Autonomic Nerve Stimulation Research Articles

Cardiac Autonomic Nerves Stimulation Improves Hemodynamics: A Pilot Study in Advanced Heart Failure Patients

Introduction Despite therapy advances in the management of heart failure, symptomatic congestion in acute heart failure is a leading cause of mortality and morbidity. The purpose of this study was to investigate transvenous cardiac autonomic nerve stimulation (CANS) effects on in-hospital hemodynamics and signs and symptoms of congestion. Methods The study was a single-center, observational, clinical investigation of CANS. Five (5) subjects with reduced left ventricular ejection fraction (LVEF Results There were no adverse events reported. LVEF increased in all subjects (mean +8% from 27% to 35%) over the stimulation period. LVEF acutely decreased a mean of -5% (from a mean of 35% to 30%) in direct association with stimulation cessation. In three (3) subjects, CANS directly modulated arterial pulse pressure (12% average change) with a neutral heart rate effect ( Conclusion Alongside concomitant medical therapy, CANS directly improved hemodynamics and was associated with improved signs and symptoms of congestion. These improvements, coupled with a positive safety profile, demonstrate that CANS holds promise as a tool to improve in-hospital hemodynamics and congestion. The present study included limited duration CANS, in a specific patient phenotype, and a small number of subjects. Future study is warranted to investigate CANS for longer durations, in expanded patient phenotypes, and in more subjects.

F36. Imaging fascicle traffic in peripheral nerve using fast neural EIT

Fast neural Electrical Impedance Tomography (EIT) is a promising technique which can potentially be used for imaging neural activity over milliseconds with unprecedented spatial resolution without penetrating nervous tissue. Here we present the first cross-sectional images of fascicular neural activity measured during compound action potentials acquired in rat sciatic nerve in in vivo experiments. EIT was collected with a cylindrical cuff electrode wrapped around the sciatic nerve in the thigh in 4 adult Sprague-Dawley rats anaesthetized with Isoflurane nerve made of silicone rubber. 16 electrodes were placed around the circumference, each 2 × 0.1 mm, made of laser-cut stainless steel foil which was then platinised. Distal fibular and tibial branches were electrically stimulated with square pulses with 0.2 ms duration, 1 mA amplitude, and 200 ms inter–stimulus interval. EIT data was acquired during consecutive injection of alternating current, with amplitude 5–75 μA and frequency 3–15 kHz, through a pair of electrodes at a time with simultaneous voltage recordings on the remaining electrodes. 16 independent current injections with 50 pulses per injection were recorded, resulting in 160 s image acquisition time. Acquired data was demodulated with 4 kHz bandwidth, averaged, and reconstructed with >0.5 ms temporal resolution. 1M-element 3D forward mesh, and 20k-element inverse mesh was used for reconstruction; 0-th order Tikhonov regularisation with coefficient of variance correction was employed. Results were displayed as a Z-score with respect to the inter-stimulus noise. Reproducible time-series images were reconstructed in each experiment, showing neural activity onset in ∼0.3–0.6 ms, after stimulus, peak at 0.6–1.5 ms, and subsequent decay at 1–2 ms. Images were obtained following electrical stimulation of the tibial or peroneal branches distally. Spatially distinguishable activity with centre-to-centre separation distance of 0.57 ± 0.04 mm (mean ± S.E.) was obtained in N = 24 experiments in n = 3 rats. EIT were much superior to those collected by Inverse Source Analysis (ISA) performed on CAPs recorded simultaneously to the EIT. Images were cross-validated with co-registered histological images. Comparison showed the position mismatch was 0.1 mm ± 0.03 mm between EIT and histology, and 0.14 mm ± 0.06 mm between EIT and inverse source imaging. Nerve fascicular traffic can be successfully imaged using EIT. This offers a potential means to identify the function of fascicles in autonomic nerve in vivo and so avoid off-target effect by selective stimulation. This could yield significant benefits in vagal nerve stimulation in epilepsy, where hoarseness is a limiting factor, and in the new field of Electroceutical treatment of disease by electrical stimulation of autonomic nerve.

