Mechanism of Glucose-dependent Insulinotropic Polypeptide (GIP) on Splanchnic Venous Capacitance in Postural Tachycardia Syndrome
试验速览
- 阶段
- 2 期
- 状态
- 招募中
- 入组人数
- 50
- 试验地点
- 1
- 主要终点
- Change in splanchnic venous capacitance in Postural Orthostatic Tachycardia Syndrome
研究概览
简要总结
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.
详细描述
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.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Crossover
- 主要目的
- Diagnostic
- 盲法
- Double (Participant, Outcomes Assessor)
盲法说明
The randomization schedule will be generated by a statistician who is not related to the study. The blinded study intervention will be infused, which medication one receives will be decided by chance, like the toss of a coin .The subjects who received saline at visit 2, will get the study drug GIP(3-30)NH2 at visit 3, and vice versa
入排标准
- 年龄范围
- 18 Years 至 50 Years（Adult）
- 性别
- All
- 接受健康志愿者
- 是
入选标准
- •Between 18 and 50years of age
- •Cases: Diagnosis of POTS with presyncope symptoms after meals Or
- •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.
排除标准
- •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.
- •On statin therapy for high cholesterol
- •Rheumatoid arthritis.
- •On oral corticosteroids,
- •Current infections
- •Documented of moderate decrease in blood volume
研究组 & 干预措施
Changes in Splanchnic venous capacitance(SVC) before and after a 75-g oral glucose challenge
To compare and measure changes in 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 hr. between participants with POTS (Postural Tachycardia Syndrome) and Healthy Control group
Various GIP hormones especially GLP-1, GLP-2, glucagon, and other GI hormones before and after a 75-gram oral glucose at different timepoints through out 3 hours of the study visit
干预措施: Measurement of Splanchnic venous capacitance(SVC)done at Baseline and after 90 min of 75 g glucose in Healthy Controls POTS patients (Diagnostic Test)
Changes in Splanchnic venous capacitance(SVC) before and after a 75-g oral glucose challenge
To compare and measure changes in 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 hr. between participants with POTS (Postural Tachycardia Syndrome) and Healthy Control group
Various GIP hormones especially GLP-1, GLP-2, glucagon, and other GI hormones before and after a 75-gram oral glucose at different timepoints through out 3 hours of the study visit
干预措施: Measurement of Splanchnic venous capacitance(SVC)done at Baseline and after 90 min of 75 g glucose in Healthy Controls (Diagnostic Test)
Effect of GIP antagonist GIP(3-30)NH2 Vs Saline on splanchnic venous capacitance on POTS patients
POTS patients who participated in Aim 1, will be and randomized to either saline versus GIP antagonist (GIP(3-30)NH2) in Visit 2.
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 using segmental impedance to measure the effect of graded positive airway pressure (CPAP) on splanchnic blood volume.
干预措施: Compare change is SVC and SMA flow due to GIP antagonist GIP(3-30)NH2 (Drug)
Effect of GIP antagonist GIP(3-30)NH2 Vs Saline on splanchnic venous capacitance on POTS patients
POTS patients who participated in Aim 1, will be and randomized to either saline versus GIP antagonist (GIP(3-30)NH2) in Visit 2.
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 using segmental impedance to measure the effect of graded positive airway pressure (CPAP) on splanchnic blood volume.
干预措施: Compare change is SVC and SMA flow due to saline (Drug)
结局指标
主要结局
Change in splanchnic venous capacitance in Postural Orthostatic Tachycardia Syndrome
时间窗: Baseline up to 180 minutes post glucose challenge
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.
Effect of glucose-induced GIP secretion on POTS postprandial symptoms.
时间窗: 0-90 mins
Compare the post prandial symptoms on the participants who got infused with GIP antagonist GIP(3-30)NH2 and compare it with Saline infused participants at baseline and 45 degree head tilt. Total of 25 participants with diagnosis of POTS will randomized at visit 2, as 1:1 saline vs GIP antagonist GIP(3-30)NH2 At visit 3, the subjects who received Saline, will get GIP antagonist GIP(3-30)NH2 , vice versa.
Effect of glucose-induced GIP secretion on splanchnic venous capacitance
时间窗: 0-180 mins
25 participants with POTS diagnosis, will be randomized them to either saline versus GIP antagonist (GIP(3-30)NH2) acute infusion. We will measure changes in 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 hr
次要结局
- Measure Glucose-dependent Insulinotropic polypeptide (GIP) hormone level in POTS patients and Controls after 75 grams of glucose ingestion(Baseline up to 180 minutes post glucose challenge)
研究者
Cyndya Shibao, MD
Associate Professor
Vanderbilt University Medical Center