CONTROLLER FOR A PACING DEVICE - Patent application

Abstract

1. A controller for a pacing device, the controller being configured to receive sensor data including respiration data, determine a respiratory sinus arrhythmia (RSA) coefficient of a pacing signal based on the sensor data, determine a cardiopulmonary phase synchronization (CRPS) coefficient of the pacing signal based on the sensor data, and provide a pacing signal for pacing a patient's heart in accordance with the RSA coefficient and the CRPS coefficient.

Description

[Technical field]

[0001] The present disclosure relates to pacing devices, and particularly, but not exclusively, to cardiac pacemaker controllers for pacing a patient's heart. [Background technology]

[0002] Pacing devices for applying pacing signals to control the pacing of a patient's heart are generally known in the art. A pacing device, such as an internal cardiac pacemaker, may include one or more sensors for sensing physiological data related to the patient, a controller for generating a pacing signal based on the physiological data, and electrodes for applying the pacing signal to the patient's heart. Such functional units are generally known in the art and therefore will not necessarily be described in detail herein.

[0003] The one or more sensors of the pacing device may include a cardiac sensor. The cardiac sensor may comprise an electrode arrangement including cardiac electrodes that may be positioned in, on, or around the heart to sense cardiac electrical activity of one or more cardiac chambers. In some pacing devices, electrodes may also be used to additionally provide pacing signals to the heart. The electrodes may comprise, for example, cardiac pacing wires implanted in the right or left ventricle.

[0004] The sensors of the pacing device may also include a respiratory sensor. The controller may utilize respiratory data from the respiratory sensor to determine the pacing signal. For example, the patient's metabolic demand may be determined by monitoring the patient's respiration. The respiratory sensor may include one or more of an airflow sensor, a motion sensor such as a thoracic abdominal motion sensor, a transthoracic impedance sensor with electrodes placed on the abdomen, a visual sensor for visualizing abdominal movement, or a strain gauge placed on the patient's chest. The respiratory data may also be determined by computer analysis of the arterial waveform. The respiratory data may include respiratory cycles determined from zero crossings of the transthoracic impedance.

[0005] Known pacing devices may also receive activity data from an activity sensor. The activity sensor may include a cardiac sensor and / or a respiratory sensor. For example, the activity data may be determined by monitoring the patient's heart rate or respiratory rate. The activity sensor may also include one or more other sensors, such as an accelerometer, a pulse oximeter, a sweat sensor, a video sensor, a temperature sensor, or other sensors known in the art. The controller may increase or decrease the pulse rate of the pacing signal in response to the activity data.

[0006] The controller may include one or more processors, which may be one or more microprocessors. The one or more processors may operate as a state machine, a central pattern generator (CPG), or according to any other implementation known in the art. The controller may generate on-demand atrial and / or ventricular pacing pulses as pacing signals for application via the electrodes. Summary of the Invention

[0007] According to a first aspect of the present disclosure, there is provided a controller for a pacing device, the controller comprising: receiving sensor data including respiratory data; determining a respiratory sinus arrhythmia (RSA) coefficient for the pacing signal based on the sensor data; determining a cardiopulmonary phase synchronization (CRPS) coefficient for the pacing signal based on the sensor data; and The pacing signal is configured to provide a pacing signal for pacing the patient's heart according to an RSA coefficient and a CRPS coefficient.

[0008] The controller may be configured to determine an activity level of the patient based on the sensor data.The controller may be configured to determine an RSA coefficient based on the activity level of the patient.

[0009] The sensor data may further include one or more of cardiological data, pulse oximeter data, accelerometer data, body temperature data, sweat data, camera data, adenosine triphosphate (ATP) levels, and adrenaline levels.

[0010] The RSA coefficient may include one or more parameters of the pacing signal that provide a higher heart rate during the inhalation portion of a respiratory cycle than during the exhalation portion of the respiratory cycle.The RSA coefficient may include one or more parameters of the pacing signal that define how much higher the heart rate will be during the inhalation portion of a respiratory cycle than during the exhalation portion of the respiratory cycle.

[0011] The CRPS coefficient may include one or more parameters of a pacing signal that provides a cardiac pulse having a respiratory phase value that repeats over an integer number of respiratory cycles. A cardiac pulse phase value repeats over an integer number of respiratory cycles if it varies from an average phase value by less than the CRPS threshold.

[0012] The controller may be configured to determine the CRPS modulus based on the RSA modulus.

[0013] The controller may be configured to provide the pacing signal in accordance with the RSA coefficient by controlling timing of pulses in the pacing signal according to a first rate when the respiratory data indicates inspiration and according to a second rate when the respiratory data indicates expiration, the first rate being greater than the second rate.

[0014] The sensor data may include cardiological data. The controller may be configured to determine a baseline heart rate from the cardiological data. The controller may be configured to set the first rate and the second rate based on the baseline heart rate.

[0015] The controller may be configured to set a ratio of the first speed to the second speed based on the baseline heart rate.

[0016] The controller can be configured to determine an activity level of the patient based on the sensor data. The controller can be configured to set a ratio of the first speed to the second speed based on the activity level of the patient.

[0017] The controller may be configured to provide a pacing signal in accordance with a CRPS index by controlling the timing of pulses in the pacing signal to correspond to the same set of respiratory phase angles in a repeating sequence over an integer number of respiratory cycles.

[0018] The controller can be configured to set the first rate and the second rate to control the timing of pulses in the pacing signal to correspond to the same set of respiratory phase angles in a repeating sequence over an integer number of respiratory cycles.

[0019] The controller may be configured to determine an activity level of the patient based on the sensor data. The controller may be configured to determine an RSA factor based on the activity level of the patient. The controller may be configured to set a ratio of the first rate to the second rate based on the RSA factor. The controller may be configured to determine a CRPS factor as values ​​of the first rate and the second rate that provide a repeating sequence based on the ratio, a baseline heart rate of the sensor data, and a respiration rate of the respiration data. The controller may be configured to provide a pacing signal based on the first rate and the second rate.

