WO2013121431A1

WO2013121431A1 - Systems and methods for monitoring heart performance

Info

Publication number: WO2013121431A1
Application number: PCT/IL2013/050141
Authority: WO
Inventors: Guy Dori; Oscar Lichtenstein; Michael Rudman; Jorge E. SCHLIAMSER; Ilia ANSHELEVICH; Mitchell Shirvan
Original assignee: D.H.S Medical Ltd.
Priority date: 2012-02-16
Filing date: 2013-02-14
Publication date: 2013-08-22

Abstract

A system for monitoring and optionally modifying heart performance and a method of using same are provided. The system includes at least one motion sensor for sensing heart movement and optionally at least one electrical sensor for sensing an electrical activity of the heart. The system further includes a processing unit for processing information from the at least one motion sensor and optionally at least one electrical sensor to thereby derive a variable from a movement of the heart, preferably as a function of a cardiac cycle.

Description

SYSTEMS AND METHODS FOR MONITORING HEART PERFORMANCE

FIELD AND BACKGROUND OF THE INVENTION

The present invention relates to systems and methods for evaluating performance of a heart and identifying and treating pathologies thereof. Specific embodiments of the present invention relate to an implantable sensor system which includes sensors for sensing heart movement and electrical activity and a processor for deriving variables from a movement of the heart as a function of a cardiac cycle. These variables serve as basis for diagnosis and treatment of heart disorders and pathologies.

The human heart is a muscle that contracts and expands on average 60-100 times per minute thereby pumping blood to the tissues of the body. Each pumping cycle of the heart depends on a well synchronized electrical and mechanical activity. The electrical activity of the heart is realized by initiation and propagation of an electric impulse through heart muscle tissue (myocardium) while mechanical activity is realized by the physical contraction and relaxation of the myocardium.

Heart diseases involving irregularities in mechanical and more often electrical activity of the heart are sometimes treated with implantable medical devices (IMD). For example, cardiac rhythm management (CRM) systems for treatment of rhythm irregularities are often realized using IMDs such as pacemakers.

Major progress in the field of IMDs for treating mechanical irregularities of heart diseases occurred with the introduction of the CRT and CRT-D devices (e.g. Renewal and Cognis by Boston Scientific. Unify and Fortify by St Jude Medical. Protecta by Medtronic). The CRT device which is designed to improve mechanical function of the heart, operates by sensing electrical events and producing appropriate stimulating signals in order to 'correct' or compensate for irregular mechanical activity.

Although sensing electrical activity provides beneficial information in such devices, lack of other more physiological inputs is a limitation.

Much of the performance of the heart is related to mechanical activity, however sensing mechanical signals related to mechanical events is not presently performed by most IMDs.

An exception is the Sorin SonR electrode (Paradym™ RF SonR CRT-D device; Ovatio CRT model 6750) which incorporates an accelerometer within the electrode, thus enabling derivation of Peak Endocardial Acceleration (PEA) which correlates with the maximal slope of the curve of the LV pressure versus time (dP/dT max). PEA is used as an input to Sorin's CRT device, which produces a cardiac stimulating signal which aims to maximize the PEA signal.

Approaches for sensing mechanical events in the heart and incorporating cardiac mechanical signals and derived variables into an IMD's decision making process has been previously described, see, for example, U.S. Pat. Nos. 7445605, 6314322, 6078835 and 7363077.

While reducing the present invention to practice, the present inventors have realized that accurate sensing of mechanical activity of the heart along with sensing of electrical activity can be used to derive meaningful information with respect to the performance of the heart to thereby identify pathologies and/or correct heart performance accordingly. SUMMARY OF THE INVENTION

According to one aspect of the present invention there is provided a system for monitoring and optionally modifying heart performance comprising: (a) at least one motion sensor for sensing heart movement; and (b) at least one electrical sensor for sensing an electrical activity of the heart; and (c) a processing unit for processing information from the at least one motion sensor and the at least one electrical sensor to thereby derive a variable from a movement of the heart as a function of a cardiac cycle.

According to further features in preferred embodiments of the invention described below, the variable is a maximum value of an angle of the heart during systole and/or diastole.

According to still further features in the described preferred embodiments the variable is a maximum value of a first derivative of an angle of the heart during systole and/or diastole.

According to still further features in the described preferred embodiments the variable is a time from peak R wave to peak angle of rotation of the heart.

According to still further features in the described preferred embodiments the at least one motion sensor includes an accelerometer and a gyroscope. According to still further features in the described preferred embodiments the variable is a time interval between an onset of motion of the heart as detected by the accelerometer and the onset of motion as detected by the gyroscope.

According to still further features in the described preferred embodiments the system further comprises a biocompatible housing for containing (a), (b) and/or (c).

According to still further features in the described preferred embodiments the at least one electrical sensor includes at least two leads configured for attachment to a myocardium.

According to still further features in the described preferred embodiments the system further comprises tissue anchors for anchoring the housing to a tissue.

According to still further features in the described preferred embodiments the system further comprises stimulating electrodes for delivering an electrical signal to the heart.

According to still further features in the described preferred embodiments a type of the electrical signal delivered by the stimulating electrodes to the heart is determined by the processing unit according to the variable.

According to another aspect of the present invention there is provided a method of monitoring heart performance comprising: (a) sensing heart movement of a subject; (b) sensing an electrical activity of the heart; and (c) processing information relating to the heart movement and the electrical activity to thereby derive a variable from a movement of the heart as a function of a cardiac cycle.

According to still further features in the described preferred embodiments (a) takes into account a posture of the subject.

According to still further features in the described preferred embodiments (a) takes into account the effects of a gravitational and non-cardiac acceleration forces on the sensing.

According to still further features in the described preferred embodiments the variable is a maximum value of an angle of the heart during systole and/or diastole.

According to still further features in the described preferred embodiments the variable is a maximum value of a first derivative of an angle of the heart during systole and/or diastole. According to still further features in the described preferred embodiments the variable is a time from peak R wave to peak angle of rotation of the heart.

According to still further features in the described preferred embodiments (a) is effected via at least one motion sensor attached to a myocardium.

According to still further features in the described preferred embodiments the at least one motion sensor includes an accelerometer and a gyroscope.

According to still further features in the described preferred embodiments the variable is a time interval between an onset of motion of the heart as detected by the accelerometer and the onset of motion as detected by the gyroscope.

According to still further features in the described preferred embodiments (b) is effected via at least one electrical sensor having at least two leads attached to a myocardium.

According to yet another aspect of the present invention there is provided a method of modifying heart performance comprising: (a) sensing heart movement of a subject; (b) sensing an electrical activity of the heart; (c) processing information relating to the heart movement and the electrical activity to thereby derive a variable from a movement of the heart as a function of a cardiac cycle; and (d) delivering an electrical signal to the heart according to the variable.

According to still further features in the described preferred embodiments (d) is effected via stimulating electrodes attached to myocardium.

According to still further features in the described preferred embodiments a type of the electrical signal delivered to the heart is determined by a processing unit according to the variable.

According to yet another aspect of the present invention there is provided a cardiac resynchronization system comprising: (a) an atrial lead and at least two ventricle leads, the leads having proximal and distal ends, wherein the proximal ends of the leads are connected to a stimulator unit and their distal ends are connected to myocardial tissues, and wherein at least two leads include means for sensing signals related to the electric activity of the heart and means for delivering electrical stimulations to the myocardial tissues, and wherein the at least two leads include further means for sensing the motion of their distal ends, and producing related signals to the motion; and (b) a stimulator unit further comprising: (i) a processing unit that includes means for receiving the sensed signals, and wherein the processing unit includes means for calculating the at least two leads distal end motion, and wherein the calculated motion of the at least two leads distal ends is used to find the optimal atrioventricular delay (AVD) and interventricular delay (VVD) stimulating timing values; and (ii) a pulse generator unit operative to deliver electrical stimulations to the right and left ventricles at the AVD and VVD timing values.

According to still further features in the described preferred embodiments the calculated motion of the at least two leads distal ends is a rotational motion, and wherein twist angles and temporal angular velocities are calculated by the processing unit.

According to still further features in the described preferred embodiments the processing unit includes means for calculating a central rotational axis (CRA) system and the motion of the at least two electrodes distal ends relative to the calculated central rotational axis system during a heart beat using the sensed signals, and wherein the calculated motion of the at least two leads distal ends relative to the calculated central rotational axis system is used to find the optimal AVD and VVD stimulating timing values.

According to still further features in the described preferred embodiments when a fixed CRA system can not be found, temporal heuristic angular velocities amplitude is calculated by the processing unit as the square root of the sum of squares of the three components of the measured angular velocities vector, and wherein a twist signal is calculated by the processing unit by integrating over time the temporal heuristic angular velocities amplitude.

According to still further features in the described preferred embodiments most of the heart rotational energy is an angular velocity motion around the calculated central rotational axis (CRA) system X axis.

According to still further features in the described preferred embodiments one lead of the at least two ventricles leads is positioned in the right ventricle apex and a second lead is positioned in the left ventricle coronary sinus (CS).

According to still further features in the described preferred embodiments the

CS lead comprises two motion sensors, one positioned in the great cardiac vein and one at the CS lead distal end inserted further down to the anterior vein. According to still further features in the described preferred embodiments the leads distal ends are provided with active fixation means to the myocardial tissue.

According to still further features in the described preferred embodiments the calculated twist angles of the motion signals of the leads in each heart beat depend on the AVD and VVD values, and wherein the peaks of the twist angles of the motion signals of the leads occur simultaneously when the delivered AVD and VVD values are optimal.

According to still further features in the described preferred embodiments the calculated angular velocities of the motion signals of the leads relative to the calculated central rotational axis in each heart beat depend on the AVD and VVD values, and wherein the peaks of the angular velocities of the motion signals of the leads occur simultaneously when the delivered AVD and VVD values are optimal.

According to still further features in the described preferred embodiments the peaks of the calculated twist angles and/or angular velocities of the two leads occur in time correlation with the aortic valve closure when the delivered AVD and VVD values are optimal.

According to still further features in the described preferred embodiments optimal AVD is determined according to the calculated right ventricle apex twist angle changing sign from negative values to positive values, and wherein the changing sign is correlated with the end of the late diastolic flow A wave that occurs at the end of the atrial contraction phase.

According to still further features in the described preferred embodiments after the AVD is determined, the optimal VVD is determined according to the calculated left ventricle CS lead maximal twist angle that occurs in synchrony with the calculated maximal twist angle of the right ventricle apex lead.

According to still further features in the described preferred embodiments the optimal AVD and VVD are determined during implantation of the system.

According to still further features in the described preferred embodiments the optimal AVD and VVD are re-calculated and may be varied every heart beat.

According to still further features in the described preferred embodiments the optimal AVD and VVD are re-calculated and may be varied every pre-defined time period. According to still further features in the described preferred embodiments the optimal AVD and VVD values are optimized according to signals selected from the group consisting of: the twist angles or the difference in twist angles of the at least two leads distal ends, the temporal angular velocities or the difference in temporal angular velocities of the at least two leads distal ends, the difference in radial velocities of the at least two leads distal ends, the difference in lateral velocities of the at least two leads distal ends, the difference in accelerations of the at least two leads distal ends, the difference in time intervals between the electric activation of the ventricle and the accelerations or velocities of the at least two leads distal ends, the temporal relation between onset of accelerations and onset of angular velocities, the relation between the amplitude of acceleration signal of the at least two leads distal ends and the amplitude of angular velocities of the at least two leads distal ends, the difference in the rate of angular velocities of the at least two leads distal ends, the maximal distance between the two electrodes and two or more options of calculated motions listed herein simultaneously.

According to still further features in the described preferred embodiments the means for sensing motion of the at least two distal ends leads is selected from the group consisting of: accelero meters, inclinometers, gyroscopes, magnetometers, inertial navigation system units, proximity sensors, inclinometers, flow meters, pressure sensors, digital compasses, microphones, Linear Variable Differential Transformer (LVDT) sensors, temperature sensors, impedance leads, stress sensors, shear stress sensors, ultrasonic transducers, RF transducers, two or more means listed herein simultaneously.

According to still further features in the described preferred embodiments the stimulator unit is an external cardiac resynchronization therapy system used to improve the response to therapy during cardiac resynchronization therapy device implantation.

According to still further features in the described preferred embodiments the external cardiac resynchronization therapy system comprises further a display connected to the processing unit and means to display the sensed signals and the calculated motion of the at least two electrodes distal ends on the display, and wherein the calculated motion of the at least two electrodes distal ends is responsive to stimulations with different AVD and VVD values, and wherein the response is used to validate and improve the leads positioning and to find the optimal AVD and VVD timings values during cardiac resynchronization therapy device implantation.

According to still further features in the described preferred embodiments the stimulator unit is a cardiac resynchronization therapy implant.

According to still further features in the described preferred embodiments the cardiac resynchronization therapy system comprises further an external processor unit connected to a display and means to receive the sensed signals and the calculated motion of the at least two electrodes distal ends to the external processor unit connected to the display, and wherein the calculated motion of the at least two electrodes distal ends is responsive to stimulations with different AVD and VVD timings values, and wherein the displayed response is used to validate and to improve lead positioning during cardiac resynchronization therapy device implantation, and wherein after implantation the motion sensors are shut off.

According to still further features in the described preferred embodiments the calculated motion of the at least two electrodes distal ends is responsive to stimulations with different AVD and VVD timings values at different patient heart conditions, and wherein the processing unit includes means to find and store the optimal AVD and VVD values at different heart conditions and to deliver dynamically cardiac resynchronization therapy with different AVD and VVD values continuously.

According to still further features in the described preferred embodiments the cardiac resynchronization therapy implant comprises further means to transmit the sensed signals and the calculated motion of the at least two electrodes distal ends to an external processor unit connected to a display in order to remotely monitor and validate the performance of the implanted cardiac resynchronization system.

According to still further features in the described preferred embodiments the processing unit includes means for calibrating the measured motion signals of the distal ends during each heart beat using a mechanical phase of the heart cycle where the variability of heart motion is minimal.

According to still further features in the described preferred embodiments the mechanical phase of the heart cycle where the variability of heart motion is minimal is selected from the group consisting of: the end of the systolic phase and the end of the diastolic phase.

According to still further features in the described preferred embodiments the processing unit includes means for testing the mechanical phase used by the system for calibrating the measured motion signals, and wherein the mechanical phase used for calibrating the measured motion signals can be selected.

According to still further features in the described preferred embodiments the processing unit includes means for resetting the calculation integrals related to the calculation of the central rotational axis and the motion of the distal end relative to the central rotational axis after each heart beat using a mechanical phase of the heart cycle where the variability of heart motion is minimal.

According to yet another aspect of the present invention there is provided a method of providing cardiac resynchronization therapy, the method comprising delivering bi-ventricular pacing with dynamically varying AVD and VVD values in a first pre-defined time interval; receiving inputs from atrial lead and at least two ventricle leads, wherein the at least two leads having proximal and distal ends, and wherein the proximal ends of the leads are connected to a stimulator unit and their distal ends are connected to myocardial tissues, wherein the at least two leads include means for sensing signals related to the electric activity of the heart, means for sensing signals related to the motion of the leads distal ends and means for delivering electrical stimulations to the myocardial tissues; calculating a central rotational axis using the received motion signals, wherein most of the distal ends leads motion is an angular velocity motion around the axis; calculating the twist angles of the at least two leads distal ends relative to the calculated central rotational axis during a heart beat; and finding the optimal AVD and VVD values from the delivered AVD and VVD values according to the calculated twist angles of the at least two leads distal ends relative to the calculated central rotational axis in the pre-defined time interval.

Delivering bi-ventricular pacing with the optimal AVD and VVD values found in the first pre-defined time interval during a second pre-defined time interval.

According to still further features in the described preferred embodiments the first time intervals within which the calculations take place is Nl heart beats, and wherein the second time intervals within which bi-ventricular pacing with the optimal AVD and VVD values found in the first pre-defined time interval is N2 heart beats, wherein Nl and N2 are integer numbers.

According to yet another aspect of the present invention there is provided a method of providing cardiac resynchronization therapy, the method comprising delivering bi-ventricular pacing with dynamically varying AVD and VVD values in a first pre-defined time interval; receiving inputs from atrial lead and at least two ventricle leads, wherein the at least two leads having proximal and distal ends, and wherein the proximal ends of the leads are connected to a stimulator unit and their distal ends are connected to myocardial tissues, wherein the at least two leads include means for sensing signals related to the electric activity of the heart, means for sensing signals related to the motion of the leads distal ends and means for delivering electrical stimulations to the myocardial tissues; calculating a central rotational axis using the received motion signals, wherein if a fixed central rotational axis can not be found, a temporal heuristic angular velocities amplitude is calculated by the processing unit as the square root of the sum of squares of the three components of the measured angular velocities vector; calculating the twist angles as the time integral of the temporal heuristic angular velocities amplitude; finding the optimal AVD and VVD values from the delivered AVD and VVD values according to the calculated twist angles of the at least two leads distal ends in the pre-defined time interval and delivering bi-ventricular pacing with the optimal AVD and VVD values found in the first pre-defined time interval during a second pre-defined time interval.

According to still further features in the described preferred embodiments one lead of the at least two leads is positioned in the right ventricle apex and a second lead is positioned in the left ventricle coronary sinus, and wherein the method further comprises finding the timing of the peak angular velocity of each of the motion signals of the at least two leads distal ends relative to the calculated central rotational axis and relative to the sensed atrial signal during a heart beat; and finding the AVD and VVD values where the timing of the peaks of angular velocities are equal.

