What is the hypothesis and importance

Cardiovascular disease is the number one cause of mortality and morbidity in the United
States. Among the risk factors for cardiovascular disease is obesity which is increasing
in prevalence and severity in children and adolescents. This can lead to “metabolic
syndrome” which includes high blood pressure, hypercholesterolemia, and insulin
resistance, the fore-runner of diabetes. Obesity increases the risk of damage to the heart
and blood vessels.
We hypothesize that obesity in adolescents is associated with early changes in very
small blood vessels and in the actions of the nervous system. We will test this by using
lasers that measure blood flow in the small vessels of the skin before and after
maneuvers that assess how blood vessels work. These will include the use of tiny tubes
placed within the skin. We will measure the way the nervous system is activated at rest
and with simple forms of stress in obesity by measuring nerve activity in the leg
peripheral nerve.
Results will determine whether abnormal blood vessel and nervous system responses
are present early during obesity. This would imply a need for intervention long before
there are obvious circulation findings.




    What are the symptoms and findings in patients

    We are recruiting overweight young people. Some may have a condition called "metabolic syndrome" in which there is increased cholesterol, high blood pressure and obesity associated with insulin resistance, a condition that can be diagnosed with simple blood tests. Metabolic syndrome places these young folk at much increased risk for cardiovascular disease.



    What is the goal of the study

    Obesity is a major risk for cardiovascular disease and is increasing in prevalence and severity in the
    United States in all age groups, especially children and adolescents. Obesity causes the Metabolic
    Syndrome which is driven by microvascular inflammation, oxidative stress, activation of the angiotensin-II (ANG-II), reduced bioavailable nitric oxide (NO) and sympathetic activation. Studying obesity in the young provides a natural window into the mechanisms involved in the early stages of these diseases. Evidence suggests that the cardiovascular deficits associated with obesity first appear in the microcirculation and later as macrocirculatory phenomena along with signs of overt disease such as hypertension and atherogenesis. We hypothesize that obesity in adolescents is associated with early microvascular evidence of abnormalities in endothelial NO (eNO), neuronal NO (nNO) and Ang-II that can precede the onset of increased central sympathetic outflow, systemic hypertension and the metabolic syndrome.
    To test the hypothesis we will identify and recruit 60 obese teenagers aged 14-21 years of both genders with a body mass index greater than 95%tile for their age and sex and 20 healthy, lean age and sex matched volunteers from an adolescent medicine practice that services Westchester, NY. We will recruit 20 obese subjects with metabolic syndrome and 20 obese subjects without metabolic syndrome. We will evaluate for comorbid or confounding medical conditions. Groups will be screened for diabetes, hyperinsulinemia, dyslipidemia, fatty liver and blood pressure.
    1. We will test the hypothesis that microvascular eNO and nNO bioavailability, and Ang-II/NO
    interactions are impaired in all obese children but not in control subjects. We will use laser Doppler
    Flowmetry (LDF) and acetylcholine dose-response obtained by intradermal microdialysis as a
    bioassay of eNO, LDF and local heating to 42oC as a bioassay of nNO, and repeat these bioassays during perfusion of losartan.
    2. We will test the hypothesis that hypertension and sympathetic outflow are increased in metabolic
    syndrome and are related to nNO and angiotensin activity by performing peroneal microneurography
    (muscle sympathetic nerve activity or MSNA) and measurements of spontaneous beat-to-beat BP
    and RR interval during Aim 1. We will therefore directly measure sympathetic outflow, relate it to local circulatory responses and regional peripheral resistance and obtain estimates of cardiovagal and sympathetic baroreflex.
    3. We will test the hypothesis that the response to classic sympathetic stressors, incremental tilt testing, exercise pressor reflex (static handgrip), and cold pressor test are impaired in all obese children but not in control subjects.

    Significance: Results will determine whether abnormal NO and Ang-II dependent microcirculatory
    responses, and abnormal sympathetic stress responses are present early in the course of obesity
    indicating a need for intervention long before the more pernicious effects of metabolic syndrome



    What can your own doctor do

    We will ask for the active participation of your doctor who can rule out other illnesses that may complicate obesity. We will ask your permission and for you doctor's permission to see an adolescent medical doctor, Dr Kelly Bethea, who is participating in this study. In particular, Dr. Bethea will  perform physical examinations and tests for metabolic syndrome which are essential to the study.