[0020] The controller can be configured to determine a first rate and a second rate that provide a modified baseline heart rate within the pacing signal for providing the repeating sequence.

[0021] The controller may be configured to adjust a ratio of the first speed to the second speed to determine a CRPS factor as values ​​of the first speed and the second speed provide a repeating sequence.

[0022] The controller may be configured to determine the first rate and the second rate based on the ratio and the baseline heart rate by accessing a lookup table.

[0023] The controller may be configured to determine a CRPS factor to reduce the number of respiratory cycles that the pacing signal repeats.

[0024] The controller can be configured to control the timing of pulses in the pacing signal to correspond to the same set of respiratory phase angles within an acceptable deviation threshold.

[0025] The controller may be configured to determine a baseline heart rate per respiratory cycle and / or a baseline phase angle based on the cardiological data and the respiratory data. The controller may be configured to determine a set of respiratory phase angles based on the baseline heart rate and / or the baseline phase angle.

[0026] The controller may be configured to determine the RSA factor and the CRPS factor based on the respiratory rate of the respiratory data.

[0027] The sensor data may include cardiological data, and the controller may be configured to determine the RSA coefficient and the CRPS coefficient based on the cardiological data.

[0028] The controller may be configured to determine the RSA factor and the CRPS factor based on the heart rate of the cardiological data.

[0029] The controller may be configured to determine the RSA factor and the CRPS factor based on a beats per time interval value of the cardiological data.

[0030] The controller may be configured to determine the RSA factor and the CRPS factor based on the beats per breath value determined from the cardiological data and the respiratory data.

[0031] The respiratory data may include minute ventilation data.

[0032] According to a second aspect of the present disclosure, there is provided a pacemaker system, the pacemaker system comprising: Any controller disclosed herein; and one or more sensors for providing sensor data; and one or more pacing electrodes for applying a pacing signal to the patient's heart.

[0033] According to a third aspect of the present disclosure, there is provided a method for providing a pacing signal for pacing a patient's heart, the method comprising: Receiving sensor data including respiratory data; determining a respiratory sinus arrhythmia (RSA) coefficient of a pacing signal based on the sensor data; determining a cardiopulmonary phase synchronization (CRPS) coefficient of a pacing signal based on the sensor data; providing a pacing signal for pacing the patient's heart in accordance with an RSA coefficient and a CRPS coefficient.

[0034] According to a fourth aspect of the present disclosure, there is provided a computer program product storing executable instructions for performing any of the methods disclosed herein.

[0035] According to a further aspect of the present disclosure, there is provided a method for providing a pacing signal for pacing a patient's heart, the method comprising: Receiving sensor data including respiratory data; The pacing mode of the controller can be changed according to the sensor data. RSA mode, and / or CRPS mode, and set it as Providing a pacing signal according to a pacing mode.

[0036] While the present disclosure is susceptible to various modifications and alternative forms, specific aspects thereof have been shown by way of example in the drawings and will be described in detail. It will be understood, however, that other embodiments beyond the specific embodiments described are also possible. All modifications, equivalents, and alternative embodiments falling within the spirit and scope of the appended claims are also covered.

[0037] The above discussion is not intended to represent every example embodiment or every implementation within the scope of the present or future set of claims. Both the drawings and the detailed description that follows illustrate example embodiments. Various example embodiments can be more fully understood in view of the following detailed description in conjunction with the accompanying drawings.

[0038] One or more embodiments will now be described, by way of example only, with reference to the accompanying figures. [Brief description of the drawings]

[0039] [Figure 1A] 1 shows plots of respiratory sinus arrhythmia (RSA) amplitude versus time for a healthy individual before, during, and after physical exercise. [Figure 1B] 1 shows plots of RSA amplitude versus time for an older individual before, during, and after physical exercise. [Figure 2A] 1B shows a synchronogram plot corresponding to the RSA plot of FIG. 1A. [Figure 2B]1B shows a synchronogram plot corresponding to the RSA plot of FIG. 1B. [Figure 2C] 1 shows simulated cardiopulmonary data of a healthy heart exhibiting RSA and an unhealthy heart exhibiting no RSA. [Figure 2D] 1 shows simulated cardiopulmonary data of an unhealthy heart exhibiting no RSA. [Diagram 3] 1 shows a schematic block diagram of a cardiac pacemaker system. [Figure 4] 1 shows a plot of the pulse sequence versus time for two successive cardiac cycles. [Diagram 5] A method of providing a pacing signal for pacing a patient's heart is presented. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0040] The present disclosure relates to a controller and associated pacing method for a cardiac pacemaker. The pacing method is derived from the inventors' observations of natural pacing in both healthy subjects and subjects with various physiological conditions under various levels of physical activity. The proposed pacing scheme aims to respond to the subject's physical demands by emulating the natural pacing observed in healthy subjects under such conditions.

[0041] The body's natural regulation of heartbeat is in phase with the breathing or respiratory cycle. Synchrony between the heart and lungs indicates a healthy cardiopulmonary system. The strength of the coupling between the heart and lungs is one of the key factors behind the increase in synchronization and the decrease in coupling strength, for example, in aging and in patients with heart failure and other cardiopulmonary disorders, resulting in a decrease in synchronization between the heart and lungs.

[0042] An example of synchrony between the heart and lungs is a decrease in heart rate during expiration (breathing out) and an increase in heart rate during inspiration (breathing in). This is called respiratory sinus arrhythmia (RSA). Loss of RSA is a predictor of cardiovascular risk and a prognostic indicator for multiple diseases, including heart failure.

[0043] An exemplary pacing system can be provided to artificially restore, maintain or enhance RSA to obtain a healthy individual profile. Applications GB1913050.9 and PCT / GB2020 / 052149 disclose such systems and are incorporated herein by reference in their entirety. The exemplary system can control the timing of the stimulation signal (pacing signal) according to a nonlinear function. The nonlinear function can be generated by a central pattern generator or a neural oscillator provided by digital simulation.

