Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Review Article
  • Published:

Mechanisms of stress (Takotsubo) cardiomyopathy

Abstract

Stress cardiomyopathy, also referred to as Takotsubo cardiomyopathy, transient apical ballooning or broken heart syndrome, is a disorder associated with transient left ventricular dysfunction. Symptoms include acute chest pain and dyspnea accompanied by electrocardiographic changes, such as ST-segment elevation and T-wave inversions, minimal elevation of cardiac enzyme levels and transient wall-motion abnormalities in the absence of substantial coronary artery obstruction. Complete recovery of contractile function has been documented in nearly all cases, but the mechanisms of disease remain unclear and the cause has not been established. Coronary artery vasospasm, microcirculation dysfunction, and transient obstruction of the left ventricular outflow tract have been proposed as possible causes of this disorder. An excessive release of catecholamines also seems to have a pivotal role in the development of stress cardiomyopathy. This Review summarizes published data on stress cardiomyopathy, focusing primarily on the most likely causes of this cardiac entity.

Key Points

  • Stress cardiomyopathy occurs in 0.7–2.5% of patients presenting with the symptoms of acute coronary syndromes

  • Postmenopausal women are the group predominantly affected by stress cardiomyopathy

  • Although the cause of stress cardiomyopathy is still unknown, excessive catecholamine levels have a major role in the pathology of this disorder

  • Catecholamine overload results in substantial structural alterations, including increased extracellular matrix, contraction band necrosis, and mild neutrophil infiltration

  • Stress cardiomyopathy is associated with increased oxidative stress and the alteration of Ca2+-handling proteins, which might be crucial for contractile dysfunction

  • An activated cell survival cascade, such as the PI3K–AKT pathway, could protect cardiomyocytes from cell death and contribute to their rapid regeneration in patients with stress cardiomyopathy

This is a preview of subscription content, access via your institution

Access options

Rent or buy this article

Prices vary by article type

from$1.95

to$39.95

Prices may be subject to local taxes which are calculated during checkout

Figure 1: Coronary angiography in patients with stress cardiomyopathy.
Figure 2: Myocytes from patients with stress cardiomyopathy.
Figure 3: PCR and immunostaining of tissue biopsies from patients with stress cardiomyopathy.
Figure 4: Superoxide production in patients with stress cardiomyopathy.
Figure 5: The pathomechanistic concept of stress cardiomyopathy.

Similar content being viewed by others

References

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

    CAS  PubMed  Google Scholar 

  2. Nef, H. M., Möllmann, H. & Elsässer, A. Tako-tsubo cardiomyopathy (apical ballooning). Heart 93, 1309–1315 (2007).

    Article  PubMed  PubMed Central  Google Scholar 

  3. Gianni, M. et al. Apical ballooning syndrome or takotsubo cardiomyopathy: a systematic review. Eur. Heart J. 27, 1523–1529 (2006).

    Article  PubMed  Google Scholar 

  4. 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 

  5. Bybee, K. A. & Prasad, A. Stress-related cardiomyopathy syndromes. Circulation 118, 397–409 (2008).

    Article  PubMed  Google Scholar 

  6. Botto, F., Trivi, M. & Padilla, L. T. Transient left midventricular ballooning without apical involvement. Int. J. Cardiol. 127, 158–159 (2008).

    Article  Google Scholar 

  7. Cacciotti, L. et al. A new variant of Tako-tsubo cardiomyopathy: transient mid-ventricular ballooning. J. Cardiovasc. Med. 8, 1052–1054 (2007).

    Article  Google Scholar 

  8. Kurowski, V. et al. Apical and midventricular transient left ventricular dysfunction syndrome (tako-tsubo cardiomyopathy): frequency, mechanisms, and prognosis. Chest 132, 809–816 (2007).

    Article  PubMed  Google Scholar 

  9. Marti, V., Carreras, F., Pujadas, S. & De Rozas, J. M. Transient left ventricular basal ballooning—“inverted” Tako-tsubo. Clin. Cardiol. 32, 20–21 (2008).

    Article  Google Scholar 

  10. Haghi, D. et al. Right ventricular involvement in Takotsubo cardiomyopathy. Eur. Heart J. 27, 2433–2439 (2006).

    Article  PubMed  Google Scholar 

  11. Nef, H. M. et al. Tako-Tsubo cardiomyopathy: intraindividual structural analysis in the acute phase and after functional recovery. Eur. Heart J. 28, 2456–2464 (2007).

    Article  PubMed  Google Scholar 

  12. Elesber, A. A. et al. Transient cardiac apical ballooning syndrome: prevalence and clinical implications of right ventricular involvement. J. Am. Coll. Cardiol. 47, 1082–1083 (2006).

