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Impacts of Renal Sympathetic Activation on Atrial Fibrillation: The Potential Role of the Autonomic Cross Talk Between Kidney and Heart.

ABSTRACT: Recent studies have demonstrated that there is a high variability of renal sympathetic nerve density distribution from proximal to distal renal artery segments. The aim of our study was to investigate the roles of renal sympathetic nerve stimulation (RSS) on atrial fibrillation and cardiac autonomic nervous activity.Twenty-eight dogs were randomly assigned to the proximal RSS group (P-RSS, N=7), middle RSS group (M-RSS, N=7), distal RSS group (D-RSS, N=7), and the control group (sham RSS, N=7). RSS was performed using electrical stimulation on the bilateral renal arteries for 3 hours. Effective refractory period and the window of vulnerability were measured at atrial and pulmonary veins sites. Superior left ganglionated plexi (SLGP) and left stellate ganglion (LSG) function and neural activity were determined. C-fos and nerve growth factor protein expression in the SLGP and LSG were examined. Only P-RSS (1) caused pronounced blood pressure rises, induced a significant decrease in effective refractory period, and generated a marked increase in cumulative window of vulnerability and effective refractory period dispersion; (2) increased the frequency and amplitude of the neural activity in the SLGP and LSG; (3) increased SLGP and LSG function; and (4) upregulated the level of c-fos and nerve growth factor expression in the SLGP and LSG.This study demonstrated that renal sympathetic nerve activation induced by 3 hours of P-RSS facilitated atrial fibrillation inducibility by upregulating cardiac autonomic nervous activity, suggesting a potential autonomic cross talk between kidney and heart.

SUBMITTER: Yu L

PROVIDER: S-EPMC5524006 | biostudies-other | 2017 Mar

REPOSITORIES: biostudies-other

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Project description:Increased macrophage accumulation occurs in the atria of patients with atrial fibrillation (AF). However, the phenotype and functions of the macrophages in AF remain unclear. We investigated the macrophage-atrial myocyte interaction in AF patients and found that the increased macrophages were mainly pro-inflammatory macrophages (iNOS+, Arg1-). Tachypacing of HL-1 atrial myocytes also led to pro-inflammatory macrophage polarization. In addition, lipopolysaccharide (LPS)-stimulated pro-inflammatory macrophages-induced atrial electrical remodeling, evidenced by increased AF incidence and decreased atrial effective refractory period and L-type calcium currents (I Ca-L) in both canine and mouse AF models. Depletion of macrophages relieved LPS-induced atrial electrical remodeling, confirming the role of pro-inflammatory macrophages in the pathogenesis of AF. We also found that the effect of LPS-stimulated macrophages on atrial myocytes was mediated by secretion of interleukin 1 beta (IL-1β), which inhibited atrial myocyte quaking protein (QKI) expression. IL-1β knockout in macrophages restored the LPS-stimulated macrophage-induced inhibition of QKI and CACNA1C (α1C subunit of L-type calcium channel) in atrial myocytes. Meanwhile, QKI overexpression in atrial myocytes restored the LPS-stimulated macrophage-induced electrical remodeling through enhanced binding of QKI to CACNA1C mRNA, which upregulated the expression of CACNA1C as well as I Ca-L. In contrast, QKI knockout inhibited CACNA1C expression. Finally, using transcription factor activation profiling plate array and chromatin immunoprecipitation, we revealed that special AT-rich sequence binding protein 1 activated QKI transcription. Taken together, our study uncovered the functional interaction between macrophages and atrial myocytes in AF. AF induced pro-inflammatory macrophage polarization while pro-inflammatory macrophages exacerbated atrial electrical remodeling by secreting IL-1β, further inhibiting QKI expression in atrial myocytes, which contributed to I Ca-L downregulation. Our study demonstrates a novel molecular mechanism underlying the pathogenesis and progression of AF and suggests that QKI is a potential therapeutic target.

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Impacts of Renal Sympathetic Activation on Atrial Fibrillation: The Potential Role of the Autonomic Cross Talk Between Kidney and Heart.

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