Guannan Meng

A potential relationship between gut microbes and atrial fibrillation: Trimethylamine N-oxide, a gut microbe-derived metabolite, facilitates the progression of atrial fibrillation

BACKGROUND Emerging evidence indicates gut microbes and their products could activate the autonomic nervous system (ANS), which plays important roles in the initiation and maintenance of atrial fibrillation (AF). Trimethylamine N-oxide (TMAO), a metabolite derived from gut microbes, is associated with cardiovascular diseases. The present study aimed to investigate the role of TMAO in the progression of AF. METHODS In part 1: TMAO or saline was locally injected into 4 major atrial ganglionated plexi (GP) to clarify its effect on cardiac ANS and AF inducibility in normal canines. In part 2: TMAO or saline was injected into 4 major atrial GP to test its effect on AF progression in a rapid atrial pacing (RAP)-induced AF model. RESULTS In part 1: Local injection of TMAO significantly increased anterior right GP (ARGP) function and neural activity, shortened ERP values. In part 2, compared with the control group, 6-hour RAP significantly shortened the ERP, widened the ∑WOV, enhanced the ARGP function and neural activity, increased the NGF and c-fos expression, and up-regulated the inflammatory cytokines. TMAO aggravated all of these changes by activating the proinflammatory p65 NF-κB signaling pathway. CONCLUSIONS TMAO could increase the instability of atrial electrophysiology in normal canines and aggravate the acute electrical remodeling in a RAP-induced AF model by exacerbating autonomic remodeling. The increased inflammatory cytokines in the GP due to the activation of p65 NF-κB signaling may contribute to these effects.

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

Background 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. Methods and Results 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. Conclusions 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.

Increased inflammation promotes ventricular arrhythmia through aggravating left stellate ganglion remodeling in a canine ischemia model

BACKGROUND Increased inflammation was found in the left stellate ganglion (LSG) in patients with malignant ventricular arrhythmia (VA). However, the role of inflammation in LSG remodeling is unknown. This study aimed to investigate whether exogenous interleukin-1β (IL-1β) could aggravate VA through regulating LSG remodeling. METHODS Twenty-four canines who received saline (Control, n=8), IL-1β injection into the LSG (n=8) or IL-1 receptor antagonist (IL-Ra) pre-injection plus IL-1β injection (n=8) were included. Ventricular electrophysiology parameters, heart rate variability (HRV), LSG activity were measured at different time points. VA was recorded for 60min after ischemia and then LSG tissues were collected for molecular detection. RESULTS Compared with the control group, IL-1β injection decreased the effective refractory period, action potential duration (APD)90 and increased the maximal slope of the restitution curve in normal hearts. Besides, the occurrence of VA was significantly increased in the IL-1β group. Additionally, IL-1β injection increased the sympathetic indices of HRV and LSG activity in normal and ischemic hearts. Mechanically, the mRNA expression of pro-inflammatory cytokines and protein expression of c-fos, nerve growth factor and neuropeptide Y in LSG were increased, whereas the expression of neuronal nitric oxide synthase was decreased in the IL-1β group. More importantly, all these effects induced by IL-1β were attenuated by IL-1Ra pre-injection. CONCLUSION Increased inflammation induced by IL-1β injection aggravates ischemia induced VA through regulating the neuronal remodeling of the LSG. Inflammation induced neuroplasticity may be a novel mechanism and therapeutic target for VA.

Atrial Fibrillation in Acute Obstructive Sleep Apnea: Autonomic Nervous Mechanism and Modulation

Background The mechanisms of atrial fibrillation (AF) induced by obstructive sleep apnea (OSA) are not completely understood. This study investigated the roles of the intrinsic and extrinsic cardiac autonomic nervous system in OSA‐induced AF and provided noninvasive autonomic nervous modulation for the suppression of OSA‐induced AF by using low‐level transcutaneous electrical stimulation (LL‐TS) of the auricular branch of the vagus nerve at the tragus. Methods and Results Eighteen dogs received tracheostomy under general anesthesia and were randomly divided into 3 groups: the OSA group (OSA was simulated via clamping of the endotracheal tube at end expiration for 1.5 minutes every 10 minutes, n=6), the LL‐TS + OSA group (simulated OSA plus LL‐TS, at 80% of the slowing sinus rate, n=6), and the control group (sham surgery without stimulation, n=6). The effective refractory period was significantly shortened after 1 hour of simulated OSA, and the window of vulnerability and plasma norepinephrine levels were both markedly increased in the OSA group. OSA dramatically increased the neural function and activity of the intrinsic and extrinsic cardiac autonomic nervous system, including the superior left ganglionated plexus, the left stellate ganglion, and the left renal sympathetic nerve. OSA also significantly upregulated the expression levels of c‐fos and nerve growth factor in the superior left ganglionated plexus and the left stellate ganglion. However, LL‐TS markedly improved these parameters. Conclusions These findings suggest that the intrinsic and extrinsic cardiac autonomic nervous system plays crucial roles in the acute stage of OSA‐induced AF. Noninvasive LL‐TS suppressed shortening of atrial refractoriness and autonomic remodeling, which prevented OSA‐induced AF.

