Abstract:
A medical device includes a VNS pulse burst generator for stimulation of the vagus nerve, and a controller for analyzing the cardiac rhythm. It further includes a sequencer that uses an estimator to calculate during a given cycle an estimate of the temporal position of the R wave of the next cycle. The controller is configured to define the moment of application of the VNS pulse burst as an instant corresponding to the estimate minus a predetermined advance delay. VNS therapy is thus delivered in a non-vulnerable period, near the end of the period of natural ventricular escape.

Description:
CROSS-REFERENCE TO RELATED APPLICATION 
     This application claims the benefit of and priority to French Patent Application No. 1353777, filed Apr. 25, 2013. French Patent Application No. 1353777 is hereby incorporated by reference in its entirety. 
     BACKGROUND 
     The invention relates to “active implantable medical devices” as defined by Directive 90/385/EEC of 20 Jun. 1990 the Council of the European Communities. The invention relates to implants for delivering vagus nerve stimulation therapies, which have been called “VNS” therapies (Vagus Nerve Stimulation). 
     Stimulation of the vagus nerve affects cardiovascular function by reducing the heart rate and myocardial contractility with decreased duration of diastole. These effects can help reduce the progression of cardiac remodeling that may lead heart failure. 
     In general, the vagus nerve can be stimulated asynchronously or synchronously (e.g., with the heartbeat). In the first case, the device may simply include a lead provided with an electrode implanted on the vagus nerve and of a generator delivering VNS pulses on this electrode. In this configuration there is no possible interference between the VNS electronics and a cardiac lead. 
     In contrast, in the case of a synchronous stimulation, for example, the device further includes one or more cardiac leads. For example, such a device may include one or more endocardial lead or one or more lead implanted in the coronary network for the collection of the cardiac depolarization waves. Such a device may optionally deliver myocardial stimulation pulses (stimulation of ventricular and/or atrial cavities) using electrodes in the heart, in addition to the VNS stimulation applied separately on the vagus nerve. 
     U.S. 2012/0303080 A1 and U.S. 2007/0233194 A1 disclose devices for synchronous stimulation of the vagus nerve. In this configuration of synchronous VNS stimulation, pacing should be delivered in a non-vulnerable period of the ventricle. 
     Particularly, if we consider an electrocardiogram ECG surface or endocardial electrogram EGM, among the different waves representative of the PQRST complex of the cardiac activity, it is known that during the QRS (ventricular depolarization) and the subsequent T wave (ventricular repolarization) the heart is in a refractory period. This ventricular refractory period includes a period called “absolute refractory period” during which no electrical stimulation will have an effect on cardiac cells, followed by a period called “relative refractory period” during which stimulation may excite some heart fibers and induce ventricular arrhythmia. 
     In the case of stimulation of the vagus nerve and in the case of a system with a ventricular lead, it is commonly accepted that VNS stimulation delivered during the relative refractory period of the ventricle is potentially harmful because charges that could be accumulated on the electrode may trigger ventricular arrhythmias. Stimulation should therefore be avoided during this period. Thus, US 2012/0303080 A1 and US 2007/0233194 A1, cited above disclose synchronizing the application of the VNS pulse burst on the detection of the R wave, in order to apply these pulses during the absolute ventricular refractory period which immediately follows this wave. Despite these prior art devices, it remains challenging and difficult to safely synchronize VNS and heart stimulation treatments. 
     SUMMARY 
     An embodiment of the invention is a device configured to deliver VNS stimulation in a period other than the absolute ventricular refractory period and yet without risks of arrhythmia. 
     The device uses a period corresponding to the end of natural the escape interval of the ventricle, located after the T wave (i.e. way beyond ventricular refractory periods) at a time corresponding to appearance of the atrial depolarization wave (P wave) of the next cardiac cycle. This device may operates with success given that i) the spontaneous activity of the vagus nerve is mainly concentrated in the PQ cardiac interval and ii) the area before the natural ventricular depolarization, typically in a window of a few tens of milliseconds before spontaneous activity thereof, may be regarded as a non-vulnerable period, that is to say not capable of generating arrhythmias. 
     To determine the time of application of the VNS therapy in this temporal window, one solution would be to have a lead for detecting atrial depolarization, to detect the onset of the P wave, and to synchronize the beginning of the delivery of the VNS pulse burst on this detection. Such a solution would, however, be complicated to implement, requiring the implantation of a lead with atrial sensing electrodes, and an adaptation of the generator, with an additional connector, dedicated internal circuits, etc. In other words, this would be a device that is a “dual chamber” stimulator. 
     One aim of the invention is to provide a solution to this problem, with a VNS pacemaker synchronized to the atrial signal but that does not require physical means for detecting atrial depolarizations, including an additional lead for detecting the P wave on which the VNS stimulation could be synchronized. The invention can thus advantageously be implemented using circuits of a “single chamber” stimulator, supplemented by VNS pulse bursts triggered by appropriate sequencer operating using inputs from a single ventricular sensing lead. 
     To this end, the invention provides a device including a generator generating VNS pulse bursts. The device further includes a circuit for analyzing the cardiac rhythm collecting a signal representative of the cardiac electrical activity, including analyzing an endocardial electrogram EGM signal and determining the duration of successive cardiac cycles. The device further includes a VNS sequencer configured to determine a moment of application of a VNS pulse burst by the generator. The VNS sequencer may include an estimation module calculating, during a given cycle, an estimate of the temporal position of the R-wave cycle of the following cycle. The sequencer can be configured to set the application time of the VNS pulse burst as being a time corresponding to the calculated estimate of the temporal position of the R-wave, anticipated by an estimated advance delay. 
     In a particular embodiment, the analysis of the cardiac rhythm further calculates an average duration and optionally a standard deviation, of the cardiac cycles over a predetermined period or over a predetermined number of cycles. The device can use such analysis of the cardiac rhythm to calculate the advance delay from the duration of the previous cardiac cycles. This may help accurately reflect the variability and evolution in the cardiac rhythm. 
     A module for analyzing the cardiac rhythm may calculate an average duration of the cardiac cycles over a predetermined period or a predetermined number of cycles, and the VNS sequencer may calculate the estimate of the temporal position of the R wave according to both said average duration and advance delay. 
     The device may further include a module for detecting spontaneous ventricular events, and can interrupt the delivery of pulses produced by the generator in the event of occurrence of a spontaneous ventricular event subsequent to the instant of application of the VNS pulse burst. It is also possible to provide means for delivering a ventricular pacing pulse in the absence of occurrence of a spontaneous ventricular event at the expiration of a predetermined escape interval. 
     One embodiment relates to a device having a VNS pulse burst generator for stimulation of the vagus nerve, and electronics analyzing cardiac rhythm. It further includes sequencer having an estimation module for calculating, during a given cycle, an estimate (R prev ) of the temporal position of the R wave of the next cycle. The sequencer can then define the moment (TVNS) of application of the VNS pulse burst as an instant corresponding to this estimate (R prev ) adjusted by a predetermined advance delay (Δ VNS ). VNS therapy is thus delivered in a non-vulnerable period, near the end of the period of natural ventricular escape. 
    
