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European Journal of Heart Failure 2008 10(9):884-891; doi:10.1016/j.ejheart.2008.07.016
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© 2008 European Society of Cardiology

Long term vagal stimulation in patients with advanced heart failure First experience in man

Peter J. Schwartza,c,d,e,*, Gaetano M. De Ferraria, Antonio Sanzoa,c, Maurizio Landolinaa, Roberto Rordorfa, Claudia Raineria, Carlo Campanaa, Miriam Reveraa, Nina Ajmone-Marsana, Luigi Tavazzia and Attilio Oderob,c

a Department of Cardiology, Fondazione IRCCS Policlinico San Matteo Pavia, Italy
b Department of Vascular Surgery, Fondazione IRCCS Policlinico San Matteo Pavia, Italy
c Department of Lung, Blood and Heart, University of Pavia Pavia, Italy
d Laboratory of Cardiovascular Genetics, IRCCS Istituto Auxologico Milan, Italy
e Cardiovascular Genetics Laboratory, Hatter Institute for Cardiovascular Research, Department of Medicine, University of Cape Town South Africa

* Corresponding author. Department of Cardiology, Fondazione IRCCS Policlinico S. Matteo, Viale Golgi, 19-27100, Pavia, Italy. Tel.: +39 0382 503567; fax: +39 0382 503002. E-mail address: peter.schwartz{at}unipv.itt (P.J. Schwartz).


   Abstract
Top
 Abstract
1. Introduction
 2. Methods
 3. Results
 4. Discussion
 5. Conclusions
 References
 
Background: Experimentally, vagal stimulation (VS) is protective in chronic heart failure (HF). In man, VS is used in refractory epilepsy but has never been used in cardiovascular diseases. Increased sympathetic and reduced vagal activity predict increased mortality in HF.

Aims: This pilot study assessed feasibility and safety and tested possible efficacy of chronic VS in HF patients.

Methods: We studied 8 patients (mean age 54 years). CardioFit (BioControl Medical), a VS implantable system delivering pulses synchronous with heart beats through a multiple contact bipolar cuff electrode, was used. VS was started 2–4 weeks after implant, slowly raising intensity; patients were followed 1, 3 and 6 months thereafter.

Results: All procedures were successful: as sole surgical side effect, one patient had transient hoarseness. VS was well tolerated, with onlymild side effects (cough and sensation of electrical stimulation). There was a significant improvement in NYHA class, Minnesota quality of life® (from 52±14 to 31±18, p<0.001), left ventricular end-systolic volume (from 208±71 to 190±83 ml, p=0.03), and a favourable trend toward reduction in enddiastolic volume.

Conclusions: This novel approach to the treatment of patients with HF is feasible, and appears safe and tolerable. The preliminary efficacy results appear promising. These findings suggest the opportunity to proceed with a larger multicentre study.

Key Words: Autonomic nervous system • Cardiomyopathy • Heart failure • Vagus nerve

Received June 12, 2008; Revised June 27, 2008; Accepted July 21, 2008


   1. Introduction
Top
 Abstract
 1. Introduction
2. Methods
 3. Results
 4. Discussion
 5. Conclusions
 References
 
The vagal control of the heart has significant potential for the prevention of life-threatening arrhythmias and for modulation of cardiovascular diseases [1]. Increased sympathetic activity and reduced vagal activity are associated with increased mortality both after myocardial infarction and in heart failure [2-6] and further vagal withdrawal has been documented to precede acute decompensation [7].

Experimental studies indicate that increased parasympathetic activity may reduce mortality both during acute myocardial ischaemia, in a chronic canine model for post-infarction sudden cardiac death [8,9] and in a post-ischaemic model of heart failure in the rat [10]. In the latter setting [10] chronic electrical vagal stimulation markedly improved haemodynamics and decreased mortality from 50 to 14%. Also in dogs with intracoronary microembolisation induced heart failure, vagal stimulation improved left ventricular function and this effect was additive to that exerted by β-blockade [11]. Potentiation of vagal reflexes, indicated by increases in baroreflex sensitivity [12] and elicited by exercise training in post-infarction dogs [13] and men [14], was associated with a striking protection from ventricular fibrillation during acute myocardial ischaemia [13] and with improved survival from cardiovascular mortality over a 10-year follow-up [14].

