High Resolution Phenotyping in Healthy Humans
| Status: | Completed |
|---|---|
| Conditions: | Cardiology |
| Therapuetic Areas: | Cardiology / Vascular Diseases |
| Healthy: | No |
| Age Range: | 18 - 50 |
| Updated: | 4/21/2016 |
| Start Date: | April 2006 |
| End Date: | February 2013 |
Blood Pressure Variability, Baroreflex Sensitivity, and Cardiovascular Responses to Sympathoexcitation in Healthy Normotensive Humans
Baroreflex sensitivity is integral to blood pressure regulation, and varies among healthy,
normotensive individuals. A reduced compensatory ability of baroreflex buffering in patients
with carotid denervation results in blood pressure variability and an elevated blood
pressure response to mental stress. Furthermore, 24-hour ambulatory blood pressure
variability may also be a significant and independent risk determinant of cardiovascular
disease. It remains unknown whether the degree of baroreflex sensitivity and ambulatory
blood pressure variability are predictive of the pressor response to sympathoexcitatory
stress in healthy humans. In this study the investigators propose a comprehensive evaluation
of the relationships among the pressor and forearm vasodilator response to
sympathoexcitation, ambulatory blood pressure variability, and baroreflex sensitivity in
healthy normotensive subjects. Ultimately this study will provide preliminary data and
protocol development for large-scale high resolution phenotyping in population-based trials
aimed at determining the functional relevance of candidate gene variation in intermediate
physiological traits pertinent to the pathogenesis of hypertension and cardiovascular
disease.
normotensive individuals. A reduced compensatory ability of baroreflex buffering in patients
with carotid denervation results in blood pressure variability and an elevated blood
pressure response to mental stress. Furthermore, 24-hour ambulatory blood pressure
variability may also be a significant and independent risk determinant of cardiovascular
disease. It remains unknown whether the degree of baroreflex sensitivity and ambulatory
blood pressure variability are predictive of the pressor response to sympathoexcitatory
stress in healthy humans. In this study the investigators propose a comprehensive evaluation
of the relationships among the pressor and forearm vasodilator response to
sympathoexcitation, ambulatory blood pressure variability, and baroreflex sensitivity in
healthy normotensive subjects. Ultimately this study will provide preliminary data and
protocol development for large-scale high resolution phenotyping in population-based trials
aimed at determining the functional relevance of candidate gene variation in intermediate
physiological traits pertinent to the pathogenesis of hypertension and cardiovascular
disease.
Growing evidence suggests an association of environmental stress with the development of
hypertension and there is strong evidence in normotensive subjects that a greater pressor
response to sympathoexcitatory stress is a harbinger of future hypertension. Pharmacological
studies have shown that individuals with HTN have a blunted baroreflex sensitivity, and
display a greater increase in blood pressure during administration of an alpha-agonist.
Furthermore, exaggerated 24-hour ambulatory blood pressure variability (BPV) is proposed to
be a risk factor for the development of cardiovascular disease. Finally, Beta-2 adrenergic
receptor-mediated forearm vasodilator responses to mental stress are blunted in Caucasian
subjects at increased risk for hypertension, in African Americans, and in mild hypertension.
We postulate that a relationship exists between these variables, even in normotensive
healthy individuals. We also believe that signs of subclinical metabolic dysfunction exist
in healthy individuals and that they may either contribute to or be affected by BPV. There
is also evidence the prematurity at birth and low birth weight are associated with
hypertension. Finally, arterial stiffness may also be related to blood pressure variability
and the pressor response. Therefore the specific aims of this study are:
1. To examine the relationship between 24-hour ambulatory BPV and baroreflex sensitivity.
By measuring the baroreflex control of heart rate during sequential boluses of
nitroprusside and phenylephrine, we hypothesize that baroreflex sensitivity will be
inversely related to the degree of 24-hour BPV.
2. To examine the relationship between 24-hour ambulatory BPV and the pressor response to
four sympathoexcitatory maneuvers: head-up tilt testing, mental stress, cold pressor
test, and isometric handgrip to fatigue. We hypothesize that greater BPV will predict
the pressor response to stress.
3. To examine the relationship between baroreflex sensitivity and the pressor
response/forearm vasodilator response to the three sympathoexcitatory maneuvers. We
hypothesize that individuals with higher baroreflex sensitivity will have a lower
pressor response and a lower forearm vasodilator response to sympathoexcitatory stress.
