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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?

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?.

The cardiovascular system can be influenced by electrically stimulating the vagal nerve. Selectivity for specific cardiac fibers may be limited when stimulating at the cervical level. Our objective was to increase effectiveness and selectivity for cardiovascular effects of vagal nerve stimulation by using local bipolar stimulation in one nerve cross section using a multi-contact cuff instead of less localized stimulation using a tripolar ring electrode. Both types of cuff electrodes were compared with respect to their relative effects on R-R interval (RRI), P-Q interval (PQI), left ventricular contractility (LVC), and left ventricular pressure (P(LV)) in seven pigs. Stimulation using the optimal bipolar configuration on the multi-contact cuff significantly affected RRI, PQI, LVC, and P(LV), whereas stimulation with the ring electrode only significantly affected RRI and PQI. The cardiovascular parameters that could be significantly influenced varied between the bipolar configurations. These novel findings may be relevant for optimizing electrode configurations for clinical cardiac applications of vagal nerve stimulation.

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.

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)

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.

In a variety of conditions excessive and/or persistent activation of the innate immune system has detrimental effects. In animals, electrical vagus nerve stimulation (VNS) inhibits the innate immune response in models of endotoxemia (administration of lipopolysaccharide [LPS]), sepsis, trauma, and hemorrhagic shock, via the so-called cholinergic anti-inflammatory pathway. However, human in vivo evidence is lacking. Up till now, VNS was possible through implantation of a cuff electrode wrapped around the nerve, which limits its use in acute inflammatory situations frequently encountered on the ICU. A novel, less invasive VNS method is transvenous VNS (tVNS).

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.

1. The influence of mean pulmonary arterial pressure (mean P(pa)) on dynamic (C(d)) and pseudostatic compliance (C(ps)) of the pulmonary artery was studied at a constant and a changing heart rate. C(d) is the change in cross-sectional area (CSA) relative to the change in P(pa) throughout a heart cycle. C(pa) is the change in mean CSA relative to the change in mean P(pa). If C(d) is known, pulmonary blood flow can be computed from the P(pa) using a windkessel model. We investigated whether C(ps) can be interchanged with C(d). 2. In nine anaesthetized pigs, we determined the mean CSA and C(d) of the pulmonary artery at various P(pa) levels, ranging from approximately 30 to 10 mmHg, established by bleeding. Two series of measurements were carried out, one series at a spontaneously changing heart rate (n = 9) and one series at a constant heart rate (n = 6). To determine CSA a conductance method was used. 3. C(ps) depended on pressure. The mean CSA versus mean P(pa) curves were sigmoid and steepest in the series with the increasing heart rate (established by bleeding). The CSA versus P(pa) loop during a heart cycle, giving C(d), was approximately linear and almost closed. The C(d) versus mean P(pa) relationship was bell shaped. Its width was smaller if the heart rate increased during the series of measurements. The pressure, where C(d) was maximum, was higher at higher heart rates. Furthermore, the maximum C(d) was not affected by the heart rate. 4. Because the pulmonary artery constricts with increasing heart rate, C(ps) will be overestimated during procedures where heart rate increases. C(d) should be determined on a beat-to-beat basis to calculate flow because it changes with mean pulmonary arterial pressure and heart rate.

A double indicator dilution technique for determining the mean cross-sectional area (CSA) of a blood vessel in vivo is presented. Analogous to the thermodilution method, dilution of hypertonic saline was measured by an electrical conductance technique. Because the change in conductance rather than absolute conductance was used to calculate CSA, pulsatile changes in shear rate of blood and conductance of surrounding tissues had no effect on the data. To calculate CSA from an ion mass balance, cardiac output was needed and estimated from the thermodilution curve using the same "cold" (hypertonic) saline injection. The mean CSA, obtained from this double indicator dilution method (CSAGD), was compared with the CSA obtained from the intravascular ultrasound method (IVUS) in 44 paired observations in six piglets. The regression line is close to the line of identity (CSAGD = -1.83 + 1.06 . CSAIVUS, r = 0.96). The difference between both CSAs was independent of the diameter of the vessel, on average -0.99 mm2 +/- 2.64 mm2 (mean CSAGD = 46.84 +/- 8.21 mm2, mean CSAIVUS = 47.82 +/- 9.08 mm2) and not significant. The results show that the double indicator dilution method is a reliable technique for estimating the CSA of blood vessels in vivo.

