Combination therapy of cardiac pacing and irreversible electroporation (IRE)

Abstract

This invention is entitled "Combined Treatment of Cardiac Pacing and Irreversible Electroporation (IRE)". The invention discloses a cardiac pacing and irreversible electroporation (IRE) device comprising a pulse generator and a shaping circuit. The pulse generator is configured to generate IRE pulses having a pre-specified shape and repetition rate. The shaping circuit is configured to: convert some of the IRE pulses into pacing pulses having a pre-specified frequency and amplitude to generate an output signal comprising some of the IRE pulses interleaved with some of the pacing pulses; and output the output signal to a probe in the patient's heart for application of the output signal to cardiac tissue.

Description

Technical Field

[0001] The present invention relates generally to electroanatomical mapping in combination with ablation, and more specifically to cardiac pacing and irreversible electroporation (IRE). Background Technology

[0002] Previously, patent literature has proposed pacing cardiac tissue to identify the source of arrhythmia, followed by ablation of the tissue. For example, U.S. Patent 9,987,081 describes a system, apparatus, and method for electroporation ablation therapy, wherein the system includes a pulse waveform signal generator for medical ablation therapy, the pulse waveform signal generator being coupled to an ablation device including at least one electrode for delivering ablation pulses to the tissue. The signal generator can generate a predetermined sequence of voltage pulses in the form of pulse waveforms and deliver them to the ablation device. In some embodiments, the system may include a cardiac stimulator configured to generate a pacing signal for cardiac stimulation during use. The cardiac stimulator may be communicatively coupled to the signal generator and is also configured to transmit an indication of the pacing signal to the signal generator. The processor of the signal generator may also be configured to generate pulse waveforms synchronously with the indication of the pacing signal, wherein the synchronization may include a predetermined offset. In other embodiments, the treatment method may include using a cardiac stimulator to electrically pace the heart to ensure pacing acquisition thereby establishing the periodicity and predictability of the cardiac cycle, and then defining a time window within the refractory period of the cardiac cycle, within which one or more pulse ablation waveforms may be delivered.

[0003] For example, U.S. Patent Application Publication 2018 / 0042674 describes a method comprising selecting a subset of electrode pairs of a multi-electrode catheter configured to be disposed around a portion of the heart. A pacing signal is transmitted to a pacing lead configured to be operatively coupled to the heart. An electrocardiogram (ECG) signal associated with cardiac function is received at a feedback module of an electrode controller. In one embodiment, during a time window associated with at least one of the pacing signal or the ECG signal, a pulsed voltage waveform is delivered to a subset of the electrode pairs according to a sequence pattern, the pulsed voltage waveform comprising a pre-polarized pulse and subsequent polarized pulses, the pre-polarized pulse being generated by utilizing a voltage spike generated by the discharge of a switched-on capacitor bank. Summary of the Invention

[0004] An exemplary embodiment of the present invention provides a cardiac pacing and irreversible electroporation (IRE) device including a pulse generator and shaping circuitry. The pulse generator is configured to generate IRE pulses having a pre-specified shape and repetition rate. The shaping circuitry is configured to: convert some of the IRE pulses into pacing pulses having a pre-specified frequency and amplitude to generate an output signal including some of the IRE pulses interleaved with some of the pacing pulses; and output the output signal to a probe in a patient's heart for applying the output signal to cardiac tissue.

[0005] In some exemplary embodiments, the device further includes a processor configured to: (a) specify the shape and repetition rate of the IRE pulse; (b) specify the frequency and amplitude of the pacing pulse; and (c) specify the interleaved output signal by specifying the number of the one or more IRE pulses and the number of the one or more pacing pulses.

[0006] In some exemplary embodiments, the shaping circuit is also configured to modify the pre-specified shape of the IRE pulse.

[0007] In one exemplary implementation, the shaping circuit is configured to interleave the IRE pulse with the pacing pulse according to a configurable protocol.

[0008] According to another exemplary embodiment of the invention, a method for applying cardiac pacing and irreversible electroporation (IRE) pulses is also provided, the method comprising generating IRE pulses having a prespecified shape and repetition rate. A portion of the IRE pulses are converted into pacing pulses having a prespecified frequency and amplitude to generate an output signal comprising a portion of the IRE pulses interleaved with a portion of the pacing pulses. The output signal is output to a probe in a patient's heart for applying the output signal to cardiac tissue.

