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  • Review Article
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Takotsubo syndrome: pathophysiological insights and innovations in patient care

Nature Reviews Cardiology (2025)Cite this article

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Abstract

Takotsubo syndrome, also known as broken heart syndrome, was first described in Japan in the 1990s and presents as acute heart failure caused by transient contractile dysfunction that mimics acute coronary syndrome but is not caused by acute coronary obstruction. Takotsubo syndrome accounts for as much as 2–3% of suspected coronary syndromes and is considerably more common in women than in men. In this Review, we discuss the historical background and clinical features of Takotsubo syndrome and our evolving understanding of its pathophysiology. The hallmark feature of Takotsubo syndrome is transient left ventricular dysfunction linked to emotional or physical stressors. Despite advances in our understanding of the clinical presentation and possible pathophysiological mechanisms of Takotsubo syndrome, this condition continues to challenge our fundamental understanding of human anatomy and physiology, particularly regarding how acute emotional and physical stressors can trigger such profound cardiovascular dysfunction. Although the definitive mechanisms remain elusive, current hypotheses largely centre on catecholamine surges and sympathetic nervous system hyperactivation. Diagnostic criteria have been developed by the Mayo Clinic and European Society of Cardiology working groups but, in the absence of randomized controlled clinical trials, no specific treatments for Takotsubo syndrome are available. In this Review, we highlight the complex pathophysiology of Takotsubo syndrome, with an emphasis on the interplay between emotional stress and cardiac health, and call for the development of evidence-based management protocols.

Key points

  • Takotsubo syndrome is an acute, stress-triggered cardiac syndrome that causes transient left ventricular dysfunction, predominantly affecting older women in postmenopause, with most patients recovering spontaneously within weeks of symptom onset.

  • Multiple mechanisms contribute to the pathophysiology of Takotsubo syndrome, including catecholamine surges, microvascular dysfunction, nitrosative stress, oestrogen deficiency, inflammation, brain–heart axis dysregulation and genetic predisposition.

  • Debate persists on whether Takotsubo syndrome is a protective cardiocirculatory response to limit fatal arrhythmias during neurohormonal stress or a maladaptive response that causes severe, albeit reversible, myocardial dysfunction.

  • Management of Takotsubo syndrome focuses on supportive care, avoidance of catecholamine therapies and addressing complications such as cardiogenic shock.

  • The absence of randomized controlled trials for Takotsubo syndrome underscores the urgent need for evidence-based therapeutic guidelines to refine care strategies.

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Fig. 1: Timeline of conceptual perspectives on the pathophysiology of Takotsubo syndrome.
Fig. 2: Perspectives on Takotsubo syndrome.
Fig. 3: Proposed pathophysiological mechanisms of Takotsubo syndrome.
Fig. 4: Anatomical variants of Takotsubo syndrome.

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References

  1. Lyon, A. R. et al. Current state of knowledge on Takotsubo syndrome: a position statement from the Taskforce on Takotsubo syndrome of the Heart Failure Association of the European Society of Cardiology. Eur. J. Heart Fail. 18, 8–27 (2016).

    Article  PubMed  Google Scholar 

  2. Ghadri, J. R. et al. International expert consensus document on Takotsubo syndrome (part I): clinical characteristics, diagnostic criteria, and pathophysiology. Eur. Heart J. 39, 2032–2046 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  3. Dote, K., Sato, H., Tateishi, H., Uchida, T. & Ishihara, M. Myocardial stunning due to simultaneous multivessel coronary spasms: a review of 5 cases [Japanese]. J. Cardiol. 21, 203–214 (1991).

    CAS  PubMed  Google Scholar 

  4. Sato, H. in Clinical Aspect of Myocardial Injury: From Ischemia to Heart Failure (eds. Kodama, K. et al.) 56–64 (Kagakuhyoronsha Publishing, 1990).

  5. Templin, C. Clinical features and outcomes of Takotsubo (Stress) cardiomyopathy. N. Engl. J. Med. 373, 929–938 (2015).

    Article  CAS  PubMed  Google Scholar 

  6. Redfors, B. et al. Mortality in takotsubo syndrome is similar to mortality in myocardial infarction - a report from the SWEDEHEART. Int. J. Cardiol. 185, 282–289 (2015).

    Article  PubMed  Google Scholar 

  7. Hasanaginica. Wikipedia https://en.wikipedia.org/wiki/Hasanaginica (2024).

  8. Hansen, C. & Phillips, B. ‘Wilt break my heart?’ Takotsubo syndrome and Shakespeare’s discourse of heartbreak in Antony and Cleopatra and King Lear. Shakespeare 1–24 https://doi.org/10.1080/17450918.2024.2319124 (2024)

  9. Case records of the Massachusetts General Hospital. Weekly clinicopathological exercises. Case 18-1986. A 44-year-old woman with substernal pain and pulmonary edema after severe emotional stress. N. Engl. J. Med. 314, 1240–1247 (1986).

