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

Overview

Obese individuals have a higher prevalence of nocturnal hypertension and non-dipping blood pressure (BP) and are associated with an increased risk of cardiovascular (CV) events and death as compared with lean individuals. The 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 controls the day-night rhythm of BP as well. The NP-BP rhythm relationship is broken down in obese individuals. Lower circulating levels of NPs, elevated renin hormone (a part of the Renin-Angiotensin-Aldosterone System [RAAS]) at nighttime may also contribute to the high nocturnal blood pressure in obese individuals and put 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.

Study Type

  • Study Type: Interventional
  • Study Design
    • Allocation: Randomized
    • Intervention Model: Factorial Assignment
    • Primary Purpose: Other
    • Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
  • Study Primary Completion Date: January 1, 2027

Detailed Description

We 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, we 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. Chronophamacology (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. We hypothesize that nighttime administration of NP augmenting and/or RAAS inhibition therapy in obese hypertensive individuals will help to improve their nocturnal BP rhythm. We 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. We will conduct a 2×2 factorial design trial, wherein individuals will be randomized to either daytime dosing or nighttime dosing of either LCZ696 or valsartan. We 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. We will also assess the effect of NP augmentation in an NP deficient population on the nocturnal BP profile in obese hypertensives with nondipping nocturnal BP. We 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

Interventions

  • Drug: Sacubitril-Valsartan 49 Mg-51 Mg Oral Tablet Morning Dose
    • The subject will be randomized, in a double-blind manner to sacubitril/valsartan 49/51 mg once in the morning and a placebo pill in the evening for a period of 7 days.
  • Drug: Sacubitril-Valsartan 49 Mg-51 Mg Oral Tablet Evening Dose
    • The subject will be randomized, in a double-blind manner to sacubitril/valsartan 49/51 mg once in the evening and a placebo pill in the morning for a period of 7 days.
  • Drug: Valsartan 80 mg Oral Tablet Morning Dose
    • The subject will be randomized, in a double-blind manner to valsartan 80 mg once in the morning and a placebo pill in the evening for a period of 7 days.
  • Drug: Valsartan 80 mg Oral Tablet Evening Dose
    • The subject will be randomized, in a double-blind manner to valsartan 80 mg once in the evening and a placebo pill in the morning for a period of 7 days.
  • Other: Standardized Study Diet
    • The standardized diet consisted with eucaloric meals of 4.5 gm sodium per day for 14 days.

Arms, Groups and Cohorts

  • Experimental: Sacubitril/Valsartan Morning Dose
    • We will enroll 40 adult obese individuals. Each participant will take the assigned dose of medication once in the morning and a placebo pill in the evening for 7 days. We evaluate Natriuretic Peptide-Renin-Angiotensin-Aldosterone System Rhythm Axis and Nocturnal Blood Pressure at baseline and after 7 days of intervention.
  • Experimental: Sacubitril/Valsartan Evening Dose
    • We will enroll 40 adult obese individuals. Each participant will take the assigned dose of medication once in the evening and a placebo pill in the morning for 7 days. We evaluate Natriuretic Peptide-Renin-Angiotensin-Aldosterone System Rhythm Axis and Nocturnal Blood Pressure at baseline and after 7 days of intervention.
  • Active Comparator: Valsartan Morning Dose
    • We will enroll 40 adult obese individuals. Each participant will take the assigned dose of medication once in the morning and a placebo pill in the evening for 7 days. We evaluate Natriuretic Peptide-Renin-Angiotensin-Aldosterone System Rhythm Axis and Nocturnal Blood Pressure at baseline and after 7 days of intervention.
  • Active Comparator: Valsartan Evening Dose
    • We will enroll 40 adult obese individuals. Each participant will take the assigned dose of medication once in the evening and a placebo pill in the morning for 7 days. We evaluate Natriuretic Peptide-Renin-Angiotensin-Aldosterone System Rhythm Axis and Nocturnal Blood Pressure at baseline and after 7 days of intervention.

Clinical Trial Outcome Measures

Primary Measures

  • Change in mean nocturnal systolic blood pressure
    • Time Frame: At Baseline and after 7 days of intervention.
    • The difference in change in mean nocturnal systolic blood pressure will be analyzed in the two study arms (morning vs. evening dose of sacubitril/valsartan or valsartan) from baseline and after 7 days of intervention.

