The Aim 1 of the study is to investigate that the worsening orthostatic tachycardia and
symptoms after glucose ingestion in POTS patients are due to a greater increase in
splanchnic venous capacitance and excessive blood pooling during an orthostatic
challenge.
Investigators will enroll POTS patients with postprandial symptoms as cases, and age, and
BMI-matched controls. The changes in their splanchnic venous capacitance and superior
mesenteric arteria flow will be measured, before and after a 75-gram of oral glucose
challenge, during supine and 75-degree head-up tilt positions (orthostatic challenge) for
up to 3-hrs. Notably, newly developed an Innovative technique to assess venous
capacitance in humans, using segmental impedance to measure the effect of graded positive
airway pressure (CPAP) on splanchnic blood volume.
Rationale for Aim 1:
Several mechanisms have been associated with the pathophysiology of postprandial symptoms
in POTS patients. Preliminary data showed that after a 75-g oral glucose load to POTS
patients resulted in: 1) excessive increase in upright HR, which was not present in
controls, 2) increased upright Heart Rate (HR), which was associated with a concomitant
decrease in upright stroke volume, and 3) POTS patients had a selective increase in GIP
secretion, which has vasodilatory properties in the splanchnic circulation.
There is consensus that the orthostatic tachycardia (increase upright HR), characteristic
of the condition, is triggered by an exaggerated sympathetic activation, which in most
cases is secondary to splanchnic venous pooling upon standing.
AIM 2 of the study, is to determine if glucose-induced GIP secretion increases splanchnic
venous capacitance, orthostatic tachycardia and worsening POTS postprandial symptoms.
For this purpose, patients who participated in Aim 1, will be randomized to either saline
versus GIP antagonist (GIP(3-30)NH2) acute infusion in 1:1 ratio. The changes in their
splanchnic venous capacitance and superior mesenteric arterial flow will be measured,
before and after a 75-g oral glucose challenge during supine and 45-degree head-up tilt
positions (orthostatic challenge) for up to 3 hr. Notably, changes in venous capacitance,
will be assessed, in humans using segmental impedance to measure the effect of graded
positive airway pressure (CPAP) on splanchnic blood volume.
If it is assumed that higher post-glucose levels of GIP in POTS can produce a greater
venodilation and a larger increase in the Y-intercept (splanchnic venous capacitance)
compared to saline infusion. Then the hypothesis would be that the GIP antagonist
GIP(3-30)NH2 will attenuate any increase in the Y-intercept in response to oral glucose
in POTS patients
Primary endpoint: Effect of glucose on splanchnic venous capacitance in Postural
Orthostatic Tachycardia Syndrome(POTS).
Secondary endpoints for aim 1 and 2 During the study, different parameters will be
measured to understand the physiological cardiovascular and neuro-hormonal changes that
occurred after an oral glucose intake and during orthostatic challenge in POTS patients
and healthy controls. Even though these parameters will be collected during the same
timepoints when the primary endpoint is collected, they are not considered study
outcomes, they will inform on additional mechanisms by which glucose exert the
hemodynamic and neuro-hormonal changes in POTS
Subject population: For Aim1; Total 50 participants, between age 18-50 years with BMI
between 18.5 to 29.9. Out of which 25 with be participants with diagnosis of POTS and 25
heathy controls (HC).
For AIM 2 : 25 participants with diagnosis of POTS, who have completed Aim 1
Study visits: Consists of 4 visits in person:
A. Visit 0: Screening visit B. Telemedicine/phone call C. Visit 1: Baseline visit D.
Visits 2 and 3 (POTS patients only)
Study procedures Visit 0/Screening visit: include EKG, urine and blood sample collection,
Orthostatic Standing Test, DXA scan (dual energy X-ray absorptiometry), Measurement of
blood volume using carbon monoxide rebreathing technique, Visit 1: Includes Tilt table
test, Oral glucose tolerance test (OGTT), Splanchnic venous capacitance measurements.
