5-Methoxytryptophan alleviates atrial structural remodeling in ibrutinib-associated atrial fibrillation

Wei Shuai; Bo Peng; Jun Zhu; Bin Kong; Hui Fu; He Huang

doi:10.1016/j.heliyon.2023.e19501

5-Methoxytryptophan alleviates atrial structural remodeling in ibrutinib-associated atrial fibrillation

Heliyon. 2023 Aug 29;9(9):e19501. doi: 10.1016/j.heliyon.2023.e19501. eCollection 2023 Sep.

Authors

Wei Shuai^{1

2

3}, Bo Peng^{1

2

3}, Jun Zhu^{1

2

3}, Bin Kong^{1

2

3}, Hui Fu^{1

2

3}, He Huang^{1

2

3}

Affiliations

¹ Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan, 430060, Hubei, PR China.
² Cardiovascular Research Institute of Wuhan University, Wuhan, 430060, Hubei, PR China.
³ Hubei Key Laboratory of Cardiology, Wuhan, 430060, Hubei, PR China.

Abstract

Background: Ibrutinib is an effective and well-tolerated treatment for B-cell lymphomas but is associated with an increased risk of atrial fibrillation (AF) by altering the structure of the atrium. 5-Methoxytryptophan (5-MTP) inhibits inflammatory and fibrotic processes. This study aimed to determine the effects and mechanisms of 5-MTP on the underlying mechanisms of AF caused by ibrutinib.

Methods: The effect of 5-MTP on ibrutinib-related AF was investigated in male Sprague Dawley rats using echocardiographic, electrophysiological, immunofluorescent, Masson staining, and molecular analyses.

Rusults: The ibrutinib+5-MTP group showed (1) a lower incidence and shorter duration of AF and accelerated atrial conduction; (2) a decreased left atrial mass and left atrial diameter; (3) decreased myocardial fibrosis in the left atrium; (4) lower atrial inflammation; (5) increased sarcoplasmic reticulum Ca²⁺-ATPase 2a protein expression, decreased phosphorylation of phospholamban at Thr17, and decreased sodium/calcium exchanger 1 protein expression and phosphorylation of ryanodine receptor 2 at S2814; and (6) decreased phosphorylation of CaMKII expression. 5-MTP treatment markedly activated the PI3K-Akt signaling. Inhibiting PI3K-Akt signaling significantly reversed the protective effect of 5-MTP on ibrutinib-related AF.

Conclusions: These findings suggest that 5-MTP administration decreases the vulnerability of ibrutinib-related AF mainly caused by ameliorated maladaptive left atrial remodeling and dysregulation of calcium handling proteins. Mechanistically, 5-MTP treatment markedly enhanced the activation of cardiac PI3K-Akt signaling.

Keywords: 5-Methoxytryptophan; Atrial fibrillation; Ibrutinib; PI3K-Akt signaling; Structural remodeling.