Patent Publication Number: US-2021177350-A1

Title: Implantable medical system for measuring a physiological parameter

Description:
CROSS-REFERENCE TO RELATED PATENT APPLICATIONS 
     This application claims the benefit of and priority to French Patent Application No. 1913677, filed Dec. 3, 2019, which is incorporated by reference herein in its entirety. 
     BACKGROUND 
     The present invention relates to an implantable medical system configured to carry out a measurement of a physiological parameter. 
     Impedance cardiography is a known technique for measuring physiological parameters, in particular haemodynamic parameters. 
     Impedance cardiography may be used for non-invasive measurements using an external device coupled to surface electrodes. 
     In the case of an implantable medical system, it is known that cardiographic impedance measurements are carried out by supplying current and measuring the voltage between two electrodes of the same lead. The prior art document US 2019/0111268 A concerns such a local impedance measurement between two electrodes of the same subcutaneous lead. The document US 2019/0111268 A proposes detecting a problem with the cardiac rhythm, more precisely cardiac arrhythmia, on the basis of cardiac events identified from an electrical signal. 
     However, it is known that problems with cardiac rhythm, such as cardiac arrhythmia, corresponding to an abnormal variation in the rhythm of the beats of the heart which affect its proper function, can be distinguished from cardiac insufficiency, which is the lack of ability of the heart to pump a sufficient quantity of blood to ensure a sufficient flow of blood throughout the body. 
     Cardiac insufficiency may affect only part of the heart, or all of it. Cardiac insufficiency is a chronic and progressive change, which is generally slow, which may take place over a number of years. 
     It has been shown that the detection of cardiac events as described in US 2019/0111268 A for identifying a cardiac rhythm problem is not suitable for monitoring cardiac insufficiency (also known as heart failure). In fact, the impedance measurement proposed in the document US 2019/0111268 A is relative to a local measurement between two electrodes of the same lead, which makes it less sensitive to pulmonary activity and to the circulation of blood in the neighboring organs. However, respiratory and haemodynamic information relating to pulmonary activity and to the circulation of blood in the neighboring organs is also information which is useful to diagnosis and to monitoring cardiac insufficiency. 
     Thus, the aim of the present invention is to improve and optimize the diagnosis and monitoring of cardiac insufficiency. 
     The aim of the present invention is achieved by means of an implantable medical system for measuring at least one physiological parameter, comprising at least one dipole emitter formed by two electrodes connected to a generator and configured in order to emit an electrical signal; at least one dipole receiver formed by two electrodes, each being distinct from the electrodes of the dipole emitter, the dipole receiver being configured to capture the electrical signal emitted by means of the dipole emitter; and an analysis module comprising at least one amplifier, an envelope detector and an analogue-to-digital converter and a processing means for processing the electrical signal captured by means of the dipole receiver; and a detection means configured to produce an electrocardiogram or an electrogram; the analysis module furthermore being configured to combine the processed electrical signal and the electrocardiogram or the electrogram in order to determine therefrom a parameter which is representative of a pre-ejection period. 
     The fact that the system has at least four electrodes, so that the dipole emitter is distinct from the dipole receiver, means that a more complete measurement of impedance can be obtained which is thus more representative of the surrounding medium, in particular more complete and more representative of the surrounding medium than a measurement between only two electrodes of the same lead. In fact, the present system can be used to recover physiological mechanical information by means of the two dipoles by analyzing the received and processed electrical signal the amplitude of which has been modulated as a function of the electrical properties of the propagation medium between the dipole emitter and the dipole receiver. 
     Thus, a parameter which is representative of a pre-ejection period may be extracted from the attenuation of the voltage between the dipole emitter and the dipole receiver by taking the electrocardiogram or the electrogram into account. The determination of the parameter which is representative of a pre-ejection period provides an indicator which is adapted to the diagnosis and monitoring of cardiac insufficiency. 
     SUMMARY 
     The present invention may be further improved by means of the following embodiments. 
     In accordance with one embodiment, the analysis module may be configured to extract from the processed electrical signal a variation in volume and/or a variation in pressure as a function of time proportional to a drop in voltage between the dipole emitter and the dipole receiver. 
     The determination of the variation in the volume of the heart and the lungs can advantageously be used to recover haemodynamic and respiratory information from the same processed electrical signal. The determination of the variation in the volume of the heart may be used to identify opening of the aortic valve. 
     In accordance with one embodiment, the determination of the pre-ejection period may comprise the detection of the R wave or the Q wave of a QRS complex captured by the detection means. 
     The onset time for the Q wave or the R wave is a parameter which is necessary in order to be able to determine the pre-ejection period. 
     Considering an electrocardiogram, the onset time for the Q wave may be identified from the R wave of the QRS complex because the R wave is more dominant than the Q wave (the R peak having a greater amplitude than that of the Q peak), and thus is easier to detect than the Q wave. 
     The detection of the R wave per se may also be used as an indicator of the onset time for the pre-ejection period and thus can be used to reduce the complexity of the analysis module of the system which is necessary for the identification of the Q wave. Detection of the R wave may be carried out from an electrocardiogram or an electrogram. 
     In accordance with one embodiment, the analysis module may be capable of also monitoring a parameter which is representative of the efficacy of a therapy by taking into account a parameter which is representative of a pre-ejection period. 
     The analysis module of the present system is thus capable of evaluating a haemodynamic parameter such as the ejection fraction or the ejection volume, which are parameters that can be used to evaluate cardiac performance. Thus, the present system is even better adapted to monitoring cardiac insufficiency and the prescribed therapy. 
     In accordance with one embodiment, the two electrodes of the dipole receiver may be configured to simultaneously capture the emitted electrical signal and an electrocardiogram or an electrogram. 
     Thus, the same electrodes may act both as detecting electrodes and as the dipole receiver. Thus, the dipole receiver has a dual function, which means that the system can be optimized, by reducing the number of electrodes which are necessary. 
     In accordance with one embodiment, the activation of the analysis module may be triggered by the detection of at least one peak of a PQRST complex captured by the detection means. 
     Thus, the energy consumption of the system may be reduced by limiting the period during which the analysis module of the system is activated. Advantageously, the analysis module may, for example, be activated during a window of time which may start from detection of at least one peak of the PQRST complex. 
     In accordance with one embodiment, the system may comprise a means which is capable of detecting a mechanical activity of the heart from an acoustic signal which is representative of the sounds of the heart and in which the analysis module may be configured in order to compare said acoustic signal with the processed electrical signal. 
     The acoustic signal can be used to reveal the mechanical activity of the cardiac valves. The analysis of the various types of signals can be used to characterize them better and to highlight information which is useful in monitoring cardiac insufficiency. 
     For this reason, the system is configured in order to detect and capture the acoustic activity of the heart. The information relative to the acoustic activity that is thus captured may be used in order to correlate the processed electrical signal captured by the analysis module of the system. 
     In accordance with one embodiment, the system may comprise a first implantable medical device provided with the dipole emitter, and a second implantable medical device which is distinct from the first implantable medical device and is provided with the dipole receiver. 
     Thus, it is possible to obtain a measurement of impedance which is more complete and thus is more representative of the surrounding medium, in particular more complete and more representative of the surrounding medium than a measurement between only two electrodes of the same lead. In fact, the dipoles are coupled together galvanically and an electric field is propagated through the human body from the dipole emitter to the dipole receiver. The electrical signal received by the dipole receiver is then modulated in amplitude. By demodulating the received signal, it is possible to recover at least one physiological parameter from which a parameter which is representative of a pre-ejection period may be defined. 
     In accordance with one embodiment, one of the first implantable medical device or the second implantable medical device may be a subcutaneous implantable cardioverter defibrillator or an event recorder; and the other of the first implantable medical device or the second implantable medical device may be an implantable endocardial device. 
     Thus, the electric field emitted by the dipole emitter is propagated through a channel which can recover both haemodynamic and respiratory information. The present implantable medical system for measuring at least one physiological parameter is therefore configured in order to use pre-existing implantable medical devices, i.e. devices which have a supplemental function in addition to the determination of a parameter which is representative of a pre-ejection period, such as a defibrillation function. 
     In accordance with one embodiment, the implantable endocardial device may be a leadless cardiac pacemaker. 
     A leadless cardiac pacemaker can be used to make an implantation procedure less invasive than implantable devices with a lead. Thus, a leadless cardiac pacemaker can be used to avoid complications linked to transvenous lead and to the subcutaneous pulse generator used in conventional cardiac pacemakers. 
    
