With prevalence estimated to be between 2.7 to 6.1 million in the U.S, AFib is considered to be the most common arrhythmia [1]. AFib is a disease that evolves with time depending on the changes in atrial substrate [2-4]. This is due to structural and electrical remodeling within the atrium over time [5]. Histologically, it is further emphasized in explanted hearts that show increased interstitial collagen in patients with persistent AFib as compared with paroxysmal AFib [6].  

Given this “vicious cycle” of AFib progression, multiple attempts have been made to prevent the development of AFib. Primary prevention, by the use of upstream therapy, aims at decreasing the incidence of AFib. For example, the PREDIMED trial suggested that the Mediterranean diet with extra-virgin olive oil can reduce the risk of AFib [7]. Other studies have noted that low levels of marine omega-3 fatty acids [8] and vitamin D [9-12] tend to have greater AFib risk. Omega-3 fatty acids and vitamin D have anti-inflammatory properties which may lead to decreased rates of interstitial fibrosis [13-15].

Albert et al further investigated the role of omega-3 fatty acid and vitamin D supplementation in the incidence of AFib. The Vital Rhythm trial is the largest and longest randomized double-blind placebo control trial that used a 2X2 factorial design. 25,871 patients were supplemented with 2,000 IU of vitamin D3 and/or 840 mg of omega-3 fatty acids. These patients met the inclusion criteria of men being at least 50 years old and women being at least 55 years old without any history of cardiovascular disease, cancer, or AFib. 51.7% of patients had hypertension, 13.7% of patients had diabetes, and 7.3% of patients were current smokers. Primary endpoint was reached after patients reported new diagnosis of AFib in their annual follow-up questionnaires, which was then confirmed by reviewing their medical records. A total of 900 patients (3.6% of population) reached primary endpoint at 5.3 years of treatment, while 526 patients (58.4%) had paroxysmal AFib, 346 patients (38.4%) had persistent AFib, and 28 (3.1%) patients were unable to be classified.

For primary endpoint (incidence of AFib), 469 patients taking omega-3 eicosapentaenoic acid/ docosahexaenoic acid (EPA/DHA) had AFib which was not statistically significant when compared to 431 patients with AFib in placebo group [HR = 1.09 (95% CI: 0.96–1.24); P = 0.19]. For secondary endpoint comparing incidence of paroxysmal AFib, 271 patients taking EPA/DHA had AFib, which was not statistically significant when compared to 255 patients with AFib in placebo group [HR = 1.07 (95% CI: 0.90–1.27); P = 0.46]. For secondary endpoint comparing incidence of non-paroxysmal AFib, 182 patients taking EPA/DHA had AFib, which was not statistically significant when compared to 164 patients with AFib in placebo group [HR = 1.11 (95% CI: 0.90–1.37); P = 0.32]. 

For primary endpoint (incidence of AF), 469 patients taking vitamin D had AF which was not statistically significant when compared to 431 patients with AFib in placebo group [HR = 1.09 (95% CI: 0.96–1.24); P = 0.19]. For secondary endpoint comparing incidence of paroxysmal AFib, 267 patients taking vitamin D had AFib, which was not statistically significant when compared to 259 patients with AFib in placebo group [HR = 1.03 (95% CI: 0.87–1.23); P = 0.76]. For secondary endpoint comparing incidence of non-paroxysmal AFib, 188 patients taking vitamin D had AFib, which was not statistically significant when compared to 158 patients with AFib in placebo group [HR = 1.20 (95% CI: 0.97–1.48); P = 0.10]. 

This study had limitations whereby AFib events were only clinically detected as these patients were not monitored for subclinical AFib. Another limitation was that patients were at fixed dose of supplements which may have been suboptimal in decreasing the risk of AFib. To note, the results of this study should not be applied to patients who are of a younger age or have a history of cardiovascular disease.

In summary, this trial showed that supplementation of 2000 IU of vitamin D3 and/or 840 mg of omega-3 fatty acids were not statistically significant in reducing or increasing the incident of AFib over a duration 5.3 years. Although this trial did not prove efficacy of omega-3 fatty acid and vitamin D supplementation in the primary prevention of AFib, this trial paves the way for investigating other promising agents in primary prevention for AFib.

