Acute Evaluation of Cardiac Ablation Lesions

Abstract

Devices, systems and methods are provided for treating cardiac disorders, particularly arrhythmias, and more particularly the occurrence of atrial fibrillation. In the treatment of atrial fibrillation, therapeutic pulsed electric field energy is delivered to portions of the heart, particularly the entrances to the pulmonary veins, to provide tissue modification. Such tissue modification creates a lesion or series of lesions that act as a conduction block in the tissue to prevent the transmission of abnormal electrical signals. The cardiovascular lesion analysis system and method provide information regarding the effectiveness of treatment during the procedure to create an electrical block in the heart that remains durable and effective over time.

Description

[Technical field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims priority to and benefit of U.S. Patent Application No. 63 / 282,521, filed November 23, 2021, and entitled "Acute Assessment of Cardiac Ablation Lesions," the disclosure of which is incorporated by reference in its entirety herein for all purposes. [Background technology]

[0002] Therapeutic energy can be applied to the heart and vasculature for the treatment of a variety of conditions, including atherosclerosis (particularly in the prevention of restenosis after angioplasty) and atrial fibrillation. Atrial fibrillation is the most common sustained cardiac arrhythmia and significantly increases the risk of mortality in affected patients, particularly by causing stroke. In this phenomenon, the occurrence of erroneous electrical impulses causes the heart to deviate from normal sinus rhythm. Atrial fibrillation is believed to initiate in the myocardial sleeve of the pulmonary veins (PVs) due to the presence of automaticity in cells within the myocardial tissue of the PVs. It is believed that the pacemaker activity of these cells results in the formation of ectopic contractions that initiate atrial fibrillation. The PVs are also believed to be important in the maintenance of atrial fibrillation because their disorganized structure and electrophysiological properties provide an environment in which atrial fibrillation can persist. Thus, the goal is to destroy or eliminate these abnormal pacemaker cells within the myocardial sleeve of the PVs, and atrial fibrillation is often treated by delivering therapeutic energy to the pulmonary veins. However, due to reports of PV stenosis, this technique has traditionally been modified to target the PV sinus to achieve conduction block between the PV and the left atrium. The PV sinus encompasses the roof and posterior wall of the left atrium, as well as the pulmonary veins, and in the case of the right pulmonary vein sinus, a portion of the interatrial septum. In some instances, this technique offers a higher success rate and lower complication rate than pulmonary vein ostium isolation.

[0003] Thermal ablation therapy, specifically radiofrequency (RF) ablation, is currently the "gold standard" in the treatment of atrial fibrillation due to localized tissue necrosis. Typically, RF ablation is used to create a ring of ablation lesions around the outside of the ostium of each of the four pulmonary veins. The RF current causes tissue desiccation by creating a localized thermal area, resulting in separate coagulation necrosis. The necrotic tissue acts as a conduction block, thereby electrically insulating the vein.

[0004] Despite improvements in techniques to restore sinus rhythm using available methods, both success rates and safety are limited by the thermal nature of these procedures. Complications include pulmonary vein stenosis, phrenic nerve injury, esophageal injury, atrioesophageal fistula, peresophageal vagus nerve injury, perforation, thromboembolism, vascular complications, and acute coronary artery occlusion, to name a few. Thus, while keeping the technique in clinical practice, safer and more versatile methods to remove or replace abnormal tissues, such as pulsed electric field therapy (PEF), have been used. However, PEF therapy exerts different cellular effects on tissues, so tissues respond differently than when subjected to RF ablation. Most notably, PEF-treated cells have an altered ability to maintain intracellular and extracellular concentration gradients. This can result in cell death, triggering a fibrotic effect comparable to wound healing, or cells can recover over a period of minutes to hours or longer. In both cases, the ability of excitable tissues, such as cardiomyocytes, to conduct action potentials is at least initially impaired, and cells are rendered non-excitable. Unfortunately, determining which regions of cells will sustain this defect is not readily detectable. During therapeutic PEF procedures, it is not possible to distinguish between tissues experiencing electrical conduction and contractility changes as a temporary effect and those that ultimately die via necrosis or programmed cell death over a period of seconds to tens of hours. As a result, traditional cues based on RF energy that physicians monitor throughout the ablation procedure are largely inapplicable and may lead to misleading acute outcomes and poor chronic outcomes, such as incomplete blockade of abnormal electrical rhythms. Determining acute ablation success remains a challenging problem for the treatment of cardiac arrhythmias with all ablation methods. Data from multiple clinical trials on patients' long-term freedom from arrhythmias confirms that a high percentage of patients receive ineffective treatment during initial procedures. Early atrial fibrillation recurrence rates remain in the range of 50-70%. There is a need to establish better techniques for predicting lesion persistence and treatment success during ablation procedures. At least some of these objectives are achieved by the systems, devices, and methods described herein. Summary of the Invention

[0005] Described herein are embodiments of devices, systems, and methods for treating target tissue, particularly cardiac tissue. The invention also relates to the following numbered clauses:

[0006] Clause 1. A cardiovascular disease analysis system comprising: an instrument configured to measure at least one voltage value of at least a portion of the cardiovascular lesion; an algorithm for evaluating the at least one voltage value to determine a permanence of the at least a portion of the cardiovascular lesion, the at least a portion of the cardiovascular lesion being created by pulsed electric field ablation; and A feedback system for communicating said persistence; The system comprising:

[0007] Clause 2. The system described in Clause 1, wherein the at least one voltage value includes at least one pre-ablation voltage value and at least one post-ablation voltage value, and the algorithm evaluates the at least one voltage value by determining a representative voltage drop value from the difference between the at least one pre-ablation voltage value and the at least one post-ablation voltage value, and the algorithm determines the likelihood of persistence based on the representative voltage drop value.

[0008] Clause 3. The system of clause 2, wherein the algorithm determines permanence by comparing the representative drop value to a threshold voltage drop value above which the lesion is deemed to be permanent.

[0009] Clause 4. A system described in any of clauses 2-3, wherein the pre-ablation voltage value is at least 0.1 volts.

[0010] Clause 5. The system of any of clauses 2-4, wherein the pre-ablation voltage value comprises an average of individual pre-ablation voltage values ​​and the post-ablation voltage value comprises an average of individual post-ablation voltage values.

[0011] Clause 6. The system described in clause 5, wherein each of the individual pre-ablation voltage values ​​is at least 0.1 volts.

[0012] Clause 7. The system of any of clauses 3-6, wherein the representative voltage drop value is expressed as a percentage of the pre-ablation voltage value.

[0013] Clause 8. The system of clause 7, wherein the threshold voltage reduction value is 89%.

[0014] Clause 9. The system of clause 7, wherein the threshold voltage reduction value is within the range of 89 to 100%.

[0015] Clause 10. The system of clauses 3-9, wherein the threshold voltage reduction value has a confidence level of at least 95%.

[0016] Clause 11. A system according to any of clauses 3 to 10, wherein the threshold voltage reduction value is dependent on a baseline voltage value.

[0017] Clause 12. The system of clause 11, wherein the threshold voltage reduction value varies in discrete steps relative to the baseline voltage value.

[0018] Clause 13. The system of clause 11, wherein the threshold voltage reduction value varies continuously relative to the baseline voltage value.

[0019] Clause 14. The system of clause 11, wherein the threshold voltage reduction value varies with confidence level.

[0020] Clause 15. The system of any preceding clause, wherein the feedback system conveys the persistence as a continuous variable that changes over time.

[0021] Clause 16. The system of clause 15, wherein the continuous variable is communicated as a percentage drop in voltage.

[0022] Clause 17. The system of clause 16, wherein the feedback system further communicates a target percentage drop in voltage.

[0023] Clause 18. The system of any of the preceding clauses, wherein any of the instrument, algorithm, and / or feedback system is integrated with an electro-anatomical mapping system.

[0024] Clause 19. The system of any of the preceding clauses, wherein the feedback system is integrated with an existing visual map provided by the electroanatomical mapping system.

[0025] Clause 20. The system of any preceding clause, wherein the feedback system conveys the persistence by providing an alert.

[0026] Clause 21. The system of clause 20, wherein the alert includes a visual alert.

[0027] Clause 22. The system of clause 21, wherein the visual alert includes a color code indicating persistence or level of persistence.

[0028] Clause 23. The system of clause 21, wherein the visual alert includes at least one letter, word, number, and / or symbol indicating persistence or a level of persistence.

[0029] Clause 24. The system of clause 21, wherein the alert includes an audible alert.

[0030] Clause 25. A system according to any one of clauses 21 to 24, wherein the alert is binary.

[0031] Clause 26. A system according to any one of clauses 21 to 24, wherein the alert changes colour gradually.

[0032] Clause 27. The system of any preceding clause, wherein the feedback system includes a map indicating an anatomical location of the at least a portion of the cardiovascular lesion.

[0033] Clause 28. The system of clause 27, wherein the feedback system includes an indication of the permanence of the at least a portion of the cardiovascular lesion at the anatomical location on the map.

[0034] Clause 29. A system according to any preceding clause, wherein the feedback system communicates the persistence to a user in real time as the instrument moves.

[0035] Clause 30. The system of any preceding clause, wherein the instrument is configured to deliver the pulsed electric field energy.

[0036] Clause 31. The system described in Clause 30, wherein the instrument comprises an electrode to which the pulsed electric field energy is delivered, the electrode being configured to be positioned against or adjacent to tissue to create at least a portion of the cardiovascular lesion.

[0037] Clause 32. The system of clause 31, wherein the at least a portion of the cardiovascular lesion is formed from a single application of the electrode to or adjacent to the tissue, and the algorithm determines the location of the next single application of the electrode.

[0038] Clause 33. The system described in clause 32, wherein the location of the subsequent single application of the electrode overlaps with at least a portion of the cardiovascular lesion formed from the single application of the electrode.

[0039] Clause 34. A system described in any of clauses 32-33, wherein the location of the subsequent single application of the electrode provides sufficient overlap of stun zones between kill zones to form a continuous, persistent lesion.

[0040] Clause 35. The system of any of the preceding clauses, wherein the pulsed electric field energy leaves the extracellular matrix of the cardiovascular lesion intact.

[0041] Clause 36. The system of any of the preceding clauses, wherein the pulsed electric field energy comprises a series of packets, each packet comprising a biphasic pulse.

[0042] Article 37. A system for determining lesion location, comprising: a catheter having an electrode configured to deliver pulsed electric field energy toward cardiovascular tissue to create a lesion, wherein a first lesion is created by delivering the pulsed electric field energy toward the cardiovascular tissue at a first location; an algorithm that determines a second location of a second lesion based on the determined persistence of the first lesion; a feedback system communicating the second position; and The system comprising:

[0043] Clause 38. The system of clause 37, wherein the determined permanence of the first lesion is generated by the algorithm by comparing a representative drop value to a threshold voltage drop value above which the first lesion is considered to be permanent.

[0044] Clause 39. The system of clause 38, wherein the representative voltage drop value is calculated as the difference between a pre-ablation voltage value and a post-ablation voltage value.

[0045] Clause 40. The system described in clause 39, wherein the pre-ablation voltage value is at least 0.1 volts.

[0046] Clause 41. The system of clause 39, wherein the pre-ablation voltage value comprises an average of individual pre-ablation voltage values ​​and the post-ablation voltage value comprises an average of individual post-ablation voltage values.

