Treatment of CRT non-responders using cardiac contractile regulation therapy

Abstract

1. A method for selecting a patient for cardiac contractile control therapy, the method comprising: selecting a patient who meets criteria for cardiac resynchronization therapy (CRT); detecting potential difficulties in effectively providing CRT to the patient; and determining that the patient can benefit from cardiac contractile control therapy despite the potential difficulties.

Description

[Technical Field]

[0001] Cross-reference of related applications This application claims the benefit of priority under § 119(e) of U.S. Provisional Patent Application No. 63 / 043,814, filed on 25 June 2020, which is incorporated herein by reference in its entirety. [Background technology]

[0002] In some embodiments, the present invention relates to cardiac contractile regulation therapy, and more specifically, to cardiac contractile regulation for cardiac resynchronization therapy (CRT) candidates, without limiting itself.

[0003] Heart failure guidelines recommend Class I cardiac resuscitation (CRT) only for patients with a QRS width of 130 milliseconds or more and a left bundle branch block (LBBB) pattern, while Class II recommendations are given for patients with a QRS width of 130 milliseconds or more and a non-LBBB pattern.

[0004] Despite careful selection criteria, approximately 30–50% of patients who received implantation did not benefit from CRT, highlighting the need for alternative device therapies in this population. [Overview of the Initiative]

[0005] According to one aspect of several embodiments, a method is provided for selecting a patient for cardiac systolic control therapy, which includes selecting a patient who meets the criteria for cardiac resynchronization therapy (CRT), detecting potential difficulties in effectively delivering CRT to the patient, and determining that, despite the potential difficulties, the patient can benefit from cardiac systolic control therapy.

[0006] In some embodiments, detection includes detecting whether pre-CRT invasive treatment is expected to be effective.

[0007] In some embodiments, detection involves receiving an indicator that the patient has one or more comorbidities selected from a list including renal failure, diabetes mellitus, chronic obstructive pulmonary disease, sleep disorders such as sleep apnea, and anemia.

[0008] In some embodiments, detection includes receiving an indicator that the patient is suffering from cardiac arrhythmia.

[0009] In some embodiments, cardiac arrhythmias include non-left bundle branch block (non-LBBB).

[0010] In some embodiments, the determination involves receiving an indicator that the patient has NYHA class II–IV heart failure.

[0011] In some embodiments, the determination involves receiving an indicator that the patient has a left ventricular ejection fraction in the range of 25% to 55%.

[0012] In some embodiments, the determination involves receiving an indicator that the patient exhibits a normal QRS width greater than 130 milliseconds.

[0013] In some embodiments, determining includes setting a pulse generator of a cardiac device with parameters of a test electric field for cardiac contractile regulation provided to the heart via at least one electrode lead, and determining that the effect of the test electric field on the patient indicates that the patient can benefit from cardiac contractile regulation therapy via at least one electrode lead.

[0014] In some embodiments, the test electric field is part of a test session that lasts up to one hour.

[0015] In some embodiments, the pulse generator is configured to be located outside the patient's body.

[0016] In some embodiments, the method includes selecting a cardiac tissue location suitable for cardiac contractility modulation and delivery of CRT therapy via at least one electrode lead.

[0017] In some embodiments, the at least one electrode lead comprises an anchor configured to fix at least a portion of the at least one electrode lead to the septum of the heart.

[0018] In some embodiments, the cardiac tissue location includes the left ventricle or the right ventricle.

[0019] In some embodiments, the electrodes of the electrode lead suitable for delivering both CRT and cardiac contractility modulation therapy have a surface area of at least 4 mm 2 and are coated with a high capacitance and low polarization coating.

[0020] In some embodiments, the method includes identifying that the effect of CRT is not the planned effect.

[0021] In some embodiments, identifying includes identifying that the effect of CRT is an insufficient effect on increasing cardiac output.

[0022] In some embodiments, identifying includes identifying that the CRT effect includes at least one undesirable side effect.

[0023] In some embodiments, at least one undesirable side effect includes pain sensation.

[0024] In some embodiments, at least one undesirable side effect includes arrhythmia.

[0025] In some embodiments, identifying includes identifying that the effect of CRT is not the planned effect at least one month after the start of CRT.

[0026] In some embodiments, the method includes selecting a treatment plan in which the dual-purpose device is configured to generate an electric field for both CRT and cardiac contractility modulation therapy.

[0027] In some embodiments, the dual-purpose device is configured to time the CCM electric field as a series of biphasic bipolar pulses during the refractory period of the heart.

[0028] In some embodiments, the CCM electric field has an amplitude of at least 5V, and the duration of each biphasic pulse ranges from 9 milliseconds to 15 milliseconds.

[0029] In some embodiments, the method includes treating the patient with cardiac contractility modulation therapy according to the result of the determination.

[0030] In some embodiments, treating includes treating the patient with cardiac contractility modulation therapy in combination with CRT.

[0031] In some embodiments, treating the patient with cardiac contractility modulation therapy includes providing an electric field during the refractory period of the right ventricle of the heart via at least one electrode lead fixed to the cardiac septum, and treating the patient with CRT includes providing an electric field via at least one electrode lead disposed in the left ventricle, the right ventricle, or a blood vessel up to 1 cm from the heart.

[0032] In some embodiments, treating includes providing the electric field for CRT and cardiac contractility modulation therapy via the same electrode.

[0033] In some embodiments, treating includes providing the electric field for CRT within the same ventricle in which cardiac contractility modulation is provided.

[0034] In some embodiments, treating includes providing an extended pacing signal for both CRT and cardiac contractility modulation therapy effects during the non-refractory period of the right ventricle.

[0035] In some embodiments, this method includes determining whether treating the patient with cardiac contractile regulation and CRT has a desired effect on cardiac output and / or cardiac contractility, and modifying the CRT therapy based on the results of the determination.

[0036] According to one aspect of several embodiments, a method is provided for selecting a patient for cardiac contractile regulation therapy, the method comprising identifying that the effect of the provided CRT is not beneficial to the patient, and modifying the settings of a cardiac device controller to generate a cardiac contractile regulation electric field based on the result of the identification.

[0037] In some embodiments, identification includes identifying that the CRT has caused one or more undesirable side effects.

[0038] In some embodiments, side effects include pain or discomfort during or after CRT administration.

[0039] In some embodiments, identification includes identifying that providing CRT to a patient does not result in a beneficial effect on cardiac output.

[0040] In some embodiments, identification includes identifying that providing a CRT to a patient does not result in a beneficial effect on at least one of the following: ejection fraction, intracardiac pressure, intracardiac pressure gradient over a selected period, NYHA class score, peak VO2, and 6-minute walk score.

[0041] In some embodiments, identification includes identifying that the effect of the provided CRT includes an insufficient effect on the increase in intracardiac pressure or an insufficient effect on the increase in intracardiac effects over a selected period of time.

[0042] In some embodiments, identification includes identifying arrhythmias in patients after CRT administration.

[0043] In some embodiments, the method includes selecting at least one previously implanted electrode lead from two or more previously implanted electrode leads to provide a cardiac contraction-modulating electric field.

[0044] In some embodiments, the method includes selecting at least one previously implanted electrode to be used for providing a cardiac systolic regulating electric field for providing a cardiac systolic regulating electric field.

[0045] In some embodiments, suitable for providing both CRT and cardiac contractile regulation therapy, at least one selected previously implanted electrode is at least 4 mm in size. 2 It has a surface area and is coated with a high capacitance and low polarization coating.

[0046] In some embodiments, the selection includes selecting at least one electrode lead located in at least one of the right ventricle, left ventricle, and a blood vessel less than 1 cm away from the heart.

[0047] In some embodiments, at least one previously implanted electrode lead selected for cardiac contraction regulation is fixed to the cardiac septum.

[0048] In some embodiments, the method includes testing whether at least one selected previously implanted electrode is suitable for providing cardiac contractile regulation.

[0049] In some embodiments, the method includes sending a signal to an embedded dual-purpose device to generate a CRT or CCM electric field.

[0050] In some embodiments, the method includes replacing an implantable CRT device with a cardiac contractile regulation device.

[0051] According to one aspect of several embodiments, a method is provided for testing at least one electrode lead for the provision of cardiac systolic therapy, the method comprising deciding to provide CRT to a patient, implanting two or more electrode leads in the patient at a location suitable for providing CRT within the heart, and testing whether at least one of the two or more electrode leads is suitable for providing cardiac systolic therapy.

[0052] In some embodiments, testing includes providing an electric field having parameter values ​​suitable for cardiac contractile regulation therapy via at least one selected electrode lead, and testing whether the provided electric field induces undesirable side effects.

[0053] In some embodiments, providing includes providing an electric field during testing by a pulse generator located outside the body.

[0054] In some embodiments, undesirable side effects include pain and / or discomfort to the patient.

[0055] In some embodiments, testing is performed during embedding.

[0056] In some embodiments, implantation includes fixing at least one electrode lead to the cardiac septum, and testing includes testing at least one fixed electrode lead.

[0057] According to one aspect of several embodiments, a system is provided for providing cardiac resynchronization therapy (CRT) and cardiac contractile regulation therapy, the system comprising: a memory; a pulse generator configured to generate an electric field having parameter values ​​suitable for CRT and cardiac contractile regulation; and at least one electrode lead electrically connected to the pulse generator and positioned within the heart or at a distance of up to 1 cm from the heart. A measurement circuit connectable to at least one sensor, configured to measure at least one physiological parameter related to cardiac output, and a control circuit electrically connected to the measurement circuit and a pulse generator, wherein the control circuit is configured to use electric field parameter values ​​stored in memory to signal the pulse generator to generate an electric field with parameter values ​​suitable for CRT or cardiac contractile regulation.

[0058] In some embodiments, the control circuit is configured to determine whether the effect of the electric field provided for the CRT is the desired effect by determining, based on a signal received from a measurement circuit, the relationship between the signal or its index and one or more desired effect indexes stored in memory.

[0059] In some embodiments, the system includes a communication circuit configured to transmit a radio signal to a remote device located outside the body, the control circuit sending a signal to the communication circuit, which includes instructions for providing cardiac contraction control therapy and / or information related to the CRT effect if the CRT effect is not the desired effect.

[0060] In some embodiments, the control circuit receives commands from a remote device to provide cardiac contractile control therapy via signals received by a communication circuit.

[0061] In some embodiments, the control circuit is configured to signal a pulse generator to generate an electric field with parameter values ​​suitable for providing cardiac contractile regulation therapy to the heart when the CRT effect is not the desired effect.

[0062] In some embodiments, the control circuit is configured to signal a pulse generator to generate an electric field having parameter values ​​suitable for CRT and / or cardiac contraction regulation, and to provide the electric field through at least one electrode lead.

[0063] In some embodiments, at least one electrode of at least one electrode lead is suitable for providing both CRT and cardiac contractile regulation therapy, and is at least 4 mm in diameter. 2 It has a surface area and is coated with a high capacitance and low polarization coating.

[0064] Some additional embodiments of several embodiments of the present invention are listed below. Features of one embodiment can be combined with one or more features of other embodiments.

[0065] Example 1. A method for providing cardiac contraction control therapy, Selecting patients who meet the criteria for cardiac resynchronization therapy (CRT), To detect potential difficulties in effectively providing the CRT to the aforementioned patient, Despite the aforementioned potential difficulties, it is determined that the patient can benefit from cardiac contractile regulation therapy, The method comprising treating the patient with cardiac contractile control therapy in accordance with the result of the determination.

[0066] Example 2. The method according to Example 1, wherein the detection includes detecting the potential need for invasive treatment before CRT is expected to be effective.

