Postural Orthostatic Tachycardia Syndrome
Conditions
Keywords
POTS, Orthostatic Intolerance, Orthostatic Tachycardia
Brief summary
Patients with POTS may not adequately expand their plasma volume in response to a high-sodium (Na+) diet. Mechanisms involved in the regulation of plasma volume, such as the renin-angiotensin-aldosterone system and renal dopamine, may be impaired in POTS and may respond inappropriately to changes in dietary sodium.The purpose of this study is to determine (1) whether a high dietary sodium level appropriately expands plasma volume in POTS; (2) whether plasma renin activity and aldosterone are modified appropriately by changes in dietary sodium in POTS; and (3) whether patients with POTS have improvements in their orthostatic tachycardia and symptoms as a result of a high dietary sodium level.
Detailed description
Study Day 1 * Start 150 milliequivalents (mEq) Na+/day diet (POTS patients as inpatients; healthy control subjects with clinical research center (CRC)- provided outpatient diet) * Start a 24h urine collection (for Na+, K+, Cr, fractionated catecholamines) * Blood work * Blood volume - carbon monoxide rebreathing Study Day 2 * Complete 24h urine * Start STUDY DIET (10 mEq Na+/day or 300 mEq Na+/day in a random order) after 3 meals of 150 mEq Na+/day are complete; water ad lib Study Day 3 - 5 * Continue STUDY DIET; water ad lib * On Day 5, a 24 hr holter combined ECG monitor will be placed on the subjects. Study Day 6 * Continue STUDY DIET; water ad lib * Remove 24h Holter combined ECG monitor and BP monitor from subject * Start a 24h urine collection (for Na+, K+, Cr, fractionated catecholamines) * Complete questionnaires * Nothing by mouth (NPO) after midnight for study next day Study Day 7 (BIG DAY) * Awaken early (\ 6am) to void (still collecting 24h urine) * Patient returns to bed, IV catheter inserted * Posture Study (in morning; between 7-8am ideally) * Blood pressure and heart rate will be measured while supine and then while standing for up to 30 minutes * We will draw 3 tablespoons of blood in each body position to measure hormones that regulate blood pressure and blood volume * Hormones to verify the subject's phase of menstrual cycle * Serum/plasma aliquots for future analysis * Subjects will rate symptoms during supine period and at end of stand using Vanderbilt Orthostatic Symptoms Score (VOSS) * Total Blood Volume (DAXOR)- using injection of iodinated I-131 tagged human serum albumin nominally 25 micro-Ci of radiation blood samples drawn through IV catheter before injection and for \ 30 minutes post-injection (total - 25 ml) * This will be done after supine assessment, but before standing the subject up * Autonomic Function Test with Cardiac Output and Brief Tilt * The subject will be tilted up to 60-75 degrees head-up tilt for up to 10 minutes to measure the changes in heart rate and blood pressure and symptoms with upright challenge. * Blood volume - carbon monoxide rebreathing * Exercise Capacity Test (in the afternoon) Will estimate maximal oxygen consumption (VO2 max) This test will be conducted on a stationary bicycle. Effort will be gradually increase while expired air is measured during exhaustive physical work. All procedures are repeated at least a month later with the 2nd level of dietary salt. (Randomized to high or low salt to the first phase, the second phase is the remaining level)
Interventions
RADIATIONBlood Volume
we will measure the amount of hemoglobin and myoglobin in the body by a procedure called CO rebreathing. One teaspoon of blood is taken before and after a small amount of CO has been absorbed into the bloodstream.
RADIATIONTotal Blood Volume
Using injection of iodinated I-131 tagged human serum albumin nominally 25 microcuries of radiation, blood samples are drawn before and 30 minutes after injection.
PROCEDUREExercise Capacity Test - Bicycle
subjects breath room air through a mouthpiece and exhale the air into a tube that connects to a machine (metabolic cart) that analyzes carbon dioxide and oxygen content, which allows the investigator to calculate the amount of oxygen they are using under resting and exercise conditions.
