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Background: Patients with a high ventricular rate during atrial fibrillation (AF) are at increased risk of receiving inappropriate implantable cardioverter defibrillator shocks. The objective was to demonstrate the feasibility of high frequency atrioventricular-nodal stimulation (AVNS) to reduce the ventricular rate during AF to prevent inappropriate implantable cardioverter defibrillator shocks., Methods and Results: Patients with a new atrial lead placement as part of a cardiac resynchronization therapy and defibrillator implant and a history of paroxysmal or persistent AF were eligible. If proper atrial lead position was confirmed, AVNS software was uploaded to the cardiac resynchronization therapy device, tested, and optimized. AVNS was delivered via a right atrial pacing lead positioned in the posterior right atrium. Software allowed initiation of high frequency bursts triggered on rapidly conducted AF. Importantly, the efficacy was evaluated during spontaneous AF episodes between 1 and 6 months after implant. Forty-four patients were enrolled in 4 centers. Successful atrial lead placement occurred in 74%. Median implant time of the AVNS lead was 37 minutes. In 26 (81%) patients, manual AVNS tests increased the ventricular interval by >25%. Between 1 and 6 months, automatic AVNS activations occurred in 4 patients with rapidly conducted AF, and in 3 patients, AVNS slowed the ventricular rate out of the implantable cardioverter defibrillator shock zone. No adverse events were associated with the AVNS software., Conclusions: The present study demonstrated the feasibility of implementation of AVNS in a cardiac resynchronization therapy and defibrillator system. AVNS increased ventricular interval >25% in 81% of patients. AVNS did not influence the safety profile of the cardiac resynchronization therapy and defibrillator system., Clinical Trial Registration: clinicaltrials.gov; Unique Identifier: NCT01095952., (© 2015 American Heart Association, Inc.)

Background: Atrioventricular (AV) node vagal stimulation (AVNVS) has recently emerged as a novel approach to controlling AV dromotropic function. Animal studies have demonstrated that selective epicardial AVNVS is effective in controlling ventricular rate (VR) acutely and in the long term. Endocardial AVNVS has been shown to significantly reduce VR acutely during atrial fibrillation (AF) in humans. However, no data are available on its long-term reproducibility., Objectives: The purpose of this study was to demonstrate that the posteroseptal right atrium is a suitable site for permanent pacing and allows AVNVS in humans both acutely and during follow-up., Methods: In 12 candidates for implantable cardioverter-defibrillator with a history of AF, the atrial lead was implanted in the posteroseptal right atrium, where advanced AV block was achieved during temporary high-frequency stimulation (HFS). On implantation and 3-month follow-up examination, HFS was delivered through the permanent lead to demonstrate the possibility to gradually slow the VR until complete AV block., Results: On implantation, VR during AF was gradually slowed until complete AV block, which was elicited at 4.3 V (0.2 ms, 50 Hz). After 3 months, this effect remained reproducible. No significant change in pacing thresholds was observed after 3 months. We observed one dislodgment and one microdislodgement of atrial leads., Conclusions: Our study demonstrates, for the first time in humans, that selective placement of the atrial lead yields electrical characteristics suitable for permanent pacing and enables VR to be significantly reduced under HFS. These results, which were reproducible during follow-up, provide data for the development of device-based control of VR during AF.

