Abstract Body: Takotsubo Cardiomyopathy (TCM) is an acute, life-threatening condition characterized by reduced ejection fraction (EF) and apical ballooning of the left ventricle (LV). TCM typically follows emotional or physical stress and predominantly occurs in women. With medical care, EF often recovers over weeks to months. Despite this, patients remain at increased risk of cardiovascular (CV) events and premature mortality. This study aimed to examine how the immune system may contribute to TCM and the associated CV event risk. TCM was induced in mice with a single 200mg/kg i.p. dose of isoproterenol (ISO). We then performed conscious echocardiography. An initial study compared ISO effects between sexes (n=4-6). ISO reduced EF in both sexes after 24 hours but was significantly lower in females (46.64±3.11%) than males (68.36±2.62, p<0.0001). A time course study in female mice demonstrated that EF begins to normalize by Day 3 (78.78±2.70 v 90.80±1.00%, p<0.001) and is fully restored by Day 7. Flow cytometry of cardiac tissue on Days 0, 1, 3 and 7 (n=4-5) revealed that neutrophils and inflammatory monocytes increased on Day 1 and dendritic cells and macrophages were elevated on Day 3, with a specific increase in CCR2+ TIM4- recruited inflammatory macrophages (p<0.0001). All immune cell subsets returned to baseline levels by Day 7. To test whether immune activation contributes to dysfunction, splenocytes from ISO- or Veh-treated mice (Day 1) were transferred to naïve recipients. Splenocytes from TCM mice induced a significant drop in EF the following day in the recipient mice (86.30±1.08%, p=0.001, n=10) and increased LV inner diameter and volume during systole. A final study tested the hypothesis that TCM history increases risk for future CV disease. Mice recovered for 10 days post-ISO or Veh, then received low-dose Angiotensin II (Ang II, 140ng/kg/min) by osmostic minipump. While baseline systolic blood pressure (SBP) was similar, mice with a history of TCM exhibited elevated SBP by week 2 of Ang II infusion (135.11±3.32 v 116.9±6.41mmhg, n=6/9, p<0.05). In summary, TCM triggers a dynamic immune response marked by early inflammatory cell activation and transient macrophage infiltration. Adoptive transfer of splenocytes from TCM mice induced LV dysfunction, implicating immune activation as a contributor. Prior TCM sensitizes mice to hypertensive stimuli, suggesting lasting immune effects that merit further investigation.