Takotsubo cardiomyopathy also known as transient apical ballooning syndrome, apical ballooning cardiomyopathy, stress-induced cardiomyopathy, stress cardiomyopathy, Gebrochenes-Herz syndrome, and the broken-heart syndrome is a form of non-ischemic cardiomyopathy  and predominantly affects post-menopausal women . It is characterized by transient regional systolic dysfunction of the left ventricle in the absence of angiographically significant coronary artery disease or acute plaque rupture. In most cases of Takotsubo cardiomyopathy, the regional wall motion abnormality extends beyond the territory perfused by a single epicardial coronary artery. The term Takotsubo is a Japanese name for an octopus trap. It has a shape that is similar to the systolic apical ballooning appearance of the left ventricle.
The exact etiology of Takotsubo cardiomyopathy is not fully understood. There are several mechanisms hypothesized as possible etiologies of Takotsubo cardiomyopathy and include sympathetic overdrive with increased catecholamines, coronary spasm, microvascular dysfunction, low estrogen levels, inflammation, or impaired myocardial fatty acid metabolism. Risk factors for the development of Takotsubo cardiomyopathy include domestic abuse, death of relatives, natural calamities, accident or major trauma, arguments, financial or gambling loss, diagnosis of an acute medical illness, stimulant drugs such as cocaine, amphetamines or even positive life events the so-called ’happy heart syndrome’.
The real incidence of Takotsubo cardiomyopathy is uncertain. It makes up for 1 to 2% of patients suspected of having acute coronary syndrome . One registry of 3265 patients with troponin positive acute coronary syndrome, reported the prevalence of 1.2%  of Takotsubo cardiomyopathy whereas a systematic review of patients presenting with suspected acute myocardial infarction the prevalence was reported to be 1.7 to 2.2% . There is a strong predilection of TC to afflict post-menopausal women however males may have a worse prognosis if affected. In the International Takotsubo Registry study (a consortium of multiple centers across Europe and America of 1750 patients) approximately 88.9% of the affected patients were females and the mean age was 66.4 years .
The precise pathophysiologic mechanism underlying Takotsubo cardiomyopathy remains elusive. Various hypotheses have been postulated and include elevated levels of circulating plasma catecholamines and its circulating metabolites due to underlying stress, microvascular dysfunction or microcirculatory disorder, inflammation, estrogen deficiency, spasm of the epicardial coronary vessels, and aborted myocardial infarction . Catecholamine hypothesis is the most widely accepted pathophysiologic mechanism of TC and elevated levels (two to threefold elevation) of plasma catecholamines and neuropeptides (norepinephrine, epinephrine, and dopamine) have been observed in patients with TC. Catecholamines can cause microvascular spasm, dysfunction, myocardial stunning or direct myocardial injury. Estrogen exerts protective effects on cardiovascular system including vasodilation, protection against atherosclerosis and endothelial dysfunction. Therefore post-menopausal women exhibit exaggerated vasoconstriction, altered endothelium-dependent vasodilatation, and sympathetic activation in response to psychosocial stress . The role of inflammation in Takotsubo cardiomyopathy is depicted by cardiac magnetic resonance imaging which shows myocardial edema, necrosis, fibrosis, and late gadolinium enhancement . Coexisting cases of myocarditis, pericarditis, or autoimmune conditions such as systemic lupus erythematosus or Sjogren’s syndrome have been described in the literature suggesting that chronic inflammatory conditions with acute flares may provide a substrate for the emergence of Takotsubo cardiomyopathy. Microvascular dysfunction is demonstrated by abnormal coronary flow reserve, thrombolysis in myocardial infarction (TIMI) frame count, TIMI perfusion grade and quantitative flow ratio . An impaired microvascular function has also been demonstrated with measuring the index of microvascular resistance by introducing a pressure wire in the coronary arteries . There is some evidence that the prevalence of diabetes mellitus is low in Takotsubo cardiomyopathy patients suggesting that blunting of autonomic response in diabetes may have a protective effect against the development of Takotsubo cardiomyopathy the so-called "Diabetes Paradox" .
