糖尿病性心肌病心肌纤维化治疗的进展

糖尿病性心肌病(DCM)是继发于糖尿病(DM)的一种特异性心肌病,可引发心肌肥大、间质纤维化和心肌细胞凋亡。高血糖、肾素-血管紧张素-醛固酮系统(RAAS)系统、炎性因子和基质金属蛋白酶(MMP)的异常增多等多种因素与其发生机制有关。本文对近年DCM纤维化改变的治疗进展予以综述,以期为临床治疗提供依据。     

糖尿病心肌病的药物治疗研究进展

糖尿病心肌病（DCM）是糖尿病性心脏病的特异性病变,是糖尿病（DM）心血管并发症的重要组成部分,也是DM患者死亡的主要原因.现已公认,DCM是一个独立的原发病,其发病不依赖于高血压、冠心病和其他已知心脏疾病.DCM早期的主要表现为心肌肥大和舒张功能不全,随后出现心室壁变厚、心肌细胞凋亡和心肌纤维化,晚期主要为收缩功能不全,容易并发心律失常、心力衰竭,甚至猝死.     

他汀类药物对糖尿病心肌病影响的研究进展

正糖尿病心肌病(diabetic cardiomyopathy,DCM)是与糖尿病代谢异常同时发生的,以左心室扩大和弥漫性室壁运动减低,特别是舒张功能低下为特点的心肌结构大范围改变,且不能用高血压性心脏病、冠心病及其他心脏病变来解释的一种独立的特异性心肌病[1]。1972年Rubler等首次提出了DCM的概念[2]。DCM在心肌代谢紊乱和心脏微血管病变的基础上,引起心肌细胞及其间质纤维化,促进心肌重构、心室扩大,出现心功能异常。舒张期功能异常、心室限制是     

心肌底物能量代谢在糖尿病心肌病中的研究进展

糖尿病性心肌病(DCM)是一种独立于高血压和冠心病的心脏舒张和收缩功能障碍,最终会发展为心力衰竭.该病的主要表现为心脏功能受损、心脏能量代谢紊乱,葡萄糖代谢降低,脂肪酸代谢增强以维持腺苷三磷酸产生.本文从脂肪酸代谢、心肌葡萄糖摄入、酮体代谢等方面,对心肌底物能量代谢在DCM中的研究进展作一综述.     

中医药防治糖尿病心肌病研究进展

<正>糖尿病心肌病(DCM)是一种独立的、特异性心肌病,由Rubler等〔1〕于1972年最早提出,其主要的病理变化是细胞凋亡、心肌肥厚和心肌纤维化等。临床上常表现为不同程度的左室收缩和舒张功能不全,其中舒张功能受损常出现于收缩功能受损之前。也可伴有心律失常、心源性休克甚至猝死。DCM作为糖尿病(DM)慢性并发症是死亡的主要原因。目前对于DCM的治疗仍以控制血糖,改善各种代谢异常以延缓和阻止     

糖尿病性心肌病的病理生理机制

<正>近年来,糖尿病的发病率逐年增高,继发于糖尿病的心血管并发症也已成为糖尿病患者死亡的主要原因,70年代已有研究发现,在除外导致心功能低下的诱因如高血压、嗜酒、先天性心脏病或瓣膜病的糖尿病患者中,观察到一种特殊的心肌功能损害。于1974年,Hambry等首次提出了糖尿病心肌病(diabetic cardiomyopathy,DCM)的概念。糖尿病心肌病是由于糖尿病状态下糖、脂代谢障碍导致心肌、血管内     

哺乳动物Ste20样激酶1在糖尿病心肌病发病中的作用机制研究进展

糖尿病心肌病(diabetic cardiomyopathy,DCM)是一种严重不可逆的心血管并发症,其临床表现主要为左心室肥厚、心肌纤维化和舒张功能受损。研究显示,线粒体过度分裂、自噬紊乱、细胞凋亡、氧化应激、炎症反应和心肌纤维化等均参与糖尿病心肌病的发病。近年来,有研究表明,哺乳动物Ste20样激酶1(Mst1)可能与糖尿病心肌病的发生和发展密切相关。本文主要围绕Mst1在糖尿病心肌病发展中的作用进行论述。     