    Article  Google Scholar 

  10. Dote, K. et al. Myocardial stunning due to simultaneous multivessel coronary spasms: a review of 5 cases. J. Cardiol. 21, 203–214 (1991).

    CAS  PubMed  Google Scholar 

  11. Brandspiegel, H. Z., Marinchak, R. A., Rials, S. J. & Kowey, P. R. A broken heart. Circulation 98, 1349 (1998).

    Article  CAS  PubMed  Google Scholar 

  12. Pavin, D., Le Breton, H. & Daubert, C. Human stress cardiomyopathy mimicking acute myocardial syndrome. Heart 78, 509–511 (1997).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Frank, N., Herrmann, M. J., Lauer, M. & Förster, C. Y. Exploratory review of the Takotsubo syndrome and the possible role of the psychosocial stress response and inflammaging. Biomolecules 14, 167 (2024).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Haghi, D. et al. Coronary artery disease in Takotsubo cardiomyopathy. Circ. J. 71, 1092–1094 (2007).

    Article  PubMed  Google Scholar 

  15. Akashi, Y. J., Nef, H. M. & Lyon, A. R. Epidemiology and pathophysiology of Takotsubo syndrome. Nat. Rev. Cardiol. 12, 387–397 (2015).

    Article  PubMed  Google Scholar 

  16. Schweiger, V. et al. Temporal trends in Takotsubo syndrome. J. Am. Coll. Cardiol. 84, 1178–1189 (2024).

    Article  PubMed  Google Scholar 

  17. Imori, Y. et al. Ethnic comparison in takotsubo syndrome: novel insights from the international takotsubo registry. Clin. Res. Cardiol. 111, 186–196 (2022).

    Article  PubMed  Google Scholar 

  18. Ghadri, J. R. et al. Differences in the clinical profile and outcomes of typical and atypical Takotsubo syndrome: data from the international Takotsubo registry. JAMA Cardiol. 1, 335–340 (2016).

    Article  PubMed  Google Scholar 

  19. Abe, Y. et al. Assessment of clinical features in transient left ventricular apical ballooning. J. Am. Coll. Cardiol. 41, 737–742 (2003).

    Article  PubMed  Google Scholar 

  20. Bybee, K. A. et al. Systematic review: transient left ventricular apical ballooning: a syndrome that mimics ST-segment elevation myocardial infarction. Ann. Intern. Med. 141, 858–865 (2004).

    Article  PubMed  Google Scholar 

  21. Thygesen, K. et al. Fourth universal definition of myocardial infarction (2018). Circulation 138, e618–e651 (2018).

    Article  PubMed  Google Scholar 

  22. Desmet, W. J. R., Adriaenssens, B. F. M. & Dens, J. A. Y. Apical ballooning of the left ventricle: first series in white patients. Heart 89, 1027–1031 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Nascimento, F. O., Larrauri-Reyes, M. C., Santana, O., Pérez-Caminero, M. & Lamas, G. A. Comparison of stress cardiomyopathy in Hispanic and non-Hispanic patients. Rev. Esp. Cardiol. 66, 67–68 (2013).

    Article  PubMed  Google Scholar 

  24. Zaghlol, R., Dey, A. K., Desale, S. & Barac, A. Racial differences in Takotsubo cardiomyopathy outcomes in a large nationwide sample. Esc. Heart Fail. 7, 1056–1063 (2020).

    Article  PubMed  PubMed Central  Google Scholar 

  25. Lyon, A. R. et al. Pathophysiology of Takotsubo syndrome: JACC state-of-the-art review. J. Am. Coll. Cardiol. 77, 902–921 (2021).

    Article  CAS  PubMed  Google Scholar 

  26. Crea, F., Iannaccone, G., La Vecchia, G. & Montone, R. A. An update on the mechanisms of Takotsubo syndrome: “at the end an acute coronary syndrome”. J. Mol. Cell. Cardiol. 191, 1–6 (2024).

    Article  CAS  PubMed  Google Scholar 

  27. Scally, C. et al. Myocardial and systemic inflammation in acute stress-induced (Takotsubo) cardiomyopathy. Circulation 139, 1581–1592 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  28. Singh, T. et al. Takotsubo syndrome: pathophysiology, emerging concepts and clinical implications. Circulation 145, 1002–1019 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Wittstein, I. S. et al. Neurohumoral features of myocardial stunning due to sudden emotional stress. N. Engl. J. Med. 352, 539–548 (2005).

    Article  CAS  PubMed  Google Scholar 

  30. Jha, S. et al. Clinical management in the Takotsubo syndrome. Expert Rev. Cardiovasc. Ther. 17, 83–93 (2019).

    Article  CAS  PubMed  Google Scholar 

  31. Ueyama, T. et al. Chronic estrogen supplementation following ovariectomy improves the emotional stress-induced cardiovascular responses by 608 indirect action on the nervous system and by direct action on the heart. Circ. J. 71, 565–573 (2007).