    Article  PubMed  Google Scholar 

  13. Akashi, Y. J. et al. The clinical features of takotsubo cardiomyopathy. QJM 96, 563–573 (2003).

    Article  CAS  PubMed  Google Scholar 

  14. Prasad, A. Apical ballooning syndrome: an important differential diagnosis of acute myocardial infarction. Circulation 115, 56–59 (2007).

    Google Scholar 

  15. Pernicova, I., Garg, S., Bourantas, C., Alamgir, F. & Hoye, A. Takotsubo cardiomyopathy: a review of the literature. Angiology 61, 166–173 (2010).

    Article  PubMed  Google Scholar 

  16. Donohue, D. & Movahed, M. R. Clinical characteristics, demographics and prognosis of transient left ventricular apical ballooning syndrome. Heart Fail. Rev. 10, 311–316 (2005).

    Article  PubMed  Google Scholar 

  17. Akashi, Y. J. et al. Left ventricular rupture associated with Takotsubo cardiomyopathy. Mayo Clin. Proc. 79, 821–824 (2004).

    Article  PubMed  Google Scholar 

  18. Nef, H. M. et al. Temporary third-degree atrioventricular block in a case of apical ballooning syndrome. Int. J. Cardiol. 113, 33–35 (2006).

    Article  Google Scholar 

  19. Nef, H. M. et al. Severe mitral regurgitation in Tako-Tsubo cardiomyopathy. Int. J. Cardiol. 132, 77–79 (2009).

    Article  Google Scholar 

  20. Bonello, L. et al. Ventricular arrhythmias during Tako-tsubo syndrome. Int. J. Cardiol. 128, 50–53 (2008).

    Article  Google Scholar 

  21. Elesber, A. A. et al. Four-year recurrence rate and prognosis of the apical ballooning syndrome. J. Am. Coll. Cardiol. 50, 448–452 (2007).

    Article  PubMed  Google Scholar 

  22. Burgdorf, C., Kurowski, V., Bonnemeier, H., Schunkert, H. & Radke, P. W. Long-term prognosis of the transient left ventricular dysfunction syndrome (Tako-Tsubo cardiomyopathy): focus on malignancies. Eur. J. Heart Fail. 10, 1015–1019 (2008).

    Article  PubMed  Google Scholar 

  23. Tarkin, J. M., Khetyar, M. & Kaski, J. C. Management of Tako-tsubo syndrome. Cardiovasc. Drugs Ther. 22, 71–77 (2008).

    Article  PubMed  Google Scholar 

  24. Tsuchihashi, K. et al. Transient left ventricular apical ballooning without coronary artery stenosis: a novel heart syndrome mimicking acute myocardial infarction. Angina Pectoris-Myocardial Infarction Investigations in Japan. J. Am. Coll. Cardiol. 38, 11–18 (2001).

    Article  CAS  PubMed  Google Scholar 

  25. Merli, E., Sutcliffe, S., Gori, M. & Sutherland, G. G. Tako-Tsubo cardiomyopathy: new insights into the possible underlying pathophysiology. Eur. J. Echocardiogr. 7, 53–61 (2005).

    Article  PubMed  Google Scholar 

  26. Ako, J. et al. Reversible left ventricular systolic dysfunction-reversibility of coronary microvascular abnormality. Jpn Heart J. 42, 355–363 (2001).

    Article  CAS  PubMed  Google Scholar 

  27. 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 

  28. Nef, H. M. et al. Abnormalities in intracellular Ca2+ regulation contribute to the pathomechanism of Tako-Tsubo cardiomyopathy. Eur. Heart J. 30, 2155–2164 (2009).

    Article  CAS  PubMed  Google Scholar 

  29. Nef, H. M. et al. Activated cell survival cascade protects cardiomyocytes from cell death in Tako-Tsubo cardiomyopathy. Eur. J. Heart Fail. 11, 758–764 (2009).

    Article  CAS  PubMed  Google Scholar 

  30. Akashi, Y., Nef, H. M., Möllmann, H. & Ueyama, T. Stress cardiomyopathy. Annu. Rev. Med. 61, 271–286 (2010).

    Article  CAS  PubMed  Google Scholar 

  31. Braunwald, E. & Kloner, R. A. The stunned myocardium: prolonged, postischemic ventricular dysfunction. Circulation 66, 1146–1149 (1982).

    Article  CAS  PubMed  Google Scholar 

  32. 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. J. Electrocardiol. 41, 621–625 (2008).

    Article  PubMed  Google Scholar 

  33. 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 

  34. Desmet, W. Dynamic LV obstruction in apical ballooning syndrome: the chicken or the egg. Eur. J. Echocardiogr. 7, 1–4 (2006).

