TECHNICAL FIELD

[0001] The invention relates generally to systems and methods for optimizing leadless pacemaker capsule cardiac resynchronization therapy (CRT) devices, and in particular to improving leadless pacemaker capsule CRT devices according to intra ventricular pressures.

BACKGROUND

[0002] About 30% of congestive heart failure (CHF) patients suffer from dyssynchrony of ventricles' contractions. The ventricles dyssynchrony results in ineffective and incoherent contractions of the right and left ventricle walls. The de- synchronized contractions of the right and left ventricles generate delayed pressure waves, the opening and closing times of the heart valves are not synchronized and the efficacy of the heart pump is reduced resulting in low stroke volume and low cardiac output.

[0003] CRT is the most effective device therapy delivered to CHF patients that suffer from ventricles dyssynchrony, poor hemodynamic performance, low stroke volume (SV) and low cardiac output (CO).

[0004] Current CRT devices have a central can and three leads connecting the can to the heart right atrium, right ventricle and left ventricle implanted using a transvenous procedure.

[0005] The CRT device implanted leads may cause various pacemaker malfunctions and future pacemaker devices may use leadless pacemaker capsules having no leads and no central can. A system of an autonumous intracardiac capsule and its implantation accessory are disclosed for example in US Patent Application Publication US2012/0330392 published December 27, 2012 by Regnier et al entitled "Autonomous (Leadless) Intracardiac Implantable Medical Device with Releasable Base and Fastener Element", the entire contents of which is incorporated herein by reference. The implantation accessory aim is to ensure reliable anchoring of the leadless pacemaker capsule to the myocardium tissue before removing the implantation accessory. The leadless pacemaker capsule comprises means for detecting intracardiac electrocardiograms, for stimulating the myocardium tissue and for transmitting/receiving wireless communication from a remote device.

[0006] CRT devices stimulate the right and left ventricles in each cardiac cycle with pre-programmed AV delay and VV interval. AV delay is the time delay between the natural sinus node triggered right atrial event and the time the right ventricle is stimulated. The VV interval is a positive or negative value time interval defined relative to the AV delay. Positive VV interval means that the left ventricle is stimulated after the right ventricle, after the VV interval value expires, and negative VV interval means that the left ventricle is stimulated before the right ventricle preceding it by the VV interval value.

[0007] Optimizing the AV delay and VV interval in each CRT patient is a difficult, time consuming and expensive task and hence most CRT patients get the default AV delay and VV values. Typically, the AV delay and VV interval are adjusted towards optimization using echocardiography, and typically in rest condition, only if a patient clinical condition has not improved or deteriorated.

[0008] It would be highly advantageous to develop a CRT system for heart failure patients based on leadless pacemaker capsules having a pressure sensor in each leadless pacemaker capsule arranged to can measure the right and left intra ventricular pressure continuously. Furthermore, it would be highly advantageous to develop a CRT system that will find the best AV delay and VV interval based on intra-cardiac ventricular pressure waveforms and will be able to transmit this clinical data to a remote monitoring system.

SUMMARY

[0009] According to an aspect of some embodiments of the present invention there is provided a leadless pacemaker capsule cardiac resynchronization therapy (CRT) system. The leadless pacemaker capsule CRT system includes three leadless pacemaker capsules, each arranged for implantation in one of the right atrium, right ventricle and left ventricle. Each of the leadless pacemaker capsules includes a pressure sensor arranged to measure the blood pressure along the cardiac cycle, an intracardiac electrogram sensing circuit, a stimulation circuit, a wireless communication unit and a processor in communication with each of the intracardiac electrogram sensing circuit, stimulation circuit, pressure sensor and the wireless communication unit. Each of the processors are arranged to obtain the respective blood pressure along the cardiac cycle and transmit information between the respective leadless pacemaker capsules. The processors of the three leadless pacemaker capsules are arranged to cooperate and determine appropriate timing and deliver stimulation via the respective stimulation circuits so as to re- synchronize the ventricles' contractions responsive to the measured right and left intra- ventricular blood pressure. According to a further feature of an embodiment of the present invention, the processors of the three leadless pacemaker capsules are configured to determine timing for stimulation to be delivered to the right ventricle responsive to a detection of atrial event sensed by the intracardiac electrogram sensing circuit of the respective leadless pacemaker capsule implanted in right atria, the stimulation delivered by the stimulation circuit of respective leadless pacemaker capsules implanted in the right ventricle.

