Respiration-associated modulation of cardiac contractility force

Abstract

A system comprising: one or more sensors for detecting a parameter of a patient's respiratory cycle; and an implantable cardiac device comprising: at least one lead comprising one or more electrodes for applying a cardiac contractility modulation stimulation to a heart; and circuitry for controlling and activating the lead, the circuitry being programmed to set a parameter of the cardiac contractility modulation stimulation in dependence on the parameter of the respiratory cycle detected by the one or more sensors.

Description

[0001] Related applications

[0002] This application claims priority to U.S. Provisional Patent Application No. 63 / 001,343 (Attorney’s File No. 79080), filed March 29, 2020, under 35 USC §119(e), the contents of which are incorporated herein by reference in their entirety.

[0003] This application is part of a joint filing of the following PCT applications filed on the same day by the same applicant: PRUCHI David et al., Agent File No. 85056, entitled "INCREASING PEAK VO2 IN PATIENTS WITH HFUSING CARDIAC CONTRACTILITY MODULATION (CCM) STIMULATION"; PRUCHI David et al., Agent File No. 85068, entitled "CARDIAC CONTRACTILITY MODULATION FOR ATRIALARRHYTHMIA PATIENTS"; PRUCHI David et al., Agent File No. 85069, entitled "METHODS FOR PLANNING AND DELIVERING CARDIAC ELECTRICAL STIMULATION". Technical Field

[0004] In some embodiments, the present invention relates to cardiac contractility modulation therapy, and more specifically, but not exclusively, to the application of cardiac contractility modulation stimuli associated with respiratory phases or conditions. Summary of the Invention

[0005] According to one aspect of some embodiments, a method for delivering cardiac contractility modulation stimulation to the heart via an implanted cardiac device is provided, comprising: determining at least one respiratory parameter; and setting one or more parameters of the cardiac contractility modulation stimulation based on the at least one respiratory parameter.

[0006] In some embodiments, at least one respiratory parameter is selected from the group consisting of: respiratory rate, relative time of expiration and / or inspiration, and duration of expiration and / or inspiration.

[0007] In some embodiments, setting one or more parameters for the cardiac contractility modulation stimulation includes setting the timing of applying the cardiac contractility modulation stimulation associated with the respiratory cycle based on the relative anatomical space between the heart and the diaphragm and / or the relative anatomical space between the heart and the phrenic nerve.

[0008] In some embodiments, the method includes synchronizing the timing of applying cardiac contractility modulation stimulation with the timing of the diaphragm being furthest from the heart and / or the timing of the phrenic nerve being furthest from the heart.

[0009] In some embodiments, setting one or more parameters for the cardiac contractility modulation stimulus includes setting a timing for applying the cardiac contractility modulation stimulus during the absolute refractory period of the cardiac cycle.

[0010] In some embodiments, determining includes measuring at least one respiratory parameter using one or more sensors.

[0011] In some embodiments, the one or more sensors are selected from the group consisting of acoustic sensors, pulse oximeters, pneumographs, and capnographs.

[0012] In some embodiments, one or more sensors include intracardiac electrodes for recording ECG, and wherein at least one respiratory parameter is determined based on ECG recording.

[0013] In some embodiments, setting one or more parameters of the cardiac contractility modulation stimulus includes setting the current intensity of the cardiac contractility modulation stimulus to the highest level that does not cause pain.

[0014] In some embodiments, setting one or more parameters of the cardiac contractility modulation stimulation includes setting the rate for applying multiple cardiac contractility modulation stimuli.

[0015] In some embodiments, the method includes increasing the rate of cardiac contractility modulation stimulation when the respiratory rate increases, and decreasing the rate of cardiac contractility modulation stimulation when the respiratory rate decreases.

[0016] In some embodiments, a cardiac device is implanted in a patient diagnosed with heart failure.

[0017] In some embodiments, setting one or more parameters of the cardiac contractility modulation stimulation includes selecting one or more intervals of the respiratory cycle to apply the cardiac contractility modulation stimulation.

[0018] In some embodiments, the selection includes testing during which one or more time intervals the application does not cause or causes only minimal sensation in the patient.

[0019] In some embodiments, the method includes selecting a time interval during inhalation for applying cardiac contractility modulation stimulation.

[0020] In some embodiments, the method includes selecting a time interval during exhalation for applying cardiac contractility modulation stimulation.

[0021] In some embodiments, the method includes recording the patient’s electrocardiogram (ECG) and selecting the timing for applying cardiac contractility modulation stimulation when the amplitude of the R wave in the current cardiac cycle is higher than the average R wave amplitude calculated based on at least 5 previous cardiac cycles.

[0022] In some embodiments, the method includes recording the patient’s ECG and selecting the time to apply cardiac contractility modulation stimulation when the R-wave amplitude of the current cardiac cycle is lower than the average R-wave amplitude calculated based on at least 5 previous cardiac cycles.

[0023] In some embodiments, the method includes recording the patient’s ECG and selecting the time to apply cardiac contractility modulation stimulation when the RR interval of the current cardiac cycle is longer than the average RR interval calculated based on at least 5 previous cardiac cycles.

[0024] In some embodiments, the method includes recording the patient’s ECG and selecting the time to apply cardiac contractility modulation stimulation when the RR interval of the current cardiac cycle is shorter than the average RR interval calculated based on at least 5 previous cardiac cycles.

[0025] In some embodiments, determining at least one respiratory parameter includes tracking the respiratory cycle to detect episodes of dyspnea and, in response, applying cardiac contractility modulation stimulation.

[0026] In some embodiments, the method includes assessing cardiac output and / or respiratory output over time and timing the application of cardiac contractility modulation stimulation accordingly.

[0027] In some embodiments, the method includes assessing whether a patient feels a cardiac contractility modulation stimulus during a selected time interval of the respiratory cycle, and if a stimulus is felt, selecting different time intervals of the respiratory cycle for applying the cardiac contractility modulation stimulus.

[0028] According to one aspect of some embodiments, a system is provided, comprising:

[0029] An implantable cardiac device includes: at least one lead including one or more electrodes for applying cardiac contractility modulation stimulation to the heart; and

[0030] A circuit for controlling and activating leads, the circuit being programmed to set at least one of the timing and intensity of a cardiac contractility-modulating stimulation current based on the detected respiratory rate.

[0031] In some embodiments, the system includes a sensor configured to detect respiratory rate.

[0032] In some embodiments, the sensor is selected from the group consisting of: acoustic sensors, pulse oximeters, respirometers, and carbon dioxide monitors.

[0033] In some embodiments, the system includes intracardiac electrodes for recording ECG; wherein the respiratory rate is determined based on the recorded ECG.

[0034] In some embodiments, the circuit includes a controller programmed to increase the rate of cardiac contractility modulation stimulation when an increase in respiratory rate is detected, and to decrease the rate of cardiac contractility modulation stimulation when a decrease in respiratory rate is detected.

[0035] In some embodiments, the device includes at least one lead, which includes one or more electrodes for applying electrical stimulation to the diaphragm and / or the phrenic nerve.

[0036] In some embodiments, the circuit includes a controller programmed to control parameters of stimulation applied to the diaphragm and / or phrenic nerve, including timing for applying the stimulation and intensity of the stimulation current.

[0037] According to one aspect of some embodiments, a method for timing the delivery of cardiac contractility modulation stimulation to the heart is provided, comprising: applying cardiac contractility modulation stimulation to the heart; determining whether the cardiac contractility modulation stimulation causes pain and / or sensation in a patient; assessing whether the pain and / or sensation is associated with stimulation of the diaphragm, phrenic nerve and / or its branches; and setting one or more parameters according to the patient's respiratory cycle to apply additional cardiac contractility modulation stimulation.

[0038] In some embodiments, setting one or more parameters includes setting a timing for applying additional cardiac contractility modulation stimulation, the timing including a time interval of respiratory cycles during which the application of cardiac contractility modulation stimulation causes minimal pain or sensation to the patient.

[0039] In some embodiments, cardiac contractility modulation stimulation is applied during the refractory period of the cardiac cycle.

[0040] According to one aspect of some embodiments, a system is provided, comprising:

[0041] One or more sensors for detecting parameters of a patient's respiratory cycle; and

[0042] An implantable cardiac device includes: at least one lead including one or more electrodes for applying cardiac contractility modulation stimulation to the heart; and circuitry for controlling and activating the lead, the circuitry being programmed to set parameters of the cardiac contractility modulation stimulation based on parameters of the respiratory cycle detected by one or more sensors.

[0043] In some embodiments, one or more sensors are configured to detect parameters selected from the group consisting of: respiratory rate, relative timing of inspiration and expiration, and ECG of the heart.

[0044] In some embodiments, the parameters of the cardiac contractility modulation stimulation include the timing of the cardiac contractility modulation stimulation and the intensity of the cardiac contractility modulation stimulation current.

[0045] According to one aspect of some embodiments, a method for timing the delivery of cardiac contractility modulation stimulation to the heart is provided, comprising: tracking a patient’s respiratory cycle; identifying one or more time periods of the respiratory cycle during which the diaphragm is not excited or minimally excited and / or cannot contract or minimally contract; and applying cardiac contractility modulation stimulation to the heart during the identified one or more time periods.

[0046] In some embodiments, the application is performed during the refractory period of the cardiac cycle.

[0047] According to one aspect of some embodiments, a method of operating an implanted cardiac device configured to deliver cardiac contractility modulation stimulation to the heart is provided, comprising:

[0048] Measuring at least one respiratory parameter using one or more sensors; and

[0049] Based on at least one measured respiratory parameter, one or more parameters of cardiac contractility modulation stimulation are automatically set at the controller of the implanted cardiac device.

[0050] In some embodiments, at least one respiratory parameter is selected from the group consisting of: respiratory rate, relative timing of exhalation and / or inspiration, and duration of exhalation and / or inspiration.

