阅读说明：本技术 用于标测和调制复极化的系统和方法 (System and method for mapping and modulating repolarization ) 是由 C·J·麦克劳德 S·J·阿斯瓦泰姆 于 2019-02-05 设计创作，主要内容包括：本文描述了用于标测和调制复极化的方法和材料。例如,本文涉及用于标测和调制复极化以靶向房性和室性心律失常以传递电刺激起搏、消融和/或电穿孔的方法和设备。(Methods and materials for mapping and modulating repolarization are described herein. For example, this document relates to methods and devices for mapping and modulating repolarization to target atrial and ventricular arrhythmias to deliver electrical stimulation pacing, ablation, and/or electroporation.)

1. A method of treating cardiac arrhythmias, the method comprising:

Receiving a repolarization signal from a first electrode on a distal portion of a mapping catheter while the distal portion of the mapping catheter is inserted into a heart of a patient such that the first electrode is located at a first location;

filtering the repolarized signal received from the first electrode;

delivering stimulation to the heart via the first electrode; and

creating a repolarization map of the heart.

2. The method of claim 1, wherein filtering the repolarized signal comprises: reducing noise from the repolarized signal.

3. The method of claim 1 or 2, wherein filtering the repolarized signal comprises:

calculating a difference of the repolarized signals; and

removing a derivative signal from the repolarized signal.

4. The method of any of claims 1-3, further comprising:

receiving an external signal from a second electrode external to the heart at a second location; and

calibrating the external signal with the repolarization signal from the first electrode.

5. The method of claim 4, wherein the first location and the second location receive signals from similar regions of the heart.

6. The method of claim 4 or 5, wherein calibrating the external signal further comprises: moving the external electrode to a third position, and wherein creating the repolarization map of the heart comprises: creating the repolarization map using the external signal.

7. The method of any of claims 4-6, wherein calibrating the external signal comprises: and carrying out first-order difference on the external signal.

8. The method of any of claims 4-7, wherein calibrating the external signal comprises: a downhill slope is measured where the baseline intersects the t-wave.

9. The method of any one of claims 1-8, further comprising delivering electroporation to the heart via the first electrode.

10. The method of claim 9, wherein delivering electroporation comprises delivering irreversible electroporation.

11. The method of claim 9 or 10, wherein delivering electroporation comprises delivering reversible electroporation.

12. The method according to any one of claims 9-11, further comprising: an electroporation signal resulting from the delivery of electroporation is received and a predictable effect of electroporation on the repolarization signal is detected.

13. The method of any one of claims 1-12, wherein delivering stimulation comprises: a first set of stimuli is delivered that is below a threshold.

14. The method of claim 13, wherein delivering stimulation further comprises: increasing a parameter of the first set of stimuli.

15. The method of claim 14, wherein delivering stimulation further comprises: a detection capture is obtained.

16. The method of claim 15, wherein delivering stimulation further comprises: decreasing the intensity of the first set of stimuli and varying the interval between pulses of the first set of stimuli.

17. The method according to any one of claims 1-16, wherein delivering stimulation further comprises: changing the heart rate of the patient via the stimulus.

18. The method of claim 17, wherein changing the heart rate of the patient causes a change in the repolarization signal of the patient.

19. The method of any one of claims 1-18, wherein creating the repolarization map comprises: the repolarization is created with magnet assisted navigation and point acquisition.

20. The method of any one of claims 1-19, wherein creating the repolarization map comprises: determining a reference point in the repolarized signal.

21. The method of claim 20, wherein creating the repolarization map comprises: creating the repolarization map using the reference point.

22. The method of claim 20 or 21, wherein the reference point is the end of repolarization.

23. The method according to any one of claims 1-22, further comprising: determining a variation of the repolarization map from a normal repolarization map.

24. The method of claim 23, wherein determining the variation of the repolarization map comprises: comparing the repolarization map to the normal repolarization map and detecting a difference between the repolarization map and the normal repolarization map.

25. A system for treating cardiac arrhythmias, the system comprising:

a first electrode;

a memory capable of storing computer executable instructions; and

a processor configured to facilitate execution of the executable instructions stored in the memory, wherein the instructions cause the processor to:

receiving a repolarization signal from a first electrode located at a first location;

filtering the repolarized signal received from the electrode;

delivering stimulation to the heart via the electrodes; and

creating a repolarization map of the heart.