糖尿病心肌病中自噬与凋亡的相互作用

糖尿病心肌病(diabetic cardiomyopathy,DCM)是糖尿病主要的心血管并发症之一.氧化应激、线粒体功能紊乱、炎症反应、心肌纤维化、细胞凋亡和自噬均参与DCM的发生发展.越来越多的证据表明,心肌细胞凋亡与自噬水平的改变贯穿于DCM的发生发展过程,且二者之间的联系可能在DCM的发病机制中发挥重要作用.目...     

FNDC5对亚临床型糖尿病心肌病的诊断价值

目的:探讨Ⅲ型纤维蛋白结构域结合蛋白5（FNDC5）对亚临床型糖尿病心肌病（DCM）的诊断价值。方法:该研究为观察性研究。入选2018年4月至2019年6月于苏州大学附属第三医院内分泌科入院的无心血管症状的2型糖尿病患者,根据超声心动图检查和门控心肌灌注显像结果将患者分为亚临床型DCM组和糖尿病不伴心功能不全组（对照组...     

microRNA与DNA甲基化在糖尿病性心肌病中的作用

<正>糖尿病心肌病(DCM)是糖尿病患者不依赖缺血性心肌病、高血压、心脏瓣膜病等心血管疾病的独立心脏并发症之一,可引起心脏收缩〔1〕/舒张功能障碍、射血分数降低、心肌代谢紊乱、心肌纤维化、微血管病变、间质炎症、氧化应激及胞内钙稳态异常,并最终导致左心室功能障碍〔2〕。近年来,针对DCM的发病机制进行了广泛深入的研究。目前的研究认为,DCM也伴随着基因表达改变。事实上,基因表达失调参与了DCM发     

扩张型心肌病的离子通道发病机制研究进展

扩张型心肌病是一侧或双侧心腔扩大、心肌收缩功能障碍为主要特征的心肌疾病。其发病机制可能与病毒感染、免疫反应以及遗传因素有关。近年来研究发现心脏钠通道基因突变可导致扩张型心肌病。因此,现重点从心肌细胞离子通道的角度来论述扩张型心肌病的发病机制,探讨其治疗的新靶点。     

Targeted deletion of Dicer in the heart leads to dilated cardiomyopathy and heart failure

Cardiovascular disease is the leading cause of human morbidity and mortality. Dilated cardiomyopathy (DCM) is the most common form of cardiomyopathy associated with heart failure. Here, we report that cardiac-specific knockout of Dicer, a gene encoding a RNase III endonuclease essential for microRNA (miRNA) processing, leads to rapidly progressive DCM, heart failure, and postnatal lethality. Dicer mutant mice show misexpression of cardiac contractile proteins and profound sarcomere disarray. Functional analyses indicate significantly reduced heart rates and decreased fractional shortening of Dicer mutant hearts. Consistent with the role of Dicer in animal hearts, Dicer expression was decreased in end-stage human DCM and failing hearts and, most importantly, a significant increase of Dicer expression was observed in those hearts after left ventricle assist devices were inserted to improve cardiac function. Together, our studies demonstrate essential roles for Dicer in cardiac contraction and indicate that miRNAs play critical roles in normal cardiac function and under pathological conditions.     

REVIEW: Sodium Channel (Dys)Function and Cardiac Arrhythmias

Cardiac voltage‐gated sodium channels are transmembrane proteins located in the cell membrane of cardiomyocytes. Influx of sodium ions through these ion channels is responsible for the initial fast upstroke of the cardiac action potential. This inward sodium current thus triggers the initiation and propagation of action potentials throughout the myocardium and consequently plays a central role in excitability of myocardial cells and proper conduction of the electrical impulse within the heart. The importance of sodium channels for normal cardiac electrical activity is emphasized by the occurrence of potentially lethal arrhythmias in the setting of inherited and acquired sodium channel disease. During common pathological conditions such as myocardial ischemia and heart failure, altered sodium channel function causes conduction disturbances and ventricular arrhythmias. In addition, sodium channel dysfunction caused by mutations in the SCN5A gene, encoding the major sodium channel in heart, is associated with a number of arrhythmia syndromes. Here, we provide an overview of the structure and function of the cardiac sodium channel, the clinical and biophysical characteristics of inherited and acquired sodium channel dysfunction, and the (limited) therapeutic options for the treatment of cardiac sodium channel disease.     