    Article  CAS  PubMed  Google Scholar 

  32. Ueyama, T. et al. Estrogen attenuates the emotional stress-induced cardiac responses in the animal model of Tako-tsubo (ampulla) cardiomyopathy. J. Cardiovasc. Pharmacol. 42, S117–S119 (2003).

    Article  CAS  PubMed  Google Scholar 

  33. Limongelli, G. et al. Takotsubo cardiomyopathy: do the genetics matter? Heart Fail. Clin. 9, 207–216 (2013).

    Article  PubMed  Google Scholar 

  34. Omerovic, E. et al. Pathophysiology of Takotsubo syndrome — a joint scientific statement from the heart failure association Takotsubo syndrome study group and myocardial function working group of the European society of cardiology — Part 1: overview and the central role for catecholamines and sympathetic nervous system. Eur. J. Heart Fail. 24, 257–273 (2022).

    Article  CAS  PubMed  Google Scholar 

  35. Omerovic, E. Takotsubo syndrome — scientific basis for current treatment strategies. Heart Fail. Clin. 12, 577–586 (2016).

    Article  PubMed  Google Scholar 

  36. Redfors, B., Shao, Y., Ali, A. & Omerovic, E. Are the different patterns of stress-induced (Takotsubo) cardiomyopathy explained by regional mechanical overload and demand: supply mismatch in selected ventricular regions? Med. Hypotheses 81, 954–960 (2013).

    Article  PubMed  Google Scholar 

  37. Anderson, K. P. Sympathetic nervous system activity and ventricular tachyarrhythmias: recent advances. Ann. Noninvasive Electrocardiol. 8, 75–89 (2003).

    Article  PubMed  PubMed Central  Google Scholar 

  38. Zeijlon, R. et al. Risk of in-hospital life-threatening ventricular arrhythmia or death after ST-elevation myocardial infarction vs. the Takotsubo syndrome. Esc. Heart Fail. 8, 1314–1323 (2021).

    Article  PubMed  PubMed Central  Google Scholar 

  39. Smilowitz, N. R., Hausvater, A. & Reynolds, H. R. Hospital readmission following Takotsubo syndrome. Eur. Heart J. Qual. Care Clin. Outcomes 5, 114–120 (2019).

    Article  PubMed  Google Scholar 

  40. Redfors, B. et al. Successful heart transplantation from a donor with Takotsubo syndrome. Int. J. Cardiol. 195, 82–84 (2015).

    Article  PubMed  Google Scholar 

  41. Paur, H. et al. High levels of circulating epinephrine trigger apical cardiodepression in a β 2-adrenergic receptor/Gi-dependent manner: a new model of Takotsubo cardiomyopathy. Circulation 126, 697–706 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Shao, Y. et al. Novel rat model reveals important roles of β-adrenoreceptors in stress-induced cardiomyopathy. Int. J. Cardiol. 168, 1943–1950 (2013).

    Article  PubMed  Google Scholar 

  43. Nguyen, T. H. et al. Enhanced no signaling in patients with Takotsubo cardiomyopathy: short-term pain, long-term gain? Cardiovasc. Drugs Ther. 27, 541–547 (2013).

    Article  CAS  PubMed  Google Scholar 

  44. Surikow, S. Y. et al. Evidence of nitrosative stress within hearts of patients dying of Tako-tsubo cardiomyopathy. Int. J. Cardiol. 189, 112–114 (2015).

    Article  CAS  PubMed  Google Scholar 

  45. Scally, C. et al. Persistent long-term structural, functional, and metabolic changes after stress-induced (Takotsubo) cardiomyopathy. Circulation 137, 1039–1048 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  46. Galiuto, L. et al. Reversible coronary microvascular dysfunction: a common pathogenetic mechanism in apical ballooning or Tako-Tsubo syndrome. Eur. Heart J. 31, 1319–1327 (2010).

    Article  PubMed  Google Scholar 

  47. Deshmukh, A. et al. Prevalence of Takotsubo cardiomyopathy in the United States. Am. Heart J. 164, 66–71.e1 (2012).

    Article  PubMed  Google Scholar 

  48. Van Gelder, I. C. et al. 2024 ESC guidelines for the management of atrial fibrillation developed in collaboration with the European Association for Cardio-Thoracic Surgery (EACTS). Eur. Heart J. 45, 3314–3414 (2024).

    Article  PubMed  Google Scholar 

  49. Abraham, J. et al. Stress cardiomyopathy after intravenous administration of catecholamines and beta-receptor agonists. J. Am. Coll. Cardiol. 53, 1320–1325 (2009).

    Article  CAS  PubMed  Google Scholar 

  50. Shao, Y. et al. A mouse model reveals an important role for catecholamine-induced lipotoxicity in the pathogenesis of stress-induced cardiomyopathy. Eur. J. Heart Fail. 15, 9–22 (2013).

    Article  CAS  PubMed  Google Scholar 

  51. Redfors, B. et al. Different catecholamines induce different patterns of Takotsubo-like cardiac dysfunction in an apparently afterload dependent manner. Int. J. Cardiol. 174, 330–336 (2014).

