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.

Low-Level Tragus Stimulation for the Treatment of Ischemia and Reperfusion Injury in Patients With ST-Segment Elevation Myocardial Infarction: A Proof-of-Concept Study.

OBJECTIVES: The aim of this study was to investigate whether low-level tragus stimulation (LL-TS) treatment could reduce myocardial ischemia-reperfusion injury in patients with ST-segment elevation myocardial infarction (STEMI). BACKGROUND: The authors' previous studies suggested that LL-TS could reduce the size of myocardial injury induced by ischemia. METHODS: Patients who presented with STEMI within 12 h of symptom onset, treated with primary percutaneous coronary intervention, were randomized to the LL-TS group (n = 47) or the control group (with sham stimulation [n = 48]). LL-TS, 50% lower than the electric current that slowed the sinus rate, was delivered to the right tragus once the patients arrived in the catheterization room and lasted for 2 h after balloon dilatation (reperfusion). All patients were followed for 7 days. The occurrence of reperfusion-related arrhythmia, blood levels of creatine kinase-MB, myoglobin, N-terminal pro-B-type natriuretic peptide and inflammatory markers, and echocardiographic characteristics were evaluated. RESULTS: The incidence of reperfusion-related ventricular arrhythmia during the first 24 h was significantly attenuated by LL-TS. In addition, the area under the curve for creatine kinase-MB and myoglobin over 72 h was smaller in the LL-TS group than the control group. Furthermore, blood levels of inflammatory markers were decreased by LL-TS. Cardiac function, as demonstrated by the level of N-terminal pro-B-type natriuretic peptide, the left ventricular ejection fraction, and the wall motion index, was markedly improved by LL-TS. CONCLUSIONS: LL-TS reduces myocardial ischemia-reperfusion injury in patients with STEMI. This proof-of-concept study raises the possibility that this noninvasive strategy may be used to treat patients with STEMI undergoing primary percutaneous coronary intervention.

Renal sympathetic stimulation and ablation affect ventricular arrhythmia by modulating autonomic activity in a cesium-induced long QT canine model.

BACKGROUND: Our previous studies showed that renal sympathetic stimulation (RS) may facilitate ischemic ventricular arrhythmia (VA) by increasing left stellate ganglion (LSG) nerve activity, whereas renal sympathetic ablation (RA) may suppress VA. OBJECTIVE: The purpose of this study was to investigate whether renal sympathetic interventions also can affect VA by modulating LSG activity in a cesium-induced long QT canine model. METHODS: Twenty-four dogs were randomly divided into RS group (n = 8), RA group (n = 8), or control group (n = 8). Serum norepinephrine, LSG function, and LSG neural activity were measured before and 3 hours after RS or RA. Increasing doses of cesium chloride then were administered until a "threshold dose" produced sustained ventricular tachycardia or ventricular fibrillation. Early afterdepolarization amplitude, VA prevalence, and tachycardia threshold dose were compared among these groups. Nerve growth factor and c-fos protein expressed in the LSG also were examined. RESULTS: Serum norepinephrine, LSG function, and LSG neural activity were all significantly increased after 3 hours of RS and all were decreased 3 hours after RA. In addition, RS significantly decreased the tachycardia threshold dose, increased the early afterdepolarization amplitude, facilitated the incidence of VAs, and increased the expression of nerve growth factor and c-fos protein. In contrast, RA induced the opposite effects. CONCLUSION: RS promotes, whereas RA suppresses, the incidence of VAs in a canine model of cesium-induced long QT. Modulation of LSG neural activity by RS and RA may be responsible for these different effects.

Noninvasive low-frequency electromagnetic stimulation of the left stellate ganglion reduces myocardial infarction-induced ventricular arrhythmia.

Noninvasive magnetic stimulation has been widely used in autonomic disorders in the past few decades, but few studies has been done in cardiac diseases. Recently, studies showed that low-frequency electromagnetic field (LF-EMF) might suppress atrial fibrillation by mediating the cardiac autonomic nervous system. In the present study, the effect of LF-EMF stimulation of left stellate ganglion (LSG) on LSG neural activity and ventricular arrhythmia has been studied in an acute myocardium infarction canine model. It is shown that LF-EMF stimulation leads to a reduction both in the neural activity of LSG and in the incidence of ventricular arrhythmia. The obtained results suggested that inhibition of the LSG neural activity might be the causal of the reduction of ventricular arrhythmia since previous studies have shown that LSG hyperactivity may facilitate the incidence of ventricular arrhythmia. LF-EMF stimulation might be a novel noninvasive substitute for the existing implant device-based electrical stimulation or sympathectomy in the treatment of cardiac disorders.

