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

Diagnostic Criteria

The diagnosis of takotsubo syndrome can be challenging because the clinical features have many similarities with acute coronary syndrome, and immediate early cardiac imaging is needed because of the rapid normalization of the left ventricular ejection fraction. The most widely used diagnostic criteria are those proposed by the Mayo Clinic in 2004[54] and subsequently revised in 2008[55] (Figure 3). Other groups have proposed slightly different diagnostic conventions, such as the Gothenburg criteria,[56] Johns Hopkins criteria,[57] the Takotsubo Italian Network proposal,[58] and the Heart Failure Association Takotsubo Syndrome Taskforce of the European Society of Cardiology criteria.[59] The underlying principle is that takotsubo syndrome is a diagnosis of exclusion because a specific diagnostic test or biomarker has yet to be defined to identify the condition. This extends to the postmortem examination of fatal cases where specific diagnostic pathological features have yet to be defined, making it currently impossible to assign this diagnosis at autopsy.

Figure 3.

Diagnostic criteria and pathway for takotsubo syndrome.

The presence of coronary artery disease may traditionally have deterred the clinician from a diagnosis of takotsubo syndrome. Despite this uncertainty, it has become evident that takotsubo syndrome can coexist in the presence of fixed coronary artery disease and can even be triggered by acute coronary syndrome.[15] It is vital to look for subtle differences in clinical presentation to avoid misdiagnosis (Table 1). Likewise, patients may be incorrectly diagnosed with takotsubo syndrome if coronary angiography reveals nonobstructive coronary artery disease, and the possibility of plaque rupture has not been ruled out, especially because stressful events are also associated with acute plaque rupture and type 1 myocardial infarction. The Inter-TAK diagnostic score[60] was developed to aid the clinician in distinguishing takotsubo syndrome from acute coronary syndrome, but its performance is variable. Because understanding of the fundamental pathophysiology of takotsubo syndrome is limited, these criteria are likely to continue to evolve with time. We provide a diagnostic pathway incorporating the Inter-TAK score to aid diagnosis (Figure 3). The hallmark of the takotsubo syndrome is ultimately the reversibility in systolic function that occurs within hours, days, or weeks, in the absence of infarct-specific myocardial fibrosis.[6,14] The clinical implication of recovery time remains unknown, and there is emerging evidence that full recovery may be slower and less complete than initially thought.