冠心病模式猪的研究进展

doi:10.11843/j.issn.0366-6964.2024.12.003

摘要/Abstract

摘要：

冠状动脉粥样硬化性心脏病(冠心病)是一种常见的心血管疾病，严重影响全球人类健康。由于其复杂的发病机制和治疗难度，冠心病的研究一直备受关注。近年来，动物模型在心血管疾病研究中发挥着关键作用，猪的心血管系统在解剖结构和病理生理机制等方面均与人类较为相似，因此模式猪已被广泛认可为动脉粥样硬化研究中的优良模型。本文旨在通过参照人类冠心病的诊断指标与高危因素，探讨建立可用于模拟人类临床冠心病的医用模式猪的评价标准和构建方法，为冠心病发病机制与临床应用前研究提供良好的实验模型。本综述将为冠心病新型诊疗药物和检测方法的开发提供参考。

关键词: 冠状动脉粥样硬化性心脏病, 模式猪, 心血管疾病

Abstract:

Coronary heart disease (CHD) is a common cardiovascular disease that seriously affects human health worldwide. Considering its complex pathogenesis and the difficulty of treatment, the study of CHD has been paid much attention. In recent years, animal models have played a key role in the study of cardiovascular diseases. The cardiovascular system of pigs is similar to that of humans in terms of anatomical structure and pathophysiological mechanism, so the model pig has been widely recognized as an excellent model in the study of atherosclerosis. By referring to the diagnostic indicators and risk factors of human CHD, this manuscript aims to explore the evaluation criteria and construction methods of pigs with CHD model similar to human, so as to provide a good experimental model for pathogenesis and clinical application studies related to CHD. This review will lay the foundation for the development of new diagnosis and treatment methods for CHD.

Key words: coronary heart disease, model pig, cardiovascular disease

中图分类号:

S858.28

骆庆龙, 袁昭顺, 张致远, 廖晓波, 印遇龙, 刘梅. 冠心病模式猪的研究进展[J]. 畜牧兽医学报, 2024, 55(12): 5349-5367.

LUO Qinglong, YUAN Zhaoshun, ZHANG Zhiyuan, LIAO Xiaobo, YIN Yulong, LIU Mei. Research Progress of Coronary Heart Disease Model Pigs[J]. Acta Veterinaria et Zootechnica Sinica, 2024, 55(12): 5349-5367.

图/表 3

表 1

表 2

不同冠心病模型构建方法及应用"

模型类别 Model category	构建方法 Building method	应用领域 Fields of application	优点 Merit	缺点 Shortcoming
高脂高糖和高钙饮食诱导模型 High fat, high sugar and high calcium diet induced model^{[15, 18, 91, 92]}	饮食诱导	慢性病预防和管理以及营养学研究	模型构建简单，无需手术干预；可以适用于多种动物；模拟了人类CHD的发病机制；易于操作可控性高	模型建立需要较长的时间；容易出现个体差异；不完全模拟人类情况，营养不均衡
冠脉损伤模型 Coronary artery damage model^{[19, 21-23]}	手术结扎冠状动脉法、LAD周围放置环状体收缩器、经皮冠状动脉球囊结合凝胶海绵联合栓塞法	心肌梗塞、慢性心肌缺血、急性心肌梗死	可在较短的时间内形成CHD模型，直接诱发病变；与人类疾病相似；成本较低	造成的心肌损伤范围难以控制，模型的稳定性较差；需要较长时间的恢复期；人工干预强烈，潜在的其他损伤
高脂/高糖/高胆固醇结合冠脉损伤模型 High fat/high sugar/high cholesterol combined with coronary artery damage model^{[27, 28]}	高脂肪/高蔗糖/高胆固醇饮食结合冠状动脉球囊损伤	糖尿病相关性CHD、药物筛选和评价	更贴近人类情况；更真实的病理过程；更好的可控性	复杂性增加；成本较高
基因编辑动物模型 Gene editing animal model^{[32, 35, 93]}	睡美人转座子、重组腺相关病毒介导的基因靶向结合体细胞核移植克隆、CRISPR/Cas9技术	低脂饮食、转基因动物研究、基因功能研究、药物治疗	模拟特定的基因变异；更高的研究效率；潜在的治疗应用；稳定的疾病模型	潜在的意外后果；成本和技术门槛高；动物福利问题
心肌缺血/再灌注模型 Myocardial ischemia/reperfusion model^{[23, 94-96]}	使用JL3 6F导管结合血管成形术球囊闭塞LAD 45 min产生	机制研究、心肌梗死、治疗靶点	模型的稳定性好，可反映冠脉介入治疗等实际治疗情况；广泛应用	操作技能要求较高；手术操作时间较长；复杂性增加
阻塞性模型 Obstructive model^{[95, 97]}	采用结扎或LAD管腔内球囊闭塞	急性心肌梗死、心力衰竭	模拟逼真；广泛应用	复杂性增加；不能完全复制人类病理生理特征
运动模型 Motion model^{[98, 99]}	近端左回旋曲冠状动脉周围用环状体收缩器结合久坐不动或运动训练	慢性冠状动脉闭塞、冠状动脉狭窄	模拟特定人群，控制变量，实验操作简便	缺乏普适性，不能完全代表一般人群中的CHD发病机制
香烟模型 Cigarette model^[100]	尼古丁注射和球囊过度扩张	健康影响研究	模拟真实环境，可控性强；多因素影响	实验操作复杂，其他发病因素的研究可能不适用
中医模型 Traditional Chinese Medicine model^{[29, 78, 101]}	前降支主干上放置Ameroid缩窄环、高脂饲料喂养结合冠状动脉血管内皮损伤法	痰瘀互结证，心肌缺血	模拟中医治疗；更好地模拟人体内外环境的综合影响；可控性强	缺乏标准化；其他治疗手段或发病机制的研究可能不适用