Changes of phenolic profiles and antioxidant activity in canaryseed (Phalaris canariensis L.) during germination.

Canaryseed is an important cereal crop in western Canada. The changes of the total phenolic content (TPC), antioxidant activities, phenolic acid profiles (free and bound) of canaryseed during germination were investigated in the present study. The growth properties also were investigated. Fresh weight, shoot length and root length increased, whereas dry mass of canaryseed decreased during germination. A 22.3% loss of dry matter was observed at 120h of germination. The total phenolic content and antioxidant activities of free and bound extracts showed a general trend of germinated seeds>raw seeds>soaked seeds. Free, bound and total phenolic content significantly increased 1042%, 120% and 741% at the end of germination as compared to raw seeds (p<0.05). DPPH, ABTS and ORAC assays were employed to evaluate the antioxidant activity of canaryseed. There were high correlations between total phenolic content and antioxidant activities. TPC and ORAC values showed the highest correlation (r=0.9984). Six phenolic acids in free phenolic extracts and seven phenolic acids in bound phenolic extracts were detected, respectively. Bound ferulic acid, the dominant phenolic acid in canaryseed, significantly increased during germination (p<0.05). Study showed that germination provided a new approach to further develop canaryseed as a functional food for human consumption.

Identification and Antioxidant Properties of Phenolic Compounds during Production of Bread from Purple Wheat Grains.

Phenolic profiles and antioxidant properties of purple wheat varieties were investigated to document the effects of bread-making. Bread crust and crumb along with samples collected after mixing, 30 min fermenting, 65 min fermenting, and baking were examined. Free phenolic content (105.4 to 113.2 mg FAE/100 g) significantly (p < 0.05) increased during mixing, fermenting, and baking (65% to 68%). Bound phenolics slightly (p > 0.05) decreased after 30 min fermentation (7% to 9%) compared to the dough after mixing, but increased significantly (p < 0.05) during 65 min fermenting and baking (16% to 27%). Their antioxidant activities followed a similar trend as observed for total phenolic content. The bread crust demonstrated increased free (103% to 109%) but decreased bound (2% to 3%) phenolic content, whereas bread crumb exhibited a reversal of these results. Total anthocyanin content (TAC) significantly (p < 0.05) decreased by 21% after mixing; however, it gradually increased to 90% of the original levels after fermenting. Baking significantly (p < 0.05) decreased TAC by 55%, resulting in the lowest value for bread crust (0.8 to 4.4 mg cyn-3-glu equiv./100 g). p-Hydroxybenzoic, vanillic, p-coumaric, and ferulic acids were detected in free-phenolic extracts, while protocatechuic, caffeic syringic, and sinapic were additional acids in bound-phenolic extracts. Cyanidin-3-glucoside was the detectable anthocyanin in purple wheat. Bread-making significantly (p < 0.05) increased the phenolic content and antioxidant activities; however, it compromised the anthocyanin content of purple wheat bread.

Spinal cord stimulation protects against ventricular arrhythmias by suppressing left stellate ganglion neural activity in an acute myocardial infarction canine model.

BACKGROUND: Previous studies have shown that spinal cord stimulation (SCS) may reduce ventricular arrhythmias (VAs) induced by acute myocardial infarction (AMI). Furthermore, activation of left stellate ganglion (LSG) appears to facilitate VAs after AMI. OBJECTIVE: The purpose of this study was to investigate whether pretreatment with SCS could protect against VAs by reducing LSG neural activity in an AMI canine model. METHODS: Thirty dogs were anesthetized and randomly divided into SCS group (with SCS, n = 15) and sham group (sham operation without SCS, n = 15). SCS was performed for 1 hour before AMI. Heart rate variability (HRV), ventricular effective refractory period (ERP), serum norepinephrine level, LSG function measured by blood pressure increases in response to LSG stimulation, and LSG neural activity were measured for 1 minute at baseline and 1 hour after SCS. AMI was induced by left anterior descending coronary artery ligation, and then HRV, LSG neural activity, and VAs were measured. RESULTS: Compared to baseline, SCS for 1 hour significantly prolonged ventricular ERP, increased HRV, and attenuated LSG function and LSG activity in the SCS group, whereas no significant change was shown in the sham group. AMI resulted in a significant decrease in HRV and increase in LSG neural activity in the sham group, which were attenuated in the SCS group (frequency: 99 ± 34 impulses/min vs 62 ± 22 impulses/min; amplitude: 0.41 ± 0.12 mV vs 0.18 ± 0.05 mV; both P <.05). The incidence of VAs was significantly lower in the SCS group than in the sham group. CONCLUSION: SCS may prevent AMI-induced VAs, possibly by suppressing LSG activity.

