Telmisartan ameliorates cardiac fibrosis and diastolic function in cardiorenal heart failure with preserved ejection fraction
Telmisartan ameliorates cardiac fibrosis and diastolic function in cardiorenal heart failure with preserved ejection fraction
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替米沙坦改善射血分数保留的心肾性心力衰竭患者的心脏纤维化和舒张功能
DOI：
10.1177/15353702211035058
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发表时间：
2021-08-03
影响因子：
3.2
通讯作者：
Ju, Shenghong
中科院分区：
文献类型：
--
作者：
Chang, Di;Xu, Ting-Ting;Ju, Shenghong
慢性肾脏病(CKD)是心力衰竭伴射血分数保留(HFpEF)的主要原因，然而心肾HFpEF的潜在机制仍不清楚。本研究的目的是研究心脏纤维化在心肾功能衰竭大鼠模型中的作用，并探讨肾素-血管紧张素-醛固酮系统(RAAS)抑制剂替米沙坦能否减轻心肾功能衰竭大鼠的心肌纤维化，保护心肾功能。雄性大鼠接受5/6肾大部切除术(SNX)或假手术(Sham)，4周后恢复，形成稳定的CKD状态。然后给予替米沙坦或赋形剂口服。(8 mg/kg/d)，共12周。采集血压、脑利钠肽(BNP)、超声心动图和心脏磁共振成像，以评估心脏结构和功能的变化。采用组织病理学染色、实时定量聚合酶链式反应(PCR)和免疫印迹等方法评价心脏重构。SNX大鼠表现为HFpEF表型，表现为BNP升高，二尖瓣血流E/A比值降低，左室肥厚增加，射血分数(EF)保留。病理结果显示，与Sham组相比，心肾HFpEF大鼠心脏纤维化增加，而替米沙坦慢性治疗显著减轻心脏纤维化，同时伴有纤维化标志物(I型胶原和III型胶原)和促纤维化细胞因子(α-平滑肌肌动蛋白、转化生长因子-β1和结缔组织生长因子)的减少。此外，替米沙坦治疗后心肌炎症减轻，这与心肌纤维化呈线性相关。替米沙坦还能逆转左室肥厚和E/A比值，提示替米沙坦能改善心肾射血分数左室重构和舒张期功能。总之，心肌纤维化是心肾功能衰竭的重要病理基础，替米沙坦对RAAS的调节能够减轻心肌纤维化，保护心脏舒张期功能不全。
Chronic kidney disease (CKD) is a major contributor to the development of heart failure with preserved ejection fraction (HFpEF), whereas the underlying mechanism of cardiorenal HFpEF is still elusive. The aim of this study was to investigate the role of cardiac fibrosis in a rat model of cardiorenal HFpEF and explore whether treatment with Telmisartan, an inhibitor of renin-angiotensin-aldosterone system (RAAS), can ameliorate cardiac fibrosis and preserve diastolic function in cardiorenal HFpEF. Male rats were subjected to 5/6 subtotal nephrectomy (SNX) or sham operation (Sham), and rats were allowed four weeks to recover and form a stable condition of CKD. Telmisartan or vehicle was then administered p.o. (8 mg/kg/d) for 12 weeks. Blood pressure, brain natriuretic peptide (BNP), echocardiography, and cardiac magnetic resonance imaging were acquired to evaluate cardiac structural and functional alterations. Histopathological staining, real-time polymerase chain reaction (PCR) and western blot were performed to evaluate cardiac remodeling. SNX rats showed an HFpEF phenotype with increased BNP, decreased early to late diastolic transmitral flow velocity (E/A) ratio, increased left ventricular (LV) hypertrophy and preserved ejection fraction (EF). Pathology revealed increased cardiac fibrosis in cardiorenal HFpEF rats compared with the Sham group, while chronic treatment with Telmisartan significantly decreased cardiac fibrosis, accompanied by reduced markers of fibrosis (collagen I and collagen III) and profibrotic cytokines (alpha-smooth muscle actin, transforming growth factor-beta 1, and connective tissue growth factor). In addition, myocardial inflammation was decreased after Telmisartan treatment, which was in a linear correlation with cardiac fibrosis. Telmisartan also reversed LV hypertrophy and E/A ratio, indicating that Telmisartan can improve LV remodeling and diastolic function in cardiorenal HFpEF. In conclusion, cardiac fibrosis is central to the pathology of cardiorenal HFpEF, and RAAS modulation with Telmisartan is capable of alleviating cardiac fibrosis and preserving diastolic dysfunction in this rat model.