达格列净对非糖尿病慢性心力衰竭兔的心功能及心肌重构影响

目的　探讨达格列净对非糖尿病慢性心力衰竭兔的心功能和心肌重构的影响。方法　将18只健康雄性新西兰大白兔随机分为假手术组、心力衰竭组和达格列净组，每组6只。假手术组只开胸不手术，心力衰竭组和达格列净组开胸后采用主动脉缩窄法经12周建立非糖尿病慢性心力衰竭模型，观察各组一般情况。术后13周达格列净组经强饲法给予达格列净1 mg/（kg·d），假手术组和心力衰竭组给予等量生理盐水，共干预10周。各组于术前、术后12周、药物干预10周后行超声心动图检查；药物干预10周后检测体质量及白细胞计数、血红蛋白、总蛋白、白蛋白、钾、钠、随机血糖、渗透压和N端前脑钠素（NT-proBNP）；处死动物后，测量全心和左心室质量，并行HE、Masson及免疫组化染色观察心肌细胞形态、纤维化程度，计算胶原组织分数和胶原（Collagen）Ⅰ或CollagenⅢ阳性面积百分比。结果　达格列净可改善心力衰竭兔的食欲减退、精神萎靡、活动减少和呼吸急促等症状。药物干预10周，达格列净组左心室射血分数较心力衰竭组明显升高，且较术后12周明显升高（P＜0.05）。3组间白细胞计数、总蛋白、白蛋白、血清钾、钠、随机血糖、血浆渗透压差异均无统计学意义，达格列净组和心力衰竭组血红蛋白水平低于假手术组，而达格列净与心力衰竭组差异无统计学意义。达格列净组心脏外形较心力衰竭组减小，且全心质量、左心室质量以及左心室/体质量均低于心力衰竭组（P＜0.05）。HE染色显示达格列净可明显改善心肌细胞的形态学变化。Masson染色显示达格列净组胶原组织分数较心力衰竭组明显降低（P＜0.05），免疫组化染色提示达格列净组心肌组织CollagenⅠ、CollagenⅢ阳性面积百分比较心力衰竭组降低（P＜0.05）。结论　达格列净可抑制心力衰竭后心肌重构，其机制可能与抑制心肌组织中CollagenⅠ和CollagenⅢ的表达和心肌纤维化有关。

Effects of dapagliflozin on cardiac function and myocardial remodeling in rabbits with non-diabetic chronic heart failure

Objective　To investigate the effects of dapagliflozin on cardiac function and myocardial remodeling in rabbits with non-diabetic chronic heart failure. Methods　A total of 18 male New Zealand white rabbits were randomly divided into the sham group, the heart failure group and the dapagliflozin group, with 6 rabbits in each group. The sham group only performed thoracotomy without operation, and the heart failure group and the dapagliflozin group were treated with aortic constriction after thoracotomy. Nondiabetic chronic heart failure model was established after 12 weeks. The general situation was observed in each group. The dapagliflozin group was given dapagliflozin 1 mg/ (kg·d) by force-feeding method 13 weeks after operation, and the sham group and the heart failure group were given the same amount of normal saline for a total of 10 weeks. Echocardiography was performed before surgery, 12 weeks after surgery and 10 weeks after drug intervention. Body weight, white blood cell (WBC) count, total protein, albumin, hemoglobin, potassium, sodium, random blood glucose, osmotic pressure and NT-proBNP were detected after 10 weeks of drug intervention. After the animals were sacrificed, whole heart and left ventricle mass were measured, the morphology and fibrosis degree of myocardial tissue were observed by HE, Masson and immunohistochemistry staining, and collagen tissue fraction and positive percentage of Collagen Ⅰ or Ⅲ area were calculated. Results　Dapagliflozin ameliorated symptoms such as loss of appetite, lethargy, reduced activity and tachypnea in animals with heart failure. After 10 weeks of drug intervention, the left ventricular ejection fraction (LVEF) was significantly higher in the dapagliflozin group than that in the heart failure group, and significantly higher than that of 12 weeks after operation (P＜0.05). There were no significant differences in levels of WBC, hemoglobin, total protein, albumin, potassium, sodium, blood glucose and osmotic pressure between the three groups. The hemoglobin concentration were lower in the dapagliflozin group and the heart failure group compared with that of the sham group, but there was no significant difference between the dapagliflozin group and the heart failure group. Compared with the heart failure group, the heart shape of dapagliflozin group was decreased, and the total heart mass, left ventricular mass and left ventricular/body mass of the dapagliflozin group were lower than those of the heart failure group (P＜0.05). HE staining showed that dapagliflozin could significantly improve the morphological changes of myocardial cells. Masson staining showed that collagen fiber fraction in myocardial tissue was significantly reduced in the dapagliflozin group compared with that of the heart failure group (P＜0.05). Immunohistochemical analysis showed that the percentage of positive Collagen Ⅰ and Collagen Ⅲ area in myocardial tissue of the dapagliflozin group was lower than that of the heart failure group (P＜0.05). Conclusion　Dapagliflozin inhibits cardiac remodeling after heart failure, the mechanism of which may be related to the inhibition of Collagen Ⅰ and Ⅲ expression in myocardial tissue and myocardial fibrosis.