Local Vasoconstriction and Sympathoexcitation in Postural Tachycardia Syndrome

 

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    Welcome

    Welcome to the Postural Tachycardia Study website. Researchers at the Center for Hypotension at New York Medical College in Valhalla NY have received renewed funding from the National Institutes of Health (NIH) to study whether neurovascular problems that can explain the findings of postural tachycardia syndrome in teenagers and young adults. Our recent data indicate that modulation of the sympathetic nervous system by angiotensin-II and nitric oxide of nNOS origin explain many of the features of POTS including exercise intolerance in important subsets of POTS.

    The Principal Investigator for this study is Julian M. Stewart  MD, PhD, Professor of Pediatrics and of Physiology at  New York Medical College.

    What comprises the study population? 
    What is the hypothesis and importance of the study?
    What are the symptoms and findings in patients?
    What is the goal of the study?
    What your own doctor can do to help diagnose POTS.
    How do I know if I’m eligible to be in this study? 
    Who pays for the exams, testing, and travel? 
    How can I get a questionnaire  for this study? 
    If I decide to participate what does the study entail?
     

     

    What comprises the study population? 

    We are seeking patients aged 15-29 years old with postural tachycardia syndrome (POTS) who may benefit from an investigation of abnormalities of regulation of blood flow. Many people are unable to remain upright for long because of symptoms such as dizziness, nausea and headache or fainting. This may occur on a day-to-day basis and may severely compromise lifestyle. The most common cause of this condition is the postural tachycardia syndrome (POTS), which is believed to affect at least a million Americans. POTS is defined by an abnormal increase in heart rate (“tachycardia”) that occurs when upright (therefore “postural”). POTS has many causes and we are attempting to determine the precise biochemical basis for POTS in patients.

    There are currently two sets of experiments: one focussing on skin to look at local vascular regulation by nitric oxide, angiotensin-II and oxidative stress and the other to look at sympathetic activation in POTS and its relation to NO, angiotensin, and oxidative stress. You will need to be over 15 years old (i.e. 15-29 years old) to enroll in the studies. 

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    What is the hypothesis and importance

    A major subset of POTS has increased peripheral resistance and low blood flow (LFP) related to increased angiotensin-II (Ang-II), and decreased nitric oxide (NO). NO deficits are reversed by Ang-II type-1 receptor (AT1R) blockade, ascorbic acid (AA) and tetrahydrobiopterin in skin suggesting the importance of oxidative stress. Preliminary data also suggest that the coupling of sympathetic nerve activity to blood vessel contraction is enhanced via ↑Ang-II and ↓NO. We hypothesize that this is due to activation of reactive oxygen species (ROS) including superoxide, which scavenges NO to generate peroxynitrite, and hydrogen peroxide. Combined measurements in the skin and the systemic circulation will be combined with local measurement of ROS production and sympathetic nerve activity will enable us to determine precisely how the autonomic nervous system is affected by the illness. Methods include cutaneous microdialysis to measure ROS, skin biopsy and blood tests to measure gene expression of nitric oxide synthase and Ang-II receptors, and peroneal microneurography to measure muscle sympathetic nerve activity (MSNA). Combined with ultrasonic femoral artery blood flow this will  yield assessment of the interactions of nerves with the blood vessels that they control. 

    If we discover specific biochemical mechanisms of POTS in patients, then we may be able to specifically treat the defect.

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    What are the symptoms of POTS

    The key feature of POTS is symptoms which are most prominent when standing. However, in some, findings are present supine (lying down)  but worsened standing. Symptoms of POTS include dizziness in all patients, exercise provoked symptoms and thus exercise intolerance, excessive fatigue, nausea and abdominal pain, headache, shortness of breath and deep breathing, weakness, shakiness and postural anxiety, pallor, and neurocognitive loss (difficulty thinking). These occur on a day-to-day basis. The symptoms overlap with the case definition of chronic fatigue syndrome (CFS) and POTS is often found in CFS in the young. Fainting is relatively uncommon during daily life. 

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    What is the goal of the study

    Our study will determine how often blood flow regulation abnormalities and abnormalities of sympathetic regulation produced by nitric oxide, angiotensin-II, and oxidative stress occur in POTS and the mechanism(s) of POTS in individual patients. Specific causes for POTS may vary from patient to patient. Patients will be compared to healthy control subjects. There is a treatment arm with a medication (losartan) that reduces the binding of angiotensin and increases NO. If we know the specific biochemical mechanism we may be able to offer further specific treatments to specific patients.

    Our Specific Aims are:
    1 In Microvascular Studies - to test whether cutaneous microvascular NO is increased in VVS and NFP and inhibits pre- and post-junctional noradrenergic neurotransmission.
    2 Microvascular Studies - to test whether nitric oxide synthase (NOS) isoforms (eNOS, iNOS and nNOS) gene expression and protein content are increased in OI
    3Macrovascular Studies - to test whether systemic NO is increased in VVS and NLP, inhibits pre and post junctional adrenergic activity, and alters the hemodynamic response to orthostatic stress.

