Abstract Background Transcutaneous low-level tragus electrical stimulation (LLTS) suppresses atrial fibrillation (AF) in canines. Objectives This study examined the antiarrhythmic and ...anti-inflammatory effects of LLTS in humans. Methods Patients with paroxysmal AF who presented for AF ablation were randomized to either 1 h of LLTS (n = 20) or sham control (n = 20). Attaching a flat metal clip onto the tragus produced LLTS (20 Hz) in the right ear (50% lower than the voltage slowing the sinus rate). Under general anesthesia, AF was induced by burst atrial pacing at baseline and after 1 h of LLTS or sham treatment. Blood samples from the coronary sinus and the femoral vein were collected at those time points and then analyzed for inflammatory cytokines, including tumor necrosis factor alpha and C-reactive protein, using a multiplex immunoassay. Results There were no differences in baseline characteristics between the 2 groups. Pacing-induced AF duration decreased significantly by 6.3 ± 1.9 min compared with baseline in the LLTS group, but not in the control subjects (p = 0.002 for comparison between groups). AF cycle length increased significantly from baseline by 28.8 ± 6.5 ms in the LLTS group, but not in control subjects (p = 0.0002 for comparison between groups). Systemic (femoral vein) but not coronary sinus tumor necrosis factor (TNF)-alpha and C-reactive protein levels decreased significantly only in the LLTS group. Conclusions LLTS suppresses AF and decreases inflammatory cytokines in patients with paroxysmal AF. Our results support the emerging paradigm of neuromodulation to treat AF.
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.
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.
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.
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.
•Trimethylamine N-oxide (TMAO) facilitate the progression of atrial fibrillation (AF).•The mechanism relies on the activation of cardiac autonomic nervous system (CANS).•Gut microbes may participate in the progression of AF via regulating CANS by TMAO.
Mitigation of cardiac autonomic dysregulation by neuromodulation technologies is emerging as a new therapeutic modality of heart failure (HF). This recent progress has necessitated the identification ...of a biomarker for the quantification of sympathovagal balance, the potential target of ‘neuromodulation’ strategies. The currently available autonomic nervous system assessment parameters do not truly reflect the sympathovagal balance of the ventricle. Protein kinase A (PKA) is an intracellular enzyme that plays a major role in the pathophysiology of functional and structural ventricular remodeling in HF. Interestingly, sympathetic and parasympathetic activations exert reciprocal influence on the activity of PKA. The current review attempts to evaluate the potential concept and feasibility of using in vitro assessment of PKA activity as a marker of sympathovagal balance in HF.
Display omitted
Post-operative atrial fibrillation (POAF) is associated with worse long-term cardiovascular outcomes.
This study hypothesized that injecting calcium chloride (CaCl
) into the major atrial ...ganglionated plexi (GPs) during isolated coronary artery bypass grafting (CABG) can reduce the incidence of POAF by calcium-induced autonomic neurotoxicity.
This proof-of-concept study randomized 200 patients undergoing isolated, off-pump CABG to CaCl
(n = 100) or sodium chloride (sham, n = 100) injection. Two milliliters of CaCl
(5%) or sodium chloride (0.9%) was injected into the 4 major atrial GPs during CABG. All patients received 7-day continuous telemetry and Holter monitoring. The primary outcome was incidence of POAF (≥30 s) in 7 days. Secondary outcomes included length of hospitalization, POAF burden, average ventricular rate during AF, plasma level of inflammatory markers, and actionable antiarrhythmic therapy to treat POAF.
The POAF incidence was reduced from 36% to 15% (hazard ratio: 0.366; 95% confidence interval: 0.211 to 0.635; p = 0.001). Length of hospitalization did not differ between the 2 groups. POAF burden (first 7 post-operative days), the use of amiodarone or esmolol, and the incidence of atrial couplets and nonsustained atrial tachyarrhythmias were significantly reduced in the CaCl
group. Heart rate variability data showed a decrease in both high-frequency and low-frequency power in the CaCl
group with a preserved low-frequency/high-frequency ratio, suggesting that the sympathetic/parasympathetic balance was not perturbed by CaCl
injection.
Injection of CaCl
into the 4 major atrial GPs reduced the POAF hazard by 63%. Inhibition of GP function by Ca-mediated neurotoxicity may underlie the therapeutic effect. (Calcium Autonomic Denervation Prevents Postoperative Atrial Fibrillation; ChiCTR1800019276).
Studies have shown that left stellate ganglion (LSG) suppression protects against ventricular arrhythmias (VAs). Optogenetics is a novel technique to reversibly regulate the activity of the targeted ...neurons.
This study aimed to investigate whether an optogenetically silenced LSG could protect against VAs induced by myocardial ischemia.
Adeno-associated virus (AAV) was used as the vector to deliver ArchT, an inhibitory light-sensitive opsin, to the LSG neurons. Twenty male beagles were randomized into the optogenetics group (n = 10, AAV2/9-CAG-ArchT-GFP microinjected into LSG) and control group (n = 10, AAV2/9-CAG-GFP microinjected into LSG). After 4 weeks, the LSG function and neural activity, heart rate variability, ventricular action potential duration, and effective refractory period were measured in the absence or presence of a light-emitting diode illumination (565 nm). Myocardial ischemia was induced by left anterior coronary artery ligation and 1 h of electrocardiography was recorded for VAs analysis.