[0044] 1A and 1B show plots of RSA amplitude versus time for a first and second individual before, during, and after physical exercise, respectively. The data in FIG. 1A was taken from a healthy individual (age 24+, height 180.5 cm, weight 88 Kg, BMI 27.0), while the data in FIG. 1B was taken from an otherwise elderly healthy individual (age 64+, height 178 cm, weight 93 Kg, BMI 29.4). In both figures, the subject is at rest at time=0 seconds. In FIG. 1A, exercise onset occurs at time=180 seconds and the exercise period ends at time=800 seconds. In FIG. 1B, exercise onset occurs at time=300 seconds and the exercise period ends at time=800 seconds.

[0045] FIG. 1A shows healthy RSA levels of approximately 0.5 Hz peak-to-peak amplitude for a first individual at rest. The first individual was subjected to gradually increasing exercise intensity from 180 s to 800 s. RSA amplitude remains high before the onset of exercise (i.e., before 180 s) and during the early phase of exercise (i.e., 180 s to 400 s). RSA amplitude decreases to below 0.1 Hz at higher exercise intensities (i.e., 500 s to 800 s). During the recovery period (i.e., after 800 s), RSA amplitude begins to increase in amplitude again.

[0046] Figure 1B shows an unhealthy level of RSA with a peak-to-peak amplitude of approximately 0.05 Hz for the second individual at rest. As can be seen, the RSA amplitude also decreases after the onset of exercise and recovers again after the end of exercise. The trend in Figure 1B is less clear than that in Figure 1A, because the resting level of RSA is relatively low from the start, resulting in a high signal-to-noise ratio.

[0047] 1A and 1B show that RSA decreases during physical activity in individuals with both healthy and unhealthy cardiopulmonary systems. RSA amplitude is high in healthy subjects at rest and decreases with increasing exercise levels. Individuals with unhealthy cardiopulmonary systems tend to have lower RSA amplitude, even at rest, which further decreases with increasing exercise.

[0048] Figures 2A and 2B show synchrogram plots corresponding to the RSA plots of Figures 1A and 1B, respectively. The synchrogram plots cardiac beat instances on the x-axis in time against respiratory phase on the y-axis, where respiratory phase defines the instantaneous phase angle of the respiratory cycle relative to the start of the respiratory cycle. The respiratory phase varies or cycles between 0 and 2π radians during one respiratory cycle in the same manner as in conventional oscillatory systems.

[0049] For the first individual (FIG. 2A), a regular heart beat pattern can be seen during the 180 second pre-exercise period with approximately 12 heart beats per respiratory cycle. This regular heart rate and high heart beats per respiratory cycle correspond to periods of high amplitude RSA. As exercise progresses and the RSA amplitude decreases, a second type of synchronization becomes identifiable in the synchogram plot - cardiopulmonary phase synchronization (CRPS). Regions of CRPS 202, 204 can be seen in the synchogram plot as regions where the respiratory phase of corresponding heart beats in adjacent respiratory cycles has a substantially constant phase. In other words, the heart beats or pulsates at the same repetitive phase angle in successive respiratory cycles. Regions of CRPS 202, 204 can be identified in the synchogram plot as substantially horizontal lines or plateaus formed by heart beat instances in adjacent respiratory cycles. CRPS is not necessarily limited to heart beats having the same phase angle in successive or adjacent respiratory cycles, and the repeating sequence of phase angles may extend over an integer number of respiratory cycles (e.g., up to one in 2, 3, 4, 6, or more respiratory cycles). As explained below in connection with Figures 2C and 2D, CRPS tends to be present continuously subject to interruptions in the respiratory cycle due to eating, yawning, hiccups, etc. Thus, Figure 2A includes regions of CRPS that are not immediately identifiable because the heart rate is relatively low (e.g., before the onset of exercise) and / or the repeating sequence of phase angles is over several respiratory cycles.

[0050] For the second individual (Figure 2B), both before and during exercise there are discernible areas of CRPS 206, 208, 210, 212. Before exercise begins there are approximately 4-5 heart beats per respiratory cycle, which increases to 5-6 beats per respiratory cycle during exercise.

[0051] Figures 2C and 2D show simulated cardiopulmonary data for a healthy heart exhibiting RSA and an unhealthy heart exhibiting no RSA, respectively. The cardiopulmonary data are plotted with the phase of the respiratory cycle (on a scale of 0 to 1, which corresponds to 0 to 2π radians in the plots of Figures 2A and 2B) plotted on the horizontal axis and the R-wave deviation from the mean plotted on the vertical axis. Here, R-wave deviation refers to the deviation of the RR interval (or cardiac beat period) from the mean RR interval.

[0052] RSA can be clearly seen in Figure 2C as periods of R-wave deviation from positive to negative values ​​and back to positive values ​​In contrast, in Figure 2D, no fluctuations in R-wave deviation are seen, indicating the absence of RSA.

[0053] Heart beats are shown in each plot of Figures 2C and 2D for multiple respiratory cycles, and the data can be seen to form clusters 214. A cluster defines multiple heart beats occurring at the same respiratory phase over several respiratory cycles. In other words, the data shows CRPS for both hearts exhibiting RSA and hearts lacking RSA. In both examples of Figures 2C and 2D, the repeating sequence of phase angles occurs over more than one respiratory cycle, as evidenced by the large number of beats per respiratory cycle. For example, if the repeating sequence exceeds two respiratory cycles, every other illustrated cluster 214 may correspond to a first respiratory cycle with intervening clusters 214 corresponding to a second respiratory cycle.

[0054] Figures 2A-2D show that both healthy and unhealthy hearts tend to naturally exhibit CRPS 202-210, regardless of the presence of RSA. Figure 2A shows that CRPS is present in healthy individuals when the cardiopulmonary system is stressed during exercise, Figure 2B shows that CRPS is present in an unhealthy cardiopulmonary system both at rest and during exercise, and Figures 2C and 2D show that CRPS is present both in the presence and absence of RSA.

