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Despite improvements in medical therapy and device-based treatment, heart failure (HF) continues to impose enormous burdens on patients and health care systems worldwide. Alterations in autonomic nervous system (ANS) activity contribute to cardiac disease progression, and the recent development of invasive techniques and electrical stimulation devices has opened new avenues for specific targeting of the sympathetic and parasympathetic branches of the ANS. The Heart Failure Association of the European Society of Cardiology recently organized an expert workshop which brought together clinicians, trialists and basic scientists to discuss the ANS as a therapeutic target in HF. The questions addressed were: (i) What are the abnormalities of ANS in HF patients? (ii) What methods are available to measure autonomic dysfunction? (iii) What therapeutic interventions are available to target the ANS in patients with HF, and what are their specific strengths and weaknesses? (iv) What have we learned from previous ANS trials? (v) How should we proceed in the future?.

Central sleep apnea syndrome, correlated with the occurrence of heart failure, is characterized by periods of insufficient ventilation during sleep. This acute study in 15 patients aims to map the venous system and determine if diaphragmatic movement can be achieved by phrenic nerve stimulation at various locations within the venous system.Subjects underwent a scheduled catheter ablation procedure. During the procedural waiting time, one multielectrode electrophysiology catheter was subsequently placed at the superior and inferior vena cava and the junctions of the left jugular and left brachiocephalic vein and right jugular and right brachiocephalic vein, for phrenic nerve stimulation (1-2 seconds ON/2-3 seconds OFF, 40 Hz, pulse width 210 μs). Diaphragmatic movement was assessed manually and by a breathing mask. During a follow-up assessment between 2 and 4 weeks postprocedure, occurrence of adverse events was assessed.In all patients diaphragmatic movement was induced at one or more locations using a median threshold of at least 2 V and maximally 7.5 V (i.e., e 3.3 mA, 14.2 mA). The lowest median current to obtain diaphragmatic stimulation without discomfort was found for the right brachiocephalic vein (4.7 mA). In 12/15 patients diaphragmatic movement could be induced without any discomfort, but in three patients hiccups occurred.Diaphragmatic stimulation from the brachiocephalic and caval veins is feasible. Potential side effects should be eliminated by adapting the stimulation pattern. This information could be used to design a catheter, combining cardiac pacing with enhancing diaphragm movement during a sleep apnea episode.

In this review, we report on electrical modalities, which do not fit the definition of pacemaker, but increase cardiac performance either by direct application to the heart (e. g., post-extrasystolic potentiation or non-excitatory stimulation) or indirectly through activation of the nervous system (e. g., vagal or sympathetic activation). The physiological background of the possible mechanisms of these electrical modalities and their potential application to treat heart failure are discussed.

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.

Aims We hypothesize that the neural component (NC) of the baroreflex sensitivity (BRS) is a better risk stratifier for ventricular tachycardia/fibrillation (VT/VF) than conventional BRS itself, because it is both independent of vessel wall stiffness and can be measured non-invasively. Methods and results NC was determined by correlating spontaneous carotid artery diameter variations with R–R interval variations using spectral analyses. In consecutive outpatient populations with chronic coronary artery disease the ability of the NC to distinguish post-myocardial infarction (MI) patients at risk for VT/VF (post-MIHIGH RISK) from post-MI less prone to arrhythmias (post-MILOW RISK) was compared with the pressure-derived BRSphenyl and BRSspectral method. Ninety-six patients, i.e. 28 post-MILOW RISK, 28 post-MIHIGH RISK [a LVEF(left ventricular ejection fraction)

Effect of parasympathetic nerve stimulation on atrial and atrioventricular nodal electrophysiological characteristics