Introduction: Respiratory sinus arrhythmia (RSA) and heart rate variability (HRV) are parameters of autonomic cardiac innervation. They decrease with age and after atrioventricular nodal modification (AVNM) suggesting vagal denervation in both situations. We hypothesized, however, that AVNM causes only a transient, functional decline in vagal activity, whereas aging causes permanent vagal denervation. A new method of analyzing RSA phase dynamics based on circle maps (CM) can potentially differentiate between both forms of reduced vagal activity., Methods: In 18 younger and 14 older healthy control subjects 24-hour Holter ECGs were recorded for HRV analysis. Repeated measurements of RSA were acquired during paced breathing (PB). In 16 consecutive patients undergoing AVNM the same measurements were applied before, 1 day and 3 months after the procedure. CM were calculated from consecutive RR intervals and the similarity between different CM quantified by the Kullback information gain (KIG)., Results: HRV analysis revealed lower HF bands, LF bands and RSA amplitudes in older vs. younger control subjects. KIG revealed less similarity between younger and older control subjects than within the respective age groups. After AVNM a decrease in HF bands was noted in HRV analysis. Three months after AVNM, HF bands returned to pre-ablation values. CM obtained before and 1 day after AVNM displayed comparable similarity to CM acquired 1 day before and 3 months after ablation., Conclusions: In contrast to conventional HRV parameters, CM of RSA are not altered by ablation in the posteroseptal space but by aging. Thus, this new method appears to differentiate between transient autonomic modification and chronic denervation.

Abstract: In the heart, acetylcholine (ACh) slows pacemaker activity, depresses contractility and slows conduction in the atrioventricular node. Beside these cardiovascular effects, ACh has also been associated with an anti-inflammatory and anti-apoptotic pathway. There is no evidence for ACh synthesis and excretion in other cell types than neuronal cells in the heart. Therefore, this study investigates whether cardiomyocytes are able to synthesize, transport and excrete ACh in the heart. We chose a rat model of different aged rats (neonatal, 6-8week = young, 20-24month = old). By real-time PCR, Western blot and immunofluorescence experiments we could demonstrate that adult, but not neonatal cardiomyocytes, express the choline acetyltransferase (ChAT). The expression level of ChAT is down-regulated in old cardiomyocytes. Furthermore, we found that young and old cardiomyocytes express the ACh transport proteins choline transporter-1 (CHT-1) and the vesicular acetylcholine transporter (VAChT). The amount of ACh excretion detected by high performance liquid chromatography (HPLC) is significantly down-regulated in old cardiomyocytes. Bromo-acetylcholine (BrACh), a specific ChAT inhibitor, significantly decreased ACh concentrations in cardiomyocyte supernatants demonstrating that ChAT is the main ACh synthesizing enzyme in cardiomyocytes. In conclusion, we could demonstrate that adult, but not neonatal, cardiomyocytes are able to synthesize, transport and excrete ACh in the rat heart. The expression level of ChAT and the ACh excretion amount are significantly down-regulated in old cardiomyocytes. This finding may provide new physiological/pathological aspects in the communication between cardiomyocytes and other cell types in the myocardium, e.g. fibrocytes, neurocytes or endothelial cells. [ABSTRACT FROM AUTHOR]

Long-Term Cardiac Neurostimulation. Introduction: The right inferior ganglionated plexus (RIGP) selectively innervates the atrioventricular node. Temporary electrical stimulation of this plexus reduces the ventricular rate during atrial fibrillation (AF). We sought to assess the feasibility of chronic parasympathetic stimulation for ventricular rate control during AF with a nonthoracotomy intracardiac neurostimulation approach. Methods and Results: In 9 mongrel dogs, the small endocardial area inside the right atrium, which overlies the RIGP, was identified by 20 Hz stimulation over a guiding catheter with integrated electrodes. Once identified, an active-fixation lead was implanted. The lead was connected to a subcutaneous neurostimulator. An additional dual-chamber pacemaker was implanted for AF induction by rapid atrial pacing and ventricular rate monitoring. Continuous neurostimulation was delivered for 1–2 years to decrease the ventricular rate during AF to a range of 100–140 bpm. Implantation of a neurostimulation lead was achieved within 37 ± 12 min. The latency of the negative dromotropic response after on/offset or modulation of neurostimulation was <1 s. Continuous neurostimulation was effective and well tolerated during a 1–2 year follow-up with a stimulation voltage <5 V. The neurostimulation effect displayed a chronaxie-rheobase behavior (chronaxie time of 0.07 ± 0.02 ms for a 50% decrease of the ventricular rate during AF). Conclusion: Chronic parasympathetic stimulation can be achieved via a cardiac neurostimulator. The approach is safe, effective, and well tolerated in the long term. The atrioventricular nodal selectivity and the opportunity to adjust the negative dromotropic effect within seconds may represent an advantage over pharmacological rate control. (J Cardiovasc Electrophysiol, Vol. 21, pp. 193-199, February 2010) [ABSTRACT FROM AUTHOR]

