Large Animal Models of Heart Failure: Reduced vs. Preserved Ejection Fraction.
Large Animal Models of Heart Failure: Reduced vs. Preserved Ejection Fraction.
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DOI：
10.3390/ani10101906
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发表时间：
2020-10-18
期刊：
影响因子：
--
通讯作者：
Richards AM
中科院分区：
文献类型：
--
作者：
Charles CJ;Rademaker MT;Scott NJA;Richards AM
人类心力衰竭是一种复杂的临床综合征，可由多种疾病引起。虽然长期的高血压和心脏病发作是主要的致病因素，但也可能有许多心脏和循环疾病导致心力衰竭的发生。尽管在过去的30年里，心力衰竭的医疗管理有了有益的改善，但与该综合征生活在一起的持续的不良影响和居高不下的死亡率意味着，无可辩驳地需要新的和改进的治疗方案。具有良好特征的动物模型已经并将继续为临床护理的进步做出很大贡献。本文将对目前主要的心衰大动物模型进行综述。利用这些大型动物模型进行的研究是在进行明确的临床试验之前开发新的药物和基于设备的疗法的关键一步。本综述将讨论不同的大动物模型心力衰竭的各种益处，并强调到目前为止的一些关键不足。显然，有必要不断开发具有临床相关性的大型动物模型。心力衰竭(HF)是多种代谢和心血管疾病的最终共同终点，在全球范围内造成巨大的医疗负担。尽管临床管理和结果有了显著改善，但发病率和死亡率仍然居高不下，仍然需要改进治疗方案，这是毋庸置疑的。心衰的病理生理机制是复杂的，涵盖了一系列的临床表现，从射血分数降低(≤40%EF)到射血分数保留的心衰(HFpEF)，尽管EF维持在50%以上，但HFpEF患者表现出心脏松弛能力降低。在过去十年之前，大多数临床试验和动物模型都是针对HFrEF的。尽管最近在了解HFpEF的潜在机制和寻找有效的治疗方法方面做出了越来越多的努力，但对HFpEF患者的临床试验未能证明死亡率的改善。HFpEF治疗创新的一个重大障碍是缺乏临床前模型，包括大型动物模型，与啮齿动物不同，这些模型允许详细的器械和广泛的成像和采样方案。虽然已经报道了几个HFpEF的大型动物模型，但没有一个符合人类疾病的所有特征，也很少有人表现出进展为坦率的失代偿性心衰。本文综述了在猪、狗和羊中已建立的HFrEF模型，并讨论了迄今为止在这些物种中建立HFpEF模型的尝试。
Human heart failure (HF) is a complex clinical syndrome that can be caused by a variety of diseases. While long-term high blood pressure and heart attacks are major contributing factors, there can be many diseases of the heart and circulation that contribute to the development of HF. Although there have been salutary improvements in the medical management of HF over the last 30 years, ongoing ill effects of living with the syndrome and the persistently high death rates mean there is an irrefutable need for new and improved treatment options. Well-characterized animal models have contributed, and continue to contribute, much to the advancement of clinical care. This review will summarize the main large animal models of HF developed to date. Studies utilizing these large animal models are an essential step leading to the development of novel pharmaceutical and device-based therapies before they can undergo definitive clinical trials. This review will discuss the various benefits of different large animal models of HF and highlight some key deficiencies to date. There is clearly a need for ongoing development of clinically relevant large animal models of HF. Heart failure (HF) is the final common end point of multiple metabolic and cardiovascular diseases and imposes a significant health care burden worldwide. Despite significant improvements in clinical management and outcomes, morbidity and mortality remain high and there remains an indisputable need for improved treatment options. The pathophysiology of HF is complex and covers a spectrum of clinical presentations from HF with reduced ejection fraction (HFrEF) (≤40% EF) through to HF with preserved EF (HFpEF), with HFpEF patients demonstrating a reduced ability of the heart to relax despite an EF maintained above 50%. Prior to the last decade, the majority of clinical trials and animal models addressed HFrEF. Despite growing efforts recently to understand underlying mechanisms of HFpEF and find effective therapies for its treatment, clinical trials in patients with HFpEF have failed to demonstrate improvements in mortality. A significant obstacle to therapeutic innovation in HFpEF is the absence of preclinical models including large animal models which, unlike rodents, permit detailed instrumentation and extensive imaging and sampling protocols. Although several large animal models of HFpEF have been reported, none fulfil all the features present in human disease and few demonstrate progression to frank decompensated HF. This review summarizes well-established models of HFrEF in pigs, dogs and sheep and discusses attempts to date to model HFpEF in these species.
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