Systems, apparatus, and methods for delivering ablation energy to tissue.

Abstract

The system includes a pulse waveform generator and an ablation device coupled to the pulse waveform generator. The ablation device includes at least one electrode configured to deliver ablation pulses to tissue during use. The pulse waveform generator is configured to deliver voltage pulses to the ablation device in the form of a pulse waveform. The pulse waveform can include multiple levels of hierarchy, and multiple sets of electrodes can be operated to interleave pulse delivery with one another. [Selection diagram] Figure 14

Description

[Technical Field]

[0001] Cross-reference of related applications This application claims the benefits of U.S. Provisional Application No. 62 / 733,968, filed September 20, 2018, entitled "SYSTEMS, APPARATUSES AND METHODS FOR DELIVERY OF ABLATIVE ENERGY TO TISSUE," and U.S. Provisional Application No. 62 / 667,950, filed May 7, 2018, entitled "SYSTEMS, APPARATUSES AND METHODS FOR DELIVERY OF ABLATIVE ENERGY TO TISSUE." This application also relates to U.S. Patent Application No. 15 / 796,375, filed October 27, 2017, entitled "SYSTEMS, APPARATUSES AND METHODS FOR DELIVERY OF ABLATIVE ENERGY TO TISSUE," which claims priority to U.S. Provisional Application No. 62 / 274,926, filed January 5, 2016, entitled "METHOD AND APPARATUS FOR DELIVERY OF PULSED ELECTRIC FIELD ABLATIVE ENERGY TO TISSUE," and is a continuation application of PCT Application No. PCT / US2016 / 057664, filed October 19, 2016, entitled "SYSTEMS, APPARATUSES AND METHODS FOR DELIVERY OF ABLATIVE ENERGY TO TISSUE." This is a divisional application of U.S. Patent Application No. 15 / 334,646, filed on October 26, 2016, entitled “ENERGY TO TISSUE.” The entire disclosures of each of the aforementioned applications are incorporated by reference. [Background technology]

[0002] While the generation of pulsed electric fields for tissue therapy has progressed from laboratory research to clinical applications in the last 20 years, the effects of short pulses of high voltage and high electric field on tissues have been investigated for over 40 years. Applying short, high DC voltages to tissue, which can generate locally high electric fields typically in the range of several hundred volts per centimeter, can disrupt cell membranes by creating pores within them. Although the exact mechanism of this electrically driven pore generation, or electroporation, is not clear, it is thought that the application of a relatively high electric field creates instability in the lipid bilayer of the cell membrane, resulting in the distribution of localized gaps or pores within the membrane. If the electric field applied to the membrane is greater than the threshold, electroporation can be irreversible, leaving the pores open and allowing for the exchange of biomolecular materials throughout the membrane, leading to necrosis and / or apoptosis (cell death). Subsequently, the surrounding tissue heals through natural processes.

[0003] Therefore, known methods of electroporation application and delivery in medicine do not address the requirements for high voltage application, electrode sequencing, tissue selectivity, and safe energy delivery, particularly in the context of ablation therapy for arrhythmias using catheter devices. Furthermore, there is an unmet need for thin, flexible, non-invasive devices that can selectively and effectively deliver high DC voltage electroporation ablation therapy to tissues within the region of interest while minimizing damage to healthy tissue, as well as for combinations of device design and delivery waveforms that enable effective, safe, and rapid clinical procedures, involving minimal or no device repositioning. [Overview of the Initiative]

[0004] This specification describes systems, devices, and methods for ablating tissue by irreversible electroporation. In some embodiments, the system may include an ablation device comprising a plurality of electrodes configured to generate an electric field for ablating a target, for example, tissue within the structure of the heart. A pulse waveform generator may be coupled to the ablation device and configured to deliver voltage pulses to the ablation device in the form of a pulse waveform. The pulse waveform comprises a first level of the pulse waveform hierarchy, which comprises a first set of pulses and a first time delay separating consecutive pulses of the first set of pulses, where each pulse in the first set of pulses may have a pulse duration. A second level of the hierarchy comprises a plurality of first sets of pulses as a second set of pulses and a second time delay separating consecutive first sets of pulses from the plurality of first sets of pulses, where each second time delay may be at least three times the duration of the first time delay. The third level of the hierarchy includes a third set of pulses consisting of multiple second sets of pulses and a third time delay that separates consecutive second sets of pulses from the multiple second sets of pulses, where each third time delay may be at least 30 times the duration of the second time delay. The fourth level of the hierarchy includes a fourth set of pulses consisting of multiple third sets of pulses and a fourth time delay that separates consecutive third sets of pulses from the multiple third sets of pulses, where each fourth time delay may be at least 10 times the duration of the third time delay.

[0005] In some embodiments, each pulse in each first set of pulses comprises a two-phase pulse, each having a voltage amplitude of at least 500 volts, and the pulse duration of each two-phase pulse ranges from about 0.5 nanoseconds to about 20 microseconds. In some embodiments, a fourth set of pulses may comprise at least two third sets of pulses and fewer than 40 third sets of pulses. In some embodiments, each fourth time delay may have a constant duration. In some embodiments, the duration of the fourth time delay varies. In some of these embodiments, the fourth time delay comprises at least one repeat value of the time delay. In some of these embodiments, each fourth time delay has a duration ranging from at least 10 times the duration of the third time delay to less than 1000 times the duration of the third time delay. In some embodiments, the duration of each fourth time delay may be greater than the cardiac cycle.

[0006] In some embodiments, the pulse waveform further includes a fifth level of hierarchy, which includes a plurality of fourth sets of pulses as a fifth set of pulses, and a fifth time delay that separates consecutive fourth sets of pulses from the plurality of fourth sets of pulses, each fifth time delay being at least 10 times the duration of at least one of the fourth time intervals. In some embodiments, the pulse waveform generator is configured to deliver voltage pulses in the form of pulse waveforms in sync with the cardiac cycle, such that consecutive second sets of pulses from a plurality of second sets of pulses are delivered during the refractory period of a separate cardiac cycle, and the delivery frame of the fourth set of pulses may extend over multiple cardiac cycles. In some of these embodiments, each second set of pulses includes at least two first sets of pulses and fewer than 40 first sets of pulses. In some of these embodiments, the cardiac stimulator may be configured to generate a pacing signal to control the timing of the cardiac cycle. In some embodiments, the pulse waveform generator is further configured to deliver voltage pulses to multiple electrode sets of the ablation device, and the voltage pulse delivered to the first electrode set may be delayed by a certain amount of time from the voltage pulse delivery to the second electrode set.

[0007] In some embodiments, the system may include an ablation device comprising a plurality of electrodes configured to generate an electric field for ablation of tissue within a target. A pulse waveform generator may be coupled to the ablation device. The pulse waveform generator may be configured to deliver voltage pulses to the ablation device in the form of a pulse waveform by interleaving voltage pulses delivered across a plurality of electrode sets. The pulse waveform includes a first level of the pulse waveform hierarchy, comprising a first set of pulses and a first time delay that separates consecutive pulses of the first set of pulses, wherein each pulse in the first set of pulses may have a pulse duration. A second level of the hierarchy includes a plurality of first sets of pulses as a second set of pulses and a second time delay that separates consecutive first sets of pulses from the plurality of first sets of pulses, wherein each second time delay may be at least three times the duration of the first time delay. The third level of the hierarchy includes a third set of pulses, which consists of a plurality of second sets of pulses, and a third time delay that separates consecutive second sets of pulses from the plurality of second sets of pulses, where each third time delay may be at least 30 times the duration of the time delay of the second level.

[0008] In some embodiments, each pulse in each first set of pulses comprises a two-phase pulse having a voltage amplitude of at least 500 volts, and the pulse duration of each two-phase pulse ranges from about 0.5 nanoseconds to about 20 microseconds.

[0009] In some embodiments, the pulse waveform generator may be configured to deliver voltage pulses by delivering voltage pulses to a first electrode set of a plurality of electrode sets with a time delay from the delivery of voltage pulses to a second electrode set of a plurality of electrode sets. In some of these embodiments, the time delay between the delivery of voltage pulses to the first electrode set and the delivery of voltage pulses to the second electrode set may be less than the duration of the second time delay, such that a first set of consecutive pulses delivered to the second electrode set follows a first set of consecutive pulses delivered to the first electrode set. In some of these embodiments, the time delay between the delivery of voltage pulses to the first electrode set and the delivery of voltage pulses to the second electrode set may be less than about 55 percent of the duration of the second time delay.

[0010] In some embodiments, the pulse waveform generator may be configured to deliver voltage pulses in sync with the cardiac cycle, so that a second set of pulses from a plurality of second sets of pulses is delivered to a given electrode set during the refractory period of a separate cardiac cycle, and a second set of pulses is delivered to at least two of the plurality of electrode sets during a single refractory period. In some of these embodiments, the cardiac stimulator may be configured to generate a pacing signal to control the timing of the cardiac cycle.

[0011] In some embodiments, the method comprises generating voltage pulses in the form of pulse waveforms, wherein the pulse waveform is a first level of a hierarchy of pulse waveforms, comprising a first set of pulses and a first time delay separating consecutive pulses of the first set of pulses, each pulse of the first set of pulses having a pulse duration, and a second level of a hierarchy comprising a plurality of first sets of pulses as a second set of pulses and a second time delay separating consecutive first sets of pulses from the plurality of first sets of pulses, each second time delay having a duration of at least three times that of the first time delay. The method may further include a second level and a fourth level, the third level of the hierarchy which includes a third set of pulses, a third set of pulses, and a third time delay that separates consecutive sets of pulses from the multiple sets of pulses, each third time delay being at least 30 times the duration of the time delay of the second level, and a fourth level of the hierarchy which includes a fourth set of pulses, a fourth time delay that separates consecutive sets of pulses from the multiple sets of pulses, each fourth time delay being at least 10 times the duration of the third time delay.

