Effect of acupuncture at Neiguan point combined with amiodarone therapy on early recurrence after pulmonary vein electrical isolation in patients with persistent atrial fibrillation.

OBJECTIVE: Early atrial fibrillation (AF) recurrences are common and have been shown to predict AF recurrences late after AF ablation during follow-up. Neiguan point acupuncture has been recognized to be therapeutic in treating AF in clinical practice. METHODS AND RESULTS: Eighty-five patients were enrolled in succession due to persistent AF. All patients were randomized divided into control group and acupuncture group. In the control group (n = 45), amiodarone was orally taken from the first day after pulmonary vein isolation (PVI). In the acupuncture group (n = 40), patients were treated with Neiguan point acupuncture for 7 days and amiodarone was prescribed as same as the control group after PVI. The levels of inflammatory factors were analyzed before operation, 1 week after the operation and 3 months later. After 3 months, the acupuncture group had a lower rate of early recurrences than the control group (5/40 [12.5%] vs 15/45 [33.3%], P = 0.039). The inflammatory factors level in the two groups were significantly increased after ablation. However, compared with the control group, the levels of TNF-α, IL-6, CRP, TGF-ß1, MMP2 in the acupuncture group significantly lower (P < 0.05). In a multivariate analysis, acupuncture was an independent factor associated with a lower rate of early recurrences during the blanking period (odds ratio, 0.17; 95% confidence interval, 0.05-0.63; P = 0.008). CONCLUSION: Neiguan point acupuncture combined with amiodarone is superior to amiodarone alone in reducing early recurrences of patients with persistent AF after PVI. The efficacy of Neiguan acupuncture therapy on the early recurrence is associated with the decreased inflammation factors.

Stimulation of ganglionated plexus attenuates cardiac neural remodeling and heart failure progression in a canine model of acute heart failure post-myocardial infarction.

BACKGROUND: Heart failure (HF) is associated with autonomic dysfunction. Vagus nerve stimulation has been shown to improve cardiac function both in HF patients and animal models of HF. The purpose of this present study is to investigate the effects of ganglionated plexus stimulation (GPS) on HF progression and autonomic remodeling in a canine model of acute HF post-myocardial infarction. METHODS AND RESULTS: Eighteen adult mongrel male dogs were randomized into the control (n=8) and GPS (n=10) groups. All dogs underwent left anterior descending artery ligation followed by 6-hour high-rate (180-220bpm) ventricular pacing to induce acute HF. Transthoracic 2-dimensional echocardiography was performed at different time points. The plasma levels of norepinephrine, B-type natriuretic peptide (BNP) and Ang-II were measured using ELISA kits. C-fos and nerve growth factor (NGF) proteins expressed in the left stellate ganglion as well as GAP43 and TH proteins expressed in the peri-infarct zone were measured using western blot. After 6h of GPS, the left ventricular end-diastolic volume, end-systolic volume and ejection fraction showed no significant differences between the 2 groups, but the interventricular septal thickness at end-systole in the GPS group was significantly higher than that in the control group. The plasma levels of norepinephrine, BNP, Ang-II were increased 1h after myocardial infarction while the increase was attenuated by GPS. The expression of c-fos and NGF proteins in the left stellate ganglion as well as GAP43 and TH proteins in cardiac peri-infarct zone in GPS group were significantly lower than that in control group. CONCLUSIONS: GPS inhibits cardiac sympathetic remodeling and attenuates HF progression in canines with acute HF induced by myocardial infarction and ventricular pacing.

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.

Low-intensity atrial ganglionated plexi stimulation decreases the serum level of inflammatory factors in canine.

BACKGROUND: Activation of efferent vagus fibers exerts an anti-inflammatory role, a mechanism known as the cholinergic anti-inflammatory pathway. We hypothesised that stimulation of atrial ganglionated plexi (GP) may also be anti-inflammatory. METHODS: Six-hour low-intensity GP stimulation was performed in eight dogs and the serum levels of acetylcholine (Ach), C reactive protein (CRP), interleukin-6 (IL-6), high-mobility group box 1 (HMGB1) were determined with enzyme-linked immunosorbent assay kits. RESULTS: The serum level of acetylcholine was significantly increased (P<0.05) while the serum levels of inflammatory factors of C reactive protein, interleukin-6 and high-mobility group box 1 were markedly decreased after six-hour GP stimulation (all P<0.05). CONCLUSIONS: These results suggest that GP stimulation exerts an anti-inflammatory role and might be a therapeutic option for inflammatory heart diseases.

Naringenin inhibits angiotensin II-induced vascular smooth muscle cells proliferation and migration and decreases neointimal hyperplasia in balloon injured rat carotid arteries through suppressing oxidative stress.

