D.
      • Fellner B.
      • Eber B.
      • Weihs W.
      • Lambert T.
      • et al.
      Electrocardiogram changes and wall motion abnormalities in the acute phase of Tako-Tsubo syndrome.
      ].

      PR Interval

      PR segment depression has been reported in TTS and is thought to be related to catecholamine surge [
      • Guerra F.
      • Giannini I.
      • Capucci A.
      The ECG in the differential diagnosis between takotsubo cardiomyopathy and acute coronary syndrome.
      ]. It is relatively specific, and is present in TTS with and without pericardial involvement, as defined on cardiac magnetic resonance (CMR) [
      • Zorzi A.
      • Baritussio A.
      • ElMaghawry M.
      • Siciliano M.
      • Migliore F.
      • Perazzolo Marra M.
      • et al.
      Differential diagnosis at admission between Takotsubo cardiomyopathy and acute apical-anterior myocardial infarction in postmenopausal women.
      ]. 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) [
      • Jesel L.
      • Berthon C.
      • Messas N.
      • Lim H.S.
      • Girardey M.
      • Marzak H.
      • et al.
      Ventricular arrhythmias and sudden cardiac arrest in Takotsubo cardiomyopathy: Incidence, predictive factors, and clinical implications.
      ]. These are thought to be transient and related to oedema and myocardial inflammatory cell infiltrate [
      • Syed I.S.
      • Prasad A.
      • Oh J.K.
      • Martinez M.W.
      • Feng D.
      • Motiei A.
      • et al.
      Apical ballooning syndrome or aborted acute myocardial infarction? Insights from cardiovascular magnetic resonance imaging.
      ,
      • Nef H.M.
      • Möllmann H.
      • Kostin S.
      • Troidl C.
      • Voss S.
      • Weber M.
      • et al.
      Tako-Tsubo cardiomyopathy: intraindividual structural analysis in the acute phase and after functional recovery.
      ].

      QRS Complex

      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 [
      • Looi J.L.
      • Wong C.W.
      • Lee M.
      • Khan A.
      • Webster M.
      • Kerr A.J.
      Usefulness of ECG to differentiate Takotsubo cardiomyopathy from acute coronary syndrome.
      ]. 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 [
      • Guerra F.
      • Giannini I.
      • Capucci A.
      The ECG in the differential diagnosis between takotsubo cardiomyopathy and acute coronary syndrome.
      ].
      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 [
      • Guerra F.
      • Giannini I.
      • Pongetti G.
      • Fabbrizioli A.
      • Rrapaj E.
      • Aschieri D.
      • et al.
      Transient QRS amplitude attenuation is associated with clinical recovery in patients with takotsubo cardiomyopathy.
      ,
      • Madias J.E.
      Transient attenuation of the amplitude of the QRS complexes in the diagnosis of Takotsubo syndrome.
      ]. 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 [
      • Jesel L.
      • Berthon C.
      • Messas N.
      • Lim H.S.
      • Girardey M.
      • Marzak H.
      • et al.
      Ventricular arrhythmias and sudden cardiac arrest in Takotsubo cardiomyopathy: Incidence, predictive factors, and clinical implications.
      ]. 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 [
      • Parodi G.
      • Salvadori C.
      • Del Pace S.
      • Bellandi B.
      • Carrabba N.
      • Gensini G.F.
      • et al.
      Left bundle branch block as an electrocardiographic pattern at presentation of patients with Tako-tsubo cardiomyopathy.
      ].

      ST Segment

      The time course of ST elevation can be variable and often lasts between 1–3 days, occurring in approximately one-third of TTS cases [
      • Namgung J.
      Electrocardiographic Findings in Takotsubo cardiomyopathy: ECG evolution and its difference from the ECG of acute coronary syndrome.
      ].
      Per Kosuge et al., the absence of ST elevation in V1 and presence of ST depression in aVR confers a high sensitivity and specificity for TTS [
      • Kosuge M.
      • Ebina T.
      • Hibi K.
      • Morita S.
      • Okuda J.
      • Iwahashi N.
      • et al.
      Simple and accurate electrocardiographic criteria to differentiate takotsubo cardiomyopathy from anterior acute myocardial infarction.
      ]. 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%) [
      • Frangieh A.H.
      • Obeid S.
      • Ghadri J.R.
      • Imori Y.
      • D'Ascenzo F.
      • Kovac M.
      • et al.
      ECG criteria to differentiate between Takotsubo (stress) cardiomyopathy and myocardial infarction.
      ].
      Figure thumbnail gr2
      Figure 2Polarity of limb leads in the standard 12-lead ECG (electrocardiograph).
      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 [
      • Rezaie S.
      REBEL EM blog [Internet].
      ].
      Takotsubo syndrome is associated with a greater ST elevation ratio in leads V4-6: V1-3 [
      • Ogura R.
      • Hiasa Y.
      • Takahashi T.
      • Yamaguchi K.
      • Fujiwara K.
      • Ohara Y.
      • et al.
      Specific findings of the standard 12-lead ECG in patients with 'Takotsubo' cardiomyopathy: comparison with the findings of acute anterior myocardial infarction.
      ], and ST elevation ≤0.2 mm is considered specific for TTS [
      • Kosuge M.
      • Ebina T.
      • Hibi K.
      • Morita S.
      • Okuda J.
      • Iwahashi N.
      • et al.
      Simple and accurate electrocardiographic criteria to differentiate takotsubo cardiomyopathy from anterior acute myocardial infarction.
      ], especially when paired with PR segment depression [
      • Zorzi A.
      • Baritussio A.
      • ElMaghawry M.
      • Siciliano M.
      • Migliore F.
      • Perazzolo Marra M.
      • et al.
      Differential diagnosis at admission between Takotsubo cardiomyopathy and acute apical-anterior myocardial infarction in postmenopausal women.
      ]. ST elevation at presentation is associated with the development of cardiac arrest (42% in the interTAK registry) [
      • Gili S.
      • Cammann V.L.
      • Schlossbauer S.A.
      • Kato K.
      • D'Ascenzo F.
      • Di Vece D.
      • et al.
      Cardiac arrest in takotsubo syndrome: results from the InterTAK Registry.
      ].
      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 [
      • Frangieh A.H.
      • Obeid S.
      • Ghadri J.R.
      • Imori Y.
      • D'Ascenzo F.
      • Kovac M.
      • et al.
      ECG criteria to differentiate between Takotsubo (stress) cardiomyopathy and myocardial infarction.
      ]. The lack of reciprocal ST segment changes in general seems to be more specific for TTS, as compared with STEMI [
      • Ogura R.
      • Hiasa Y.
      • Takahashi T.
      • Yamaguchi K.
      • Fujiwara K.
      • Ohara Y.
      • et al.
      Specific findings of the standard 12-lead ECG in patients with 'Takotsubo' cardiomyopathy: comparison with the findings of acute anterior myocardial infarction.
      ].

