Takotsubo syndrome (TTS) is an acute heart failure (AHF) syndrome that mimics the symptoms of acute myocardial infarction (AMI) and is often preceded by psychological or physical stress1. TTS comprises 2-3% of suspected acute coronary syndrome (ACS) cases presenting to the emergency department2. Since up to 90% of patients are female, this amounts to up to 10% of female ACS patients3. Incidence has been estimated to be 10/100.000/year4. However, contrary to earlier conceptions, TTS is associated with substantial mortality2 as well as lasting symptom burden accompanied by subclinical cardiac dysfunction in survivors5. Despite frequent recovery of left ventricular ejection fraction (LVEF), mortality after hospital discharge accumulates to 5% per patient year with a five-year mortality of 22.6% and up to 54.9% in very high-risk patients2,6,7. Health-related quality of life (QoL) and psychological well-being were reported lower after TTS compared to AMI or the general population8.

With respect to pathophysiology, a causative role of catecholamines has been suggested based on excessive systemic and cardiac catecholamine release9,10, increased heart rate with QT prolongation11, and contraction band necrosis in human myocardial biopsies9. These findings are supported by catecholamine-driven reversible AHF in mice12, rats13, and humans14, which recapitulates key findings of TTS15, 16, 17. Data from the InterTAK registry showed that a troponin >10x the upper limit of normal or an LVEF below 45% on admission both predict adverse outcome2. Interestingly, case reports of TTS triggered by immune checkpoint inhibitors, suggest that lymphocyte activation is sufficient to trigger TTS18. Cardiac magnetic resonance imaging (CMR) in TTS revealed acute macrophage-driven myocardial inflammation with persistent edema. Moreover, modulation of the overall monocyte population and increased serum IL-6 and troponin levels were observed up to 5-month follow-up. Thus, the acute inflammatory response has been suggested as a promising therapeutic target19.

There is currently no evidence-based or pathophysiology-directed treatment option available. Several cohort studies evaluated the association between renin-angiotensin-aldosterone inhibitor (RAASi) or betablocker intake and mortality in TTS with divergent results2,20. The following RCTs are currently investigating therapeutic options in TTS: the BROKEN-SWEDEHEART study is a randomized, parallel, open-label multicenter trial to test the impact of adenosine and apixaban in TTS (NCT04666454)21. The Beta-blockers in Takotsubo syndrome (TTS) (β-Tako) trial, is a multicenter RCT aiming to assess the efficacy of beta-blockers (NCT06509074)22. The N-AcetylCysteine and RAMipril in Takotsubo Syndrome Trial (NACRAM) is a multi-centre, randomised, placebo-controlled trial, sequentially testing the impact of intravenous N-acetylcysteine(NAC), followed by oral ramipril (ACTRN12616000781448)23. Here, we present the rationale and design of a phase II randomized controlled trial (RCT) to assess the first anti-inflammatory treatment option of TTS.