The Diurnal Rhythm in Natriuretic Peptide Levels

• Sponsor: University of Alabama at Birmingham (Other)
• Overall Status: Completed
• CT.gov ID: NCT03834168
• Collaborator: (none)
• Enrollment: 42
• Location: 1
• Arm: 1
• Actual Duration (Months): 24
• Patients Per Site Per Month: 1.8

Study Details

Study Description

Brief Summary

The purpose of the study to assess the diurnal rhythm in natriuretic peptide levels and its temporal relationship with nocturnal blood pressure in obese and African-American individuals as compared with lean and white individuals.

Condition or Disease	Intervention/Treatment	Phase
Natriuretic Peptides; Obesity; Nocturnal Blood Pressure	Other: standardized Study Diet	N/A

Detailed Description

Obese and African-American individuals are at greater risk for cardiovascular morbidity and mortality than lean and white individuals. One of the key reasons for this health disparity is a higher risk of hypertension among obese and African-American individuals. The reasons for why these disparities develop are not well understood.

Natriuretic peptides are hormones produced by the heart and have a wide range of favorable cardiovascular effects such as natriuresis (sodium excretion), vasodilation, and direct inhibition of the renin-angiotensin-aldosterone system. Human studies showed the existence of 24-hour (diurnal) variations in the circulating natriuretic peptide levels.

Prior work from the investigators and others demonstrated that individuals with genetically-determined lower circulating natriuretic peptides levels have higher blood pressure and greater risk of hypertension. Further, the investigators have shown that obesity and African-American race are associated with lower natriuretic peptide levels, suggesting that relatively low natriuretic peptide levels may be a biologic determinant contributing to health disparities.

Obese and African-American individuals have a greater prevalence of nocturnal hypertension [nighttime blood pressure >120/80 mmHg], which is an independent risk factor for cardiovascular events. The underlying reasons for 24-hour variations in blood pressure are unknown.

The investigators hypothesize that loss of the natural 24-hour rhythm of natriuretic peptide levels plays a role in the development of nocturnal hypertension in obese and

African-American individuals. The aims of this study are:

1. to examine whether there is a presence of a 24-hour rhythm in natriuretic peptide levels among normotensive obese and African-American individuals and whether there is a difference in the rhythmicity of natriuretic peptide levels between obese and lean as well as in African-Americans and whites;

2. to examine whether there is an existence of a relationship between 24-hour variability of natriuretic peptide levels and 24-hour patterns of blood pressure and whether this relationship of rhythmicity of natriuretic peptide levels and nocturnal blood pressure differed in obese and lean individuals and by race.

Study Design

• Study Type: Interventional
• Actual Enrollment: 42 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Other
• Official Title: The Diurnal Rhythm in Natriuretic Peptide Levels and Relationship With Nocturnal Blood Pressure
• Actual Study Start Date: Apr 1, 2019
• Actual Primary Completion Date: Mar 31, 2021
• Actual Study Completion Date: Mar 31, 2021

Arms and Interventions

Arm

Intervention/Treatment

Other: Study Individuals Healthy self-identified African-American and white male participants will be screened. Study consent will be obtained, medical history and physical examination administered, and study eligibility determined based on the inclusion and exclusion criteria. Eligible subjects will meet a bio-nutritionist who will explain the 5 days of standardized diet at the screening visit and will review instructions for complying with the diet. If the subject agrees to adhere to the study diet, they will then be enrolled in the study (stratified by race).

Other: standardized Study Diet; Standardized diet consisted with eucaloric meals with 4.5 gm of sodium per day for 5 days.

Outcome Measures

Primary Outcome Measures

1. Plasma MRproANP [About 24 hours on the in-patient study visit day after consuming study meals for 5 days]

   Assess the diurnal rhythm in circulating MRproANP levels among obese individuals and compared it with lean individuals

Secondary Outcome Measures

1. Acrophase Difference in Hours Between the MR-proANP and Systolic BP Rhythm [About 24 hours on the in-patient study visit day after consuming study meals for 5 days]

   Assess relationship between 24-hour variability of MRproANP levels and 24-hour patterns of blood pressure and whether this relationship of rhythmicity of MRproANP levels and nocturnal blood pressure differed in obese and lean individuals and by race

Other Outcome Measures

1. Plasma MRproANP [About 24 hours on the in-patient study visit day after consuming study meals for 5 days]

   Assess the diurnal rhythm in circulating MRproANP levels among African-American individuals and compared it with white individuals

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 40 Years
• Sexes Eligible for Study: Male
• Accepts Healthy Volunteers: Yes

Inclusion Criteria:

• Age 18 to 40 years

• Blood pressure less than 140/90

• Body Mass Index between 18.5 to 25 kg/m2 (lean) or 30 to 45 kg/m2 (obese)

