Metoprolol is clinically used to treat postural tachycardia syndrome (POTS) in children, but its effectiveness is unsatisfactory. Biomarkers to predict therapeutic efficacy are needed. We aimed to explore changes in the plasma copeptin level for assessing the therapeutic efficacy of metoprolol for POTS in children. We included 49 children with POTS and 25 healthy children as controls. Patients received metoprolol for 1.5 to 3 months. The plasma copeptin level was measured by sandwich immunoluminometric assay. The area under the receiver operating characteristic curve was used to explore the predictive value of the plasma copeptin level. The baseline plasma copeptin level was higher in children with POTS than controls (10.524 ± 2.016 vs 8.750 ± 1.419 pmol/L, p <0.001) and was lower for responders than nonresponders to metoprolol (9.377 ± 1.411 vs 12.054 ± 1.662 pmol/L, p = 0.003). The area under the receiver operating characteristic curve was 0.889 (95% confidence interval 0.799 to 0.980). With a baseline plasma copeptin level of 10.225 pmol/L as a cutoff, the sensitivity was 90.5% and specificity 78.6% in predicting the efficacy of metoprolol in children with POTS. In conclusion, the baseline plasma copeptin level can be used as a biomarker to predict the therapeutic effectiveness of metoprolol in children with POTS.
Postural tachycardia syndrome (POTS) is one of the main manifestations of orthostatic intolerance, whereby a change from a supine to an upright position causes tachycardia, followed by light-headedness, headache, chest tightness, even syncope, but not low blood pressure, which seriously threaten the health of children. Because tachycardia is the basic characteristic of this syndrome, β-adrenergic receptor blockers can be used, theoretically functioning by restraining the activity of the sympathetic nervous system, reducing the stimulus to the heart baroreceptor and blocking the high level of catecholamine in the circulation. Previous studies showed that this kind of medicine could relieve the heart rate and other symptoms in POTS. However, Chen et al reported a cure rate of only 42.1% after 3 to 6 months’ treatment with metoprolol in 19 children with POTS. Thus, biomarkers predicting the efficacy of β-blocker therapy for patients are needed. Relative hypovolemia and hyperadrenergic status comprise the key pathogenesis of POTS. During the position changes, the frequent stimulus of excessively reduced venous return and central blood volume may increase the arginine vasopressin (AVP) in patients with POTS. Meanwhile, increased catecholamine levels under hyperadrenergic status in some POTS cases may inhibit secretion of AVP, and a low AVP level might be reflective of hyperadrenergic condition. However, AVP is unstable in vivo, which limits its clinical application as a biomarker. Copeptin, a joint glycopeptide of AVP, could be released equally with AVP, and they remain at stable levels in the blood. Therefore, in the present study, we aimed to examine the variation in the plasma level and predictive value of plasma copeptin for efficacy of metoprolol treatment in children with POTS.
Methods
We included 49 children with POTS (7 to 16 years old) and 25 normal controls (11 to 13 years old). The diagnostic criteria for POTS in children is (1) normal heart rate when supine and no evidence of any cardiovascular disease; (2) after standing up or getting up, ≥2 of dizziness, chest distress, chest pain, headache, palpitation, pale face, amaurosis, fatigue, discomfort, or syncope; (3) symptoms relieved or diminished by recumbence and symptoms for ≥1 month; (4) a positive response to head-up test or head-up tilt test (within 10 minutes after the head-up or tilt position, the heart rate increases >40 beats/min or the maximum heart rate is >120 beats/min, with decrease in blood pressure to <20/10 mm Hg); and (5) cardiovascular or neurogenic diseases excluded after electrocardiogram, electroencephalography, magnetic resonance imaging, or other related technologies.
The study was authorized by the Ethics Committee of Peking University First Hospital, and informed consent was obtained from parents.
Children who were lying quietly for 10 minutes in a warm dim-lighted condition for head-up test underwent heart rate and blood pressure measurements and routine electrocardiogram with a multilead physiological monitor (Dash 2000; General Electric, Schenectady, New York). Then, children changed to an upright position for 10 minutes and underwent the same measurements.
All children fasted before experiments. The experimental conditions were quiet, dim light, and proper temperature. Children underwent electrocardiogram, blood measurement, and monitoring of symptoms or premonitory symptoms of syncope with a multilead physiological monitor. Children were required to lie quietly for 10 minutes and underwent basal arterial blood pressure and heart rate measurements and electrocardiogram. Then, children stood on a tilt table at 60° (HUT-821; Beijing Juchi, Beijing, China) and underwent blood pressure and heart rate measurements, electrocardiogram, and clinical monitoring until positive reactions appeared or for 45 minutes.