The use of low-level electromagnetic fields to suppress atrial fibrillation.

BACKGROUND: Extremely low-level electromagnetic fields have been proposed to cause significant changes in neural networks. OBJECTIVE: We sought to investigate whether low-level electromagnetic fields can suppress atrial fibrillation (AF). METHODS: In 17 pentobarbital anesthetized dogs, bilateral thoracotomies allowed the placement of multielectrode catheters in both atria and at all pulmonary veins. AF was induced by rapid atrial pacing (RAP) or programmed atrial extrastimulation. At baseline and end of each hour of RAP, during sinus rhythm, atrial programmed stimulation gave both the effective refractory period (ERP) and the width of the window of vulnerability. The latter was a measure of AF inducibility. Microelectrodes inserted into the anterior right ganglionated plexi recorded neural firing. Helmholtz coils were powered by a function generator inducing an electromagnetic field (EMF; 0.034 µG, 0.952 Hz). The study sample was divided into 2 groups: group 1 (n = 7)-application of EMF to both cervical vagal trunks; group 2 (n = 10)-application of EMF across the chest so that the heart was located in the center of the coil. RESULTS: In group 1, EMF induced a progressive increase in AF threshold at all pulmonary vein and atrial sites (all P < .05). In group 2, the atrial ERP progressively shortened and ERP dispersion and window of vulnerability progressively increased (P < .05 compared to baseline values) during 3 hours of RAP and then returned to baseline values during 3 hours of combined application of RAP and EMF (P < .05 compared to the end of the third hour of RAP). The frequency and amplitude of the neural activity recorded from the anterior right ganglionated plexi were markedly suppressed by EMF in both groups. CONCLUSION: Pulsed EMF applied to the vagal trunks or noninvasively across the chest can significantly reverse AF inducibility.

Low-level transcutaneous electrical stimulation of the auricular branch of vagus nerve ameliorates left ventricular remodeling and dysfunction by downregulation of matrix metalloproteinase 9 and transforming growth factor ß1.

Vagus nerve stimulation improves left ventricular (LV) remodeling by downregulation of matrix metalloproteinase 9 (MMP-9) and transforming growth factor ß1 (TGF-ß1). Our previous study found that low-level transcutaneous electrical stimulation of the auricular branch of the vagus nerve (LL-TS) could be substituted for vagus nerve stimulation to reverse cardiac remodeling. So, we hypothesize that LL-TS could ameliorate LV remodeling by regulation of MMP-9 and TGF-ß1 after myocardial infarction (MI). Twenty-two beagle dogs were randomly divided into a control group (MI was induced by permanent ligation of the left coronary artery, n = 8), an LL-TS group (MI with long-term intermittent LL-TS, n = 8), and a normal group (sham ligation without stimulation, n = 6). At the end of 6 weeks follow-up, LL-TS significantly reduced LV end-systolic and end-diastolic dimensions, improved ejection fraction and ratio of early (E) to late (A) peak mitral inflow velocity. LL-TS attenuated interstitial fibrosis and collagen degradation in the noninfarcted myocardium compared with the control group. Elevated level of MMP-9 and TGF-ß1 in LV tissue and peripheral plasma were diminished in the LL-TS treated dogs. LL-TS improves cardiac function and prevents cardiac remodeling in the late stages after MI by downregulation of MMP-9 and TGF-ß1 expression.

Chronic intermittent low-level transcutaneous electrical stimulation of auricular branch of vagus nerve improves left ventricular remodeling in conscious dogs with healed myocardial infarction.

BACKGROUND: Vagus nerve stimulation attenuates left ventricular (LV) remodeling after myocardial infarction (MI). Our previous study found a noninvasive approach to deliver vagus nerve stimulation by transcutaneous electric stimulation of auricular branch of vagus nerve. So we hypothesize that chronic intermittent low-level tragus stimulation (LL-TS) could attenuate LV remodeling in conscious dogs with healed MI. METHODS AND RESULTS: Thirty beagle dogs were randomly divided into 3 groups, MI group (left anterior descending artery and major diagonal branches ligation to introduce MI, n=10), LL-TS group (MI plus chronic intermittent LL-TS, n=10), and control group (sham surgery without stimulation, n=10). Tragus stimulation was delivered to bilateral tragus with ear-clips connected to a custom-made stimulator. The voltage slowing sinus rate was used as the threshold for setting LL-TS at 80% below that. LL-TS group was given 4 hours stimulation at 7-9 am and 4-6 pm on conscious dogs. At the end of 90-day follow-up, LL-TS group significantly reduced LA and LV dilatation, improved LV contractile and diastolic function, reduced infarct size by ≈50% compared with MI group. LL-TS treatment alleviated cardiac fibrosis and significantly decreased protein expression level of collagen I, collagen III, transforming growth factor ß1, and matrix metallopeptidase 9 in LV tissues. The plasma level of high-specific C-reactive protein, norepinephrine, N-terminal pro-B-type-natriuretic peptide in LL-TS group was significantly lower than those in MI group from the 7th day to the end of follow-up. CONCLUSIONS: Chronic intermittent low-level transcutaneous electric stimulation of auricular branch of vagus nerve can attenuate LV remodeling in conscious dogs with healed MI.