[0067] Example 3. The method according to any one of the prior examples, wherein the detection involves diagnosing the patient with one or more comorbidities selected from the list, including renal failure, diabetes mellitus, chronic obstructive pulmonary disease, sleep disorders such as sleep apnea, and anemia.

[0068] Example 4. The method according to any one of the prior examples, wherein the detection includes diagnosing the patient with cardiac arrhythmia.

[0069] Example 5. The method according to Example 4, wherein the cardiac arrhythmia includes a non-left bundle branch block (non-LBBB).

[0070] Example 6. The method according to any one of the prior examples, wherein the determination comprises diagnosing the patient with NYHA class II-IV heart failure.

[0071] Example 7. The method according to any one of the prior examples, wherein the determination includes diagnosing the patient with a left ventricular ejection fraction in the range of 25% to 55%.

[0072] Example 8. The method according to either Example 6 or 7, wherein the determination comprises diagnosing the patient with a normal QRS width greater than 130 milliseconds.

[0073] Example 9. The method according to any one of the prior examples, wherein the determination includes providing a test electric field with cardiac contractile control parameters provided to the heart via at least one electrode lead, and determining that the effect of the test electric field on the patient indicates that the patient can benefit from cardiac contractile control therapy via the at least one electrode lead.

[0074] Example 10. The method according to Example 9, wherein the test electric field is provided as part of a test session lasting up to 1 hour.

[0075] Example 11. The method according to any one of claims 9 or 10, wherein the test electric field is provided by a pulse generator located outside the patient's body.

[0076] Example 12. The method according to any one of the prior examples, comprising implanting at least one electrode lead in a position suitable for cardiac contraction regulation and provision of CRT therapy, following the determination described above.

[0077] Example 13. The method according to Example 12, wherein the implantation includes fixing the at least one electrode lead to the cardiac septum.

[0078] Example 14. The method according to either Example 12 or 13, wherein the implantation includes implanting the at least one electrode lead in the left ventricle or the right ventricle.

[0079] Example 15. The electrode of the electrode lead suitable for providing both CRT and cardiac contractile regulation therapy is at least 4 mm 2 The method according to any one of Examples 12 to 14, having a surface area and coated with a high capacitance and low polarization coating.

[0080] Example 16. Providing the patient with CRT following the detection via at least one electrode lead, This includes identifying that the effect of the provided CRT is not the planned effect for the patient, The method according to any one of Examples 12 to 15, wherein the treatment comprises, following the identification, treating the patient with the cardiac contractile regulation therapy using the at least one electrode lead.

[0081] Example 17. The method of Example 16, wherein identifying is that the effect of the provided CRT is insufficient for increasing cardiac output.

[0082] Example 18. The method according to either Example 16 or 17, wherein the identification includes identifying that the provided CRT effect includes at least one undesirable side effect.

[0083] Example 19. The method according to Example 18, wherein the at least one undesirable side effect includes pain.

[0084] Example 20. The method according to either one of Example 18 or 19, wherein the at least one undesirable side effect includes arrhythmia.

[0085] Example 21. The method according to any one of Examples 16 to 20, wherein the identification is made at least one month after the commencement of CRT provision that the CRT effect is not a planned effect.

[0086] Example 22. The method according to any one of Examples 12 to 21, comprising implanting a dual-purpose device configured to provide both CRT and cardiac systolic regulation therapy.

[0087] Example 23. The method according to any one of the prior examples, wherein the treatment is performed with cardiac contractile control therapy, comprising providing an electric field to the heart as a biphasic bipolar pulse train during the cardiac refractory period.

[0088] Example 24. The method according to Example 23, wherein the electric field provided has an amplitude of at least 5V and is transmitted as one or more biphasic pulses, and the duration of each biphasic pulse is in the range of 9 milliseconds to 15 milliseconds.

[0089] Example 25. The method according to any one of the prior examples, wherein the treatment comprises treating the patient with cardiac systolic regulation therapy in combination with CRT.

[0090] Example 26. The method according to Example 25, wherein treating the patient with cardiac contractile control therapy comprises providing an electric field during the refractory period of the right ventricle of the heart via at least one electrode lead fixed to the intercardiac septum, and treating the patient with CRT comprises providing an electric field via at least one electrode lead positioned in the left ventricle, right ventricle, or in a blood vessel at a distance of up to 1 cm from the heart.

[0091] Example 27. The method of Example 26, wherein the treatment comprises providing the electric field and cardiac contraction regulation therapy for CRT via the same electrodes.

[0092] Example 28. The method according to any one of Examples 25-27, wherein the treatment comprises providing an electric field for CRT within the same ventricle where cardiac contractile regulation is provided.

[0093] Example 29. The method according to any one of Examples 25-28, wherein the treatment comprises providing an adipose pacing signal for both CRT and cardiac systolic regulation therapeutic effects during the non-refractory period of the right ventricle.

[0094] Example 30. Determining whether treating the patient with the cardiac contractile regulation and the CRT has the desired effect on cardiac output and / or cardiac contractile, The method according to any one of Examples 25 to 29, comprising modifying the CRT therapy based on the results of the aforementioned determination.

[0095] Example 31. A method for providing cardiac contraction control therapy, Providing cardiac resynchronization therapy (CRT) to patients, To identify that the effects of the provided CRT are not beneficial to the patient, The method comprising treating the patient with cardiac contractile control therapy based on the results of the identification.

[0096] Example 32. The method according to Example 31, wherein the identification includes identifying that the CRT provided to the patient causes one or more undesirable side effects.

[0097] Example 33. The method according to Example 32, wherein the side effects include pain or discomfort during or after CRT administration.

[0098] Example 34. The method according to any one of Examples 31 to 33, wherein the identification includes identifying that the provision of CRT to the patient does not result in a beneficial effect on cardiac output.

[0099] Example 35. The method according to any one of Examples 31-34, wherein the identification includes identifying that the provision of the CRT to the patient does not result in a beneficial effect on at least one of the following: ejection fraction, intracardiac pressure, intracardiac pressure gradient over a selected period, NYHA class score, peak VO2, and 6-minute walk score.

[0100] Example 36. The method according to any one of Examples 31-35, wherein the identification includes identifying that the effect of the provided CRT includes an insufficient effect on the increase in intracardiac pressure or an insufficient effect on the increase in intracardiac effects over a selected period of time.

[0101] Example 37. The method according to any one of Examples 31 to 36, wherein the identification includes identifying an arrhythmia in the patient after the provision of the CRT.

[0102] Example 38. The method according to any one of Examples 31 to 37, comprising selecting at least one previously implanted electrode lead from two or more previously implanted electrode leads to provide the cardiac contractile regulation therapy during the treatment.

[0103] Example 39. The method according to any one of Examples 31 to 37, comprising selecting at least one previously implanted electrode to be used for providing the cardiac systolic regulation therapy.

[0104] Example 40. Suitable for providing both CRT and cardiac contractile regulation therapy, the selected at least one previously implanted electrode is at least 4 mm 2 The method according to Example 39, having a surface area and coated with a high capacitance and low polarization coating.

[0105] Example 41. The method according to either Example 38 or 39, wherein the selection includes selecting at least one electrode lead located in at least one of the right ventricle, left ventricle, and a blood vessel less than 1 cm away from the heart.

[0106] Example 42. The method according to any one of Examples 38-41, wherein the selected at least one previously implanted electrode lead is fixed to the cardiac septum for cardiac contractile regulation therapy.

[0107] Example 43. The method according to any one of Examples 38 to 42, comprising testing whether the selected at least one previously implanted electrode lead is suitable for providing the cardiac contractile regulation therapy before the treatment.

[0108] Example 44. The method of Example 43, wherein the test includes providing an electric field having parameter values ​​suitable for cardiac contractile regulation therapy via the selected at least one previously implanted electrode lead, and testing whether the provided electric field induced cardiac contractile regulation therapy and / or caused pain or discomfort to the patient.

[0109] Example 45. The method according to any one of Examples 31 to 44, comprising implanting a dual-purpose device configured to provide both CRT and cardiac contractile regulation before the treatment, and the treatment comprising signaling the device to provide the CRT therapy.

[0110] Example 46. The method according to any one of Examples 31 to 44, comprising implanting a CRT device before the provision and replacing the implanted CRT device with a cardiac contractile regulating device before the treatment.

[0111] Example 47. A method for testing at least one electrode lead for providing cardiac contraction control therapy, The decision to provide CRT to the patient, Implanting two or more electrode leads in the heart of the patient at a location suitable for providing the CRT, The method comprising testing whether at least one of two or more electrode leads is suitable for providing cardiac contraction control therapy.

[0112] Example 48. The method of Example 47, wherein the test includes providing an electric field having parameter values ​​suitable for cardiac contractile regulation therapy via the at least one selected electrode lead, and testing whether the provided electric field induces undesirable side effects.

[0113] Example 49. The method of Example 48, wherein providing the electric field during the test is provided by a pulse generator located outside the body.

[0114] Example 50. The method according to either one of Example 48 or 49, wherein the undesirable side effect includes pain and / or discomfort to the patient.

[0115] Example 51. The method according to any one of Examples 47 to 50, wherein the test is performed during the embedding.

[0116] Example 52. The method according to any one of Examples 47 to 51, wherein the implantation comprises fixing the at least one electrode lead to the cardiac septum, and the testing comprises testing the at least one fixed electrode lead.

[0117] Example 53. A system for providing cardiac resynchronization therapy (CRT) and cardiac contractile regulation therapy, Memory and A pulse generator configured to generate an electric field having parameter values ​​suitable for CRT and cardiac contraction control, At least one electrode lead electrically connected to the pulse generator and positioned inside the heart or at a distance of up to 1 cm from the heart, A measurement circuit connectable to at least one sensor, the measurement circuit configured to measure at least one physiological parameter related to cardiac output, The measurement circuit and the control circuit electrically connected to the pulse generator are provided, The system wherein the control circuit is configured to use the electric field parameter values ​​stored in the memory to signal the pulse generator to generate an electric field having parameter values ​​suitable for CRT or cardiac contraction regulation.

[0118] Example 54. The system according to Example 53, wherein the control circuit is configured to determine whether the effect of the electric field provided for the CRT is a desired effect by determining, based on a signal received from the measurement circuit, the relationship between the signal or its index and one or more desired effect indexes stored in the memory.

[0119] Example 55. The system according to Example 54, comprising a communication circuit configured to transmit a wireless signal to a remote device located outside the body, wherein the control circuit transmits a signal to the communication circuit, which includes instructions for providing cardiac contraction control therapy and / or, if the CRT effect is not the desired effect, information relating to the CRT effect.

[0120] Example 56. The system according to Example 55, wherein the control circuit receives commands from a remote device to provide cardiac contraction control therapy via signals received by the communication circuit.

[0121] Example 57. The system according to any one of Examples 54 to 56, wherein the control circuit is configured to send a signal to the pulse generator to generate an electric field having parameter values ​​suitable for providing cardiac contraction control therapy to the heart when the CRT effect is not the desired effect.

[0122] Example 58. The system according to any one of Examples 53 to 57, wherein the control circuit is configured to send a signal to the pulse generator to generate the electric field having parameter values ​​suitable for CRT and / or cardiac contraction regulation, and to provide the electric field through the at least one electrode lead.

[0123] Example 59. At least one electrode of the at least one electrode lead is suitable for providing both CRT and cardiac contractile regulation therapy, and is at least 4 mm long. 2 The system according to any one of Examples 53 to 58, having a surface area and coated with a high capacitance and low polarization coating.

[0124] Unless otherwise defined, all technical and / or scientific terms used herein have the same meaning as those generally understood by those skilled in the art to which the present invention pertains. Similar or equivalent methods and materials may be used in the practice or testing of embodiments of the present invention, although exemplary methods and / or materials are described below. In case of any conflict, the patent specification, including definitions, shall prevail. Furthermore, materials, methods, and examples are illustrative and not necessarily intended to be limiting.

