中医药心力衰竭动物模型的研究现状

心力衰竭是临床常见的一种心血管综合征.中医药治疗心衰采用的动物模型主要有疾病动物模型和病症结合动物模型.常用的疾病动物模型复制方法为缩窄腹主动脉法、结扎冠状动脉法、快速心室起搏法、戊巴比妥钠静脉注射法、阿霉素法和异丙肾上腺素注射法;常用的病症结合动物模型为心阳虚衰症急性心力衰竭动物模型、心气虚症心力衰竭动物模型、肾阳虚...     

舒张性心力衰竭实验动物模型的研究进展

舒张性心力衰竭患者在并发高血压、糖尿病、心肌缺血和老龄化时可显著增加心衰的发病率,目前其潜在发病机制尚不完全清楚。随着我国人口老龄化的加剧,舒张性心力衰竭的患病率和死亡率明显上升,严重影响人们的生活质量和寿命。建立实验动物模型时尽量模拟临床发病诱因和特征,可以更真实地揭示疾病的发病机制或药物的作用机制。本文从舒张性心力衰竭的主要诱因重点综述构建舒张性心力衰竭实验动物模型的方法和各自的特点,为将来更多的研究舒张性心力衰竭发病机制的研究者提供依据。     

快速起搏致心力衰竭猪模型的研究进展

制作心力衰竭动物模型的方法较多,而持续快速心脏起搏诱发的心衰在血流动力学、神经激素变化及病理改变等方面均与人的慢性心衰极相似,因此是一种较为理想的心衰动物模型。尤其是快速起搏诱导的猪心衰模型,更由于猪在生理功能、解剖结构上与人的相似而更具有应用价值。     

心气虚病证动物模型及其评价体系的构建

目的　研究心气虚病证动物模型及其评价体系的构建。方法　移植心肌梗塞致心力衰竭大鼠的制作模型 ,运用中西医结合虚证和血瘀证的全国统一诊断标准、将其定性的问诊内容代以定量的同等意义的指标测试进行心气虚证动物模型评价。结果　本研究制作的动物模型再现了从一个正常大鼠→以血瘀为主要损伤→形成心气虚证的过程 ;心气虚证动物模型具有时相性、功能性和与功能相关的组织结构物质性改变。结论　将中西医临床和或基础研究中规范的、成熟的、统一的方法和标准引入中医动物模型的研究 ,并注重吸取中医已取得的临床经验和研究成果 ,是指导中医病证动物模型建立的基本思路     

糖尿病动物模型心功能评价方法

糖尿病心血管并发症（ cardiovascular complications of diabetes , CCD）是糖尿病患者最主要的死亡原因,其中糖尿病心肌病（ diabetic cardiomyopathy , DC）是心力衰竭的主要原因。对于分析糖尿病心肌病的机制、早期诊断以及改进和优化治疗,心脏功能评估起到重要桥梁作用,而糖尿病动物模型直接或间接反映糖尿病的发生和发展过程,是一个良好的研究载体。本文旨在综述国内外糖尿病动物模型心脏功能评价的重要方法。     

兔急性缺血性心力衰竭模型的建立

兔急性缺血性心力衰竭模型的建立侯应龙１臧益民张宁仔１王跃民（第四军医大学生理学教研室,１唐都医院;西安７１００３２）既往人们多采用结扎犬左冠状动脉前降支的方法来制备急性缺血性心力衰竭（心衰）动物模型,而很少使用兔作为制模动物。本文通过结扎兔冠状动脉左...     

