Pathophysiology of Takotsubo Syndrome

Article Author:
Nauman Khalid
Article Author (Archived):
Sarah Ahmad
Article Editor:
Lovely Chhabra
6/27/2019 7:12:03 PM
PubMed Link:
Pathophysiology of Takotsubo Syndrome


Transient left ventricular (LV) apical ballooning syndrome, Takotsubo cardiomyopathy, Takotsubo syndrome (TTS), or Stress-induced cardiomyopathy are interchangeable terms and have all been utilized to define a syndrome characterized by transient left ventricular systolic and diastolic dysfunction, electrocardiographic features and myocardial enzyme elevation similar to the acute myocardial infarction but in the absence of obstructive epicardial coronary artery disease. First described in Japan in the 1990s, the syndrome has gained worldwide attention from the scientific community in the past few decades.[1] The disease manifests predominantly in postmenopausal females in the presence of triggers such as severe physical or emotional stress, natural disasters such as earthquakes, unexpected death of relatives, acute medical illnesses, etc.  Concerted efforts have been made to define various pathophysiologic aspects of TTS; however, the precise etiologic understanding remains unclear. Some of the mechanisms proposed for development of TTS include elevated levels of circulating plasma catecholamines and its metabolites, microvascular dysfunction, inflammation, estrogen deficiency, spasm of the epicardial coronary vessels, and aborted myocardial infarction. Herein,  we define each mechanism in further detail.[2]


Although the precise etiology of the syndrome is not known, the most plausible cause responsible for TTS is the sudden release of stress hormones, such as norepinephrine, epinephrine, and dopamine, causing cardiac stunning. Stunning the heart triggers changes in the cardiac myocytes and coronary perfusion.

Although roughly about one-fourth patients have no clear triggers, TTS is typically triggered by an unexpected emotionally or physically stressful event.

Events that have been reported to trigger TC include:

  • Domestic abuse or relationship conflict
  • Sudden loss of a loved one
  • Natural disasters
  • An accident or major trauma
  • A fierce argument
  • Severe financial or gambling losses
  • An unexpected surprise like winning a lottery
  • Being diagnosed with a serious acute medical condition or medical illness such as a stroke or a terminal illness
  • Exhausting physical effort
  • Surgery
  • Head trauma
  • Public speaking
  • Extreme fright
  • Use of drugs such as cocaine, excessive stimulant use or inadvertent overdose of catecholamines
  • Drug withdrawal

Researchers have no answer for the reasons why a specific stressful event will trigger this condition, but at a similar event may not do so at a different time. Post-menopausal women are most likely affected by TTS suggesting a possible role of estrogen deficiency. Patients with certain psychiatric conditions or mood disorders are also more likely to have TTS.


Supraphysiologic levels (two to threefold elevation) of plasma catecholamines and neuropeptides (norepinephrine, epinephrine, and dopamine) have been observed in patients with TTS.[3] Gs-mediated positive and Gi-mediated negative effects of beta-2-adrenoceptor stimulation on myocardial contractility has been reported previously in knockout mice. In TTS increased catecholamine levels stimulate beta-2 coupling from Gs to Gi leading to negative inotropy and resultant left ventricular contractile dysfunction.[4] This effect has been called ‘Stimulus trafficking’ and can plausibly explain the apical forms of TTS where beta-adrenergic receptors are the highest in numbers, however, does not elucidate the other forms of TTS. Clinical features of TTS are reproducible by intravenous administration of catecholamines and beta-adrenergic agonists.[5] Accordingly, beta blockers are useful in the management of TTS. Catecholamine hypothesis is perhaps the most widely accepted pathophysiologic mechanism in TTS.

Estrogen provides direct cardioprotective effects including vasodilation, vascular protection, and effects against atherosclerosis and endothelial dysfunction.[6] More than 90% of the TTS patients are postmenopausal women suggesting that estrogen deficiency may correlate with increased risk of TTS.[7] Studies have shown that lack of estrogen replacement therapy may predispose women to TTS.[8] Furthermore, the cardioprotective effects of estrogen are further elucidated in murine models in which ovariectomy correlated with loss of cardiac protection and development of TTS in response to a stressful trigger; the protective effect returned after long-term estradiol replacement therapy. Also, there are suggestions that estrogen down-regulates beta-adrenergic receptors. 