According to still further features in the described preferred embodiments one lead of the at least two leads is positioned in the right ventricle apex and a second lead is positioned in the left ventricle coronary sinus, and wherein the method further comprises storing patterns of the motion sensors signals of the at least two leads distal ends relative to the sensed atrial signal during a heart beat; and optimizing the AVD and VVD values according to the stored patterns of the motion sensors signals.

According to still further features in the described preferred embodiments one lead of the at least two leads is positioned in the right ventricle apex and a second lead is positioned in the left ventricle coronary sinus, and wherein the method comprises further the steps of:

finding the AVD according to the calculated right ventricle apex twist angle changing sign from negative values to positive values, and wherein the changing sign is correlated with the end of the late diastolic flow A wave that occurs at the end of the atrial contraction phase; and finding the VVD value according to the calculated left ventricle CS lead maximal twist angle that occurs in synchrony with the calculated maximal twist angle of the right ventricle apex lead.

According to still further features in the described preferred embodiments the method comprises further the step of subtracting the measured accelerations of the at least two leads motion sensors in order to calculate the relative motion of the two motion sensors, thus removing common body motion acceleration, noise and gravitational acceleration components.

According to still further features in the described preferred embodiments additional motion sensors are added to the implanted CRT device can, the method comprises further the step of subtracting the device can acceleration from the at least two leads motion sensors acceleration in order to calculate the relative motion of the two motion sensors to the can, thus removing common body motion acceleration, noise and gravitational acceleration components.

According to yet another aspect of the present invention there is provided method of validating the response to cardiac resynchronization therapy, the method comprising implanting an atrial lead and at least two ventricle leads in first locations in the right ventricle apex and left ventricle coronary sinus, wherein the at least two leads having proximal and distal ends, and wherein the proximal ends of the leads are connected to a stimulator unit and their distal ends are connected to myocardial tissues, wherein the at least two leads include means for sensing signals related to the electric activity of the heart, means for sensing signals related to the motion of the leads distal ends and means for delivering electrical stimulations to the myocardial tissues; delivering bi-ventricular pacing with varying atrio-ventricular (AV) delay and interventricular (VV) interval values; calculating a central rotational axis using the received motion signals, wherein most of the motion of leads distal ends is an angular velocity motion around the central rotational axis; calculating the twist angle and / or the temporal angular velocity of the at least two leads distal ends relative to the calculated central rotational axis during a heart beat; displaying the angular velocities signal on a display; finding the optimal AVD and VVD values from the delivered AVD and VVD values according to the calculated motion of the at least two leads distal ends relative to the calculated central rotational axis, wherein if the calculated peak angular velocities are less than a first pre-defined value for the coronary sinus lead and less than a second pre-defined value for the apex lead, a new location for the leads in the coronary sinus and/or the apex is tested and validated.

According to still further features in the described preferred embodiments the step of calculating the central rotational axis further comprising measuring three angular velocities Ox' , COy' and COz' using motion sensor located at the distal end of each the at least two leads; defining a function F of rotational angles Qx, Qy and Qz, and the measured angular velocities wherein the function F is a measure of the rotational velocity energies in the perpendicular direction to a central rotational axis; searching for the rotational angles Qx, Qy and Qz that minimize F; and defining the central rotational axis as the axis in perpendicular direction to the two rotational axes, and wherein most of the rotational velocity energies of the leads distal ends are around the central rotational axis.

The present invention successfully addresses the shortcomings of the presently known configurations by providing a system for monitoring and optionally modifying heart performance and methods of utilizing same in heart therapy.

Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. Although methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present invention, suitable methods and materials are described below. In case of conflict, the patent specification, including definitions, will control. In addition, the materials, methods, and examples are illustrative only and not intended to be limiting. Implementation of the method and system of the present invention involves performing or completing selected tasks or steps manually, automatically, or a combination thereof. Moreover, according to actual instrumentation and equipment of preferred embodiments of the method and system of the present invention, several selected steps could be implemented by hardware or by software or a combination thereof. For example, as hardware, selected steps of the invention could be implemented as a chip or a circuit. As software, selected steps of the invention could be implemented as a plurality of software instructions being executed by a processing unit. BRIEF DESCRIPTION OF THE DRAWINGS

The invention herein described, by way of example only, with reference to the accompanying drawings. 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 drawings:

FIG. 1 illustrates one embodiment of the present system superimposed on an illustration of a subject. In this embodiment of the present system, the IMD is implanted in a subcutaneous pocket (e.g. in the upper left chest) and connected via three leads to the heart. RA - right atrium; LA - left atrium; RV- right ventricle; LV - left ventricle; PA- pulmonary artery; CS - coronary sinus; SVC - superior vena cava; IVC- inferior vena cava; RVA - right ventricle apex.

FIGs. 2-3 schematically illustrate the distal end of one embodiment of an implantable lead (FIG. 2) and the components of the processing and control unit connected thereto (FIG. 3). FIG. 4A illustrates the calculation of the heart CRA system from raw gyroscope data in a flow chart, according to embodiments of the present invention.

FIG. 4B illustrates the calculation of the heart CRA system from integrated gyroscope data in a flow chart, according to embodiments of the present invention.

FIG. 4C illustrates the calculation of the temporal lead's distal end position from gyroscopes and accelerometers data in a flow chart.

FIG. 5 illustrates the rotation of the calculated angular velocity vector to the heart CRA system, according to embodiments of the present invention.

FIG. 6 illustrates left ventricle pressure and ECG signal on the upper part synchronized with rotational angles of the apex lead's distal end and the coronary sinus lead's distal end on the lower part acquired in a pre-clinical experiment.

FIG. 7 illustrates in a cross correlation diagram the left ventricle pressure and the coronary sinus gyroscope twist angle, according to embodiments of the present invention.

FIG. 8 illustrates in a two angles' plane diagram the gyroscope's angular velocity vector orientation before and after rotation to the CRA system, according to embodiments of the present invention.

FIG. 9 illustrates the enhancement of the twist angle calculated in the CRA system, according to embodiments of the present invention.

FIG. 10 illustrates the correlation of the leads temporal angular velocity signal with the transmitral inflow E and A waves, according to embodiments of the present invention.

FIG. 11 illustrates the correlation of the gyroscope twist angle with the transmitral tissue Doppler E and A waves, according to embodiments of the present invention.

FIG. 12 illustrates cardiac resynchronization therapy system that includes further an external processor unit and a display, according to embodiments of the present invention.

FIG. 13 illustrates a method for providing cardiac resynchronization therapy, according to embodiments of the present invention. FIG. 14 illustrates a method for optimizing the positioning of cardiac resynchronization therapy device leads, according to embodiments of the present invention.

FIG. 15 illustrates a method for optimizing the AVD and VVD of a cardiac resynchronization therapy device, according to embodiments of the present invention.

FIG. 16 is a graph obtained from an animal (pig) trial. In the upper panel the ECG (black, thin line), left ventricular (dashed line), and aortic (thick line) pressures are shown. The second panel from the top illustrates accelerometer data. This signal is a composite signal which equals the square root of the sum of the square of each of the signals from each of the 3 orthogonal accelerometer s. The third panel (from top) illustrates gyroscope data. This signal shows the angular velocity of the gyroscope in degrees per second. The bottom panel is a signal resulting from integration of the gyroscope data (dashed, non-zero line). This panel shows the angles "traveled" by the sensor. Each panel is divided into three parts using vertical dashed lines. The left part illustrates the baseline state, the middle part illustrates the effect of esmolol on the signals and the right part illustrates the effect of adrenaline on the signals.

FIG. 17 illustrates the left ventricular (dashed line) aortic (thick line) pressures and the ECG (thin line) - top panel, and the accelerometer signal from each of the orthogonal sensors (axis X- second panel from top; Y - third panel from top; Z- fourth panel from top).

FIG. 18 is a graph showing the relationship between contractility and the pressure gradient. Contractility is measured via peak to peak acceleration within a cardiac cycle, and pressure is measured via peak to peak pressure in the left ventricle within the same cardiac cycle. Three states are shown: baseline (circles), under the effect of esmolol (crosses), and under the effect of epinephrine (boxes).

FIG. 19 is a "zoom in" of the data presented in FIG. 16; left panel - baseline, middle panel - esmolol, right panel - epinephrine. In each of the panels three vertical lines are drawn. Each of the lines are numbered 1-3 in small boxes. Vertical line number 1 from left shows the peak of the QRS signal. Vertical line number 2 shows the time of an event sensed by the accelerometer. Specifically, the accelerometer signal has a maximum and a minimum (designated by two black arrows). A point in the middle, between the maximum and minimum, is a reproducible point, designating the event sensed by the accelerometer. This event is probably the closure of the mitral valve, or the closure of the tricuspid valve or the tension produced by the myocardial tissue as activation develops, or a combination thereof. Vertical line number 3 shows the termination of the event sensed by the accelerometer.

FIG. 20 illustrates left ventricular (dashed line), aortic (thick line) pressures, and the ECG (thin line) - top panel. Accelerometer signal - second panel from top, gyroscope signal - third panel from top, and the angles traveled by the sensor - bottom panel. The latter measure is obtained by integrating the signal of the panels above. The left most vertical line (1) shows where the QRS starts, the second line (2) shows a point in the middle between the minimum and maximum of the accelerometer signal. The right most vertical line (3) shows where the onset of rotation began, e.g. crossing of the zero line by the gyroscope.

FIG. 21 is a graph obtained from animal (pig) trial showing the ECG (thin, black) and left ventricular pressure (pink) - top panel, the heart rotation (twist-untwist) in degrees - middle panel and a tissue Doppler (TD) imaging signal acquired from pig's body surface - bottom panel.

FIGs. 22A-I illustrate data used by the present invention to calculate a 3D trajectory of a heart. FIGs. 22A-C illustrate 3 ECG traces which are identical. FIGs. 22D-F illustrate 3 cylindrical coordinates (Θ - angle, p - short radius, and z - long radius) of the distal end of the RV apical lead. FIGs. 22G-I illustrate Θ, p, and z for the distal end of the lead positioned in the coronary sinus (CS). The ordinates of FIGs. 22D-I represent relative change, rather than absolute change.

FIG. 23 illustrates 3D trajectories of a distal end of a lead positioned in the apex of the RV (the big trajectory) and a distal end of a lead positioned in the CS (small trajectory, somewhat on the left and as if elevated in the 3D space) of a pig heart. The larger trajectory represents the motion of the distal end of the lead positioned in the apex of the RV, whereas the smaller trajectory represents the motion of the distal end of the lead positioned in the CS. Both trajectories are described using thick black line for the systolic part, squares for the early filling phase of the diastole, thin black line for the diastasis, and circles for the late filling phase of the diastole.

FIG. 24 presents the typical data resulting from experiments performed with pigs. The upper panel of FIG. 24 displays the ECG recorded from body surface of animal (black), the pressure acquired from within the left ventricle (LV) PLV (pink), and the pressure acquired from the aorta (green, PAO). The panel second from top displays the acceleration signal (blue) which is calculated from the three acceleration signals (Accx, Accy, Accz) acquired by each of the orthogonal acceleration sensors. The signal of acceleration presented here equals the square root of the sum of Accx 2 +Accy 2 +Accz 2. In the third panel from top the angular velocity signal acquired by the gyroscope (on axis X) is displayed (red). The lowest panel shows the time integral of the angular velocity acquired by gyroscope X which is the angle the gyroscope rotated as a function of time.

FIG. 25 shows the effect of increasing doses of Epinephrine (abscissa) on the systolic acceleration signal (ordinate) acquired from the right ventricle apex (RVA) lead in three different animals (circles, diamonds, and boxes).

FIG. 26 displays the effect of increasing doses of Epinephrine (abscissa) on the twist which is the amount of angle travelled by the gyroscope located on the RVA lead, during systole (ordinate) in three different animals (circles, diamonds, and boxes).

FIG. 27 shows the effect of increasing heart rate by external atrial pacing

(abscissa) on the systolic acceleration signal (ordinate) acquired from the RVA lead in three different animals (circles, diamonds, and boxes).

FIG. 28 shows the effect of increasing heart rate by external atrial pacing (abscissa) on the twist which is the amount of angle travelled by the gyroscope located on the RVA lead, during systole (ordinate) in three different animals (circles, diamonds, and boxes).

FIG. 29 shows the effect of increasing heart rate by external atrial pacing (abscissa) on the untwist which is the amount of angle travelled by the gyroscope located on the RVA lead, during diastole (ordinate) in three different animals (circles, diamonds, and boxes).

FIG. 30 shows the effect of increasing heart rate by external atrial pacing (abscissa) on the peak angular velocity acquired during late diastole by the gyroscope located on the CS lead (ordinate) in three different animals (circles, diamonds, and boxes). The angular velocity signal acquired during late diastole correlates with the tissue Doppler signal acquired by echocardiography from body surface of the animal during atrial contraction (shown in FIG. 21). FIG. 31 shows the effect of intravenous volume (saline) overloading (abscissa) on the twist which is the amount of angle travelled by the gyroscope located on the RVA lead, during systole (ordinate) in three different animals (circles, diamonds, and boxes).

FIG. 32 shows the effect of intravenous volume (saline) overloading (abscissa) on the untwist which is the amount of angle travelled by the gyroscope located on the RVA lead, during diastole (ordinate) in three different animals (circles, diamonds, and boxes).

FIG. 33 is a table summarizing 3 pig trials. The columns show the variables that were investigated, whereas the rows indicate the interventions performed. Arrows pointing upwards indicate an "increase effect", and arrows pointing downwards indicate a "decrease effect". Interventions: row 1 - administration of increasing doses of epinephrine, row 2 - increasing heart by external atrial pacing, row 3 - the effect of volume (saline) overload. The measures investigated (from right column to left): systolic acceleration signal acquired from RVA sensor, twist (systolic rotation) signal acquired from RVA sensor, peak systolic angular velocity acquired from RVA sensor, untwist (diastolic rotation) signal acquired from RVA sensor, systolic acceleration signal acquired from CS sensor, twist (systolic rotation) signal acquired from CS sensor, peak systolic angular velocity acquired from CS sensor, peak late diastolic angular velocity signal acquired from CS sensor.

DESCRIPTION OF THE PREFERRED EMBODIMENTS

The present invention is of a system and method which can be used to monitor and modify cardiac performance. Specifically, the present invention can be used to obtain and process heart-related information from one or more heart motion sensors and one or more heart electrical sensors to thereby derive a variable from a movement of the heart as a function of a cardiac cycle. The variable can be used to determine the time and type of electrical signal provided to the heart via stimulating electrodes.

The principles and operation of the present invention may be better understood with reference to the drawings and accompanying descriptions.

Before explaining at least one embodiment of the invention in detail, it is to be understood that the invention is not limited in its application to the details set forth in the following description or exemplified by the Examples. The invention is capable of other embodiments or of being practiced or carried out in various ways. Also, it is to be understood that the phraseology and terminology employed herein is for the purpose of description and should not be regarded as limiting.

In a previous application (PCT/IB2010/054023), Applicants described an IMD designed to sense the time point at which rapid left ventricle (LV) filling terminates. This specific time point was obtained by using motion sensors to sense the motion of the heart. The relationship between this time variable to the duration of the diastole, was used to generate a stimulating signal to the heart in order to increase cardiac output.

While further experimenting with sensing of heart motion and the cardiac electrical cycle, the present inventors discovered that correlation between the cardiac cycle and heart mechanical motion can be used to derive additional meaningful information. Such information can be used to asses heart mechanical function and identify pathology, as well as be used to provide stimulating electrical signals to correct or compensate for heart insufficiencies or irregularities (e.g. reduced heart performance).

As is further described herein, the present invention integrates information from mechanical and electrical sensors to derive data which can be used to assess heart function. By providing this information as real-time, continuous, beat-to-beat, physiological (or pathological) data, the present invention enables accurate diagnosis of chronotropic incompetence (CI) in patients with heart failure and preserved ejection fraction (HFPEF) and therapy for CI in HFPEF patients.

Thus, according to one aspect of the present invention there is provided a system for monitoring and optionally modifying heart performance.

As used herein, the phrase "heart performance" is a measure of heart function, i.e. a measure of the ability of the heart to pump blood. Heart performance is typically non-invasively measured by echocardiography. From the echo exam parameters are derived which characterize heart performance, e.g. ejection fraction, fraction of shortening, end-systolic volume, end-diastolic volume, among others.

The system of the present invention is configured for sensing the movement of a heart of an individual (mammal, e.g. human) and its electrical activity and processing this information to thereby derive a variable from a movement of the heart as a function of a cardiac cycle. Several approaches can be used to obtain and process information on heart movement and electrical activity.

Heart movement can be detected using external (extracorporeal) sensors or internal (implanted) sensors, while electrical activity can be detected using externally mounted leads (standard ECG electrodes) or by using implanted leads.

Movement sensors can be any sensors capable of sensing acceleration, velocity, displacement, tilt, inclination and rotation about any axis, where accelerometers and gyroscopes are preferred. As is further described hereinunder, the present invention preferably utilizes both accelerometers and gyroscopes for measuring movements since the combination of these two types of sensors provides unexpected and beneficial results.

Regardless of the sensors used, the information retrieved thereby is processed to yield a variable that relates to movement of a heart as a function of a cardiac cycle.

The heart performs a complex motion throughout which it relaxes, expands and fills with blood (diastole) and then contracts (systole) to eject blood. Heart contraction involves rotational and linear motion.