[0047] Clause 42. The system described in clause 41, wherein each of the individual pre-ablation voltage values ​​is at least 0.1 volts.

[0048] Clause 43. A system according to any of clauses 39 to 42, wherein the representative voltage drop value is expressed as a percentage of the pre-ablation voltage value.

[0049] Clause 44. The system of clause 43, wherein the threshold voltage reduction value is 89%.

[0050] Clause 45. The system of clause 43, wherein the threshold voltage reduction value is within the range of 89 to 100%.

[0051] Clause 46. A system according to any of clauses 43 to 45, wherein the threshold voltage reduction value has a confidence level of at least 95%.

[0052] Clause 47. A system described in any of clauses 37 to 46, wherein the impedance of the cardiovascular tissue remains below a threshold corresponding to impedance produced by thermal ablation.

[0053] Clause 48. A system described in any of clauses 37 to 47, wherein the pulsed electric field energy comprises a series of packets, each packet comprising a biphasic pulse.

[0054] Clause 49. A cardiovascular disease analysis system comprising: a catheter having at least one electrode; a pulsed electric field generator connectable to the catheter, the pulsed electric field generator including an algorithm configured to deliver at least one dose of pulsed electric field energy through at least one of the at least one electrodes to a region of cardiovascular tissue to create a lesion, and measure at least one voltage value of at least a portion of the cardiovascular lesion through at least one of the at least one electrodes, the algorithm using the at least one voltage value to determine a permanence of the at least a portion of the cardiovascular lesion; The system comprising:

[0055] Clause 50. The system of clause 49, wherein the at least one voltage value includes a representative voltage drop value, and the algorithm determines permanence by comparing the representative drop value to a threshold voltage drop value above which the lesion is deemed to be permanent.

[0056] Clause 51. The system of clause 50, wherein the representative voltage drop value is expressed as a percentage of a pre-ablation voltage value.

[0057] Clause 52. The system of clause 51, wherein the threshold voltage reduction value is 89%.

[0058] Clause 53. The system of clause 51, wherein the threshold voltage reduction value is within the range of 89 to 100%.

[0059] Clause 54. A system described in any of clauses 51 to 53, wherein the pre-ablation voltage value is at least 0.1 volts.

[0060] Clause 55. The system of any one of clauses 51-53, wherein the pre-ablation voltage value comprises an average of the individual pre-ablation voltage values.

[0061] Clause 56. The system described in clause 55, wherein each of the individual pre-ablation voltage values ​​is at least 0.1 volts.

[0062] Clause 57. A system described in any of clauses 50 to 56, wherein the threshold voltage reduction value has a confidence level of at least 95%.

[0063] Clause 58. A system described in any of clauses 49 to 57, wherein the pulsed electric field energy leaves the extracellular matrix of the cardiovascular lesion intact.

[0064] Clause 59. A system described in any of clauses 49 to 58, wherein the pulsed electric field energy comprises a series of packets, each packet comprising a biphasic pulse.

[0065] Clause 60. A system as described in any of clauses 49 to 59, wherein the algorithm provides the persistence to a visual map including the region of cardiovascular tissue.

[0066] Clause 61. The system described in clause 60, wherein the visual map is provided by an electroanatomical mapping system.

[0067] Clause 62. A system described in any of clauses 60-61, wherein the visual map indicates an anatomical location of the at least a portion of the cardiovascular lesion.

[0068] Clause 63. The system of clause 62, wherein the feedback system includes an indication of the permanence of the at least a portion of the cardiovascular lesion at the anatomical location on the map.

[0069] Clause 64. A system according to any of clauses 49 to 63, wherein the algorithm provides the persistence as an alert.

[0070] Clause 65. The system of clause 64, wherein the alert includes a visual alert.

[0071] Clause 66. The system of clause 65, wherein the visual alert includes a color code indicating persistence or level of persistence.

[0072] Clause 67. The system of clause 65, wherein the visual alert includes at least one letter, word, number, and / or symbol indicating persistence or a level of persistence.

[0073] Clause 68. The system of clause 64, wherein the alert includes an audible alert.

[0074] Clause 69. A system according to any of clauses 64 to 68, wherein the alert is binary.

[0075] Clause 70. A system as described in any of clauses 64 to 68, wherein the alert is gradually changed in colour.

[0076] Article 71. A method for assessing the persistence of a lesion in cardiovascular tissue of a patient, comprising: delivering at least one pulse of electric field energy to a region of said cardiovascular tissue to create a lesion; determining a representative voltage drop value for said lesion; determining the permanence of the lesion by comparing the representative voltage drop value to a threshold voltage drop value above which the lesion is deemed to be permanence; The method comprising:

[0077] Clause 72. The method of clause 71, wherein the representative voltage drop value is calculated as the difference between a pre-ablation voltage value and a post-ablation voltage value.

[0078] Clause 73. The method of clause 72, wherein the pre-ablation voltage value is at least 0.1 volts.

[0079] Clause 74. The method of clause 72, wherein the pre-ablation voltage value comprises an average of individual pre-ablation voltage values ​​and the post-ablation voltage value comprises an average of individual post-ablation voltage values.

[0080] Clause 75. The method of clause 74, wherein each of the individual pre-ablation voltage values ​​is at least 0.1 volts.

[0081] Clause 76. The method of clause 71, wherein the representative voltage drop value is expressed as a percentage of the pre-ablation voltage value.

[0082] Clause 77. The method of clause 76, wherein the threshold voltage reduction value is 89%.

[0083] Clause 78. The method of clause 76, wherein the threshold voltage reduction value is in the range of 89 to 100%.

[0084] Clause 79. The method of clause 71, wherein the threshold voltage reduction value has a confidence level of at least 95%.

[0085] Clause 80. The method of clause 71, wherein the lesion comprises part of a whole lesion.

[0086] Clause 81. The method of clause 80, wherein the gross lesion has a ring shape.

[0087] Clause 82. The method of clause 81, wherein the ring shape surrounds at least one entrance to a pulmonary vein.

[0088] Clause 83. The method of clause 80, wherein the entire lesion has a linear shape.

[0089] Clause 84. The method of clause 83, wherein the straight shape forms a cavotricuspid isthmus line.

[0090] Clause 85. The method of clause 71, wherein delivering at least one dose of pulsed electric field energy is accomplished by positioning an electrode near or against said region of said cardiovascular tissue.

[0091] Clause 86. The method of clause 85, wherein the electrode is positioned against the area with a contact force of at least 10 grams.

[0092] Clause 87. The method of clause 85, wherein the electrode has a continuous solid surface positionable near or against the region of the cardiovascular tissue such that the lesion has a disk shape.

[0093] Clause 88. The method of clause 71, further comprising delivering at least one additional pulse of electric field energy to the lesion if the representative decrease value falls below the threshold voltage decrease value.

[0094] Clause 89. The method of clause 71, wherein said determining step is accomplished within about 30 minutes of said delivering step.

[0095] Clause 90. The method of clause 71, wherein the pulsed electric field energy is below the threshold for inducing coagulative thermal damage in the cardiovascular tissue.

[0096] Clause 91. The method of clause 71, wherein the pulsed electric field energy comprises a series of packets, each packet comprising a biphasic pulse.

[0097] Clause 92. The method of clause 90, wherein each packet has a maximum length of 1 second.

[0098] Clause 93. The method of clause 71, wherein the threshold voltage reduction value is dependent on a baseline voltage value.

[0099] Clause 94. The method of clause 93, wherein the threshold voltage reduction value varies continuously relative to the baseline voltage value.

[0100] Clause 95. The method of clause 93, wherein the threshold voltage reduction value is changed in steps relative to the baseline voltage value.

[0101] Clause 96. The method of clause 93, wherein said threshold reduction depends on a confidence level.

[0102] Clause 97. The method of clause 71, wherein the threshold voltage drop value is determined from a voltage drop threshold curve.

[0103] Clause 98. A method for producing a permanent lesion in cardiovascular tissue of a patient, comprising: delivering a dose of pulsed electric field energy to the region of cardiovascular tissue; determining a voltage drop value in said region of said cardiovascular tissue after delivering said dose; delivering one or more additional doses of pulsed electric field energy to said region of said cardiovascular tissue until said voltage drop is at least 89% of the value that will result in formation of said permanent lesion; The method comprising:

[0104] Clause 99. Determining the voltage drop value determining a representative pre-ablation voltage value within the region of the cardiovascular tissue prior to delivering the dose of the voltage reduction; determining a representative post-ablation voltage value within the region of the cardiovascular tissue after the delivery of the dose of the voltage reduction; calculating a difference between the representative pre-ablation voltage value and the representative post-ablation voltage value; 99. The method according to claim 98, comprising:

[0105] Clause 100. The method of clause 99, wherein the representative pre-ablation value is at least 0.1 mV.

[0106] Clause 101. The method of clause 99, wherein the representative pre-ablation voltage value comprises an average of pre-ablation voltage values ​​and / or the representative post-ablation voltage value comprises an average of post-ablation voltage values.

[0107] Clause 102. The method of clause 98, wherein the persistent lesion comprises multiple overlapping doses.

[0108] These and other embodiments are described in further detail in the following description taken in conjunction with the accompanying drawings.

[0109] Incorporation by Reference All publications, patents, and patent applications mentioned in this specification are herein incorporated by reference to the same extent as if each individual publication, patent, or patent application was specifically and individually indicated to be incorporated by reference.

[0110] In the drawings, which are not necessarily drawn to scale, like numbers may describe like components in different figures. Like numbers with different letter suffixes may represent different instances of similar components. The drawings illustrate generally, by way of example, but not by way of limitation, various embodiments discussed in the present document. [Brief description of the drawings]

[0111] [Figure 1] 1 illustrates one embodiment of a tissue modification system. [Diagram 2] 1 provides a schematic diagram of a similar tissue modification system. [Diagram 3] An example of treating tissue point-by-point using a treatment catheter is shown. [Figure 4] Lesions with death and stun zones are shown. [Diagram 5] Shows a continuous ring of lesion divided into sections formed around the left superior and inferior pulmonary veins. [Figure 6A] Voltage maps of the patients are shown in Table 1. [Figure 6B] Voltage maps of the patients are shown in Table 1. [Figure 6C] Voltage maps of the patients are shown in Table 1. [Figure 7A] 4 illustrates exemplary desired voltage drop value thresholds that vary with exemplary baseline voltage values. [Figure 7B] 4 illustrates exemplary desired voltage drop value thresholds that vary with exemplary baseline voltage values. [Figure 7C] 4 illustrates exemplary desired voltage drop value thresholds that vary with exemplary baseline voltage values. [Figure 8]1 provides a visual depiction of exemplary desired voltage drop value thresholds varying with exemplary baseline voltage values ​​including confidence levels. [Figure 9] 1 illustrates one embodiment of a waveform of a signal defined by an energy delivery algorithm. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0112] Devices, systems and methods are provided for treating cardiac disorders, particularly arrhythmias, and more particularly the occurrence of atrial fibrillation. The devices, systems and methods deliver therapeutic energy to portions of the heart, particularly the entrances to the pulmonary veins, to effect tissue modification in the treatment of atrial fibrillation. Such tissue modification creates a lesion or series of lesions that act as a conduction block in the tissue to prevent the transmission of abnormal electrical signals. Generally, tissue modification systems include a specialized treatment catheter, a high voltage waveform generator, and at least one different energy delivery algorithm. Additional accessories and equipment are also utilized, particularly electroanatomical mapping (EAM) systems. EAM systems allow an operator to generate an anatomical shape of the heart and record intracardiac electrical activation with respect to specific anatomical locations within the heart by capturing measured electrical signal metrics (strength, delay of signal arrival from remote stimulation, etc.). Thus, EAM technology allows one to precisely determine the location of arrhythmia occurrence, define the shape of the ventricles in three dimensions, delineate anatomically significant regions, and manipulate and position catheters without fluoroscopic guidance. Additionally, the devices, systems, and methods described herein provide information regarding the efficacy of treatment during a procedure to create electrical blockages in the heart that remain durable and effective over time. In some examples, the devices, systems, and methods described herein evaluate target tissue characteristics at the level of desired characteristics, such as within a single lesion (e.g., to identify zones of different therapeutic effects within a lesion and then use that lesion to determine where to create additional lesions), within a single lesion (e.g., to identify whether a single lesion is likely to remain durable over time), or within a series of consecutive lesions (e.g., to identify gaps between lesions or areas of inadequacy along the path of a lesion or blockage), to name a few. Such devices, systems, and methods may utilize, at least in part, the capabilities provided by EAM technology. In some examples, EAM information is generated using a mapping catheter, and in other examples, this is accomplished by technology incorporated into specialized treatment catheters.For ease of explanation, an embodiment is provided in which the technology is incorporated into a specialized treatment catheter, but is not so limited.

