The Influence of Mitochondrial-Derived Reactive Oxygen Species on Racial Disparities in Neurovascular Function

Auburn University60 enrolled

Overview

Black individuals are at increased cardiovascular disease risk. The central goal of the study is to determine if mitochondrial reactive oxygen species influence blood vessel function and nervous system regulation of blood pressure differentially in black, compared to white individuals. These findings may help to explain a potential mechanism that contributes to racial disparities in blood pressure and cardiovascular disease risk. A secondary goal is to determine if mitochondrial reactive oxygen species improves blood pressure and vascular function in individuals with elevated blood pressure and stage 1 hypertension.

The prevalence of hypertension in black adults is higher than in any other race/ethnicity in the US, and among the highest in the world. Hypertension is a risk factor for several major cardiovascular diseases. Racial disparities in blood vessel function are well documented. Moreover, racial disparities in hypertension persist despite advances in pharmacotherapies. Therefore, a major knowledge gap remains in identifying the mechanism(s) underlying racial disparities in hypertension, and ultimately cardiovascular diseases. Our goal is to investigate reasons for the higher prevalence of blood vessel dysfunction and hypertension in black individuals, and to identify effective preventive strategies. Excess free radicals contribute to blood vessel dysfunction, kidney dysfunction, and thus hypertension as both blood vessel health and the kidneys contribute to blood pressure regulation. Moreover, excess free radicals contribute to blood vessel dysfunction in black adults. Mitochondria are a major source of free radicals. Mitochondria antioxidants improve blood vessel function in rodents and in human trials. A prior aging study demonstrated that acute MitoQ (single 160mg-dose mitoquinone) restored blood vessel function in older adults. Anohter recent study demonstrated that a single 80mg dose elicited similar improvements in adults with peripheral artery disease. however, the role of mitochondrial free radicals in racial disparites in blood vessel function is unclear. Our central hypothesis is that mitochondrial free radicals play a role in reduced blood vessel function and kidney in black adults. We will test our hypothesis using a randomized, placebo-controlled, crossover design, acute MitoQ supplement study in black and white adults (we will not exclude other races though). We will also measure blood pressure and urine biomarkers that are indicative of kidney injury in this proposal. Regarding methodology, we will perform blood draws, vascular testing, and record nervous system activity before and one hour after acute MitoQ and placebo consumption. We will also measure urine biomarkers of kidney function and blood pressure in the hours following acute MitoQ and placebo consumption in adults (19-75 years old).

Eligibility

Sex: ALLMin age: 19 YearsMax age: 75 YearsHealthy volunteers:

Medical Language ↔ Plain English

Inclusion Criteria: * Are between the ages of 19-75. * Have blood pressure no higher than 150/90 mmHg. * Have a BMI below 35 Kg/m2 (otherwise healthy) * Free from metabolic disease (diabetes or renal disease), pulmonary disorders (e.g., COPD \& cystic fibrosis), and cardiovascular disease (peripheral vascular, cardiac, or cerebrovascular). * Do not have any precluding medical issues that prevent participants from exercising (i.e., cardiovascular issues, or muscle/joint issues including painful arthritis) or giving blood (e.g., blood thinners). * Are not currently smoking, using smokeless tobacco, nor smoked within the past 12 months. Exclusion Criteria: * Known allergy to MitoQ * High blood pressure - greater the 150/90 mmHg * Low blood pressure - less than 90/50 mmHg * History of cardiovascular disease * History of cancer * History of diabetes * History of kidney disease * Obesity (BMI \> 30 kg/m2) * Smoking or tobacco use * Current pregnancy * Nursing mothers * Communication barriers

Outcomes

Primary Outcomes

Changes in flow-mediated dilation (FMD)

Flow-mediated vasodilation will be assessed using continuous measures of brachial artery diameter and velocity via duplex Doppler ultrasound (Hitachi Arietta 70). The brachial artery will be imaged in the longitudinal plane proximal to the medial epicondyle using a high-frequency (6-12 MHz) linear-array probe. The ultrasound probe will be stabilized using a custom-built clamp. Shear rate (sec-1) will be calculated as \[(blood flow velocity (cm\*s-1) \*4)/blood vessel diameter (mm)\] The image will be recorded throughout a 60-s baseline, a 300-s ischemic stimulus (250 mmHg), and 180 seconds post deflation. FMD will be expressed as % dilation (final diameter-baseline diameter/baseline diameter x 100) and also normalized to the shear stimulus. Allometric scaling will be used if appropriate, including if there are baseline differences in artery diameter by race or condition.

Time frame: Before and one hour after supplementation or placebo

Changes in indices of arterial stiffness

The investigators will use the SphygmoCor XCEL system to assess pulse wave analysis (PWA) and pulse wave velocity (PWV). A high-fidelity strain-gauge transducer is used to obtain the pressure waveform at the carotid and radial pulse. Distances from the carotid artery sampling site to the femoral artery (upper leg instrumented with a thigh cuff for oscillometric sphygmomanometry), and from the carotid artery to the suprasternal notch will be recorded. The investigators will also assess forward and reflective wave magnitudes. PWV will be expressed as cm/s and PWA will be expressed as % (calculated as augmentation pressure divided by the pulse pressure).

Time frame: Before and one hour after supplementation or placebo

Changes in muscle sympathetic nerve activity (MSNA) and sympathetic transduction

The investigators will directly record MSNA using an active tungsten microelectrode inserted into a nerve near the fibular head or popliteal fossa using standard microneurography techniques. The raw signal will be amplified, band-pass filtered, rectified, and integrated using a nerve traffic analyzer. The presence of MSNA will be confirmed by a pulse-synchronous signal that responds to an end-expiratory breath-hold and stimulation of muscle (tendon tapping), but not skin afferents (gentle skin stroke and/or startle stimulus). MSNA will be expressed as bursts per minute and per 100 cardiac cycles. Further, the investigators will measure common femoral artery blood flow using ultrasound and mean arterial pressure using photoplethysmography. This will allow determination of sympathetic transduction (the vasoconstrictor and pressor effects of MSNA) expressed as changes in blood pressure (mmHg) or changes in vascular conductance (ml blood flow/mmHg).

Time frame: Before and one hour after supplementation or placebo

Changes in blood pressure reactivity

The investigators will measure systolic and diastolic pressure using photoplethysmography at the finger. Systolic and diastolic blood pressure will be assessed at rest and during handgrip exercise. Blood pressure reactivity will be expressed as a change in pressure (mmHg) from baseline to a predetermined time during the stressor (e.g., minute one average and minute two average).

Time frame: Before and one hour after supplementation or placebo

Changes in circulating reactive oxygen species

We will use electron paramagnetic resonance to measure reactive oxygen species (spectra units) in whole blood samples treated with a spin probe.

Time frame: Before and one hour after supplementation or placebo

Changes in blood biomarkers of nitric oxide bioavailability

The investigators will measure nitric oxide metabolites (nitrate and nitrite nanomolar concentration).

Time frame: Before and one hour after supplementation or placebo

Secondary Outcomes

Objective sleep duration and quality

Philips actiwatch spectrum will be used to quantify sleep duration. Participants will wear the watch units for 7 days. We will assess qualitative sleep scores and cross-check actigraphy wear times with a sleep diary.