[0051] In some embodiments, automatically setting one or more parameters of the cardiac contractility modulation stimulation includes setting the timing of applying the cardiac contractility modulation stimulation associated with the respiratory cycle based on the relative anatomical space between the heart and the diaphragm and / or the relative anatomical space between the heart and the phrenic nerve.

[0052] In some embodiments, the method includes synchronizing the timing of applying cardiac contractility modulation stimulation with the timing of the diaphragm being furthest from the heart and / or the timing of the phrenic nerve being furthest from the heart.

[0053] In some embodiments, setting one or more parameters for the cardiac contractility modulation stimulus includes setting a timing for applying the cardiac contractility modulation stimulus during the absolute refractory period of the cardiac cycle.

[0054] In some embodiments, the one or more sensors are selected from the group consisting of acoustic sensors, pulse oximeters, respirometers, and carbon dioxide monitors.

[0055] In some embodiments, one or more sensors include intracardiac electrodes for recording ECG, and wherein at least one respiratory parameter is determined based on ECG recording.

[0056] In some embodiments, automatically setting one or more parameters of the cardiac contractility modulation stimulus includes setting the current intensity of the cardiac contractility modulation stimulus to the highest level that does not cause pain.

[0057] In some embodiments, automatically setting one or more parameters of the cardiac contractility modulation stimulation includes setting the rate for applying multiple cardiac contractility modulation stimuli.

[0058] In some embodiments, the method includes increasing the rate of cardiac contractility modulation stimulation when an increase in respiratory rate is measured, and decreasing the rate of cardiac contractility modulation stimulation when a decrease in respiratory rate is measured.

[0059] In some embodiments, a cardiac device is implanted in a patient diagnosed with heart failure.

[0060] In some embodiments, automatically setting one or more parameters of the cardiac contractility modulation stimulation includes selecting one or more intervals of the respiratory cycle to apply the cardiac contractility modulation stimulation.

[0061] In some embodiments, the selection includes testing during which time intervals the test will not cause or will only cause minimal or no sensation in the patient.

[0062] In some embodiments, the method includes selecting a time interval during inhalation for applying cardiac contractility modulation stimulation.

[0063] In some embodiments, the method includes selecting a time interval during exhalation for applying cardiac contractility modulation stimulation.

[0064] In some embodiments, the method includes recording the patient’s ECG and selecting the timing for applying cardiac contractility modulation stimulation when the amplitude of the R wave in the current cardiac cycle is higher than the average R wave amplitude calculated based on at least 5 previous cardiac cycles.

[0065] In some embodiments, the method includes recording the patient’s ECG and selecting the time to apply cardiac contractility modulation stimulation when the R-wave amplitude of the current cardiac cycle is lower than the average R-wave amplitude calculated based on at least 5 previous cardiac cycles.

[0066] In some embodiments, the method includes recording the patient’s ECG and selecting the time to apply cardiac contractility modulation stimulation when the RR interval of the current cardiac cycle is longer than the average RR interval calculated based on at least 5 previous cardiac cycles.

[0067] In some embodiments, the method includes recording the patient’s ECG and selecting the time to apply cardiac contractility modulation stimulation when the RR interval of the current cardiac cycle is shorter than the average RR interval calculated based on at least 5 previous cardiac cycles.

[0068] In some embodiments, measuring at least one respiratory parameter includes tracking the respiratory cycle to detect episodes of dyspnea and, in response, applying a cardiac contractility-modulating stimulus.

[0069] In some embodiments, the method further includes assessing cardiac output and / or respiratory output over time based on at least one measured respiratory parameter, and timing the application of cardiac contractility modulation stimulation accordingly.

[0070] In some embodiments, the method includes assessing whether the patient has felt a cardiac contractility modulation stimulus during a selected time interval of the respiratory cycle, and if a stimulus is felt, selecting different time intervals of the respiratory cycle for applying the cardiac contractility modulation stimulus.

[0071] According to one aspect of some embodiments, a system is provided, comprising:

[0072] Implantable cardiac devices, including:

[0073] At least one lead, comprising one or more electrodes for applying cardiac contractility-modulating stimulation to the heart; and

[0074] A circuit for controlling and activating the leads, the circuit being programmed to set at least one of the timing and intensity of a cardiac contractility-modulating stimulation current based on the detected respiratory rate.

[0075] In some embodiments, the system includes a sensor configured to detect respiratory rate.

[0076] In some embodiments, the sensor is selected from the group consisting of: acoustic sensors, pulse oximeters, respirometers, and carbon dioxide monitors.

[0077] In some embodiments, the system includes intracardiac electrodes for recording ECG; wherein the respiratory rate is determined based on the recorded ECG.

[0078] In some embodiments, the circuit includes a controller programmed to increase the rate of cardiac contractility modulation stimulation when an increase in respiratory rate is detected, and to decrease the rate of cardiac contractility modulation stimulation when a decrease in respiratory rate is detected.

[0079] In some embodiments, the device includes at least one lead, which includes one or more electrodes for applying electrical stimulation to the diaphragm and / or the phrenic nerve.

[0080] In some embodiments, the circuit includes a controller programmed to control parameters of stimulation applied to the diaphragm and / or phrenic nerve, including timing for applying the stimulation and intensity of the stimulation current.

[0081] According to one aspect of some embodiments, a method for timing the delivery of cardiac contractility modulation stimulation to the heart is provided, comprising: determining whether the cardiac contractility modulation stimulation applied to the heart causes pain and / or sensation in the patient;

[0082] Assess whether the pain and / or sensation are related to stimulation of the diaphragm, phrenic nerve, and / or its branches; and

[0083] One or more parameters are set according to the patient's respiratory cycle to apply additional cardiac contractility modulation stimulation.

[0084] In some embodiments, setting one or more parameters includes setting a timing for applying additional cardiac contractility modulation stimulation, the timing including a time interval of respiratory cycles during which the application of cardiac contractility modulation stimulation causes minimal pain or sensation in the patient.

[0085] In some embodiments, cardiac contractility modulation stimulation is applied during the refractory period of the cardiac cycle.

[0086] According to one aspect of some embodiments, a system is provided, comprising:

[0087] One or more sensors for detecting parameters of a patient's respiratory cycle; and

[0088] Implantable cardiac devices, including:

[0089] At least one lead, including one or more electrodes for applying cardiac contractility-modulating stimulation to the heart; and

[0090] A circuit for controlling and activating leads, the circuit being programmed to set parameters for cardiac contractility modulation stimulation based on parameters of the respiratory cycle detected by one or more sensors.

[0091] In some embodiments, one or more sensors are configured to detect parameters selected from the group consisting of: respiratory rate, relative timing of inspiration and expiration, and ECG of the heart.

[0092] In some embodiments, the parameters of the cardiac contractility modulation stimulation include the timing of the cardiac contractility modulation stimulation and the intensity of the cardiac contractility modulation stimulation current.

[0093] In some embodiments, the circuit is configured to set parameters for cardiac contractility modulation stimulation associated with the respiratory cycle based on the relative anatomical space between the heart and the diaphragm and / or the relative anatomical space between the heart and the phrenic nerve.

[0094] In some embodiments, the circuit is configured to synchronize the timing of applying cardiac contractility modulation stimulation with the timing of the diaphragm being furthest from the heart and / or the timing of the phrenic nerve being furthest from the heart.

[0095] In some embodiments, the circuit is configured to time the application of cardiac contractility modulation stimulation during the absolute refractory period of the cardiac cycle.

[0096] In some embodiments, the one or more sensors are selected from the group consisting of acoustic sensors, pulse oximeters, respirometers, and carbon dioxide monitors.

[0097] In some embodiments, one or more sensors include intracardiac electrodes for recording ECG, and wherein at least one respiratory parameter is determined based on ECG recording.

[0098] In some embodiments, the circuit is configured to set the current intensity of the cardiac contractility modulation stimulus to the highest level that does not cause pain.

[0099] In some embodiments, the circuit is configured to set the rate for applying multiple cardiac contractility modulation stimuli.

[0100] In some embodiments, the circuit is configured to increase the rate of cardiac contractility modulation stimulation when an increase in respiratory rate is measured, and decrease the rate of cardiac contractility modulation stimulation when a decrease in respiratory rate is measured.

[0101] In some embodiments, a cardiac device is implanted in a patient diagnosed with heart failure.

[0102] In some embodiments, the circuit is configured to perform tests using one or more sensors during time intervals in which the application of cardiac contractility modulation stimulation does not cause or at least causes sensation in the patient.

[0103] In some embodiments, the circuit is configured to time the application of cardiac contractility modulation stimulation during inhalation.

[0104] In some embodiments, the circuit is configured to time the application of cardiac contractility modulation stimulation during exhalation.

[0105] In some embodiments, the circuit is configured to time the application of cardiac contractility modulation stimulation based on ECG recordings obtained from one or more sensors.

[0106] According to one aspect of some embodiments, a method is provided for timing the delivery of cardiac contractility modulation stimulation to the heart via an implanted cardiac device, comprising:

[0107] Track the patient's respiratory cycle;

[0108] Identify one or more time periods in the respiratory cycle during which the diaphragm is not excited or minimally excited and / or does not contract or minimally contract; and

[0109] The command applies cardiac contractility modulation stimulation during one or more identified time periods.

[0110] In some embodiments, the command is given during the refractory period of the cardiac cycle.

[0111] Unless otherwise defined, all technical and / or scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention pertains. While similar or equivalent methods and materials may be used in the practice or testing of embodiments of the invention, exemplary methods and / or materials are described below. In case of conflict, the patent specification, including definitions, shall prevail. Furthermore, these materials, methods, and examples are illustrative only and are not intended to be restrictive.

[0112] The implementation of the methods and / or systems of the present invention may involve performing or completing selected tasks manually, automatically, or in combination thereof. Furthermore, the actual instruments and devices according to embodiments of the methods and / or systems of the present invention may use an operating system to implement several selected tasks through hardware, software, or firmware, or combinations thereof.

