Studies

This page publicizes the research of DINET's medical advisors. If you are a physician who would like your research included on this page, please contact DINET at: staff@dinet.org.

Studies are provided for informational purposes only. DINET cannot guarantee satisfaction from any of the following research studies.

- Vascular Dysfunction in CFS – CFS with and without POTS
- Local Vasoconstriction in Postural Tachycardia Syndrome
- Pathophysiology and Therapy of Orthostatic Intolerance
- Hyperpnea in Postural Tachycardia
- Autonomic Dysfunction in IBS
- Clinical Study of Droxidopa in Patients With Neurogenic Orthostatic Hypotension
 

Vascular Dysfunction in CFS – CFS with and without POTS

We are investigating “Vascular Dysfunction in CFS” in the young (aged 15-29 years). This means problems with blood vessels and circulation. In many young CFS patients we have already demonstrated a circulatory problem called postural tachycardia syndrome or POTS. Our understanding of the mechanisms of POTS is incomplete and not all young CFS patients have POTS. We have proposed that even though some CFS patients do not have POTS, they may still have problems with small blood vessels that can be detected in skin.

When you come for your testing, we will perform a type of tilt testing and other simple noninvasive tests to determine whether you have POTS or not. We will also determine the type of POTS. If you do not have POTS, we will complete testing over a total of two days. using a technique called intradermal microdialysis (explained in the consent and in the website). There is a total subject fee of $300.

If you do have POTS, we invite to stay two additional days to undergo tests specific to POTS (4 days in total). On the first of the two days we will study tests of breathing and the function of the nervous system. This is listed on our website as “Hyperpnea in Postural Tachycardia” and carries a subject fee of $300. On the second of the two days we will test specific treatments for POTS which carries a subject fee of $150.

Further details of the research and representative consent forms can be found on my web-site, syncope.org.

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Local Vasoconstriction in Postural Tachycardia Syndrome

We are seeking patients aged 15-29 years old with postural tachycardia syndrome (POTS) for 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. 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). POTS is defined by an abnormal increase in heart rate (“tachycardia”) and symptoms that occur when upright (therefore “postural”).

POTS has many causes, all related to an abnormal decrease in the amount of blood returning to the heart. It is a problem in blood flow regulation. Blood flow regulation is partly due to the autonomic nervous system and partly due to local factors. It is these local factors that we are currently studying.

Your own doctor can rule out other illnesses which can produce similar symptoms. In addition you may have seen a cardiologist, a neurologist, or an endocrinologist. Tests such as tilt table tests may have already been performed. Some of these tests may be repeated.

However, we will perform other minimally invasive tests that are not ordinarily available to your doctor. They are, however, all approved ways of measuring how blood vessels work. The tests performed during the study may help us determine what treatment is best for you.

If you would like to take part in this study, please read further at our website, www.syncope.org where there is a link to detailed study information. Then, please get in touch with us. The study coordinator will contact you to arrange for an appointment for the study. Testing lasts two days. The study may help to determine the specific biochemical causes of POTS and will point towards improved medical therapy for young patients.

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Pathophysiology and Therapy of Orthostatic Intolerance

Studies to identify the role of the brain, the autonomic nervous system and the vasculature in Orthostatic Intolerance

All participants are adults. Blood pressure and heart rate are measured lying down and standing at regular intervals. Blood samples are drawn for hormones affecting blood pressure control. Some studies involve medication administration.

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Hyperpnea in Postural Tachycardia

Study Purpose: In this proposal we address the clinical problem of hyperpnea in orthostatic intolerance and propose a line of investigation which we hope will lead to better understanding of autonomic cardiovascular regulation in postural tachycardia syndrome.

We are seeking patients aged 18-29 years old with postural tachycardia syndrome (POTS) who may benefit from an investigation of abnormalities of regulation of  respiration and sympathetic nervous system regulation. Many people are unable to remain upright for long because of symptoms such as dizziness, nausea and headache or fainting. We and others have now shown that there is frequent upright increased breathing and shortness of breath in many POTS patients. 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.

We hypothesize that excessive baroreflex unloading during orthostatic stress (upright positioning) is the initiating event in POTS which results in two additional physiological consequences leading to hypocapnic hyperpnea (low carbon dioxide caused by markedly increased ventilation): a) reduced inhibition of chemoreceptor activity centrally and b) frank stimulation of peripheral chemoreceptor activity due to sympathetically induced reductions in blood flow to the carotid body. Increased chemoreceptor activity leads to hyperpnea which activates pulmonary stretch receptors. 

Our study will determine how often respiratory abnormalities occur in POTS and their relationship to excessive activation of the sympathetic nervous system, the branch of the autonomic nervous system that regulates blood flow and cardiac contraction.  Specific causes for POTS may vary from patient to patient. Patients will be compared to healthy control subjects. If we know the specific mechanism, we may be able to offer specific treatment to specific patients.

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Autonomic Dysfunction in IBS

Irritable Bowel Syndrome (IBS) is a common yet poorly understood category of disease. One reason for the difficulty in treating patients arises from the heterogeneous nature of IBS pathophysiology. Understanding IBS is important to understanding normal physiology of vascular control and its relationship to the elicitation of gastrointestinal symptoms that are associated with IBS. The goals of this study are therefore to further our understanding of the relationships between the gastrointestinal system and the autonomic nervous system.