    Article  PubMed  Google Scholar 

  52. Y-Hassan, S. Clinical features and outcome of epinephrine-induced Takotsubo syndrome: analysis of 33 published cases. Cardiovasc. Revasc. Med. 17, 450–455 (2016).

    Article  PubMed  Google Scholar 

  53. Y-Hassan, S. & Falhammar, H. Pheochromocytoma- and paraganglioma-triggered Takotsubo syndrome. Endocrine 65, 483–493 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Chiang, Y.-L., Chen, P.-C., Lee, C.-C. & Chua, S.-K. Adrenal pheochromocytoma presenting with Takotsubo-pattern cardiomyopathy and acute heart failure: a case report and literature review. Medicine 95, e4846 (2016).

    Article  PubMed  PubMed Central  Google Scholar 

  55. Sverrisdóttir, Y. B., Schultz, T., Omerovic, E. & Elam, M. Sympathetic nerve activity in stress-induced cardiomyopathy. Clin. Auton. Res. 22, 259–264 (2012).

    Article  PubMed  PubMed Central  Google Scholar 

  56. Ito, K., Sugihara, H., Kinoshita, N., Azuma, A. & Matsubara, H. Assessment of Takotsubo cardiomyopathy (transient left ventricular apical ballooning) using 99mTc-tetrofosmin, 123I-BMIPP, 123I-MIBG and 99mTc-PYP myocardial SPECT. Ann. Nucl. Med. 19, 435–445 (2005).

    Article  PubMed  Google Scholar 

  57. Y-Hassan, S. Plasma epinephrine level and its causal link to Takotsubo syndrome revisited: critical review with a diverse conclusion. Cardiovasc. Revasc. Med. 20, 907–914 (2019).

    Article  PubMed  Google Scholar 

  58. Wittstein, I. S. Acute stress cardiomyopathy. Curr. Heart Fail. Rep. 5, 61–68 (2008).

    Article  CAS  PubMed  Google Scholar 

  59. Kume, T. et al. Local release of catecholamines from the hearts of patients with Tako-Tsubo-like left ventricular dysfunction. Circ. J. 72, 106–108 (2008).

    Article  CAS  PubMed  Google Scholar 

  60. Redfors, B. et al. Contrast echocardiography reveals apparently normal coronary perfusion in a rat model of stress-induced (Takotsubo) cardiomyopathy. Eur. Heart J. Cardiovasc. Imaging 15, 152–157 (2014).

    Article  PubMed  Google Scholar 

  61. Nayar, J. et al. A review of nuclear imaging in Takotsubo cardiomyopathy. Life 12, 1476 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. Miyajima, K., Tawarahara, K. & Saito, N. Serial changes of myocardial perfusion imaging in takotsubo and reverse Takotsubo cardiomyopathy. J. Nucl. Cardiol. 29, 2599–2611 (2021).

    Article  PubMed  PubMed Central  Google Scholar 

  63. Testa, M. & Feola, M. Usefulness of myocardial positron emission tomography/nuclear imaging in Takotsubo cardiomyopathy. World J. Radiol. 6, 502–506 (2014).

    Article  PubMed  PubMed Central  Google Scholar 

  64. Dong, F. et al. Takotsubo syndrome is a coronary microvascular disease: experimental evidence. Eur. Heart J. 44, 2244–2253 (2023).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  65. Waqar, A. et al. Cardioprotective role of estrogen in Takotsubo cardiomyopathy. Cureus https://doi.org/10.7759/cureus.22845 (2022).

    Article  PubMed  PubMed Central  Google Scholar 

  66. Liao, X. et al. Cardiac macrophages regulate isoproterenol-induced Takotsubo-like cardiomyopathy. JCI Insight 7, e156236 (2022).

    Article  PubMed  PubMed Central  Google Scholar 

  67. Pozzi, G. et al. Pre-existing psychiatric morbidity is strongly associated to Takotsubo syndrome: a case-control study. Front. Cardiovasc. Med. 9, 925459 (2022).

    Article  PubMed  PubMed Central  Google Scholar 

  68. Oliveri, F. et al. Role of depression and anxiety disorders in Takotsubo syndrome: the psychiatric side of broken heart. Cureus 12, e10400 (2020).

    PubMed  PubMed Central  Google Scholar 

  69. Pelliccia, F. et al. Comorbidities frequency in Takotsubo syndrome: an international collaborative systematic review including 1109 patients. Am. J. Med. 128, 654–654 (2015).

    Article  Google Scholar 

  70. Galli, F., Bursi, F. & Carugo, S. Traumatic events, personality and psychopathology in Takotsubo syndrome: a systematic review. Front. Psychol. 10, 2742 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  71. Radfar, A. et al. Stress-associated neurobiological activity associates with the risk for and timing of subsequent Takotsubo syndrome. Eur. Heart J. https://doi.org/10.1093/eurheartj/ehab029 (2021).