26. The system of claim 25, wherein filtering the repolarized signal comprises: reducing noise from the repolarized signal.

27. The system of claim 25 or 26, wherein filtering the repolarized signal comprises:

calculating a difference of the repolarized signals; and

removing a derivative signal from the repolarized signal.

28. The system of any one of claims 25-27, wherein the instructions further cause the processor to:

receiving an external signal from a second electrode external to the heart at a second location; and

calibrating the external signal with the repolarization signal from the first electrode.

29. The system of claim 28, wherein the first location and the second location receive signals from similar regions of the heart.

30. The system of claim 28 or 29, wherein creating the repolarization map of the heart comprises: creating the repolarization map using the external signal.

31. The system of any one of claims 28-30, wherein calibrating the external signal comprises: and carrying out first-order difference on the external signal.

32. The system of any one of claims 28-31, wherein calibrating the external signal comprises: a downhill slope is measured where the baseline intersects the t-wave.

33. The system of any one of claims 25-32, wherein the instructions further cause the processor to deliver electroporation to the heart via the first electrode.

34. The system of claim 33, wherein delivering electroporation comprises delivering irreversible electroporation.

35. The system of claim 33 or 34, wherein delivering electroporation comprises delivering reversible electroporation.

36. The system of any one of claims 33-35, wherein the instructions further cause the processor to receive an electroporation signal resulting from delivering electroporation and detect a predictable effect of electroporation on the repolarization signal.

37. The system of any one of claims 25-36, wherein delivering stimulation comprises: a first set of stimuli is delivered that is below a threshold.

38. The system of claim 37, wherein delivering stimulation further comprises: increasing a parameter of the first set of stimuli.

39. The system of claim 38, wherein delivering stimulation further comprises: a detection capture is obtained.

40. The system of claim 39, wherein delivering stimulation further comprises: decreasing the intensity of the first set of stimuli and varying the interval between pulses of the first set of stimuli.

41. The system according to any one of claims 25-40, wherein delivering stimulation further comprises: changing the heart rate of the patient via the stimulus.

42. The system of claim 41, wherein changing the heart rate of the patient causes a change in the repolarization signal of the patient.

43. The system of any one of claims 25-42, wherein creating the repolarization map comprises: the repolarization is created with magnet assisted navigation and point acquisition.

44. The system of any one of claims 25-43, wherein creating the repolarization map comprises: determining a reference point in the repolarized signal.

45. The system of claim 44, wherein creating the repolarization map comprises: creating the repolarization map using the reference point.

46. The system of claim 44 or 45, wherein the reference point is the end of repolarization.

47. The system of any one of claims 25-46, wherein the instructions further cause the processor to determine a variant of the repolarization map from a normal repolarization map.

48. The system of claim 47, wherein determining the variation of the repolarization map comprises: comparing the repolarization map to the normal repolarization map and detecting a difference between the repolarization map and the normal repolarization map.

Technical Field

This document relates to methods and materials for mapping and modulating repolarization. For example, this document relates to methods and devices for mapping and modulating repolarization to target atrial and ventricular arrhythmias to deliver electrical stimulation pacing, ablation, and/or electroporation.

Background

Abnormalities in cardiac repolarization, such as abnormalities in spatial heterogeneity and temporal fluctuations, promote abnormal electrophysiological substrates that are intrinsically linked to the occurrence of cardiac arrhythmias, especially sudden cardiac death arrhythmias, ventricular fibrillation and polymorphic ventricular tachycardia. Current cardiac mapping techniques, such as acquiring local electrograms, detect abnormalities that are of interest to cardiac activation sequences and depolarizations, which may be the smallest cause of these sudden death arrhythmias.

More than half of fatal cardiac arrhythmias are related to repolarization abnormalities, such as tosides de Pointes, ventricular fibrillation triggered early after depolarization, and various arrhythmias found in congenital and acquired long QT syndrome. The electrical activation may be mapped and displayed. The electrical activation can be displayed and registered as a three-dimensional electro-anatomical structure to enable more efficient ablation recording for arrhythmia management. The mapping may help physicians identify and diagnose abnormalities based on cardiac depolarization. Various methods for cardiac mapping and ablation, modulation, and pacing techniques have been developed for cardiac depolarization.