      T Wave

      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 [
      • Guerra F.
      • Giannini I.
      • Capucci A.
      The ECG in the differential diagnosis between takotsubo cardiomyopathy and acute coronary syndrome.
      ]. It is present in up to 40–45% of TTS in the first 12 hours [
      • Zorzi A.
      • Baritussio A.
      • ElMaghawry M.
      • Siciliano M.
      • Migliore F.
      • Perazzolo Marra M.
      • et al.
      Differential diagnosis at admission between Takotsubo cardiomyopathy and acute apical-anterior myocardial infarction in postmenopausal women.
      ,
      • Frangieh A.H.
      • Obeid S.
      • Ghadri J.R.
      • Imori Y.
      • D'Ascenzo F.
      • Kovac M.
      • et al.
      ECG criteria to differentiate between Takotsubo (stress) cardiomyopathy and myocardial infarction.
      ], and up to 75% at 48 hours [
      • Bennett J.
      • Ferdinande B.
      • Kayaert P.
      • Wiyono S.
      • Dubois C.
      • Sinnaeve P.
      • et al.
      Time course of electrocardiographic changes in transient left ventricular ballooning syndrome.
      ]. TWI in TTS is usually deeper and more widespread compared to acute coronary syndrome [
      • Looi J.L.
      • Wong C.W.
      • Lee M.
      • Khan A.
      • Webster M.
      • Kerr A.J.
      Usefulness of ECG to differentiate Takotsubo cardiomyopathy from acute coronary syndrome.
      ]. This has been described as “giant”, usually seen after 24–72 hours as a second phase post an initial smaller TWI [
      • Mitsuma W.
      • Kodama M.
      • Ito M.
      • Tanaka K.
      • Yanagawa T.
      • Ikarashi N.
      • et al.
      Serial electrocardiographic findings in women with Takotsubo cardiomyopathy.
      ] (Figure 4). Initial ECGs showing T wave inversion as opposed to ST elevation may reflect a later presentation of TTS.
      Figure thumbnail gr3
      Figure 3ECG progression of the ST segment and T wave changes in anterolateral STEMI vs Takotsubo syndrome.
      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.
      Figure thumbnail gr4
      Figure 4Spiked helmet sign.
      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. [
      • Littmann L.
      • Monroe M.H.
      The “spiked helmet” sign: a new electrocardiographic marker of critical illness and high risk of death.
      ].
      Abbreviation: ECG, electrocardiograph.
      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% [
      • Looi J.L.
      • Wong C.W.
      • Lee M.
      • Khan A.
      • Webster M.
      • Kerr A.J.
      Usefulness of ECG to differentiate Takotsubo cardiomyopathy from acute coronary syndrome.
      ]. Arrhythmia risk remains elevated until normalisation of TWI or QTc prolongation [
      • Dib C.
      • Prasad A.
      • Friedman P.A.
      • Ahmad E.
      • Rihal C.S.
      • Hammill S.C.
      • et al.
      Malignant arrhythmia in apical ballooning syndrome: risk factors and outcomes.
      ]. Early TWI on admission is also associated with cardiac arrest [
      • Gili S.
      • Cammann V.L.
      • Schlossbauer S.A.
      • Kato K.
      • D'Ascenzo F.
      • Di Vece D.
      • et al.
      Cardiac arrest in takotsubo syndrome: results from the InterTAK Registry.
      ], but paradoxically TWI is also associated with a lower risk of ventricular arrhythmia [
      • Jha S.
      • Zeijlon R.
      • Enabtawi I.
      • Espinosa A.S.
      • Chamat J.
      • Omerovic E.
      • et al.
      Electrocardiographic predictors of adverse in-hospital outcomes in the Takotsubo syndrome.
      ].

