PRECISION-BP: Precision Chronopharamacotherapy Targeting NP-RAAS-BP Rhythm Axis

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

Obese individuals have a higher prevalence of nocturnal hypertension and non-dipping blood pressure (BP). These conditions are associated with an increased risk of cardiovascular (CV) events and death. Natriuretic Peptides (NPs) are hormones produced by the heart which directly regulate BP by causing dilation of blood vessels and by removing sodium and water from the body. NPs have a 24-hour day-night rhythm and this controls the day-night rhythm of BP as well. The NP-BP rhythm relationship is broken down in obese individuals. Obese individuals also have lower circulating NP levels. Lower circulating levels of NPs and elevated renin hormone (a part of the Renin-Angiotensin-Aldosterone System [RAAS]) at nighttime may contribute to the high nocturnal blood pressure in obese individuals which puts them at a higher risk of developing CV events. This current study seeks to determine the biological implications of chronopharmacology for synchronizing NP-RAAS-based blood pressure therapy with the physiological diurnal rhythms to restore the normal diurnal rhythm of blood pressure in obese individuals.

The investigators have demonstrated that there exists a diurnal rhythm of natriuretic peptides (NPs) which tracks closely with the BP rhythm and is in an antiphase relationship with the rhythm of the RAAS (Renin-Angiotensin-Aldosterone System) hormones. The NP levels are lowest at night, and the renin and aldosterone levels are highest at nighttime. Furthermore, the investigators have demonstrated that obese individuals have a putative deficiency of NPs, and this is due to decreased production alongside increased clearance of NPs. 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 among obese alongside the lower levels of NPs at nighttime and the increased activity of RAAS at night may contribute to the high-risk nocturnal non-dipping BP profile among obese individuals. Chronopharmacology (controlling the time of medication administration) to synchronize the NP-RAAS axis targeting anti-hypertensive medications with the inherent biological NP-RAAS-BP rhythm axis may help in controlling the high-risk nocturnal BP non-dipping in obese. Investigators hypothesize that nighttime administration of NP augmenting and/or RAAS inhibition therapy in obese hypertensive individuals will help to improve their nocturnal BP rhythm. The investigators aim to conduct a patient-oriented physiological clinical trial to assess the effect of timing of administration of NP-RAAS axis therapy on restoring the normal BP rhythm. This study is a 2x2 factorial design trial, wherein individuals will be randomized to either daytime dosing or nighttime dosing of either LCZ696 or valsartan. The investigators will study the effect of timing of NP augmenting and/or RAAS inhibiting therapy on the nighttime BP profile in obese hypertensive patients with nondipping nocturnal BP. The investigators will also assess the effect of NP augmentation in an NP deficient population on the nocturnal BP profile, i.e., in obese hypertensives with nondipping nocturnal BP. The investigators will also examine the impact of NP augmenting-RAAS inhibiting therapy on the NP levels and the physiological diurnal rhythms.

This study will assess the physiological implications of chronopharmacology of anti-hypertensive therapy and assess a potentially novel approach of using the inherent biological rhythms to reduce the normal BP rhythmicity in a high-risk population

Inclusion Criteria:

• Age more than or equal to 18 years of age
• Body Mass Index between 30 to 45 kg/m^2
• Blood pressure: Systolic BP more than or equal to 130mmHg and less than or equal to 160mmHg and diastolic blood pressure more than or equal to 80mmHg and less than or equal to 100mmHg. Individuals with hypertension as per the 2017 ACC/AHA Guidelines will be eligible for enrollment

Exclusion Criteria:

• Age less than 18, at screening.
• Systolic BP <130 or >160mmHg at baseline, or diastolic BP <80 or >100 mmHg at baseline
• BMI <30 kg/m^2 or >45 kg/m^2
• History of pulmonary hypertension
• Have any past or present illness of cardiovascular disease including myocardial infarction, angina, cardiac arrhythmia, diabetes, stroke, TIA, or seizure.
• Participants who are taking 3 or more classes of hypertension medications on the maximum dose or with resistant hypertension
• History of angioedema
• Estimated glomerular filtration rate (GFR) < 60 ml/min/1.73 m2 (CKD-EPI equation); urine albumin creatinine ratio ≥30 mg/g
• Hepatic Transaminase (AST and ALT) levels >3x the upper limit of normal;
• Significant psychiatric illness
• Anemia (men, Hct < 38%; women, Hct <36%)
• Participants working night shifts or swing shifts
• Women who are pregnant or breastfeeding or who can become pregnant and not practicing an acceptable method of birth control during the study (including abstinence)