[0009] In some exemplary embodiments, the application method further includes using a processor to specify the shape and repetition rate of the IRE pulses; specifying the frequency and amplitude of the pacing pulses; and specifying the interleaved output signal by specifying the number of the one or more IRE pulses and the number of the one or more cycles of the RF signal. Attached Figure Description

[0010] The invention will be more fully understood from the following detailed description of embodiments thereof, taken in conjunction with the accompanying drawings, wherein:

[0011] Figure 1A schematic diagram of a cardiac pacing and irreversible electroporation (IRE) combined system according to an exemplary embodiment of the present invention;

[0012] Figure 2 According to an exemplary embodiment of the present invention Figure 1 A schematic block diagram of the system's pacing pulse and IRE pulse combination generator; and

[0013] Figure 3 The use of the invention is illustrated in the example embodiment of the invention. Figure 1 The flowchart shows a method for combining cardiac pacing and irreversible electroporation (IRE) using a system. Detailed Implementation

[0014] Overview

[0015] Cardiac arrhythmias (defined as variations in the normal sinus rhythm of the heart) can originate in or be conducted through different parts of the cardiac tissue (hereinafter referred to as "arrhythmogenic sites"). One possible method for locating arrhythmogenic sites is to electrically stimulate selected locations on the surface of the patient's cardiac tissue using bipolar electrical signals. Such stimulation, which can be performed using electrode pairs on a catheter, can induce an electrocardiogram (ECG) signal pattern that meets one or more criteria to identify the stimulated site as an arrhythmogenic focal point or pathway. This invasive diagnostic procedure is called "pacing."

[0016] Treatment of the identified arrhythmogenic site is accomplished, for example, by irreversible electroporation (IRE) at that site, which generates a high electric field that kills the target tissue cells, potentially reducing or eliminating the arrhythmia in question. However, pacing and subsequent precise application of IRE at the same site can be challenging, partly due to cardiac motion. Furthermore, even if maintaining the same location during pacing and subsequent IRE is adequately achieved, for example, using a single catheter for both procedures, two different sets of drive electronics (e.g., generators) are still required due to different voltage requirements.

[0017] The exemplary embodiments of the invention described below provide a combined technique that uses a combination of cardiac pacing pulses and IRE pulses to generate and apply diagnostic pacing and IRE treatment of arrhythmias at a given cardiac tissue location substantially simultaneously and / or sequentially. While the high voltage requirements of the IRE can be in the kilovolt range, the power requirements are relatively low, in the tens of milliwatts range. Therefore, a large portion of the circuitry used for both IRE pulse generation and pacing can be identical, with the only difference being the pulse sequence and amplitude.

[0018] In the disclosed techniques, a pacing pulse sequence and an IRE pulse sequence are applied substantially simultaneously to the same tissue location by interleaving one or more pacing pulses with one or more IRE pulses. In some exemplary embodiments, a cardiac pacing and IRE therapy device is provided, comprising a pulse generator and shaping circuitry. The pulse generator is configured to generate IRE pulses with a prespecified shape and repetition rate. The shaping circuitry is configured to convert some of the IRE pulses into pacing pulses with a prespecified frequency and amplitude to generate an output signal comprising some of the IRE pulses interleaved with some of the pacing pulses; and to output the output signal to a probe in the patient's heart for application to cardiac tissue. A processor can modify the output waveform to apply pacing pulses only, IRE pulses only, or M IRE pacing pulses and N IRE pulses RFA interleaved together (where M≥1, N≥1). A catheter is configured for insertion into the patient's heart and application of the output signal to cardiac tissue.

[0019] Other characteristics of the sequence can be configured via a processor that controls the generator, such as the IRE pulse shape and repetition rate, and pacing parameters such as the pacing frequency. For example, for IRE, the generator can generate biphasic pulses with peak-to-peak voltages up to 4 kV and typical pulse widths in the microsecond range. For pacing, the generator can generate pulses with peak voltages up to several volts in the range of several hundred cycles per minute.

[0020] Typically, a processor is programmed in software containing a specific algorithm that enables the processor to perform each of the processor-related steps and functions described above.

[0021] The pacing and IRE combination technology disclosed in this invention can improve the clinical outcomes of invasive treatments for arrhythmias while reducing the workload experienced by physicians performing the procedures.

[0022] System Description

[0023] Figure 1 This is a schematic diagram of a cardiac pacing and irreversible electroporation (IRE) combination system 20 according to an exemplary embodiment of the present invention. System 20 can be configured to stimulate and analyze substantially any electrophysiological (EP) parameter or combination of such parameters. For this purpose, the console 46 of system 20 includes a pacing / IRE pulse combination generator 33 that generates interleaved pacing / IRE waveforms and applies the interleaved pacing / IRE waveforms to cardiac tissue in the heart 34 of a patient 26 via probe 24.