The variable obtained relates to rotational and/or linear motion of the heart. Linear motion is more relevant for evaluating heart filling patterns, whereas rotational motion is more relevant for evaluating heart performance measures, such as contractility.

The present invention constructs a model of heart operation and integrates acquired motion and electrical signals from an actual heart. Based on this model, acquired signals are processed, and calculations of variables for acquired signals are performed. Variables from each model may be used for further analysis, and combinations of models and related variables can also be used for diagnosis and treatment.

The algorithm used by the present invention detects, quantifies and analyzes each component of heart motion. The heart rotational motion is around a main rotational axis. Calculating the main rotational axis (also termed here central rotational axis, CRA) and the angular velocity thereabout enables assessment of the rotational component of heart motion, e.g. the systolic twist and diastolic untwist motions of heart. By calculating the CRA it is possible to simulate the tissue Doppler (TD) signals acquired by body surface echocardiography and provide more accurate data continuously and on a beat-to-beat basis. More meaningful information can be obtained from such a rotational axis model than from echocardiographic TD and as such, any diagnosis or treatment based on presently used TD can also be based on the rotational model of the present invention.

The main rotational axis can be the longitudinal axis of the heart (according to cardiac convention that is the axis formed by an imaginary line drawn from the apex of the heart to the center of the base of the heart). The 3D motion of the heart can be reconstructed, in real-time, for the purpose of heart therapy.

Several steps can be used for 3D motion reconstruction:

(i) Detecting a heart cycle using electrical leads (external or internal).

(ii) Detecting the orientation of motion sensors (endocardial) relative to a 3D axis frame which is external to heart, using the signals obtained from the sensors. The 3D axis frame can be an axis frame established by external axis points (of the lab environment) or the orientation of another 3D sensor in a discrete location for example within a housing of the present device.

(iii) Detecting the direction of gravity. The direction of the gravitational force must be detected in order to remove this force from the measurements of the sensing units (e.g. accelerometers). Since the endocardial sensors are in constant motion, unique instants are defined in the cardiac cycle, where motion is characterized by signals having low standard deviation. During such instants it is possible to detect the direction of force of gravitation and to remove it from sensor measurements. Such unique instants within a heart cycle include, but are not limited to, end of systole, and middle of diastasis.

(iv) Removing integration errors. During each cardiac cycle the motion of the heart repeats itself, and approximately returns to the same point in 3D space. This fact is used for removing integration errors, and reconstructing a 3D motion of heart. An example of a method of removing integration errors accumulated by integrating accelerometer signal follows. There are specific points where the gyroscope changes its direction of rotation, for example at end of systole. This point in time is used for comparing the value of integration of accelerometer signal in cycle j with the value of integration of accelerometer signal in cycle j+1. The difference between these values is used for removing integration error in the following cycles.

(v) Calibration of sensors is performed prior to implantation within heart, however, during unique time intervals, calibration protocols can be operated following implantation. For example, when the present device detects a period of minimal body motion, e.g. during a supine position while sleeping, it can self-trigger a calibration protocol. Comparing calibration parameters from different time periods enables realtime assessment of reliability of operation. Calibration also provides an indication that the sensor operates appropriately, and maintains its spatial orientation.

Using the steps described above, 6 degrees of freedom can be detected and analyzed by the present invention. However one degree of freedom cannot be determined. Adding a magnetometer or a sensor that transmits a signal for detecting a known initial direction can provide this "missing" degree of freedom.

The steps described above can also provide the angular velocity of the right ventricular apex and coronary sinus. A ratio between these two velocities correlates with the flow of blood from left atrium to left ventricle, that is the transmitral blood flow. The integrated gyroscope signal (Figure 3, bottom panel) can be correlated with pressure difference within the left ventricle (Figure 3, dashed line in the upper panel).

Figures 1 illustrates an implantable system for monitoring and optionally modifying a heart performance which is referred to herein as system 10.

System 10 includes a housing 12 which is fabricated from a biocompatible material such as titanium using approaches well known in the art. Typical dimensions for housing 12 are: length - 25-55 mm, width - 5-15 mm, height - 25-55 mm and internal volume - 3-50 cm .

Housing 12 can be implanted within or against the heart (e.g. heart apex) or preferably in a subcutaneous tissue pocket formed in the chest (as shown in Figure 1), abdomen, back and the like.

As is shown in Figure 2, housing 12 includes a processing unit 18, power unit 16 (e.g. Li-Ion battery) for powering sensors 20 and pulse generator 19 and sensors 20 which can include electrical leads 27, accelerometer 28 and/or gyroscope 30 (sensors 20 are further described below). Housing 12 further includes anchors 14 (e.g. hooks) for attaching housing 12 to soft or hard tissue. Anchors can be hooks, loops and the like which are self attachable to the tissue or are attachable thereto via sutures, staples and the like.

System 10 further includes heart anchored sensors 20 which are electrically connected to housing 12. Sensors 20 included in housing 12 or anchored to heart tissue can include one or more of the following:

(i) Electrical leads 24 for measuring electric signals from the heart myocardium, such leads are provided as wires extending 30-60 cm from housing 12 and include tissue anchors 26 (e.g. coil shown in Figure 3) for self anchoring into the myocardium at apex of right ventricle and coronary sinus. Electrical leads 24 can also function as stimulating electrodes for providing an electrical signal to the myocardium by conducting an electrical signal generated by pulse generator 19 and power unit 16 (and controlled by processing unit 18) to the myocardium (e.g. pacing).

(ii) Electrical leads 27 for measuring a heart electrical signal at housing 12. Electrical leads 27 can be flat metallic contacts formed on the outer surface of housing 12.

(iii) Accelerometer 28 is capable of sensing linear acceleration of heart in three dimensions; accelerometer 28 can be provided within housing and/or it can be integrated into electrical leads 24.

(iv) Gyroscope 30 measures rotation of heart in three dimensions; gyroscope 30 can be provided within housing and/or it can be integrated into electrical leads 24.

Processing unit 18 can include an ASIC processor which includes input port for sensors 20, an analog to digital converter for each sensor 20 and a signal conducting unit for transferring the measured signals to a sensor register. A digital motion processor processes the digitized sensors data and outputs the temporal angular velocity vectors. Such data can be integrated with the electrical sensor data (processed via the same processor or a second processor) to yield a variable which can further be used in an open loop (e.g. diagnosis of heart motion irregularities) or closed loop (e.g. therapy such as resynchronization) manner.

Several configurations of system 10 are envisaged herein. Table 1 below lists several exemplary configuration of system 10. Table 1

Configuration Lead 1 Lead 2 lead 3 Lead 4 Processing/Stimulation

Monitoring Lead with Lead with Description below heart motion gyroscope gyroscope

sensor in sensor and

RV apex accelerometer

(RVa) in housing - required for

reducing

background

motion

Calculating rotational movement variables (angular velocity, angle change, central rotational axis). This configuration monitors the response of the heart to various interventions (inotropic, chronotropic, volume administration, drugs, etc). Using this lead it is possible to assess how an intervention affects a heart. This configuration can be used in the implementation of examples 2, 3, and 8, below. Motion signals acquired from RVa (i.e. heart) must be related to motion signals acquired from non-heart body (e.g. housing of device is a subcutaneous pocket), therefore it is required to measure the latter signals.

and setting a sensor and sensor and

lower heart electric accelerometer

rate. sensor and in housing -

Optimizing conductor required for

atrioin RVa reducing

ventricular background

dissociation motion

Calculating rotational movement variables as described in 1. In addition, the electric sensor can measure time interval between consecutive electric ventricular activations. This variable is processed in the processor yielding a decision whether to emit a stimulating signal to the RVa. This configuration differs from 1 in that it can apply treatment (not only monitor), and in that input to the processor includes electric and motion signals. In addition, this configuration can integrate between the motion and electric data. For example, pacing the RVa can be established by sensing ventricular electric activation and by sensing motion variables. In particular, sensing consecutive electric activations (QRS complexes) from the RVa yield a variable related to the time interval between them. Comparing this variable with a predetermined time threshold yields a decision to stimulate the RVa. However, in addition to the electric variable a motion variable is sensed, i.e. the motion of the late diastolic flow from left atrium (LA) to LV, associated with atrial contraction. If this signal is sensed before the electric signal exceeds the threshold, it serves as an independent indicator for emitting a stimulus to the RVa. This sensing will improve atrio-ventricular dissociation. This configuration can be used when implementing example 9, below. Motion signals acquired from RVa (i.e. heart) must be related to motion signals acquired from non-heart body (e.g. housing of device is a subcutaneous pocket), therefore it is required to measure the latter signals.

Monitoring, Lead with Lead Lead with Description below and optimizing motion with gyroscope

heart sensors electric sensor and

performance, (gyroscope sensor in accelerometer

mainly LV and right in housing - filling accelerome atrium required for

ter) and (RA) reducing

electric background

sensor and motion

conductor

in RVa

In this configuration an additional lead with electric sensor and conductor is installed in the RA. This lead can deliver a pacing stimulus to the RA providing a more physiological route of heart activation. Starting from the RA propagating to the left atrium (LA), AV node, bundle of His and the ventricles via the natural conducting system. This configuration is preferred over configuration 2 when the natural conducting system is normal. This configuration can overcome a fault in the natural conducting system of the heart. For example, if a pacing stimulus is required and provided to the RA, but does not propagate to the ventricles, the RVa lead senses this fault and emits a stimulating signal to the RVa, bypassing the conduction defect. This configuration can be used when implementing examples 4, 5 below. Motion signals acquired from RVa (i.e. heart) must be related to motion signals acquired from non-heart body (e.g. housing of device is a subcutaneous pocket), therefore it is required to measure the latter signals.

Monitoring, Lead with Lead Lead Lead with Description below and motion with with gyroscope

optimizing sensors electric motion sensor and

heart (gyroscope sensor sensors accelerometer

performance, and and (gyrosco in housing -

LV filling acceleromete conducto pe and required for

and LV r) and r in right accelero reducing

synchronized electric atrium meter) background

activation sensor and (RA) and motion

conductor in electric

RVa sensor

and

conducto

r in

coronary

sinus

(CS)

This configuration senses electrical and mechanical signals of a heart at 4 distinct locations. This configuration stimulates a heart at 3 distinct locations. As in configurations 3 and 4, the lead located in

RA stimulates the heart when needed in a physiological manner (using almost all the components of the natural conducting system, except for the SA node). The RVa and CS leads can deliver a stimulating signal to the LV according to a unique adaptable time scheme thereby synchronizing the activity of the heart. This configuration can provide cardiac resynchronization therapy (example 6 below), and also cardiac desynchronization therapy (exampl e 7 below). Motion signals acquired from RVa (i.e. heart) must be related to motion signals acquired from non-heart body (e.g. housing of device is a subcutaneous pocket), therefore it is required to measure the latter signals.

Monitoring, Lead with Lead Lead Description below and motion with with

optimizing sensors electric motion

heart (gyroscope sensor sensors

performance, and and (gyrosco

LV filling acceleromete conducto pe and

and LV r) and r in right accelero

synchronized electric atrium meter)

activation sensor and (RA) and

conductor in electric

RVa sensor

and

conducto

r in

coronary

sinus

(CS)

This configuration senses electrical and mechanical sig nals of a heart at 2 distinct locations: RVa and

CS. This confij juration stimulates a heart at 3 distinct locations. As in configurations 3 and 4, the lead located in RA stimulates the heart when needed in a physiological manner (using almost all the components of the natural conducting system, except for the SA node). The RVa and CS leads can deliver a stimulating signal to the LV according to a unique adaptable time scheme thereby synchronizing the activity of the heart. This configuration can provide cardiac resynchronization therapy (example 6 below), and also cardiac desynchronization therapy (example 7 below). This configuration differs from configurations 1-4 in that it does not relate motion signals acquired from heart to those acquired outside the heart (e.g. in the casing, housing of the device). It is estimated that some of the variables which are acquired form heart motion sensors can be analyzed regardless of the background motion signals. One such variable is a variable analogous to the deceleration time measured by trans-mitral flow velocity echocardiography. This variable is the time interval starting at the peak of the early diastolic untwist (see below) ending at the onset of diastasis. It can be detected and accurately calculated regardless of background motion and can be used to control the intervention provided by the present system. This variable can be used in patients with clinical heart failure with preserved ejection fraction and an intraventricular conduction defect reflected by an incomplete left bundle branch block on the EKG. The conduction defect imposes heterogeneous activation of the excitable myocardial tissue. Due to the inhomogeneity of activation, various parts of the myocardial tissue are excited at different times, resulting in dys synchronization. The activation problem results in a difficulty in heart undergoing relaxation. Since the myocardial tissue undergoes excitation in a dyssynchronized manner the relaxation process also ensues in a dyssynchronized manner. This variable can be measured under various sets of ventricle-ventricle delay (VVD) times in order to identify a VVD which results in the "best" variable value for each patient (according to, for example, baseline data etc). See Example 7 hereinbelow for further detail.

For example, in a system configured for resynchronization therapy (further described hereinbelow), power unit 16 (a pulse generator) is operative to deliver electrical stimulations to the right and left ventricles with varying atrioventricular delay (AVD) and interventricular delay (VVD) values. In such a system 10 configuration, a first lead 24 including a motion sensor 28 and/or 30 can be implanted in the right ventricle apex and a second lead 24 including a motion sensor 28 and/or 30 can be implanted in the left ventricle coronary sinus (CS). Processing unit 18 receives the motion information from the sensors and calculates a central rotational axis (CRA) and the motion of the distal ends of at least two leads 24 relative to the calculated CRA during a heart beat. The calculated motion of leads 24 relative to the calculated CRA may be used to find the optimal AVD and VVD values delivered by power unit 16. Use of system 10 for applying optimal AVD and VVD electrical signal to the myocardium is further described hereinunder with respect to hear resynchronization therapy.

Any number of leads 24 can be used by system 10. Preferred configurations of system 10 include at least two or at least three leads 24. Such leads 24 can provide sensory functionality only, or sensory and stimulatory functionality. Leads 24 include a proximal and a distal ends adjoined via an insulated electric conductor. The distal end is connected to the myocardium via tissue anchoring elements. The distal end is fabricated for example from platinized platinum or titanium nitride in order to conduct an electrical signal from the myocardium to the proximal end of the lead which is connected to housing 12 or from housing to the myocardium (in cases where electrical leads 24 also provide stimulatory electrode functions). Commercially available leads that can be used with the present invention include for example: CapSure series by Medtronic or Tendril by St. Jude medical.

As is shown in Figure 3, accelerometer 28 and gyroscope 30 are integrated into the distal end of electrode 24. Accelerometer 28 can be a MEMS accelerometer such as ADXL346 by Analog device, Inc. Gyroscope 30 can be a MEMS gyroscope such as L3G4200D by ST, Inc. Additional sensors such as, inclinometers, inertial navigation system units, proximity sensors, flow meters, pressure sensors, digital compasses, microphones, LVDT sensors, temperature sensors, impedance leads, stress sensors, shear stress sensors, ultrasonic transducers, RF transducers and the like can also be integrated into leads 24

Accelerometer 28 and gyroscope 30 are electrically connected to housing 12 via wires 38 which conduct the signals acquired by accelerometer 28 and gyroscope 30 to processing unit 18. In order to reduce the number of wires, a digital multiplexer (DMP) can output the digitized signals of the different motion sensors sequentially using the same wire. The signals are relayed to the processing unit within the housing of the device, using less wires, conductors, and sockets. Since there is an association between the number of wires and wire failure (e.g. breaking of a wire), reducing the number of wires reduces the chances of failure.

Although the processing of the motion signals is effected using processing unit 18, a motion signal can be preprocessed by accelerometer 28 and gyroscope 30, in order to, for example, convert an analog motion signal to digital form.

Although heart movement can be detected via an accelerometer or gyroscope alone, motion of the myocardium includes linear and rotational components and as such, using a motion sensor which includes both accelerometer 28 and gyroscope 30 substantially increases the amount of information that can be obtained with respect to movement of the heart.

The electrical and motion signals collected by electrical leads 24 and accelerometer 28 and gyroscope 30 are conducted (as described above) to processing unit 18.

Processing unit 18 processes the electrical and motion signals in order to derive a variable. The signals from the motion sensors within housing 12 and those mounted on the leads 20 can be processed and analyzed simultaneously and variables from each source may be compared in the analysis unit of processing unit 18.

A variable obtained by processing unit 18 is an integrated function of mechanical and electrical activities of the heart. For example, a motion signal may be the angular velocity of the distal end of an electrode 24 (measured in degrees per second) about a predetermined axis. This axis may be the longitudinal axis of electrode 24, or the longitudinal axis of the left ventricle (LV), or a central rotational axis calculated from gyroscope 30. The raw signal of the angular velocity, sensed by gyroscope 30, transmitted from the proximal end of electrode 24 is conducted to processing unit 18 where it is integrated with electrical activity of the heart to obtain integrated angular velocity data which include the angle as a function of cardiac cycle over the measured time frame; the angle as a function of cardiac cycle at selected (discrete) time points forms the variable.

Any number of variables can be used for diagnosis and treatment. In some cases single variables can be used in decision making, whereas in others, several variables can be combined to create a novel variable, and to use the latter for decision making.

The variable obtained can be used as an indication for action or for no action in a closed loop system in which case it can be used to trigger and send a signal through electrical leads 24 to the myocardium. Alternatively, the variable can be used as an indication for action or for no action in an open loop system in which case, the variable information is relayed to an extracorporeal control unit (via wired or wireless communication) and a decision is made by an operator of the control unit.

