Cuthbert Joseph J, Pellicori Pierpaolo, Clark Andrew L
Department of Academic Cardiology, Hull York Medical School, Hull and East Yorkshire Medical Research and Teaching Centre, Castle Hill Hospital, Kingston upon Hull HU16 5JQ, UK.
Robertson Institute of Biostatistics and Clinical Trials Unit, University of Glasgow, University Avenue, Glasgow G12 8QQ, UK.
Ther Clin Risk Manag. 2020 Aug 4;16:715-726. doi: 10.2147/TCRM.S234772. eCollection 2020.
One of the defining features of heart failure (HF) is neurohormonal activation. The renin-angiotensin-aldosterone-system (RAAS) and sympathetic nervous system (SNS) cause vasoconstriction and fluid retention and, in response, the secretion of natriuretic peptides (NPs) from volume and pressure-overloaded myocardium promotes vasodilation and diuresis. Inhibition of the RAAS with either angiotensin-converting enzyme inhibitors (ACEI) or angiotensin receptor blockers (ARB) has been the cornerstone of medical treatment for HF with a reduced ejection fraction (HFrEF) but, until recently, it was unclear how the beneficial effects of NPs may be augmented in patients with HF. Neprilysin, a metalloproteinase widely distributed throughout the body, plays a role in degrading the gross excess of circulating NPs in patients with HF. Early studies of neprilysin inhibition suggested possible physiological benefits. In 2014, the PARADIGM-HF trial found that sacubitril-valsartan, a combination of the ARB valsartan, and the neprilysin inhibitor sacubitril, was superior to enalapril in patients with HFrEF, reducing the relative risk of cardiovascular (CV) death or first hospitalisation with HF by 20%. Almost half of the patients with HF symptoms have a "preserved" ejection fraction (HFpEF); however, the PARAGON-HF study found that sacubitril-valsartan in patients with LVEF ≥45% had no effect on CV death or first and recurrent hospitalisations with HF compared to valsartan. Guidelines across the world have changed to include sacubitril-valsartan for patients with HFrEF yet, nearly 6 years after PARADIGM-HF, there is still uncertainty as to when and in whom sacubitril-valsartan should be started. Furthermore, there may yet be subsets of patients with HFpEF who might benefit from treatment with sacubitril-valsartan. This review will describe the mechanisms behind the outcome benefit of sacubitril-valsartan in patients with HFrEF and to consider its future role in the management of patients with HF.
神经激素激活是心力衰竭（HF）的一个决定性特征。肾素-血管紧张素-醛固酮系统（RAAS）和交感神经系统（SNS）会导致血管收缩和液体潴留，作为响应，容量和压力超负荷心肌分泌利钠肽（NPs）可促进血管舒张和利尿。使用血管紧张素转换酶抑制剂（ACEI）或血管紧张素受体阻滞剂（ARB）抑制RAAS一直是射血分数降低的心力衰竭（HFrEF）药物治疗的基石，但直到最近，尚不清楚如何在HF患者中增强NPs的有益作用。中性肽链内切酶是一种广泛分布于全身的金属蛋白酶，在降解HF患者体内大量循环的NPs中发挥作用。早期对中性肽链内切酶抑制的研究表明可能具有生理益处。2014年，PARADIGM-HF试验发现，AR B缬沙坦和中性肽链内切酶抑制剂沙库巴曲的组合药物沙库巴曲缬沙坦，在HFrEF患者中优于依那普利，将心血管（CV）死亡或首次因HF住院的相对风险降低了20%。几乎一半有HF症状的患者射血分数“保留”（HFpEF）；然而，PARAGON-HF研究发现，与缬沙坦相比，LVEF≥45%的患者使用沙库巴曲缬沙坦对CV死亡或首次及再次因HF住院没有影响。世界各地的指南已做出改变，将沙库巴曲缬沙坦纳入HFrEF患者的治疗方案，但在PARADIGM-HF试验近6年后，对于何时以及哪些患者应开始使用沙库巴曲缬沙坦仍存在不确定性。此外，可能仍有部分HFpEF患者可能从沙库巴曲缬沙坦治疗中获益。本综述将描述沙库巴曲缬沙坦在HFrEF患者中产生预后益处的机制，并探讨其在HF患者管理中的未来作用。