Reply: Optogenetic Neuromodulation of Stellate Ganglia for Patients With Ventricular Arrhythmias, Atrial Fibrillation, Angina, and Takotsubo?

We thank Dr. Madias for the valuable comments and totally agree with the idea of combining optogenetic neuromodulation (ON) with direct monitoring of sympathetic autonomic nerve activity (SANA) for precision therapy. Left stellate ganglion (LSG) plays an important role in modulating ventricular

Mast cells modulate the pathogenesis of leptin-induced left stellate ganglion activation in canines

BACKGROUND Leptin is an adipocytokine predominantly secreted by adipose tissue that participates in immune modulation. Mast cells are important immune cells that are related to altered sympathetic activity. Previous study has shown that leptin promotes activation of the left stellate ganglion (LSG) directly via the leptin receptor. This study aims to investigate whether mast cells play a key role in indirect activation. METHODS Twenty-eight canines were randomly divided into 3 groups: the control group (saline, n = 8), leptin group (leptin, n = 9), and DSCG group (disodium cromoglycate plus leptin, n = 11). Drugs were locally microinjected into the LSG. The function and neural activity of the LSG were evaluated to investigate LSG activation. Tryptase was adopted to identify activated mast cells in the LSG. RESULTS Compared with the control group, leptin injection (18 μg) markedly increased the function and neural activity of the LSG. Leptin also upregulated c-fos, nerve growth factor (NGF), and tryptase expression in the LSG. However, these effects of leptin were attenuated by pre-injection of DSCG (25 mg). Additionally, the immunofluorescence analysis revealed that many mast cells were present in the LSG and that those cells were located close to sympathetic neurons. The presence of leptin receptors on the mast cells was verified. CONCLUSIONS Immune mast cells play an important supplementary role in the pathogenesis of leptin-induced LSG activation.

Regulation of the NRG1/ErbB4 Pathway in the Intrinsic Cardiac Nervous System Is a Potential Treatment for Atrial Fibrillation

Background: The NRG1/ErbB4 signaling mechanism has been widely studied in the central nervous system for many years. However, the role of this pathway in modulating the intrinsic cardiac nervous system is largely unknown. Objective: The present study investigated whether the NRG1/ErbB4 signaling system affects the activity of major atrial ganglionated plexi (GP) in a paroxysmal atrial fibrillation (AF) model by 6-h rapid atrial pacing (RAP). Methods: Twenty-four dogs were randomly divided into (1) a control group (saline microinjections into GP), (2) RAP group (saline microinjections into GP plus 6 h-RAP), (3) NRG1 group (microinjections of neuregulin-1 into GP plus 6 h-RAP) and (4) NRG1 + ERA group (microinjections of neuregulin-1 and ErbB4 receptor antagonist-ERA into GP plus 6 h-RAP). The effective refractory period (ERP), window of vulnerability (WOV), anterior right GP (ARGP) function and neural activity were measured. ARGP tissues were excised for histological study and western blotting. Results: When compared to the control group, 6 h-RAP produced a significant (1) decrease in ERP, an increase in ΣWOV, (2) an increase in ARGP neural activity and neural function, and (3) an increase in c-fos and nerve growth factor protein expression in the ARGP. However, microinjection of NRG1 into the ARGP prior to RAP prevented ERP shortening and AGRP activity enhancement and inhibited the expression of c-Fos and NGF proteins. Furthermore, these changes were significantly attenuated by pretreatment with an ErbB4 receptor antagonist. Conclusion: The NRG1/ErbB4 signaling pathway may exist in the GP, and activation of this pathway suppressed RAP-induced GP activation, atrial electrical remodeling and AF.

OPTOGENETIC APPROACH MODULATES CARDIAC SYMPATHETIC GANGLION TO PROTECT AGAINST ISCHEMIA RELATED VENTRICULAR ARRHYTHMIAS

Background: Studies have shown that left stellate ganglion (LSG) ablation protects against myocardial ischemia related ventricular arrhythmias (VAs). Optogenetics is a transient, precise and controllable method and has been widely used in neuroscience to regulate the activity of neurons. This study

GUT MICROBES-DERIVED METABOLITE TRIMETHYLAMINE N-OXIDE FACILITATES THE PROGRESSION OF “ATRIAL FIBRILLATION BEGETS ATRIAL FIBRILLATION”: A POTENTIAL LINK BETWEEN GUT MICROBES AND ATRIAL FIBRILLATION

Background: Evidences show that gut microbes and their products could activate the autonomic nervous system, which plays an important role in the modulation of atrial electrophysiology and arrhythmogenesis. Trimethylamine N-oxide (TMAO), a gut microbes-derived metabolite, has been proved to be