[0010] According to a further feature of an embodiment of the present invention, the processors of the three leadless pacemaker capsules are further configured to determine timing for stimulation to be delivered to the left ventricle responsive to a predetermined event sensed by the intracardiac electrogram sensing circuit of the respective leadless pacemaker capsule implanted in right atria, the stimulation delivered by the stimulation circuit of respective leadless pacemaker capsules implanted in left ventricle with a determined interval to the stimulation delivered to the right ventricle.

[0011] According to a further feature of an embodiment of the present invention, the communication units are further arranged to transmit and receive messages with one of an external programmer and an external remote telemedicine service.

[0012] According to a further feature of an embodiment of the present invention, the processors are arranged to store an intra-ventricular pressure waveforms, the communication units arranged to transmit to each other leadless pacemaker capsules and to an external programmer or external remote computerized monitoring service the stored intra-ventricular pressure waveforms.

[0013] According to a further feature of an embodiment of the present invention, the processors of the three leadless pacemaker capsules are further arranged to cooperate and calculate a pressure waveform correlation function, F(AV,VV), of two intra-ventricular pressure waveforms. [0014] According to a further feature of an embodiment of the present invention, the processors of the three leadless pacemaker capsules are further arranged to cooperate and determine the AV delay and VV interval that minimize, or maximize, the calculated pressure waveform correlation function F(AV,VV).

[0015] According to a further feature of an embodiment of the present invention, the pressure waveform correlation function, F(AV,VV), is proportional to the left ventricular peak systolic pressure divided by the absolute value of the time difference of the right and left ventricular pressure rise times.

[0016] According to a further feature of an embodiment of the present invention, the pressure waveform correlation function, F(AV,VV), is defined as the integral of the left ventricle pressure during a cardiac cycle.

[0017] According to a further feature of an embodiment of the present invention, the pressure waveforms, the pressure waveform correlation function, F(AV,VV), and the AV delay and VV interval that minimize, or maximize, the pressure waveform correlation function are transmitted to an external programmer or to a remote computerized monitoring service.

[0018] According to a further feature of an embodiment of the present invention, the processors of the three leadless pacemaker capsules are further arranged to cooperate and correct for pressure variations not related to the ventricle contractions by subtracting average diastolic pressure measurements determined by the three leadless pacemaker capsule processors.

[0019] According to a further feature of an embodiment of the present invention, a method for synchronization of ventricle contractions of heart failure patients is provided. The method comprising providing three leadless pacemaker capsules; implanting a first leadless pacemaker capsule in the right atria, a second leadless pacemaker capsule in the right ventricle and a third leadless pacemaker capsule in the left ventricle; detecting a right atrial event by the first leadless pacemaker capsule in each heart beat; transmitting a message regarding the detected right atrial event from the first leadless pacemaker capsule to each of the second and third leadless pacemaker capsule; stimulating the right and left ventricles with an AV delay and VV interval responsive to the received right atrial event detection message; measuring the right and left intra- ventricular pressures by the respective second and third leadless pacemaker capsules; transmitting the measured pressure waveforms from the second and third leadless pacemaker capsules to the first leadless pacemaker capsule; calculating a pressure waveform correlation function, F(AV,VV), of the two intraventricular pressure waveforms; and varying the AV delay and VV interval values in order to maximize, or minimize, the calculated pressure waveform correlation function F(AV,VV).

[0020] According to a further feature of an embodiment of the present invention, calculating a pressure waveform correlation function and the varying the AV delay and VV interval may be performed by the first leadless pacemaker capsule.

[0021] According to a further feature of an embodiment of the present invention, the step of varying the AV delay and VV interval values in order to maximize, or minimize, the calculated pressure waveform correlation function F(AV,VV) may use a closed loop adaptation scheme.

[0022] According to a further feature of an embodiment of the present invention, the closed loop adaptation scheme may use adaptive filters, gradient descent schemes, gradient ascent schemes, neural network learning schemes and reinforcement learning schemes.

[0023] Additional features and advantages of the invention will become apparent from the following drawings and description.