Depolarization maps may be used to find the source of various atrial and ventricular arrhythmias and to modulate depolarization using pacing, ablation, and other energy delivery, including electroporation. Monophasic Action Potential (MAP) can be recorded ex vivo. Drugs and ablation techniques focus on depolarization, but they aggravate the propensity for arrhythmias by creating more arrhythmogenic repolarization curves, which are unrecognizable to electrophysiologists. However, many genetic and acquired arrhythmias rely on or are triggered by abnormal cardiac repolarization.

Disclosure of Invention

Methods and materials for mapping and modulating repolarization are described herein. For example, this document relates to methods and devices for mapping and modulating repolarization to target atrial and ventricular arrhythmias to deliver electrical stimulation pacing, ablation, and/or electroporation.

In one aspect, the present disclosure is directed to a method of treating cardiac arrhythmias. The method may include receiving a repolarization signal from a first electrode. The electrodes may be located on a distal portion of the mapping catheter while the distal portion of the mapping catheter is inserted into the patient's heart such that the first electrode is located at a first location. The method can comprise the following steps: filtering a repolarized signal received from the first electrode; delivering stimulation to the heart via the first electrode; and creating a repolarization map of the heart. In some cases, filtering the repolarized signal may include: noise from the repolarized signal is reduced. In some cases, filtering the repolarized signal may include: calculating a difference of the repolarized signal, and removing the derivative signal from the repolarized signal.

In some cases, the method may include receiving an external signal from a second electrode external to the heart at a second location and calibrating the external signal with a repolarization signal from the first electrode. In some cases, the first location and the second location may receive signals from similar regions of the heart. In some cases, calibrating the external signal may include: moving the external electrode to the third position and creating a repolarization map of the heart may comprise: external signals are used to create a repolarization map. In some cases, calibrating the external signal may include: the external signal is first order differentiated. In some cases, calibrating the external signal may include: a downhill slope is measured where the baseline intersects the t-wave.

In some cases, the method may include: the electroporation is delivered to the heart via the first electrode. In some cases, the method may include: delivering electroporation includes delivering electroporation that is irreversible. In some cases, the method may include: delivering electroporation includes delivering electroporation that is reversible. In some cases, the method may include: an electroporation signal resulting from the delivery of electroporation is received and a predictable effect of electroporation on the repolarized signal is detected.

In some cases, delivering the stimulus may include: a first set of stimuli is delivered that is below a threshold. In some cases, delivering the stimulus may include: parameters of the first set of stimuli are increased. In some cases, delivering the stimulus may include: a detection capture is obtained. In some cases, delivering the stimulus may include: the intensity of the first set of stimuli is reduced and the interval between pulses of the first set of stimuli is varied. In some cases, delivering the stimulus may include: the heart rate of the patient is changed via the stimulation. In some cases, changing the heart rate of the patient causes a change in the repolarization signal of the patient.

In some cases, creating the repolarization map may include: the repolarization is created with magnet assisted navigation and point acquisition. In some cases, creating the repolarization map may include: a reference point in the repolarized signal is determined. In some cases, creating the repolarization map may include: the reference points are used to create a repolarization map. In some cases, the reference point may be the end of the repolarization. In some cases, the method may include: determining a variation of the repolarization map from the normal repolarization map. In some cases, determining a variation of the repolarization map may include comparing the repolarization map to a normal repolarization map and detecting a difference between the repolarization map and the normal repolarization map.

In another aspect, the present disclosure is directed to a system for treating cardiac arrhythmia. The system may include a first electrode, a memory capable of storing computer-executable instructions, and a processor configured to facilitate execution of the executable instructions stored in the memory. The instructions may cause the processor to: the method includes receiving a repolarized signal from a first electrode located at a first location, filtering the repolarized signal received from the electrode, delivering stimulation to the heart via the electrode, and creating a repolarization map of the heart. In some cases, filtering the repolarized signal may include: noise from the repolarized signal is reduced. In some cases, filtering the repolarized signal may include: calculating a difference of the repolarized signal, and removing the derivative signal from the repolarized signal. In some cases, the instructions may cause the processor to: an external signal is received from a second electrode external to the heart at a second location and calibrated with the repolarized signal from the first electrode. In some cases, the first location and the second location may receive signals from similar regions of the heart.