[0055] Thus, the heart can be considered to have three operating states: (i) asynchronous, without CRPS or RSA, which is especially common when the heart is under severe stress and / or when there is respiratory interruption, (ii) phase-locked CRPS without RSA, which is especially common when engaging in activity such as exercise, and (iii) phase-locked CRPS with RSA, which is especially common when a healthy heart is at rest or engaged in a moderate amount of activity compared to the underlying fitness. In various embodiments of the present disclosure, a controller for a pacing device is provided that may tend to move the heart state upward from state (i) to state (iii) depending on the demands on the heart (such as activity) compared to the underlying fitness and / or health of the tissue.

[0056] The present disclosure takes into account two types of natural cardiopulmonary synchrony in healthy individuals: RSA at rest (and low levels of activity corresponding to the individual's fitness level) and a continuing tendency toward CRPS. The present disclosure provides a controller for a pacing system that can provide a pacing signal for pacing a patient's heart with an RSA component while maintaining CRPS. Specifically, the controller can determine (i) an RSA coefficient of the pacing signal for inducing RSA in the patient, and (ii) a CRPS coefficient of the pacing signal for inducing cardiopulmonary phase synchrony (CRPS) in the patient. The controller can determine the two coefficients based on sensor data associated with the patient. The sensor data includes respiratory data to aid in synchronizing the timing of the pacing signal according to the RSA coefficient and the CRPS coefficient.

[0057] In some examples, the controller may determine the RSA coefficient based on the patient's activity level as indicated by the sensor data. The controller may decrease the amount of RSA in the pacing signal in proportion to (or as a nonlinear function of) the increase in activity level. When the activity level increases beyond the upper (safety) limit of the patient's individual strength / tissue health, the controller may determine the RSA coefficient as zero (or one, depending on the implementation) to provide a pacing signal that does not induce any RSA. In this way, when the sensor data indicates that the cardiopulmonary system is under temporary increased stress, such as during vigorous exercise or other vigorous activity, the controller may not attempt to induce RSA. As a result, the controller provides a pacing signal that advantageously replicates the natural pacing of a healthy cardiopulmonary system at rest and when stress levels increase.

[0058] The controller may advantageously provide pacing signals to induce both RSA and CRPS. In this manner, the controller may induce both RSA and CRPS when the sensor data indicates that the cardiopulmonary system is not under increased stress, such as when the patient is stationary or engaged in moderate levels of activity.

[0059] In some examples, if the sensor data indicates that the patient is under a severe level of stress that exceeds a safety threshold, the controller may also determine the RSA and CRPS coefficients so as not to induce either RSA or CRPS. The controller may also not induce any type of synchronization during a calibration mode or a free running mode, in which the controller may determine the patient's baseline health or fitness based on a baseline set of sensor data. For example, the controller may determine the patient's underlying fitness / disease state by entering a diagnostic mode in which the patient performs a known activity, such as a 6-minute walking test. The controller may then determine the baseline average pulse rate and the level of RSA and CRPS coefficient adjustments to apply to the pacing signal per unit change in respiration rate. In the calibration mode, the controller may determine a set of cardiac-respiratory relationship data that defines the relationship between cardiac sensor data and respiratory sensor data across various activity levels. For example, the controller may be configured to determine an ideal heart rate for a particular patient as a function of non-cardiac sensor data based on the relationship between cardiac sensor data and non-cardiac sensor data during the calibration mode.

[0060] Pacing devices implementing a controller as disclosed herein can slow disease progression, reverse myocardial damage (myocardial remodeling), or obtain better cardiac pumping function from remaining viable myocardium to improve the quality of life of subjects using the cardiac devices.

[0061] 3 shows a schematic block diagram of a cardiac pacemaker system 300 including a pacing device 302 with a controller 308, according to one or more embodiments of the present disclosure. The cardiac pacemaker system 300 includes the cardiac pacing device 302, one or more sensors 304, and one or more pacing electrodes 306. The pacing system 300 is an electronic device for artificially inducing both (i) the biological RSA process present in healthy individuals at rest, and (ii) the biological CRPS process to which all hearts tend in the absence of respiratory or cardiac interruption. The provision of such a device may also prove advantageous in patients where RSA and / or CRPS naturally occur, using such a device to apply RSA and / or CRPS at a higher level or periodically than naturally occurs.

[0062] The one or more sensors 304 may include a respiration sensor for providing respiration data as sensor data to the controller 308. The respiration sensor may include, for example, an electromyographic sensor or a thoracic impedance sensor. The respiration sensor may be configured to sense a signal indicative of the subject's respiration. The one or more sensors 304 may further include a cardiac sensor and / or an activity sensor for providing respective cardiological and / or activity data associated with the subject. Use of such data by the controller 308 is further described below.

[0063] The respiratory data may include minute ventilation data. The controller may be configured to determine a minute ventilation parameter based on the minute ventilation data. Minute ventilation (VE) is defined as the amount of gas inspired (inspired minute ventilation) or expired (expired minute ventilation) from a person's lungs per minute. Minute ventilation can be written as: VE=TV×f Where TV = tidal volume f = breathing frequency

[0064] Tidal volume is a measure of the amount of air moved during normal inhalation and exhalation without extra effort. Minute ventilation (VE) is proportional to breathing effort and breathing frequency. The controller 308 may determine the activity level based on the minute ventilation parameters.

[0065] Any of the one or more sensors 304 may be provided by conventional sensors used in the art (such as those described in the Background section above) and may include mechanisms or adhesives for coupling the one or more sensors 304 to a subject. The cardiac pacing device 302 may be configured to communicate with the one or more sensors 304 via a wireless or wired communication link. For example, a short-range communication link may operate through the patient's tissue such that one of i) the cardiac pacing device 302 and ii) the one or more sensors 304 is provided internally and the other is provided externally.