    
     
       BRIEF DESCRIPTION OF THE DRAWINGS 
       The invention and its advantages will now be explained in more detail below by means of preferred embodiments, in particular made with reference to the accompanying figures, in which: 
         FIG. 1  represents a diagrammatic view of an implantable medical system in accordance with the present invention; 
         FIG. 2  represents a diagrammatic view of the propagation of an electrical signal between a dipole emitter and a dipole receiver in accordance with the present invention; 
         FIG. 3  represents the integration of the implantable medical system in accordance with the present invention into a subcutaneous implantable device; 
         FIG. 4  represents the integration of the implantable medical system in accordance with the present invention into a multi-device system; 
         FIG. 5  represents an electrocardiogram and a processed electrical signal obtained by the implantable medical system in accordance with the present invention integrated into the multi-device system of  FIG. 4 ; 
         FIG. 6  shows a correlation between the processed electrical signal obtained by the implantable medical system in accordance with the present invention integrated into the multi-device system of  FIG. 4  and graphs representing the pressure variations in the left ventricle and the aorta; 
         FIG. 7  shows a correlation between the processed electrical signal obtained by the implantable medical system in accordance with the present invention integrated into the multi-device system of  FIG. 4  and a graph representing the variations in volume of the left ventricle; and 
         FIG. 8  represents an electrocardiogram, a phonocardiogram, and electrical signals obtained by the implantable medical system in accordance with the present invention integrated into the subcutaneously implantable device of  FIG. 3 . 
     