Diadenosine Polyphosphates Suppress the Effects of Sympathetic Nerve Stimulation in Rabbit Heart Pacemaker.

The modulatory influence of diadenosine tetraphosphate (Ap4A) and diadenosine pentaphosphate (Ap5A) on the effect of intramural autonomic nerve stimulation in isolated rabbit sinoatrial node were examined. Electrical activity of the sinoatrial node was recorded intracellularly. Against the background of blockade of adrenergic effects with propranolol (3×10-6 M) or in preparations isolated 2 h after injection of reserpine (2 mg/kg), nerve stimulation induced short-term membrane hyperpolarization and diminished the sinus node firing rate. These phenomena were not affected by Ap4A or Ap5A (10-5 M). Under the action of atropine (3×10-6 M) that completely eliminated the cholinergic influences, nerve stimulation enhanced the sinus node firing rate by 17.30±3.45% from the initial rate. Both Ap4A and Ap5A moderated the stimulation-induced elevation of firing rate to 9.9±2.8 and 10.5±2.9%, respectively. The data suggest that diadenosine polyphosphates significantly modulate the sympathetic influences on the heart rhythm, but have no effect on the parasympathetic control over activity of sinoatrial node.

Detection of Norepinephrine in Whole Blood via Fast Scan Cyclic Voltammetry.

Bioelectronic Medicines is an emerging field that capitalizes on minimally-invasive technology to stimulate the autonomic nervous system in order to evoke therapeutic biomolecular changes at the end-organ. The goal of Bioelectronic Medicines is to realize both 'precision and personalized' medicine. 'Precise' stimulation of neural circuitry creates biomolecular changes targeted exactly where needed to maximize therapeutic effects while minimizing off-target changes associated with side-effects. The therapy is then 'personalized' by utilizing implanted sensors to measure the biomolecular concentrations at, or near, the end-organ of interest and continually adjusting therapy to account for patient-specific biological changes throughout the day. To realize the promise of Bioelectronic Medicines, there is a need for minimally invasive, real-time measurement of biomarkers associated with the effects of autonomic nerve stimulation to be used for continuous titration of therapy. In this study we examine the feasibility of using fast scan cyclic voltammetry (FSCV) to measure norepinephrine levels, a neurochemical relevant to end-organ function, directly from blood. FSCV is a well-understood method for measuring electroactive neurochemicals in the central nervous system with high temporal and high spatial resolution that has yet to be adapted to the study of the autonomic nervous system. The results demonstrate that while detecting the electroactive neurochemical norepinephrine in blood is more challenging than obtaining the same FSCV measurements in a buffer solution due to biofouling of the electrode, it is feasible to utilize a minimally invasive FSCV electrode to obtain neurochemical measurements in blood.

Postprocessing algorithm for automated analysis of pelvic intraoperative neuromonitoring signals

Abstract Two dimensional pelvic intraoperative neuromonitoring (pIONM®) is based on electric stimulation of autonomic nerves under observation of electromyography of internal anal sphincter (IAS) and manometry of urinary bladder. The method provides nerve identification and verification of its’ functional integrity. Currently pIONM® is gaining increased attention in times where preservation of function is becoming more and more important. Ongoing technical and methodological developments in experimental and clinical settings require further analysis of the obtained signals. This work describes a postprocessing algorithm for pIONM® signals, developed for automated analysis of huge amount of recorded data. The analysis routine includes a graphical representation of the recorded signals in the time and frequency domain, as well as a quantitative evaluation by means of features calculated from the time and frequency domain. The produced plots are summarized automatically in a PowerPoint presentation. The calculated features are filled into a standardized Excel-sheet, ready for statistical analysis.

The Pre-Anschluss Vienna School of Medicine - The medical scientists: Karl Landsteiner (1868-1943) and Otto Loewi (1873-1961).

