Homocysteine and atrial fibrillation: novel evidences and insights

Submitted: February 20, 2022
Accepted: April 9, 2022
Published: April 20, 2022
Abstract Views: 1597
PDF: 603
Publisher's note
All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article or claim that may be made by its manufacturer is not guaranteed or endorsed by the publisher.


Atrial fibrillation (AF) is one of the most prevalent rhythm disorders worldwide, with around 37.574 million cases around the globe (0.51 % global population).  Different studies showed a high informative value of different biomarkers, including such related to the systemic inflammation, biomechanical stress and fibrosis. In this review article we aimed to study only the relation of homocysteine to the AF development. Homocysteine is a sulfur-containing amino acid, that is produced in the process of methionine metabolism. Which is a non-canonical amino acid, that is derived from the food proteins. From the scientific point of view there is a relation between hyperhomocysteinemia and myocardial fibrosis, but these mechanisms are complicated and not sufficiently studied. Homocysteine regulates activity of the ion channels through their redox state. Elevated homocysteine level can condition electrical remodeling of the cardiomyocytes through the increase of sodium current and change in the function of rapid sodium channels, increase of inwards potassium current and decrease in amount of rapid potassium channels. High homocysteine concentration also leads to the shortening of the action potential, loss of the rate adaptation of the action potential and persistent circulation of the re-entry waves. In a series of experimental studies on mice there was an association found between the homocysteine level and activity of vascular inflammation. Elevation of homocysteine level is an independent factor of the thromboembolic events and AF relapses. Population studies showed, that homocysteine is an independent risk factor for AF. So, homocysteine is an interesting target for up-stream therapy.



PlumX Metrics


Download data is not yet available.