Inflammation is thought to play a critical role in the development of TTS.[9][10][11] Cardiac magnetic resonance (CMR) imaging has demonstrated myocardial edema, necrosis, and fibrosis in patients with TTS. Previously thought to be absent, late gadolinium enhancement (LGE) is shown to be present in up to 10% of patients with TTS.[10] The enhancement patterns for TTS are focal or patchy following a segmental distribution; this is in contrast to LGE observed in myocarditis (mid-wall or sub-epicardial) or ischemia (subendocardial or transmural) and can help differentiate. Moreover, the LGE noted in TTS is present in the acute phase and usually resolves on follow-up imaging. There have also been reports of macrophage recruitment, change in the balance of monocyte subtypes and increased circulating pro-inflammatory cytokines with some of these changes persisting beyond 5 months.[11] Coexisting cases of myocarditis, pericarditis, or autoimmune conditions such as systemic lupus erythematosus or Sjogren’s syndrome have also been reported suggesting that chronic inflammatory conditions with acute flares may provide a substrate for the emergence of TTS.[12][13][14] This is in contrast to practice guidelines (The Mayo clinic criteria and the European Society of Cardiology - Heart Failure Association) which mandate absence of myocarditis as one of the diagnostic criteria to fulfill the diagnosis of TTS.[15][16]  Histologic specimens of patients with TTS show areas of contraction band necrosis, inflammatory cell recruitment, and focal fibrosis which possibly develop as a result of cardiotoxic effects of catecholamines and its metabolites.

Microvascular dysfunction has been shown in TTS patients with several catheter-based and imaging modalities.[17] Catheter-based techniques applied in the catheterization laboratory include placement of a guidewire and measuring coronary flow reserve velocity. Quantitative coronary flow assessment with thrombolysis in myocardial infarction (TIMI) frame count (TFC) have shown prolonged corrected TFC in either the left anterior descending (LAD) alone or all three coronary arteries.[2][18][19] The prolonged TFC is likely related to disordered resistance to the flow or microvascular dysfunction observed in TTS patients.[20] Other parameters include reduced TIMI perfusion grade and quantitative flow ratio (QFR). Some of the non-invasive methodologies include myocardial contrast-enhanced echocardiography also demonstrating abnormal coronary flow velocity reserve, diastolic dysfunction and deformation abnormalities (untwist rate and time to peak untwisting), positron-emission tomography studies showing reduced apical uptake of F-18 fluorodeoxyglucose, and abnormal global longitudinal strain.[21] However microvascular dysfunction may not be present in all cases of TC. An interesting phenomenon observed in patients with TTS is the low prevalence of diabetes mellitus. The risk factor profile of TTS patients is similar to the patients with coronary artery disease; however, diabetes mellitus is much less prevalent in TTS compared with age-matched controls. Some researchers have speculated that autonomic dysfunction in diabetes mellitus may blunt the catecholamine secretion in TTS patients which may play a protective role against the development of this disease.[22][23]

There is a hypothesis that TTS is a form of an aborted myocardial infarction in which there is indeed formation of acute thrombus with quick and complete lysis of thrombus with spontaneous resolution of the infarct. Detailed intravascular imaging has shown eccentric atherosclerotic plaques in the mid LAD of patients with TTS that were thought to be normal on coronary angiography.[24] Presence of such plaques along with thin cap fibroatheromas without evidence of rupture was also present on optical coherence tomography analysis of patients with TTS.[25] Coronary artery vasospasm has also been postulated as a credible causative factor for TTS. In the original studies by Sato and colleagues, the rates of coronary artery spasm and coronary vasoconstriction were reported in 23% and 54% of the patients respectively.[26] More recent studies have also demonstrated coronary spasm on provocative testing with acetylcholine.[27]

Clinical Significance

Various pathophysiologic mechanisms have been proposed for Takotsubo syndrome. While considerable progress has been made, several knowledge gaps still do exist. Improved understanding of this illness will help optimize patient outcomes in the future. 