BRIEF DESCRIPTION OF THE DRAWINGS [0024] For a better understanding of the invention and to show how the same may be carried into effect, reference will now be made, purely by way of example, to the accompanying drawings in which like numerals designate corresponding elements or sections throughout.

[0025] With specific reference now to the drawings in detail, it is stressed that the particulars shown are by way of example and for purposes of illustrative discussion of the preferred embodiments of the present invention only, and are presented in the cause of providing what is believed to be the most useful and readily understood description of the principles and conceptual aspects of the invention. In this regard, no attempt is made to show structural details of the invention in more detail than is necessary for a fundamental understanding of the invention, the description taken with the drawings making apparent to those skilled in the art how the several forms of the invention may be embodied in practice. In the accompanying drawings: [0026] FIG. 1 illustrates a leadless pacemaker capsule according to certain embodiment of the present invention;

[0027] FIG. 2 illustrates a CRT device leadless pacemaker capsules, according to embodiments of the present invention;

[0028] FIG. 3 illustrates right and left intra ventricular pressure waveforms and intra cardiac electrograms, according to embodiments of the present invention;

[0029] FIG. 4 illustrates de- synchronized early right and delayed left intra ventricular pressure waveforms, according to embodiments of the present invention;

[0030] FIG. 5 illustrates de- synchronized delayed right and early left intra ventricular pressure waveforms, according to embodiments of the present invention;

[0031] FIG. 6 illustrates re- synchronized right and left intra ventricular pressure waveforms, according to embodiments of present invention; and

[0032] FIG. 7 is a flow chart description of a method for synchronization of ventricle contractions of heart failure patients, according to embodiments of the present invention.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0033] A leadless pacemaker capsule CRT system and method are disclosed herein. The CRT system includes three leadless pacemaker capsules, each arranged for implantation in one of the right atrium, right ventricle and left ventricle. Each of the leadless pacemaker capsules includes a pressure sensor arranged to measure the blood pressure along the cardiac cycle, an intracardiac electrogram sensing circuit, a stimulation circuit, a wireless communication unit and a processor in communication with each of the intracardiac electrogram sensing circuit, stimulation circuit, pressure sensor and said wireless communication unit.

[0034] Each of the processors is arranged to obtain the respective blood pressure along the cardiac cycle and transmit information between the respective leadless pacemaker capsules. The processors of the three leadless pacemaker capsules are arranged to cooperate and determine appropriate timing and deliver stimulation via the respective stimulation circuits so as to re- synchronize the ventricles' contractions responsive to the measured right and left intra-ventricular blood pressure. [0035] The CRT system leadless pacemaker capsules comprise a communication unit configured to transmit and receive messages between the leadless pacemaker capsules.

[0036] The CRT system is configured to deliver stimulation to the right ventricle with an AV delay triggered by the right atria leadless pacemaker capsule sensing circuit and to deliver stimulations to the left ventricle with a VV interval measured relative to the right ventricle stimulation.

[0037] The CRT system leadless pacemaker capsule's processor may be configured to calculate a pressure waveform correlation function, F(AV,VV), of two intra ventricular pressure waveforms and to find the AV delay and VV interval that minimize, or maximize, the calculated pressure waveform correlation function. The pressure waveform correlation function, F(AV,VV), may be defined as the overlap integral of the left ventricle pressure and the right ventricle pressure during a cardiac cycle.

[0038] Optionally, The CRT system leadless pacemaker capsules comprise a communication unit configured to transmit and receive messages between the leadless pacemaker capsules and an external programmer and/or external telemedicine service.

[0039] FIG. 1 illustrates a leadless pacemaker capsule 100. The leadless pacemaker capsule 100 comprises a processor 130, a memory 140, a pressure sensor 150, an intracardiac electrogram sensing circuit 160, a stimulating circuit 170, a sensing and stimulating electrode 110 and a communication unit 120. The sensing and stimulating electrode is shown on the left 110 and communication unit 120 is shown on the right side of capsule 100. The leadless pacemaker capsule 100 diameter may be in the range of 0.5 to 4 millimeters and the length of the leadless pacemaker capsule 100 may be in the range of 5 to 30 millimeters, with typical dimensions of 3 mm by 20 mm illustrated for ease of understanding. Communication unit 120 is a wireless communication unit. Processor 130 is in communication with each of memory 140, pressure sensor 150, stimulating circuit 110, intracardiac electrogram sensing circuit and communication unit 120 and memory 140 is arranged to have stored thereon processor readable instructions so as to perform the method of resynchronization described herein.