Altogether, these data provide a strong rationale for exploring the potential benefit of direct vagal stimulation in patients with advanced cardiovascular diseases at high risk for cardiac mortality, sudden and non-sudden. Vagus nerve stimulation has been approved and is being frequently used for the treatment of drug-refractory epilepsy [15-17], and more recently also for depression [18,19].

On this basis the present single-centre pilot study was designed with the objective to assess feasibility and safety of vagal stimulation in patients with advanced heart failure. A secondary objective was to collect preliminary information of efficacy.


   2. Methods
Top
 Abstract
 1. Introduction
 2. Methods
3. Results
 4. Discussion
 5. Conclusions
 References
 
The present study was a single-centre single arm interventional phase II feasibility study performed in patients with severe congestive heart failure.

The protocol was approved by the independent Ethical Committee of the Fondazione IRCCS Policlinico San Matteo, Pavia, and every patient signed a written informed consent in order to participate in the study.

2.1. End-points of the study
Since the main goals of the study were safety and feasibility, the primary end-point was the incidence of all adverse events (system or procedure related) during the study. Secondary end-points were the changes vs. baseline of the following parameters: NYHA functional class, quality of life by the Minnesota Living with Heart Failure® questionnaire, exercise capacity (by 6-minute walk), left ventricular end-systolic, end-diastolic volumes, and ejection fraction as well the plasma levels of IL-6.

2.2. Study population
Patients aged 18 to 75 years, with left ventricular ejection fraction <35% and a history of chronic heart failure in NYHA class II-III were eligible for the study. Patients had to be in sinus rhythm, clinically stable for at least 3 months with no change in treatment (with optimised medical therapy) for at least 1 month prior to enrolment.

To be included in the study the patients had to show at a screening Holter ECG an average 24-hour heart rate ≥65 beats/min and/or at least two episodes of HR ≥80 beats/min in the absence of physical exercise and to be capable to perform a 6-minute walk test.

2.3. Exclusion criteria
Exclusion criteria included the presence of acute coronary syndrome, myocardial revascularisation or acute decompensation in the previous 3 months, a previous stroke, severe valvular heart disease, insulin-dependent diabetes mellitus, active peptic disease, asthma or severe chronic obstructive pulmonary disease, glaucoma. Also excluded were patients with a history of atrial fibrillation, patients with 1st degree AV block with PR interval >240 ms, patients with 2nd and 3rd degree AV block, patients with a history of syncope or sustained ventricular tachycardia in the absence of an implanted ICD, patients with severe renal or hepatic failure. Finally, patients with left bundle branch block and/or with an indication for cardiac resynchronisation therapy were excluded.

2.4. Protocol of the study
Patients underwent a baseline examination including full medical history and physical examination, a Holter recording, routine blood tests and the assessment of all parameters described as secondary end-points of the study (quality of life, 6-minute walk, echocardiogram). Thereafter, they underwent implantation of the CardioFitTM 5000 device.

2.5. CardioFitTM system
The CardioFit (model 5000, BioControl Medical Ltd.) is an implantable neuro-stimulator system, capable of delivering low current electrical pulses, with adjustable parameters, to stimulate the vagus nerve. Parameters can be remotely programmed using a dedicated wireless communication system. The stimulator is designed to sense the heart rate (via an intracardiac electrode) and deliver stimulation at a fixed delay (70 ms) from the R wave. The stimulator microprocessor responds to the sensed heart rate and can adjust the stimulation accordingly. Specifically, a bradycardia limit was set at 55 beats/min in order to interrupt vagal stimulation whenever this heart rate limit was reached.

The stimulation lead is an asymmetric bipolar multi-contact cuff electrode specifically designed for cathodic induction of action potentials in the vagus nerve, while simultaneously applying asymmetrical anodal blocks which are expected to lead to preferential, but not exclusive, activation of efferent fibres. The electrode size can be specifically adjusted for each patient, with a selection of 7 different sizes and an internal diameter ranging between 2.0 and 3.5 mm.