[0024] In this description, by way of example, it is assumed that the signals being analyzed are intracardiac and / or extracardiac (surface) ECG potential-time relationships. To adequately characterize such relationships, signals at various locations need to be shifted relative to each other for reference, such as, for example, when generating a Local Activation Time (LAT) mapping. Time reference is accomplished by measuring relative to a reference time (e.g., a moment) (such as the start of each QRS complex of the ECG reference signal (i.e., the start of each heartbeat)). Methods for generating LAT mappings are described in U.S. Patent 9,050,011, cited above.

[0025] In the following description, system 20 uses a pacing and IRE probe 24 to stimulate (i.e., pace) the heart 34. System 20 uses probe 24 itself and / or an additional probe 14 to measure the resulting electrical activity of the heart 34. It is assumed that the distal end 32 of probe 24 has an electrode 22. Among other uses, the measured signals are used to create a LAT mapping of at least a portion of the wall tissue of the heart 34.

[0026] Typically, probe 24 includes a mapping catheter, which is inserted into the body of patient 26 during mapping procedures performed by physician 28 using system 20. (See illustration 25.) Figure 1 The protocol implemented uses a pacing and IRE pulse combination generator 33 and employs an M1-M2 bipolar electrode pair configuration of probe 24 to pace (i.e., for EP stimulation) and to perform IRE treatment on tissue sites identified as arrhythmogenic. In an exemplary embodiment, the catheter is also configured to acquire intracardiac electrophysiological signals.

[0027] In this procedure, it is assumed that patient 26 is attached to a grounding electrode (i.e., a grounding patch) 23. Furthermore, it is assumed that electrode 29 is attached to the skin of patient 26 in the region of heart 34.

[0028] System 20 is controlled by system processor 40, which includes processing unit 42 communicating with memory 44. In some exemplary embodiments, memory 44, included in system processor 40, stores EP mapping maps 62 of at least a portion of the wall tissue of patient 26's heart 34. Processor 40 is typically mounted in console 46, which includes (a) a patient interface unit 43 to which all catheters are coupled; and (b) a workstation having operating controls 38, which typically include pointing devices 39, such as a mouse or trackball, used by physician 28 to interact with the processor.

[0029] Processor 40 (specifically, processing unit 42) runs software including probe tracker module 30; ECG module 36, which includes an arrhythmia analysis module; and graphical user interface (GUI) 35, which is used by operating system 20 and / or to graphically analyze and present (using EP mapping map 62 stored in memory 44) from Figure 3 The results of the disclosed cardiac pacing and IRE treatment workflow are, for example, to identify the source of arrhythmia and treat these sources using IRE.

[0030] In one exemplary embodiment, ECG module 36 is coupled to receive electrical signals from electrodes 22 and 29. The module is configured to analyze the electrical signals and can present the results of the analysis on display 48 in a standard ECG format (typically a time-shifting graphical representation).

[0031] The probe tracker module 30 typically tracks the position of the distal end 32 of the probe 24 within the heart of the patient 26. This tracker module can use any method known in the art for probe position tracking. For example, module 30 can operate a magnetic field-based position tracking subsystem. (For simplicity, components of such a subsystem are not described in the text.) Figure 1 (As shown in the image.)

[0032] Alternatively or otherwise, the tracker module 30 can track the probe 24 by measuring the impedance between electrodes 23 and 22, as well as the impedance to other electrodes that may be located on the probe. (In this case, electrode 22 can provide both an ECG signal and a position tracking signal.) Manufactured by Biosense-Webster (Irvine, Califomia) The system uses both magnetic field position tracking and impedance measurement for position tracking.

[0033] Using tracker module 30, processor 40 is able to measure the position of distal end 32. Furthermore, using both tracker module 30 and ECG module 36, processor is able to measure the position of distal end and the LAT of electrical signals detected at these specific positions.

[0034] The results of the operations performed by processor 40 are presented to physician 28 on display 48, which typically presents a graphical user interface, a visual representation of the ECG signals sensed by electrodes 22, and / or an image or mapping of the heart 34 under study. In one embodiment, GUI 35 presents physicians with an updated EP mapping of one or more locations on the mapping (where the identified arrhythmia originates from or propagates through). The software may be downloaded to processor 40, for example, electronically via a network, or alternatively or otherwise, the software may be provided and / or stored on a non-transitory tangible medium such as magnetic storage, optical storage, or electronic storage.

[0035] The combination of cardiac pacing and irreversible electroporation (IRE)

[0036] Figure 2 According to an exemplary embodiment of the present invention Figure 1 A schematic block diagram of the system's pacing pulse and IRE pulse combination generator 33. In the exemplary embodiment shown, generator 33 includes an IRE pulse generator 50 and a pacing / IRE waveform shaper and interleaver 55, both of which can be configured and controlled by processor 40.

[0037] As shown in the figure, the IRE pulse generator 50 generates a sequence 52 of predefined high-voltage IRE biphase pulses for use in the IRE.

