Is there any link between vitamin D deficiency and vasovagal syncope?

Abstract Background This study aimed to investigate serum 25[OH]D levels between patients with vasovagal syncope (VVS) diagnosed with head‐up tilt table test (HUTT) and age‐matched healthy people. Methods The study included 75 consecutive patients (32.3 ± 10.7 years), who presented with syncope and underwent HUTT and 52 healthy controls (32.9 ± 14.1 years). HUTT patients were divided into two groups according to whether there was syncope response to the test. Patients underwent cardiac, psychiatric, and neurological investigation. Serum 25[OH]D levels were measured by chemiluminescent microparticle immunoassay method. Results There was no difference between the two groups in terms of age, gender, body mass index (BMI), echocardiographic findings (P > .05). Mean serum 25[OH]D (24.5 ± 6.3 vs 20.1 ± 8.8 ng/mL, P = .003) and vitamin B12 levels (436.4 ± 199.2 vs 363.1 ± 107.6 pg/mL, P = .009) was lower in syncope patients when compared to the control group. In correlation analyses, syncope was shown as correlated with the vitamin D (r = −264, P = .003) and vitamin B12 levels (r = −233, P = .009). But, multivariate regression analyses showed that only vitamin D increased risk of syncope [OR: 0.946, 95% CI (0.901‐0.994)]. There was no difference in terms of age, gender, BMI, echocardiographic findings between the in HUTT positive (n = 45) and negative groups (n = 29). Only vitamin D level was significantly lower in HUTT positive group (17.5 ± 7.7 vs 24.4 ± 9.1 ng/mL, P = .002). There was no difference among in the vasovagal subgroups in terms of vitamin D level and other features. Conclusion Vitamin D and B12 levels were reasonably low in syncope patients, but especially low Vitamin D levels were associated with VVS diagnosed in HUTT.


| INTRODUC TI ON
Syncope is a transient loss of consciousness because of decreased blood flow to the brain and usually improves spontaneously. However, the prevalence and incidence of syncope vary according to population, vasovagal syncope (VVS) is one of the most common causes, it constitutes approximately half of the patients who admit with loss of consciousness. 1,2 VVS is often associated with emotional stress, pain, fear, prolonged standing, and crowded environments. 2 The etiology of VVS syncope is because of interaction involving in the autonomic nervous system, which causes the predominance of the parasympathetic system and consequently development of bradycardia and hypotension. 3 The initial assessment of VVS begins with history, physical examination and electrocardiography (ECG), followed by risk stratification and additional diagnostic tests, that is, blood test, cardiac imaging (transthoracic echocardiography), stress test, cardiac monitoring (in-hospital telemetry, trans telephonic monitor, external loop recorder, patch recorder, mobile heart polyclinic telemetry), electrophysiological study (for the evaluation of selected patients with suspicious arrhythmic syncope), head-up tilt table test (HUTT), carotid sinus massage, neurological test, and psychiatric evaluation. 1 Although the prognosis of VVS is generally good, mortality is two-fold increased in cardiac syncope (arrhythmias, structural heart disease). 4 Treatment of syncope varies according to the underlying disease and aims to reduce symptoms by training and tune. 5 The deficiency of serum 25-hydroxyvitamin D (25[OH]D) is one of the underlying causes of a variety of disorders, including coronary artery disease, arrhythmias, neurological diseases, and cancers. [6][7][8][9] So far, there have been a large number of studies in the literature analysing the association of serum 25[OH]D and cardiovascular autonomic dysfunction, but studies involving the evaluation of the syncope with HUTT are very limited. [10][11][12] In our study, we aimed to compare serum 25[OH]D levels between patients with VVS diagnosed with HUTT and age-matched healthy people. In the second step of the study, the patients who developed syncope during the HUTT test and who did not develop syncope were compared.

| ME THODS
The study was a single-center, retrospective study and data were obtained from patients who were admitted with syncope and had HUTT performed between 2016 and 2019. Fifty-two consecutive healthy persons and 75 syncope patients were included in the study, and syncope patients were categorised based on their HUTT results (positive, n = 45 vs negative, n = 29) ( Figure 1).
Patients with vagal syncope were divided into two groups as those with vitamin D levels above and below 20 ng/mL for determining factors underlying low vitamin D levels. And the subgroups of patients with VVS (vaso-depressor, cardio-inhibitor, and mixed type) were compared in terms of vitamin D levels and demographic characteristics, blood sample results, and echocardiographic findings.
Patients with parathyroid hormone disorders, chronic metabolic diseases, and any type of cancers, pregnancy, neurological and psychological diseases were excluded. We performed 12 lead ECG, conventional 2D echocardiography, extensive blood tests, carotid ultrasonography, 24-hour rhythm and blood pressure Holter recordings, neurological and psychiatric evaluations, and HUTT to all of the patients.

