Department of Cardiology, The Affiliated Suzhou Hospital of Nanjing Medical University, 242 Guangji Road, Suzhou, 215008, Jiangsu Province, People's Republic of China.
Department of Endocrinology and Metabolism, The First Affiliated Hospital of Soochow University, Suzhou, 215006, Jiangsu Province, People's Republic of China.
Cardiovasc Diabetol. 2019 Aug 20;18(1):107. doi: 10.1186/s12933-019-0914-1.
BACKGROUND: Heart failure with preserved ejection fraction (HFpEF) is a difficult disease with high morbidity and mortality rates and lacks an effective treatment. Here, we report the therapeutic effect of dapagliflozin, a sodium-glucose cotransporter 2 inhibitor (SGLT2i), on hypertension + hyperlipidemia-induced HFpEF in a pig model. METHODS: HFpEF pigs were established by infusing a combination of deoxycorticosterone acetate (DOCA) and angiotensin II (Ang II), and Western diet (WD) feeding for 18 weeks. In the 9th week, half of the HFpEF pigs were randomly assigned to receive additional dapagliflozin treatment (10 mg/day) by oral gavage daily for the next 9 weeks. Blood pressure, lipid levels, echocardiography and cardiac hemodynamics for cardiac structural and functional changes, as well as epinephrine and norepinephrine concentrations in the plasma and tissues were measured. After sacrifice, cardiac fibrosis, the distribution of tyrosine hydroxylase (TH), inflammatory factors (IL-6 and TNF-α) and NO-cGMP-PKG pathway activity in the cardiovascular system were also determined. RESULTS: Blood pressure, total cholesterol (TC), triglyceride (TG) and low-density lipoprotein (LDL) were markedly increased in HFpEF pigs, but only blood pressure was significantly decreased after 9 weeks of dapagliflozin treatment. By echocardiographic and hemodynamic assessment, dapagliflozin significantly attenuated heart concentric remodeling in HFpEF pigs, but failed to improve diastolic function and compliance with the left ventricle (LV). In the dapagliflozin treatment group, TH expression and norepinephrine concentration in the aorta were strongly mitigated compared to that in the HFpEF group. Moreover, inflammatory cytokines such as IL-6 and TNF-α in aortic tissue were markedly elevated in HFpEF pigs and inhibited by dapagliflozin. Furthermore, the reduced expression of eNOS and the PKG-1 protein and the cGMP content in the aortas of HFpEF pigs were significantly restored after 9 weeks of dapagliflozin treatment. CONCLUSION: 9 weeks of dapagliflozin treatment decreases hypertension and reverses LV concentric remodeling in HFpEF pigs partly by restraining sympathetic tone in the aorta, leading to inhibition of the inflammatory response and NO-cGMP-PKG pathway activation.
背景：射血分数保留的心力衰竭（HFpEF）是一种发病率和死亡率都很高的难治性疾病，目前缺乏有效的治疗方法。在这里，我们报告了钠-葡萄糖协同转运蛋白 2 抑制剂（SGLT2i）达格列净对猪模型中高血压+高血脂诱导的 HFpEF 的治疗效果。
方法：通过输注去氧皮质酮（DOCA）和血管紧张素 II（Ang II）的组合以及西方饮食（WD）喂养 18 周，建立 HFpEF 猪模型。在第 9 周，将一半 HFpEF 猪随机分为两组，其中一组给予达格列净（10mg/天）灌胃治疗，共 9 周。测量血压、血脂水平、超声心动图和心功能，以评估心脏结构和功能的变化，以及肾上腺素和去甲肾上腺素在血浆和组织中的浓度。处死动物后，还测定了心脏纤维化、心血管系统中酪氨酸羟化酶（TH）的分布、炎症因子（IL-6 和 TNF-α）和 NO-cGMP-PKG 通路活性。
结果：HFpEF 猪的血压、总胆固醇（TC）、甘油三酯（TG）和低密度脂蛋白（LDL）明显升高，但仅在给予达格列净 9 周后血压明显下降。通过超声心动图和血流动力学评估，达格列净显著减轻了 HFpEF 猪的心脏向心性重构，但未能改善左心室（LV）的舒张功能和顺应性。在达格列净治疗组，与 HFpEF 组相比，主动脉中 TH 表达和去甲肾上腺素浓度明显减轻。此外，HFpEF 猪主动脉组织中炎症细胞因子如 IL-6 和 TNF-α明显升高，而达格列净可抑制其表达。此外，HFpEF 猪主动脉中 eNOS 和 PKG-1 蛋白的表达以及 cGMP 含量降低，在给予达格列净 9 周后明显恢复。
结论：9 周的达格列净治疗可降低血压并逆转 HFpEF 猪的 LV 向心性重构，这在一定程度上是通过抑制主动脉中的交感神经张力，从而抑制炎症反应和 NO-cGMP-PKG 通路激活来实现的。
Cardiovasc Diabetol. 2020-1-10
Am J Hypertens. 2019-4-22
Ann Noninvasive Electrocardiol. 2025-9
Theranostics. 2025-5-24
J Appl Physiol (1985). 2025-6-1
J Geriatr Cardiol. 2025-1-28
Expert Opin Drug Metab Toxicol. 2018-11-29
N Engl J Med. 2018-11-10
Cardiovasc Diabetol. 2018-5-22
Cardiovasc Drugs Ther. 2018-4
Zotero 插件