Background Application of the Stewart-Hamilton equation in the thermodilution technique requires flow to be constant. In patients in whom ventilation of the lungs is controlled, flow modulations may occur leading to large errors in the estimation of mean cardiac output. Methods To eliminate these errors, a modified equation was developed. The resulting flow-corrected equation needs an additional measure of the relative changes of blood flow during the period of the dilution curve. Relative flow was computed from the pulmonary artery pressure with use of the pulse contour method. Measurements were obtained in 16 patients undergoing elective coronary artery bypass surgery. In 11 patients (group A), pulmonary artery pressure was measured with a catheter tip transducer, in a partially overlapping group of 11 patients (group B), it was measured with a fluid-filled system. For reference cardiac output we used the proven method of four uncorrected thermodilution estimates equally spread over the ventilatory cycle. Results A total of 208 cardiac output estimates was obtained in group A, and 228 in group B. In group B, 48 estimates could not be corrected because of insufficient pulmonary artery pressure waveform quality from the fluid-filled system. Individual uncorrected Stewart-Hamilton estimates showed a large variability with respect to their mean. In group A, mean cardiac output was 5.01 l/min with a standard deviation of 0.53 l/min, or 10.6%. After flow correction, this scatter decreased to 5.0% (P < 0.0001). With no bias, the corresponding limits of agreement decreased from +/- 1.06 to +/- 0.5 l/min after flow correction. In group B, the scatter decreased similarly and the limits of agreement also became +/- 0.5 l/min after flow correction. Conclusion It was concluded that a single thermodilution cardiac output estimate using the flow-corrected equation is clinically feasible. This is obtained at the cost of a more complex computation and an extra pressure measurement, which often is already available. With this technique it is possible to reduce the fluid load to the patient considerably.

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)

INTRODUCTION Drug therapy to reduce the ventricular rate during atrial fibrillation (AF) is effective in only 50% of the patients and limited by side effects. Currently available pacing algorithms are even less effective. The aim of this study was to test the feasibility of chronic AV-Node Inhibition (AVNI) by intra-cardiac parasympathetic nerve stimulation. Our ultimate goal is to develop a pacemaker device with a feature to inhibit AV node function to decrease ventricular rate during AF. METHODS Leads were implanted in the right atrial appendage and right ventricular apex and connected to a pacemaker for AF induction. In addition, an atrial lead (’AVNI lead’) connected to an implantable high frequency neurostimulator was implanted at a site with a strong prolongation of the PQ-time. Immediately after implantation optimal settings, optimal location, acute effects of AVNI on ventricular rate and the possible pro-arrhythmic effects of AVNI were assessed. The ’safety window’ for AVNI was defined as the difference between the output at the AVNI lead that produced atrial capture and the output that produced AVNI. One week after implantation, AF was maintained for one week by burst pacing via the lead in the right atrial appendage. After this 2 week period, the chronic effects of AVNI were assessed weekly for periods ranging from 3 weeks to 7 months. RESULTS In total, 5 goats were studied . The optimal location for AVNI was located at the junction of the coronary sinus and inferior vena cava. Optimal AVNI was found at a stimulation frequency of 30Hz and pulse width of 180 μs in each animal. During the implant procedure “a safety window” appeared to be present. However, it became smaller after a longer period of AVNS. The acute effect of AVNI (averaged over the experiments) was a prolongation of the median R-R interval of 37 % (SD = 21%), which was not significantly different from the chronic effect at the end of the study (average = 32% (SD = 18%). CONCLUSIONS Chronic intra-cardiac AV-node inhibition to reduce the ventricular rate during AF is feasible. Atrial pro-arrhythmic effects can be avoided by optimization of the stimulus parameters and location.

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.

An ultrasound technique to assess velocity and shear distribution in arteries noninvasively was developed . Accurate assessment of velocities close to the wall, a prerequisite for reliable determination of WSR, is achieved by tracking of the arterial wall and adaptive filtering of the wall signal. Velocity (v) distribution in the vessel is obtained by RF cross correlation of the signals in between the walls, and determination of dv/dr throughout the cardiac cycle provides shear distribution. Maximum dv/dr near the wall is taken as peak WSR and average shear over the cardiac cycle as mean WSR. Wall shear stress (WSS) is estimated by multiplying WSR by whole blood viscosity. The system also allows assessment of arterial diameter, diameter changes, and intima‐media thickness (IMT). In studies on humans it could be shown that at a younger age in the common carotid artery (CCA) MWSS is close to 1.5 Pa, a value in agreement with minimal expenditure of energy. MWSS, however, is not optimally regulated, because it decreases with age. In the CCA, WSR close to the bifurcations were lower than and associated with larger IMT than more upstream. Reflections from downstream are held responsible for these differences in WSR.

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.