| Head-up tilt testing protocol
Since it was first described by Kenny et al the HUTT has been performed in various protocols. 13 The patients were taken to the procedure room with 12 hours of fasting. To prevent the patient from falling during the procedure, the patient was wrapped with a support strap. Venous cannulation was placed in the appropriate position on the patient's left or right arm. Before the test, the patient was stabilized in a supine position for 5 minutes.
In our clinic, the Italian protocol is used for the tilt test. 14 After 20 minutes of passive phase, the provocation phase was initiated in patients without syncope; 300-400 µg sublingual nitroglycerine was given after 20 minutes of the test. 14 Throughout the procedure, patients were continuously monitored with a 3-lead electrode. Arterial blood pressure was measured every 3 minutes and also re-evaluated when the patient had symptoms. In patients who had positive HUTT, the classification of VVS was done according to the ESC guidelines: Vaso-depressor type, cardio-inhibitor type and mixed type. 15

| Serum 25(OH)D measurement method
After initial evaluation for syncope, blood samples were taken for the assessment of serum 25[OH]D, complete blood count, renal functions, liver functions, vitamin B12 level, thyroid function tests, and serum electrolyte levels after at least 8 hours of fasting. Serum 25[OH]D levels were measured by chemiluminescent microparticle immunoassay method (Architect, Abbott Diagnostics). After each sample was taken the standard protocol was applied: initially centrifuged at 3500 G at +4°C, then kept frozen at −20°C until analysis.

| Echocardiography
In accordance with the recommendations of the American Society of Echocardiography (17)

| Statistical analysis
All statistical analyses were performed using SPSS version 20 (IBM Corporation). Quantitative variables reported as mean ± standard deviation (SD), and qualitative variables are expressed as a percentage (%). The baseline characteristics of the patients were compared using the Student's t test for continuous variables and the χ 2 Pearson's test for categorical variables. In multivariate logistic regression, variables that were significantly associated with syncope were selected. Pearson's chi-squared analysis was showed relationship for vitamin D deficiency in women gender and low BMI patients.
One-way ANOVA was used to assess the relationship between VVS subgroups and vitamin D level. A P value of less than .05 was considered statistically significant. Demographic, echocardiographic, and laboratory findings of healthy subjects and patients with syncope were compared (Table 1).

| RE SULTS
There was no difference between the two groups when compared on BMI, gender, EF, RA, LA, thyroid-stimulating hormone (TSH), glucose, creatinine, sodium, potassium, calcium, white blood cell, hemoglobin, and platelet values (Table 1).

F I G U R E 2 Vitamin D levels between head-up tilt test (HUTT) positive and negative
with suspected VVS. It has been suggested that strong contractions of a volume-emptied ventricle cause activation of cardiac C fibers (myelin-free fibers in the atrium, ventricles, and pulmonary artery).
Stimulation of these afferent C fibers leads to a "paradoxical'' withdrawal of peripheral sympathetic tone and an increase in vagal tone, which in turn causes varying degrees of hypotension and bradycardia with syncope or presyncope. 3 The One of the reasons for syncope is impaired heart muscle func-  21,22 Studies also have shown that deficiency of vitamin D increases the tendency to heart failure. 21,22 As a result, vitamin D deficiency is an important independent risk factor for heart muscle dysfunction. In our study, the cardiac function measured via the echocardiography was normal in both syncope and healthy group.
Another factor that plays a role in the etiology of VVS is the disruption of neuronal conduction in the baroreflex mechanism.
Vitamin D, which is also present in the central and peripheral ner-  The HUTT test was investigated in the management of syncope as well as in the diagnosis. But the HUTT has limited ability to assess the response of patients with syncope to treatment and prevent recurrent syncope. 5

| Study limitations
Limitations of our study were the small number of patients, retrospective characterization and being a single-centre study. The same study was not performed before; for this reason, we could not compare the strength of the study. The importance of the study may be increased if we can determine that syncope numbers may decrease after vitamin D treatment in patients with lower vitamin D levels. Numerous studies are needed to understand the role of vitamin D in syncope.

| CON CLUS ION
To the best of our knowledge, our study is the first to investigate serum vitamin D levels in patients who had syncope with the HUTT and in patients who did not have syncope. We found that serum vitamin D levels were low in patients with syncope, especially in patients diagnosed with VVS by HUTT test. Therefore, measurement of serum vitamin D levels might be offered in VVS patients. In further studies, whether vitamin D supplementation will help improve VVS symptoms can be investigated. Larger randomised controlled trials in the future will shed light on association between vitamin D deficiency and syncope.

CO N FLI C T O F I NTE R E S T
Authors declare no conflict of interests for this article. Written informed consent was obtained from all patients before participating in the study

AUTH O R CO NTR I B UTI O N
All authors contributed toward the content, concept, writing, drafting and revisions of this manuscript and have approved the final version.