Takotsubo syndrome diagnosis: the biomarker-based BioTAK score

Takotsubo syndrome (TTS) closely mimics acute coronary syndrome (ACS). Early differentiation remains challenging because diagnosis currently relies on medical, psychiatric, and neurological history, repeated cardiac imaging, and exclusion of a culprit epicardial coronary artery lesion, generally with invasive coronary angiography (ICA). The aim of this study was to develop and externally validate a biomarker-based diagnostic score supporting the early differentiation of TTS from ACS before ICA.

In this study, 3615 patients with ACS or TTS from overlapping registries were investigated. Circulating levels of established and emerging cardiovascular biomarkers were measured before ICA. A biomarker-based diagnostic score for TTS (BioTAK) was developed in a cohort of 1823 patients (ACS n = 1754; TTS n = 69) using machine learning-guided feature selection and logistic regression and externally validated in an independent cohort of 1792 patients (ACS n = 1715; TTS n = 77).

The final five-item score incorporated biomarkers reflecting myocardial stress (N-terminal pro-B-type natriuretic peptide), vasoconstriction and anxiety regulation (peptidylglycine α-amidating monooxygenase), atherosclerotic plaque instability (soluble lectin-like oxidized low-density lipoprotein receptor-1), and lipid metabolism (low-density lipoprotein cholesterol), along with sex. BioTAK demonstrated excellent discrimination between TTS and ACS in the development cohort [area under the receiver operating characteristic curve (AUC) .97, 95% confidence interval (CI) .95-.98] and maintained high performance on external validation (AUC .93, 95% CI .90-.96), with good calibration. Using predefined rule-in and rule-out thresholds, the score stratified almost 90% of patients to a likely diagnosis prior to ICA.

TTS is characterized by a distinct biomarker profile reflecting pathophysiological differences from ACS. The non-subjective biomarker-based BioTAK score can support the early identification of TTS, help streamline diagnostic pathways, and might reduce potentially avoidable invasive procedures in patients presenting with suspected ACS.

NCT01000701, NCT01947621.