[0113] FIG. 1 shows an example of a tissue modification system 100. In this embodiment, the tissue modification system 100 includes a specialized catheter 102, a high voltage waveform generator 108, and at least one different energy delivery algorithm 152. In this embodiment, the generator 108 includes a user interface 150, one or more energy delivery algorithms 152, a processor 154, a data storage / acquisition unit 156 (such as a memory and / or database), and an energy storage subsystem 158 that generates and stores the energy to be delivered. In some embodiments, one or more capacitors are used for energy storage / delivery, although any other suitable energy storage elements may be used. Additionally, one or more communication ports are included. In this embodiment, an external cardiac monitor 110 is included and connected to an external electrode 172 that is applied to the patient P to acquire an ECG. In this embodiment, the treatment catheter 102 is designed to be monopolar, with the distal end of the catheter 102 having at least one delivery electrode and a return electrode 106 placed on the skin outside the body, typically on the thigh, lower back, or back. In this embodiment, the heart H is accessed via the right femoral vein FV by a suitable access procedure, such as the Seldinger technique. Typically, an introducer sheath 112 is inserted into the femoral vein FV, which serves as a conduit through which various catheters and / or tools, including the treatment catheter 102, may be advanced. The distal end of the catheter 102 is advanced through the inferior vena cava, through the right atrium, and via a transseptal puncture to the left atrium to access the pulmonary vein entrance. In this embodiment, the catheter 102 is used to perform cardiac mapping, which refers to the process of identifying the temporal and spatial distribution of myocardial potentials during a particular cardiac rhythm. Cardiac mapping during abnormal cardiac rhythms aims to elucidate the mechanism of the cardiac rhythm, describe the propagation of activation from initiation to completion within a region of interest, and identify sites of origin or critical conduction to serve as targets for therapy. Once the desired treatment site is identified, the catheter 102 is used to deliver the therapeutic energy.

[0114] The embodiments described herein include a catheter 102 with a delivery electrode 122, shown as a "solid-tip" electrode, with a cylindrical shape with a distal surface having a continuous surface. In some embodiments, the cylindrical shape has a distal diameter of about 2-3 mm, a length along the shaft 120 of about 1 mm, 2 mm, 1-2 mm, 3 mm, 4 mm, 3-4 mm, 5 mm, 6 mm, 7 mm, 8 mm, 9 mm, 10 mm, etc. It is understood that such electrodes are typically hollow, but are referred to as solid for visual appearance. Similarly, such electrodes may include holes for irrigation flow and / or mechanical flexibility. Energy is provided to the catheter 102 via a cable 130 that is connectable to the generator 108, and thus to the delivery electrode 122. Energy is delivered in a sequential manner, such as by repeatedly applying energy point by point, such as around a pulmonary vein or along a line to create a circular treatment zone. This is considered a "targeted local therapy." It is understood that various other catheter 102 designs may be utilized. In some embodiments, the catheter 102 is designed to perform a "one-shot" therapy. One-shot therapy is considered to be a therapy in which energy is delivered via the delivery electrode to the entire circumference of the ostium of the pulmonary vein in a "one-shot", one-time delivery of energy, although such delivery may be repeated if desired. Thus, the electrode 122 often has a loop or flower shape. The electrode 122 may be optionally reapplied, and the electrode 122 may be rotated between "shots" if desired.

[0115] Additional exemplary embodiments of the energy delivery catheter 102 configured to provide targeted local therapy are described in International Patent Application No. PCT / US2018 / 067504, entitled "OPTIMIZATION OF ENERGY DELIVERY FOR VARIOUS APPLICATIONS," which claims priority to Provisional Patent Application No. 62 / 610,430, filed December 26, 2017, and U.S. Provisional Patent Application No. 62 / 693,622, filed July 3, 2018, all of which are incorporated herein by reference for all purposes. As another example, in some embodiments, the energy delivery catheter 102 may have various end effectors according to Provisional Patent Application No. 63 / 159,331, entitled "DEVICES FOR THE DELIVERY OF PULSED ELECTRIC FIELDS IN THE TREATMENT OF CARDIAC TISSUE," filed March 10, 2021, all of which are incorporated herein by reference for all purposes. Similarly, the therapeutic energy may be delivered with various catheter designs, optionally using various attachments, for example, according to International Patent Application No. PCT / US2020 / 066205, entitled "TREATMENT OF CARDIAC TISSUE WITH PULSED ELECTRIC FIELDS," filed on December 18, 2020, which claims priority to Provisional Patent Application No. 62 / 949,633, filed on December 18, 2019, Provisional Patent Application No. 63 / 000,275, filed on March 26, 2020, and Provisional Patent Application No. 63 / 083,644, filed on September 25, 2020, all of which are incorporated by reference for all purposes.

[0116] In the embodiment of FIG. 1, the proximal end of the treatment catheter 102 is electrically connected to an interface connector 10 that is electrically connected to a waveform generator 108 and a separate external device 12, such as, for example, an apparatus capable of providing an electroanatomical mapping procedure (e.g., the CARTO® system, the EnSite™ system, the RHYTHMIA HDX™ system, the KODEX-EPD system, the AcQMap™ system, etc.). The interface connector 10 minimizes any possible interference between the various equipment connected to the contacts (e.g., electrodes, sensors, etc.) of the cardiac treatment catheter. However, it should be understood that in some embodiments, the treatment catheter 102 is directly connected to the generator 108, the external device 12, and / or other devices. Additionally, in this embodiment, the generator 108 is connected to an external cardiac monitor 110 to enable delivery of energy in coordination with sensed cardiac signals from the patient P.

[0117] It should be appreciated that in some instances, the interface connector 10 is connected directly to an electro-anatomical mapping system, such as, for example, a patient interface unit of an electro-anatomical mapping system, using a cable. However, it should also be appreciated that in other embodiments, the interface connector 10 is connected to a pin box, breakout box, input / output box, junction box, or other input module 171, which is then connected to the electro-anatomical mapping system, such as, for example, using a dedicated cable, as shown in FIG. 2. The dedicated cable allows the multi-cable lines to span into individual component connectors or tip pins that are insertable into receptacles in the pin box. This allows individual access to each electrode. The pin box then connects to the electro-anatomical mapping system. It should also be appreciated that the interface connector 10 may include the functionality of a pin box to eliminate a separate pin box. Thus, the interface connector 10 may include a receptacle for receiving the tip pin and associated electronics.

[0118] Exemplary EAM systems include Biosense Webster / Johnson & Johnson's CARTO® system, St. Jude Medical / Abbott's EnSite™ system, Philips' KODEX-EPD system, Acutus Medical's AcQMap system, and Boston Scientific's Rhythmia HDX™ system, to name a few. The CARTO mapping system is one of the most widely used mapping systems and is used herein, for example. The CARTO mapping system utilizes low-level magnetic fields transmitted from three separate coils in a locator pad under the patient. The strength of the magnetic field from each coil is detected by a position sensor embedded near the tip of a specialized treatment catheter. The magnetic field strength of each coil measured by the position sensor is inversely proportional to the distance between the sensor and the coil. Thus, by integrating the magnetic field strength of each coil and converting this measurement to distance, the position sensor (and therefore the catheter tip position) can be triangulated in space. Specialized treatment catheters typically include a proximal electrode pair and a distal electrode pair, as well as a tip electrode capable of delivering therapeutic energy. The catheter can be moved along the surface of the heart to record local endocardial activation times for arrhythmia mapping and simultaneously record location points to generate 3D ventricular geometry. The catheter can be moved along the surface of the heart to record local endocardial activation times for arrhythmia mapping and simultaneously record location points to generate 3D ventricular geometry. CARTO provides the ability to accurately represent ventricular geometry and generate isochronal activation maps and reproducible propagation maps. CARTO also has the ability to record the location of important anatomical landmarks (e.g., His bundle), electrical scar regions (e.g., to create voltage / scar maps), and blood vessels (e.g., coronary sinus, pulmonary veins). CARTO allows for the recording of ablation lesion locations to facilitate the creation of ablation lines.

[0119] Prior to arrhythmia mapping, a stable position reference is established. This is accomplished by placing a position magnet, a triangular device containing three magnetic coils, under the patient and table. The position of this magnet is aligned with any location within the circumference defined at the beginning of the procedure. A reference patch is affixed to the patient's back approximately located over the target ventricle. Should the position reference magnet or patch be displaced during the procedure, its original position is recorded by CARTO, allowing for appropriate repositioning. This allows for accurate tracking of the mapping catheter position, consistency of the location of anatomical landmarks and ablation lesions, and accurate reconstruction of ventricular geometry.

[0120] Once the location reference is stably placed, an appropriate timing reference and window is selected. The timing reference is a selected recording, such as an intracardiac electrogram (EGM) or a surface ECG lead, that represents the ventricular activation of the arrhythmia origin. Intracardiac EGMs are often selected as the timing reference because they are generally more consistent in appearance and more accurate in timing than surface ECG recordings, resulting in more reliable results. Any component of the electrogram may be chosen for the timing reference, including maximum (peak positive) deflection, minimum (peak negative) deflection, maximum upslope (dV / dT), or maximum downslope. In addition to using electrical signal metrics based on timing within the incoming signal, the time delay for the electrical signal itself to reach the location of interest from a natural or induced propagation event may also be measured.