[1] Dote K,Sato H,Tateishi H,Uchida T,Ishihara M, [Myocardial stunning due to simultaneous multivessel coronary spasms: a review of 5 cases]. Journal of cardiology. 1991;     [PubMed PMID: 1841907]
[2] Khalid N,Iqbal I,Coram R,Raza T,Fahsah I,Ikram S, Thrombolysis In Myocardial Infarction Frame Count in Takotsubo Cardiomyopathy. International journal of cardiology. 2015 Jul 15;     [PubMed PMID: 25965614]
[3] Wittstein IS,Thiemann DR,Lima JA,Baughman KL,Schulman SP,Gerstenblith G,Wu KC,Rade JJ,Bivalacqua TJ,Champion HC, Neurohumoral features of myocardial stunning due to sudden emotional stress. The New England journal of medicine. 2005 Feb 10;     [PubMed PMID: 15703419]
[4] Lyon AR,Rees PS,Prasad S,Poole-Wilson PA,Harding SE, Stress (Takotsubo) cardiomyopathy--a novel pathophysiological hypothesis to explain catecholamine-induced acute myocardial stunning. Nature clinical practice. Cardiovascular medicine. 2008 Jan;     [PubMed PMID: 18094670]
[5] Paur H,Wright PT,Sikkel MB,Tranter MH,Mansfield C,O'Gara P,Stuckey DJ,Nikolaev VO,Diakonov I,Pannell L,Gong H,Sun H,Peters NS,Petrou M,Zheng Z,Gorelik J,Lyon AR,Harding SE, High levels of circulating epinephrine trigger apical cardiodepression in a β2-adrenergic receptor/Gi-dependent manner: a new model of Takotsubo cardiomyopathy. Circulation. 2012 Aug 7;     [PubMed PMID: 22732314]
[6] Moolman JA, Unravelling the cardioprotective mechanism of action of estrogens. Cardiovascular research. 2006 Mar 1;     [PubMed PMID: 16532550]
[7] Khalid N,Ahmad SA,Shlofmitz E,Chhabra L, Racial and gender disparities among patients with Takotsubo syndrome. Clinical cardiology. 2018 Dec 7;     [PubMed PMID: 30525217]
[8] Kuo BT,Choubey R,Novaro GM, Reduced estrogen in menopause may predispose women to takotsubo cardiomyopathy. Gender medicine. 2010 Feb;     [PubMed PMID: 20189157]
[9] Eitel I,von Knobelsdorff-Brenkenhoff F,Bernhardt P,Carbone I,Muellerleile K,Aldrovandi A,Francone M,Desch S,Gutberlet M,Strohm O,Schuler G,Schulz-Menger J,Thiele H,Friedrich MG, Clinical characteristics and cardiovascular magnetic resonance findings in stress (takotsubo) cardiomyopathy. JAMA. 2011 Jul 20;     [PubMed PMID: 21771988]
[10] Eitel I,Lücke C,Grothoff M,Sareban M,Schuler G,Thiele H,Gutberlet M, Inflammation in takotsubo cardiomyopathy: insights from cardiovascular magnetic resonance imaging. European radiology. 2010 Feb;     [PubMed PMID: 19705125]
[11] Scally C,Abbas H,Ahearn T,Srinivasan J,Mezincescu A,Rudd A,Spath N,Yucel-Finn A,Yuecel R,Oldroyd K,Dospinescu C,Horgan G,Broadhurst P,Henning A,Newby DE,Semple S,Wilson H,Dawson DK, Myocardial and Systemic Inflammation in Acute Stress-Induced (Takotsubo) Cardiomyopathy. Circulation. 2018 Nov 11;     [PubMed PMID: 30586731]
[12] Chhabra L,Khalid N,Kluger J,Spodick DH, Lupus myopericarditis as a preceding stressor for takotsubo cardiomyopathy. Proceedings (Baylor University. Medical Center). 2014 Oct;     [PubMed PMID: 25484500]
