The Pathophysiological Role of Adrenergic Antibodies in Postural Tachycardia Syndrome (Aims #1&2)
试验速览
- 阶段
- 不适用
- 状态
- 招募中
- 入组人数
- 125
- 试验地点
- 2
- 主要终点
- The proportion of alpha-1 Ab titer positive subjects
研究概览
简要总结
Objective: In this pilot study, we will test the hypothesis that patients with POTS (age 18-60 years) will have a higher percentage of functional antibodies to adrenergic receptors compared with control subjects without POTS.
详细描述
Background & Rationale:
Postural Tachycardia Syndrome (POTS) is a chronic state of orthostatic tachycardia (> 30 bpm increment from lying to standing) and typical symptoms that are worse on standing, and are relieved by lying down. Typical orthostatic symptoms include palpitation, lightheadedness, chest pains, dyspnea, tremulousness, blurred vision and mental clouding. POTS often occurs in younger individuals with a female predominance (4-5 fold). Using the RAND36 quality of life (QOL) tool, we showed that POTS patients had lower quality of life (QOL) scores than healthy subjects for both physical (26±9 vs. 54±6; P<0.0001) and mental health domains (43±11 vs. 52±10; P<0.0001). These QOL scores are similar to scores for chronic obstructive pulmonary disease and congestive heart failure.
In collaboration with the Kem/Yu lab (Oklahoma University), the investigators sought to determine whether POTS patients had functionally significant adrenergic receptor (AR) Abs. Samples from 14 POTS patients (included 7 blinded, well-characterized samples from Vanderbilt) and 10 healthy control subjects. Using the rat cremaster artery assay, the sera/immunoglobulin (IgG) of the POTS patients demonstrated significantly greater arteriolar contractile activity (69±3% of baseline vessel diameter) compared to the control subjects (91±1% of baseline; P<0.001). This contractility was suppressed with prazosin, an α1-AR blocker. With the addition of POTS sera, the phenylephrine dose-response curve was shifted to the right. In other words, a higher dose of phenylephrine was required to achieve the same degree of vasoconstriction, suggests that the α1-AR Ab is actually a partial-agonist/antagonist.
Using a cell-based cyclic AMP (cAMP) reporter assay, all POTS sera had dose-dependent β1-AR activation (max: +30±3% from buffer baseline) compared to control sera (-1±2% from buffer baseline; P<0.001), and 7/14 POTS patients (but no control subjects) had elevated β2-AR activation. The excessive β1-AR activation could be blocked with propranolol. With the addition of POTS sera, the isoproterenol dose-response curve was shifted to the left (a lower isoproterenol dose was required to achieve the same receptor activation in the presence of the POTS sera). These data suggest that the β1-AR Ab is actually a straight agonist.
Big Picture:
研究设计
- 研究类型
- Observational
- 观察模型
- Case Control
- 时间视角
- Cross Sectional
入排标准
- 年龄范围
- 18 Years 至 60 Years（Adult）
- 性别
- All
- 接受健康志愿者
- 是
入选标准
- •Patients who have been previously diagnosed with POTS
- •Control subjects (patients not diagnosed with POTS)
- •Age between 18 - 60 years
- •Males and Females (Give that >80% of POTS patients are female, we will attempt to enroll a similar percentage of female control subjects)
- •Able and willing to provide consent
排除标准
- •Overt cause for postural tachycardia, i.e., acute dehydration
- •Significant cardiovascular, pulmonary, hepatic, or hematological disease by history or prior testing
- •Highly trained athletes
- •Subjects with somatization or severe anxiety symptoms will be excluded
- •Use of drospirenone (a spironolactone analogue) containing oral contraceptive agent
- •Hypertension defined as supine resting BP>145/95 mmHg off medications or needing antihypertensive medication
- •Other factors which in the investigator's opinion would prevent the participant from completing the protocol, including poor compliance during previous studies or an unpredictable schedule
- •Unable to give informed consent
研究组 & 干预措施
Postural Tachycardia Syndrome (POTS)
Patients with postural tachycardia syndrome; patients will receive both IV phenylephrine and IV isoproterenol
干预措施: Phenylephrine (Drug)
Postural Tachycardia Syndrome (POTS)
Patients with postural tachycardia syndrome; patients will receive both IV phenylephrine and IV isoproterenol
干预措施: Isoproterenol (Drug)
Healthy (control) Subjects
Healthy volunteers that are gender and age-matched (by groups) to the POTS patients; healthy subjects will receive both IV phenylephrine and IV isoproterenol
干预措施: Phenylephrine (Drug)
Healthy (control) Subjects
Healthy volunteers that are gender and age-matched (by groups) to the POTS patients; healthy subjects will receive both IV phenylephrine and IV isoproterenol
干预措施: Isoproterenol (Drug)
结局指标
主要结局
The proportion of alpha-1 Ab titer positive subjects
时间窗: 1 Year (to measure Adrenergic antibody assay)
The primary comparison will be the proportion of Ab titers between POTS patients compared to control subjects.
次要结局
- Antibody Positivity by Clinical Autoimmune Syndromes(1 Year (to measure Adrenergic antibody assay))
- Isoproterenol HR Increase (PD25)(1 Year (to measure Adrenergic Antibody assay))
- Phenylephrine Systolic BP Increase (PD25)(1 Year (to measure Adrenergic Antibody assay))
- Antibody Positivity by Joint Hypermobility Status(1 Year (to measure Adrenergic antibody assay))
- Antibody Positivity by Viral Onset of POTS(1 Year (to measure Adrenergic Antibody assay))
- The proportion of beta adrenergic Ab titer positive subjects(1 Year (to measure Adrenergic Antibody assay))
研究者
Dr. Satish Raj
Professor
University of Calgary