ArchT was successfully expressed in all dogs. Transient light-emitting diode illumination significantly suppressed the LSG function, LSG neural activity, and sympathetic nerve indices of heart rate variability as well as prolonged left ventricular effective refractory period and APD90 only in the optogenetics group. Thirty-minute illumination further enhanced these changes in the optogenetics group. Importantly, all of these changes returned to baseline within 2 h after illumination was turned off. Moreover, the ischemia-induced VAs were significantly suppressed by illumination only in the optogenetics group.
Optogenetic modulation could reversibly inhibit the neural activity of LSG, thereby increasing electrophysiological stability and protecting against myocardial ischemia–induced VAs.
Display omitted
The mechanisms underlying atrial fibrillation are yet to be elucidated. We sought to investigate the interactions among autonomic remodeling, epicardial adipose tissue, inflammation, and atrial ...fibrillation.
Myocardium and adjacent epicardial adipose tissue of the left atrial appendage, right atrial appendage, and pulmonary vein muscle sleeves were obtained from 61 consecutive patients (35 with atrial fibrillation, 26 with no atrial fibrillation) during mitral valve surgeries. Patients were divided into the atrial fibrillation group and no atrial fibrillation group according to the history and Holter monitoring before surgery. Sympathetic and parasympathetic innervation were evaluated by tyrosine hydroxylase and choline acetyltransferase staining, respectively. Atrial fibrosis as well as cytokines/adipokines and related inflammatory proteins and signaling pathways in the epicardial adipose tissue were examined.
Immunohistochemical studies revealed significantly increased tyrosine hydroxylase (+) and choline acetyltransferase (+) neural elements in the left atrial appendage and pulmonary vein muscle sleeve myocardium, as well as adjacent epicardial adipose tissue in the atrial fibrillation group, particularly the pulmonary vein muscle sleeve sites. The receiver operating curve identified a threshold ratio (tyrosine hydroxylase/choline acetyltransferase) of 0.8986 in the epicardial adipose tissue (sensitivity = 82.86%; specificity = 80.77%; area under the curve = 0.85, 95% confidence interval = 0.76-0.95, P < .0001). More patients with a higher tyrosine hydroxylase/choline acetyltransferase ratio (≥0.8986) had atrial fibrillation. Expression levels of the genes and related proteins of the β1 adrenergic, mitogen-activated protein kinase, and nuclear factor kappa B signaling pathways were higher in patients with a higher tyrosine hydroxylase/choline acetyltransferase ratio. The tyrosine hydroxylase/choline acetyltransferase ratio also correlated with fibrosis.
Differentially enhanced autonomic remodeling and proinflammatory and profibrotic cytokines/adipokines in the epicardial adipose tissue adjacent to the pulmonary vein muscle sleeve site may work synergistically to promote atrial fibrillation.
Display omitted
Pulmonary vein (PV) isolation has become the mainstay acute procedural end point for paroxysmal atrial fibrillation (AF) ablation.
To examine the incidence of conduction recovery in the PVs in ...patients without clinical recurrence of AF after paroxysmal AF ablation.
From August 2008 to March 2011, 392 patients with drug-refractory PAF underwent catheter ablation in our center, a wide area circumferential ablation approach guided with a circular mapping catheter was performed with the intended endpoint of entrance block in all PVs. 276 (70.4%) of them were free from recurrence at one year follow-up, and 32 of them were enrolled to assess the incidence of PV reconnection. Forty-three patients with clinical recurrence after ablation were analyzed for comparison. The regions of gap were mapped and characterized in all of the reconnected PVs.
Among patients without recurrence, recovery of PV conduction was observed in 29 of 32 (90.6%) patients: 10/32 (31.2%) reconnection in 4 veins, 7/32 (21.9%) in 3 veins, 10/32 (31.2%) in 2 veins, and 2/32 (6.2%) in 1 vein. No anatomic propensity was seen because reconnection was evenly distributed throughout all veins (left superior pulmonary vein 21, left inferior pulmonary vein 20, right superior pulmonary vein 19, and right inferior pulmonary vein 23). When compared to patients with recurrence, no significant differences were seen in the proportion of patients with reconnection (P = 1.0) or in left atrium-PV intervals (73.4 ± 43.3 ms vs 61.9 ± 31.8 ms; P > .05).
A high incidence of PV reconnection was similarly observed in patients with and without recurrence of AF, suggesting that sustained PV isolation may not be required for freedom from clinical recurrence of AF.
Low-level transcutaneous vagus nerve stimulation at the tragus (LLTS) is anti-adrenergic. We aimed to evaluate the acute effects of LLTS on left ventricular (LV) function and autonomic tone. Patients ...with diastolic dysfunction and preserved LV ejection fraction were enrolled in a prospective, randomized, double-blind, 2 × 2 cross-over study. Patients received two separate, 1-h sessions, at least 1 day apart, of active LLTS (20 Hz, 1 mA below the discomfort threshold) and sham stimulation. Echocardiography was performed after LLTS or sham stimulation to assess cardiac function. A 5-min ECG was performed to assess heart rate variability (HRV). Twenty-four patients were enrolled. LV global longitudinal strain improved by 1.8 ± 0.9% during active LLTS compared to sham stimulation (
p
= 0.001). Relative to baseline, HRV frequency domain components (low frequency, high frequency, and their ratio) were favorably altered after LLTS compared to sham stimulation (all
p
< 0.05). We concluded that LLTS acutely ameliorates cardiac mechanics by modulating the autonomic tone. Trial registration: NCT02983448
PDF