References:

1. Centers for Disease Control and Prevention. Atrial Fibrillation. Centers for Disease Control and Prevention. 2020. https://www.cdc.gov/heartdisease/atrial_fibrillation.htm.

2. Haïssaguerre M, Jaïs P, Shah DC, Takahashi A, Hocini M, Quiniou G et al. Spontaneous initiation of atrial fibrillation by ectopic beats originating in the pulmonary veins. N Engl J Med. 1998;339(10):659-66. doi:10.1056/nejm199809033391003.

3. Haïssaguerre M, Marcus FI, Fischer B, Clémenty J. Radiofrequency catheter ablation in unusual mechanisms of atrial fibrillation: report of three cases. J Cardiovasc Electrophysiol. 1994;5(9):743-51. doi:10.1111/j.1540-8167.1994.tb01197.x.

4. Jaïs P, Haïssaguerre M, Shah DC, Chouairi S, Gencel L, Hocini M et al. A focal source of atrial fibrillation treated by discrete radiofrequency ablation. Circulation. 1997;95(3):572-6. doi:10.1161/01.cir.95.3.572.

5. Allessie M, Ausma J, Schotten U. Electrical, contractile and structural remodeling during atrial fibrillation. Cardiovascular Research. 2002;54(2):230-46. doi:10.1016/s0008-6363(02)00258-4

6. Xu J, Cui G, Esmailian F, Plunkett M, Marelli D, Ardehali A et al. Atrial extracellular matrix remodeling and the maintenance of atrial fibrillation. Circulation. 2004;109(3):363-8. doi:10.1161/01.Cir.0000109495.02213.52

7. Martínez-González MÁ, Toledo E, Arós F, et al. Extravirgin olive oil consumption reduces risk of atrial fibrillation: the PREDIMED (Prevención con Dieta Mediterránea) trial. Circulation 2014; 130:18.

8. Kirkegaard Ellen, Svensson My, Strandhave Charlotte, Schmidt Erik Berg, Jørgensen Kaj Anker, Christensen Jeppe Hagstrup. Marine n-3 fatty acids, atrial fibrillation and QT interval in haemodialysis patients. Br. J. Nutr. 2012 Mar;107 (6):903–9

9. Fusaro M, Gallieni M, Rebora P, Rizzo MA, Luise MC, Riva H, et al. Atrial fibrillation and low vitamin D levels are associated with severe vascular calcifications in hemodialysis patients. J Nephrol. 2016;29(3):419–426. doi: 10.1007/s40620-015-0236-7

10. Rienstra M, Cheng S, Larson MG, et al. Vitamin D status is not related to development of atrial fibrillation in the community. Am Heart J. 2011;162(3):538-541. doi:10.1016/j.ahj.2011.06.013

11. Bie L. The Status and Research Progress on Vitamin D Deficiency and Atrial Fibrillation. Braz J Cardiovasc Surg. 2019;34(5):605-609. Published 2019 Dec 1. doi:10.21470/1678-9741-2018-0322

12. Zhang Z, Yang Y, Ng CY, Wang D, Wang J, Li G, Liu T. Meta-analysis of Vitamin D Deficiency and Risk of Atrial Fibrillation. Clin Cardiol. 2016 Sep;39(9):537-43. doi: 10.1002/clc.22563. Epub 2016 Aug 24. PMID: 27556176; PMCID: PMC6490727.

13. Cocco T, Di Paola M, Papa S, Lorusso M. Arachidonic acid interaction with the mitochondrial electron transport chain promotes reactive oxygen species generation. Free Radic. Biol. Med. 1999 Jul;27 (1-2):51–9. 

14. Cannell JJ, Grant WB, Holick MF. Vitamin D and inflammation. Dermatoendocrinol 2014;6:e983401. doi:10.4161/19381980.2014.983401

15. Guillot X, Semerano L, Saidenberg-Kermanac'h N, et al. Vitamin D and inflammation. Joint Bone Spine 2010;77:552–7. doi:10.1016/j.jbspin.2010.09.018