[0012] In some embodiments, the fourth set of pulses may include at least two third sets of pulses and fewer than 40 third sets of pulses. In some embodiments, the duration of the fourth time delay may vary, with each fourth time delay having a duration ranging from at least 10 times the duration of the third time delay to less than 1000 times the duration of the third time delay.

[0013] In some embodiments, the method may further include generating a set of pacing signals in a cardiac stimulator and delivering the set of pacing signals to the heart. Voltage pulses are delivered in sync with the set of pacing signals such that each second set of pulses of a plurality of second sets of pulses is delivered during the refractory period associated with each pacing signal in the set of pacing signals, and the delivery frame of a fourth set of pulses may span multiple cardiac cycles of the heart.

[0014] In some of these embodiments, the duration of each fourth time delay may be greater than a certain time that separates the successful pacing signal from the set of pacing signals. In some embodiments, the pulse waveform further includes a fifth level of hierarchy which includes a plurality of fourth sets of pulses as a fifth set of pulses, and a fifth time delay which separates the consecutive fourth sets of pulses from the plurality of fourth sets of pulses, and each fifth time delay may be a duration of at least 10 times one of the fourth time intervals.

[0015] In some embodiments, the method comprises generating voltage pulses in the form of a pulse waveform, the pulse waveform being at a first level of a hierarchy of pulse waveforms comprising a first set of pulses and a first time delay separating consecutive pulses in the first set of pulses, wherein each pulse in the first set of pulses has a pulse duration; a second level of the hierarchy comprising a plurality of first sets of pulses as a second set of pulses, and a second time delay separating consecutive first sets of pulses in the plurality of first sets of pulses, wherein each second time delay has a duration of at least three times that of the first time delay; and a third level of the hierarchy comprising a plurality of second sets of pulses as a third set of pulses, and a third time delay separating consecutive second sets of pulses in the plurality of second sets of pulses, wherein each third time delay has a duration of at least thirty times that of the second level time delay. The method may further comprise delivering voltage pulses to a plurality of electrode sets of an ablation device by interleaving voltage pulses delivered to at least two of the electrode sets of the plurality of electrode sets such that the one or more electrode sets generate a pulsed electric field to ablate tissue in a subject.

[0016] In some embodiments, a voltage pulse may be delivered to a first electrode set of the at least two electrode sets offset by a period of time from delivery of a voltage pulse to a second electrode set of the at least two electrode sets. In some embodiments, the period of time offsetting delivery of the voltage pulse to the first electrode set from delivery of the voltage pulse to the second electrode set may be less than about 55 percent of a duration of the second time delay.

[0017] In some embodiments, the method may further comprise generating a set of pacing signals with a cardiac stimulation device, and delivering the set of pacing signals to the heart. Voltage pulses delivered in synchrony with the set of pacing signals may be configured such that each second set of pulses of the plurality of second sets of pulses is delivered during a refractory period associated with a separate pacing signal of the set of pacing signals, and a second set of pulses delivered to at least two electrode sets among the plurality of electrode sets may be delivered during a single refractory period. BRIEF DESCRIPTION OF THE DRAWINGS

[0018] [Figure 1] FIG. 1 is a schematic view of a catheter, according to an embodiment, having a plurality of electrodes arranged along a distal shaft and placed epicardially to tightly wrap around the pulmonary vein of a cardiac structure. [Figure 2] FIG. 2 is an exemplary waveform showing successive voltage pulses with a defined pulse width for each pulse, according to an embodiment. [Figure 3] FIG. 3 schematically illustrates a hierarchy of pulses, showing pulse width, inter-pulse intervals, and grouping of pulses, according to an embodiment. [Figure 4] FIG. 4 provides a schematic diagram of a nested hierarchy of monophasic pulses, showing different levels of the nested hierarchy, according to an embodiment. [Figure 5] FIG. 5 is a schematic diagram of a nested hierarchy of biphasic pulses, showing different levels of the nested hierarchy, according to an embodiment. [Figure 6] FIG. 6 schematically shows a circle of numbered catheter electrodes according to an embodiment, wherein the set of electrodes can be sequentially selected for application of voltage pulse waveforms in a corresponding order. [Figure 7] FIG. 7 schematically illustrates a time series of an electrocardiogram and cardiac pacing signals together with atrial and ventricular refractory periods, showing the time frame of irreversible electroporation ablation, according to an embodiment. [Figure 8]Figure 8 schematically shows the time series of electrode set operation, which, according to the embodiment, is delivered as a series of waveform packets over a corresponding series of consecutive heartbeats. [Figure 9] Figure 9 is a schematic diagram of an irreversible electroporation system according to an embodiment, including a system console, which includes a voltage / signal generator, a controller configured to apply voltage to a subset of selected electrodes and communicated with a computer or processor along with a user interface, and a switching unit configured to electrically isolate other equipment from voltage pulses that may be delivered from the voltage generator to the ablation catheter. [Figure 10] Figure 10 is a schematic diagram of the user interface in its initial configuration according to an embodiment. [Figure 11] Figure 11 is a schematic diagram of the user interface showing the engagement of the initialization function according to the embodiment. [Figure 12] Figure 12 is a schematic diagram of the user interface showing the steps required after initialization according to an embodiment. [Figure 13] Figure 13 is a schematic diagram of the user interface showing a configuration in which the system is ready for ablation energy delivery after the previous step has been completed. In this configuration, depending on the embodiment, the user interface includes a button for ablation. [Figure 14] Figure 14 schematically shows the pulse hierarchy according to the embodiment, illustrating the pulse width, the interval between pulses, and the grouping of pulses. [Figure 15] Figure 15 schematically shows the pulse hierarchy according to the embodiment, illustrating the pulse width, the interval between pulses, and the grouping of pulses relative to the electrode pair. [Figure 16] Figure 16 schematically shows the pulse groups and the time delay between pulse groups relative to the electrode pair according to the embodiment. [Figure 17] Figure 17 schematically shows a group of interleaved pulses from two electrode sets of a two-element small group electrode set according to an embodiment. [Figure 18] Figure 18 schematically shows an ablation energy delivery sequence delivered throughout the heartbeat, according to an embodiment. [Figure 19] Figure 19 schematically shows the pulse hierarchy according to the embodiment, illustrating the pulse width, the interval between pulses, and the grouping of pulses relative to the electrode pair. [Modes for carrying out the invention]

[0019] This specification describes systems, devices, and methods for ablating tissue by irreversible electroporation. Generally, a system for delivering pulse waveforms to tissue may include a pulse waveform generator and an ablation device coupled to the pulse waveform generator. The ablation device may include at least two electrodes configured to deliver ablation pulses to tissue during use. The pulse waveform generator may be configured to deliver voltage pulses to the ablation device in the form of pulse waveforms.

[0020] Pulse waveforms for electroporation energy delivery, such as those disclosed herein, can enhance the safety, efficiency, and effectiveness of energy delivery to tissue by lowering the electric field threshold associated with irreversible electroporation, and thus, along with a reduction in the total energy delivered, can result in more effective ablation damage. In some embodiments, the voltage pulse waveforms disclosed herein may be hierarchical and have a nested structure. For example, the pulse waveform may include a hierarchical group of pulses having a relevant time scale. In some embodiments, the methods, systems, and devices disclosed herein may include one or more of the methods, systems, and devices described in one or more of the International Patent Application No. PCT / US2016 / 057664 filed October 19, 2016, U.S. Patent Application No. 15 / 334,646 filed October 26, 2016, and U.S. Patent Application No. 15 / 796,375 filed October 27, 2017, which are referenced and incorporated above.

[0021] In some embodiments, the system includes a pulse waveform generator and an ablation device coupled to the pulse waveform generator. The ablation device includes at least one electrode configured to deliver ablation pulses to tissue during use. The pulse waveform generator is configured to deliver voltage pulses to the ablation device in the form of pulse waveforms. A first level of the pulse waveform hierarchy applied to a given electrode includes a first set of pulses, each pulse having a pulse duration and a first time interval (i.e., a first time delay) separating consecutive pulses. A second level of the pulse waveform hierarchy includes, as a second set of pulses, a plurality of first sets of pulses and a second time interval (i.e., a second time delay) separating consecutive first sets of pulses, where the second time interval is at least three times the duration of the first time interval. The third level of the pulse waveform hierarchy includes, as a third set of pulses, multiple second sets of pulses and a third time interval (i.e., a third time delay) separating consecutive second sets of pulses, where the third time interval is at least 30 times the length of the second time interval. The fourth level of the pulse waveform hierarchy includes, as a fourth set of pulses, multiple third sets of pulses and a fourth time interval (i.e., a fourth time delay) separating consecutive third sets of pulses, where the fourth time interval is at least 10 times the length of the third time interval.

[0022] In some embodiments, the system includes single-phase pulses, where each pulse in a first set has a pulse duration ranging from about 1 microsecond to about 300 microseconds. In some embodiments, the system includes two-phase pulses, where each pulse in a first set has a pulse duration ranging from about 0.5 nanoseconds to about 20 microseconds. In some embodiments, the second time interval is at least 10 times the pulse duration. In some embodiments, the third time interval is in the range of about several hundred milliseconds or a few tenths of a second. In some embodiments, the fourth time interval is in the range of about a few seconds to about a few minutes. In some embodiments, the fourth time interval may vary or not be constant across a series of third sets of pulses. In some embodiments, the fourth time interval may, lastly, include a repeating value of one time delay.

