TGFβ Is Specifically Upregulated on Circulating CD14++ CD16+ and CD14+ CD16++ Monocytes in Patients with Atrial Fibrillation and Severe Atrial Fibrosis

Abstract

Background/Aims: Fibrotic remodeling of the atria plays a key role in the pathogenesis of atrial fibrillation (AF). As little is known about the contribution of circulating monocytes in atrial remodeling and the pathophysiology of AF, we investigated profibrotic factors in different subsets of circulating monocytes obtained from patients with atrial fibrillation undergoing catheter ablation. Methods: A 3D high density voltage mapping was performed in sinus rhythm to evaluate the extent of low-voltage areas (LVAs) in the atria of 71 patients with persistent AF. Low-voltage was defined as signals of < 0.5mV during sinus rhythm. Prior to ablation, blood was drawn and monocytes were analyzed by FACS. Based on the expression of CD14 and CD16, three subgroups including CD14⁺⁺ CD16^- (‘classical’), CD14⁺⁺ CD16⁺ (‘intermediate’), and CD14⁺ CD16⁺⁺ (‘non-classical’) were analyzed for the expression of TGFb, CD147, and MMP-9, representing pivotal profibrotic pathways in myocardial remodeling. Results: Expression of TGFb was increased in CD14⁺ monocytes of patients with extensive LVAs compared to patients with a low extend of LVAs. While CD14⁺⁺ CD16^- monocytes showed no difference, CD14⁺⁺ CD16⁺ and CD14⁺ CD16⁺⁺ monocytes showed a strong increase of TGFb abundance. Although CD147 and MMP-9 are strongly associated with myocardial fibrosis, we found no difference in expression between the two groups in any monocyte subsets. Conclusion: TGFb is specifically upregulated on CD14⁺⁺ CD16⁺ and CD14⁺ CD16⁺⁺ monocytes in patients with extensive LVAs undergoing catheter ablation.

RETRACTED ARTICLE: Anti-fibrotic mechanism of SPP1 knockdown in atrial fibrosis associates with inhibited mitochondrial DNA damage and TGF-β/SREBP2/PCSK9 signaling

“…SPP1 is capable of promoting the expression and activation of transforming growth factor-β 1 (TGF-β1), increasing the production of fibrous matrix proteins in lung cells exposed to multi-walled carbon nanotubes [ 7 ]. TGF-β has been detected to be upregulated in CD14++ CD16+ and CD14+ CD16++ monocytes in patients with atrial fibrillation and severe atrial fibrosis [ 8 ]. Meanwhile, activation of the TGF-β pathway contributes to atrial fibrosis in an atrial fibrillation experimental model and patients [ 9 ].…”

Atrial Myopathy Underlying Atrial Fibrillation

“…[ 93 ] In addition, TGFbeta1 expression is specifically upregulated in patients with extensive low-voltage areas undergoing ablation. [ 94 ] Serum TGF-beta1 has been shown to be an independent risk factor for AF recurrence after ablation in both paroxysmal and persistent AF. [ 93 , 95 ] Interestingly, Kishima et al found lower concentrations of TGF-beta1 in patients with recurrence after ablation.…”

Circulating intermediate monocytes and atrial structural remodeling associated with atrial fibrillation recurrence after catheter ablation

“…Zhou et al reported that an increase in circulating microRNA served as SRM 35 . Transforming growth factor‐beta was specifically upregulated in intermediate monocytes in patients with progressed 36 . Previous studies have reported that SRM detected by LGE‐MRI is a strong and independent predictor of arrhythmia recurrence after CA 14,21,22 .…”