    
    
     DETAILED DESCRIPTION 
     The invention will now be described in more detail using advantageous embodiments by way of example and with reference to the figures. The embodiments described are simply configurations which are possible and it should be borne in mind that the individual features as described above may be provided independently of each other or may be omitted altogether when carrying out the present invention. 
       FIG. 1  illustrates an implantable medical system  10  in accordance with the present invention. In addition, the lower portion of  FIG. 1  illustrates electrical signals V 0  to V 4 . 
     The implantable medical system  10  in accordance with the present invention comprises a dipole emitter  12  and a dipole receiver  14 . The dipole emitter  12  is formed by a pair of electrodes E 1 , E 2 . The dipole receiver  14  is formed by a pair of electrodes E 3 , E 4 . The electrodes E 1 , E 2  are distinct from the electrodes E 3 , E 4 . 
     The two electrodes E 1 , E 2  of the dipole emitter  12  are connected to a generator  16  which is configured to generate an electrical input signal V 0  at a defined frequency f 0 . It should be noted that the frequency f 0  must be sufficiently high not to stimulate the heart of a patient by interfering with the normal cardiac activity of the patient. In particular, the defined frequency f 0  is more than 1 kHz; in particular, it may be more than 10 kHz. The generator  16  may be a voltage or current generator. 
     The implantable medical system  10  also comprises an analysis module  18 . The analysis module  18  comprises an amplifier  20 , in particular a low noise band pass amplifier which can be used to amplify the signal V 1  at the frequency f 0 . 
     The amplifier  20  may comprise an analogue filter. 
     In a variation, the amplifier  20  may be constituted by a plurality of low noise amplifiers. In this variation, the selection of one of the low noise amplifiers is made as a function of the mutual position of the dipole emitter  12  and of the dipole receiver  14  which affects the attenuation of the electrical signal. In this manner, the energy consumption of the system  10  may be optimized by activating only the low noise amplifier necessary for providing sufficient detection of the electrical signal for the measurement, i.e. which satisfies a certain predefined signal-to-noise ratio. 
     In another variation, the amplifier  20  may be a variable gain amplifier and/or a programmable gain amplifier. 
     The analysis module  18  furthermore comprises an envelope detector  22  and an analogue-to-digital converter  24  which are configured for processing an electrical signal captured by means of the dipole receiver  14 . 
     The analysis module  18  additionally comprises a processing means  25 . The processing means  25  is a processor  25 . The processor  25  may comprise a digital filter means in order to digitally process the electrical signal V 4 . In a variation, the digital filter means is disposed between the analogue-to-digital converter  24  and the processor  25 . 
     The processor  25  is connected to a detection means  26  which is configured to produce an electrocardiogram or an electrogram. 
     In one embodiment in which the detection means  26  is a subcutaneous device such as an implantable subcutaneous defibrillator or an implantable loop recorder, the detection means  26  is configured to produce an electrocardiogram, in particular a subcutaneous electrocardiogram. Thus, the detection means  26  is capable of detecting a PQRST complex, and in particular the P, Q and R waves. 
     In another embodiment in which the detection means  26  is an implantable endocardial device such as an implantable leadless cardiac pacemaker in the form of a capsule, the detection means  26  is configured to produce an electrogram. Thus, the detection means  26  is capable of detecting the R wave from a local measurement of the depolarization of the right ventricle. Activation of the analysis module  18  may be triggered by signals from the detection means  26 , in particular by detection of the R wave in order to optimize the operating duration of the active components of the analysis module  18  and thus to reduce the required energy consumption of the system  10 . 
     In order to further reduce the energy consumption of the system  10 , the measurement of the parameter which represents a pre-ejection period may be carried out only during a predetermined window of time, at regular intervals. The frequency of the measurement intervals may also be reduced in order to save energy. 
     The two electrodes E 3 , E 4  of the dipole receiver  14  may be configured to capture the electrical signal at the same time. 
     In a variation, the two electrodes E 3 , E 4  of the dipole receiver  14  are configured to capture the emitted electrical signal and the electrocardiogram at the same time. 
     The processor  25  of the analysis module  18  is further configured to combine the processed electrical signal and the electrocardiogram in order to determine a parameter which is representative of a pre-ejection period therefrom. 
     The operation of the implantable medical system  10  is explained in more detail below by using the electrical signals V 0  to V 4  illustrated in  FIG. 1 .  FIG. 1  illustrates an electrical input signal V 0  with a fixed amplitude. In a variation, the electrical input signal V 0  may have a variable amplitude in order to improve the signal-to-noise ratio. 
