Introduction
Vasovagal syncope (VVS) is a common type of orthostatic intolerance in the pediatric population [
1]. Although the prognosis is regarded as benign, injuries associated with syncope may occur in 33% of patients with VVS [
2]. Recurrent syncope may lead to not only physical trauma but also mental disorders and poor quality of life in affected children [
3,
4]. Unfortunately, no pharmacological treatment with high-quality evidence has been proven to be effective for treating pediatric VVS. Metoprolol is a widely used type of β-adrenergic receptor blocker and is commonly used for treating pediatric VVS [
5]. The possible mechanisms for the action of β-blockers in treating patients with VVS include antagonizing increased sympathetic nerve activity [
6] and/or the elevated levels of circulating epinephrine (EP) and norepinephrine (NE) [
7]. However, the therapeutic effect of metoprolol in pediatric VVS patients is unsatisfactory [
8]. This phenomenon may be explained by the fact that not all children with VVS exhibit increased sympathetic activity. Therefore, biomarkers that represent the sympathetic activation status are urgently needed to predict the therapeutic efficacy of metoprolol. According to a mechanism-based study, sympathetic stimulation may boost the binding, movement, and formation of proplatelets in megakaryocytes [
9]. The mean platelet volume (MPV) has been reported to be closely associated with enhanced sympathetic nerve activity in VVS [
10]. Therefore, this study aimed to determine whether platelet-related parameters could predict the outcomes of metoprolol therapy in children with VVS.
Discussion
Our study focused on developing a therapeutic prediction model for metoprolol in pediatric patients with VVS. We found that the MPV and PDW in the treatment-effective group were greater than those in the treatment-ineffective group. Based on multivariate logistic regression, age and the MPV were used to predict therapeutic efficacy. According to the ROC analysis, PR curve, calibration plot, and Hosmer–Lemeshow test, the model demonstrated moderate predictive accuracy and a strong fit between its predictions and the observed data. According to the DCA, the predictive model could lead to improved clinical outcomes.
By comparing the baseline characteristics of the children suffering from VVS treated with metoprolol, we found that the baseline MPV and PDW in the treatment-effective group were greater than those in the treatment-ineffective group. Although there is currently no unified standard reference range for PDW in children, Hu's research pointed out that the range for PDW in a healthy control group with a median age of 12 years was 12.1% (10.8%, 13.1%) [
19]. The median age of the children included in our study was also 12 years, and the PDW range was 12.4% (11.2%, 12.9%), which was similar to that in Hu’s research [
19]. In our research, there was no significant difference in heart rate between the treatment-effective and treatment-ineffective groups, which was in accordance with the previous studies by Yuan et al. [
20] and Kong et al. [
21]. There are different phenotypes of VVS, including vasoinhibitory, cardioinhibitory, and mixed VVS. Our results showed that there was no relationship between the different phenotypes of VVS and the metoprolol efficacy. We speculated that the reason that the effective rate was similar among the patients with three phenotypes of VVS might be associated with the resting catecholamine levels. No difference in 24-hour urine NE levels was found between the vasoinhibitory and mixed subtypes of VVS in children [
21], which supported our speculation.
The MPV represents the average platelet size of a blood sample. Newly generated platelets are larger than older platelets; therefore, a high MPV may imply that the bone marrow produces new platelets at an increased speed under different stimuli. The PDW reflects the variability in platelet size and is considered as a marker of platelet activation. A high PDW indicates that platelet size varies greatly, usually resulting from platelet activation and an increased number of newly generated platelets. Therefore, a high MPV and PDW are related to platelet activation and increased platelet production. VVS is known as the most common type of neurally mediated syncope [
22], and increased sympathetic activity has been found in some patients with neurally mediated syncope [
23], while enhanced sympathetic activity is directly related to platelet production according to several previous studies [
10].
The mechanisms by which sympathetic excitation promotes platelet production and activation may be explained as follows: (1) two primary sympathetic transmitters, NE and EP, can drive platelet activation. An increase in arterial plasma EP concentrations significantly stimulates blood platelet parameters [
24]. In vitro, NE mediated platelet activation in a concentration- and time-dependent manner [
25]; (2) NE and EP can boost megakaryocyte attachment, movement, and proplatelet formation via adrenoceptor-mediated extracellular signal-regulated kinase stimulation, which causes a noticeable increase in platelet production [
9]; (3) activation of adrenergic receptors may stimulate circulating platelets by boosting surface levels of P-selectin, enhancing conformational modifications of the glycoprotein IIb/IIIa receptor [
26,
27]. These studies support the hypothesis that the increased MPV and PDW may indicate increased sympathetic activity among patients in the treatment-effective group. Furthermore, these findings partially explain the favorable response to the β-adrenergic receptor blocker metoprolol observed in our study. However, the PDW was not included in the prediction model after logistic regression, which might imply that the influence of the PDW on therapeutic outcomes was not sufficiently weighted.