Secondary Measures

  • Change in percent nocturnal dipping blood pressure
    • Time Frame: At Baseline and after 7 days of intervention.
    • Change in percent nocturnal dipping blood pressure will be analyzed in the two study arms (morning vs. evening dose of sacubitril/valsartan or valsartan) from baseline and after 7 days of intervention.
  • Change in 24-hour mean systolic blood pressure
    • Time Frame: At Baseline and after 7 days of intervention.
    • Change in 24-hour mean systolic blood pressure will be analyzed in the two study arms (morning vs. evening dose of sacubitril/valsartan or valsartan) from baseline and after 7 days of intervention.
  • Change in 24-hour mean diastolic blood pressure
    • Time Frame: At Baseline and after 7 days of intervention.
    • Change in 24-hour mean diastolic blood pressure will be analyzed in the two study arms (morning vs. evening dose of sacubitril/valsartan or valsartan) from baseline and after 7 days of intervention.
  • Change in mean daytime systolic blood pressure
    • Time Frame: At Baseline and after 7 days of intervention
    • Change in mean daytime systolic blood pressure will be analyzed in the two study arms (morning vs. evening dose of sacubitril/valsartan or valsartan) from baseline and after 7 days of intervention.
  • Change in mean daytime diastolic blood pressure
    • Time Frame: At Baseline and after 7 days of intervention
    • Change in mean daytime diastolic blood pressure will be analyzed in the two study arms (morning vs. evening dose of sacubitril/valsartan or valsartan) from baseline and after 7 days of intervention.
  • Change in mean nocturnal diastolic blood pressure
    • Time Frame: At Baseline and after 7 days of intervention.
    • Change in mean nocturnal diastolic blood pressure will be analyzed in the two study arms (morning vs. evening dose of sacubitril/valsartan or valsartan) from baseline and after 7 days of intervention.
  • Change in the daytime, nocturnal, and total urinary excretion parameters (Urine Sodium, Urine Potassium, Urine Creatinine, Urine Albumin).
    • Time Frame: At Baseline and after 7 days of intervention
    • Change in the daytime, nocturnal, and total urinary excretion parameters (Urine Sodium, Urine Potassium, Urine Creatinine, Urine Albumin) will be analyzed in the two study arms (morning vs. evening dose of sacubitril/valsartan or valsartan) from baseline and after 7 days of intervention.
  • Change in 24-hour, daytime, and nocturnal natriuretic peptide and renin-angiotensin-aldosterone system hormone levels
    • Time Frame: At Baseline and after 7 days of intervention
    • Change in 24-hour, daytime, and nocturnal natriuretic peptide levels (ANP, MRproANP, BNP, NTproBNP, renin, aldosterone) will be analyzed in the two study arms (morning vs. evening dose of sacubitril/valsartan or valsartan) from baseline and after 7 days of intervention.
  • Change in rhythm parameters (mesor, amplitude, and phase) for ANP, MRproANP, BNP, NTproBNP, renin, aldosterone, systolic BP, diastolic BP, melatonin, and cortisol rhythms.
    • Time Frame: At Baseline and after 7 days of intervention
    • Change in rhythm parameters (mesor, amplitude, and phase) for ANP, MRproANP, BNP, NTproBNP, renin, aldosterone, systolic BP, diastolic BP, melatonin, and cortisol rhythms will be analyzed in the two study arms (morning vs. evening dose of sacubitril/valsartan or valsartan) from baseline and after 7 days of intervention.

Participating in This Clinical Trial

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 140mmHg and less than or equal to 160 mmHg and diastolic blood pressure more than or equal to 80mmHg and less than or equal to 100mmHg. Exclusion Criteria:

  • Age less than 18, at screening. – Systolic BP <140 or >160 mm Hg at baseline, or diastolic BP <80 or >100 mm Hg 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 more than 2 hypertension medications. – History of angioedema; – Estimated 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 (assessed using validated MINI International Neuropsychiatry Interview questionnaires); – Anemia (men, Hct < 38%; women, Hct <36%); – Participants working night shifts or swing shifts. – Have any past or present illness of sleeping disorders including sleep apnea. – 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).

Gender Eligibility: All

Minimum Age: 18 Years

Maximum Age: N/A

Are Healthy Volunteers Accepted: Accepts Healthy Volunteers

Investigator Details

  • Lead Sponsor
    • University of Alabama at Birmingham
  • Provider of Information About this Clinical Study
    • Principal Investigator: Pankaj Arora, MD, Assistant Professor, Division of Cardiovascular Disease, Department of Medicine – University of Alabama at Birmingham
  • Overall Official(s)
    • Pankaj Arora, MD, FAHA, Principal Investigator, University of Alabama at Birmingham
  • Overall Contact(s)
    • Vibhu Parcha, MD, 205-934-7936, vparcha@uabmc.edu

References

Parcha V, Patel N, Gutierrez OM, Li P, Gamble KL, Musunuru K, Margulies KB, Cappola TP, Wang TJ, Arora G, Arora P. Chronobiology of Natriuretic Peptides and Blood Pressure in Lean and Obese Individuals. J Am Coll Cardiol. 2021 May 11;77(18):2291-2303. doi: 10.1016/j.jacc.2021.03.291.

Arora P, Wu C, Hamid T, Arora G, Agha O, Allen K, Tainsh RET, Hu D, Ryan RA, Domian IJ, Buys ES, Bloch DB, Prabhu SD, Bloch KD, Newton-Cheh C, Wang TJ. Acute Metabolic Influences on the Natriuretic Peptide System in Humans. J Am Coll Cardiol. 2016 Feb 23;67(7):804-812. doi: 10.1016/j.jacc.2015.11.049.

Bajaj NS, Gutiérrez OM, Arora G, Judd SE, Patel N, Bennett A, Prabhu SD, Howard G, Howard VJ, Cushman M, Arora P. Racial Differences in Plasma Levels of N-Terminal Pro-B-Type Natriuretic Peptide and Outcomes: The Reasons for Geographic and Racial Differences in Stroke (REGARDS) Study. JAMA Cardiol. 2018 Jan 1;3(1):11-17. doi: 10.1001/jamacardio.2017.4207.

Arora P, Reingold J, Baggish A, Guanaga DP, Wu C, Ghorbani A, Song Y, Chen-Tournaux A, Khan AM, Tainsh LT, Buys ES, Williams JS, Heublein DM, Burnett JC, Semigran MJ, Bloch KD, Scherrer-Crosbie M, Newton-Cheh C, Kaplan LM, Wang TJ. Weight loss, saline loading, and the natriuretic peptide system. J Am Heart Assoc. 2015 Jan 16;4(1):e001265. doi: 10.1161/JAHA.114.001265.

Parcha V, Kalra R, Li P, Oparil S, Arora G, Arora P. Nocturnal blood pressure dipping in treated hypertensives: insights from the SPRINT trial. Eur J Prev Cardiol. 2020 Nov 29. pii: zwaa125. doi: 10.1093/eurjpc/zwaa125. [Epub ahead of print]

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