Authors : Saharish M. Khan

Volume/Issue : Volume 10 - 2025, Issue 11 - November

Google Scholar : https://tinyurl.com/bp8mmvse

Scribd : https://tinyurl.com/3hec3ewp

DOI : https://doi.org/10.38124/ijisrt/25nov080

Note : A published paper may take 4-5 working days from the publication date to appear in PlumX Metrics, Semantic Scholar, and ResearchGate.

Note : Google Scholar may take 30 to 40 days to display the article.

Abstract : Background: Atrial fibrillation (AF) is the most common sustained cardiac arrhythmia worldwide and a major cause of cardiovascular morbidity and mortality. Despite major therapeutic advances, the molecular determinants of AF initiation and persistence remain incompletely defined.  Methods: Current genomic and functional evidence were synthesised from large-scale genome-wide association studies (GWAS), transcriptomic, proteomic, and epigenomic investigations. Key molecular pathways implicated in calcium handling, fibrosis, and transcriptional regulation were reviewed with reference to translational models.  Results: Over one hundred AF-associated loci have been identified, most located within non-coding regulatory regions. The 4q25 locus near PITX2 shows the strongest and most reproducible association. Variants at this site influence calcium- handling proteins (SERCA2, RyR2) and modulate atrial electrophysiology. Integrative multi-omic analyses reveal disturbed Wnt, Notch, and BMP signalling, enhanced atrial fibrosis, and altered metabolic gene expression. Polygenic risk scores improve AF prediction beyond traditional risk factors.  Conclusions: AF results from the interaction of genetic predisposition and environmental stressors that converge on shared molecular pathways controlling calcium flux, structural remodelling, and inflammation. Translational integration of genomic and physiological data offers a pathway towards precision-based prevention and therapy.

Keywords : Atrial fibrillation; Genomics; PITX2; Calcium Signalling; Polygenic Risk; Fibrosis; Precision Cardiology.

References :