[0125] As those skilled in the art will understand, some embodiments of the present invention can be implemented as systems, methods, or computer program products. Accordingly, some embodiments of the present invention may take the form of entirely hardware embodiments, entirely software embodiments (including firmware, resident software, microcode, etc.), or embodiments combining software and hardware embodiments, all of which may be referred to herein as “circuits,” “modules,” or “systems.” Furthermore, some embodiments of the present invention may take the form of computer program products implemented on one or more computer-readable media, including computer-readable program code embodied thereon. Implementation of some embodiments of the present invention, methods and / or systems, may involve performing and / or completing selected tasks manually, automatically, or in combination thereof. Furthermore, according to the actual apparatus and equipment of some embodiments of the methods and / or systems of the present invention, some selected tasks can be implemented by hardware, software, or firmware, and / or in combination thereof, for example, using an operating system.

[0126] For example, hardware for performing selected tasks according to some embodiments of the present invention may be implemented as a chip or circuit. As software, selected tasks according to some embodiments of the present invention may be implemented as a set of software instructions executed by a computer using any suitable operating system. In exemplary embodiments of the present invention, one or more tasks according to some exemplary embodiments of the method and / or system described herein are performed by a data processor, such as a computing platform, for executing a set of instructions. Optionally, the data processor includes volatile memory for storing instructions and / or data, and / or non-volatile storage for storing instructions and / or data, such as a magnetic hard disk and / or removable media. Optionally, network connectivity is also provided. A display and / or user input device, such as a keyboard and mouse, is also optionally provided.

[0127] Any combination of one or more computer-readable media may be used for some embodiments of the present invention. A computer-readable media may be a computer-readable signal medium or a computer-readable storage medium. A computer-readable storage medium may be, for example, an electronic, magnetic, optical, electromagnetic, infrared, or semiconductor system, apparatus, or device, or any preferred combination thereof. More specific examples of computer-readable storage media may include electrical connections having one or more communication lines, portable computer diskettes, hard disks, random access memory (RAM), read-only memory (ROM), erasable programmable read-only memory (EEPROM or flash memory), optical fibers, compact disk read-only memory (CD-ROM), optical storage devices, magnetic storage devices, or any preferred combination thereof. In the context of this document, a computer-readable storage medium may be any tangible medium that can contain or store programs for use by, or in connection with, an instruction execution system, apparatus, or device.

[0128] A computer-readable signal medium may include, for example, a propagating data signal having computer-readable program code implemented herein, either in a broadband or as part of a carrier wave. Such propagating signals may take any of various forms, including but not limited to electromagnetic, optical, or any combination thereof. The computer-readable signal medium may be any computer-readable medium, rather than a computer-readable storage medium, that can communicate, propagate, or transport a program for use by, or in connection with, an instruction execution system, apparatus, or device.

[0129] Program code implemented on a computer-readable storage medium may be transmitted using any suitable medium, including but not limited to wireless, wired, fiber optic cable, RF, or any suitable combination thereof.

[0130] Computer program code for performing operations for some embodiments of the present invention may be written in any combination of one or more programming languages, including, for example, object-oriented programming languages ​​such as Java, Smalltalk, and C++, and conventional procedural programming languages ​​such as, for example, the "C" programming language or a similar programming language. The program code may run entirely on the user's computer, partially on the user's computer, as a standalone software package, partially on the user's computer, partially on a remote computer, or entirely on a remote computer or server. In the latter scenario, the remote computer may be connected to the user's computer via any type of network, including a local area network (LAN) or a wide area network (WAN), or to an external computer (for example, via the Internet using an Internet Service Provider).

[0131] Some embodiments of the present invention may be described below with reference to flowcharts and / or block diagrams of methods, apparatus (systems), and computer program products according to embodiments of the present invention. It will be understood that each block in a flowchart and / or block diagram, as well as combinations of blocks in a flowchart and / or block diagram, can be implemented by computer program instructions. These computer program instructions may be provided to a general-purpose computer processor, a dedicated computer, or other programmable data processing device for manufacturing machines, thereby creating means for performing functions / actions specified in a block or a plurality of blocks in a flowchart and / or block diagram, through which instructions executed via the processor of the computer or other programmable data processing device.

[0132] Furthermore, these computer program instructions may be stored in a computer-readable medium that can instruct a computer, other programmable data processing device, or other device to function in a particular way, thereby manufacturing a product which includes instructions that perform functions / actions specified in a block or a series of block flowcharts and / or block diagrams.

[0133] Computer program instructions may be loaded onto a computer, other programmable device, or other device to create a computer implementation process, such that the instructions executed on the computer or other programmable device perform a series of operational steps, providing a process for carrying out functions / actions specified in a block or multi-block flowchart and / or block diagram.

[0134] Some of the methods described herein are generally designed for computer use only and may not be feasible or practical to be performed purely manually by a human expert. A human expert who wishes to perform a similar task manually, such as identifying that a CRT effect is not the desired effect, may be expected to use entirely different methods, such as leveraging their expertise and the pattern recognition capabilities of the human brain. This would be far more efficient than manually performing the steps of the methods described herein.

[0135] Several embodiments of the present invention will be described herein, merely illustrative, with reference to the accompanying drawings. Particular emphasis will be placed on the details shown in the drawings, emphasizing that these details are intended to illustrate the embodiments of the present invention. In this regard, the description with reference to the drawings will make it clear to those skilled in the art how embodiments of the present invention may be carried out. [Brief explanation of the drawing]

[0136] [Figure 1A] This is a graph showing cardiac contraction regulation pulses according to some exemplary embodiments of the present invention. [Figure 1B] This is a flowchart of a process for identifying undesirable responses to CRT and providing cardiac contractile regulation therapy, according to some exemplary embodiments of the present invention. [Figure 2] This is a schematic diagram showing the placement of electrode leads within the heart suitable for providing cardiac contractile regulation therapy according to some exemplary embodiments of the present invention. [Figure 3A] This is a flowchart of a process for treating patients selected for CRT in combination with cardiac contractile regulation therapy, according to some exemplary embodiments of the present invention. [Figure 3B] This is a flowchart illustrating a process for identifying CRT non-responder patients according to some exemplary embodiments of the present invention, prior to the implantation and provision of cardiac contractile regulation therapy to these patients. [Figure 4A]This is a flowchart illustrating a process for providing cardiac contraction control therapy when a pacing device, such as a CRT device, is already implanted in the body, according to some exemplary embodiments of the present invention. [Figure 4B] This is a flowchart illustrating a process for providing cardiac contraction control therapy when a pacing device, such as a CRT device, is already implanted in the body, according to some exemplary embodiments of the present invention. [Figure 5] This is a block diagram of a system for providing cardiac contractile regulation according to some exemplary embodiments of the present invention. [Figure 6] This is a flowchart of a process for identifying undesirable responses to CRT therapy and providing cardiac contractile regulation therapy by device action, according to some exemplary embodiments of the present invention. [Modes for carrying out the invention]

[0137] In some embodiments, the present invention relates to cardiac contractile regulation therapy, and more specifically, to cardiac contractile regulation for cardiac resynchronization therapy (CRT) candidates, without limiting itself.

[0138] One aspect of several embodiments relates to the selection of a patient for cardiac systolic regulation therapy. In some embodiments, the patient is a candidate for CRT treatment. In some embodiments, the patient is selected for cardiac systolic regulation therapy based on the probability that they will not respond to CRT treatment, or that the response to CRT treatment will not produce the desired therapeutic effect. In some embodiments, the patient is selected for cardiac systolic regulation therapy before a cardiac pulse generator is implanted in the patient's body.

[0139] As used herein in some embodiments of the present invention, the CRT includes providing synchronous therapy having a typical configuration of at least three leads, e.g., a right atrial lead positioned in the right atrium, a right ventricular lead positioned in the right ventricle adjacent to the interventricular septum, and a left ventricular lead inserted into one of the left ventricular veins via the coronary sinus. In some embodiments, one or more of the CRT leads include at least one anchor configured to fix at least a portion of the lead, e.g., the distal portion of the lead, to cardiac tissue. In some embodiments, the at least one anchor includes a screw configured to allow screwing in at least a portion of the lead into cardiac tissue. In some embodiments, one or more CRT leads are used to sense electrical signals from the myocardium and pace the heart. In some embodiments, the pacing pulse, e.g., an electric field configured to generate cardiac pacing, has an amplitude of a value or range of values ​​of 3V to 7V, e.g., 3V to 6V, 4V to 5.5V, 4.5V to 6V, 5V to 7V, 4V, 5V, or any intermediate, smaller or larger. In some embodiments, the electric field provided has a duration, e.g., pulse width, in the range of values ​​from 0.1 milliseconds (ms) to 0.8 ms, e.g., 0.1 ms to 0.5 ms, 0.3 ms to 0.6 ms, 0.4 ms to 0.6 ms, 0.5 ms to 0.6 ms, 0.6 ms to 0.8 ms, or an intermediate, shorter, or longer value. In some embodiments, the pulse width has a duration of at least 0.3 ms, e.g., 0.4 ms, 0.5 ms, 0.6 ms, or any intermediate, shorter, or longer duration.

[0140] As used herein in some embodiments of the present invention, cardiac contractile regulation therapy includes providing electric field pulses during the ventricular refractory period, for example, during the period when electrical signals cannot induce new myocardial contractions, as shown in Figure 1A, for example. In some embodiments, during cardiac contractile regulation therapy, one or more biphasic bipolar pulses are transmitted from the same location, for example, as a biphasic pulse train, with an amplitude 103 of at least 4V, e.g., 5V, 6V, 7V, 8V, 9V, or an intermediate, smaller or larger value. In some embodiments, the duration of each biphasic pulse 105 is in the range of 8 to 15 milliseconds (ms), e.g., 8 to 10 ms, 9 to 12 ms, 10 to 10.5 ms, 10 to 11 ms, 10 to 12 ms, or an intermediate, smaller or larger range of values. In some embodiments, a train of one, two, three, four, or any intermediate, smaller or larger number of biphasic pulses is transmitted. In some embodiments, three consecutive trains of biphasic pulses are transmitted, as shown in Figure 1A, for example. In some embodiments, cardiac contractile regulation therapy has parameters described, for example, in PCT application IB2020 / 050534.

[0141] According to some embodiments, CRT candidates are selected for cardiac contractile regulation based on at least one clinical parameter, for example, a history of atrial fibrillation (AF), a diagnosis of ischemic cardiomyopathy, or a low percentage of CRT pacing, for example, the mean ratio between CRT pacing beats and heart rate over a selected period being less than 90%, e.g., less than 80%, less than 70%, or any intermediate, smaller, or larger value. In some embodiments, the period selected to measure the ratio is at least one day, e.g., one day, one week, one month, three months, or any intermediate, shorter, or longer period.

[0142] Alternatively or additionally, CRT candidates are selected for cardiac systolic regulation if the patient is diagnosed with one, two or more comorbidities, such as renal failure, diabetes mellitus, chronic obstructive pulmonary disease, sleep disorders such as sleep apnea, and anemia. In some embodiments, CRT candidates are selected for cardiac systolic regulation based on the results of electrophysiological analysis of the heart, for example, in patients showing non-left bundle branch block.

[0143] One aspect of several embodiments relates to treating a patient receiving cardiac respiration therapy (CRT) in conjunction with cardiac recompression therapy. In some embodiments, the activation mode of the device used to provide CRT is modified to provide cardiac recompression therapy. Alternatively, the device used to provide CRT is replaced with a device configured to provide cardiac recompression therapy. In some embodiments, a patient receiving CRT is switched to receiving cardiac recompression therapy based on a measurement of at least one clinical or physiological parameter related to cardiac contractility and / or the propagation of electrical signals within the heart.

