High Resolution Phenotyping in Healthy Humans
Condition: Pressor Response; Baroreflex Sensitivity; Blood Pressure Variability; Heart Rate Variability; Arterial Catecholamines
MeSH terms: Hypersensitivity
Study type: Observational

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.
    

Intervention name(s): Physiological maneuvers
Intervention type(s): Other
Intervention description(s): These healthy subjects undergo physiological testing, which includes aortic augmentation index, pulse wave velocity, orthostatic stress, baroreflex sensitivity (modified Oxford protocol), mental stress, cold pressor test, isometric handgrip, heart rate variability, 24-hour ambulatory blood pressure monitoring.
Observational model: Cohort
Time perspective: Prospective
Sampling method: Non-Probability Sample
Study population: 
        Residents of Southeast Minnesota
      
Biospecimen description: 
      serum, white cells
    
Keywords: Physiology; Phenotype; Genetics; Genomics; Stress; Baroreflex; Blood Pressure; Arterial stiffness