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 Course

Despite its transient nature, patients are at substantial risk of complications during the initial hospitalization period, with 1 in 5 patients at risk of serious adverse events and 1 in 25 dying.[9] These events occur as a consequence of acute complications from the takotsubo syndrome itself (cardiogenic shock, cardiac arrest, and congestive heart failure) or the critical underlying illness (respiratory failure, acute renal failure, stroke, and sepsis).[9,10,12,61] The overall rate of in-hospital complications is comparable to that of patients with acute coronary syndrome (21% versus 19%; Figure 4).[9,11,13]

Figure 4.

Outcomes in takotsubo syndrome.
A, In-hospital complications in patients with takotsubo syndrome (blue) and patients with acute coronary syndrome (red). B, Long-term outcomes in patients with takotsubo cardiomyopathy. C, Kaplan-Meier curves for long-term mortality in patients with takotsubo syndrome compared with patients with acute coronary syndrome. Reprinted from Ghadri et al15 with permission. Copyright © 2018, the Authors. NSTE-ACS indicates non–ST-segment–elevation acute coronary syndrome; and STE-ACS, ST-segment–elevation acute coronary syndrome.

Fifteen percent to 20% of patients with takotsubo syndrome develop hypotension, which varies in severity.[61] Hypotension likely reflects the underlying left ventricular systolic dysfunction, although vasodilatation, left ventricular outflow tract obstruction, and mitral regurgitation may contribute. However, the extent and severity of left ventricular systolic dysfunction does not appear to correlate with systolic blood pressure or clinical heart failure. Patients with apical takotsubo syndrome are more likely to sustain a greater degree of left ventricular dysfunction than those with atypical forms. Ten percent of patients with takotsubo syndrome will develop cardiogenic shock, although these rates are surprisingly low given the magnitude and extent of left ventricular systolic dysfunction.[61] Patients who sustain an anterior ST-segment–elevation myocardial infarction and a similar degree of left ventricular systolic dysfunction are often more compromised.

Left ventricular outflow tract obstruction occurs in 10% to 15% of patients and may exacerbate left ventricular apical ballooning and dysfunction because it exposes the apex to higher wall stress than the basal myocardium.[59] Similarly, mitral regurgitation occurs in 10% to 20% of patients[61] because of tethering and systolic anterior motion of the mitral valve leaflet. These abnormalities resolve with the subsequent associated improvements in left ventricular contractility.

Atrial and ventricular arrhythmias are seen frequently, with atrial fibrillation being the most common (3%). Life-threatening arrhythmias, such as torsade de pointes and polymorphic ventricular tachycardia, occur occasionally.[9,13]

Systemic thromboembolism is an important complication of takotsubo syndrome, which is often underappreciated. Rates of ischemic stroke are higher than those seen after an acute coronary syndrome and occur in 1% to 2% of acute hospitalizations.[9,13,62] An elevated stroke risk appears to extend beyond the acute episode and is much more prominent than subsequent rates of myocardial infarction that are low (1.7% versus 0.3%; Figure 4).[47] The most likely embolic origin is left ventricular mural thrombus attributable to blood stasis within the akinetic ventricular segments (Figure 2). The spontaneous improvement in left ventricular myocardial function may initiate embolization and consequent stroke. The GEIST registry (German Italian Stress Syndrome) demonstrated that the presence of left ventricular thrombi was associated with embolic cerebrovascular events in 17% of patients.[49]

Several studies[8–11,13] have demonstrated that long-term mortality is similar to that of acute coronary syndrome: all-cause death in 5.6% of patients per year (Figure 4).[9] Cardiovascular deaths are the most common cause of death in both takotsubo and acute coronary syndromes.[8] More recently, Redfors et al[13] demonstrated that long-term mortality for takotsubo syndrome is comparable to patients with non–ST-segment–elevation myocardial infarction, but lower than those presenting with ST-segment–elevation myocardial infarction. Age <50 years, male sex, physical trigger, left ventricular ejection fraction <45%, presence of atrial fibrillation, cardiac troponin concentration >10-fold the upper limit of normal, and acute neurological disease were independent predictors of 1-year mortality,[8–10,12] but not the location (apical, basal, midventricular, focal) of myocardial ballooning.[32]