[0144] According to some embodiments, a pulse generator providing cardiac respiration (CRT) to a patient, such as an implantable pulse generator (IPG), measures at least one physiological parameter indicating the cardiac response to CRT during and / or after the delivery of electric field pulses to the heart. Alternatively or additionally, at least one parameter is measured by a different device, such as an implanted or extracorporeal device. In some embodiments, the at least one physiological parameter indicates cardiac output and / or cardiac contraction. In some embodiments, the at least one physiological parameter includes at least one of ejection fraction, cardiac output, intracardiac pressure, intracardiac pressure gradient over a selected period, NYHA class score, peak VO2, and 6-minute walk score.

[0145] According to some embodiments, the device controller determines, based on at least one measured physiological parameter, that the patient's response to a provided CRT, e.g., a provided electric field, is not a desired response. In some embodiments, if the determined response is not a desired response, the device modifies the value of at least one activation parameter of the pulse generator, e.g., to enable the provision of cardiac contractile regulating therapy to the heart. In some embodiments, the at least one activation parameter includes at least one of electric field strength, timing of electric field provision with respect to myocardial contractility, and / or electric field duration. Alternatively or additionally, the at least one activation parameter includes the number and / or position of electrodes for providing cardiac contractile regulating therapy.

[0146] According to some embodiments, if the determined response is not a desired response, the device used to provide CRT is replaced with a cardiac systolic regulation device configured to provide cardiac systolic regulation therapy. In some embodiments, the cardiac systolic regulation device is connected to at least some of the electrode leads used to provide CRT. Alternatively or additionally, at least one new electrode lead is connected to and implanted to position electrodes at the ends of the electrode leads at specific locations within the heart, for example, selected to provide cardiac systolic regulation. Optionally, two or more new electrode leads carrying electrodes are implanted in the body to provide cardiac systolic regulation therapy. In some embodiments, existing implantable CRT ventricular leads are used for cardiac systolic stimulation or cardiac systolic regulation testing.

[0147] According to some embodiments, the CRT is provided in combination with cardiac systolic regulation therapy, for example, by a dual-purpose device. In some embodiments, the CRT is combined with cardiac systolic regulation therapy if the response, for example, the patient's physiological or clinical response to the CRT alone, is not the desired response. In some embodiments, cardiac systolic regulation therapy is provided in sync with the CRT.

[0148] According to some embodiments, at least one of the electrode leads connected to the dual-purpose device is used to provide pacing, for example, as part of a CRT, and at least one different electrode lead is used to provide cardiac contractile regulation. Alternatively, at least one of the electrode leads connected to the dual-purpose device is used to provide both cardiac contractile regulation therapy and pacing at different time points.

[0149] According to some embodiments, cardiac systolic regulation is provided by at least one electrode located in the right ventricle (RV) of the heart, and pacing is provided by at least one different electrode located in the left ventricle (LV) of the heart. Alternatively, cardiac systolic regulation therapy is provided by at least one electrode located in the RV and at least one electrode located in the LV, and pacing is provided by at least one different electrode in the LV, or by the same electrode located in the LV for providing cardiac systolic regulation therapy. In some embodiments, both cardiac systolic regulation therapy and pacing are provided to the RV and LV by different electrodes or by at least one shared electrode.

[0150] According to some embodiments, cardiac contraction regulation is provided in sync with the provision of pacing and / or in sync with cardiac contraction. In some embodiments, the electric field for cardiac contraction regulation stimulation is generated with parameter values, e.g., intensity, amplitude, and / or frequency suitable for the dual effect of pacing and cardiac contraction regulation in the same stimulation pulse. Optionally, the dual effect of pacing and cardiac contraction regulation is generated using at least one electrode lead, e.g., a CRT lead, positioned in the heart at a location suitable for generating the dual effect in the heart.

[0151] According to some embodiments, cardiac systolic pacing is provided after the S wave timing shown in the electrocardiogram (ECG), for example, representing the depolarization of Purkinje fibers. In some embodiments, cardiac systolic pacing is provided up to 0.06 seconds, for example, up to 0.04 seconds, up to 0.03 seconds, or up to 0.02 seconds, after detecting ventricular contraction. In some embodiments, at least one electrode lead positioned in the right ventricle is used to detect ventricular contraction and provide an electric field with parameter values ​​suitable for cardiac systolic pacing therapy. In some embodiments, two or more electrode leads, for example, three or four electrode leads in the right ventricle, are used for sensing and providing cardiac systolic pacing.

[0152] According to some embodiments, cardiac systolic regulation therapy is provided during or after pacing in the LV, for example, when combined with CRT. In some embodiments, cardiac systolic regulation is provided for up to 0.06 seconds, for example, up to 0.04 seconds, up to 0.03 seconds, or up to 0.02 seconds, after detecting right ventricular contraction or following the provision of CRT. In some embodiments, a potential benefit of providing cardiac systolic regulation therapy during or after pacing in the LV may be to promote cardiac contraction in the LV tissue.

[0153] According to some embodiments, CRT is added to cardiac systolic regulation therapy provided to the heart. In some embodiments, if the addition of CRT does not improve cardiac contractility, CRT is stopped while maintaining cardiac systolic regulation therapy. In some embodiments, cardiac systolic regulation is provided after CRT pacing if, under certain conditions, for example, the measured heart rate is higher than 0%, 5%, 10%, 20%, 40%, or an intermediate, smaller, or larger value than the patient's average heart rate. Alternatively or additionally, cardiac systolic regulation is provided after CRT pacing during sleep or a specific sleep stage, such as deep sleep, rapid eye movement (REM) sleep, or non-REM sleep. Alternatively or additionally, cardiac systolic regulation is provided after CRT pacing if an atrial arrhythmia is detected.

[0154] One aspect of several embodiments relates to using at least one existing implanted electrode lead, such as a CRT lead, for cardiac contraction control therapy. In some embodiments, at least one previously implanted electrode lead is selected from two or more previously implanted electrode leads for providing cardiac contraction control therapy. In some embodiments, the at least one electrode lead is selected by providing a test electric field having parameters for cardiac contraction control therapy through at least one electrode lead and determining the effect of the provided electric field. Alternatively, the test electric field is provided through two or more previously implanted electrode leads, and at least one electrode lead more suitable for providing cardiac contraction control therapy is selected from two or more previously implanted electrode leads. Optionally, at least one electrode lead previously used in CRT is selected for providing cardiac contraction control therapy alone or for providing cardiac contraction control therapy in combination with CRT.

[0155] According to some embodiments, the appearance of undesirable side effects, such as pain or discomfort after and / or during the provision of the electric field, is determined. In some embodiments, based on the appearance of undesirable side effects, at least one electrode lead for cardiac contraction regulation therapy is optionally selected from two or more electrode leads. In some embodiments, at least one electrode lead is selected for cardiac contraction regulation if the provision of a test electric field through the electrode did not cause undesirable side effects in the patient, or if it caused acceptable undesirable side effects. In some embodiments, if undesirable side effects are detected, at least one different electrode lead is selected for the provision of a test electric field.

[0156] According to some embodiments, at least one electrode lead is selected from two or more electrode leads to provide cardiac contractile regulation based on the measurement of at least one clinical or physiological parameter indicating cardiac output and / or cardiac contraction, following the provision of a test electric field.

[0157] According to some embodiments, at least one electrode lead, such as a CRT lead, is pre-embedded at a location where it can be used to provide cardiac contractility modulation therapy. Optionally, two or more CRT leads, such as 2, 3, or 4 CRT leads, are pre-embedded at locations where they can be used to provide cardiac contractility modulation therapy. In some embodiments, at least one location suitable for providing cardiac contractility modulation includes the right ventricle (RV), left ventricle (LV), right atrium (RA), or any combination of two or more CRT leads at these locations.

[0158] According to some exemplary embodiments, at least one electrode of an electrode lead configured to provide both CRT and cardiac contractility modulation therapy is embedded in the RV. In some embodiments, the electrode is actively fixed, for example, using an electrical active helix.

[0159] According to some embodiments, the electrodes of an electrode lead configured to provide both CRT and cardiac contractility modulation have a surface area of at least 2 mm 2 , for example, at least 4 mm 2 , at least 6 mm 2 or any intermediate, smaller, or larger surface area. Additionally or alternatively, the electrodes are coated with a high-capacity, low-polarization coating such as titanium nitride or iridium oxide.

[0160] One aspect of some embodiments relates to providing an electric field having parameter values suitable for cardiac contractility modulation therapy to induce cardiac pacing. In some embodiments, the electric field is provided to patients who do not respond to CRT or are predicted not to respond to CRT. In some embodiments, an electric field having cardiac contractility modulation parameter values is provided to induce pacing and facilitate cardiac contractility modulation therapy to the heart.

[0161] According to some embodiments, an electric field having cardiac contractile regulation parameter values ​​is provided to induce pacing by at least one electrode lead positioned in the right and / or left ventricle. In some embodiments, an extended pacing signal is provided for the CRT and cardiac contractile regulation, as described, for example, in U.S. Patent No. 7460907B1.

[0162] Before describing in detail at least one embodiment of the present invention, it should be understood that the application of the present invention is not necessarily limited to the structural and configuration details of the components and / or methods described below and / or shown in the drawings and / or examples. Other embodiments of the present invention are possible, or it can be practiced or carried out in various ways.

[0163] Example of a general process for providing cardiac contractile regulation to patients who do not respond to CRT According to some exemplary embodiments, cardiac contractility regulation is provided to patients who do not show a desired response to CRT treatment, for example, patients who do not show desired myocardial contractility after CRT. Figure 1B hereby refers to a general process for providing cardiac contractility regulation therapy to patients showing an undesirable response to CRT according to some exemplary embodiments of the present invention.

[0164] According to some exemplary embodiments, in block 102, an undesirable response to CRT therapy is identified. In some embodiments, an undesirable response is a patient's cardiac and / or physical response that exhibits a lower effect than the desired effect of CRT therapy. In some embodiments, an undesirable response is identified based on the measurement of at least one physiological parameter related to cardiac activity.

[0165] According to some exemplary embodiments, undesirable effects of CRT are identified by measuring at least one parameter related to cardiac output, such as cardiac ejection fraction and / or stroke volume. In some embodiments, undesirable effects of CRT are detected at least 24 hours after the start of CRT, for example, at least one week, at least one month, or any intermediate, shorter, or longer period.

[0166] According to some exemplary embodiments, the response to a CRT is measured from within the body, for example, by at least one implanted electrode. Optionally, at least one implanted electrode is connected to an implanted CRT device. Alternatively, at least one electrode is connected to another measuring device, either implanted in or outside the body.

[0167] According to some exemplary embodiments, the response to the CRT is measured externally by at least one electrode placed on the outer surface of the skin. Alternatively, or additionally, the response to the CRT is measured by at least one imaging device, such as an ultrasound device, a magnetic resonance imaging (MRI) device, and / or a computed tomography (CT) device. In some embodiments, at least one imaging device, such as an ultrasound device, is implanted in the body.

[0168] According to some exemplary embodiments, when an undesirable response to the CRT is identified, a cardiac systolic regulation device configured to provide cardiac systolic regulation therapy is implanted in block 104. In some embodiments, the implanted cardiac systolic regulation device replaces an existing CRT device that has been removed from the patient's body. In some embodiments, the newly implanted cardiac systolic regulation device is electrically connected to one or more CRT leads already implanted in the body, for example, in the heart. Alternatively, the implanted cardiac systolic regulation device is implanted in addition to an existing CRT device already implanted in the body. In some embodiments, the implanted cardiac systolic regulation device is electrically connected to at least one CRT lead, which is optionally also connected to a CRT device.