In some cases, creating a repolarization map of the heart may include: external signals are used to create a repolarization map. In some cases, calibrating the external signal may include: the external signal is first order differentiated. In some cases, calibrating the external signal may include: a downhill slope is measured where the baseline intersects the t-wave. In some cases, the instructions may cause the processor to deliver the electroporation to the heart via the first electrode. In some cases, delivering electroporation may include delivering electroporation irreversibly. In some cases, delivering electroporation can include delivering electroporation that is reversible.

In some cases, the instructions may cause the processor to receive an electroporation signal resulting from the delivery of electroporation and detect a predictable effect of electroporation on the repolarization signal. In some cases, delivering the stimulus may include: a first set of stimuli is delivered that is below a threshold. In some cases, delivering the stimulus may include: parameters of the first set of stimuli are increased. In some cases, delivering the stimulus may include: a detection capture is obtained. In some cases, delivering the stimulus may include: the intensity of the first set of stimuli is reduced and the interval between pulses of the first set of stimuli is varied.

In some cases, delivering the stimulus may include: the heart rate of the patient is changed via the stimulation. In some cases, changing the heart rate of the patient causes a change in the repolarization signal of the patient. In some cases, creating the repolarization map may include: the repolarization is created with magnet assisted navigation and point acquisition. In some cases, creating the repolarization map may include: a reference point in the repolarized signal is determined. In some cases, creating the repolarization map may include: the reference points are used to create a repolarization map. In some cases, the reference point is the end of repolarization. In some cases, the instructions may cause the processor to determine a variation of the repolarization map from the normal repolarization map. In some cases, determining a variation of the repolarization map may include: the repolarization map is compared to the normal repolarization map and differences between the repolarization map and the normal repolarization map are detected.

Particular embodiments of the subject matter described herein can be implemented to realize one or more of the following advantages. The apparatus and method may better characterize the electrical properties of the heart, such as for treating cardiac arrhythmias. Additionally, mapping abnormal and normal cardiac repolarization may improve understanding, risk stratification, and treatment of cardiac arrhythmias such as polymorphic ventricular tachycardia and ventricular fibrillation. The apparatus and method may be used to map both ventricular and atrial tissue. In addition, the apparatus and method may receive data regarding monophasic action potentials, thereby providing information regarding cardiac repolarization. The apparatus and method may provide a pressure sensor in the tip of the catheter so that the proximal electrode may remain in the blood pool and excessive catheter tip pressure does not distort the cellular environment and associated repolarization characteristics. In addition, the apparatus and method can simultaneously detect cardiac repolarization abnormalities and provide therapeutic energy. Moreover, the apparatus and method may reduce the time and labor burden while increasing spatial resolution.

Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. Although methods and materials similar or equivalent to those described herein can be used in the practice of the present invention, suitable methods and materials are described herein. All publications, patent applications, patents, and other references mentioned herein are incorporated by reference in their entirety. In case of conflict, the present specification, including definitions, will control. In addition, the materials, methods, and examples are illustrative only and not intended to be limiting.

The details of one or more embodiments of the invention are set forth in the accompanying drawings and the description below. Other features, objects, and advantages of the invention will be apparent from the description and drawings, and from the claims.

Drawings

Fig. 1 is a schematic view of a mapping catheter according to some embodiments provided herein.

Fig. 2 is a method of measuring and optimizing repolarization times to treat cardiac arrhythmias according to some embodiments provided herein.

Fig. 3 is a method of providing stimulation and determining the end of repolarization according to some embodiments provided herein.

Like reference numerals designate corresponding parts throughout the several views.

Detailed Description

Methods and materials for mapping and modulating repolarization are described herein. For example, this document relates to methods and devices for mapping and modulating repolarization to target atrial and ventricular arrhythmias to deliver electrical stimulation pacing, ablation, and/or electroporation.

Abnormalities in cardiac repolarization, such as abnormalities in spatial heterogeneity and temporal fluctuations, promote abnormal electrophysiological substrates that are intrinsically linked to the occurrence of cardiac arrhythmias, especially sudden cardiac death arrhythmias, ventricular fibrillation and polymorphic ventricular tachycardia. More than half of fatal arrhythmias are related to repolarization abnormalities, such as tosides dePointes, ventricular fibrillation triggered early after depolarization, and various arrhythmias found in congenital and acquired long QT syndrome. While depolarization is a discrete event that can be easily mapped due to the difference in start and end points, repolarization is progressive, which is difficult to map. Repolarization can also occur over longer periods of time, making start and stop times more difficult to determine. Additionally, the frequency and/or amplitude of the repolarization may be similar to electrical noise. Therefore, filtering background noise from the repolarized signal can be problematic.

