Background: Takotsubo Syndrome (TTS) presents a transient acute heart failure (AHF) syndrome in the absence of coronary artery occlusion, suggested to be facilitated by catecholamine storm due to emotional and/or physical stress. Understanding of molecular pathophysiology remains hitherto limited, with impaired long-term outcome, increased patient mortality and a lack of specific therapeutic approaches. Endothelin 1 (ET-1) activates the G protein-coupled endothelin receptor type A (ETAR) and is a very potent endogenous vasoconstrictor with lasting impact on cardiac hypertrophy, inflammation, and cardiovascular disease. Previous work has shown that signaling via the sympathetic (SY-) but not the cardiomyocyte (CM-) ETAR exacerbates chronic heart failure by reuptake inhibition of local cardiac norepinephrine (NE) from the synaptic cleft. Therefore, we investigated the role of ET-1, SY- and CM-ETAR in experimental TTS.  

Methods: To investigate the role of ET-1 and the ETAR in TTS, mice were subjected to epinephrine-induced AHF (EPI) or NaCl and treated with ET-1 with subsequent functional and molecular analysis. To dissect the role of the sympathetic and cardiomyocyte ETAR in experimental TTS, mice harboring a SY-ETAR- or a CM-ETAR- Knockout (KO) underwent EPI-induced AHF with subsequent functional assessment. 

Results: Surprisingly, ET-1 rescued AHF (mean EF 49.97% vs. 28.49% at 2 hours, n=3-5/group, 2-way-ANOVA, Fig. 1A) and reduced markers of left ventricular (LV) fibrosis at 4 months (mean 1.55 vs. 0.73, n=5-9/group, one-way ANOVA; Fig. 1B). Conversely, SY-ETAR-KO mice suffered from worsened AHF compared to Wild-type (WT) littermates (mean 36.55% vs. 18.08% at 5 hours, n=8-10/group, 2-way ANOVA; Fig. 2) and CM-ETAR-KO mice displayed elevated high-sensitive Troponin T (hs-TnT) (mean 2436 vs. 6152, n=9-10/group, one-way ANOVA; Fig. 3A) and increased mortality (n=10/group, Log-rank test; Fig. 3B). ET-1 restored EPI-induced blunted phospholamban Ser16 and Thr17 phosphorylation (Fig. 4A-B) as well as a downregulation of the proapoptotic BAX/BCL-2 protein quota (Fig. 4C). Additionally, ET-1 restored Ser-282 phosphorylation of myosin binding protein (P-MyBP) (Fig. 4D). 

Conclusion: ET-1 restores cardiac function, while genetic ablation of the ETAR in both cardiomyocytes and sympathetic neurons exacerbates experimental TTS. The sympathetic ETAR contributes to contractility, while the cardiomyocyte ETAR prevents cardiomyocyte damage and improves survival. Further studies are warranted to assess a potential therapeutical benefit of ET-1 in TTS-facilitated cardiogenic shock.