2.6. CardioFit implantation procedure
Under local anaesthesia and fluoroscopic visualisation, an intracardiac sensing electrode was positioned at the right ventricular apex using a subclavian puncture. Thereafter, under general anaesthesia, mechanical ventilation was initiated; a longitudinal incision similar but slightly shorter than that of carotid endoarterectomy was used to expose the right vagus. Once the nerve was exposed, an appropriate size for the cuff electrode was determined according to visual inspection and impedance assessment. The vagal electrode was positioned on the cervical vagus approximately 3 cm below the carotid artery bifurcation (see Fig. 1). At this level the vagus consists of a single trunk which includes cardiac and non-cardiac fibres. Both efferent and afferent fibres are stimulated. Positioning around the cervical vagus was confirmed by a brief stimulation test during general anaesthesia that had to document a >10% heart rate reduction. The stimulation lead was then tunnelled under the skin and over the clavicle to join the intracardiac sensing electrode and the stimulator in a subcutaneous pocket in the right subclavicular region. Prior to closure, a continuity test and heart rate reduction by stimulation test were performed to ensure proper device functioning.


Figure 01
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  		Fig. 1 The figure shows a photograph taken in the operating theatre during isolation of the right cervical vagus nerve (A, above) and a schematic representation of the whole system implanted (B, below).

 
2.7. Stimulation up-titration protocol
Two-four weeks after implantation, the device was first activated. Stimulation was started with 1 ms pulse/beat delivered 70 ms after the R wave and an amplitude of 1 mAmp. Pulses were applied intermittently, with an ON time of 2-10 s followed by 6-30 s of OFF time. During the 3-week titration phase consisting of 3-4 visits/week, the current was raised slowly in each visit until the patient reported discomfort and was then set just below this level. Targets were the attainment of either 5.5 mAmp, a heart rate reduction of 5-10 beats or onset of side effects. Stimulation parameters were further fine-tuned during follow-up visits in cases of significant side effects, or sub-optimal heart rate reductions.

2.8. Follow-up
Follow-up visits were conducted 1, 3 and 6 months after the optimisation period. The patients were examined for physical signs and asked for any symptoms or adverse events. In addition, a quality of life questionnaire (the Minnesota Living with Heart Failure® questionnaire) was completed. A full set of evaluations, similar to those performed at baseline were repeated at each visit (including Holter recording), while stimulation was ongoing, except for echocardiography that was performed without stimulation.

Echocardiograms were recorded on an optical disk (System 7, GE, Milwaukee, WI, USA). The data used for the analyses derive from a subsequent off-line blinded evaluation performed by the same investigator (CR). All measurements were performed in triplicate and averaged.

2.9. Statistical analysis
Data are expressed as mean±SD or median and interquartile range for normal and non-normal distributions, respectively. Data on follow-up variables were analysed with ANOVA for repeated measures followed by pre-specified contrasts between baseline and 1, 3 and 6 months or Kruskal-Wallis ANOVA for non-normal data. A p value of 0.05 was considered the limit for significance.


   3. Results
Top
 Abstract
 1. Introduction
 2. Methods
 3. Results
4. Discussion
 5. Conclusions
 References
 
Eight male patients (mean age: 54 years, range: 31-70) were enrolled in this pilot study. Five patients had a cardiomyopathy of ischaemic origin and three suffered from non-ischaemic dilated cardiomyopathy, which was of familial origin in two. Seven of the eight patients were in functional NYHA class III and they all were either on cardiac transplant list, or had contraindications, or had refused it. The average LVEF was 23.8% (range 14-30%). Two patients were diabetic and two were active smokers. The average Body Mass Index was 29.8 (range 22.5-35.3). Table 1 provides a detailed description of the principal clinical characteristics of the enrolled patients.


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  		Table 1 Medical characteristics of the patients at baseline

 
Medical treatment in these eight patients included diuretics and nitrates in all, β-blockers and ACE-inhibitors in 7/8, warfarin in 2/8, statins in 6/8, aldosterone antagonists in 4/8 and angiotensin receptor blockers in 2/8. The only change in therapy during follow-up was represented by minor adjustments in the doses of diuretics.