[0040] FIG. 2 illustrates CRT device leadless pacemaker capsules 100, according to embodiments of present invention. A first leadless pacemaker capsule 100 may be implanted in the right atria 210, a second leadless pacemaker capsule 100 may be implanted in the right ventricle apex 220 and a third leadless pacemaker capsule 100 may be implanted in the left ventricle apex 230.

[0041] The leadless pacemaker capsule CRT system 200 is configured to deliver stimulations to the right ventricle with an AV delay and to deliver stimulations to the left ventricle with a VV interval. The leadless pacemaker capsule CRT system 200 is configured to transmit and receive messages between the leadless pacemaker capsules 100. For example, when an atrial event is detected in the right atria 210 leadless pacemaker capsule 100 in right atria 210 transmits an atrial detection message to the leadless pacemaker capsules 100 located respectively in right ventricle 220 and left 230 ventricles. Leadless pacemaker capsules 100 in right ventricle 220 and left 230 ventricle set their internal timers for stimulating the ventricles after the AV delay and VV interval responsive to the received atrial detection message.

[0042] FIG. 3 illustrates right and left ventricles' pressure waveforms and intracardiac electrograms, according to embodiments of present invention. The leadless pacemaker capsule's processor 130 is configured to input the intra ventricular pressures measured by the pressure sensor 150 and store same in a portion of memory 140. The stored intra ventricular pressure values, during a cardiac cycle, form pressure waveforms illustrated for example in FIG. 3 showing simulated right (RVP, 310) and left (LVP, 320) ventricle pressure waveforms. The right atrial intracardiac electrogram events 330 and 332 are illustrated in FIG. 3 to illustrate the timing correlation between the heart electrical activity and the heart mechanical activity. The right atrial intracardiac electrogram events 330 and 332 are the detection of the natural sinus node electrical activity of a healthy heart, and are used to determine the beginning of a cardiac cycle and the cardiac rhythm, the heart rate. The right atrial intracardiac electrogram event 330 occurs at the end of the diastolic phase and is the source of the depolarization wave that propagates to the left atrium and the right and left ventricles. The depolarization wave induces the atrial contraction P wave, called also the atrial kick, which starts the active filling phase that fills the ventricle with additional blood at the end of the diastolic phase, and later the ventricles' contractions with the AV node delay.

[0043] The right ventricle intracardiac electrogram event 340 occurs typically 150 millisecond after the right atrial intracardiac electrogram event 330 due to the conduction delay of the AV node that separates the atrial and the ventricles conduction systems. The AV delay plays a central role in CRT device optimization as discussed further herein below. The left ventricle intracardiac electrogram event 350 occurs in healthy hearts in synchrony with the right ventricle intracardiac electrogram event 340. The right and left ventricles' contractions compress the blood in the two ventricles in the systolic isovolumetric phase. The blood pressure rises sharply 322 and typically reaches 120-140 mmHg during the isovolumetric phase. At this peak systolic blood pressure 324 the aortic valve opens and blood is ejected through the aortic valve to the body. After the blood is ejected and the pressure at the aorta rises and becomes equal to the left intra ventricular pressure, the aortic valve closes. After a time period of about 250 milliseconds, a relaxation T wave (not shown in FIG. 3) occurs due to electrical polarization wave that starts the diastolic phase. The electrical polarization wave induces expansion of the heart muscles that then return to their non- contracted state. The intra ventricular blood pressure falls sharply 326 close to 0 mmHg 328 after the T wave occurs. The mitral valve opens and blood flows from the atria to the ventricle during the passive diastolic phase in preparation to the next systolic phase of the next cardiac cycle.

[0044] The intra ventricular pressure waveform described above plays a vital and active role in the blood pumping efficacy of the heart. The intra ventricular pressure variations allow opening and closing the ventricle valves at the appropriate timings along the cardiac cycle allowing blood inflow in the diastolic phase through the mitral and tricuspid valves and blood outflow to the aorta and the pulmonary vein in the systolic phase through the aortic and pulmonary valves. The timings of the valves opening and closing depend on the intra ventricular pressures that are triggered by the electrical activity (i.e. the polarization and depolarization waves as detected by the implanted electrodes 330-350) that generates the mechanical contraction and relaxation of the heart muscles.

