Sacubitril/valsartan increased survival via inhibiting inflammation and myocardiofibrosis in Takotsubo-like cardiomyopathy

Abstract Background: Takotsubo syndrome mostly manifests as stress-induced cardiomyopathy after physical or emotional stress. However, the exact pathological mechanism of TTS remains unclear, and specific therapies are still lacking. Therefore, we investigated the potential therapeutic effect and mechanism of sacubitril/valsartan (sac/val) on preventing myocarditis and fibrosis in patients with TTS. This study detected inflammatory responses, myocardial edema, fibrosis, etc., in TTS individuals and investigated whether sac/val increased the survival of TTS patients and reversed the remodeling of TTS animal hearts in vivo and investigated the effects of anti-myocardial inflammation and fibrosis in vitro. Methods: Based on the Chinese Takotsubo syndrome (ChiTTS) registry, clinical cases were enrolled to investigate survival. Isoprenaline-induced Takotsubo-like animal models were established, and the animals were pretreated with sac/val. In addition, the effects of isoprenaline on cardiomyocyte and myocardial fibroblasts and protection from rhBNP were studied in detail. Results: In the TTS group diagnosed with an LVEF ≤ 0.45, hyperglycemia, emotional stress and inflammation were found to be independent risk factors. Moreover, the baseline characteristics of the TTS patients, heart rate, emotional triggers, female sex (%), WBC count, IL-6 concentration, PCT, ALT, AST and TG were significantly associated with decreasing left ventricular ejection fraction. Sac/val decreased inflammation, as indicated by white blood cells and interleukin-6, in TTS patients compared with that in patients not receiving sac/val on day 30. During the follow-up, the percentage of surviving patients increased significantly in the TTS group treated with sac/val compared with the group not treated with sac/val at 30 days and 1 year. In animal models, Sac/val improved cardiac dysfunction in ISO-induced TTS-like cardiomyopathy and decreased myocardial inflammatory responses (IL-18 and Mac-3) by inhibiting the TLR4/NF-κB pathway and fibrosis through the inhibition of the TGFβ1/Smad pathway. Conclusions: This study revealed that sac/val decreased inflammatory responses, myocardial edema, fibrosis, etc., resulting in an increase in the percentage of surviving TTS patients. Like in vivo and in vitro experiments, Sac/val exerted cardioprotective effects by decreasing the inflammatory response and reversing myocardial remodeling. Overall, these findings demonstrate the anti-inflammatory and antifibrotic effects of sac/val in individuals with TTS.