表 2

表 3

冠心病模型常用动物比较"

种属 Species	优点 Merit	缺点 Shortcoming	应用领域 Fields of application
小型猪 Miniature pig^{[7, 101, 115]}	解剖结构和心血管系统与人类相似，尤其是心脏大小和形态；可以进行侵入性手术和介入性操作，模拟人类CHD的治疗和手术；允许长期随访和观察，适用于长期药物治疗的研究	成本较高，实验周期较长，模型的稳定性和可复制性有待加强	研究CHD的发病机制和治疗方法；评估新型介入治疗方法的有效性和安全性；研究长期药物治疗对CHD进展的影响
大鼠 Rat^{[3, 116, 117]}	大鼠具有养护便捷、抵抗力强、存活率高、成本低廉、食性与人相似等特点；心脏解剖结构和功能与人类较为接近；可以进行一些侵入性手术以及介入性操作，同时适用于评估一些非侵入性指标，如心电图和超声心动图	部分血管解剖结构与人类有差异，无胆囊，对外源性胆固醇的吸收率极低；冠脉结扎后心肌梗死区域较小，斑块形成不易稳定；部分治疗手段评价可能存在限制	研究CHD的发病机制和治疗方法；评估介入治疗方法的有效性和药物筛选；适用于研究冠状AS、心肌缺血再灌注损伤、心肌梗死和心肌重构等
小鼠 Mouse^{[2, 118, 119]}	成本低廉，易于饲养和管理，繁殖周期短；可以进行基因编辑和转基因操作，研究CHD的遗传基础；提供了快速筛选药物和基因治疗方法；对于某些药物或治疗手段评价具有高灵敏度	心脏大小和解剖结构与人类有较大差异，小鼠体型过小也使得介入支架等大型手术无法进行；冠脉结扎后梗死区域小，只能评估心电图和超声心动图等非侵入性指标	研究CHD的遗传基础和发病机制；评估新型药物和基因治疗方法的有效性；适用于研究冠状AS、心肌缺血再灌注损伤、心肌梗死、心肌纤维化和分子生物学等领域
兔 Rabbit^{[4, 120, 121]}	心脏解剖结构和功能与人类相似；兔具有易吸收外源性胆固醇，对血液中的脂质清除能力较差的特点；冠脉球囊扩张术后可形成稳定斑块；可评估侵入性指标，如心导管检查和组织病理学等	对于AS的研究可能不如其他模型，病变部位有差异，且个体差异大，需要更多动物样本进行实验	研究CHD的发病机制和治疗方法；适用于研究CHD的诊断以及介入治疗、药物治疗和心脏移植等
犬 Dog^{[5, 122, 123]}	犬易于沟通与训练，心脏解剖结构和功能与人类相似；可以进行侵入性手术和介入性操作；冠脉结扎或外科手术可建立稳定的冠状AS模型；心肌梗死区域较广	成本相对较高，管理和饲养需要专门设备和资源；伦理问题，受到动物权益保护组织的关注；品系和生理状态差异大，需要个体化操作	研究CHD的发病机制和治疗方法；评估介入治疗方法的有效性；用于进行心脑血管疾病、消化系统疾病、器官移植、外科手术和药物安评；研究冠状AS、冠状动脉供血不足和心功能障碍等
非人类灵长动物 Non-human primates^{[6, 124]}	解剖结构和生理功能与人类非常接近，可以更准确地模拟人类CHD的发展和治疗	周期较长，成本高昂，管理和饲养需要大量资源；受到严格的伦理审查限制，多数非人类灵长动物都为受保护物种，使用限制较大	研究CHD的发病机制和治疗方法；评估介入治疗方法的有效性；进行AS的复杂因素研究

表 3

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生化指标 Biochemical index	观测指标 Observation index	方法 Method
内皮损伤指标 Endothelial injury index	s ICAM-1、s VCAM-1、ET-1、vWF、AngⅠ、AngⅡ	ELISA试剂盒
脂质代谢指标 Lipid metabolism index	TC、TG、HDL-C、LDL-C、AI	ELISA试剂盒AI=(TC-HDL-C)/HDL-C；Friedewald方程计算LDL-C
黏附分子指标 Adhesion molecular index	E-selectin	ELISA试剂盒
金属蛋白酶 Metalloproteinase	MMP-2、MMP-9	ELISA试剂盒
同型半胱氨酸 Homocysteine	Hcy	ELISA试剂盒；循环酶法
炎症介质指标 Inflammatory mediators	TNF-α、NF-κB、IP-10、LHP、IL-1β、IL-6、hs-CRP	ELISA试剂盒全自动生化分析仪
凝血功能指标 Indicators of coagulation function	PT、TT、APTT	Thromboscreen 400C自动血液凝血分析仪；STA-R型全自动凝血分析仪
其他指标 Other indicators	LP(a)、cTnT、CK、CK-MB、SOD、MDA、NO、NOS、LDH、apoA、apoB、TBIL、DBil、IBiL、UA、TBA、CREA、SAA、TMAO等	ELISA试剂盒

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