Natriuretic Peptide-Renin-Angiotensin-Aldosterone System Rhythm Axis and Nocturnal Blood Pressure

项目总结 即使在接受治疗的高血压患者中，非下降型夜间血压(BP)也很常见 与心血管不良事件的风险增加近两倍相关。肥胖影响近40% 美国成年人和肥胖者的高血压和非浸润型高血压患病率很高。 夜间血压。利钠肽(NPs)是心脏产生的调节血压节律的激素 通过引起血管扩张、钠排泄和抑制肾素-血管紧张素-醛固酮 系统(RAAS)。我们已经证明了NPs存在一种昼夜节律(24小时节律)，这是 与BP节律密切相关，与RAAS节律呈反相关系 荷尔蒙。肥胖者全天NP水平较低，NP-RAAS-BP错位 节奏。LCZ696是FDA批准的neprilysin(一种NP降解酶)的抑制剂，它可以增强 NP水平，并抑制RAAS。因此，推定的NP缺乏症和NP- 肥胖者RAAS-BP节律失调可能是夜间血压不下降的高危因素 通常见于肥胖者。时间药理学(控制用药时间 同步NP-RAAS-BP轴固有的生物节律可能有助于控制 肥胖者夜间血压下降模式。我们假设夜间服用NP- 肥胖高血压患者的RAAS-BP轴治疗将使他们的生理节律重新同步 并有助于改善它们的夜间血压特征。我们计划进行一场以病人为本的 评估NP-RAAS-BP轴疗法(TO)给药时机影响的生理学和临床试验 针对节律失调)和NP-RAAS-BP轴治疗的类型(针对NP缺乏症) 非降压恢复肥胖高血压患者夜间血压下降。我们将进行2x2阶乘 设计试验，将个体随机分成四组中的一组：1)白天服用LCZ696； 2)夜间给予LCZ696；3)白天给予valsartan；或4)夜间给予valsartan。我们会 研究NP-RAAS-BP轴药物抑制治疗时机的影响(因素1：早晨与晚上 剂量)对夜间血压不下降的肥胖高血压患者夜间血压的影响。我们会 还要评估NP-RAAS-BP轴疗法的类型(因子2：LCZ696与valsartan)对 夜间血压不下降的肥胖高血压患者的夜间血压谱。我们将研究以下影响： NP-RAAS-BP轴治疗的时机和类型对NP水平、RAAS水平及其昼夜节律的影响。 这项研究将评估一种创新的生理驱动的精确医学方法，使用 重新同步NP-RAAS-BP节律轴和恢复正常血压的时间药理学 非降血压的肥胖型高血压患者的节律。

PROJECT SUMMARY Non-dipping type of nocturnal blood pressure (BP) is common even among treated hypertensives and is associated with a nearly two-fold higher risk of adverse cardiovascular events. Obesity impacts nearly 40% of American adults, and obese individuals have a high prevalence of hypertension and non-dipping type of nocturnal BP. The natriuretic peptides (NPs) are hormones produced by the heart that regulate BP rhythm by causing dilatation of vessels, sodium excretion, and inhibition of the renin-angiotensin-aldosterone system (RAAS). We have demonstrated that there exists a diurnal rhythm (24-hour rhythm) of NPs, which tracks closely with the BP rhythm and is in an antiphase relationship with the rhythm of the RAAS hormones. Obese individuals have lower NP levels throughout the day and a misaligned NP-RAAS-BP rhythm. LCZ696 is an FDA approved inhibitor of neprilysin (an NP degrading enzyme) that augments the NP levels and also suppresses the RAAS. Hence, the confluence of putative NP deficiency and the NP- RAAS-BP rhythm misalignment in obese may contribute to the high-risk nocturnal non-dipping BP profile seen commonly among obese individuals. Chronophamacology (controlling the time of medication administration) to synchronize the NP-RAAS-BP axis inherent biological rhythms may help control the nocturnal BP dipping pattern in obese individuals. We hypothesize that nighttime administration of NP- RAAS-BP axis therapy in obese hypertensive individuals will resynchronize their physiological rhythm patterns and help to improve their nocturnal BP profile. We plan to conduct a patient-oriented physiological, clinical trial to assess the effect of timing of administration of NP-RAAS-BP axis therapy (to target the rhythm misalignment) and the type of NP-RAAS-BP axis therapy (to target NP deficiency) on restoring the nocturnal BP dipping in obese hypertensives with non-dipping. We will conduct a 2x2 factorial design trial, wherein individuals will be randomized to one of the four arms; 1) daytime dosing of LCZ696; 2) nighttime dosing of LCZ696; 3) daytime dosing of valsartan; or 4) nighttime dosing of valsartan. We will study the effect of timing of NP-RAAS-BP axis medication inhibiting therapy (factor 1: morning vs. evening dose) on the nighttime BP profile in obese hypertensive patients with nondipping nocturnal BP. We will also assess the effect of the type of NP-RAAS-BP axis therapy (factor 2: LCZ696 vs. valsartan) on the nocturnal BP profile in obese hypertensives with nondipping nocturnal BP. We will examine the impact of timing and type of NP-RAAS-BP axis therapy on the NP levels, RAAS levels, and their diurnal rhythms. This study will assess an innovative physiologically-driven precision medicine approach of using chronopharmacology for resynchronizing the NP-RAAS-BP rhythm axis and restoring the normal BP rhythm in obese hypertensives with non-dipping BP.