Pathophysiology of Takotsubo Syndrome

Article Author:
Nauman Khalid
Article Author:
Sarah Ahmad
Article Author:
Evan Shlofmitz
Article Editor:
Lovely Chhabra
Updated:
4/16/2020 2:42:28 AM
PubMed Link:
Pathophysiology of Takotsubo Syndrome

Introduction

Transient left ventricular (LV) apical ballooning syndrome, Takotsubo cardiomyopathy, Takotsubo syndrome (TTS), broken heart syndrome, ampulla cardiomyopathy or stress-induced cardiomyopathy are interchangeable terms and have all been applied 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 within the scientific community in the past few decades.[1] The disease manifests predominantly in postmenopausal females in the presence of stressful triggers such as severe physical or emotional stress, natural disasters such as earthquakes, unexpected death of relatives, acute medical illnesses, etc. 

Initially thought to be a benign condition recent reports have demonstrated that TTS may be associated with severe complications and mortality similar to acute coronary syndrome. 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 the development of Takotsubo syndrome 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]

The typical patient will present with chest pain, ECG showing ST-segment elevation and increased troponin. However, when patients undergo cardiac catheterization, the left ventricle has apical ballooning and no evidence of coronary artery disease. The shape of the left ventricle during systole appears like an 'octopus pot.

The modified Mayo Clinic criteria are used to make the diagnosis of Takotsubo cardiomyopathy and include the following:

  1. Absence of coronary artery disease on angiography
  2. Transient dyskinesis, hypokinesis or akinesis of the left ventricle midsegments with or without apical involvement
  3. ECG evidence of ST-segment elevation and/or T wave inversion
  4. Modest elevation of troponin levels
  5. Absence of myocarditis or pheochromocytoma

The exact number of people with the disorder remains unknown because not all patients undergo angiography following chest pain. The majority of patients are Asians or Caucasians and present with symptoms in the 6th decade of life. Close to 90% of cases have been reported in postmenopausal females.

Issues of Concern

Takotsubo syndrome must be distinguished from other entities that involve cardiac enzyme elevation with non-obstructive coronary arteries.  Symptomatic non-obstructive coronary artery disease (NOCAD) occurs with less than 50% coronary luminal stenosis. [3] Further functional and physiologic assessment of coronary endothelial function and the coronary microvascular system should be considered in these patients. Myocardial Infarction in the Absence of Obstructive Coronary Artery Disease (MINOCA) occurs in as many as 5% of patients presenting with myocardial infarction who undergo coronary angiography. [4] Optical coherence tomography (OCT) and cardiac magnetic resonance imaging (MRI) are two imaging modalities which can play an important diagnostic role in the determination of MINOCA. [5] [6] Both MINOCA and NOCAD should be considered once TTS and other entities have been excluded.  Other entities to include in the differential diagnosis includes spontaneous coronary artery dissection, a non-traumatic, non-iatrogenic entity that occurs predominantly in young postpartum females [7]

Causes

Although the precise etiology of the syndrome is not known, the most plausible cause responsible for Takotsubo syndrome 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, Takotsubo syndrome 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 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 Takotsubo syndrome. Recently reports have also described patients developing Takotsubo syndrome after a positive emotional experience the so-called term, Happy heart syndrome [8].

Clinical Pathology

The clinical presentation of Takotsubo syndrome is the same as that of a patient with an acute myocardial infarction or acute coronary syndrome. Chest pain and dyspnea are common symptoms, but others may also present with nausea, palpitations, syncope, and vomiting. In many cases, the patient may describe a physical or an emotionally stressful event prior to the onset of symptoms. Unlike acute coronary syndrome which presents during the early morning hours, Takotsubo syndrome tends to present in the mid-afternoon. The history will also reveal that patients with Takotsubo syndrome have a lower incidence of traditional coronary disease risk factors.

The physical exam is nonspecific and may be normal. However, some patients may be diaphoretic and have palpitations. Murmurs and rales may be present if pulmonary edema and left heart failure are present.