[0066] The one or more pacing electrodes 306 may be provided by conventional pacing electrodes configured to apply electrical stimulation to a subject. The one or more pacing electrodes 306 may include a mechanism or adhesive for attaching the one or more pacing electrodes 306 to a subject. The one or more pacing electrodes 306 may also provide the functionality of a cardiac sensor.

[0067] The cardiac pacemaker device 302 includes a controller 308 and an electrical stimulus generator 310. The controller 308 may include one or more processors. The one or more processors may operate as a state machine, a central pattern generator (CPG), or according to any other implementation known in the art. The controller 308 may generate on-demand atrial and / or ventricular pacing pulses as stimulation signals for application via the pacing electrodes 306.

[0068] The controller 308 is configured to receive sensor data, including respiration data, from the one or more sensors 304 at a sensor signal input 312. The controller 308 is configured to determine RSA and CRPS coefficients for a pacing signal based on the sensor data and provide a pacing signal for pacing the patient's heart according to the RSA and CRPS coefficients. The controller 308 may provide the pacing signal to an electrical stimulus generator 310, which may provide a corresponding stimulation signal to the patient's heart via one or more pacing electrodes 306. In other examples, the electrical stimulus generator may form part of the controller 308, and the controller may provide the pacing signal directly to the one or more pacing electrodes 306 as a stimulation signal. The pacing and stimulation signals may include a sequence of pulses having timing that corresponds to the timing of induced cardiac beats in the patient's heart.

[0069] The cardiac pacing device 302 may be an implantable device. For example, the cardiac pacing device 302 may have a housing that may be biologically inert or non-reactive. The housing may have dimensions of, for example, 10 cm or less by 5 cm or less. The cardiac pacing device 302 may include a power source for providing power to the device 302.

[0070] The electrical stimulus generator 310 is configured to generate a stimulation signal based on a pacing signal provided by the controller 308. The electrical stimulus generator 310 may be provided, for example, by conventional pulse generation hardware and may be configured to provide a stimulation signal to the one or more pacing electrodes 306.

[0071] The controller 308 may be provided by hardware, software, or a combination of hardware and software. In one example, the controller 308 may be provided as a software module executed by hardware, for example.

[0072] According to a first aspect, a controller 308 of the pacing device 302 is configured to receive sensor data including respiration data. The controller 308 may receive the sensor data from one or more sensors 304. The controller 308 is configured to determine an RSA coefficient for the pacing signal based on the sensor data, determine a CRPS coefficient for the pacing signal dependent on the sensor data, and provide a pacing signal for pacing the patient's heart in accordance with the RSA coefficient and the CRPS coefficient.

[0073] As described above, the controller 308 may determine the RSA coefficient and therefore provide a pacing signal to artificially induce RSA in the patient. The pacing signal may include a sequence of pulses with each pulse to induce a heartbeat in the patient. The controller 308 may control the timing of the pulses in the pacing signal according to the RSA coefficient based on timing information in the respiratory data. For example, the controller 308 may control the timing of the pulses at a first rate when the respiratory data indicates inspiration and at a second rate when the respiratory data indicates expiration, where the first rate is greater than the second rate. For example, the first rate may be 0.1-1.0 Hz, preferably 0.2-0.5 Hz, greater than the second rate. In another example, the first rate may be increased by 10-15 beats per minute (BPM) for an upper level of RSA. The upper level may correspond to an increase of 15 BPM at a heart rate of 100 BPM. The lower level may correspond to a 15 BPM increase in heart rate of 45 BPM.

[0074] Alternatively, the first rate may be scaled relative to the second rate. For example, the first rate may be 5-100% higher than the second rate. The RSA modulus may correspond to a ratio between the first rate to the second rate.

[0075] The sensor data may further include cardiological data related to the patient's heart. The controller 308 may receive the cardiological data from a cardiac sensor. The cardiac sensor may include a pacing electrode 306. The controller 308 may also determine the RSA coefficient based on timing information in the cardiological data. For example, a baseline heart rate may be determined from the cardiological data, and the first rate and the second rate may be based on the baseline heart rate.

[0076] As described further below, the sensor data may further include activity data representative of an activity level of the patient. The controller 308 may determine the RSA coefficient based on the activity data. For example, the controller 308 may scale the first rate and / or the second rate based on the activity level indicated by the activity data.

[0077] The controller 308 may scale the magnitude of the RSA coefficient (first rate divided by second rate) based on any combination of respiratory data, cardiac data, or patient activity level. For example, the controller may adjust the magnitude of the RSA coefficient with increasing heart rate, respiratory rate, and / or patient activity level. The controller may further scale the magnitude of the RSA coefficient based on one or more of age, fitness level, and comorbidities.

[0078] The controller 308 may determine a CRPS factor to induce or maintain CRPS in the patient. The controller 308 may determine the CRPS factor based on timing information in the respiratory data. For example, the controller 308 may control the timing of a sequence of pulses in the pacing signal to occur at the same set of phase angles for consecutive respiratory cycles or over an integer number of respiratory cycles. In this manner, the controller 308 may control the timing of the pulses such that the respiratory phase of corresponding cardiac beats in adjacent respiratory cycles or sets of adjacent respiratory cycles is substantially constant, where substantially constant may be defined as the variation in phase angle between corresponding cardiac beats in adjacent respiratory cycles being less than a CRPS threshold, e.g., 0.1, 0.2, 0.3, 0.4, or 0.5 radians.

