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

Abstract and Introduction


Takotsubo syndrome is a condition characterized by acute transient left ventricular systolic dysfunction, which at presentation can be challenging to distinguish from acute myocardial infarction. Although previously thought to be a benign, self-limiting condition, recent studies have confirmed that patients with takotsubo syndrome have persistent subtle ongoing cardiac dysfunction, and many continue to have limiting symptoms despite restoration of left ventricular ejection fraction. Moreover, these patients have a substantial burden of morbidity and mortality, as well, with high rates of subsequent major adverse cardiovascular events that approach those of patients with acute coronary syndrome. The mechanisms behind this condition remain elusive. Despite substantial research, the medical community continues to have an incomplete understanding of its underlying pathogenesis and pathophysiology. Catecholamine-induced myocardial injury is the most established and well-known theory, but this does not explain all the clinical features and presentations of the condition, and numerous other pathways and abnormalities are emerging. Because of the poor understanding of its underlying pathophysiology, there is a lack of evidence-based interventions to treat the acute episode, to avoid recurrences, and to prevent major adverse cardiovascular events. This highlights the need for further research to gain a better understanding of the underlying pathophysiology to inform appropriate randomized controlled trials of interventions targeting the causative pathways. Only then can evidence-based management strategies be established to improve clinical outcomes of this potentially lethal condition.


He first deceased; she for a little tried
To live without him; liked it not, and died.
—Sir Henry Wootton, 1651

Takotsubo syndrome was first named by Sato et al in 1990,[1] although sudden and rapid death after intense psychological stress was described by Engel[2] and Rees and Lutkins[3] >50 years ago. After some initial skepticism, awareness of this potentially fatal condition has substantially increased over the past 10 to 15 years[4,5] and is now an established increasingly frequent and important cause of acute cardiac presentations.[5]

Takotsubo syndrome has several unique characteristics that distinguish it from other acute cardiac emergencies. It is typified by nonobstructed coronary arteries associated with a characteristic anteroseptal-apical dyskinetic ballooning of the left ventricle with hyperkinetic basal segments (Figure 1). These features spontaneously resolve to restore apparently normal left ventricular function.[6,7] Despite being described 30 years ago, its pathogenesis and pathophysiology remain poorly understood and the lack of treatments often presents a clinical dilemma for physicians. Previously believed to be a benign self-limiting condition,[8–13] takotsubo syndrome is now known to be associated with substantial short- and long-term morbidity and mortality. The purpose of this review is to provide an update on the current understanding of the clinical features of this condition, to discuss the latest theories regarding its pathogenesis and pathophysiology, and to highlight the need for future therapeutic interventions to reduce and to prevent the major morbidity and mortality.

Figure 1.

Takotsubo syndrome: anatomic variants.
Left ventriculogram demonstrating apical (A and B) ballooning of the left ventricle, similar to the shape of a Japanese octopus trap (C). Basal (D and E), midventricular (F and G), and focal (H and I) variations of takotsubo syndrome.