SGLT2 inhibition animal models cardiac remodeling diabetes heart failure myocardial metabolism
下载

摘要

BACKGROUND:Empagliflozin cardiac benefits in the EMPA-REG OUTCOME (Empagliflozin Cardiovascular Outcome Event Trial in Type 2 Diabetes Mellitus Patients) trial cannot be explained exclusively by its antihyperglycemic activity.
OBJECTIVES:The hypothesis was that empagliflozin's cardiac benefits are mediated by switching myocardial fuel metabolism away from glucose toward ketone bodies (KB), which improves myocardial energy production.
METHODS:Heart failure was induced in nondiabetic pigs (n = 14) by 2-h balloon occlusion of the proximal left anterior descending artery. Animals were randomized to empagliflozin or placebo for 2 months. Animals were evaluated with cardiac magnetic resonance imaging and 3-dimensional echocardiography. Myocardial metabolite consumption was analyzed by simultaneous blood sampling from coronary artery and coronary sinus. Myocardial samples were obtained for molecular evaluation. Nonmyocardial infarction animals served as comparison.
RESULTS:Despite similar initial ischemic myocardial injury in both groups, the empagliflozin group showed amelioration of adverse remodeling at 2 months (lower left ventricular [LV] mass, reduced LV dilatation, less LV sphericity) versus the control group. LV systolic function (LV ejection fraction and echocardiography-derived strains) was improved, as was neurohormonal activation. Compared with nonmyocardial infarction, control animals increased myocardial glucose consumption mainly through anaerobic glycolysis while reducing utilization of free fatty acid (FFA) and branched-chain amino acid (BCAA). Empagliflozin-treated pigs did not consume glucose (reduction in myocardial glucose uptake, and glucose-related enzymes) but instead switched toward utilization of KB, FFA, and BCAA (increased myocardial uptake of these 3 metabolites, and enhanced expression/activity of the enzymes implicated in the metabolism of KB/FFA/BCAA). Empagliflozin increased myocardial ATP content and enhanced myocardial work efficiency.
CONCLUSIONS:Empagliflozin ameliorates adverse cardiac remodeling and heart failure in a nondiabetic porcine model. Empagliflozin switches myocardial fuel utilization away from glucose toward KB, FFA, and BCAA, thereby improving myocardial energetics, enhancing LV systolic function, and ameliorating adverse LV remodeling.

译文

背景: EMPA-REG 结果 (2 型糖尿病患者的 Empagliflozin 心血管结果事件试验) 试验中的 Empagliflozin 心脏益处不能仅仅由其抗高血糖活性来解释。
目的: 假设 empagliflozin 的心脏益处是通过将心肌燃料代谢从葡萄糖转向酮体 (KB) 来介导的,酮体可以提高心肌能量的产生。
方法: 在非糖尿病猪 (n = 14) 中,通过 2 小时左前降支近端动脉的气囊闭塞来诱导心力衰竭。动物被随机分配给 empagliflozin 或安慰剂 2 个月。用心脏磁共振成像和三维超声心动图对动物进行评估。通过从冠状动脉和冠状静脉窦同时采血来分析心肌代谢物的消耗。获得心肌样本进行分子评价。非心肌梗死动物作为比较。
结果: 尽管两组的初始缺血性心肌损伤相似,但 empagliflozin 组在 2 个月时表现出不良重构的改善 (左心室 [LV] 质量降低,LV 扩张减少,LV 球度降低) 对比对照组。左室收缩功能 (左室射血分数和超声心动图衍生的应变) 得到改善,神经激素激活也得到改善。与非心肌梗死相比,对照组动物主要通过无氧糖酵解增加心肌葡萄糖消耗,同时减少游离脂肪酸 (FFA) 和支链氨基酸 (BCAA) 的利用。Empagliflozin 处理的猪不消耗葡萄糖 (心肌葡萄糖摄取和葡萄糖相关酶的减少),而是转而利用 KB,FFA, 和 BCAA (增加这 3 种代谢物的心肌摄取,并增强与 KB/FFA/BCAA 代谢相关的酶的表达/活性)。Empagliflozin 增加心肌 ATP 含量,增强心肌工作效率。
结论: Empagliflozin 可改善非糖尿病猪模型的不良心脏重构和心力衰竭。Empagliflozin 将心肌燃料利用从葡萄糖转向 KB 、 FFA 和 BCAA,从而改善心肌能量学,增强 LV 收缩功能,并改善不利的 LV 重构。

Ventricular remodeling

心血管 心肌细胞 临床研究术语
概述  :  

广义而言,心室重塑不仅包括心肌细胞形态、结构和数量分布的改变,也包括细胞外间质含量、种类及分布的改变,以及心肌实质与间质比例失衡和心室形状结构的变化。从病理基础讲,心室重塑过程一方面是指心肌细胞肥厚,心肌细胞凋亡、坏死及增生,甚至纤维化;另一方面是指细胞外基质的胶原沉积和纤维化。心腔容量负荷增加可使心肌细胞延长,心腔呈球形发展,致心室重塑。病理性心肌重塑时,实质与间质不成比例,细胞外间质增生是引起心功能由代偿转向失代偿及心衰发生发展的重要原因之一。当间质胶原含量由正常的3%-5%增至8-12

Ventricular  [ven'trɪkjʊlə]   [vɛn'trɪkjəlɚ] 

释义   adj. 心室的;脑室的;膨胀的;腹部的

短语   ventricular hypertrophy []心室肥大

ventricular septal defect []室中隔缺损

例句   Therefore, the results suggest that echocardiography examination might be helpful in the evaluation of right ventricular function. 

因此:超声心动图检查用以评价右心室功能有一定的临床意义。

 

Remodeling [ri'mɔdliŋ] 

释义   n. 重塑;重构(remodel进行式);改建

例句   Aim: To investigate the role of BMP in tooth development and periodontal

 remodeling.

目的:研究BMP在牙齿生长发育和牙周组织改建中的作用


请扫描右侧二维码,免费查看词汇专业知识背景