     In another variation, the amplitude of the electrical input signal V 0  may be adjusted from the feed-back from the dipole receiver  14  which, in this variation, is furthermore configured for transmission via telemetry with a third party device, for example an external device. 
     The dipole receiver  14  captures an electrical signal V 1  which differs from V 0  because the electric field has been propagated, following application of the electrical signal V 0 , through a volume, also termed a channel, for example human tissue, for which the impedance is non-zero. 
     The electrical signal V 1  is then amplified by means of the amplifier  20 , resulting in an amplified electrical signal V 2 . The envelope of the electrical signal V 2 , represented by the signal V 3 , is determined by means of the envelope detector  22 , in particular by an amplitude demodulation of the electrical signal V 2 . The envelope of the electrical signal V 3  is then sampled by the analogue-to-digital converter  24  in a manner such as to obtain a digital signal V 4 ( n ) in which n represents the number of samples. 
     The digital signal V 4  may be processed by means of the processor  25  and digitally filtered further in order to distinguish the respiratory information from the haemodynamic information recovered from the processed electrical signal. 
     It should be noted that the cutoff frequency of the filters may be adjusted as a function of the characteristics of each physiological parameter to be determined. As an example, a low pass filter with a cutoff frequency f c  in the range f c =0.5 Hz to 5 Hz, in particular f c =1 Hz, is used to isolate respiratory signals, while a band pass filter with f c1 =1 Hz and f c 2=30 Hz is used to isolate haemodynamic signals from the processed electrical signal V 4 . 
     From the processed electrical signal, the analysis module  18  is configured to extract therefrom a variation in volume and/or a variation in pressure as a function of time which is proportional to a reduction in the voltage between the dipole emitter  12  and the dipole receiver  14 . 
       FIG. 2  diagrammatically illustrates the propagation of an electrical signal V 0  from the dipole emitter  12  formed by the pair of electrodes E 1 , E 2  up to the dipole receiver  14  formed by the pair of electrodes E 3 , E 4  of the implantable medical system  10  in accordance with the present invention. 
     The elements with the same reference numerals already used for the description of  FIG. 1  will not be described again in detail; reference should be made to their descriptions above. 
     In the implanted state of the device and by applying the signal V 0 , the dipole emitter  12  is used to generate an electric field E propagating through the tissues of a human body to the dipole receiver  14 . The dipole receiver  14  detects a potential difference which depends on the electric field E, illustrated in  FIG. 2  by the electrical signal V 1 . The electrical signal V 1  which is detected principally depends on four factors, which are: the length “d” of the propagation channel, i.e. the distance between the dipole emitter  12  and the dipole receiver  14 ; the orientation “a” of the dipoles  12 ,  14  with respect to each other; the inter-electrode distances “d e1 ” and “d e2 ” for the dipoles  12 ,  14 , i.e. the distance between the electrodes E 1 , E 2  and the distance between the electrodes E 3 , E 4 ; and the electrical properties of the propagation medium. 
     As can be seen in  FIG. 2 , the electrodes E 3 , E 4  form a dipole receiver the orientation of which differs from that of the dipole receiver formed by the electrodes E 3 , E 4 ′. The difference in orientation between the dipoles E 3 , E 4  and E 3 , E 4 ′ is illustrated by the angle α in  FIG. 2 . When the implantable medical system  10  is implanted in a human body, in particular in or in the vicinity of the heart, the electrical signal V 1  of the dipole receiver  14  is modulated in amplitude. This results from the fact that respiration changes the properties of the environment, in particular the quantity of oxygen present in the lungs, which causes the attenuation of the electrical signal to vary during its transmission along the propagation channel, and thus causes a variation in the amplitude of the electrical signal V 1 . 
     In accordance with a second embodiment,  FIG. 3  represents the integration of the implantable medical system  10  in accordance with the present invention into an implanted device  100 , in this case an implantable subcutaneous defibrillator. In a variation, the device  100  is an event recorder, for example an implantable loop recorder. 
     The implantable subcutaneous device  100  as shown in  FIG. 3  comprises a housing  102 , three electrodes  104 ,  106 ,  108  and a defibrillation electrode  110 . The housing  102  of the implantable subcutaneous device  100  may comprise a telemetry module (not shown). 
     The implantable subcutaneous device  100  is suitable for integrating the implantable medical system  10  in accordance with the present invention, because it comprises at least a dipole emitter and a dipole receiver wherein the electrodes of each dipole are distinct from each other. Table 1 below lists configurations of the dipole emitters and dipole receivers which may be used in the implantable subcutaneous device  100  in order to operate the system  10  in accordance with the present invention. 
     
