Elevated β1-Adrenergic Receptor Autoantibody Levels Increase Atrial Fibrillation Susceptibility by Promoting Atrial Fibrosis

Shang, Luxiang; Zhang, Ling; Shao, Mengjiao; Feng, Min; Shi, Jia; Dong, Zhenyu; Guo, Qilong; Xiaokereti, Jiasuoer; Xiang, Ran; Sun, Haixiang; Zhou, Xianhui

doi:10.3389/fphys.2020.00076

Cited by 13 publications

(22 citation statements)

References 51 publications

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“…Endocardial electrophysiological parameters were measured to evaluate the atrial electrical stability under the β1-AAb stimulation. As reported in our prior work [13], β1-AAb shortened the AERP and stretched the WOV in the rabbits responding to active immunization, which were reversed by blocking β1AR (respectively, P<0.05, Figure 2D,E and Supplementary Figure S2). AF inducibility was significantly elevated in the β1-AAb group under the burst pacing, as well as the AF duration.…”

Section: The β1-aab Decreases the Atrial Electrical Instability And I...supporting

confidence: 83%

“…With the developing studies, the higher titers of β1-AAbs are detected in approximately 50% of patients with atrial and ventricular arrhythmias [ 10 , 11 , 12 ]. Our recent work substantiated that elevated β1-AAbs positively correlate with left atrial diameters in paroxysmal AF patients and exacerbate the atrial fibrosis [ 13 ]. Accumulating evidence from basic experiments supported the contributions of β1-AAbs in arrhythmia susceptibilities through promoting numerous adverse cardiac phenotypes, including apoptosis, autophagy, and vulnerable electrophysiologic properties [ 14 , 15 , 16 ].…”

Section: Introductionsupporting

confidence: 59%

“…results [13], systemic β1-AAb abundance keeps on the rise throughout the experiment, accompanied with the positive cardiac response. A successful autoimmune model in favor of performing the electrophysiology study.…”

Section: Discussionmentioning

confidence: 64%

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Increased β1-adrenergic receptor antibody confers a vulnerable substrate for atrial fibrillation via mediating Ca2+ mishandling and atrial fibrosis in active immunization rabbit models

Sun

Song

et al. 2023

Clinical Science

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Background: Autoimmune disorder is the emerging mechanism of atrial fibrillation (AF).The β1-adrenergic receptor antibody (β1-AAb) is associated with AF progress. Our study aims to investigate whether β1-AAbs involves in atrial vulnerable substrate by mediating Ca2+ mishandling and atrial fibrosis in autoimmune associated AF. Methods: Active immunization models were established via subcutaneous injection of the second extracellular loop (ECL2) peptide for β1 adrenergic receptor (β1AR). Invasive electrophysiologic study and ex vivo optical mapping were used to evaluate the changed electrophysiology parameters and calcium handling properties. Phospho-proteomics combined with molecular biology assay were performed to identify the potential mechanisms of remodeled atrial substrate elicited by β1-AAbs. Exogenous β1-AAbs were used to induce the cellular phenotypes of HL-1 cells and atrial fibroblasts to AF propensity. Results: β1-AAbs aggravated the atrial electrical instability and atrial fibrosis. Bisoprolol alleviated the alterations of action potential duration (APD), Ca2+ transient duration (CaD) and conduction heterogeneity challenged by β1-AAbs. β1-AAbs prolonged calcium transient refractoriness and promoted arrhythmogenic atrial alternans and spatially discordant alternans, which were partly counteracted through blocking β1AR. Its underlying mechanisms are related to β1AR-drived CaMKII/RyR2 activation of atrial cardiomyocytes and the myofibroblasts phenotype formation of fibroblasts. Conclusion: Suppressing β1-AAbs effectively protects the atrial vulnerable substrate by ameliorating intracellular Ca2+ mishandling and atrial fibrosis, preventing the process of the autoimmune associated AF.

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Section: The β1-aab Decreases the Atrial Electrical Instability And I...supporting

confidence: 83%

Section: Introductionsupporting

confidence: 59%

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Increased β1-adrenergic receptor antibody confers a vulnerable substrate for atrial fibrillation via mediating Ca2+ mishandling and atrial fibrosis in active immunization rabbit models

Sun

Song

et al. 2023

Clinical Science

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“…Transthoracic echocardiography was performed weekly beginning in the first postinfarction week and lasting until the fifth week. Echocardiographic examination was implemented with a Philips HD11XE transthoracic Doppler ultrasound imaging system (Philips Inc., Bothell, WA, USA) as described in our previous work [ 21 ]. The short-axis views of the left ventricle were recorded by two-dimensional M-mode tracing at the level of the papillary muscle.…”

