Over the past decade, soluble guanylate cyclase (sGC) activators and stimulators have been developed and studied to improve outcomes in patients with heart failure with reduced ejection fraction (HFrEF). The sGC enzyme plays an important role in the nitric oxide (NO)-sGC-cyclic guanosine monophosphate (cGMP) pathway, that has been largely untargeted by current guideline directed medical therapy (GDMT) for HFrEF. Disruption of the NO-sCG-cGMP pathway can be widely observed in patients with HFrEF leading to endothelial dysfunction. The disruption is caused by an oxidized state resulting in low bioavailability of NO and cGMP. The increase in reactive oxygen species can also result in an oxidized, and subsequently heme free, sGC enzyme that NO is unable to activate, furthering the endothelial dysfunction. The novel sGC stimulators enhance the sensitivity of sGC to NO, and independently stimulate sGC, while the sGC activators target the oxidized and heme free sGC to stimulate cGMP production. This review will discuss the pathophysiologic basis for sGC stimulator and activator use in HFrEF, review the pre-clinical and clinical data, and propose a place in the HFrEF armamentarium for this novel pharmacotherapeutic class.

在过去十年中，已开发和研究了可溶性鸟苷酸环化酶 (sGC) 激活剂和刺激剂，以改善射血分数降低 (HFrEF) 心力衰竭患者的预后。sGC 酶在一氧化氮 (NO)-sGC-环磷酸鸟苷 (cGMP) 途径中发挥重要作用，目前 HFrEF 的指导性药物治疗 (GDMT) 在很大程度上没有针对该途径。在导致内皮功能障碍的 HFrEF 患者中可以广泛观察到 NO-sCG-cGMP 通路的破坏。破坏是由氧化状态引起的，导致 NO 和 cGMP 的生物利用度低。活性氧的增加还可以导致氧化的，随后不含血红素的 sGC 酶，NO 无法激活，进一步加剧了内皮功能障碍。新型 sGC 刺激剂增强了 sGC 对 NO 的敏感性，并独立刺激 sGC，而 sGC 激活剂靶向氧化和无血红素的 sGC 以刺激 cGMP 的产生。这篇综述将讨论 sGC 刺激剂和激活剂在 HFrEF 中使用的病理生理学基础，回顾临床前和临床数据，并提出在 HFrEF 设备中为这一新型药物治疗类别提供一席之地。