Mechanisms

Supraphysiologic levels (two to threefold elevation) of plasma catecholamines and neuropeptides (norepinephrine, epinephrine, and dopamine) have been observed in patients with Takotsubo syndrome.[9] Gs-mediated positive and Gi-mediated negative effects of beta-2-adrenoceptor stimulation on myocardial contractility have been reported previously in knockout mice. In Takotsubo syndrome, increased catecholamine levels stimulate beta-2 coupling from Gs to Gi leading to negative inotropy and resultant left ventricular contractile dysfunction.[10] This effect has been called ‘Stimulus trafficking’ and can plausibly explain the apical forms of Takotsubo syndrome where beta-adrenergic receptors are the highest in numbers, however, they do not elucidate the other forms of Takotsubo syndrome. Clinical features of Takotsubo syndrome are reproducible by intravenous administration of catecholamines and beta-adrenergic agonists.[11] Accordingly, beta-blockers are useful in the management of Takotsubo syndrome. The catecholamine hypothesis is perhaps the most widely accepted pathophysiologic mechanism in Takotsubo syndrome.

Estrogen provides direct cardioprotective effects including vasodilation, vascular protection, and effects against atherosclerosis and endothelial dysfunction.[12] More than 90% of the TTS patients are postmenopausal women suggesting that estrogen deficiency may correlate with increased risk of Takotsubo syndrome.[13] Studies have shown that lack of estrogen replacement therapy may predispose women to TTS.[14][15][14] Furthermore, the cardioprotective effects of estrogen are further elucidated in murine models in which ovariectomy correlated with loss of cardiac protection and development of Takotsubo syndrome 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. The lack of direct cardioprotective effects of estrogen may also predispose men to develop Takotsubo syndrome and its associated complications; additionally, although Takotsubo syndrome is less prevalent in males they generally have a worse prognosis than females [16]

Inflammation is thought to play a critical role in the development of Takotsubo syndrome.[17][18][19] Cardiac magnetic resonance (CMR) imaging has demonstrated myocardial edema, necrosis, and fibrosis in patients with Takotsubo syndrome. Previously thought to be absent, late gadolinium enhancement (LGE) is shown to be present in up to 10% of patients with TTS.[18] 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.[19] 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.[20][21][22] This is in contrast to practice guidelines (The Mayo clinic criteria and the European Society of Cardiology - Heart Failure Association) which mandate the absence of myocarditis as one of the diagnostic criteria to fulfill the diagnosis of TTS.[23][24]  Histologic specimens of patients with Takotsubo syndrome 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 Takotsubo syndrome patients with several catheter-based and imaging modalities.[25][26][25] Catheter-based techniques applied in the catheterization laboratory include the placement of a coronary pressure-wire 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][27][28] The prolonged TFC is likely related to disordered resistance to the flow or microvascular dysfunction observed in patients with Takotsubo syndrome.[29] 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.[30] However microvascular dysfunction may not be present in all cases of Takotsubo syndrome. An interesting phenomenon observed in patients with TTS is the low prevalence of diabetes mellitus. The risk factor profile of Takotsubo syndrome patients is similar to the patients with coronary artery disease; however, diabetes mellitus is much less prevalent in Takotsubo syndrome compared with age-matched controls. Some researchers have speculated that autonomic dysfunction in diabetes mellitus may blunt the catecholamine secretion in patients with Takotsubo syndrome which may play a protective role against the development of this disease.[31][32]

There is a hypothesis that Takotsubo syndrome is a form of an aborted myocardial infarction in which there is indeed the formation of acute thrombus with quick and complete lysis of thrombus with spontaneous resolution of the infarct. Detailed intravascular imaging with intravascular ultrasound (IVUS) and OCT has shown eccentric atherosclerotic plaques in the mid LAD of patients with TTS that were thought to be normal on coronary angiography.[33] [34] The presence of such plaques along with thin cap fibroatheromas without evidence of rupture was also present on OCT analysis of patients with Takotsubo syndrome.[35] Coronary artery vasospasm has also been postulated as a credible causative factor for Takotsubo syndrome. 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.[36] More recent studies have also demonstrated coronary spasm on provocative testing with acetylcholine.[37]

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 Takotsubo syndrome will help optimize patient outcomes in the future. 

The prognosis in Takotsubo syndrome is excellent with nearly full recovery within 6-8 weeks. About 1-2% of patients experience recurrence. Mortality rates of 3-4% have been reported. Complications do occur in at least 1/4th of patients and include the following:

  • Mitral regurgitation mild to moderate
  • Left heart failure
  • Cardiogenic shock
  • Left ventricular outflow tract obstruction which is dynamic
  • Development of LV mural thrombus
  • Ventricular arrhythmias
  • Rupture of the ventricular wall
  • Death

