Immune Activation Promotes Cardiac Remodeling in a Mouse Model of Takotsubo Cardiomyopathy
Authors: Fehrenbach Daniel J. , Wassenaar Jean W. , Smart C. Duncan , Zhong Lin , Miller Francis J. , Madhur Meena S. 
Published: May 2024

Takotsubo Cardiomyopathy (TCM) is an acute, life-threatening condition characterized by a drop in ejection fraction (EF) and apical ballooning of the left ventricle (LV). TCM is most frequently observed in women and is associated with an emotional or physical stressor. Importantly, with medical intervention, cardiac dysfunction is transient, and EF is often restored over weeks to months. Despite this, patients who experience TCM are at an increased risk of additional cardiovascular events and premature mortality. The precise etiology of TCM is unknown but a wave of excess circulating catecholamines is thought to be a trigger. Furthermore, the cause for increased cardiovascular risk post-TCM is unknown. The goal of this study is to understand how the immune system may contribute to TCM and the associated cardiovascular event risk. To induce TCM, mice were given a single dose of 200mg/kg isoproterenol (ISO), i.p. and cardiac function was assessed by conscious echocardiography (ECG). An initial study compared the effect of ISO between sexes (n=4-6). Though ISO induced a drop in EF in both sexes after 24 hours (p<0.001 compared to vehicle (Veh)), females exhibited lower EF (46.64±3.11%) than males (68.36±2.62%, p<0.0001). This mirrors the increased prevalence of clinically defined TCM in females in human populations. For this reason, female mice were used for the following experiments. A time course study demonstrated that EF begins to normalize by Day 3 (78.78±2.70 v 90.80±1.00%, p<0.001) and is restored to baseline levels by Day 7 (90.65±1.17%). Flow cytometry was used to identify changes in immune cell populations in the heart on Days 0, 1, 3 and 7 (n=4-5). Neutrophils and inflammatory monocytes increased on Day 1, returning to baseline by Day 3. Dendritic cells and macrophages were elevated on Day 3 post-ISO, with a specific increase in CCR2+ TIM4- recruited inflammatory macrophages (p<0.0001). Across all subsets, the number of immune cells returned to baseline levels by Day 7. Due to the robust immune response observed, we tested the specific hypothesis that transfer of immune cells from mice who have experienced TCM would induce cardiac dysfunction in naïve recipient mice. Donor mice were treated with either Veh or ISO and 1 day later splenocyte isolation and transfer was performed. Importantly, transfer of splenocytes from mice who had TCM induced a significant drop in EF the following day in the recipient mice (86.30±1.08%, p=0.001, n=10) concurrent with an increase in LV inner diameter and volume during systole. A final study tested the hypothesis that a history of TCM would increase risk for future cardiovascular disease. Veh or ISO-treated mice were allowed to recover for 10 days. Tail-cuff plethysmography showed no significant difference in baseline blood pressure and minipumps were implanted to deliver a constant infusion of Angiotensin II (Ang II, 140ng/kg/min). Mice with a history of TCM exhibited higher blood pressures compared to controls (135.11±3.32 v 116.9±6.41mmhg, n=6/9, p<0.05) by week 2 of Ang II infusion. These results together demonstrated that TCM is associated with a robust immune response and points to a possible causal contribution of immune activation to the cardiac dysfunction observed in TCM. Furthermore, a history of TCM promotes a hypertensive phenotype, but additional studies are needed to test whether this is through immunological mechanisms. AHAPOST837441 DJF, 19EIA34480023-MSM, and 1R01 HL161212-MSM. This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.