Endomyocardial biopsy of patients with Takotsubo cardiomyopathy demonstrates reversible focal lysis of myocytes, mononuclear infiltrates, and contraction band necrosis.
Takotsubo cardiomyopathy presentation is similar to the acute coronary syndrome. This disorder is frequently triggered by intense emotional or physical stress, for example, the unexpected death of a family member, domestic abuse, significant confrontation, medical diagnosis, natural disaster, and/or financial loss. In the International Takotsubo Registry study, most common symptoms are chest pain, dyspnea, and syncope. Some patients may present with symptoms and signs of heart failure, tachyarrhythmias, bradyarrhythmias, sudden cardiac arrest, or severe mitral regurgitation. On auscultation, there may be a late-peaking systolic murmur due to left ventricular outflow tract obstruction. There also may be symptoms and signs of transient ischemic attack or stroke-like presentation due to embolization from apical thrombus. Approximately, 10% of patients with stress cardiomyopathy develop cardiogenic shock.
The diagnosis of stress cardiomyopathy should be suspected in adults (particularly postmenopausal women) who present with a suspected acute coronary particularly when the clinical manifestations and electrocardiographic abnormalities are out of proportion to the degree of elevation in cardiac biomarkers. It is important to emphasize that because of the indistinguishable features with the acute coronary disease, Takotsubo cardiomyopathy is a diagnosis of exclusion which can only be made after coronary angiography . There are several diagnostic criteria proposed for the diagnosis of Takotsubo cardiomyopathy including the Mayo Clinic criteria, the International Takotsubo Diagnostic Criteria (InterTAK Diagnostic Criteria) and others.
The most widely accepted criteria are the Mayo Clinic diagnostic criteria for identification of stress cardiomyopathy. Outlined below are the key features; all are required to meet the diagnosis :
Electrocardiographic findings Patients with TC often exhibit a dynamic pattern of electrocardiographic (ECG) changes akin to the ECG staging in pericarditis . ST-segment elevation develops in stage 1 followed by normalization of the ST segment in stage 2. T wave inversions develop in stage 3 whereas complete normalization of T waves or very rarely persistence of T wave inversions occur in stage 4. There may be some overlap in stages 2 and 3 and all patients may not exhibit all stages.
Laboratory findings Cardiac biomarkers including troponins and CK-MB show mild elevation. According to the International, Takotsubo Registry study, the median initial troponin was 7.7 times the upper limit of normal. Levels of brain natriuretic peptide (BNP) or N-terminal pro-BNP are elevated in most patients with stress cardiomyopathy and exceeded those seen in a matched cohort of patients with the acute coronary syndrome (median 5.89 versus 2.91 times the upper limit of normal) .
Transthoracic echocardiography demonstrates the wall motion abnormalities classified as:
Most patients with stress cardiomyopathy have reduced overall left ventricular systolic function, and right ventricular dysfunction has been reported too.
Cardiovascular magnetic resonance imaging may be helpful in the diagnosis and evaluation of stress cardiomyopathy, particularly when the echocardiogram is suboptimal, or there is coexistent coronary artery disease. Cardiovascular magnetic resonance may assist in the differential diagnosis, delineate the full extent of ventricular abnormalities, and identify associated complications. It may also demonstrate myocardial edema, necrosis, fibrosis, and occasionally late gadolinium enhancement.
Radionuclide myocardial perfusion imaging is not indicated in most patients presenting with Takotsubo cardiomyopathy since most of the common presentation is acute coronary syndrome requiring cardiac catheterization. In a low to intermediate risk non-ST elevation acute coronary syndrome, radionuclide myocardial perfusion imaging may be helpful.
Cardiac catheterization is an invasive procedure of choice when Takotsubo cardiomyopathy present as ST-elevation acute coronary syndrome or troponin positive acute coronary syndrome. Coronary angiography will show normal coronary anatomy or mild to moderate coronary atherosclerosis.