    Article  PubMed  PubMed Central  Google Scholar 

  72. Marafioti, V. & Benfari, G. Takotsubo syndrome: a neurocardiac syndrome inside the autonomic nervous system. Heart Fail. Rev. 24, 227–227 (2018).

    Article  Google Scholar 

  73. Suzuki, H. et al. Evidence for brain activation in patients with Takotsubo cardiomyopathy. Circ. J. 78, 256–258 (2014).

    Article  PubMed  Google Scholar 

  74. Nagai, M., Hoshide, S. & Kario, K. The insular cortex and cardiovascular system: a new insight into the brain-heart axis. J. Am. Soc. Hypertension 4, 174–182 (2010).

    Article  Google Scholar 

  75. Nagai, M., Förster, C. Y. & Dote, K. Sex hormone-specific neuroanatomy of Takotsubo syndrome: is the insular cortex a moderator? Biomolecules 12, 110 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  76. Templin, C. et al. Altered limbic and autonomic processing supports brain-heart axis in Takotsubo syndrome. Eur. Heart J. 40, 1183–1187 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  77. El-Sayed, A. M., Brinjikji, W. & Salka, S. Demographic and co-morbid predictors of stress (Takotsubo) cardiomyopathy. Am. J. Cardiol. 110, 1368–1372 (2012).

    Article  PubMed  Google Scholar 

  78. Limongelli, G. et al. Genetics of Takotsubo syndrome. Heart Fail. Clin. 12, 499–506 (2016).

    Article  PubMed  Google Scholar 

  79. Vriz, O. et al. Analysis of β1 and β2-adrenergic receptors polymorphism in patients with apical ballooning cardiomyopathy. Acta Cardiologica 66, 787–790 (2011).

    Article  PubMed  Google Scholar 

  80. Figtree, G. A. et al. No association of G-protein-coupled receptor kinase 5 or β-adrenergic receptor polymorphisms with Takotsubo cardiomyopathy in a large Australian cohort. Eur. J. Heart Fail. 15, 730–733 (2013).

    Article  CAS  PubMed  Google Scholar 

  81. Couch, L. S. et al. Circulating microRNAs predispose to Takotsubo syndrome following high-dose adrenaline exposure. Cardiovasc. Res. 118, 1758–1770 (2022).

    Article  CAS  PubMed  Google Scholar 

  82. Jaguszewski, M. et al. A signature of circulating microRNAs differentiates takotsubo cardiomyopathy from acute myocardial infarction. Eur. Heart J. 35, 999–1006 (2014).

    Article  CAS  PubMed  Google Scholar 

  83. Izarra, A. et al. miR-133a enhances the protective capacity of cardiac progenitor cells after myocardial infarction. Stem Cell Rep. 3, 1029–1042 (2014).

    Article  CAS  Google Scholar 

  84. Rube Goldberg Machine. Wikipedia https://en.wikipedia.org/wiki/Rube_Goldberg_machine (2024).

  85. Cartwright, N. Rigour versus the need for evidential diversity. Synthese 199, 13095–13119 (2021).

    Article  PubMed  PubMed Central  Google Scholar 

  86. Lyon, A. et al. Current state of knowledge on Takotsubo syndrome: a position statement from the taskforce on Takotsubo syndrome of the Heart Failure Association of the European Society of Cardiology. Eur. J. Heart Fail. 18, 8–27 (2016).

    Article  PubMed  Google Scholar 

  87. Ghadri, J. et al. International expert consensus document on Takotsubo syndrome (Part II): diagnostic workup, outcome, and management. Eur. Heart J. 39, 2047–2062 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  88. Randhawa, M. S., Dhillon, A. S., Taylor, H. C., Sun, Z. & Desai, M. Y. Diagnostic utility of cardiac biomarkers in discriminating Takotsubo cardiomyopathy from acute myocardial infarction. J. Card. Fail. 20, 2–8 (2014).

    Article  PubMed  Google Scholar 

  89. Jha, S. et al. Early changes in myocardial stunning and biomarkers after ST-elevation myocardial infarction compared to the Takotsubo syndrome. Eur. Heart J. https://doi.org/10.1093/eurheartj/ehac544.1430 (2022).

    Article  Google Scholar 

  90. Khan, H. et al. A systematic review of biomarkers in Takotsubo syndrome: a focus on better understanding the pathophysiology. Int. J. Cardiol. Heart Vasc. 34, 100795 (2021).

    PubMed  PubMed Central  Google Scholar 

  91. Fröhlich, G. et al. Takotsubo cardiomyopathy has a unique cardiac biomarker profile: NT-proBNP/myoglobin and NT-proBNP/troponin T ratios for the differential diagnosis of acute coronary syndromes and stress induced cardiomyopathy. Int. J. Cardiol. 154, 328–332 (2012).

    Article  PubMed  Google Scholar 

  92. Dagrenat, C. et al. Value of cardiac biomarkers in the early diagnosis of Takotsubo syndrome. J. Clin. Med. 9, 2985 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  93. Couch, L. S. et al. Comparison of troponin and natriuretic peptides in Takotsubo syndrome and acute coronary syndrome: a meta-analysis. Open Heart 11, e002607 (2024).

