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.

心肌代谢异常是公认的慢性心力衰竭改变，其影响可能导致进行性心功能不全。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腔扩张的慢性影响来部分介导其有害影响尚不确定。因此，我们旨在确定二甲双胍的作用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的心脏功能和线粒体结构变化的给药 [每日皮下注射 0.02 mg/kg 低剂量异丙肾上腺素 (ISO) 7 个月]。超声心动图用于评估体内 LV 尺寸和功能，并使用透射电子显微镜评估线粒体和肌原纤维排列。7 个月的低剂量 ISO 给药增加了 LV 舒张直径 (mm) [控制 (CONT): 7.29 ± 0.19 vs. ISO: 8.76 ± 0.21; P = 0.001]，这种效应被二甲双胍减弱（ISO + MET：7.63 ± 0.29 vs. ISO：P= 0.001) 管理。同样，ISO 增加了 LV 收缩末期直径（CONT：4.43 ± 0.16 对比 ISO：5.49 ± 0.16：P < 0.0001），二甲双胍阻止了这种影响（ISO + MET：4.04 ± 0.25 对比 ISO：P < 0.0001）。此外，长期 ISO 给药降低了 LV 心内膜缩短分数 ( P = 0.0001)、中壁缩短分数 ( P = 0.0001) 和射血分数 ( P = 0.0001)，二甲双胍给药同样可以防止效果。此外，通过 ISO 给药产生了线粒体排列和相对线粒体面积的变化（CONT：37.7 ± 2.2 vs. ISO：28.1 ± 2.9；P = 0.05），影响通过二甲双胍。总之，二甲双胍对慢性交感神经诱导的 LV 扩张和收缩功能障碍提供心脏保护。这些数据支持心肌代谢变化在介导心脏病中慢性神经体液激活产生的 LV 扩张和 LV 功能障碍中的作用。