Morphological characteristics in diabetic cardiomyopathy associated with autophagy

Diabetic cardiomyopathy, clinically diagnosed as ventricular dysfunction in the absence of coronary atherosclerosis or hypertension in diabetic patients, is a cardiac muscle-specific disease that increases the risk of heart failure and mortality. Its clinical course is characterized initially by diastolic dysfunction, later by systolic dysfunction, and eventually by clinical heart failure from an uncertain mechanism. Light microscopic features such as interstitial fibrosis, inflammation, and cardiomyocyte hypertrophy are observed in diabetic cardiomyopathy, but are common to failing hearts generally and are not specific to diabetic cardiomyopathy. Electron microscopic studies of biopsy samples from diabetic patients with heart failure have revealed that the essential mechanism underlying diabetic cardiomyopathy involves thickening of the capillary basement membrane, accumulation of lipid droplets, and glycogen as well as increased numbers of autophagic vacuoles within cardiomyocytes. Autophagy is a conserved mechanism that contributes to maintaining intracellular homeostasis by degrading long-lived proteins and damaged organelles and is observed more often in cardiomyocytes within failing hearts. Diabetes mellitus (DM) impairs cardiac metabolism and leads to dysregulation of energy substrates that contribute to cardiac autophagy. However, a “snapshot” showing greater numbers of autophagic vacuoles within cardiomyocytes may indicate that autophagy is activated into phagophore formation or is suppressed due to impairment of the lysosomal degradation step. Recent in vivo studies have shed light on the underlying molecular mechanism governing autophagy and its essential meaning in the diabetic heart. Autophagic responses to diabetic cardiomyopathy differ between diabetic types: they are enhanced in type 1 DM, but are suppressed in type 2 DM. This difference provides important insight into the pathophysiology of diabetic cardiomyopathy. Here, we review recent advances in our understanding of the pathophysiology of diabetic cardiomyopathy, paying particular attention to autophagy in the heart, and discuss the therapeutic potential of interventions modulating autophagy in diabetic cardiomyopathy.     

Clinical features of myocardial triglyceride in different types of cardiomyopathy assessed by proton magnetic resonance spectroscopy: comparison with myocardial creatine

BackgroundMyocardial lipid overstorage may produce cardiomyopathy, leading to dysfunction, but advanced heart failure may cause lipolysis via sympathetic nerve activation. In the failing heart, the creatine kinase system may also be impaired. The aims of this study were to assess myocardial triglyceride (TG) and creatine (CR) in different types of cardiomyopathy and to investigate whether they are related to the severity of cardiac dysfunction.Methods and ResultsIn patients with hypertrophic cardiomyopathy (HCM, n = 8), dilated cardiomyopathy (DCM, n = 12) or ischemic cardiomyopathy (ICM, n = 10), and normal subjects (NML, n = 22), myocardial TG and CR were evaluated using proton magnetic resonance spectroscopy. To assess cardiac sympathetic nerve activity, myocardial MIBG (a radioactive guanethidine analog) uptake was measured in DCM. Myocardial TG was significantly lower in hypertrophic cardiomyopathy (HCM) (1.92 ± 0.99 μmol/g), but higher in ICM (7.59 ± 4.36 μmol/g) than in NML hearts (4.05 ± 1.94 μmol/g). There was no significant difference in TG between DCM (4.84 ± 6.45 μmol/g) and NML. Myocardial CR in HCM (20.4 ± 8.4 μmol/g), DCM (14.8 ± 4.8 μmol/g), and ICM (19.4 ± 6.3 μmol/g) was significantly lower than that in NML hearts (27.1 ± 4.3 μmol/g). Overall, myocardial CR correlated positively with the severity of heart failure estimated by ejection fraction or myocardial BMIPP (a radioactive fatty acid analog) uptake, but TG did not. In DCM, myocardial TG correlated with body mass index, but not with MIBG uptake.ConclusionsMyocardial TG may be related to the specific cause of disease rather than the severity of cardiac dysfunction. In contrast, myocardial CR reflects the severity of heart failure despite different pathoetiologic mechanisms of dysfunction. In DCM, myocardial TG may be affected by an overweight state rather than cardiac sympathetic nerve dysfunction. Thus, myocardial CR has a closer relationship to heart failure severity than does myocardial TG.     

