Skip to main content
SpringerLink
Log in

Insulin and takotsubo syndrome: plausible pathophysiologic, diagnostic, prognostic, and therapeutic roles

  • Perspectives
  • Published:
Acta Diabetologica Aims and scope Submit manuscript

Abstract

The pathophysiology of takotsubo syndrome (TTS) is elusive. Heightened adrenergic surge via the sympathetic nervous system (mainly by norepinephrine secretion) and/or elevated blood-borne catecholamines (mainly epinephrine, secreted by the adrenals) probably mediate TTS. Patients with TTS have a low prevalence of diabetes mellitus (DM), and it has been postulated that DM, via its associated neuropathy, prevents the emergence of TTS. Insulin, in animal experiments, has been shown to greatly attenuate the effects of NE on the cardiomyocytes; also, insulin in a limited clinical experience, has been found to improve heart function in patients with neurogenic stress-cardiomyopathy and TTS. Accordingly, it is postulated that high levels of insulin encountered in patients with type 2 DM are at the roots of the protective effect of DM for the emergence of TTS. Thus, a role of insulin in the pathophysiology, diagnosis, prognosis, and therapy of TTS appears to be plausible, and needs exploration.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1

Reproduced from Fig. 2 of [34] with adaptation of the figure legend, with the permission of the American Journal of Physiology

Fig. 2

Reproduced from Fig. 1 of [34], with adaptation of the figure legend, with the permission of the American Journal of Physiology

Fig. 3

Reproduced from Fig. 1 of [43], with adaptation of the figure legend, with the permission of the Journal of Neurosurgery)

Similar content being viewed by others

References

  1. Ghadri JR, Wittstein IS, Prasad A et al (2018) International expert consensus document on takotsubo syndrome (part I): clinical characteristics, diagnostic criteria, and pathophysiology. Eur Heart J 39:2032–2046

    PubMed  PubMed Central  Google Scholar 

  2. Pelliccia F, Kaski JC, Crea F, Camici PG (2017) Pathophysiology of takotsubo syndrome. Circulation 135:2426–2441

    CAS  PubMed  Google Scholar 

  3. Dias A, Núñez Gil IJ, Santoro F et al (2019) Takotsubo syndrome: state-of-the-art review by an expert panel—part 1. Cardiovasc Revasc Med 20:70–79

    PubMed  Google Scholar 

  4. Wittstein IS, Thiemann DR, Lima JA et al (2005) Neurohumoral features of myocardial stunning due to sudden emotional stress. N Engl J Med 352:539–548

    CAS  PubMed  Google Scholar 

  5. Sham Y, De Palma R (2017) Contemporary review on the pathogenesis of takotsubo syndrome: the heart shedding tears: norepinephrine churn and foam at the cardiac sympathetic nerve terminals. Int J Cardiol 228(528):536

    Google Scholar 

  6. Madias JE (2020) Blood norepinephrine/epinephrine/dopamine measurements in 108 patients with takotsubo syndrome from the world literature: pathophysiological implications. Acta Cardiol. https://doi.org/10.1080/00015385.2020.1826703

    Article  PubMed  Google Scholar 

  7. Dias A, Núñez Gil IJ, Santoro F et al (2019) Takotsubo syndrome: state-of-the-art review by an expert panel—part 2. Cardiovasc Revasc Med 20:153–166

    PubMed  Google Scholar 

  8. Ghadri JR, Wittstein IS, Prasad A et al (2018) International expert consensus document on takotsubo syndrome (part ii): diagnostic workup, outcome and management. Eur Heart J 39:2047–2062

    PubMed  PubMed Central  Google Scholar 

  9. Madias JE (2019) Management of takotsubo syndrome. In: Maurer G, Serruys P, John CA, Luscher TF (eds) The ESC textbook of cardiovascular medicine, 3rd edn. Oxford University Press, New York

    Google Scholar 

  10. Madias JE (2016) Low prevalence of diabetes mellitus in patients with takotsubo syndrome: a plausible “protective” effect with pathophysiologic connotations. Eur Heart J Acute Cardiovasc Care 5:164–170