Proliferation and migration of vascular smooth muscle cells (VSMCs) play pivotal roles in the development of restenosis after angioplasty and oxidative stress involves both processes. Naringenin, a flavanone compound found in citrus fruits, has been widely evaluated for antioxidant activity. This study was designed to explore whether naringenin could inhibit angiotensin II-induced VSMCs proliferation and migration and decrease neointimal hyperplasia in balloon injured rat carotid arteries. VSMCs were treated with or without naringenin before stimulation with 1 µM angiotensin II and twenty-four rats were subjected to carotid arteries injury and the carotid arteries were harvested at 14 d after balloon injury. The results showed naringenin led to a significant inhibition of angiotensin II-induced VSMCs proliferation and migration. Naringenin significantly attenuated the reactive oxygen species production, increased the superoxide dismutase activity and decreased the nicotinamide adenine dinucleotide phosphate (NADPH) oxidase activity, reduced phosphorylation of extracellular signal-regulated kinases 1 and 2 (ERK1/2) and p38 mitogen-activated protein kinase (MAPK) and the nuclear translocation of nuclear factor (NF)-κB p65 in angiotensin II-treated VSMCs. Moreover, naringenin decreased the ratio of neointima to media by 63.8% in balloon injured rat carotid arteries, and the serum level of 8-iso-prostaglandin F2α in naringenin-treated rats was significantly decreased. These results indicated naringenin exhibited antioxidant activity on angiotensin II-treated VSMCs and balloon injured rat carotid arteries and could be a potential protective agent for restenosis after angioplasty.

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 ganglionated plexus stimulation facilitates atrial fibrillation: in vivo and in vitro studies.

OBJECTIVES: The purpose of the present study was to investigate whether long term low level autonomic activation can form electrophysiological substrate for atrial fibrillation (AF). METHODS AND RESULTS: In 16 anesthetized open-chest dogs, electrodes on the anterior right ganglionated plexuses (GP) and superior left GP allowed 6-h low-level GP stimulation (LL-GPS) inducing a 10% decrease in sinus rate. Similar low-level stimulation (without myocardial capture) was delivered to the myocardium remote from the GP for 6h in another 16 dogs as control group. LL-GPS: a) induced shortening of the atrial effective refractory period and increase of the window of vulnerability for AF; b) significantly increased acetylcholine-regulated potassium current (I(KACh)) at left superior pulmonary vein (LSPV) while reduced the density of L-type calcium current (I(CaL)) at LSPV and both atria, the protein expression of the channel subunit showed a consistent alteration, however both without significant changes in mRNA level. CONCLUSIONS: Six-hour LL-GPS induced significant changes in atrial electrophysiology and facilitated the initiation of AF, indicating that long-term low level autonomic activation would form electrophysiological substrate for AF. The underlying mechanism may be associated with a post-transcriptional regulation of increased I(KACh) and decreased I(CaL).

The role of ganglionated plexi in apnea-related atrial fibrillation.

OBJECTIVES: This study was conducted to simulate sleep apnea-induced atrial fibrillation (AF) in an experimental model and to determine whether neural ablation will prevent AF. BACKGROUND: An increasing number of clinical reports have associated sleep apnea and AF, and many possible mechanisms responsible for this relationship have been proposed. METHODS: Thirty dogs anesthetized with Na-pentobarbital were ventilated by a positive pressure respirator. Protocol 1 (n = 14): After a right thoracotomy, atrial and pulmonary vein programmed pacing at 2x and 4x threshold determined the shortest atrial refractory period. Obstructive apnea was induced by turning off the respirator during end expiration for 2 min. During apnea, programmed pacing was performed with S1-S2 = 5 to 10 ms earlier than the atrial refractory period. Neural activity was monitored from the ganglionated plexi (GP) adjacent to the right pulmonary veins. Protocol 2 (n = 16): Electrical stimulation identified the GP at the right pulmonary artery (RPA). Programmed pacing was again instituted, below atrial refractory period, during 2 min of apnea. After radiofrequency ablation of the RPA GP, continuous programmed pacing was again repeated during 2 min of apnea. In 5 dogs, blood gases were determined at baseline and at 2 min of apnea. RESULTS: Protocol 1: During apnea, S1-S2 induced AF within 85 +/- 38 s (9 of 10). In 1 case, AF occurred spontaneously at 1 min 36 s of apnea. Recorded GP neural activity progressively increased before AF onset. Systolic but not diastolic blood pressure rose significantly before AF (149 +/- 26 mm Hg to 193 +/- 38 mm Hg, p < 0.05). In 4 dogs, autonomic blockade prevented apnea-induced AF. Protocol 2: AF induced by pacing occurred in 8 of 11 dogs within the 2-min period of apnea, before neural ablation. After ablation, 0 of 6 showed AF during 2 min of apnea (p = 0.009). CONCLUSIONS: This experimental model of apnea shows a reproducible incidence of AF. After neural ablation of the RPA GP or autonomic blockade, AF inducibility was significantly inhibited.

