Kuang Jiangying, Jia Zhiyi, Chong Tou Kun, Chen Jian, Liu Kan, Wang Xin, Li Zhaohua, Zhang Jing, Kong Yanru, Deng Lin, Cadieras Martin, Sun Yuanyuan, Sun Rong, Lu Qinghua, Liu Yusheng
Department of Cardiology, The Second Hospital, Cheeloo College of Medicine, Shandong University, Jinan, Shandong 250031, PR China.
Department of Cardiology, Kiang Wu Hospital, Macao Special Administrative Region of the People's Republic of China, PR China.
J Mol Cell Cardiol. 2025 Mar;200:24-39. doi: 10.1016/j.yjmcc.2025.01.003. Epub 2025 Jan 18.
Takotsubo syndrome (TTS) primarily manifests as a cardiomyopathy induced by physical or emotional stress, remains a poorly understood condition with no established treatments. In this study, we investigated the potential of sacubitril/valsartan (sac/val) to increase the survival of TTS patients and reduce inflammation and myocardial fibrosis in experimental models.
This study aimed to evaluate whether sac/val could improve survival rates in TTS patients, mitigate cardiac remodeling in vivo, and explore its anti-inflammatory and antifibrotic mechanisms in vitro.
Clinical cases from the Chinese Takotsubo syndrome (ChiTTS) registry were analyzed to assess patient survival rates. In addition, we used isoprenaline (ISO)-induced TTS-like animal models, pre-treated with sac/val, to evaluate cardiac function and inflammatory response. Additionally, the effects of isoprenaline on cardiomyocytes and myocardial fibroblasts, as well as protection from rhBNP, were thoroughly studied.
In TTS patients with a left ventricular ejection fraction (LVEF) ≤ 0.45, hyperglycemia, emotional stress, and inflammation were identified as 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. In TTS patients, sac/val reduced inflammation, evidenced by lower levels of white blood cells and interleukin 6, compared to patients who did not receive sac/val by day 30. 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 TGFβ/Smad pathway.
This study revealed that sac/val decreased inflammatory responses, myocardial edema, and fibrosis, resulting in an increased percentage of survivors in the TTS group. Similar to findings from in vivo and in vitro experiments, sac/val exerted cardioprotective effects by reducing the inflammatory response and reversing myocardial remodeling mediated by the TLR4/NF-κB and TGFβ/Smad pathways. In conclusion, these findings highlight the anti-inflammatory and antifibrotic effects of sac/val in individuals with TTS.
应激性心肌病（TTS）主要表现为由身体或情绪应激诱发的心肌病，目前仍是一种了解甚少且尚无既定治疗方法的疾病。在本研究中，我们研究了沙库巴曲缬沙坦（沙库/缬沙坦）提高TTS患者生存率以及减轻实验模型中炎症和心肌纤维化的潜力。
本研究旨在评估沙库/缬沙坦是否能提高TTS患者的生存率，减轻体内心脏重塑，并在体外探索其抗炎和抗纤维化机制。
分析中国应激性心肌病（ChiTTS）登记处的临床病例以评估患者生存率。此外，我们使用经沙库/缬沙坦预处理的异丙肾上腺素（ISO）诱导的类TTS动物模型来评估心脏功能和炎症反应。此外，还深入研究了异丙肾上腺素对心肌细胞和心肌成纤维细胞的影响以及重组人脑钠肽的保护作用。
在左心室射血分数（LVEF）≤0.45的TTS患者中，高血糖、情绪应激和炎症被确定为独立危险因素。此外，TTS患者的基线特征、心率、情绪触发因素、女性比例（%）、白细胞计数、白细胞介素-6浓度、降钙素原、谷丙转氨酶、谷草转氨酶和甘油三酯与左心室射血分数降低显著相关。在TTS患者中，与未接受沙库/缬沙坦治疗的患者相比，到第30天时，沙库/缬沙坦降低了炎症反应，表现为白细胞和白细胞介素-6水平较低。在动物模型中，沙库/缬沙坦改善了ISO诱导的类TTS心肌病中的心脏功能障碍，并通过抑制TLR4/NF-κB途径降低了心肌炎症反应（白细胞介素-18和Mac-3），并通过抑制TGFβ/Smad途径减轻了纤维化。
本研究表明，沙库/缬沙坦降低了炎症反应、心肌水肿和纤维化，从而使TTS组的幸存者比例增加。与体内和体外实验结果相似，沙库/缬沙坦通过减少炎症反应和逆转由TLR4/NF-κB和TGFβ/Smad途径介导的心肌重塑发挥心脏保护作用。总之，这些发现突出了沙库/缬沙坦在TTS患者中的抗炎和抗纤维化作用。