      QT Interval

      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 [
      • Kurisu S.
      • Kihara Y.
      Tako-tsubo cardiomyopathy: clinical presentation and underlying mechanism.
      ], and tends to be longer than that seen in STEMI patients (86 ms vs 31 ms in one study) [
      • Looi J.L.
      • Wong C.W.
      • Lee M.
      • Khan A.
      • Webster M.
      • Kerr A.J.
      Usefulness of ECG to differentiate Takotsubo cardiomyopathy from acute coronary syndrome.
      ]. QTc prolongation is seen in up to 90% of TTS presenters [
      • Jesel L.
      • Berthon C.
      • Messas N.
      • Lim H.S.
      • Girardey M.
      • Marzak H.
      • et al.
      Ventricular arrhythmias and sudden cardiac arrest in Takotsubo cardiomyopathy: Incidence, predictive factors, and clinical implications.
      ]. 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 [
      • Dib C.
      • Prasad A.
      • Friedman P.A.
      • Ahmad E.
      • Rihal C.S.
      • Hammill S.C.
      • et al.
      Malignant arrhythmia in apical ballooning syndrome: risk factors and outcomes.
      ]. 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 [
      • Perazzolo Marra M.
      • Zorzi A.
      • Corbetti F.
      • De Lazzari M.
      • Migliore F.
      • Tona F.
      • et al.
      Apicobasal gradient of left ventricular myocardial edema underlies transient T-wave inversion and QT interval prolongation (Wellens' ECG pattern) in Tako-Tsubo cardiomyopathy.
      ].
      QTc prolongation is widely reported to be associated with ventricular arrhythmias in TTS [
      • Madias C.
      • Fitzgibbons T.P.
      • Alsheikh-Ali A.A.
      • Bouchard J.L.
      • Kalsmith B.
      • Garlitski A.C.
      • et al.
      Acquired long QT syndrome from stress cardiomyopathy is associated with ventricular arrhythmias and torsades de pointes.
      ]. It reflects prolonged repolarisation, likely via elevated cyclic adenosine monophosphate (cAMP) levels and decreased potassium channel activity [
      • Petrov I.S.
      • Tokmakova M.P.
      • Marchov D.N.
      • Kichukov K.N.
      Is everything clear about Tako-tsubo syndrome?.
      ]. In TTS, the QTc is often in the interval of >460 ms [
      • El-Battrawy I.
      • Lang S.
      • Ansari U.
      • Tülümen E.
      • Schramm K.
      • Fastner C.
      • et al.
      Prevalence of malignant arrhythmia and sudden cardiac death in takotsubo syndrome and its management.
      ], but can be markedly prolonged (600–650 ms) when associated with TdP [
      • Singh K.
      • Carson K.
      • Hibbert B.
      • Le May M.
      Natural history of cardiac arrest in patients with Takotsubo cardiomyopathy.
      ], which is often associated with predisposing conditions such as bradycardia, electrolyte disturbance and medications [
      • Samuelov-Kinori L.
      • Kinori M.
      • Kogan Y.
      • Swartzon M.
      • Shalev H.
      • Guy D.
      • et al.
      Takotsubo cardiomyopathy and QT interval prolongation: who are the patients at risk for torsades de pointes?.
      ]. QT interval change can persist over weeks, sometimes beyond the duration of arrhythmia [
      • Samuelov-Kinori L.
      • Kinori M.
      • Kogan Y.
      • Swartzon M.
      • Shalev H.
      • Guy D.
      • et al.
      Takotsubo cardiomyopathy and QT interval prolongation: who are the patients at risk for torsades de pointes?.
      ].
      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 [
      • Littmann L.
      • Monroe M.H.
      The “spiked helmet” sign: a new electrocardiographic marker of critical illness and high risk of death.
      ,
      • Lin Y.K.
      • Chen K.C.
      • Huang Y.N.
      • Chang H.
      The 'spiked-helmet' sign in patients with myocardial injury.
      ]. 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 [
      • Simon A.
      • Járai Z.
      Is the spiked helmet sign the manifestation of long QT syndrome?.
      ]. 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) [
      • Gerald W.
      • Dorn I.
      Adrenergic signaling polymorphisms and their impact on cardiovascular disease.
      ].
      Animal work has shown that β2AR receptors have the highest concentration at the cardiac apex, creating an apico-basal gradient [
      • Lyon A.R.
      • Rees P.S.
      • Prasad S.
      • Poole-Wilson P.A.
      • Harding S.E.
      Stress (Takotsubo) cardiomyopathy--a novel pathophysiological hypothesis to explain catecholamine-induced acute myocardial stunning.
      ]. 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 [
      • Lyon A.R.
      • Rees P.S.
      • Prasad S.
      • Poole-Wilson P.A.
      • Harding S.E.
      Stress (Takotsubo) cardiomyopathy--a novel pathophysiological hypothesis to explain catecholamine-induced acute myocardial stunning.
      ,
      • Paur H.
      • Wright P.T.
      • Sikkel M.B.
      • Tranter M.H.
      • Mansfield C.
      • O'Gara P.
      • et al.
      High levels of circulating epinephrine trigger apical cardiodepression in a β2-adrenergic receptor/Gi-dependent manner: a new model of Takotsubo cardiomyopathy.
      ,
      • Nef H.M.
      • Möllmann H.
      • Hilpert P.
      • Troidl C.
      • Voss S.
      • Rolf A.
      • et al.
      Activated cell survival cascade protects cardiomyocytes from cell death in Tako-Tsubo 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 [
      • Ellison G.M.
      • Torella D.
      • Karakikes I.
      • Purushothaman S.
      • Curcio A.
      • Gasparri C.
      • et al.
      Acute beta-adrenergic overload produces myocyte damage through calcium leakage from the ryanodine receptor 2 but spares cardiac stem cells.
      ]. 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 [
      • Borchert T.
      • Hübscher D.
      • Guessoum C.I.
      • Lam T.D.
      • Ghadri J.R.
      • Schellinger I.N.
      • et al.
      Catecholamine-dependent β-adrenergic signaling in a pluripotent stem cell model of Takotsubo cardiomyopathy.
      ], 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. [
      • Nef H.M.
      • Möllmann H.
      • Kostin S.
      • Troidl C.
      • Voss S.
      • Weber M.
      • et al.
      Tako-Tsubo cardiomyopathy: intraindividual structural analysis in the acute phase and after functional recovery.
      ] 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 [
      • Karch S.B.
      • Billingham M.E.
      Myocardial contraction bands revisited.
      ,
      • Rona G.
      Catecholamine cardiotoxicity.
      ]. 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 [
      • Samuels M.A.
      The brain and heart connection.
      ].
      Despite extensive beta-adrenoceptor work, the genetic underpinnings of TTS likely lie outside of variations in these receptors alone [
      • Goodloe A.H.
      • Evans J.M.
      • Middha S.
      • Prasad A.
      • Olson T.M.
      Characterizing genetic variation of adrenergic signalling pathways in Takotsubo (stress) cardiomyopathy exomes.
      ], 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 [
      • Nef H.M.
      • Möllmann H.
      • Troidl C.
      • Kostin S.
      • Böttger T.
      • Voss S.
      • et al.
      Expression profiling of cardiac genes in Tako-Tsubo cardiomyopathy: insight into a new cardiac entity.
      ].