BACKGROUND Early recurrences within 10 minutes after termination of an atria[ tachyarrhythmia, such as atria[ tachycardia (AT), atrial flutter, or atrial fibrillation (AF) episodes, account for a large part of paroxysmal AT/AF episodes. It is unclear whether these arrhythmias can be suppressed by overdrive pacing.OBJECTIVE We set out to prove that overdrive pacing is effective in preventing early recurrences of AT/AF.METHODS This AT500 (DDDRP device, Bakken Research Center Medtronic, Maastricht, The Netherlands) post-mode switch overdrive pacing (PMOP) study is a randomized controlled trial designed to test the efficacy of overdrive pacing on the suppression of early recurring AT/AF episodes. With the PMOP feature, overdrive pacing is activated 12 ventricular beats after device-confirmed termination of an AT/AF episode with a programmed duration and rate. If at least four episodes of 1 minute in duration occurred within the run-in period of 1 month, patients were randomized to one of the three settings (PMOP off and PMOP 10 minutes at 90 bpm or 120 bpm) for 2 months. At 2 and 4 months, patients were crossed over to another arm. At 6 months, all patients were programmed with PMOP on at 90 bpm for 30 minutes.RESULTS We enrolled 122 and randomized 50 patients. Sixty percent of all stored AT/AF episodes occurred within 10 minutes after a previous episode; 31% occurred after device-determined termination and before the device reached the overdrive rate (17-27 ventricular beats after termination), and 29% of the episodes occurred white the device was pacing at the programmed overdrive rate. Thirty-seven percent of the average percentage of episodes during the overdrive period was prevented by the randomized settings of PMOP 90 bpm/10 min (P =.01, paired t-test, n = 39) and 120 bpm/10 min (P =.03, n = 35). In addition, for the nonrandomized setting of PMOP 90 bpm/30 min, the average number of episodes during the overdrive period was significantly smaller than the percentage of episodes occurring during the corresponding off period of 30 minutes (P =.05, n = 33). No significant differences in burden and episodes were found between the PMOP settings and the corresponding off periods.CONCLUSIONS This is the first randomized controlled clinical trial to prove that overdrive pacing is effective in preventing early recurrences of AT/AF. However, shortcomings of the PMOP algorithm, such as late activation, need further improvement.

To assess locally deviating structural and mechanical properties of arterial walls, the spatial variance in end-diastolic intima media thickness (IMT) and the change in IMT during the cardiac cycle (ΔIMT) were determined along a short segment of the common carotid artery (15.86 mm), at 16 positions simultaneously. Intrasubject spatial inhomogeneities along the artery were revealed by a spatial variance significantly larger than the temporal variance over several beats. If differences between positions were confirmed, the extent of the inhomogeneity was obtained by comparison of IMT and ΔIMT at each position with their spatial medians ± the least-significant difference. Because no intersubject comparisons were necessary, a single session of several measurements was sufficient to assess inhomogeneities in the arterial wall properties of a subject, making the method independent of biological variability between subjects. The method was evaluated on 47 presumed healthy subjects (age range 21–75 yr). In 22 subjects, spatial inhomogeneities in ΔIMT occurred ( P < 0.05). In young subjects, ΔIMT was locally decreased, i.e., in systole inhomogeneities were less compressed than their surrounding tissue. In older subjects, ΔIMT was locally increased, i.e., the inhomogeneity was locally more compressed than its surrounding wall tissue.

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.

The reciprocal of the arterial pulse wave velocity contains crucial information about the mechanical characteristics of the arterial wall but is difficult to assess noninvasively in vivo. In this paper, a new method to assess local pulse wave velocity (PWV) is presented. To this end, multiple adjacent distension waveforms are determined simultaneously along a short arterial segment, using a single 2D-vessel wall tracking system with a high frame rate (651 Hz). Each B-mode image consists of 16 echo lines spanning a total width of 15.86 mm. Dedicated software has been developed to extract the end-diastolic diameter from the B-mode image and the distension waveforms from the underlying radiofrequency (rf) information for each echo-line. The PWV is obtained by determining the ratio of the temporal and spatial gradient of adjacent distension velocity waveforms. The proposed method is verified in a phantom and in the common carotid artery (CCA) of humans. Phantom experiments show a high concordance between the PWV obtained from 2D distension velocity waveforms (4.21 ± 0.02 m/s) and the PWV determined using two pressure catheters (4.26 ± 0.02 m/s). Assuming linear spatial gradients, the PWV can also be obtained in vivo for CCA and averages to 5.5 ± 1.5 m/s (intersubject variation, n = 23), which compares well to values found in literature. Furthermore, intrasubject PWV compares well with those calculated using the Bramwell-Hill equation. It can be concluded that the PWV can be obtained from the spatial and temporal gradient if the spatial gradient is linear over the observed length of the artery, i.e. the artery should be homogenous in diameter and distension and the influence of reflections must be small.

