The study was designed to explore flow-mediated vasodilation (FMD) and endothelium function in children with postural orthostatic tachycardia syndrome (POTS). The patient group consisted of 46 children 12 ± 3 years of age who were diagnosed with POTS from June 2008 to January 2009 by head-up test or head-up tilt test at Peking University First Hospital. Twenty healthy children 12 ± 4 years of age were selected for the control group. Plasma concentrations of nitric oxide (NO) and activity of NO synthase (NOS) were determined in the patient and control groups. FMD of each participant’s brachial artery was measured using color Doppler vascular ultrasound and a comparison of FMDs and plasma NO and NOS activities between the 2 groups was done using independent t test. No significant differences were found between the POTS and control groups in age, sex ratio, height, body weight, baseline blood pressure, heart rate, and baseline brachial artery diameter. Patients in the POTS group had larger FMD (10.8 ± 4.4%) than children in the control group (5.7 ± 2.2%), and this difference was significant (p <0.01). Plasma NO and NOS levels were significantly higher in the POTS group than in the control group (NO 74 ± 19 μmol/L in POTS group vs 62 ± 6 μmol/L in control group, p <0.01; NOS 21 ± 3 U/mL in POTS group vs 15 ± 1 U/mL in control group, p <0.01). In addition, there was a significant correlation between FMD and the NOS activity. In conclusion, augmented FMD and abnormal function of vascular endothelium may play an important role in POTS in children.
Endothelium plays a key role in the regulation of vascular tone, control of coagulation, and regulation of leukocyte adhesion and migration. Previous studies have proved that dysfunction of endothelium is related to many cardiovascular diseases, such as atherosclerosis, primary hypertension, heart failure, and so on. However, despite the abnormal vascular tone shown in patients with postural orthostatic tachycardia syndrome (POTS), few studies on POTS have been conducted in children. Color Doppler vascular ultrasound was used as a noninvasive way to measure the function of endothelium and examine flow-mediated vasodilation (FMD) of the brachial artery. Nitric oxide (NO) produced by vascular endothelium is believed to participate in the process of FMD. Therefore, the aim of our study was to explore FMD and endothelium functions in children with POTS.
Methods
The patient group consisted of 46 children 12 ± 3 years of age who complained of orthostatic intolerance and were diagnosed with POTS by head-up test (HUT) or head-up tilt test (HUTT) from June 2008 to January 2009 at Peking University First Hospital. Twenty healthy children 12 ± 4 years of age were selected for the control group. None of the 66 participants had had fever or had ingested substances such as caffeine, high-fat food, or vitamin C in the 2 weeks before examination. All 20 children in the control group had negative results for HUT and had no history of orthostatic intolerance. This study was approved by the ethics committee of Peking University First Hospital and all participants’ guardians were fully informed of the purpose and method of the study.
There exists no standard definition for POTS in children. However, our study referred to the following criteria to define POTS. (1) A child has a normal heart rate when supine and no evidence of cardiovascular diseases. (2) After standing up or getting up, a child has ≥3 of the following symptoms: dizziness, chest distress, chest pain, headache, palpitation, pale face, amaurosis, fatigue, discomfort, or syncope. These symptoms should be relieved or decreased by recumbence. In addition, symptoms should occur repeatedly for ≥1 month. (3) Despite symptoms of orthostatic intolerance, a child has a heart rate increase ≥30 beats/min or a heart rate >120 beats/min within the first 10 minutes after standing or during HUT or HUTT. Simultaneously, decrease of blood pressure should be <20/10 mm Hg. (4) A child with other diseases that cause symptoms of the autonomic nervous system (such as anemia, arrhythmia, hypertension, or endocrine disorders) and cardiogenic or neurogenic diseases that would induce syncope should be excluded.
The protocol of HUT or HUTT was developed and practiced in the department of pediatrics of Peking University First Hospital. Subjects fasted for 12 hours, and drugs that could influence normal activity of the autonomic nervous system were avoided for ≥3 days before the test. The test was performed in a quiet, softly lit, and temperature-controlled room equipped with medical resuscitation facilities. Electrocardiogram and blood pressure of subjects were continuously monitored by a Dash 2000 Multi-Lead Physiological Monitor (General Electric Company, New York, New York), and data were recorded until the end point of the test or a positive response appeared. Subjects’ baseline heart rates and blood pressure while in a supine position were measured after a 10-minute resting period. For HUT, subjects stood up after a 10-minute rest. If a positive response (as defined in the criteria for POTS) appeared within 10 minutes after standing, the test would be discontinued and a diagnosis of POTS would be reached. If changes in heart rate and blood pressure were in normal ranges during HUT, subjects would undergo the HUTT, which consisted of placing subjects on an electrically motorized tilt table with a footboard and tilting it at an angle of 60° after a 10-minute rest period in a supine position. HUTT would be terminated when a positive response appeared or when subjects completed the test after being tilted for 45 minutes with a negative result. Positive responses in HUTT have been mentioned in previous studies.
