R01HL160982

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

Chronopharmacology (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 non-dipping 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 non-dipping 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.

University Of Alabama At Birmingham

TO FOSTER HEART AND VASCULAR RESEARCH IN THE BASIC, TRANSLATIONAL, CLINICAL AND POPULATION SCIENCES, AND TO FOSTER TRAINING TO BUILD TALENTED YOUNG INVESTIGATORS IN THESE AREAS, FUNDED THROUGH COMPETITIVE RESEARCH TRAINING GRANTS. SMALL BUSINESS INNOVATION RESEARCH (SBIR) PROGRAM: TO STIMULATE TECHNOLOGICAL INNOVATION, USE SMALL BUSINESS TO MEET FEDERAL RESEARCH AND DEVELOPMENT NEEDS, FOSTER AND ENCOURAGE PARTICIPATION IN INNOVATION AND ENTREPRENEURSHIP BY SOCIALLY AND ECONOMICALLY DISADVANTAGED PERSONS, AND INCREASE PRIVATE-SECTOR COMMERCIALIZATION OF INNOVATIONS DERIVED FROM FEDERAL RESEARCH AND DEVELOPMENT FUNDING. SMALL BUSINESS TECHNOLOGY TRANSFER (STTR) PROGRAM: TO STIMULATE TECHNOLOGICAL INNOVATION, FOSTER TECHNOLOGY TRANSFER THROUGH COOPERATIVE R&D BETWEEN SMALL BUSINESSES AND RESEARCH INSTITUTIONS, AND INCREASE PRIVATE SECTOR COMMERCIALIZATION OF INNOVATIONS DERIVED FROM FEDERAL R&D.

93.837 - Cardiovascular Diseases Research

National Heart Lung and Blood Institute (NHLBI) [HHS - NIH]

Birmingham, Alabama 352331709 United States

Single Zip Code

Research Project Grant (Parent R01 Clinical Trial Required) (PA-20-183)

Amendment Since initial award the total obligations have increased 395% from $735,106 to $3,638,089.