Two famous medical scientists are described whose major advances were made largely from laboratory-based research. Karl Landsteiner, who received the Nobel Prize in 1930, was the discoverer or co-discoverer of the blood groups and the Rhesus factor. He contributed to the understanding of poliomyelitis, syphilis and typhus. He made major contributions to immunology, inter alia by isolating haptens. After World War I, he left Austria and continued his work initially in the Netherlands and then at the Rockefeller Institute in the USA. Otto Loewi, a pharmacologist, received his Nobel Prize (jointly with his life-long friend, Sir Henry Dale) in 1936 for his discovery that acetylcholine was the chemical agent for the stimulation of autonomic nerves to transmit to the organs they govern. He also made numerous other contributions including the demonstration that amino acids could be converted by animals to proteins. He left Austria after the Anschluss and settled in the USA.

Electrophysiology-based quality assurance of nerve-sparing in laparoscopic rectal cancer surgery: Is it worth the effort?

After low anterior resection for rectal cancer, visual assessment of pelvic autonomic nerve preservation can be difficult due to the complexity of neuroanatomy, as well as surgery- and patient-related factors. The present study aimed to evaluate nerve-sparing quality assurance using the laparoscopic neuromapping (LNM) technique. We prospectively investigated a series of 30 patients undergoing laparoscopic low anterior resection. Nerve-sparing was evaluated both visually and electrophysiologically. LNM was performed using stimulation of pelvic autonomic nerves under simultaneous cystomanometry and processed electromyography of the internal anal sphincter. Urogenital and anorectal functions were evaluated using validated and standardized questionnaires preoperatively, at short-term follow-up, and at mid-term follow-up at a median of 9months (range 6-12months) after surgery. One patient reported new onset of urinary dysfunction, and another patient reported new onset of anorectal dysfunction. Of the 20 sexually active patients, five reported sexual dysfunction. Visual assessment by laparoscopy confirmed complete nerve preservation in 28 of 30 cases. For prediction of urinary and anorectal function, LNM sensitivity, specificity, positive and negative predictive value, and overall accuracy were each 100%. LNM with combined assessment for prediction of sexual function yielded a sensitivity of 80%, specificity of 93%, positive predictive value of 80%, negative predictive value of 93%, and overall accuracy of 90%. LNM is an appropriate method for reliable quality assurance of laparoscopic nerve-sparing.

Effect of intra-operative autonomic nerve stimulation on pelvic nerve preservation during radical laparoscopic proctectomy.

This study assessed the effect of intra-operative electrical nerve stimulation (INS) on pelvic autonomic nerve preservation (PANP) during laparoscopic resection for rectal cancer. A total of 189 consecutive cases of radical laparoscopic proctectomy were included. PANP was assessed visually or with INS. Urinary function was evaluated by residual urine volume (RUV), International Prostatic Symptom Score (IPSS) and recatheterization rate. Erectile function was evaluated using the International Index of Erectile Function (IIEF-5) scale. INS successfully confirmed PANP in 65 (91.5%) patients, while direct vision confirmed PANP in only 72 (61.0%) patients. Compared with the successfully confirmed patients, failed patients in the INS group exhibited higher postoperative RUV (100.0 ± 34.6 vs 25.2 ± 13.6 ml, P = 0.003), higher IPSS (7 days, 20.0 ± 8.6 vs 6.5 ± 2.4, P = 0.012; 1 month, 13.5 ± 6.0 vs 5.3 ± 1.9, P = 0.020; 6 months, 11.7 ± 5.1 vs 4.5 ± 1.7, P = 0.018), a greater number of incidences of a micturition disorder (66.7% vs 1.5%, P = 0.000), higher recatheterization rates (33.3% vs 1.5%, P = 0.017) and a lower IIEF score at 3 months (8.25 ± 0.96 vs 10.93 ± 1.99, P = 0.012) and 6 months (12.50 ± 1.29 vs 15.63 ± 1.65, P = 0.001) postoperatively. Compared with the vision group, the INS group had less deterioration in postoperative RUV (31.5 ± 26.4 vs 54.0 ± 46.7 ml, P = 0.000), lower IPSS (7 days, 7.7 ± 5.0 vs 11.0 ± 6.6, P = 0.000; 1 month, 6.0 ± 3.3 vs 7.6 ± 5.4, P = 0.012) and higher IIEF score (3 months, 10.69 ± 2.07 vs 9.42 ± 2.05, P = 0.001; 6 months, 15.36 ± 1.85 vs 13.64 ± 2.00, P = 0.000) as well as a lower incidence of urination disorders (7.0% vs 17.8%, P = 0.038). INS is effective for the accurate evaluation of PANP during radical laparoscopic proctectomy. Combined with INS, laparoscopic proctectomy is more effective in urogenital function protection.