Pretreatment with B-type natriuretic peptide protects the heart from ischemia-reperfusion injury by inhibiting myocardial apoptosis.

The therapy for acute myocardial infarction (AMI) has been improved; yet, AMI remains a major cause of death and heart failure in industrialized countries. B-type natriuretic peptide (BNP), a hormone secreted from the heart, has been shown cardioprotective effects during myocardial ischemia/reperfusion. In the present study, we aimed to examine whether BNP could inhibit myocardial apoptosis during ischemia/reperfusion. Rabbits were randomly divided into three groups (12 animals for each group): sham-operated control and ischemia-reperfusion animals with or without BNP treatment. Occlusion of the left circumflex coronary for 45 min was followed by 3-h reperfusion with infusion of physiological saline (untreated group) or BNP (treated group) starting 5 min before reperfusion and throughout the whole reperfusion. The infarct size, measured by triphenyltetrazolium chloride staining, was reduced by 44% with BNP treatment (P < 0.01). Accordingly, serum levels of creatine kinase and lactate dehydrogenase were markedly reduced in BNP-treated group (P < 0.05) compared with the untreated group. BNP significantly attenuated apoptotic cells (TUNEL-positive cardiomyocyte nuclei) in the myocardium (P < 0.01). The BNP-mediated attenuation of apoptosis was associated with the increased expression of an anti-apoptotic protein Bcl-2 and the reduced expression of a pro-apoptotic protein Bax. Moreover, BNP treatment significantly decreased the magnitude of caspase-3 activation caused by myocardial ischemia-reperfusion. In conclusion, pretreatment with BNP shortly before the onset of reperfusion not only reduces necrosis, but also attenuates myocardial apoptosis. BNP appears to be an ideal pharmacological agent applied as an adjuvant therapy to current myocardial reperfusion strategies.

Autonomic mechanism for initiation of rapid firing from atria and pulmonary veins: evidence by ablation of ganglionated plexi.

AIMS: Previous studies showed that autonomic activation by high-frequency electrical stimulation (HFS) during myocardial refractoriness evokes rapid firing from pulmonary vein (PV) and atria, both in vitro and in vivo. This study sought to investigate the autonomic mechanism underlying the rapid firings at various sites by systematic ablation of multiple ganglionated plexi (GP). METHODS AND RESULTS: In 43 mongrel dogs, rapid firing-mediated atrial fibrillation (AF) was induced by local HFS (200 Hz, impulse duration 0.1 ms, train duration 40 ms) to the PVs and atria during myocardial refractoriness. The main GP in the atrial fat pads or the ganglia along the ligament of Marshall (LOM) were then ablated. Ablation of the anterior right GP and inferior right GP significantly increased the AF threshold by HFS at the right atrium and PVs. The AF threshold at left atrium and PVs was significantly increased by ablation of the superior left GP and inferior left GP, and was further increased by ablation of the LOM. Ablation of left- or right-sided GP on the atria had a significant effect on contralateral PVs and atrium. Administration of esmolol (1 mg/kg) or atropine (1 mg) significantly increased AF threshold at all sites. CONCLUSION: HFS applied to local atrial and PV sites initiated rapid firing via activation of the interactive autonomic network in the heart. GP in either left side or right side contributes to the rapid firings and AF originating from ipsolateral and contralateral PVs and atrium. Autonomic denervation suppresses or eliminates those rapid firings.

Atrial fibrillation begets atrial fibrillation: autonomic mechanism for atrial electrical remodeling induced by short-term rapid atrial pacing.