[0113] For example, hardware for performing selected tasks according to embodiments of the invention may be implemented as a chip or circuit. As software, the selected task according to embodiments of the invention may be implemented as a plurality of software instructions executed by a computer using any suitable operating system. In exemplary embodiments of the invention, one or more tasks according to exemplary embodiments of the methods and / or systems described herein are performed by a data processor such as a computing platform for executing multiple instructions. Optionally, the data processor includes volatile memory for storing instructions and / or data and / or non-volatile memory 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 a user input device such as a keyboard or mouse are also optionally provided. Attached Figure Description

[0114] This document describes some embodiments of the invention by way of example only, with reference to the accompanying drawings. Reference will now be made in detail to the drawings, with emphasis placed on the fact that the details shown are exemplary and for the purpose of illustrative discussion of embodiments of the invention. In this regard, the description taken in conjunction with the drawings will make it apparent to those skilled in the art how to practice embodiments of the invention.

[0115] In the attached diagram:

[0116] Figure 1A This is a flowchart of a method for setting at least one parameter of a cardiac contractility modulating stimulus based on at least one respiratory-related condition, according to some embodiments.

[0117] Figure 1B This is a flowchart of a method for reducing or avoiding patient pain during cardiac contractility modulation stimulation, according to some embodiments;

[0118] Figure 1C This is a schematic diagram illustrating, according to some embodiments, the factors considered when setting cardiac contractility regulation parameters;

[0119] Figure 1D The illustration schematically depicts a "by-activation" effect, which is related to distance from the heart and potentially caused by cardiac contractility modulation signals applied to the heart, according to some embodiments.

[0120] Figure 2A -B schematically illustrates the relative positions of the heart, diaphragm, and phrenic nerve during normal inspiration and expiration according to some embodiments;

[0121] Figure 2C The illustration schematically shows the anatomical changes in the heart of a patient, such as one with heart failure.

[0122] Figure 3AAn implantable device configured to apply cardiac contractility modulation stimulation according to some embodiments is illustrated schematically;

[0123] Figure 3B A cardiac device comprising multiple leads is schematically illustrated according to some embodiments;

[0124] Figure 4 These are exemplary graphs illustrating the relationship between respiratory cycles and cardiac cycles (such as those recorded by ECG), according to some embodiments;

[0125] Figure 5 This is a flowchart of a method for selecting one or more time intervals of the respiratory cycle to apply cardiac contractility modulation stimulation, according to some embodiments;

[0126] Figure 6 It is a graph showing exemplary timing for applying cardiac contractility modulation stimulation associated with the respiratory cycle, according to some embodiments;

[0127] Figure 7 This is a flowchart of a method for applying cardiac contractility modulation stimulation to the heart and for stimulating the diaphragm and / or phrenic nerve, according to some embodiments;

[0128] Figure 8 This is a block diagram of an implantable system according to some embodiments, configured to apply cardiac contractility modulation stimulation to the heart and to stimulate the diaphragm; and

[0129] Figure 9 This is a flowchart of a method for timing cardiac stimulation based on the excitation state and / or contraction level of the diaphragm, according to some embodiments. Detailed Implementation

[0130] In some embodiments of the present invention, the invention relates to cardiac contractility modulation (CCM) therapy, and more specifically, but not exclusively, to the application of CCM stimulation associated with respiratory phases or conditions.

[0131] Some embodiments involve broad aspects of cardiac contractility modulation stimulation, selecting parameters thereto reduce or prevent pain and / or sensation in the patient. Some embodiments involve cardiac contractility modulation therapy that takes into account the patient's respiratory cycle when determining therapeutic parameters such as timing, stimulation current intensity, stimulation rate, treatment duration, and / or other therapeutic parameters.

[0132] One aspect of some embodiments relates to timing cardiac contractility modulation stimulation according to the respiratory cycle. In some embodiments, one or more time intervals and / or phases of the respiratory cycle are selected for applying cardiac contractility modulation stimulation. In some embodiments, the time interval is selected for the time when cardiac contractility modulation stimulation applied to the heart, such as stimulation by “side effects” generated by cardiac contractility modulation signals, does not affect (or only minimally affects) the diaphragm or phrenic nerve. In some embodiments, the time interval is selected based on the relative anatomical distance between the heart and the diaphragm and / or the relative anatomical distance between the heart and the phrenic nerve (and / or its branches). Since the relative anatomical distance varies with different phases of the respiratory cycle (such as at the onset of inspiration, peak of inspiration, onset of expiration, peak of expiration, etc.), applying cardiac contractility modulation when the stimulated heart is at a greater distance from the diaphragm and / or its innervating nerves can reduce or prevent pain caused by by-stimulation of these tissues. Optionally, the time interval for applying cardiac contractility modulation is selected at the time when the diaphragm is furthest from the heart, such as at peak of inspiration, so that the stimulation applied to the heart does not affect (or only minimally affects) the diaphragm. In some embodiments, cardiac motion during the respiratory and / or cardiac cycles is considered when setting the parameters of the cardiac contractility modulation stimulation. In some embodiments, hemodynamic conditions and / or changes are considered when setting the parameters of the cardiac contractility modulation stimulation. For example, the cardiac contractility modulation stimulation may be timed to occur when blood is about to flow into the heart, thereby potentially increasing blood flow and / or velocity.

[0133] In some embodiments, the rate of cardiac contractility modulation stimulation and / or the intensity of the stimulation current are controlled according to the respiratory cycle (e.g., by a controller of the implanted cardiac device). For example, if the respiratory rate increases, the rate of cardiac contractility modulation stimulation is increased. For example, if the respiratory rate decreases, the rate of cardiac contractility modulation stimulation is decreased. In some embodiments, the controller commands one or more leads of the cardiac device to be energized using a stimulation signal. Optionally, the command sets the timing and / or intensity of the stimulation signal to be applied to the heart. In some embodiments, according to the command generated by the controller, the current is conducted via one or more leads and optionally to tissue contacted by one or more leads.

[0134] In some embodiments, the characteristics of the respiratory cycle are tracked and / or estimated. In some embodiments, one or more sensors provide indications based on which the respiratory cycle is evaluated. In some embodiments, sensors are configured to measure the respiratory cycle outside the body. Such sensors may include, for example, acoustic sensors (e.g., transducers); pulse oximeters, carbon dioxide monitors, wearable devices such as breath recorders, impedance sensors, etc. Additionally or alternatively, one or more internal (e.g., implanted) sensors are used. In one example, intracardiac electrodes, epicardial electrodes, and / or subcutaneous electrodes are configured to acquire an ECG signal and, for example, calculate and / or estimate the respiratory cycle based on a known correlation between the ECG signal and the respiratory cycle. In some embodiments, cardiac contractility modulation therapeutic parameters are determined based on ECG measurements such as the amplitude and / or RR interval of the QRS complex. For example, to track the respiratory cycle, the R-wave amplitude and / or RR interval of the ECG signal may be tracked. A low R-wave amplitude and a long RR interval may indicate the onset of expiration; a high R-wave amplitude and a short RR interval may indicate the end of expiration. In some embodiments, cardiac contractility modulation stimulation is delivered at timing during a low R-wave amplitude to potentially enhance contractility. Additionally or alternatively, cardiac contractility modulation stimulation is delivered at timing during a high R-wave amplitude to maximize contractility at its peak.

[0135] In some embodiments, cardiac pacing is provided, for example, via one or more device electrodes. Optionally, signals for pacing the heart are delivered to synchronize the application of cardiac contractility modulation (provided during the refractory period in some embodiments) with the respiratory cycle. For example, the heart may be intentionally made too fast or too slow to deliver cardiac contractility modulation stimulation at selected time intervals of the respiratory cycle.

[0136] In some embodiments, the time interval of the respiratory cycle suitable for delivering cardiac contractility modulation can be intentionally altered, for example, by pacing the heart and / or by stimulating (in this example, pacing) the diaphragm, as described below.

[0137] One aspect of some embodiments involves dual stimulation of the heart and the diaphragm (and / or its innervating nerves). In some embodiments, diaphragmatic contraction and / or relaxation is intentionally induced or enhanced by stimulating the diaphragm and / or the phrenic nerve (or its branches). In some embodiments, diaphragmatic stimulation is synchronized with cardiac contractility modulation stimulation. For example, stimulation may be applied to contract (or enhance) the diaphragm, and then cardiac contractility modulation stimulation may be applied to the heart immediately thereafter. Because the diaphragm may be farther from the heart during contraction compared to its relaxed position, applying cardiac contractility modulation during and / or immediately following contraction can reduce or prevent pain or sensation in the patient.

[0138] The potential advantages of dual stimulation of the heart and diaphragm may include the optional simultaneous improvement of cardiac contractility and respiratory capacity and / or respiratory rate. In some cases, a synergistic effect may occur due to one of these measures indirectly influencing the others (e.g., enhanced cardiac contractility may indirectly improve respiratory efficiency, as evidenced by clinical trials showing higher peak oxygen uptake (peak VO2) in patients treated with contractility modulation) (see, for example, "Does Contractility Modulation have a Role in the Treatment of Heart Failure?", Daniel Burkhoff, Curr Heart Fail Rep, DOI 10.1007 / s11897-011-0067-3). In some embodiments, this synergistic effect may potentially reduce the required dose and / or total duration of cardiac contractility modulation therapy. In one example, dual stimulation may be advantageous for heart failure patients who may also have respiratory muscle weakness that can lead to reduced respiratory capacity, in addition to cardiac dysfunction.