    PubMed  Google Scholar 

  11. Madias JE (2018) Diabetes mellitus prevalence in patients with takotsubo syndrome: the case of the brain-heart disconnect. Heart Lung 47:222–225

    PubMed  Google Scholar 

  12. Madias JE (2019) Prevalence of diabetes mellitus in patients with takotsubo syndrome according to age and sex. Am J Cardiol 123:1190–1191

    PubMed  Google Scholar 

  13. Ahuja KR, Nazir S, Jain V et al (2021) Takotsubo syndrome: does “diabetes paradox” exist? Heart Lung 50:316–322

    PubMed  Google Scholar 

  14. Bill V, El- Battrawy I, Behnes M et al (2016) “ Diabetes paradox” in takotsubo cardiomyopathy. Int J Cardiol 224:88–89

    PubMed  Google Scholar 

  15. Stiermaier T, Moeller C, Oehler K et al (2016) Long-term excess mortality in takotsubo cardiomyopathy: predictors, causes and clinical consequences. Eur J Heart Fail 18:650–656

    PubMed  Google Scholar 

  16. Stiermaier T, Santoro F, El-Battrawy I et al (2018) Prevalence and prognostic impact of diabetes in takotsubo syndrome: insights from the International. Multicenter GEIST Regist Diabetes Care 41:1084–1088

    Google Scholar 

  17. Syed M, Muhammad Khan MZ, Osman M et al (2020) Comparison of outcomes in patients with takotsubo syndrome with-vs-without cardiogenic shock. Am J Cardiol 136:24–31

    PubMed  Google Scholar 

  18. Samuels MA (2007) The brain-heart connection. Circulation 116:77–84

    PubMed  Google Scholar 

  19. Fripp RR, Lee JC, Downing ES (1981) Inotropic responsiveness of the heart in catecholamine cardiomyopathy. Am Heart J 101:17–21

    CAS  PubMed  Google Scholar 

  20. Shams Y, Tornvall P (2018) Epidemiology, pathogenesis, and management of takotsubo syndrome. Clin Auton Res 28:53–65

    Google Scholar 

  21. Moussouttas M, Mearns E, Walters A et al (2015) Plasma catecholamine profile of subarachnoid hemorrhage patients with neurogenic cardiomyopathy. Cerebrovasc Dis Extra 5:57–67

    PubMed  PubMed Central  Google Scholar 

  22. Paur H, Wright PT, Sikkel MB et al (2012) High levels of circulating epinephrine trigger apical cardiodepression in a β2-adrenergic receptor/Gi-dependent manner: a new model of takotsubo cardiomyopathy. Circulation 126:697–706

    CAS  PubMed  PubMed Central  Google Scholar 

  23. Sato H, Tateishi H, Uchida T (1990) Takotsubo-like left ventricular dysfunction due to multivessel coronary spasm. In: Kodama K, Haze K, Hon M (eds) Clinical aspect of myocardial injury: from ischemia to heart failure. Kagakuhyouronsya, Tokyo

    Google Scholar 

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

    CAS  PubMed  Google Scholar 

  25. Shams Y, Yamasaki K (2013) History of takotsubo syndrome: is the syndrome really described as a disease entity first in 1990? some inaccuracies. Int J Cardiol 166:736–737

    Google Scholar 

  26. Wilke RA, Hillard CJ (1994) Decreased adrenal medullary catecholamine release in spontaneously diabetic BB-wistar rats. Role Hypoglycemia Diabet 43:724–729

    CAS  Google Scholar 

  27. Russell JS, Griffith TA, Helman T et al (2019) Chronic type 2 but not type 1 diabetes impairs myocardial ischemic tolerance and preconditioning in C57Bl/6 mice. Exp Physiol 104:1868–1880

    CAS  PubMed  Google Scholar 

  28. Caviezel F, Picotti GB, Margonato A et al (1982) Plasma adrenaline and noradrenaline concentrations in diabetic patients with and without autonomic neuropathy at rest and during sympathetic stimulation. Diabetologia 23:19–23