The Examples section which follows provides several examples detailing how variables are obtained by the present system and illustrating use for such variable in diagnosis and treatment.

In order to facilitate transmission of system 10 data (raw or processed sensor information), system 10 further includes a transceiver 34 (Figure 2). Transceiver 34 can be used to relay processed information to an extracorporeal control unit (as described above) as well as transmit data from sensors 20 or processing unit 18 for further analysis, data storage, generation of medical alerts and the like.

For example, a signal transmitted via RF (e.g. Bluetooth or NFC) to an extracorporeal receiving unit (e.g. a smartphone of the subject) can be relayed (via a network connection) to a treating physician for assessment and diagnosis. The physician can use such data to get an indication of the condition of the subject and to advise the subject to take medication, to rest, or to seek medical care.

The transmitted data can be stored as raw signals, processed signals, variables related to the raw signals or the processed signals, decisions for action, time, etc. and used to track the condition of the subject over time and measure the affect of treatment thereon.

To enable tracking, the data transmitted by system 10 preferably includes a time stamp which is linked or associated with variables processed and raw sensor data. Transmitted data can further include information on the posture of the individual i.e. whether the individual is standing or lying down. Posture information may be useful in interpreting heart performance variables of an individual.

The variables resulting from the processing in processing unit 18 can be transferred to an analysis unit for the purpose of comparing variable values with reference or predetermined values. The reference values may be calculated previously from earlier cardiac cycles and stored for later use in the analysis unit. Alternatively, reference value may be predetermined and pre- stored in the analysis unit. Reference values can also be calculated in real-time and also stored within the analysis unit.

For example, the angle of rotation as a function of time, from N cycles may be stored and used as reference value. This value may be multiplied by a factor to produce a safety range. The value may be compared with the angle of rotation calculated in the last cardiac cycle. The outcome of the analysis is a decision that may be transferred to a signal generator (for producing a stimulatory signal) or may be stored for later use.

If the comparison in the analysis unit results in an indication that an action is required, the analysis unit instructs the signal generator to generate and transmit a signal via lead 24 to the myocardium.

System 10 can further include a drug reservoir for releasing a drug to the circulation or locally upon a triggering signal from the analysis unit. The drug can be released from lead 24 or from a dedicated drug release port/cannula. The drug released by system 10 can be, for example, a steroids or anti-inflammatory/immune suppressant; a growth factor or a cytokine. System 10 of the present invention is deployed as follows. The patient lies in the supine position. The upper part of the chest, below the collar bone, is sterilized and anesthesia is administered. A cut is made through the skin and a pocket is made under the skin. A near-by vein is detected and the leads are inserted through the vein into the right atrium, right ventricle and coronary sinus. Positioning the leads is done using an X- ray machine that projects an image of the thorax and the leads on a screen. After implantation of the distal end of the leads, the proximal ends of the leads are connected to the implantable medical device.

There is a mode of installation which is unique to the present system. Prior to threading the lead into a vein, a lead having a motion sensor is connected to and positioned on the housing of the system. Then, a mode of orientation is activated. This mode aligns the orientation of the sensor on lead with the sensor in the housing. The orientation is automatic and requires no special conditions apart for the location of the lead on the housing. When this mode terminates, both sensors are aligned, and the present system can follow the orientation of the lead sensor relative to the housing sensor. This orientation procedure is performed before the insertion of each lead into a vein.

Once leads are anchored in the heart, housing 12 is anchored to the pocket by standard procedures as known in the art. Then, the skin is sutured. Patient must relax for 6 hours without moving the upper extremities. Following implantation clinical assessment is performed according to standard procedures.

System 10 is then calibrated taking into account two main calibration problems: gyro-to-accelerometer orientation, and linear errors.

The first simply deals with the fact that the two (different) sensors are manually positioned on a mutual platform. The orientation of the two sets of triaxial sensors relative to each other is not that of complete agreement.

The second calibration problem deals with a problem of linear transformation existing between the real measurements and what is read by the data acquisition (DAQ) interface.

To address the first problem, the sensor is fixed to a cube, and its output is recorded in six different trials. In the first three, the cube is laid down on three orthogonal sides and the recording is at rest. In the next three, the cube is again laid down on three orthogonal sides, and is rotated around, always around the laboratory's e3 (but in the cube's frame of reference, laboratory's e3 coincides with a different vector each time). The idea is to have a lot of energy in the recorded signals, and to rotate the readings so that, on average, the energy is maximized in one direction, and is minimized in the two orthogonal directions. The cube serves as a common platform for both sensors. Thus, for each sensor, the transformation matrix is calculated from its triaxial position in space relative to the cube's own frame of reference. Then, using both these matrices, it is possible (by multiplying one by the transpose of the other) to obtain the transformation matrix between both. It is possible to organize the two in three different ways, so the solution should be that for which the angles are minimal.

The second problem is much more pronounced in the gyros than in the accelerometers. The assumption is that the real rate orientation values are composed of a scaling of the measured value, plus a certain offset, where the offset is largely negligible (but is calculated anyway). To measure the linear dependence, the cube is again laid down on three orthogonal sides, and for each side, the cube is rotated (again about the laboratory's e3) to a predetermined large angle, (say by 270 degrees), but making stops at two other predetermined angles before (say, 90 and 180 degrees), so that the end result when plotting the graph of rotation vs. time (after rotating the data back to the cube's system and integrating) is that of three steps with plateaus between them. After having all three recordings, the first thing is to make sure that no offset is required. Then, the three scaling parameters are sought by finding the most likely ones that, when used, produce the correct angles in all three directions.

Thus, the present system can provide continuous, real-time, beat-to-beat, information on the mechanical activity of the heart and enables closed or open loop modification of heart mechanical function according to the information obtained and processed thereby.

As is mentioned hereinabove, the present system can be used to improve heart function as well as diagnose and repair heart irregularities and pathologies.

The following describes several uses for the present system starting with heart resynchronization. Heart Resynchronization

In approximately 30% of patients with heart failure (HF), an abnormality in the heart's electrical conducting system, called intraventricular conduction delay or bundle branch block, causes the two ventricles to beat in an asynchronous fashion. That is, instead of beating simultaneously, the two ventricles beat slightly out of phase. This asynchrony greatly reduces the efficiency of the ventricles in patients with heart failure, whose hearts are already damaged. Cardiac Resynchronization Therapy (CRT) re- coordinates the beating of the two ventricles by pacing both ventricles simultaneously. This differs from typical pacemakers, which pace only the right ventricle. When the work of the two ventricles is coordinated, the heart's efficiency increases, and the amount of work it takes for the heart to pump blood is reduced. Studies with CRT have demonstrated its ability to improve the symptoms, the exercise capacity, and the feeling of well-being of many patients with moderate to severe heart failure. Studies have also shown that CRT can improve both the anatomy and function of the heart - tending to reduce the size of the dilated left ventricle, and therefore improving the left ventricular ejection fraction (LVEF). Perhaps most importantly, CRT can improve the survival of patients with heart failure.

Blood pumping function of the heart is composed of at least three distinct motions of the LV walls muscle: (a) linear contraction of the muscle, specifically the shortening of the radii of the LV during contraction, (b) longitudinal motion due to the linear contraction of the muscle and (c) a twist motion of the heart which is similar to a wringing motion where the left ventricle base and the right ventricle apex are rotating in opposite directions along a rotational axis. These three (or more) motion components are intertwined and are difficult to separate and analyze.

While reducing the present invention to practice, the present inventors conducted pre-clinical experiments and uncovered that a central rotational axes (CRA) system may be found, where most of the rotational motion of the heart, sensed by accelerometers and gyroscopes located at the distal end of implanted leads, occur around one axis and only negligible rotational motion occurs around the two perpendicular axes of the CRA system. Furthermore, the inventors of the present invention discovered that during the systolic phase the rotation of the RV apex lead around the CRA is clockwise and in the diastolic phase the rotation of the RV apex lead is anticlockwise. The rotation of the LV base lead around the CRA is inverted and is anticlockwise in the systolic phase and clockwise in the diastolic phase. The rotation motion in the systolic phase is named herein the twist motion and the angle of rotation calculated as the time integral of the measured temporal angular velocities is named the twist angle. The rotation motion in the diastolic phase is named herein untwist motion and angle of rotation calculated as the time integral of the measured temporal angular velocities is named the untwist angle. The twist and untwist rotations are correlated with the cardiac cycle events and phases (as sensed by electrical activity) to derive variables as described herein below.

The inventors of the present invention have found that a function of the lead's distal end rotational angles Qx, Qy and Qz, and angular velocities COx' , COy' and COz' , measures the rotational energy in the perpendicular direction to the main axis in the CRA system, and the orientation of the CRA may be defined as the orientation of the X axis of the CRA system that minimize this function.

Following identification of the CRA system, the measured temporal angular velocities and the twist angles are rotated to the CRA system and excellent correlations with left ventricle pressure (PLV), Electrocardiogram (ECG) T wave and Echocardiography transmitral inflow E and A waves for example, are achieved.

The measured and calculated temporal angular velocities and twist angles may be used to optimize AVD and VVD parameters during implantation, to re-position the implanted leads and to adjust AVD and VVD later in clinical follow-ups or dynamically in a closed loop CRT systems as described herein below.

According to embodiments of the present invention, the CRA system may be calculated in the systolic phase, in the diastolic phase E wave and A wave and also in between the systolic and the diastolic phases. The calculated angular velocities and twist angles may be rotated to the CRA system in each phase.

According to embodiments of the present invention, if a fixed CRA system is not found, temporal heuristic angular velocity amplitude may be calculated as the square root of the sum of squares of the three components of the measured angular velocities vector. A twist signal may still be calculated by integrating over time the temporal heuristic angular velocity amplitude, and optimization of AVD and VVD may be performed using the temporal heuristic angular velocity amplitude. Figure 4a illustrates the calculation of the heart CRA system from raw gyroscope data in a flow chart, according to embodiments of the present invention. The rotational velocities COx', COy' and COz' are measured by gyroscopes located at the lead's distal end 410. The rotational velocities have units of degree per second. Next, a function F of three angles (Q_x Q_y , Q_z ) and the measured temporal angular velocities are calculated as defined in Eqs. 1-3 below where R_x R_y and R_z are rotational matrixes of angles (Q_x Q_{y ;} Q_z ). Processing unit (e.g. 18 in Figure 1) is configured capable of performing a search for the angles Q_x Q_y , Q_z that minimize the rotational energy in the two perpendicular axes to the X axis 420. The processing unit rotates the angular velocities to the CRA system 430.

The rotational matrixes are defined below -

1 0 0

R_X(0) = O cos# -sin# Eq. la

0 sin Θ cos Θ cos Θ 0 sin Θ

0 1 0 Eq. lb

- sin Θ 0 cos Θ

cos Θ - sin Θ 0

R_z(0) = sm0 cos# 0 Eq. lc

0 0 1

The F function used to minimize the rotational energy in the Y and Z axes is defined below in Eqs 2 and 3:

F_t(Q_x Q_y ¾) = (0 1 0)*R_x(Q_x)*

+ (0 0 D*R_x(Q_x)*Ry(Qy)*R_z(Q_z)

F (Q_X Q_y Q_Z ) =∑F (Q_X Q_y Q_z ) Eq. 3

The rotation to the CRA system is performed using Eq. 4 below and where the CRA main rotational axis is the X axis-

CRA(Q_x Q_y Q_z ) = R_x (Q_x ) * R_y (Q_y ) * R_z (Q_z ) * Eq. 4

Figure 4b illustrates the calculation of the heart CRA system from integrated gyroscope data in a flow chart, according to embodiments of the present invention. The rotational velocities COx', COy' and COz' measured by gyroscopes 420 located at the lead's distal end are integrated over time 422 and gives an angles Qx, Qy and Qz that replace the three rotational velocities COx' , COy' and COz' in Eq. 2,3 and 4. The integration is performed during each heart beat where the calculation is synchronized using the detected QRS complex if ECG signal is available, or using the motion sensors to detect the "silent periods", i.e. the end of systolic phases, were the motion signal vanishes every heart beat. According to embodiments of the present invention, linear drifts of the calculated rotational angles may be removed using the accelerometer data 424. The processing unit performs a search for the angles Q_x Q_{y ,} Q_z that minimize the rotational energy in the two perpendicular axes to the X axis 426. The processing unit rotates the angular velocities to the CRA system 428.

Figure 4c illustrates the calculation of the temporal lead's distal end position from gyroscopes and accelerometers data in a flow chart. The temporal three components of the lead's distal end angular velocities COx' , COy' and COz' 430 and accelerations Ax, Ay, Az 432 are measured. Rotation to the CRA system is performed 434. A low pass filter function is applied to the measured accelerations rotated to the CRA system to extract the gravitational accelerations in the CRA system (Gx', Gy' and Gz') 434. The gravitational accelerations are subtracted from the measured accelerations and the linear accelerations in the CRA system are calculated 436. Reset loop 438 is used to synchronize the calculation to the cardiac cycle by detecting the "silent phases", i.e. the end systolic phases, where the linear acceleration almost vanish and use this information to calibrate and to re-start integration in each cardiac cycle. The 3 velocities Vx, Vy and Vz are calculated from the linear velocities by integration 440. The 3 components of the lead's distal end position X_t, Y_t and Z_t are calculated from the integrated velocities by integration 442.

Figure 5 illustrates the rotation of the calculated angular velocity vector to the heart CRA system, according to embodiments of the present invention. The X, Y and Z components of the measured temporal angular velocity vector are shown in Figure 5 510. Before rotation to the CRA system they do not point to any specific direction in space. After the CRA system is found 520 the temporal angular velocities are rotated as shown in Figure 5 530 such that the temporal angular velocity X' axis is parallel to the main CRA system X' axis. Most of the temporal angular velocity is seen around the X' axis. The direction of rotation changes from clockwise in the systolic phase to anticlockwise in the diastolic phase around the CRA system X' axis. Radial motion component and longitudinal motion component relative to the found CRA may also contribute to the total motion relative to the CRA system 520 and may be used to optimize AVD and VVD alone or in combination with the main angular velocity component X' 530 in the CRA system.

Figure 6 illustrates left ventricle pressure and ECG signal on the upper part synchronized with rotational angles of the apex lead's distal end and the CS lead's distal end on the lower part acquired in a pre-clinical experiment. Left ventricle pressure (PLV) signal 610 shows the pressure recorded in the heart left ventricle. The PLV signal is low at the diastolic phases (about 30 mmHg) and increases to a maximal value (about 80 mmHg) during the systolic phases periodically. Electrical cardiogram signal (ECG) 620, shows the atrial P wave 620, the QRS complex 622 and the T wave 624, in each cardiac cycle. The PLV and ECG signals are shown as a time reference of the cardiac cycle events for analysis of the two motion sensor signals shown at the bottom of Figure 6. As shown, the right ventricle apex lead's distal end angle of rotation 630 around the CRA has high correlation with the PLV signal 610. During the systolic phase the apex lead' s distal end rotates in the anti-clockwise direction and reaches a maximal value of about 10 degrees in each cardiac cycle.

The apex lead rotation begins just after the ventricle contracts as shown by the

ECG QRS complex 622 and the rise of PLV signal 610. The back rotation of the apex lead occurs after the T wave 624 shown also with the vertical lines 650 that were added to highlight the end of the systolic phase in each cardiac cycle. The CS lead's distal end rotation starts just after the atrial P wave 620 is seen in the anti-clockwise direction from negative angle of -10 degrees to about positive 2 angles. After the QRS complex occurs 622 the CS lead's distal end flips the rotational direction, and rotates in the clockwise direction around the CRA back to about -10 degrees during the systolic phase. As shown in FIG. 6, the apex and the CS rotation angles reach a maximal and minimal value respectively simultaneously at the end of the systolic phase highlighted with the vertical lines 650 every cardiac cycle.

According to embodiments of the present invention, the twist motion, i.e. the rotation angles of the apex and CS leads and their time correlation with the systolic phase end may be used to resynchronize the heart contractions. The inventors of the present invention propose that a key to a successful resynchronization therapy scheme may be the twist angle of the two leads' distal ends rotated to the calculated CRA system. Accordingly, the AVD and VVD parameters of a CRT device may be found such that the RV apex and the LV CS leads' twist angles will be maximal and/or will occur in synchrony. Furthermore, According to embodiments the present invention, the difference in twist angle of the RV apex and LV CS leads' distal ends, i.e. RV Apex Twist angle - LV CS Twist angle, may be used to remove drifts and noise from the measured signals and hence the twist angle, and more particularly the twist angles difference, may be favorable measure that includes the clinical information of the cardiac cycle (correlation with PLV, T wave and transmitral inflows for example) and where the subtracted twist angle signal has a high magnitude of about 20 degrees maximally and a reduced noise.

Figure 7 illustrates in a cross correlation diagram the left ventricle pressure and the CS gyroscope twist angle, according to embodiments of the present invention. The left ventricle pressure in mmHg is shown on the vertical axis and the CS gyroscope twist angle is shown on the horizontal axis. The cross correlation is high, -0.959, which means that after the CRA system is found and a rotation of the measured angular velocities to the CRA system is performed, the twist angle changes from about 4 degrees (correlated with PLV of 70 mmHg) to about 12 degrees (correlated with PLV of 140 mmHg). The very high correlation of the twist angle with the left ventricle pressure makes the twist angle a key to cardiac resynchronization scheme of the heart ventricles contraction. The maximal time derivative of the pressure, dp/dt max (maximal contractility) is correlated with the maximal temporal angular velocity and thus an optimization of AVD and VVD can be performed where the optimization target would be the maximal temporal angular velocity and hence maximal contractility (dp/dt max). When calculating the AVD and VVD the propagation delay in both the RV and the LV has to be taken into account, where the propagation delay is the time delay (typically 1- 30 milli seconds) between the time the stimulation is applied and the time that mechanical contraction of the two ventricles occur.

