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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.
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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
manifest.
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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.
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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.
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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.
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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 indu_taneja@nymc.edu or stewart@nymc.edu 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.
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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 indu_taneja@nymc.edu
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Microvasular Function in Metabolic Syndrome