[0079] The controller 308 may also determine the CRPS coefficient based on timing information in the cardiological data. For example, the controller 308 may determine a baseline heart rate per respiratory cycle from the cardiological data and set the phase angle of the pulse based on the baseline heart rate per respiratory cycle. The controller may also determine a set of baseline phase angles and set the phase angle of the pulse based on the set of baseline phase angles. The baseline phase angle may correspond to an average phase angle over several adjacent respiratory cycles or a set of several adjacent respiratory cycles. As a simplified example in which RSA is not present, the controller 308 may determine a baseline heart rate per respiratory cycle of 5.5 beats per respiratory cycle and average phase angles of 0, 2π / 11, 4π / 11, 6π / 11, 8π / 11, 10π / 11, π / 11, 3π / 11, 5π / 11, 7π / 11, and 9π / 11 over a set of two adjacent respiratory cycles. The controller 308 may control the timing of pulses of the pacing signal according to the CRPS coefficients to maintain a predetermined number of beats per respiratory cycle (e.g., 5.5) and an average phase angle per respiratory cycle. The CRPS coefficients may include one or more parameters that provide a repeating set of respiratory phase angles over an integer number of respiratory cycles. For example, the CRPS coefficients may include a set of respiratory angles, a respiratory angle period that corresponds to the difference between successive respiratory phase angles within the set of respiratory angles, and either a set of respiratory angles having the same respiratory angle period as a set of respiratory angles with a fixed time offset, or first and second rate values ​​that provide an offset set of respiratory angles.

[0080] In one or more examples, the controller may determine the CRPS factor based on the RSA coefficient. For example, the controller may determine the RSA coefficient based on the patient's activity level. The controller may then determine a ratio of the first rate (for the pacing signal during inspiration) to the second rate (for the pacing signal during expiration) based on the RSA coefficient. For example, the controller may set the ratio equal to the RSA coefficient. The dependency of the RSA coefficient on the activity level may be calibrated or pre-determined for each patient and may depend on factors such as age, BMI, health status, etc. The controller may determine the CRPS factor based on the ratio or the RSA coefficient. The controller may determine the CRPS factor based on the ratio (RSA coefficient) and the measured baseline heart rate from the cardiological data of the sensor data.

[0081] The controller may set the first and second rates of the pacing signal such that the baseline (average) heart rate is maintained and has a determined ratio / RSA factor. However, in some examples, this may not result in CRPS, or may only result in CRPS that repeats over a very large number of respiratory cycles, since the resulting values ​​of the first and second rates do not result in a repeating sequence of respiratory phase values ​​over an integer number of respiratory cycles. Thus, the controller may determine the CRPS factor as the value of the first and second rates that adjusts the determined ratio based on the RSA factor to result in a repeating sequence over a reduced number of respiratory cycles. Alternatively, or additionally, the controller may adjust the first and / or second rates (CRPS factor) to provide a pacing signal with a baseline (average) pulse rate that differs from the measured baseline heart rate, resulting in a repeating sequence over a reduced number of respiratory cycles.

[0082] The controller may define a set of stable operating modes with fixed CRPS factors with fixed first and second speeds. The CRPS factors may correspond to a repeating sequence occurring over only a few respiratory cycles (such as 1, 2, 3, or 4 respiratory cycles). Each stable operating mode may correspond to a range of baseline heart rates and a range of RSA factors. For example, a first stable operating mode may correspond to a first speed of 6.0 beats per respiratory cycle and a second speed of 5.0 beats per respiratory cycle. The ratio of the first speed to the second speed is 1.2. The baseline heart rate is 5.5 beats per respiratory cycle and the phase angle will repeat over each set of two respiratory cycles. The controller may determine the RSA factor as 1.19 based on the patient's activity level and measure a baseline heart rate of 5.48. The controller may select the first stable operating mode because the RSA factor and baseline heart rate are within a threshold range of values ​​for the first stable operating mode. In this manner, the controller determines the CRPS coefficients as a stable operating mode having a range that encompasses the determined RSA coefficient and the measured baseline heart rate. The controller may include a look-up table with a set of CRPS coefficients that correspond to a range of RSA coefficients and baseline heart rates, or stable operating modes. The controller may access the look-up table to determine the CRPS coefficients. The look-up table may be predetermined based on past patient data, including, for example, observed heart rate data, or modeled data.

[0083] During operation, the timing of heartbeats may vary from beat to beat due to biological processes. However, during CRPS, the short-term average phase value tends to repeat over an integer number of respiratory periods. In other words, the phase value of a heartbeat pulse may be considered to repeat over an integer number of respiratory cycles if it varies from the average phase value by less than the CRPS threshold.

[0084] The controller may be configured to monitor two different short-term averages to determine if the pacing signal needs to move to a new stable operating mode. First, the controller may be configured to monitor the difference between the short-term average heart rate generated by the device (e.g., over a short period of time such as 5-10 seconds, over one, two, three or more respiratory cycles, or over an integral number of heart beats) and an ideal baseline heart rate (e.g., determined using any of the methods described above based on the respiratory data and the relationship data determined in the calibration mode). If the difference exceeds a threshold for a pre-determined time, the controller may set the pacing parameters to correspond to the next stable operating mode. In this manner, the controller may maintain a stable operating condition while the short-term average heart rate is substantially equal to the ideal heart rate determined from the non-cardiological data and the calibration data, and may change to a new operating condition when the average heart rate persistently exceeds a CRPS error threshold.

[0085] As a second option, the controller may monitor the short-term average phase value difference. For good agreement between the pacing pattern and respiration, the short-term average should be about 0 (i.e., phase locked, but jitter and biological processes will cause the average difference to vary). The short-term average phase difference may be measured, for example, over a period of less than 1, 2, or 5 cardiac cycles, or over a pre-determined period. If the difference exceeds a threshold over a pre-determined period and in the bias direction (which may be consistently above a positive threshold), the controller may move to the next stable operating mode.

[0086] The controller may integrate or long-term filter the cardiological data to determine an average value over a pre-determined period. In this way, the controller may maintain stable operating conditions while the short-term average phase value is substantially constant and change to a new operating condition when the average phase difference is persistently above the CRPS error threshold. The controller may include a phase detection capability based on changes in the respiratory window. The controller may implement a neuronal network for such phase detection capability.