    
     
       BRIEF DESCRIPTION OF THE FIGURES 
         FIG. 1  is an overview presentation of the device, showing the generator, the myocardium, the vagal nerve and the leads used, according to an exemplary embodiment. 
         FIG. 2  is a schematic block view corresponding to the main features of the generator of the device, according to an exemplary embodiment. 
         FIG. 3  is a prior art timing diagram showing, in two successive cardiac cycles, the cardiac depolarization wave with its different characteristic periods and the instants of application of the VNS pulse bursts. 
         FIG. 4  is a counterpart of  FIG. 3 , presenting the advantageous technique of the present invention, according to an exemplary embodiment. 
         FIG. 5  is a timing diagram illustrating the variability in the RR interval in a series of consecutive cardiac cycles. 
         FIGS. 6 a  to 6 c    are timing diagrams illustrating the method to determine the instant of application of the VNS stimulation pulses according to the technique of the invention in different situations, respectively: with (a) a normal detection of consecutive R wave, (b) with detection of a premature R wave, and (c) without detection of a consecutive R wave. 
         FIG. 7  is a flow diagram a method for providing VNS therapy according to an exemplary embodiment. 
     
    
    
     DETAILED DESCRIPTION 
     According to various exemplary embodiments, a pacemaker includes a programmable microprocessor provided with circuits for shaping and delivering stimulation pulses to implantable electrodes. The pacemaker may include appropriate programming code (e.g., executable code) for adjusting the VNS stimulator according to the activities described herein. In other words, the algorithms described herein may be contained in computer readable media (e.g., non-transient computer readable media) of the pacemaker device and executed by a microcontroller or a digital signal processor of the pacemaker. For the sake of clarity, the various processing applied will be broken down and diagrammed by a number of different functional blocks in the form of interconnected circuits, however this representation is only illustrative, these circuits having common elements and in practice corresponding to a plurality of functions overall performed by a single software. 
     In  FIG. 1 , a device includes a housing of an implantable generator  10  for vagus nerve stimulation. This stimulation is delivered by a lead  12  bearing at its distal portion an electrode implanted on the vagus nerve  14  for stimulation of the latter by application of train pulses produced by the generator  10 . To allow delivery of VNS pulses in synchronism with the cardiac rhythm, the generator  10  also has a cardiac lead  16  provided at its distal end of an electrode  18  for collecting the electrical activity of the myocardium  20 . This lead collects EGM endocardial electrogram signals that will drive the generator  10  so that it delivers to the vagus nerve  14  VNS stimulation pulses at the same rate as the heart beats and at the most appropriate moment of the cardiac depolarization wave. It should be noted that the use of an endocardial EGM may be substituted for other monitoring techniques suitable for obtaining a signal representative of the cardiac electrical activity. 
       FIG. 2  schematically illustrates the features of the generator  10  of the device of the invention. The generator  10  includes a generator circuit  22  configured to produce bursts of VNS pulses delivered to the vagus nerve via the lead  12 . The generator circuit  22  is controlled by a control circuit  24 . An input to the control circuit is the EGM signal gathered by the lead  16 . 
       FIG. 3  illustrates a prior art example, on two consecutive cardiac cycles, of the cardiac depolarization wave an EGM collected with successively the different representative waves of the cardiac activity: P-wave (depolarization of the atria), QRS (depolarization of the ventricles) and T wave (repolarization of the ventricles). 
