Association between vitamin D deficiency and vasovagal syncope: A systematic review and meta‐analysis

Abstract Vasovagal syncope (VVS) is the most prevalent type of syncope and its management includes pharmacologic and non‐pharmacologic interventions. Recently, studies have investigated vitamin D levels in VVS patients. In this systematic review and meta‐analysis, we aim to review these studies to find possible associations between vitamin D deficiency and vitamin D levels with VVS. International databases including Scopus, Web of Science, PubMed, and Embase were searched with keywords related to “vasovagal syncope” and “vitamin D.” Studies were screened and the data were extracted from them. Random‐effect meta‐analysis was conducted to calculate the standardized mean difference (SMD) and 95% confidence interval (CI) for vitamin D levels in comparison to VVS patients and controls. Also, VVS occurrence was measured and the odds ratio (OR) and 95% CI were calculated for comparison of vitamin D deficient cases and nondeficient individuals. Six studies were included with 954 cases investigated. Meta‐analysis showed that patients with VVS had significantly lower vitamin D serum levels in comparison to non‐VVS cases (SMD −1.05, 95% CI −1.54 to −0.57, p‐value < .01). Moreover, VVS occurrence was higher in vitamin D‐deficient individuals (OR 5.43, 95% CI 2.40 to 12.27, p‐value < .01). Our findings which show lower vitamin D levels in VVS patients can have clinical implications in order for clinicians to pay attention to this when approaching VVS. Further randomized controlled trials are certainly warranted to assess the role of vitamin D supplementation in individuals with VVS.


vitamin D deficiency and vitamin D levels with VVS. International databases
including Scopus, Web of Science, PubMed, and Embase were searched with keywords related to "vasovagal syncope" and "vitamin D." Studies were screened and the data were extracted from them. Random-effect meta-analysis was conducted to calculate the standardized mean difference (SMD) and 95% confidence interval (CI) for vitamin D levels in comparison to VVS patients and controls. Also, VVS occurrence was measured and the odds ratio (OR) and 95% CI were calculated

| INTRODUCTION
Syncope is a common chief complaint in patients visiting emergency departments, mostly in women with a peak age of 15 years. 1,2 Syncope is divided into three categories based on the cause of occurrence-reflex (neurally mediated) syncope, syncope due to orthostatic hypotension, and cardiac syncope. 3 Vasovagal syncope (VVS), the most prevalent type of reflex syncope, is a transient loss of consciousness characterized by a sudden reduction in heart rate (HR) and blood pressure (BP) and can be associated with negative or positive head-up tilt test (HUTT). 3,4 Diagnosis of VVS is mainly based on physical examination and careful history-taking without the need for further neurologic examinations in typical forms of VVS 3,4 ; however, HUTT can be assistive in some cases. The positive HUTT is classified by VVS International Study (VASIS) criteria. 5 These criteria categorize VVS based on BP and HR changes in HUTT which can be summarized as (1) mixed BP and HR decrease without severe bradycardia; (2A) cardioinhibitory response (BP fall before HR); (2B) severe cardioinhibitory response (HR fall before BP and/or asystole); (3) BP decrease without HR fall.
In patients with a diagnosis of VVS, the management ranges from lifestyle modifications and counterpressure maneuvers to pharmacologic prevention. 6 Lifestyle changes are the first line of treatment in most patients. 7 VVS triggers include but are not limited to a standing posture, heat exposure, the sight of blood, and fear. 8 Although triggers of VVS are well-known, there is a lack of evidence regarding predisposing factors in these patients.
Vitamin D is a key player in the pathogenesis of several diseases. 9,10 Hypovitaminosis D or vitamin D deficiency (serum 25-hydroxyvitamin D < 50 nmol/L or <20 ng/mL) is related to prolonged hospitalization and mortality, development of chronic diseases, and worse outcomes. [11][12][13] The exact link between vitamin D levels or hypovitaminosis D and VVS occurrence is still unknown. Some studies reported lower serum vitamin D and a higher rate of hypovitaminosis D in patients with VVS. 14,15 However, this association has not been yet confirmed in a pooled analysis. In this study, we compared the vitamin D levels between VVS patients and controls. Moreover, the rate of VVS was compared between patients with vitamin D deficiency and nonvitamin D-deficient ones.

| METHODS
This systematic review and meta-analysis was conducted in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) 2020 guidelines. 16  Finally, we evaluated the reference list of included studies.

| Inclusion and exclusion criteria
We included any clinical studies measuring vitamin D levels in VVS patients and healthy individuals. We excluded studies without controls and studies without reporting the circulating levels of vitamin D in VVS patients and healthy individuals. Moreover, non-English abstracts, preclinical evaluations, reviews, case reports, conference abstracts, and letters were excluded.

| Quality assessment
We used the "Newcastle-Ottawa Quality Assessment Scale" (NOS) for observational studies to evaluate the risk of bias in included studies (A. K. and A. H. B). 17 Three categories of bias according to NOS are selection, compatibility, and outcome. On this scale, a score of ≥7 was considered "low risk", while 4−6 and 0−3 were regarded as "high risk" and "very high risk," respectively.

| Statistical analysis
We used the random-effect meta-analysis to compare vitamin D levels between VVS patients and controls by calculating the standardized mean difference (SMD) and its 95% confidence interval (CI). To compare the rate of VVS between vitamin D-deficient and non-vitamin D-deficient individuals, we calculated the odds ratio (OR) and 95% CI using the random-effects DerSimonian-Laird model. As there was a zero event in one of the studies, outcome, rare event analysis by Peto's method was performed. 18

| Meta-analysis of vitamin D levels in VVS patients
Random-effect meta-analysis was performed for vitamin D levels in VVS patients versus controls. It was shown that vitamin D levels were lower in VVS patients (SMD −1.05, 95% CI −1.54 to −0.57, p < .01, Figure 2 and Table 2). The heterogeneity was found to be high (I 2 : 91.01%).  Figure 3 and Table 2). We found high heterogeneity with an I 2 of 79.65%.  Vitamin D has significant roles in inflammation, the autoimmune system, and the cardiovascular system. 31 Also, vitamin D receptors have been found in arterial wall cells, 32 cardiomyocytes, 33 and immune cells, 34 all of which are major contributors to the cardiovascular system.

Moreover, metabolites of vitamin D involve in cardiovascular function
and disease pathways such as thrombosis, the renin-angiotensin system, and inflammation. 35 Similar to our findings showing lower vitamin D in VVS patients, a recent study indicated that there is a relationship between hypovitaminosis D and orthostatic hypotension. 36 The mechanism by which hypovitaminosis D can lead to VVS is controversial. The pathophysiology by which VVS occurs is the autonomous system's abnormal reaction to triggers such as standing position which leads to the stimulation of aortic, carotid, and cardiopulmonary receptors. 37