To elicit vessel wall inhomogeneities in diameter and distension along an arterial segment, a 2-D vessel wall-tracking system based on fast B-mode has been developed. The frame rate of a 7.5-MHz linear-array transducer (length 36 mm) is enhanced by increasing the pulse-repetition frequency to 10 kHz, decreasing the number of echo lines per frame from 128 to 64, or increasing the interspacing between echo lines with a factor of two or four. Dedicated software has been developed to extract for each echo-line the end-diastolic diameter from the B-mode image and the 2-D distension waveform from the underlying radiofrequency (RF) information. The method is validated in tubes with various focal lesion sizes. Straight segments of presumably homogeneous common carotid arteries have also been tested. The temporal and spatial SD of diameter or distension reveals inhomogeneities in time or space (i.e., inhomogeneities in artery characteristics). The method can be implemented in echo systems supporting high frame rates and real-time processing of radiofrequency data.

Abstract —In the common carotid artery, reflections originating from the periphery and the flow divider may affect the shape of the flow velocity profile and, hence, near-wall shear rate (WSR) differently just before the bifurcation (location B) than 20 to 30 mm farther upstream (location A). Recent developments in ultrasound technology allow the assessment of WSR and intima-media thickness (IMT) at the same site in the carotid artery in vivo. We therefore determined WSR at locations A and B and investigated whether the differences between both sites, if any, were associated with different IMTs and different mechanical properties of the arterial wall. The effect of age on the possible differences was assessed as well. The study was performed on presumably healthy volunteers (n=53). In all individuals, IMT was larger at location B than at location A. The relative difference in IMT between both locations was not affected by age. No significant differences in diameter and distension were found between locations. Near peak systolic and near mean WSR at the posterior wall (PWSR p and MWSR p , respectively) were significantly lower at location B than at location A. The relative differences in PWSR p and MWSR p between both locations within subjects were independent of age. The velocity profiles were more blunted at location A than at location B. PWSR p and MWSR p significantly decreased and IMT significantly increased with age at both locations. IMT was negatively correlated with PWSR P and MWSR P at location B, but this correlation was not significant at location A. In summary, in the common carotid artery, the lower WSR near the bifurcation, as compared with 20 to 30 mm upstream, is associated with a larger IMT than at the more proximal site. The relative difference between both locations within subjects is independent of age.

Background Control of atrioventricular (AV) nodal conduction by endocardial stimulation of efferent AV nodal vagal fibers [atrioventricular nodal vagal stimulation (AVNS)] is a promising approach for long-term device-based modulation of ventricular rate during atrial fibrillation (AF). However, few data on the efficacy of AVNS delivered as high-frequency stimulus packages (burst AVNS) in humans are available. Objective The purpose of this study was to determine whether burst AVNS can to modulate AV nodal conduction during AF and whether burst AVNS delivered during sinus rhythm (SR) in the effective atrial refractory period allows safe implantation of a permanent lead in a position suitable for AVNS. Methods Twenty patients (10 in SR and 10 in AF) who were candidates for dual-chamber pacemaker implantation for sick sinus syndrome were enrolled in the study. The posteroseptal right atrium was mapped to identify a location at which burst AVNS would achieve AV nodal conduction modulation (lengthening of PR interval in SR and reduction of ventricular rate in AF). Subsequently, a lead was screwed in at that site and burst stimulation (pulse rate 50 Hz, burst duration 180 ms) was delivered at different burst rates, pulse durations, and amplitudes. Results In all SR patients, PR-interval prolongation was evoked at 90 and 120 bursts/minute with pulse durations ≤1 ms. Specifically, the mean voltages required to obtain PR-interval prolongation and advanced AV block were 4.3 ± 2.2 V and 5.4 ± 1.8 V (at 90 bursts/minute and 1 ms), respectively. Similarly, ventricular rate reduction was obtained in all AF patients, starting from 90 bursts/minute and 0.5-ms pulse duration (at 5.4 ± 1.8 V). Ventricular arrhythmias were never induced during AVNS. Conclusion Endocardial right atrial burst AVNS reduces ventricular rate during AF. Burst AVNS delivered during SR in the effective atrial refractory period allows optimization of lead positioning for AVNS.