[0139] In some embodiments, a system is provided comprising an implantable pulse generation device, one or more leads for applying cardiac contractility modulation stimulation to the heart, and one or more leads for applying stimulation to the diaphragm and / or its innervating nerves. In some embodiments, the system includes one or more sensors for tracking respiration and is capable of modifying cardiac contractility modulation treatment parameters and / or diaphragm stimulation parameters based on indications received from these sensors. In some embodiments, the system includes ECG sensing electrodes implanted in the heart and is capable of modifying cardiac contractility modulation treatment parameters and / or diaphragm stimulation parameters based on recorded ECG signals. In some embodiments, diaphragmatic pacing is performed. By pacing the diaphragm, the respiratory cycle is at least partially controlled, which allows for precise synchronization of cardiac contractility modulation stimulation with respect to the respiratory cycle.

[0140] One aspect of some embodiments involves timing cardiac stimulation based on the excitation and / or contractile state of the diaphragm. In some embodiments, cardiac stimulation, such as cardiac contractility modulation stimulation, is applied during periods when the diaphragm cannot contract or contracts only minimally, for example, immediately following the peak of contraction. In some embodiments, cardiac contractility modulation stimulation is applied during periods when the diaphragm is non-excitable or only minimally affected by stimulation. In some embodiments, timing is selected when there is an overlap between the non-refractory period of the cardiac cycle and the non-excitable / non-contractile period of the diaphragm. Potential advantages of timing cardiac contractility modulation stimulation based on the excitation and / or contractile state of the diaphragm may include reducing or preventing pain caused by undesirable side stimulation of the diaphragm and / or excessive contraction of the diaphragm due to side stimulation.

[0141] As mentioned herein, the “timing” of a stimulus signal (e.g., a cardiac contractility modulation signal) may refer to one or more of the following: timing relative to a measured and / or estimated cardiac cycle; timing relative to a measured and / or estimated respiratory cycle; timing relative to the cardiac refractory period (e.g., when the signal is delivered precisely during the refractory period); timing relative to a sensed parameter, such as timing relative to a sensed cardiac contraction signal; timing relative to a measured and / or estimated anatomical distance; determining whether to deliver the signal within a certain cycle (respiratory or cardiac cycle), or whether to skip one or more cycles before delivering the signal; defining the duration of the signal (pulse length); (e.g., a preset timing initially programmed in the device); and / or other settings for the relative or absolute time of delivering the stimulus signal.

[0142] In some cases, the timing and / or intensity of the stimulation signal are selected and / or optimized for a specific patient. Optionally, inter-patient anatomical differences and / or breathing patterns can affect the level of pain perceived by a patient.

[0143] Before explaining at least one embodiment of the invention in detail, it should be understood that the invention is not necessarily limited in its implementation to the construction details and arrangements of the components and / or methods listed in the following description and / or shown in the drawings and / or examples. The invention can have other embodiments or can be practiced or performed in various ways.

[0144] Before explaining at least one embodiment of the present invention in detail, it should be understood that the invention is not necessarily limited in its application to the details listed in the following description or illustrated in the embodiments. The invention can have other embodiments, or can be practiced or implemented in various ways.

[0145] Now refer to the attached diagram, Figure 1A This is a flowchart of a method, according to some embodiments, for setting at least one parameter of a cardiac contractility modulation stimulus to the heart based on at least one respiratory-related condition.

[0146] In some embodiments, a decision is made to treat the patient (100) by applying cardiac contractility modulation stimulation to the heart. In some embodiments, the cardiac contractility modulation signal is optionally a non-excitatory signal applied to the heart during the relative and / or absolute refractory period of the heart. In some embodiments of the invention, the signal is selected to increase ventricular contractility when the electric field of the signal stimulates ventricular tissue such as, for example, the left ventricle, right ventricle, and / or ventricular septum. In some embodiments of the invention, contractility modulation is provided by phosphorylation of phosphoproteins induced by the signal. In some embodiments of the invention, contractility modulation is caused by changes in protein transcription and / or mRNA production induced by the signal, optionally in the form of reversal of fetal genetic programs.

[0147] Unless otherwise stated, the term “cardiac contractility modulation” is used herein as a general expression for all such signals. It should be noted that in some embodiments, the cardiac contractility modulation signal may be excitable to tissues other than the tissue to which it is applied. Various mechanisms that the cardiac contractility modulation signal can operate on are described, for example, in “Cardiac contractility modulation: mechanisms of action in heart failure with reduced ejection fraction and beyond” C. Tschope et al., European Journal of Heart Failure (2018), doi:10.1002 / ejhf.1349, which can be used to guide the selection of signal application parameters to utilize and / or comply with one or more of these mechanisms.

[0148] In some embodiments, patients selected for treatment are those suffering from heart failure, congestive heart failure, and / or similar symptoms. In some embodiments, patients selected for treatment are those with impaired cardiac pumping action, which may affect blood flow and / or oxygen supply. In some embodiments, patients selected for treatment are those with impaired cardiac output and / or cardiac contractility that can be improved by applying cardiac contractility modulation therapy. In some cases, one or more effects of cardiac contractility modulation therapy, such as higher peak oxygen uptake, can improve breathing.

[0149] In some embodiments, a cardiac device configured to apply cardiac contractility modulation stimulation is implanted in the patient (101). In some embodiments, the device includes a pulse generator optionally implanted outside the heart, such as in the subclavian region, and one or more leads for stimulating the heart and optionally contacting the ventricular septum.

[0150] In some embodiments, respiratory-related status is determined (103). In some embodiments, the status of each specific patient is assessed. In some embodiments, respiratory-related status includes parameters of the respiratory cycle, such as respiratory rate, relative timing of expiration and / or inspiration, duration of inspiration and / or duration of expiration and / or others. In some embodiments, respiratory-related status includes anatomical parameters, such as the relative anatomical space between the heart and lungs, the anatomical space between the heart and the phrenic nerve, the anatomical space between the heart and the diaphragm, and the distance between the stimulation lead and anatomical structures, such as the distance between the stimulation lead and the phrenic nerve (right phrenic nerve and / or left phrenic nerve).

[0151] In some embodiments, one or more sensors are used to estimate and / or measure respiratory-related conditions. In some embodiments, parameters of the respiratory cycle are determined based on input from one or more sensors.

[0152] In some embodiments, one or more implantable sensors are used, optionally implanted together with a cardiac contractility modulation stimulation device. In one example, intracardiac electrodes measure and optionally record an electrocardiogram. Optionally, heart rate is calculated based on RR intervals.

[0153] In some embodiments, the intracardiac electrode used for ECG measurements is the same electrode that applies cardiac contractility modulation stimulation.

[0154] In some embodiments, one or more external non-invasive sensors are used to measure and / or estimate respiratory-related conditions. Examples include acoustic sensors (e.g., transducers and / or other sensors suitable for measuring sounds indicating breathing); pulse oximeters, carbon dioxide monitors, wearable devices such as ventilators, and impedance sensors. In some embodiments, breathing is measured and / or monitored by tracking (e.g., counting) chest rise.

[0155] In some embodiments, one or more sensors, for example, transmit signals to a device controller to communicate with the implanted cardiac device.

[0156] In some embodiments, respiratory parameters (e.g., rate) are continuously monitored. Additionally or alternatively, periodic measurements may be performed, for example, before, during, and / or after the cardiac device is implanted.

[0157] In some embodiments, parameters (105) of the cardiac contractility modulation stimulation are set based on a determined (e.g., selected and programmed into the cardiac device controller) respiratory condition. Parameters of the cardiac contractility modulation therapy include, for example: dosage (e.g., timing of stimulation, number of stimulations); stimulation current intensity; safety threshold; stimulation rate and / or other parameters.

[0158] Figure 1B This is a flowchart of a method for reducing or avoiding patient pain during cardiac contractility modulation stimulation, according to some embodiments.

[0159] In some embodiments, stimulation applied by the implanted cardiac device may cause sensation or pain in the patient. Such sensation may be the result of direct and / or indirect stimulation of nerves, such as nerves located along the stimulation path through which the electric current flows. In some cases, the device stimulation path is close to and / or passes through nerve-innervated tissue, which may cause discomfort or even pain in the patient.

[0160] In some cases, stimulation applied by cardiac devices can affect the nerve innervation tissues of the diaphragm and / or its innervating nerves, such as the phrenic nerve and / or its branches (e.g., the left and / or right phrenic nerves).

[0161] In some embodiments, reducing or avoiding patient sensation can be achieved by one or more of the following: reducing the intensity of the stimulating current, reducing the number of stimuli, or reducing or stopping stimulation when pain is felt. However, these modifications can lead to suboptimal cardiac contractility modulation therapy.

[0162] According to some embodiments, the following methods describe the application of cardiac contractility modulation, which takes into account reducing or avoiding the patient's sensations and / or pain, in some cases which may be associated with phrenic nerve activation and / or diaphragmatic activation. In some embodiments, the reduction or avoidance of pain associated with phrenic nerve activation is achieved by synchronizing cardiac contractility modulation therapy with respiratory parameters and / or condition.

[0163] In some embodiments, a cardiac device (121) is implanted and configured to apply cardiac contractility modulation stimulation. In some embodiments, one or more cardiac contractility modulation stimuli are applied (123). In some embodiments, whether the cardiac contractility modulation stimulation causes sensation or pain is determined, for example by asking the patient to report their feelings, during and / or after the application of the cardiac contractility modulation stimulation (125).

[0164] In some embodiments, if the sensation or pain is caused by a stimulus, an assessment of the source of pain is performed, such as whether the sensation or pain is caused by activation and / or stimulation of the phrenic nerve or its branches (127). Optionally, the assessment is based on reports from the patient indicating the level of pain and / or the area of ​​the body where pain is felt.

[0165] In some embodiments, one or more parameters (129) for applying cardiac contractility modulation stimulation are set according to the patient's respiratory cycle. Since the phrenic nerve (and / or its branches) is expected to move with respiration, e.g., pushed towards the heart by the lungs during inspiration; pushed towards the heart by the diaphragm during expiration; and / or other relative changes in movement or position, setting cardiac contractility modulation stimulation synchronized with the respiratory cycle can reduce or prevent pain, for example, by reducing the stimulatory effect of cardiac contractility modulation signals on the phrenic nerve or its branches. In some embodiments, the reduction of pain or sensation is achieved by delivering cardiac contractility modulation signals when the phrenic nerve is further away from the heart.