The devices and methods provided herein may better characterize the electrical properties of the heart, such as for treating cardiac arrhythmias. In addition, the apparatus and method may collect data on monophasic action potentials, thereby providing information on cardiac repolarization. In addition, the apparatus and method can simultaneously detect cardiac repolarization abnormalities and provide therapeutic energy. The apparatus and method may provide feedback electroporation and stimulation based modulation for measuring and optimizing repolarization times to prevent malignant cardiac arrhythmias.

Referring to fig. 1, a mapping catheter 100 is shown. The mapping catheter 100 may include a catheter sheath 102 and a probe 106. In some cases, the probe 106 may include a tip portion 104. In some cases, the probe 106 may include one or more electrodes 108.

The catheter sheath 102 may be used to navigate the mapping catheter 100 into the patient's heart. Thus, the catheter sheath 102 may have sufficient maneuverability. In some cases, the catheter may be used for placement outside the heart. In some cases, the catheter sheath 102 may be inserted into the heart through a percutaneous venous or arterial access. In some cases, the mapping catheter 100 or components thereof may be coupled to an external monitoring system. In some cases, an external monitoring system may provide filtering, signal processing, monitoring, catheter position, and ablation capabilities. In some cases, the external monitoring system may include a pulse generator to generate direct current and/or alternating current stimulation pulses. In some cases, the catheter sheath 102 and/or the stylet 106 can include an internal lumen. In some cases, the internal lumen may provide suction and/or irrigation functions. In some cases, irrigation may be used to improve ablation. In some cases, the internal cavity may be associated with decreased thrombus and/or clotting in and around the ablation site.

The tip portion 104 may be inserted into a portion of the heart. In some cases, the tip portion 104 may be an electrode. In some cases, the tip portion 104 may include an electrode. In some cases, the tip portion 104 may include a plurality of electrodes. Alternatively, the tip portion 104 may be a blunt atraumatic tip that will contact the myocardium but not cause penetration of the myocardium. In some cases, one or more electrodes may be located on or near the tip portion 104. In some cases, the tip portion 104 may be a single spoke (spoke), tine, hook, spiral, or other component capable of piercing (pierce) tissue. In some cases, the tip portion 104 may include an opening that provides access to the lumen of the catheter sheath 102 and/or the probe 106. In some cases, the tip portion 104 may be registered (register) using impedance-based monitoring or electromagnetic field location. In some cases, impedance-based monitoring or electromagnetic field location may be used to determine the location and/or orientation of the mapping catheter 100.

In some cases, the electrode 108 may be located on the free end of the probe (e.g., near the tip portion 104). The electrodes 108 may be linearly spaced along the probe 106. In some cases, the electrodes 108 may be used for data collection. In some cases, electrodes 108 may be used to provide stimulation. In some cases, the electrodes 108 may be unipolar, bipolar, multi-polar, and the like. In some cases, the electrodes 108 may be spaced apart such that sufficient separation is provided for a reference potential and such that the tip portion 104 of the probe 106 is in contact with the endocardial or epicardial surface of the heart. In some cases, the electrode 108 may be spaced apart from the tip portion 104 such that the tip portion 104 may pierce tissue while the electrode 108 remains outside of the tissue.

In some cases, the electrodes 108 may record monophasic action potentials of the heart or other tissue. In some cases, the electrodes 108 may record monopolar and/or bipolar electrograms. In some cases, the electrodes 108 may record simple electrical activity (e.g., cardiac depolarization). In some cases, the electrodes 108 may provide stimulation (e.g., electroporation, ablation, etc.). In some cases, the electrodes 108 may be connected to a multi-channel central terminal via wires for filtering, signal processing, and/or interpretation. In some cases, conductors may be used to transmit signals from the electrodes 108 to a central processing terminal. In some cases, the signal or the processed signal may be displayed on a user interface. In some cases, the signal or processed signal may be displayed for real-time interpretation. In some cases, the signals and the location of the mapping catheter 100 may be combined into an image. In some cases, the images may show cardiac activation and/or repolarization characteristics. In some cases, images may be derived from monophasic action potential recordings.