[0087] FIG. 4 shows a plot of a pulse sequence in a CRPS mode versus time for two successive respiratory cycles 402, 404. The plot is a synchronogram plot of the type described above with reference to FIGS. 2A and 2B, where the heart beat instances on the x-axis are plotted in time versus the respiratory phase on the y-axis. In this example, each respiratory cycle contains five heart beats. Each heart beat in a first respiratory cycle 402 is in phase with a respective heart beat in a subsequent second respiratory cycle 404. Each heart beat occurs at a specific time (i.e., after a certain period of time has elapsed) relative to the start of that respiratory cycle. The corresponding heart beat of the subsequent respiratory cycle occurs at the same point in time relative to the start of that respiratory cycle. CRPS is evident in the repeating sequence across each respiratory cycle.

[0088] 3, in one or more examples, the controller 308 can be configured to operate in a free-running mode for one or more respiratory cycles and not provide a pacing signal or to provide a pacing signal without pulses. In this manner, the controller 308 can monitor changes in the baseline heart rate, baseline heart rate per respiratory cycle, or baseline phase angle.

[0089] In one or more examples, the controller 308 may be calibrated. For example, sensor data including cardiological data may be monitored for a patient undergoing exercise at various intensity levels to determine a set of baseline cardiological data for a range of respiration rates. The controller 308 may store the set of baseline cardiological data. During operation, the controller 308 may control the timing of pulses of the pacing signal based on the respiration rate and the set of baseline cardiological data.

[0090] As outlined above, the controller 308 may be configured to control the timing of pulses in the pacing signal according to an RSA coefficient and a CRPS coefficient to induce both RSA while maintaining CRPS. For example, the controller may control the timing of pulses according to a first rate during inspiration and a second rate during expiration, and with a set of fixed phase angles for a number of adjacent respiratory cycles or for a set of adjacent respiratory cycles.

[0091] The controller 308 may further control the timing of pulses in the pacing signal according to methods known in the art. For example, the controller may control the timing of the stimulation signal according to a nonlinear function that may be provided, for example, by a neural oscillator. The neural oscillator may be provided, for example, by an analog circuit implementing a CPG or by a digital simulation as disclosed in co-pending patent applications GB1913050.9 and PCT / GB2020 / 052149.

[0092] The controller 308 is configured to provide a pacing signal based on the sensor data. The controller 308 may determine an RSA factor greater than 1 (ratio>1) to induce RSA via a pacing signal if the sensor data indicates that the cardiopulmonary system is functioning within normal ranges without significantly increased stress or load. The controller may determine an RSA factor equal to 1 (ratio equal to 1) if the sensor data indicates that the cardiopulmonary system is functioning under a temporary increased stress or load. The cardiopulmonary system may function under a temporary increased stress when the patient is physically exerted, such as during exercise or heavy lifting. Increased stress may also be present when the patient is mentally stressed or after eating. Cardiopulmonary stress may also depend on one or more of the following: ambient temperature, O2 content (thin air), body position, dehydration, fever, starvation, noise, cold exposure, bleeding (menstrual cycle), psychological factors, immunological factors, pain, and disease. The system may include one or more sensors to determine the level of one or more of these stress factors.

[0093] The controller 308 may determine an activity level of the patient based on the sensor data and determine the RSA coefficient depending on the activity level, which may indicate a temporary increase in stress on the cardiopulmonary system.

[0094] The controller 308 may determine the patient's activity level based on the respiratory data. For example, the controller may determine the activity level based on the minute ventilation data as described above and determine the RSA factor accordingly. As a further example, the controller may determine the RSA factor to be greater than 1 if the respiratory rate is less than or equal to the respiratory rate threshold, and may determine the RSA factor to be equal to 1 if the respiratory rate is greater than the respiratory rate threshold.

[0095] The sensor data may include cardiological data, and the controller 308 may determine the patient's activity level based on the cardiological data. For example, the controller may determine an RSA factor greater than 1 if the heart rate is below the heart rate threshold, and may determine an RSA factor equal to 1 if the heart rate is above the heart rate threshold. The controller may also set a pacing mode depending on the respiratory data and the number of beats per respiratory cycle indicated by the cardiological data.

[0096] The sensor data may include other data to indicate the patient's activity level. For example, the controller 308 may receive sensor data including one or more of cardiological data, pulse oximeter data, accelerometer data, body temperature data, sweat data, camera data, adenosine triphosphate (ATP) levels, adrenaline levels, or other data suitable for determining activity levels known in the art. The other sensor data may be received from one or more corresponding sensors known in the art, such as an accelerometer, a pulse oximeter, a thermometer, or a camera. The sensors may form part of the cardiac pacemaker system 300 or may be external to the system.

[0097] FIG. 5 illustrates a method 500 for determining a periodic or cyclic electrical stimulation signal temporally modulated by a respiratory signal, which may be performed by the controller described above with reference to FIG.

[0098] 1. A method 500 for providing a pacing signal for pacing a patient's heart, the method comprising: Receiving 502 sensor data including respiratory data; determining 504 an RSA coefficient for the pacing signal based on the sensor data; determining 506 a CRPS coefficient for the pacing signal based on the sensor data; and providing 508 a pacing signal according to the RSA coefficient and the CRPS coefficient.

[0099] Using a first input signal indicative of respiration to control the generation of the timing of the stimulation signal means that the method 500 provides direct physiological feedback.

[0100] The controller may be configured to perform any of the methods described herein, including method 500 as a computer-implementable method. The controller may include one or more processors and memory, and the memory may include computer program code configured to cause the processor to perform any of the methods described herein.

[0101] A computer program may be provided that, when executed on a computer, causes the computer to configure any device, including a controller for a cardiac pacemaker, to perform any of the methods disclosed herein. The computer program may be software-implemented. The computer may comprise suitable hardware, including one or more processors and memory configured to execute the methods defined by the computer program.

[0102] According to a further aspect of the present disclosure, a computer-readable storage medium is provided that includes a computer program code configured to cause a processor to execute any of the computer-implementable methods described herein. The computer-readable storage medium may be a non-transitory computer-readable storage medium. The computer program may be provided on a computer-readable medium that is a physical computer-readable medium, such as a disk or a memory device, or may be embodied as a transitory signal. Such a transitory signal may be a network download, including an Internet download.

