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Baseline left ventricular ejection fraction associated with symptom improvements in both children and adolescents with postural tachycardia syndrome under metoprolol therapy

Abstract Background: Postural tachycardia syndrome (POTS) is a common childhood disease that seriously affects the patient's physical and mental health. This study aimed to investigate whether pre-treatment baseline left ventricular ejection fraction (LVEF) and left ventricular fractional shortening (LVFS) values were associated with symptom improvement after metoprolol therapy for children and adolescents with POTS. Methods: This retrospective study evaluated 51 children and adolescents with POTS who received metoprolol therapy at the Peking University First Hospital between November 2010 and July 2019. All patients had completed a standing test or basic head-up tilt test and cardiac echocardiography before treatment. Treatment response was evaluated 3 months after starting metoprolol therapy. The pre-treatment baseline LVEF and LVFS values were evaluated for correlations with decreases in the symptom score after treatment (ΔSS). Multivariable analysis was performed using factors with a P value of <0.100 in the univariate analyses and the demographic characteristics. Results: A comparison of responders and non-responders revealed no significant differences in demographic, hemodynamic characteristics, and urine specific gravity (all P > 0.050). However, responders had significantly higher baseline LVEF (71.09% ± 4.44% vs. 67.17% ± 4.88%, t = −2.789, P = 0.008) and LVFS values (40.00 [38.00, 42.00]% vs. 36.79% ± 4.11%, Z = −2.542, P = 0.010) than the non-responders. The baseline LVEF and LVFS were positively correlated with ΔSS (r = 0.378, P = 0.006; r = 0.363, P = 0.009), respectively. Logistic regression analysis revealed that LVEF was independently associated with the response to metoprolol therapy in children and adolescents with POTS (odds ratio: 1.201, 95% confidence interval: 1.039–1.387, P = 0.013). Conclusions: Pre-treatment baseline LVEF was associated with symptom improvement after metoprolol treatment for children and adolescents with POTS.


Introduction
Postural tachycardia syndrome (POTS) is a common form of orthostatic intolerance (OI) and is associated with excessive orthostatic tachycardia. [1][2][3] The incidence of POTS is approximately 6.80% among children and adolescents, [4] and this condition seriously affects their physical health, psychological health, and quality of life. [5,6] Beta-blockers are important treatment option for POTS in children and adolescents, [7,8] but they only improve symptoms in approximately 57.10% to 57.89% of children. [9,10] Therefore, to better guide personalized therapy, it would be useful to identify pre-treatment indexes that can predict symptom improvement in children and adolescents with POTS.
Previous research has suggested that the poor efficacy of metoprolol treatment for POTS is related to its complex pathogenesis, which can involve autonomic dysfunction, high catecholamine status, excessive vasodilation, and low central blood volume. Furthermore, previous studies have indicated that the efficacy of metoprolol treatment (a betaadrenoceptor blocker) for POTS in children and adolescents was related to plasma concentrations of norepinephrine, [11] copeptin, [12] and C-type natriuretic peptide, [13] as well as heart rate (HR) variability from a 24-h dynamic electrocardiography (Holter) assessment. [14] However, these indicators can be unstable and relatively difficult to evaluate, which limits their clinical use. Therefore, stable, non-invasive, and easily evaluable indicators are needed to predict symptom improvement in response to metoprolol treatment for POTS.
Left ventricular ejection fraction (LVEF) and left ventricular fractional shortening (LVFS) are relatively stable echocardiography parameters that reflect the contractile function of the left ventricle. Furthermore, these markers reflect the state of catecholamine and sympathetic activity, [15,16] and can be easily evaluated in a non-invasive manner. Previous studies have also shown that sympathetic activity is at least partially predicted by clinicodemographic characteristics, including age, height, weight, HR, blood pressure (BP), and urine specific gravity (Usg). [17,18] We hypothesized that the response to metoprolol treatment for children and adolescents with POTS might be associated with echocardiography-derived indexes (LVEF and LVFS), demographic characteristics, and/or hemodynamic parameters. This pilot study aimed to determine whether these pre-treatment factors could predict the response to metoprolol therapy and guide personalized treatment strategies in this setting.

Ethical approval
The study protocol was approved by the Ethics Committee of Peking University First Hospital, China (No. 2018 [202]). All parents or guardians of the patients were informed of the study's purpose and provided written informed consent.

Subjects
This retrospective study evaluated 56 children and adolescents with POTS who received metoprolol treatment as outpatients or inpatients at the Peking University First Hospital between November 2010 and July 2019. Followup was performed via telephone and inpatient/outpatient visits after 3 months to evaluate treatment response, although five patients (8.90%) were lost to follow-up. Thus, the study included 51 children and adolescents with POTS (28 males, median age: 12.0 ± 2.2 years). Figure 1 shows the study flowchart.