Aims: Ventricular rate control is considered as an initial choice of therapy in many patients with atrial fibrillation (AF). We could previously show that electrostimulation of the right inferior ganglionated plexus (RIGP), which supplies the AV node, instantly decreases ventricular rate during AF. This study describes the development of a technique to reliably implant a chronic lead inside the RIGP. [ABSTRACT FROM PUBLISHER]

Introduction: Catheter stimulation of the inferior interatrial ganglionated parasympathetic plexus decreases the ventricular rate during atrial fibrillation (AF) in humans. However, the relatively high stimulation voltages might prevent implementation of neurostimulation in chronic implantable devices. From myocardial electrostimulation it is known that the required impulse energy and charge is lowest at the chronaxie time. In order to lower energy requirements for cardiac neurostimulation, the present study evaluates the impulse-strength versus impulse-duration relationship for a neurostimulation lead that was implanted into the inferior interatrial ganglionated plexus. Methods and Results: In nine dogs, permanent epicardial bipolar screw-in electrodes were fixed in the inferior interatrial ganglionated plexus. AF was maintained via rapid atrial pacing. During AF, neural stimulation was performed at various frequencies (1–100 Hz), impulse durations (0.05–2 msec), and voltages (0.02–11.5 V). There was a linear correlation between R-R interval lengthening and stimulus voltage (R = 0.99; P < 0.001) and a bell-shaped relationship between stimulation frequency and negative dromotropic effect with maximum rate slowing at 30–50 Hz. The rheobase for a 50% R-R interval prolongation during AF was 1.81 V and 2.72 V for high-grade AVB yielding a chronaxie time of 0.14 msec and 0.18 msec, respectively. The impulse energy (charge) at the chronaxie time was 4–6 μJ (6–8 μC). Conclusions: Cardiac neurostimulation follows a chronaxie/rheobase behavior. Energy, charge, and voltage values needed to achieve significant negative dromotropic effects are within the limits of conventional cardiac pacemaker outputs, which may allow implementation of neurostimulation capabilities in current pacemaker technology. [ABSTRACT FROM AUTHOR]

Introduction: In previous reports, we demonstrated a technique for parasympathetic nerve stimulation (PNS) within the superior vena cava, pulmonary artery, and coronary sinus to control rapid ventricular rates during atrial fibrillation (AF). In this report, we describe another vascular site, the inferior vena cava (IVC), at which negative dromotropic effects during AF could consistently he obtained. Moreover, stimulation at this site also induced dual AV nodal electrophysiology. Methods and Results: PNS was performed in ten dogs using rectangular stimuli (0.1 msec/20 Hz) delivered through a catheter with an expandable electrode basket at its tip. Within 3 minutes and without using fluoroscopy, the catheter was positioned at an effective PNS site in the IVC at the junction of the right atrium. AF was induced and maintained by rapid atrial pacing. During stepwise increase of the PNS voltage from 2 to 34 V, a graded response of ventricular rate slowing during AF was observed (266 ± 79 msec without PNS vs 1,539 ± 2,460 msec with PNS at 34 V; P = 0.005 hy analysis of variance), which was abolished hy atropine and hlunted hy hexamethonium. In three animals, PNS was performed during sinus rhythm. Dual AV nodal electrophysiology was present in I of 3 dogs in control, whereas with PNS, dual AV nodal electrophysiology was observed in all three dogs. PNS did not significantly change sinus rate or arterial blood pressure during ventricular pacing. Conclusion: Stable and consistent transvenous electrical stimulation of parasympathetic nerves innervating the AV node can be achieved in the IVC, a transvenous site that is rapidly and readily accessible. The proposed catheter approach for PNS can be used to control ventricular rate during AF in this animal model. [ABSTRACT FROM AUTHOR]