[0045] The pressure sensor hardware and software used to provide the intra ventricular pressure waveforms shown in FIG. 3 (310 and 320) are known, are known to those skilled in the art, and may be integrated in each leadless pacemaker capsule 100.

[0046] Optionally, the pressure sensor may be used furthermore to harvest energy from the intra ventricular pressure waves.

[0047] FIG. 4 illustrates desynchronized early right and delayed left intra ventricular pressure waveforms, according to embodiments of present invention. The right ventricle pressure 410 rises and reaches its peak systolic value 412 before the left ventricle pressure 420 rises and reaches its peak systolic value 422. The falls of the pressure waves may also be desynchronized in heart failure patients 414 and 424.

[0048] FIG. 5 illustrates desynchronized delayed right and early left intra ventricular pressure waveforms, according to embodiments of present invention. The left intra ventricular pressure 510 rises and reaches its peak systolic value 512 before the right intra ventricle pressure 520 rises and reaches its peak systolic value 522. The falls of the pressure waves may also be delayed as shown 514 and 524.

[0049] FIG. 6 illustrates resynchronized right and left intra ventricular pressure waveforms, according to embodiments of present invention. The left intra ventricular pressure 610 overlaps the right intra ventricular pressure 620. The improved overlap of the pressure waveforms, during the diastolic phase and the systolic phase, during the pressure rise time in the isovolumetric phase and in their fall time in the relaxation phase, ensures efficient blood pumping with simultaneous valve opening and closing along the cardiac cycle. Thus, the right and left intra ventricle pressure waveforms overlap may be a preferred physiologic measurable function to optimize in order to resynchronize the ventricle contractions of heart failure patients.

[0050] Optionally, the leadless pacemaker capsule processor 130 may store the measured intra ventricle pressure waveform received from the respective leadless pacemaker capsule 100 in the memory 140 thereof and may transmit the stored waveform to a second leadless pacemaker capsule 100 via its communication unit 120. The leadless pacemaker capsule processor 130 may be configured to calculate a pressure waveform correlation function of two intra ventricular pressure waveforms. For example, the first leadless pacemaker capsule 100 implanted in the right atria (FIG. 2, 210) may receive the pressure waveforms transmitted from the second and third leadless pacemaker capsules 100 implanted in the right and left ventricles (FIG.2 220 and 230) respectively. Processor 130 of first leadless pacemaker 100 may calculate a pressure waveforms correlation function, F(AV,VV), and may use it to find the AV delay and VV interval values that minimize, or maximize, the calculated pressure waveforms correlation function.

[0051] According to embodiments of the present invention, the intra-ventricular pressure waveforms correlation function, F(AV,VV), may be defined as the overlap integral of the left ventricle pressure and the right ventricle pressure during a cardiac cycle. The calculated overlap integral will be maximal if the pressure waveforms overlap like illustrated in FIG. 6 and will have lower value if the pressure waveforms are de-synchronized as illustrated in FIG' s 4 and 5.

[0052] Optionally, the intra ventricle pressure waveforms correlation function, F(AV,VV), may be calculated according to EQ. 1 below - LVP(t) * RVP(t)dt

F(AV,W) = ^ EQ. 1

Wherein LVP(t) is the left intra ventricular pressure (FIG. 3, 320), RVP(t) is the right ventricular pressure (FIG. 3, 310), T _\ is the time of the sensed atrial event and Tp is the cardiac cycle time period. The cardiac cycle period may be determined according to the time difference between sensed atrial events (FIG. 3, 330 and 332) or according to the time difference between adjacent systolic peaks.

[0053] Optionally, CRT devices based on three leadless pacemaker capsules 100, wherein at least two leadless pacemaker capsules 100 include pressure sensors may be used to find the best AV delay and VV interval that resynchronize the two ventricle contractions and relaxations along the cardiac cycle that includes the systolic contraction, ejection phases, the diastolic passive and active filling phases.