Although Takotsubo cardiomyopathy is thought to be a benign condition the recent observation data suggest that the rates of cardiogenic shock and death are comparable to patients with the acute coronary syndrome. Thus initial management should focus on identifying and close monitoring of patients at risk for serious complications. Predictors of adverse in-hospital outcomes include: physical trigger, acute neurologic or psychiatric diseases, initial troponin greater than 10× upper reference limit, and admission left ventricular ejection fraction less than 45% . Male patients have up to three-fold increased rate of death and major adverse cardiac and cerebrovascular events primarily due to an increased burden of comorbidities . Guidelines on the management of Takotusbo cardiomyopathy are lacking as there are no prospective randomized data in this regard, thus management is based on clinical experience and expert consensus (evidence level C). Since the initial presentation of Takotsubo cardiomyopathy is similar to an acute coronary syndrome, the initial treatment involves aspirin, beta blocker, ACE inhibitor, a lipid-lowering agent, and coronary angiography to rule out obstructive coronary artery disease . The therapy is guided by the patient’s clinical presentation and hemodynamic status. In stable patients, treatment modalities include cardioselective beta-blockers and ACE inhibitor for a short period around 3-6 months, with serial imaging studies to determine wall motion abnormalities and ventricular ejection fraction to determine progression or improvement. Anticoagulation is usually reserved for those with documented ventricular thrombus or evidence of embolic events; that occurs in 5% of patient with Takotsubo cardiomyopathy. In a patient with more unstable hemodynamics, or those who present in cardiogenic shock, and in the absence of left ventricular outflow obstruction, should be treated with inotropes. Alternatively, patients may derive further benefit from mechanical hemodynamic support with an intra-aortic balloon pump or rarely, left ventricular assist devices. If left ventricular outflow obstruction is present with cardiogenic shock, inotropes should be avoided, and phenylephrine is the pressor agent of choice often combined with beta-blocker agents.
The main differentials to consider include acute coronary syndrome, cocaine-related coronary syndrome, coronary artery spasm, esophageal spasm, myocarditis, pericarditis, and pheochromocytoma.
Although most patients with Takotsubo cardiomyopathy recover the risk of complications among hospitalized patients is similar to that of acute myocardial infarction. The reported mortality among patients with Takotsubo cardiomyopathy ranges from 0 to 8%  with a mortality of 4.1% in the International Takotsubo Registry study . Prognosis of Takotsubo cardiomyopathy depends upon its underlying trigger and TC should be subclassified into primary and secondary forms. Primary TC occurs due to emotional/psychological stimuli and secondary forms occur due to physical factors in hospitalized setting such as sepsis, trauma, surgery or other critical illnesses. Secondary TC is associated with worse in-hospital and long-term outcomes . Despite the low prevalence of Takotsubo cardiomyopathy in males they often have a worse prognosis. This can possibly be explained by the fact that males possess a higher prevalence of acute critical illnesses with elevated circulating catecholamines which may result in higher in-hospital mortality .
The main complications include left ventricular outflow tract obstruction, life-threatening ventricular arrhythmias, paroxysmal or persistent atrial fibrillation, hypotension, low output syndrome, cardiogenic shock, heart failure, and thromboembolism. The incidence of the second event in patients who survive the initial event is about 5% and mostly occurring 3 weeks to 3.8 years after the first event .
The diagnosis and management of anginal pain are with an interprofessional team that consists of the primary care provider, nurse practitioner, cardiologist, radiologist, and pharmacist. When patients with chest pain are encountered, healthcare workers should consider Takotsubo cardiomyopathy in the differential diagnosis. Since the initial presentation of Takotsubo cardiomyopathy mimics acute coronary syndrome, initial treatment involves aspirin, beta blocker, ACE inhibitor, a lipid-lowering agent, and coronary angiography to rule out obstructive coronary artery disease. Takotsubo cardiomyopathy is a temporary condition, and hence the goals of treatment are usually conservative and supportive care. The therapy is guided by the patient’s clinical presentation and hemodynamic status. In stable patients, treatment modalities include cardioselective beta-blockers and ACE inhibitor for a short period around 3 to 6 months, with serial imaging studies to determine wall motion abnormalities and ventricular ejection fraction to determine progression or improvement. Anticoagulation is usually reserved for those with documented ventricular thrombus or evidence of embolic events; that occurs in 5% of patient with Takotsubo cardiomyopathy. The outlook in most patients with treatment is good, especially with a coordinated interprofessional team managing the case, as outlined above, with the chest pain resolving in a matter of weeks.
