Association of Vitamin B12 and Folate Deficiency with Vasovagal Syncope: A Case-Control Study
-
Arya Aminorroaya
,
Ali Vasheghani Farahanni
,
Hamed Tavolinejad
,
Zahra Aryan
,
Somayeh Yadangi
,
Ali Bozorgi
,
Saeed Sadeghian
,
Mohammadali Boroumand
,
Masud Yunesian
,
Masih Tajdini
Abstract
Background: Clinical evidence suggests an association between vitamin B12 deficiency and vasovagal syncope (VVS) in pediatric patients. This study investigated the association of vitamin B12 and folate deficiency with VVS in adults.
Methods: In this case-control study, adult patients with VVS who presented to the tertiary syncope unit for head-up tilt table testing comprised the case group. Age- and sex-matched individuals without syncope history from the population-based Tehran Cohort Study served as the control group. Exclusion criteria included but were not limited to the use of vitamin B supplements, carbamazepine, or phenobarbital, and sleeve gastrectomy. Serum vitamin B12, folate, and homocysteine levels were measured and compared.
Results: From February 2020 through February 2021, 44 patients comprised the case group, matched with 44 controls (mean age, 37.9 years; 23 [52.3%] females in each group). No statistically significant difference existed between the groups in vitamin B12 or folate deficiency or serum levels. Serum vitamin B12 levels were significantly lower in patients with frequent VVS (≥3 lifetime episodes) than in patients with infrequent VVS (<3 lifetime episodes) (233.8 [80.7] vs 305.2 [118.1] pg/mL; P=0.042), and the association remained significant after adjustment for confounders (P=0.026).
Conclusion: No association existed between vitamin B12 or folate deficiency or serum levels and VVS. Frequent VVS was associated with lower serum vitamin B12 levels than infrequent VVS.
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2. Brignole M, Moya A, de Lange FJ, Deharo JC, Elliott PM, Fanciulli A, et al. 2018 ESC Guidelines for the diagnosis and management of syncope. Eur Heart J. 2018;39(21):1883-1948.
3. Babaei M, Tajdini M, Bozorgi A, Sadeghian S, Taebi M, Tavolinejad H, et al. Age and sex differences in vasovagal syncope: triggers, clinical presentation, prodromal symptoms, and head-up tilt test results. Eur Heart J Open. 2025;5(3):oeaf061.
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5. Ruwald MH, Hansen ML, Lamberts M, Kristensen SL, Wissenberg M, Olsen AM, et al. Accuracy of the ICD-10 discharge diagnosis for syncope. Europace. 2013;15(4):595-600.
6. Tajdini M, Behnoush AH, Khalaji A, Raj SR. Vasovagal syncope: a review of current and emerging therapies. J Tehran Univ Heart Cent. 2024;19(1):1-11.
7. Behnoush AH, Khalaji A, Aminorroaya A, Tavolinejad H, Yadangi S, Tajdini M. Mystery of situational syncope: a case series. Res Heart Yield Transl Med. 2025;20(1):74-78.
8. Sun BC. Quality-of-life, health service use, and costs associated with syncope. Prog Cardiovasc Dis. 2013;55(4):370-375.
9. Rafighdoust A, Tayebi M, Poorzand H. Syncope as the clinical presentation of pulmonary thromboembolism. Res Heart Yield Transl Med. 2020;2(1):49-53.
10. Jorge JG, Raj SR, Teixeira PS, Teixeira JAC, Sheldon RS. Likelihood of injury due to vasovagal syncope: systematic review and meta-analysis. Europace. 2021;23(7):1092-1099.
11. Sun BC, Emond JA, Camargo CA Jr. Direct medical costs of syncope-related hospitalizations in the United States. Am J Cardiol. 2005;95(5):668-671.
12. Aminorroaya A, Tavolinejad H, Sadeghian S, Jalali A, Alaeddini F, Emkanjoo Z, et al. COMFORTS trial: rationale and design for a multicenter randomized controlled trial. Am Heart J. 2021;237:5-12.
13. Tavolinejad H, Bozorgi A, Emkanjoo Z, Oraii A, Shahabi J, Mollazadeh R, et al. Using compression stockings to prevent recurrence of vasovagal syncope: randomized sham-controlled trial. J Am Coll Cardiol. 2025;86(6):412-422.