Measurement was performed by a color Doppler ultrasound system (ultrasound cardiograph, HP2500, Philips Healthcare, Andover, Massachusetts) and the frequency of the transducer was 7.5 MHz. The protocol of measurement used in this study for endothelium-dependent FMD in the brachial artery was recommended by the American College of Cardiology and other sources. In preparation, participants were told to fast for ≥8 to 12 hours and avoid caffeine, high-fat foods, vitamin C, and vasoactive drugs for >4 1/2 times. Exercise was also avoided for 4 to 6 hours before examination. For female children, investigators inquired about menstrual cycles and menstrual phases were avoided. All assessments were done in the morning (8 a.m. to 9 a.m. ). The participant was supine, with his or her arm in a comfortable position for imaging of the brachial artery. The transducer was placed longitudinally on the skin of the upper arm about 5 to 10 cm above the antecubital fossa, and a mercurial sphygmomanometer cuff was placed around the forearm. The baseline image of the brachial artery was obtained to measure the diameter (baseline diameter) of the vascular lumen and blood flow was evaluated by pulse-wave Doppler velocity signal (detection angle 40°). Then the cuff was inflated to about 40 to 50 mm Hg higher than systolic pressure to create an arterial occlusion. The inflation was kept for 5 minutes. When the cuff was deflated, a high-flow stimulus was produced and the brachial artery dilated resulting from increased shear stress. The image of the brachial artery and evaluation of blood flow were obtained again at the same position within 2 minutes after deflation of the cuff. Maximum diameter of the vascular lumen during dilation was recorded. FMD was calculated as (maximum diameter − baseline diameter)/baseline diameter × 100%.
All FMD measurements were done by the same operator. Stability and reproducibility of detection were tested before measurements. The equipment and frequency of the transducer were the same as those described in the previous paragraph. The operator detected the brachial artery diameters 2 times (the transducer was placed at the same site) for 10 volunteers. Two values of diameter from each volunteer were obtained. Paired t test was used to evaluate reproducibility of the results.
The same preparations as those done before FMD detection were required. A blood sample of 2 ml was obtained from each participant’s cubital vein after he or she had fasted for ≥8 hours at rest in the morning (7 a.m. to 8 a.m. ), and was collected in a tube containing ethylenediaminetetra-acetic acid and aprotinin. Blood samples were immediately stored at 4°C and centrifuged at 2,000 minute −1 for 20 minutes at 4°C within 12 hours after collection. Plasma was immediately frozen and stored at −20°C until measurement. NO was determined by a nitrate reductase method and NO synthase (NOS) activity was determined by a chemical colorimetric method.
Statistical analysis was completed by SPSS 13.0 (SPSS, Inc., Chicago, Illinois). Measurement data were presented as mean ± SD. Numeration data were stated as cases. Comparisons between the POTS and control groups were performed by independent t test for measurement data and chi-square test for numeration data. Paired t test was used to compare the 2 values of brachial artery diameter in each volunteer for detection reproducibility. Correlation analysis was done to explore the relation between FMD and NO level and NOS activity. A p value <0.05 was considered statistically significant.
Results
Twenty-five of 46 children diagnosed POTS demonstrated syncope (54.3%). There were no statistical differences between the POTS and control groups in age, sex ratio, height, body weight, baseline brachial artery diameter, baseline supine blood pressure, and heart rate ( Table 1 ).
| Characteristics | POTS Group (n = 46) | Control Group (n = 20) | t or Chi-Square Value | p Value |
|---|---|---|---|---|
| Male/female subjects | 23/23 | 8/12 | 0.560 | 0.454 |
| Age (years) | 12 ± 3 | 12 ± 4 | 0.635 | 0.531 |
| Height (cm) | 155 ± 14 | 146 ± 20 | 1.707 | 0.099 |
| Body weight (kg) | 45 ± 13 | 46 ± 22 | −0.088 | 0.930 |
| Baseline diameter of brachial artery (mm) | 3.3 ± 0.4 | 3.1 ± 0.5 | 1.888 | 0.064 |
| Supine mean arterial blood pressure (mm Hg) | 83 ± 8 | 79 ± 10 | 1.798 | 0.077 |
| Supine heart rate (beats/min) | 77 ± 11 | 77 ± 13 | 0.249 | 0.804 |
According to results of paired t test, there was no significant difference between the 2 values of each brachial artery diameter (p = 0.299; Table 2 ), indicating that detection results were reproducible.
| Volunteer | First Value (mm) | Second Value (mm) |
|---|---|---|
| 1 | 2.9 | 3.0 |
| 2 | 3.2 | 3.1 |
| 3 | 3.4 | 3.3 |
| 4 | 3.0 | 3.0 |
| 5 | 3.2 | 3.3 |
| 6 | 3.6 | 3.6 |
| 7 | 2.6 | 2.7 |
| 8 | 2.9 | 3.0 |
| 9 | 3.0 | 3.1 |
| 10 | 3.6 | 3.5 |
Endothelium-dependent FMD of the brachial artery was examined for all participants and comparison between the 2 groups was done by independent t test. Patients in the POTS group had greater FMD than those in the control group. The difference was significant (p <0.01; Table 3 ).
| Baseline Diameter (mm) | Maximum Diameter (mm) | FMD (%) | |
|---|---|---|---|
| Group with postural orthostatic tachycardia syndrome (n = 46) | 3.3 ± 0.4 | 3.6 ± 0.4 ⁎ | 10.8 ± 4.4 ⁎ |
| Control group (n = 20) | 3.1 ± 0.5 | 3.2 ± 0.5 | 5.7 ± 2.2 |
| p value | 0.064 | 0.001 | <0.001 |
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