Section: Methodsmentioning

confidence: 99%

Cholinergic Elicitation Prevents Ventricular Remodeling via Alleviations of Myocardial Mitochondrial Injury Linked to Inflammation in Ischemia-Induced Chronic Heart Failure Rats

Zhao

Sun

et al. 2021

Mediators of Inflammation

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Background. Cholinergic anti-inflammatory pathway (CAP) is implicated in cardioprotection in chronic heart failure (CHF) by downregulating inflammation response. Mitochondrial injuries play an important role in ventricular remodeling of the CHF process. Herein, we aim to investigate whether CAP elicitation prevents ventricular remodeling in CHF by protecting myocardial mitochondrial injuries and its underlying mechanisms. Methods and Results. CHF models were established by ligation of anterior descending artery for 5 weeks. Postoperative survival rats were assigned into 5 groups: the sham group (sham, n = 10 ), CHF group (CHF, n = 11 ), Vag group (CHF+vagotomy, n = 10 ), PNU group (CHF+PNU-282987 for 4 weeks, n = 11 ), and Vag+PNU group (CHF+vagotomy+PNU-282987 for 4 weeks, n = 10 ). The antiventricular remodeling effect of cholinergic elicitation was evaluated in vivo, and H9C2 cells were selected for the TNF-α gradient stimulation experiment in vitro. In vivo, CAP agitated by PNU-282987 alleviated the left ventricular dysfunction and inhibited the energy metabolism remodeling. Further, cholinergic elicitation increased myocardium ATP levels and reduced systemic inflammation. CAP induction alleviates macrophage infiltration and cardiac fibrosis, of which the effect is counteracted by vagotomy. Myocardial mitochondrial injuries were ameliorated by CAP activation, including the reserved ultrastructural integrity, declining ROS overload, reduced myocardial apoptosis, and enhanced mitochondrial fusion. In vitro, TNF-α intervention significantly exacerbated the mitochondrial damage in H9C2 cells. Conclusion. CAP elicitation effectively improves ischemic ventricular remodeling by suppressing systemic and cardiac inflammatory response, attenuating cardiac fibrosis and potentially alleviating the mitochondrial dysfunction linked to hyperinflammation reaction.

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“…In adaptive immunity, it has previously been shown that patients with AF have higher levels of autoantibodies, including anti-β1adrenergic receptor (anti-β1-AR) and anti-M2-muscarinic receptor (anti-M2-R) (Yalcin et al, 2015). Anti-M2-R can predict the degree of left atrial fibrosis in pAF patients and β1-AR autoantibody may promote the development of AF by regulating atrial fibrosis (Gurses et al, 2015;Shang et al, 2020). Moreover, the levels of circulating immunoglobulin-free light chains, kappa and lambda, were higher in individuals with AF (Matsumori et al, 2020).…”

Section: Evidence For Immune Remodelingmentioning

confidence: 99%

Immune remodeling and atrial fibrillation

et al. 2022

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Atrial fibrillation (AF) is a highly prevalent arrhythmia that causes high morbidity and mortality. However, the underlying mechanism of AF has not been fully elucidated. Recent research has suggested that, during AF, the immune system changes considerably and interacts with the environment and cells involved in the initiation and maintenance of AF. This may provide a new direction for research and therapeutic strategies for AF. In this review, we elaborate the concept of immune remodeling based on available data in AF. Then, we highlight the complex relationships between immune remodeling and atrial electrical, structural and neural remodeling while also pointing out some research gaps in these field. Finally, we discuss several potential immunomodulatory treatments for AF. Although the heterogeneity of existing evidence makes it ambiguous to extrapolate immunomodulatory treatments for AF into the clinical practice, immune remodeling is still an evolving concept in AF pathophysiology and further studies within this field are likely to provide effective therapies for AF.

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Elevated β1-Adrenergic Receptor Autoantibody Levels Increase Atrial Fibrillation Susceptibility by Promoting Atrial Fibrosis

Cited by 13 publications

References 51 publications

Increased β1-adrenergic receptor antibody confers a vulnerable substrate for atrial fibrillation via mediating Ca2+ mishandling and atrial fibrosis in active immunization rabbit models

Increased β1-adrenergic receptor antibody confers a vulnerable substrate for atrial fibrillation via mediating Ca2+ mishandling and atrial fibrosis in active immunization rabbit models

Cholinergic Elicitation Prevents Ventricular Remodeling via Alleviations of Myocardial Mitochondrial Injury Linked to Inflammation in Ischemia-Induced Chronic Heart Failure Rats

Immune remodeling and atrial fibrillation

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