    Article  PubMed  PubMed Central  Google Scholar 

  94. Gassanov, N. et al. Novel ECG-based scoring tool for prediction of Takotsubo syndrome. Clin. Res. Cardiol. 108, 222 (2018).

    Article  PubMed  Google Scholar 

  95. Ogura, R. et al. Specific findings of the standard 12-lead ECG in patients with ‘Takotsubo’ cardiomyopathy: comparison with the findings of acute anterior myocardial infarction. Circulation J. 67, 687–690 (2003).

    Article  Google Scholar 

  96. Madias, J. Electrocardiogram features predictive of takotsubo syndrome. Clin. Res. Cardiol. 108, 221 (2018).

    Article  PubMed  Google Scholar 

  97. Madias, J. Transient attenuation of the amplitude of the QRS complexes in the diagnosis of Takotsubo syndrome. Eur. Heart J. Acute Cardiovasc. Care 3, 28–36 (2014).

    PubMed  PubMed Central  Google Scholar 

  98. Looi, J. et al. Usefulness of ECG to differentiate Takotsubo cardiomyopathy from acute coronary syndrome. Int. J. Cardiol. 199, 132–140 (2015).

    Article  PubMed  Google Scholar 

  99. Scally, C. et al. The early dynamic of ECG in Takotsubo syndrome presenting with ST-elevation: a comparison with age and gender-matched ST-elevation myocardial infarction. Int. J. Cardiol. https://doi.org/10.1016/j.ijcard.2020.07.025 (2020).

    Article  PubMed  Google Scholar 

  100. Citro, R. et al. Multimodality imaging in Takotsubo syndrome: a joint consensus document of the European association of cardiovascular imaging (EACVI) and the Japanese society of echocardiography (JSE). J. Echocardiogr. 18, 199–224 (2020).

    Article  PubMed  PubMed Central  Google Scholar 

  101. Bossone, E. et al. Takotsubo cardiomyopathy: an integrated multi-imaging approach. Eur. Heart J. Cardiovasc. Imaging 15, 366–377 (2014).

    Article  PubMed  Google Scholar 

  102. Izumo, M. & Akashi, Y. J. Role of echocardiography for Takotsubo cardiomyopathy: clinical and prognostic implications. Cardiovasc. Diagn. Ther. 8, 90–100 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  103. Citro, R. et al. Echocardiographic correlates of acute heart failure, cardiogenic shock, and in-hospital mortality in Tako-Tsubo cardiomyopathy. JACC Cardiovasc. Imaging 7, 119–129 (2014).

    Article  PubMed  Google Scholar 

  104. Meimoun, P. et al. Non-invasive detection of tako-tsubo cardiomyopathy vs. acute anterior myocardial infarction by transthoracic Doppler echocardiography. Eur. Heart J. Cardiovasc. Imaging 14, 464–470 (2013).

    Article  PubMed  Google Scholar 

  105. Napp, L. C. et al. Coexistence and outcome of coronary artery disease in takotsubo syndrome. Eur. Heart J. 41, 3255–3268 (2020).

    Article  PubMed  Google Scholar 

  106. Redfors, B., Råmunddal, T., Shao, Y. & Omerovic, E. Takotsubo triggered by acute myocardial infarction: a common but overlooked syndrome? J. Geriatr. Cardiol. 11, 171–173 (2014).

    PubMed  PubMed Central  Google Scholar 

  107. Puchner, S. et al. High-risk plaque detected on coronary CT angiography predicts acute coronary syndromes independent of significant stenosis in acute chest pain: results from the ROMICAT-II trial. J. Am. Coll. Cardiol. 64, 684–692 (2014).

    Article  PubMed  PubMed Central  Google Scholar 

  108. Gonzalez, J. A. et al. Meta-analysis of diagnostic performance of coronary computed tomography angiography, computed tomography perfusion, and computed tomography-fractional flow reserve in functional myocardial ischemia assessment versus invasive fractional flow reserve. Am. J. Cardiol. 116, 1469–1478 (2015).

    Article  PubMed  PubMed Central  Google Scholar 

  109. Eitel, I. et al. Clinical characteristics and cardiovascular magnetic resonance findings in stress (takotsubo) cardiomyopathy. JAMA 306, 277–286 (2011).

    CAS  PubMed  Google Scholar 

  110. Pontone, G. et al. Prognostic benefit of cardiac magnetic resonance over transthoracic echocardiography for the assessment of ischemic and nonischemic dilated cardiomyopathy patients referred for the evaluation of primary prevention implantable cardioverter–defibrillator therapy. Circ. Cardiovasc. Imaging 9, e004956 (2016).

    Article  PubMed  Google Scholar 

  111. Vermes, E. et al. Cardiac magnetic resonance for assessment of cardiac involvement in Takotsubo syndrome: do we still need contrast administration? Int. J. Cardiol. https://doi.org/10.1016/j.ijcard.2020.03.039 (2020).