       
         
           
               
               
               
             
               
                 TABLE 1 
               
               
                   
               
               
                 # 
                 Dipole emitter 
                 Dipole receiver 
               
               
                   
               
             
            
               
                   
               
            
           
           
               
               
               
            
               
                 1 
                 104-106 
                 108-102 
               
               
                 2 
                 104-108 
                 106-102 
               
               
                 3 
                 110-106 
                 108-102 
               
               
                 4 
                 110-108 
                 106-102 
               
               
                 5 
                 104-102 
                 106-108 
               
               
                 6 
                 104-102 
                 110-106 
               
               
                 7 
                 104-102 
                 110-108 
               
               
                 8 
                 110-102 
                 106-108 
               
               
                 9 
                 110-102 
                 104-106 
               
               
                 10 
                 110-102 
                 104-108 
               
               
                 11 
                 108-102 
                 104-106 
               
               
                 12 
                 106-102 
                 104-108 
               
               
                 13 
                 108-102 
                 110-106 
               
               
                 14 
                 106-102 
                 110-108 
               
               
                 15 
                 106-108 
                 104-102 
               
               
                 16 
                 110-106 
                 104-102 
               
               
                 17 
                 108-102 
                 104-102 
               
               
                 18 
                 106-108 
                 110-102 
               
               
                 19 
                 104-106 
                 110-102 
               
               
                 20 
                 104-108 
                 110-102 
               
               
                   
               
            
           
         
       
     