[0169] According to some exemplary embodiments, a novel implantable cardiac contractile regulation device provides cardiac contractile regulation therapy in block 106.

[0170] According to some exemplary embodiments, when an undesirable response to the CRT is identified, in block 108, the CRT device used to provide the CRT is switched to a cardiac contractile regulated therapy activation protocol. In some embodiments, in block 108, the cardiac contractile regulated therapy protocol is activated on the CRT device, e.g., a dual-purpose device. Alternatively, different electrodes connected to the CRT device are used to provide cardiac contractile regulated therapy. Optionally, the values ​​of one or more parameters of the electric field, e.g., pulse duration, amplitude, and / or frequency, are modified to provide cardiac contractile regulated therapy.

[0171] According to some exemplary embodiments, when an undesirable response to the CRT is identified, at least one cardiac systolic regulation therapy protocol or its parameters is added in block 110 to an already implanted CRT device. In some embodiments, at least one cardiac systolic regulation therapy protocol or its parameters is uploaded to the implanted CRT device from outside the body. In some embodiments, the implanted device provides both CRT and cardiac systolic regulation in combination, for example, by providing pacing via at least one electrode lead and by providing cardiac systolic regulation via at least one different electrode lead, with both electrodes connected to the same device. In some embodiments, the CRT and cardiac systolic regulation therapy protocols are synchronized, for example, by providing cardiac systolic regulation pulses immediately after pacing is provided and following left ventricular contraction. In some embodiments, cardiac systolic regulation pulses are configured to be provided immediately after pacing is provided and during the cardiac refractory period.

[0172] According to some exemplary embodiments, CRT and cardiac contractile regulation therapy are provided by the same device in block 112. In some embodiments, CRT and cardiac contractile regulation therapy are provided synchronously. Alternatively or additionally, CRT and cardiac contractile regulation therapy are provided intermittently by the same device, for example, by the same implantable device.

[0173] Examples of locations for cardiac contractile regulation therapy According to some exemplary embodiments, one or more electrode leads are implanted in the heart. In some embodiments, one or more electrodes on the electrode leads are implanted in positions suitable for providing pacing, for example, as part of CRT. In some embodiments, at least some of the electrode positions used for pacing are also suitable for providing cardiac systolic regulation. Figure 2 hereby refers to showing in-heart positions suitable for CRT and cardiac systolic regulation therapy according to some exemplary embodiments of the present invention.

[0174] According to some exemplary embodiments, at least one electrode lead, for example, two electrode leads, three electrode leads, four electrode leads, or any more electrode leads, is implanted in the heart. In some embodiments, each electrode lead includes at least one electrode, for example, two, three, four, five, or any more electrodes. In some embodiments, at least some of the electrode leads, for example, the distal ends of the electrode leads, are fixed to cardiac tissue.

[0175] According to some exemplary embodiments, at least one electrode lead used to provide CRT, for example electrode lead 208, is fixed within the heart 200. In some embodiments, at least one electrode lead used to provide CRT, for example electrode lead 208, is fixed within the right ventricle 204 of the heart. Alternatively or additionally, at least one electrode lead, for example lead 212 used for CRT, is fixed within the right atrium 210. Alternatively or additionally, at least one CRT electrode lead 216 is inserted through the coronary sinus and positioned to provide an electric field to the left ventricle (LV).

[0176] According to some exemplary embodiments, the CRT is provided by at least one electrode lead positioned in the right ventricle 204, e.g., electrode lead 208 or 220, and optionally at least one electrode lead positioned in or near the left ventricle 214, e.g., electrode lead 216 inserted via the coronary sinus. Optionally, the electrode lead positioned in the ventricle 214 is used for cardiac systolic regulation, CRT, or a combination of both CRT and cardiac systolic regulation therapy.

[0177] According to some exemplary embodiments, the CRT lead is electrically connected to an implantable pulse generator (IPG), such as IPG202. In some embodiments, the IPG202 is configured to provide both cardiac contractile regulation and CRT via electrode leads. In some embodiments, the IPG202 is configured to provide both CRT and cardiac contractile regulation via the same leads. Alternatively, at least one lead connected to the IPG202 is used to provide CRT, and at least one different lead is used to provide cardiac contractile regulation therapy. In some embodiments, at least one electrode lead, for example electrode lead 220, is used to provide cardiac contractile regulation only.

[0178] According to some exemplary embodiments, if the IPG is configured to provide only CRT, the cardiac systolic IPG is implanted and electrically connected to at least one electrode lead already implanted in the heart at a location suitable for providing cardiac systolic therapy. Alternatively, at least one new electrode lead for cardiac systolic therapy is implanted, for example, when implanting a cardiac systolic IPG, at a preferred location in the heart or surrounding blood vessels to provide cardiac systolic therapy.

[0179] According to some exemplary embodiments, at least one electrode lead is pre-implanted to enable the provision of cardiac systolic therapy to the heart. In some embodiments, at least one electrode lead suitable for providing cardiac systolic therapy is pre-implanted within the right ventricle 204 or the left ventricle 214. Alternatively or additionally, at least one electrode lead suitable for providing cardiac systolic therapy is pre-implanted in a blood vessel at a distance of up to 1 cm, for example, up to 0.5 cm, up to 0.1 cm, or any intermediate, smaller, or larger distance from the heart. In some embodiments, the blood vessel includes a vein of the heart, such as the coronary sinus. In some embodiments, at least one electrode lead suitable for providing cardiac systolic therapy is pre-fixed to the intercardiac septum. In some embodiments, two or more electrode leads, pre-implanted, for example when implanting a CRT device and / or CRT leads, are provided to provide cardiac systolic therapy.

[0180] Examples of cardiac contractile regulation therapy for previously identified CRT nonresponders According to some exemplary embodiments, patients who are candidates for CRT are evaluated, and, for example, the potential effect of CRT in each patient is determined. In some embodiments, if the potential effect is lower than the desired effect, cardiac contractile regulation therapy is considered as an alternative to or in combination with CRT. Optionally, if the potential effect of CRT is the desired effect, cardiac contractile regulation therapy may also be provided after implantation, for example, during CRT delivery, using at least a portion of the implanted components, for example, at least a portion of the implanted electrode leads, if a lower effect of CRT is identified.

[0181] Figure 3A hereby refers to a process for treating patients selected for CRT in combination with cardiac contractile regulation therapy when potential difficulties in providing CRT are detected, according to some exemplary embodiments of the present invention.

[0182] According to some exemplary embodiments, the patient is diagnosed in block 303. In some embodiments, the patient is diagnosed by measuring at least one physiological parameter related to cardiac function, e.g., cardiac output and / or at least one parameter indicating myocardial contraction. Additionally or alternatively, electrophysiological analysis and / or imaging analysis are performed to monitor cardiac function, e.g., at least one of ECG, echocardiography, CT and / or MRI. Furthermore, during the diagnosis, the patient's and / or the patient's family medical history is collected and examined.

[0183] According to some exemplary embodiments, the patient is selected for CRT in block 305. In some embodiments, the patient is selected for CRT based on the results of a diagnosis performed in block 303. In some embodiments, the patient is selected for CRT if the results of the diagnosis performed in block 303 indicate irregular cardiac contractions and / or insufficient cardiac output.

[0184] According to some exemplary embodiments, in block 307, potential difficulties in providing CRT treatment are detected. In some embodiments, detecting potential difficulties in providing CRT includes detecting that providing CRT results in undesirable side effects, e.g., unpleasant sensations. Alternatively or additionally, detecting potential difficulties includes detecting that providing CRT to a patient does not result in a beneficial effect on heart failure state parameters, e.g., a beneficial effect on heart rate and / or cardiac output. In some embodiments, detecting that providing CRT to a patient does not result in a beneficial effect includes detecting that providing CRT results in a lower effect of at least 2%, e.g., at least 5%, at least 10%, at least 15%, at least 20%, or any intermediate, smaller or larger percentage from the desired beneficial effect.

[0185] According to some exemplary embodiments, detecting potential difficulties in providing CRT includes detecting that an invasive procedure, such as a resection, needs to be performed on the patient in order to benefit from CRT. In some embodiments, detecting potential difficulties in providing CRT includes diagnosing the patient with at least one of the following: atrial fibrillation (AF), ischemic cardiomyopathy, or a low percentage of CRT pacing, for example, the mean ratio between CRT pacing beats and heart rate over a selected period being less than 90%, e.g., less than 80%, less than 70%, or any intermediate, smaller, or larger value. In some embodiments, the period selected to measure the ratio is at least one day, e.g., one day, one week, one month, three months, or any intermediate, shorter, or longer period.

[0186] According to some exemplary embodiments, detecting potential difficulties in providing CRT includes diagnosing the patient with one or more comorbidities selected from a list including renal failure, diabetes mellitus, chronic obstructive pulmonary disease, sleep disorders such as apnea, and anemia. Alternatively or additionally, detecting potential difficulties in providing CRT includes diagnosing the patient with cardiac arrhythmias, such as non-left bundle branch block (non-LBBB).

[0187] According to some exemplary embodiments, detecting potential difficulties in providing CRT includes detecting that providing CRT to a patient does not result in a beneficial effect on cardiac output, e.g., an increase of at least 0.5 ml in cardiac output, e.g., at least 1 ml, at least 3 ml, at least 5 ml, or any intermediate, smaller, or larger desired increase in cardiac output.

[0188] Alternatively or additionally, detecting potential difficulties in providing CRT includes detecting that providing CRT to a patient does not result in a beneficial effect on ejection fraction, for example, an increase of at least 0.5% of ejection fraction, for example, at least 1%, at least 3%, at least 5%, or any intermediate, smaller, or larger desired percentage increase in ejection fraction.

[0189] Alternatively or additionally, detecting potential difficulties in providing CRT includes detecting that providing CRT to a patient does not result in a beneficial effect on at least one of the following parameters: intracardiac pressure, intracardiac pressure gradient over a selected period, NYHA class score, peak VO2, and / or 6-minute walk score. In some embodiments, a beneficial effect includes improvement in the parameter compared to baseline values ​​measured before and / or after CRT implantation.

[0190] According to some exemplary embodiments, block 309 determines whether the patient is eligible for cardiac systolic regulation therapy. In some embodiments, determining whether the patient is eligible for cardiac systolic regulation therapy includes diagnosing the patient with heart failure. In some embodiments, determining whether the patient is eligible for cardiac systolic regulation includes diagnosing the patient with NYHA class II–IV heart failure. Alternatively or additionally, the patient is diagnosed with a left ventricular ejection fraction in the range of 25%–55%, e.g., 25%–40%, 30%–45%, 40%–55%, or any intermediate smaller or larger range. In some embodiments, determining whether the patient is eligible for cardiac systolic regulation includes diagnosing the patient with a QRS width greater than normal, e.g., greater than 120 ms, e.g., greater than 130 ms, greater than 140 ms, or any intermediate smaller or larger QRS width.

[0191] According to some exemplary embodiments, the patient is treated with cardiac systolic therapy in block 311. In some embodiments, the patient is treated with cardiac systolic therapy based on the results of a determination made in block 311. In some embodiments, cardiac systolic therapy includes providing electric field pulses during the ventricular refractory period, for example, during the period when electrical signals cannot induce new myocardial contractions. In some embodiments, during cardiac systolic therapy, a biphasic bipolar pulse train is transmitted from the same location with an amplitude of at least 5V, e.g., 5V, 6V, 7V, 8V, 9V, or an intermediate, smaller or larger value. In some embodiments, the biphasic bipolar pulse train is transmitted for a period of time in the range of 8ms to 13ms, e.g., 8ms to 10ms, 9ms to 10.5ms, 9.5ms to 12ms, 9ms to 13ms, or any intermediate, smaller or larger value range.