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    What can your own doctor do

    Your doctor can rule out other illnesses such as infectious and inflammatory conditions which can produce similar symptoms. For example, most blood tests can be performed by your own physician. In addition you may have seen a cardiologist, a neurologist, or an endocrinologist. Tests such as tilt table tests may have been performed which is a standard means to diagnose POTS and has been used to assess VVS. Thus, in most cases POTS and VVS will have been diagnosed during a clinical assessment by your own doctors. 
    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 the autonomic nervous system work. If there is NO excess, the tests performed during the study may help us determine a specific treatment. We will provide you and your doctor with all test results.

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

    All postural VVS patients are eligible if they have had 3 or more episodes in the past 12 months. All "normal flow", splanchnic pooling neuropathic POTS patients are eligible. It can be difficult to distinguish those with different causes of POTS prior to entry into a  study. However, our concurrent study entitled "Local Vasoconstriction in Low Flow POTS" can make this distinction in one day of testing. Therefore prior POTS subjects  diagnosed with neuropathic or current subjects will be eligible.

    The diagnosis of VVS or POTS may be made by your doctor or your consulting doctors. The diagnosis of neuropathic POTS may also be made through contact with our center which will include a standard tilt table evaluation. 

    Exclusion:  Criteria for initial exclusion will include a condition known to be associated with endothelial dysfunction, an active medical condition that may explain the diagnosis, a previous medical condition with undocumented resolution that may explain the diagnosis, past or present major psychiatric disorder, or substance abuse within 2 years before onset of symptoms.

    Inclusion: Cases will be between the ages of 15 and 29 years old referred for evaluation of orthostatic intolerance with 3 or more of the following symptoms for at least 3 months: dizziness, nausea and vomiting, palpitations, fatigue, headache, exercise intolerance, blurred vision, abnormal sweating, heat. Cases will have the diagnosis of symptomatic postural tachycardia made during a screening tilt table test. Cases will have normal physical examination, and normal electrocardiographic and echocardiographic evaluations. 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, morbid obesity 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?

    The diagnosis of POTS is a clinical diagnosis that may be made by your doctors or by our center. In either case clinically appropriate fees may be incurred. There is no charge to you for any of the the testing  directly related to this study. We will pay each participant a daily fee to help defray any expenses in participating in the study.

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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 courtney_terilli@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 nurse study coordinator, Courtney Terilli will contact you to go over questionnaire material and discuss arranging for the study. She 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. 

    Testing lasts most of a week and you will also be asked to have a measurement of blood volume. We will make appointments to come to our center for your visits. You’ll arrive at 9:30 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 our nurse coordinator Courtney Terilli, and Drs. Julian Stewart and Marvin Medow who, along with other staff, will review the study with you, and answer any questions you may have. After obtaining your or your parents informed consent you’ll answer a few questions, have a brief physical examination, give a urine sample, and be taken to the laboratory area.

    You will undergo tests of how the blood vessels function.  We will measure blood flow properties of the leg and arm vein using noninvasive techniques while lying flat. You will then have a brief tilt table test for at most 10 minutes so that we can confirm POTS and measure whether there are important fluid shifts when upright. On another day we will measure the impact of gradual tilting on memory. 

    There are currently two active sets of experiments: one to look strictly at local regulation in the skin and the other to look at sympathoactivation in POTS and its relation to NO and angiotensin. We will test whether antioxidant therapy can reduce overall abnormalities in blood flow and sympathetic activation. We will also sample blood for certain biochemicals, for nitric oxide, and for the  expression  of gene activity (not measuring DNA) which may be important in POTS. If you are in the "low flow" group of POTS patients we will request that you enroll in a study of the effects of the angiotensin receptor blocker, losartan, on chronic POTS and ask that you return for follow up visits. 

    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 five  probes placed on the first day of testing and five  probes on the second day. This will enable us to measure how much NO, angiotensin, and ROS 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.  These are FDA approved. 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 by using gentle local heat over a small area of skin. These tests take a number of hours and are more boring than anything else. 

    Later on and after local anesthesia, we will also obtain two tiny amounts of skin from your leg to look for genetic expression related to nitric oxide and angiotensin. thus, we will have laser blood flow measurements, response to medications and antioxidants, and gene expression from the same organ (skin) at one time.

    The second set of experiments investigates more specific regulation of sympathetic outflow from the central nervous system by nitric oxide and angiotensin-II. In these experiments sympathetic nerve activity is measured in a leg nerve using a tiny electrode. We can  measure changes in blood flow regulation and autonomic nervous system control during the administration of drugs that can increase or decrease nitric oxide and angiotensin-II in the central nervous system. An ultrasound of the femoral (leg) artery on the opposite side will enable us to tell whether the problems in blood flow regulation arise from the nerve itself or from the conversion of the sympathetic nerve signal into blood vessel contraction.

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

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Up
Mechanisms of Vasovagal Syncope
Local Vasoconstriction and Sympathoexcitation in Postural Tachycardia Syndrome
Brain Fog in CFS and POTS
Vascular Dysfunction in the Chronic Fatigue Syndrome
Hyperpnea in Postural Tachycardia