14. Benditt DG, Ermis C, Padanilam B, Samniah N, Sakaguchi S. Catecholamine response during upright posture in individuals with and without vasovagal syncope. Europace. 2003;5(1):65-70.
15. Goldstein DS, Holmes C, Frank SM, Naqibuddin M, Dendi R, Snader S, et al. Sympathoadrenal imbalance before neurocardiogenic syncope. Am J Cardiol. 2003;91(1):53-58.
16. Alboni P, Dinelli M, Gruppillo P, Bondanelli M, Bettiol K, Marchi P, et al. Haemodynamic changes early in prodromal symptoms of vasovagal syncope. Europace. 2002;4(3):333-338.
17. Olgunturk R, Turan L, Tunaoglu FS, Kula S, Gokcora N, Karabacak NI, et al. Abnormal sympathetic nervous function in pediatric neurocardiogenic syncope. Pacing Clin Electrophysiol. 2003;26(10):1926-1930.
18. Vanderheyden M, Goethals M, Nellens P, Andries E, Brugada P. Humoral responses during head-up tilt among patients with neurocardiogenic syncope. Am Heart J. 1998;135(1):67-73.
19. Sra JS, Murthy V, Natale A, Jazayeri MR, Dhala A, Deshpande S, et al. Circulatory and catecholamine changes during head-up tilt testing in vasovagal syncope. Am J Cardiol. 1994;73(1):33-37.
20. Harvey R, Ferrier D. Lippincott’s Illustrated Reviews: Biochemistry. 5th ed. Philadelphia: Lippincott Williams & Wilkins; 2011.
21. Huotari M, Gogos JA, Karayiorgou M, Koponen O, Forsberg M, Raasmaja A, et al. Brain catecholamine metabolism in COMT-deficient mice. Eur J Neurosci. 2002;15(2):246-256.
22. Oner T, Guven B, Tavli V, Mese T, Yilmazer MM, Demirpence S. Postural orthostatic tachycardia syndrome and vitamin B12 deficiency in adolescents. Pediatrics. 2014;133(1):e138-e142.
23. Pektas A, Koken R, Koca HB. Serum vitamin B12 in children with vasovagal syncope. Asia Pac J Clin Nutr. 2018;27(1):176-181.
24. Kovalchuk T, Boyarchuk O, Balatska N. The effects of vitamin B and D supplementations on autonomic functions and quality of life in children after vasovagal syncope. Front Pediatr. 2025 Mar 11;13:1553428. PMID: 40134906.
25. Sadeghian S, Aminorroaya A, Tajdini M. The Syncope Unit of Tehran Heart Center. Eur Heart J. 2020;42(2):148-150.
26. Poorhosseini H, Abbasi SH. The Tehran Heart Center. Eur Heart J. 2018;39(29):2695-2696.
27. Shafiee A, Saadat S, Shahmansouri N, Jalali A, Alaeddini F, Haddadi M, et al. Tehran Cohort Study: design and recruitment data. Glob Epidemiol. 2021;3:100051.
28. Bartoletti A, Alboni P, Ammirati F, Brignole M, Del Rosso A, Foglia Manzillo G, et al. The Italian protocol: simplified tilt testing with oral nitroglycerin. Europace. 2000;2(4):339-342.
29. Brignole M, Menozzi C, Del Rosso A, Costa S, Gaggioli G, Bottoni N, et al. New haemodynamic classification of vasovagal syncope. Europace. 2000;2(1):66-76.
30. Tajdini M, Aminorroaya A, Tavolinejad H, Tofighi S, Jalali A, Sadeghian S, et al. Atomoxetine for preventing vasovagal syncope: pilot randomized trial. IJC Heart Vasc. 2021;34:100789.
31. Iwase S, Nishimura N, Mano T. Role of sympathetic nerve activity in fainting. Front Physiol. 2014;5:343.
32. Sharada K, Reddy G, Narasimhan C. Cobalamin deficiency presenting as refractory vasovagal syncope. Int J Cardiol. 2012;156(1):e7-e8.
33. Ghaznain M, Donnelly TM, Halpenny L. Tilt-table outcome in patients with vitamin D and B12 deficiency. Age Ageing. 2017;46(Suppl 1):60.
34. Aysin E, Urhan M. Dietary supplement use during COVID-19. Curr Dev Nutr. 2021;5(Suppl 2):207.
35. Cimke S, Yildirim Gurkan D. Interest in vitamin use during COVID-19: Google Trends analysis. Nutrition. 2021;85:111138.