Two independent studies have revealed a potential limitation of post-mode switch overdrive pacing (PMOP), which is its delayed start. We conducted a prospective, randomized, single blind, crossover design study (the post-long pause overdrive pacing study) to test the efficacy of an improved version of PMOP (PMOPenhanced). A total of 45 patients were enrolled, of whom 41 were analysed. The median number of atrial tachycardia/atrial fibrillation (AT/AF) episodes per day (1.38 vs. 1.19), the median number of early recurrences of atrial fibrillation (ERAF) per day (0.56 vs. 0.51), and the median AT/AF burden (time per day spent in AT/AF) (2.47 vs. 2.51 h) were not significantly different during the control and active study periods. Based on the median number of episodes per week recorded 90 days prior to enrolment, the patients were stratified by the median and then split into two groups, Group A (lower 2-Quartiles) and Group B (upper 2-Quartiles). The median AT/AF burden was significantly lower in Group B during the active study period (3.71 vs. 1.71 h, P = 0.02).The median number of AT/AF episodes per day and the median number of ERAF per day in Group B showed a trend towards reduction when the algorithm was turned on (3.79 vs. 2.44 and 2.77 vs. 1.86, respectively). In contrast, in Group A we did not demonstrate any difference in AT/AF frequency, ERAF frequency, or burden. The main finding of this study is that temporary overdrive pacing at 90 bpm for 10 min starting just prior to device-classified AT/AF termination does not show a positive effect on the overall study population. However, when enabled in patients who suffer from a high percentage of ERAF, a significant reduction in the AT/AF burden could be demonstrated. Based on these findings, further prospective studies on a more targeted patient population are needed to confirm our results. (Less)

Post-operative atrial fibrillation (POAF) is a common complication after cardiac surgery and often leads to poorly tolerated fast ventricular rates. Negative dromotropic drugs are not always effective and may not be well tolerated in heart failure patients. Aim of this study is to verify if high-frequency stimulation of the right inferior fat pad (RIFPS) allows an effective decrease in ventricular rate (VR) during POAF.We enrolled 32 consecutive patients submitted to bypass; during surgery, a temporary heart wire was implanted in a site where RIFPS evoked a functional AV block. During POAF, RIFPS was delivered from the heart wire to decrease VR.Intra-operative RIFPS evoked complete AV block in 29 patients (91%). Fourteen patients (44%) developed POAF (mean VR 127 +/- 12 bpm). In these patients, RIFPS achieved a 25% reduction of VR and complete AV block with 6.0 +/- 1.9 and 7.5 +/- 1.8 V (duration 0.2 ms, frequency 50 Hz), respectively.Epicardial RIFPS represents an effective and feasible technique to decrease VR during POAF.

Skin biopsies in patients with pseudoxanthoma elasticum (PXE) show elastic fiber fragmentation and calcium and proteoglycans accumulation. Assuming such changes to be present in the artery wall as well, we studied the influence of such alterations on function and structure of the human common carotid artery (CCA). Indeed, elastin fragmentation and increased calcium and proteoglycans content were present in the arteries of the two PXE patients examined. Internal diameter, distension and intima-media thickness (IMT) in the CCA of PXE patients (n = 19) and controls (n = 39) were determined by ultrasound (US). Pulse pressure was assessed in the brachial artery. The distensibility and compliance coefficients as well as the Young's modulus were calculated. Diameter and pulse pressure were not significantly different in PXE patients and controls. The distensibility and compliance coefficients were significantly greater in older PXE patients than in older controls. The distensibility coefficient decreased with age in both PXE patients and in controls. Unlike in controls, the compliance coefficient did not decrease and the Young's modulus barely increased with age in PXE patients. IMT was significantly greater at both younger and older ages and the Young's modulus was significantly smaller at older ages in PXE patients than in controls. The carotid artery is thicker and more elastic in PXE patients than in control subjects; differences are most pronounced at older ages. These alterations might be explained by the elastin fragmentation and proteoglycans accumulation as observed in these patients.

