Mechanisms and Models in Heart Failure: A Translational Approach.
Mechanisms and Models in Heart Failure: A Translational Approach.
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DOI：
10.1161/circresaha.121.318158
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发表时间：
2021-05-14
影响因子：
20.1
通讯作者：
Felker GM
中科院分区：
文献类型：
--
作者：
Mann DL;Felker GM
尽管多次尝试提出一个统一的假设来解释射血分数降低的心力衰竭（HFrEF）的病理生理学，但没有一个单一的概念模型经受住了时间的考验。在本综述中，我们讨论了 HFrEF 最近成功的 III 期临床开发计划的结果如何建立在现有药物开发概念模型的基础上。我们还将讨论最近在临床试验中取得的成功与现有模型不相符的地方，以确定可能需要进一步完善当前范式的领域。为了为本次综述提供必要的结构，我们将首先简要概述 HFrEF 的病理生理学，然后概述当前的 HFrEF 概念模型，最后分析四种改善 HFrEF 临床结果的新治疗药物类别的科学原理和临床开发计划。讨论的四种新治疗类别是血管紧张素受体脑啡肽酶抑制剂 (ARNI)、钠-葡萄糖共转运蛋白 2 抑制剂 (SGLT2i)、可溶性鸟苷酸环化酶刺激剂和肌球蛋白激活剂。除 SGLT2 抑制剂外，所有这些治疗进展都是基于现有心力衰竭概念模型提供的见解。尽管对 SGLT2i 作用机制的探索仍在进行中，但此类治疗药物可能代表了近几十年来心血管治疗领域最重要的进展，并可能导致重新思考或扩展我们当前的 HFrEF 概念模型。
Despite multiple attempts to develop a unifying hypothesis that explains the pathophysiology of heart failure with a reduced ejection fraction (HFrEF), no single conceptual model has withstood the test of time. In the present review we discuss how the results of recent successful phase III clinical development programs in HFrEF are built upon existing conceptual models for drug development. We will also discuss where recent successes in clinical trials do not fit existing models, in order to identify areas where further refinement of current paradigms may be needed. To provide the necessary structure for this review, we will begin with a brief overview of the pathophysiology of HFrEF, followed by an overview of the current conceptual models for HFrEF, and end with an analysis of the scientific rationale and clinical development programs for four new therapeutic classes of drugs that have improved clinical outcomes in HFrEF. The four new therapeutic classes that discussed are angiotensin receptor neprilysin inhibitors (ARNIs), sodium-glucose co-transoporter-2 inhibitors (SGLT2i), soluble guanylate cyclase stimulators and myosin activators. With the exception of SGLT2 inhibitors, each of these therapeutic advances were informed by the insights provided by existing conceptual models of heart failure. Although the quest to determine the mechanism of action of SGLT2i’s is ongoing, this therapeutic class of drugs may represent the most important advance in cardiovascular therapeutics of recent decades, and may lead to rethinking or expanding our current conceptual models for HFrEF.