In some cases, mapping catheter 100 may map cardiac depolarization, cardiac repolarization, and/or provide a stable reference for pressure sensing. In some cases, a constant or substantially constant pressure may be used to prevent or limit damage to heart cells. In addition, a constant or substantially constant pressure may maintain a stable action potential reflection. In some cases, the mapping catheter 100 may include a pressure sensing component and/or a force sensing component. In some cases, pressure and/or force sensing components may be located in the tip portion 104. In some cases, the pressure and/or force sensing component may be an elastic element coupled between the distal tip (e.g., tip portion 104) and the proximal end portion of the mapping catheter 100.

Referring to fig. 2, a method 200 of measuring and optimizing repolarization times to treat cardiac arrhythmias is shown. The method 200 may include: feeding a catheter into the heart at 202; puncturing the heart with an electrode at 204; filtering signals received from the electrodes at 206; delivering a stimulus at 208; calibrating the external signal at 210; delivering electroporation at 212; a repolarization map is created at 214 and variants are determined from normal at 216.

Feeding the catheter into the heart at 202 may include placing the catheter in the heart. In some cases, the catheter may be a mapping catheter 100. In some cases, the catheter may include an external monitoring system. The external monitoring system may be capable of recording at a variable sampling rate. In some cases, the sampling rate may be high (e.g., greater than 5000 Hz). In some cases, the external monitoring system may also include a variable dynamic range for timed recording of repolarization. In some cases, the dynamic range may be large (e.g., 2-20dB, 100 dB, or more). In some cases, the catheter may be capable of recording simultaneous repolarization signals to provide spatial resolution. In some cases, the catheter may record depolarization and repolarization as a single signal.

Piercing the heart with the electrode at 204 may include piercing the heart with the tip portion 104 of the mapping catheter 100. Puncturing the heart with the electrodes at 204 may include obtaining recordings from the electrodes. In some cases, puncturing the heart may result in the rupture of heart cells, which may be recorded using electrodes. In some cases, puncturing the heart can lead to disturbance (dispersion) of cell repolarization, which can be recorded with electrodes. In some cases, puncturing the heart may result in repolarization artifacts that are different from the actual repolarization signal. In some cases, the undisturbed repolarized signal has a different duration than the duration of the disturbed repolarized signal. In some cases, this difference in duration may be predictable, such that the repolarized signal may reflect the normal signal as well as the signal caused by the insertion of the electrode, which may be broken down into different portions. In some cases, the repolarization signal caused by the insertion electrode may be a sudden repolarization.

Filtering the signal received from the electrode at 206 may include reducing and/or removing noise in the signal. In some cases, filtering may help to enhance detection of repolarization changes. In some cases, filtering may enable isolation of important cardiac structure (e.g., purkinje, epicardial, and supravalvular structures) electrical signals. In some cases, vital cardiac structure electrical signals may be isolated separately or from the normal endocardium. In some cases, filtering the signals may include calculating a difference in signals (e.g., electrograms) received from electrodes on the mapping catheter 100. In some cases, the difference may be calculated over multiple electrograms. In some cases, the electrodes may be located on multiple sides of the myocardium, and each signal may be separately filtered. For example, the difference may be calculated on an electrogram tested at wide and narrow filter settings. Filtering the signal may distinguish between myocardial damage caused by cardiac puncture at 204 and an electrogram showing repolarization intervals. In some cases, the signal may be filtered while the derivative is acquired, such that the derivative signal is filtered out, the insertion electrode artifacts are removed and a repolarized signal is obtained. In some cases, the high frequency components may be filtered out. In some cases, high frequency components may be filtered out when acquiring the signal derivative.

Delivering the stimulation at 208 may include delivering a set of stimulation pulses. In some cases, delivering stimulation at 208 may include delivering stimulation via electrodes 108 on the mapping catheter 100. In some cases, delivery of the stimulus may be performed simultaneously with recording. In some cases, stimulation may be delivered on a first subset of electrodes 108, and signals may be recorded on a second subset of electrodes 108. The delivery stimulus at 208 is described in more detail with respect to fig. 3.