      Atrial Arrhythmias

      Atrial arrhythmias, most commonly atrial fibrillation (AF) but also atrial flutter, occur in about 5–15% of TTS patients [
      • Medina de Chazal H.
      • Del Buono M.G.
      • Keyser-Marcus L.
      • Ma L.
      • Moeller F.G.
      • Berrocal D.
      • et al.
      Stress cardiomyopathy diagnosis and treatment: JACC state-of-the-art review.
      ]. These are usually transient and are associated with heart failure, sepsis and hypoxia [
      • Jesel L.
      • Berthon C.
      • Messas N.
      • Lim H.S.
      • Girardey M.
      • Marzak H.
      • et al.
      Atrial arrhythmias in Takotsubo cardiomyopathy: incidence, predictive factors, and prognosis.
      ]. 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 [
      • Chen P.-S.
      • Chen L.S.
      • Fishbein M.C.
      • Lin S.-F.
      • Nattel S.
      Role of the autonomic nervous system in atrial fibrillation: pathophysiology and therapy.
      ]. 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 [
      • Meimoun P.
      • Stracchi V.
      • Boulanger J.
      • Martis S.
      • Botoro T.
      • Zemir H.
      • et al.
      The left atrial function is transiently impaired in Tako-tsubo cardiomyopathy and associated to in-hospital complications: a prospective study using two-dimensional strain.
      ].
      Interestingly, AF occurs more commonly in patients who have TTS with life threatening ventricular arrhythmias [
      • Gili S.
      • Cammann V.L.
      • Schlossbauer S.A.
      • Kato K.
      • D'Ascenzo F.
      • Di Vece D.
      • et al.
      Cardiac arrest in takotsubo syndrome: results from the InterTAK Registry.
      ,
      • El-Battrawy I.
      • Lang S.
      • Ansari U.
      • Tülümen E.
      • Schramm K.
      • Fastner C.
      • et al.
      Prevalence of malignant arrhythmia and sudden cardiac death in takotsubo syndrome and its management.
      ]. Though a harbinger of increased all-cause mortality [
      • Prasitlumkum N.
      • Kittipibul V.
      • Limpruttidham N.
      • Rattanawong P.
      • Chongsathidkiet P.
      • Boondarikpornpant T.
      The presence of atrial fibrillation in Takotsubo cardiomyopathy is predictive of mortality: Systematic review and meta-analysis.
      ,
      • Stiermaier T.
      • Santoro F.
      • Eitel C.
      • Graf T.
      • Möller C.
      • Tarantino N.
      • et al.
      Prevalence and prognostic relevance of atrial fibrillation in patients with Takotsubo syndrome.
      ], atrial arrhythmias do not independently predict mortality once inflammatory burden is accounted for [
      • Jesel L.
      • Berthon C.
      • Messas N.
      • Lim H.S.
      • Girardey M.
      • Marzak H.
      • et al.
      Atrial arrhythmias in Takotsubo cardiomyopathy: incidence, predictive factors, and prognosis.
      ,
      • Yassin A.S.
      • Subahi A.
      • Adegbala O.
      • Abubakar H.
      • Dawdy J.
      • Mishra T.
      • et al.
      Clinical impact of atrial fibrillation on short-term outcomes and in-hospital mortality in patients with Takotsubo syndrome: a propensity-matched national study.
      ].
      The stroke risk in TTS is reported to be 2–9% in patients without AF, due to the formation of left ventricular thrombus [
      • Medina de Chazal H.
      • Del Buono M.G.
      • Keyser-Marcus L.
      • Ma L.
      • Moeller F.G.
      • Berrocal D.
      • et al.
      Stress cardiomyopathy diagnosis and treatment: JACC state-of-the-art review.
      ]. The greatest risk of this occurs at days 2–5, when left ventricular ejection fraction is most depressed [
      • Heckle M.R.
      • McCoy C.W.
      • Akinseye O.A.
      • Khouzam R.N.
      Stress-induced thrombus: prevalence of thromboembolic events and the role of anticoagulation in Takotsubo cardiomyopathy.
      ,
      • Santoro F.
      • Stiermaier T.
      • Tarantino N.
      • De Gennaro L.
      • Moeller C.
      • Guastafierro F.
      • et al.
      Left ventricular thrombi in Takotsubo syndrome: incidence, predictors, and management: results from the GEIST (German Italian Stress Cardiomyopathy) Registry.
      ]. The incidence of stroke in TTS patients with AF is not well delineated, likely due to low event rates in small sub-cohort in studies [
      • El-Battrawy I.
      • Lang S.
      • Ansari U.
      • Behnes M.
      • Hillenbrand D.
      • Schramm K.
      • et al.
      Impact of concomitant atrial fibrillation on the prognosis of Takotsubo cardiomyopathy.
      ,
      • de Gregorio C.
      • Grimaldi P.
      • Lentini C.
      Left ventricular thrombus formation and cardioembolic complications in patients with Takotsubo-like syndrome: a systematic review.
      ]. 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 [
      • Chong C.R.
      • Neil C.J.
      • Nguyen T.H.
      • Stansborough J.
      • Law G.W.
      • Singh K.
      • et al.
      Dissociation between severity of takotsubo cardiomyopathy and presentation with shock or hypotension.
      ]. 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 [
      • Medina de Chazal H.
      • Del Buono M.G.
      • Keyser-Marcus L.
      • Ma L.
      • Moeller F.G.
      • Berrocal D.
      • et al.
      Stress cardiomyopathy diagnosis and treatment: JACC state-of-the-art review.
      ].

