Risk of adverse events in takotsubo syndrome compared to heart failure: observations from a global federated network

Background Takotsubo Syndrome (TTS) shares key pathophysiological mechanisms with Heart Failure (HF), including impaired myocardial contractility, neurohormonal activation, and long-term cardiovascular risk. However, data on its long-term outcomes compared to HF remain limited, leaving uncertainty regarding its true prognostic impact. Purpose To assess the risk of adverse events in patients with TTS compared to those with HF with both reduced or preserved ejection fraction. Methods Retrospective study using data from a large multinational electronic health record network (TriNetX). Adult patients (≥18 years) diagnosed with TTS (ICD-10-CM I51.81) or HF (ICD-10-CM I50.x) between 2018 and 2023 were included in the analysis and categorized into two different groups. Primary outcomes were the risks of all-cause death and of a composite of hospital admission, acute HF, acute myocardial infarction, stroke and ventricular arrhythmias. Secondary outcomes were the risks for each component of the composite outcome and new onset atrial fibrillation. We used Cox regression analysis to calculate hazard ratio (HR) and 95% confidence interval (CI) after propensity score matching (PSM) 1:1. Results We identified 12802 TTS patients (age 66.3±15.3 years, 73.7% females) and 687319 HF patients (69.5±15.9 years, 44.4% females). Before PSM, TTS patients were younger, predominantly female, and with a lower cardiovascular burden compared to HF patients. After PSM, 12800 matched pairs were analyzed. TTS patients showed a lower risk of all-cause death (HR 0.89, 95%CI 0.84-0.95) and composite outcome (HR 0.84, 95%CI 0.82-­0.86) compared to HF patients. Regarding secondary outcomes, TTS patients had a lower risk of acute HF (HR 0.81, 95%CI 0.78-­0.85), ventricular arrhythmias (HR 0.77, 95%CI 0.71-0.85) and new onset atrial fibrillation (HR 0.68, 95%CI 0.59-0.77). Although, they showed a higher risk of acute myocardial infarction (HR 1.44, 95%CI 1.37-1.52) and a similar risk of stroke (HR 1.03, 95%CI 0.95-1.13) (Figure 1, Figure 2). These associations persisted when comparing TTS to HF patients’ subgroups with reduced or preserved ejection fraction. Conclusion TTS patients are at generally lower risk of adverse events compared to HF patients, but have a risk of ischemic complications (acute myocardial infarction, stroke) similar to HF. These findings challenge the conventional view of TTS as a transient condition, highlighting the need for further investigation into its long-term pathophysiological mechanisms.