Department of Cardiology, Mount Sinai School of Medicine, New York, New York, USA.
Department of Cardiology, Mount Sinai School of Medicine, New York, New York, USA.
JACC Cardiovasc Imaging. 2021 Feb;14(2):393-407. doi: 10.1016/j.jcmg.2020.07.042. Epub 2020 Oct 29.
The purpose of this study was to investigate the effect of empagliflozin on diastolic function in a nondiabetic heart failure with reduced ejection fraction (HFrEF) scenario and on the pathways causing diastolic dysfunction.
This group demonstrated that empagliflozin ameliorates adverse cardiac remodeling, enhances myocardial energetics, and improves left ventricular systolic function in a nondiabetic porcine model of HF. Whether empagliflozin also improves diastolic function remains unknown. Hypothetically, empagliflozin would improve diastolic function in HF mediated both by a reduction in interstitial myocardial fibrosis and an improvement in cardiomyocyte stiffness (titin phosphorylation).
HF was induced in nondiabetic pigs by 2-h balloon occlusion of proximal left anterior descending artery. Animals were randomized to empagliflozin or placebo for 2 months. Cardiac function was evaluated with cardiac magnetic resonance (CMR), 3-dimensional echocardiography, and invasive hemodynamics. In vitro relaxation of cardiomyocytes was studied in primary culture. Myocardial samples were obtained for histological and molecular evaluation. Myocardial metabolite consumption was analyzed by simultaneous blood sampling from coronary artery and coronary sinus.
Despite similar initial ischemic myocardial injury, the empagliflozin group showed significantly improved diastolic function at 2 months, assessed by conventional echocardiography (higher e' and color M-mode propagation velocity, lower E/e' ratio, myocardial performance Tei index, isovolumic relaxation time, and left atrial size), echocardiography-derived strain imaging (strain imaging diastolic index, strain rate at isovolumic relaxation time and during early diastole, and untwisting), and CMR (higher peak filling rate, larger first filling volume). Invasive hemodynamics confirmed improved diastolic function with empagliflozin (better peak LV pressure rate of decay (-dP/dt), shorter Tau, lower end-diastolic pressure-volume relationship (EDPVR), and reduced filling pressures). Empagliflozin reduced interstitial myocardial fibrosis at the imaging, histological and molecular level. Empagliflozin improved nitric oxide signaling (endothelial nitric oxide synthetase [eNOS] activity, nitric oxide [NO] availability, cyclic guanosine monophosphate (cGMP) content, protein kinase G [PKG] signaling) and enhanced titin phosphorylation (which is responsible for cardiomyocyte stiffness). Indeed, isolated cardiomyocytes exhibited better relaxation in empagliflozin-treated animals. Myocardial consumption of glucose and ketone bodies negatively and positively correlated with diastolic function, respectively.
Empagliflozin ameliorates diastolic function in a nondiabetic HF porcine model, mitigates histological and molecular remodeling, and reduces both left ventricle and cardiomyocyte stiffness.
本研究旨在探讨恩格列净在射血分数降低的非糖尿病心力衰竭（HFrEF）情况下对舒张功能的影响，以及对导致舒张功能障碍的途径的影响。
本研究小组证明，在非糖尿病猪心力衰竭模型中，恩格列净可改善不良的心脏重构、增强心肌能量代谢，并改善左心室收缩功能。恩格列净是否也能改善舒张功能尚不清楚。推测恩格列净通过减少间质心肌纤维化和改善心肌细胞僵硬度（连接蛋白磷酸化）来改善 HF 中的舒张功能。
通过 2 小时球囊阻塞左前降支近端，在非糖尿病猪中诱导 HF。动物随机分为恩格列净或安慰剂治疗 2 个月。通过心脏磁共振（CMR）、三维超声心动图和侵入性血流动力学评估心功能。在原代培养的心肌细胞中研究细胞松弛。获取心肌样本进行组织学和分子评估。通过同时从冠状动脉和冠状窦采血分析心肌代谢物消耗。
尽管初始缺血性心肌损伤相似，但恩格列净组在 2 个月时通过常规超声心动图（更高的 e'和彩色 M 模式传播速度、更低的 E/e'比值、心肌性能 Tei 指数、等容松弛时间和左心房大小）、超声心动图衍生应变成像（应变成像舒张指数、等容松弛时间和舒张早期的应变率以及解旋）和 CMR（更高的峰值充盈率、更大的首次充盈量）评估显示出明显改善的舒张功能。侵入性血流动力学证实恩格列净改善了舒张功能（更好的 LV 峰值压力下降率（-dP/dt）、更短的 Tau、更低的舒张末期压力-容积关系（EDPVR）和降低的充盈压）。恩格列净在影像学、组织学和分子水平上减少了间质心肌纤维化。恩格列净改善了一氧化氮信号（内皮型一氧化氮合酶[eNOS]活性、一氧化氮[NO]可用性、环鸟苷单磷酸[cGMP]含量、蛋白激酶 G[PKG]信号）并增强了连接蛋白磷酸化（这是心肌细胞僵硬度的原因）。事实上，在恩格列净治疗的动物中，分离的心肌细胞表现出更好的松弛。心肌对葡萄糖和酮体的消耗与舒张功能呈负相关和正相关。
恩格列净可改善非糖尿病 HF 猪模型的舒张功能，减轻组织学和分子重构，并降低左心室和心肌细胞僵硬度。