1. Fuster V, Ryden LE, Cannom DS, et al. ACC/AHA/ESC guidelines for the management of patients with atrial fibrillation. Eur Heart J 2001;22:1852–1923.
2. Chen LY, Sotoodehnia N, Bůžková P, Lopez FL, Yee LM, Heckbert SR. Epidemiology of atrial fibrillation: a growing public-health problem. Heart 2018;104:1989–1996.
3. Krijthe BP, Kunst A, Benjamin EJ, et al. Projections on the number of individuals with atrial fibrillation in the European Union, from 2000 to 2060. Eur Heart J 2013;34:2746–2751.
4. Kirchhof P, Camm AJ, Goette A, et al. Comprehensive risk factor management in atrial fibrillation: insights from the 2020 ESC consensus statement. Eur Heart J 2020;41:111–124.
5. Hindricks G, Potpara T, Dagres N, et al. 2020 ESC Guidelines for the diagnosis and management of atrial fibrillation. Eur Heart J 2021;42:373–498.
6. Markides V, Schilling RJ. Atrial electrophysiology and mechanisms of atrial fibrillation. Heart 2003;89:939–943.
7. Gudbjartsson DF, Arnar DO, Helgadottir A, et al. Variants conferring risk of atrial fibrillation on chromosome 4q25. Nature 2007;448:353–357.
8. Newton-Cheh C, Larson MG, Benjamin EJ, et al. Common variants at 1q21 and 16q22 associated with atrial fibrillation. Nat Genet 2009;41:956–960.
9. Ellinor PT, Lunetta KL, Glazer NL, et al. Meta-analysis of genome-wide association studies identifies six new loci for atrial fibrillation. Nat Genet 2010;42:240–245.
10. Kany S, Hofmann S, Steimle JD, et al. Translational genomics in atrial fibrillation. Eur Heart J 2021;42:3609–3621.
11. Herraiz-Martínez A, Llach A, Tarifa C, et al. PITX2 modulates calcium-handling proteins in human atrial myocytes. J Mol Cell Cardiol 2019;128:69–80.
12. Nattel S, Harada M. Atrial remodeling and atrial fibrillation: recent advances and translational perspectives. Cardiovasc Res 2020;116:1523–1536.
13. van Ouwerkerk AF, Bosada FM, Liu C, et al. Genome-wide association studies of atrial fibrillation: translating genetics to mechanisms. Circ Res 2020;127:4–19.
14. Aguirre LA, Alonso ME, Badía-Careaga C, et al. Long-range chromatin architecture at the 4q25 atrial fibrillation locus. Nat Commun 2015;6:8081.
15. Baudic A, Laurila P, Toren P, et al. Enhancer–promoter interactions regulating PITX2 expression in atrial tissue. Eur Heart J 2024;45:1120–1134.
16. Dobrev D, Wehrens XHT. Calcium dysregulation in atrial fibrillation: the missing link? Nat Rev Cardiol 2017;14:573–590.
17. Rienstra M, Van Gelder IC, Van Gilst WH, et al. Animal models of atrial fibrillation. Cardiovasc Res 2012;95:397–409.
18. Steimle JD, Moskowitz IP. Wnt signalling and cardiac development: implications for arrhythmogenesis. Circ Res 2022;131:450–465.
19. Syeda B, Kirchhof P, Fabritz L. Ethnic differences in atrial fibrillation genetics and clinical presentation. Heart 2017;103:178–185.
20. Ayoub KH, Nauffal V, Al-Kindi SG, et al. Polygenic risk scores for atrial fibrillation and implications for early detection. Eur Heart J 2022;43:2150–2160.
21. Kullo IJ, Shameer K, Olson TM, et al. Cross-ancestry evaluation of polygenic risk scores for atrial fibrillation. Genet Med 2022;24:1353–1362.
22. Ahn J, Lee D, Kim H, et al. Polygenic risk and heart failure development in early-onset atrial fibrillation. Heart Rhythm 2025;22:520–528.
23. Choi SH, Lee S, Kim JY, et al. Ethnicity-specific polygenic risk scores for atrial fibrillation prediction. Heart 2021;107:1901–1909.
24. Landmesser U, Boriani G, Camm AJ, et al. Anticoagulation and stroke prevention in atrial fibrillation: 2024 ESC update. Eur Heart J 2024;45:1550–1562.
25. Newman CM, Jones R, Williams T, et al. Heart failure and atrial fibrillation interplay: therapeutic insights. Heart 2024;110:245–256.
26. Báez Cabanillas N, Fernández-Martínez J, Costa M, et al. Neurohormonal pathways linking atrial fibrillation and heart failure. Eur J Heart Fail 2023;25:112–124.
27. Bansal N, Fan D, Hsu CY, et al. Atrial fibrillation and risk of chronic kidney disease outcomes. Circulation 2016;133:203–212.
28. Nakase T, Yamamoto T, Okada Y, et al. Atrial fibrillation and cognitive decline: epidemiological evidence. J Am Heart Assoc 2023;12:e028970.
29. Dai Z, Wang H, Zhao Y, et al. Epigenetic regulation and chromatin modification in atrial fibrillation. Front Cardiovasc Med 2024;11:1509–1523.
30. Babini GS, Mancini D, Carpentieri A, et al. Human iPSC-derived cardiomyocyte models of atrial fibrillation. Stem Cell Reports 2024;19:100–112.
31. Wu L, Zhang X, Gao S, et al. Computational models for atrial fibrillation prediction and simulation. Eur Heart J Digital Health 2021;2:34–47.
32. Reyat H, Dura M, Hirt MN, et al. Single-cell transcriptomics of PITX2-deficient atrial tissue. Nat Commun 2020;11:4829.
33. Wang Y, Zhou M, Wang Y, et al. Matrix metalloproteinases and atrial remodelling in chronic atrial fibrillation. Circulation 1996;93:117–125.
34. Sun X, Chen H, Wang Y, et al. Chromatin accessibility changes underlying atrial fibrillation. Circ Res 2019;125:708–725.
35. Vinciguerra M, Leone V, Greco M, et al. Histone deacetylation and atrial structural remodelling. Heart 2024;110:192–204.
36. Heijman J, Erdemir A, Ashihara T, et al. Integrative computational modelling in atrial fibrillation. Prog Biophys Mol Biol 2021;162:3–18.
37. Liu J, Chen R, Yu J, et al. Metabolic reprogramming and mitochondrial dysfunction in atrial fibrillation. J Mol Cell Cardiol 2023;181:63–76.
38. Furukawa T, Ebana Y. Role of KCNN3 potassium channels in atrial electrophysiology. J Physiol 2012;590:3729–3740.
39. Antoinette van Ouwerkerk A, Bosada FM, Liu C, et al. Translating atrial fibrillation genetics to mechanism. Circ Res 2020;127:4–19.
40. Ebana Y, Yagi T, Harada M, et al. Functional consequences of PITX2 deficiency in murine atria. Cardiovasc Res 2017;113:112–123.
41. Reyat H, et al. BMP10-mediated signalling in PITX2-deficient atrial cardiomyocytes. Nat Commun 2020;11:4829.
42. Wang Y, Chen H, Zhang X, et al. Proteomic signatures of atrial fibrillation. Circulation 1996;93:117–125.
43. Sun X, Wang Y, Zhou M, et al. Epigenomic reprogramming in atrial fibrillation. Circ Res 2019;125:708–725.
44. Vinciguerra M, Leone V, Greco M, et al. Histone deacetylation and atrial remodelling. Heart 2024;110:192–204.
45. Dai Z, Zhao Y, Wang H, et al. Epigenetic regulation in atrial fibrillation: therapeutic perspectives. Front Cardiovasc Med 2024;11:1509–1523.