3.1. Safety and tolerability
The CardioFit implantation two-step procedure (RV lead insertion under local anaesthesia and implantation of the cervical stimulation lead and of the stimulator under general anaesthesia) lasted between 3 and 4 h. Fig. 2 shows a chest X-ray of the implanted system. Patients were discharged from hospital 3-5 days after the intervention on their usual treatment and oral antibiotics. Procedures and recovery were uneventful in all cases, with the exception of a transient mild voice alteration that occurred after the first intervention.


Figure 02
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  		Fig. 2 Chest X-ray after implantation in one patient. The figure allows good visualisation of the stimulator, the vagal electrode and the intracardiac electrode.

 
The intensity of stimulation reached at the end of the titration phase was 4.3±0.9 mAmp (range 2-5.5 mAmp). The up-titration phase of the current amplitude was generally limited by patient's discomfort or pain rather than by attainment of a heart rate reduction >10 beats/min or of an amplitude >5.5 mAmp.

Side effects that were related to the stimulation included: cough in 4 patients, pain at stimulation site in 4 patients, mandibular pain in 3 patients, voice alteration in 2 patients (in addition to the one occurred following surgery and before device activation). These side effects were expected, not severe and all resolved.

In two patients stimulus artefacts on the ECG were not associated with any symptom nor with any sign of device dysfunction. Additional adverse events, mostly unrelated to vagal stimulation, occurred during the 6-month follow-up. One patient had transient episodes of nausea possibly related to the treatment, while episodes of abdominal discomfort with uncertain correlation with the study treatment occurred in two patients. There were two episodes of hypotension, one of thoracic pain, and one syncope which were considered unlikely to be related to the experimental therapy.

The potential for interaction between vagal stimulation with CardioFit and ICD sensing was assessed in two patients who had an ICD implanted either before (one patient) or during the follow-up of the current study (one additional patient). Both patients received a single-chamber ICD (Entrust D 154VRC and Marquis VR 7230, Medtronic) connected to a true bipolar single-coil defibrillation lead (Sprint Fidelis, Medtronic) screwed into the right ventricular septum via left subclavian approach. In one patient vagal stimulation at high intensity was performed (≥10 mAmp) while the patient was on general anaesthesia for defibrillation threshold testing. During vagal stimulation ICD sensitivity was set at 0.3 mV: a significant decrease in heart rate was obtained while no interferences from vagal stimulation were recognized by the ICD nor were detectable on the intracardiac electrogram of the device. During the entire follow-up no episodes of oversensing potentially related to vagal stimulation were identified.

3.2. Clinical effects
Fig. 3 shows the heart rate changes observed during vagal stimulation (10 s ON time: red crosses, 30 s OFF time: blue crosses) in patient # 4. However, a clear heart rate reduction during stimulation at the intensity level that was reached for chronic stimulation was visible only in 3/8 patients. Nonetheless, the resting heart rate during the follow-up visits was significantly, albeit slightly, reduced. Table 2 illustrates the most important clinical variables under study.


Figure 03
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  		Fig. 3 Heart rate observed during vagal stimulation (5.5 mAmp, 10 s ON time: red crosses, 30 s OFF time: blue crosses) in patient # 4. A reduction of almost 10 beats/min, starting from a baseline heart rate of 110 beats/min occurs during the 10 s train of pulses.

 


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  		Table 2 Clinical variables during follow-up

 
The NYHA class was significantly reduced during the study, particularly at months 1 and 3. At 6 months 3/7 class III patients were back in class III presumably due to the extreme severity of their underlying disease. The quality of life, assessed with the Minnesota Living with Heart Failure® questionnaire markedly improved already at month 1 and remained significantly better throughout the entire study. The 6-minute walk test distance was significantly increased. The plasma IL-6 level changes did not reach significance mostly because of the worsening observed in some patients between month 3 and 6 but at 3 months IL-6 had decreased significantly (p<0.02). While no significant change was observed in LV ejection fraction, LV volumes decreased during the follow-up with LV end-systolic volume reaching statistical significance; the individual values throughout the study are shown in Fig. 4.