     During the phase of ventricular activity QRST, the heart is in refractory period with an absolute refractory period PRA during which no excitement, including any electrical stimulation, will act on cardiac cells, followed by a relative refractory period PRR during which an excitation may cause depolarization of certain cardiac fibers. If a VNS therapy has to be delivered in the form of a burst of electrical pulses, the instant T VNS  of delivery of this burst, and the number and duration of pulses of the burst are often all delivered during the absolute refractory period PRA. This is to avoid triggering ventricular arrhythmia due to a potential ventricular capture by local current fields that may cause deleterious effects, which could occur if the VNS pulses were delivered during the relative refractory period PRR. To meet this requirement, certain prior art stimulation techniques operate in the manner illustrated in  FIG. 3 , in synchronizing the instant T VNS  of the beginning of the burst of VNS pulses relative to the detection of the R wave, i.e. the moment when the detection lead collects spontaneous activity having its origin in the ventricle. Specifically, in U.S. 2012/0303080 A1 cited above, the therapy delivery is calculated based on the PP interval, while in U.S. 2007/0233194 A1 also cited above, VNS stimulation is delivered with a predetermined delay calculated based on the R-wave. 
     The invention proposes to operate differently, delivering VNS therapy during another period of the cardiac cycle, located outside the natural ventricular refractory periods, particularly outside the relative refractory period PRR, and without risk of arrhythmia. 
     As shown in  FIG. 4 , a VNS therapy is caused at the end of the natural escape interval of the ventricle, corresponding to an atrial non vulnerable PNVA period during which the P wave of atrial depolarization happens, well before the activity phase of the ventricle (QRST complex). 
     Even if the implant does not have the capability to accurately detect the atrial activity, the device may estimate the temporal position of the next ventricular wave and time the delivery of VNS stimulation relative to this estimated position. To do this, as shown in  FIG. 5 , the device follows the ventricular activity and determines the moments R of collection of spontaneous ventricular activity. Based on these detections, the device calculates the average ventricular period RR moy  and its variability, corresponding to the standard deviation ET RR  of the parameter RR. 
     Depending on RR moy , and optionally also on ET RR , the device calculates an estimate interval RR prev , for example by a function of the type:
 
 RR   prev   =RR   moy   −α·ET   RR .
 
     If α=1, it is estimated that 85% of the RR cycles are longer than RR prev , in the case of a Gaussian distribution of the RR intervals. This allows obtaining an estimated temporal position R prev  of the R wave of the next cycle. 
     As shown in  FIG. 6 a   , the instant T VNS  of application of the VNS pulse burst will be determined from this estimated R prev , anticipated of an advanced period Δ VNS , typically of the order of ET RR  (if α=1). 
     In the normal case (shown in  FIG. 6 a   ), the delivery of VNS therapy is followed by the detection of spontaneous activity DetR, in principle close to the estimated position R prev . 
     In the case (shown in  FIG. 6 b   ) of a premature spontaneous activity DetR such that it occurs at a time when the VNS pulse burst has not finished being delivered, the device immediately stops this delivery to avoid stimulation during a ventricular refractory period. 
     In another case (shown in  FIG. 6 c   ) wherein no spontaneous ventricular event has been detected at the end of the ventricular escape interval IEV (interval counted from the previous R detection), then a ventricular stimulation StimV is delivered by the device. 
       FIG. 7  is a flowchart describing the sequence of different actions that has just been described. Upon detection of a ventricular activity DetR (test  26 ), the device calculates or recalculates the values of the interval RR moy  and of the standard deviation ET RR  (block  28 ). 
     If VNS stimulation should be applied (test  30 ), then the device estimates the expected duration of the next RR interval from the mean and standard deviation of the preceding RR intervals (block  32 ). VNS therapy is then applied, by triggering the delivery of VNS pulse bursts according to the estimated instant, determined in the previous step, of the temporal position of the next R wave (block  34 ). 
     If during the delivery of the pulse burst ventricular depolarization DetR is detected (test  36 ), then this delivery is interrupted and the method is reset (back to test  26 ). Otherwise, the delivery of the VNS therapy is continued until the last pulse of the burst, and the method is repeated (back to block  28 ). Upon arriving at the end of the VNS therapy (test  38 ), the method may be fully reset (back to test  26 ). In any case, in the absence of detection DetR (test  26 ) at the end of the ventricular escape interval IE (test  40 ), a ventricle stimulation StimV (see  FIG. 6( c ) ) is delivered to the device (block  42 ).