[0192] Figure 3B hereby shows a process for providing cardiac contractile regulation therapy to a patient identified as a CRT non-responder prior to CRT device implantation, according to some exemplary embodiments of the present invention.

[0193] According to some exemplary embodiments, the patient is diagnosed in block 302. In some embodiments, during the diagnosis of the patient, clinical data and / or medical history are collected for the patient and, optionally, for the patient's family. In some embodiments, during the diagnosis, at least one cardiac parameter, e.g., electrical activity of the heart, contractility of at least a portion of the heart, e.g., left ventricular contraction, and / or heart rate, is measured. Alternatively or additionally, during the diagnosis of the patient, electrical conduction, e.g., through cardiac tissue and / or between the atria and ventricles, is measured. In some embodiments, during the diagnosis, diagnostic information regarding cardiac contractile conditions, e.g., atrial fibrillation, is collected. Alternatively or additionally, during the diagnosis, information related to heart failure, e.g., QRS width, is collected. In some embodiments, at least a portion of the information is collected using at least one imaging technique, e.g., ultrasound and / or echocardiography. Alternatively or additionally, at least a portion of the information is collected using electrocardiogram analysis.

[0194] According to some exemplary embodiments, a patient is diagnosed with heart failure at block 302. Furthermore, the patient is diagnosed with left bundle branch block (LBBB) with a QRS width of 120 ms or greater, e.g., 125 ms, 130 ms, or any intermediate, smaller, or larger value. Alternatively, a patient, e.g., diagnosed with heart failure, is also diagnosed with non-LBBB with a QRS width of 150 ms or greater, e.g., 155 ms, 160 ms, 170 ms, or any intermediate, smaller, or larger value. Additionally or alternatively, during the diagnosis at block 302, the patient is classified according to the New York Heart Association (NYHA) stage of heart failure.

[0195] According to some exemplary embodiments, the need for a patient to receive CRT is determined in block 304. In some embodiments, patients are selected for CRT based on the results of the patient diagnosis performed in block 302. In some embodiments, patients with left bundle branch block (LBBB) having a QRS width greater than 100 ms, e.g., greater than 110 ms, greater than 120 ms, greater than 130 ms, or any intermediate, smaller, or greater value of QRS width are selected for CRT. In some embodiments, patients of New York Heart Association (NYHA) classification II, III, or IV who do not have LBBB and have a QRS width greater than 130 ms, e.g., greater than 140 ms, greater than 150 ms, greater than 160 ms, or any intermediate, smaller, or greater value are selected for CRT.

[0196] According to some exemplary embodiments, in block 306, the risk that a patient selected for CRT is a CRT non-responder is estimated. In some embodiments, the risk that a patient selected for CRT is a CRT non-responder is calculated in block 306 based on data collected during patient diagnosis, for example, using at least one of an algorithm and / or a lookup table.

[0197] According to several exemplary embodiments, a patient's treatment plan is selected based on a calculated risk index. In some embodiments, if the calculated risk index is low, for example below a predetermined value, a CRT device with CRT leads is implanted to provide, for example, CRT therapy. In some embodiments, if the risk is very high, for example above a predetermined value, CRT is not considered a potential treatment, and in block 308, a cardiac systolic control device with cardiac systolic control leads is implanted to provide, for example, cardiac systolic control therapy only. In some embodiments, if the risk index is moderate, for example, too high to provide CRT only, but lower than the index to provide cardiac systolic control therapy only, a dual-purpose device is implanted, and in block 312, both CRT and cardiac systolic control therapy can be provided. Alternatively, a CRT device with at least one cardiac systolic control lead is implanted in block 318 to provide CRT in block 320, while maintaining the option to replace the device with a cardiac systolic control device or a dual-purpose device, and if CRT provision is ineffective, cardiac systolic control therapy using previously implanted electrode leads is provided.

[0198] According to some exemplary embodiments, if the risk of the patient not responding to CRT with a desired response is higher than a predetermined value, a cardiac systolic regulation device is implanted in the patient in block 308. In some embodiments, the implanted cardiac systolic regulation device is configured to provide the patient with cardiac systolic regulation only. In some embodiments, at least one electrode lead, for example, two, three, four, or five electrode leads configured to provide cardiac systolic regulation therapy, is implanted in a position convenient for providing cardiac systolic regulation therapy, for example, with the electrodes fixed to the right ventricular septum.

[0199] In some embodiments, at least one of the implantable electrode leads is implanted in a position suitable for providing a CRT.

[0200] According to some exemplary embodiments, once a cardiac contractile regulation device and electrode leads are implanted, cardiac contractile regulation therapy is provided in block 310.

[0201] According to some exemplary embodiments, if the risk of a patient not responding to CRT with a desired response is higher than a predetermined value, a dual-purpose device configured to provide both CRT and cardiac systolic regulation is implanted in the patient at block 311. In some embodiments, the dual-purpose device is implanted with at least one electrode lead configured to provide CRT at a suitable location for providing CRT, and at least one additional electrode lead configured to provide cardiac systolic regulation at a suitable location for providing cardiac systolic regulation therapy. Alternatively, the dual-purpose device is implanted at block 311 at a suitable location within the heart for providing both CRT and cardiac systolic regulation therapy, for example, in the right ventricular septum, with at least one electrode configured to provide both CRT and cardiac systolic regulation therapy.

[0202] According to some exemplary embodiments, once a dual-purpose device and at least one electrode are implanted, CRT and cardiac contractile regulation are provided in block 312. Optionally, CRT and cardiac contractile regulation therapy are provided synchronously. In some embodiments, CRT and cardiac contractile regulation therapy are provided intermittently. Optionally, CRT and cardiac contractile regulation therapy are provided according to the cardiac contraction sequence, for example, according to the timing of atrial and ventricular contractions.

[0203] According to some exemplary embodiments, if there is a high risk that the patient will not respond to CRT with a desired response, for example, above a predetermined value, a CRT device is implanted in block 318, comprising at least one electrode lead configured to provide CRT and at least one electrode lead configured to provide cardiac systolic regulation. In some embodiments, the at least one electrode configured to provide CRT is implanted in a position convenient for providing CRT to the patient's heart. In addition, the at least one electrode lead configured to provide cardiac systolic regulation therapy is implanted in a position convenient for providing CCM therapy to the patient's heart. Alternatively, at least one electrode lead configured to provide both CRT and cardiac systolic regulation therapy is implanted in a position convenient for both CRT and cardiac systolic regulation therapy, as illustrated, for example, in Figure 2.

[0204] According to some exemplary embodiments, the CRT is provided in block 320. In some embodiments, the CRT is provided while monitoring the effect of the provided CRT on cardiac contraction. In some embodiments, the effect of the CRT on the patient's heart becomes apparent at least 24 hours, at least 2 days, at least 1 week, or any intermediate, shorter, or longer period from the start of CRT provision. In some embodiments, the evaluation of the effect of the provided CRT is performed at least 1 month, e.g., at least 2, 3, 4, 5, 6, 7, 8 months, or any intermediate, shorter, or longer period after the initial provision of the CRT. In some embodiments, the effect of the provided CRT is monitored by evaluating changes in heart failure parameters after CRT provision, for example, compared to baseline values ​​or any other criterion.

[0205] According to some exemplary embodiments, if the monitored CRT effect is lower than the desired effect, the CRT device is replaced in block 322 with a dual-purpose device configured to provide both CRT and cardiac contractile regulation therapy. In some embodiments, the dual-purpose device is electrically connected to one or more of the previously implanted electrode leads.

[0206] According to some exemplary embodiments, if the monitored CRT effect is lower than the desired effect, the CRT device is replaced with a device configured to provide only cardiac contractile regulation, such as a cardiac contractile regulation device. In some embodiments, the cardiac contractile regulation device is electrically connected to one or more previously implanted leads configured to provide cardiac contractile regulation therapy, for example, positioned in a location suitable for providing cardiac contractile regulation therapy.

[0207] According to some exemplary embodiments, the decision of whether to implant a cardiac contraction regulation-only device or a dual-purpose CRT and cardiac contraction regulation device depends on the effect of the CRT on the patient. In some embodiments, a dual-purpose device is implanted when the effect of the CRT is not the desired effect, but the combination of CRT and cardiac contraction regulation is expected to produce the desired effect. In some embodiments, a cardiac contraction regulation-only device is implanted when the effect of the CRT is less than the desired effect, and it is expected that combining CRT with cardiac contraction regulation therapy will not produce the desired effect.

[0208] According to some exemplary embodiments, if the CRT effect is not the desired effect and the patient's clinical condition is expected to be unstable, a dual-purpose CRT and cardiac contraction control device may be implanted, for example, to allow for flexibility in future treatments.

[0209] Examples of cardiac systolic control therapy after CRT provision According to some exemplary embodiments, the decision of whether to provide cardiac contractile regulation therapy to a patient is made after the patient has received CRT, based on the results of the CRT provided. Figures 4A and 4B hereby refer to the process for providing cardiac contractile regulation to a patient already receiving CRT, according to some exemplary embodiments of the present invention.

[0210] According to some exemplary embodiments, the patient is diagnosed and the need for CRT is determined in block 304.

[0211] According to some exemplary embodiments, a CRT device is embedded in block 402. In some embodiments, the CRT device is configured to receive radio signals and transmit them to a device located outside the body.

[0212] According to some exemplary embodiments, in block 404, at least one electrode lead comprising one or more electrodes is implanted in a position suitable for providing CRT to the patient's heart.

[0213] According to some exemplary embodiments, in block 406, at least one electrode lead comprising one or more electrodes is implanted in a position suitable for providing cardiac contractile regulation therapy to the patient's heart.

[0214] Alternatively or additionally, at least one electrode lead comprising one or more electrodes is implanted in a position suitable for providing CRT and cardiac contractile regulation to the heart.

[0215] According to some exemplary embodiments, the CRT is supplied to the heart in block 408. In some embodiments, the CRT is supplied via one or more of the electrodes implanted in block 404.

[0216] According to some exemplary embodiments, in block 410, an index relating to the low effectiveness of the CRT is received. In some embodiments, the index is received based on a measurement of at least one parameter related to cardiac contraction, e.g., a measurement performed outside and / or inside the body. In some embodiments, the index is transmitted from the implanted CRT device to a device, e.g., a computer located outside the body, and / or a mobile phone or mobile phone. In some embodiments, the index is provided to a remote server and / or remote cloud storage. In some embodiments, the index is provided to a physician, nurse, or person monitoring the patient's clinical condition.

[0217] According to some exemplary embodiments, if the implantable device is a dual-purpose device configured to provide both CRT and cardiac systolic therapy based on received indicators, a signal is sent to the device to switch to cardiac systolic therapy only. In some embodiments, the signal provided to the implantable device includes information regarding at least one cardiac systolic therapy protocol, values ​​of at least one cardiac systolic therapy parameter, e.g., electric field strength, electric field frequency, duration of each pulse, and / or information regarding the synchronization of cardiac systolic therapy pulses with cardiac contraction and / or heart rhythm. In some embodiments, the signal provided to the implantable device in block 412 includes information regarding which implantable electrode to use when providing cardiac systolic therapy. In some embodiments, the signal provided to the implantable device in block 412 includes instructions to use at least one electrode implanted in a position suitable for cardiac systolic therapy.

[0218] According to some exemplary embodiments, if the implantable device is a dual-purpose device configured to provide both CRT and cardiac systolic therapy based on received indicators, then in block 414, a signal is sent to the device to combine cardiac systolic therapy with CRT. In some embodiments, the signal provided to the implantable device includes at least one of the following: a cardiac systolic therapy protocol, a value for at least one cardiac systolic therapy parameter, e.g., electric field strength, electric field frequency, duration of each pulse, and / or information regarding cardiac contraction, heart rhythm, and / or synchronization of cardiac systolic therapy pulses with CRT. In some embodiments, the signal provided to the implantable device in block 414 includes instructions regarding which electrode or electrode lead to use for cardiac systolic therapy and which electrode or electrode lead to use for CRT.

