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

利钠肽-肾素-血管紧张素-醛固酮系统节律轴与夜间血压

基本信息

批准号：
10342142
负责人：
Pankaj Arora
金额：
$ 73.51万
依托单位：
UNIVERSITY OF ALABAMA AT BIRMINGHAM
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-01-05 至 2026-12-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10342142
关键词：
Adult Affect Age Ambulatory Blood Pressure Monitoring American Antihypertensive Agents Biological Biological Rhythm Blood Pressure Body mass index Cardiac Cardiovascular system Clinical Clinical Trials Diastolic blood pressure Dilatation - action Diurnal Rhythm Dose Double-Blind Method Endocrine system Enrollment Enzymes Event Excretory function Exhibits FDA approved Fibrinogen Heart High Prevalence Hormones Hour Hydrocortisone Hypertension Individual Inpatients Melatonin Natriuresis Natriuretic Peptides Neprilysin Obesity Outcome Outcome Study Participant Patients Pattern Periodicity Pharmaceutical Preparations Phase Physiological Play Population Prevalence Protocols documentation Race Randomized Renin-Angiotensin-Aldosterone System Rest Role Sodium Sodium Chloride Standardization Testing Thinness Time Vasodilation Visit Work adult obesity arm base blood pressure medication blood pressure regulation cardiovascular risk factor eligible participant high risk hypertensive hypertensives improved inhibitor innovation medication administration obese person patient oriented precision medicine primary endpoint secondary endpoint sex trial design urinary valsartan vasoconstriction

项目摘要

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.

项目概要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，并且不良心血管事件的风险增加近两倍。肥胖影响近 40% 的美国成年人和肥胖者的高血压和非浸渍型高血压患病率很高夜间血压。钠尿肽 (NP) 是心脏产生的调节血压节律的激素通过引起血管扩张、钠排泄和肾素-血管紧张素-醛固酮抑制系统（RAAS）。我们已经证明NPs存在昼夜节律（24小时节律），与 BP 节律密切跟踪，并与 RAAS 节律呈反相关系荷尔蒙。肥胖个体全天 NP 水平较低，且 NP-RAAS-BP 失调韵律。 LCZ696 是 FDA 批准的脑啡肽酶（一种 NP 降解酶）抑制剂，可增强 NP 水平也抑制 RAAS。因此，假定的 NP 缺乏和 NP- 肥胖者的 RAAS-BP 节律失调可能导致高风险夜间非下降血压曲线常见于肥胖人群。时间药理学（控制服药时间管理）同步 NP-RAAS-BP 轴固有的生物节律可能有助于控制肥胖个体夜间血压下降模式。我们假设夜间施用 NP- 肥胖高血压患者的 RAAS-BP 轴疗法将重新同步其生理节律模式并有助于改善他们的夜间血压状况。我们计划开展以患者为中心的生理学、临床试验，评估 NP-RAAS-BP 轴治疗给药时机的影响（以针对节律错位）和 NP-RAAS-BP 轴疗法的类型（针对 NP 缺乏）恢复肥胖高血压患者夜间血压的下降与非下降。我们将进行 2x2 阶乘设计试验，其中个体将被随机分配到四个组之一； 1) LCZ696日间给药； 2) LCZ696夜间给药； 3) 白天服用缬沙坦；或 4) 夜间服用缬沙坦。我们将研究 NP-RAAS-BP 轴药物抑制治疗时机的影响（因素 1：早上与晚上剂量）对夜间血压不下降的肥胖高血压患者夜间血压曲线的影响。我们将还评估了 NP-RAAS-BP 轴治疗类型（因素 2：LCZ696 与缬沙坦）对夜间血压不下降的肥胖高血压患者的夜间血压概况。我们将研究影响 NP-RAAS-BP 轴治疗对 NP 水平、RAAS 水平及其昼夜节律的时间和类型。这项研究将评估一种创新的生理驱动精准医学方法，该方法使用用于重新同步 NP-RAAS-BP 节律轴并恢复正常血压的时间药理学血压不下降的肥胖高血压患者的节律。