Mechanism of Glucose-dependent Insulinotropic Polypeptide (GIP) on Splanchnic Venous Capacitance in Postural Tachycardia Syndrome
Mechanism of Glucose-dependent Insulinotropic Polypeptide (GIP) on Splanchnic Venous Capacitance in Postural Tachycardia Syndrome
Postural tachycardia syndrome (POTS) affects ≈3 million young people, characterized by chronic presyncopal symptoms characterized by dizziness, lightheadedness, and orthostatic tachycardia that occur while standing. Across-sectional survey found that 25% of these patients complains that meals rich in carbohydrates are among the factors that further exacerbate POTS's symptoms and cause a myriad of gastrointestinal symptoms.
The splanchnic circulation is the largest blood volume reservoir of the human body, storing ≈25% of the total blood volume and contributing to sudden, and large, fluctuations in the stroke volume (SV). The orthostatic changes in systemic hemodynamics are particularly magnified after meals, due to increased blood volume sequestration triggered by the release of gastrointestinal peptides with vasodilatory properties. The purpose of this study is to determine if 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 on standing as compare to Healthy controls.
The study will also determine if glucose-induced GIP secretion increases splanchnic venous capacitance, orthostatic tachycardia and worsening POTS postprandial symptoms. For this purpose subjects will be further randomized to either saline versus GIP(3-30)NH2 acute infusion, to measure the changes their splanchnic venous capacitance and superior mesenteric arterial flow before and after a 75-g oral glucose challenge during supine and 45-degree head-up tilt positions (orthostatic challenge) for up to 3 hours.
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.
Inclusion Criteria:
Controls:
Exclusion Criteria:
pedro.ortiz.saavedra@vumc.org689-233-2623
meenakshi.golchha@vumc.org615-322-3447