[13] Khalid N,Ahmad SA,Umer A,Chhabra L, Takotsubo cardiomyopathy and myopericarditis: Unraveling the inflammatory hypothesis. International journal of cardiology. 2015 Oct 1;     [PubMed PMID: 26114444]
[14] Khalid N,Chhabra L, Takotsubo Cardiomyopathy and Viral Myopericarditis: An Association Which Should be Considered in the Differential Diagnosis. Angiology. 2016 Apr;     [PubMed PMID: 25969569]
[15] Madhavan M,Prasad A, Proposed Mayo Clinic criteria for the diagnosis of Tako-Tsubo cardiomyopathy and long-term prognosis. Herz. 2010 Jun;     [PubMed PMID: 20582391]
[16] Lyon AR,Bossone E,Schneider B,Sechtem U,Citro R,Underwood SR,Sheppard MN,Figtree GA,Parodi G,Akashi YJ,Ruschitzka F,Filippatos G,Mebazaa A,Omerovic E, 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. European journal of heart failure. 2016 Jan;     [PubMed PMID: 26548803]
[17] Khalid N,Chhabra L, Takotsubo cardiomyopathy and microcirculatory dysfunction. Nature reviews. Cardiology. 2015 Aug;     [PubMed PMID: 26076951]
[18] Khalid N, Microcirculatory disorder hypothesis in Takotsubo cardiomyopathy. International journal of cardiology. 2015 Sep 15;     [PubMed PMID: 26022795]
[19] Khalid N,Ikram S, Coronary flow assessment in Takotsubo cardiomyopathy with TIMI frame count. International journal of cardiology. 2015 Oct 15;     [PubMed PMID: 26142964]
[20] Khalid N,Ikram S, Microvascular dysfunction in Takotsubo cardiomyopathy: Prognostic implications. International journal of cardiology. 2015 Dec 15;     [PubMed PMID: 26288330]
[21] Khalid N,Ahmad SA,Umer A, Coronary flow reserve assessment via invasive and noninvasive means in Takotsubo cardiomyopathy. International journal of cardiology. 2016 Jan 1;     [PubMed PMID: 26447665]
[22] Khalid N,Ahmad SA,Umer A,Chhabra L, Role of Microcirculatory Disturbances and Diabetic Autonomic Neuropathy in Takotsubo Cardiomyopathy. Critical care medicine. 2015 Nov;     [PubMed PMID: 26468716]
[23] Khalid N,Chhabra L,Ahmad SA,Sareen P,Spodick DH, Autonomic Dysfunction and Takotsubo Cardiomyopathy. The American journal of medicine. 2015 Nov;     [PubMed PMID: 26500214]
[24] Ibanez B,Navarro F,Cordoba M,M-Alberca P,Farre J, Tako-tsubo transient left ventricular apical ballooning: is intravascular ultrasound the key to resolve the enigma? Heart (British Cardiac Society). 2005 Jan;     [PubMed PMID: 15604352]
[25] Eitel I,Stiermaier T,Graf T,Möller C,Rommel KP,Eitel C,Schuler G,Thiele H,Desch S, Optical Coherence Tomography to Evaluate Plaque Burden and Morphology in Patients With Takotsubo Syndrome. Journal of the American Heart Association. 2016 Dec 22;     [PubMed PMID: 28007746]
[26] Pelliccia F,Sinagra G,Elliott P,Parodi G,Basso C,Camici PG, Takotsubo is not a cardiomyopathy. International journal of cardiology. 2018 Mar 1;     [PubMed PMID: 29242100]
[27] Angelini P, Transient left ventricular apical ballooning: A unifying pathophysiologic theory at the edge of Prinzmetal angina. Catheterization and cardiovascular interventions : official journal of the Society for Cardiac Angiography     [PubMed PMID: 18288755]