Nakashima Hiroka, Shinohara Keisuke, Matsumoto Sho, Nakashima Ryosuke, Yoshida Daisuke, Ono Yoshiyasu, Miyamoto Ryohei, Ikeda Shota, Matsushima Shouji, Hashimoto Toru, Katsuki Shunsuke, Ikeda Masataka, Yoshida Keimei, Kinugawa Shintaro, Abe Kohtaro
Department of Cardiovascular Medicine, Faculty of Medical Sciences, Kyushu University, Fukuoka, Japan.
Division of Cardiovascular Medicine, Research Institute of Angiocardiology, Faculty of Medical Sciences, Kyushu University, Fukuoka, Japan.
Hypertens Res. 2025 Feb;48(2):672-680. doi: 10.1038/s41440-024-02025-7. Epub 2024 Nov 28.
The pathogenesis of heart failure with preserved ejection fraction (HFpEF) remains unclear, and effective treatments are limited. HFpEF is more prevalent in females, indicating potential gender differences in its pathogenesis. However, no female HFpEF model animals have been established. Hypertension is a major contributor to HFpEF, and sympathetic activation is thought to play a role in both conditions. This study aimed to establish a female HFpEF model using hypertensive Dahl salt-sensitive rats and to assess the presence of sympathetic activation. Seven-week-old female Dahl salt-sensitive rats were fed an 8% high-salt diet (HS group, n = 6), while a low-salt diet group (LS group, n = 9) served as controls. The HS group exhibited increased systolic blood pressure and heart rate. Echocardiography revealed an increased left ventricular (LV) wall thickness, a decreased E/A ratio, and an increased E/e' ratio, all indicative of diastolic dysfunction without reduced LV ejection fraction. Additionally, the HS group showed elevated LV end-diastolic pressure, LV weight, and lung weight, along with histological cardiomyocyte hypertrophy and interstitial fibrosis. Gene expression markers for cardiac hypertrophy and fibrosis were also increased. Renal function was significantly impaired, and plasma norepinephrine levels were elevated, consistent with heightened pre-sympathetic neuronal activity in the brain. In conclusion, high salt loading from 7 weeks of age in female Dahl salt-sensitive rats induced hypertensive HFpEF phenotypes with LV hypertrophy and fibrosis, and sympathetic activation by 16 to 19 weeks of age. This model provides a valuable tool for studying HFpEF pathophysiology in women.
射血分数保留的心力衰竭（HFpEF）的发病机制仍不清楚，有效的治疗方法也很有限。HFpEF在女性中更为普遍，这表明其发病机制可能存在性别差异。然而，尚未建立雌性HFpEF模型动物。高血压是HFpEF的主要促成因素，交感神经激活被认为在这两种情况中都起作用。本研究旨在使用高血压Dahl盐敏感大鼠建立雌性HFpEF模型，并评估交感神经激活的存在情况。7周龄的雌性Dahl盐敏感大鼠喂食8%的高盐饮食（HS组，n = 6），而低盐饮食组（LS组，n = 9）作为对照。HS组的收缩压和心率升高。超声心动图显示左心室（LV）壁厚度增加、E/A比值降低和E/e'比值增加，所有这些都表明存在舒张功能障碍而左心室射血分数未降低。此外，HS组的左心室舒张末期压力、左心室重量和肺重量升高，同时伴有组织学上的心肌细胞肥大和间质纤维化。心脏肥大和纤维化的基因表达标志物也增加。肾功能明显受损，血浆去甲肾上腺素水平升高，这与大脑中交感神经节前神经元活动增强一致。总之，7周龄开始对雌性Dahl盐敏感大鼠进行高盐负荷诱导了伴有左心室肥大和纤维化的高血压HFpEF表型，并在16至19周龄时出现交感神经激活。该模型为研究女性HFpEF的病理生理学提供了有价值的工具。