BACKGROUND: The mechanism(s) for acute changes in electrophysiological properties of the atria during rapid pacing induced atrial fibrillation (AF) is not completely understood. We sought to evaluate the contribution of the intrinsic cardiac autonomic nervous system in acute atrial electrical remodeling and AF induced by 6-hour rapid atrial pacing. METHODS AND RESULTS: Continuous rapid pacing (1200 bpm, 2x threshold [TH]) was performed at the left atrial appendage. Group 1 (n=7) underwent 6-hour pacing immediately followed by ganglionated plexi (GP) ablation; group 2 (n=7) underwent GP ablation immediately followed by 6-hour pacing; and group 3 (n=4) underwent administration of autonomic blockers, atropine (1 mg/kg), and propranolol (0.6 mg/kg) immediately followed by 6-hour pacing. The effective refractory period (ERP) and window of vulnerability (WOV, in milliseconds), ie, the difference between the longest and the shortest coupling interval of the premature stimulus that induced AF, were measured at 2xTH and 10xTH at the left atrium, right atrium, and pulmonary veins every hour before and after GP ablation or autonomic blockade. In group 1, ERP was markedly shortened in the first 2 hours and then stabilized both at 2xTH and 10xTH; however, WOV was progressively widened throughout the 6-hour period. After GP ablation, ERP was significantly longer than before ablation and AF could not be induced (WOV=0) at either 2xTH or 10xTH. In groups 2 and 3, rapid atrial pacing failed to shorten the ERP. AF could not be induced in 6 of 7 dogs in group 2 and all 4 dogs in group 3 during the 6-hour pacing period. CONCLUSIONS: The intrinsic cardiac autonomic nervous system plays a crucial role in the acute stages of atrial electrical remodeling induced by rapid atrial pacing.

Autonomic mechanism to explain complex fractionated atrial electrograms (CFAE).

OBJECTIVE: To simulate complex fractionated atrial electrograms (CFAE) during sustained atrial fibrillation (AF) in experimental animals. BACKGROUND: The mechanism(s) underlying CFAE has not been fully elucidated. METHODS: Twenty-two dogs were subjected to a right and/or left thoracotomy. A gauze patch soaked with acetylcholine (ACh) was placed on the right atrial appendage (RAA) to induce sustained AF. During AF, varying concentrations of ACh (1, 10, 100 mM) were "painted" on the RA where electrograms showed regular organized activity. In another six dogs, anterior right ganglionated plexi (ARGP) near the sino-atrial node and inferior right GP (IRGP) at the junction of inferior vena cava and atria were sequentially ablated. In five dogs, ACh was injected into ARGP to induce CFAE. RESULTS: During sustained AF, local "painting" with ACh 1 mM and 10 mM induced intermittent CFAE in 1 of 11 and 10 of 11 dogs, respectively. With 100 mM ACh, all 11 showed CFAE (two intermittent, nine continuous). In six other dogs, continuous CFAE induced by topical application of 100 mM ACh were markedly attenuated by ARGP + IRGP ablation. In another five of five dogs, ACh injection into ARGP induced a gradient of CFAE with the continuous CFAE always occurring near the ARGP and CFAE also occurring at left pulmonary vein-atrial junctions. During ARGP ablation, AF was terminated in all five dogs immediately after regularization of the rotor-like electrograms or continuous CFAE. CONCLUSIONS: This study demonstrates an autonomic basis for CFAE formation, suggesting that graded hyperactive states of the autonomic nervous system (ANS) may induce various types of CFAE observed clinically.

Ganglionated plexi modulate extrinsic cardiac autonomic nerve input: effects on sinus rate, atrioventricular conduction, refractoriness, and inducibility of atrial fibrillation.

OBJECTIVES: This study sought to systematically investigate the interactions between the extrinsic and intrinsic cardiac autonomic nervous system (ANS) in modulating electrophysiological properties and atrial fibrillation (AF) initiation. BACKGROUND: Systematic ganglionated plexi (GP) ablation to evaluate the extrinsic and intrinsic cardiac ANS relationship has not been detailed. METHODS: The following GP were exposed in 28 dogs: anterior right GP (ARGP) near the sinoatrial node, inferior right ganglionated plexi (IRGP) at the junction of the inferior vena cava and atria, and superior left ganglionated plexi (SLGP) near the junction of left superior pulmonary vein and left pulmonary artery. With unilateral vagosympathetic trunk stimulation (0.6 to 8.0 V, 20 Hz, 0.1 ms in duration), sinus rate (SR), and ventricular rate (VR) during AF were compared before and after sequential ablation of SLGP, ARGP, and IRGP. RESULTS: The SLGP ablation significantly attenuated the SR and VR slowing responses with right or left vagosympathetic trunk stimulation. Subsequent ARGP ablation produced additional effects on SR slowing but not VR slowing. After SLGP + ARGP ablation, IRGP ablation eliminated VR slowing but did not further attenuate SR slowing with vagosympathetic trunk stimulation. Unilateral right and left vagosympathetic trunk stimulation shortened the effective refractory period and increased AF inducibility of atrium and pulmonary vein near the ARGP and SLGP, respectively. The ARGP ablation eliminated ERP shortening and AF inducibility with right vagosympathetic trunk stimulation, whereas SLGP ablation eliminated ERP shortening but not AF inducibility with left vagosympathetic trunk stimulation. CONCLUSIONS: The GP function as the "integration centers" that modulate the autonomic interactions between the extrinsic and intrinsic cardiac ANS. This interaction is substantially more intricate than previously thought.