     As indicated in Table 1, one of the electrodes may be constituted by the housing  102  of the device  100 . Any of the combinations of electrodes may be used, including the defibrillation electrode  110 . 
     The implantable subcutaneous device  100  may also comprise a detection means formed by at least one pair of electrodes from those listed in Table 1, configured in order to produce a subcutaneous electrocardiogram from which a PQRST complex can be detected. Thus, the R and Q waves in particular are identifiable from the PQRST complex. 
     Thus, the system  10  in accordance with the present invention may be implemented by means of a pre-existing device. In addition, a practitioner may advantageously select the configuration of the dipole emitter and the dipole receiver which is the most suitable for the physiological parameters that are to be captured. 
     In a variation, the system  10  comprises an accelerometer integrated into the implantable subcutaneous device  100 , which can be used to detect a mechanical activity of the heart. The mechanical activity of the heart may be compared with the captured electrical signal in order to establish a correlation between the signals. 
     In accordance with a third embodiment,  FIG. 4  represents the integration of the implantable medical system  10  in accordance with the present invention into a multi-device system  100 ,  200 . The multi-device system  100 ,  200  shown in  FIG. 4  comprises an implantable subcutaneous device  100  in accordance with the second embodiment and an endocardial device, such as a cardiac pacemaker, in particular a leadless pacemaker  200 . 
     The elements with the same reference numerals already used for the description of  FIG. 3  will not be described again in detail; reference should be made to their descriptions above. 
     In a variation, an event recorder or an implantable loop recorder could be used in place of the implantable subcutaneous device  100 . An event recorder or implantable loop recorder of this type may comprise a detection means, formed by at least one pair of electrodes of said recorder, and configured to produce a subcutaneous electrocardiogram from which a PQRST complex could be detected. Thus, the R and Q waves in particular are identifiable from the PQRST complex. 
     The leadless pacemaker  200  comprises a tip electrode  202  disposed at one end of the leadless pacemaker  200 , a first ring electrode  204  and a second annular electrode  206 . The electrodes  202 ,  204  or  202 ,  206  or  204 ,  206  may form a dipole receiver or a dipole emitter. The leadless pacemaker  200  may comprise a telemetry module (not shown). 
     The leadless pacemaker  200  may furthermore comprise a detection means, formed by a pair of electrodes comprising two of the electrodes  202 ,  204 ,  206  and configured to produce an electrogram from which the R wave may be detected. 
     The implantable subcutaneous device  100  and the leadless cardiac pacemaker  200  each comprises electrodes which may act as the dipole receiver and dipole emitter. Thus, both the implantable subcutaneous device  100  and also the leadless cardiac pacemaker  200  may act as an emitter or receiver in the implantable system  10  of the present invention. 
     The implantation of the implantable subcutaneous device  100  and of the leadless cardiac pacemaker  200  as illustrated in  FIG. 4  is adapted for a trans-thoracic measurement and can be used to detect changes in the volume of a chamber of the heart other than that in which the leadless cardiac pacemaker  200  is implanted. 
     As an example, by using the implantable subcutaneous device  100  as the emitter and the leadless cardiac pacemaker  200  implanted in the right ventricle as the receiver, information relative to the contraction of the atrium (“atrial kick”) may be recovered by the leadless cardiac pacemaker  200 , given that the mechanical activity of the atrium modifies both the quantity of blood present in the right ventricle and the orientation of the leadless cardiac pacemaker  200 . The information relative to the contraction of the atrium may be used by the leadless cardiac pacemaker  200  in order to adapt the stimulation to the normal activity of the atrium. 
     In addition, because the system  10  has at least four electrodes such that the dipole emitter is distinct from the dipole receiver, it is possible to obtain a measurement of the impedance which is more complete and thus more representative of the surrounding medium than a measurement between only two electrodes of the same lead. 
     Furthermore, the two devices  100 ,  200  are configured in order to integrate the dipole emitters and dipole receivers: each of the devices  100 ,  200  may therefore act as the emitter and also as the receiver, depending on the practitioner&#39;s requirements. Thus, it is possible to select the configuration of the dipoles which is the most sensitive and/or the most energy-saving, in particular during the lifetime of a patient in whom the devices  100 ,  200  are implanted. This selection may be carried out in real time using a telemetry module. 
     In a variation, the implantable medical system of the present invention may be integrated into a multi-device system comprising an implantable subcutaneous device such as the device  100  and two leadless pacemakers, each being of the type of pacemaker  200  (one provided for implantation in the right ventricle and the other in the right atrium), each of the implantable subcutaneous device and the leadless pacemakers comprising at least one dipole emitter and/or receiver electrode. A system of this type is suitable for a trans-thoracic measurement and can be used to detect the changes in volume observed in the right ventricle and in the right atrium. A system of this type can thus be used to provide a more exhaustive view of the trans-thoracic measurement. Furthermore, one of the two leadless pacemakers is adapted to stimulate the heart in the right atrium. In an alternative to this variation, one of the two leadless pacemakers is provided for implantation in the left ventricle, instead of the right atrium. The fact that one pacemaker is implanted in the left ventricle and the other is implanted in the right ventricle renders inter-ventricular resynchronization to be carried out. 
     In another variation, the implantable medical system of the present invention may be integrated into a multi-device system comprising an implantable subcutaneous device such as the device  100  and three leadless pacemakers, each like the pacemaker  200  (one is provided for implantation in the right ventricle, another in the right atrium and yet another in the left ventricle), each of the implantable subcutaneous device and the leadless pacemakers comprising at least one dipole emitter and/or receiver electrode. A system of this type constitutes an implantable Cardiac Resynchronization Therapy (CRT) system known as a “triple chamber” system (right ventricle, right atrium and left ventricle) which is not only suitable for diagnosis, but also for the treatment of cardiac insufficiency (also known as heart failure). In fact, an implantable cardiac resynchronization system needs a leadless pacemaker for stimulation in the left ventricle in order to synchronize intra-ventricular and interventricular contraction. 