Carotid baroreceptor stimulation prevents arrhythmias induced by acute myocardial infarction through autonomic modulation.

: Electrical carotid baroreceptor stimulation (CBS) has shown therapeutic potential for resistant hypertension and heart failure by resetting autonomic nervous system, but the impacts on arrhythmias remains unclear. This study evaluated the effects of CBS on ventricular electrophysiological properties in normal dog heart and arrhythmias after acute myocardial infarction (AMI). In the acute protocol, anesthetized open chest dogs were exposed to 1 hour left anterior descending coronary occlusion as AMI model. Dogs were received either sham treatment (Control group, n = 8) or CBS (CBS group, n = 8), started 1 hour before AMI. CBS resulted in pronounced prolongation of ventricular effective refractory period and reduction of the maximum action potential duration restitution slope (from 0.85 ± 0.15 in the baseline state to 0.67 ± 0.09 at the end of 1 hour, P < 0.05) before AMI. Number of premature ventricular contractions (277 ± 168 in the Control group vs. 103 ± 84 in the CBS group, P < 0.05) and episodes of ventricular tachycardia/ventricular fibrillation (7 ± 3 in the Control group vs. 3 ± 2 in the CBS group, P < 0.05) was decreased compared with the control group during AMI. CBS buffered low-frequency/high-frequency ratio raise during AMI. Ischemic size was not affected by CBS. CBS may have a beneficial impact on ventricular arrhythmias induced by AMI through modulation of autonomic tone.

Effects of low-intensity atrial ganglionated plexi stimulation on ventricular electrophysiology and arrhythmogenesis.

BACKGROUND: Atrial ganglionated plexi (GP) have been shown to modulate sinus rate, atrioventricular conduction and atrial electrophysiology. The aim of this study was to investigate the effect of low-intensity GP stimulation (GPS) on ventricular electrophysiological properties in normal heart and on ventricular arrhythmogenesis after acute myocardial ischemia (AMI) in canine. METHODS AND RESULTS: Thirty-nine dogs were assigned into the normal heart group (n=12) and the acute myocardial ischemia (AMI) group (n=27, 12 in control and 15 in low-intensity GPS). In the normal heart group, ventricular effective refractory period (ERP), dynamic restitution and electrical alternans were measured at baseline and after 6-hour low-intensity GPS. In the AMI group, the incidence of ventricular arrhythmias was determined during 1-hour recording after AMI was induced. In the normal heart, 6-hour low-intensity GPS significantly prolonged ventricular ERP and action potential duration (APD) at each site (all P<0.05) but did not change their spatial dispersions when compared with baseline. Low-intensity GPS also caused an upward shift of ventricular restitution curves in each site but did not change the slope of restitution curves. APD alternans after low-intensity GPS occurred at longer pacing cycle length at each site when compared with baseline (all P<0.05). In the AMI heart, the incidence of ventricular arrhythmias in low-intensity GPS group was significantly lower than that in control group (P<0.05). CONCLUSIONS: Low-intensity GPS induces no increase in the risk of ventricular arrhythmias in the normal heart as well as protects against ventricular arrhythmogenesis during AMI.

Low-level transcutaneous electrical stimulation of the auricular branch of the vagus nerve: a noninvasive approach to treat the initial phase of atrial fibrillation.

