Mechanism of Glucose-dependent insulinotropic polypeptide (GIP) on Splanchnic Venous Capacitance in Postural Tachycardia Syndrome

项目摘要 姿势性心动过速综合征（POTS）影响美国约300万成年人。这些患者的 由于慢性晕厥前症状和站立时发生的心动过速导致生活质量差。我们 研究表明富含碳水化合物的膳食显著加重POTS中的晕厥前症状， 然而，解释这种临床观察结果的潜在机制仍然未知。 因此，本课题组进行了初步的研究，以评估POTS过度的病理生理学， 葡萄糖摄入后直立性心动过速;我们调查了血流动力学和神经激素的变化， POTS患者和健康人在75 gr口服葡萄糖激发2小时（餐后阶段）后发生 对照与空腹状态相比，摄入葡萄糖可加重POTS患者的直立位心动过速 与健康人相比， 对照关于POTS患者的直立每搏输出量不成比例的减少，这可能， 部分原因是内脏循环中有大量血液汇集。内脏循环是 是人体最大的血液储存库，储存约25%的总血量。在站立时， 存在主要发生在内脏静脉中的显著的血液汇集。最后，我们的研究还 表明摄入75克葡萄糖后30分钟，POTS患者的分泌选择性增加， 葡萄糖依赖性促胰岛素多肽（GIP）激素与健康对照组相比。这 激素在内脏循环中具有血管舒张特性。重要的是，GIP分泌的增加 与POTS患者摄入葡萄糖后直立心搏量下降呈时间依赖性相关。 因此，这些发现表明GIP在增加的病理生理学中的潜在贡献 POTS患者餐后直立性心动过速和晕厥前症状。因此， 本研究旨在探讨直立性心动过速加重的机制， 葡萄糖摄入引起的POTS晕厥前症状。具体而言，我们将评估 GIP对口服葡萄糖后和直立姿势时内脏静脉容量变化的影响 POTS患者。

Project summary Postural Tachycardia Syndrome (POTS) affects ~3 million adults in the United States. These patients have a poor quality of life due to chronic presyncopal symptoms and tachycardia that occur upon standing. Our research has shown that meals rich in carbohydrates significantly exacerbate presyncopal symptoms in POTS, however, the underlying mechanism that explains this clinical observation remains unknown. Accordingly, our group conducted a preliminary study to evaluate the pathophysiology of POTS’ excessive orthostatic tachycardia after glucose intake; we surveyed the hemodynamic and neurohormonal changes that occurred after a 75-gr oral glucose challenge for up to 2-hrs (postprandial period) in POTS patients and healthy controls. Compared with fasting conditions, the ingestion of glucose worsened upright tachycardia in POTS patients, which was associated with a more robust reduction in upright stroke volume compared with healthy controls. With regards to the disproportionate decrease in upright stroke volume in POTS patients, this could, in part, be explained by a significant blood pooling in the splanchnic circulation. The splanchnic circulation is the largest blood volume reservoir of the human body, storing ~25% of the total blood volume. Upon standing, there is a significant blood pooling, which occurs mostly in the splanchnic veins. Finally, our study has also shown that 30-min after the ingestion of 75-gr of glucose, POTS patients had a selectively increased secretion of the glucose-dependent insulinotropic polypeptide (GIP) hormone compared with healthy controls. This hormone has vasodilatory properties in the splanchnic circulation. Importantly, the increase in GIP secretion was time-dependently associated with a fall in upright stroke volume after glucose intake in POTS. Consequently, these findings point to the potential contribution of GIP in the pathophysiology of the increased postprandial orthostatic tachycardia and presyncopal symptoms in POTS patients. As such, the overall goal of this proposal is to investigate the mechanisms underlying the exacerbation of orthostatic tachycardia and POTS presyncopal symptoms in response to glucose ingestion. Specifically, we will evaluate the contribution of GIP on the changes in the splanchnic venous capacitance after oral glucose and during upright posture in POTS patients.