Electrical Stimulation of Vascular Autonomic Nerves: Effects on Heart Rate, Blood Pressure, and Arrhythmias.

Recent clinical studies have shown conflicting results of the efficacy of renal sympathetic denervation (RSD) to mitigate hypertension. In this study, we compared electrical stimulation (ES) of autonomic nerves on the surface of the left pulmonary artery (LPA) and renal arteries (RAs) on heart rate (HR), systolic blood pressure (SBP) and diastolic blood pressure (DBP), and cardiac arrhythmias. In 16 pentobarbital anesthetized dogs, standard electrocardiography leads and blood pressure (BP) were continuously recorded. After a left thoracotomy, a circumferential multielectrode catheter was secured around the LPA. Atrial pacing was coupled to the ES applied around the LPA during the QRS complex to avoid ventricular excitation. Flank incisions allowed retroperitoneal expose of the RAs and the aortico-renal ganglia (ARG). HR and SBP/DBP were determined at baseline (BL) and during ES of LPA, RA, or ARG. During ES applied to the LPA, HR was unchanged compared to BL values. In four of six animals, ventricular tachyarrhythmias were induced by ES. SBP increased significantly (BL vs ES, 129 ± 17 mm Hg vs 163 ± 21 mm Hg, P ≤ 0.05). ES applied to the RAs and ARG did not affect the HR, but significantly increased SBP/DBP (baseline: 134 ± 24/96 ± 18 mm Hg; RAs stimulation: 157 ± 26/114 ± 18 mm Hg; ARG stimulation: 207 ± 44/147 ± 26 mm Hg, P < 0.05). ES of vascular autonomic nerves on LPA, RAs, and ARG significantly increased BP but without effects on HR. ES of ARG induced substantially greater hypertensive responses than ES of RAs, implying that ES of ARG may serve as a biomarker or ablation targets for RSD.

Atrial fibrillation electrical remodelling via ablation of the epicardial neural networks and suprathreshold stimulation of vagosympathetic nerve.

BackgroundNumerous studies have shown that the cardiac autonomic nervous system (CANS) is involved in the occurrence and persistence of atrial fibrillation (AF). The CANS is commonly considered to consist of the extrinsic and intrinsic autonomic nerves. The influence of exogenous and endogenous nerve stimulation plexus ablation on pulmonary vein sleeves and atrial myocardium provides important information in understanding the occurrence and persistence of AF. Vagosympathetic nerve stimulation and epicardial neural networks are important participants in atrial electrical remodelling (AER). Elucidation of the changes in the electrophysiological indicators of the atrial and pulmonary veins caused by epicardial neural network ablation and autonomic nerve stimulation may provide a theoretical basis for the clinical treatment of AF.Material/MethodsA total of 13 beagle dogs were randomly divided into 2 groups: the control group (n=6), which was treated with a simple rapid atrial pacing (RAP) for 6 h, and the experimental group (n=7), which was treated with RAP+vagus nerve stimulation (VNS) for 6 h. Both groups were treated with epicardial ganglia plexus (GP) ablation after 6 h. We measured the monophasic action potential (MAP), various parts of the effective refractory period (ERP), and AF induction rate before and after pacing or ablation.ResultsWith the extension of the pacing time, the atrial MAP and ERP of the 2 groups shortened and returned to normal after ablation plexus. After GP ablation, the atrial AF-induced rate did not decrease significantly compared with that of the pulmonary vein.ConclusionsVagus nerve threshold stimulation exacerbated the deterioration of electrical remodelling, whereas the epicardial neural network ablation blocked or reversed the AER.