[0023] In some embodiments, each second set of pulses includes at least two first sets of pulses and fewer than 40 first sets of pulses. In some embodiments, each third set of pulses includes at least two second sets of pulses and fewer than 30 second sets of pulses. In some embodiments, each fourth set of pulses includes at least two third sets of pulses and fewer than 40 third sets of pulses.

[0024] In some embodiments, the pulse waveform includes a fifth level of hierarchy, where the pulse waveform includes a plurality of fourth sets of pulses as a fifth set of pulses, and a fifth time interval separating consecutive fourth sets of pulses. In some embodiments, each fifth set of pulses includes approximately 50 fourth sets of pulses, ranging from at least one fourth set of pulses.

[0025] By using an ordered set of electrode pairs, the efficiency and / or rate of energy delivery during the heartbeat may be increased through electroporation energy delivery. This may be useful in completing the delivery of ablation energy within a given time period (e.g., within a heartbeat, a refractory frame of a cardiac chamber, and / or similar). For example, ablation delivery may be completed within time frames of less than about 100 ms, less than about 150 ms, less than about 200 ms, and less than about 250 ms in various embodiments.

[0026] In some embodiments, ablation energy delivery may be performed as sequential delivery of pulses using different sets of electrode pairs over a predetermined number of consecutive or separate heartbeats. In particular, ablation delivery may be ordered using sets of electrode pairs. For example, one or more groups of pulses may be delivered in consecutive electrode pairs with group delays between consecutive groups of pulses for each electrode pair. In some of these embodiments, each electrode pair may include a set of cathodes and a paired set of anodes. Thus, energy delivery may be interleaved across multiple sets of electrode pairs over one or more heartbeats. During the group delay associated with a first set of paired electrodes, one or more groups of pulses may be delivered using a second set of paired electrodes.

[0027] In some embodiments, a first level of the pulse waveform hierarchy applied to a given electrode includes a first set of pulses, each pulse having a pulse duration and a first time interval separating consecutive pulses. A second level of the pulse waveform hierarchy may include, as a second set of pulses, a plurality of first sets of pulses and a second time interval separating consecutive first sets of pulses. The second time interval may be at least three times the length of the first time interval. A third level of the pulse waveform hierarchy may include, as a third set of pulses, a plurality of second sets of pulses. Consecutive second sets of pulses may be separated by a third time interval. The third time interval may be at least 30 times the length of the second time interval. A fourth level of the pulse waveform hierarchy may include, as a fourth set of pulses, a plurality of third sets of pulses. Consecutive fourth sets of pulses may be separated by a fourth time interval. The fourth time interval may be at least 10 times the length of the third time interval.

[0028] The pulse waveforms for electroporation energy delivery disclosed herein can enhance the safety, efficiency, and effectiveness of energy delivery by lowering the electric field threshold associated with irreversible electroporation, resulting in more effective ablation damage while delivering a reduced total energy. This can broaden the scope of clinical applications of electroporation, including the therapeutic treatment of various arrhythmias.

[0029] This disclosure addresses the need for devices and methods for rapid, selective, and safe delivery of irreversible electroperforation therapy, generally using multiple devices, which in some embodiments can reduce and / or minimize peak electric field values ​​while simultaneously maintaining a sufficiently high electric field intensity in the area where tissue ablation is desired. This also reduces the possibility of excessive tissue damage or the generation of electric arc discharge and localized temperature increases.

[0030] When used herein in relation to reference numerical indicators, the terms “approximately” and “about” mean a reference numerical indicator that is up to 10% plus or minus that indicator. For example, the phrase “approximately 50” units or “about 50” units means from 45 units to 55 units. As used herein, the term “electroporation” refers to the application of an electric field to a cell membrane that alters the permeability of the cell membrane to the extracellular environment. As used herein, the term “reversible electroporation” refers to the application of an electric field to a cell membrane that temporarily alters the permeability of the cell membrane to the extracellular environment. For example, when a cell undergoes reversible electroporation, the temporary and / or intermittent formation of one or more pores is observed in the cell membrane, which close when the electric field is removed. As used herein, the term “irreversible electroporation” refers to the application of an electric field to a cell membrane that permanently alters the permeability of the cell membrane to the extracellular environment. For example, when a cell undergoes irreversible electroporation, the formation of one or more pores is observed in the cell membrane, which persist even after the electric field is removed. overview

[0031] Figure 1 is a schematic diagram of a catheter 15 having multiple electrodes arranged along its shaft. Figure 1 shows the catheter in relation to the heart 7, and the catheter 15 has electrodes, indicated by dark bands (such as the band indicated by reference letter 17 in Figure 1), that wrap around the pulmonary veins of the left atrium epicardally, and / or loop around the pulmonary veins 10, 11, 12, 13 of the left atrium, and / or around their contours, indicated by reference letters 10, 11, 12, and 13 (upper left, lower left, upper right, and lower right in Figure 1, respectively). In some embodiment, the catheter ends 8 and 9 are held together inside a tool (not shown) that is tightly pulled and secured to ensure that the catheter electrodes wrap tightly around the pulmonary veins 10, 11, 12, 13. A method and apparatus using a subxiphoid pericardial access site and a guidewire delivery method to achieve placement of a multi-electrode ablation catheter around a pulmonary vein is described in PCT publication International Publication No. 2014 / 025394, entitled "Catheters, Catheter Systems and Methods for Puncturing Through a Tissue Structure and Ablating a Tissue Region," the entire disclosure of which is incorporated herein by reference.

[0032] In some embodiments, the catheter electrodes 17 can be constructed in the form of metal strips or rings. In some embodiments, each electrode 17 can be constructed to be flexible. For example, the electrodes 17 can be in the form of a metal coil spring or helical winding around the shaft of the catheter 15. In another example, the electrodes 17 may be in the form of a series of metal strips or rings arranged along the shaft and electrically connected together, with the flexible portion of the catheter shaft between the electrodes providing flexibility to the electrodes as a whole. In some embodiments, at least a portion of the electrodes 17 may include a biocompatible metal such as titanium, palladium, silver, platinum, and / or platinum alloys, but are not limited to this. In some embodiments, at least a portion of the electrodes 17 may include platinum and / or platinum alloys. In some embodiments, the catheter shaft may consist of a flexible polymer material such as polytetrafluoroethylene, a polyamide such as nylon, or a polyether block amide (for the purposes of non-limiting examples only). The electrode 17 can be connected to an insulated lead (not shown) leading to the proximal handle portion (not shown) of the catheter 15, and the insulation on each lead allows a potential difference of at least 700V across its thickness to be maintained without induced breakdown. Although the catheter 15 is placed epicardally, i.e., below the pericardium, as shown in Figure 1, in alternative embodiments, an ablation catheter may be useful for additional or alternative placement in the endocardium.

[0033] The specific ablation devices and other examples provided herein are described for illustrative purposes only and it should be understood that various other ablation devices configured for use in various tissue types and biostructures may benefit from the use of the waveforms described herein without departing from the scope of the present invention. Electrode Ordering

[0034] Described herein are systems, devices, and methods for delivering electroporation energy using ordered sets of electrode pairs that incorporate time delays and interleave across multiple sets of electrode pairs during one or more heartbeats. In some embodiments, each electrode pair may include a set of cathodes and a paired set of anodes. As will be described in more detail herein, during a group delay following a group of pulses associated with a first set of paired electrodes, a group of pulses associated with at least a second set of paired electrodes may be delivered to interleave the group of pulses being delivered. This sequential delivery of pulses may occur across multiple sets of electrode pairs during each heartbeat between a predetermined number of consecutive or separate heartbeats. In particular, for each electrode pair, multiple groups of pulses may be delivered with group delays between consecutive groups of pulses.

[0035] Ablation energy may be delivered over a predetermined number of heartbeats using any of the ablation systems and devices described herein. In some embodiments, a set of m electrode pairs may be selected to deliver a set of pulses in a predetermined electrode pair order. The m electrode pairs may be divided into n subgroups. At least one of the n subgroups may include two or more sets of anode-cathode electrode pairs.

[0036] At a minimum, a small group corresponds to an anode-cathode pair of electrode subsets. However, a small group generally refers to a set of multiple electrode pairs (each pair accompanied by an anode-cathode electrode subset). For example, the first electrode pair of cathodes c1 and c2 and anode a1 may be represented by the notation (a1-(c1,c2)), which defines a pair of electrode subsets. A single pair of such electrode subsets may define a small group on its own. More broadly, a small group may contain multiple such pairs of electrode subsets. One useful embodiment or structure of a small group is one containing two pairs of electrode subsets. Assuming m pairs of electrode subsets in a sequence of such pairs, if m is even, these m pairs may be divided into m / 2 small groups, each containing two pairs of electrode subsets. If m is odd, one of the small groups will contain a single pair of electrode subsets, and the other small group will contain two pairs of electrode subsets.

[0037] In another example, the order of electrode pairs for the first heartbeat may include the following three electrode pairs (a1-(c1,c2)), (a2-(c2,c3)), and (a3-(c3,c4)), where the first subgroup includes the first and second electrode pairs (a1-(c1,c2)) and (a2-(c2,c3)), and the second subgroup includes the third electrode pair (a3-(c3,c4)).

[0038] A set of electrode pairs may deliver multiple groups of pulses, with a time group delay between consecutive groups of pulses. In some applications, the time group delay may be relatively long (e.g., several hundred or several thousand microseconds), and this delay may be significantly longer than the duration of a single group of pulses. However, during the time group delay period for the first electrode pair, the group of pulses may be delivered using a second electrode pair to interleave groups of pulses from different electrode pairs.