快速心室起搏制备扩张型心肌病心力衰竭犬模型的方法学探讨

目的　应用快速心室起搏的方法制备扩张型心肌病心力衰竭犬模型 ,并对其方法学进行改进。方法　 6只成年健康杂种犬麻醉后先通过射频消融希氏束致Ⅲ度房室传导阻滞 ,再经静脉植入心内膜起搏电极 ,脉冲发射器为技术处理后的人用永久起搏器。起搏频率为 2 5 0次 min ,起搏时间持续 (2 3 6± 2 5 7)d。结果　除有相应症状、体征外 ,所有动物均成功制备为扩张型心肌病心力衰竭模型 ;B超和病理解剖检查证实有心脏扩大、心室壁变薄以及肝瘀血、肺瘀血 ;病理切片显示心肌细胞空泡变性、肝窦扩张充血、肺泡内含铁血黄素沉积。结论　改进后的快速心室起搏制备充血性心力衰竭动物模型的方法更为安全、可靠、实用。     

一种大鼠急性心力衰竭动物模型的建立方法

目的 建立一种简便易行的大鼠急性心力衰竭动物模型复制方法.方法 选用体重280～350 g的雄性SD大鼠,麻醉后于舌下静脉快速推注盐酸普鲁帕酮注射液10.5 ,mg/kg,观察记录造模后1小时内动物心率、左心室内压最大上升速率( dp/dtmax)、左心室内压最大下降速率(-dp/dtmax).结果 大鼠造模后数秒内心率即显著减少, dp/dtmax显著下降,-dp/dtmax显著上升,持续数十分钟.与空白组比较有极显著性差异.参附注射液和白附片水煎液显著恢复模型动物心率、 dp/dtmax、-dp/dtmax,与模型组比较有显著性或极显著性差异.结论 采用普鲁帕酮注射液复制大鼠急性心阳虚衰动物模型是一种简便可靠的方法.     

基于物理方法的皮肤创伤动物模型构建及评价指标研究进展

皮肤创伤已成为全球性公共问题,尤其是慢性伤口的难愈合严重影响了患者的健康生活。目前,物理方法构建皮肤创伤动物模型是研究皮肤创面的主要方法,而不同的皮肤创伤动物模型其生物学特点不同。因此,本文通过检索Pubmed、中国知网近5年与皮肤创伤动物模型构建的相关资料,以小鼠、大鼠、其他动物的皮肤创伤模型进行分类,总结并分析了基于物理方法的皮肤创伤动物模型的构建方法及评价指标,并评价不同动物模型的优缺点,旨在对皮肤创伤动物模型的合理构建及药物的研究开发提供思路。     

人致病支原体实验感染动物模型的研究进展

人致病支原体实验感染动物模型的建立对于研究支原体感染的发病机制,宿主的免疫反应,以及研发防治支原体感染新的抗生素和疫苗是不可缺少的。目前国内外已成功建立多种人致病支原体的动物模型,并且各具特色。选择一个适合的实验动物模型,是实验能否成功的关键。     

Animal models of heart failure with preserved ejection fraction

Heart failure with preserved ejection fraction (HFpEF) constitutes a clinical syndrome in which the diagnostic criteria of heart failure are not accompanied by gross disturbances of systolic function, as assessed by ejection fraction. In turn, under most circumstances, diastolic function is impaired. Although it now represents over 50 % of all patients with heart failure, the mechanisms of HFpEF remain understood, precluding effective therapy. Understanding the pathophysiology of HFpEF has been restricted by both limited access to human myocardial biopsies and by the lack of animal models that fully mimic human pathology. Animal models are valuable research tools to clarify subcellular and molecular mechanisms under conditions where the comorbidities and other confounding factors can be precisely controlled. Although most of the heart failure animal models currently available represent heart failure with reduced ejection fraction, several HFpEF animal models have been proposed. However, few of these fulfil all the features present in human disease. In this review we will provide an overview of the currently available models to study HFpEF from rodents to large animals as well as present advantages and disadvantages of these models.     