      Ventricular Arrhythmias

      The prevalence of life-threatening arrhythmias in TTS ranges from 4–14% across studies [
      • Medina de Chazal H.
      • Del Buono M.G.
      • Keyser-Marcus L.
      • Ma L.
      • Moeller F.G.
      • Berrocal D.
      • et al.
      Stress cardiomyopathy diagnosis and treatment: JACC state-of-the-art review.
      ,
      • El-Battrawy I.
      • Lang S.
      • Ansari U.
      • Tülümen E.
      • Schramm K.
      • Fastner C.
      • et al.
      Prevalence of malignant arrhythmia and sudden cardiac death in takotsubo syndrome and its management.
      ,
      • Auzel O.
      • Mustafic H.
      • Pillière R.
      • El Mahmoud R.
      • Dubourg O.
      • Mansencal N.
      Incidence, characteristics, risk factors, and outcomes of Takotsubo cardiomyopathy with and without ventricular arrhythmia.
      ,
      • Möller C.
      • Eitel C.
      • Thiele H.
      • Eitel I.
      • Stiermaier T.
      Ventricular arrhythmias in patients with Takotsubo syndrome.
      ,
      • Stiermaier T.
      • Eitel C.
      • Denef S.
      • Desch S.
      • Schuler G.
      • Thiele H.
      • et al.
      Prevalence and clinical significance of life-threatening arrhythmias in Takotsubo cardiomyopathy.
      ], usually in the setting of QTc prolongation [
      • Madias C.
      • Fitzgibbons T.P.
      • Alsheikh-Ali A.A.
      • Bouchard J.L.
      • Kalsmith B.
      • Garlitski A.C.
      • et al.
      Acquired long QT syndrome from stress cardiomyopathy is associated with ventricular arrhythmias and torsades de pointes.
      ]. 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 [
      • Möller C.
      • Eitel C.
      • Thiele H.
      • Eitel I.
      • Stiermaier T.
      Ventricular arrhythmias in patients with Takotsubo syndrome.
      ]. VA can be the presenting complaint, or develop early during hospital admission, usually within the first 24 hours [
      • Jesel L.
      • Berthon C.
      • Messas N.
      • Lim H.S.
      • Girardey M.
      • Marzak H.
      • et al.
      Ventricular arrhythmias and sudden cardiac arrest in Takotsubo cardiomyopathy: Incidence, predictive factors, and clinical implications.
      ,
      • El-Battrawy I.
      • Lang S.
      • Ansari U.
      • Tülümen E.
      • Schramm K.
      • Fastner C.
      • et al.
      Prevalence of malignant arrhythmia and sudden cardiac death in takotsubo syndrome and its management.
      ]. Monomorphic VT seems to confer an increased mortality rate as compared to TdP [
      • Möller C.
      • Eitel C.
      • Thiele H.
      • Eitel I.
      • Stiermaier T.
      Ventricular arrhythmias in patients with Takotsubo syndrome.
      ], despite the higher prevalence of TdP-induced VF in TTS. Electrocardiographic predictors of VA include presence of a J wave (associated with VT) [
      • Möller C.
      • Eitel C.
      • Thiele H.
      • Eitel I.
      • Stiermaier T.
      Ventricular arrhythmias in patients with Takotsubo syndrome.
      ].
      The mechanisms of VA in TTS are best appreciated using the classic electrophysiological paradigms of re-entry, triggered activity and automaticity.
      Re-entry around a focal area of scar is an established mechanism in monomorphic VT [
      • Wang L.
      • Gharbia O.A.
      • Horáček B.M.
      • Sapp J.L.
      Noninvasive epicardial and endocardial electrocardiographic imaging of scar-related ventricular tachycardia.
      ]. However, there is a lack of imaging findings of ‘scar’, either on echocardiography or CMR in TTS [
      • Syed I.S.
      • Prasad A.
      • Oh J.K.
      • Martinez M.W.
      • Feng D.
      • Motiei A.
      • et al.
      Apical ballooning syndrome or aborted acute myocardial infarction? Insights from cardiovascular magnetic resonance imaging.
      ,

      Neil C. Tako-Tsubo (stress) cardiomyopathy: pathophysiology and natural history [dissertation]: The University of Adelaide; 2012.

      ]. Late gadolinium enhancement, even if present on CMR, is usually below standard threshold values [
      • Kohan A.A.
      • Levy Yeyati E.
      • De Stefano L.
      • Dragonetti L.
      • Pietrani M.
      • Perez de Arenaza D.
      • et al.
      Usefulness of MRI in takotsubo cardiomyopathy: a review of the literature.
      ]. 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 [
      • Möller C.
      • Eitel C.
      • Thiele H.
      • Eitel I.
      • Stiermaier T.
      Ventricular arrhythmias in patients with Takotsubo syndrome.
      ,

      Neil C. Tako-Tsubo (stress) cardiomyopathy: pathophysiology and natural history [dissertation]: The University of Adelaide; 2012.