促红细胞生成素衍生肽抑制小鼠糖尿病心肌病损伤的作用研究

目的 探讨促红细胞生成素衍生肽又称螺旋B表面肽（helix B surface peptide,HBSP）在糖尿病小鼠心肌病中的保护作用及其可能机制。 方法 80只（20~25）g雄性昆明小鼠随机分为对照组（n=20）、对照+HBSP组（n=20）、糖尿病心肌病（DCM）组（n=20）、DCM+HBSP组（n=20）。链脲佐菌素（STZ）对小鼠腹腔注射诱导1型糖尿病,最后1次STZ注射完成后第5日,血糖仪检测小鼠尾静脉血葡萄糖水平,3次测量随机血糖均≥16.7 mmol/L的视为糖尿病小鼠。糖尿病小鼠继续喂养12周,小动物超声检测提示心功能减退的为DCM小鼠。从中随机选出20只,腹腔注射HBSP 30 μg/（kg·d）,连续4周,为DCM+HBSP组。采用小动物超声分别检测各组小鼠心功能,TUNEL法检测各组小鼠心肌组织细胞凋亡率,天狼星红染色观察各组小鼠的心肌纤维化程度,Western blot检测心肌组织Akt、p-Akt、GSK3β和p-GSK3β的表达。 结果 与DCM组相比,DCM+HBSP组左室射血分数〔LVEF（%）〕及左室短轴缩短率〔［LVFS（%）〕增加（P<0.05）,左心室收缩末期容积（LVESV）和左心室舒张末期容积（LVEDV）降低（P<0.05）、心肌组织细胞凋亡率降低（P<0.05）、心肌纤维化程度减少（P<0.01）、p-Akt表达增加（P<0.05）,p-GSK3β的表达增加（P<0.01）。 结论 HBSP能够抑制小鼠DCM心肌细胞凋亡、减轻心肌间质纤维化、改善心功能,Akt-GSK3β通路的激活可能参与了HBSP减轻小鼠DCM损伤的保护作用。     

Diabetic cardiomyopathy--fact or fiction?

Epidemiologic as well as clinical studies confirm the close link between diabetes mellitus and heart failure. Diabetic cardiomyopathy (DCM) is still a poorly understood ??entity??, however, with several contributing pathogenetic factors which lead in different stages of diabetes to characteristic clinical phenotypes. Hyperglycemia with a shift from glucose metabolism to increased beta-oxidation and consecutive free fatty acid damage (lipotoxicity) to the myocardium, insulin resistance, renin-angiotensin-aldosterone system (RAAS) activation, altered calcium homeostasis and structural changes from the natural collagen network to a stiffer matrix due to advanced glycation endproduct (AGE) formation, hypertrophy and fibrosis contribute to the respective clinical phenotypes of DCM. We propose the following classification of cardiomyopathy in diabetic patients:

1. Diastolic heart failure with normal ejection fraction (HFNEF) in diabetic patients often associated with hypertrophy without relevant hypertension. Relevant coronary artery disease (CAD), valvular disease and uncontrolled hypertension are not present. This is referred to as stage 1 DCM.
2. Systolic and diastolic heart failure with dilatation and reduced ejection (HFREF) in diabetic patients excluding relevant CAD, valvular disease and uncontrolled hypertension as stage 2 DCM.
3. Systolic and/or diastolic heart failure in diabetic patients with small vessel disease (microvascular disease) and/or microbial infection and/or inflammation and/or hypertension but without CAD as stage 3 DCM.
4. If heart failure may also be attributed to infarction or ischemia and remodeling in addition to stage 3 DCM the term should be heart failure in diabetes or stage 4 DCM.