• Self identified African-American or white individuals

• Willingness to comply with the study diet

• Provide informed consent

Exclusion Criteria:

• History of hypertension

• History of cardiovascular, renal, or liver disease

• Diabetes or use of glucose-lowering medications

• Use of vasoactive or diuretic medications

• Atrial fibrillation

• Anemia (Hematocrit <41%)

• Abnormal serum sodium or potassium

• Abnormal liver function tests (>3x upper limit of normal)

• Current smokers

• Regular users of non-steroid anti-inflammatory medications

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	University of Alabama at Birmingham	Birmingham	Alabama	United States	35294

Sponsors and Collaborators

• University of Alabama at Birmingham

Investigators

• Principal Investigator: Pankaj Arora, MD, University of Alabama at Birmingham
• Principal Investigator: Orlando M Gutierrez, MMSc, University of Alabama at Birmingham

Study Documents (Full-Text)

• Study Protocol and Statistical Analysis Plan - Jan 20, 2021
• Informed Consent Form - Jan 20, 2021

More Information

Publications

• 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.
• 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.
• Goetze JP, Jørgensen HL, Sennels HP, Fahrenkrug J. Diurnal plasma concentrations of natriuretic propeptides in healthy young males. Clin Chem. 2012 Apr;58(4):789-92. doi: 10.1373/clinchem.2011.178921. Epub 2012 Jan 26.

• Responsible Party: Pankaj Arora, MD, Assistant Professor, University of Alabama at Birmingham
• ClinicalTrials.gov Identifier: NCT03834168
• Other Study ID Numbers: IRB-300002114
• First Posted: Feb 7, 2019
• Last Update Posted: Aug 31, 2021
• Last Verified: Aug 1, 2021

• Individual Participant Data (IPD) Sharing Statement: No
• Plan to Share IPD: No
• Studies a U.S. FDA-regulated Drug Product: No
• Studies a U.S. FDA-regulated Device Product: No
• Keywords provided by Pankaj Arora, MD, Assistant Professor, University of Alabama at Birmingham: Diurnal Rhythm; Race

Study Results

Participant Flow

Pre-assignment Detail	A total of 42 participants agreed to participate in the study following the completion of the informed consent process and were assigned to each Arm/group. We had one study dropout and one participant was not able to complete the protocol. A total of 40 participants completed the study.

Arm/Group Title	Lean	Obese
Arm/Group Description	Healthy self-identified African-American and white male lean participants will be screened. Study consent will be obtained, medical history and physical examination administered, and study eligibility determined based on the inclusion and exclusion criteria. Eligible subjects will meet a bio-nutritionist who will explain the 5 days of standardized diet at the screening visit and will review instructions for complying with the diet. If the subject agrees to adhere to the study diet, they will then be enrolled in the study (stratified by race). standardized Study Diet: Standardized diet consisted with eucaloric meals with 4.5 gm of sodium per day for 5 days.	Healthy self-identified African-American and white male obese participants will be screened. Study consent will be obtained, medical history and physical examination administered, and study eligibility determined based on the inclusion and exclusion criteria. Eligible subjects will meet a bio-nutritionist who will explain the 5 days of standardized diet at the screening visit and will review instructions for complying with the diet. If the subject agrees to adhere to the study diet, they will then be enrolled in the study (stratified by race). standardized Study Diet: Standardized diet consisted with eucaloric meals with 4.5 gm of sodium per day for 5 days.
Period Title: Overall Study
STARTED	19	23
Total Participant Screened for the Purpose of Eligibility	22	30
Ineligible Participants	3	7
Unable to Complete the Protocol	0	1
Study Dropouts	1	0
Participants Received 5 Days of Standardized Meals	19	23
Participants Returned for the 24-h Inpatient Protocol	18	23
COMPLETED	18	22
NOT COMPLETED	1	1

