Healthy, Pre Hypertension
Conditions
Keywords
Racial differences
Brief summary
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.
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.
Interventions
Each participant's maximal oxygen capacity will be determined using a modified Bruce treadmill protocol.
DIETARY_SUPPLEMENTStandardized meals
Participants will consume the standardized study diet for 3 days provided by the clinical research unit's metabolic kitchen (at UAB).
OTHERExercise challenge
Each participant will walk at 70 % of his/her VO2max for 20 minutes on treadmill.
Each participant will receive metoprolol succinate starting at 50mg/day, titrated bi-weekly up to 200 mg/day for total duration of 6 weeks.
Sponsors
National Heart, Lung, and Blood Institute (NHLBI)
University of Alabama at Birmingham
Study design
Allocation
NON_RANDOMIZED
Intervention model
PARALLEL
Primary purpose
OTHER
Masking
SINGLE (Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to 40 Years
Healthy volunteers
Yes
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change in Plasma BNP After 6-weeks of Beta-Blocker | 6 weeks | Mean percentage change in plasma BNP concentrations in response to 6 weeks of Beta-Blocker between Black participants and White participants |
| Change in Plasma NT-proBNP After 6-weeks of Beta-Blocker | 6 weeks | Mean percentage change in plasma NT-proBNP concentrations in response to 6 weeks of Beta-Blocker between Black participants and White participants |
| Change in Plasma MR-proANP After 6-weeks of Beta-Blocker | 6 weeks | Mean percentage change in plasma MR-proANP concentrations in response to 6 weeks of Beta-Blocker between Black participants and White participants |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change in Plasma BNP After Standardized Exercise Challenge | Mean percentage change in plasma BNP concentrations from baseline to 20 minutes post-exercise (immediately after exercise) | Mean percentage change in plasma BNP concentrations in response to exercise |
| Change in Plasma NT-proBNP After Standardized Exercise Challenge | Mean percentage change in plasma NT-proBNP concentrations from baseline to 20 minutes post-exercise (immediately after exercise) | Mean percentage change in plasma NT-proBNP concentrations in response to exercise |
| Change in Plasma MR-proANP After Standardized Exercise Challenge | Mean percentage change in plasma MR-proANP concentrations from baseline to 20 minutes post-exercise (immediately after exercise) | Mean percentage change in plasma MR-proANP concentrations in response to exercise |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Black Participants 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.
Exercise capacity VO2 max determination: Each participant's maximal oxygen capacity will be determined using a modified Bruce treadmill protocol.
Standardized meals: Participants will consume the standardized study diet for 3 days provided by the clinical research unit's metabolic kitchen (at UAB).
Exercise challenge: Each participant will walk at 70 % of his/her VO2max for 20 minutes on treadmill.
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. | 40 |
| White Participants 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.
Exercise capacity VO2 max determination: Each participant's maximal oxygen capacity will be determined using a modified Bruce treadmill protocol.
Standardized meals: Participants will consume the standardized study diet for 3 days provided by the clinical research unit's metabolic kitchen (at UAB).
Exercise challenge: Each participant will walk at 70 % of his/her VO2max for 20 minutes on treadmill.