Topography of the extrinsic internal anal sphincter nerve supply during laparoscopic-assisted TAMIS TME: five key zones of risk from the surgeons' view.

Sparing the extrinsic autonomic innervation of the internal anal sphincter during total mesorectal excision is important for the preservation of anal sphincter function. This study electrophysiologically confirmed the topography of the internal anal sphincter nerve supply during laparoscopic-assisted transanal minimally invasive surgery for total mesorectal excision. This prospective study was conducted at two large multispecialty referral centers. Six patients (five males and one female) aged between 45 and 65years with low rectal cancer (≤5cm from the anal verge) were enrolled. Surgery was performed under electric stimulation of the pelvic autonomic nerves with observation of the electromyographic signals of the internal anal sphincter. The minimally invasive transanal surgical approach enabled advantageous visualization of the pelvic autonomic nerves in all patients. In particular, extrinsic innervation to the internal anal sphincter near the levator muscle was consciously spared under electrophysiological confirmation. The evoked absolute electromyographic amplitudes of the internal anal sphincter during transanal minimally invasive surgery were significantly lower than the initial results of the laparoscopic approach [3.7μV (interquartile range 2.4; 5.7) vs. 4.3μV (interquartile range 3.1; 8.6); p = 0.002]. Five key zones of risk for pelvic autonomic nerve damage were identified. No complications occurred. The electromyographic results of this preliminary study indicate advantages for sparing the internal anal sphincter innervation during transanal minimally invasive mesorectal dissection considering the specific in situ neuroanatomical topography.

Atomoxetine resulting in Takotsubo syndrome: Is the locally-released norepinephrine from the autonomic sympathetic cardiac nerves or the blood-borne catecholamines the cause?

To the Editor, The case report byYamaguchi et al. published on line ahead of print on November 14, 2013 in the Journal [5] about an 11year-old boy with attention-deficit/hyperactivity disorder (ADHD) treated for 2 years with atomoxetine, who suffered Takotsubo syndrome (TTS), implicating this drug, is of interest to clinicians managing patients with ADHD and for a possible TTS pathophysiological connotation. Atomoxetine, as the authors state, is a noncentral nerve-stimulating agent blocking reuptake of noradrenalin, and, as such, it can lead to cardiac responses similar to the ones resulting from intense efferent autonomic cardiac sympathetic nerve stimulation [2]. The pathophysiology of TTS is still elusive, but the currently prevailing theory implicates high catecholamines (both epinephrine and norepinephrine) as mediators for the resulting cardiomyocyte toxicity/injury [1, 3, 4]. There is a variation in the opinion about the exact pathomechanism in the sense that it is believed that either blood-borne catecholamines, resulting from the “spillover” from the autonomic cardiac sympathetic nerve terminals and the adrenal secretion [1, 3, 4]; or norepinephrine secreted locally by the autonomic cardiac sympathetic nerve terminals [2] is causing the cardiomyocyte toxicity/ injury. The clinical picture of the patient in this report, showing initially tachycardia and hypotension and subsequently bradycardia, electrocardiogram (ECG) T wave inversions, QTc interval prolongations, and multiple premature ventricular contractions, is exactly what has been described in human experiences and animal experiments, as a result of autonomic cardiac sympathetic nerve hyperactivity [2]. The fact that these injurious effects on the heart were not prevented by adrenalectomy in animal models of TTS [2] supports the primacy of the direct sympathetic cardiac nerve hyperactivity, with its local consequences (norepinephrine release) on the cardiomyocytes as opposed to blood-borne catecholamines as the mediator for the TTS phenotype. While this remains to be settled in the future, pediatricians and psychiatrists should be vigilant in monitoring their patients with ADHD treated with atomoxetine for a possible adverse effect of this drug with a similar outcome as the one in this reported case. Accordingly, hypertension, tachycardia, and extrasystoles, evaluated during history taking and physical examination, most probably, should be considered as harbingers of a possible impending attack of TTS, since the ECGmanifestations (ST elevations, T wave inversions, bradycardia, and QTc prolongation) are manifested after the disease is already in progress. However, recording an ECG, as the authors advise [5], to evaluate whether a child has a prolonged QTc syndrome before the initiation of therapy with atomoxetine or before an increase of its dose is sensible.

