Department of Cardiovascular Medicine (S. Furusawa, M.I., T.I., T.K., H.D.M., K.A., K.I., M.W., Y.T., R.M., S. Fujita, T.T., S.M., H.T.), Faculty of Medical Sciences, Kyushu University, Fukuoka, Japan.
Division of Cardiovascular Medicine, Research Institute of Angiocardiology (S. Furusawa, M.I., T.I., T.K., H.D.M., K.A., K.I., M.W., Y.T., R.M., S. Fujita, S.M., H.T.), Faculty of Medical Sciences, Kyushu University, Fukuoka, Japan.
Circ Heart Fail. 2023 Oct;16(10):e010347. doi: 10.1161/CIRCHEARTFAILURE.122.010347. Epub 2023 Jul 31.
Cardiac autoantibodies (cAAbs) are involved in the progression of adverse cardiac remodeling in heart failure (HF). However, our understanding of cAAbs in HF is limited owing to the absence of relevant animal models. Herein, we aimed to establish and characterize a murine model of cAAb-positive HF after myocardial infarction (MI), thereby facilitating the development of therapeutics targeting cAAbs in post-MI HF.
MI was induced in BALB/c mice. Plasma cAAbs were evaluated using modified Western blot-based methods. Prognosis, cardiac function, inflammation, and fibrosis were compared between cAAb-positive and cAAb-negative MI mice. Rapamycin was used to inhibit cAAb production.
Common cAAbs in BALB/c MI mice targeted cTnI (cardiac troponin I). Herein, 71% (24/34) and 44% (12/27) of the male and female MI mice, respectively, were positive for cAAbs against cTnI (cTnIAAb). Germinal centers were formed in the spleens and mediastinal lymph nodes of cTnIAAb-positive MI mice. cTnIAAb-positive MI mice showed progressive cardiac remodeling with a worse prognosis (=0.014, by log-rank test), which was accompanied by cardiac inflammation, compared with that in cTnIAAb-negative MI mice. Rapamycin treatment during the first 7 days after MI suppressed cTnIAAb production (cTnIAAb positivity, 59% [29/49] and 7% [2/28] in MI mice treated with vehicle and rapamycin, respectively; <0.001, by Pearson χ test), consequently improving the survival and ameliorating cardiac inflammation, cardiac remodeling, and HF in MI mice.
The present post-MI HF model may accelerate our understanding of cTnIAAb and support the development of therapeutics against cTnIAAbs in post-MI HF.
心脏自身抗体（cAAbs）参与心力衰竭（HF）中不良心脏重构的进展。然而，由于缺乏相关的动物模型，我们对 HF 中 cAAbs 的了解有限。在此，我们旨在建立并表征心肌梗死后 cAAb 阳性 HF 的小鼠模型，从而促进针对 MI 后 HF 中 cAAbs 的治疗药物的开发。
在 BALB/c 小鼠中诱导心肌梗死。使用改良的基于 Western blot 的方法评估血浆 cAAbs。比较 cAAb 阳性和 cAAb 阴性 MI 小鼠的预后、心功能、炎症和纤维化。使用雷帕霉素抑制 cAAb 的产生。
BALB/c MI 小鼠中的常见 cAAbs 靶向 cTnI（心肌肌钙蛋白 I）。在此，分别有 71%（24/34）和 44%（12/27）的雄性和雌性 MI 小鼠对 cTnI（cTnIAAb）呈 cAAb 阳性。cTnIAAb 阳性 MI 小鼠的脾和纵隔淋巴结中形成生发中心。与 cTnIAAb 阴性 MI 小鼠相比，cTnIAAb 阳性 MI 小鼠表现出进行性心脏重构和预后较差（=0.014，对数秩检验），同时伴有心脏炎症。MI 后 7 天内给予雷帕霉素治疗可抑制 cTnIAAb 的产生（cTnIAAb 阳性率分别为 MI 小鼠给予载体和雷帕霉素治疗的 59%[29/49]和 7%[2/28]；Pearson χ 检验，<0.001），从而改善 MI 小鼠的存活率并改善心脏炎症、心脏重构和 HF。
本 MI 后 HF 模型可能加速我们对 cTnIAAb 的理解，并支持针对 MI 后 HF 中 cTnIAAb 的治疗药物的开发。