Diagnosis and data collection
The diagnosis of POTS had been based on the following factors: (1) the condition mainly affects older children; (2) the condition is often associated with predisposing factors, such as a rapid change from the supine position to the upright position or prolonged standing; (3) symptoms of OI, such as dizziness, headache, fatigue, blurred vision, chest tightness, palpitations, hand tremors, and syncope; (4) a HR increase of ≥40 beats per minute (bpm) or a maximum HR of ≥130 bpm (for 6-12-year-old children) or ≥125 bpm (for 13-18-yearold adolescents) without orthostatic hypotension (BP decrease of >20/10 mmHg) during the first 10 min of the standing test or basic head-up tilt test; and (5) exclusion of other diseases that can cause OI symptoms, such as organic cardiovascular diseases, metabolic diseases, neurological diseases, or mental illness. [14,[19][20][21] Patients also underwent evaluations to collect data regarding their medical history, physical status, Usg index, electrocardiography echocardiography parameters, standing test, electroencephalography, cranial computed tomography or magnetic resonance imaging, basic head-up tilt test, and psychological tests. The treatment response was evaluated after 3 months of metoprolol treatment, based on the difference between the pre-treatment and post-treatment symptom scores (SS), as described below. Figure 1 displays a flow-chart explaining the inclusion of participants in this study.

Quality assurance
Before the start of the study, all researchers were required to complete professional training and a written assessment before they judged and entered data regarding the patients' eligibility and treatment response.

Standing test and basic head-up tilt test
The standing test was performed in an environment with dim light. The patient rested in the supine position for 10 min and the HR and BP values were continuously monitored using a Dash 2000 multi-channel physiological monitor (General Electric Company, New York, NY, USA). The patient was then asked to stand upright for 10 min for additional monitoring of the HR and BP values. [20] All drugs that could affect autonomic function were discontinued for at least five half-lives before the basic head-up tilt test and patients were required to fast for >4 h before the test. The patient was asked to rest in the supine position for 10 to 30 min on an adjustable bed (HUT-821; Beijing Juchi, Beijing, China) in a quiet, warm, and dimly Chinese Medical Journal 2021;134 (16) www.cmj.org lit environment. The HR, BP, and electrocardiography parameters were continuously evaluated using a multi-lead monitor (General Electric Company) until the HR and BP values stabilized. The bed was then tilted to 60°and the HR, BP, and electrocardiography parameters were again monitored until a positive reaction appeared or until the patient completed the 45 min examination. [19,22] Measurement and calculation of LVEF and LVFS The patients were confirmed that they had no vomiting, diarrhea, other fluid loss symptoms, iatrogenic supplements, rehydration, or diuretic use immediately before the echocardiographic measurements of LVEF and LVFS. The pre-treatment measures of LVEF and LVFS were performed with the patient in the supine position by professionally trained staff using Doppler color echocardiography (Aplio Artida SSH-880CV, TOSHIBA, Japan) with a linear 2.50 to 5.00 MHz transducer. The long-axis section of the parasternal ventricle was evaluated using Mmode echocardiography to determine the left ventricular end-diastolic diameter (LVDd) and the left ventricular endsystolic diameter (LVDs), which were then used to calculate the LVEF and LVFS values: Evaluating treatment response using DSS Each patient's SS was calculated for OI-related symptoms, which include syncope, dizziness, headache, chest tightness, nausea, palpitations, hand tremors, sweating, blurred vision, and inattention. Symptoms were scored as 0 point (no occurrence), 1 point (once per month), 2 points (2-4 times per month), 3 points (2-7 times per week), or 4 points (more than once per day), with the patient's total score calculated by adding the scores for each symptom. The pre-treatment baseline SS, the 3-month follow-up SS, and the change in the SSs (DSS) were evaluated. A decrease of ≥2 points was used to identify "responders" (ie, treatment was effective) and a decrease of <2 points was used to identify "non-responders." [14,23] Treatment and follow-up plan After the initial diagnosis of POTS, the patients had received oral metoprolol treatment for 2.0 (1.0, 3.0) months (median [interquartile range, IQR]). The initial metoprolol dose was 0.5 mg·kg À1 ·day À1 (twice daily) and was gradually increased as tolerable and necessary to a maximum dose of 2.0 mg·kg À1 ·day À1 . [19,24] After 3 months, the post-treatment SS scores were evaluated via telephone or inpatient/ outpatient hospital visits. Drug adherence, OI symptom frequency, and adverse drug reactions were recorded during the follow-up.