BACKGROUND: We studied the effects of transcutaneous electrical stimulation at the tragus, the anterior protuberance of the outer ear, for inhibiting atrial fibrillation (AF). OBJECTIVE: To develop a noninvasive transcutaneous approach to deliver low-level vagal nerve stimulation to the tragus in order to treat cardiac arrhythmias such as AF. METHODS: In 16 pentobarbital anesthetized dogs, multielectrode catheters were attached to pulmonary veins and atria. Three tungsten-coated microelectrodes were inserted into the anterior right ganglionated plexi to record neural activity. Tragus stimulation (20 Hz) in the right ear was accomplished by attaching 2 alligator clips onto the tragus. The voltage slowing the sinus rate or atrioventricular conduction was used as the threshold for setting the low-level tragus stimulation (LL-TS) at 80% below the threshold. At baseline, programmed stimulation determined the effective refractory period (ERP) and the window of vulnerability (WOV), a measure of AF inducibility. For hours 1-3, rapid atrial pacing (RAP) was applied alone, followed by concomitant RAP+LL-TS for hours 4-6 (N = 6). The same parameters were measured during sinus rhythm when RAP stopped after each hour. In 4 other animals, bivagal transection was performed before LL-TS. RESULTS: During hours 1-3 of RAP, there was a progressive and significant decrease in ERP, increase in WOV, and increase in neural activity vs baseline (all P < .05). With RAP+LL-TS during hours 4-6, there was a linear return of ERP, WOV, and neural activity toward baseline levels (all P < .05, compared to the third-hour values). In 4 dogs, bivagal transection prevented the reversal of ERP and WOV despite 3 hours of RAP+LL-TS. CONCLUSIONS: LL-TS can reverse RAP-induced atrial remodeling and inhibit AF inducibility, suggesting a potential noninvasive treatment of AF.

Interactions between atrial electrical remodeling and autonomic remodeling: how to break the vicious cycle.

BACKGROUND: The mechanism(s) underlying the maintenance of atrial fibrillation (AF) during the first few hours after AF was initiated remains poorly understood. OBJECTIVE: To investigate the roles of the intrinsic cardiac autonomic nervous system in the maintenance of AF at the early stage. METHODS: In 10 anesthetized dogs, we attached multielectrode catheters on atria and pulmonary veins. Microelectrodes inserted into the anterior right ganglionated plexi recorded neural activity. At baseline, programmed stimulation determined the effective refractory period (ERP) and window of vulnerability (WOV), a measure of AF inducibility. For the next 6 hours, AF was simulated by rapid atrial pacing (RAP) and the same parameters were measured hourly during sinus rhythm. A circular catheter was positioned in the superior vena cava for high-frequency stimulation (20 Hz) of the adjacent vagal preganglionics. During 4-6 hours of RAP, we delivered low-level vagal stimulation in the superior vena cava (LL-SVCS), 50% below that which induced slowing of the sinus rate. RESULTS: During the 6-hour RAP, there was a progressive decrease in the ERP and an increase in ERP dispersion, WOV, and neural activity. With LL-SVCS during 4-6-hour RAP, ERP, WOV, and neural activity returned toward baseline levels (all P <.05, compared with the third-hour RAP values). CONCLUSIONS: RAP not only induces atrial electrical remodeling but also promotes autonomic remodeling. These 2 remodeling processes may form a vicious cycle and each may perpetuate the other. These findings may help to explain how AF maintains itself in its very early stage. LL-SVCS both reversed remodeling processes and can potentially break the vicious cycle of "AF begets AF" in the first few hours of AF.

Low-level right vagal stimulation: anticholinergic and antiadrenergic effects.

INTRODUCTION: We sought to extend the use of low-level vagal stimulation by applying it only to the right vagus nerve (LL-RVS) to suppress atrial fibrillation (AF). METHODS: In 10 pentobarbital anesthetized dogs, LL-RVS (20 Hz, 0.1 ms pulse width) was delivered to the right vagal trunk via wire electrodes at voltages 50% below that which slowed the sinus rate (SR) or atrio-ventricular conduction. Electrode catheters were sutured at multiple atrial and pulmonary vein (PV) sites to record electrograms. LL-RVS continued for 3 hours. At the end of each hour, 40 ms of high-frequency stimulation (HFS; 100 Hz, 0.01 ms pulse width) was delivered 2 ms after atrial pacing (during the refractory period) to determine the AF threshold (AF-TH) at each site. Other electrodes were attached to the superior left ganglionated plexi (SLGP) and right stellate ganglion (RSG) so that HFS (20 Hz, 0.1 ms pulse width) to these sites induced SR slowing and acceleration, respectively. Microelectrodes inserted into the anterior right ganglionated plexi (ARGP) recorded neural activity. RESULTS: (1) Three hours of LL-RVS induced a progressive increase in AF-TH at all sites (all P < 0.05). (2) The SR slowing and acceleration response induced by SLGP and RSG stimulation, respectively, was blunted by LL-RVS. (3) The frequency and amplitude of the neural activity recorded from the ARGP were markedly inhibited by LL-RVS. CONCLUSIONS: LL-RVS suppressed AF inducibility and the chronotropic responses to parasympathetic and sympathetic stimulation. Inhibition of neural activity in the GP may be a mechanism underlying these results.