PROCEDUREPosture Study
Blood pressure and heart rate will be measured while supine and then while standing for up to 30 minutes. Blood will be drawn in each position to measure hormones that regulate blood pressure and blood volume.
Sponsors
National Institutes of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Vanderbilt University
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
BASIC_SCIENCE
Masking
NONE
Intervention model description
Randomization tables will be used to determine whether the 10 mEq sodium/day or 300 mEq sodium/day diet will be consumed first. Both diets will be completed on each subject (randomized crossover study), so all of the study procedures (after screening) will be repeated.
Eligibility
Sex/Gender
ALL
Age
18 Years to 50 Years
Healthy volunteers
Yes
Inclusion criteria
* Diagnosed with postural tachycardia syndrome by the Vanderbilt Autonomic Dysfunction Center * Increase in heart rate ≥30 beats/min with position change from supine to standing (10 minutes) * Chronic symptoms consistent with POTS that are worse when upright and get better with recumbence * Age between 18-50 years old * Non-smokers * Premenopausal patients with POTS and healthy volunteers * Only female participants are eligible. * Since 80-90% of POTS patients are female, and there can be differences in measures with the menstrual cycle, including a small number of males might introduce a significant amount of noise. * Able and willing to provide informed consent
Exclusion criteria
* Smokers * Overt cause for postural tachycardia, i.e., acute dehydration * Significant cardiovascular, pulmonary, hepatic, or hematological disease by history or screening results * Pregnant (positive pregnancy test) or breastfeeding * Hypertension defined as supine resting BP\>145/95 mmHg off medications or needing antihypertensive medication * Other factors which in the investigator's opinion would prevent the participant from completing the protocol, including poor compliance during previous studies or an unpredictable schedule * Unable to give informed consent
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Plasma Volume | after 7 days of each dietary sodium level | Plasma volume (PV) was determined by the indicator tracer-dilution technique, using the DAXOR Blood Volume Analyzer (BVA)-100 system (DAXOR Corporation), on Day 7 of the low sodium and high sodium dietary interventions. Outcome data are the absolute values for PV on Day 7 for each diet. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Magnitude of Suppression of Plasma Renin Activity (From Low Sodium to High Sodium Diets) | Upright blood samples were collected after up to 30 minutes of standing on the 7th day of each dietary sodium intervention | Whether upright plasma renin activity was modified appropriately by changes in dietary sodium in POTS & healthy controls. Outcome data are the absolute values for upright plasma renin activity on Day 7 of each diet. |
Other
| Measure | Time frame | Description |
|---|---|---|
| Magnitude of Suppression of Serum Aldosterone (From Low Sodium to High Sodium Diets) | Upright blood samples were collected after up to 30 minutes of standing on the 7th day of each dietary sodium intervention | Whether upright serum aldosterone was modified appropriately by changes in dietary sodium in POTS patients & healthy controls. Outcome data are the absolute values for upright serum aldosterone on Day 7 of each diet. |
| Magnitude of Orthostatic Tachycardia | Supine and upright heart rates were measured on Day 7 of High Sodium and Low Sodium diet. | Whether the magnitude of the heart rate increase that occurs in patients with POTS when moving from a supine to an upright position is attenuated by a High Sodium diet relative to a Low Sodium diet. Heart rate was assessed after overnight rest and fasting after midnight, following at least 60 minutes of lying quietly. Heart rate was then measured at intervals after subjects had been standing for up to 30 minutes (as tolerated). Orthostatic tachycardia was calculated as the difference between standing and lying heart rates. Data are presented for 5 minutes standing (or maximal stand if \<5 minutes) since several patients were unable to stand for 10 minutes. Data in POTS patients were compared to that of Healthy Controls. |
| Upright Symptom Score | Upright symptoms were assessed on the 7th day of diet. | Whether upright symptoms were improved in patients with POTS on a High Sodium diet relative to a Low Sodium diet. Patients were asked to report their standing symptom burden at the end of the Stand portion of the posture study, using the Vanderbilt Orthostatic Symptoms Scale (VOSS). They rated the severity of nine symptoms (palpitations, lightheadedness, mental confusion, blurred vision, shortness of breath, tremulousness, chest discomfort, headache, and nausea) on a scale from a minimum of 0 (reflecting an absence of symptoms) to a maximum of 10. The sum of the scores for the 9 symptoms was used to measure orthostatic symptom burden. Higher scores represent worse symptoms. |
Countries
United States
Participant flow
Pre-assignment details
Healthy Participants: 17 were enrolled and randomized. 1 withdrew due to scheduling. 1 withdrew with migraines in phase 1 (low Na+). 2 withdrew in phase 1 (high Na+): 1 unable to tolerate study diet and another had difficulty cooperating with investigators. Postural Tachycardia Syndrome (POTS): 21 were enrolled and randomized. 6 withdrew before baseline due to age (1), pregnancy (1), prohibited meds (3), and scheduling (1). A 7th patient withdrew during phase 1 (high Na+) due to family illness.