Lippi G, Sanchis-Gomar F, Cervellin G. Global epidemiology of atrial fibrillation: An increasing epidemic and public health challenge. Int J Stroke 2021;16:217-21.
Leong DP, Eikelboom JW, Healey JS, Connolly SJ. Atrial fibrillation is associated with increased mortality: causation or association? Eur Heart J 2013;34:1027-30. DOI: https://doi.org/10.1093/eurheartj/eht044
Zima AV, Blatter LA. Redox regulation of cardiac calcium channels and transporters. Cardiovasc Res 2006;71:310-21. DOI: https://doi.org/10.1016/j.cardiores.2006.02.019
Magnani JW, Rienstra M, Lin H, et al. Atrial fibrillation: current knowledge and future directions in epidemiology and genomics. Circulation 2011;124:1982-93. DOI: https://doi.org/10.1161/CIRCULATIONAHA.111.039677
Kornej J, Börschel CS, Benjamin EJ, Schnabel RB. Epidemiology of atrial fibrillation in the 21st century: Novel methods and new insights. Circ Res 2020;127:4-20. DOI: https://doi.org/10.1161/CIRCRESAHA.120.316340
Begg GA, Lip GY, Plein S, Tayebjee MH. Circulating biomarkers of fibrosis and cardioversion of atrial fibrillation: A prospective, controlled cohort study. Clin Biochem 2017;50:11-5. DOI: https://doi.org/10.1016/j.clinbiochem.2016.09.008
Blanda V, Bracale UM, Di Taranto MD, Fortunato G. Galectin-3 in cardiovascular diseases. Int J Mol Sci 2020;21:9232. DOI: https://doi.org/10.3390/ijms21239232
Watson CJ, Glezeva N, Horgan S, et al. Atrial tissue pro-fibrotic M2 Macrophage marker CD163+, gene expression of procollagen and B-type natriuretic peptide. J Am Heart Assoc 2020;9:e013416. DOI: https://doi.org/10.1161/JAHA.119.013416
Li X, Ma C, Dong J, et al. The fibrosis and atrial fibrillation: is the transforming growth factor-beta 1 a candidate etiology of atrial fibrillation. Med Hypotheses 2008;70:317-9. DOI: https://doi.org/10.1016/j.mehy.2007.04.046
Patel D, Druck A, Hoppensteadt D, et al. Relationship between 25-hydroxyvitamin D, renin, and collagen remodeling biomarkers in atrial fibrillation. Clin Appl Thromb Hemost 2020;26:1076029619899702. DOI: https://doi.org/10.1177/1076029619899702
Seccia TM, Caroccia B, Maiolino G, et al. Arterial hypertension, aldosterone, and atrial fibrillation. Curr Hypertens Rep 2019;21:94. DOI: https://doi.org/10.1007/s11906-019-1001-4
Chen S, Yang F, Xu T, et al. Appraising the causal association of plasma homocysteine levels with atrial fibrillation risk: A two-sample mendelian randomization study. Front Genet 2021;12:619536. DOI: https://doi.org/10.3389/fgene.2021.619536
Luo ZF, Kong XY, Jiang C, et al. [Relationship between C-reactive protein level and incidence of left atrial spontaneous echocardiographic contrast in patients with nonvalvular atrial fibrillation].[Article in Chinese]. Zhonghua Xin Xue Guan Bing Za Zhi 2020;48:223-7.
Cesari M, Rossi GP, Sticchi D, Pessina AC. Is homocysteine important as risk factor for coronary heart disease? Nutr Metab Cardiovasc Dis 2005;15:140-7. DOI: https://doi.org/10.1016/j.numecd.2004.04.002
Maron BA, Loscalzo J. The treatment of hyperhomocysteinemia. Annu Rev Med 2009;60:39-54.
Kaplan P, Tatarkova Z, Sivonova MK, et al. Homocysteine and mitochondria in cardiovascular and cerebrovascular systems. Int J Mol Sci 2020;21:7698. DOI: https://doi.org/10.3390/ijms21207698
Maron BA, Loscalzo J. The treatment of hyperhomocysteinemia. Annu Rev Med 2009;60:39-54. DOI: https://doi.org/10.1146/annurev.med.60.041807.123308
Zaric BL, Obradovic M, Bajic V, et al. Homocysteine and hyperhomocysteinaemia. Curr Med Chem 2019;26:2948-61. DOI: https://doi.org/10.2174/0929867325666180313105949
Kubota Y, Alonso A, Heckbert SR, et al. Homocysteine and incident atrial fibrillation: The atherosclerosis risk in communities study and the multi-ethnic study of atherosclerosis. Heart Lung Circ 2019;28:615-22. DOI: https://doi.org/10.1016/j.hlc.2018.03.007
Han L, Tang Y, Li S, et al. Protective mechanism of SIRT1 on Hcy-induced atrial fibrosis mediated by TRPC3. J Cell Mol Med 2020;24:488-510.
Yao Y, Shang M, Dong J, Ma C. Homocysteine in non-valvular atrial fibrillation: Role and clinical implications. Clinica Chimica Acta 2017;475:85–90. DOI: https://doi.org/10.1016/j.cca.2017.10.012
Han L, Tang Y, Li S, et al. Protective mechanism of SIRT1 on Hcy-induced atrial fibrosis mediated by TRPC3. J Cell Mol Med 2020;24:488-510. DOI: https://doi.org/10.1111/jcmm.14757
Cai BZ, Gong DM, Liu Y, et al. Homocysteine inhibits potassium channels in human atrial myocytes. Clin Exp Pharmacol Physiol 2007;34:851-5. DOI: https://doi.org/10.1111/j.1440-1681.2007.04671.x