    Many of the tests we will be performing are not ordinarily available to your doctor. They are, however, all approved ways of measuring how blood vessels and nerves work. The tests performed during the study may help us determine whether any specific treatment is useful for you. We will provide you and your doctor with test results and treatment information.



    How do I know if I’m eligible to be in this study? 

    Inclusion:All obese young people of aged 14-21 are potentially eligible.

    Exclusion:  Criteria for initial exclusion will include a condition known to be associated with endothelial dysfunction or sympathetic nervous system abnormalities. Additional exclusion will be for any active medical condition , a previous medical condition with undocumented resolution, past or present systemic disorder. Only those free from heart disease, and from systemic illness will be eligible to participate. This excludes patients with illnesses and disease states known to be associated with endothelial cell dysfunction such as diabetes, renal disease, congestive heart failure, systemic hypertension, acute and chronic inflammatory diseases, neoplasm, immune mediated disease, trauma, and peripheral vascular disease. At the time of testing all patients and control subjects must refrain from vasoactive drugs for two weeks. Please check with us about any medication that you are taking.



    Who pays for the exams, or testing?

    There is no charge to you for any of the the testing  directly related to this study. We will pay each participant who completes the study $125 as a token of appreciation for their time.



    How can I get a questionnaire for this study? 

    You can click on the Questionnaire icon, and download and print out the application and mail it to us. The mailing address is on the last page of the form. Alternatively you can email the application to or or you can also fax us the application at 914-593-8890. Or, you can call us at 914-593-8888, leave your name and address on the voicemail and we’ll mail you an application. 


    What happens if I’m eligible to be in the study and decide to participate? 

    If you would like to take part in these studies, the study coordinator will contact you to go over questionnaire material and discuss arranging for the physical examination and testing with Dr. Bethea. We will also arrange for lab testing on a single day. The study coordinator will review the consent form with you and we will also review the consent and any questions you may have when you arrive for the study. You and your parents (if applicable) should understand the study, and its risks and benefits. You can click on the icon for Consent Form to read about our study. 

    A clinical appointment with Dr. Bethea will be arranged. Testing lasts one day usually on a Monday, Tuesday, or Friday. We will make appointments to come to our center for your visits. You’ll arrive at 9 AM on the day of your appointment. We ask that you not eat or drink anything after 6 AM that morning. Please wear comfortable clothing and bring along a pair of shorts and a short sleeve shirt. 

    We will meet you at the Bradhurst Building and take you to the laboratory area. Here then you will meet Dr. Indu Taneja and Dr. Julian Stewart who, along with the coordinator or a technician, will review the study with you, and answer any questions you may have. After obtaining your or your parents informed consent and informed assent if appropriate,  you’ll answer a few questions, , and be taken to the laboratory area.

    You will undergo tests of how the nerves and blood vessels function.  We will measure blood flow properties of the leg and arm vein using noninvasive techniques while lying flat. We will examine   local regulation of nitric oxide and angiotensin using a technique called microdialysis and we will examine sympathetic nerve function using microneurography.

    In the first set of experiments we use Laser-Doppler flowmetry (LDF) to measure skin blood flow while lying flat. This uses a small beam of reflected light which you cannot feel. LDF will be combined with microdialysis in which we put tiny tubes called microdialysis probes within the skin of the leg using a small needle. There will be four probes placed. This will enable us to measure how much NO and related biochemicals are being locally produced and will allow us to administer small amounts of chemicals into the skin, testing the ability of the blood vessels to react normally.  The method only affects the tiny area of skin tested and has no effect on overall circulation. Thus, we can test how blood vessels work without disturbing the natural workings of the heart and circulation. We will stimulate local blood flow in two ways: One uses gentle local heating over a small area of skin. The other uses a blood pressure cuff that is inflated for 4 minutes on your leg to a pressure above your highest blood pressure. This causes blood vessels to widen and stimulates the production of NO. On the second day of testing we will also examine blood flow in response to acetylcholine in combination with other medications. We believe that this study will help to determine the specific biochemical causes of POTS and will point towards improved medical therapy for young patients.

    We will also examine the specific regulation of sympathetic outflow from the central nervous system and how it relates to nitric oxide and angiotensin-II. Sympathetic nerve activity is measured in a leg nerve using a tiny electrode.

     We expect that the lab visit will take about 6-7 hours.

    If you have further questions about the study, please feel free to call:
    914-593-8888 for more information. 
    or Email at