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 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.

Grant Number: 5R01HL160982-04
NIH Institute/Center: NIH
Principal Investigator: Pankaj Arora