Dept. of Cardiovascular Medicine/Cardiac Catheterization Lab. Second Xiangya Hospital, Central South University, No.139 Middle Renmin Road, Changsha, Hunan, 410011, People's Republic of China.
CCU department, affiliated hospital of traditional Chinese medicine, Xinjiang medical university, Urumqi, Xinjiang Province, China.
BMC Cardiovasc Disord. 2020 Feb 3;20(1):50. doi: 10.1186/s12872-020-01359-7.
Previous studies demonstrated impaired lipid metabolism and augmented aerobic glycolysis in AF. The authors aimed to investigate whether the use of metformin, an AMPK activator, could reverse this metabolic remodeling in chronic AF and to explore the underlying mechanisms.
We conducted chronic AF animal models with 18 beagle dogs and divided them into SR (pacemaker implanted without pacing), AF (pacemaker implanted with sustained pacing at a frequency of 400 beats/min for 6 weeks), and metformin+AF group (daily oral administration of metformin was initiated 1 week before surgery and continued throughout the study period). After electrophysiological measurements, the left atrial appendage tissue samples were taken from the beating heart for further analysis. Protein expression, histological analysis, and biochemical measurements were conducted.
The AF groups showed decreased expression of FAT/CD36, CPT-1, VLCAD, increased concentration of free fatty acid and triglyceride, and increased lipid deposition. The activation of AMPK/PGC-1α/PPARα pathway was decreased. The key factors of the Warburg effect, including HIF-1α, GLUT-1, PDK1, HK, and LDH, increased in AF group compared to SR group. The expression of PDH decreased significantly, accompanied by increased atrial lactate production. The extent of fibrosis increased significantly in the left atrial appendage of AF group. dERP, ∑WOV, and AF inducibility increased while ERP decreased in AF group compared to SR group. The use of metformin attenuated all these changes effectively.
Metformin improves lipid metabolism and reverses the Warburg effect in chronic AF via AMPK activation. It attenuates atrial electrical and structural remodeling.
先前的研究表明，房颤（AF）存在脂质代谢受损和有氧糖酵解增强。作者旨在研究二甲双胍（一种 AMPK 激活剂）的应用是否可以逆转慢性 AF 中的这种代谢重塑，并探讨其潜在机制。
我们建立了 18 只比格犬的慢性 AF 动物模型，将它们分为窦性心律（SR）组（植入起搏器但不起搏）、AF 组（植入起搏器以 400 次/分的频率持续起搏 6 周）和二甲双胍+AF 组（在手术前 1 周开始每日口服二甲双胍，并在整个研究期间持续使用）。在电生理测量后，从跳动的心脏中取出左心耳组织样本进行进一步分析。进行了蛋白表达、组织学分析和生化测量。
AF 组 FAT/CD36、CPT-1、VLCAD 的表达降低，游离脂肪酸和甘油三酯浓度升高，脂质沉积增加。AMPK/PGC-1α/PPARα 通路的激活降低。Warburg 效应的关键因素，包括 HIF-1α、GLUT-1、PDK1、HK 和 LDH，在 AF 组中均高于 SR 组。PDH 的表达显著降低，同时左心耳中乳酸生成增加。与 SR 组相比，AF 组左心耳中的纤维化程度显著增加。dERP、∑WOV 和 AF 易感性在 AF 组中增加，而 ERP 降低。与 AF 组相比，二甲双胍的使用有效减弱了所有这些变化。
二甲双胍通过激活 AMPK 改善慢性 AF 中的脂质代谢并逆转 Warburg 效应。它可减轻心房电重构和结构重构。