[0121] In addition to facilitating activation mapping, the EAM system provides location mapping capabilities that allow recording of anatomically relevant sites, areas of low endocardial voltage indicative of scar, and areas of ablation. Ablation induces a variety of cellular responses ranging from stunning to death and death, as described in further detail herein. Cardiomyocytes at each of these stages do not conduct electricity immediately after ablation. Stunned cardiomyocytes recover and regain the ability to conduct electricity, a process that occurs over minutes to hours. Dead or dying cardiomyocytes do not conduct electricity in the long term. Over the course of 1-4 weeks after ablation, the dead cells are cleared from the body and replaced by scar tissue, and the accumulated dead zone is used to create a durable conduction block. Specific anatomical locations targeted include the superior vena cava, inferior vena cava, right pulmonary veins, left pulmonary veins, right atrium, right atrial appendage, left atrium, left atrial appendage, right ventricle, left ventricle, right ventricular outflow tract, left ventricular outflow tract, interventricular septum, left ventricular apex, myocardial scar area, myocardial infarction border area, myocardial infarction channel, endocardium, epicardium, papillary muscles, and Purkinje system, to name a few. Treatments are performed at separate sites or as a series of consecutive treatments. Treatment types include left atrial roof line, left atrial posterior / inferior line, posterior wall isolation, lateral mitral isthmus line, septal mitral isthmus line, left atrial appendage, right cavotricuspid isthmus (CTI) creation, pulmonary vein isolation, superior vena cava isolation, Marshallian vein, complex split atrial potential (CFAE) targeted lesion creation, local impulse and rotor modulation (FIRM) targeted lesion creation, and targeted ganglion ablation creation. Such tissue modification creates a conduction block within the tissue to prevent the transmission of abnormal electrical signals.

[0122] In the embodiments described herein, tissue modification is accomplished through the use of pulsed electric field energy, examples of which are provided in later sections of the present specification. A pulsed electric field (PEF) is provided by a generator 108 and delivered to the tissue via a delivery electrode 122 positioned on or near a target tissue region within the heart H. One or more energy delivery algorithms 152 specify electrical signals that provide the PEF energy delivered to the cardiac tissue to cause cell death by non-thermal effects (e.g., energy below threshold for thermal ablation, energy below threshold for inducing coagulation thermal damage, energy below threshold damage to the extracellular matrix, etc.), reduce or avoid inflammation, and / or prevent denaturation of interstitial proteins within anatomical structures (e.g., prevent stenosis) in sensitive sites responsible for treatment morbidity or mortality, such as the phrenic nerve, esophagus, and vasculature. Thus, delivery of energy to the target tissue results in little or no destruction of important anatomical structures, such as tissue-level architectural proteins between the extracellular matrix, thereby leaving the extracellular matrix intact. It should be understood that non-thermal energy is also not cryogenic (i.e., above the threshold for thermal damage caused by freezing). Thus, the temperature of the target tissue remains in a range between baseline body temperature (e.g., 35°C-37°C, but may go down to 30°C) and the thermal ablation threshold. Thus, target ranges of tissue temperature include 30-65°C, 30-60°C, 30-55°C, 30-50°C, 30-45°C, and 30-35°C. Thus, since the tissue temperature remains below the thermal ablation threshold (e.g., 65°C), no subcellular lesions within the cardiac tissue are created by the thermal damage. Additionally, the impedance of the tissue typically remains below the threshold created by thermal ablation. The charring or thermal damage of the tissue causes a change in the conductivity of the cardiac tissue. This increase in impedance / decrease in conductivity is often indicative of a burn and reduces the ability of the tissue to receive further energy. In some examples, the impedance of the system circuit from the cathode to the anode remains in the range of 25-250 Ω, 50-200 Ω, or 75-125 Ω during delivery of PEF energy.Generally, the algorithms 152 are tuned to affect tissue to a predetermined depth and / or volume and / or to target a particular type of cellular response to the delivered energy.

[0123] A variety of electrical signals can be used to generate PEF energy. Such signals are typically characterized by the length of time that the energy is delivered continuously. Continuous energy delivery can lead to thermal damage. Therefore, PEF energy is not delivered continuously, but in packets. Each energy packet includes a series of high voltage pulses separated by rest periods. Typically, a series of packets is delivered to create a lesion. Packet lengths can vary, but are typically up to 1 second. In some embodiments, packet lengths are up to 0.5 seconds, up to 0.1 seconds, or up to 1 millisecond. Such signals are characterized by a variety of additional parameters, which are discussed in more detail in later sections.

[0124] As discussed above, in some embodiments, tissue modification is accomplished by treating tissue point-by-point using the treatment catheter 102. FIG. 3 illustrates using the treatment catheter 102 (with mapping assistance) to treat tissue around the openings of the left superior pulmonary vein LSPV and the left inferior pulmonary vein LIPV point-by-point to create an elliptical treatment zone of overlapping lesion L around the pulmonary vein LSPV, LIPV. The catheter 102 includes a delivery electrode 122, and in some embodiments, the catheter 102 includes one or more additional electrodes 125 (e.g., ring electrodes) disposed along the shaft 120 proximal to the delivery electrode 122. In some embodiments, some or all of the additional electrodes can be used for stimulation and recording (for electrophysiological mapping), such that a separate cardiac mapping catheter is not required when using the catheter 102 for lesion creation or for other purposes, such as sensing.

[0125] During treatment, the physician looks at several clues to determine where to treat next, point by point. For example, the physician may consider impedance measurements, electrogram signals, mapping system placement (e.g., measured distance relative to marked previous treatment delivery sites, fluoroscopy, etc.). In the field of radiofrequency ablation, known protocols are often employed, such as the CLOSE protocol. However, such protocols are not applicable to the delivery of PEF energy and would erroneously direct the physician to utilize lesion placements that would create gaps in the intended ablation area, thus failing the conduction block and leading to treatment failure. This is often due to the transient effect of energy delivery at the lesion, considered a "stun" effect on the cells.

[0126] As mentioned above, when PEF energy is used to create a lesion L, some of the cells that receive the energy are killed by the PEF therapy, and the tissue is eventually replaced by a transmural fibrous scar. Another portion of the tissue is also stunned by the PEF therapy, acutely experiencing a significant reduction in electrical conduction (i.e., "stunned"), but eventually recovering from the PEF injury. This stunning phenomenon may be the result of a peripheral zone of injured but not dead cells in the area surrounding the fatally affected tissue. Injured cells lose the ability to maintain a concentration gradient between the intracellular and extracellular environments due to a temporary compromise of membrane integrity. This causes injured cells to temporarily lose the ability to be excited by adjacent cells and to passively conduct electrical signals to adjacent excitable cells. This effect may have a significant impact on clinical outcomes by confounding the ability to accurately judge the therapeutic effect during the procedure. To ensure a durable clinical effect of PEF cardiac ablation procedures, it is important that the acute electrical insulation does not depend on stunned cells, but instead reflects dead cells that give rise to a durable fibrous scar. Therefore, the stunning effect can cause "false positive" electrical isolation results in cardiac ablation procedures.

[0127] FIG. 4 illustrates a lesion L having a kill zone 107 and a stun zone 109. PEF energy typically creates these treatment zones that extend radially outward from the delivery electrode 122. As shown, the zone closest to the delivery electrode 122 (i.e., zone 107) will endure immediate or eventual cell death due to activated programmed cell death mechanisms, while the surrounding zones (i.e., zone 109) will be stunned and may not lead to sustained or permanent cell death.

[0128] Various measures have been taken to identify the border between the stunned and dead regions. In some cases, a porcine heart model has been utilized. A 7F catheter with a 3.5 mm ablation electrode (TactiCath, Abbott) was connected to a pulsed electric field (PEF) generator (CENTAURI, Galaxy Medical) and placed in the right ventricle RV and left ventricle LV of two closed-chest pigs under EnSite guidance. Biphasic PEF current was delivered between the ablation electrode and a skin patch to 13 sites in the RV (28Amp, total pulse width 1.4ms, 4 pulses) and 19 sites in the LV (35Amp, 1.6ms, 7 pulses). Two hours after ablation, triphenyltetrazolium chloride (TTC, a mitochondrial activity marker) was administered. The pigs were killed and the hearts were removed and fixed in formalin. The hearts were sectioned and stained with hematoxylin and eosin (H&E) and Masson's trichrome. Cytochrome c oxidase (COX) staining was also performed to examine mitochondrial activity and delineate the border between stunning and dead lesions.

[0129] The ablation lesion was clearly demarcated with TTC staining, showing a dense central area surrounded by a pale border. Histology showed destruction of myocyte architecture within the pale border. A rim of hyperstaining (dark red) beyond the pale border indicated the stun zone. COX staining showed absent or low mitochondrial activity within the pale border, consistent with the ablated area. Enhanced activity in COX staining extended into unaffected normal myocardium, consistent with the stun zone. This area is consistent with a hyperstained red rim of TTC surrounding the ablation zone. This increase in mitochondrial activity indicates that cells are losing muscle tissue damaged by PEF and needing ATP (e.g., Na) to restore the proper electrolyte concentration gradient in the process. + -K + These extra energy demands require mitochondrial activity to be upregulated. Thus, the acute ventricular lesions produced by PEF ablation show clear distinctions by TTC staining. COX staining suggests that the dead parts of the lesion are surrounded by areas actively undergoing recovery from the cellular injury, indicative of stunned areas (transient cellular injury that impedes cellular electrical conduction and contractility).

[0130] Additionally, studies have been performed to assess the temporal evolution of changes in voltage signals in response to local PEF protocols to determine the recovery patterns of stunned versus dead tissue. Preclinical animal experimental studies have characterized the temporal evolution of stunning effects to determine whether there is a predictable rate of treatment size reduction over time. Such preclinical studies are used to ensure adequate treatment overlap of clinically created lesions to compensate for the presence of stunned tissue and to select optimal follow-up time points to assess acute effects.

[0131] In one of these preclinical animal experimental studies, a pig model was used where multiple sites within the heart were targeted with PEF energy and voltage signals were measured at specific time segments using a conventional EAM system. At the start of the study, the pig's ventricles were voltage mapped with the EAM system. Locations for PEF energy delivery were then defined on the EAM system to allow sufficient space between lesions. Spheres of 8 mm size centered on the proposed PEF delivery locations were defined on the EAM system. Using a treatment catheter, focal lesions were created within the ventricle at each proposed location, targeting a contact force of 10 g. Ablation parameters and separation distances that provided distinct, non-overlapping lesions were used. In this study, four treatment sites were generated, one in each of the four ventricles. Each ventricle was then remapped such that voltage measurements were taken from the endocardial surface of each ventricle at locations at and around where the PEF energy was applied.

[0132] In addition, a cavotricuspid isthmus (CTI) line was created. Linear ablation of the cavotricuspid isthmus has become the standard of care for typical atrial flutter. In animal studies, a treatment catheter was repeatedly placed and a series of PEF activations were performed at EAM markers spaced 3 mm apart along the CTI to generate an isolation line. Using mapping and / or treatment catheters, the time delay between opposing points of the CTI ablation line was measured to verify the blockade of energy transmission through it.

[0133] Serial voltage remapping was performed to determine the temporal evolution of voltage measurements from approximately 5 min to more than 5 h after PEF treatment. Additionally, adenosine testing was utilized to determine whether the voltage maps would change accordingly. Adenosine was delivered in incremental increments (6, 12, 18, … mg) until AV block was reached while generating voltage maps at a given local site. Following adequate map generation at the target site, time was given for the heart to recover from the adenosine challenge before moving on to the next local lesion, and the voltage maps during adenosine challenge were repeated at the new site. This process was repeated for each local lesion.

