Race, Natriuretic Peptides and Physiological Perturbations

Racial Differences in the Natriuretic Peptide Response to Exercise and Beta-blockers

The purpose of the study is to understand the origins of differential response to beta-blockers in African-Americans and may provide insight regarding racial differences in cardiovascular risk.

Study Overview

• Status: Active, not recruiting
• Conditions: Healthy; Pre Hypertension
• Intervention / Treatment: Other: Exercise capacity VO2 max determination; Dietary supplement: Standardized meals; Other: Exercise challenge; Drug: Metoprolol Succinate ER

Detailed Description

The heart is an endocrine organ. The natriuretic peptides are hormones produced in the heart and are secreted in response to increased wall stress in atria and ventricles. The principal circulating NPs are Atrial Natriuretic Peptide (ANP) and B-type Natriuretic Peptide (BNP). The endocrine actions of NPs are natriuresis and dilatation of peripheral arteries.

The NPs concentrations are elevated in heart failure (HF) and hypertension (HTN) due to volume and pressure overload. Therefore, NPs are used as diagnostic and prognostic markers in heart failure. However, NPs role in healthy individuals is not known.

Previous studies have shown that reduced NP levels are associated with a greater risk of HTN. Moreover, African-Americans have lower resting NP levels than Caucasians. We hypothesize that relative NP deficiency in African American compared to Caucasian has the potential to contribute to increase risk of all-cause mortality, HTN, HF and its sequelae.

Evidence from multiple clinical trials has positioned beta-blockers as a standard heart failure therapy. Beta-blocker therapy leads to increased NP levels and suppression of Renin-aldosterone-angiotensin system (RAAS) system. Suppression of renin levels by beta-blockers has been shown as a potential mechanism of benefit in HF. However, study shows that beta-blockers are less effective in African-Americans compared to Caucasians in HF treatment. So, the investigators have proposed a pilot study to look for race-based differences in the NP and RAAS response to metoprolol in healthy individuals.

Additionally, exercise has been reported to increase NP levels. ANP increases more than BNP with exercise. But there is no data of NP changes in African-American with exercise. So the investigators have proposed a sub-study of race-based difference in ANP and BNP response to exercise.

40 African-American and 40 Caucasians normotensive or pre-hypertensive (healthy) individuals will be enrolled.

• Study Type: Interventional
• Enrollment (Actual): 80
• Phase: Phase 2

Contacts and Locations

• Study Contact: Name: Leigh Powell, MSN, RN; Phone Number: 205-975-9859; Email: lcpowell@uabmc.edu
• Study Contact Backup: Name: Nehal Vekariya, MS; Phone Number: 205-934-7173; Email: nvekariya@uabmc.edu

Study Locations

• United States
  • Alabama
    • Birmingham, Alabama, United States, 35294
      • University of Alabama at Birmingham

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 40 years (Adult)
• Accepts Healthy Volunteers: Yes

Description

Inclusion Criteria:

• 18 to 40 years
• Blood pressure less than 140/90 mm Hg
• Able to perform exercise capacity test
• BMI 18-30 kg/m2
• Willing to adhere to study drug

Exclusion Criteria:

• History of cardiovascular disease or use of medications for CVD
• History of hypertension or use of BP lowering medications
• Blood pressure less than 100/60 mm Hg
• Heart rate less than 60 beats/min
• Depression
• Diabetes or use of anti-diabetic medications
• Renal disease (eGFR < 60ml/min/1.73m2)
• Current or prior smokers
• Pregnant or use of Hormone Replacement Therapy (HRT) or oral contraceptives (OCP) or steroids

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Other
• Allocation: Non-Randomized
• Interventional Model: Parallel Assignment
• Masking: Single

