Heart failure is a leading cause of morbidity and mortality^1,2. Elevated intracardiac pressures and myocyte stretch in heart failure trigger the release of counter-regulatory natriuretic peptides, which act through their receptor (NPR1) to affect vasodilation, diuresis and natriuresis, lowering venous pressures and relieving venous congestion^3,4,5,6,7,8. Recombinant natriuretic peptide infusions were developed to treat heart failure but have been limited by a short duration of effect^9,10. Here we report that in a human genetic analysis of over 700,000 individuals, lifelong exposure to coding variants of the NPR1 gene is associated with changes in blood pressure and risk of heart failure. We describe the development of REGN5381, an investigational monoclonal agonist antibody that targets the membrane-bound guanylate cyclase receptor NPR1. REGN5381, an allosteric agonist of NPR1, induces an active-like receptor conformation that results in haemodynamic effects preferentially on venous vasculature, including reductions in systolic blood pressure and venous pressure in animal models. In healthy human volunteers, REGN5381 produced the expected haemodynamic effects, reflecting reductions in venous pressures, without obvious changes in diuresis and natriuresis. These data support the development of REGN5381 for long-lasting and selective lowering of venous pressures that drive symptomatology in patients with heart failure.

心力衰竭是 发病率和死亡率 ^1,2 的主要原因 。心力衰竭中心内压升高和肌细胞拉伸会触发反调节利钠肽的释放，这些肽通过其受体 （NPR1） 发挥作用，影响血管舒张、利尿和利钠，降低静脉压并缓解静脉充血 ^3,4,5,6,7,8 。重组利钠肽输注被开发用于治疗心力衰竭，但受到效果持续时间短的限制 ^9,10 。在这里，我们报告了在对超过 700,000 人的人类基因分析中，终生暴露于 NPR1 基因的编码变异与血压变化和心力衰竭风险有关。我们描述了 REGN5381 的开发，这是一种靶向膜结合鸟苷酸环化酶受体 NPR1 的研究性单克隆激动剂抗体。REGN5381 是 NPR1 的变构激动剂，可诱导活性样受体构象，优先对静脉脉管系统产生血流动力学影响，包括降低动物模型中的收缩压和静脉压。在健康的人类志愿者中，REGN5381产生了预期的血流动力学效应，反映了静脉压的降低，而利尿和利钠没有明显变化。这些数据支持开发持久和选择性降低静脉压REGN5381，这些静脉压是心力衰竭患者症状的驱动因素。