Participants by arm
| Arm | Count |
|---|---|
| Healthy Participants-Low Na+ Then High Na+ Healthy controls were randomly assigned the order of dietary sodium (Na+) levels. After 1 day on diet with 150 mEq sodium/day, participants consumed low Na+ diet (10 mEq sodium/day; LS) for 6 days followed in at least 1 month by 1 day of 150 mEq sodium/day and 6 days of high Na+ diet (300 mEq sodium/day; HS). All procedures were performed at both levels. | 11 |
| Healthy Participants-High Na+ Then Low Na+ Healthy controls were randomly assigned the order of dietary sodium (Na+) levels. After 1 day on diet with 150 mEq sodium/day, participants consumed high Na+ diet (300 mEq sodium/day; HS) for 6 days followed in at least 1 month by 1 day of 150 mEq sodium/day and 6 days of low Na+ diet (10 mEq sodium/day; LS). All procedures were performed at both levels. | 2 |
| Patients With POTS-Low Na+ Then High Na+ Patients with POTS were randomly assigned the order of dietary sodium (Na+) levels. After 1 day on diet with 150 mEq sodium/day, participants consumed low Na+ diet (10 mEq sodium/day; LS) for 6 days followed in at least 1 month by 1 day of 150 mEq sodium/day and 6 days of high Na+ diet (300 mEq sodium/day; HS). All procedures were performed at both levels. | 8 |
| Patients With POTS-High Na+ Then Low Na+ Patients with POTS were randomly assigned the order of dietary sodium (Na+) levels. After 1 day on diet with 150 mEq sodium/day, participants consumed high Na+ diet (300 mEq sodium/day; HS) for 6 days followed in at least 1 month by 1 day of 150 mEq sodium/day and 6 days of low Na+ diet (10 mEq sodium/day; LS). All procedures were performed at both levels. | 6 |
| Total | 27 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 |
|---|---|---|---|---|---|
| Overall Study | Physician Decision | 0 | 1 | 1 | 3 |
| Overall Study | Withdrawal by Subject | 1 | 2 | 1 | 2 |
Baseline characteristics
| Characteristic | Healthy Participants-Low Na+ Then High Na+ | Total | Patients With POTS-High Na+ Then Low Na+ | Patients With POTS-Low Na+ Then High Na+ | Healthy Participants-High Na+ Then Low Na+ |
|---|---|---|---|---|---|
| Age, Continuous | 31 years STANDARD_DEVIATION 6 | 33 years STANDARD_DEVIATION 7 | 32 years STANDARD_DEVIATION 6 | 36 years STANDARD_DEVIATION 9 | 35 years STANDARD_DEVIATION 10 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 1 Participants | 2 Participants | 1 Participants | 0 Participants | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 10 Participants | 25 Participants | 5 Participants | 8 Participants | 2 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 1 Participants | 1 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 1 Participants | 1 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 9 Participants | 25 Participants | 6 Participants | 8 Participants | 2 Participants |
| Region of Enrollment United States | 11 participants | 27 participants | 6 participants | 8 participants | 2 participants |
| Sex: Female, Male Female | 11 Participants | 27 Participants | 6 Participants | 8 Participants | 2 Participants |
| Sex: Female, Male Male | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk |
|---|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 13 | 0 / 13 | 0 / 14 | 0 / 14 |
| other Total, other adverse events | 0 / 13 | 1 / 13 | 0 / 14 | 0 / 14 |
| serious Total, serious adverse events | 0 / 13 | 0 / 13 | 0 / 14 | 0 / 14 |
Outcome results
Primary
Plasma Volume
Plasma volume (PV) was determined by the indicator tracer-dilution technique, using the DAXOR Blood Volume Analyzer (BVA)-100 system (DAXOR Corporation), on Day 7 of the low sodium and high sodium dietary interventions. Outcome data are the absolute values for PV on Day 7 for each diet.