MicroRNA-192 suppresses cell proliferation and induces apoptosis in human rheumatoid arthritis fibroblast-like synoviocytes by downregulating caveolin 1

Heart disease causing cardiac cell death due to ischemia–reperfusion injury is a major cause of morbidity and mortality in the United States. Coronary heart disease and cardiomyopathies are the major cause for congestive heart failure, and thrombosis of the coronary arteries is the most common cause of myocardial infarction. Cardiac injury is followed by post-injury cardiac remodeling or fibrosis. Cardiac fibrosis is characterized by net accumulation of extracellular matrix proteins in the cardiac interstitium and results in both systolic and diastolic dysfunctions. It has been suggested by both experimental and clinical evidence that fibrotic changes in the heart are reversible. Hence, it is vital to understand the mechanism involved in the initiation, progression, and resolution of cardiac fibrosis to design anti-fibrotic treatment modalities. Animal models are of great importance for cardiovascular research studies. With the developing research field, the choice of selecting an animal model for the proposed research study is crucial for its outcome and translational purpose. Compared to large animal models for cardiac research, the mouse model is preferred by many investigators because of genetic manipulations and easier handling. This critical review is focused to provide insight to young researchers about the various mouse models, advantages and disadvantages, and their use in research pertaining to cardiac fibrosis and hypertrophy.     

Sarcoplasmic reticulum Ca-ATPase-phospholamban interactions and dilated cardiomyopathy

Dilated cardiomyopathy is a disease of the heart muscle resulting from a diverse array of conditions that damages the heart and impairs myocardial function. Heart failure occurs when the heart is unable to pump blood at a rate which can accommodate the heart muscle's metabolic requirements. Several signaling pathways have been shown to be involved in the induction of cardiac disease and heart failure. Many of these pathways are linked to cardiac sarcoplasmic reticulum (SR) Ca cycling directly or indirectly. A large body of evidence points to the central role of abnormal Ca handling by SR proteins, Ca-ATPase pump (SERCA2a) and phospholamban (PLN), in pathophysiological heart conditions, compromising the contractile state of the cardiomyocytes. This review summarizes studies which highlight the key role of these two SR proteins in the regulation of cardiac function, the significance of SERCA2a-PLN interactions using transgenic approaches, and the recent discoveries of human PLN mutations leading to disease states. Finally, we will discuss extrapolation of experimental paradigms generated in animal models to the human condition.     

Zebrafish heart failure models: opportunities and challenges

Heart failure is a complex pathophysiological syndrome of pumping functional failure that results from injury, infection or toxin-induced damage on the myocardium, as well as genetic influence. Gene mutations associated with cardiomyopathies can lead to various pathologies of heart failure. In recent years, zebrafish, Danio rerio, has emerged as an excellent model to study human cardiovascular diseases such as congenital heart defects, cardiomyopathy, and preclinical development of drugs targeting these diseases. In this review, we will first summarize zebrafish genetic models of heart failure arose from cardiomyopathy, which is caused by mutations in sarcomere, calcium or mitochondrial-associated genes. Moreover, we outline zebrafish heart failure models triggered by chemical compounds. Elucidation of these models will improve the understanding of the mechanism of pathogenesis and provide potential targets for novel therapies.

     

Clinical trials of endothelin antagonists in heart failure: a question of dose?

Circulating plasma endothelin (ET)-1 concentrations are substantially elevated, and correlate with the hemodynamic severity and New York Heart Association (NYHA) class, in patients with chronic heart failure (CHF). In early preclinical studies involving different models of experimental heart failure, ET antagonists reduced cardiac pressures, increased cardiac output, and prolonged survival. ET receptor antagonists also impressively improved systemic and pulmonary hemodynamics in patients with CHF, without causing neurohormonal activation. However, recent clinical trials, including the ENABLE (Endothelin Antagonist Bosentan for Lowering Cardiac Events in Heart Failure) and EARTH (Endothelin A Receptor Antagonist Trial in Heart Failure) studies, have shown neutral effects in terms of mortality and symptoms. This paper describes the possible reasons why benefit was not seen in these clinical studies, and suggests what lessons can be learnt from the way the studies were undertaken to apply to future studies.     

