Deciphering novel pathomechanisms initiating and maintaining atrial fibrillation
by Aiste Liutkute
Date of Examination:2025-02-25
Date of issue:2025-06-17
Advisor:Prof. Dr. Niels Voigt
Referee:Prof. Dr. Niels Voigt
Referee:Prof. Dr. Thomas Meyer
Persistent Address:
http://dx.doi.org/10.53846/goediss-11315
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Abstract
English
Atrial fibrillation (AF) is the most common arrhythmia and AF burden is projected to rise in the next years. This may be partially attributed to limited efficacy of current antiarrhythmic therapies and interventions. A deeper understanding of the mechanisms underlying and driving AF is crucial to recognize the pitfalls in existing standard treatment strategies as well as to uncover novel therapeutic targets. To this end, two independent research projects were conducted, resulting in two scientific articles that investigate the pathomechanisms of AF initiation and maintenance in underexplored AF contexts where conventional therapies show limited efficacy. Article I examines the potential AF triggering mechanisms associated with mutations in the nucleoskeletal protein lamin A/C. Atrial induced pluripotent stem cell-derived cardiomyocytes harboring previously clinically reported LMNA variants were subjected to integrated multiomics and functional assays, which collectively revealed that LMNA mutations lead to upregulation of the voltage-dependent L-type calcium (Ca2+) channel subunit α1D of Cav1.3 resulting in higher Ca2+ influx, which overloads sarcoplasmic reticulum Ca2+ content and triggers arrhythmogenic spontaneous Ca2+ release events. Further analyses suggested the potential enhancement of RNA cytidine acetyltransferase-dependent epitranscriptomic regulation, contributing to Cav1.3-associated atrial arrhythmogenesis and which can be mitigated through the pharmacological treatment with the RNA cytidine acetyltransferase inhibitor remodelin. In Article II, the role of the right atrium in AF maintenance was investigated using a proteomic approach. While catheter ablation primarily targets the left atrium, recent clinical evidence of widespread AF rotors suggests that both atrial chambers may contribute to AF persistence. To explore this, a spectral proteomic library was established using human heart samples, enabling the analysis of atrial tissues from persistent AF (persAF) and sinus rhythm patients obtained during open-heart surgeries or from donor hearts. Proteome profiling revealed a significant role of right atrium in AF maintenance, demonstrating hallmark features of AF-associated remodelling, which contribute to enhanced left–right atrial proteome symmetry in persAF. This suggests an equally distributed substrate maintaining AF and provides a rationale for why targeting only the left atrium during catheter ablation may be insufficient to effectively terminate persAF. Collectively, these findings unveil novel insights into the mechanisms underlying AF initiation and maintenance, which may contribute to the development of more effective therapeutic strategies.
Keywords: Atrial fibrillation; Lamin; Calcium; Arrhythmia