Baseline Characteristics

Arm/Group Title	Lean	Obese	Total
Arm/Group Description	Healthy self-identified African-American and white lean participants will be screened. Study consent will be obtained, medical history and physical examination administered, and study eligibility determined based on the inclusion and exclusion criteria. Eligible subjects will meet a bio-nutritionist who will explain the 5 days of standardized diet at the screening visit and will review instructions for complying with the diet. If the subject agrees to adhere to the study diet, they will then be enrolled in the study (stratified by race). standardized Study Diet: Standardized diet consisted with eucaloric meals with 4.5 gm of sodium per day for 5 days.	Healthy self-identified African-American and white obese participants will be screened. Study consent will be obtained, medical history and physical examination administered, and study eligibility determined based on the inclusion and exclusion criteria. Eligible subjects will meet a bio-nutritionist who will explain the 5 days of standardized diet at the screening visit and will review instructions for complying with the diet. If the subject agrees to adhere to the study diet, they will then be enrolled in the study (stratified by race). standardized Study Diet: Standardized diet consisted with eucaloric meals with 4.5 gm of sodium per day for 5 days.	Total of all reporting groups
Overall Participants	18	22	40
Age (years) [Median (Inter-Quartile Range) ]
Median (Inter-Quartile Range) [years]	30.5	33.0	31.0
Sex: Female, Male (Count of Participants)
Female	8 44.4%	12 54.5%	20 50%
Male	10 55.6%	10 45.5%	20 50%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%	0 0%	0 0%
Asian	0 0%	0 0%	0 0%
Native Hawaiian or Other Pacific Islander	0 0%	0 0%	0 0%
Black or African American	10 55.6%	16 72.7%	26 65%
White	0 0%	0 0%	0 0%
More than one race	8 44.4%	6 27.3%	14 35%
Unknown or Not Reported	0 0%	0 0%	0 0%
Body Mass Index (kg/m^2) [Median (Inter-Quartile Range) ]
Median (Inter-Quartile Range) [kg/m^2]	24.3	32.2	29.6
Hip circumference (cm) [Median (Inter-Quartile Range) ]
Median (Inter-Quartile Range) [cm]	97.3	111.4	106.1
Waist circumference (cm) [Median (Inter-Quartile Range) ]
Median (Inter-Quartile Range) [cm]	76.9	103.6	97.6
Systolic Blood Pressure (mmHg) [Median (Inter-Quartile Range) ]
Median (Inter-Quartile Range) [mmHg]	110.7	116.5	116.2
Diastolic Blood Pressure (mmHg) [Median (Inter-Quartile Range) ]
Median (Inter-Quartile Range) [mmHg]	69.5	73.7	71.0
Heart rate (beats/min) [Median (Inter-Quartile Range) ]
Median (Inter-Quartile Range) [beats/min]	76.5	77.0	77.0
Fasting Glucose (mg/dL) [Median (Inter-Quartile Range) ]
Median (Inter-Quartile Range) [mg/dL]	85.0	91.5	87.5
Renal Function (mg/dL) [Median (Inter-Quartile Range) ]
Blood Urea Nitrogen (BUN)	12.0	12.0	12
Serum Creatinine	0.9	0.9	0.9
Serum Electrolytes (mEq/L) [Median (Inter-Quartile Range) ]
Sodium, mEq/L	137.5	138.0	138.0
Potassium, mEq/L	4.2	4.2	4.2
Chloride, mEq/L	102.5	103.5	103.0
Bicarbonate, mEq/L	26.0	26.0	26.0
Serum Calcium (mg/dL) [Median (Inter-Quartile Range) ]
Median (Inter-Quartile Range) [mg/dL]	9.6	9.6	9.6
Liver Function (mg/dL) [Median (Inter-Quartile Range) ]
Total bilirubin	0.5	0.5	0.5
Alanine transaminase (ALT)	13.5	17.0	14.0
Aspartate transaminase (AST)	17.0	17.0	17.0
Gamma-glutamyl transferase (GGT)	16.0	22.5	20.0
Hematological Parameters (cells*10,000/mm^3) [Median (Inter-Quartile Range) ]
WBC, * 10,000/mm3	5.3	5.5	5.4
RBC, * 1,000,000/mm3	4.7	4.7	4.7
Platelet, * 100,000/mm3	217.7	248.7	243.4
Hemoglobin (g/dL) [Median (Inter-Quartile Range) ]
Median (Inter-Quartile Range) [g/dL]	14.0	14.2	14.2
Hematocrit (%) [Median (Inter-Quartile Range) ]
Median (Inter-Quartile Range) [%]	40.5	41.0	41.0
Mean Corpuscular Volume (MCV) (fl) [Median (Inter-Quartile Range) ]
Median (Inter-Quartile Range) [fl]	87.5	89.0	88.0
Mean Corpuscular Hemoglobin (MCH) (pg) [Median (Inter-Quartile Range) ]
Median (Inter-Quartile Range) [pg]	30.0	31.0	30.0
Mean Corpuscular Hemoglobin Concentration (MCHC) (g/dL) [Median (Inter-Quartile Range) ]
Median (Inter-Quartile Range) [g/dL]	34.0	34.0	34.0
Red Cell Distribution Width (RDW) (%) [Median (Inter-Quartile Range) ]
Median (Inter-Quartile Range) [%]	13.5	13.3	13.5
Mean Platelet Volume (MPV) (fL) [Median (Inter-Quartile Range) ]
Median (Inter-Quartile Range) [fL]	9.0	8.0	9.0

Outcome Measures

1. Primary Outcome

Title	Plasma MRproANP
Description	Assess the diurnal rhythm in circulating MRproANP levels among obese individuals and compared it with lean individuals
Time Frame	About 24 hours on the in-patient study visit day after consuming study meals for 5 days

