Race, Natriuretic Peptides and Physiological Perturbations

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.

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.

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.

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.

Each participant's maximal oxygen capacity will be determined using a modified Bruce treadmill protocol.

Participants will consume the standardized study diet for 3 days provided by the clinical research unit's metabolic kitchen (at UAB).

Each participant will receive metoprolol succinate starting at 50mg/day, titrated bi-weekly up to 200 mg/day for total duration of 6 weeks.

Fold change in plasma NTproBNP concentrations in response to 6 weeks of metoprolol between African-Americans and whites

Fold change in plasma BNP, NTproANP and MRproANP concentrations in response to 6 weeks of metoprolol between African-Americans and whites

Inclusion Criteria: 18 to 40 years Blood pressure less than 140/90 mm Hg Able to perform exercise capacity test BMI 18-25 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

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