    CAS  PubMed  Google Scholar 

  29. Burgdorf C, Richardt D, Kurz T et al (2003) Norepinephrine release is reduced in cardiac tissue of type 2 diabetic patients. Diabetologia 46:520–523

    CAS  PubMed  Google Scholar 

  30. Galderisi M, de Simone G, Innelli P et al (2007) Impaired inotropic response in type 2 diabetes mellitus: a strain rate imaging study. Am J Hypertens 20:548–555

    PubMed  Google Scholar 

  31. Downing SE, Less JC (1978) Effects of insulin on experimental catecholamine cardiomyopathy. Am J Patho 93(2):339

    CAS  Google Scholar 

  32. Werner JC, Lee JC, Downing SE (1980) Preservation of left ventricular function by insulin in experimental catecholamine cardiomyopathy. Am J Physiol 238:H257–H262

    CAS  PubMed  Google Scholar 

  33. Lee JC, Downing SE (1976) Effects of insulin on cardiac muscle contraction and responsiveness to norepinephrine. Am J Physiol 230:1360–1365

    CAS  PubMed  Google Scholar 

  34. Nudel DB, Lee JC, Downing SE (1977) Reciprocal inhibition of cardiac responses to norepinephrine and insulin. Am J Physiol 233:H665–H669

    CAS  PubMed  Google Scholar 

  35. Dabir D, Luetkens J, Kuetting DLR et al (2019) Cardiac magnetic resonance including parametric mapping in acute takotsubo syndrome: preliminary findings. Eur J Radiol 113:217–224

    PubMed  Google Scholar 

  36. Sethi P, Chang GV, Gowda SN, Elnair R, Fenner R, Lamfers R (2020) Recurrent catecholamine-induced cardiomyopathy and hypertensive emergencies: a presentation of pheochromocytoma and related concerns. Case Rep S D Med 73:78–80

    Google Scholar 

  37. Shahim B, Ljung Faxén U, Stern R, Freyschuss A (2019) Cardiogenic shock triggered by phaeochromocytoma crisis after an oral glucose tolerance test: a case report. Eur Heart J Case Rep 3:1–7

    PubMed  PubMed Central  Google Scholar 

  38. Shepherd PR, Kahn BB (1999) Glucose transporters and insulin action–implications for insulin resistance and diabetes mellitus. N Engl J Med 341:248–257

    CAS  PubMed  Google Scholar 

  39. Zimmerman C, Albanese-O’Neill A, Haller MJ (2019) Advances in type 1 diabetes technology over the last decade. Eur Endocrinol 15:70–76

    PubMed  PubMed Central  Google Scholar 

  40. Scally C, Rudd A, Mezincescu A et al (2018) Persistent long-term structural, functional, and metabolic changes after stress-induced (takotsubo) cardiomyopathy. Circulation 137:1039–1048

    PubMed  PubMed Central  Google Scholar 

  41. Kato K, Di Vece D, Cammann VL et al (2019) Takotsubo recurrence: morphological types and triggers and identification of risk factors. J Am Coll Cardiol 73:982–984

    PubMed  Google Scholar 

  42. Dawson DK (2018) Takotsubo: the myth of rapid and complete recovery. Eur Heart J 39:3762–3763

    PubMed  Google Scholar 

  43. Vanderschuren A, Hantson P (2009) Hyperinsulinemic euglycemia therapy for stunned myocardium following subarachnoid hemorrhage. J Neurosurg 110:64–66

    PubMed  Google Scholar 

  44. Devos J, Peeters A, Wittebole X, Hantson P (2012) High-dose insulin therapy for neurogenic-stunned myocardium after stroke. BMJ Case Rep, bcr2012006620

  45. Linganna RE, Leong RL, Yeom RS et al (2020) Takotsubo cardiomyopathy-navigating the challenges of diagnosis and management in heart transplantation. J Cardiothorac Vasc Anesth. https://doi.org/10.1053/j.jvca.2020.10.054