These clinical phenotypes of diabetic cardiomyopathy can be separated by biomarkers, non-invasive (echocardiography, cardiac magnetic resonance imaging) and invasive imaging methods (levocardiography, coronary angiography) and further analysed by endomyocardial biopsy for concomitant viral infection. The role of specific diabetic drivers to the clinical phenotypes, to macro- and microangiopathy as well as accompanying risk factors or confounders, e.g. hypertension, autoimmune factors or inflammation with or without viral persistence, need to be identified in each individual patient separately. Thus hyperglycemia, hyperinsulinemia and insulin resistance as well as lipotoxicity by free fatty acids (FFAs) are the factors responsible for diabetic cardiomyopathy. In stage 1 and 2 DCM diabetic cardiomyopathy is clearly a fact. However, precise determination of to what degree the various underlying pathogenetic processes are responsible for the overall heart failure phenotype remains a fiction.     

Causes and characteristics of diabetic cardiomyopathy

Type 1 and type 2 diabetic patients are at increased risk of cardiomyopathy and heart failure is a major cause of death for these patients. Cardiomyopathy in diabetes is associated with a cluster of features including decreased diastolic compliance, interstitial fibrosis and myocyte hypertrophy. The mechanisms leading to diabetic cardiomyopathy remain uncertain. Diabetes is associated with most known risk factors for cardiac failure seen in the overall population, including obesity, dyslipidemia, thrombosis, infarction, hypertension, activation of multiple hormone and cytokine systems, autonomic neuropathy, endothelial dysfunction and coronary artery disease. In light of these common contributing pathologies it remains uncertain whether diabetic cardiomyopathy is a distinct disease. It is also uncertain which factors are most important to the overall incidence of heart failure in diabetic patients. This review focuses on factors that can have direct effects on diabetic cardiomyocytes: hyperglycemia, altered fuel use, and changes in the activity of insulin and angiotensin. Particular attention is given to the changes these factors can have on cardiac mitochondria and the role of reactive oxygen species in mediating injury to cardiomyocytes.     

miR-1 mediated suppression of Sorcin regulates myocardial contractility through modulation of Ca2+ signaling

MicroRNAs are negative gene regulators and play important roles in cardiac development and disease. As evident by cardiomyopathy following cardiac-specific Dicer knockdown they also are required for maintaining normal cardiac contractile function but the specific role of miR-1 in the process is poorly understood. To characterize the role of miR-1 in particular and to identify its specific targets we created a tamoxifen-inducible, cardiac-specific Dicer knockdown mouse and demonstrated that Dicer downregulation results in a dramatic and rapid decline in cardiac function concurrent with significantly reduced levels of miR-1. The importance of miR-1 was established by miR-1 antagomir treatment of wild-type mice, which replicated the cardiac-specific Dicer knockdown phenotype. Down-regulation of miR-1 was associated with up-regulation of its predicted target Sorcin, an established modulator of calcium signaling and excitation-contraction coupling, subsequently verified as a miR-1 target with luciferase constructs. siRNA-mediated knockdown of Sorcin effectively rescued the cardiac phenotypes after Dicer or miR-1 knockdown affirming Sorcin as a critical mediator of the acute cardiomyopathy observed. The regulatory relationship between miR-1 and Sorcin was further confirmed in cultured mouse cardiomyocytes where modulation of miR-1 was associated with discordant Sorcin levels and dysregulation of calcium signaling. Pathological relevance of our findings included decreased miR-1 and increased Sorcin expression in end-stage cardiomyopathy. These findings demonstrate the importance of miR-1 in cardiac function and in the pathogenesis of heart failure via Sorcin-dependent calcium homeostasis.