4. To draw a venous blood sample for future screening of genetic polymorphisms of
interest, which may include nitric oxide synthase (NOS), alpha-adrenergic and
beta-adrenergic receptor polymorphisms. We hypothesize that genetic variation in these
key regulatory systems might explain some of the differences in baroreflex sensitivity,
BPV, the pressor response and forearm vasodilator response to sympathoexcitation.
5. To examine the relationship between 24-hour ambulatory BPV and the pressor response to
sympathoexcitatory maneuvers and insulin resistance, dyslipidemia, and body fat
distribution. We hypothesize that greater BPV will be associated with insulin
resistance, dyslipidemia, and increase waist-hip ratio.
6. To examine the relationship between 24-hour ambulatory BPV and arterial stiffness using
measurements of pulse wave velocity. We hypothesize that greater BPV will be associated
with increased pulse wave velocity, an index of arterial stiffness.
7. To examine the relationship between 24-hour ambulatory BPV and the pressor response to
sympathoexcitatory maneuvers with birth weight and post-conceptual age at birth. We
will ask each subject to provide this data based on their birth certificate and/or
knowledge of their medical history.
hypertension and there is strong evidence in normotensive subjects that a greater pressor
response to sympathoexcitatory stress is a harbinger of future hypertension. Pharmacological
studies have shown that individuals with HTN have a blunted baroreflex sensitivity, and
display a greater increase in blood pressure during administration of an alpha-agonist.
Furthermore, exaggerated 24-hour ambulatory blood pressure variability (BPV) is proposed to
be a risk factor for the development of cardiovascular disease. Finally, Beta-2 adrenergic
receptor-mediated forearm vasodilator responses to mental stress are blunted in Caucasian
subjects at increased risk for hypertension, in African Americans, and in mild hypertension.
We postulate that a relationship exists between these variables, even in normotensive
healthy individuals. We also believe that signs of subclinical metabolic dysfunction exist
in healthy individuals and that they may either contribute to or be affected by BPV. There
is also evidence the prematurity at birth and low birth weight are associated with
hypertension. Finally, arterial stiffness may also be related to blood pressure variability
and the pressor response. Therefore the specific aims of this study are:
1. To examine the relationship between 24-hour ambulatory BPV and baroreflex sensitivity.
By measuring the baroreflex control of heart rate during sequential boluses of
nitroprusside and phenylephrine, we hypothesize that baroreflex sensitivity will be
inversely related to the degree of 24-hour BPV.
2. To examine the relationship between 24-hour ambulatory BPV and the pressor response to
four sympathoexcitatory maneuvers: head-up tilt testing, mental stress, cold pressor
test, and isometric handgrip to fatigue. We hypothesize that greater BPV will predict
the pressor response to stress.
3. To examine the relationship between baroreflex sensitivity and the pressor
response/forearm vasodilator response to the three sympathoexcitatory maneuvers. We
hypothesize that individuals with higher baroreflex sensitivity will have a lower
pressor response and a lower forearm vasodilator response to sympathoexcitatory stress.
4. To draw a venous blood sample for future screening of genetic polymorphisms of
interest, which may include nitric oxide synthase (NOS), alpha-adrenergic and
beta-adrenergic receptor polymorphisms. We hypothesize that genetic variation in these
key regulatory systems might explain some of the differences in baroreflex sensitivity,
BPV, the pressor response and forearm vasodilator response to sympathoexcitation.
5. To examine the relationship between 24-hour ambulatory BPV and the pressor response to
sympathoexcitatory maneuvers and insulin resistance, dyslipidemia, and body fat
distribution. We hypothesize that greater BPV will be associated with insulin
resistance, dyslipidemia, and increase waist-hip ratio.
6. To examine the relationship between 24-hour ambulatory BPV and arterial stiffness using
measurements of pulse wave velocity. We hypothesize that greater BPV will be associated
with increased pulse wave velocity, an index of arterial stiffness.
7. To examine the relationship between 24-hour ambulatory BPV and the pressor response to
sympathoexcitatory maneuvers with birth weight and post-conceptual age at birth. We
will ask each subject to provide this data based on their birth certificate and/or
knowledge of their medical history.
Inclusion Criteria:
- Men age 18-40
- Non-pregnant women age 18-50
Exclusion Criteria:
- Any medical conditions affecting the cardiovascular system
- Any prescribed chronic medications (except contraceptives)
- Extremes of fitness (not totally sedentary, not highly exercise-trained)
- BMI greater than 28
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