[0166] In some embodiments, the parameters for cardiac contractility modulation therapy are set relative to the respiratory cycle.

[0167] In some embodiments, parameters for cardiac contractility modulation therapy are set, for example, during the first and / or periodic configuration of the cardiac device in a laboratory or clinic. In some embodiments, settings are chosen based on patient anatomy—for example, anatomical variations between patients may cause sensation and / or pain in some patients, while others may not feel or experience discomfort from the applied stimulation.

[0168] In some embodiments, cardiac contractility modulation parameters, such as signal timing, may be selected optionally immediately after implantation. In some embodiments, timing may be selected based on respiratory rate, optionally for a specific patient. In some embodiments, cardiac contractility modulation timing is matched in real time to the tracked respiratory rate. In some embodiments, respiratory is continuously monitored, for example, based on ECG recordings and / or input received from sensors, and closed-loop control is performed to set cardiac contractility modulation parameters (e.g., timing and / or current intensity). In one example, a higher respiratory rate may be detected in a patient engaging in physical activity, and the rate at which cardiac contractility modulation stimulation is applied may be increased in response. Optionally, the rate of cardiac contractility modulation may be increased to deliver stimulation during the refractory period of each cardiac cycle.

[0169] In some embodiments, the patient’s average respiratory rate is derived, and the cardiac contractility adjustment timing and / or stimulation current intensity are set based on the average rate.

[0170] In some embodiments, the application of stimulation is set and / or controlled in response to changes in respiratory rate. For example, in some embodiments, if an increase in respiratory rate is sensed (e.g., by one or more sensors), cardiac contractility modulation can be applied at a higher rate, optionally timed for selected intervals of the respiratory cycle.

[0171] In some embodiments, the parameters of cardiac contractility modulation are set and / or controlled by a user, such as a physician. Additionally or alternatively, the parameters of cardiac contractility modulation therapy are set and / or controlled by the patient; for example, if pain is felt, the patient may request a shortening or cessation of the stimulation, and / or a reduction in the intensity of the stimulation. Additionally or alternatively, the parameters of cardiac contractility modulation therapy are set and / or controlled automatically, for example, via a device controller. Optionally, the parameters are controlled in response to indications received from one or more sensors, such as indications related to the currently sensed respiratory rate.

[0172] One potential advantage of setting respiratory-related cardiac contractility modulation parameters may include utilizing natural anatomical changes that occur during respiration, such as positioning the phrenic nerve or its branches further away from the heart at certain times of the respiratory cycle, and / or moving the diaphragm further away from the heart at certain times of the respiratory cycle, to potentially alleviate patient pain caused by phrenic nerve activation and / or diaphragmatic activation.

[0173] In some embodiments, cardiac contractility modulation parameters are selected and / or controlled to improve breathing, optionally improving breathing over time. For example, enhancing cardiac contractility can indirectly improve breathing. In certain situations, such as in HF, patients experience low-volume, “shallow” breathing. Improving cardiac contractility in such patients can improve respiratory capacity. In another example, if an episode of dyspnea is detected in a patient with an implanted cardiac device, cardiac contractility modulation can be applied at a higher rate and / or intensity to potentially improve breathing.

[0174] In some embodiments, a cardiac contractility modulation stimulus is delivered to intentionally stimulate the diaphragm. Optionally, indirect stimulation occurs when the cardiac contractility modulation stimulus is applied to the heart. Additionally or alternatively, in some embodiments, for example in… Figure 7-8 As further described, the implanted device is configured to directly stimulate the diaphragm by stimulating the diaphragm itself and / or the phrenic nerve.

[0175] In some embodiments, an accelerometer and / or motion sensor are provided for detecting posture or posture changes. Optionally, parameters for cardiac contractility modulation stimulation are selected based on input from the accelerometer, for example, the stimulation is timed when the patient's posture is one in which minimal or no pain is felt during the application of cardiac contractility modulation. Such postures (or a set of posture / position ranges) can be detected during initial testing, and device settings can be configured accordingly.

[0176] In some embodiments, the implantable device may be configured to deliver signals that partially or completely block nerves. Optionally, the nerve block signal is delivered before the application of cardiac contractility modulation. In one example, conduction via the phrenic nerve may be partially blocked to reduce or avoid pain associated with phrenic nerve activation of the diaphragm.

[0177] Figure 1C This is a schematic diagram, according to some embodiments, used to illustrate the factors considered when setting cardiac contractility regulation parameters.

[0178] In some embodiments, the system controller 151 is programmed and / or configured to automatically select cardiac contractility modulation settings, including, for example, the timing of signal delivery, the strength of the signal, the rate at which the signal is applied, the duration of the treatment process (e.g., stimulation provided for several minutes and / or hours), and the total duration of treatment (e.g., overall treatment lasting several weeks or months).

[0179] In some embodiments, one or more parameters related to the heart 153, such as: cardiac cycle (e.g., as shown in ECG recording 155); relative anatomical position of the heart (optionally for each patient and / or each respiratory phase or condition); level of cardiac contractility; size and / or mass of the heart; pumping capacity; cardiac output; stroke volume; ejection fraction; etiology of HF and / or general patient parameters such as height, BMI, comorbidities, sex, age, are considered to select cardiac contractility regulation parameters.

[0180] In some embodiments, one or more parameters associated with the respiratory system 157, such as: respiratory cycle (e.g., indicated by recorded respiratory signal 159); respiratory rate; anatomical location and changes during the respiratory cycle (e.g., lungs, diaphragm, phrenic nerve, pleural cavity, etc.); respiratory phases and their lengths; lung volume; and respiratory depth, are considered to select cardiac contractility regulation parameters.

[0181] In some embodiments, taking into account hemodynamic effects, such as blood flow into and / or out of the heart, the cardiac contractility regulation parameters may optionally be selected in relation to blood flow into and / or out of the heart associated with respiratory phases (e.g., inspiration, expiration, peak inspiration, end of expiration, and / or others).

[0182] In some embodiments, cardiac contractility modulation is timed to be delivered during specific respiratory phases, such as during inspiration or expiration. In this case, cardiac contractility modulation may not be delivered in every cardiac cycle, but rather in an alternating manner (one cardiac cycle - yes, the next cardiac cycle - no) and / or in other modes. In some embodiments, to compensate for “missed” cardiac cycles (i.e., cycles in which cardiac contractility modulation was not delivered), treatment parameters, such as treatment duration, current intensity, the number of cardiac contractility modulation stimuli delivered during cardiac systole and / or during respiratory cycles, and / or other parameters, are modified. For example, the treatment time is prolonged. For example, the amplitude of the stimulation current is reduced to allow for a longer duration of stimulation. For example, the amplitude of the stimulation current is increased to strengthen contraction.

[0183] Figure 1D The illustration schematically depicts a “paraactivation” effect, which is related to distance from the heart and potentially caused by cardiac contractility modulation signals applied to the heart, according to some embodiments.

[0184] In some embodiments, cardiac contractility modulation stimulation is applied to the heart, for example, via an electrode 171 positioned to contact the ventricular diaphragm 173. In some embodiments, the applied electrical signal (in addition to intentionally enhancing contractility) may cause “by-activation” of neural tissue and / or nearby organs. For example, the cardiac contractility modulation signal may stimulate the left and / or right phrenic nerves adjacent to the heart and diaphragm.

[0185] In some cases, “paraactivation” of nerve tissue and / or nearby organs can cause pain or discomfort in a patient. In some embodiments, to reduce or prevent pain, the “paraactivation” distance (denoted as “d” in the figure) can be calculated or estimated. Optionally, pain can be reduced or prevented by timing cardiac contractility-modulating stimulation as far away from the heart as possible from the paraactivated nerves and / or organs.

[0186] Figure 2A -B schematically illustrates the relative positions of the heart, diaphragm, and phrenic nerve during normal inspiration and expiration according to some embodiments.

[0187] Figure 2A The relative positions of the heart 201, diaphragm 203, and phrenic nerve (left 205 and right 207) at peak inspiration are shown. As can be observed, during inspiration, the diaphragm contracts and pulls downward, creating a vacuum in the thoracic cavity, thereby inflating the lungs.

[0188] Figure 2B The relative positions of the heart 201, diaphragm 203, and phrenic nerve (left 205 and right 207) at the end of exhalation are shown. As can be observed, during exhalation, the diaphragm relaxes and moves closer to the heart, causing the lungs to contract.

[0189] In some embodiments, the cardiac contractility modulation therapeutic parameters are set based on the relative anatomical positions of the heart and diaphragm and / or the heart and phrenic nerve during respiration. For example, in some embodiments, the application of the cardiac contractility modulation signal is set when the diaphragm is furthest from the heart, such as at or during peak inhalation. For example, the application of the cardiac contractility modulation signal is set when the phrenic nerve (e.g., the right and / or left branches) is furthest from the heart.

[0190] When timing signals that regulate cardiac contractility, other distances and / or relative anatomical locations may be considered, such as the expansion and contraction of the thoracic cavity, the expansion and contraction of the lungs, the contraction of the heart, the movement of the pectoral muscles, and / or others.

[0191] Figure 2CThe diagram schematically illustrates anatomical changes in the heart of patients, such as those with heart failure. In some cases, in patients with heart diseases such as HF, the size of the heart may increase, for example, due to the constant need to pump more blood. In some cases, the heart may produce more muscle mass. The magnified heart is represented by dashed lines in this diagram.

[0192] In some cases, the left ventricle enlarges, optionally more than other parts of the heart. In some cases, anatomical changes in heart size, dimensions, and / or position can cause the heart to be closer to the diaphragm and / or the phrenic nerve through the diaphragm. Therefore, in such cases, applying cardiac contractility-modulating stimuli (e.g., through nerve stimulation) to an enlarged heart can more easily affect nearby structures such as the diaphragm and / or the phrenic nerve.