    Article  PubMed  Google Scholar 

  112. Mannil, M. et al. Prognostic value of texture analysis from cardiac magnetic resonance imaging in patients with Takotsubo syndrome: a machine learning based proof-of-principle approach. Sci. Rep. 10, 20537 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  113. Roifman, I., Connelly, K., Wright, G. & Wijeysundera, H. Echocardiography vs. cardiac magnetic resonance imaging for the diagnosis of left ventricular thrombus: a systematic review. Can. J. Cardiol. 31, 785–791 (2015).

    PubMed  Google Scholar 

  114. Okuyama, K. & Akashi, Y. J. Takotsubo syndrome: changes in diagnostic criteria and role of nuclear imaging. Ann. Nuclear Cardiol. 4, 101–104 (2018).

    Article  Google Scholar 

  115. Anderson, J. L. et al. Spectrum of radionuclide perfusion study abnormalities in Takotsubo cardiomyopathy. J. Nucl. Cardiol. 29, 1034–1046 (2020).

    Article  PubMed  Google Scholar 

  116. Suzuki, H., Takanami, K., Takase, K., Shimokawa, H. & Yasuda, S. Reversible increase in stress-associated neurobiological activity in the acute phase of Takotsubo syndrome; a brain 18F-FDG-PET study. Int. J. Cardiol. https://doi.org/10.1016/j.ijcard.2021.09.057 (2021).

    Article  PubMed  Google Scholar 

  117. Ibrahim, T. et al. Simultaneous positron emission tomography/magnetic resonance imaging identifies sustained regional abnormalities in cardiac metabolism and function in stress-induced transient midventricular ballooning syndrome: a variant of Takotsubo cardiomyopathy. Circulation 126, e324–e326 (2012).

    Article  PubMed  Google Scholar 

  118. Boutagy, N. E. & Sinusas, A. J. Recent advances and clinical applications of PET cardiac autonomic nervous system imaging. Curr. Cardiol. Rep. 19, 33 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  119. Sethi, Y. et al. Broken heart syndrome: evolving molecular mechanisms and principles of management. J. Clin. Med. 12, 125 (2022).

    Article  PubMed  PubMed Central  Google Scholar 

  120. Omerovic, E. How to think about stress-induced cardiomyopathy? – Think “out of the box”! Scand. Cardiovasc. J. 45, 67–71 (2011).

    Article  PubMed  Google Scholar 

  121. Petursson, P. et al. Effects of pharmacological interventions on mortality in patients with Takotsubo syndrome: a report from the SWEDEHEART registry. Esc. Heart Fail. 11, 1720–1729 (2024).

    Article  PubMed  PubMed Central  Google Scholar 

  122. Santoro, F. et al. Assessment of the German and Italian stress cardiomyopathy score for risk stratification for in-hospital complications in patients with takotsubo syndrome. JAMA Cardiol. 4, 892–899 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  123. Schneider, B. et al. Complications in the clinical course of tako-tsubo cardiomyopathy. Int. J. Cardiol. 176, 199–205 (2014).

    Article  PubMed  Google Scholar 

  124. Scudiero, F. et al. Prognostic relevance of GRACE risk score in Takotsubo syndrome. Eur. Heart J. Acute Cardiovasc. Care 9, 721–728 (2020).

    PubMed  Google Scholar 

  125. Ding, K. J. et al. Intraventricular thrombus formation and embolism in Takotsubo syndrome: insights from the international Takotsubo registry. ATVB 40, 279–287 (2020).

    Article  CAS  Google Scholar 

  126. De Filippo, O. et al. Machine-learning based prediction of in-hospital death for patients with Takotsubo syndrome: the InterTAK-ML model. Eur. J. Heart Fail. https://doi.org/10.1002/ejhf.2983 (2023).

    Article  PubMed  Google Scholar 

  127. Wischnewsky, M. et al. Prediction of short- and long-term mortality in Takotsubo syndrome: the InterTAK prognostic score. Eur. J. Heart Fail. 21, 1469–1472 (2019).

    Article  PubMed  Google Scholar 

  128. Kato, K., Lyon, A. R., Ghadri, J. R. & Templin, C. Takotsubo syndrome: aetiology, presentation and treatment. Heart 103, 1461–1469 (2017).

    Article  PubMed  Google Scholar 

  129. Madias, J. E. Takotsubo cardiomyopathy: current treatment. J. Clin. Med. 10, 3440 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  130. Santoro, F. et al. Current knowledge and future challenges in Takotsubo syndrome: Part 2 — treatment and prognosis. J. Clin. Med. 10, 468 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  131. Akhtar, M. M., Cammann, V. L., Templin, C., Ghadri, J. R. & Lüscher, T. F. Takotsubo syndrome: getting closer to its causes. Cardiovasc. Res. 119, 1480–1494 (2023).

    Article  CAS  PubMed  Google Scholar 

  132. Santoro, F. et al. Beta-blockers and renin-angiotensin system inhibitors for Takotsubo syndrome recurrence: a network meta-analysis. Heart https://doi.org/10.1136/heartjnl-2023-322980 (2023).