Effects of low-intensity autonomic nerve stimulation on atrial electrophysiology.

Background and ObjectivesThe cardiac autonomic nervous system is an emerging target for therapeutic control of atrial fibrillation (AF). We evaluated the effects of low-intensity autonomic nerve stimulation (LI-ANS) on atrial electrophysiology, AF vulnerability, and neural remodeling.Subjects and MethodsFourteen dogs were subjected to 3 hours rapid atrial pacing (RAP, 5 Hz) and concomitant high frequency LI-ANS (20 Hz, at voltages 40% below the threshold) as follows: no autonomic stimulation (control, n=3); or right cervical vagus nerve (RVN, n=6), anterior right ganglionated plexi (ARGP, n=3), and superior left ganglionated plexi (SLGP, n=2) stimulation. Programmed and burst atrial pacing were performed at baseline and at the end of each hour to determine atrial effective refractory period (ERP), window of vulnerability (WOV), and inducibility of sustained AF.ResultsAtrial ERP was significantly shortened by 3 hours RAP (in control group, ΔERP=-47.9±8.9%, p=0.032), and RAP-induced ERP shortening was attenuated by LI-ANS (in LI-ANS group, ΔERP=-15.4±5.9%, p=0.019; vs. control, p=0.035). Neither WOV for AF nor AF inducibility changed significantly during 3 hours RAP with simultaneous LI-ANS. There was no significant difference between the control and LI-ANS group in nerve density and sprouting evaluated by anti-tyrosine hydroxylase and anti-growth associated protein-43 staining. Among the various sites for LI-ANS, the ARGP-stimulation group showed marginally lower ΔWOV (p=0.077) and lower nerve sprouting (p=0.065) compared to the RVN-stimulation group.ConclusionLow-intensity autonomic nerve stimulation significantly attenuated the shortening of atrial ERP caused by RAP. ARGP may be a better target for LI-ANS than RVN for the purpose of suppressing atrial remodeling in AF.

Effects of electrical stimulation of autonomic nerves to the ovary on the ovarian testosterone secretion rate in rats

Previously, we demonstrated that electrical stimulation of the superior ovarian nerve (SON), but not the ovarian nerve plexus (ONP), reduces the secretion rate of estradiol from the ovary via activation of alpha 2-adrenoceptors in rats. The inhibitory effect of SON on estradiol secretion may be due to reduced production of testosterone, a direct precursor of estradiol. Here, we examined the effects of electrical stimulation of the SON and the ONP on ovarian testosterone secretion in rats. On the day of estrous, ovarian venous blood samples were collected intermittently from the ovarian vein. The secretion rate of testosterone from the ovary was calculated from the difference in the testosterone concentration between ovarian venous plasma and systemic arterial blood plasma, and the rate of ovarian venous plasma flow. Stimulation of either the SON or ONP reduced the secretion rate of testosterone from the ovary. The reduction of the testosterone secretion rate by SON stimulation was not influenced by an alpha 2-adrenoceptor antagonist (yohimbine), but it was abolished by an alpha 1-adrenoceptor antagonist (prazosin). Our results show that ovarian nerves have an inhibitory role in ovarian testosterone secretion, via activation of alpha 1-adrenoceptors, but not alpha 2-adrenoceptors. This, therefore, indicates that the reduction of estradiol secretion by SON stimulation is independent of the reduction of testosterone secretion.