Time frame: after 7 days of each dietary sodium level
Population: No data analysis for 1 healthy control who had poor venous access on Day 7 of the high sodium diet.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Healthy Participants Who Consumed Low Sodium Diet as Intervention A or Intervention B | Plasma Volume | 2805 mL |
| Healthy Participants Who Consumed High Sodium Diet as Intervention A or Intervention B | Plasma Volume | 3032 mL |
| Postural Tachycardia Syndrome (POTS) Participants Who Consumed Low Sodium Diet. | Plasma Volume | 2362 mL |
| Postural Tachycardia Syndrome (POTS) Participants Who Consumed High Sodium Diet. | Plasma Volume | 2633 mL |
Secondary
Magnitude of Suppression of Plasma Renin Activity (From Low Sodium to High Sodium Diets)
Whether upright plasma renin activity was modified appropriately by changes in dietary sodium in POTS & healthy controls. Outcome data are the absolute values for upright plasma renin activity on Day 7 of each diet.
Time frame: Upright blood samples were collected after up to 30 minutes of standing on the 7th day of each dietary sodium intervention
Population: Healthy Controls on Low Sodium diet - 1 missing blood sample; Healthy Controls on High Sodium diet - 3 missing blood samples, 2 samples with insufficient volume for analysis; POTS patients on Low Sodium diet - 1 missing blood sample; POTS patients on High Sodium diet - 2 missing blood samples
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Healthy Participants Who Consumed Low Sodium Diet as Intervention A or Intervention B | Magnitude of Suppression of Plasma Renin Activity (From Low Sodium to High Sodium Diets) | 7.8 ng/mL/hr |
| Healthy Participants Who Consumed High Sodium Diet as Intervention A or Intervention B | Magnitude of Suppression of Plasma Renin Activity (From Low Sodium to High Sodium Diets) | 1.0 ng/mL/hr |
| Postural Tachycardia Syndrome (POTS) Participants Who Consumed Low Sodium Diet. | Magnitude of Suppression of Plasma Renin Activity (From Low Sodium to High Sodium Diets) | 24.4 ng/mL/hr |
| Postural Tachycardia Syndrome (POTS) Participants Who Consumed High Sodium Diet. | Magnitude of Suppression of Plasma Renin Activity (From Low Sodium to High Sodium Diets) | 2.7 ng/mL/hr |
Other Pre-specified
Magnitude of Orthostatic Tachycardia
Whether the magnitude of the heart rate increase that occurs in patients with POTS when moving from a supine to an upright position is attenuated by a High Sodium diet relative to a Low Sodium diet. Heart rate was assessed after overnight rest and fasting after midnight, following at least 60 minutes of lying quietly. Heart rate was then measured at intervals after subjects had been standing for up to 30 minutes (as tolerated). Orthostatic tachycardia was calculated as the difference between standing and lying heart rates. Data are presented for 5 minutes standing (or maximal stand if \<5 minutes) since several patients were unable to stand for 10 minutes. Data in POTS patients were compared to that of Healthy Controls.