Figure 8 illustrates in a two angles' plane diagram the gyroscope's angular velocity vector orientation before and after rotation to the CRA system, according to embodiments of the present invention. The angle Φ is the azimuthally angle in the YZ plane, perpendicular to the CRA system X axis and the angle Θ is an altitude angle relative to the CRA system X axis. Each point in the plot represents the temporal orientation of the angular velocity vector of the lead's distal end. Before rotation to the CRA system, the angles appear in the two angles' plane as shown with black dots and have high density around circles 810 and 811 in the mid two angles' plane diagram in arbitrary location in the plane. After rotation to the CRA system the angles' dots are shown in red and their density now is high around circles 820 and 821, located around 0 degrees during the systolic phase where rotation is clockwise around the CRA system X axis, and around 180 degrees during the diastolic phase where the rotation direction flips and is anticlockwise. The azimuthally angle Φ changes between 0 and 20 degrees and is maximal when the temporal velocity vector is not oriented around the CRA X axis in between the systolic and the diastolic phases. The high density points shown around 0 degrees and flipped 180 degrees of Θ angle prove that the CRA system is a real physiological system of axes that may be found in each patient's heart and that the rotation of the RV apex lead's distal end is in the clockwise direction during systolic phase and flips to anti-clockwise direction in the diastolic phase in each heart beat while the rotation of LV coronary sinus lead's is flipped in 180 degrees and is anti-clockwise during the systolic phase and flips to clockwise direction in the diastolic phase in each heart beat.

Figure 9 illustrates the enhancement of the twist angle calculated in the CRA system, according to embodiments of the present invention. Left ventricle pressure and ECG signal 910 show the cardiac cycle events timings used as a reference for the measured gyroscopes twists shown in the middle 920 and lower 930 parts of FIG. 9. The middle part figures show the three gyroscopes twist angles 911 X axis, 912 Y axis, and 913 Z axis. Before rotation to the CRA system, the calculated twist around the X axis is the dominant twist, having maximal twist angle of about 7 degrees in a cardiac cycle. However, the twist angle around the Y axis 912 is comparable and shows maximal twist angle of about 4 degrees while the Z axis twist 913 is somewhat weaker with maximal value of about 2-3 degrees. On the bottom figure 920, rotation to the CRA system was performed and the X axis 921 is aligned now with the CRA system. The dominant X axis twist angle increased to about 10 to 11 degrees. Furthermore, the Y axis twist angle 921 is much weaker now having a maximal value less than 2 degrees. FIG. 9 proves in a pre-clinical experiment that the minimization scheme that searches for minimal rotation in the perpendicular directions to the main X axis is effective. Note also that the maximal twist angle occurs at the peak of the ECG T wave timing at the end of the systolic phase and hence the timing of the maximal twist value includes information of the underlying cardiac cycle.

Figure illustrates the correlation of the leads temporal angular velocity signal with the transmitral inflow E and A waves. The left ventricle pressure and ECG signals are shown on the upper part of FIG. 10 synchronized with the gyroscope angular velocities on the middle part and with Echocardiogram measurement on the lower part. Left ventricle pressure and ECG signal 1010 show the cardiac cycle timings used as time reference for the analysis of the measured gyroscope angular velocity 1020. The temporal angular velocity signal 1011 changes more rapidly during the cardiac cycle and includes more information comparing to the twist angle signal shown in Figure 8. The angular velocity signal 1011 is sensitive to the left ventricle filling phase of the diastolic cycle and the correlation with the transmitral inflow E and A waves signal is shown in FIG. 10 bottom part 1021. The early passive transmitral inflow blood filling E wave 1022 and the transmitral inflow active blood filling A wave 1024 recorded with Echocardiography can be seen with the leads' distal end temporal angular velocity signal 1012 and 1014.

Transmitral inflow E and A waves are blood flows transmitted to the left ventricular through the mitral valve during the diastolic filling phase. The E wave is related to early filling of the left ventricle while the A wave is related to the following atrial component of blood filling (called also atrial kick). The angular velocity signal correlation with the transmitral inflow E wave and A wave shown in Figure 10 can be used as a target function of an optimization scheme similar to Echocardiography based optimization scheme. As shown in Figure. 10, the end of the atrial kick A wave may be determined using the temporal angular velocity signal replacing the Echocardiograph and the AVD value may be determined and programmed to the CRT device accordingly.

Figure 11 illustrates the correlation of the gyroscope twist angle with the transmitral tissue Doppler E and A waves, according to embodiments of the present invention. The left ventricle pressure and ECG signals are shown on the upper part of Figure 11 synchronized with the gyroscope twist 1110 on the middle part and with Echocardiogram measurement 1120 on the lower part. Left ventricle pressure and ECG signal 1110 show the cardiac cycle timings used as a time reference for the measured gyroscope twist 1120. The twist angle 1111 changes more slowly during the cardiac cycle comparing to the temporal angular velocity signal shown in Figure 10 since it is an integration result of the temporal angular velocity signal that averages and smoothes the signal. The twist angle 1111 is still sensitive to the ventricles filling phases during the diastolic cycle and the correlation with the transmitral tissue Doppler E and A waves is shown in Figure 11 bottom part 1121. The passive blood filling E wave 1122 and active blood filling A wave 1124 can be observed with the twist angle 1112 and 1114. The twist angle correlation with the transmitral tissue Doppler E and A waves is seen although smoother and having a time delay. Thus, the twist angle can also be used as a target function of a CRT device optimization scheme where the AVD may be determined in correlation with the twist angle correlated with the A wave.

According to embodiments of the present invention, a CRT implant may include further means to transmit the sensed signals and the calculated motion of the at least two electrodes distal ends to an external processor unit connected to a display in order to remotely monitor and validate the performance of the cardiac resynchronization implant. According to embodiments of the present invention, CRT implants may vary AVD and VVD dynamically, beat after beat, according to the temporal angular velocities or the calculated twist angles.

According to embodiments of the present invention, the calculated twist angles in each heart beat depend on AVD and VVD values, and when the AVD and VVD values are optimal the peaks of the twist angles occur simultaneously and in correlation with the aortic valve closure.

According to embodiments of the present invention, the optimal AVD may be determined according to the calculated right ventricle apex twist angle changing sign from negative values to positive values, and wherein the changing sign is correlated with the end of the late diastolic flow A wave correlated further with the end of the atrial contraction. Next, after the optimal AVD is determined, optimal VVD may be determined according to the calculated left ventricle CS lead twist angle having maximal value in synchrony with the calculated right ventricle apex lead twist angle. According to embodiments of the present invention, the optimal AVD and VVD may be determined during implantation of the CRT system, may be re-calculated and may vary dynamically every heart beat, or may be re-calculated and vary dynamically every predefined, pre-programmed time period.

According to embodiments of the present invention, the distance between the at least two leads distal ends (typically the distance from the RV apex to the LV base) may be calculated continuously, and AVD and VVD that maximize the calculated distance may be determined as optimal AVD and VVD values.

According to embodiments of the present invention, the stimulator's processing unit may include means for calibrating the leads' distal end motion sensors during each heart beat using a mechanical phase of the heart cycle where the variability of heart motion is minimal. The mechanical phase may be the end of the systolic phase as a non- limiting example. Other cardiac cycle events may be used to calibrate the motion sensors and are in the scope of the present invention.

According to embodiments of the present invention, part of the body motion, gravitational field accelerations and noise may be removed by subtracting the measured accelerations of the at least two leads motion sensors. Acceleration data received from the at least two motion sensors and processed as described for example in Figure 4c may be subtracted by the stimulator processing unit and the common components of body motion, gravitational field accelerations and noise may be thus removed.

Furthermore, according to embodiments of the present invention, additional motion sensors may be added to the CRT system stimulator unit (as shown in FIG. lb) in order to subtract body movements, gravitational field accelerations and noise from the at least two leads motion sensors signals.

According to embodiments of the present invention, a clinician implanting the resynchronization system, can activate a test provided within the processor unit that detects the mechanical phase used by the resynchronization system for calibrating measured motion signals, and alternatively the clinician may select another mechanical phase of the heart cycle for the calibration of the motion sensors.

According to embodiments of the present invention, the processing unit includes means for resetting the calculation integrals related to the calculation of the CRA system and the motion of the distal end relative to the CRA system after each heart beat in the systolic phase end where the heart motion is minimal.

Figure 12 illustrates cardiac resynchronization therapy system that includes further an external processor unit and a display, according to embodiments of the present invention. The cardiac resynchronization therapy system includes an implant 1200 an external processor unit 1280 and a display 1290. Cardiac resynchronization therapy system 1200 includes atrial lead 1210 right ventricle lead 1220 and left ventricle lead 1230. Stimulator unit 1240 includes further a processing unit 1250 and pulse generator 1260. Atrial lead 1210 right ventricle lead 1220 and left ventricle lead 1230 have a proximal end connected to stimulator unit 1240 and a distal end attached to the myocardium tissue such that the electrical activity of the right atrium, right ventricle and left ventricle myocardium tissue may be sensed and stimulation may be delivered to the tissues through the leads. At least one ventricle lead, and preferably both leads, includes means for sensing the motion of the lead's distal end. Processing unit 1250 includes further means for calculating the CRA system of the heart motion during heart beats and the motion of the lead's distal ends relative to the CRA system. Cardiac resynchronization therapy system implant 1200 includes further means to transmit the sensed signals and the calculated motion of the at least two leads' distal ends to external processor unit 1280 connected to a display 1290 in order to remotely monitor and validate the performance of the cardiac resynchronization system.

Figure 13 illustrates a method for providing cardiac resynchronization therapy, according to embodiments of the present invention. The method includes the steps of: (a) delivering bi-ventricular pacing with dynamically varying AVD and VVD values in a first pre-defined time interval 1310 (b) receiving inputs from atrial lead and at least two ventricle leads 1320, wherein the at least two leads having proximal and distal ends, and wherein the proximal ends of the leads are connected to a stimulator unit and their distal ends are connected to myocardial tissues, wherein the at least two leads include means for sensing signals related to the electric activity of the heart, means for sensing signals related to the motion of the leads distal ends and means for delivering electrical stimulations to the myocardial tissues, (c) calculating the CRA system using the received motion signals 1330, wherein most of the distal ends leads angular motion is an angular velocity motion around the CRA system X axis, (d) calculating the twist angles of the at least two leads distal ends relative to the calculated CRA during a heart beat 1340, (e) finding the optimal AVD and VVD values from the delivered AVD and VVD values according to the calculated twist angles of the at least two leads distal ends relative to the calculated CRA system in the pre-defined time interval 1350 and (f) delivering bi-ventricular pacing with the optimal AVD and VVD values found in the first pre-defined time interval during a second pre-defined time interval 1360.

The cardiac resynchronization therapy method described above includes further the steps of selecting the first time interval within which the calculations takes place that may be every other heart beat or every integer number Nl heart beats. The cardiac resynchronization therapy method described above includes further selecting the second pre-defined time interval within which bi-ventricular pacing with the optimal AVD and VVD values found in the first pre-defined time interval takes place. The second predefined time interval may be every other heart beat or every integer number N2 heart beats.

According to embodiments of the present invention, the provided method includes further the steps of: finding the timing of the peak angular velocity of each of the motion signals of the at least two leads distal ends relative to the calculated CRA and relative to the sensed atrial signal during a heart beat, and finding the AVD and VVD values where the timing of the peaks of angular velocities are equal which means that both ventricles contract in synchrony.

According to embodiments of the present invention, the provided method includes further the step of finding the AVD and VVD values where the timing of the peaks of angular velocities are not equal but the peaks values are maximal which means that hemodynamic functions like stroke volume, cardiac contractility and / or cardiac output are optimal.

According to embodiments of the present invention, the provided method includes further the step of: finding the AVD value that generates the maximal peak angular velocity value of the right ventricle apex lead relative to the calculated CRA system during a heart beat, and finding the VVD value that generates the maximal peak angular velocity of the CS lead relative to the calculated CRA system during a heart beat.

Figure 14 illustrates a method for validating the response to cardiac resynchronization therapy, according to embodiments of the present invention. The method of validating the response to cardiac resynchronization therapy includes the steps of: (a) implanting 1410 an atrial lead and at least two ventricle leads in first locations in the right ventricle apex and left ventricle coronary sinus, wherein the at least two leads having proximal and distal ends, and wherein the proximal ends of the leads are connected to a stimulator unit and their distal ends are connected to myocardial tissues, wherein the at least two leads include means for sensing signals related to the electric activity of the heart, means for sensing signals related to the motion of the leads distal ends and means for delivering electrical stimulations to the myocardial tissues, (b) delivering 1420 bi-ventricular pacing with varying AVD and VVD values, (c ) calculating 1430 a CRA system using the received motion signals, wherein most of the motion of the leads distal ends is an angular velocity motion around the CRA system X axis, (d ) calculating 1440 the angular velocity of the at least two leads distal ends relative to the calculated CRA during a heart beat, (e) displaying 1450 the calculated twist angles or the measured temporal angular velocities signal on a display, (f) Repositioning 1460 leads if the twist angles signals are less than a first predefined value for the coronary sinus lead and less than a second pre-defined value for the apex lead. If the twist angles signals are weak a new location for the leads in the coronary sinus and/or the apex is tested and validated.

According to embodiments of the present invention, alternatively the twist angles difference or the temporal angular velocities signals may be used to determine a satisfactory response.

According to embodiments of the present invention, the clinician may reposition one of the leads, or both leads, if optimal AVD and VVD are not found.

Furthermore, according to embodiments of the present invention, clinicians may reposition the RV apex lead, the LV CS lead or both leads in order to improve the response to stimulation with different AVD and VVD values.

Figure 15 illustrates a method for optimizing the AVD and VVD of a cardiac resynchronization therapy device, according to embodiments of the present invention. The method of validating the response to cardiac resynchronization therapy includes the steps of: (a) implanting 1510 an atrial lead and at least two ventricle leads in first locations in the right ventricle apex and left ventricle coronary sinus, wherein the at least two leads having proximal and distal ends, and wherein the proximal ends of the leads are connected to a stimulator unit and their distal ends are connected to myocardial tissues, wherein the at least two leads include means for sensing signals related to the electric activity of the heart, means for sensing signals related to the motion of the leads distal ends and means for delivering electrical stimulations to the myocardial tissues, (b) delivering 1520 bi- ventricular pacing with varying AVD and VVD values, (c ) calculating 1530 the CRA system using the received motion signals, wherein most of the motion of leads distal ends is an angular velocity motion around the CRA system X axis, (d ) calculating 1540 the angular velocity of the at least two leads distal ends relative to the calculated CRA during a heart beat, (e ) displaying 1550 the angular velocities signal on a display, (f) finding 1560 the optimal AVD and VVD values from the delivered AVD and VVD values according to the calculated motion of the at least two leads distal ends relative to the calculated CRA system.

According to embodiments of the present invention, the calculated twist angle signals rotated to the calculated CRA system in each heart beat depend on the AVD and VVD values, and wherein the peak values of the twist angles are maximal when the delivered AVD and VVD values are optimal. Accordingly, a CRT system may be programmed with the AVD and VVD values that produce the maximal twist angles values during implantation and furthermore, a closed loop CRT system may vary AVD and VVD dynamically according to the calculated twist angles rotated to the CRA system.

According to embodiments of the present invention, the peak of the angular velocity motion signal of the leads relative to the calculated CRA system in each heart beat may be correlated with the transmitral inflow E wave (early diastolic flow), transmitral inflow A (late diastolic flow) waves, E' (early diastolic Doppler velocity), and A' (late diastolic Doppler velocity) waves measured with echocardiography. Accordingly, a CRT system may be optimized and programmed with the AVD and VVD values that does not cut the A wave similar to Echocardiography based CRT optimization follow-up scheme and wherein the A wave form is extracted from the measured temporal angular velocities or the calculated twist angles.

According to embodiments of the present invention, the optimal AVD and VVD values may be the values where the RV apex lead's and the LV CS base lead's untwist angles, change sign (from negative to positive value and from positive to negative value). The untwist angles sign change occurs when the heart base and RV apex rotations change direction at the onset of the systolic phase, i.e. the end of the atrial contraction A wave at the end of the diastolic phase.

According to embodiments of the present invention, the optimal AVD and VVD values may be the values where the untwist angles are maximal during a heart beat. The maximal untwist angles values are indication to the efficacy of the atrial contraction to fill more blood to the LV before the onset of the systolic phase.

According to embodiments of the present invention, the optimal AVD and VVD values may be the values where the iso-volumetric phase of both RV and LV occurs simultaneously at the beginning of the systolic phase, i.e. the ventricles are mechanically re- synchronized. The iso-volumetric phase might be identified using the temporal angular velocities signals as the maximal angular velocities signal. The temporal angular velocity signal exhibit strong oscillation during the QRS complex in the iso-volumetric phase. According to embodiments of the present invention, simultaneous maximal value of angular velocities signal of both RV and LV leads distal end is equivalent to LV maximal contractility (dp/dt max). According to embodiments of the present invention, the optimal AVD and VVD values may be optimized according to calculated twist angles or difference in twist angles of the at least two leads distal ends, to the temporal angular velocities or the difference in temporal angular velocities of the at least two leads distal ends, to the difference in radial velocities of the at least two leads distal ends, to the difference in lateral velocities of the at least two leads distal ends, to the difference in accelerations of the at least two leads distal ends, to the difference in time intervals between the electric activation of the ventricle and the accelerations or velocities of the at least two leads distal ends, to the temporal relation between onset of accelerations and onset of angular velocities, to the relation between the amplitude of acceleration signal of the at least two leads distal ends and the amplitude of angular velocities of the at least two leads distal ends, the maximal distance between the two electrodes and to two or more combinations of motions listed hereinabove.