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Lean	Obese
Arm/Group Description	Healthy self-identified African-American and white lean participants will be screened. Study consent will be obtained, medical history and physical examination administered, and study eligibility determined based on the inclusion and exclusion criteria. Eligible subjects will meet a bio-nutritionist who will explain the 5 days of standardized diet at the screening visit and will review instructions for complying with the diet. If the subject agrees to adhere to the study diet, they will then be enrolled in the study (stratified by race). standardized Study Diet: Standardized diet consisted with eucaloric meals with 4.5 gm of sodium per day for 5 days.	Healthy self-identified African-American and white obese participants will be screened. Study consent will be obtained, medical history and physical examination administered, and study eligibility determined based on the inclusion and exclusion criteria. Eligible subjects will meet a bio-nutritionist who will explain the 5 days of standardized diet at the screening visit and will review instructions for complying with the diet. If the subject agrees to adhere to the study diet, they will then be enrolled in the study (stratified by race). standardized Study Diet: Standardized diet consisted with eucaloric meals with 4.5 gm of sodium per day for 5 days.
Measure Participants	18	22
Median (Inter-Quartile Range) [pmol/l]	17.92	15.51

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Lean
	Comments
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.003
	Comments
	Method	Regression (Cosinor Fit)
	Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Lean, Obese
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments
	Method	Regression, Linear
	Comments

2. Secondary Outcome

Title	Acrophase Difference in Hours Between the MR-proANP and Systolic BP Rhythm
Description	Assess relationship between 24-hour variability of MRproANP levels and 24-hour patterns of blood pressure and whether this relationship of rhythmicity of MRproANP levels and nocturnal blood pressure differed in obese and lean individuals and by race
Time Frame	About 24 hours on the in-patient study visit day after consuming study meals for 5 days

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Lean	Obese
Arm/Group Description	Healthy self-identified African-American and white lean participants will be screened. Study consent will be obtained, medical history and physical examination administered, and study eligibility determined based on the inclusion and exclusion criteria. Eligible subjects will meet a bio-nutritionist who will explain the 5 days of standardized diet at the screening visit and will review instructions for complying with the diet. If the subject agrees to adhere to the study diet, they will then be enrolled in the study (stratified by race). standardized Study Diet: Standardized diet consisted with eucaloric meals with 4.5 gm of sodium per day for 5 days.	Healthy self-identified African-American and white obese participants will be screened. Study consent will be obtained, medical history and physical examination administered, and study eligibility determined based on the inclusion and exclusion criteria. Eligible subjects will meet a bio-nutritionist who will explain the 5 days of standardized diet at the screening visit and will review instructions for complying with the diet. If the subject agrees to adhere to the study diet, they will then be enrolled in the study (stratified by race). standardized Study Diet: Standardized diet consisted with eucaloric meals with 4.5 gm of sodium per day for 5 days.
Measure Participants	18	22
Mean (Standard Error) [Hours]	-0.7 (0.03)	-4.9 (0.05)

3. Other Pre-specified Outcome

Title	Plasma MRproANP
Description	Assess the diurnal rhythm in circulating MRproANP levels among African-American individuals and compared it with white individuals
Time Frame	About 24 hours on the in-patient study visit day after consuming study meals for 5 days

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

Adverse Events

Time Frame	1 month
Arm/Group Title	Lean		Obese
Arm/Group Description	Healthy self-identified African-American and white lean participants will be screened. Study consent will be obtained, medical history and physical examination administered, and study eligibility determined based on the inclusion and exclusion criteria. Eligible subjects will meet a bio-nutritionist who will explain the 5 days of standardized diet at the screening visit and will review instructions for complying with the diet. If the subject agrees to adhere to the study diet, they will then be enrolled in the study (stratified by race). standardized Study Diet: Standardized diet consisted with eucaloric meals with 4.5 gm of sodium per day for 5 days.		Healthy self-identified African-American and white obese participants will be screened. Study consent will be obtained, medical history and physical examination administered, and study eligibility determined based on the inclusion and exclusion criteria. Eligible subjects will meet a bio-nutritionist who will explain the 5 days of standardized diet at the screening visit and will review instructions for complying with the diet. If the subject agrees to adhere to the study diet, they will then be enrolled in the study (stratified by race). standardized Study Diet: Standardized diet consisted with eucaloric meals with 4.5 gm of sodium per day for 5 days.
All Cause Mortality
	Lean		Obese
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/18 (0%)		0/22 (0%)
Serious Adverse Events
	Lean		Obese
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/18 (0%)		0/22 (0%)
Other (Not Including Serious) Adverse Events
	Lean		Obese
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/18 (0%)		0/22 (0%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

All Principal Investigators ARE employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.