       FIG. 5  illustrates an electrocardiogram  30  and a processed electrical signal  32 . The electrocardiogram  30  is captured by the generator  16  and an electrical signal is captured and processed by the analysis module  18  of the system  10  integrated into the multi-device system  100 ,  200 , as can be seen in  FIG. 4 . 
     The elements with the same reference numerals already used for the description of  FIGS. 1 to 4  will not be described again in detail; reference should be made to their descriptions above. 
     The analysis module  18 , in particular the processor  25 , is configured to combine the processed electrical signal  32  and the electrocardiogram  30  in order to determine therefrom a parameter which is representative of a pre-ejection period. 
     In haemodynamics, the pre-ejection period corresponds to the isovolumetric contraction which precedes systolic ejection. It is under the dependency of the sympathetic nervous system and reflects myocardial contractility. 
     A pre-ejection period is defined as the duration between the onset of the QRS complex, i.e. a Q wave or R wave, and opening of the aortic valve. 
     The electrocardiogram  30 , shown in  FIG. 5 , can be used to identify the peak of the Q wave from the R peak of the PQRST complex. In fact, the R peak is easier to detect than the peak of the Q wave because the R peak has a larger amplitude than the Q peak. 
     Thus, identification of the Q peak, indicated by the reference T 1  in  FIG. 5 , can be used to determine the onset of the pre-ejection period. 
     In a variation, the detection of the R wave is used as is as an indicator of the onset time for the pre-ejection period, which means that the complexity of the analysis module  18  of the system  10  necessary for the identification of the Q wave can be reduced. 
     In another variation, detection of the R wave is carried out from an electrogram. 
     The opening of the aortic valve is determined by means of the processed electrical signal  32  which has been processed by the analysis module  18  of the system  10 . The processed electrical signal  32  has been digitized by means of the analogue-to-digital converter  24  of the system  10  and digitally filtered in order to distinguish respiratory information from haemodynamic information comprised in the electrical signal. A 0.5 Hz to 30 Hz band pass filter is used to recover the haemodynamic information, while a low pass filter, preferably with a cutoff frequency f c  in the range 0.5 Hz and 5 Hz, in particular f c =1 Hz, is used to recover the respiratory information. The range of frequencies of 0.5 Hz to 30 Hz of the band pass filter can be used both to filter the respiratory artefact by cutting out frequencies below 0.5 Hz and to filter high frequency noise, i.e. noise with a frequency of more than 30 Hz. 
     In a variation, when an adjustment of the frequencies is necessary, the values for the frequencies for the band pass filter and low pass filters are adjusted by means of the processor  25 . 
     The person skilled in the art will understand that the respiratory information is relative to a change in the volume of the lungs, causing a modification to the propagation of the electric field which is in turn detected by the dipole receiver. 
     As illustrated in  FIG. 5 , it has been shown that opening of the aortic valve indicated by T 2  corresponds to the first local minimum  34  of the processed electrical signal  32  following the onset of the Q wave, i.e. from T 1 . 
     For this reason, the duration between the onset of the Q wave detected by means of the electrocardiogram  30  and opening of the aortic valve detected by means of the processed electrical signal  32 , i.e. the duration between T 1  and T 2 , can be used to determine the pre-ejection period indicated in  FIG. 6  by the reference ΔPEP. T 2  therefore corresponds to the onset time for ejection. 
     The duration of the pre-ejection period ΔPEP may act as an indicator when monitoring cardiac insufficiency. As an example, the higher the pre-ejection period ΔPEP is, the less the heart is assumed to be functioning efficiently. 
     The system  10  of the present invention can in particular be used to overcome difficulties encountered in the determination of the end of the pre-ejection period by means of prior art methods which are known to the person skilled in the art. 
     In a variation, the analysis module  18  is also capable, from the processed electrical signal  32 , of monitoring a parameter which is representative of the efficacy of a therapy, such as the ejection fraction or the ejection volume, by taking into account the change in the measured pre-ejection period ΔPEP over a long period, in particular a period of a few weeks, months or years. To this end, the values for the measured pre-ejection periods ΔPEP may be transferred to an external device by means of a telemetry module of the system  10 . In a variation, the values for the pre-ejection periods ΔPEP which are measured may be recorded on a storage means, for example a storage means of one of the devices  100 ,  200  of the system  10 . 
     In another variation, the system  10  is capable of detecting a mechanical activity of the heart from an acoustic signal which is representative of the sounds from the heart. The analysis module  18  is then configured in order to compare said acoustic signal with the processed electrical signal. In yet another variation, the system  10  comprises an accelerometer, for example integrated into the implantable subcutaneous device  100 , which can be used to detect a mechanical activity of the heart. 
     For this reason, the system  10  may be configured in order to detect and capture the mechanical/acoustic activity of the heart. The information which is captured in this manner regarding the mechanical/acoustic activity may be used to correlate the processed electrical signal  32  captured by the analysis module  18  of the system  10 . 
       FIG. 6  represents the comparison between variations in aortic pressure and left ventricular pressure and the captured and processed electrical signal  32  represented in  FIG. 5 . 
     The elements with the same reference numerals already used for the description of  FIGS. 1 to 5  will not be described again in detail; reference should be made to their descriptions above. 
     The variations in left ventricular pressure, represented by the plot  36  of  FIG. 6 , and the variations in aortic pressure, represented by the plot  38  in  FIG. 6 , were acquired by means of two intraventricular Millar pressure catheters placed in the aorta and in the left ventricle, in accordance with a method which is known by the person skilled in the art. 
     In  FIG. 6 , T 3  indicates the onset of contraction of the ventricle. In fact, as shown by reference numeral  37  on the plot  36  of  FIG. 6 , beyond T 3 , the pressure in the left ventricle is increasing. 
     As shown by reference numeral  40  on the plot  38  of  FIG. 6 , beyond T 2 ′, the aortic pressure increases when blood circulates in the artery. 