Figure 04
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  		Fig. 4 Individual values of left ventricular end-systolic volume throughout the study. The overall reduction in volume was statistically significant (p=0.03).

 
As diabetes often alters vagal responsiveness, we repeated the analysis after exclusion of the two diabetic patients. The most important consequence was that, despite the decrease in numbers, the reduction in both end-diastolic and end-systolic LV volumes now reached statistical significance (Table 3). Interestingly, also the changes in IL-6 became highly significant at 3 months when, compared to baseline, these values decreased from 14.1±7.66 to 4.93±4.14 (p=0.02).


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  		Table 3 Clinical variables during follow-up in non-diabetic patients (n=6)

 

   4. Discussion
Top
 Abstract
 1. Introduction
 2. Methods
 3. Results
 4. Discussion
5. Conclusions
 References
 
This is the first human experience of chronic vagal stimulation in patients with heart failure. All of them had a long history of heart failure and no indication for CRT. Seven of the eight patients had a very severe clinical condition. The results in these seriously ill patients indicate that this treatment is feasible and suggest that it is safe, tolerable and possibly beneficial. These preliminary findings in a very small population raise the intriguing possibility that careful modulation of cardiac autonomic activity may soon play a contributory role in the management of selected high risk patients with cardiovascular diseases, especially those with advanced heart failure but possibly also those at risk for recurrent ventricular fibrillation [8,20].

4.1. Side effects and safety
Despite their very poor clinical condition, the surgical procedure was uneventful in all patients. The first four were transferred after surgery in the cardiac intensive care unit to recover, but this was considered not necessary for the subsequent four patients who returned directly to the ward after surgery. The only side effect related to surgery was one case of mild voice alteration (hoarseness) that subsided within 3 weeks and was not due to cordal paralysis as ascertained by laringoscopy.

Two episodes of hypotension occurred in two patients. They were unlikely to be related to the experimental treatment and more likely to be due to the underlying disease, also given the fact that no change in blood pressure occurred during the study. One patient suffered a syncopal episode and was evaluated in the Emergency Room of a different hospital. He was released a few hours later after saline infusion with a diagnosis of dehydration due to intense heat. Thus, we considered this adverse event unlikely to be due to the experimental treatment. On the other hand, side effects were present during, and/or related to, electrical stimulation. Almost every patient reported some discomfort or light pain during the up-titration phase of stimulation. Two distinct categories of side effects related to stimulation were observed. One began with the onset of stimulation and disappeared abruptly with the end of stimulation and included discomfort or light pain at the lateral portion of the neck, in close proximity with the electrode, as well as cough or hoarseness. The other type of side effect was referred pain, generally in the jaw or external ear and built-up slowly in the first few hours after a significant increase in current amplitude occurring during the up-titration phase.

Overall, the side effect frequency and intensity were those expected on the basis of the large experience gathered in patients with epilepsy [15-17].

4.2. Heart rate effects
At variance with what is done with epileptic patients, in whom the stimulated nerve is the left vagus, we chose to stimulate the right vagus. This was done on the basis of the previous successful animal experience [8,10] and because of the greater influence of the right-sided vagus nerve on heart rate [2,21]. We also considered that the heart rate effect could facilitate correct positioning of the stimulating electrode during surgery as well as give us an estimate of the intensity of stimulation reached during follow-up.

To our surprise, the heart rate effect that was obtained at the tolerated current settings was modest, being clearly visible in only three of eight patients. Nonetheless, definite clinical effects were observed during follow-up. Several tenable explanations can account for the presence of clinically appreciable effects during chronic treatment even in the presence of negligible acute effects on heart rate. The presence of a small but significant decrease of baseline heart rate during follow-up may suggest the presence of a trend toward a more favourable sympatho-vagal balance which could be a counterpart of the improvement in the severity of heart failure. However, it is speculatively more tempting to correlate this finding to the demonstration that the diminished parasympathetic control observed in experimental heart failure and attributed at least in part to abnormal ganglionic transmission [22], can be prevented by intermittent pharmacological ganglionic activation [23]. Similarly, electrical vagal stimulation that is sub-threshold, in terms of heart rate lowering effects, could still provide a modest but frequent firing leading to an improvement of the abnormal transmission at the level of the cardiac parasympathetic ganglia.