[0039] Figure 15 shows the time group delay 1531 (length t). dThis shows p groups of pulses, including a packet 1551 for a single electrode pair, each with a group of pulses 1523, 1543 separated by ). A set of two-phase pulses 1505 may form a first group of pulses 1523. A second group of pulses 1543 is also shown, with p groups of such pulses in a packet 1551 corresponding to a given electrode pair in one heartbeat. Although this example illustrates two-phase pulses, single-phase pulses may also be used in some embodiments. Consecutive two-phase pulses 1505 may be separated by a first level time interval 1512. Consecutive groups of pulses 1523 may be separated by a second level time interval 1531 (e.g., a group delay of time). In some embodiments, the length of the second level time interval 1531 may be at least three times the length of the first level time interval 1512. Some packets 1551, 1571 of pulses may form a third level structure or third level set (i.e., a superpacket) of pulses. The consecutive pulse packets 1551, 1571 may be separated by a third level time interval 1561. In some embodiments, the length of the third level time interval 1561 may be at least 30 times the length of the second level time interval 1531.

[0040] Figure 16 shows sets of pulse groups 1603 and 1607, and a time delay 1611 between the pulse groups. In particular, the first group of pulses 1603 and the second group of pulses 1607 have a duration or length t d The group delays are separated by a time interval 1611. In the interleaved (e.g., multiplexed) ordering scheme disclosed herein, a group of pulses from a second electrode pair set may be interleaved with a group of pulses from a first electrode pair set among all subgroups of electrode pair sets. For example, a group of pulses corresponding to the first electrode pair set followed by t d2After the time interval, a group of pulses corresponding to the second electrode pair set may be delivered. Figure 17 shows interleaved groups of pulses from two electrode sets of a two-element subpopulation electrode pair set. In this way, complete energy delivery over the desired electrode sequence can be performed efficiently. Instead of the interleaving shown in Figure 17, if p groups of pulses for each electrode pair are delivered sequentially across the set of electrode pairs, ablation energy delivery will take twice as long. The first electrode pair set of the first subpopulation may deliver a set of pulse groups 1703, 1705, 1707, indicated by the thin brackets in Figure 17. Similarly, the second electrode pair set of the first subpopulation may deliver a set of pulse groups 1723, 1725, indicated by the thick brackets in Figure 17. The pulse groups of the first electrode pair set have a duration or length t d1 and may be separated by a time interval 1754 having . A pulse group 1703 in the first electrode pair set may be followed by a pulse group 1723 in the second electrode pair set. For example, the pulse group 1723 of the second electrode set follows the pulse group 1703 of the first electrode pair set, and has a duration or length t d2 and is delivered at a time interval 1751 having . In some embodiments, the duration t d2 is t d1 about one half of (e.g., t d1 less than about 55 percent of ). In some embodiments, the time interval 1751 between pulse groups of different electrode pair sets corresponds to the group delay time for a given electrode pair set, and may be another ratio of time to the time interval 1754 (that is, for example, t d1 such as one third or less than one quarter of t d1 a ratio other than about one half of ), it should be understood.

[0041] In pulse delivery, a group of interleaved pulses may be provided for all subgroups of electrode pair sets, and for two electrode sets within all subgroups (and without interleaving if the last subgroup contains only one electrode set). A time delay interval (e.g., period t) may be provided. d2 (accompanied by) may be provided between consecutive groups of pulses, corresponding to a consecutive small group of electrode pair sets.

[0042] In some embodiments, the pulse delivery sequence shown in Figure 17 may be applied using the electrode pairs (a1-(c1,c2)), (a2-(c2,c3)), and (a3-(c3,c4)) described herein, where the first subgroup includes the first electrode pair (a1-(c1,c2)) and the second electrode pair (a2-(c2,c3)). The second subgroup may include the third electrode pair (a3-(c3,c4)). In the first subgroup of electrode pair sets, p pulses of the first electrode pair (a1-(c1,c2)), such as groups 1703, 1705, 1707, may be interleaved with p pulses of the second electrode pair (a2-(c2,c3)), such as groups 1723, 1725. d2 After a time delay, groups of p pulses may be delivered to the third electrode pair (a3-(c3,c4)) of the second subgroup without interleaving.

[0043] Figure 18 schematically shows an ablation delivery sequence delivered over a single heartbeat according to an embodiment. A first supergroup (or packet) 1871 of pulses for a first subgroup ((a1-(c1,c2)) and (a2-(c2,c3))) is followed by a second supergroup 1875 of pulses for a second subgroup (a3-(c3,c4)). The first supergroup 1871 of pulses may include sets of pulses for a first electrode pair (a1-(c1,c2)), such as groups 1811, 1813, and another set of pulses for a second electrode pair (a2-(c2,c3)), such as groups 1821, 1823, interleaving (e.g., alternating, multiplexing) over p groups of pulses corresponding to each electrode set. A time delay 1863 may separate the pulse delivery of pulse 1871 of the first subgroup (a1-(c1,c2)) from the pulse delivery of pulse 1875 of the second subgroup (a2-(c2,c3)). The second supergroup 1875 of pulses may include sets of pulse groups 1831, 1833 consisting only of the third electrode pair (a3-(c3,c4)) of the second subgroup. The pulse groups 1831, 1833 may have a duration or length t corresponding to the group delay. d The system may include p groups, each separated by a time interval of 1865. In some embodiments, the group delay (such as the group delays in the examples herein) may be between approximately 10 μs and approximately 50 ms. Although Figure 18 shows ordered ablation delivery for one heartbeat, similar sequences may be delivered for a predetermined number of heartbeats.

[0044] It should be noted that any number of electrode pair sets may be defined and used as convenient for the implementation at hand, and the above examples are provided for clarity and illustrative purposes only. In some embodiments, the methods, systems, and devices disclosed herein may comprise one or more of the methods, systems, and devices described in one or more of International Application PCT / US2018 / 029552 filed April 26, 2018, the contents of which are incorporated herein by reference in their entirety.

[0045] Similarly, although the specific examples provided above show pairwise ordering in which a two-element subgroup is defined, more broadly, a subgroup of n elements of an electrode set may be defined in an interleaved order defined across the n elements of each subgroup, similar to the specific examples provided herein.

[0046] The interleaving or multiplexing processes described herein may increase the efficiency or speed of delivering the ablation energy sequence with each heartbeat. This may be useful when there are time constraints in delivering the entire ablation sequence across heartbeats and / or within the refractory frames of the cardiac chambers. In some embodiments, the ablation sequence of electrode pair sets may be defined independently for each heartbeat. In this case, the specific subgroups defined for each heartbeat may be different. However, the interleaving of the sequence may occur similarly to those described herein.

[0047] While the interleaving or multiplexing of pulse waveforms is described in relation to groups of pulses (e.g., a first set of pulses), as illustrated in Figures 17 and 18, it can be understood that higher levels of the pulse waveform hierarchy can be interleaved between sets of electrodes. For example, voltage pulses delivered to a first set of electrodes and a second set of electrodes can be interleaved at higher levels of the hierarchy, including, for example, a third level of the hierarchy (e.g., interleaving a second set of pulses), a fourth level of the hierarchy (e.g., interleaving a third set of pulses), and so on.

[0048] In addition, in some embodiments, a particular order of interleaved electrode sets can vary over several heartbeats, corresponding collectively to the delivery of a second set of pulses (e.g., a third set of pulses) to each set of electrode pairs. For example, consecutive interleaved electrode sets (a1-c1, a2-c2), (a3-c3, a4-c4) (with interleaves between each set of electrodes in parentheses) may be delivered during the first heartbeat, while consecutive interleaved electrode sets (a3-c3, a4-c4), (a1-c1, a2-c2) may be delivered during the second heartbeat.

[0049] Furthermore, in some embodiments, one or more electrode sets may not appear in the ablation sequence for all heartbeats. For example, an interleaved electrode set (a1-c1, a2-c2) may appear in the ablation sequences for the first and third heartbeats, but not for the second heartbeat. Generally, a second consecutive set of pulses for a given electrode set is delivered during separate heartbeats, but not necessarily across consecutive heartbeats. Hierarchical waveform

[0050] Figure 2 shows pulse voltage waveforms in the form of consecutive rectangular double pulses, where each pulse, such as pulse 101, is associated with a pulse width or duration. The pulse width / duration can be approximately 0.5 microseconds, approximately 1 microsecond, approximately 5 microseconds, approximately 10 microseconds, approximately 25 microseconds, approximately 50 microseconds, approximately 100 microseconds, approximately 125 microseconds, approximately 140 microseconds, and approximately 150 microseconds, including all values ​​and partial ranges between them. The pulse waveforms in Figure 2 show a set of single-phase pulses where all pulses have the same polarity (measured from a zero baseline, all are positive in Figure 2). In some embodiments, such as for applications of irreversible electroporation, the height or voltage amplitude of each pulse 101 can be approximately 400 volts, approximately 1000 volts, approximately 5000 volts, approximately 10,000 volts, and approximately 15,000 volts, including all values ​​and partial ranges between them. As shown in Figure 2, pulse 101 is separated from adjacent pulses by a time interval 102, sometimes also called the first time interval. The first time interval can be about 1 microsecond, about 10 microseconds, about 50 microseconds, about 100 microseconds, about 200 microseconds, about 500 microseconds, about 800 microseconds, or about 1 millisecond, including all values ​​and subranges between them, in order to generate irreversible electroporation.

