Local Vasoconstriction in Postural Tachycardia Syndrome
| Status: | Completed |
|---|---|
| Conditions: | Cardiology |
| Therapuetic Areas: | Cardiology / Vascular Diseases |
| Healthy: | No |
| Age Range: | 14 - 29 |
| Updated: | 1/16/2019 |
| Start Date: | July 2010 |
| End Date: | June 2015 |
The investigators 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 the investigators know the specific biochemical
mechanism the investigators may be able to offer further specific treatments to specific
patients.
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 the investigators know the specific biochemical
mechanism the investigators may be able to offer further specific treatments to specific
patients.
Chronic orthostatic intolerance due to the postural tachycardia syndrome (POTS) severely
impairs daily life in over a million Americans, mostly young women. POTS is defined by
symptoms of orthostatic intolerance associated with excessive upright heart rate. While there
is general agreement that abnormalities in vascular regulation and autonomic activity account
for the tachycardia and symptoms of POTS, its pathophysiology is heterogeneous and only
partially characterized.
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.
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.
impairs daily life in over a million Americans, mostly young women. POTS is defined by
symptoms of orthostatic intolerance associated with excessive upright heart rate. While there
is general agreement that abnormalities in vascular regulation and autonomic activity account
for the tachycardia and symptoms of POTS, its pathophysiology is heterogeneous and only
partially characterized.
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.
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.
Inclusion Criteria:
- Cases will be between the ages of 14 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.
Exclusion Criteria:
- 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
- Substance abuse within 2 years before onset of symptoms.
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