[0219] According to some exemplary embodiments, based on received indicators, the CRT device implanted in block 402 is replaced in block 416 with a device configured to provide only cardiac contraction regulation. In some embodiments, the CRT device is removed from the body. Alternatively, the cardiac contraction regulation device is implanted while the CRT device remains in the body.

[0220] According to some exemplary embodiments, the cardiac contraction regulating device is connected to at least one electrode lead, for example, an electrode lead already implanted in block 406, and positioned in a location suitable for providing cardiac contraction regulation.

[0221] According to some exemplary embodiments, in block 420, a signal is provided to an implanted cardiac contractile control device to initiate cardiac contractile control therapy.

[0222] According to some exemplary embodiments, based on received indicators, the CRT device implanted in block 402 is replaced in block 422 with a dual-purpose device configured to provide CRT and cardiac systolic regulation therapy. In some embodiments, the dual-purpose device is electrically connected in block 424 to at least one electrode lead positioned suitable for providing CRT and at least one electrode lead positioned suitable for providing cardiac systolic regulation. Optionally, the dual-purpose device is electrically connected to at least one electrode lead positioned suitable for providing both CRT and cardiac systolic regulation therapy.

[0223] Examples of devices Figure 5 hereby shows a device for providing cardiac contraction regulation therapy according to some exemplary embodiments of the present invention.

[0224] According to some exemplary embodiments, a device for providing cardiac contraction regulation therapy comprises an implantable pulse generator (IPG) unit, such as unit 502, electrically connected to at least one electrode lead placed in the body. In some embodiments, the IPG unit 502 comprises at least one control circuit 512 and at least one pulse generator 504 electrically connected to the control circuit 512. In some embodiments, the pulse generator 504 is electrically connected to at least one, for example, two, three, four, five, six or more electrode leads implanted in the body. In some embodiments, each electrode lead includes at least one, for example, two, three, four, five, six or more electrodes suitable for providing an electric field as part of, for example, CRT and / or cardiac contraction regulation.

[0225] According to some exemplary embodiments, the casing of the IPG unit 502, for example, the casing 503, is shaped and sized to be implantable in the body, for example, subcutaneously. In some embodiments, the outer surface of the casing 503 is smooth and optionally planar. In some embodiments, the IPG unit is located outside the body and connected to at least one lead implanted in the body.

[0226] According to some exemplary embodiments, the IPG unit 502 includes a memory 514 for storing at least one cardiac contraction regulation protocol or its parameters. Furthermore, the memory stores at least one CRT protocol or its parameters.

[0227] According to some exemplary embodiments, the pulse generator 504 is configured to provide at least one electrode, for example, cardiac contractile regulation therapy, and is electrically connected to a cardiac contractile regulation electrode 506 positioned in a location suitable for providing cardiac contractile regulation therapy, as illustrated, for example, in Figure 2. In addition, the pulse generator 504 is configured to provide at least one electrode, for example, CRT, and is electrically connected to a CRT electrode 508 positioned in a location suitable for providing CRT, as shown, for example, in Figure 2.

[0228] According to some exemplary embodiments, the control circuit 512 sends a signal to the pulse generator 504, which generates and provides parameter values ​​suitable for the CRT via the CRT electrode 508, such as electric field amplitude, electric field frequency, electric field pulse duration, and electric field.

[0229] According to some exemplary embodiments, the control circuit 512 sends a signal to the pulse generator 504, which generates and provides parameter values ​​suitable for cardiac contractile control therapy, such as electric field amplitude, electric field frequency, electric field pulse duration, via the cardiac contractile control electrode 506.

[0230] According to some exemplary embodiments, the IPG unit 502 includes at least one measurement circuit 516 electrically connected to a control circuit 512. In some embodiments, the at least one measurement circuit 516 is connected to at least one cardiac sensor, e.g., a cardiac sensor 520, configured to record electrical signals, such as electrophysiological signals related to cardiac activity. In some embodiments, the cardiac sensor 520 is configured to record signals related to cardiac contraction, e.g., contraction of at least one atrial, contraction of the left ventricle and / or contraction of the right ventricle. In some embodiments, the at least one cardiac sensor 520 is configured to record signals related to the electrical conductance of cardiac tissue, e.g., conductivity of cardiac tissue and / or impedance of cardiac tissue.

[0231] According to some exemplary embodiments, the measurement circuit 516 is connected to at least one additional sensor, such as a body sensor 518 configured to record signals related to electrophysiological parameters not related to cardiac activity, such as an implantable bioimpedance sensor in the heart, or an intracardiac pressure sensor capable of measuring cardiac performance parameters such as ejection fraction, cardiac output, intracardiac pressure, and intracardiac pressure gradient over time.

[0232] According to some exemplary embodiments, the control circuit is configured to evaluate or determine the effect of the CRT delivered to the heart by the IPG unit 502 based on signals received from sensors 518 and 520 via the measurement circuit 516. In some embodiments, the control circuit 512 stores the signals or indices recorded from the electrodes in a memory 514.

[0233] According to some exemplary embodiments, the IPG unit 502 includes a communication circuit, e.g., a communication circuit 524, configured to send and receive signals, e.g., wireless signals, to and from at least one external device located outside the body, e.g., a computer or a mobile device. In some embodiments, the communication circuit 524 is configured to receive signals from at least one sensor located outside the body, e.g., at least one skin electrode. In some embodiments, the communication circuit 524 is configured to receive signals from the external device, including at least one of a cardiac contraction regulation protocol, a CRT protocol, parameter values ​​for the electric field used in CRT, and parameter values ​​for the electric field used in cardiac contraction regulation therapy. In some embodiments, the information received via the communication circuit 524 is stored in a memory 514.

[0234] According to some exemplary embodiments, the IPG unit 502 includes a power supply, for example, a power supply 522. In some embodiments, the power supply is a rechargeable power supply that can be recharged from outside the body, for example, via radio inductive charging. In some embodiments, the power supply 522 is configured to supply power to a component of the IPG unit 502, for example, a pulse generator 504.

[0235] Figure 6 illustrates, in some exemplary embodiments of the present invention, the activities of a device, for example, activities performed by an IPG unit.

[0236] According to some exemplary embodiments, the CRT is provided in block 602. In some embodiments, the control circuit 512 of the IPG unit 502 sends a signal to a pulse generator 504 that generates an electric field with parameter values ​​selected for the CRT. In some embodiments, the generated CRT electric field is supplied to the heart via at least one electrode, for example, a CRT electrode 508.

[0237] According to some exemplary embodiments, the effect of the CRT, for example, the effect of the CRT electric field, is measured in block 604. In some embodiments, the control circuit 512 measures the CRT effect based on signals received from at least one cardiac sensor 520 and / or at least one body sensor 518. Optionally, the control circuit 512 measures the CRT effect using at least one algorithm stored in memory 514. In some embodiments, the CRT effect is measured by at least one external device located outside the body, for example, an imaging device. In some embodiments, the results of the external device analysis are transmitted to the IPG unit 502 via the communication circuit 524.

[0238] According to some exemplary embodiments, the control circuit 512 determines in block 606 that the measured CRT effect is not the desired effect. In some embodiments, the control circuit 512 determines that the measured CRT effect is not the desired effect by determining the relationship between the measured CRT effect and at least one criterion, for example, a criterion stored in memory 514. In some embodiments, the control circuit 512 determines that the measured CRT effect is not the desired effect using at least one algorithm or at least one lookup table stored in memory 514.

[0239] According to some exemplary embodiments, the control circuit 512 generates a score for the provided CRT based on the measured CRT effect. In some embodiments, the control circuit 512 determines, based on the generated score, that the CRT effect is not the desired effect, for example, by determining the relationship between the generated score and at least one reference value or reference index stored in memory 514.

[0240] According to some exemplary embodiments, if the CRT effect is not the desired effect, a cardiac contraction regulation protocol is selected in block 608. In some embodiments, the control circuit 512 selects a cardiac contraction regulation protocol in block 608, for example, a cardiac contraction regulation protocol stored in memory 514. In some embodiments, the cardiac contraction regulation protocol is selected according to measurements performed in block 604, according to the CRT therapeutic effect, and / or according to the clinical or physiological state of the heart. In some embodiments, the cardiac contraction regulation protocol includes at least one of the parameter values ​​of the electric field configured for cardiac contraction regulation therapy, at least one activation parameter of the pulse generator 504, and / or information about electrodes that can be used to provide a cardiac contraction regulation electric field, for example, electrode positions.

[0241] According to some exemplary embodiments, the value of at least one parameter of cardiac contraction regulation therapy is adjusted in block 610. In some embodiments, the at least one parameter includes a cardiac contraction regulation electric field parameter and / or a parameter of a cardiac contraction regulation protocol.

[0242] According to some exemplary embodiments, the electrode configuration is selected in block 612, for example, by a control circuit 512. In some embodiments, an electrode configuration is selected in block 612, comprising a set of two or more electrodes arranged to provide cardiac contractile regulation therapy from a plurality of electrodes connected to an IPG unit. In some embodiments, at least one of the two or more electrodes connected to the IPG unit is selected for providing cardiac contractile regulation, for example, based on electrode position, electrode characteristics, and / or based on a measurement of the CRT effect or other measurement of the clinical and physiological state of the heart.

[0243] According to some exemplary embodiments, cardiac contraction control therapy is provided in block 614. In some embodiments, cardiac contraction control therapy is provided by signaling a pulse generator 504 to generate an electric field at parameter values ​​selected for cardiac contraction control therapy and / or to provide the generated electric field through one or more electrodes selected in block 612. In some embodiments, the control circuit 512 is configured to signal the pulse generator 504 to generate and provide a cardiac contraction control electric field in synchronization with cardiac activity, for example, in synchronization with cardiac contraction and / or in synchronization with the depolarization state of at least one anatomical region of the heart. In some embodiments, the control circuit 512 controls the timing of the generation and / or provision of the electric field based on signals received from one or more sensors measuring cardiac activity, for example, the cardiac sensor 520 shown in Figure 5.

[0244] According to some exemplary embodiments, the effect of cardiac contractile regulation therapy on the heart is evaluated in block 616. In some embodiments, the effect of cardiac contractile regulation therapy is evaluated based on signals received from at least one sensor, e.g., a cardiac sensor 520. Alternatively, the effect of cardiac contractile regulation therapy is evaluated based on measurements performed by at least one measuring device located outside the heart or outside the body. In some embodiments, the evaluation results or indices are transmitted to the IPG unit 502, e.g., via a communication circuit 524.

[0245] According to some exemplary embodiments, in block 618, a different cardiac systolic therapy protocol is optionally selected based on the results of the evaluation of cardiac systolic therapy performed in block 616. Alternatively or additionally, in block 610, the value of at least one cardiac systolic therapy parameter is optionally adjusted based on the results of the evaluation of cardiac systolic therapy. Alternatively or additionally, in block 612, at least one different electrode for providing a cardiac systolic electric field is optionally selected, or a different set of electrodes is optionally selected, based on the results of the evaluation of cardiac systolic therapy.

[0246] According to some exemplary embodiments, instead of providing cardiac systolic regulation, in block 620, synchronization between CRT and cardiac systolic regulation therapy is performed. In some embodiments, synchronization includes timing synchronization between providing an electric field having selected parameter values ​​for CRT and providing an electric field having selected parameter values ​​for cardiac systolic regulation therapy. Alternatively or additionally, synchronization includes synchronizing one or both of CRT and cardiac systolic regulation therapy with cardiac activity and the contraction of one or more cardiac compartments, for example, including the left atrium, left ventricle, right atrium, and right ventricle, and / or with the propagation of electrical signals through cardiac tissue. In some embodiments, synchronization is performed by a control circuit 512 using optionally at least one lookup table containing at least one synchronization algorithm and one or more synchronization indices, stored in memory 514.

