Institute of Biomedicine, Pharmacology, University of Helsinki, FI-00014 Helsinki, Finland.
J Hypertens. 2009 Oct;27(10):2094-107. doi: 10.1097/HJH.0b013e32832f0ce4.
Diabetes increases the risk for fatal myocardial infarction and development of heart failure. Levosimendan, an inodilator acting both via calcium sensitization and opening of ATP-dependent potassium channels, is used intravenously for acute decompensated heart failure. The long-term effects of oral levosimendan on postinfarct heart failure are largely unknown.
To examine whether oral treatment with levosimendan could improve cardiac functions and prevent cardiac remodeling after myocardial infarction in a rodent model of type 2 diabetes, the Goto-Kakizaki rat.
Myocardial infarction (MI) was induced to diabetic Goto-Kakizaki and nondiabetic Wistar rats by coronary ligation. Twenty-four hours after surgery, Goto-Kakizaki and Wistar rats were randomized into four groups: MI group without treatment, MI group with levosimendan for 12 weeks (1 mg/kg per day), sham-operated group, sham-operated group with levosimendan. Blood pressure, cardiac functions as wells as markers of cardiac remodeling were determined.
In Goto-Kakizaki rats, MI induced systolic heart failure, pronounced cardiac hypertrophy in the remote area, and sustained cardiomyocyte apoptosis. Postinfarct cardiac remodeling was associated with increased atrial natriuretic peptide, interleukin-6 and connective tissue growth factor mRNA expressions, as well as three-fold increased cardiomyocyte senescence, measured as cardiac p16 mRNA expression. Levosimendan improved cardiac function and prevented postinfarct cardiomyocyte hypertrophy, cardiomyocyte apoptosis, and cellular senescence. Levosimendan also ameliorated MI-induced atrial natriuretic peptide, IL-6, and connective tissue growth factor overexpression as well as MI-induced disturbances in calcium-handling proteins (SERCA2, Na-Ca exchanger) without changes in diabetic status or systemic blood pressure. In nondiabetic Wistar rats, MI induced systolic heart failure; however, the postinfarct cardiac remodeling was associated with less pronounced cardiac hypertrophy, cardiomyocyte apoptosis, inflammatory reaction, and induction of cellular senescence. Levosimendan only partially prevented postinfarct heart failure and cardiac remodeling in Wistar rats.
Our findings suggest a therapeutic role for oral levosimendan in prevention of postinfarct heart failure and cardiac remodeling in type 2 diabetes and underscore the importance of sustained cardiomyocyte apoptosis and induction of cellular senescence in the pathogenesis.
糖尿病会增加致命性心肌梗死和心力衰竭的风险。左西孟旦是一种通过钙敏化和打开三磷酸腺苷（ATP）依赖性钾通道起作用的新型正性肌力药和血管扩张药，临床上用于治疗急性失代偿性心力衰竭。然而，口服左西孟旦对心肌梗死后心力衰竭的长期影响尚不清楚。
在 2 型糖尿病模型（Goto-Kakizaki 大鼠）中，研究口服左西孟旦是否可以改善心肌梗死后的心功能并预防心脏重构。
通过冠状动脉结扎诱导糖尿病 Goto-Kakizaki 大鼠和非糖尿病 Wistar 大鼠发生心肌梗死（MI）。手术后 24 小时，将 Goto-Kakizaki 大鼠和 Wistar 大鼠随机分为四组：未治疗的 MI 组、12 周（每天 1 毫克/千克）左西孟旦治疗的 MI 组、假手术组和假手术+左西孟旦治疗组。测定血压、心功能以及心脏重构标志物。
在 Goto-Kakizaki 大鼠中，MI 诱导收缩性心力衰竭，导致远隔区心肌明显肥大，并持续诱导心肌细胞凋亡。心肌梗死后的心脏重构与心房利钠肽、白细胞介素-6 和结缔组织生长因子 mRNA 表达增加有关，以及心肌细胞衰老标志物（心脏 p16 mRNA 表达）增加三倍。左西孟旦改善心功能并预防梗死后心肌肥大、心肌细胞凋亡和细胞衰老。左西孟旦还改善了 MI 诱导的心房利钠肽、白细胞介素-6 和结缔组织生长因子过表达，以及 MI 诱导的钙处理蛋白（SERCA2、Na+-Ca2+ 交换体）改变，而不改变糖尿病状态或全身血压。在非糖尿病 Wistar 大鼠中，MI 诱导收缩性心力衰竭；然而，梗死后的心脏重构与心肌肥大、心肌细胞凋亡、炎症反应和细胞衰老的诱导程度较轻有关。左西孟旦仅部分预防了 Wistar 大鼠的梗死后心力衰竭和心脏重构。
我们的研究结果表明，口服左西孟旦在预防 2 型糖尿病心肌梗死后心力衰竭和心脏重构方面具有治疗作用，并强调了持续的心肌细胞凋亡和细胞衰老在发病机制中的重要性。