[0051] Figure 3 illustrates a pulse waveform with a nested pulse hierarchical structure. Figure 3 shows a series of single-phase pulses, such as pulse 115, where the pulse width / pulse duration w is separated by time intervals (sometimes called the first time interval or time delay) such as 118, with a period t1 between consecutive pulses, and several m1 consecutive pulses are arranged to form a group of pulses 121 (sometimes called the first set of pulses). Furthermore, the waveform has several m2 such groups of pulses (sometimes called the second set of pulses), separated by time intervals 119 (sometimes called the second time interval or time delay) with a period t2 between consecutive groups. A set of m2 such pulse groups, marked 122 in Figure 3, constitutes the next level of the hierarchy and can be called a packet and / or second set of pulses. Both the pulse width w and the period t1 of the time interval 118 between pulses can range from microseconds to several hundred microseconds, including all values ​​and subranges between them. In some embodiments, the period t2 of time interval 119 can be at least three times larger than the period t1 of time interval 118. In some embodiments, the ratio t2 / t1 can be in the range between about 3 and about 300, including all values ​​and subranges in between.

[0052] Figure 4 further details the structure of a nested pulse hierarchy waveform. In this figure, a series of m1 pulses (individual pulses are not shown) form a group of pulses 130 (e.g., a first set of pulses). A series of m2 such groups, separated by a time interval 142 between groups, with a period t2 (e.g., a second time interval or time delay) between one group and the next, form a packet 132 (e.g., a second set of pulses). A series of m3 such packets, separated by a time interval 144, which is a period t3 (e.g., a third time interval) between one packet and the next, form the next level in the hierarchy, i.e., a superpacket (e.g., a third set of pulses) named 134 in the figure. In some embodiments, the time interval t3 can be at least about 30 times larger than the time interval t2. In some embodiments, the time interval t3 can be at least 50 times larger than the time interval t2. In some embodiments, the ratio t3 / t2 can be in the range between about 30 and about 800, including all values ​​and subranges between them. The amplitude of each voltage pulse in the pulse hierarchy can be any value in between and within a range of 500 volts to 7,000 volts or more. Each pulse in the first set of pulses may be either a single-phase pulse or a two-phase pulse, or it may include a combination of single-phase and two-phase pulses.

[0053] Figure 14 illustrates the structure of a nested pulse hierarchy waveform in more detail. In this figure, a series of m1 pulses (individual pulses are not shown) form a group of pulses 1420 (e.g., a first set of pulses). A series of m2 such groups, separated by a time interval 1422 between groups, with a period t2 (e.g., a second time interval or time delay) between one group and the next, form a packet 1430 (e.g., a second set of pulses). A series of m3 such packets, separated by a time interval 1432, with a period t3 (e.g., a third time interval or time delay) between one packet and the next, form the next level in the hierarchy, i.e., a superpacket (e.g., a third set of pulses) named 1440 in the figure. In some embodiments, the period t3 of the time interval 1432 can be at least about 30 times larger than the period t2 of the time interval 1422. In some embodiments, the period t3 of the time interval 1432 can be in the range of about several hundred milliseconds or a few tenths of a second. Furthermore, there can be a series or variety of m4 superpackets, such as 1440, separated by time intervals of 1442, including a further level of hierarchy (e.g., a fourth set of pulses), called super-superpackets. In some embodiments, the number of superpackets m4 can be any integer ranging from 1 to 50, including all values ​​and subranges in between. In some embodiments, the period t4 with a time interval of 1442 can be at least 10 times larger than the period t3 with a time interval of 1432. In some embodiments, the period t4 with a time interval of 1442 can range from about a few seconds to about a few minutes. In some embodiments, the ratio t4 / t3 can range between about 10 and about 1000, including all values ​​and subranges in between. In some embodiments, the period t4 with a time interval of 1442 between individual superpackets can be constant across all m4 superpackets. Alternatively, the period t4 with a time interval of 1442 can vary depending on the different pairs of superpackets. One or more of the 1442 time intervals may have a duration exceeding the minimum threshold period, which may be manually selected or set randomly.The minimum threshold period may be in the range of several seconds (e.g., 5 seconds or more). In some embodiments, the time interval 1442 may have different durations depending on the order or pattern. For example, a group of superpackets within m4 superpackets may have a duration t. 4,1 , t 4,2 , t 4,3 , ...t 4,q Includes pairs of superpackets that are separated consecutively at consecutive time intervals with (q being any integer greater than 1), t 4,1 , t 4,2 , t 4,3 , ...t 4,q The value can be selected within a suitable range (for example, a period within the range of a few seconds, tens of seconds, or a few minutes). Consecutive time intervals t 4,1 , t 4,2 , t 4,3 , ...t 4,q Furthermore, this can be repeated multiple times across additional groups of superpackets to generate additional portions of the pulse waveform. The amplitude of individual voltage pulses in the pulse hierarchy can be any range from 500 volts to over 7,000 volts, including all values ​​and subranges in between.

[0054] In some embodiments, when pulse waveforms are delivered in sync with the cardiac cycle, individual superpackets (e.g., a third set of pulses) can spread across multiple cardiac cycles by delivering packets of pulses containing one or more groups of pulses during each cardiac cycle (e.g., during the refractory period of the cardiac cycle). In some embodiments, each time interval or time delay between consecutive superpackets (e.g., a third time interval or third time delay) can roughly correspond to the duration of a cardiac cycle so that consecutive superpackets can be delivered during consecutive cardiac cycles (e.g., during the refractory period of the cardiac cycle). In some embodiments, each time interval or time delay separating consecutive superpackets (e.g., a fourth time interval or time delay) can be greater than the cardiac cycle. In some embodiments, as described herein, the system and method may include a cardiac stimulator or cardiac stimulator that can generate pacing pulses to synchronize the delivery of pulse waveforms with the cardiac cycle.

[0055] A variety of third levels of pulses, including a fourth set of pulses, may provide more effective treatment or therapeutic delivery. Nanopores in the cell membrane, which are reversibly opened by a single third set of pulses, may be irreversibly opened by applying a variety of third sets of pulses, thereby generating a larger ablation zone. For example, in a clinical application, after the delivery of the first third set of pulses for ablation delivery, there may be a time interval or pause t4 ranging from about 5 seconds to about 500 seconds before the delivery of the second third set of pulses to continue the ablation delivery. This type of ablation delivery may be beneficial from a therapeutic standpoint and may deliver a more complete treatment for certain arrhythmic conditions. For example, it may ensure the generation of an ablation zone that is close and transwalled across the atrial wall. In some embodiments, subsequent third sets of pulses may also be delivered. In some embodiments, the time intervals between consecutive third sets of pulses may be different rather than fixed. In some embodiments, the minimum value of the period t4, which is the time interval between a third consecutive set of pulses, may be set by the generator to support this delivery to a higher level of hierarchy in the pulse waveform structure. In some embodiments, the minimum value of the time interval period t4 may be at least about 5 seconds.

[0056] Figure 19 further details the structure of a pulse hierarchy waveform according to an embodiment. The waveform shown in Figure 19 has another level of hierarchy added on top of the waveform shown and described with respect to Figure 14. In particular, the waveform in Figure 19 includes the nested pulse hierarchy waveform structure of Figure 14 and can include other levels in various pulse hierarchies.

[0057] As described in Figure 14, the fourth level of the nested pulse hierarchy waveform can contain a series or variety of m4 superpackets forming an ultra-superpacket. Each superpacket can contain a series or variety of m3 packets, each packet can contain a series or variety of m2 groups, and each group can contain a series or variety of m1 pulses.

[0058] The concept of hierarchy can be further generalized to iterative patterns, with reference to Figure 19. As depicted in Figure 19, a series of superpackets 1950 (each containing a series of m4 superpackets, though not shown in Figure 19) can be separated by time intervals 1952 with a period t5. The entire duration of each superpacket 1950 and time interval 1952 can be different or the same across the series of superpackets 1950 and time intervals 1952. This series of superpackets 1950 can form a higher level of the pulse waveform hierarchy (e.g., a fifth set of pulses), which can be called a hyperpacket.

[0059] A fourth level with a variety of pulses, including a fifth set of pulses, can provide more effective treatment or therapeutic delivery under certain conditions. While the waveform shown in Figure 19 is described as including a fifth level in a hierarchy with a fifth set of pulses, it is understandable that a continuous generation of waveforms could occur where several higher levels in the hierarchy include higher levels of pulses. For example, waveforms with a sixth level, a seventh level, etc., can be generated to include a sixth set of pulses, a seventh set of pulses, and so on, respectively.

[0060] Each level in the pulse hierarchy can be defined by a diverse or sequence of pulses from the next lowest level in the hierarchy, with each set of pulses from the lowest level separated from the next level by a time interval or time delay. The duration of the time interval separating a sequence of pulses from the lowest level in the hierarchy can be constant or different over that sequence, as described above with respect to Figure 14. For example, the r-th level in the hierarchy is defined by a sequence of pulses from the r-1 level and the time interval t separating each set of pulses from the r-1 level. r It can include this.

