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


Takotsubo syndrome is increasing in incidence, which may reflect the rising prevalence of modern life stressors and the greater awareness and detection of the condition by the clinical cardiology community, as well.[5,9] Takotsubo syndrome accounts for ≈2% to 3% of all patients and 5% to 6% of female patients presenting with acute coronary syndrome,[9,14,15] although it may be underappreciated and underdiagnosed especially in patients who have coexisting coronary artery disease.[16]

Whereas the condition can occur in any age group, it characteristically affects women in the sixth decade of life, although patients <50 years of age account for ≈10% of cases.[17] Younger patients are more likely to be male, or have atypical takotsubo, fewer comorbidities, and acute neurological or psychiatric disorders, and to develop in-hospital complications.[17]

Although increasing age may be a risk factor for developing takotsubo syndrome,[15] the underlying mechanism remains unknown, but can be explained in part by the influences of age and sex on the sympathetic nervous system. Sympathetic nervous system activity increases with age, particularly in women, and cardiac sympathetic stimulation is augmented because of an imbalance in neuronal norepinephrine homeostasis.[18,19] With age, there is a decrease in vagal tone and baroreflex sensitivity with a concomitant increase in sympathetic activation,[18] potentially rendering the myocardium more susceptible to enhanced levels of catecholamines. Although increasing age may be a risk factor for developing takotsubo syndrome, it is not an independent risk factor for in-hospital mortality which contrasts with the well-recognized age-related mortality seen in patients with acute coronary syndrome.[9]

Although most patients (80%–90%) who develop takotsubo syndrome are women,[15,20] the mechanism underlying this large sex disparity is unknown. Several hypotheses have been proposed and centered on estrogen deprivation occurring postmenopause and its role in regulating sympathetic drive and microvascular blood flow through endothelium-dependent and -independent mechanisms.

Familial takotsubo syndrome has been described,[21] although multigenerational Mendelian inheritance does not occur, suggesting that a genetic predisposition may interact with environmental factors or have a polygenic cause. Polymorphisms of the β1- and β2-adrenoreceptor genes have been associated with reduced left ventricular function in patients with takotsubo syndrome, but results are conflicting and inconclusive.[22,23] Larger studies are currently underway to explore potential genetic associations (GENETIC [Is There a Genetic Predisposition for Acute Stress-induced {Takotsubo}Cardiomyopathy], NCT04513054).