Tia Patel

Background: Atrial fibrillation is defined to be uncoordinated rapid contractions of the atria.¹ The rate of heartbeats during atrial fibrillation can be up to 400 to 500 beats per minute.¹ The decreased beats lead to decreased ventricular filling and in turn decreased cardiac output causing heart failure.¹ Development of atrial fibrillation is diverse ranging from age, drugs, alcohol use or genetics.³ Computational modeling discovered that RyR2 protein dysfunction may play a role in atrial fibrillation.^1,2 RyR2 protein located on the sarcoplasmic reticulum of heart cells might have gating dysfunctions via upstream mechanistic dysfunction leading to increased calcium leakage.² The calcium leakage is reduced by the sodium-calcium exchanger triggering increased delayed afterdepolarizations that may occur during diastole leading to possible atrial fibrillations.²

Objective: This narrative review explores various upstream mechanistic dysfunctions that lead to RyR2 dysfunction

Search Methods: Online search using the PubMed database from 2018-2025 was using the keywords, “RyR2” and “Atrial Fibrillation” and “Computational Modeling”

Results: It was predicted that inflammation could possibly trigger atrial fibrillation via the NLRP3/procaspase 1 pathway leading to activation of CaMKII and subsequent hyperphosphorylation of the RyR2 protein.⁷ A computational model was used to assess the gating dysfunction of RyR2.⁷ The results further indicated that the inflammation did trigger the NLRP3 pathway which led to CaMKII activation and hyperphosphorylation of RyR2 leading to calcium mishandling and increased DADs which increased the risk of atrial fibrillation.⁷ Another experiment further indicated upstream dysfunction such as in CaMKII may lead to RyR2 gating dysfunction.⁵ The results indicated that when CaMKII was inhibited, the risk of arrhythmias decreased.⁵ However, when CaMKII was upregulated and working with PKA, the risk of DADs increased.⁵ Another mechanism displayed similar results. The results showed that when the molecule CaM upstream was inhibited, RyR2 open probability was much higher, once again contributing to arrhythmias.⁸ The location of the dysfunction of the RyR2 protein was also important.⁶ Results showed calcium sparks were the greatest near the sarcolemma, and could pave way for therapeutic targets.⁶ Furthermore, the M201 drug led to increased E’ wave which means increased ventricular relaxation which combats risk of atrial fibrillation.⁹ Human study trials displayed the safety of the drug itself.⁹ Individuals who faced symptoms only displayed mild symptoms, many of which resolved on their own.⁹

Conclusion: The results displayed that there is a possible link between RyR2 dysfunction and atrial fibrillation.^5,6,7,8,9 Through mechanistic pathways it is displayed that hyperphosphorylation of RyR2 and increased calcium leakage through the direct method involving CaMKII and CaM-RyR2 but also indirectly via inflammation.^5,7,8 Furthermore, the location such as near the sarcolemma may be important for detecting calcium sparks and for possible therapeutic targets.⁶ Therapeutic targets such as M201A drug displays a possible approach in atrial fibrillation.⁹

Works Cited:

1. Dridi H, Kushnir A, Zalk R, Yuan Q, Melville Z, Marks AR. Intracellular calcium leak in heart failure and atrial fibrillation: a unifying mechanism and therapeutic target. Nat Rev Cardiol. 2020;17(11):732-747. doi:10.1038/s41569-020-0394-8
2. Chang Y, Zou Q. Mitochondrial calcium homeostasis and atrial fibrillation: Mechanisms and therapeutic strategies review. Curr Probl Cardiol. 2025;50(3):102988. doi:10.1016/j.cpcardiol.2025.102988
3. Nesheiwat Z, Goyal A, Jagtap M. Atrial Fibrillation.In: StatPearls [Internet]. Treasure Island (FL). 2023 Apr 26; Available from: https://www.ncbi.nlm.nih.gov/books/NBK526072/
4. Ko D, Chung MK, Evans PT, Benjamin EJ, Helm RH. Atrial Fibrillation: A Review. JAMA. 2025;333(4):329–342. doi:10.1001/jama.2024.22451
5. Ni H, Morotti S, Zhang X, Dobrev D, Grandi E. Integrative human atrial modelling unravels interactive protein kinase A and Ca2+/calmodulin-dependent protein kinase II signalling as key determinants of atrial arrhythmogenesis. Cardiovasc Res. 2023;119(13):2294-2311. doi:10.1093/cvr/cvad118
6. Tarifa C, Vallmitjana A, Jiménez-Sábado V, et al. Spatial Distribution of Calcium Sparks Determines Their Ability to Induce Afterdepolarizations in Human Atrial Myocytes. JACC Basic Transl Sci. 2022;8(1):1-15. Published 2022 Nov 23. doi:10.1016/j.jacbts.2022.07.013
7. Heijman J, Muna AP, Veleva T, et al. Atrial Myocyte NLRP3/CaMKII Nexus Forms a Substrate for Postoperative Atrial Fibrillation. Circ Res. 2020;127(8):1036-1055. doi:10.1161/CIRCRESAHA.120.316710
8. Greene D, Shiferaw Y. Mechanistic link between CaM-RyR2 interactions and the genesis of cardiac arrhythmia. Biophys J. 2021;120(8):1469-1482. doi:10.1016/j.bpj.2021.02.016
9. Kaneko N, Smith GL, Loughrey CM, et al. Pharmacological study of the safety, efficacy, and potential of M201-A on paroxysmal and persistent atrial fibrillation. J Pharmacol Exp Ther. 2025;392(8):103652. doi:10.1016/j.jpet.2025.103652