Advantageously, the present invention cardiac resynchronization therapy systems may be used to optimize the AVD and VVD according to calculated twist angles and/or temporal angular velocities measured with motion sensors included in the implanted lead's distal end.

Another advantage of the cardiac resynchronization therapy systems described above is that means to calculate the heart's CRA system, the twist angles and the temporal angular velocities in the CRA system are provided. Most of the rotational energy is seen in the CRA system X axis, and thus the rotation around the CRA system X axis may be used to optimize AVD and VVD values.

Another advantage of the cardiac resynchronization therapy systems described above is that if a fixed CRA system can not be found, a temporal heuristic angular velocity amplitude and twist angle may still be calculated and optimization of AVD and VVD can be performed.

Another advantage of the cardiac resynchronization therapy systems described above is that re-positioning of the implanted leads can be performed during implantation of the CRT system using the calculated twist angles and/or the temporal angular velocities as indications of the response to therapy. Another advantage of the cardiac resynchronization therapy systems described above is that response to CRT may be improved during implantation based on the calculated twist angles and/or temporal angular velocities.

Another advantage of the cardiac resynchronization therapy systems described above is that the temporal position and thus the distance between two leads distal end may be calculated continuously.

Another advantage of the cardiac resynchronization therapy systems described above is that a closed loop CRT system may vary AVD and VVD dynamically beat after beat according to calculated twist angles and/or temporal angular velocities.

In summary, the present system calculates and utilizes variable that relate to heart twist motion and electrical activity and thus enables to optimize lead's positioning and AVD and VVD values during implantation and continuously in a closed loop system. Systolic tension onset signal ( STOS )

The initial systolic mechanical event sensed by the motion sensors is the systolic tension onset signal (STOS) produced by the abrupt contraction of the myocardium or the closure of the atrio -ventricular valves or a combination thereof. The duration of the STOS, DSTOS, is a short rapidly decaying signal (approximately 120 msec, see Figure 4, between vertical lines 1 and 2). It typically terminates prior to the onset of a signal indicating rotation of the heart. The amplitude of STOS is proportional to the state of contractility of the myocardium (as seen in Figure 3) where the amplitude at baseline is: 0.5 g, decreasing to 0.25 g under the effect of esmolol, and increasing to >1 g under the effect of epinephrine.

The amplitude of STOS can be correlated with the isovolumic contraction time

(ICT). Hence, STOS can be incorporated as a new cardiac performance measure (similar to the Tei-index - Journal of the American Society of Echocardiography Volume 15, Issue 9, Pages 864-868, September 2002). The DSTOS is proportional to a state of contractility (Figure 5, panel 2). Hence, the present invention provides, for the first time, an approach for following the contractility of the heart on a beat-to-beat basis. As is known in the art, contractility of a heart depends on preload, afterload, and heart rate. However, such parameters are not measured on a beat to beat time scale and as such cannot be used for assessment of contractility of a heart on a beat-to-beat basis.

The contractility measured by the present invention can also be compared at various postures of the individual. For example, posture sensing sensors (e.g. accelerometers) in the housing can be used to provide information on the posture of the human body, while time counting unit in the housing can provide the time of day of posture measurement. Such integrated data can be used to asses the contractility of the heart at specific time intervals. Furthermore, the standard deviation of the STOS can be used to assess how contractility varies from beat to beat, a heart parameter which is new and unique to the present approach.

As shown in Figure 6, at baseline the DSTOS is approximately 80 msec (from onset to termination). It remains approximately 80 msec under the effect of esmolol, and shortens to approximately 60 msec under the effect of epinephrine. It is interesting to note that under the effect of epinephrine the duration of conduction from peak R wave to the point between the minimum and maximum of the accelerometer signal (second vertical line from left) shortens significantly. STOS may also be used as an indicator of the contractility of the heart. Systolic rotation signal (SRS)

After the electric signal propagates through the myocardium, systolic wall tension builds up. A peak of this tension is represented by STOS and DSTOS. Within approx 30 msec from the center of STOS (the point between max. and min. STOS signal) the motion sensors utilized by the present invention indicate the onset of a rotational motion. The time from the center of STOS (or another measure for relating STOS event to a following event) to the onset of rotation is a new physiologic measure indicating the time required for building sufficient force to begin the rotation motion of the heart. This time is also a part of the isovolumic contraction time (ICT). ICT is difficult to measure by non-invasive means such as echocardiography. The present invention provides a measure proportional to ICT on a beat to beat basis. At present, ICT and IRT (isovolumic relaxation time) are used by the Tei index for assessing cardiac performance. The present invention provides a continuous means for assessing these variables in real-time, and on a beat-to-beat basis.

Quantifying systolic rotational motion

By integrating data from several sensors and deriving variables, the present invention can also be used to quantify systolic rotational motion. For example, the present invention can be used to provide peak rotational velocity (Figure 7, second panel from bottom), maximal angle obtained during systolic rotation (Figure 7, bottom panel), main axis of rotation, direction of main axis of rotation relative to a plane vertical to the direction of the gravitation force and duration of rotation (Figure 7).

Each of these measures provides information regarding the motion of the heart and can be correlated with other information. For example, a correlation between the TD signal obtained during systole, also known as the S' wave, and the duration of rotation (Figure 8) can be established using the present invention. The area of the S' wave correlates with the maximal angle of rotation during systole. The rotation signal provided by the present invention is more accurate and reproducible than a standard TD signal obtained from the body surface.

The data obtained by the present invention is compared to a TD image in Figure 8. Five vertical lines are shown in Figure 8, (from left): line (1) designates the time of peak R wave and line (2) shows the onset of systolic rotation, also termed systolic twist in the literature. The timing of onset of rotation can be clearly discerned form the signals generated by the present invention, yet it is difficult to identify this event in the TD signal (bottom panel). Line (3) indicates peak and termination of systolic twist in the present data, yet the TD signal still records a signal in the direction of the transducer. The isovolumic relaxation phase detectable at this point in time cannot be easily identified by the TD signal. Such a phase can be detected from the rotation signal - following a peak systolic rotation there is a short plateau (approximately 50-100 msec) followed by an untwist phase ("backward" rotation) to the fourth vertical line.

Line (4) delineates the onset of the diastasis. Between line (3) and (4), the TD signal shows an E' wave reflecting the motion of the tissue during the early phase of LV filling. According to the TD, the E' wave terminates prior to the first component of the untwist. Between line (4) and (5) the heart does not rotate, and only after the P wave (of the ECG) it is possible to see the heart untwist further [this is between line (5) and line (2)] . According to the signals shown in Figure 8 there is a delay between the P wave and the (backward) rotation, untwist, associated with it, starting with line (5).

This time interval from the peak of the P wave to the onset of the second component of the untwist is an important interval. Standard pacemakers usually measure the time between P wave and onset of QRS complex in order to evaluate whether a spontaneous ventricular cycle follows atrial activation. However, the present invention provides information regarding the electric activation of the atria and the resulting mechanical untwist (component 2 of the untwist). This is important especially in HFPEF since the contribution of the atrium to LV filling is significant. It is important to synchronize atrial contraction with ventricular contraction in order to maximize the contribution of the atria. It is well known that when the PR interval is prolonged the volume ejected by the atria to the LV may flow backwards to the LA according to pressure gradients, and this accounts, at least in part, for decreased LV filling. The present invention enables accurate identification of the timing of mechanical atrial and ventricular events and thus a more effective treatment. Such optimization of cardiac mechanical events is more accurate and more effective when performed based on the mechanical events, rather than electrical events as is currently practiced in the art.

The data obtained by the present invention can also be used to synchronize the ventricular activation with that of the atrium and thereby prevent non- synchronization between the chambers which results in reduced LV filling followed by reduced cardiac output. The present invention can detect right atrium mechanical activity and use this input as a trigger for stimulating the right ventricle, thereby coordinating the contraction of both chambers. Thus two inputs trigger the pacing of the right ventricle: (1) time interval from last ventricular activity, and (2) sensing of RA contraction. If the mechanical activity of the right atrium is sensed (temporally) before a threshold time interval has elapsed, then pacing of the RV takes place in a coordinated manner relative to right atrium contraction. If during the threshold time interval right atrium contraction was not detected, then the right ventricle is activated by stimulation at the termination of the threshold time interval. Diastolic tension release onset signal (DTROS)

The STOS occurs during systole following the electric triggering event (represented by the QRS peak) while the diastole starts with a short DTROS event (Figure 4, vertical line 3). DTROS is shorter in duration and smaller in amplitude than its systolic counterpart (STOS). DTROS indicates a rapid decrease of tension in the walls of the LV or the closure of the aortic and/or pulmonic valves or a combination thereof. The center of DTROS is the time indicating the onset of LV pressure fall. The amplitude of DTROS correlates with the rapidity of fall of LV pressure, that is minus dP/dt, (-dP/dt). Where the latter is an index of relaxation, which is a difficult parameter to obtain using present day approaches since it is an invasive metric and there are at least two ways of calculating the related exponential. The DTROS is easily obtained with the present invention and provides data on a beat-to-beat basis. DTROS may provide valuable information regarding the contribution of the elastic recoil or diastolic suction mechanism since it is hypothesized that the amplitude of DTROS is proportional to the elastic recoil.

Within milliseconds from the center of DTROS, an "untwist" like rotation event initiates. Often the DTROS is weak and detected concomitantly with the untwist motion. During untwist the heart muscle rotates in a characteristic way - a clockwise rotation of the apex of the heart and a counter-clockwise rotation at the base of the heart (the convention is viewing the heart from the apex to the base along the long axis of the heart). The time from the center of DTROS (a typical metric for delineating DTOS, although other measures may be used) to the onset of untwist is proportional to the isovolumic relaxation time (IRT). Prior to the DTROS, the twist motion terminates and the direction of rotation changes from twist to an untwist motion. Following the DTROS, direction of rotation continues as untwist. The initial untwist motion duration (Figure 8, vertical line 3 to 4, from left) correlates with the volume of the rapid filling of the LV.

Diastolic minimal motion period (DMMP)

The interval between line 4 and 5 (from left to right) of Figure 8 demonstrates that the angle measured by a gyroscope and the TD signal indicate almost 0 velocity. This part of diastole is the diastasis, where the filling of LV is minimal, and compatible with this event is the fact that wall motion of the heart as measured by TD is minimal; it separates the rapid filling of LV, preceding the DMMP, from the atrial contraction following the DMMP. Detecting this phase is important since it serves as an anchor in time for synchronizing a stimulation to the heart if found necessary by the algorithm.

Contractility

A maximum value of a first derivative of an angle of the heart during systole can be used to evaluate contractility (intensity of heart contraction), rate of contraction and the manner of contraction, i.e. it can be used to assess the different phases of heart contraction. For example, the heart may start its contraction rapidly and slow down late in systole or alternatively start slow and augment contraction late in systole. Characterizing heart contraction may be important in assessing the effect of various drugs administered to a subject. Torsion (twist, untwist at heart apex and base, and the difference between them) A combination of the variables described above can also be used. For example the torsion of the heart, which is a general measure, is calculated from a sensor located in the apex and a sensor located in the heart base (e.g. coronary sinus). The data of rotation from two locations is integrated to form a torsion snapshot. From these data torsion rate may be calculated. To emphasize, torsion refers to the difference between rotational motion measured at the heart apex and the rotational motion measured at the heart base. Systolic torsion refers to the difference between counterclockwise rotation of the apex of the heart and the clockwise rotation of the base of the heart. Diastolic torsion refers to the difference between clockwise rotation of the apex of the heart and the counterclockwise rotation of the base of the heart. The untwist motion as recorded using TD (see Figure 10, index 1020) comprises 3 different components: E' (1022), A' (1024) and an interval between them where the angular velocity is minimal. There are variables measured by the motion sensors that correlate with E' (see fig.10, index 1012). Also there are variables measured by the motion sensors that correlate with A' (see fig.10, index 1014). In addition to the above, the present invention also enables correlating electro-mechanical events with echo signals and LV and aortic pressure signals, or evaluating LV performance measures such as stroke work (SW) or LV function measures such as ejection fraction (EF) and preload reserve SW (PRSW) or LV contractility measures such as dP/dtmax or end-systolic elastance (Ees).

System capable of switching between two modes of operation

The present system can switch between two operating modes, thereby enabling detection of two distinct events and/or enabling treatment of two distinct disorders or pathologies. For example, a first operation mode can be used for detecting and optimizing the effect of CRT therapy on heart performance by synchronizing the events of peak systolic angular velocities measured at the apex of the heart and the base of the heart. By allowing the peaks of such angular velocities to coincide, the most appropriate ejection fraction is obtained. Once this goal is achieved (based on a systolic variable, i.e. peak angular velocities), a second operation mode can be used for optimization of cardiac output (when patient exercises) based on analysis of a variable derived from motion during diastole. For example, the duration of the diastasis is calculated per beat, and a heart rate is increased by pacing to a point where the duration of the diastasis is less than a threshold duration. While the algorithm operates and paces the heart to increase heart rate (second operation mode), the systolic variable is continuously measured. If during pacing the peak angular velocities lose their synchronization, then the system switches back to the first operation mode.

Assessing safety of operation mode

The present system calculates real time variables that can be used to deliver safe therapy to a heart. For example, while activity sensors indicate that heart rate should be increased, monitoring variables acquired by the present system may indicate that an upper limit for increasing heart rate has been obtained and that heart rate should not be further increased.

Increasing heart rate with pacing can lead to progressive shortening of the diastasis segment and at a certain heart rate, elimination of diastasis. In other words, the early diastolic rapid blood flow from the left atrium (LA) to the left ventricle (LV) fuses with the late diastolic flow from LA to LV. The early rapid flow is represented by the echocardio graphic tissue Doppler (TD) signal termed E' wave, whereas the late diastolic flow is represented by the TD signal termed A' wave. The present system provides excellent temporal correlation between E' and A' waves and measured variables and thus can be used to increase heart rate by external pacing to a first safety point which is the elimination of the diastasis. Crossing the first safety point allows pacing to increase heart rate further. However when the A' wave starts (ascending limb of the A') at the middle of the descending limb of the E' wave the second safety point is obtained. When this point is obtained the heart cannot be paced at a greater rate.

Since the present system provides measures which correlate with TD signals and trans-mitral flow velocity signals the former can be used as alert flags while the system operates. For example, the system can provide a variable that correlates with the deceleration time of the E wave of the trans-mitral flow velocity signal. The deceleration time indicates state of relaxation function of heart. Therefore, using DHS system it is possible to follow relaxation function of the heart. If deceleration time significantly changes during exercise this indicates that exercise should be modified and decreased. DHS system can provide such a safety measure in real time.

The present system also provides indication of LV filling state when a pacing signal is about to be discharged. This variable protects from stimulating the heart when the LV is not significantly full.

Thus, the present invention provides variables that describe heart physiological events. Such events can be used to diagnose and treat heart conditions as is further described below. The variables described herein can be used to assess heart physiology on a beat-to-beat basis, continuously and their dependency on preload and afterload may be learned from such measurements.

Once heart performance is determined using the present invention, a treatment course including drug therapy, electrical stimulation (pacing) and the like can be prescribed by a physician in order to modify heart mechanical function and improve performance.

The approach of the invention can be practiced using extracorporeal sensors and processing unit, a combination of implanted sensors (motion sensors and electrical leads) and extracorporeal processing unit [in which case the sensors communicate with a processing unit via wired or wireless (RF) communication], or as a fully implantable, system which includes the sensors power unit and processing unit. In the implanted configuration, the motion sensors (e.g. accelerometer and/or gyroscope) are preferably implanted at the apex of the heart or at the coronary sinus or at both locations.

The latter configuration is presently preferred since it provides numerous advantages such as:

(i) improved accuracy of sensing cardiac motion and electric activity;

(ii) improved means of coordinating a timely therapy for heart, be it pacing therapy or other therapy; and

(iii) securing patient's mobilization while providing patient with means for improving cardiac performance.

In addition to the above, the present system can be used to treat patient populations that are not treatable with presently available solutions. Currently available systems can be used to treat HFrEF (CRT/CRT-D and ICD), however, such systems are not suitable for treating HFpEF. The present system can be used for treating both HFpEF as well as HFrEF and medical conditions related thereto and as such can serve a much wider patient population.

As used herein the term "about" refers to ± 10 %.

Additional objects, advantages, and novel features of the present invention will become apparent to one ordinarily skilled in the art upon examination of the following examples, which are not intended to be limiting. Additionally, each of the various embodiments and aspects of the present invention as delineated hereinabove and as claimed in the claims section below finds experimental support in the following examples.