Rationale and design of the SMART Heart study

Left ventricular hypertrophy (LVH) is an independent risk factor for the development of heart failure, coronary heart disease and stroke. LVH develops in response to haemodynamic overload, e.g. hypertension. LVH was originally thought to start as an adaptive and beneficial response required to normalise wall stress. However, this concept has been challenged by recent animal experiments suggesting that any degree of LVH is detrimental for the preservation of cardiac function and survival. If confirmed in humans, these findings imply that an increase in LV mass should be prevented, e.g. by lifestyle or pharmacological interventions. To facilitate and optimise interventions, the SMART Heart study was recently set up to develop a prediction model, also involving single nucleotide polymorphism data, for the identification of subjects at high risk of developing LVH in hypertension. For this purpose 1000 subjects with chronic hypertension will undergo cardiac MR imaging. In addition, this study allows the extrapolation of animal experimental genetic research into the human situation. (Neth Heart J 2007;15:295-8).     

Regulation of expression of atrial and brain natriuretic peptide,biomarkers for heart development and disease

The mammalian heart expresses two closely related natriuretic peptide (NP) hormones, atrial natriuretic factor (ANF) and brain natriuretic peptide (BNP). The excretion of the NPs and the expression of their genes strongly respond to a variety of cardiovascular disorders. NPs act to increase natriuresis and decrease vascular resistance, thereby decreasing blood volume, systemic blood pressure and afterload. Plasma levels of BNP are used as diagnostic and prognostic markers for hypertrophy and heart failure (HF), and both ANF and BNP are widely used in biomedical research to assess the hypertrophic response in cell culture or the development of HF related diseases in animal models. Moreover, ANF and BNP are used as specific markers for the differentiating working myocardium in the developing heart, and the ANF promoter serves as platform to investigate gene regulatory networks during heart development and disease. However, despite decades of research, the mechanisms regulating the NP genes during development and disease are not well understood. Here we review current knowledge on the regulation of expression of the genes for ANF and BNP and their role as biomarkers, and give future directions to identify the in vivo regulatory mechanisms. This article is part of a Special Issue entitled: Heart failure pathogenesis and emerging diagnostic and therapeutic interventions.     

结缔组织生长因子在心衰后心室重构的研究进展

心力衰竭是各种心血管疾病发展的终末阶段,而心室重构贯穿于心衰发生、发展的全过程,阻断心室重构是防治心衰不容忽视的一个重要环节。结缔组织生长因子是一种新发现的具有多种生物学功能的成纤维细胞生长因子,在病理情况下,能抑制心肌细胞外基质的降解,促进心肌细胞的凋亡,与动脉粥样硬化、器官纤维化、创伤后修复及组织瘢痕形成等密切相关。作为参与心力衰竭后心室重构的细胞因子,不仅能够成为评价心衰患者临床预后的指标,还有望成为抗纤维化治疗的新靶点。     

Aortic banding in rat as a model to investigate malnutrition associated with heart failure

Heart failure is a severe pathology, which has displayed a dramatic increase in the occurrence of patients with chronic heart disease in developed countries, as a result of increases in the population's average age and in survival time. This pathology is associated with severe malnutrition, which worsens the prognosis. Although the cachexia associated with chronic heart failure is a well-known complication, there is no reference animal model of malnutrition related to heart failure. This study was designed to evaluate the nutritional status of rats in a model of loss of cardiac function obtained by ascending aortic banding. Cardiac overload led to the development of cardiac hypertrophy, which decompensates to heart failure, with increased brain natriuretic peptide levels. The rats displayed hepatic dysfunction and an associated renal hypotrophy and renal failure, evidenced by the alteration in renal function markers such as citrullinemia, creatininemia, and uremia. Malnutrition has been evidenced by the alteration of protein and amino acid metabolism. A muscular atrophy with decreased protein content and increased amino acid concentrations in both plasma and muscle was observed. These rats with heart failure displayed a multiorgan failure and malnutrition, which reflected the clinical situation of human chronic heart failure.