[0054] Alternatively, the intra ventricle pressure waveforms correlation function, F(AV,VV), may be calculated according to EQ. 2 below - V P

F(AV,VV) = — EQ. 2

LV ¹ RV ¹

Wherein LVSP is the left intra ventricular peak systolic pressure (FIG. 3, 324), T _L v is the rise time of the left intra ventricular pressure (calculated for example as the time the left intra ventricular pressure reaches its half peak systolic value) and TRV is the rise time of the right intra ventricular pressure (calculated for example as the time the right intra ventricular pressure reaches its half peak systolic value).

[0055] Alternatively, the intra ventricle pressure waveforms correlation function, F(AV,VV), may be calculated according to EQ. 3 below - LVP(t)dt

F(AV,W) = ^

Wherein LVP(t) is the left intra ventricular pressure (FIG. 3, 320). [0056] Optionally or alternatively, the intra ventricle pressure waveforms correlation function, F(AV,VV), may be calculated according to other mathematical formulas, other than EQs. 1-3 disclosed hereinabove, that are given merely as non- limiting examples, and such other pressure waveforms correlation functions are in the scope of the present invention.

[0057] Optionally, leadless pacemaker processor 240 may be collocated within right atrial leadless pacemaker capsule 100 which is typically not used to stimulate the right atrium in CRT patients and may be thus arranged to find the appropriate AV delay and VV interval, for calculating the pressure waveforms correlation function and for communications with an external programmer. The second and third leadless pacemaker capsules 100 that are used to stimulate the right and left ventricles in each cardiac cycle consume more power for the ventricle stimulations and thus processor 130 of the first leadless pacemaker capsules 100 located in right atrium 210 may be used to reduce the computation power consumption of the second and third leadless pacemaker capsules 100 located respectively in the right and left ventricles.

[0058] Optionally, the intra- ventricular pressure waveforms may be transmitted to an external programmer (not shown) and may be used for remote monitoring of the patient ventricular pressures as part of a remote telemedicine monitoring system.

[0059] FIG. 7 is a flow chart description of method 700 for synchronization of ventricle contractions of heart failure patients, according to embodiments of present invention. Method 700 may include the following steps: (710) providing three leadless pacemaker capsules comprising further pressure sensors and communication means; (720) implanting a first leadless pacemaker capsule in the right atria, a second leadless pacemaker capsule in the right ventricle and a third leadless pacemaker capsule in the left ventricle; (730) sensing right atrial intracardiac electrogram and detecting a right atrial event by the first leadless pacemaker capsule in each heart beat; (740) transmitting a message regarding the detected right atrial event from the first leadless pacemaker capsule to each of the second and third leadless pacemaker capsule; (750) stimulating the right and left ventricles with an AV delay and VV interval responsive to the received right atrial event detection message; (760) measuring the right and left intra ventricular pressures by the second and third leadless pacemaker capsules; (770) transmitting the measured pressure waveforms from the second and third leadless pacemaker capsule to the leadless pacemaker processor 130 preferably of the first leadless pacemaker capsule; (780) calculating a pressure waveform correlation function, F(AV,VV) of the two intra ventricular pressure waveforms; and (790) varying the AV delay and VV interval values in order to maximize, or minimize, the calculated pressure waveform correlation function, F(AV,VV).

[0060] The above has been described in an embodiment wherein all of the processing is performed in one or more of the leadless pacemaker capsules 100, however this is not meant to be limiting in any way, and an additional implantable processor, or an external processor may be utilized without exceeding the scope.

[0061] Optionally, the pressure waveforms correlation function may be defined as the overlap integral of the right ventricle to left ventricle pressure waveforms during each cardiac cycle. Other pressure waveforms correlation functions may be defined and used and are in the scope of the present invention.

[0062] Optionally, finding the AV delay and the VV interval values that maximize, or minimize, the calculated pressure waveforms correlation function, F(AV,VV), may be performed by a closed loop adaptation scheme. The closed loop adaptation scheme may include adaptive filters, gradient descent schemes, gradient ascent schemes, neural network learning schemes, reinforcement learning schemes as non limiting examples of adaptation schemes and other adaptation schemes may be used and are in the scope of the present invention.