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]. 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] Widmer RJ,Samuels B,Samady H,Price MJ,Jeremias A,Anderson RD,Jaffer FA,Escaned J,Davies J,Prasad M,Grines C,Lerman A, The functional assessment of patients with non-obstructive coronary artery disease: expert review from an international microcirculation working group. EuroIntervention : journal of EuroPCR in collaboration with the Working Group on Interventional Cardiology of the European Society of Cardiology. 2019 Mar 20     [PubMed PMID: 30561368]
[4] Tamis-Holland JE,Jneid H,Reynolds HR,Agewall S,Brilakis ES,Brown TM,Lerman A,Cushman M,Kumbhani DJ,Arslanian-Engoren C,Bolger AF,Beltrame JF, Contemporary Diagnosis and Management of Patients With Myocardial Infarction in the Absence of Obstructive Coronary Artery Disease: A Scientific Statement From the American Heart Association. Circulation. 2019 Apr 30     [PubMed PMID: 30913893]
[5] Ferreira VM, CMR Should Be a Mandatory Test in the Contemporary Evaluation of "MINOCA". JACC. Cardiovascular imaging. 2019 Jun 8     [PubMed PMID: 31202763]
[6] Iwańczyk S,Skorupski W,Grygier M,Sikora T,Araszkiewicz A,Lesiak M, Myocardial infarction with nonobstructive coronary arteries in a young woman: the key role of optical coherence tomography. Kardiologia polska. 2019 Aug 23     [PubMed PMID: 31246179]
[7] Khalid N,Rogers T,Waksman R, Spontaneous dissections involving multiple coronary arteries and a vertebral artery over 7 years. European heart journal. 2019 Jan 14     [PubMed PMID: 30500890]
[8] Ghadri JR,Sarcon A,Diekmann J,Bataiosu DR,Cammann VL,Jurisic S,Napp LC,Jaguszewski M,Scherff F,Brugger P,Jäncke L,Seifert B,Bax JJ,Ruschitzka F,Lüscher TF,Templin C, Happy heart syndrome: role of positive emotional stress in takotsubo syndrome. European heart journal. 2016 Oct 1     [PubMed PMID: 26935270]
[9] 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]
[10] 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]
[11] 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]
[12] Moolman JA, Unravelling the cardioprotective mechanism of action of estrogens. Cardiovascular research. 2006 Mar 1;     [PubMed PMID: 16532550]
[13] 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]
[14] Kuo BT,Choubey R,Novaro GM, Reduced estrogen in menopause may predispose women to takotsubo cardiomyopathy. Gender medicine. 2010 Feb;     [PubMed PMID: 20189157]
[15] Khalid N,Ahmad SA,Shlofmitz E,Umer A,Chhabra L, Takotsubo cardiomyopathy: prognostication is affected by the underlying trigger. Journal of cardiovascular medicine (Hagerstown, Md.). 2019 Jun     [PubMed PMID: 31045855]
[16] Khalid N,Ahmad SA,Umer A,Chhabra L, Factors Impacting Prognosis Among Patients with Tako-tsubo Syndrome. Revista espanola de cardiologia (English ed.). 2019 Aug     [PubMed PMID: 31171453]
[17] 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]
[18] 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]
[19] 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]
[20] 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]
[21] 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]
[22] 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]
[23] 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]
[24] 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]
[25] Khalid N,Chhabra L, Takotsubo cardiomyopathy and microcirculatory dysfunction. Nature reviews. Cardiology. 2015 Aug;     [PubMed PMID: 26076951]
[26] Khalid N,Ahmad SA,Shlofmitz E,Umer A,Chhabra L, Sex disparities and microvascular dysfunction. International journal of cardiology. 2019 May 1     [PubMed PMID: 30851944]
[27] Khalid N, Microcirculatory disorder hypothesis in Takotsubo cardiomyopathy. International journal of cardiology. 2015 Sep 15;     [PubMed PMID: 26022795]
[28] Khalid N,Ikram S, Coronary flow assessment in Takotsubo cardiomyopathy with TIMI frame count. International journal of cardiology. 2015 Oct 15;     [PubMed PMID: 26142964]
[29] Khalid N,Ikram S, Microvascular dysfunction in Takotsubo cardiomyopathy: Prognostic implications. International journal of cardiology. 2015 Dec 15;     [PubMed PMID: 26288330]
[30] 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]
[31] 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]
[32] 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]
[33] 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]
[34] Shlofmitz E,Zhu B,Khalid N, Intravascular Ultrasound (IVUS) . 2019 Jan     [PubMed PMID: 30725704]
[35] 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]
[36] 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]
[37] 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]