Heart failure with preserved ejection fraction (HFpEF) represents one of the greatest challenges facing cardiovascular medicine today. Despite being the most common form of heart failure worldwide, there has been limited success in developing therapeutics for this syndrome. This is largely due to our incomplete understanding of the biology driving its systemic pathophysiology and the heterogeneity of clinical phenotypes, which are increasingly being recognized as distinct HFpEF phenogroups. Development of efficacious therapeutics fundamentally relies on robust preclinical models that not only faithfully recapitulate key features of the clinical syndrome but also enable rigorous investigation of putative mechanisms of disease in the context of clinically relevant phenotypes. In this review, we propose a preclinical research strategy that is conceptually grounded in model diversification and aims to better align with our evolving understanding of the heterogeneity of clinical HFpEF. Although heterogeneity is often viewed as a major obstacle in preclinical HFpEF research, we challenge this notion and argue that embracing it may be the key to demystifying its pathobiology. Here, we first provide an overarching guideline for developing HFpEF models through a stepwise approach of comprehensive cardiac and extra-cardiac phenotyping. We then present an overview of currently available models, focused on the 3 leading phenogroups, which are primarily based on aging, cardiometabolic stress, and chronic hypertension. We discuss how well these models reflect their clinically relevant phenogroup and highlight some of the more recent mechanistic insights they are providing into the complex pathophysiology underlying HFpEF.

中文翻译：

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射血分数保留的心力衰竭：异质综合征，多样化的临床前模型


射血分数保留的心力衰竭（HFpEF）是当今心血管医学面临的最大挑战之一。尽管是世界范围内最常见的心力衰竭形式，但在开发这种综合征的治疗方法方面取得的成功有限。这主要是由于我们对驱动其系统病理生理学的生物学和临床表型的异质性的不完全理解，这些临床表型越来越被认为是不同的 HFpEF 表型。有效疗法的开发从根本上依赖于强大的临床前模型，这些模型不仅忠实地概括了临床综合征的关键特征，而且还能够在临床相关表型的背景下严格研究疾病的假定机制。在这篇综述中，我们提出了一种临床前研究策略，该策略在概念上以模型多样化为基础，旨在更好地符合我们对临床 HFpEF 异质性不断发展的理解。尽管异质性通常被视为临床前 HFpEF 研究的主要障碍，但我们挑战这一观点，并认为接受它可能是揭开其病理学神秘面纱的关键。在这里，我们首先通过全面的心脏和心脏外表型分析的逐步方法提供开发 HFpEF 模型的总体指南。然后，我们概述了当前可用的模型，重点关注 3 个主要表型组，这些表型组主要基于衰老、心脏代谢应激和慢性高血压。我们讨论这些模型如何很好地反映其临床相关表型组，并重点介绍它们为 HFpEF 背后的复杂病理生理学提供的一些最新机制见解。