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

• 批准号: 10545747
• 负责人: Pankaj Arora
• 金额: $ 73.76万
• 依托单位: UNIVERSITY OF ALABAMA AT BIRMINGHAM
• 依托单位国家: 美国
• 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/10545747
• 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; 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; 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; 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; 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; 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

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.

项目摘要 即使在治疗的高血压中，非浸水类型的夜间血压（BP）也很常见，IS 与不良心血管事件的风险更高相关。肥胖会影响近40％ 美国成年人和肥胖个体的高血压患病率很高 夜间bp。亚位尿肽（NP）是由调节BP节奏的心脏产生的激素 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NP的昼夜节奏（24小时节奏）， 与BP节奏紧密轨迹，与RAAS的节奏有反相关系 激素。肥胖个体全天的NP水平较低，NP-RAAS-BP不对 韵律。 LCZ696是FDA批准的Neprilysin抑制剂（NP降解酶），可增强该酶 NP水平，也抑制RAA。因此，假定的NP缺乏症和NP的汇合 肥胖的RAAS-BP节奏未对准可能有助于高风险的夜间非浸入BP概况 在肥胖个体中通常看到。年流学（控制药物的时间 执行）同步NP-RAAS-BP轴固有的生物节奏可能有助于控制 肥胖个体中的夜间BP浸入模式。我们假设NP的夜间管理 肥胖高血压个体中的RAAS-BP轴治疗将重新同步其生理节奏 模式并有助于改善其夜间BP轮廓。我们计划进行以患者为导向的 生理，临床试验，以评估NP-RAAS-BP轴治疗时间的影响（TO 靶向节奏未对准）和NP-RAAS-BP轴治疗（靶向NP缺陷）的类型 在肥胖高血压中恢复夜间BP浸入，不浸润。我们将进行2x2阶乘 设计试验，其中个人将被随机分为四个臂之一； 1）LCZ696的白天给药； 2）LCZ696的夜间给药； 3）瓦尔萨坦的白天给药；或4）瓦尔萨坦的夜间给药。我们将 研究NP-RAAS-BP轴药物抑制治疗的时间的影响（因子1：早上与傍晚 夜间BP的剂量）肥胖的高血压患者，夜间夜间BP。我们将 还要评估NP-RAAS-BP轴治疗类型（因子2：LCZ696与Valsartan）对 非夜间BP的肥胖高血压中的夜间BP轮廓。我们将研究 NP-RAAS-BP轴治疗的时间和类型在NP水平，RAAS水平及其昼夜节奏上。 这项研究将评估一种创新的生理驱动的精确医学方法 用于重新同步NP-RAAS-BP节律轴并恢复正常BP 肥胖高血压的节奏，非浸入BP。