Statistical analysis
All analyses were performed using SPSS software (version 23.0; IBM Corp., Armonk, NY, USA). Continuous data were reported as mean ± standard deviation or median (IQR), and the Shapiro-Wilk test was used to evaluate normality. Normally distributed data were analyzed using the independent sample t-test and non-normally distributed data were analyzed using the Mann-Whitney U test. Categorical data were reported as number (%) and analyzed using the Chi-squared test. Spearman correlation analysis was used to evaluate whether the DSS was correlated with LVEF or LVFS. Variables with univariate P values of <0.100 were selected to enter into a multivariable logistic regression model with conditional forward selection. Differences were considered statistically significant at P values of <0.050. 36.79% ± 4.11%, Z = À2.542, P = 0.010) [ Figure 2].

Correlations between the DSS and baseline LVEF or LVFS
As a marker for treatment response, a DSS was weakly correlated with the baseline LVEF value (r = 0.378, P = 0.006) and the baseline LVFS value (r = 0.363, P = 0.009) [ Figure 3].

Multivariable logistic regression analysis
The multivariable model was adjusted for sex, age, BMI, LVEF and LVFS, which revealed that LVEF was independently associated with the likelihood of response to metoprolol treatment in children and adolescents with POTS. Each 1% increase in the baseline LVEF value was associated with an approximately 21% higher likelihood of response to metoprolol treatment (odds ratio: 1.201, 95% confidence interval: 1.039-1.387, P = 0.013) [ Table 2].

Discussion
This study indicates that pre-treatment baseline LVEF and LVFS values were associated with symptom improvement after metoprolol treatment for children and adolescents with POTS. Furthermore, the pre-treatment baseline LVEF value was independently associated with symptom improvement after metoprolol treatment.    Chinese Medical Journal 2021;134 (16) www.cmj.org Among children and adolescents, POTS is a common type of OI [25] that can seriously affect their physical health, mental health, and quality of life. [26] Therefore, active and effective treatment is important for children and adolescents with POTS. One potential treatment option is b-blockers, although previous studies have revealed conflicting findings regarding their efficacy, which may be related to the complex and diverse pathogenesis of POTS. For example, the pathogenesis of POTS mainly involves high catecholamine status, [11] overexcitement of sympathetic activity, [27] low central blood volume, [23,28] and excessive vasodilation. [29,30] Neuro-humoral factors, including hydrogen sulfide and sulfur dioxide, catecholamines and vasoactive peptides, siginificantly regulate cardiac structure and function. Metoprolol (a b-blocker) helps block the b-adrenoceptors of the myocardium, which suggests that metoprolol treatment for POTS may be effective only for children with sympathetic hyperactivity or b-receptor hypersensitivity. [31] Therefore, identifying sympathetic hyperactivity in children and adolescents with POTS might guide effective treatment selection. We have previously reported that response to metoprolol treatment was predicted by plasma concentrations of norepinephrine, copeptin, and C-type natriuretic peptide, as well as HR variability from a 24-h Holter evaluation. [11][12][13][14] However, these evaluations are invasive and/or time consuming, which can limit their clinical utility. Therefore, we attempted to identify relatively stable, non-invasive, and easily evaluable markers for predicting response to metoprolol treatment for POTS.
Values for LVEF and LVFS are relatively stable and readily obtainable using non-invasive echocardiography and are widely used to diagnose syncope in children. Furthermore, LVEF and LVFS values increase in humans and animals with sympathetic hyperactivity. [32][33][34][35] Moreover, previous studies have indicated that ventricular function indexes (LVEF, LVFS, or left ventricle volume) increased significantly during upright exercise in healthy humans (vs. the resting state) and that plasma catecholamine concentrations were positively correlated with LVEF changes or left ventricle volume. [36,37] However, the resting LVEF value decreased significantly after metoprolol treatment for coronary artery disease, [38] and children with vasovagal syncope experience symptom improvement after metoprolol treatment. [39] The above facts attracted us to design the present study to evaluate if LVEF might be associated with symptom improvement after metoprolol treatment for children and adolescents with POTS.
The present study revealed that responders had considerably high LVEF and LVFS values (vs. non-responders), which suggests that patients with sympathetic hyperactivi-ty would respond well to metoprolol treatment. We also found that the baseline LVEF and LVFS values were positively correlated with the DSS, which is an indicator of treatment response. Furthermore, the logistic regression analysis revealed that the baseline LVEF value predicted response to metoprolol treatment in children and adolescents with POTS. These results suggest that patients with a low baseline LVEF value would be less likely to experience symptom improvement after metoprolol treatment. Therefore, evaluation of the pre-treatment LVEF may be useful for predicting the response to metoprolol therapy in children and adolescents with POTS, which may guide more personalized treatment selection.
The present study still has several limitations, however. The follow-up period was short. The sample size was relatively small. Also, direct blood volume measurements were not performed in the study. In the future, large-size based multicenter studies with prolonged follow-up period are needed.