The external signal may be calibrated at 210 after the repolarization time is established. In some cases, the external signal may include recordings from an external recording system, intracardiac electrodes, pericardial electrodes, or other electrodes. In some cases, calibrating the external signal may include acquiring a record from an external system in a similar location as the insertion electrode. In some cases, once the area in which the electrodes are inserted is mapped, the surface electrodes may be moved to generate a map of the entire heart. In some cases, calibrating the external signal may include first differentiating the signal. In some cases, calibrating the external signal may include measuring a downhill slope where the baseline intersects the t-wave. In some cases, calibration of external signals may be used to verify non-invasive recordings and/or other intracardiac recordings. In some cases, calibrating the external signal may help limit the number of locations for deploying the insertion electrode. In some cases, once the insertion electrode and the surface electrode (or other electrodes) are calibrated, the surface electrode may be moved and used to determine a map of the heart without moving the insertion electrode.

Delivering electroporation at 212 may include delivering an electric field pulse across the cell. In some cases, the electric field pulse may comprise a short (e.g., microsecond) pulse. In some cases, the electric field pulse may comprise a high intensity pulse. In some cases, electroporation may be delivered such that irreversible defects (pores) occur in the lipid layer of the cell membrane. In some cases, irreversible electroporation can result in loss of cellular homeostasis, resulting in cell death by apoptosis. By delivering irreversible electroporation using electrical stimulation, the acellular tissue structure may be left unaffected, thereby limiting significant damage to the cardiac tissue surrounding the location of the electroporation. In some cases, delivering electroporation can include delivering electroporation that is reversible. In some cases, reversible electroporation can alter transmembrane current in order to affect repolarization and depolarization intervals. In some cases, reversible electroporation can cause predictable effects in repolarization and depolarization. In some cases, hyperpolarization may be caused by electroporation at varying coupling intervals. Thus, as additional titrations (titrations) of reversible electroporation are delivered, a predictable effect on repolarization may be detected until an irreversible electroporation dose is reached. In some cases, electroporation may be delivered at low voltages (e.g., 10 to 2000mV) and long pulse durations (e.g., 0.5 to 1 second). In some cases, electroporation may be delivered at a high voltage (e.g., 10 to 50V) and a short pulse duration (e.g., 0.001 milliseconds).

Creating a repolarization map at 214 may include creating a single repolarization map or multiple repolarization maps. In some cases, creating the repolarization map may include creating a three-dimensional drawing image. In some cases, three-dimensional maps may be created by magnet-assisted navigation and point acquisition. In some cases, the three-dimensional transmural repolarization map may be superimposed with depolarization map(s) acquired simultaneously. In some cases, the three-dimensional transmural repolarization map may be displayed separately from the depolarization map(s) acquired at the same time.

Determining variants from normal at 216 may include using a repolarization map and/or a depolarization map to determine points of variants and pathology from normal. In some cases, the three-dimensional repolarization map may be compared to a template for normal and/or desired timing of depolarization sequences. In some cases, after determining the point of variant and pathology from normal, electroporation can be delivered to the site of pathology (e.g., as described with respect to step 212). In some cases, recorded repolarization times can be used to titrate electroporation in real time. In some cases, the electroporation may be titrated so that the delivered energy may be increased to an irreversible dose. In some cases, if a beneficial effect has occurred, electroporation can be stopped before an irreversible dose is reached. In some cases, the beneficial effect may include a change toward the normal mode detected via comparison to the template plot.

In some cases, method 300 may also include changing the heart rate. In some cases, changing the heart rate may include providing a stimulus to the heart to modify the heart rate. In some cases, varying the heart rate may vary the repolarization signal. In some cases, by varying the heart rate, the pattern created by the insertion electrodes may saturate. In some cases, the heart rate may be varied, and repolarization may be mapped for multiple heart rates. In some cases, if repolarization shows similar activity in multiple repolarization plots, it may be determined that these plots do show repolarization. In some cases, if repolarization does not show similar activity across multiple repolarization graphs, a new repolarization reference point may be selected to create a repolarization graph.

Referring to fig. 3, a method 300 of providing stimulation and determining the end of repolarization is shown. Method 300 may include delivering a first set of stimuli at 302, increasing the stimulus intensity at 304, determining capture at 306, decreasing the stimulus and changing the stimulus interval at 308, and determining the end of repolarization at 310. Some or all of method 300 may be used to deliver stimulation at 208 of method 200.

