Abstract Body (Do not enter title and authors here): Background: Serotonin-norepinephrine reuptake inhibitors (SNRIs) inhibit the presynaptic reuptake of serotonin and norepinephrine and are widely used in the treatment of depression and neuropathic pain. Some studies suggest that the use of SNRIs may play a role in the etiology of takotsubo cardiomyopathy.

Objectives: We aim to evaluate the impact of serotonin-norepinephrine reuptake inhibitors on the clinical outcomes of patients with takotsubo cardiomyopathy.

Method: The authors retrospectively analyzed the deidentified patient data from TriNetX research network. Patients aged ≥18 years with a principal diagnosis of takotsubo cardiomyopathy were identified from January 1, 2003, to December 31, 2023. Patients with a history of myocarditis, pheochromocytoma, acute myocardial infarction, cocaine-related disorders, opioid-related disorders, and patients on with an active prescription for 5-fluorouracil, capecitabine, gemcitabine, and trastuzumab were excluded. Additionally, patients on selective serotonin reuptake inhibitors, tricyclic antidepressants, modafinil, armodafinil, methylphenidate, bupropion and atomoxetine were excluded. We used propensity score matching to adjust for potential confounders. The final study population was divided into two cohorts: Patients on SNRIs (duloxetine, venlafaxine, and desvenlafaxine) and patients not on SNRIs. The primary outcome was all-cause mortality, and the secondary outcome was takotsubo cardiomyopathy-related complications.

Results: A total of 16,853 patients with a diagnosis of takotsubo cardiomyopathy were identified, of which 2,482 (14.7%) were on SNRIs at the time of diagnosis. The SNRIs cohort was slightly older (mean age 64.1 vs. 63.4 years). Patients on SNRI had a higher proportion of Whites (76.2% vs. 66.5%). After propensity score matching, patients on SNRI had lower 7-day mortality (OR, 0.59; 95% CI, 0.41 – 0.84, p<0.01), cardiac arrest (OR, 0.58; 95% CI, 0.40 – 0.84, p<0.01), ventricular fibrillation (OR, 0.496; 95% CI, 0.248 – 0.995, p=0.04), and atrial fibrillation and flutter (OR, 0.74; 95% CI, 0.57 – 0.97, p=0.03). At 1 year, patients on SNRI had lower mortality (OR, 0.80; 95% CI, 0.67 – 0.96, p=0.02). On subgroup analysis, the use of duloxetine or venlafaxine alone was independently associated with lower 7-day mortality.

Conclusion: The use of SNRIs among patients presenting with takotsubo cardiomyopathy is associated with lower mortality and lower takotsubo cardiomyopathy-related complications.