Visit 2&3: For Aim 2: These visit will be performed under the same conditions described
in Visit 1. A total of 25 POTS patients will be randomized according to a
computer-generated, randomization schedule that will randomize the order of the
medication order assignment (IV saline then GIP 3-30 NH2 or vice versa).The blinded study
intervention will be infused at 800 pmol/kg/min for 180 minutes
Data and Safety Monitoring Plan: The DSMB will meet at least 3 times, once to review and
ratify its charter, a second time to evaluate the safety data after 5 POTS patients
finish the study, and every 6 months until year 5. These reports will provide information
regarding recruiting, safety reporting, data quality, and efficacy. The committee will
assess safety data including common adverse events, hospitalizations, and other serious
adverse events.
Statistical Considerations: Standard graphing and screening techniques to detect outliers
and to ensure data accuracy. The summary statistics for both continuous and categorical
variables will be provided by subject groups for Aim 1. All hypotheses will be tested at
the level of α=0.05. Open-source statistical package R (R Core Team, 2020) for analyses
will be used.
For Aim 1, the primary endpoint is splanchnic venous capacitance (SVC). The comparison
between POTS and HC groups on this endpoint will be made using either the two-sample
t-test or the Wilcoxon Rank Sum test. Furthermore, this endpoint will be analyzed using
the general linear model (GLM) with a set of covariates including age, body mass index in
addition to the baseline measure of adjusted in the model. Other endpoints will be
analyzed similarly as the primary endpoint.
Hemodynamic Parameters and Autonomic Measurements:
Hemodynamic data will be recorded using the WINDAQ data acquisition system (DI220, DATAQ,
Akron, OH, 14 Bit, 1000Hz), and will be processed off-line using a custom written
software in PV-Wave language (PV-wave, Visual Numerics Inc., Houston, TX). Detected
beat-to-beat values of R-R intervals (RRI) and blood pressure will be interpolated and
low-pass filtered (cutoff 2 Hz).
Data segments of at least 180 seconds will be used for spectral analysis. Linear trends
will be removed, and power spectral density will be estimated with the FFT-based Welch
algorithm. The total power (TP) and the power in the low (LF: 0.04 to <0.15 Hz), and high
(HF: 0.15 to < 0.40 Hz) frequency ranges will be calculated . Cross spectra, coherence
and transfer function analysis will be used to capture interrelationships between R-R
interval and systolic blood pressure.
The baroreflex gain will be determined as the mean magnitude value of the transfer
function in the low-frequency band, with a negative phase and squared coherence value
greater than 0.5. Beat-to-beat stroke volume will be estimated by pulse contour analysis
of arterial pressure curves (Modelflow algorithm) using a finger photo plethysmography
volume-clamp BP device (Nexfin, BMEYE) and by impedance cardiography. An appropriate size
cuff will be wrapped around the right middle or index finger and a height correction
system will be used to adjust for hydrostatic height differences between the hand and the
heart. Beat-to-beat BP data will be calibrated to brachial artery pressure and
intermittently checked against oscillometric BP measurements (Dinamap ProCare, GE
Healthcare). Then cardiac output will be calculated by multiplying stroke volume by the
heart rate obtained from oscillometric BP measurements. Systemic vascular resistance will
be estimated by dividing oscillometric mean arterial pressure (MAP) by cardiac output.
Superior Mesenteric Artery Flow Assessment: The superior mesenteric artery (SMA) flow
will be studied using a sonographic system with real-time B-mode imaging coupled with
pulsed Doppler and colour coded Doppler imaging (Philips EPIC 7C). Examination will be
performed with a 3.5-Mhz phased array sector scanning probe (Philips C5-1 curved array
transducer). The Doppler sample volume will be put about 2-cm downstream of the vessel's
origin from the aorta. The peak systolic (S) and peak end-diastolic (D) Doppler
frequencies will be measured on the time-frequency Doppler spectrum, and the resistance
index (RI) will be calculated as: RI=(S-D)xS-1.