EXAMPLES

Reference is now made to the following examples, which together with the above descriptions illustrate the invention in a non limiting fashion. EXAMPLE 1

Early detection of pulmonary edema

Pulmonary edema is a life threatening condition where the patient suffers from a significant shortness of breath which in severe cases requires mechanical ventilation. Pulmonary edema is thought to occur when pressure in the pulmonary capillaries is high enough to favor exit of fluid (blood) from the capillaries into the interstitial and alveolar space (i.e. into lung tissue). This shift of fluids from lung capillaries to lung tissue is due to an increase in hydrostatic pressure within the pulmonary capillaries and veins. The latter results from an increased pressure in the left atrium which results from a disorder of the left ventricle to relax distend and fill with blood (flowing from the left atrium (LA) into the left ventricle (LV)). The pressure in the pulmonary capillaries is approximately equal to the pressure in the LA and LV during the filling phase, when the mitral valve is open.

It is known in the art that an increased blood pressure affects the relaxation of the LV. However, if blood pressure has increased and remained undetected LV relaxation would be delayed. As a result the LA-LV pressure gradient which is responsible for the filling of the LV decreases. If the pressure gradient decreases, more blood remains in the LA, thereby increasing the pressure in the LA, and upstream in the pulmonary veins and pulmonary capillaries. If this process is significant, it will result in various clinical symptoms of difficulty breathing, which if sustained will eventually develop into pulmonary edema.

The present system can be used to detect this situation and transmit an alert to a patient, or caregiver (e.g. treating physician). An alert signal enables intervention in the form of blood pressure measurement, a phone call from a caregiver, an instruction to take another medication, etc.

The present invention continuously monitors the filling pattern of the LV by measuring the duration of early filling phase (on beat to beat basis) and calculating the ratio between the duration of early filling and the duration of diastole. If this ratio decreases or changes from a baseline value, the present system transmits an alert signal. There are other variables which correlate with the change in pressure in the LA, pulmonary veins and capillaries, such as the time of deceleration of the E wave. Gandhi et al (The pathogenesis of acute pulmonary edema associated with hypertension. NEJM 2001; 344: 17-22) showed that during pulmonary edema the deceleration time measured by echocardiography was shorter than that measured after treatment. By monitoring the ratio of duration of early filling phase to the duration of diastole the present system provides a variable which correlates closely with the deceleration time, and can provide an alert signal indicating that the patient should be clinically evaluated.

EXAMPLE 2

Monitoring changes in the diastolic dysfunction grade

Current approaches for evaluating cardiac diastolic function utilize echocardiography. Echocardiography is a "snapshot" approach in that the examination is performed periodically. At present there are no approaches for evaluating diastolic function in a continuous manner. The present system provides a continuous signal which correlates with the E and A waves of the transmittal flow velocity measured by echocardiography. Moreover, it can be used to produce another signal which correlates with the TD signal of echocardiography. Thus, the present system can be used to detect the diastolic function of the heart on a beat to beat basis. A medical professional can assess this information (routinely, periodically or upon alert), and based thereupon administer drugs such as nitrates or diuretics. EXAMPLE 3

Effects of drugs on the heart

Since the present system is capable of evaluating the mechanical activity of a heart on a beat to beat basis it is ideal for evaluating the effects of drugs on the mechanical activity of the heart. For example, the present system can be used to record mechanical heart activity mapped in 3D space or characterized by another variable, prior to and following administration of, for example, a beta blocker which slows heart rate, and reduces contractility or drugs from other groups such as angiotensin converting enzymes inhibitors, calcium channel blocker, digitalis preparations, amiodarone. At present the effects of a drug can only be monitored via heart rate, either by manually taking the radial pulse, or performing an ECG, or using a Holter device. Such prior art approach cannot report how cardiac contractility changes in response to the administration of a drug. The present system provides real-time monitoring of the effect of the drug on systolic and diastolic components of heart components and enables actual quantification of the affect on the mechanical activity.

EXAMPLE 4

Chronotropic incompetence in HFPEF patients

Patients with heart failure and preserved ejection fraction (HFPEF) constitute half of all heart failure (HF) subjects. Twenty percent of HFPEF patients suffer from an inability to increase heart rate (HR) on exercise a condition termed chronotropic incompetence [Borlaug et al. Impaired chronotropic and vasodilator reserves limit exercise capacity in patients with heart failure and a preserved ejection fraction. Circulation, 114 (2006), pp. 2138-2147].

The etiology for this limitation is not clear and it is not dependent on whether patients are treated with beta blockers or not. If the basal HR is low and does not increase during exercise, it makes sense to pace the heart at a rate compatible with the level of exertion. However, increasing HR by pacing does not promise an increased cardiac output. It should be verified that HR increases and stroke volume does not decrease at the same time. Since cardiac output is the product of stroke volume and heart rate, if one wishes to increase cardiac output then the components of the product, on average, must increase. That is, either both HR and stroke volume increase (from a baseline state), or at least one of the components increases to a degree greater than the decrease in the other component.

The present system provides means for calculating HR, the ratio between the duration of early filling to the duration of diastole, and assessing whether increasing HR will result in increased cardiac output.

By using exercise monitoring sensors (e.g. body-mounted accelerometers), the present system can detect whether basal HR is well-matched to the level of exercise. In addition, the system provides means for calculating whether increasing HR (by pacing) will result in an increase in cardiac output and apply appropriate pacing stimuli to the heart. If calculations predict that pacing the heart will increase CO then the heart will be paced. EXAMPLE 5

Exercise in HFPEF patients

HFPEF patients are limited in their ability to exercise, a somewhat different condition from the strict definition of chronotropic incompetence mentioned above, because these patients can increase heart rate (HR), however not to a level expected by the level of exertion. Indeed these patients are often treated with beta adrenergic blocking medications. Therefore they have difficulty increasing HR to the required level.

The present system provides means for pacing the heart of HFPEF patients. The system can sense the level of exertion from exertion sensors and predict the appropriate required level of HR (e.g. Wilkoff model - A mathematical model of the cardiac chronotropic response to exercise. J Electro- physiol. 1989; 3: 176-180). Next, the system can sense whether the heart adjusted its rate to the expected level of HR. If not, it analyzes whether pacing the heart faster will increase cardiac output. It should be realized that pacing the heart at a faster rate does not promise an increased cardiac output. If the analysis shows that faster pacing will also increase cardiac output then the system paces the heart. The system also analyzes whether increasing HR will also increase cardiac output by detecting the event of termination of early rapid filling. Accurate detection of this event relative to the duration of the whole diastole is crucial since early termination of the rapid filling phase in diastole increases HR and cardiac output.

This example is somewhat similar to the chronotropic incompetence example above, however the population here is much wider and is not restricted by the definition of chronotropic incompetence.

EXAMPLE 6

Synchronizing CRT upon installation and continuously on a beat to beat basis

Cardiac Resynchronization Therapy (CRT) is a method of biventricular pacing therapy. Two stimulating electrodes positioned at two different locations (typically right ventricular apex and coronary sinus) are used to pace the heart. The rationale for this method is improving left ventricle (LV) contraction and the resulting ejection fraction, by an optimally timed stimulation. This rationale sounds attractive however, there is no consensus of how to maximize efficacy of this timely synchronization. In fact, only 6-7 out of every 10 patients implanted with a CRT device benefit from the device. Sorin developed an electrode which senses a physiological variable they term: peak endocardial acceleration (PEA). The latter is reported to correlate with dP/dt (the first derivative of the pressure in the LV as a function of time). According to Sorin the parameters of their CRT device are tuned as to maximize PEA.

The present system measures physiological signals of motion from the right ventricular apex and the coronary sinus. These signals correlate with stroke volume, and as such, it is possible to activate bi-ventricular pacing in a way which increases stroke volume. Specifically, by changing the time difference between the activations of the two stimulating electrodes, it is possible to optimize the physiological signals acquired by the system. For example, it is possible to temporally align the peak of the rotation signal from the right ventricular apex with that of the coronary sinus. When these peaks are aligned the wringing action of the heart is maximal and the ejection fraction is maximized. Other variables calculated by the system may be used by for this purpose. To note, the system provides a means for synchronizing the contraction of the LV upon installation, that is a method for determining the parameters of the device for maximizing EF upon the procedure of installation.

In addition, the present invention provides closed-loop control for maximizing EF. Parameters are measured on beat to beat basis and in response to these parameters the values of pacing are varied all in order to maximize EF.

EXAMPLE 7

Cardiac Desynchronization Therapy

There are heart diseases which result in thickening of heart walls, such as heart failure and preserved ejection fraction (HFPEF), or hypertrophic obstructive cardiomyopathy or amyloidosis. A thickened heart wall generates a force during systole which may be in excess of the force required for optimal performance. If the latter is the case then oxygen consumption is inappropriately increased because excess force is generated (which is not truly required). There are conditions/disorders which limit blood flow to tissue, for example, narrowing of blood vessels. Also, if the muscular contraction produces high tension (within the muscle) blood flow in such territories is decreased and delayed. The endocardium (the inner layer of the heart muscle) is the most susceptible layer for such blood flow limitation. An outcome of the excessive muscle force production is the inefficacy of elastic recoil.

Elastic recoil (also called diastolic suction) is the elastic "spring-like" energy released from the heart muscle when it moves from a volume at end of contraction to the expanding volume of the filling phase. This energy is similar to the energy released from a spring which is contracted/squeezed to a length shorter than its resting length (the length where the spring produces zero force). This elastic energy helps to decrease the pressure within the left ventricle (LV) which in turn augments the pressure gradient between the left atrium and ventricle, which translates into a more efficient filling of LV.

To maximally utilize this potential energy, the process of freeing the muscle from its contracted stated, letting it expand, must occur rapidly, similar to letting a spring recoil. If the contraction is too forceful then this process of releasing the muscle from the contracted state might be suboptimal (too slow). In such a case the decrease in LV pressure is not instant enough to optimally augment the pressure gradient between the left atrium and ventricle.

The present system can be used to detect such a condition and by changing pacing parameters it can eliminate the suboptimal utilization of the elastic recoil. In particular, the system can be used to detect a state in which the elastic recoil is suboptimal, and to change the time delay between the electric biventricular stimulations causing a slight desynchronization between the ventricles. The effect of desynchronization will decrease the intensity of contraction and improve the freeing of the muscle from its contracted stated. The elastic recoil will improve, thereby augmenting the pressure difference between the left atrium and ventricle thus resulting in an improved LV filling.

Detection of the effect of desynchronization on LV diastolic function can be effected via variable such as duration of early rapid filling, and variables characterizing the untwist motion of the heart (untwist maximal angle of rotation, maximal rate of untwist, etc).

EXAMPLE 8

Syncope

From a hemodynamic point of view, syncope, fainting is related to 3 variables: systemic vascular resistance (SVR), heart rate (HR), and stroke volume (SV). The product of the latter two equals cardiac output (CO). In every syncope workup, the question is: what is the etiology of syncope? Is it arrhythmia? Bradycardia only? Is it bradycardia and inappropriate vasodilation?

The present system can also be used to diagnose the etiology of syncope. The system can be used to document HR and heart contractility during an event. It is accepted that cerebral perfusion is proportional to the product: SVR*HR*SV. During syncope there is a critical fall in this product and the subject faints. Present cardiac rhythm management systems (CRMs) can be used to retrieve data relating to the HR component during syncope, however they cannot be used to retrieve data relating to SVR or SV.

The present system provides data regarding the contractility of the heart during a syncopal event by providing 2 of the 3 variables that define a syncopal event. For example, in the most common case of vasovagal syncope two variables cause the hemodynamic failure: HR decreases, and SVR decreases, both in an inappropriate manner. Using presently available CRMs it is possible to identify HR during the event but possible SVR decrease remains unknown. The present system provides additional useful data, for example if no changes in HR are identified or HR increases, and contractility also increases during syncope, then the single mechanism causing syncope is a significant decrease in SVR, i.e. inappropriate vasodilation. Alternatively, if HR and contractility do not increase during syncope, then SVR must have decreased severely.

In addition, it is important to study these variables prior to fainting and monitor how they change over time. Is syncope an abrupt event or is it preceded by mechanisms trying to compensate for a failure of response of one of the variables: SVR, HR, and SV.

The present system enables a treating physician to understand if HR or contractility were recruited prior to syncope and if an increase in either of the two variables occurred prior to syncope?

In addition, if a patient is prescribed with a drug from the alpha blocker group (such as doxazosin) the present system makes it possible to detect drug effect on the hemodynamic response to posture change, and thereby detect impending syncope due to orthostatism.

It is obvious that once a clue regarding the etiology of syncope is obtained, the system provides therapy in the form of appropriate pacing. EXAMPLE 9

Improving a standard WI pacemaker

Patients with cardiac rhythm disorder such as atrio-ventricular block usually require a pacemaker with two electrodes, with one electrode positioned in the right atrium (RA) and the other in the right ventricle (RV). Both electrodes sense and pace the respective chamber. However, the procedure of installing two electrodes is twice as long (compared with installing a single electrode), and at times the patients are elderly with a limited functional capacity, thus making them less suitable for a longer procedure which will not provide benefits associated with improved functional capacity. If a "lower rate" device, securing the lowest heart rate allowed, is good enough, a single electrode pacemaker is installed in the RV. This electrode senses and paces the RV and provides a means for securing a lower heart rate. However, if the RA is contracting according to some rhythm (e.g. a sinus rhythm, or atrial flutter), which is not synchronized with the rhythm of the LV then desynchronization occurs. This will occur when some atrio- ventricular conduction defect or arrhythmia is present. Then, the RV electrode will sense that an activation is late and will trigger an RV stimulus, resulting in the contraction of the RV followed by the LV. Such a pacemaker will induce desynchrony between the activation of the RA and the RV since it cannot coordinate the activation of the RA and the RV with a single lead.

The activity of the RV electrode is triggered by a time interval from the last ventricular activation, whereas the activity of the RA is triggered by the sinus node, or some other supraventricular source. Desynchronization between RA and RV results in reduced efficacy of the heart since the filling of the RV/LV cannot utilize the contribution of the contraction of the RA/LA, respectively.

The present system detects RA mechanical activity and based on this input a signal stimulating the RV can be emitted, thereby coordinating the contraction of both chambers using a single electrode. Two inputs trigger the pacing of the RV: (1) time interval from last RV/LV activation, and (2) sensing of RA contraction. If the mechanical activity of the RA is sensed before a threshold time interval had occurred then pacing of the RV takes place in a coordinated manner relative to the RA contraction. If during the threshold time interval no RA contraction was detected then the trigger for the RV is the threshold time interval. This example represents other possible combinations for sparing an installation of a pacemaker lead. In particular, the idea is to replace any "electric" lead (not having heart movement sensing ability) with a lead also sensing heart movement, and using heart movement data and variables for the purpose of sparing an installation of a lead.

EXAMPLE 10

Atrial fibrillation

Atrial fibrillation is the most common arrhythmia in humans. Atria fibrillation is characterized by waves of weak disorganized contractions flowing within the walls of the atria. This non-productive, rapid (250-350 cycles per minute) mechanical activity of the atria leads to adverse outcomes.

The filling pressure produced by the right and left atrium during fibrillation is a result of the pressure within the vena cava veins and pulmonary veins, respectively. This means that the atria do not contribute a true pressure support to the filling of the ventricles. Since the atria are electrically activated by rapid disorganized waves of electric stimulation, the atrio-ventricular node (AVN), which conducts the electric impulse from the atria to the ventricles, sustains a bombardment of electric stimulations. These electric impulses render the AVN electrically inactive most of the time. This means that most of the electric stimuli arriving at the AVN will not conduct further to the ventricles. However, some of the stimuli arrive at the AVN when the latter is not refractory and manage to activate it, thereby conducting an electric impulse to the ventricles. This manner of electric activation of the ventricles is also irregular in that the time interval between consecutive ventricular contractions is irregular. Some of the intervals are short and some are long.

The present system can be used to overcome the long and medium interventricular intervals by detecting a long or medium duration interval and then trimming it by electrically activating a ventricle (pacing). The advantage of such intervention stems from the ability of the present system to increase heart rate and cardiac output. This is important especially when atrial fibrillation is slow. The present system differs from a regular VVI pacemaker, which only senses electric events and related time intervals, in that it senses mechanical events of the heart and can trigger electric stimulation in response to these events and not only to the electric events. EXAMPLE 11

Synchronizing computer tomography angiography (CTA) scan of the heart with motion of heart

In some embodiments of the invention, CTA scanning is synchronized with heart movement based on data from sensors used in the present invention. Presently, a CTA machine scans the heart continuously. Off-line synchronization of images to the electric activity of the heart (specifically to the R wave peak) is performed. This creates a set of images all taken at a similar time instant within the cardiac cycle. However, there is limited success in synchronizing a desired mechanical cardiac event (diastasis) with an electric event (peak of the ECG R wave). Since some embodiments of the present invention can indicate specific time instants of diastole, for example the end of rapid filling and the beginning of the slow filling (diastasis), it is possible to synchronize CTA imaging to this mechanical event (diastasis). This decreases the amount of radiation to which the patient is exposed, because CTA images are taken only during diastasis and not during all cardiac cycle.

EXAMPLE 12

Detecting changes in the motion characteristics in a heart post revascularization

The present system can also be used for tracking cardiac revascularization. This can be effected by recording one or more motion variables during the LV filling cycle following cardiac revascularization, recording the same motion variables during the LV filling cycle following cardiac revascularization, comparing the two recording, and determining whether differences between the first recording and the second recording indicate a change in the efficacy of the cardiac revascularization.

Monitoring LV wall characteristics provides data for yet another intervention for improving LV wall function, and optionally optimizing CO. Such data correlated with metabolic and activity data may suggest, in some cases, that ischemia may be underlying LV wall dysfunction. The present invention provides a way to assess real-time myocardial ischemia and a way to monitor whether coronary revascularization therapy was efficient.