|||Baltzer Nielsen S,Stanislaus S,Saunamäki K,Grøndahl C,Banner J,Jørgensen MB, Can acute stress be fatal? A systematic cross-disciplinary review. Stress (Amsterdam, Netherlands). 2019 Feb 15; [PubMed PMID: 30767612]|
|||Nandal S,Castles A,Asrar Ul Haq M,van Gaal W, Takotsubo cardiomyopathy triggered by status epilepticus: case report and literature review. BMJ case reports. 2019 Jan 29; [PubMed PMID: 30700451]|
|||Awad HH,McNeal AR,Goyal H, Reverse Takotsubo cardiomyopathy: a comprehensive review. Annals of translational medicine. 2018 Dec; [PubMed PMID: 30603648]|
|||Douglas TM,Wengrofsky P,Haseeb S,Kupferstein E,Kariyanna PT,Schwartz J,Salciccioli L,McFarlane SI, Takotsubo Cardiomyopathy Mimicking Myocardial Infarction in a Man with Myasthenic Crisis: A Case Report and Literature Review. American journal of medical case reports. 2018; [PubMed PMID: 30533522]|
|||Zhang L,Piña IL, Stress-Induced Cardiomyopathy. Heart failure clinics. 2019 Jan; [PubMed PMID: 30449379]|
|||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]|
|||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]|
|||Khalid N,Ahmad SA,Shlofmitz E,Chhabra L, Racial and gender disparities among patients with Takotsubo syndrome. Clinical cardiology. 2019 Jan [PubMed PMID: 30525217]|
|||Kurowski V,Kaiser A,von Hof K,Killermann DP,Mayer B,Hartmann F,Schunkert H,Radke PW, Apical and midventricular transient left ventricular dysfunction syndrome (tako-tsubo cardiomyopathy): frequency, mechanisms, and prognosis. Chest. 2007 Sep [PubMed PMID: 17573507]|
|||Gianni M,Dentali F,Grandi AM,Sumner G,Hiralal R,Lonn E, Apical ballooning syndrome or takotsubo cardiomyopathy: a systematic review. European heart journal. 2006 Jul [PubMed PMID: 16720686]|
|||Prasad A,Dangas G,Srinivasan M,Yu J,Gersh BJ,Mehran R,Stone GW, Incidence and angiographic characteristics of patients with apical ballooning syndrome (takotsubo/stress cardiomyopathy) in the HORIZONS-AMI trial: an analysis from a multicenter, international study of ST-elevation myocardial infarction. Catheterization and cardiovascular interventions : official journal of the Society for Cardiac Angiography & Interventions. 2014 Feb 15 [PubMed PMID: 22121008]|
|||Templin C,Ghadri JR,Diekmann J,Napp LC,Bataiosu DR,Jaguszewski M,Cammann VL,Sarcon A,Geyer V,Neumann CA,Seifert B,Hellermann J,Schwyzer M,Eisenhardt K,Jenewein J,Franke J,Katus HA,Burgdorf C,Schunkert H,Moeller C,Thiele H,Bauersachs J,Tschöpe C,Schultheiss HP,Laney CA,Rajan L,Michels G,Pfister R,Ukena C,Böhm M,Erbel R,Cuneo A,Kuck KH,Jacobshagen C,Hasenfuss G,Karakas M,Koenig W,Rottbauer W,Said SM,Braun-Dullaeus RC,Cuculi F,Banning A,Fischer TA,Vasankari T,Airaksinen KE,Fijalkowski M,Rynkiewicz A,Pawlak M,Opolski G,Dworakowski R,MacCarthy P,Kaiser C,Osswald S,Galiuto L,Crea F,Dichtl W,Franz WM,Empen K,Felix SB,Delmas C,Lairez O,Erne P,Bax JJ,Ford I,Ruschitzka F,Prasad A,Lüscher TF, Clinical Features and Outcomes of Takotsubo (Stress) Cardiomyopathy. The New England journal of medicine. 2015 Sep 3 [PubMed PMID: 26332547]|
