Cardiovascular Pathophysiology and Genomics Research Unit, School of Physiology, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, South Africa; and.
Endocrinology and Metabolism Research Laboratory, School of Physiology, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, South Africa.
J Cardiovasc Pharmacol. 2022 Mar 1;79(3):289-295. doi: 10.1097/FJC.0000000000001172.
Myocardial metabolic abnormalities are well-recognized alterations in chronic heart failure, effects that may contribute to progressive cardiac dysfunction. However, whether metabolic alterations in-part mediate their deleterious effects by modifying the chronic impact of excess low-dose sympathetic stimulation on cardiac chamber dilatation is uncertain. We therefore aimed to determine the effect of metformin administration on cardiac function and mitochondrial architectural changes in a rat model of chronic sympathetic-induced left ventricular (LV) remodeling and systolic dysfunction [daily subcutaneous isoproterenol (ISO) injection at a low dose of 0.02 mg/kg for 7 months]. Echocardiography was used to assess in vivo LV dimensions and function, and mitochondrial and myofibril arrangement was assessed using transmission electron microscopy. Seven months of low-dose ISO administration increased LV diastolic diameter (in mm) [control (CONT): 7.29 ± 0.19 vs. ISO: 8.76 ± 0.21; P = 0.001], an effect that was attenuated by metformin (ISO + MET: 7.63 ± 0.29 vs. ISO: P = 0.001) administration. Similarly, ISO increased LV end-systolic diameter (CONT: 4.43 ± 0.16 vs. ISO: 5.49 ± 0.16: P < 0.0001), an effect prevented by metformin (ISO + MET: 4.04 ± 0.25 vs. ISO: P < 0.0001). Moreover, chronic ISO administration reduced LV endocardial fractional shortening (P = 0.0001), midwall fractional shortening (P = 0.0001), and ejection fraction (P = 0.0001), effects similarly prevented by metformin administration. Furthermore, changes in mitochondrial arrangement and relative mitochondrial area (CONT: 37.7 ± 2.2 vs. ISO: 28.1 ± 2.9; P = 0.05) were produced by ISO administration, effects prevented by metformin. In conclusion, metformin offers cardiac protection against chronic sympathetic-induced LV dilatation and systolic dysfunction. These data support a role for myocardial metabolic changes in mediating LV dilatation and LV dysfunction produced by chronic neurohumoral activation in cardiac disease.
心肌代谢异常是慢性心力衰竭中公认的改变，这些影响可能导致心脏功能进行性恶化。然而，代谢改变是否通过改变过量低剂量交感神经刺激对心脏腔室扩张的慢性影响来部分介导其有害作用尚不确定。因此，我们旨在确定二甲双胍给药对慢性交感神经诱导的左心室（LV）重塑和收缩功能障碍大鼠模型中心功能和线粒体结构变化的影响[每天皮下给予异丙肾上腺素（ISO）低剂量 0.02mg/kg，持续 7 个月]。超声心动图用于评估体内 LV 尺寸和功能，使用透射电子显微镜评估线粒体和肌原纤维排列。7 个月低剂量 ISO 给药增加 LV 舒张直径（mm）[对照组（CONT）：7.29 ± 0.19 与 ISO：8.76 ± 0.21；P = 0.001]，二甲双胍给药可减弱此作用（ISO + MET：7.63 ± 0.29 与 ISO：P = 0.001）。同样，ISO 增加 LV 收缩末期直径（CONT：4.43 ± 0.16 与 ISO：5.49 ± 0.16：P < 0.0001），此作用也可被二甲双胍预防（ISO + MET：4.04 ± 0.25 与 ISO：P < 0.0001）。此外，慢性 ISO 给药降低 LV 心内膜节段缩短率（P = 0.0001）、中膜节段缩短率（P = 0.0001）和射血分数（P = 0.0001），这些作用也可被二甲双胍给药预防。此外，ISO 给药引起线粒体排列和相对线粒体面积的变化（CONT：37.7 ± 2.2 与 ISO：28.1 ± 2.9；P = 0.05），这些作用也可被二甲双胍预防。总之，二甲双胍可提供心脏保护，防止慢性交感神经诱导的 LV 扩张和收缩功能障碍。这些数据支持心肌代谢变化在介导心脏疾病中慢性神经激素激活引起的 LV 扩张和 LV 功能障碍中的作用。