[0038] Shaping circuit 55 (hereinafter also referred to as “pacing / IRE waveform shaper and interleaver 55”) converts input sequence 52 into an interleaved pacing / IRE sequence 57 of output waveform, which, by way of example, includes M=2 IRE shaped pulses interleaved with N=10 pacing pulses.

[0039] The pacing / IRE waveform shaper and pulse interleaver 55 includes pulse shaper circuitry and waveform interleaver circuitry. The biphasic pulse shaper circuitry is configured to modify the IRE pulses of sequence 52 to the desired shape and repetition rate for pacing pulses. Typically, generator 33 includes electrical components, such as enhanced isolation amplifiers, to convert the waveform voltage from the high-voltage domain of the IRE pulses to the low-voltage domain of the pacing pulses.

[0040] The pulse shaper may include a capacitor array that generates different rise and fall times for the pulse. Finally, the waveform interleaver includes switching circuitry to switch between the IRE input pulse delivered to catheter 24 and the pacing pulse.

[0041] Figure 2 The exemplary configuration shown was chosen solely for clarity of concept. In alternative embodiments, the disclosed techniques may be used with any other suitable pulse generation and shaping scheme.

[0042] Cardiac pacing and IRE combination therapy

[0043] Figure 3 The use of the invention is illustrated in the example embodiment of the invention. Figure 1 The flowchart shows a method for combining cardiac pacing and irreversible electroporation (IRE) using a system.

[0044] According to the presented exemplary embodiment, the algorithm performs the following process, which begins at catheter insertion step 70, where physician 28 inserts catheter 24 into heart 34. Next, at protocol selection step 72, physician 28 selects, for example, a predefined protocol with a pacing / IRE combined waveform to be delivered to the tissue. As described above, physician 28 may choose to begin with a pacing signal only, for example, to initiate an initial diagnosis.

[0045] Assuming the initial diagnostic session has ended and the physician 28 selects to administer a mixture of pacing pulses and IRE pulses, such as those from... Figure 2 As shown in waveform 57, physician 28 specifies, for example, the interleaving sequence of the IRE / RFA waveform as specified by the selected protocol at the interleaving sequence selection step 74. For example, physician 30 may select the {M=15, N=3} sequence as defined above.

[0046] Next, at catheter positioning step 76, physician 30 manipulates catheter 24 to establish contact between electrodes M1-M2 of catheter 24 and tissue (such as the ostium of the pulmonary veins). Next, at pacing / RFA application step 78, physician 28 applies an interleaved sequence of selected pacing / IRE pulses to the tissue.

[0047] Immediately after treatment, at diagnostic step 80 following pacing / IRE application, physician 28 uses electrodes M1-M2 of catheter 24 as diagnostic electrodes to acquire an electrogram to examine the extent to which isolation was achieved in treatment step 78. If, at examination step 82, the physician finds adequate isolation achieved, physician 30 then removes the catheter from the patient at catheter retraction step 84. Otherwise, physician 28 may cycle back to step 76 to reposition the catheter and continue the session.

[0048] Although the exemplary embodiments described herein are primarily geared towards cardiac applications, the methods and systems described herein can also be used in a variety of other medical applications.

[0049] Therefore, it should be understood that the embodiments described above are cited by way of example, and the invention is not limited to what is specifically shown and described above. Rather, the scope of the invention includes combinations and sub-combinations of the various features described above, as well as variations and modifications thereof, which will occur to those skilled in the art upon reading the above description and which are not disclosed in the prior art. Documents incorporated herein by reference are considered an integral part of this application, except that if any terminology defined in such incorporated documents conflicts with the definitions expressly or implicitly given in this specification, only the definitions in this specification shall be considered.

Claims

1. A cardiac pacing and irreversible electroporation (IRE) device, comprising: A pulse generator configured to generate IRE pulses with a pre-specified shape and repetition rate; as well as A shaping circuit is configured to: receive the IRE pulses from the pulse generator and convert some of the received IRE pulses into pacing pulses having a pre-specified frequency and amplitude to generate an output signal including some of the IRE pulses interleaved with some of the pacing pulses; and output the output signal to a probe in the patient's heart for applying the output signal to cardiac tissue.

2. The device of claim 1, further comprising a processor configured to: Specify the shape and repetition rate of the IRE pulse; Specify the frequency and amplitude of the pacing pulse; and The interleaved output signal is specified by specifying the number of IRE pulses and the number of pacing pulses.

3. The device according to claim 1, wherein, The shaping circuit is also configured to modify the pre-specified shape of the IRE pulse.

4. The device according to claim 1, wherein, The shaping circuit is configured to interleave the IRE pulse with the pacing pulse according to a configurable protocol.

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