Clinical trial NCT00943774: High Resolution Phenotyping in Healthy Humans
Official title: Blood Pressure Variability, Baroreflex Sensitivity, and Cardiovascular Responses to Sympathoexcitation in Healthy Normotensive Humans
Study type: OBSERVATIONAL
Overall status: COMPLETED
Conditions: Pressor Response
Baroreflex Sensitivity
Blood Pressure Variability
Heart Rate Variability
Arterial Catecholamines
Keywords: Physiology
Phenotype
Genetics
Genomics
Stress
Baroreflex
Blood Pressure
Arterial stiffness
Lead sponsor: Mayo Clinic
Sponsor class: OTHER
Collaborators: name: National Heart, Lung, and Blood Institute (NHLBI)
First posted: 2009-07-22
Enrollment: 300
Sex: ALL
Minimum age (years): 18
Maximum age (years): 50
Standard ages: ADULT
Accepts healthy volunteers: yes
Observational model: COHORT
Time perspective: PROSPECTIVE
Sampling method: NON_PROBABILITY_SAMPLE
Study population: Residents of Southeast Minnesota

Brief summary: 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.

Detailed description: 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.

Eligibility criteria: 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

Primary outcomes:
measure: Blood Pressure Response to Sympathoexcitation
timeFrame: On day of study
Secondary outcomes:
measure: Baroreflex Sensitivity
timeFrame: On day of study
Other outcomes:
Locations:
city: Rochester
country: United States
facility: Mayo Clinic
state: Minnesota
Study officials:
References:
citation: Ramirez-Marrero FA, Charkoudian N, Hart EC, Schroeder D, Zhong L, Eisenach JH, Joyner MJ. Cardiovascular dynamics in healthy subjects with differing heart rate responses to tilt. J Appl Physiol (1985). 2008 Nov;105(5):1448-53. doi: 10.1152/japplphysiol.90796.2008. Epub 2008 Aug 28.
citation: Ramirez-Marrero FA, Charkoudian N, Zhong L, Hesse C, Eisenach JH. Balance between sympathetic response to head-up tilt and cardiac vagal factors in healthy humans. Clin Auton Res. 2007 Aug;17(4):227-30. doi: 10.1007/s10286-007-0427-y. Epub 2007 Aug 23.
citation: Hesse C, Charkoudian N, Liu Z, Joyner MJ, Eisenach JH. Baroreflex sensitivity inversely correlates with ambulatory blood pressure in healthy normotensive humans. Hypertension. 2007 Jul;50(1):41-6. doi: 10.1161/HYPERTENSIONAHA.107.090308. Epub 2007 May 14.