Claims

1. 1. A controller for a pacing device, comprising: receiving sensor data including respiratory data; determining a respiratory sinus arrhythmia (RSA) coefficient for a pacing signal for inducing RSA in the patient based on the sensor data; determining a cardiopulmonary phase synchronization (CRPS) coefficient of the pacing signal for inducing CRPS in a patient based on the sensor data; and A controller configured to provide the pacing signal for pacing a patient's heart in accordance with the RSA coefficients and the CRSP coefficients.

2. The RSA coefficient is comprising one or more parameters of a pacing signal that provides a higher heart rate during an inhalation portion of a respiratory cycle than during an exhalation portion of a respiratory cycle. The controller of claim 1 .

3. The CRPS coefficient is: one or more parameters of a pacing signal that provides cardiac pulses having respiratory phase values ​​that repeat over an integer number of respiratory cycles; The controller of claim 1 .

4. determining an activity level of the patient based on the sensor data; and The controller of claim 1 , configured to determine the RSA coefficient based on an activity level of the patient.

5. The controller of any one of claims 1 to 4, wherein the sensor data further comprises one or more of cardiological data, pulse oximeter data, accelerometer data, body temperature data, sweat data, camera data, adenosine triphosphate (ATP) levels, and adrenaline levels.

6. The controller of any one of claims 1 to 5, wherein the controller is configured to determine the CRSP coefficient based on the RSA coefficient.

7. The controller: a first rate when the respiratory data indicates inspiration; and a second rate when the respiratory data indicates expiration, thereby providing the pacing signal in accordance with the RSA coefficient; The controller of any preceding claim, wherein the first speed is greater than the second speed.

8. the sensor data includes cardiological data, and the controller determining a baseline heart rate from the cardiological data; and The controller of claim 7 , configured to set the first rate and the second rate based on the baseline heart rate.

9. The controller of claim 8 , wherein the controller is configured to set a ratio of the first rate to the second rate based on the baseline heart rate.

10. The controller: determining an activity level of the patient based on the sensor data; and A controller according to any one of claims 7 to 9, configured to set a ratio of the first rate to the second rate based on an activity level of the patient.

11. 11. The controller of claim 1, wherein the controller is configured to provide the pacing signal in accordance with the CRSP coefficients by controlling timing of pulses in the pacing signal to correspond to the same set of respiratory phase angles in a repeating sequence over an integer number of respiratory cycles.

12. 12. The controller of claim 11, wherein the controller is configured to set a first rate when the respiratory data indicates inspiration and a second rate when the respiratory data indicates expiration to control the timing of the pulses in the pacing signal to correspond to the same set of respiratory phase angles in a repeating sequence over an integer number of respiratory cycles.

13. the sensor data includes cardiological data, and the controller determining an activity level of the patient based on the sensor data; determining the RSA factor based on an activity level of the patient; setting a ratio of the first speed to the second speed based on the RSA coefficient; determining the CRPS coefficients as values ​​of the first and second rates for providing the repeating sequence based on the ratio, a baseline heart rate of the sensor data, and a respiration rate of the respiration data; and The controller of claim 12 , configured to provide the pacing signal based on the first rate and the second rate.

14. 14. The controller of claim 13, wherein the controller is configured to determine a first rate and a second rate that provide a modified baseline heart rate in the pacing signal to provide the repeating sequence.

15. 14. The controller of claim 13, wherein the controller is configured to adjust the ratio of the first rate to the second rate to determine the CRSP coefficient as values ​​of the first rate and second rate at which the repeating sequence is provided.

16. 16. The controller of claim 13, wherein the controller is configured to determine the first rate and the second rate based on the ratio and the baseline heart rate by accessing a lookup table.

17. The controller of any one of claims 11 to 16, wherein the controller is configured to determine the CRPS coefficient to reduce the number of respiratory cycles through which the pacing signal repeats.

18. 18. The controller of claim 11, wherein the controller is configured to control the timing of the pulses in the pacing signal to correspond to the same set of respiratory phase angles within an acceptable deviation threshold.

19. the sensor data includes cardiological data, and the controller determining a baseline cardiac rate and / or a baseline phase angle per respiratory cycle based on the cardiological data and the respiratory data; and The controller of claim 11 , configured to determine the set of respiratory phase angles based on the baseline heart rate and / or the baseline phase angle.

20. A controller according to any preceding claim, wherein the controller is configured to determine the RSA coefficients and the CRPS coefficients based on a respiratory rate of the respiratory data.

21. 21. The controller of claim 1, wherein the sensor data includes cardiological data, and the controller is configured to determine the RSA coefficients and the CRSP coefficients based on the cardiological data.

22. The controller of claim 21 , wherein the controller is configured to determine the RSA coefficient and the CRPS coefficient based on a heart rate of the cardiological data.

23. 23. The controller of claim 21 or 22, wherein the controller is configured to determine the RSA coefficient and the CRPS coefficient based on a beats per time interval value of the cardiological data.

24. 23. The controller of claim 21 or 22, wherein the controller is configured to determine the RSA coefficient and the CRPS coefficient based on a beats per breath value determined from the cardiological data and the respiratory data.

25. 1. A pacemaker system comprising: A controller according to any one of claims 1 to 24; one or more sensors for providing said sensor data; one or more pacing electrodes for applying the pacing signal to the patient's heart.

26. 1. A method for providing a pacing signal for pacing a patient's heart, the method comprising: Receiving sensor data including respiratory data; determining a respiratory sinus arrhythmia (RSA) coefficient of a pacing signal for inducing RSA in the patient based on the sensor data; determining a cardiopulmonary phase synchronization (CRPS) coefficient of the pacing signal for inducing CRPS in a patient based on the sensor data; providing the pacing signal for pacing the heart of the patient in accordance with the RSA coefficient and the CRSP coefficient.

27. 27. A computer program product storing executable instructions for performing the method of claim 26.

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