Delivering the first set of stimuli at 302 may include delivering subthreshold stimuli. In some cases, the first set of stimuli has an amplitude below a threshold. In some cases, the first set of stimuli has an intensity below a threshold. In some cases, the first set of stimuli may include stimulation pulses. In some cases, a first set of stimuli may be delivered via a first set of electrodes, while the resulting signals may be received from a second set of electrodes. In some cases, subthreshold stimulation may result in a smaller post potential (e.g., in monophasic signals). In some cases, the post-potential may be caused by stimulation when the refractory period of the heart ends. In some cases, the sub-threshold stimulation may generate a post-potential when the repolarization time has expired.

Increasing the stimulation intensity at 304 may include increasing a parameter of the stimulation. In some cases, increasing the stimulus intensity may include increasing the amplitude of the stimulus. In some cases, increasing the intensity of the stimulus may include increasing the intensity of the stimulus until a threshold is exceeded. In some cases, the stimulation intensity may be increased until capture is obtained. In some cases, capture may be used to determine whether the insertion electrode is located at a position sufficient to determine the end of repolarization. In some cases, the supra-threshold stimulus may produce a second action potential, but the second action potential will not be produced within the true refractory period.

Determining capture at 306 may include determining that capture is obtained when the stimulation intensity exceeds a threshold. Optionally, determining capture may include determining when a signal responsive to the stimulus exceeds a threshold. In some cases, steps 302-306 may be repeated at various depths of the myocardium. In some cases, steps 302-306 may be repeated at various heights of the myocardium.

Reducing the stimulus and varying the stimulus interval at 308 can include reducing a stimulus intensity of the stimulus. In some cases, reducing the stimulus intensity may include reducing the amplitude of the stimulus. In some cases, varying the stimulation interval may include decreasing the time interval between stimulation pulses. In some cases, changing the stimulation interval may include modifying the time interval between stimulation pulses until no post-potential is detected. In some cases, the system can confirm that the repolarized signal is not filtered out of the signal by modifying the time interval and checking for the post-potential or lack of post-potential.

Determining the end of repolarization at 310 may include: when no back potential is detected, the end of repolarization is determined. In some cases, determining the end of repolarization may be used as a reference to create a repolarization map. In some cases, other reference points may be detected. For example, a starting point, a middle point, or other reference point may be used as a reference point for repolarization. In some cases, the repolarization map(s) may be based on other reference points. In some cases, various reference points may be determined and compared to determine which reference point or points are more relevant to creating the repolarization map. After determining the end of the repolarization or determining another reference point at 310, the signal may be calibrated as described in step 210 of method 200, as described with respect to fig. 2.

In some cases, the methods 200 and 300 may be used with other electrode configurations. In some cases, the electrode configuration may include a multi-electrode basket. In some cases, the multi-electrode basket may be deployed in the pericardial space or within the heart. In some cases, the multi-electrode basket may include nanoscale electrodes. In some cases, the multi-electrode basket may include a stretched and/or conductive graphene or graphene-like material. In some cases, the electrodes used to perform method 200 and/or method 300 may be located in an extracardiac structure. In some cases, extra-cardiac structures may include gastrointestinal tract, bronchial smooth muscle, electrical activity of the skin, neural and brain activity of the peripheral autonomic and central nervous systems, and the like.

While this specification contains many specific implementation details, these should not be construed as limitations on the scope of any inventions or of what may be claimed, but rather as descriptions of features specific to particular embodiments of particular inventions. Certain features that are described in this specification in the context of separate embodiments can also be implemented in combination in a single embodiment. Conversely, various features that are described in the context of a single embodiment can also be implemented in multiple embodiments separately or in any suitable subcombination. Moreover, although features may be described herein as acting in certain combinations and even initially claimed as such, one or more features from a claimed combination can in some cases be excised from the combination, and the claimed combination may be directed to a subcombination or variation of a subcombination.

Similarly, while operations are depicted in the drawings in a particular order, this should not be understood as requiring that such operations be performed in the particular order shown or in sequential order, or that all illustrated operations be performed, to achieve desirable results. In some cases, multitasking and parallel processing may be advantageous. Moreover, the separation of various system modules and components in the embodiments described herein should not be understood as requiring such separation in all embodiments, and it should be understood that the described program components and systems can generally be integrated together in a single product or packaged into multiple products.

Specific embodiments of the present subject matter have been described. Other embodiments are within the scope of the following claims. For example, the actions recited in the claims can be performed in a different order and still achieve desirable results. As one example, the processes depicted in the accompanying figures do not necessarily require the particular order shown, or sequential order, to achieve desirable results. In some implementations, multitasking and parallel processing may be advantageous.