After initial strategies targeting inotropism and congestion, the neurohormonal interpretative model of heart failure (HF) pathophysiology has set the basis for current pharmacological management of HF, as most of guideline recommended drug classes, including beta-blockers, angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, and mineralocorticoid receptor antagonists, blunt the activation of detrimental neurohormonal axes, namely sympathetic and renin–angiotensin–aldosterone (RAAS) systems. More recently, sacubitril/valsartan, a first-in-class angiotensin receptor neprilysin inhibitor, combining inhibition of RAAS and potentiation of the counter-regulatory natriuretic peptide system, has been consistently demonstrated to reduce mortality and HF-related hospitalization. A number of novel pharmacological approaches have been tested during the latest years, leading to mixed results. Among them, drugs acting directly at a second messenger level, such as the soluble guanylate cyclase stimulator vericiguat, or other addressing myocardial energetics and mitochondrial function, such as elamipretide or omecamtiv-mecarbil, will likely change the therapeutic management of patients with HF. Sodium glucose cotransporter 2 inhibitors, initially designed for the management of type 2 diabetes mellitus, have been recently demonstrated to improve outcome in HF, although mechanisms of their action on cardiovascular system are yet to be elucidated. Most of these emerging approaches have shifted the therapeutic target from neurohormonal systems to the heart, by improving cardiac contractility, metabolism, fibrosis, inflammation, and remodeling. In the present paper, we review from a pathophysiological perspective current and novel therapeutic strategies in chronic HF.

在针对正性肌力作用和充血的初步策略之后，心力衰竭 (HF) 病理生理学的神经激素解释模型为目前 HF 的药理学管理奠定了基础，因为大多数指南推荐的药物类别，包括 β 受体阻滞剂、血管紧张素转换酶抑制剂、血管紧张素受体阻滞剂和盐皮质激素受体拮抗剂可减弱有害神经激素轴的激活，即交感神经和肾素-血管紧张素-醛固酮 (RAAS) 系统。最近，沙库巴曲/缬沙坦是一种一流的血管紧张素受体脑啡肽酶抑制剂，结合了 RAAS 的抑制和反调节利钠肽系统的增强作用，一直被证明可以降低死亡率和 HF 相关的住院治疗。近年来，已经测试了许多新的药理学方法，导致结果好坏参半。其中，直接作用于第二信使水平的药物，例如可溶性鸟苷酸环化酶刺激剂 vericiguat，或其他解决心肌能量学和线粒体功能的药物，例如 elamipretide 或 omecamtiv-mecarbil，可能会改变 HF 患者的治疗管理。最初设计用于治疗 2 型糖尿病的钠葡萄糖协同转运蛋白 2 抑制剂最近已被证明可改善 HF 的预后，尽管它们对心血管系统的作用机制尚未阐明。这些新兴方法中的大多数已经将治疗目标从神经激素系统转移到心脏，通过改善心脏收缩性、新陈代谢、纤维化、炎症、和改造。在本文中，我们从病理生理学的角度回顾了慢性 HF 的当前和新的治疗策略。