[0134] Next, the target tissue was explanted from the heart. The heart-lung complex was perfused with saline along with 500 ml of heparinized NaCl solution using the native vasculature (aorta to coronary arteries). After irrigation, the heart-lung complex was perfused with 500 ml of 10% formalin for 1 h to preserve the anatomical shape during fixation. After a minimum of 2 days of formalin fixation, the heart was opened to grossly measure the ablation lesion and process the tissue for histological evaluation.

[0135] It should be understood that a decrease in voltage measured during the voltage map signifies a decrease in energy delivery as the area targeted for ablation shows reduced excitability. This is the desired outcome when creating a lesion. During successive remapping, the size of the voltage amplitude reduced area decreased over time, up to at least 1 hour after treatment and beyond. This result of a decrease in voltage amplitude size over time indicates that a clear "stunning" effect was occurring at least along the periphery of the lesion, indicating that the stunned tissue was recovering over time. As the size of the voltage amplitude reduced area continued to decrease at least over time, it was shown that the traditional timing of remapping at 20 minutes after ablation to confirm proper ablation cannot accurately confirm that the ablated tissue has a persistent chronic voltage reduction. The period associated with the recovery of voltage amplitude correlated with the distance from the delivered lesion, with the furthest areas recovering the fastest, followed by a gradual recovery of voltage as one approached the final lesion over time. This indicates a correlation between the treatment intensity (as treatment intensity decreases exponentially with distance from the tissue-electrode interface for PEF delivery) and the voltage recovery of the electrogram.

[0136] Because recovery from stunning occurs over a timescale of at least several hours, traditional acute intraoperative lesion permanence assessments developed for thermal ablation techniques cannot be trusted to guide treatment with PEF energy. Doing so would lead the user to mistakenly believe that a particular area or associated lesion has been effectively ablated when in fact it was reversibly affected stunning tissue. This error may result in gaps in the formation of the chronic continuous transmural scar required for conduction blockade, resulting in lesion isolation that is not permanent and may ultimately lead to the recurrence of arrhythmic symptoms.

[0137] Here, methods, systems, and devices are provided that account for this stunning effect and provide reliable acute intraoperative assessment of lesion permanence so that a long-term complete conduction block can be achieved. In one embodiment, methods, systems, and devices are provided for intraoperatively assessing a series of individual lesions in succession in the creation of an electrical block (e.g., a global lesion) and ensuring that such block is durable in the long term. In this embodiment, a tissue modification system 100 is utilized to deliver therapeutic PEF energy to a portion of the heart, such as to create a ring of lesions L around the entrance to a pulmonary vein as shown in FIG. 3, for example, as in the treatment of atrial fibrillation. Such tissue modification aims to create a conduction block in the tissue to prevent the transmission of abnormal electrical signals. In this embodiment, a voltage map is generated using the EAM system before and after the creation of the lesion L. Such a voltage map provides multiple voltage values ​​for locations along and around the lesion L. Thus, a set of pre-ablation voltage values ​​is generated and a set of post-ablation voltages is generated for various locations.

[0138] FIG. 5 shows a continuous ring of lesion L' representing the individual lesion of FIG. 3 formed around the left superior pulmonary vein LSPV and the left inferior pulmonary vein LIPV. In this embodiment, the ring of lesion L' is divided into a plurality of sections, such as, for example, eight sections as shown in FIG. 4, where the plurality of sections includes a first section 300, a second section 302, a third section 304, a fourth section 306, a fifth section 308, a sixth section 310, a seventh section 312, and an eighth section 314. Within each section, a region is defined that includes at least three anatomical points having both pre-ablation and post-ablation voltage values. Thus, the anatomical points are selected due to their ability to be correlated in the pre-ablation voltage map and the post-ablation voltage map. In this embodiment, the anatomical points are selected whose pre-ablation voltage exceeds a minimum activation threshold, such as, for example, 0.1 mV or 0.2 mV. For a given anatomical point, the difference between the pre-ablation voltage value and the post-ablation voltage value is determined and considered as the voltage drop value at that anatomical point. In this embodiment, the voltage drop value is expressed as a percentage drop in voltage between the pre-ablation voltage value and the post-ablation voltage value. Then, in this embodiment, the voltage drop values ​​at each of the three anatomical points are collected and the median is considered as the representative voltage drop value. If the representative voltage drop value is less than 89%, the section is considered to contain at least one lesion L that is not persistent. Thus, the desired representative voltage drop value for persistence is 89% or more, including 89%, at least 89%, 90%, at least 90%, 91%, at least 91%, 92%, at least 92%, 93%, at least 93%, 94%, at least 94%, 95%, at least 95%, 96%, at least 96%, 97%, at least 97%, 98%, at least 98%, 99%, at least 99%, 100%. Identification of the sections allows for re-treatment of at least some of the sections during the procedure to avoid reversal of lesion formation over time. Re-treatment can be performed after analysis of one section, multiple sections, or all sections.It should be appreciated that this process can be repeated as many times as desired until each section is deemed permanent. Once this process is complete, the entire ring of lesion L' is deemed permanent and electrical blockade is complete.

[0139] It should be appreciated that any number of anatomical points may be selected to determine representative voltage drop values, such as 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 2-5, 3-4, 5-10, at least 3, at least 5, at least 10, etc. Also, it should be appreciated that a continuous series of lesions, such as a ring of lesions L', may be divided into any number of sections, such as 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 2-5, 3-4, 6-8, 5-10, at least 3, at least 5, at least 8, at least 10, etc. Similarly, shapes other than rings may be analyzed, including lines, arcs, angles, and irregular shapes, to name a few. Additionally, it should be appreciated that sections may be selected such that each section includes a single lesion L. In such an example, each lesion L may be evaluated as persistent or non-persistent, rather than multiple lesions being evaluated at one time.

[0140] In the above-described embodiment, the subject % reduction threshold was derived using the representative technique described, using actual clinical data analyzing pre-treatment and post-treatment voltage maps, and 90-day retreatment data to derive where inadequate electrical insulation permanence occurred due to stunning effects on tissue (all patients achieved acute electrical conduction block at the time of procedure). The desired threshold of ≥89% representative voltage reduction value is based on data analysis of the ECLIPSE AF (Atrial Fibrillation) clinical trial data. The ECLIPSE AF clinical trial was conducted by Galaxy Medical, Inc. (San Carlos, CA) and evaluated catheter ablation of atrial fibrillation using pulsed electric field (PEF) ablation with the CENTAURI™ system (e.g., generator 108) connected to a CE-marked local contact force sensing catheter (e.g., treatment catheter 102). This multicenter study included patients undergoing first-time catheter ablation for paroxysmal atrial fibrillation (PAF) or short-term (<1 year) persistent atrial fibrillation (PerAF). Data included pre- and post-ablation voltage mapping measurements. Lesion persistence was checked during 90-day remapping. The analysis included 160 sections defined and measured as described above. Statistical analysis revealed a sensitivity of 97.9% for an optimal voltage reduction threshold of 88.7% (89%) and a positive predictive value of 98.6% (p<0.05). Thus, the analysis had a high sensitivity rate and high predictive power.

[0141] Exemplary voltage mapping data for patient lesions is provided in Table 1. Note that a value of X indicates insufficient data for calculation. Here, a ring of lesion L' was analyzed around the left pulmonary vein LPV and another ring of lesion L' was analyzed around the right pulmonary vein RPV. Each ring of lesion L' was divided into eight sections. The percentage of voltage drop was calculated by dividing the post-treatment voltage by the pre-treatment voltage at the same approximate location. The median voltage drop is shown along with the corresponding pre-ablation and post-ablation voltage values.

[0142]

Table 1

[0143] 6A-6C show voltage maps for the patient in Table 1. FIG. 6A is a voltage map 600 taken before treatment. The voltage map is a three-dimensional rendering of the posterior aspect of the anatomy of the heart H. Thus, the left superior pulmonary vein LSPV and the left inferior pulmonary vein LIPV are visible on the left, and the right superior pulmonary vein RSPV and the right inferior pulmonary vein RIPV are visible on the right. Typically, such voltage maps are color-coded, with grey areas corresponding to non-excitable tissue (electrogram amplitude <0.2 mV), purple areas corresponding to normal voltage amplitude (electrogram amplitude >0.5 mV), and red / yellow representing areas of reduced (low) electrogram voltage amplitude (electrogram amplitude 0.2-0.5 mV). Here, the purple areas are represented by hatch marks and extend from the surface of the heart H to each of the pulmonary veins LSPV, LIPV, RSPV, and RIPV. Treatment of this patient included the formation of a ring of lesion L' around the left pulmonary vein LPV and another ring of lesion L" around the right pulmonary vein RPV (indicated by double hatch marks) as shown in Figure 3. Figure 6B is a voltage map of the same patient and a similar image of the heart taken intraoperatively after treatment. As shown, the rings of lesions L',L" create an electrical block such that the hatch mark areas representing purple areas (potential amplitude >0.5 mV) do not extend beyond the rings of lesions L',L" into the pulmonary veins LSPV, LIPV, RSPV, and RIPV. The contralateral areas of the lesions L',L" (covering the pulmonary veins LSPV, LIPV, RSPV, and RIPV) are gray representing amplitudes less than 0.2 mV. Figure 6C is a voltage map of the same patient and a similar image of the heart H taken 90 days after treatment. As shown, the lesion L” around the right pulmonary vein RSPV, RIPV maintained electrical block. This is consistent with the data shown in Table 1, where the voltage drop values ​​in each of the eight sections around the right pulmonary vein were greater than 89%. Thus, all lesions were permanent. However, the lesion L’ around the left pulmonary vein LSPV, LIPV did not maintain electrical block, and the hatched area, which represents the purple area, here extends beyond the lesion L’ into the left pulmonary vein LSPV, LIPV. This is consistent with the data shown in Table 1, where the voltage drop values ​​in section 2 and section 4 were less than 89%. Thus, the lesions in these sections were not permanent in the long term.

[0144] It will therefore be appreciated that in some instances, a target tissue region has one of three general states. If the baseline voltage of the target tissue region is below a minimum activation threshold, such as 0.1 mV or 0.2 mV, the region is considered initially non-excitable. If the voltage drop value of the target tissue was above the minimum activation threshold, but is treated and then is at or exceeds the desired voltage drop value, such as at least 89%, the region is considered permanently treated. If the voltage drop value of the target tissue was above the minimum activation threshold, but is treated and then is below the desired voltage drop value, such as at least 89%, the region is considered non-permanently treated and will benefit from re-treatment or supplemental treatment to achieve permanency.

[0145] In some embodiments, the desired voltage reduction value varies with the baseline voltage value. For example, in some embodiments, a tissue region that initially had a moderate baseline voltage will meet a lower desired voltage reduction value threshold upon treatment for the treatment to be considered durable. For example, FIG. 7A provides a visual illustration of exemplary desired voltage reduction value thresholds varying with exemplary baseline voltage values. Here, four different thresholds are shown: a first threshold level 650 of a baseline voltage up to a first baseline voltage value (e.g., 0.1 mV), a second threshold level 652 of a baseline voltage between the first and second baseline voltage values ​​(e.g., 0.1 mV to 0.5 mV), a third threshold level 654 of a baseline voltage between the second and third baseline voltage values ​​(e.g., 0.5 mV to 1.0 mV), and a fourth threshold level 656 of a baseline voltage between the third and fourth baseline voltage values ​​(e.g., 1.0 mV or greater). In this example, the first threshold level 650 is essentially zero at which the tissue region meets the threshold without treatment since the tissue region is deemed appropriately non-excitable from the start. Additionally, the second threshold level 652 exceeds the first threshold level, the third threshold level 654 exceeds the second threshold level 652, and the fourth threshold level 656 exceeds the third threshold level 654. It should be understood that the number of threshold levels and the value of each threshold level may vary depending on the circumstances. Similarly, in some embodiments, the desired voltage reduction value varies continuously with the baseline voltage value rather than in discrete steps. For example, FIGS. 7B-7C provide a visual illustration of an exemplary desired voltage reduction value threshold that varies continuously with an exemplary baseline voltage value, thus creating a desired voltage reduction value threshold curve 660.