    Article  PubMed  Google Scholar 

  133. Schultz, T. et al. Stress-induced cardiomyopathy in Sweden: evidence for different ethnic predisposition and altered cardio-circulatory status. Cardiology 122, 180–186 (2012).

    Article  PubMed  Google Scholar 

  134. Omerovic, E. et al. Rationale and design of BROKEN-SWEDEHEART: a registry-based, randomized, parallel, open-label multicenter trial to test pharmacological treatments for broken heart (takotsubo) syndrome. Am. Heart J. 257, 33–40 (2023).

    Article  CAS  PubMed  Google Scholar 

  135. Møller, J. E. et al. Microaxial flow pump or standard care in infarct-related cardiogenic shock. N. Engl. J. Med. 390, 1382–1393 (2024).

    Article  PubMed  Google Scholar 

  136. Jang, S.-J. et al. Early clinical outcomes of patients with stress-induced cardiomyopathy receiving acute mechanical support in the US. J. Soc. Cardiovasc. Angiogr. Interv. 2, 101185 (2023).

    PubMed  PubMed Central  Google Scholar 

  137. Santoro, F. et al. Lack of efficacy of drug therapy in preventing Takotsubo cardiomyopathy recurrence: a meta-analysis. Clin. Cardiol. 37, 434–439 (2014).

    Article  PubMed  PubMed Central  Google Scholar 

  138. Pelliccia, F. et al. Long-term prognosis and outcome predictors in Takotsubo syndrome. JACC Heart Fail. 7, 143–154 (2019).

    Article  PubMed  Google Scholar 

  139. Ghadri, J. R. et al. Long-term prognosis of patients with Takotsubo syndrome. J. Am. Coll. Cardiol. 72, 874–882 (2018).

    Article  PubMed  Google Scholar 

  140. Pison, L., De Vusser, P. & Mullens, W. Apical ballooning in relatives. Heart 90, e67 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  141. Kawai, S. et al. Guidelines for diagnosis of Takotsubo (Ampulla) cardiomyopathy. Circ. J. 71, 990–992 (2007).

    Article  PubMed  Google Scholar 

  142. Prasad, A., Lerman, A. & Rihal, C. S. Apical ballooning syndrome (Tako-Tsubo or stress cardiomyopathy): a mimic of acute myocardial infarction. Am. Heart J. 155, 408–417 (2008).

    Article  PubMed  Google Scholar 

  143. Wittstein, I. S. Stress cardiomyopathy: a syndrome of catecholamine-mediated myocardial stunning? Cell Mol. Neurobiol. 32, 847–857 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  144. Redfors, B., Shao, Y. & Omerovic, E. Stress-induced cardiomyopathy (Takotsubo)- broken heart and mind? Vasc. Health Risk Manag. 9, 149–154 (2013).

    PubMed  PubMed Central  Google Scholar 

  145. Parodi, G. et al. Revised clinical diagnostic criteria for Tako-tsubo syndrome: the Tako-tsubo Italian network proposal. Int. J. Cardiol. 172, 282–283 (2014).

    Article  PubMed  Google Scholar 

  146. Madias, J. E. Why the current diagnostic criteria of Takotsubo syndrome are outmoded: a proposal for new criteria. Int. J. Cardiol. 174, 468–470 (2014).

    Article  PubMed  Google Scholar 

  147. Redfors, B., Shao, Y., Lyon, A. R. & Omerovic, E. Diagnostic criteria for Takotsubo syndrome: a call for consensus. Int. J. Cardiol. 176, 274–276 (2014).

    Article  PubMed  Google Scholar 

  148. Olsson, E. M. G. et al. The e-mental health treatment in Stockholm myocardial infarction with non-obstructive coronaries or Takotsubo syndrome study (E-SMINC): a study protocol for a randomised controlled trial. Trials 23, 597 (2022).

    Article  PubMed  PubMed Central  Google Scholar 

  149. Ong, G. J. et al. The N-AcetylCysteine and RAMipril in Takotsubo syndrome trial (NACRAM): rationale and design of a randomised controlled trial of sequential N-Acetylcysteine and ramipril for the management of Takotsubo syndrome. Contemp. Clin. Trials 90, 105894 (2020).

    Article  PubMed  Google Scholar 

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Authors and Affiliations

  1. Department of Cardiology, Sahlgrenska University Hospital, Gothenburg, Sweden

    Elmir Omerovic & Björn Redfors

  2. Department of Molecular and Clinical Medicine, Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden

    Elmir Omerovic & Björn Redfors

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  1. Elmir Omerovic
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E.O. researched data for the article and wrote the manuscript. Both authors contributed substantially to discussion of content and reviewed and/or edited the manuscript before submission.

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Omerovic, E., Redfors, B. Takotsubo syndrome: pathophysiological insights and innovations in patient care. Nat Rev Cardiol (2025). https://doi.org/10.1038/s41569-025-01211-5

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