[0193] Figure 3A An implantable device configured to apply cardiac contractility modulation stimulation according to some embodiments is illustrated schematically.

[0194] In some embodiments, the implantable device 301 includes a pulse generator 303. In some embodiments, the pulse generator 303 includes a housing 309 that encapsulates, for example, a power supply (e.g., a battery), control circuitry (e.g., a controller) configured to time and generate electrical pulses, sensing circuitry, communication circuitry, storage device, and / or other operating modules.

[0195] In some embodiments, one or more stimulation leads, such as 305 or 307, are connected to and extend outward from the housing. In some embodiments, the leads comprise one or more wires surrounded by an external insulation layer. In some embodiments, the leads consist of two wires with different polarities. In some embodiments, the wires of the leads are coiled.

[0196] In some embodiments, the pulse generator 303 is implanted outside the heart, such as in the subclavian region. Optionally, the implantation is performed via a minimally invasive procedure.

[0197] In some embodiments, the housing of the pulse generator 303 is implanted subcutaneously, near the left chest.

[0198] In some embodiments, leads 305 and 307 extend from the pulse generator 303, and at least the distal segments of the leads are implanted within the heart 311. In some embodiments, as shown, both leads pass through the right atrium 313 and contact the ventricular septum 315 at their distal ends. In some embodiments, each lead contacts the septum at a different location.

[0199] Note that, additionally or alternatively, a single lead comprising two spaced-apart stimulation electrodes may be used.

[0200] It should also be noted that while these figures show both leads located in the right ventricle 331 adjacent to the interventricular septum 315, one or more stimulation leads may be located in other locations, thus having different effect loops and / or targeting different tissues. In some embodiments, the leads are located inside the heart, on its right side, optionally taking advantage of two potential benefits: a. less extracardiac tissue is stimulated; and b. less invasiveness and / or presence compared to the left ventricle.

[0201] In some embodiments, one lead is implanted outside the heart, and the other lead is implanted inside the heart.

[0202] In some embodiments, each lead terminates with a tip electrode (see 317 of lead 307, 319 of lead 305). The tip electrode may be configured as a contact electrode, a screw-in electrode, a stitched electrode, a free-floating electrode, and / or other types.

[0203] In some embodiments, one or both leads include a ring electrode (see 321 of lead 307, 323 of lead 305) positioned along the lead near the tip electrode.

[0204] In some embodiments, the electrode is implanted in the right ventricle or right atrium of the heart.

[0205] In some embodiments, the tip electrode is threaded so that it can be screwed into the tissue. Alternatively, the tip electrode is simply positioned to contact the tissue.

[0206] In some embodiments, one or both leads include a defibrillation coil (see 325 of lead 305). Optionally, coil 325 is positioned along the lead, near the tip electrode and / or near the loop electrode.

[0207] In some embodiments, the coil is implanted in the right ventricle, right atrium, or vena cava.

[0208] In some embodiments, one or two leads are configured to deliver non-excitatory signals, such as cardiac contractility modulation signals.

[0209] In some embodiments, the cardiac contractility modulation signal is applied in contact with or within the ventricular tissue.

[0210] In some embodiments, a cardiac contractility modulation signal is applied to the heart during the relative and / or absolute refractory period of the heart. In some embodiments, the signal is selected to increase ventricular contractility when the electric field of the signal stimulates ventricular tissues such as the left ventricle, right ventricle, and / or ventricular septum. In some embodiments of the invention, contractility modulation is provided by phosphorylation of phosphoproteins induced by the signal. In some embodiments of the invention, contractility modulation is caused by changes in protein transcription and / or mRNA production induced by the signal, optionally in the form of fetal genetic program reversal. Unless otherwise stated, the term “cardiac contractility modulation” is used herein as a general expression for all such signals. It should be noted that in some embodiments, the cardiac contractility modulation signal may be excitable to tissues other than the tissue to which it is applied.

[0211] While not limited to a single pulse sequence, the term cardiac contractility modulation is used to describe a group comprising any signal that: is an important component applied during the absolute refractory period and has a clinically significant effect on cardiac contractility in a rapid / or chronic manner and / or leads to reversal of fetal genetic programs and / or increases phosphoprotein phosphorylation. In some embodiments, the signal may be excitatory to one part of the heart but non-excitatory to others. For example, the signal may be excitatory in the atria but applied at a time when it is not excitatory in the ventricles (relative to ventricular activation).

[0212] In some embodiments of the invention, the signal, while potentially stimulating during the receptive period of the cardiac cycle, is non-excitatory due to its timing. Specifically, the signal is applied during the refractory period of the affected tissue and optionally during the absolute refractory period.

[0213] In some embodiments, a device electrode, such as a cardiac contractility modulation application electrode, is used to measure the R-wave amplitude and / or RR interval of the cardiac cycle.

[0214] Figure 3B A cardiac device comprising multiple leads is schematically illustrated according to some embodiments. In some embodiments, the device 3300 is configured for delivering cardiac contractility modulation stimulation to the heart. In some embodiments, the device 3300 is also configured to function as a cardiac defibrillator (ICD).

[0215] In some embodiments, the device 3300 includes multiple leads. In the illustrated example, a first lead 3310 extends to the right atrium of the heart 3316; a second lead 3311, such as for applying cardiac contractility modulation stimulation, extends to the right ventricle, optionally contacting the interventricular septum; a third lead 3312 extends to the right ventricle, optionally contacting the interventricular septum; and a fourth lead 3314 extends, for example, through the coronary sinus to the left ventricle. In some embodiments, one or more leads include defibrillation coils. In this example, lead 3312 includes a superior vena cava shock coil 3330 and a right ventricular shock coil 3332.

[0216] In some embodiments, multiple leads are connected to the device housing 3320 via multiple ports (not shown). In some embodiments, activation of one or more leads is controlled via a switching circuit, such as the switching circuit of a device controller.

[0217] Figure 4 This is an exemplary graph showing the relationship between respiratory cycles and cardiac cycles (such as those recorded by ECG) according to some embodiments.

[0218] The figure shows the ECG signal 401 (voltage versus time) recorded in relation to tracking respiration 403. In this example, a chest impedance sensor was used to measure respiration.

[0219] In some embodiments, cardiac cycle characteristics are measured or evaluated to determine the timing and / or rate of delivery of cardiac contractility modulation signals. In some embodiments, ECG recordings are obtained and measurements of the signals are determined or calculated. For example, signal amplitudes such as R-wave amplitude are tracked. For example, time intervals such as RR intervals are tracked.

[0220] In some embodiments, measurements include R-wave amplitude parameters such as peak, average, and minimum values ​​(RWP, RWA, RWM). In some embodiments, RR interval parameters such as the longest interval, shortest interval, and average interval are measured. Optionally, measurements are performed over multiple cardiac cycles, such as 2, 10, 100, 1000, or a higher or lower number of cycles.

[0221] In some embodiments, to set cardiac contractility modulation parameters, measurements obtained during the current cardiac cycle are compared with parameters obtained from one or more previous cardiac cycles. In some embodiments, the cardiac contractility modulation stimulus is configured to be delivered during cardiac cycles in which the parameters meet selected criteria, for example, the following cardiac cycles, wherein:

[0222] The R-wave amplitude is higher than that of the RWA;

[0223] The R-wave amplitude is higher than RWA+(RWP-RWA) / 2;

[0224] The R-wave amplitude is lower than that of the RWA;

[0225] The R-wave amplitude is less than RWA-(RWA-RWM) / 2;

[0226] The RR interval is longer than the average RR interval;

[0227] The RR interval is shorter than the average RR interval;

[0228] and / or other standards.

[0229] In some embodiments, if the parameters of the currently measured cardiac cycle are within the standard range, a cardiac contractility modulation stimulus is delivered during the ventricular refractory period of that cardiac cycle.

[0230] As can be seen from the exemplary diagram, the cardiac cycle is related to the respiratory cycle. For example, the heart rate (as shown by the decrease in the RR interval) increases at the end of expiration and decreases at the end of inspiration.

[0231] Figure 5 This is a flowchart of a method for selecting one or more time intervals of the respiratory cycle to apply cardiac contractility modulation stimulation, according to some embodiments.

[0232] In some embodiments, cardiac contractility modulation therapy parameters, such as the timing of the stimulation pulse, the length of the pulse, the rate at which the stimulation pulse is applied, and the pulse current intensity, are selected in sync with the respiratory cycle.

[0233] In some embodiments, cardiac contractility modulation stimulation is applied during one or more selected time intervals of the respiratory cycle.

[0234] In some embodiments, the patient's respiratory cycle may optionally be continuously tracked (501). Optionally, the respiratory cycle may be determined, for example, by directly measuring respiration using one or more sensors as described above. Additionally or alternatively, the respiratory cycle may be derived from or calculated from other measurements, such as from recorded ECG signals.

[0235] In some embodiments, one or more time intervals of the respiratory cycle are selected for applying cardiac contractility modulation stimulation.

[0236] Some examples of time intervals may include:

[0237] * Apply cardiac contractility modulation stimulation during a time interval shorter than a complete respiratory cycle (i.e., a complete cycle including a single complete inhalation and a single complete exhalation); optionally, the time interval begins at the start of inhalation;

[0238] * Apply cardiac contractility modulation stimulation during the time interval between 0-100% of the inspiratory phase;

[0239] * Apply cardiac contractility modulation stimulation during the time interval between 0-100% of the expiratory phase;

[0240] * A cardiac contractility modulation stimulus is applied after an RR interval shorter than the set percentile of RR intervals measured during one or more previous cardiac cycles (e.g., shorter than at least 70%, at least 80%, or at least 90% of the RR intervals measured in 2, 3, 4, 5, 6, 10, 20, 30, 100, or an intermediate, larger, or smaller number of previous cardiac cycles). In some embodiments, cardiac contractility modulation is delivered during the ventricular refractory period for a time interval of 20-100 ms, 30-60 ms, 50-120 ms, or an intermediate, longer, or shorter period after the detection of the R wave.