4.3. Clinical effects
Quality of life improved markedly during the follow-up and the NYHA class decreased significantly. A placebo effect is likely to have contributed to this improvement and some albeit questionable [24] reports of antidepressive effects of vagal stimulation have been published [25]. However, the magnitude of the change, observed in patients with a long history of heart failure and in the absence of pharmacologic change, strongly suggests that a true biological effect also played an important role.

The reduction in left ventricular volumes (significant for systolic volume) also speaks against a pure placebo effect. It is in good agreement with the findings observed with the same nerve stimulating device in the canine model of heart failure [11]. The smaller-than-anticipated reduction in heart rate underlines the fact that both the mechanisms of the apparent beneficial effect and the potential best candidates for this intervention still need to be assessed. For this purpose, we performed an analysis of left ventricular function excluding the two diabetic patients. The rationale to analyse separately diabetic patients lies in the marked parasympathetic dysfunction linked to diabetic neuropathy [26,27]. Evaluation of non-diabetic patients revealed a more evident reduction of left ventricular volumes, as shown in Table 3. The transient decrease in inflammatory markers, such as IL-6 at 3 months, fits with the experimental evidence for an anti-inflammatory activity of vagal stimulation [11,28].


   5. Conclusions
Top
 Abstract
 1. Introduction
 2. Methods
 3. Results
 4. Discussion
 5. Conclusions
References
 
The present pilot study demonstrates the feasibility of chronic vagal stimulation in patients with advanced heart failure; it also suggests that this is a safe procedure with the potential of benefiting some of these seriously ill patients especially for what concerns quality of life, functional class and left ventricular volumes. This novel therapeutic approach, which interacts with the autonomic nervous system with the goal of modulating the neural control of the heart to favourably modify the evolution of advanced heart failure, appears promising and warrants further investigation.


   Acknowledgements
 
We are grateful to Dr. Omry Ben-Ezra, CardioFit Medical Manager, to Drs. Stefano Pirrelli, Maurizio Lovotti, Guido Bellinzona and Giulia Ticozzelli for their help in performing the surgical procedures, to Dr. Giuliana Piccoli for her help in patients management, to Dr. Mara De Amici for laboratory determinations, and to Pinuccia De Tomasi, BS, for her expert editorial support.

Funding sources and disclosure of interest: The study was sponsored by BioControl Ltd., Yehud, Israel. PJS and GMDF served as consultants to BioControl and are members of the Steering Committee of an ongoing multicentre international trial on vagal stimulation in heart failure.


   References
Top
 Abstract
 1. Introduction
 2. Methods
 3. Results
 4. Discussion
 5. Conclusions
 References
 

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Cardiac autonomic neural remodeling and susceptibility to sudden cardiac death: effect of endurance exercise training
Am J Physiol Heart Circ Physiol, October 1, 2009; 297(4): H1171 - H1193.
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 CirculationHome page
J. C. Lopshire, X. Zhou, C. Dusa, T. Ueyama, J. Rosenberger, N. Courtney, M. Ujhelyi, T. Mullen, M. Das, and D. P. Zipes
Spinal Cord Stimulation Improves Ventricular Function and Reduces Ventricular Arrhythmias in a Canine Postinfarction Heart Failure Model
Circulation, July 28, 2009; 120(4): 286 - 294.
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 Eur J Heart FailHome page
J. G.F. Cleland, A. P. Coletta, A. L. Clark, and D. Cullington
Clinical trials update from the American College of Cardiology 2009: ADMIRE-HF, PRIMA, STICH, REVERSE, IRIS, partial ventricular support, FIX-HF-5, vagal stimulation, REVIVAL-3, pre-RELAX-AHF, ACTIVE-A, HF-ACTION, JUPITER, AURORA, and OMEGA
Eur J Heart Fail, June 1, 2009; 11(6): 622 - 630.
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