[0063] Advantageously, the CRT system computation effort may be divided between the three leadless pacemaker capsules 100 such that the total power consumption of each leadless pacemaker capsule 100 is minimized. For example, the second and third leadless pacemaker capsules 100 implanted in the right and left ventricles are used to stimulate the ventricles while the first capsule implanted in the right atria is typically not used to stimulate the atria and it is only used to sense the natural sinus node electrical activity. Hence, the first leadless pacemaker capsule 100 processor 130 may be used to perform more computations than the second and third leadless pacemaker capsule processors 130.

[0064] Furthermore, the atria and the ventricles activities occur at different timings in the cardiac cycle, the atria event occurs at the diastolic phase while stimulation of the ventricles occurs typically 150 millisecond later, thus the computation effort may be further divided temporally according to the cardiac cycle events in order to efficiently use the computation power of the three capsules' processors 130. [0065] Optionally, calculating a pressure waveform correlation function, F(AV,VV), and varying the AV delay and VV interval are performed by processor 130 responsive to instructions stored in memory 140 thereof of first leadless pacemaker capsule 100 implanted in the right atria 210 in order to reduce the computational effort from processor 130 of the second and third leadless pacemaker capsules 100 implanted in ventricles 220, 230.

[0066] Optionally, artifacts related to external pressure variations, such as atmospheric pressure variations, may be corrected by subtraction of the average intraventricular diastolic pressure measured by the leadless pacemaker capsules during a relatively long time period that includes many cardiac cycles (for example an average of the diastolic pressure over 1000 cardiac cycles).

[0067] Advantageously, the present invention CRT system based on leadless pacemaker capsules may be used for resynchronization of the ventricle contractions according to intra ventricular pressure waveform correlation function, F(AV,VV).

[0068] Another advantage of the CRT system described above is that any intra ventricular pressure sensor technology may be used.

[0069] Another advantage of the CRT system described above is that the pressure sensor may be used to additionally harvest energy from the intra-ventricular pressure waves.

[0070] Another advantage of the CRT system described above is that the leadless pacemaker capsules includes communication units arranged to transmit and receive messages from each other and to an external programmer and hence the valuable clinical data of the patient intra ventricular pressures may be monitored by a remote monitoring service.

[0071] Another advantage of the CRT system described above is that the overall system computational effort may be divided between the three leadless pacemaker capsules 100 in order to minimize the power consumption of each leadless pacemaker capsule 100.

[0072] Another advantage of the CRT system described above is that the first leadless pacemaker capsule 100 implanted in right atrial 210, that typically is not used to stimulate the right atrium in CRT patients, may be configured to perform most of the computation effort reducing the power consumption of the right and left ventricles' leadless pacemaker capsule 100 due to computations. [0073] Another advantage of the CRT system described above is that varying the AV delay and VV interval values in order to maximize, or minimize, the calculated pressure waveform correlation function, F(AV,VV), may be performed by a closed loop adaptation scheme.

[0074] Another advantage of the CRT system described above is that the closed loop adaptation scheme that may be used to find the AV delay and VV interval values may use adaptive filters, gradient descent schemes, gradient ascent schemes, neural network learning schemes and reinforcement learning schemes.

[0075] It is appreciated that certain features of the invention, which are, for clarity, described in the context of separate embodiments, may also be provided in combination in a single embodiment. Conversely, various features of the invention which are, for brevity, described in the context of a single embodiment, may also be provided separately or in any suitable sub-combination.

[0076] Unless otherwise defined, all technical and scientific terms used herein have the same meanings as are commonly understood by one of ordinary skill in the art to which this invention belongs. Although methods similar or equivalent to those described herein can be used in the practice or testing of the present invention, suitable methods are described herein.

[0077] All publications, patent applications, patents, and other references mentioned herein are incorporated by reference in their entirety. In case of conflict, the patent specification, including definitions, will prevail. In addition, the materials, methods, and examples are illustrative only and not intended to be limiting.

[0078] It will be appreciated by persons skilled in the art that the present invention is not limited to what has been particularly shown and described hereinabove. Rather the scope of the present invention is defined by the appended claims and includes both combinations and sub-combinations of the various features described hereinabove as well as variations and modifications thereof, which would occur to persons skilled in the art upon reading the foregoing description. While preferred embodiments of the present invention have been shown and described, it should be understood that various alternatives, substitutions, and equivalents can be used, and the present invention should only be limited by the claims and equivalents thereof.