[0061] As previously described with respect to the waveform shown in Figure 14, the nanopores of the cell membrane, which are reversibly opened by a single set of r pulses, may be irreversibly opened by applying a diverse set of r pulses, thereby generating a larger ablation zone. For example, in some clinical applications, when r is greater than 3, there may be a time interval or pause ranging from about 5 seconds to about 500 seconds between the delivery of the first set of r pulses for ablation delivery and before the delivery of the second set of r pulses to continue the ablation delivery. This type of ablation delivery may be beneficial from a therapeutic standpoint and may deliver a more complete treatment for certain arrhythmia conditions. For example, it may ensure the generation of an ablation zone that is close to and transwalled across the atrial wall. In some embodiments, subsequent sets of r pulses may also be delivered. In some embodiments, the time interval between consecutive sets of r pulses may be different rather than fixed. In some examples, the treatment strategy may be formulated to include ablation delivery with waveforms having different levels of hierarchy, including different time intervals, different numbers of pulses, and / or different pulse intensities. For example, a treatment approach may include ablation delivered using a waveform with continuously increasing or decreasing levels of hierarchy, a number of continuously increasing or decreasing pulses at each level of hierarchy, or time intervals between pulses at each level of hierarchy, to achieve more complete treatment for a particular arrhythmia condition. In some embodiments, the minimum time interval between consecutive sets of r pulses may be set by the generator to support this delivery mode for higher levels of hierarchy in the pulse waveform structure. In some embodiments, when r is greater than 3, the minimum time interval may be at least about 5 seconds.

[0062] Figure 5 provides an example of a biphasic waveform sequence with a hierarchical structure. In the example shown in the figure, a biphasic pulse such as 151 has both a positive and a negative voltage portion to complete one cycle of the pulse. Between adjacent cycles of period t1 there is a time delay 152 (e.g., a first time interval), and n1 such cycles form a group of pulses 153 (e.g., a first set of pulses). A series of n2 such groups, separated by a time interval 156 (e.g., a second time interval) of period t2 between one group and the next, form a packet 158 ​​(e.g., a second set of pulses). The figure also shows a second packet 162 with a period t3 of time delay 160 (e.g., a third time interval) between packets. As with single-phase pulses, higher levels of the hierarchical structure can also be formed. The amplitude of each pulse or the voltage amplitude of a biphasic pulse can be any range from 500 volts to over 7,000 volts, including all values ​​and subranges in between. The pulse width / pulse duration can range from nanoseconds or sub-nanoseconds to tens of microseconds, while the delay t1 can range from zero to several microseconds. The time interval t2 between groups can be at least 10 times larger than the pulse width. In some embodiments, the time interval t3 can be at least about 20 times larger than the time interval t2. In some embodiments, the time interval t3 can be at least 50 times larger than the time interval t2.

[0063] Embodiments disclosed herein include waveforms constructed as hierarchical waveforms, comprising waveform elements / pulses at various levels of the hierarchy. Individual pulses, such as 115 in Figure 3, constitute a first level of the hierarchy and have associated pulse durations and a first time interval between consecutive pulses. A set of pulses, i.e., elements of the first level structure, forms a second level of the hierarchy, such as a group of pulses / second set of pulses 121 in Figure 3. Other parameters, as relating to the waveform, include the total duration of the second set of pulses (not shown), the total number of first level elements / first set of pulses, and a second time interval between consecutive first level elements that describes the second level structure / second set of pulses. In some embodiments, the total duration of the second set of pulses can be between approximately 20 microseconds and approximately 10 milliseconds, including all values ​​and subranges between them. A set of groups, second sets of pulses, or elements of the second level structure, forms a third level of the hierarchy, such as a group of packets / third set of pulses 122 in Figure 3. Other parameters include the total duration of the third set of pulses (not shown), the total number of second level elements / second set of pulses, and the third time interval between consecutive second level elements, which describes the third level structure / third set of pulses. In some embodiments, the total duration of the third set of pulses can be between approximately 60 microseconds and approximately 250 milliseconds, including all values ​​and subranges between them.

[0064] In some embodiments, a grouped third set of pulses may form a fourth level of the hierarchy, such as a superpacket containing a diverse third set of pulses (e.g., third set of pulses 1430) that defines a fourth set of pulses (e.g., fourth set of pulses 1440), as shown in Figure 14. Furthermore, a diverse or series of fourth sets of pulses (e.g., superpackets) may form a fifth level of the hierarchy, such as in the waveform shown in Figure 19, as described with respect to Figure 19. While specific levels of the hierarchy are described with respect to the figures, it can be understood that, depending on the elements and / or requirements of a particular procedure, ablation procedures can be performed using iterative generation of waveforms with several higher levels of the hierarchy, including higher levels of pulses. Such generalization of higher levels is described above with respect to Figure 19.

[0065] Other parameters include the total duration of the fourth set of pulses (not shown), the total number of fourth level elements / fourth set of pulses, and the fourth time interval between consecutive fourth level elements, which describes the fifth level structure. In some embodiments, the total duration of the fourth set of pulses may be between approximately 100 milliseconds and approximately 15 minutes, including all values ​​and subranges between them. The duration between consecutive fourth sets of pulses can vary between approximately 5 seconds and 500 seconds. The generally repetitive or nested structure of the waveform can continue up to multiple higher levels, such as 10 levels of structure.

[0066] In some embodiments, hierarchical waveforms with nested structures and time interval hierarchies, as described herein, are useful for ablation energy delivery in irreversible electroporation and provide good control and selectivity for application in different tissue types. Various hierarchical waveforms can be generated with suitable pulse generators. While the examples herein distinguish between monophasic and biphasic waveforms for clarity, it should be noted that combined waveforms, in which some parts of the waveform hierarchy are monophasic while others are biphasic, can also be generated / implemented.

[0067] In embodiments relating to cardiac ablation procedures, the pulse waveforms described above can be applied to two electrodes selected from a set of electrodes on a catheter, such as an ablation catheter. A subset of the catheter electrodes can be selected as the anode, while another subset of the ablation catheter electrodes can be selected as the cathode, and the voltage waveform is applied between the anode and cathode. In a non-limiting example, in an example where the ablation catheter is placed on the epicardium, the catheter can wrap around a pulmonary vein, and one electrode can be selected as the anode and the other as the cathode. Figure 6 shows an exemplary circular catheter configuration in which approximately diametrically opposed electrode pairs (e.g., electrodes 603 and 609, electrodes 604 and 610, electrodes 605 and 611, and electrodes 606 and 612) can operate as an anode-cathode set. Any of the disclosed pulse waveforms can be applied gradually or sequentially across a successive set of such electrodes. In a non-limiting example, Figure 6 depicts the operation of a successive set of electrodes. In the first step, electrodes 603 and 609 are selected as the anode and cathode, respectively, and a voltage waveform having the hierarchical structure described herein (e.g., the waveform in Figure 14) is applied across these electrodes. With a small time delay (e.g., less than about 5 milliseconds), in the next step, electrodes 604 and 610 are selected as the anode and cathode, respectively, and the waveform is again applied across this set of electrodes. After a small time delay, in the next step, electrodes 605 and 611 are selected as the anode and cathode, respectively, for the next application of the voltage waveform. In the next step, after a small time delay, electrodes 606 and 612 are selected as the anode and cathode, respectively, for the application of the voltage waveform. In some embodiments, as described in more detail herein, one or more of the waveforms applied across the electrode pair are applied during the refractory period of the cardiac cycle.

[0068] In some embodiments, the ablation pulse waveforms described herein are applied during the refractory period of the cardiac cycle to avoid disruption of the cardiac sinus rhythm. In some embodiments, the procedure involves electrically pacing the heart with a cardiac stimulator to ensure pacing capture to establish the periodicity and predictability of the cardiac cycle, and then defining time frames within the refractory period of the cardiac cycle in which one or more pulse ablation waveforms can be delivered. Figure 7 shows an example in which both atrial and ventricular pacing are applied (for example, using pacing leads or catheters located in the right atrium and right ventricle, respectively). With time on the horizontal axis, Figure 7 shows a series of ECG waveforms 60 and 61 driven by the pacing signals, along with a series of ventricular pacing signals such as 64 and 65, and a series of atrial pacing signals such as 62 and 63. As shown in Figure 7 by the thick arrows, there are atrial refractory time frames 68 and ventricular refractory time frames 69 following the atrial pacing signal 62 and ventricular pacing signal 64, respectively. As shown in Figure 7, period T is located within both the atrial and ventricular refractory time frames 68 and 69. r A common refractory time frame 66 can be defined. In some embodiments, electroporation ablation waveforms can be applied to this common refractory time frame 66. The start of this refractory time frame 68 is shifted from the pacing signal 64 by a time offset 59, as shown in Figure 7. In some embodiments, the time offset 59 can be less than about 25 milliseconds. For the next heartbeat, a similarly defined refractory time frame 67 is the next time frame available for the application of ablation waveforms. Thus, for each heartbeat remaining within the common refractory time frame, ablation waveforms can be applied over a series of heartbeats. In one embodiment, each packet of pulses in the pulse waveform hierarchy, as defined above, can be applied to a given set of electrodes for one heartbeat, so that a series of packets are applied over a series of heartbeats.

[0069] The timing sequence of electrode activation across a series of electrode sets is shown in Figure 8 according to an embodiment. Using an exemplary scenario, in some embodiments, cardiac pacing is utilized as described above, with a hierarchical ablation waveform applied to j electrode sets (each electrode set generally including at least one anode and at least one cathode). A packet of pulses (e.g., including one or more pulse groups or one or more sets of pulses) is first applied to electrode set 1, with a small time delay t d With only a delay of about 100 μs or less, a pulse packet is applied to electrode set 2. Subsequently, with another time delay, a pulse packet is applied to electrode set 3, and so on to electrode set j. This sequence 632 of applying pulse packets to all j electrode sets is delivered within the refractory time frame of a single heartbeat (common refractory time frame 66 or 67, etc.), and each application to an electrode set constitutes one packet for that electrode set. Now, consider the case of a single-phase hierarchical waveform. Returning to the example of a single-phase waveform shown in Figure 3, the waveform has a series of single-phase pulses, each with a pulse width w, separated by a time interval t1 between consecutive pulses, and several m1 single-phase pulses are arranged to form a group of pulses. Furthermore, the waveform has several m2 such groups of pulses separated by a time interval t2 between consecutive groups, thereby defining a packet. When this waveform is applied sequentially across j electrode sets as described herein, the following inequality can be expressed.

