Arrhythmogenic Ventricular Remodeling by Next-Generation Bruton’s Tyrosine Kinase Inhibitor Acalabrutinib

Autor: Yanan Zhao, Praloy Chakraborty, Julianna Tomassetti, Tasnia Subha, Stéphane Massé, Paaladinesh Thavendiranathan, Filio Billia, Patrick F. H. Lai, Husam Abdel-Qadir, Kumaraswamy Nanthakumar
Jazyk: angličtina
Rok vydání: 2024
Předmět:
Zdroj: International Journal of Molecular Sciences, Vol 25, Iss 11, p 6207 (2024)
Druh dokumentu: article
ISSN: 25116207
1422-0067
1661-6596
DOI: 10.3390/ijms25116207
Popis: Cardiac arrhythmias remain a significant concern with Ibrutinib (IBR), a first-generation Bruton’s tyrosine kinase inhibitor (BTKi). Acalabrutinib (ABR), a next-generation BTKi, is associated with reduced atrial arrhythmia events. However, the role of ABR in ventricular arrhythmia (VA) has not been adequately evaluated. Our study aimed to investigate VA vulnerability and ventricular electrophysiology following chronic ABR therapy in male Sprague–Dawley rats utilizing epicardial optical mapping for ventricular voltage and Ca2+ dynamics and VA induction by electrical stimulation in ex-vivo perfused hearts. Ventricular tissues were snap-frozen for protein analysis for sarcoplasmic Ca2+ and metabolic regulatory proteins. The results show that both ABR and IBR treatments increased VA vulnerability, with ABR showing higher VA regularity index (RI). IBR, but not ABR, is associated with the abbreviation of action potential duration (APD) and APD alternans. Both IBR and ABR increased diastolic Ca2+ leak and Ca2+ alternans, reduced conduction velocity (CV), and increased CV dispersion. Decreased SERCA2a expression and AMPK phosphorylation were observed with both treatments. Our results suggest that ABR treatment also increases the risk of VA by inducing proarrhythmic changes in Ca2+ signaling and membrane electrophysiology, as seen with IBR. However, the different impacts of these two BTKi on ventricular electrophysiology may contribute to differences in VA vulnerability and distinct VA characteristics.
Databáze: Directory of Open Access Journals
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