      ,
      • Sharkey S.W.
      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 [
      • Chen P.-S.
      • Chen L.S.
      • Fishbein M.C.
      • Lin S.-F.
      • Nattel S.
      Role of the autonomic nervous system in atrial fibrillation: pathophysiology and therapy.
      ]. 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 [
      • El-Battrawy I.
      • Zhao Z.
      • Lan H.
      • Schünemann J.-D.
      • Sattler K.
      • Buljubasic F.
      • et al.
      Estradiol protection against toxic effects of catecholamine on electrical properties in human-induced pluripotent stem cell derived cardiomyocytes.
      ]. The QTc prolongation observed in TTS may be related to the rate-independent component (T wave apex to end) of the QT interval [
      • Merri M.
      • Benhorin J.
      • Alberti M.
      • Locati E.
      • Moss A.J.
      Electrocardiographic quantitation of ventricular repolarization.
      ], with giant T waves contributing to this.
      Human enzymatic evidence of minimal myocardial necrosis in TTS [
      • Wittstein I.S.
      • Thiemann D.R.
      • Lima J.A.
      • Baughman K.L.
      • Schulman S.P.
      • Gerstenblith G.
      • et al.
      Neurohumoral features of myocardial stunning due to sudden emotional stress.
      ] suggests that catecholamine excess possibly contributes to arrhythmogenesis by the alternative mechanism of increased cardiomyocyte automaticity [
      • Paur H.
      • Wright P.T.
      • Sikkel M.B.
      • Tranter M.H.
      • Mansfield C.
      • O'Gara P.
      • et al.
      High levels of circulating epinephrine trigger apical cardiodepression in a β2-adrenergic receptor/Gi-dependent manner: a new model of Takotsubo cardiomyopathy.
      ,
      • Möller C.
      • Eitel C.
      • Thiele H.
      • Eitel I.
      • Stiermaier T.
      Ventricular arrhythmias in patients with Takotsubo syndrome.
      ,
      • Wittstein I.S.
      • Thiemann D.R.
      • Lima J.A.
      • Baughman K.L.
      • Schulman S.P.
      • Gerstenblith G.
      • et al.
      Neurohumoral features of myocardial stunning due to sudden emotional stress.
      ].
      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 [
      • El-Battrawy I.
      • Lang S.
      • Ansari U.
      • Tülümen E.
      • Schramm K.
      • Fastner C.
      • et al.
      Prevalence of malignant arrhythmia and sudden cardiac death in takotsubo syndrome and its management.
      ]. Independent predictors of adverse outcome in VA include concomitant atrial fibrillation, depressed left ventricular ejection fraction [
      • Jesel L.
      • Berthon C.
      • Messas N.
      • Lim H.S.
      • Girardey M.
      • Marzak H.
      • et al.
      Ventricular arrhythmias and sudden cardiac arrest in Takotsubo cardiomyopathy: Incidence, predictive factors, and clinical implications.
      ,
      • El-Battrawy I.
      • Lang S.
      • Ansari U.
      • Tülümen E.
      • Schramm K.
      • Fastner C.
      • et al.
      Prevalence of malignant arrhythmia and sudden cardiac death in takotsubo syndrome and its management.
      ], cardiogenic shock and a glomerular filtration rate <60 mL/min [
      • El-Battrawy I.
      • Lang S.
      • Ansari U.
      • Tülümen E.
      • Schramm K.
      • Fastner C.
      • et al.
      Prevalence of malignant arrhythmia and sudden cardiac death in takotsubo syndrome and its management.
      ], reflecting a more unwell population.
      Beta blockade may protect against malignant arrhythmias [
      • Dib C.
      • Prasad A.
      • Friedman P.A.
      • Ahmad E.
      • Rihal C.S.
      • Hammill S.C.
      • et al.
      Malignant arrhythmia in apical ballooning syndrome: risk factors and outcomes.
      ]; 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 [
      • Osteraas N.D.
      • Lee V.H.
      ]. Magnesium sulfate and defibrillation remain common treatment modalities for TdP, with caution regarding amiodarone [
      • El-Battrawy I.
      • Santoro F.
      • Stiermaier T.
      • Möller C.
      • Guastafierro F.
      • Novo G.
      • et al.
      Prevalence, management, and outcome of adverse rhythm disorders in takotsubo syndrome: insights from the international multicenter GEIST registry.
      ] and beta blocker [
      • Migliore F.
      • Zorzi A.
      • Peruzza F.
      • Perazzolo Marra M.
      • Tarantini G.
      • Iliceto S.
      • et al.
      Incidence and management of life-threatening arrhythmias in Takotsubo syndrome.
      ] 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 [
      • Santoro F.
      • Ieva R.
      • Musaico F.
      • Ferraretti A.
      • Triggiani G.
      • Tarantino N.
      • et al.
      Lack of efficacy of drug therapy in preventing takotsubo cardiomyopathy recurrence: a meta-analysis.
      ], 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 [
      • Samuels M.A.
      The brain and heart connection.
      ]. Exceptions to this practice include observed paradoxical vasodilation as described in Chong et al. [
      • Chong C.R.
      • Neil C.J.
      • Nguyen T.H.
      • Stansborough J.
      • Law G.W.
      • Singh K.
      • et al.
      Dissociation between severity of takotsubo cardiomyopathy and presentation with shock or hypotension.
      ], 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 [
      • Stiermaier T.
      • Moeller C.
      • Oehler K.
      • Desch S.
      • Graf T.
      • Eitel C.
      • et al.
      Long-term excess mortality in takotsubo cardiomyopathy: predictors, causes and clinical consequences.
      ,
      • Zalewska-Adamiec M.
      • Bachórzewska-Gajewska H.
      • Dobrzycki S.
      Cardiac rupture-the most serious complication of Takotsubo syndrome: a series of five cases and a systematic review.
      ].
      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 [
      • Gili S.
      • Cammann V.L.
      • Schlossbauer S.A.
      • Kato K.
      • D'Ascenzo F.
      • Di Vece D.
      • et al.