[0146] In other embodiments, a confidence value is provided for each desired voltage drop value. Thus, in some embodiments, the desired voltage drop value may be utilized or selected based on a desired confidence value or confidence level. For example, the desired voltage drop values ​​in the embodiments described herein above were based on a high confidence level, such as a 95% confidence level. Such a desired voltage drop value would be used when circumstances suggest a high confidence of permanence. However, in some instances, such as for certain tissue types or treatment locations, a lower confidence level may be appropriate. In such instances, a lower desired voltage drop value (e.g., a desired voltage drop value less than 89%) may be acceptable to consider the lesion as persistent. In some embodiments, the user is provided with the voltage drop value and / or confidence value during the procedure. This allows the user to obtain data and a sense of persistence, which can be interpreted to some extent by the user to determine the appropriate permanence of the lesion based on surrounding data such as the region of the heart, the user's experience, the thickness of the heart in this region, or the density and dose of the ablation treatment applied to that region. FIG. 8 provides a visual illustration of exemplary desired voltage drop value thresholds varying with exemplary baseline voltage values, with confidence levels also shown. Here, a high confidence curve 670 of a desired voltage drop value threshold is shown varying with an exemplary baseline voltage value, such as having a 95% confidence level that the persistence information is accurate. Further, a low confidence curve 672 of a desired voltage drop value threshold is shown varying with an exemplary baseline voltage value, such as having a 90% confidence level that the persistence information is accurate. Further, an even lower confidence curve 674 of a desired voltage drop value threshold is shown varying with an exemplary baseline voltage value, such as having an 85% confidence level that the persistence information is accurate. It should be understood that these confidence levels may be based on, for example, experimental data or selected as standard deviations from an absolute threshold. Exemplary confidence intervals include 95% confidence for persistence, 90% confidence, 85% confidence, 80% confidence, etc. Such confidence values ​​may be provided to the user in graphical or numerical form, to name a few. Alternatively, continuously variable confidence levels may be provided to the user.For example, such confidence values ​​may be graphed over time as the user moves the ablation catheter over a region of the heart, or the confidence values ​​may be provided on a final voltage map.

[0147] It should be appreciated that in some embodiments, the representative voltage drop value is not expressed as a percentage drop, but rather the voltage value is expressed in absolute terms (e.g., in millivolts) as the voltage value itself. In other embodiments, the representative voltage drop value is instead a target minimum voltage threshold, such as 0.05 mV, 0.1 mV, 0.2 mV, 0.3 mV, 0.4 mV, 0.5 mV, 0.6 mV, 0.7 mV, 0.8 mV, 0.9 mV, or 1.0 mV, to name a few. In such embodiments, after administering one or more PEF treatments, a section or area of ​​lesion, t, i.e., voltage value, is generated and compared to the target minimum voltage threshold. For example, 20 minutes after completing a treatment procedure, the user may generate a voltage map and examine it for any areas that exceed the target minimum voltage threshold. Any areas with voltages that exceed this target minimum voltage threshold may be considered to be solely affected by stunning. The user may then modify this area and strategically place lesions in areas that have not been fully treated to improve confidence in the permanence of the electrical conduction block in these areas. In some embodiments, the EAM system also highlights specific areas where thresholds have not been met, helping to guide the user as to where additional treatment may be desired.

[0148] It should be appreciated that the lesion analysis may be provided to the user in a variety of ways. In some embodiments, the lesion analysis and feedback to the user is provided by an analysis system built into the EAM system, or by an analysis system that is separate but works in conjunction with the EAM system, such as using an algorithm that integrates with or coordinates with existing functionality of the EAM system. For example, in some embodiments, the lesion analysis (e.g., section analysis) is performed automatically as the treatment progresses using an algorithm, such that feedback is provided to the user in real time throughout the treatment, such as after the generation of each section of the lesion. In such an example, the sections are pre-determined such that the completion of the section is the trigger event. Such pre-determination may be built into the algorithm or may be determined by user input, such as by entering information such as the type of procedure, the type of lesion, the location of the lesion, the geometry of a device such as a treatment catheter, a time period, or any combination of these, to name a few. When a section is considered a single lesion, the completion of the lesion is the trigger event.

[0149] In some embodiments, the feedback is provided by an alert, such as a visual and / or audio alert. Exemplary visual alerts include words such as "complete", "persistent", and "temporary". Other visual alerts include numbers or letters such as D for permanent or I for incomplete. Alternatively, a 1 for permanent and a 0 for non-persistent. It should be appreciated that such visual alerts include at least one letter, word, number, and / or symbol, to name a few. In other embodiments, the visual alert includes a color code indicating the persistence or level of persistence, such as green for persistent and red for non-persistent. Alternatively, the color shading between persistent and non-persistent indicates how close the lesion is to being persistent or indicates a confidence level of the persistence assessment. In some embodiments, the alert is an audio alert, such as a particular sound indicating the creation of a persistent lesion, or optionally a different sound indicating the creation of a non-persistent lesion. In some embodiments, the feedback is binary (e.g., persistent / not persistent), while in other embodiments the feedback is gradual (e.g., persistence with a particular confidence level, or an indication of how close the lesion is to sufficient persistence). In some embodiments, the feedback is provided as a continuous variable (e.g., % drop) that is plotted or tabulated. When plotted over time, a recommended baseline % drop value (e.g., 89% drop, 90% drop, etc.) may be overlaid so that the user may gain some confidence in the persistence of any given voltage drop area.

[0150] In some embodiments, the feedback is provided in an integrated manner with the existing visual map provided by the EAM system, while in other embodiments, a separate map or information display regarding the lesion persistence status is provided, such as in each of the sections. In other embodiments, the lesion analysis and feedback is separate from the EAM system and utilizes information generated by one or more other devices, such as the generator 108, external cardiac monitor 110, other system accessories, or a combination thereof. In such embodiments, the lesion analysis may similarly be performed automatically as the treatment progresses using algorithms, such that feedback is provided to the user in real time throughout the treatment, such as after the generation of each lesion or section of a lesion.

[0151] It should be understood that analysis of lesion permanence may similarly be performed using other data generated from other systems, such as the EAM system or generator, cardiac monitor, or accessories. Exemplary parameters for such use include unipolar or bipolar electrogram amplitude reduction (absolute or %), frequency domain changes (frequency content, ratio of high frequency to low frequency content, power at a particular frequency or frequency band, etc.), local voltage gradient change, absolute voltage change, absolute voltage magnitude, percent drop in voltage amplitude, local gradient of voltage, frequency content, local gradient change, time domain features (rise time, fractional measurements, timing of zero crossings, local conduction delay, duration of waveform rise above a threshold such as zero, etc.), unipolar EGM, bipolar EGM, combined unipolar and bipolar EGM, regional analysis by sector, normalization to baseline map, spatial pattern of voltage, spatial pattern of change, dimension of area of ​​potential reduction, frequency content, to name a few. It should be appreciated that in some embodiments, the EAM system or electrogram recording system tracks or indicates metrics of interest relative to predefined thresholds in real time as the ablation catheter moves.

[0152] In other embodiments, the EAM system is used to compare pre- and post-treatment information throughout a treatment session to check for areas of suspected permanence. In one embodiment, the EAM system plots and displays (e.g., side-by-side) pre-treatment and post-treatment voltage maps to allow the user to visualize regionalizations that experienced stronger or weaker signal drops. In another embodiment, the EAM system performs mathematical operations between pre- and post-treatment signal metrics. For example, in one embodiment, the EAM system divides the captured voltage values ​​on the post-treatment map by the pre-treatment values ​​from the same approximate (or interpolated) location. In this way, a % drop EAM map is generated, which allows the user to quickly visualize areas that have undergone stronger and weaker drops. This region may use a specific threshold criterion, such as 89% drop, whereby the EAM system flags all areas that do not meet the >89% drop criterion. This gives the user a quick, at-a-glance view of the success of the treatment and the expected permanence of the generated electrical insulation. In some embodiments, if an area does not meet the criteria, the user may follow up further to "fix" the target area with additional lesion placements to increase confidence in the permanence of the electrical conduction block.

[0153] In another embodiment, pre- and post-treatment maps of the same region may be compared for other signals, such as changes in absolute voltage drop, or other suitable electrical properties (e.g., phase, split time domain), and these maps may be used in a similar manner as described above.

[0154] In some embodiments, the time elapsed between the pre-treatment and post-treatment maps is used to adjust the resulting outcome metrics. This is because some lesions may already begin to heal during treatment, especially if a significant amount of time is spent completing a series of point-by-point lesions. The healing rate of lesions treated at the beginning of treatment is expected to be higher than that of lesions treated later in the treatment. Thus, the recorded metrics are scaled according to the relative time, resulting in a uniform assessment regardless of the post-treatment map.

[0155] In some embodiments, post-treatment maps are generated at one or more intervals to assess the permanence of electrical signal reduction following a determined amount of stun recovery time. For example, post-treatment maps may be generated immediately after completing one or more lesions, immediately after completing an entire set of lesions, or at intervals such as 5 minutes, 10 minutes, 20 minutes, 30 minutes, 45 minutes, 60 minutes, 120 minutes, or 180 minutes after treatment. For example, a dwell period of 20 minutes may be used before performing a treatment remap, in this way, more subtle stunned areas may be detected and visualized with less interference, since the least affected stunned tissue areas have already recovered signal.

[0156] As mentioned above, in some embodiments, lesion analysis is done automatically as the treatment progresses using an algorithm, so that feedback is provided in real time throughout the treatment. In some embodiments, the algorithm utilizes this information to determine the location of the next lesion, such as when performing ablation point by point along a ring or line. As mentioned above, overlap of lesions is desirable to ensure that no gaps remain between lesions, especially after stun zone recovery. Thus, the location of the next single application of energy provides sufficient overlap of stun zones between kill zones to form a continuous and persistent lesion.

[0157] In some embodiments, the next energy application is directed to the same location as the first energy application. This may be desirable if the first application or dose is insufficient for permanence. For example, the voltage drop value may have been below a threshold for permanence, such as less than 89%. In such instances, additional energy applications may be provided until the lesion is deemed sufficiently permanence.