[0241] * Apply cardiac contractility modulation stimulation after an RR interval that is longer than the set percentile of the RR interval measured during one or more previous cardiac cycles (e.g., at least 70%, at least 80%, at least 90% longer than the RR interval of the previous 2, 3, 4, 5, 6, 10, 20, 30, 100 or more, larger or smaller number of cardiac cycles).

[0242] In some embodiments, an optimization test is used to select the time interval for applying cardiac contractility modulation stimulation. Optionally, the optimization test is performed during or immediately after implantation when configuring device settings. During such an optimization test, the patient's respiratory cycle can be divided into multiple time intervals, each shorter than a full cycle (e.g., dividing a full cycle into 2, 3, 4, 5, 6, or an intermediate, smaller, or larger number of time intervals). In some embodiments, cardiac contractility modulation stimulation is applied during each time interval. Optionally, the current intensity of the applied signal is gradually increased until it reaches an intensity felt by the patient. Then, in some embodiments, the time interval for delivering cardiac contractility modulation stimulation is selected as the time interval for applying the highest current intensity value that does not cause pain or sensation.

[0243] In some embodiments, the cardiac device is programmed to apply cardiac contractility modulation stimulation (505) at selected time intervals. Optionally, the timing and / or intensity of the stimulation are modified if the patient experiences pain. Optionally, different time intervals are selected to apply the signal.

[0244] Optionally, the timing (507) for applying cardiac contractility modulation is modified in response to changes in the respiratory cycle or respiratory rate. For example, in some embodiments, the device is programmed to increase the rate of cardiac contractility modulation stimulation when an increase in respiratory rate is sensed; and / or decrease the rate of cardiac contractility modulation stimulation when a decrease in respiratory rate is sensed. Optionally, respiratory monitoring is performed in real time, and indications of the current respiratory rate and / or changes in respiratory rate (such as from one or more sensors tracking respiratory rate) are transmitted to a device controller. In some embodiments, the device controller modifies cardiac contractility modulation therapy (dose, time, etc.) based on closed-loop feedback from the sensors. In one example, the device is configured to change parameters of cardiac contractility modulation therapy in response to the detection of respiratory distress, for example, that is clearly visible from tracking respiratory rate. In one example, respiratory distress leads to an increased respiratory rate; to potentially prevent or reduce “overactivation” of the diaphragm (by unintentionally stimulating the diaphragm itself and / or the phrenic nerve), cardiac contractility modulation may be delivered at the onset of inspiration when the diaphragm and / or the phrenic nerve may be sufficiently distant from the heart, and thus sufficiently distant from the stimulating electrodes.

[0245] Figure 6 This is a diagram showing exemplary timing for applying cardiac contractility modulation stimulation in relation to the respiratory cycle, according to some embodiments.

[0246] In the example shown, for instance, a cardiac contractility modulation stimulus is applied at point "A" to indicate the start of inspiration. In some embodiments, the duration of the applied cardiac contractility modulation pulse is, for example, between 20-30 milliseconds, 15-40 milliseconds, 30-45 milliseconds, 25-50 milliseconds, or an intermediate, longer, or shorter duration.

[0247] Figure 7 This is a flowchart of a method for applying cardiac contractility modulation stimulation to the heart and for stimulating the diaphragm and / or phrenic nerve, according to some embodiments.

[0248] In some embodiments, the diaphragm and / or its innervating nerves are intentionally stimulated. Optionally, stimulation is applied to enhance diaphragmatic contraction. Optionally, stimulation is applied to induce diaphragmatic relaxation.

[0249] In some embodiments, the physician (and / or other medical personnel) decides to treat the patient with both cardiac contractility modulation and diaphragmatic pacing stimulation (701).

[0250] In some embodiments, a cardiac contractility modulation device is implanted into a patient. In some embodiments, in addition to the cardiac contractility modulation lead, the device includes one or more leads configured to deliver stimulation to the diaphragm and / or the phrenic nerve. In some embodiments, the diaphragmatic pacing lead extends from the implantation device housing to the diaphragmatic muscle, optionally contacting at an upper opposite side location.

[0251] In some embodiments, such as as described herein, cardiac contractility modulation stimulation (703) is applied.

[0252] In some embodiments, diaphragmatic pacing stimulation (705) is applied. The applied stimulation causes the diaphragm to contract, thereby causing the user to inhale. In some embodiments, the stimulation is applied directly to the tissue of the diaphragm. Additionally or alternatively, stimulation is applied to the phrenic nerve.

[0253] In some embodiments, cardiac contractility modulation stimulation and diaphragmatic pacing stimulation are synchronized (707). Optionally, the timing of cardiac contractility modulation stimulation is set relative to diaphragmatic pacing stimulation. For example, cardiac contractility modulation stimulation is applied immediately after diaphragmatic pacing stimulation, when the diaphragm contracts and is likely in its furthest position from the heart.

[0254] The potential advantages of simultaneously providing cardiac contractility modulation stimulation and diaphragmatic stimulation may include the optional simultaneous improvement of both cardiac contractility and the patient's respiratory capacity. In addition to stimulating the diaphragm to enhance respiration, stimulating the heart to enhance its contractility can lead to a synergistic effect, where improved cardiac condition improves respiration and / or improved respiration improves cardiac function. Dual therapy including cardiac and diaphragmatic stimulation may potentially reduce the overall length of treatment, improve patient health, reduce or prevent pain during the application of cardiac contractility modulation, and / or other benefits.

[0255] Figure 8 This is a block diagram of an exemplary system configured to apply cardiac contractility modulation stimulation to the heart and to stimulate the diaphragm, according to some embodiments.

[0256] In some embodiments, system 801 is configured to stimulate the heart and optionally the diaphragm and / or its innervating nerves (e.g., the phrenic nerve). In some embodiments, the system (or a component of the system) is implanted in a patient. In one example, the device housing includes circuitry configured to control and activate one or more leads extending from the housing. In some embodiments, at least one lead enters the heart to stimulate it; and at least one lead extends to the diaphragm and / or to the phrenic nerve to stimulate them.

[0257] In some embodiments, one or more leads for stimulating the diaphragm are positioned across the right brachiocephalic vein and / or at the left pericardial vein, adjacent to the phrenic nerve. Alternatively or additionally, one or more leads for stimulating the diaphragm are positioned across the azygos vein.

[0258] In some embodiments, system 801 includes controller 813. Optionally, the controller is programmed with operating settings such as: cardiac contractility-modulated therapeutic dose (e.g., timing, rate, stimulation intensity), diaphragmatic pacing settings (e.g., timing, rate, stimulation intensity), safety thresholds, and / or other control parameters.

[0259] In some embodiments, system 801 includes a cardiac contractility modulation stimulation module 803 configured to activate at least one intracardiac cardiac contractility modulation stimulation electrode 805. In some embodiments, the system includes a diaphragm stimulation module 807 configured to activate at least one diaphragm stimulator 809 (e.g., including electrode leads).

[0260] In some embodiments, the system includes an ECG sensing electrode 811, which may be located inside or outside the heart. Optionally, the sensing electrode 811 continuously monitors the cardiac cycle. Alternatively, the sensing electrode 811 periodically monitors the cardiac cycle. Additionally or alternatively, the sensing electrode monitors the cardiac cycle as needed, such as in response to instructions received from a controller 813.

[0261] In some embodiments, the system includes a respiratory sensor 819. The sensor may be an implantable sensor or an external sensor. The respiratory sensor may monitor breathing continuously, periodically, and / or as needed.

[0262] In some embodiments, the system includes a power source, such as a battery 815. The battery may be a primary (e.g., replaceable) battery or a rechargeable battery.

[0263] In some embodiments, the system includes a communication module 817. In some embodiments, the communication module sends and / or receives signals from one or more external devices. For example, the communication module receives input and / or sends data to a user interface. The user interface may be configured on a doctor's computer, a doctor's or patient's mobile application, a lab-based computer, and / or others. In some embodiments, the communication module sends and / or receives data from a cloud server. Optionally, the data is stored (e.g., on cloud storage and / or on device memory) for analysis, for example, to determine future treatment plans.

[0264] Figure 9 This is a flowchart of a method for timing cardiac stimulation based on the excitation state and / or contraction level of the diaphragm, according to some embodiments.

[0265] In some embodiments, such as as described herein, the patient’s respiratory cycle is tracked (901). In some embodiments, the diaphragm activation time is determined (903) based on the stage of the respiratory cycle.

[0266] In some embodiments, the timing of cardiac stimulation (such as cardiac contractility modulation stimulation) is set for a "post-activation" period of the diaphragm. In some embodiments, the "post-activation" period is the time immediately following the natural neural stimulation of the diaphragm that causes it to contract. In some embodiments, the "post-activation" period is the time immediately following the contraction itself, for example, immediately following the peak of the diaphragmatic contraction ("immediately following" can include, for example, 1 millisecond, 2 milliseconds, 5 milliseconds, 10 milliseconds, or an intermediate, longer, or shorter time).

[0267] In some embodiments, the "post-activation" period is the time during which neural stimulation (such as unintentional neural stimulation as a byproduct of cardiac contractility regulation) does not cause or causes only minimal diaphragmatic contraction. In some embodiments, the "post-activation" period is the time during which the diaphragm cannot contract further, so that neural stimulation (such as unintentional neural stimulation as a byproduct of cardiac contractility regulation) does not cause or causes only minimal diaphragmatic contraction.