      Cardiac arrest in takotsubo syndrome: results from the InterTAK Registry.
      ], 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 [
      • Stiermaier T.
      • Rommel K.-P.
      • Eitel C.
      • Möller C.
      • Graf T.
      • Desch S.
      • et al.
      Management of arrhythmias in patients with Takotsubo cardiomyopathy: Is the implantation of permanent devices necessary?.
      ].
      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 [
      • Gili S.
      • Cammann V.L.
      • Schlossbauer S.A.
      • Kato K.
      • D'Ascenzo F.
      • Di Vece D.
      • et al.
      Cardiac arrest in takotsubo syndrome: results from the InterTAK Registry.
      ]. The cause of death remains unknown in a significant proportion of cases followed prospectively [
      • Gili S.
      • Cammann V.L.
      • Schlossbauer S.A.
      • Kato K.
      • D'Ascenzo F.
      • Di Vece D.
      • et al.
      Cardiac arrest in takotsubo syndrome: results from the InterTAK Registry.
      ,
      • Stiermaier T.
      • Moeller C.
      • Oehler K.
      • Desch S.
      • Graf T.
      • Eitel C.
      • et al.
      Long-term excess mortality in takotsubo cardiomyopathy: predictors, causes and clinical consequences.
      ], but recurrence of cardiac arrest is reported to be low [
      • Singh K.
      • Carson K.
      • Hibbert B.
      • Le May M.
      Natural history of cardiac arrest in patients with Takotsubo cardiomyopathy.
      ].
      The temporal relationship between TTS and arrhythmogenesis can be uncertain, with studies showing that cardiogenic shock is an independent predictor of adverse arrhythmias [
      • El-Battrawy I.
      • Santoro F.
      • Stiermaier T.
      • Möller C.
      • Guastafierro F.
      • Novo G.
      • et al.
      Prevalence, management, and outcome of adverse rhythm disorders in takotsubo syndrome: insights from the international multicenter GEIST registry.
      ]. 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 [
      • Singh K.
      • Carson K.
      • Hibbert B.
      • Le May M.
      Natural history of cardiac arrest in patients with Takotsubo cardiomyopathy.
      ,
      • Madias J.E.
      Cardiac arrest-triggered takotsubo syndrome vs. takotsubo syndrome complicated by cardiac arrest.
      ]. Further clouding the picture is the high use of catecholamine vasopressors in certain cohorts [
      • Stiermaier T.
      • Eitel C.
      • Desch S.
      • Fuernau G.
      • Schuler G.
      • Thiele H.
      • et al.
      Incidence, determinants and prognostic relevance of cardiogenic shock in patients with Takotsubo cardiomyopathy.
      ] 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 [
      • El-Battrawy I.
      • Santoro F.
      • Stiermaier T.
      • Möller C.
      • Guastafierro F.
      • Novo G.
      • et al.
      Prevalence, management, and outcome of adverse rhythm disorders in takotsubo syndrome: insights from the international multicenter GEIST registry.
      ]. These include complete atrioventricular (AV) block and asystole [
      • Jesel L.
      • Berthon C.
      • Messas N.
      • Lim H.S.
      • Girardey M.
      • Marzak H.
      • et al.
      Ventricular arrhythmias and sudden cardiac arrest in Takotsubo cardiomyopathy: Incidence, predictive factors, and clinical implications.
      ,
      • El-Battrawy I.
      • Lang S.
      • Ansari U.
      • Tülümen E.
      • Schramm K.
      • Fastner C.
      • et al.
      Prevalence of malignant arrhythmia and sudden cardiac death in takotsubo syndrome and its management.
      ], with prevalence of 0.6–2.9% [
      • Templin C.
      • Ghadri J.R.
      • Diekmann J.
      • Napp L.C.
      • Bataiosu D.R.
      • Jaguszewski M.
      • et al.
      Clinical features and outcomes of Takotsubo (stress) cardiomyopathy.
      ,
      • Syed F.F.
      • Asirvatham S.J.
      • Francis J.
      Arrhythmia occurrence with takotsubo cardiomyopathy: a literature review.
      ] and approximately 2.5% [
      • Dib C.
      • Prasad A.
      • Friedman P.A.
      • Ahmad E.
      • Rihal C.S.
      • Hammill S.C.
      • et al.
      Malignant arrhythmia in apical ballooning syndrome: risk factors and outcomes.
      ,
      • Stiermaier T.
      • Eitel C.
      • Denef S.
      • Desch S.
      • Schuler G.
      • Thiele H.
      • et al.
      Prevalence and clinical significance of life-threatening arrhythmias in Takotsubo cardiomyopathy.
      ] in studies respectively. Sinoatrial block has also been observed in 1.3% of patients in cohort studies [
      • Syed F.F.
      • Asirvatham S.J.
      • Francis J.
      Arrhythmia occurrence with takotsubo cardiomyopathy: a literature review.
      ].
      The mechanism of bradyarrhythmia is unclear, although some authors posit a secondary increase in vagal tone as a compensation for catecholamine surge [
      • Syed F.F.
      • Asirvatham S.J.
      • Francis J.
      Arrhythmia occurrence with takotsubo cardiomyopathy: a literature review.
      ]. The late phase of autonomic storm in neurogenic heart disease is also characterised by enhanced parasympathetic activity [
      • Samuels M.A.
      The brain and heart connection.
      ].
      Patients with AV block and TdP display abnormally prolonged QTc at slower heart rates than those without AV conduction disorder [
      • Nakajima T.
      • Kaneko Y.
      • Kurabayashi M.
      Unveiling specific triggers and precipitating factors for fatal cardiac events in inherited arrhythmia syndromes.
      ], increasing the risk of early after depolarisations. Pause-dependent QTc prolongation has been reported by Madias et al. [
      • Madias C.
      • Fitzgibbons T.P.
      • Alsheikh-Ali A.A.
      • Bouchard J.L.
      • Kalsmith B.
      • Garlitski A.C.
      • et al.
      Acquired long QT syndrome from stress cardiomyopathy is associated with ventricular arrhythmias and torsades de pointes.
      ], with each 10 ms increment in QTc conferring a 1.28-fold increase in the odds of developing VA.

