University Medical Center Groningen, Thorax Center, Department of Cardiology, University of Groningen, The Netherlands.
Am J Physiol Heart Circ Physiol. 2011 Aug;301(2):H459-68. doi: 10.1152/ajpheart.00054.2011. Epub 2011 May 13.
Metformin is the first choice drug for the treatment of patients with diabetes, but its use is debated in patients with advanced cardiorenal disease. Epidemiological data suggest that metformin may reduce cardiac events, in patients both with and without heart failure. Experimental evidence suggests that metformin reduces cardiac ischemia-reperfusion injury. It is unknown whether metformin improves cardiac function (remodeling) in a long-term post-MI remodeling model. We therefore studied male, nondiabetic, Sprague-Dawley rats that were subjected to either myocardial infarction (MI) or sham operation. Animals were randomly allocated to treatment with normal water or metformin-containing water (250 mg·kg(-1)·day(-1)). At baseline, 6 wk, and 12 wk, metabolic parameters were analyzed and oral glucose tolerance tests (OGTT) were performed. Echocardiography and hemodynamic parameters were assessed 12 wk after MI. In the MI model, infarct size was significantly smaller after 12-wk metformin treatment (29.6 ± 3.2 vs. 38.0 ± 2.2%, P < 0.05). Moreover, metformin resulted in less left ventricular dilatation (6.0 ± 0.4 vs. 7.6 ± 0.6 mm, P < 0.05) and preservation of left ventricular ejection fraction (65.8 ± 3.7% vs. 48.6 ± 5.6%, P < 0.05) compared with MI control. The improved cardiac function was associated with decreased atrial natriuretic peptide mRNA levels in the metformin-treated group (50% reduction compared with MI, P < 0.05). Insulin resistance did not occur during cardiac remodeling (as indicated by normal OGTT) and fasting glucose levels and the pattern of the OGTT were not affected by metformin. Molecular analyses suggested that altered AMP kinase phosphorylation status and low insulin levels mediate the salutary effects of metformin. Altogether our results indicate that metformin may have potential to attenuate heart failure development after myocardial infarction, in the absence of diabetes and independent of systemic glucose levels.
二甲双胍是治疗糖尿病患者的首选药物，但在患有晚期心肾疾病的患者中，其使用存在争议。流行病学数据表明，二甲双胍可能减少心力衰竭和无心力衰竭患者的心脏事件。实验证据表明，二甲双胍可减少心脏缺血再灌注损伤。尚不清楚二甲双胍是否可改善长期心肌梗死后重塑模型中的心脏功能（重塑）。因此，我们研究了雄性非糖尿病 Sprague-Dawley 大鼠，这些大鼠接受心肌梗死（MI）或假手术。动物被随机分配接受普通水或含二甲双胍的水（250mg·kg(-1)·天(-1)）治疗。在基线、6 周和 12 周时，分析代谢参数并进行口服葡萄糖耐量试验（OGTT）。MI 后 12 周评估超声心动图和血流动力学参数。在 MI 模型中，12 周二甲双胍治疗后梗死面积明显缩小（29.6 ± 3.2%比 38.0 ± 2.2%，P < 0.05）。此外，与 MI 对照组相比，二甲双胍导致左心室扩张（6.0 ± 0.4 毫米比 7.6 ± 0.6 毫米，P < 0.05）和左心室射血分数（65.8 ± 3.7%比 48.6 ± 5.6%，P < 0.05）的保存。与 MI 相比，接受二甲双胍治疗的组心房利钠肽 mRNA 水平降低（降低 50%，P < 0.05），心脏功能得到改善。在心脏重塑期间未发生胰岛素抵抗（如正常 OGTT 所示），并且空腹血糖水平和 OGTT 模式不受二甲双胍影响。分子分析表明，改变 AMP 激酶磷酸化状态和低胰岛素水平介导了二甲双胍的有益作用。总之，我们的结果表明，在没有糖尿病和独立于全身血糖水平的情况下，二甲双胍可能具有减轻心肌梗死后心力衰竭发展的潜力。