36. Moynihan R, Sanders S, Michaleff ZA, Scott AM, Clark J, To EJ, et al. Impact of COVID-19 pandemic on healthcare use: systematic review. BMJ Open. 2021;11(3):e045343.
37. Oh R, Brown DL. Vitamin B12 deficiency. Am Fam Physician. 2003;67(5):979-986.
2. Brignole M, Moya A, de Lange FJ, Deharo JC, Elliott PM, Fanciulli A, et al. 2018 ESC Guidelines for the diagnosis and management of syncope. Eur Heart J. 2018;39(21):1883-1948.
3. Babaei M, Tajdini M, Bozorgi A, Sadeghian S, Taebi M, Tavolinejad H, et al. Age and sex differences in vasovagal syncope: triggers, clinical presentation, prodromal symptoms, and head-up tilt test results. Eur Heart J Open. 2025;5(3):oeaf061.
4. Tajdini M, Tavolinejad H, Aminorroaya A, Aryan Z, Jalali A, Alaeddini F, et al. Clinical associations of injuries caused by vasovagal syncope: a cohort study from a tertiary syncope unit. J Am Heart Assoc. 2023;12(1):e027272.
5. Ruwald MH, Hansen ML, Lamberts M, Kristensen SL, Wissenberg M, Olsen AM, et al. Accuracy of the ICD-10 discharge diagnosis for syncope. Europace. 2013;15(4):595-600.
6. Tajdini M, Behnoush AH, Khalaji A, Raj SR. Vasovagal syncope: a review of current and emerging therapies. J Tehran Univ Heart Cent. 2024;19(1):1-11.
7. Behnoush AH, Khalaji A, Aminorroaya A, Tavolinejad H, Yadangi S, Tajdini M. Mystery of situational syncope: a case series. Res Heart Yield Transl Med. 2025;20(1):74-78.
8. Sun BC. Quality-of-life, health service use, and costs associated with syncope. Prog Cardiovasc Dis. 2013;55(4):370-375.
9. Rafighdoust A, Tayebi M, Poorzand H. Syncope as the clinical presentation of pulmonary thromboembolism. Res Heart Yield Transl Med. 2020;2(1):49-53.
10. Jorge JG, Raj SR, Teixeira PS, Teixeira JAC, Sheldon RS. Likelihood of injury due to vasovagal syncope: systematic review and meta-analysis. Europace. 2021;23(7):1092-1099.
11. Sun BC, Emond JA, Camargo CA Jr. Direct medical costs of syncope-related hospitalizations in the United States. Am J Cardiol. 2005;95(5):668-671.
12. Aminorroaya A, Tavolinejad H, Sadeghian S, Jalali A, Alaeddini F, Emkanjoo Z, et al. COMFORTS trial: rationale and design for a multicenter randomized controlled trial. Am Heart J. 2021;237:5-12.
13. Tavolinejad H, Bozorgi A, Emkanjoo Z, Oraii A, Shahabi J, Mollazadeh R, et al. Using compression stockings to prevent recurrence of vasovagal syncope: randomized sham-controlled trial. J Am Coll Cardiol. 2025;86(6):412-422.
14. Benditt DG, Ermis C, Padanilam B, Samniah N, Sakaguchi S. Catecholamine response during upright posture in individuals with and without vasovagal syncope. Europace. 2003;5(1):65-70.
15. Goldstein DS, Holmes C, Frank SM, Naqibuddin M, Dendi R, Snader S, et al. Sympathoadrenal imbalance before neurocardiogenic syncope. Am J Cardiol. 2003;91(1):53-58.
16. Alboni P, Dinelli M, Gruppillo P, Bondanelli M, Bettiol K, Marchi P, et al. Haemodynamic changes early in prodromal symptoms of vasovagal syncope. Europace. 2002;4(3):333-338.
17. Olgunturk R, Turan L, Tunaoglu FS, Kula S, Gokcora N, Karabacak NI, et al. Abnormal sympathetic nervous function in pediatric neurocardiogenic syncope. Pacing Clin Electrophysiol. 2003;26(10):1926-1930.
18. Vanderheyden M, Goethals M, Nellens P, Andries E, Brugada P. Humoral responses during head-up tilt among patients with neurocardiogenic syncope. Am Heart J. 1998;135(1):67-73.