The following 10 symptoms were monitored for symptom scores : syncope, light-headedness, vertigo, chest tightness, nausea, palpitations, headache, hand tremors, sweating, blurred vision, and inattention. Scores are 0, never; 1, once per month; 2, twice to 4 times per month; 3, twice to 7 times per week; and 4, more frequent than once per day. The total scores were the sum of all symptoms.
All children with POTS received metoprolol (0.5 mg/kg, twice a day) for 1.5 to 3 months; head-up test examination was repeated during follow-up and syncope symptoms were scored. Children with a heart rate change when moving from the supine to upright position <30 beats/min in the head-up test after treatment or score decrease ≥2 were considered responders, and children with a heart rate change when moving from the supine to upright position >30 beats/min, maximum heart rate >120 beats/min, or score decrease <2 after treatment were considered nonresponders.
Normal children and children with POTS before treatment fasted for at least 8 hours, and venous blood was drawn in children at 8:30 a.m. in the morning and stored in an ethylene diamine tetraacetic acid anticoagulant tube. Plasma was obtained after centrifugation at 2,000 g for 20 minutes at 4° and cryopreserved in an −80° refrigerator. Measurements involved the double antibody sandwich enzyme-linked immune sorbent method (R&D System Company, Minneapolis, MN), and only 10-μL plasma sample was needed.
The data were analyzed with SPSS 13.0 (SPSS, Chicago, Illinois) and are expressed as mean ± SD. The independent-samples t test or chi-square test was used to compare data for 2 groups, and analysis of variance was used to compare 3 groups. The prognostic value of plasma copeptin level for metoprolol treatment in children with POTS was evaluated by the area under the receiver operating characteristic curve. p Value <0.05 was considered statistically significant.
Results
We included 49 children with POTS (24 girls) and 25 healthy children (11 girls) as controls. The 2 groups did not differ in sex ratio, age, height, weight, or body mass index (p >0.05; Table 1 ). The baseline plasma copeptin level was higher for children with POTS than controls (p <0.001; Table 1 ). In the control group, the baseline plasma copeptin level correlated with neither age (p >0.05) nor body mass index (p >0.839).
| Group | Cases | Male/Female | Age (Years) | Height (cm) | Weight (kg) | Body Mass Index (kg/m 2 ) | Copeptin (pmol/L) |
|---|---|---|---|---|---|---|---|
| POTS | 49 | 25/24 | 12 ± 2 | 154 ± 14 | 45 ± 12 | 17.712 ± 2.893 | 10.524 ± 2.016 |
| Control | 25 | 14/11 | 12 ± 1 | 153 ± 7 | 46 ± 15 | 19.500 ± 5.482 | 8.750 ± 1.419 |
| p value | — | 0.685 | 0.666 | 0.638 | 0.415 | 0.151 | <0.001 |
All children with POTS received metoprolol (0.5 mg/kg, twice a day) for 1.5 to 3 months. Symptom scores and heart rate were lower after than before treatment ( Table 2 ).
| Treatment | Symptom Score (n = 49) | △HR (Beats/min) |
|---|---|---|
| Pre-treatment | 4 ± 2 | 41 ± 8 |
| Post-treatment | 2 ± 2 | 27 ± 8 |
| p value | <0.001 | <0.001 |
The baseline plasma copeptin level was lower for responders than nonresponders (p <0.001; Table 3 and Figure 1 ). After treatment, symptom scores and change in heart rate were lower for responders than nonresponders (p <0.001).
| Subjects | n | Pre-Treatment Symptom Score | Pre-Treatment △HR (Beats/min) | Post-Treatment Symptom Score | Post-Treatment △HR (Beats/min) | Copeptin (pmol/L) |
|---|---|---|---|---|---|---|
| Responders | 28 | 4 ± 2 | 38 ± 6 | 1 ± 1 | 20 ± 7 | 9.377 ± 1.411 |
| Nonresponders | 21 | 4 ± 2 | 41 ± 10 | 3 ± 2 | 32 ± 6 | 12.054 ± 1.662 |
| p value | 0.666 | 0.842 | <0.001 | <0.001 | <0.001 |
The area under the receiver operating characteristic curve was 0.889 (95% confidence interval 0.799 to 0.980) for response to metoprolol, which suggested that the baseline plasma copeptin level had high predictive value for treatment. With a plasma copeptin cutoff of 10.255 pmol/L, the sensitivity and specificity were 90.5% and 78.6%, respectively ( Figure 2 ).