     After depolarization of the ventricles represented by the QRS complex of the electrocardiogram  30 , the cardiac muscle contracts, increasing the pressure of the left ventricle, as can be seen at time T 4  on the plot  36 . The pressure increases until it reaches a value which is sufficient to open the aortic valve at time T 2 ′. The time comprised between T 4  and T 2 ′ represents the duration of the isovolumetric contraction of the heart, which is thus termed because the blood volume in the chambers does not change (the valves are not yet open). At T 2 ′, the aortic valve opens, allowing the blood to circulate through the aorta, thereby increasing the pressure of the artery, as can be seen in plot  38  of  FIG. 6 , indicated by the reference numeral  40 . 
     The variation in the aortic pressure  40  is then used to measure the time T 2 ′ corresponding to the onset of an ejection. 
     As can be seen in  FIG. 6 , the processed electrical signal  32  in accordance with the invention has a first local minimum  34  which essentially corresponds to the onset of the increase in the aortic pressure  40  at T 2 ′ of the plot  38 . 
       FIG. 6  shows that T 2 ′=T 2 , i.e. that the abscissa of the observed local minimum on the processed electrical signal  32  may be attributed to the time of opening of the aortic valve. 
     The variation in aortic pressure  40  may also be used to determine the duration of left ventricular ejection, indicated in  FIG. 6  by the reference LVET, for “left ventricular ejection time”, which corresponds to the period between T 2 ′ and T 4 . 
       FIG. 7  represents the comparison between the variation in volume of the left ventricle determined from a sonometric measurement and an electrical signal captured and processed by the analysis module  18  of the system  10  integrated into the multi-device system  100 ,  200 , as can be seen in  FIG. 4 . 
     The elements with the same reference numerals already used for the description of  FIGS. 1 to 6  will not be described again in detail; reference should be made to their descriptions above. 
     The variation in the left ventricular volume, indicated by the plot  42  in  FIG. 7 , was determined by means of a sonometric measurement in accordance with a method known to the person skilled in the art. 
     The comparison of plot  33  and plot  42  of  FIG. 7  shows that the peaks, in particular the peaks included in the intervals  44  and  46 , as well as the period of the signals, in particular the pre-ejection periods ΔPEP 1  and ΔPEP 2 , are preserved from one plot to the other. In addition, the plots  33  and  42  in  FIG. 7  proves that the motifs are repetitive, such as the repetition of the intervals  44  and  46 . For this reason, the processed electrical signal  32  has a variation which is similar to that of the volume of the left ventricle represented by the plot  42 , thereby illustrating the correlation between the processed electrical signal and the haemodynamic properties of the heart. 
       FIG. 8  illustrates an electrocardiogram  48 , a phonocardiogram  50 , an electrical signal  52 , a respiratory signal  54  and a haemodynamic signal  56 . 
     The elements with the same reference numerals already used for the description of  FIGS. 1 to 7  will not be described again in detail; reference should be made to their descriptions above. 
     The electrical signal  52  is an electrical signal captured by the analysis module  18  of the system  10  integrated into the implantable subcutaneous device  100 , as can be seen in  FIG. 3 . 
     The electrical signal  52  represented in  FIG. 8  is a raw signal, i.e. it has not yet been digitally processed by a filter provided for this purpose, as described with reference to  FIG. 1 . 
     The phonocardiogram  50  represented in  FIG. 8  was determined by means of an acoustic measurement in accordance with a method known to the person skilled in the art. 
     In one embodiment, the system  10  may comprise acoustic measuring means which are suitable for capturing a phonocardiogram. In a variation, the system  10  may comprise an accelerometer. Thus, the system  10  may be configured in order to detect and capture the mechanical/acoustic activity of the heart. The information captured in this manner relating to the mechanical/acoustic activity may be used to correlate the electrical signal  52  captured by the analysis module  18  of the system  10 . 
     The respiratory signal  54  and the haemodynamic signal  56  have been extracted from the electrical signal  52  and distinguished by digital processing. In particular, a 1 Hz to 30 Hz band pass filter is used to recover haemodynamic information, while a low pass filter, in particular with a cutoff frequency f c  in the range 0.5 Hz and 5 Hz, in particular f c =1 Hz, is used to recover respiratory information from the electrical signal  52 . 
     As was explained with reference to  FIGS. 5 to 7 , the electrocardiogram  48  can be used to determine the onset of a pre-ejection period. 
     The time T 1  of  FIG. 8  corresponds to the onset time of a pre-ejection period determined from detection of a Q wave, T 1  corresponding to the peak Q. 
     The time T 1 ′ of  FIG. 8  corresponds to the onset time of a pre-ejection period determined from detection of an R wave, T 1 ′ corresponding to the peak R. 
     T 1  and T 1 ′ can thus each indicate the onset of the pre-ejection period. 
       FIG. 8  can be used to compare the haemodynamic signal  56  captured, processed and extracted from the system  100  with the signal from the phonocardiogram  50  and to thereby illustrate the correlation between these two signals  50 ,  52 . 
     As can be seen in  FIG. 8 , it has been shown that opening of the aortic valve indicated by T 2  corresponds to the second local maximum 58 of the haemodynamic signal  56  following the onset of the Q wave or R wave, i.e. respectively from T 1  or T 1 ′. 
     Thus, a pre-ejection period ΔPEP determined from the Q wave of  FIG. 8  corresponds to ΔPEP=T 2 −T 1 . 
     A pre-ejection period ΔPEP′ determined from the R wave of  FIG. 8  corresponds to ΔPEP′=T 2 −T 1 ′. 
     The duration of the pre-ejection period ΔPEP may therefore be determined from the implantable subcutaneous device  100  and may act as an indicator during monitoring of cardiac insufficiency. 
     The present system therefore provides a simplified means for recovering information, both respiratory and haemodynamic, in order to determine a parameter which is representative of a pre-ejection period. Thus, the present system can be used to determine a pre-ejection period without it being necessary to resort to cardiac sound sensors, from which the detection of a pre-ejection period is difficult, in particular because of the high signal/noise ratio in the signal obtained. 
     The determination of the pre-ejection period provides an indicator which is suitable for the diagnosis and monitoring of cardiac insufficiency. Furthermore, in the variation in which the system comprises at least one telemetry module, a warning message can be transmitted to care personnel when the analysis module detects an abnormal increase in the duration of the pre-ejection period over time, which could be an indication of cardiac insufficiency. 
     Thus, the present system is suitable for evaluating and optimizing a cardiac resynchronization therapy where the objective is to reduce the pre-ejection period without modifying the left ventricular ejection time.