19. Sra JS, Murthy V, Natale A, Jazayeri MR, Dhala A, Deshpande S, et al. Circulatory and catecholamine changes during head-up tilt testing in vasovagal syncope. Am J Cardiol. 1994;73(1):33-37.
20. Harvey R, Ferrier D. Lippincott’s Illustrated Reviews: Biochemistry. 5th ed. Philadelphia: Lippincott Williams & Wilkins; 2011.
21. Huotari M, Gogos JA, Karayiorgou M, Koponen O, Forsberg M, Raasmaja A, et al. Brain catecholamine metabolism in COMT-deficient mice. Eur J Neurosci. 2002;15(2):246-256.
22. Oner T, Guven B, Tavli V, Mese T, Yilmazer MM, Demirpence S. Postural orthostatic tachycardia syndrome and vitamin B12 deficiency in adolescents. Pediatrics. 2014;133(1):e138-e142.
23. Pektas A, Koken R, Koca HB. Serum vitamin B12 in children with vasovagal syncope. Asia Pac J Clin Nutr. 2018;27(1):176-181.
24. Kovalchuk T, Boyarchuk O, Balatska N. The effects of vitamin B and D supplementations on autonomic functions and quality of life in children after vasovagal syncope. Front Pediatr. 2025 Mar 11;13:1553428. PMID: 40134906.
25. Sadeghian S, Aminorroaya A, Tajdini M. The Syncope Unit of Tehran Heart Center. Eur Heart J. 2020;42(2):148-150.
26. Poorhosseini H, Abbasi SH. The Tehran Heart Center. Eur Heart J. 2018;39(29):2695-2696.
27. Shafiee A, Saadat S, Shahmansouri N, Jalali A, Alaeddini F, Haddadi M, et al. Tehran Cohort Study: design and recruitment data. Glob Epidemiol. 2021;3:100051.
28. Bartoletti A, Alboni P, Ammirati F, Brignole M, Del Rosso A, Foglia Manzillo G, et al. The Italian protocol: simplified tilt testing with oral nitroglycerin. Europace. 2000;2(4):339-342.
29. Brignole M, Menozzi C, Del Rosso A, Costa S, Gaggioli G, Bottoni N, et al. New haemodynamic classification of vasovagal syncope. Europace. 2000;2(1):66-76.
30. Tajdini M, Aminorroaya A, Tavolinejad H, Tofighi S, Jalali A, Sadeghian S, et al. Atomoxetine for preventing vasovagal syncope: pilot randomized trial. IJC Heart Vasc. 2021;34:100789.
31. Iwase S, Nishimura N, Mano T. Role of sympathetic nerve activity in fainting. Front Physiol. 2014;5:343.
32. Sharada K, Reddy G, Narasimhan C. Cobalamin deficiency presenting as refractory vasovagal syncope. Int J Cardiol. 2012;156(1):e7-e8.
33. Ghaznain M, Donnelly TM, Halpenny L. Tilt-table outcome in patients with vitamin D and B12 deficiency. Age Ageing. 2017;46(Suppl 1):60.
34. Aysin E, Urhan M. Dietary supplement use during COVID-19. Curr Dev Nutr. 2021;5(Suppl 2):207.
35. Cimke S, Yildirim Gurkan D. Interest in vitamin use during COVID-19: Google Trends analysis. Nutrition. 2021;85:111138.
36. Moynihan R, Sanders S, Michaleff ZA, Scott AM, Clark J, To EJ, et al. Impact of COVID-19 pandemic on healthcare use: systematic review. BMJ Open. 2021;11(3):e045343.
37. Oh R, Brown DL. Vitamin B12 deficiency. Am Fam Physician. 2003;67(5):979-986.
| Files | ||
| Issue | Vol 21 No 1 (2026) | |
| Section | Original Article(s) | |
| DOI | https://doi.org/10.18502/jthc.v21i1.21279 | |
| Keywords | ||
| Syncope Vasovagal Folic Acid Deficiency Vitamin B12 Vitamin B12 Deficiency Homocysteine | ||
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How to Cite
1.
Aminorroaya A, Vasheghani Farahanni A, Tavolinejad H, Aryan Z, Yadangi S, Bozorgi A, Sadeghian S, Boroumand M, Yunesian M, Tajdini M. Association of Vitamin B12 and Folate Deficiency with Vasovagal Syncope: A Case-Control Study. Res Heart Yield Transl Med. 2026;21(1):12-19.