[0070] j[m2(m1w+t1(m1-1))+t2(m2-1)]+t d (j-1) <T r (1)

[0071] In the formula, the entire ablation pulse delivery is refractory to the time frame T. r For it to occur within the time frame, pulse waveform parameters m1 and m2 must satisfy a given number j of the electrode set. In some embodiments, the refractory time frame T rThis can be approximately 140 milliseconds or less. The time offset, which is the start of the refractory frame for the pacing signal, can be less than approximately 10 milliseconds. Time intervals w, t1, t2, and t d While can be arbitrary, when implemented in a finite state machine such as a computer processor, it is an integer that is measured in several preferred units (e.g., microseconds, nanoseconds, or multiples of the clock time of the base processor). Assuming several electrode sets j, equation (1) represents a Diophantine inequality that mutually constrains pulse waveform parameters (pulse width, time interval, and number of pulses and groups) such that the total duration of waveform application across j electrode sets is less than a given common refractory period. In some embodiments, a set of solutions to the Diophantine inequality can be found based on partial constraints on the pulse waveform parameters. For example, if the generator has, for example, pulse width w and time delay t d This may require input of several pulse waveform parameters and / or relational parameters, after which the system console determines the remaining pulse waveform parameters. In this case, the number of electrode sets j is also an input to the system that constrains the determination of the solution. In one embodiment, the system console may display two or more sets of such possible solutions for the waveform parameters for the user to make a selection, while in an alternative embodiment, the system performs automatic selection or determination of the waveform parameters. In some embodiments, the solution can be calculated and executed directly in a predetermined form, for example, on the system console of the pulse generator. For example, all pulse waveform parameters may be predetermined to satisfy a Diophantine inequality similar to equation (1), and the waveform may be pre-programmed on the system, and in some cases the predetermined solution(s) may depend on the number of electrode sets j, or alternatively, the solution(s) may be predetermined assuming a maximum number of electrode sets. In some embodiments, two or more solutions may be predetermined and made available for user selection on the system console.

[0072] Diophantine inequality (1) holds for the delivery of a single waveform packet over a single refractory time frame, whereas the entire waveform can sometimes consist of multiple packets. The number of packets can be predetermined and, in one embodiment, can range from 1 to 28 packets, including all values ​​and subranges between them. Appropriate refractory time frame T r In one embodiment, this can be determined and / or defined in advance, or in an alternative embodiment, it can be selected by the user from a certain predetermined range. Although inequality (1) was explicitly written for a single-phase hierarchical waveform, similar inequalities may be written for a biphase waveform, or for a waveform that combines single-phase and biphase elements.

[0073] Figure 8 provides a schematic diagram illustrating how an ablation waveform is delivered across multiple electrode sets j by a series of packets at the highest level of the waveform hierarchy. The first waveform packet 632 is delivered to j successive electrode sets across the entire electrode sequence, and the waveform parameters of this sequence satisfy Diophantine inequalities such as equation (1). This entire voltage waveform sequence is delivered within a defined refractory time frame of a single paced heartbeat. After a packet delay t3 equal to one pacing period, the next waveform packet 633 is delivered to j successive electrode sets across the entire electrode sequence with the same waveform parameters. Waveform delivery continues over a predetermined number of packets until the last waveform packet 636 is delivered to j successive electrode sets. Thus, ablation delivery occurs over as many paced heartbeats as there are packets. Preferably, the voltage amplitude of the waveform can spread between approximately 700V and approximately 10,000V, and between approximately 1,000V and approximately 8,000V, including all values ​​and sub-ranges, to be suitable and convenient for clinical applications.

[0074] In some embodiments, a complete sequence of electrode sets can be further divided into smaller subsequences of electrode sets / electrode subsets. For example, a complete sequence of j electrode sets can be divided into a first subsequence / first subset containing j1 electrode sets, a second subsequence / second subset containing j2 electrode sets, and so on, in an Nth subsequence containing j N It can be further divided into N subsequences, each involving a set of j electrodes. A waveform packet is applied first to a first subsequence of j1 electrode sets, then to a second subsequence of j2 electrode sets, and so on, with cardiac pacing being used throughout, and all waveform packets being applied within an appropriate refractory time frame.

[0075] Furthermore, waveform delivery across each subsequence of electrode sets may be multiplexed in the manner described herein to increase the efficiency and / or speed of ablation delivery, and may include electrode subsets in which small groups form one, two, three, four or more pairs, as described herein.

[0076] While pulse waveform delivery is described herein when each second set of packets or pulses is delivered within the signal refractory period of the cardiac cycle, it can be understood that in other embodiments, parameters (e.g., the number of pulses, groups, packets, etc., and the duration of the time interval or time delay) can be varied to allow higher levels of the pulse waveform hierarchy to be delivered within a single refractory period. For example, in an embodiment, multiple second sets of pulses (e.g., superpackets) can be configured to be delivered within a single refractory period by adjusting the number of pulses, groups, packets, etc., and the duration of the first, second, etc. time interval or delay to fit all three levels of the hierarchy within a single refractory period. system

[0077] Figure 9 is a schematic diagram of the system architecture for an ablation system 200 configured for the delivery of pulsed voltage waveforms. The system 200 includes a system console 215, which includes a pulse waveform generator and controller 202, a user interface 203, and a switch 205 for isolating a connection box 210 (to which multiple catheters may be connected) from the voltage pulses delivered by the generator. In some embodiments, the generator / controller 202 may include a processor, which can be any suitable processing device configured to operate and / or execute a set of instructions or codes. The processor may be, for example, a general-purpose processor, a field-programmable gate array (FPGA), an application-specific integrated circuit (ASIC), a digital signal processor (DSP), and / or similar. The processor may be configured to operate and / or execute application processes, and / or other modules, other processes, and / or other functions related to the system and / or a network associated with the system (not shown).

[0078] In some embodiments, the system 200 may also include memory and / or a database (not shown) configured to store, for example, pacing data, waveform information, and / or similar. The memory and / or database may independently be, for example, random access memory (RAM), memory buffers, hard drives, databases, erasable programmable read-only memory (EPROM), electrically erasable read-only memory (EEPROM), read-only memory (ROM), flash memory, and / or others. The memory and / or database may store instructions that cause the generator / controller 202 to execute modules, processes, and / or functions related to the system 200, such as pulse waveform generation and / or cardiac pacing.

[0079] System 200 can communicate with other devices (not shown) via, for example, one or more networks, each of which may be any type of network, such as a local area network (LAN), wide area network (WAN), virtual network, telecommunications network, and / or the internet, and may be implemented as a wired and / or wireless network. Any or all communications may be secure (e.g., encrypted) or insecure, as known in the art. System 200 may include, and / or encompass, personal computers, servers, workstations, tablets, mobile devices, cloud computing environments, applications or modules running on any of these platforms, and / or similar.

[0080] The system console 215 delivers ablation pulses to an ablation catheter 209, which is suitably positioned in the patient's biostructure, for example, in a loop around the patient's pulmonary veins within the pericardial cavity of the patient's heart. The intracardiac ECG recording and pacing catheter 212 is coupled to the ECG recording system 208 via a connection box 210. The ECG recording system 208 is connected to a cardiac stimulator or pacing unit 207. The cardiac stimulator 207 can send pacing output to the recording and pacing catheter 212, and generally both atrial and ventricular pacing signals can be generated as outputs from the cardiac stimulator 207. In some embodiments, there may be separate atrial and ventricular pacing catheters (not shown) or leads within the heart, which can then be placed and / or positioned in the appropriate cardiac chambers, respectively. The same pacing output signals are also sent to the ablation system console 215. The pacing signal is received by the ablation system console, and based on the pacing signal, the ablation waveform can be generated by the generator / controller 202 within a common refractory frame as described herein. In some embodiments, the common refractory frame may begin substantially immediately after (or after a very small delay of) the ventricular pacing signal and then last for a period of approximately 250 ms or less. In this case, the entire ablation waveform packet is delivered within this period as previously described.

[0081] The user interface 203 associated with the ablation system console 215 can be implemented in various forms to suit the application. The epicardial ablation catheter is delivered by a subxiphoid access method and, once positioned around the pulmonary veins in the epicardium as shown in Figure 1, may be cinched in place by passing ends 8 and 9 through a cinch tool. Depending on the size of the specific left atrium biostructure, a subset of electrodes may be positioned around the pulmonary veins in a surrounding manner, while the rest of the electrodes may be pulled inside a cinch tool (not shown in Figure 1) and thus not exposed. In such embodiments, the surrounding / exposed electrodes can be selectively used to deliver ablation energy. A schematic illustration of a suitable embodiment of the user interface for use with the ablation catheter is shown in Figure 10. In Figure 10, the user may select the number of proximal electrodes inside the scintillator and the number of distal electrodes inside the scintillator, as shown in windows 653 and 654, respectively, after the user has made selections 650 and 651, respectively. Complementary electrodes / subsets of electrodes on the catheter (taken from the complete set of catheter electrodes), not inside the scintillator, are exposed electrodes used to deliver pulsed electric fields for electroperforation ablation. The amplitude of the delivered waveform is controlled by an input mechanism, such as a slider 658 that can move over a predetermined voltage range, as shown 657 in Figure 10. Once the voltage amplitude is selected, the user prepares the ablation system for energy delivery by pressing an initialization button 655 provided on the user interface. In one example, this may take the form of a trigger to charge a capacitor bank to store energy for subsequent delivery to the catheter.

