Paneni Francesco, Costantino Sarah, Cosentino Francesco
G Ital Cardiol (Rome). 2015 Apr;16(4):225-31. doi: 10.1714/1848.20186.
Despite clear advances in reperfusion therapy and pharmacological treatment, a large proportion of patients with an acute myocardial infarction will die of its consequences. In this regard, it is very important to understand the molecular processes underpinning ischemia-reperfusion injury and occurrence of left ventricular dysfunction, with the aim to develop mechanism-based therapeutic strategies. Experimental evidence indicates that metformin, a biguanide often used in the treatment of diabetes, has favorable effects on left ventricular function. This effect is largely mediated by activation of AMP-activated protein kinase (AMPK), a key molecule orchestrating many biochemical processes such as glucose uptake, glycolysis, oxidation of free fatty acids and mitochondrial biogenesis. These processes significantly contribute to raise ATP levels and restore myocardial contractile efficiency. AMPK also activates endothelial nitric oxide synthase and promotes autophagy, thus preventing inflammation and cellular death. These basic studies prompted many researchers to test the cardioprotective effects of metformin in the clinical setting. In diabetic patients with ST-elevation myocardial infarction (STEMI), retrospective analyses showed that metformin is associated with reduced infarct size as compared to non-metformin-based strategies, implicating beneficial effects beyond glucose control. A recent randomized trial, the GIPS-III study, has postulated that metformin may improve left ventricular function following STEMI even in patients without diabetes. Metformin (500 mg twice/day), administered 3h after percutaneous coronary intervention, did not result in improved left ventricular ejection fraction after 4-month follow-up. Based on these results, it remains unclear whether metformin exerts a cardioprotective effect regardless of glycemic control. Further randomized studies in diabetic and nondiabetic patients are required to address these important questions. The present review critically discusses established knowledge and evidence gaps on the effects of metformin on left ventricular function in diabetic and nondiabetic patients with myocardial infarction.
尽管在再灌注治疗和药物治疗方面取得了明显进展，但很大一部分急性心肌梗死患者仍会死于其并发症。在这方面，了解缺血再灌注损伤和左心室功能障碍发生的分子机制非常重要，目的是制定基于机制的治疗策略。实验证据表明，二甲双胍（一种常用于治疗糖尿病的双胍类药物）对左心室功能有有益影响。这种作用很大程度上是由AMP激活的蛋白激酶（AMPK）的激活介导的，AMPK是协调许多生化过程的关键分子，如葡萄糖摄取、糖酵解、游离脂肪酸氧化和线粒体生物发生。这些过程显著有助于提高ATP水平并恢复心肌收缩效率。AMPK还激活内皮型一氧化氮合酶并促进自噬，从而预防炎症和细胞死亡。这些基础研究促使许多研究人员在临床环境中测试二甲双胍的心脏保护作用。在患有ST段抬高型心肌梗死（STEMI）的糖尿病患者中，回顾性分析表明，与非基于二甲双胍的策略相比，二甲双胍与梗死面积减小有关，这意味着其有益作用超出了血糖控制范围。最近一项随机试验，即GIPS-III研究，推测即使在没有糖尿病的患者中，二甲双胍也可能改善STEMI后的左心室功能。经皮冠状动脉介入治疗后3小时给予二甲双胍（500毫克，每日两次），4个月随访后左心室射血分数并未改善。基于这些结果，尚不清楚二甲双胍是否无论血糖控制情况如何都能发挥心脏保护作用。需要在糖尿病和非糖尿病患者中进行进一步的随机研究来解决这些重要问题。本综述批判性地讨论了关于二甲双胍对糖尿病和非糖尿病心肌梗死患者左心室功能影响的现有知识和证据空白。