|||Khalid N,Ahmad SA,Chhabra L, Pathophysiology of Takotsubo Syndrome . 2019 Jan [PubMed PMID: 30844187]|
|||Pelliccia F,Kaski JC,Crea F,Camici PG, Pathophysiology of Takotsubo Syndrome. Circulation. 2017 Jun 13 [PubMed PMID: 28606950]|
|||Martin EA,Prasad A,Rihal CS,Lerman LO,Lerman A, Endothelial function and vascular response to mental stress are impaired in patients with apical ballooning syndrome. Journal of the American College of Cardiology. 2010 Nov 23 [PubMed PMID: 21087714]|
|||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]|
|||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]|
|||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]|
|||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]|
|||Khalid N, Microcirculatory disorder hypothesis in Takotsubo cardiomyopathy. International journal of cardiology. 2015 Sep 15 [PubMed PMID: 26022795]|
|||[PubMed PMID: 26076951]|
|||[PubMed PMID: 20058057]|
|||[PubMed PMID: 26142964]|
|||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]|
|||Rivero F,Cuesta J,García-Guimaraes M,Bastante T,Alvarado T,Antuña P,Alfonso F, Time-Related Microcirculatory Dysfunction in Patients With Takotsubo Cardiomyopathy. JAMA cardiology. 2017 Jun 1 [PubMed PMID: 28273298]|
|||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]|
|||[PubMed PMID: 27636833]|
|||[PubMed PMID: 26500214]|
|||Medina de Chazal H,Del Buono MG,Keyser-Marcus L,Ma L,Moeller FG,Berrocal D,Abbate A, Stress Cardiomyopathy Diagnosis and Treatment: JACC State-of-the-Art Review. Journal of the American College of Cardiology. 2018 Oct 16; [PubMed PMID: 30309474]|
|||Cusmà-Piccione M,Longobardo L,Oteri A,Manganaro R,Di Bella G,Carerj S,Khandheria BK,Zito C, Takotsubo cardiomyopathy: queries of the current era. Journal of cardiovascular medicine (Hagerstown, Md.). 2018 Nov; [PubMed PMID: 30234685]|
|||Manfredini R,Fabbian F,De Giorgi A,Cappadona R,Zucchi B,Storari A,Rodriguez Borrego MA,Carmona Torres JM,Lopez Soto PJ, Takotsubo syndrome and dialysis: an uncommon association? The Journal of international medical research. 2018 Nov; [PubMed PMID: 30178683]|
|||[PubMed PMID: 29850871]|
|||[PubMed PMID: 18294473]|
|||[PubMed PMID: 15583228]|
|||[PubMed PMID: 30661722]|
|||[PubMed PMID: 22877807]|
|||[PubMed PMID: 29850820]|
|||[PubMed PMID: 11451258]|
|||[PubMed PMID: 15687136]|
|||Akashi YJ,Musha H,Kida K,Itoh K,Inoue K,Kawasaki K,Hashimoto N,Miyake F, Reversible ventricular dysfunction takotsubo cardiomyopathy. European journal of heart failure. 2005 Dec [PubMed PMID: 16397924]|
|||Chhabra L,Sareen P,Mwansa V,Khalid N, Mortality in Takotsubo cardiomyopathy should also be accounted based on predisposing etiology. Annals of noninvasive electrocardiology : the official journal of the International Society for Holter and Noninvasive Electrocardiology, Inc. 2019 Jun 2 [PubMed PMID: 31155779]|
|||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]|
|||Khalid N,Ikram S, Microvascular dysfunction in Takotsubo cardiomyopathy: Prognostic implications. International journal of cardiology. 2015 Dec 15 [PubMed PMID: 26288330]|
|||[PubMed PMID: 20117439]|