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). These 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 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. Primary endpoint: Effect of glucose on splanchnic venous capacitance in Postural Orthostatic Tachycardia Syndrome(POTS). Rationale: Several mechanisms have been associated with the pathophysiology of POTS, yet, there is consensus that the orthostatic tachycardia, characteristic of the condition, is triggered by an exaggerated sympathetic activation, which in most cases is secondary to splanchnic venous pooling upon standing. Meals have been shown to significantly increase the mesenteric arterial blood flow in healthy subjects. A previous study showed that 75-gr glucose ingestion further potentiates the orthostatic tachycardia in POTS patients, but not in healthy controls. However, the exact mechanisms underlying this condition are not known. Subject population: 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). Study visits: 3 visits, 2 in person and 1 telemedicine, Study procedures 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, Tilt table test, Oral glucose tolerance test (OGTT), Splanchnic venous capacitance measurements. 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.

Splanchnic venous capacitance(SVC), the comparison between participants with POTS (Postural Tachycardia Syndrome) and Healthy Control group.

Tilt Test/ Oral glucose tolerance tests (OGTT), Blood Vomume measurement by CO rebreathing technique, Dxa scan ( dual energy X-ray absorptiometry)

The changes in splanchnic venous capacitance and superior mesenteric arterial flow will be measured, before and after a 75 gram of oral glucose challenge. It will compared in POTS and Healthy controls. While segmental bio impedance is monitored, continuous positive airway pressure (CPAP) will be applied sequentially at 0, 4, 8, 12 and 16 cm H2O for about 30 seconds each; this positive airway pressure will increase the intrathoracic pressure, which is transmitted to the venous circulation. Pressure (CPAP pressure, x-axis) - volume (splanchnic vascular volume measured by segmental impedance and expressed as % change from baseline, y-axis) relationships are then constructed to assess for splanchnic venous capacitance.

Measure Glucose-dependent Insulinotropic polypeptide (GIP) hormone level in POTS patients and Controls after 75 grams of glucose ingestion

Measure and compare various GIP hormones (GLP-1, GLP-2, GIP, Vasoactive Intestinal Peptide(VIP)and glucagon) after ingesting 75-gram glucose for up to 180 minutes in POTS patients and healthy controls of similar age and BMI. Sequential blood draw will done to measure GIP hormones

Inclusion Criteria: Between 18 and 50years of age Cases: Diagnosis of POTS with presyncope symptoms after meals Or Controls: With no significant past medical history, non-smokers and not on chronic medications. Body mass index (BMI) between 18.5 to 29.9 kg/m2 If pre-menopausal women: must have regular menstrual cycle. Exclusion Criteria: BMI above ≥30 kg/m2 Irregular menstrual cycle Intolerance to CPAP. Chronic use of acetaminophen Heart problems: myocardial infarction, angina, heart failure, stroke Undergone any heart related procedures or stents or on pacemaker. Uncontrolled hypertension. Type 1 or type 2 diabetes mellitus Pregnant or breast-feeding women. Impaired liver function Impaired Kidney function test. Anemia (Hematocrit<34%). Ongoing substance abuse. Subjects with abnormal EKG History of seizures. Diagnosed with neuropathy due to any reason History of neck surgery. Smoker, On statin therapy for high cholesterol Rheumatoid arthritis. On oral corticosteroids, Current infections Documented of moderate decrease in blood volume

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