Hemodialysis (HD) patients commonly show abnormalities of the arterial system. Only a few studies have focused on arterial wall properties in patients with early stages of renal insufficiency and patients on peritoneal dialysis (PD) therapy. In this study, the distensibility coefficient (DC), a marker of arterial stiffening and intima media thickness (IMT) of the common carotid artery (CCA) and a surrogate marker of atherosclerosis, was assessed in four age-matched groups of patients: 18 HD patients, 36 PD patients, 30 patients with chronic renal failure (CRF) not yet on dialysis therapy with a creatinine clearance (CCl) between 10 and 70 mL/min, and 25 normotensive controls with normal renal function. Arterial wall properties were assessed by an automated vessel wall detection system. In patients with CRF and HD patients, but not PD patients, the DC of the CCA was significantly reduced (P < 0.05) compared with controls (CRF, 12.6 +/- 7.5 10(-3)/kPa; HD, 11.6 +/- 7.6 10(-3)/kPa; and PD, 14.7 +/- 6.2 10(-3)/kPa compared with controls, 16.7 +/- 4.6 10(-3)/kPa). In patients with CRF, a significant relationship was found between CCl and the DC (r = 0.41; P = 0.02). IMT was not different among patients with CRF (589 +/- 115 microm), HD (622 +/- 115 microm) and PD patients (585 +/- 121 microm), and controls (668 +/- 150 microm). In conclusion, compared with controls, the DC of the CCA was significantly reduced in HD patients and those with CRF, but not PD patients. In patients with CRF, the DC correlated significantly with CCl. IMT did not differ between groups of renal patients and controls.

Objective and design Recently we developed a non-invasive ultrasound technique, enabling the determination of end-diastolic diameter and distension (increase in diameter during cardiac cycle) over a long time period. Using this technique we test the hypothesis that low-frequency variations derived from non-invasively determined common carotid artery diameter signals are superior to those derived from non-invasively determined arterial pressure to predict heart rate variability, a method used to assess baroreceptor sensitivity. Moreover, we investigate whether the reduced baroreflex sensitivity in the elderly persists after eliminating the influence of the stiffness of the vessel wall and can be attributed to an impairment of the neural baroreflex pathways. Results The main finding of the present study is that variability in distension rate, i.e. increase in diameter during the cardiac cycle per systolic time interval, of the common carotid artery is a considerably more accurate predictor of R–R interval variability than variability in systolic arterial finger pressure. Moreover, distension rate variability is a more accurate predictor of R–R interval variability than distension and diameter variability. The reduced baroreflex sensitivity in the elderly persists in spite of the elimination of the influence of the stiffness of the vessel wall. Conclusions We conclude that: (1) in the evaluation of baroreceptor sensitivity the assessment of variations in parameters derived from carotid arterial diameter is superior to the assessment of parameters derived from peripheral arterial finger pressure; and (2) conduction by the neural baroreflex pathways deteriorates with age.

Contains fulltext : 154339.pdf (Publisher’s version ) (Open Access) INTRODUCTION: Vagus nerve stimulation (VNS) exerts beneficial anti-inflammatory effects in various animal models of inflammation, including collagen-induced arthritis, and is implicated in representing a novel therapy for rheumatoid arthritis. However, evidence of anti-inflammatory effects of VNS in humans is very scarce. Transvenous VNS (tVNS) is a newly developed and less invasive method to stimulate the vagus nerve. In the present study, we determined whether tVNS is a feasible and safe procedure and investigated its putative anti-inflammatory effects during experimental human endotoxemia. METHODS: We performed a randomized double-blind sham-controlled study in healthy male volunteers. A stimulation catheter was inserted in the left internal jugular vein at spinal level C5-C7, adjacent to the vagus nerve. In the tVNS group (n = 10), stimulation was continuously performed for 30 minutes (0-10 V, 1 ms, 20 Hz), starting 10 minutes before intravenous administration of 2 ng kg(-1) Escherichia coli lipopolysaccharide (LPS). Sham-instrumented subjects (n = 10) received no electrical stimulation. RESULTS: No serious adverse events occurred throughout the study. In the tVNS group, stimulation of the vagus nerve was achieved as indicated by laryngeal vibration. Endotoxemia resulted in fever, flu-like symptoms, and hemodynamic changes that were unaffected by tVNS. Furthermore, plasma levels of inflammatory cytokines increased sharply during endotoxemia, but responses were similar between groups. Finally, cytokine production by leukocytes stimulated with LPS ex vivo, as well as neutrophil phagocytosis capacity, were not influenced by tVNS. CONCLUSIONS: tVNS is feasible and safe, but does not modulate the innate immune response in humans in vivo during experimental human endotoxemia. TRIAL REGISTRATION: Clinicaltrials.gov NCT01944228 . Registered 12 September 2013.