[0268] In some embodiments, when there is at least some overlap (temporally) between the cardiac refractory period and the cardiac "post-activation" period, the application of cardiac contractility modulation is timed to be delivered during the cardiac refractory period. In one example, cardiac contractility modulation is timed to be delivered at the beginning of the inspiratory phase, optionally after the start of inspiratory in which the diaphragm is minimally or unaffected by stimulation, thereby potentially alleviating the patient's pain. The terms "comprising," "including," "containing," "having," and their related terms mean "including but not limited to."

[0269] The term "composed of" means "including and limited to".

[0270] The term "consistently made of" means that a composition, method, or structure may include additional ingredients, steps, and / or portions, provided that the additional ingredients, steps, and / or portions do not materially alter the basic and novel character of the claimed composition, method, or structure.

[0271] As used herein, the singular forms “a,” “an,” and “the” include plural references unless the context clearly specifies otherwise. For example, the terms “a compound” or “at least one compound” can include a variety of compounds, including mixtures thereof.

[0272] Throughout this application, various embodiments of the invention may be presented in a range format. It should be understood that the range format is merely for convenience and brevity and should not be construed as an inflexible limitation of the scope of the invention. Therefore, the range description should be considered to have specifically disclosed all possible subranges and individual numerical values ​​within that range. For example, a description of a range such as 1 to 6 should be considered to have specifically disclosed subranges, such as from 1 to 3, from 1 to 4, from 1 to 5, from 2 to 4, from 2 to 6, from 3 to 6, etc., and individual numbers within that range, such as 1, 2, 3, 4, 5, and 6. This applies regardless of the width of the range.

[0273] Whenever a range of numbers is indicated herein, it is intended to include any referenced number (fraction or integer) within the indicated range. The phrases “range between the first and second indicated digits” and “range / range from the first indicated digit to the second indicated digit” are used interchangeably herein and are intended to include the first and second indicated digits and all decimals and integers in between.

[0274] As used herein, the term “method” means, means, techniques and procedures for accomplishing a given task, including but not limited to those known or readily adopted by practitioners in the fields of chemistry, pharmacology, biology, biochemistry and medicine, and those developed from known means, means, techniques and procedures.

[0275] As used herein, the term “treatment” includes eliminating, substantially inhibiting, slowing or reversing the progression of a condition, substantially improving the clinical or aesthetic symptoms of a condition, or substantially preventing the occurrence of the clinical or aesthetic symptoms of a condition.

[0276] It should be understood that, for clarity, certain features of the invention described in the context of a single embodiment may also be provided in combination in a single embodiment. Conversely, for brevity, various features of the invention described in the context of a single embodiment may also be provided individually or in any suitable sub-combination or in embodiments suitable for any other description of the invention. Certain features described in the context of various embodiments should not be considered as essential features of those embodiments unless the embodiments would not function without these elements.

[0277] Although the invention has been described in conjunction with specific embodiments thereof, it will be apparent to those skilled in the art that many alternatives, modifications, and variations will be readily apparent. Therefore, it is intended to cover all such alternatives, modifications, and variations falling within the spirit and broad scope of the appended claims.

[0278] All publications, patents, and patent applications mentioned in this specification are incorporated herein by reference in their entirety to the same extent that each individual publication, patent, or patent application is specifically and individually indicated to be incorporated herein by reference. Furthermore, any reference or designation of any reference in this application should not be construed as an admission that such reference is prior art to the invention. The use of section headings should not be construed as necessarily limiting. Additionally, any priority documents of this application are incorporated herein by reference in their entirety.

Claims

1. An implantable cardiac stimulation system, comprising: An implantable cardiac device, comprising: At least one lead, comprising one or more electrodes for applying non-excitatory cardiac contractility-modulating stimulation to the heart; and A circuit for controlling and activating the leads, the circuit being programmed to set at least one of the timing and intensity of the cardiac contractility-modulating stimulation current according to a detected respiratory rate, the respiratory rate being a parameter indicating respiration; wherein the timing includes one or more time intervals of the respiratory cycle during which the cardiac contractility-modulating stimulation is applied, the one or more time intervals being selected such that, during the one or more time intervals, the relative anatomical distance between the heart and diaphragm and / or the relative anatomical distance between the heart and phrenic nerve is greater than the relative anatomical distance during other time intervals of the respiratory cycle, thereby reducing patient pain or causing minimal sensation by reducing collateral stimulation of the diaphragm and / or phrenic nerve.

2. The system of claim 1, further comprising a sensor configured to detect the respiratory rate, wherein, The circuit is programmed to apply the cardiac contractility modulation stimulus during a period when the patient's diaphragm is non-excitable or minimally affected only by the cardiac contractility modulation stimulus; wherein the timing is selected when there is an overlap between the refractory period of the cardiac cycle and the non-excitable / non-contractile period of the diaphragm.

3. The system according to claim 2, wherein, The sensor is selected from the group consisting of: acoustic sensors, pulse oximeters, respirometers, and carbon dioxide monitors.

4. The system according to any one of claims 1 to 3, comprising intracardiac electrodes for recording ECG; wherein, The respiratory rate was determined based on the recorded ECG.

5. The system according to any one of claims 1 to 3, wherein, The circuit includes a controller programmed to increase the rate of cardiac contractility modulation stimulation when an increase in respiratory rate is detected, and to decrease the rate of cardiac contractility modulation stimulation when a decrease in respiratory rate is detected.

6. The system according to claim 1, wherein, The device includes at least one lead comprising one or more electrodes for applying electrical stimulation to the diaphragm or phrenic nerve, wherein the circuitry is programmed to synchronize the electrical stimulation applied to the diaphragm or phrenic nerve with the non-excitatory cardiac contractility modulation stimulation; wherein the synchronization includes timing the application of the non-excitatory cardiac contractility modulation during or immediately following the application of the electrical stimulation to the diaphragm or phrenic nerve.

7. The system according to claim 6, wherein, The circuit includes a controller programmed to control parameters of stimulation applied to the diaphragm and / or the phrenic nerve, the parameters including the duration of stimulation and the intensity of the stimulation current.

8. An implantable cardiac stimulation system, comprising: One or more sensors used to track parameters of a patient's respiratory cycle; and Implantable cardiac devices, including: At least one lead, including one or more electrodes for applying non-excitatory cardiac contractility modulating stimulation to the heart; Pulse generator; and A circuit for controlling and activating the leads, the circuit being programmed to set parameters of the non-excitatory cardiac contractility modulation stimulus based on the parameters of the respiratory cycle tracked by the one or more sensors; The circuit is programmed to set the parameters such that the cardiac contractility modulation stimulation is applied during one or more time intervals of the respiratory cycle, during which the relative anatomical distance between the heart and the patient's diaphragm and / or the relative anatomical distance between the heart and the patient's phrenic nerve is greater than the relative anatomical distance during other time intervals of the respiratory cycle, thereby reducing the secondary stimulation of the diaphragm and / or the phrenic nerve.

9. The system according to claim 8, wherein, The one or more sensors are configured to detect parameters selected from the group consisting of: respiratory rate, relative timing of inspiration and expiration, and ECG of the heart; wherein the circuitry is programmed to apply the cardiac contractility modulation stimulation during a period in which the patient's diaphragm is non-excitable or minimally affected only by the cardiac contractility modulation stimulation; wherein the period in which the cardiac cycle overlaps with a period of non-excitable / non-contractile activity of the diaphragm is selected.

10. The system according to claim 8, wherein, The parameters of the cardiac contractility modulation stimulation include the timing of the cardiac contractility modulation stimulation and the intensity of the cardiac contractility modulation stimulation current.

11. The system according to claim 8, wherein, One or more selected time intervals of the respiratory cycle include one or more time intervals in which there is a greater relative anatomical space between the heart and diaphragm and / or a greater relative anatomical space between the heart and phrenic nerve, compared to the relative anatomical space during the expiratory phase of the respiratory cycle.

12. The system according to claim 11, wherein, One or more selected time intervals of the respiratory cycle include one or more time intervals in which the diaphragm is furthest from the heart and / or the phrenic nerve is furthest from the heart.

13. The system according to claim 8, wherein, The circuit is configured to time the application of the cardiac contractility modulation stimulus during the absolute refractory period of the cardiac cycle.

14. The system according to claim 8, wherein, The one or more sensors are selected from the group consisting of: acoustic sensors, pulse oximeters, respirometers, and carbon dioxide monitors.

15. The system according to claim 8, wherein, The one or more sensors include intracardiac electrodes for recording ECG, and wherein parameters for tracking the respiratory cycle via the one or more sensors are based on the ECG recording.

16. The system according to claim 8, wherein, The circuit is configured to set the current intensity of the cardiac contractility modulation stimulus to the highest level that does not cause pain.

17. The system according to claim 8, wherein, The circuit is configured to set the rate for applying multiple cardiac contractility-modulating stimuli.

18. The system according to claim 17, wherein, The circuit is configured to increase the rate of cardiac contractility modulation stimulation when an increase in respiratory rate is measured, and decrease the rate of cardiac contractility modulation stimulation when a decrease in respiratory rate is measured.

19. The system according to claim 8, wherein, The cardiac device was implanted in a patient diagnosed with heart failure.

20. The system according to claim 8, wherein, The circuit is configured to use the one or more sensors to test one or more time intervals of the respiratory cycle to determine a time interval during which applying the cardiac contractility modulation stimulation will not cause or will cause only minimal sensation in the patient; and wherein the circuit is further configured to apply the cardiac contractility modulation stimulation during the determined time interval.

21. The system according to claim 8, wherein, The circuit is configured to time the application of the cardiac contractility modulation stimulus during inhalation.

22. The system according to claim 8, wherein, The circuit is configured to time the application of the cardiac contractility modulation stimulus during exhalation.

23. The system of claim 8, wherein the circuitry is configured to time the application of cardiac contractility modulation stimulation based on ECG recordings obtained from the one or more sensors.

24. The system according to claim 8, wherein, The circuit is configured to skip the application of the cardiac contractility modulation stimulation during one or more cardiac cycles or during one or more respiratory cycles, based on the parameters of the tracked respiratory cycle.

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