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: African-American; Healthy lean (BMI 18-25 kg/m2) African-American participants will be enrolled and each will undergo a physical exam and screening tests to determine participants' eligibility. Participants will perform exercise capacity VO2 max determination test, followed by 3 days of standardized meals and exercise challenge test. After exercise challenge test, all the participants will receive metoprolol succinate starting at 50mg/day, titrated bi-weekly up to 200 mg/day.	Other: Exercise capacity VO2 max determination; Each participant's maximal oxygen capacity will be determined using a modified Bruce treadmill protocol.; Dietary supplement: Standardized meals; Participants will consume the standardized study diet for 3 days provided by the clinical research unit's metabolic kitchen (at UAB).; Other: Exercise challenge; Each participant will walk at 70 % of his/her VO2max for 20 minutes on treadmill.; Drug: Metoprolol Succinate ER; Each participant will receive metoprolol succinate starting at 50mg/day, titrated bi-weekly up to 200 mg/day for total duration of 6 weeks.
Active Comparator: Caucasians (White); Healthy lean (BMI 18-25 kg/m2) white participants will be enrolled and each will undergo a physical exam and screening tests to determine participants' eligibility. Participants will perform exercise capacity VO2 max determination test, followed by 3 days of standardized meals and exercise challenge test. After exercise challenge test, all the participants will receive metoprolol succinate starting at 50mg/day, titrated bi-weekly up to 200 mg/day.	Other: Exercise capacity VO2 max determination; Each participant's maximal oxygen capacity will be determined using a modified Bruce treadmill protocol.; Dietary supplement: Standardized meals; Participants will consume the standardized study diet for 3 days provided by the clinical research unit's metabolic kitchen (at UAB).; Other: Exercise challenge; Each participant will walk at 70 % of his/her VO2max for 20 minutes on treadmill.; Drug: Metoprolol Succinate ER; Each participant will receive metoprolol succinate starting at 50mg/day, titrated bi-weekly up to 200 mg/day for total duration of 6 weeks.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in plasma NTproBNP after 6-weeks of beta-blocker	Fold change in plasma NTproBNP concentrations in response to 6 weeks of metoprolol between African-Americans and whites	6 weeks
Change in plasma BNP after Exercise	Fold change in plasma BNP concentrations in response to exercise	About 3 hours on the exercise challenge visit day after consuming study meals for 3 days

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in plasma BNP, NTproANP and MRproANP	Fold change in plasma BNP, NTproANP and MRproANP concentrations in response to 6 weeks of metoprolol between African-Americans and whites	6 weeks

Collaborators and Investigators

• Sponsor: University of Alabama at Birmingham
• Collaborators: National Heart, Lung, and Blood Institute (NHLBI)
• Investigators: Principal Investigator: Pankaj Arora, MD, University of Alabama at Birmingham

Publications and helpful links

General Publications

• Davis ME, Richards AM, Nicholls MG, Yandle TG, Frampton CM, Troughton RW. Introduction of metoprolol increases plasma B-type cardiac natriuretic peptides in mild, stable heart failure. Circulation. 2006 Feb 21;113(7):977-85. doi: 10.1161/CIRCULATIONAHA.105.567727. Epub 2006 Feb 13.
• Trowbridge CA, Gower BA, Nagy TR, Hunter GR, Treuth MS, Goran MI. Maximal aerobic capacity in African-American and Caucasian prepubertal children. Am J Physiol. 1997 Oct;273(4):E809-14. doi: 10.1152/ajpendo.1997.273.4.E809.
• Hunter GR, Weinsier RL, McCarthy JP, Enette Larson-Meyer D, Newcomer BR. Hemoglobin, muscle oxidative capacity, and VO2max in African-American and Caucasian women. Med Sci Sports Exerc. 2001 Oct;33(10):1739-43. doi: 10.1097/00005768-200110000-00019.
• Steele IC, McDowell G, Moore A, Campbell NP, Shaw C, Buchanan KD, Nicholls DP. Responses of atrial natriuretic peptide and brain natriuretic peptide to exercise in patients with chronic heart failure and normal control subjects. Eur J Clin Invest. 1997 Apr;27(4):270-6. doi: 10.1046/j.1365-2362.1997.1070653.x.

Study record dates

Study Major Dates

• Study Start (Actual): April 30, 2017
• Primary Completion (Actual): September 30, 2023
• Study Completion (Estimated): June 30, 2024

Study Registration Dates

• First Submitted: February 28, 2017
• First Submitted That Met QC Criteria: February 28, 2017
• First Posted (Actual): March 3, 2017

Study Record Updates

• Last Update Posted (Actual): March 29, 2024
• Last Update Submitted That Met QC Criteria: March 27, 2024
• Last Verified: March 1, 2024

More Information

Terms related to this study

• Keywords: Racial differences
• Additional Relevant MeSH Terms: Cardiovascular Diseases; Vascular Diseases; Prehypertension; Physiological Effects of Drugs; Adrenergic beta-Antagonists; Adrenergic Antagonists; Adrenergic Agents; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action; Anti-Arrhythmia Agents; Antihypertensive Agents; Autonomic Agents; Peripheral Nervous System Agents; Sympatholytics; Adrenergic beta-1 Receptor Antagonists; Metoprolol
• Other Study ID Numbers: IRB-170214001; K23HL146887 (U.S. NIH Grant/Contract)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: UNDECIDED

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No