[0158] As described above, lesions L and sections of lesions created using PEF energy may be analyzed. In the system 100 shown in FIG. 1, a pulsed electric field (PEF) is provided by a generator 108 and delivered to tissue via delivery electrodes 122 positioned on or near a target tissue region. In some embodiments, high voltage, brief, biphasic electrical pulses are delivered through the electrodes 122 in proximity to the target tissue. These electrical pulses are provided by at least one energy delivery algorithm 152. In some embodiments, each energy delivery algorithm 152 defines a signal having a waveform that includes a series of energy packets, each energy packet including a series of high voltage pulses. In such embodiments, the algorithm 152 specifies parameters of the signal such as the energy amplitude (e.g., voltage) and duration of the applied energy, consisting of the number of packets, the number of pulses within a packet, and the fundamental frequency of the pulse sequence, to name a few. Additional parameters may include switch times between polarities of biphasic pulses, dead times between biphasic cycles, and pause times between packets, as described in more detail herein. There may be a fixed pause between packets, or the packets may be gated to the cardiac cycle and vary with the patient's heart rate, there may be an intentional varying pause algorithm, or no pause may be applied between packets, there may be a feedback loop based on sensor information, an auto-stop specification, etc.

[0159] FIG. 9 illustrates one embodiment of a signal wave 400 defined by the energy delivery algorithm 152. Here, two packets are shown, a first packet 402 and a second packet 404, separated by a rest period 406. In this embodiment, each packet 402, 404 consists of a first biphasic cycle (including a first positive pulse peak 408 and a first negative pulse peak 410) and a second biphasic cycle (including a second positive pulse peak 408' and a second negative pulse peak 410'). The first and second biphasic pulses are separated by a dead time 412 (i.e., a rest) between each biphasic cycle. In this embodiment, the biphasic pulses are symmetric such that the set voltage 416 is the same at the positive and negative peaks. Here, the biphasic symmetric wave is a square wave such that the magnitude and time of the positive voltage wave are approximately equal to the magnitude and time of the negative voltage wave.

[0160] A. Voltage The voltages used and contemplated may be the peaks of a square waveform, the peaks of a sinusoidal or sawtooth waveform, or the RMS voltage of a sinusoidal or sawtooth waveform. In some embodiments, the energy is delivered in a unipolar manner, and each high voltage pulse or set voltage 416 is between about 500V and 10,000V, specifically about 3500V to 4000V, about 3500V to 5000V, about 3500V to 6000V, including all values ​​and subranges therebetween, including about 250V, 500V, 1000V, 1500V, 2000V, 2500V, 3000V, 3500V, 4000V, 4500V, 5000V, 5500V, and 6000V, to name a few. The voltage delivered to the tissue may be determined based on the set point of the generator 104, taking into account electrical losses along the length of the device 102 due to the inherent impedance of the device 102, or without taking into account losses along the length, i.e., the voltage delivered may be measured at the tip of the generator or instrument.

[0161] It should be appreciated that the set voltage 416 may vary depending on whether the energy is delivered in a monopolar or bipolar manner. In a bipolar delivery, a lower voltage may be used due to the smaller, more directional electric field. The bipolar voltage selected for use in treatment depends on the electrode separation distance, but in a monopolar electrode configuration using one or more separate dispersive pad electrodes, the energy may be delivered without much consideration of the exact placement of the catheter electrode and the dispersive electrode placed on the body. In monopolar electrode embodiments, larger voltages are typically used with effective separation distances on the order of 10 cm to 100 cm due to the dispersive behavior of the delivered energy passing through the body to the dispersive electrode. Conversely, in a bipolar electrode configuration, the separation distance has a large impact on the concentration of electrical energy delivered to the tissue and the effective dose, since the active areas of the electrodes are relatively close, on the order of 0.5 mm to 10 cm, including 1 mm to 1 cm. For example, if the targeted voltage to distance ratio is 3000V / cm to elicit the desired clinical effect at the appropriate tissue depth (1.3mm), then if the separation distance is changed from 1mm to 1.2mm, this would increase the treatment voltage from 300V to approximately 360V, a change of 20%.

[0162] It should be understood that in various embodiments, the output is controlled or altered to achieve the desired current rather than voltage. In some embodiments, the energy is delivered in a monopolar manner and has a current of 20 amps, 21 amps, 22 amps, 23 amps, 24 amps, 25 amps, 26 amps, 27 amps, 28 amps, 29 amps, 30 amps, 31 amps, 32 amps, 33 amps, 34 amps, or 35 amps, to name a few.

[0163] B.Frequency It should be understood that if the signal is continuous, the number of biphasic cycles per second of time is the frequency. In some embodiments, biphasic pulses are utilized to reduce undesired muscle stimulation, particularly myocardial stimulation. In other embodiments, the pulse waveform is monophasic and has no well-defined inherent frequency. Instead, the fundamental frequency may be considered by doubling the length of the monophasic pulse to derive the frequency. In some embodiments, the frequency of the signal ranges from 50 kHz to 1 MHz, more specifically from 50 kHz to 1000 kHz. It should be understood that at some voltages, frequencies of 100-250 kHz or less may cause undesired muscle stimulation. Thus, in some embodiments, the signal has a frequency in the range of 300-800 kHz, 400-800 kHz, or 500-800 kHz, e.g., 300 kHz, 400 kHz, 450 kHz, 500 kHz, 550 kHz, 600 kHz, 650 kHz, 700 kHz, 750 kHz, 800 kHz, etc. Additionally, cardiac synchronization is typically utilized to reduce or avoid unwanted myocardial stimulation during sensitive rhythm periods. It should be appreciated that even higher frequencies may be used with the use of components that minimize signal artifacts.

[0164] C. Voltage and Frequency Balance The frequency of the delivered waveform may be varied relative to the synchronous treatment voltage to maintain the appropriate therapeutic effect. Such synergistic changes would include a reduction in frequency causing a stronger effect combined with a reduction in voltage causing a weaker effect. For example, in some cases treatment may be delivered using 3000V in a monopolar fashion with a waveform frequency of 600kHz, while in other cases treatment may be delivered using 2000V with a waveform frequency of 400kHz.

[0165] D. Packet As discussed above, the algorithm 152 typically defines a signal having a waveform that includes a series of energy packets, each of which includes a series of high voltage pulses. The number of cycles 420 is half the number of pulses in each biphasic packet. With reference to FIG. 9, the number of cycles 420 for the first packet 402 is 2 (i.e., 4 biphasic pulses). In some embodiments, the number of cycles 420 is set between 2 and 1000 per packet, including all values ​​and subranges therebetween. In some embodiments, the cycle number 420 is between 5 and 1000 per packet, between 2 and 10 per packet, between 2 and 20 per packet, between 2 and 25 per packet, between 10 and 20 per packet, between 20 and 30 per packet, between 25 per packet, between 20 and 40 per packet, between 30 per packet, between 30 and 45 per packet, between 45 per packet, between 20 and 50 per packet, between 30 and 60 per packet, up to 60 per packet, up to 80 per packet, up to 100 per packet, up to 1,000 per packet, or up to 2,000 per packet, including all values ​​and subranges therebetween.

[0166] The duration of the packet is determined by the number of cycles, among other factors. For matching pulse durations (or sequences of positive and negative pulse durations for a biphasic waveform), the more cycles, the longer the packet duration and the greater the amount of energy delivered. In some embodiments, the packet duration is in the range of about 50-1000 microseconds, such as 50 μs, 60 μs, 70 μs, 80 μs, 90 μs, 100 μs, 125 μs, 150 μs, 175 μs, 200 μs, 250 μs, 100-250 μs, 150-250 μs, 200-250 μs, 500-1000 μs, to name a few. In other embodiments, the packet duration is in the range of about 100-1000 microseconds, such as 150 μs, 200 μs, 250 μs, 500 μs, or 1000 μs.

[0167] The number of packets, or packet count, delivered during a treatment typically includes 1-250 packets, including all values ​​and subranges therebetween, in some embodiments, the number of packets delivered during a treatment includes 2-5 packets, 3 packets, 5 packets, 5-10 packets, 10 packets, 12 packets, 10-15 packets, 15 packets, 20 packets, 15-20 packets, 25 packets, 30 packets, or more than 30 packets.

[0168] E. Downtime In some embodiments, the time between packets, referred to as the idle period 406, is set between about 0.001 seconds and about 5 seconds, including all values ​​and subranges therebetween. In other embodiments, the idle period 406 is in the range of about 0.01 to 0.1 seconds, including all values ​​and subranges therebetween. In some embodiments, the idle period 406 is between about 0.5 milliseconds and 500 milliseconds, between 1 millisecond and 250 milliseconds, or between 10 milliseconds and 100 milliseconds, to name a few.

[0169] F. Batch In some embodiments, the signal is synchronized with the heart rhythm such that each packet is delivered synchronously within a designated period relative to the heart beat, so that the resting periods coincide with the heart beat. It should be understood that the packets delivered within each designated period relative to the heart beat may be considered a batch or bundle. Thus, each batch has a desired number of packets such that a desired total number of packets is delivered at the end of the treatment period. While each batch may have the same number of packets, in some embodiments, the batches have a varying number of packets.

[0170] In some embodiments, only one packet is delivered between heartbeats. In such instances, the pause period may be considered the same as the period between batches. However, if multiple packets are delivered between batches, the pause period is typically different from the period between batches. In such instances, the pause period is typically much shorter than the period between batches. In some embodiments, each batch includes 1-10 packets, 1-5 packets, 1-4 packets, 1-3 packets, 2-3 packets, 2 packets, 3 packets, 4 packets, 5 packets, 5-10 packets, to name a few. In some embodiments, each batch has a period of 0.5 ms-1 sec, 1 ms-1 sec, 10 ms-1 sec, 10 ms-100 ms, to name a few. In some embodiments, the period between batches is variable depending on the patient's heart rate. In some instances, the period between batches is 0.25-5 seconds.

[0171] Treatment of the tissue area continues until the desired number of batches have been delivered to the tissue area. In some embodiments, between 2 and 50 batches are delivered per treatment, with a treatment being considered a treatment of a particular tissue area. In other embodiments, a treatment may include between 5 and 40 batches, between 5 and 30 batches, between 5 and 20 batches, between 5 and 10 batches, between 5 and 6 batches, between 7 and 8 batches, between 9 and 10 batches, between 10 and 15 batches, etc.

[0172] G. Switching time and dead time The switch time, also known as the interphase delay, is the delay in energy or the period of no energy delivered between the positive and negative peaks of a biphasic pulse, as shown in Figure 9. In some embodiments, the switch time is in the range of about 0 and about 1 microseconds, including all values ​​and subranges therebetween. In other embodiments, the switch time is in the range of about 1 and 20 microseconds, including all values ​​and subranges therebetween. In other embodiments, the switch time is in the range of about 2 and about 8 microseconds, including all values ​​and subranges therebetween.

[0173] A delay may also be inserted between each biphasic cycle, referred to as "dead time" or inter-pulse delay. Dead time is within a packet, but occurs between biphasic pulses. This is in contrast to a quiescent period or inter-packet delay, which occurs between packets. In other embodiments, the dead time 412 ranges from about 0 to 0.5 microseconds, 0 to 10 microseconds, 2 to 5 microseconds, 0 to 20 microseconds, about 0 to about 100 microseconds, or about 0 to about 100 milliseconds, including all values ​​and subranges therebetween. In some embodiments, the dead time 412 ranges from 0.2 to 0.3 microseconds. Dead time may also be used to define the period between individual monophasic pulses within a packet.

[0174] Delays such as switch times or dead times are introduced into the packets to mitigate the effects of biphasic cancellation in the waveform. In some instances, both the switch time and the dead time are increased together to enhance the effect. In other instances, only the switch time or only the dead time is increased to induce this effect.