We are seeking 3 different populations;  all adolescents and young adults aged 14-19 years with 1) patients with IBS and autonomic symptoms such as excessive sweating, pallor and lightheadedness; 2) patients with IBS without autonomic symptoms and 3) healthy age and sex-matched control subjects without IBS and autonomic symptoms. The determination of IBS will be made according to the Rome III criteria.

We hypothesize that generalized sympathetic responses are reduced in all patients with IBS, regardless of presentation of autonomic symptoms. To test this,  we will measure blood volume and we will continuously measure heart rate and blood pressure and assess peripheral and segmental blood flow using segmental impedance plethysmography to ask the following question: 

We also hypothesize that subjects with IBS and autonomic symptoms have increased evidence of autonomic dysfunction and specifically increased splanchnic blood flow and splanchnic blood volume during orthostatic challenge. To test this we will measure various aspects of cardiovascular control and response when subjects are placed upright at an angle of 70^o for a maximum of 10 minutes.

The proposed studies are anticipated to provide useful information regarding the status of autonomic function exhibited by subjects diagnosed with IBS and the cause of their pain. It is anticipated that these differences will likely be exhibited by IBS patients who describe  “autonomic” symptoms such as lightheadedness, sweating and pallor that may accompany their gastrointestinal symptoms, rather than by IBS patients without these accompanying symptoms. These subjects may be shown to have differences in heart rate variability or blood pressure variability.  This may also manifest itself as differences in the way in which IBS patients can regulate changes in blood distribution during the imposition of an orthostatic challenge. 

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Clinical Study of Droxidopa in Patients with Neurogenic Orthostatic Hypotension

The purpose of this study is to see whether Droxidopa is effective in treating symptoms of neurogenic orthostatic hypotension in patients with Primary Autonomic Failure (Pure Autonomic Failure, Multiple System Atrophy, Parkinson's Disease), Non-diabetic neuropathy, or Beta Hydroxylase deficiency.

Systolic blood pressure is transiently and minimally decreased in healthy individuals upon standing. Normal physiologic feedback mechanisms work through neurally-mediated pathways to maintain the standing blood pressure, and thus maintain adequate cerebral perfusion. The compensatory mechanisms that regulate blood pressure upon standing are dysfunctional in subjects with orthostatic hypotension (OH), a condition that may lead to inadequate cerebral perfusion with accompanying symptoms of syncope, dizziness or lightheadedness, unsteadiness and blurred or impaired vision, among other symptoms.

The autonomic nervous system has a central role in the regulation of blood pressure. Primary Autonomic Failure is manifested in a variety of syndromes. Orthostatic hypotension is a usual presenting symptom. Primary Autonomic Failure may be the primary diagnosis, and classifications include pure autonomic failure (PAF), also called idiopathic orthostatic hypotension (Bradbury-Eggleston syndrome) autonomic failure with multiple system atrophy (Shy-Drager syndrome) and also Parkinson's disease. Regardless of the primary condition, autonomic dysfunction underlies orthostatic hypotension.

Orthostatic hypotension may be a severely disabling condition which can seriously interfere with the quality of life of afflicted subjects. Currently available therapeutic options provide some symptomatic relief in a subset of subjects, but are relatively ineffective and are often accompanied by severe side effects that limit their usefulness. Support garments (tight-fitting leotard) may prove useful in some subjects, but is difficult to don without family or nursing assistance, especially for older subjects. Midodrine, fludrocortisone, methylphenidate, ephedrine, indomethacin and dihydroergotamine are among some of the pharmacological interventions that have been used to treat orthostatic hypotension, although only midodrine is specifically approved for this indication. The limitations of these currently available therapeutic options, and the incapacitating nature and often progressive downhill course of disease, point to the need for an improved therapeutic alternative.

The current withdrawal design study will measure the efficacy of droxidopa on symptoms of neurogenic orthostatic hypotension in patients randomized to continued droxidopa treatment versus placebo, following 14 days of double-blind treatment.

Droxidopa

Droxidopa [also, known as L-threo-3,4-dihydroxyphenylserine, L-threo-DOPS, or L-DOPS] is the International non-proprietary name (INN) for a synthetic amino acid precursor of norepinephrine (NE), which was originally developed by Sumitomo Pharmaceuticals Co., Limited, Japan. It has been approved for use in Japan since 1989. Droxidopa has been shown to improve symptoms of orthostatic hypotension that result from a variety of conditions including Shy Drager syndrome (Multiple System Atrophy), Pure Autonomic Failure, and Parkinson's disease. There are four stereoisomers of DOPS; however, only the L-threo-enantiomer (droxidopa) is biologically active.

The exact mechanism of action of droxidopa in the treatment of symptomatic NOH has not been precisely defined; however, its NE replenishing properties with concomitant recovery of decreased noradrenergic activity are considered to be of major importance.

Droxidopa has been marketed in Japan since 1989. Data from clinical studies and post-marketing surveillance programs conducted in Japan show that the most commonly reported adverse drug reactions with droxidopa are increased blood pressure, nausea, and headache. In clinical studies, the prevalence and severity of droxidopa adverse effects appear to be similar to those reported by the placebo control arm.

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