[0082] As shown in Figure 11, the initialization button 660 can also function as a status indicator to show that the initialization process is ongoing. The status can be indicated by text (such as "Initializing..." as shown in Figure 11, and / or by a color such as yellow to indicate that initialization has not yet started or is still in progress). When the initialization process is complete (e.g., the capacitor bank is fully or satisfactorily charged), the same button 663 now indicates the completion of the process ("Initialized"), as shown in Figure 12, and in some embodiments as illustrated, it can change color (e.g., change from yellow to green) and / or shape to further indicate the completion of initialization. Meanwhile, the ablation system awaits the reception of a pacing signal from the cardiac stimulator or pacing unit. Once the pacing signal is detected and / or confirmed along with the completion of the initialization process, a second button 665 becomes available so that the user can engage to confirm pacing capture. If the pacing signal is not detected by the ablation system console, the second button 665 is not available. The user can monitor the ECG display (not shown) to view the pacing output of the cardiac stimulator in conjunction with the intracardiac ECG recording to confirm pacing acquisition (this confirms that atrial and ventricular contractions are actually driven by the pacing signal to establish a predictable common refractory frame). After visually confirming pacing acquisition from the ECG data, the user can then confirm pacing acquisition on the ablation system by pressing the "Confirm Pacing Acquisition" button 665.

[0083] As shown in Figure 13, once pacing acquisition is confirmed on the ablation system, the system becomes available for ablation or pulsed electric field delivery. The pacing acquisition confirmation button then changes its appearance 670 (the appearance can change color, shape, and / or similar elements) to indicate that it is ready for ablation delivery, as indicated by 670. Furthermore, the ablation delivery button 675 becomes available to the user. The user can press the ablation delivery button 675 to deliver ablation in sync with the paced heart rhythm. In some embodiments, the user presses the button 675 during the ablation delivery, and finally, the button changes shape or color to indicate the completion of ablation delivery. In some embodiments, if the user releases the button 675 before the completion of ablation delivery, the ablation delivery stops immediately, for example, with only a small time difference of 20 ms or less. In some embodiments, if the user has not pressed the ablation button 675 after it has been indicated as available, a safety mechanism causes the button to remain pressable for a limited duration only, after which it becomes unusable. In some embodiments, the ablation button 675 may be a software or graphic button on a user interface display; in other embodiments, it may be a mechanical button whose response depends on an activated or available state determined by the system; or in yet another embodiment, the button 675 may be any form of a variety of control input devices, without limitation, such as a lever, joystick, or computer mouse. In one embodiment, the ablation system may have an additional emergency stop button for further safety, for example, when it is desired to immediately deactivate the system. In one embodiment, the ablation console may be mounted on a turntable or wheeled cart, and the user may control the system using a touch panel interface located in the sterile field.The touch panel may be, for example, an LCD touch panel in a plastic housing that can be attached to a standard medical fence or post, and the touch panel may have minimal functionality as described above. The interface may be covered, for example, with a transparent plastic sterile drape.

[0084] Waveform parameters as disclosed herein can be determined by the design of the signal generator, and in some embodiments, the parameters can be predetermined. In some embodiments, at least a subset of the waveform parameters may be determined by user control so as to be convenient for a given clinical application. The specific examples and descriptions herein are illustrative in nature, and modifications can be developed by those skilled in the art based on the materials taught herein without departing from the scope of the embodiments disclosed herein.

[0085] One or more embodiments described herein relate to computer storage products comprising a non-temporary computer-readable medium (which may also be called a non-temporary processor-readable medium) having instructions or computer code for performing various operations performed by a computer. The computer-readable medium (or processor-readable medium) is non-temporary in the sense that it does not contain temporary propagating signals themselves (e.g., propagating electromagnetic waves that carry information on a transmission medium such as space or a cable). The medium and computer code (which may also be called code or algorithm) may be designed and constructed for one or more specific purposes. Examples of non-temporary computer-readable media include, but are not limited to, magnetic storage media such as hard disks, floppy disks, and magnetic tapes; optical storage media such as compact disks / digital video discs (CDs / DVDs), compact disk read-only memory (CD-ROMs), and holographic devices; magneto-optical storage media such as optical discs; carrier signal processing modules; and hardware devices specifically configured to store and execute program code, such as application-specific integrated circuits (ASICs), programmable logic devices (PLDs), read-only memory (ROMs), and random access memory (RAM) devices. Other embodiments described herein relate to computer program products that may include the instructions and / or computer code disclosed herein.

[0086] One or more embodiments and / or methods described herein can be carried out by software (running on hardware), hardware, or a combination thereof. Hardware modules may include, for example, general-purpose processors (or microprocessors or microcontrollers), field-programmable gate arrays (FPGAs), and / or application-specific integrated circuits (ASICs). Software modules (running on hardware) can be expressed in a variety of software languages ​​(e.g., computer code), including C, C++, Java®, Ruby, Visual Basic®, and / or other object-oriented, procedural, or other programming languages ​​and development tools. Examples of computer code include, but are not limited to, microcode or microinstructions, machine instructions such as those produced by a compiler, code used to generate web services, and files containing higher-level instructions executed by a computer using an interpreter. Further examples of computer code include, but are not limited to, control signals, encryption code, and compression code.

[0087] Although the epicardial catheter illustrated is considered as an example herein, it should be understood that endocardial catheters and other medical devices with multiple electrodes for the delivery of pulsed electric field (PEF) energy and tissue ablation may benefit from the multiplexing and interleaving disclosed herein for efficient electrode ordering and PEF ablation delivery. In some embodiments, the methods, systems, and devices disclosed herein may comprise one or more of the methods, systems, and devices described in one or more of International Application PCT / US2018 / 29938, filed April 27, 2018, the contents of which are incorporated herein by reference in their entirety.

[0088] While various embodiments have been described above, it should be understood that these are not limiting but merely examples. If the methods described above describe specific events occurring in a particular order, the order of those events can be modified. In addition, the specific events may occur not only sequentially as described above, but also simultaneously in parallel processes, where possible.

Claims

1. An ablation device comprising multiple electrodes configured to generate an electric field for ablation of tissue within a target, A pulse waveform generator that can be coupled to the ablation device and is configured to deliver voltage pulses to the ablation device in the form of a pulse waveform, wherein the pulse waveform is A first level of the pulse waveform hierarchy, comprising a first set of pulses and a first time delay that separates the consecutive pulses of the first set of pulses, wherein each pulse in the first set of pulses has a pulse duration, A second level of the hierarchy, comprising a plurality of first sets of pulses as a second set of pulses, and a second time delay that separates a sequence of first sets of pulses from the plurality of first sets of pulses, wherein each second time delay is at least three times the duration of the first time delay. A third level of the hierarchy, comprising a plurality of second sets of pulses as a third set of pulses, and a third time delay that separates consecutive second sets of pulses from the plurality of second sets of pulses, wherein each third time delay is at least 30 times the duration of the second time delay, A fourth level of the hierarchy, comprising a plurality of third sets of pulses as a fourth set of pulses, and a fourth time delay that separates consecutive third sets of pulses from the plurality of third sets of pulses, wherein each fourth time delay is at least 10 times the duration of the third time delay, A system comprising a pulse waveform generator, wherein the third time delay is set such that a plurality of second sets of pulses are delivered during the refractory period of separate cardiac cycles of the heart.

2. The system according to claim 1, wherein each pulse in each first set of pulses comprises a two-phase pulse having a voltage amplitude of at least 500 volts, and the pulse duration of each two-phase pulse is in the range of 0.5 nanoseconds to 20 microseconds.

3. The system according to claim 1, wherein the fourth set of pulses includes at least two third sets of pulses and fewer than 40 third sets of pulses.

4. The system according to claim 1, wherein each fourth time delay has a certain period of time.

5. The system according to claim 1, wherein the duration of the fourth time delay is different.

6. The system according to claim 5, wherein the fourth time delay includes at least one repeating value of the time delay.

7. The system according to claim 5, wherein each fourth time delay has a period ranging from at least 10 times the duration of the third time delay to less than 1000 times the duration of the third time delay.

8. The system according to claim 1, wherein the duration of each fourth time delay is greater than the cardiac cycle.

9. The system according to claim 1, wherein the pulse waveform further includes a fifth level of hierarchy comprising a plurality of fourth sets of pulses as a fifth set of pulses, and a fifth time delay that separates consecutive fourth sets of pulses from the plurality of fourth sets of pulses, each fifth time delay being at least 10 times the duration of at least one of the fourth time delays.

10. The system according to claim 1, wherein the pulse waveform generator is configured to deliver the voltage pulses in the form of the pulse waveform in sync with the cardiac cycle, such that a successive second set of pulses of a plurality of second sets of pulses is delivered during the refractory period of a separate cardiac cycle of the heart, and the delivery frame of the fourth set of pulses extends over a plurality of cardiac cycles of the heart.

11. The system according to claim 10, wherein each second set of pulses comprises at least two first sets of pulses and fewer than 40 first sets of pulses.

12. The system according to claim 10, further comprising a cardiac stimulator configured to generate pacing signals in order to control the timing of the cardiac cycle of the heart.

13. The system according to claim 1, wherein the pulse waveform generator is further configured to deliver the voltage pulses to a plurality of electrode sets of the ablation device, and the voltage pulse delivered to the first electrode set is delayed by a certain amount of time from the voltage pulse delivery to the second electrode set.

Images