    Article  PubMed  Google Scholar 

  35. Kloner, R. A., Bolli, R., Marban, E., Reinlib, L. & Braunwald, E. Medical and cellular implications of stunning, hibernation, and preconditioning: an NHLBI workshop. Circulation 97, 1848–1867 (1998).

    Article  CAS  PubMed  Google Scholar 

  36. Ibanez, B., Choi, B. G., Navarro, F. & Farre, J. Tako-tsubo syndrome: a form of spontaneous aborted myocardial infarction? Eur. Heart J. 27, 1509–1510 (2006).

    Article  PubMed  Google Scholar 

  37. Pilgrim, T. M. & Wyss, T. R. Takotsubo cardiomyopathy or transient left ventricular apical ballooning syndrome: A systematic review. Int. J. Cardiol. 124, 283–292 (2008).

    Article  PubMed  Google Scholar 

  38. Kume, T. et al. Relationship between coronary flow reserve and recovery of regional left ventricular function in patients with tako-tsubo-like transient left ventricular dysfunction. J. Cardiol. 43, 123–129 (2004).

    PubMed  Google Scholar 

  39. Gibson, C. M. et al. TIMI frame count: a quantitative method of assessing coronary artery flow. Circulation 93, 879–888 (1996).

    Article  CAS  PubMed  Google Scholar 

  40. Kurisu, S. et al. Myocardial perfusion and fatty acid metabolism in patients with tako-tsubo-like left ventricular dysfunction. J. Am. Coll. Cardiol. 41, 743–748 (2003).

    Article  CAS  PubMed  Google Scholar 

  41. Bybee, K. A. et al. Clinical characteristics and thrombolysis in myocardial infarction frame counts in women with transient left ventricular apical ballooning syndrome. Am. J. Cardiol. 94, 343–346 (2004).

    Article  PubMed  Google Scholar 

  42. Akashi, Y. J., Goldstein, D. S., Barbaro, G. & Ueyama, T. Takotsubo cardiomyopathy: a new form of acute, reversible heart failure. Circulation 118, 2754–2762 (2008).

    Article  PubMed  PubMed Central  Google Scholar 

  43. Inoue, T. et al. Vasodilatory capacity of coronary resistance vessels in dilated cardiomyopathy. Am. Heart J. 127, 376–381 (1994).

    Article  CAS  PubMed  Google Scholar 

  44. El Mahmoud, R. et al. Prevalence and characteristics of left ventricular outflow tract obstruction in Tako-Tsubo syndrome. Am. Heart J. 156, 543–548 (2008).

    Article  PubMed  Google Scholar 

  45. Park, J. H. et al. Left ventricular apical ballooning due to severe physical stress in patients admitted to the medical ICU. Chest 128, 296–302 (2005).

    Article  PubMed  Google Scholar 

  46. Volz, H. C., Erbel, C., Berentelg, J., Katus, H. A. & Frey, N. Reversible left ventricular dysfunction resembling Takotsubo syndrome after self-injection of adrenaline. Can. J. Cardiol. 25, e261–e262 (2009).

    Article  PubMed  PubMed Central  Google Scholar 

  47. Litvinov, I. V., Kotowycz, M. A. & Wassmann, S. Iatrogenic epinephrine-induced reverse Takotsubo cardiomyopathy: direct evidence supporting the role of catecholamines in the pathophysiology of the “broken heart syndrome”. Clin. Res. Cardiol. 98, 457–462 (2009).

    Article  PubMed  Google Scholar 

  48. Kassim, T. A., Clarke, D. D., Mai, V. Q., Clyde, P. W. & Mohamed Shakir, K. M. Catecholamine-induced cardiomyopathy. Endocr. Pract. 14, 1137–1149 (2008).

    Article  PubMed  Google Scholar 

  49. Prasad, A., Madhavan, M. & Chareonthaitawee, P. Cardiac sympathetic activity in stress-induced (Takotsubo) cardiomyopathy. Nat. Rev. Cardiol. 6, 430–434 (2009).

    Article  PubMed  Google Scholar 

  50. Akashi, Y. J. et al. 123I-MIBG myocardial scintigraphy in patients with “takotsubo” cardiomyopathy. J. Nucl. Med. 45, 1121–1127 (2004).

    PubMed  Google Scholar 

  51. Movahed, A. et al. Norepinephrine-induced left ventricular dysfunction in anesthetized and conscious, sedated dogs. Int. J. Cardiol. 45, 23–33 (1994).

    Article  CAS  PubMed  Google Scholar 

  52. Yamanaka, O. et al. “Myocardial stunning”-like phenomenon during a crisis of pheochromocytoma. Jpn Circ. J. 58, 737–742 (1994).

