Takotsubo syndrome diagnosis: the biomarker-based BioTAK score

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Abstract
Background and Aims: 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. Methods: 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). Results: 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. Conclusions: 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. Clinical Trial Registration: NCT01000701, NCT01947621
Funding Information
  • Schweizerische Herzstiftung
  • UZH Foundation
  • Universität Zürich
  • Kurt und Senta Herrmann Stiftung
  • Theodor und Ida Herzog-Egli-Stiftung
  • Schweizerischer Nationalfonds zur Förderung der Wissenschaftlichen Forschung (SPUM 33CM30-124112)
  • Schweizerischer Nationalfonds zur Förderung der Wissenschaftlichen Forschung (32473B_163271)
  • AstraZeneca Schweiz
  • Eli Lilly and Company
  • Medtronic
  • Merck Sharp and Dohme United Kingdom
  • Roche Diagnostics
  • Sanofi
  • St. Jude Medical
  • PAM Theragnostics GmbH
  • 4TEEN4 GmbH

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