For example, a LV filling pattern according to any of the sensed variables may be recorded at a first point in time, such as a velocity pattern, a pressure pattern, a strain pattern, and so on. A second pattern of the same variables may be recorded at a later time, and the two patterns compared. If the first pattern differs significantly from the first pattern, a development associated with myocardial ischemia may be suspected. EXAMPLE 13

Mapping heart movement

The present invention also enables identification and mapping of a three dimensional trajectory of a lead attached to the heart.

Figures 9 and 10 illustrate 3D trajectory as determined using the present invention. Figures 9a-c illustrate 3 ECG traces displayed as a function of time (in seconds). The 3 traces are identical and serve as time reference for the panels of Figures 9d-f and 9g-i. Figures 9d-f illustrate 3 cylindrical coordinates of the distal end of the RV apical lead. These coordinates vary as a function of time. Figure 9d illustrates Θ, Figure 9e illustrates p and Figure 9f illustrates z. Θ is the angle between lab axes and the direction of gravitation, p is the radius of an imaginary cylinder, on which surface the lead moves and z is the long axis of the cylinder, on which surface the lead moves. The abscissa in Figures 9a-i is time in seconds. The direction of gravitation (termed g in this Figure) is signified by the broken line. The direction of the central rotational axis is represented by the black line and the letter w.

Figures 9g-i illustrate Θ, p, and z for the distal end of the lead positioned in the coronary sinus (CS). The ordinate of Figures d-i represent relative change, rather than absolute change. Θ, p, and z may be used for calculating the volume of the cylinder or at least the relative change in volume of the cylinder. This change correlates with the absolute volume of the heart.

Figure 10 illustrates two 3D trajectories: the larger trajectory on the right hand side of the Figure represents the 3D motion of the distal end of a lead positioned in the apex of the RV of a pig, whereas the smaller trajectory (on the right hand side of the Figure) represents the motion of the distal end of a lead positioned in the CS. The thick black line signifies the systolic part of the motion. The squares represent the period of rapid early filling of diastole. The diastasis is represented by the thin black line, whereas the circles represent the late filling portion of the diastole. The spatial relation between the two trajectories is arbitrary in this Figure. The trajectories are manually separated in this display for the purpose of visualization. From this Figure it is possible to calculate a volume which is restricted by the trajectories and correlates with the real volume of the heart.

When a lead is installed in the heart of a patient an operator typically utilizes X- ray imaging or information related to the conductivity or impedance of the installed lead in order to monitor the installation procedure and verify correct positioning of the lead.

The present invention may be used to verify that the location of the lead has not changed with time. Following installation of a lead, an operator can determine a 3D trajectory of the lead using the present invention and use and use such information to monitor the position of the lead over time. For example, if it suspected that a position of a lead has shifted over time, the present invention can be used to reimage lead trajectory and compare it with the trajectory documented following installation.

A 3D trajectory of a lead can be affected by various factors, such as ischemia (see US patent no. 7,445,605), changes in blood volume and the like. However, if a lead detaches from a myocardium, its trajectory would not follow a path but would rather be random. The present invention can detect lead detachment automatically, periodically, or by activating a test mode. The latter will document the 3D trajectory of the distal end of a lead at time Ti and compare it with the trajectories documented at previous time points. If the difference is greater than a predetermined threshold the present system can transmit an alert indicating lead failure even before such failure becomes clinically significant. An example for a threshold may be the sum of the spatial distance between points k on a sample trajectory at time T and points k on a mean trajectory calculated at time of installation.

The present invention also enables evaluation of heart volume from changes in 3D trajectory. The trajectories in 3D can be used to estimate at least the relative change in volume of the heart, i.e. how the volume of the heart changes from diastole to systole. This index is crucial in patients with heart failure which require medical assistance due to a difficulty in breathing. It is often difficult to differentiate the cause of dyspnea in patients with HF and other co-morbidities such as chronic lung disease or asthma or acute bronchitis. Changes in heart volume can indicate a state of hypervolemia (heart volume increase), and an excess of fluid volume in the circulation which can be treated via diuretics. In contrast, if the invention indicates that no change has occurred lately then another cause for the dyspnea should be sought.

The present invention can monitor the volume of a heart over extended periods of time (e.g. weeks). Similarly to monitoring of pulmonary artery pressure, the present invention can be used to monitor changes in heart volume over extended time periods; in a population of HF patients, a slow, persistent increase in the volume of the heart may indicate an imminent HF decompensation.

Another example of the significance of the 3D lead trajectory is real-time monitoring of the effects of arrhythmias. Arrhythmias are at times dangerous because they impair the function of the heart. There are many physiological mechanisms which are used to explain why tachycardia (fast pace) or bradycardia (slow pace) impair myocardial function. However, at present there is no approach for evaluating the realtime effect on the myocardium. The present invention can monitor, quantify, and alert if necessary, when a function of a heart changes significantly during arrhythmias.

EXAMPLE 14

Porcine Studies

Ten porcine studies were conducted to asses the operability of the present system. The first 7 studies were designed for gaining experience with the experimental protocol and instrumentation, and with data acquisition, recording, and documentation.

Materials and Methods

The pigs were anesthetized and placed in a supine position on an operating table; the following catheterizations were performed:

(i) peripheral vein (ears) for administering saline, drugs, taking blood

tests.

(ii) left jugular vein for introducing a CS lead.

(iii) right jugular vein for introducing a RVa lead.

(iv) left femoral artery for measuring LV Pressure.

(v) left femoral vein for measuring RA pressure.

(vi) right femoral artery for measuring Aortic pressure.

(vii) right femoral vein for inserting a pacing electrode to RA. (viii) urinary bladder for easing stress that may increase HR.

In addition, 3 sets of ECG electrodes were attached to each limb (1 for monitor, 1 for echo, 1 for ECG recording).

Motion sensors comprising a 3D accelerometer and 3D gyroscope mounted on a standard pacing lead having a screw anchor at the distal end were deployed in the RVa (see iii above) and CS (see ii above).

Throughout a study, motion signals were recorded and stored from motion sensors (see ii and iii above), pressure signals were recorded and stored from pressure sensors (see iv, vi, and v above) and electrical signals were recorded and stored from ECG leads connected to each limb of the animal.

In addition, each step of the study was documented by trans-thoracic echocardiography. The major steps of preparing the animal for the study were documented by X-ray films and pictures.

Studies 8-10 included the following steps: (A) Instrumentation. (B) Volume overloading. (C) External pacing. (D) Effects of drugs.

Results and Conclusions

The results of the three different animal studies from experiments 8, 9 and 10 (the three different animals are represented by circles, diamonds, and boxes on the graphs) are shown in Figures 24-32. Figure 33 summarizes the results in a table.

Figure 24 presents typical data resulting from experiments 8-10 in pigs. This figure shows the standard, reference signals: LV pressure, aortic pressure, and ECG, which were acquired during the studies in order to detect the interventions. Another reference signal which is not shown in this figure is the standard transthoracic echocardiography. The signals acquired from the accelerometers and gyroscopes are shown in the 3 panels from bottom to top. These signals serve as input signals for the described system. The novelty of the described system is observed in figure 24. It is possible to see the various mechanical events, first shown together with this system. No other system presents these events together and relates one event to another. In particular, the onset of heart cycle/beat starts with the electrical event of the QRS signal of the ECG (first vertical line from left), rapidly followed by s systolic tension onset signal (STOS) which terminates with the second from left vertical line. Between the second and third lines from left it is possible to detect the ejection phase best observed in the lower panel demonstrating the rotation from about -5 degrees to approx. +10 (just after the third vertical line from left). It is then when diastole begins with an E wave (shown in panel 3 from top) followed by diastasis (arrow, bottom panel), and terminating with the A wave (shown in panel 3 from top). E and A waves are used here because of the temporal correlation of these waves with the E' and A' waves of the tissue Doppler signals acquired by echocardiography. The first vertical line from right indicates where the next heart beat starts. These mechanical events (presented here by the signals) are very significant in describing heart performance. Each of these events can be monitored by the system. Variables derived from these events may be calculated and used as controllers for monitoring heart performance. One example is the duration of the diastasis which serves as a control variable for increasing heart rate. Heart rate is increased up to a point where the duration of the diastasis is below a threshold value. Then the algorithm of increasing heart rate changes its mode of action.

Figure 25 shows the effect of increasing doses of Epinephrine (abscissa) on the systolic acceleration signal (ordinate, termed here contractility) acquired from the right ventricle apex (RVA) lead in the three different animals. The positive correlation between the dose of epinephrine injected and the systolic acceleration response is easily observed and expected from the literature as well. This graph shows the very early phase of contractility measured as the onset of systolic tension (see STOS above). Figure 26 displays the effect of increasing doses of Epinephrine (abscissa) on the twist which is the amount of angle travelled by the gyroscope located on the RVA lead, during systole (ordinate) in the three different animals. This graph shows a positive correlation between Epinephrine doses and twist. The greater the dose of Epinephrine the greater is the systolic rotation (twist). One may detect that this correlation is bounded and for two animals the peak response has been obtained (circles and diamonds), whereas for the third animal (boxes) the peak response has not been obtained with the doses of Epinephrine used. A very similar correlation was demonstrated between Epinephrine doses and peak systolic angular velocity (not shown). Similar results were obtained for systolic acceleration, and twist measured from the coronary sinus (not shown). Figure 27 shows the effect of increasing heart rate by external atrial pacing (abscissa) on the systolic acceleration signal (ordinate) acquired from the RVA lead in the three different animals. A linear correlation is demonstrated with a very similar slope (response) for the three animals. The peak systolic angular velocity had a similar response to increasing heart rate (not shown). The same signals obtained from the CS lead demonstrated similar results (not shown). Figure 28 shows the effect of increasing heart rate by external atrial pacing (abscissa) on the twist which is the amount of angle travelled by the gyroscope located on the RVA lead, during systole (ordinate) in the three different animals. This graph shows an interesting response which was not expected. The twist increased slightly in 2 animals (boxes and circles) whereas it decreased in the third animal (diamonds). In general, as the pacing rate increased, the systolic rotation (twist) decreased. Since only heart rate was artificially increased by pacing, whereas the total workload was not, it is hypothesized that the physiologic control mechanisms of the animals operated in a direction to offset the intervention by decreasing twist (decreasing energy spent). Figure 29 shows the effect of increasing heart rate by external atrial pacing (abscissa) on the untwist which is the amount of angle travelled by the gyroscope located on the RVA lead, during diastole (ordinate) in the three different animals. This graph shows a negative correlation between the increased heart rate and the diastolic rotation (untwist). This response is similar to that observed for the systolic twist. Figure 30 shows the effect of increasing heart rate by external atrial pacing (abscissa) on the peak angular velocity acquired during late diastole by the gyroscope located on the CS lead (ordinate) in three different animals. The angular velocity signal acquired during late diastole correlates with the tissue Doppler signal acquired by echocardiography from body surface of the animal during atrial contraction (shown in Figure 21). This graph shows that increasing heart rate by pacing increased the late diastolic rotation signal (untwist) acquired from the CS (and the RVa, however not shown here). Figure 31 shows the effect of intravenous volume (saline) overloading (abscissa) on the twist - the amount of angle travelled by the gyroscope located on the RVA lead - during systole (ordinate) in the three different animals. Figure 32 shows the effect of intravenous volume (saline) overloading (abscissa) on the untwist - the amount of angle travelled by the gyroscope located on the RVA lead - during diastole (ordinate) in three different animals. In both Figures 31 and 32 it is possible to see that the physiologic control mechanisms of the animals operate to offset the intervention. It is possible that volume overloading recruited the Frank-Starling mechanism thereby increasing contractility. In order to decrease this effect systolic and diastolic rotations (twist and untwist) decreased.

The table presented in Figure 33 summarizes the pig trials. The columns show the variables that were investigated, whereas the rows indicate the interventions performed. Arrows pointing upwards indicate an "increase effect", and arrows pointing downwards indicate a "decrease effect". Interventions: row 1 - administration of increasing doses of epinephrine, row 2 - increasing heart by external atrial pacing, row 3 - the effect of volume (saline) overload. The measures investigated (from right column to left): systolic acceleration signal acquired from RVA sensor, twist (systolic rotation) signal acquired from RVA sensor, peak systolic angular velocity acquired from RVA sensor, untwist (diastolic rotation) signal acquired from RVA sensor, systolic acceleration signal acquired from CS sensor, twist (systolic rotation) signal acquired from CS sensor, peak systolic angular velocity acquired from CS sensor, peak late diastolic angular velocity signal acquired from CS sensor.

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 subcombination.

Although the invention has been described in conjunction with specific embodiments thereof, it is evident that many alternatives, modifications and variations will be apparent to those skilled in the art. Accordingly, it is intended to embrace all such alternatives, modifications and variations that fall within the spirit and broad scope of the appended claims. All publications, patents and patent applications mentioned in this specification are herein incorporated in their entirety by reference into the specification, to the same extent as if each individual publication, patent or patent application was specifically and individually indicated to be incorporated herein by reference. In addition, citation or identification of any reference in this application shall not be construed as an admission that such reference is available as prior art to the present invention.

Claims

WHAT IS CLAIMED IS:

1. A system for monitoring and optionally modifying heart performance comprising:

(a) at least one motion sensor for sensing heart movement; and

(b) at least one electrical sensor for sensing an electrical activity of the heart; and

(c) a processing unit for processing information from said at least one motion sensor and said at least one electrical sensor to thereby derive a variable from a movement of said heart as a function of a cardiac cycle.

2. The system of claim 1, wherein said variable is a maximum value of an angle of said heart during systole and/or diastole.

3. The system of claim 1, wherein said variable is a maximum value of a first derivative of an angle of said heart during systole and/or diastole.

4. The system of claim 1, wherein said variable is a time from peak R wave to peak angle of rotation of said heart.

5. The system of claim 1, wherein said at least one motion sensor includes an accelerometer and a gyroscope.

6. The system of claim 5, wherein said variable is a time interval between an onset of motion of said heart as detected by said accelerometer and said onset of motion as detected by said gyroscope.

7. The system of claim 1, further comprising a biocompatible housing for containing (a), (b) and/or (c).

8. The system of claim 1, wherein said at least one electrical sensor includes at least two leads configured for attachment to a myocardium.

9. The system of claim 7, further including tissue anchors for anchoring said housing to a myocardium.

10. The system of claim 1, further comprising stimulating electrodes for delivering an electrical signal to the heart.

11. The system of claim 10, wherein a type of said electrical signal delivered by said stimulating electrodes to the heart is determined by said processing unit according to said variable.

12. The system of claim 1, wherein said variable represents an optimal AVD and VVD stimulating timing value.

13. The system of claim 12, further comprising a pulse generator for delivering an electrical pulse to the right and/or left ventricles or right atrium according to said optimal AVD and VVD stimulating timing value.

14. The system of claim 1, wherein said processing unit processes information from said at least one motion sensor and said at least one electrical sensor to thereby derive two independent variables from a movement of said heart as said function of said cardiac cycle.

15. The system of claim 14, further comprising a pulse generator for delivering a first electrical pulse as a response to a first variable of said two independent variables, and a second electrical pulse as a response to a second variable of said two independent variables.

16. The system of claim 15 wherein said first pulse is for synchronizing peak systolic angular velocity events and said second pulse is for pacing the heart to a point where a duration of a diastasis is less than a threshold duration.

17. A method of monitoring heart performance comprising:

(a) sensing heart movement of a subject;

(b) sensing an electrical activity of the heart; and

(c) processing information relating to said heart movement and said electrical activity to thereby derive a variable from a movement of said heart as a function of a cardiac cycle.

18. The method of claim 17, wherein (a) takes into account a posture of said subject.

19. The method of claim 17, wherein (a) takes into account the effects of a gravitational and a non-cardiac acceleration force on said sensing.

20. The method of claim 17, wherein said variable is a maximum value of an angle of said heart during systole and/or diastole.

21. The method of claim 17, wherein said variable is a maximum value of a first derivative of an angle of said heart during systole and/or diastole.

22. The method of claim 17, wherein said variable is a time from peak R wave to peak angle of rotation of said heart.

23. The method of claim 17, wherein (a) is effected via at least one motion sensor attached to a myocardium.

24. The method of claim 23, wherein said at least one motion sensor includes an accelerometer and a gyroscope.

25. The method of claim 24, wherein said variable is a time interval between an onset of motion of said heart as detected by said accelerometer and said onset of motion as detected by said gyroscope.

26. The method of claim 17, wherein (b) is effected via at least one electrical sensor having at least two leads attached to a myocardium.

27. A method of modifying heart performance comprising:

(a) sensing heart movement of a subject;

(b) sensing an electrical activity of the heart;

(c) processing information relating to said heart movement and said electrical activity to thereby derive a variable from a movement of said heart as a function of a cardiac cycle; and

(d) delivering an electrical signal to the heart according to said variable.

28. The method of claim 27, wherein (d) is effected via stimulating electrodes attached to myocardium.

29. The method of claim 27, wherein a type of said electrical signal delivered to the heart is determined by a processing unit according to said variable.

30. A system for monitoring and optionally modifying heart performance comprising:

(a) at least one motion sensor positionable at the apex of a heart and being for sensing heart movement; and

(b) a processing unit for processing information from said at least one motion sensor to thereby derive a motion signal selected from the group consisting of:

(i) peak linear acceleration;

(ii) peak systolic angular velocity;

(iii) early and late peaks and patterns of diastolic angular velocities; and

(iv) the time intervals between (i), (ii) and (iii).