    Article  CAS  PubMed  Google Scholar 

  53. Nef, H. M. et al. Expression profiling of cardiac genes in Tako-Tsubo cardiomyopathy: insight into a new cardiac entity. J. Mol. Cell. Cardiol. 44, 395–404 (2008).

    Article  CAS  PubMed  Google Scholar 

  54. Stein, B. et al. Relation between contractile function and regulatory cardiac proteins in hypertrophied hearts. Am. J. Physiol. 270, H2021–H2028 (1996).

    CAS  PubMed  Google Scholar 

  55. Boluyt, M. O. et al. Isoproterenol infusion induces alterations in expression of hypertrophy-associated genes in rat heart. Am. J. Physiol. 269, H638–H647 (1995).

    CAS  PubMed  Google Scholar 

  56. Babu, G. J. et al. Targeted overexpression of sarcolipin in the mouse heart decreases sarcoplasmic reticulum calcium transport and cardiac contractility. J. Biol. Chem. 281, 3972–3979 (2006).

    Article  CAS  PubMed  Google Scholar 

  57. Asahi, M. et al. Cardiac-specific overexpression of sarcolipin inhibits sarco(endo)plasmic reticulum Ca2+ ATPase (SERCA2a) activity and impairs cardiac function in mice. Proc. Natl Acad. Sci. USA 101, 9199–9204 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Linck, B. et al. Long-term beta adrenoceptor-mediated alteration in contractility and expression of phospholamban and sarcoplasmic reticulum Ca++-ATPase in mammalian ventricle. J. Pharmacol. Exp. Ther. 286, 531–538 (1998).

    CAS  PubMed  Google Scholar 

  59. Lipskaia, L. & Lompré, A. M. Alteration in temporal kinetics of Ca2+ signaling and control of growth and proliferation. Biol. Cell 96, 55–68 (2004).

    Article  CAS  PubMed  Google Scholar 

  60. 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. Nat. Clin. Pract. Cardiovasc. Med. 5, 22–29 (2008).

    Article  CAS  PubMed  Google Scholar 

  61. Heubach, J. F., Ravens, U. & Kaumann, A. J. Epinephrine activates both Gs and Gi pathways, but norepinephrine activates only the Gs pathway through human beta2-adrenoceptors overexpressed in mouse heart. Mol. Pharmacol. 65, 1313–1322 (2004).

    Article  CAS  PubMed  Google Scholar 

  62. Heubach, J. F., Blaschke, M., Harding, S. E., Ravens, U. & Kaumann, A. J. Cardiostimulant and cardiodepressant effects through overexpressed human beta2-adrenoceptors in murine heart: regional differences and functional role of beta1-adrenoceptors. Naunyn Schmiedebergs Arch. Pharmacol. 367, 380–390 (2003).

    Article  CAS  PubMed  Google Scholar 

  63. Ueyama, T. Emotional stress-induced Tako-tsubo cardiomyopathy: animal model and molecular mechanism. Ann. NY Acad. Sci. 1018, 437–444 (2004).

    Article  CAS  PubMed  Google Scholar 

  64. Ueyama, T., Umemoto, S. & Senba, E. Immobilization stress induces c-fos and c-jun immediate early genes expression in the heart. Life Sci. 59, 339–347 (1996).

    Article  CAS  PubMed  Google Scholar 

  65. Ueyama, T. et al. Molecular mechanism of emotional stress-induced and catecholamine-induced heart attack. J. Cardiovasc. Pharmacol. 41 (Suppl. 1), 115–118 (2003).

    Google Scholar 

  66. Khullar, M., Datta, B. N., Wahi, P. L. & Chakravarti, R. N. Catecholamine-induced experimental cardiomyopathy—a histopathological, histochemical and ultrastructural study. Indian Heart J. 41, 307–313 (1989).

    CAS  PubMed  Google Scholar 

  67. Grohé, C. et al. Cardiac myocytes and fibroblasts contain functional estrogen receptors. FEBS Lett. 416, 107–112 (1997).

    Article  PubMed  Google Scholar 

  68. Bupha-Intr, T. & Wattanapermpool, J. Regulatory role of ovarian sex hormones in calcium uptake activity of cardiac sarcoplasmic reticulum. Am. J. Physiol. Heart Circ. Physiol. 291, 1101–1108 (2006).

    Article  Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Holger M. Nef.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Nef, H., Möllmann, H., Akashi, Y. et al. Mechanisms of stress (Takotsubo) cardiomyopathy. Nat Rev Cardiol 7, 187–193 (2010). https://doi.org/10.1038/nrcardio.2010.16

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nrcardio.2010.16

This article is cited by

Search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing