糖尿病心肌病的发病机制研究

糖尿病心肌病(DC)是排除了高血压性心脏病、冠状动脉粥样硬化心脏病、心脏瓣膜病及其他心脏病变所致的心肌损伤后诊断的一种特异性心肌病,是糖尿病的主要并发症之一。临床表现为心脏收缩和舒张功能障碍,最终导致心力衰竭、心律失常和猝死。目前的研究认为,心肌细胞的代谢紊乱、心脏微血管和自主神经病变及其他神经内分泌因素在DC的发生发展中均起了重要的作用,该文就DC的发病机制予以综述。     

自噬相关通路在糖尿病心肌病中的研究进展

糖尿病心肌病定义为无冠状动脉疾病和高血压的糖尿病患者发生的心肌功能障碍。据报道,糖尿病心肌病的发病机制与炎症、心肌纤维化、线粒体损伤、心肌细胞凋亡、自噬等因素相关。自噬是维持细胞器功能和细胞内营养环境的关键因素,也参与了系统的代谢稳态,这对于维持心脏功能和活性具有重要作用,其调节失调可能造成心肌细胞损伤。自噬相关信号通路包括m TOR信号通路及Beclin-1信号通路。糖尿病心肌病中自噬的影响因素包括高糖血症、游离脂肪酸过度积累、氧化应激、胰岛素抵抗、内质网应激等,该文就自噬相关通路在糖尿病心肌病发病机制中的研究进展进行综述。     

内质网应激在糖尿病心肌病中的研究进展

糖尿病心肌病(diabetic cardiomyopathy,DCM)是相对于冠状动脉粥样硬化心脏病、高血压心脏病、心脏瓣膜性病变、先天心脏病及其他一致心脏疾病与糖尿病特异相关的心肌性病变来说独立存在的疾病,病理表现为心肌代谢紊乱以及微血管病变所致的心肌细胞肥大、间质纤维化、坏死和凋亡。内质网是多种重要细胞功能的中心场所,糖尿病患者心肌细胞内的内质网肿胀、出现功能紊乱,高血糖状态能引发内质网应激(endoplasmic reticulum stress,ERS),提示ERS可能参与DCM进程的发生和发展。基于此,该文从糖尿病心肌病的发病机制、未折叠蛋白反应、DCM中ERS的相关作用等方面综述了ERS在糖尿病心肌病中的研究进展。     

Fas/FasL对糖尿病心肌病的影响

糖尿病心肌病(DCM)是指排除了高血压性心脏病、冠状动脉粥样硬化心脏病、心脏瓣膜病及其他心脏病变所致的心肌损伤后诊断的一种特异性心肌病变。心肌细胞凋亡为其重要的发病机制,晚期主要表现为心室重塑和心脏功能障碍。 Fas/FasL是重要的凋亡信号通路,主要是Fas/FasL为主的膜受体通路作用于细胞凋亡过程,在糖尿病的形成过程中起有重要作用,从而对糖尿病心肌病产生影响。本文阐述了Fas/FasL在DCM病理、生理中的作用,以及对未来治疗DCM的展望。     

格列本脲对GK大鼠心肌的保护作用实验研究

<正>糖尿病心肌病(diabetic cardiomyopathy,DCM)指由糖尿病引起心脏微血管病变、心肌代谢紊乱和心肌纤维化等所致的心肌广泛结构异常的一种疾病状态[1]。近年来的研究发现,血管紧张素(Ang-Ⅱ)增多、游离脂肪酸(IFFA)在DCM的发病中起着重要的作用。     

Nrf2在糖尿病心肌病中的作用及中药干预研究进展

糖尿病心肌病(diabetic cardiomyopathy, DCM)作为糖尿病的心血管并发症,严重影响糖尿病患者的预后。近年来,糖尿病心肌病的发病率和死亡率持续增高,成为人们重点关注的研究问题。糖尿病心肌病的发病机制复杂,多种信号通路参与其进展过程。核因子E2相关因子2(nuclear factor NF-E2-related factor 2, Nrf2)作为一种强效抗氧化基因,通过与其他信号因子相互关联增强心肌抵抗氧化应激的能力,并发挥抗炎症反应、抗心肌纤维化以及抗细胞凋亡等作用。大量研究文献显示,中药有效成分可以通过增强Nrf2的表达,影响Nrf2与其他信号因子的相互关联来改善糖尿病心肌病的心肌损伤。故本文就Nrf2在糖尿病心肌病中的作用及中药干预研究进行文献综述,为糖尿病心肌病的防治提供参考。     

糖尿病性心肌病的诊治探讨

糖尿病性心肌病是糖尿病特异的独立病变。是微血管病变及心肌代谢紊乱导致的心肌广泛灶性纤维化。发病机制及病理特点均不同于冠心病和原发性心肌病。本文总结了 2 6例糖尿病性心肌病 ,以探讨本病的诊治经验。1　资料与方法1.1　一般资料　 2 6例患者 ,男 10例 ,女 16例 ,年龄 5 6岁～80岁。糖尿病诊断标准符合 1999年WHO诊断标准 ,病史在 10a～ 2 3a ,心功能IV级。具有以下糖尿病性心肌病的临床特点 :有糖尿病病史 ;有心力衰竭症状 (心悸、气喘、咳嗽、水肿等 ) ;口唇紫绀、肺部湿 口罗音、下肢水肿、颈静脉怒张 ;ESG示 :ST -T改变、…     

糖尿病心肌病中离子通道研究进展

糖尿病心肌病是一个日益严重的公共健康问题，患者心脏会出现功能和结构的改变。心脏中钾通道、钠通道、钙通道及TRPM7通道与该疾病息息相关，本综述分析了相关心脏离子通道，以了解其在糖尿病心肌病的病理生理和发病机制中的潜在作用。     

脉冲组织多普勒超声评价2型糖尿病患者左右心室功能的价值

糖尿病性心肌病是指发生在糖尿病中,不能用高血压、冠心病、心脏瓣膜病及其他心脏病来解释的心肌疾病[1]。糖尿病性心肌病是糖尿病的重要致死因素之一,其发病原因不明,可能与心肌壁内微血管病变及血管周边间质纤维化等相关[2]。早期诊断、治疗及预防是改善糖尿病性心肌病预后的关键。本研究采用脉冲组织多普勒超声(pulsed wave tissue doppler imaging,PW-TDI)评价2型糖尿病性患者左、右心室     

糖尿病心肌病发病机制及对心功能影响的研究进展

1972年,Rubler等首次提出糖尿病心肌病(diabetic cardiomyopathy,DCM)的概念[1],近40年来,相关学者在DCM 的领域中进行了大量的基础和临床研究,发现DCM通常表现为心肌顺应性降低和舒张期充盈受阻为主的心室功能异常,可诱发心力衰竭、心源性休克和猝死等并发症.而对于其发病机制的研究也更加深入.     

绞股蓝总苷对糖尿病心肌病大鼠心脏功能的影响

目的探讨绞股蓝总苷(gypenosides,GP)对糖尿病心肌病大鼠心脏功能的影响。方法SD大鼠50只,随机分为对照组,糖尿病心肌病组,绞股蓝总苷低、中、高剂量治疗组。后4组腹腔注射链脲佐菌素55 mg.kg-1制备糖尿病模型。造型后第7周起,对照组和糖尿病心肌病组给予纯净水,绞股蓝总苷低、中、高剂量治疗组分别给予绞股蓝总苷501、002、00 mg.kg-1.d-1,连续给药6周。第12周末测定大鼠心室内压,分析心功能,电镜观察心肌细胞超微结构改变情况,同时测定心肌一氧化氮含量及一氧化氮合酶、Ca2-+ATP酶和Na+-K-+ATP酶活性。结果糖尿病心肌病组大鼠的左室收缩压、左心室舒张末期压、左室内压最大上升和下降速率、左室内压上升达最大速率所需时间等心功能指标和一氧化氮合酶、Ca2-+ATP酶及Na+-K-+ATP酶活性均明显低于对照组(P<0.01),而绞股蓝总苷中、高剂量治疗组上述指标显著高于糖尿病心肌病组(P<0.05);糖尿病心肌病组心肌细胞肌小节失去正常结构,肌原纤维坏死、溶解,线粒体水肿,嵴消失,绞股蓝总苷中、高剂量可明显减轻上述病变。结论绞股蓝总苷可减轻心肌超微结构损伤,改善糖尿病心肌病大鼠左心室功能。     

Diabetic cardiomyopathy and its prevention by metallothionein: experimental evidence, possible mechanisms and clinical implications

Cardiac failure is a leading cause for the mortality of diabetic patients, in part due to a specific cardiomyopathy, referred to as diabetic cardiomyopathy, which occurs with or without co-existence of vascular diseases. Although several mechanisms responsible for diabetic cardiomyopathy have been proposed, oxidative stress is widely considered as one of the major causes for the pathogenesis of the disease. Thus, a few laboratories are trying to develop antioxidants used to prevent diabetic cardiomyopathy. Metallothioneins (MTs) are cysteine-rich metal-binding proteins with several biological roles including antioxidant property. We and others have indicated the significant cardiac protection of MT against diabetes using cardiac-specific MT-overexpressing transgenic mice and OVE26MT mice (cross-bred of cardiac MT transgenic mice with genetically engineered diabetic OVE26 mice). Several possible mechanisms responsible for MT's cardiac protection from diabetes were revealed. These include MT's important roles in calcium regulation, zinc homeostasis, insulin sensitization, and antioxidant action. Since MT is ubiquitously expressed in mammalian tissues and is highly inducible by a variety of reagents such as zinc, the clinical potential for inducing cardiac MT as an antioxidant by zinc supplementation to prevent various diabetic complications, including cardiomyopathy, has been explored in diabetic animal models and patients. Since zinc has been therapeutically used for several other non-diabetic diseases in clinics, it provides further potential use of zinc for diabetic patients. Therefore, this review will briefly introduce the biochemical features of MT along with its critical roles in redox homeostasis and antioxidant function in the heart, and then discuss the current research on the prevention of diabetic cardiomyopathy by MT with an emphasis on experimental evidence, possible mechanisms, and clinical implications.     

Effects of mesenchymal stromal cells on diabetic cardiomyopathy

Diabetic cardiopathy includes a specific cardiomyopathy, which occurs in the absence of coronary heart disease under diabetes mellitus. Hallmarks of diabetic cardiomyopathy are besides others, interstitial inflammation, cardiac oxidative stress, interstitial and perivascular fibrosis, cardiac apoptosis, intramyocardial microangiopathy, endothelial dysfunction, abnormal intracellular Ca2?-handling, cardiomyocyte hypertrophy, and impaired cardiac stem cells. Since mesenchymal stromal cells have been shown to have anti-diabetic as well as cardioprotective features, we summarize in this review how they can indirectly affect diabetic cardiomyopathy via their influence on the metabolic trigger hyperglycemia, and how they can directly influence the cardiac cellular consequences typical for diabetic cardiomyopathy via their immunomodulatory, anti-oxidative, anti-fibrotic, anti-apoptotic, pro-angiogenic, and endothelial-protective features, and their ability to activate cardiac progenitor cells. Furthermore, the dysfunctionality of (bone marrow-derived) mesenchymal stromal cells under diabetes mellitus and potential strategies to overcome this impairment in cell functionality are outlined.     

糖尿病心肌病68例临床特点分析

目的分析探讨糖尿病心肌病的临床特点。方法选择本院2001年8月～2010年7月治疗的糖尿病患者200例,其中伴有糖尿病心肌病患者108例。将糖尿病心肌病患者随机分为两组：糖尿病合并心肌病组和糖尿病无心肌病组。比较两组的一般特征、心脏超声特点及血脂代谢情况。结果两组在性别、年龄比例方面,差异无统计学意义（P〉0.05）,但是病程差异有统计学意义（P〈0.05）。两组三酰甘油、高密度脂蛋白胆固醇和低密度脂蛋白胆固醇比较,差异有统计学意义（P〈0.05）,但是总胆固醇差异无统计学意义（P〉0.05）。糖尿病心肌病患者左心室舒张功能较对照组减弱,心功能异常（射血分数、每搏量及左心室内径缩短率均减小）。结论糖尿病病程时间的长短以及血清三酰甘油的浓度是糖尿病心肌病发病的危险因素。     

Diabetic cardiomyopathy: electromechanical cellular alterations

Diabetic patients show a higher incidence of cardiac arrhythmias, including ventricular fibrillation and sudden death. However, although diabetic cardiomyopathy is a frequent and important complication of diabetes mellitus, its physiological basis is not completely known. The electrocardiogram of diabetic patients shows several alterations from normal patterns, most of them related to the QT interval and T wave. Recently, different alterations in cardiac ionic currents have been described in myocytes isolated from diabetic hearts, mainly a reduction in potassium repolarizing currents. Three different mechanisms could be involved in these alterations. First, direct metabolic alterations of the cardiac myocyte, such as impaired activity of protein kinases and phosphatases, intracellular pH regulation, intracellular calcium handling, and others. Second, impaired support of extra cardiac factors regulating cardiac activity, such as sympathetic regulation of heart rate and contractility. Thus, diabetic autonomic neuropathy leads to diminished noradrenaline release in cardiac ventricle in response to standing, exercise or cold stress. Besides, diabetic cardiomyopathy reduces cardiac myocyte response to acute noradrenaline exposure and finally, impairs support of different trophic factors responsible for the regulation of ionic channel expression. Thus, basal noradrenaline release in the ventricles, necessary to maintain adequate potassium channel expression, is reduced by sympathetic neuropathy. Moreover, the levels of insulin and other trophic factors required for the maintenance of adequate ionic channel expression are also altered in diabetic patients. Therefore, different physiopathological mechanisms are involved in diabetic cardiomyopathy. Thus, further research is needed in order to prevent the development of this long-term complication, and to improve the pharmacological management of diabetic patients.     

Taxifolin prevents diabetic cardiomyopathy in vivo and in vitro by inhibition of oxidative stress and cell apoptosis

Diabetic cardiomyopathy has been increasingly recognized as an important cause of heart failure in diabetic patients. Excessive oxidative stress has been suggested to play a critical role in the development of diabetic cardiomyopathy. The objective of this study was to investigate the potential protective effects and mechanisms of taxifolin on cardiac function of streptozotocin-induced diabetic mice and on hyperglycemia-induced apoptosis of H9c2 cardiac myoblasts. In vivo study revealed that taxifolin improved diastolic dysfunction, ameliorated myocardium structure abnormality, inhibited myocyte apoptosis and enhanced endogenous antioxidant enzymes activities. Interestingly, taxifolin reduced angiotensin II level in myocardium, inhibited NADPH oxidase activity, and increased JAK/STAT3 activation. In vitro investigation demonstrated that taxifolin inhibited 33 mM glucoseinduced H9c2 cells apoptosis by decreasing intracellular ROS level. It also inhibited caspase-3 and caspase-9 activation, restored mitochondrial membrane potential, and regulated the expression of proteins related to the intrinsic pathway of apoptosis, thus inhibiting the release of cytochrome c from mitochondria into the cytoplasm. In conclusion, taxifolin exerted cardioprotective effects against diabetic cardiomyopathy by inhibiting oxidative stress and cardiac myocyte apoptosis and might be a potential agent in the treatment of diabetic cardiomyopathy.     

A novel endothelin receptor antagonist CPU0213 improves diabetic cardiac insufficiency attributed to up-regulation of the expression of FKBP12.6, SERCA2a, and PLB in rats

The depressed sarcoplasmic reticulum (SR) Ca2+-ATPase (SERCA2a) and Ca2+-release channels (ryanodine receptor RyR2) are involved in the diabetic cardiomyopathy. However, an implication of a down-regulation of FK506-binding protein or calstabin-2 (FKBP12.6) is undefined. It was hypothesized that the down-regulation of FKBP12.6 and SERCA2a of the intracellular calcium handling system is closely related to an up-regulated endothelin (ET) system. An ET receptor antagonist CPU0213 is newly discovered and expected to ameliorate cardiac insufficiency which is mediated by the depressed FKBP12.6 and SERCA2a in diabetic rat heart. Diabetes was developed in male Sprague-Dawley rats 8 weeks after an injection of streptozotocin (60 mg/kg IP), and CPU0213 was instituted 30 mg/kg, SC in the last 4 weeks. The assessment of the cardiac function, cardiac calcium handling proteins, endothelin system, and redox enzyme system were conducted. The compromised cardiac function in diabetic rats was accompanied by a significant down-regulation of expression of FKBP12.6 as well as SERCA2a and phospholamban. These were closely linked with an increased ET-1 and up-regulation of endothelin converting enzyme, PropreET1, and inducible nitric oxide synthase mRNA in diabetic cardiomyopathy. After 4-week treatment, CPU0213 was capable to attenuate completely the down-regulated FKBP12.6 and SERCA2a, and up-regulated ET system in association with a recovery of the cardiac insufficiency of diabetic cardiomyopathy.     

Long-term administration of fasudil improves cardiomyopathy in streptozotocin-induced diabetic rats

Inhibition of Rho kinase (ROCK) has been shown to improve diabetic-related disorders. In this study, the cardio-protective effects and potential mechanisms of fasudil, a selective ROCK inhibitor, on diabetic cardiomyopathy were investigated in a streptozotocin (STZ)-induced diabetic rat model. Eight weeks after diabetes was induced by a single tail vein injection of 60 mg/kg STZ, rats were administered long-term fasudil or captopril as a control over a four-week period. Similar to the effect of captopril, fasudil treatment significantly protected against STZ-induced hemodynamic, histopathologic changes and decreased serum lactate dehydrogenase and creatine phosphokinase. Moreover, fasudil significantly down-regulated ROCK I mRNA expression and ROCK activity, reduced cardiac collagen deposition, and decreased the incidence of apoptosis and ratio of Bax/Bcl-2 protein expression. Additionally, fasudil potently elevated superoxide dismutase activity and suppressed the extent of lipid peroxidation in sera and hearts of diabetic rats. Our findings indicated that long-term treatment with fasudil could improve cardiac dysfunction, attenuate myocardial injury and prevent pathological changes in a rat model of diabetic cardiomyopathy. These effects could be attributed to regulation of antioxidative activities, suppression of myocardial hypertrophy, apoptosis, fibrosis and subsequent cardiac remodeling. These results may help to expand the clinical application of fasudil for diabetic cardiomyopathy.     

Diabetic cardiomyopathy: how much does it depend on AGE?

Diabetic cardiomyopathy refers to dysfunction of cardiac muscle in patients with diabetes that cannot be directly ascribed to hypertension, coronary heart disease or other defined cardiac abnormalities per se. The development of diabetic cardiomyopathy may involve several distinct mechanisms, including increased formation of advanced glycation end products (AGEs) secondary to hyperglycaemia. AGEs may alter structural proteins and lead to increased arterial and myocardial stiffness. Therefore, therapies that prevent or retard development of AGEs in diabetes may be valuable strategies to treat or prevent diabetic cardiomyopathy. In this issue of British Journal of Pharmacology, Wu and colleagues demonstrate that aminoguanidine (inhibitor of AGE formation and protein cross-linking) treatment of a rat model of type I diabetes (rats made insulin deficient with streptozotocin and nicotinamide treatment) ameliorates detrimental changes in left ventricular structure and function. Results from this study are in agreement with previous investigations, suggesting that aminoguanidine is effective in preventing cardiac hypertrophy and arterial stiffening in experimental animal models of diabetes and emphasize the potential pathogenic role of AGEs in diabetic cardiomyopathy.     

氯沙坦对糖尿病心肌病患者脑钠肽和C反应蛋白的影响研究

目的探讨氯沙坦对糖尿病心肌病患者血浆BNP及CRP变化水平影响。方法研究对象分为糖尿病对照组（30例）和糖尿病心肌病组（30例）,并测定血浆BNP及CRP水平;继将糖尿病心肌病组随机分为常规治疗组及氯沙坦治疗组,采取相应治疗,12周后检测其心功能变化及血浆BNP、CRP的水平变化。结果糖尿病心肌病组患者的BNP,CRP明显高于糖尿病对照组（P〈0.05）,且随心肌病损的加重而增加,呈正相关;氯沙坦治疗组的血浆BNP及CRP水平明显低于常规治疗组（P〈0.05）,LVEF高于常规治疗组（P〈0.01）,LVEDd低于常规治疗组（P〈0.05）。结论 BNP与CRP水平升高能作为临床反映糖尿病心肌病变严重程度的血清学指标,而氯沙坦能降低其水平,并改善心功能,显示其对糖尿病心肌病具有较好的疗效。