[0247] According to some exemplary embodiments, CRT and cardiac contraction control therapy are provided in block 622. In some embodiments, the control circuit 512 signals the pulse generator 504 to generate and / or provide the CRT electric field and the cardiac contraction control electric field to the cardiac tissue via at least one electrode, in accordance with the synchronization performed in block 620.

[0248] According to some exemplary embodiments, block 624 evaluates the effectiveness of a dual therapy including CRT and cardiac contractility control therapy. In some embodiments, block 624 evaluates the effectiveness of the provided CRT and cardiac contractility control therapy on the heart, e.g., cardiac output and / or myocardial contractility. In some embodiments, the effectiveness of the provided CRT and cardiac contractility control therapy is evaluated based on signals received from at least one sensor connected to the IPG unit 502 and / or signals from at least one sensor or at least one device located outside the body, as described, for example, in blocks 604 and 616. In some embodiments, the control circuit 512 performs the evaluation automatically, for example, based on information from at least one sensor connected to the IPG unit 502. Alternatively, the control circuit 512 receives the evaluation results via the communication circuit 524.

[0249] According to some exemplary embodiments, the effects of the provided CRT and cardiac systolic regulation therapy are evaluated in block 624 for at least one week after the start of treatment, for example, at least one month, at least three months, at least six months, or any shorter or longer period. In some embodiments, the effects of the provided CRT and cardiac systolic regulation include effects on ejection fraction, myocardial contractility, intracardiac pressure, intracardiac pressure gradient over a selected period, NYHA class score, peak VO2, and 6-minute walk score, at least one of these.

[0250] According to some exemplary embodiments, if the evaluation results indicate that providing CRT does not produce the desired effect and / or that providing cardiac contraction control therapy is sufficient to achieve the desired effect, the CRT is stopped in block 625. In some embodiments, based on the evaluation results, the control circuit 512 signals the pulse generator to stop generating the CRT electric field or to stop signaling to the pulse generator 504 to generate the CRT electric field. Optionally, if the CRT is stopped, an instruction signal is sent to an external device via the communication circuit 524.

[0251] According to some exemplary embodiments, the value of at least one CRT parameter is optionally modified in block 626, for example, by a control circuit 512. In some embodiments, the value of the CRT parameter is modified based on the results of an evaluation performed in block 624. In some embodiments, the synchronization between the provided CRT and cardiac contractile regulation therapy is modified in block 626. Alternatively, a different CRT protocol is optionally selected.

[0252] According to some exemplary embodiments, in block 628, a different cardiac contraction regulation protocol is optionally selected, for example, by the control circuit 512. In some embodiments, the different cardiac contraction regulation protocol is selected based on the results of an evaluation performed in block 624. Alternatively, at least one cardiac contraction regulation parameter is optionally adjusted in block 610 based on the results of an evaluation performed in block 628.

[0253] The terms "comprises," "comprising," "includes," "including," "has," and "having," as well as their cognates, all mean "including but not limited to."

[0254] The phrase "consisting of" means "including and limited to."

[0255] The phrase "consisting essentially of" means that the configuration, method, or structure may include additional components, steps, and / or parts, but only if the additional components, steps, and / or parts do not substantially alter the basic and novel characteristics of the claimed configuration, method, or structure.

[0256] As used herein, unless otherwise clearly indicated by the context, the singular forms "a," "an," and "the" include multiple references.

[0257] Throughout this application, embodiments of the present invention may be presented in relation to range format. It should be understood that the range format is for convenience and brevity only and should not be interpreted as an inflexible limitation on the scope of the invention. Therefore, a range description should be considered to specifically disclose not only the individual numerical values ​​within that range, but also all possible subranges. For example, a range description such as "1 to 6" should be considered to include "1 to 3," "1 to 4," "1 to 5," "2 to 4," "2 to 6," "3 to 6," etc., as well as the specifically disclosed subranges of the individual numerical values ​​within that range, such as 1, 2, 3, 4, 5, 6, etc. This applies regardless of the width of the range.

[0258] Whenever a numerical range is indicated herein (for example, "10-15", "10-15", or a pair of numbers linked by any other such range indication), it means that it includes any number (fraction or integer) within the indicated range limit, including the range limit, unless the context explicitly indicates otherwise. The phrases "range / ranging / ranges between" between a first indicated number and a second indicated number, and "range / ranging / ranges from" between the first indicated number and the second indicated number "to", "up to", "until", or "through" (or any other such range indicator), are used interchangeably herein and mean that they include the first indicated number and the second indicated number, and all fractional and integer numbers between them.

[0259] Unless otherwise indicated, the numerical values ​​used herein and any numerical ranges derived therefrom are approximations within reasonable measurement accuracy and rounding tolerances as understood by those skilled in the art.

[0260] For clarity, it is understood that certain features of the present invention described in the context of separate embodiments may also be provided in combination in a single embodiment. Conversely, for brevity, various features of the present invention described in the context of a single embodiment may also be provided separately, in any preferred partial combination, or as preferred in any other described embodiment of the present invention. Certain features described in the context of various embodiments should not be considered essential features of those embodiments unless the embodiments would not function without those elements.

[0261] Although the present invention has been described in relation to its specific embodiments, it is obvious that many alternatives, modifications, and variations will be apparent to those skilled in the art. Therefore, it is intended to encompass all such alternatives, modifications, and variations that fall within the spirit and broad scope of the appended claims.

[0262] All publications, patents, and patent applications described herein are incorporated herein by reference to the same extent that each individual publication, patent, or patent application is explicitly and individually indicated as being incorporated herein by reference. Furthermore, any citation or specification of any reference in this application should not be construed as an acknowledgment that such reference is available as prior art of the present invention. Where section headings are used, they should not necessarily be construed as restrictive. Furthermore, any one of the priority documents of this application is incorporated herein by reference in its entirety.

Claims

1. A system for providing cardiac resynchronization therapy (CRT) and cardiac contractile regulation therapy to human patients suffering from heart failure, Memory and A pulse generator configured to generate both an electric field having parameter values ​​used for CRT and an electric field having parameter values ​​used for cardiac contraction regulation, At least one electrode lead, electrically connected to the pulse generator, is molded and configured to be implanted in or at a distance of up to 1 cm from the heart, A measurement circuit connectable to at least one sensor, the measurement circuit configured to measure at least one physiological parameter related to cardiac output, The measurement circuit and the control circuit electrically connected to the pulse generator are provided, The control circuit is configured to receive a measurement signal from the measurement circuit. The system wherein, based on at least one physiological parameter related to the cardiac output measured by the measurement circuit, the control circuit is configured to send a signal to the pulse generator to generate an electric field having parameter values ​​for treating heart failure by CRT, or an electric field having parameter values ​​for treating heart failure by cardiac contractile regulation, and the parameter values ​​of the electric field suitable for cardiac contractile regulation or CRT are stored in the memory.

2. The system according to claim 1, wherein the physiological parameters related to cardiac output include at least one of ejection fraction, intracardiac pressure, intracardiac pressure gradient over a selected period, NYHA class score, peak VO2, and 6-minute walk score.

3. The control circuit, based on the measurement signal of at least one physiological parameter related to cardiac output, (a) the measurement signal or the index of the measurement signal, and (b) One or more desired effect indicators stored in the memory, The system according to claim 1 or 2, configured to determine whether the effect of the electric field provided for the CRT is a desired effect by determining the relationship between the two.

4. The system according to claim 3, comprising a communication circuit configured to transmit a wireless signal to a remote device located outside the body, wherein if the effect of the CRT determined based on the measurement signal is an undesirable effect, the control circuit signals the communication circuit to transmit a wireless signal containing information related to the undesirable effect of the CRT.

5. The system according to claim 4, wherein the control circuit signals the communication circuit to transmit a wireless signal containing instructions for providing cardiac contraction control therapy.

6. The system according to claim 4 or 5, wherein the control circuit receives a command from a remote device to provide cardiac contraction control therapy via a signal received by the communication circuit.

7. The system according to any one of claims 3 to 6, wherein the control circuit is configured to send a signal to the pulse generator to generate an electric field having parameter values ​​for providing cardiac contraction control therapy to the heart when the effect of the CRT determined based on the signal received from the measurement circuit is an undesirable effect.

8. The system according to any one of claims 1 to 7, wherein the control circuit is configured to send a signal to the pulse generator to generate the electric field having parameter values ​​for CRT and / or cardiac contraction regulation, and to provide the electric field through the at least one electrode lead.

9. At least one electrode of the at least one electrode lead is configured to be used for providing both CRT and cardiac contractile control therapy, and is at least 4 mm long. ２ The system according to any one of claims 1 to 8, having a surface area and coated with a high capacitance and low polarization coating.

10. The system according to claim 7, wherein the aforementioned undesirable effect is insufficient to increase cardiac output.

11. The system according to claim 7, wherein the aforementioned undesirable effect includes an identified arrhythmia.

12. The system according to claim 1, wherein the at least one sensor includes an intracardiac pressure sensor configured to measure cardiac output.

13. The aforementioned control circuit is (a) an electric field having parameter values ​​for the treatment of heart failure by CRT, (b) an electric field having parameter values ​​for the treatment of heart failure by regulating cardiac contractility, The system according to claim 1, configured to be synchronized during the generation of

14. The system according to any one of claims 1 to 13, wherein the control circuit is configured to control the pulse generator to deliver a test electric field for cardiac contractile control therapy through at least one electrode lead to the heart as part of a test session lasting up to one hour, or as part of a test session performed while the at least one electrode lead is implanted, and to determine whether the patient can benefit from the cardiac contractile control therapy through the at least one electrode lead based on the effect of the test session on the patient.

15. The system according to any one of claims 1 to 14, wherein the control circuit is configured to identify that the effect of the CRT includes at least one undesirable effect.

16. The system according to any one of claims 1 to 15, configured to treat a patient with cardiac contractile regulation therapy in combination with CRT.

17. The system according to any one of claims 1 to 16, wherein the pulse generator is configured to provide an diastolic pacing signal to be initiated during the non-refractory period of the right ventricle for the effects of CRT and cardiac contractile regulation therapy.

18. The system according to claim 17, wherein the at least one electrode lead is located in the right ventricle and / or left ventricle.

19. The system according to any one of claims 1 to 18, wherein the control circuit is configured to determine whether treating the patient with the cardiac contractile regulation and the CRT has a desired effect on cardiac output and / or cardiac contractile, and is further configured to modify the CRT based on the result of the determination.

20. The system according to any one of claims 1 to 19, wherein the control circuit is configured to identify, based on at least one physiological parameter related to cardiac output, that providing the CRT to the patient would not result in a beneficial effect on at least one of ejection fraction, intracardiac pressure, intracardiac pressure gradient over a selected period, NYHA class score, peak VO2, and 6-minute walk score.

21. The system according to claim 20, wherein the control circuit is configured to identify, based on at least one physiological parameter relating to the cardiac output, that the effect of the provided CRT includes an insufficient effect on the increase in intracardiac pressure or an insufficient effect on the increase in the intracardiac pressure gradient over a selected period of time.

22. The system according to any one of claims 1 to 21, wherein the control circuit is configured to identify an arrhythmia occurring in the patient after the provision of the CRT, and the arrhythmia is an atrial arrhythmia or a non-left bundle branch block (non-LBBB).

23. The system according to any one of claims 1 to 22, wherein the system is configured to use a previously implanted electrode used for providing the cardiac contraction regulating electric field.

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