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

Future Directions

With advances in imaging, patients being examined for takotsubo syndrome should undergo multimodal noninvasive imaging. Not only does this increase the accuracy of the diagnosis, but it also allows for risk stratification and prognostication. The precise diagnosis of takotsubo syndrome does rely on the combination of clinical context, echocardiography, cardiac catheterization, and cardiac magnetic resonance imaging. Future exploration of a single sensitive and specific diagnostic test would greatly simplify clinical care pathways and would give added impetus to future therapeutic trials by identifying a more homogeneous patient population.

There is a major lack of evidence to guide management in patients with takotsubo syndrome, and this needs to be the focus of future research. Two main therapeutic domains need addressing. First, the management of acute takotsubo syndrome needs to be defined, especially guidance on the treatment of severe complications, such as cardiogenic shock. Second, the prevention of recurrent major adverse cardiac and cerebrovascular events is crucial. This includes the role of heart failure therapies to prevent reoccurrence of takotsubo syndrome, anticoagulant therapies to prevent ischemic strokes and psychiatric interventions, specifically in those with underlying mental health problems. Randomized controlled trials such as NACRAM (N-Acetylcysteine and Ramipril Takotsubo Syndrome Trial, ACTRN12616000781448)[95] and BROKEN-SWEDEHEART (Optimized Pharmacological Treatment for Broken Heart [Takotsubo] Syndrome, NCT04666454) are currently assessing potential interventions and will be invaluable in informing treatment guidelines.

Given the presence of substantial and protracted myocardial inflammation, a potential role for anti-inflammatory therapies may have a role in the recovery from takotsubo syndrome. Long-term cardiac energetic impairment may also be 1 reason why patients continue to have symptoms and are prone to recurrent episodes despite apparent recovery of left ventricular ejection fraction. Interventions targeting these impairments of cardiac metabolism could be beneficial. For example, the benefits of sodium-glucose transporter 2 inhibitor therapy in heart failure may be related to an improvement in cardiac efficiency because of a shift in cardiac metabolism and could potentially be applicable to the takotsubo syndrome.[96,97] Further studies of specific substrate use and enhancement of cardiomyocyte metabolic pathways are an attractive investigative pathway.

Patients with takotsubo syndrome have persistent symptomatic and functional impairment, and recurrent major events, as well, and it is essential that future studies focus on the long-term assessment of cardiac function, metabolism, symptoms, and clinical outcomes. This will be the focus of the Inter-TAK registry (International Takotsubo Registry, NCT01947621),[11,47] which has launched a 10-year follow-up study in patients with takotsubo syndrome. This will also help identify different subtypes of takotsubo syndrome that may require distinct cause-specific interventions.