Time frame: Supine and upright heart rates were measured on Day 7 of High Sodium and Low Sodium diet.
Population: Data is not included for 1 patient with POTS on a Low Sodium diet since that patient was unable to stand for even 1 minute.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Healthy Participants Who Consumed Low Sodium Diet as Intervention A or Intervention B | Magnitude of Orthostatic Tachycardia | 23 beats per minute |
| Healthy Participants Who Consumed High Sodium Diet as Intervention A or Intervention B | Magnitude of Orthostatic Tachycardia | 19 beats per minute |
| Postural Tachycardia Syndrome (POTS) Participants Who Consumed Low Sodium Diet. | Magnitude of Orthostatic Tachycardia | 60 beats per minute |
| Postural Tachycardia Syndrome (POTS) Participants Who Consumed High Sodium Diet. | Magnitude of Orthostatic Tachycardia | 46 beats per minute |
Other Pre-specified
Magnitude of Suppression of Serum Aldosterone (From Low Sodium to High Sodium Diets)
Whether upright serum aldosterone was modified appropriately by changes in dietary sodium in POTS patients & healthy controls. Outcome data are the absolute values for upright serum aldosterone on Day 7 of each diet.
Time frame: Upright blood samples were collected after up to 30 minutes of standing on the 7th day of each dietary sodium intervention
Population: Samples were analyzed from each participant
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Healthy Participants Who Consumed Low Sodium Diet as Intervention A or Intervention B | Magnitude of Suppression of Serum Aldosterone (From Low Sodium to High Sodium Diets) | 444 ng/dL |
| Healthy Participants Who Consumed High Sodium Diet as Intervention A or Intervention B | Magnitude of Suppression of Serum Aldosterone (From Low Sodium to High Sodium Diets) | 74 ng/dL |
| Postural Tachycardia Syndrome (POTS) Participants Who Consumed Low Sodium Diet. | Magnitude of Suppression of Serum Aldosterone (From Low Sodium to High Sodium Diets) | 455 ng/dL |
| Postural Tachycardia Syndrome (POTS) Participants Who Consumed High Sodium Diet. | Magnitude of Suppression of Serum Aldosterone (From Low Sodium to High Sodium Diets) | 64 ng/dL |
Other Pre-specified
Upright Symptom Score
Whether upright symptoms were improved in patients with POTS on a High Sodium diet relative to a Low Sodium diet. Patients were asked to report their standing symptom burden at the end of the Stand portion of the posture study, using the Vanderbilt Orthostatic Symptoms Scale (VOSS). They rated the severity of nine symptoms (palpitations, lightheadedness, mental confusion, blurred vision, shortness of breath, tremulousness, chest discomfort, headache, and nausea) on a scale from a minimum of 0 (reflecting an absence of symptoms) to a maximum of 10. The sum of the scores for the 9 symptoms was used to measure orthostatic symptom burden. Higher scores represent worse symptoms.
Time frame: Upright symptoms were assessed on the 7th day of diet.
Population: Upright symptom scores were inadvertently not obtained for the following number of participants:~Healthy Participants on Low Sodium diet: 3 Healthy Participants on High Sodium diet: 2 Patients with POTS on Low Sodium diet: 5 Patients with POTS on High Sodium diet: 6
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Healthy Participants Who Consumed Low Sodium Diet as Intervention A or Intervention B | Upright Symptom Score | 1 score on a scale |
| Healthy Participants Who Consumed High Sodium Diet as Intervention A or Intervention B | Upright Symptom Score | 0 score on a scale |
| Postural Tachycardia Syndrome (POTS) Participants Who Consumed Low Sodium Diet. | Upright Symptom Score | 30 score on a scale |
| Postural Tachycardia Syndrome (POTS) Participants Who Consumed High Sodium Diet. | Upright Symptom Score | 19 score on a scale |