      Device Therapy

      Prognostically, malignant arrhythmias tend not to recur and seem to be confined to the acute phase [
      • Stiermaier T.
      • Rommel K.-P.
      • Eitel C.
      • Möller C.
      • Graf T.
      • Desch S.
      • et al.
      Management of arrhythmias in patients with Takotsubo cardiomyopathy: Is the implantation of permanent devices necessary?.
      ]. However, several late TTS deaths are unexplained and possibly arrhythmic [
      • Stiermaier T.
      • Moeller C.
      • Oehler K.
      • Desch S.
      • Graf T.
      • Eitel C.
      • et al.
      Long-term excess mortality in takotsubo cardiomyopathy: predictors, causes and clinical consequences.
      ]. 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 [
      • Stiermaier T.
      • Rommel K.-P.
      • Eitel C.
      • Möller C.
      • Graf T.
      • Desch S.
      • et al.
      Management of arrhythmias in patients with Takotsubo cardiomyopathy: Is the implantation of permanent devices necessary?.
      ,
      • El-Battrawy I.
      • Erath J.W.
      • Lang S.
      • Ansari U.
      • Behnes M.
      • Gietzen T.
      • et al.
      Takotsubo syndrome and cardiac implantable electronic device therapy.
      ]. Interrogation of implanted defibrillators shows that therapies are not utilised after the acute phase, supporting the reversible nature of most VA in TTS [
      • Stiermaier T.
      • Rommel K.-P.
      • Eitel C.
      • Möller C.
      • Graf T.
      • Desch S.
      • et al.
      Management of arrhythmias in patients with Takotsubo cardiomyopathy: Is the implantation of permanent devices necessary?.
      ].
      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) [
      • Stiermaier T.
      • Rommel K.-P.
      • Eitel C.
      • Möller C.
      • Graf T.
      • Desch S.
      • et al.
      Management of arrhythmias in patients with Takotsubo cardiomyopathy: Is the implantation of permanent devices necessary?.
      ]. Permanent pacemaker implantation is undertaken more frequently than permanent defibrillator implantation [
      • Jesel L.
      • Berthon C.
      • Messas N.
      • Lim H.S.
      • Girardey M.
      • Marzak H.
      • et al.
      Ventricular arrhythmias and sudden cardiac arrest in Takotsubo cardiomyopathy: Incidence, predictive factors, and clinical implications.
      ], 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 [
      • Jesel L.
      • Berthon C.
      • Messas N.
      • Lim H.S.
      • Girardey M.
      • Marzak H.
      • et al.
      Ventricular arrhythmias and sudden cardiac arrest in Takotsubo cardiomyopathy: Incidence, predictive factors, and clinical implications.
      ,
      • El-Battrawy I.
      • Lang S.
      • Ansari U.
      • Tülümen E.
      • Schramm K.
      • Fastner C.
      • et al.
      Prevalence of malignant arrhythmia and sudden cardiac death in takotsubo syndrome and its management.
      ], observed beyond the recovery of left ventricular dysfunction [
      • Stiermaier T.
      • Rommel K.-P.
      • Eitel C.
      • Möller C.
      • Graf T.
      • Desch S.
      • et al.
      Management of arrhythmias in patients with Takotsubo cardiomyopathy: Is the implantation of permanent devices necessary?.
      ]. Le et al. suggest erring on the side of pacemaker implantation if AV block does note resolve “rapidly” [
      • Le M.T.
      • Grimard C.
      • Varenne O.
      • Jakamy R.
      • Rosencher J.
      Tako-Tsubo cardiomyopathy and high-degree atrio-ventricular block: do we need to wait left ventricular function recovery to implant a pacemaker?.
      ]. 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 [
      • Stiermaier T.
      • Rommel K.-P.
      • Eitel C.
      • Möller C.
      • Graf T.
      • Desch S.
      • et al.
      Management of arrhythmias in patients with Takotsubo cardiomyopathy: Is the implantation of permanent devices necessary?.
      ].

      Conclusion

      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.
      ArrhythmiaIncidencePutative mechanismTreatment
      Atrial fibrillation5-15%Sympathetic stimulation → diastolic calcium leak → early afterdepolarisations → triggered atrial activitySupportive treatment of underlying sepsis, hypoxia; digoxin, amiodarone

      Beta blockade if blood pressure allows

      Anticoagulation based on CHADS2VASc score
      Life-threatening ventricular arrhythmia4-14%
      Ventricular tachycardia∼1-5%If monomorphic, re-entry around an area of functional block due to myocardial oedemaMagnesium 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 afterdepolarisationsMagnesium 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 block0.6-2.9%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
      Asystole2.5%
      Sinoatrial block1.3%
      Abbreviations: TTS, Takotsubo syndrome; AV, atrioventricular.

      Supplementary Data

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