An inflammatory single-cell RNA sequencing signature driven by metabolic stress in a new mouse model of heart failure with preserved ejection fraction and its reversion by the SGLT2 inhibitor dapagliflozin [RNA-Seq macrophages]. An inflammatory single-cell RNA sequencing signature driven by metabolic stress in a new mouse model of heart failure with preserved ejection fraction and its reversion by the SGLT2 inhibitor dapagliflozin [RNA-Seq macrophages]

Heart failure with preserved ejection fraction (HFpEF) is a public health problem with increasing incidence and prevalence. Different phenotypes have been identified based on related risk factors, cardiac structural alterations, biomarkers and prognosis. Among these, the one with the worst prognosis is characterized by metabolic dysfunction . This clinical phenotype exhibits high levels of biomarkers related to dysregulated metabolism and TNF-a–mediated inflammation, thus underlying its close association with metabolic dysfunction and inflammation. The aim of our work is to better comprehend the involvement of the immune cells in the pathogenesis of metabolic HFpEF and to determine whether treating metabolic dysfunction with SGLT2i could ameliorate HFpEF by decreasing myocardial inflammation. Overall design: 7–8-week-old male C57BL/6J (RRID:IMSR_JAX:000664) and ApoE KO (B6.129P2-Apoe tm1Unc/J) mice (Charles River, France) were fed with standard chow (CD) or a high fat (HFD) (Western diet, high fat/high cholesterol 0.21%; Sniff EF D12079) diet for 7 or. After 8 weeks, mice were randomly assigned to either treatment or control group. The treatment group received intragastric dapagliflozin (AstraZeneca) through gavage, 1.0 mg/kg/d for 12-weeks, while mice in the control group and in another group of wild-type (WT) C57BL/6J mice were given vehicle.

射血分数保留型心力衰竭（Heart failure with preserved ejection fraction, HFpEF）是一类发病率与患病率持续攀升的公共卫生难题。目前已基于相关危险因素、心脏结构改变、生物标志物及预后特征，明确了多种不同的临床表型。其中预后最差的表型以代谢功能异常为核心表征。该临床表型呈现出与代谢紊乱及肿瘤坏死因子-α（TNF-α）介导的炎症相关的高水平生物标志物表达，由此凸显其与代谢功能异常及炎症反应的紧密关联。
本研究的核心目标在于：深入解析免疫细胞在代谢性射血分数保留型心力衰竭发病机制中的参与作用，并探究采用钠-葡萄糖协同转运蛋白2抑制剂（SGLT2i）干预代谢功能异常，是否可通过减轻心肌炎症来改善HFpEF病症。
实验整体设计如下：选取7~8周龄的雄性C57BL/6J（RRID:IMSR_JAX:000664）与载脂蛋白E敲除（ApoE KO，B6.129P2-Apoe tm1Unc/J）小鼠（购自法国Charles River公司），分别给予标准饲料（CD）或高脂饲料（HFD，即西方饮食，含0.21%高脂肪/高胆固醇成分；Sniff EF D12079）喂养7或[原文此处疑似存在输入遗漏]周。饲养8周后，将小鼠随机分配至治疗组与对照组。治疗组通过灌胃给予达格列净（AstraZeneca），剂量为1.0 mg/kg/d，持续干预12周；对照组及另一组野生型（WT）C57BL/6J小鼠则给予赋形剂处理。