Blood Pressure and Autonomic Responses to Electrical Stimulation of the Renal Arterial Nerves Before and After Ablation of the Renal Artery

Radiofrequency (RF) catheter ablation of the renal artery is therapeutic in patients with drug-refractory essential hypertension. This study was designed to examine the role of the renal autonomic nerves and of RF application from inside the renal artery in the regulation of blood pressure (BP). An open irrigation catheter was inserted into either the left or right renal artery in 8 dogs. RF current (17 ± 2 watts) was delivered to one renal artery. Electrical autonomic nerve stimulation was applied to each renal artery before and after RF ablation. BP, heart rate, indices of heart rate variability, and serum catecholamines were analyzed. Before RF ablation, electrical autonomic nerve stimulation of either renal artery increased BP from 150 ± 16/92 ± 15 to 173 ± 21/105 ± 16 mm Hg. After RF ablation, BP increased similarly when the nonablated renal artery was electrically stimulated, although the rise in BP was attenuated when the ablated renal artery was stimulated. Serum catecholamines and sympathetic nerve indices of heart rate variability increased when electrical autonomic nerve stimulation was applied before RF ablation and to the nonablated renal artery after RF ablation, although it changed minimally when the ablated renal artery was stimulated, suggesting interconnectivity between afferent renal nerve stimulation and systemic sympathetic activity. Renal artery angiogram showed no apparent injury after RF ablation. In conclusion, electrical stimulation of the renal arterial autonomic nerves increases BP via an increase in central sympathetic nervous activity. This response might be used to determine the target ablation site and end point of renal artery RF ablation.

To the Editor—Disease Modification by Autonomic Nerve Stimulation

The Editorial Commentary by Oh1 regarding the article by Yu et al2 in the May 2012 issue of HeartRhythm requires some clarification. Dr. Oh states, “They found that low-level superior vena cava (SVC) stimulation [that was 50% below threshold] restored the neural activities at the anterior right ganglionated plexus to the baseline level and suppressed AF inducibility.” Omitted was (italicized), “50% below the threshold for slowing the heart rate.” In a recent study, Zhang et al3 found that only when heart rate was slowed by ≥60% was burst pacing able to induce AF.

Potential players in the hood

Pharmacologic treatment of cardiac arrhythmias has been mostly confined to drugs that alter the electrical function of the myocytes of the heart. In fact, big players in this market have been the adrenergic blocking agents. By virtue of modulation of autonomic tone, this class of drugs can be helpful. However in the case of atrial fibrillation (Af), most current agents are not that helpful and the course of Af is little changed. It is possible that other players in the neighbor “hood” of cells may gain importance. In the paper of Mao et al. [1], autonomic modulation takes on an additional meaning in that in this study, it is the modulation of atrial neural networks, namely those of the fat pads, that these authors believe promote Af. This is consistent with their ideas that autonomic nerve stimulation or autonomic denervation modulates autonomic activity in physiologic and/or pathophysiologic functions. Notably, the experiments of Mao et al. were completed using naive control animals and not animals susceptible to persistent Af. In fact, the longest Af duration noted was 33 min in the presence of acetylcholine (Ach), which was used to mimic the neurotransmitter released with stimulation of the left and right ganglionated plexi (GPs). It is not known whether the same outcomes would occur in animals with highly remodeled or even aged atria as well as if remodeled GPs had been used. The mechanism of remodeling of the Af substrate by atrial neural networks was not explored in this study and thus remains unknown. We know that disease-associated disruptions of adrenergic/cholinergic signaling would be a form of functional denervation and if these paths serve to maintain the adult cardiac phenotype (and if functional and anatomic denervation have equivalent effects) then that could lead to additional myocyte remodeling. There are clear examples in the literature that Af produced by rapid atrial pacing, and VT, Vf and sudden death are associated with heterogeneous atrial innervation in the form of nerve sprouting [2]. Atrial cell electrical [3–6] or autonomic remodeling [7] may be just a reflection of an altered antagonism between the parasympathetic and sympathetic controls of the atria. It is known that vagal input can inhibit sympathetic neurotransmission via (Ach) receptors on the sympathetic nerve terminals. Sympathetic stimulation can produce long-lived vagal inhibition. This latter effect is thought to be caused by neuropeptideY (NPY) which colocalizes with Norepinephrine in sympathetic nerve terminals. NPY effects are varied showing both acute and chronic effects on cardiac cells. Using myocardial neuronal cocultures, labs have now defined some aspects of how neurons first impact the cardiac phenoptype [8–10]. One of us has studied intensely how sustained sympathetic innervation regulates ion channel expression and autonomic responsiveness and how some of these effects can be ascribed to NPY acting as a trophic factor [11, 12]. Mao et al. suggest that another peptide, VIP, may play a role. VIP effects are less well defined. It is released with Ach but causes a marked increase in HR. Whether it too has trophic effects is not known. Obviously more needs to be done here using cardiac tissues. This study was supported by grant HL 66140 from the National Heart Lung and Blood Institute, Bethesda, MD, USA. P. A. Boyden : R. B. Robinson Department of Pharmacology, Center for Molecular Therapeutics, Columbia University, New York, NY 10032, USA

