Takotsubo Syndrome: Pathophysiology, Emerging Concepts, and Clinical Implications

Trisha Singh, BM; Hilal Khan, MB BCh BAO, MRCP; David T. Gamble, MPharm, MBBS; Caroline Scally, MBChB; David E. Newby, DM, PhD; Dana Dawson, MD, DPhil


Circulation. 2022;145(13):1002-1019. 

In This Article

Clinical Features

Patients with takotsubo syndrome classically present with acute-onset chest pain, dyspnea, and changes on the ECG occurring in association with an acute stressful event.[15] This presentation mimics, and is often initially managed as, an acute coronary syndrome (Table 1). When marked, it can include presentations consistent with an acute ST-segment–elevation myocardial infarction. In extreme circumstances, patients can present with severe heart failure, cardiogenic shock, or arrhythmias requiring hemodynamic and sometimes ventilatory support.

A precipitating stressful event is typically considered to be unexpected bereavement, conflict, or a major life event. However, it is important to appreciate that one-third of patients do not recognize an identifiable stressor, and this is reflected in the latest diagnostic criteria.[15] This figure may be an overestimate because some patients may be reluctant to discuss personal stressful circumstances, or clinicians may not fully explore or probe underlying stress-related or mental health problems. Furthermore, protracted previous stress may contribute, and this is often undisclosed and underappreciated. Takotsubo syndrome can also be precipitated after major events resulting in community stress, such as earthquakes (New Zealand 2010, 2011, and 2016),[26] and more recently, anxiety related to the COVID-19 pandemic.[27]

Noncardiac medical conditions, in particular, neurological, such as intracranial hemorrhage, pheochromocytoma, and epilepsy, or severe acute critical illnesses can induce takotsubo syndrome.[28–30] Cancer is increasingly recognized as a precipitant, and this may relate to the direct mental stress from receiving a diagnosis of malignancy or the combined mental and physical stress of cancer treatments.[31] Stresses from a range of physical illnesses or procedures are also recognized and include acute exacerbations of asthma or chronic obstructive pulmonary disease, endoscopic examinations, cardioversions, and many others.

Acute or chronic mental health conditions, such as depression and anxiety, are present in one-third of patients with takotsubo syndrome.[8,9,32] Rates of psychiatric or neurological disorders are 7-fold higher than in patients with acute coronary syndrome, with a high prevalence of type-D personality characteristics (negative emotions, social inhibition) suggesting a predisposing element that has not been fully explored by psychiatrists or clinical psychologists.[33] Patients affected by depression and anxiety also demonstrate overactivity of the sympathetic nervous system in response to physical or emotional stress, implying greater susceptibility to takotsubo syndrome.[33]

The multicenter Spanish RETAKO (Registry for Takotsubo syndrome)[10] and Inter-TAK (the International Takotsubo Registry)[11,32] have shown that patients with an emotional stressor are more likely to be female, present with chest pain, and have better outcomes. Those with a physical stressor (infection, surgery, trauma, neurological disorder, and hypoxia) are more likely to be men, have comorbidities, present with syncope and dyspnea, develop the basal pattern of left ventricular dysfunction, and have acute complications.[8,10,32]