[0175] G. Waveform FIG. 9 shows an embodiment of a waveform 400 having symmetric pulses such that the voltage and duration of the pulse in one direction (i.e., positive or negative) is equal to the voltage and duration of the pulse in the other direction. It should be understood that in other embodiments, the waveform 400 has a voltage imbalance. For example, each packet 402, 404 consists of a first biphasic cycle (including a first positive pulse peak 408 having a first voltage V1 and a first negative pulse peak 410 having a second voltage V2) and a second biphasic cycle (including a second positive pulse peak 408' having a first voltage V1 and a second negative pulse peak 410' having a second voltage V2), where the first voltage V1 exceeds the second voltage V2. The first and second biphasic cycles are separated by a dead time 412 between each pulse. Thus, the voltage in one direction (i.e., positive or negative) exceeds the voltage in the other direction such that the area under the positive portion of the curve is not equal to the area under the negative portion of the curve. This unbalanced waveform may result in a more pronounced therapeutic effect. It should be understood that in some embodiments, the imbalance includes pulses having pulse widths of unequal duration. In some embodiments, a biphasic waveform is unbalanced so that the voltage in one direction is equal to the voltage in the other direction, but the duration of one direction (i.e., positive or negative) exceeds the duration of the other direction, so that the area under the curve of the positive portion of the waveform is not equal to the area under the negative portion of the waveform.

[0176] Although the detailed examples contained herein are described in terms of PEF energy, it should be understood that aspects of the methods, systems, and devices described herein are applicable to all energy sources (e.g., radiofrequency therapy, cryogenic therapy, laser therapy, etc.).

[0177] The above detailed description includes reference to the accompanying drawings, which form a part of the detailed description. The drawings show, by way of illustration, specific embodiments in which the invention may be practiced. These embodiments are also referred to herein as "examples." Such examples may include elements in addition to those shown or described. However, the inventors also contemplate examples in which only the elements shown or described are provided. Moreover, the inventors also contemplate examples using any combination or permutation of the elements shown or described (or one or more aspects thereof) with respect to the particular example (or one or more aspects thereof) or with respect to other examples (or one or more aspects thereof) shown or described herein.

[0178] In the event of a conflict of usage between this document and a document incorporated by reference, the usage in this document takes precedence.

[0179] In this document, as is common in patent documents, the terms "a" or "an" are used to include one or more, regardless of any other instance or usage of "at least one" or "one or more." In this document, the term "or" is used to refer to a non-exclusive or, so that "A or B" includes "A but not B," "B but not A," "A and B," unless otherwise specified. In this document, the terms "including" and "in which" are used as the plain English equivalents of the terms "comprising" and "wherein," respectively. Also, in the following claims, the terms "including" and "comprising" are open-ended; that is, a system, device, article, composition, formulation, or process that includes elements in addition to those recited after such terms in a claim is still considered to be within the scope of that claim. Moreover, in the following claims, the terms "first," "second," "third," etc. are used merely as labels and are not intended to impose numerical requirements on their objects.

[0180] The above description is intended to be illustrative, not limiting. For example, the above-described examples (or one or more aspects thereof) may be used in combination with each other. Other embodiments may be used by one of ordinary skill in the art upon reviewing the above description. The Abstract is provided in compliance with 37 CFR §1.72(b) to allow the reader to quickly ascertain the nature of the technical disclosure. The Abstract is submitted with the understanding that it will not be used to interpret or limit the scope or meaning of the claims. Also, in the above Detailed Description, various features may be grouped together to streamline the disclosure. This should not be construed as intending that an unclaimed disclosed feature is essential to any claim. Rather, the subject matter of the invention may lie in less than all features of a particular disclosed embodiment. Accordingly, it is contemplated that the following claims are incorporated into the Detailed Description as examples or embodiments, with each claim standing on its own as a separate embodiment, and that such embodiments can be combined with each other in various combinations or permutations. The scope of the invention should be determined with reference to the appended claims, along with the full scope of equivalents to which such claims are entitled.

Claims

1. 1. A cardiovascular disease analysis system, comprising: an instrument configured to measure at least one voltage value of at least a portion of the cardiovascular lesion; an algorithm for evaluating the at least one voltage value to determine permanence of at least a portion of the cardiovascular lesion, wherein at least a portion of the cardiovascular lesion is created by pulsed electric field ablation; and a feedback system that communicates the persistence; A system comprising:

2. 2. The system of claim 1, wherein the at least one voltage value includes at least one pre-ablation voltage value and at least one post-ablation voltage value, the algorithm evaluates the at least one voltage value by determining a representative voltage drop value from a difference between the at least one pre-ablation voltage value and the at least one post-ablation voltage value, and the algorithm determines the likelihood of persistence based on the representative voltage drop value.

3. The system of claim 2 , wherein the algorithm determines permanence by comparing the representative voltage drop value to a threshold voltage drop value above which the lesion is considered to be persistent.

4. The system of any one of claims 2 to 3, wherein the pre-ablation voltage value is at least 0.1 volts.

5. The system of claim 2 , wherein the pre-ablation voltage value comprises an average of individual pre-ablation voltage values ​​and the post-ablation voltage value comprises an average of individual post-ablation voltage values.

6. The system of claim 5 , wherein each of the individual pre-ablation voltage values ​​is at least 0.1 volts.

7. The system of claim 3 , wherein the representative voltage drop value is expressed as a percentage of the pre-ablation voltage value.

8. The system of claim 7, wherein the threshold voltage reduction value is in the range of 89-100%.

9. The system of claim 3 , wherein the threshold voltage reduction value has a confidence level of at least 95%.

10. The system of claim 3 , wherein the threshold voltage drop value is dependent on a baseline voltage value.

11. The system of claim 10 , wherein the threshold voltage drop value varies in discrete steps relative to the baseline voltage value.

12. The system of claim 10 , wherein the threshold voltage drop value varies continuously relative to the baseline voltage value.

13. The system of claim 10 , wherein the threshold voltage drop value varies with confidence level.

14. The system of claim 1 , wherein the feedback system conveys the persistence as a continuous variable that changes over time.

15. The system of claim 14 , wherein the continuous variable is communicated as a percentage drop in voltage.

16. The system of claim 15 , wherein the feedback system further communicates a target percentage drop in voltage.

17. The system of claim 1 , wherein any of the instrument, the algorithm, and / or the feedback system is integrated with an electro-anatomical mapping system.

18. The system of claim 1 , wherein the feedback system is integrated with an existing visual map provided by the electroanatomical mapping system.

19. The system of claim 1 , wherein the feedback system communicates the persistence by providing an alert.

20. The system of claim 19 , wherein the alert comprises a visual alert.

21. 21. The system of claim 20, wherein the visual alert includes a color code indicating permanence or level of permanence.

22. 21. The system of claim 20, wherein the visual alert includes at least one letter, word, number, and / or symbol indicating permanence or a level of permanence.

23. The system of any one of claims 21 to 22, wherein the alert is binary.

24. The system of any one of claims 21 to 22, wherein the alert is gradually changed in color.

25. The system of claim 1 , wherein the feedback system includes a map indicating the anatomical location of at least a portion of the cardiovascular lesion.

26. 26. The system of claim 25, wherein the feedback system includes an indication of the permanence of at least a portion of a cardiovascular lesion at an anatomical location on the map.

27. The system of claim 1 , wherein the feedback system communicates the persistence to a user in real time as the instrument moves.

28. 10. The system of claim 1, wherein the instrument is configured to deliver the pulsed electric field energy, the instrument comprising an electrode to which the pulsed electric field energy is delivered, the electrode configured to be placed against or adjacent to tissue to create at least a portion of the cardiovascular lesion.

29. 30. The system of claim 28, wherein at least a portion of the cardiovascular lesion is formed from a single application of the electrode to or adjacent the tissue, and the algorithm determines the location of a next single application of the electrode.

30. 30. The system of claim 29, wherein the location of a subsequent single application of the electrode overlaps at least a portion of the cardiovascular lesion formed from the single application of the electrode.

31. 31. The system of any one of claims 29-30, wherein the location of a subsequent single application of the electrodes provides sufficient overlap of stunning zones between kill zones to form a continuous, persistent lesion.

32. 10. The system of claim 1, wherein the pulsed electric field energy leaves the extracellular matrix of the cardiovascular lesion intact.

33. 10. The system of claim 1, wherein the pulsed electric field energy comprises a series of packets, each packet comprising a biphasic pulse.

34. 1. A system for determining lesion location, comprising: a catheter having electrodes configured to deliver pulsed electric field energy toward cardiovascular tissue to create a lesion, wherein a first lesion is created by delivering the pulsed electric field energy toward cardiovascular tissue at a first location; an algorithm that determines a second location of a second lesion based on the determined permanence of the first lesion; a feedback system communicating the second position; and A system comprising:

35. 35. The system of claim 34, wherein the determined permanence of the first lesion is generated by the algorithm by comparing a representative voltage drop value to a threshold voltage drop value above which the first lesion is considered to be persistent, the representative voltage drop value being calculated as the difference between a pre-ablation voltage value and a post-ablation voltage value.

36. 36. The system of claim 35, wherein the pre-ablation voltage value comprises an average of individual pre-ablation voltage values ​​and the post-ablation voltage value comprises an average of individual post-ablation voltage values.

37. 37. The system of claim 36, wherein each of the individual pre-ablation voltage values ​​is at least 0.1 volts.

38. The system of any one of claims 36 to 37, wherein the representative voltage drop value is expressed as a percentage of the pre-ablation voltage value.

39. 35. The system of claim 34, wherein the impedance of the cardiovascular tissue remains below a threshold corresponding to impedance produced by thermal ablation.

40. 35. The system of claim 34, wherein the pulsed electric field energy comprises a series of packets, each packet comprising a biphasic pulse.

41. 1. A cardiovascular disease analysis system, comprising: a catheter having at least one electrode; a pulsed electric field generator connectable to the catheter, the pulsed electric field generator including an algorithm configured to deliver at least one dose of pulsed electric field energy to a region of cardiovascular tissue through at least one of the at least one electrodes to create a lesion and measure at least one voltage value of at least a portion of the cardiovascular lesion through at least one of the at least one electrodes, the algorithm using the at least one voltage value to determine permanence of at least a portion of the cardiovascular lesion; A system comprising:

42. 42. The system of claim 41, wherein the at least one voltage value comprises a representative voltage drop value, and the algorithm determines permanence by comparing the representative voltage drop value to a threshold voltage drop value above which the lesion is considered to be persistent.

43. 43. The system of claim 42, wherein the representative voltage drop value is expressed as a percentage of a pre-ablation voltage value.

44. 44. The system of any of claims 43, wherein the pre-ablation voltage value comprises an average of individual pre-ablation voltage values.

45. 45. The system of claim 44, wherein each of the individual pre-ablation voltage values ​​is at least 0.1 volts.

46. 42. The system of claim 41, wherein the pulsed electric field energy comprises a series of packets, each packet comprising a biphasic pulse.

47. 42. The system of claim 41, wherein the algorithm provides the persistence to a visual map including the region of cardiovascular tissue.

48. 48. The system of claim 47, wherein the visual map is provided by an electro-anatomical mapping system, the visual map indicating the anatomical location of at least some of the cardiovascular lesions.

49. 49. The system of claim 48, wherein the feedback system includes an indication of persistence of at least a portion of a cardiovascular lesion at an anatomical location on the map, and wherein the algorithm provides the persistence as an alert.

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