心肌病动物模型:从分子机制解析到临床转化的核心桥梁

Animal models of cardiomyopathy:bridging molecular mechanisms and clinical translation

摘要:

心肌病是一组异质性心肌疾病,是心力衰竭和心源性猝死的主要病因,因此需要精确的动物模型来解析其复杂的病理生理学机制。本综述系统评估了扩张型心肌病(DCM)、肥厚型心肌病(HCM)、致心律失常型心肌病(ACM)及限制型心肌病(RCM)研究中所使用的关键动物模型,并指出其科学价值取决于具体的研究目标。以小鼠、斑马鱼为代表的小型动物模型,凭借繁殖周期短、饲养成本低的特点具备高通量优势,且依托成熟的遗传编辑技术,成为解析疾病初始分子机制的重要基础。相比之下,以猪、犬为代表的大型动物模型,因心脏生理特征、血流动力学表现及疾病进展过程与人类高度相似,构成了药物与器械疗效评估的关键临床前研究平台。本综述的分析框架与疾病的病因学紧密结合:对于主要由单基因突变驱动的HCM、ACM和RCM,综述重点聚焦于能精确复现人类致病突变的遗传工程模型；而针对病因异质的DCM,则系统梳理了涵盖遗传、药物/化学因素及血流动力学应激等因素的多样化模型。此外,本综述凸显了猫HCM模型和拳师犬ACM模型等自发性大型动物模型在模拟疾病自然病程中的独特价值,并讨论了各类模型的局限性与适用场景。

Abstract:

Cardiomyopathies, a heterogeneous group of myocardial disorders, represent a principal cause of heart failure and sudden cardiac death, necessitating precise animal models to dissect their complex pathophysiology. This review systematically evaluates the key animal models used in research on dilated cardiomyopathy (DCM), hypertrophic cardiomyopathy (HCM), arrhythmogenic cardiomyopathy (ACM), and restrictive cardiomyopathy (RCM), and points out that their scientific value depends on specific research objectives. Small animal models, exemplified by mice and zebrafish, serve as the cornerstone for elucidating initial molecular pathogenesis, owing to their short breeding cycles, low husbandry costs, high-throughput screening potertial and mature genetic eding systems. In contrast, large animal models, such as swine and canines, constitute a critical platform for preclinical evaluation of pharmacological and device-based therapies, given their high fidelity to human cardiac physiology, hemodynamics, and disease progression. The analytical framework of this review is tightly coupled to disease etiology:for HCM, ACM and RCM, which are predominantly driven by monogenic mutations, this review focuses on genetically engineered models that precisely recapitulate human pathogenic mutations; for the etiologically diverse DCM, this review systematically summarizes a full spectrum of models, including those induced by genetic defects, pharmaceutical/chemical factors, and hemodynamic stress. In addition, this review highlights the unique value of spontaneous large animal models, specifically the feline HCM model and the Boxer dog ACM model, in simulating the natural history of the disease, while also discussing the limitations and specific application scenarios of each model category.