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. | 40 |
| Total | 80 |
Baseline characteristics
| Characteristic | White Participants | Black Participants | Total |
|---|---|---|---|
| Age, Continuous | 25 years | 27 years | 26 years |
| Alanine Aminotransferase (ALT) | 14.5 U/L | 14.0 U/L | 14.0 U/L |
| Aspartate Aminotransferase (AST) | 17.0 U/L | 17.0 U/L | 17.0 U/L |
| Body Mass Index (BMI) | 24.1 kg/m² | 25.1 kg/m² | 24.5 kg/m² |
| B-type Natriuretic Peptide (BNP) | 15.0 ng/L | 16.0 ng/L | 15.0 ng/L |
| Creatinine | 0.9 mg/dL | 1.0 mg/dL | 0.9 mg/dL |
| Diastolic Blood Pressure (DBP) | 70 mmHg | 67 mmHg | 69 mmHg |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants | 0 Participants | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 40 Participants | 40 Participants | 80 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Fasting Glucose | 86.5 mg/dL | 83.0 mg/dL | 85.0 mg/dL |
| Heart Rate | 70 beats per minute | 69 beats per minute | 70 beats per minute |
| Hemoglobin | 14.1 g/dL | 13.3 g/dL | 13.5 g/dL |
| Insulin | 5.9 mg/dL | 6.5 mg/dL | 6.2 mg/dL |
| Left Atrial Enlargement | 23.3 Percentage of Participants | 4.8 Percentage of Participants | 15.7 Percentage of Participants |
| Left Ventricular Hypertrophy | 6.7 Percentage of Participants | 0.0 Percentage of Participants | 3.9 Percentage of Participants |
| Midregional pro- Atrial Natriuretic Peptide (MRproANP) | 47 pmol/L | 43 pmol/L | 44 pmol/L |
| N-terminal pro-Btype Natriuretic Peptide (NTproBNP) | 20 ng/L | 17 ng/L | 19 ng/L |
| Sex: Female, Male Female | 19 Participants | 21 Participants | 40 Participants |
| Sex: Female, Male Male | 21 Participants | 19 Participants | 40 Participants |
| Systolic Blood Pressure (SBP) | 108 mmHg | 109 mmHg | 109 mmHg |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 40 | 0 / 40 |
| other Total, other adverse events | 6 / 40 | 7 / 40 |
| serious Total, serious adverse events | 0 / 40 | 0 / 40 |
Outcome results
Primary
Change in Plasma BNP After 6-weeks of Beta-Blocker
Mean percentage change in plasma BNP concentrations in response to 6 weeks of Beta-Blocker between Black participants and White participants
Time frame: 6 weeks
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Black Participants | Change in Plasma BNP After 6-weeks of Beta-Blocker | 45 Percentage Change in Plasma BNP levels |
| White Participants | Change in Plasma BNP After 6-weeks of Beta-Blocker | 74 Percentage Change in Plasma BNP levels |
Primary
Change in Plasma MR-proANP After 6-weeks of Beta-Blocker
Mean percentage change in plasma MR-proANP concentrations in response to 6 weeks of Beta-Blocker between Black participants and White participants
Time frame: 6 weeks
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Black Participants | Change in Plasma MR-proANP After 6-weeks of Beta-Blocker | 18 Percentage Change in Plasma MR-proANP |
| White Participants | Change in Plasma MR-proANP After 6-weeks of Beta-Blocker | 16 Percentage Change in Plasma MR-proANP |
Primary
Change in Plasma NT-proBNP After 6-weeks of Beta-Blocker
Mean percentage change in plasma NT-proBNP concentrations in response to 6 weeks of Beta-Blocker between Black participants and White participants
Time frame: 6 weeks
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Black Participants | Change in Plasma NT-proBNP After 6-weeks of Beta-Blocker | 95 Percentage Change in Plasma NT-proBNP |
| White Participants | Change in Plasma NT-proBNP After 6-weeks of Beta-Blocker | 99 Percentage Change in Plasma NT-proBNP |
Secondary
Change in Plasma BNP After Standardized Exercise Challenge
Mean percentage change in plasma BNP concentrations in response to exercise
Time frame: Mean percentage change in plasma BNP concentrations from baseline to 20 minutes post-exercise (immediately after exercise)
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Black Participants | Change in Plasma BNP After Standardized Exercise Challenge | 59 Percentage change in Plasma BNP |
| White Participants | Change in Plasma BNP After Standardized Exercise Challenge | 61 Percentage change in Plasma BNP |
Secondary
Change in Plasma MR-proANP After Standardized Exercise Challenge
Mean percentage change in plasma MR-proANP concentrations in response to exercise
Time frame: Mean percentage change in plasma MR-proANP concentrations from baseline to 20 minutes post-exercise (immediately after exercise)
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Black Participants | Change in Plasma MR-proANP After Standardized Exercise Challenge | 35 Percentage change in Plasma MR-proANP |
| White Participants | Change in Plasma MR-proANP After Standardized Exercise Challenge | 43 Percentage change in Plasma MR-proANP |
Secondary
Change in Plasma NT-proBNP After Standardized Exercise Challenge
Mean percentage change in plasma NT-proBNP concentrations in response to exercise
Time frame: Mean percentage change in plasma NT-proBNP concentrations from baseline to 20 minutes post-exercise (immediately after exercise)
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Black Participants | Change in Plasma NT-proBNP After Standardized Exercise Challenge | 11 Percentage change in Plasma NT-proBNP |
| White Participants | Change in Plasma NT-proBNP After Standardized Exercise Challenge | 23 Percentage change in Plasma NT-proBNP |