    Article  PubMed  Google Scholar 

  46. Kenigsberg BB, Barnett CF, Mai JC et al (2019) Neurogenic stunned myocardium in severe neurological injury. Curr Neurol Neurosci Rep 19(11):1–9

    Google Scholar 

  47. Madias JE (2018) There should not be much doubt that neurogenic stress cardiomyopathy in cardiac donors is a phenotype of takotsubo syndrome. JACC Heart Fail 6:346

    PubMed  Google Scholar 

  48. Santoro F, Ieva R, Ferraretti A et al (2016) Takotsubo cardiomyopathy and betablockers: “On the wall of the cave, only the shadows are true.” Cardiovasc Ther 34:290–291

    PubMed  Google Scholar 

  49. Madias JE (2016) Esmolol for patients with takotsubo syndrome and left ventricular outflow tract obstruction. Cardiovasc Ther 34:292–293

    PubMed  Google Scholar 

  50. Kawano H, Yamasa T, Arakawa S, Matsumoto Y, Sato O, Maemura K (2017) Landiolol dramatically improved Takotsubo cardiomyopathy in an older patient. Geriatr Gerontol Int 17:2622–2623

    PubMed  Google Scholar 

  51. Madias JE (2018) Cardioselective ultra-short-acting β-blockers for patients with takotsubo syndrome? Geriatr Gerontol Int 18:816–817

    PubMed  Google Scholar 

  52. Redfors B, Oras J, Shao Y, Seemann-Lodding H, Ricksten SE, Omerovic E (2014) Cardioprotective effects of isoflurane in a rat model of stress-induced cardiomyopathy (takotsubo). Int J Cardiol 176:815–821

    PubMed  Google Scholar 

  53. Redfors B, Shao Y, Ali A, Sun B, Omerovic E (2015) Rat models reveal differences in cardiocirculatory profile between takotsubo syndrome and acute myocardial infarction. J Cardiovasc Med (Hagerstown) 16:632–638

    Google Scholar 

  54. Ueyama T (2004) Emotional stress-induced tako-tsubo cardiomyopathy: animal model and molecular mechanism. Ann N Y Acad Sci 1018:437–444

    CAS  PubMed  Google Scholar 

  55. Shao Y, Redfors B, Scharin Täng M et al (2013) Novel rat model reveals important roles of β-adrenoreceptors in stress-induced cardiomyopathy. Int J Cardiol 168:1943–1950

    PubMed  Google Scholar 

  56. Madias JE (2016) An animal model of diabetic peripheral neuropathy and the pathophysiology of takotsubo syndrome: a proposal of an experiment. Int J Cardiol 222:882–884

    PubMed  Google Scholar 

  57. Rasmussen KG, Ryan DA, Mueller PS (2006) Blood glucose before and after ECT treatments in type 2 diabetic patients. J ECT 22:124–126

    PubMed  Google Scholar 

  58. Suzuki H, Matsumoto Y, Kaneta T et al (2014) Evidence for brain activation in patients with takotsubo cardiomyopathy. Circ J 78:256–258

    PubMed  Google Scholar 

  59. Kimura BJ, DeMaria AN (2020) Contextual imaging. Circulation 142:1025–1027

    PubMed  Google Scholar 

Download references

Funding

No funding was received for this work.

Author information

Authors and Affiliations

  1. Icahn School of Medicine at Mount Sinai, New York City, NY, USA

    John E. Madias

  2. Division of Cardiology, Elmhurst Hospital Center, 79-01, Broadway, Elmhurst, NY, 11373, USA

    John E. Madias

Authors
  1. John E. Madias
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to John E. Madias.

Ethics declarations

Conflict of interest

The authors declare that they have no conflict of interest.

Ethical approval

Not applicable.

Informed consent

Not applicable.

Additional information

Managed by Massimo Federici.

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Madias, J.E. Insulin and takotsubo syndrome: plausible pathophysiologic, diagnostic, prognostic, and therapeutic roles. Acta Diabetol 58, 989–996 (2021). https://doi.org/10.1007/s00592-021-01709-7

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00592-021-01709-7

Keywords

Search

Navigation