Furthermore, in a recent study, proteomic analysis revealed that the expression of platelet-related proteins was upregulated in patients with postural orthostatic tachycardia syndrome (POTS), another type of orthostatic intolerance characterized by an increase in sympathetic activity [
28]. Although no similar studies have been conducted in patients with VVS, the results observed in the context of POTS are consistent with our findings.
Univariate analysis also revealed that the proportion of females in the treatment-effective group was greater than that in the treatment-ineffective group. Age was included in the prediction model, which indicated that younger children with VVS may respond better to metoprolol treatment. These results suggest age- and sex-related differences in the efficacy of metoprolol. A study based on the influence of sex on heart rate variability in children revealed that female children presented significantly greater values than male children did in terms of the standard deviation of the RR intervals and absolute high frequency [
29]. A large multicohort study on the development of the cardiac autonomic nervous system in children revealed that sympathetic activity decreased linearly with age, whereas parasympathetic activity increased from infancy to childhood, plateaued during middle childhood, and then decreased slightly throughout adolescence [
30]. These results indicate that the development of autonomic nervous system activity varies with age and sex, which may account for the distinct responses to adrenergic receptor blockers. However, further research is needed to confirm this phenomenon and its underlying mechanisms to provide information for the treatment and management of autonomic nervous system diseases, including VVS.
All factors were included in an LASSO regression, a notable feature of which is the incorporation of the penalty term λ for variable selection in the model. It is widely used in the medical field for model construction [
31,
32]. Based on the non-zero values, five variables, namely, age, duration of hospitalization, sex, MPV, and PDW, were included in the logistic regression. Based on logistic regression, the prediction model was constructed with the following equation: logit(
p) = − 14.511 − 0.267 × age + 1.725 × MPV. This study demonstrated the feasibility and importance of nomograms for therapeutic prediction [
33]. We successfully developed a nomogram based on this model. The nomogram showed satisfactory predictive ability and clinical applicability.
In numerous studies, traditional methods, including ROC curves [
34], PR curves [
35], calibration curves [
36], and the Hosmer–Lemeshow test [
37], have been used to evaluate the efficacy of prediction models. As an alternative assessment method, DCA has been widely adopted in recent research studies [
38,
39]. This approach allows the calculation of the “net benefit” in clinical practice concerning prediction models [
40], thereby integrating the preferences of decision-makers into the analysis. As a predictive tool, our model showed satisfactory performance at a threshold value of 0.5, with AUCs of 0.85 and 0.9 for the ROC and PR curves, respectively. According to the calibration plot and Hosmer–Lemeshow test, the model demonstrated moderate predictive accuracy and a strong fit between the predictions and observations. According to the DCA, our predictive model could lead to improved clinical outcomes, with a net improvement ranging from 0.01 to 0.58. In addition to a limited threshold probability range, treatment based on the prediction model could yield substantial benefits in comparison to treating all or none of the patients.
Although prior studies have used several factors, such as 24-hour urine NE [
21], the Poincaré plot [
20], baroreflex sensitivity [
13], and the left-ventricular ejection fraction [
41], to predict the therapeutic efficacy of metoprolol, each has restrictions in terms of cost, operability, or exponential stability. Our study provides the first nomogram based on this model to enhance its clinical applicability. A prediction model comprising age and the MPV is convenient to apply, because all the included factors are easy to collect in clinical practice. For practical reasons, we hope that this study will not only serve as a conclusion but also as a new beginning for future well-designed studies that include larger cohorts and investigate the therapeutic efficacy of metoprolol in children with VVS.
Nonetheless, our study is subject to certain limitations. Firstly, the study was limited by the use of a single hospital with an insufficient number of patients, which could introduce a potential bias that may understate the influence of factors on therapeutic efficacy. Secondly, the biomarkers were measured only at baseline; however, it may be worthwhile to continue monitoring them and examining their dynamic changes over time. Thirdly, the follow-up period was considerably short. Long-term follow-up helps gain a deeper understanding of the progress and prognosis of the disease. Furthermore, due to dysfunction of the autonomic nervous system, another limitation could be the lack of analysis of heart rate variability and NE-level measurements. We concur that further research encompassing large-scale investigations with multiple factors and robust designs is warranted to validate or refute our findings.
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