Heijman J, Algalarrondo V, Voigt N, et al. The value of basic research insights into atrial fibrillation mechanisms as a guide to therapeutic innovation: a critical analysis. Cardiovasc Res 2016;109:467-79. DOI: https://doi.org/10.1093/cvr/cvv275
Acampa M, Lazzerini PE, Martini G. Postoperative atrial fibrillation and ischemic stroke: The role of homocysteine. Eur Stroke J 2018;3:92-3 DOI: https://doi.org/10.1177/2396987317732648
Galea R, Cardillo MT, Caroli A, et al. Inflammation and C-reactive protein in atrial fibrillation: cause or effect? Tex Heart Inst J 2014;41:461-8. DOI: https://doi.org/10.14503/THIJ-13-3466
Hofmann MA, Lalla E, Lu Y, et al. Hyperhomocysteinemia enhances vascular inflammation and accelerates atherosclerosis in a murine model. J Clin Invest 2001;107:675-83. DOI: https://doi.org/10.1172/JCI10588
Jones DP, Mody VC Jr, Carlson JL, et al. Redox analysis of human plasma allows separation of pro-oxidant events of aging from decline in antioxidant defenses. Free Radic Biol Med 2002;33:1290-300. DOI: https://doi.org/10.1016/S0891-5849(02)01040-7
Lippi G, Sanchis-Gomar F, Cervellin G. Global epidemiology of atrial fibrillation: An increasing epidemic and public health challenge. Int J Stroke 2021;16:217-21. DOI: https://doi.org/10.1177/1747493019897870
Takahashi N, Ishibashi Y, Shimada T, et al. Atrial fibrillation impairs endothelial function of forearm vessels in humans. J Card Fail 2001;7:45-54. DOI: https://doi.org/10.1054/jcaf.2001.22107
Han L, Liu Y, Duan S, et al. DNA methylation and hypertension: emerging evidence and challenges. Brief Funct Genomics 2016;15:460-9. DOI: https://doi.org/10.1093/bfgp/elw014
Sbodio JI, Snyder SH, Paul BD. Regulators of the transsulfuration pathway. Br J Pharmacol 2019;176:583-93. DOI: https://doi.org/10.1111/bph.14446
Go YM, Park H, Koval M, et al. A key role for mitochondria in endothelial signaling by plasma cysteine/cystine redox potential. Free Radic Biol Med 2010;48:275-83. DOI: https://doi.org/10.1016/j.freeradbiomed.2009.10.050
Hansen BJ, Zhao J, Fedorov VV. Fibrosis and atrial fibrillation: Computerized and optical mapping; A view into the human atria at submillimeter resolution. JACC Clin Electrophysiol 2017;3:531-46. DOI: https://doi.org/10.1016/j.jacep.2017.05.002
Iyer SS, Ramirez AM, Ritzenthaler JD, et al. Oxidation of extracellular cysteine/cystine redox state in bleomycin-induced lung fibrosis. Am J Physiol Lung Cell Mol Physiol 2009;296:L37-45. DOI: https://doi.org/10.1152/ajplung.90401.2008
Škovierová H, Vidomanová E, Mahmood S, et al. The molecular and cellular effect of homocysteine metabolism imbalance on human health. Int J Mol Sci 2016;17:1733. DOI: https://doi.org/10.3390/ijms17101733
Nasso G, Bonifazi R, Romano V, et al. Increased plasma homocysteine predicts arrhythmia recurrence after minimally invasive epicardial ablation for nonvalvular atrial fibrillation. J Thorac Cardiovasc Surg 2013;146:848-53. DOI: https://doi.org/10.1016/j.jtcvs.2012.07.099
Snezhitsky VA, Yatskevich ES, Doroshenko EM, et al. [Homocysteine as a prognostic marker of atrial remodeling and clinical picture in patients with paroxysmal and persistent forms of atrial fibrillation].[Article in Russian]. Klin Med (Mosk) 2016;94:16-22. DOI: https://doi.org/10.18821/0023-2149-2016-94-1-16-22
Wang L, Zhang Y. Role of hyperhomocysteine, thyroid dysfunction and their interaction in ischemic stroke patients with non-valvular atrial fibrillation. Sci Rep 2020;10:12419. DOI: https://doi.org/10.1038/s41598-020-69449-2
Svenningsson MM, Svingen GFT, Lysne V, et al. Transsulfuration metabolites and the association with incident atrial fibrillation - An observational cohort study among Norwegian patients with stable angina pectoris. Int J Cardiol 2020;317:75-80. DOI: https://doi.org/10.1016/j.ijcard.2020.05.010
Rong H, Huang L, Jin N, et al. Elevated homocysteine levels associated with atrial fibrillation and recurrent atrial fibrillation. Int Heart J 2020;61:705-12. DOI: https://doi.org/10.1536/ihj.20-099
Dong XJ, Wang BB, Hou FF, et al. Homocysteine (HCY) levels in patients with atrial fibrillation (AF): A meta-analysis. Int J Clin Pract 2021;75:e14738. DOI: https://doi.org/10.1111/ijcp.14738
Marcucci R, Betti I, Cecchi E, et al. Hyperhomocysteinemia and vitamin B6 deficiency: New risk markers for nonvalvular atrial fibrillation? Am Heart J 2004;148:456-61. DOI: https://doi.org/10.1016/j.ahj.2004.03.017

How to Cite

Ivanov, Valeriy, Yuliia Smereka, Volodymyr Rasputin, and Kostiantyn Dmytriiev. 2022. “Homocysteine and Atrial Fibrillation: Novel Evidences and Insights”. Monaldi Archives for Chest Disease 93 (1). https://doi.org/10.4081/monaldi.2022.2241.