Effects of Percutaneous Stimulation of Both Sympathetic and Parasympathetic Cardiac Autonomic Nerves on Cardiac Function in Dogs

Effects of Percutaneous Stimulation of Both Sympathetic and Parasympathetic Cardiac Autonomic Nerves on Cardiac Function in Dogs

Effects of Percutaneous Stimulation of Both Sympathetic and Parasympathetic Cardiac Autonomic Nerves on Cardiac Function in Dogs

Augmentation of left ventricular (LV) contractility and heart rate (HR) by sympathetic nerve stimulation and amelioration of heart failure by vagal nerve stimulation has been reported. However, the effects of concomitant electrical stimulation of both sympathetic and parasympathetic cardiac nerves in tissues such as those of the cardiac plexus remain unclear. This study sought to assess acute changes in cardiac function and hemodynamics in response to endovascular cardiac plexus stimulation (CPS). Twelve dogs received endovascular CPS via a bipolar catheter within the right pulmonary artery. Stimulation frequency (20 Hz) and pulse width (4 milliseconds) were fixed; voltage varied (range, 15-60 V). Results fell into three categories: 1, no response (n = 4); 2, an increase in systemic arterial pressure that was dependent on electrode placement (n = 4); and 3, a very reproducible and stable increase in aortic pressure (n = 4). In the third group, mean systolic aortic pressures, maximum value of the first derivative of LV pressure, and LV stroke work increased with stimulation (P < 0.02 for all parameters) as did cardiac output, end-systolic elastance, and preload recruitable stroke work (P = 0.03). Systemic and pulmonary vascular resistance, central venous pressure, pulmonary arterial pressure, and HR remained unchanged (P > 0.05). In contrast to conventional inotropic agents, endovascular CPS induced significant and selective increases in LV contractility without increasing HR. Efforts to optimize electrode placement and fixation will improve the reproducibility of endovascular CPS treatment.

Autonomic Modulation

A variety of experimental and clinical reports have engendered a different approach to cardiac arrhythmias as well as other cardiovascular conditions. The focus of a new paradigm is the autonomic nervous system and its important role in various pathological states. From an overall standpoint, this new paradigm can be encompassed by the term “autonomic modulation,” which would include autonomic nerve stimulation or autonomic denervation to modulate the autonomic activity in physiological or pathophysiological functions of the heart as well as other visceral organ systems. Article see p 279 Vaso-vagal syncope is the most common form of neurally mediated syncope.1 The pathophysiology of vaso-vagal syncope is still controversial, but it is thought to be related to prolonged orthostatic stress, which causes increased peripheral venous pooling with a subsequent fall in venous return to the heart. This in turn causes a hypercontractile state, which leads to activation of ventricular mechanoreceptors and a sudden increase in the afferent neural traffic to the brain. The result is sympathetic withdrawal and parasympathetic enhancement that manifests as hypotension (vasodepressor type), bradycardia (cardioinhibitory type), and syncope.1 In other words, vaso-vagal syncope is a disorder caused by an abnormally amplified autonomic reflex involving both sympathetic and parasympathetic components. Over the past 2 decades, β-blockers, α-agonists, mineralocorticoids, selective serotonin reuptake inhibitors, and dual-chamber pacemaker implantation all produced initial promising but later disappointing results.1–3 Vaso-vagal syncope continues to be a vexing clinical arrhythmia. In this issue of Circulation Arrhythmia and Electrophysiology , Yao et al4 reported 10 patients who had drug-refractory, frequent, and highly symptomatic vaso-vagal syncope. Based on the hypothesis that …