A DEVICE FOR TREATMENT OF THE LEFT ATRIAL APPENDAGE

Abstract

A device (10) to occlude the left atrial appendage (1) of a heart of a subject comprises an implantable occlusion apparatus (30) configured for radial expansion upon deployment to fluidically occlude the left atrial appendage, an elongated catheter member (80) having a distal end attachable to the implantable occlusion apparatus for transluminal delivery of the implantable occlusion apparatus to the left atrial appendage, a tissue energising module (20) having a plurality of electrodes (26) disposed around a circumference of the implantable occlusion apparatus in which each electrode is configured to contact a wall of the left atrial appendage at a tissue focal point upon deployment of the implantable occlusion apparatus, and an electrical controller (40) including a pulsed field energy delivery generator operably attachable to an electrical power source (50) and the plurality of electrodes and configured to energise the electrodes in a pulsed field ablation modality. The electrical controller is configured to independently energise each of the plurality of electrodes to apply a non-uniform pulsed field ablation treatment circumferentially around the wall of the left atrial appendage.

Claims

1. A device (10) to occlude the left atrial appendage (1) of a heart of a subject, comprising: an implantable occlusion apparatus (30) configured for radial expansion upon deployment to fluidically occlude the left atrial appendage; an elongated catheter member (80) having a distal end attachable to the implantable occlusion apparatus for transluminal delivery of the implantable occlusion apparatus to the left atrial appendage; a tissue energising module (20) having a plurality of electrodes (26) disposed around a circumference of the implantable occlusion apparatus in which each electrode is configured to contact a wall of the left atrial appendage at a tissue focal point upon deployment of the implantable occlusion apparatus; and an electrical controller (40) including a pulsed field energy delivery generator operably attachable to an electrical power source (50) and the plurality of electrodes (26) and configured to energise the electrodes in a pulsed field ablation modality, in which the electrical controller (40) is configured to energise the plurality of electrodes (26) independently to apply a non-uniform pulsed field ablation treatment circumferentially around the wall of the left atrial appendage characterised in that the device comprises a processor (60) operably coupled to the electrical controller (40) and configured to generate an electrical parameter profile of the LAA comprising electrical parameter measurements taken at a plurality of sections around the circumference of the wall of the LAA and modify the output of the electrical controller so as to independently energise the electrodes (26) or sets of electrodes in a pattern synergistic with the tissue parameter profile to energise some electrodes or sets of electrodes with greater ablative power than others to create a non-uniform tissue ablation circumferentially around the wall of the LAA, tuned to the specific anatomy of the subject.

2. A device according to claim 1, comprising a tissue parameter sensor configured to obtain the electrical parameter measurements.

3. A device according to claim 2 in which the electrical parameter of the tissue is electrical impedance.

4. A device according to claim 3, in which the tissue parameter sensor is configured to measure an electrical parameter of the tissue at a plurality of circumferential or radial sections around the wall of the LAA.

5. A device according to claim 4, in which the tissue parameter sensor comprises the electrical controller (40) and the tissue energising module (20), and in which the processor is configured to actuate the controller and tissue energising module in at least two separate modalities selected from: a tissue ablation modality configured to deliver a pulsed field ablation treatment at one or more sections around the circumference of the wall of the LAA; and a tissue parameter measurement modality to measure an electrical parameter of tissue at the plurality of sections around the circumference of the wall of the LAA.

6. A device according to claim 5, in which the processor is configured to (a) compare the electrical parameter measurement for a section of the wall with a reference electrical parameter value, (b) calculate a pulsed field ablation power to be delivered to the section based on the comparison, and (c) modify the output characteristics of the electrical controller to independently energise selected electrodes to deliver pulse field ablation therapy to the section of tissue at the calculated power.

7. A device according to claim 6, in which the processor is configured to perform steps (a), (b) and (c) for each of a plurality of sections of the wall of the LAA.

8. A device according to claim 7, in which the plurality of sections together make up a full circumference of the LAA.

9. A device according to claim 8, in which the controller is configured to measure electrical impedance across a section of the wall of the LAA by configuring one pair of electrodes to supply measuring current and a separate pair of electrodes to detect voltage drop produced by current flowing across the section of tissue.

10. A device according to claim 9, having at least four electrodes circumferentially spaced around the wall of the occlusion apparatus.

11. A device according to claim 10, having six to twelve electrodes circumferentially spaced around the wall of the occlusion apparatus.

12. A device according to claim 11, in which the device is configured to: deliver by the controller and electrodes a pulsed field ablation treatment at a section of the wall of the body lumen, determine by the controller and electrodes an electrical impedance value of the tissue at the treated section; and correlate by the processor an output indication of electrical isolation of the section of the wall of the body lumen based on the electrical impedance value.

13. A device according to claim 12, in which the processor is configured to receive as an input the measured electrical impedance value for the section of tissue, compare the value with one or more reference electrical impedance values, and calculate an output indication of electrical isolation of the section of the wall based on the comparison.

14. A device according to claim 11, in which the device is configured to: determine by the controller and electrodes a first electrical parameter value selected from an electrical impedance or electrical activity of tissue at a section of the wall of the body lumen, deliver by the controller and electrodes a pulsed field ablation treatment at the section of the wall of the body lumen, determine by the controller and electrodes a second electrical parameter value selected from an electrical impedance or electrical activity of the tissue at the treated section; and calculate by the processor an output indication of electrical isolation of the section of the wall of the body lumen based on a comparison of the first and second electrical parameter measurements.

15. A device according to claim 14, including an earth electrode configured for attachment to a surface of the subjects body, in which the processor is configured to determine the electrical parameter of the tissue at a specific location using an electrode of the tissue energising module and the earth electrode.

16. A device according to claim 15, in which the pulsed field energy delivery generator is configured to deliver at least one pulse train of energy to the tissue of the body lumen, each pulse train of energy including: at least 60 pulses, an inter-phase delay between 0 s and 5 s, an inter-pulse delay of 2 to 500 s, a pulse width of 1 to 15 s, and a voltage of 500 to 2500 V.

17. A device according to claim 16, in which the generator is configured to deliver at least one pulse train of energy with inter-pulse delay is about 2 to about 400 s.

18. A device according to claim 16, in which the generator is configured to deliver at least one pulse train of energy with inter-pulse delay is about 2 to about 250 s.

Description

BRIEF DESCRIPTION OF THE FIGURES

[0135] FIG. 1 is a sectional view of left atrial appendage (LAA) illustrating the non-uniformity of the thickness of the wall of the LAA.

[0136] FIG. 2 is a sectional view of left atrial appendage illustrating the non-uniformity of the electrical impedance of the tissue along circumferential sections.

[0137] FIG. 3 illustrates the device of the invention including delivery catheter, implantable occlusion apparatus, electrical controller and processor.

[0138] FIG. 4 illustrates in detail a deployable device of the invention including a circumferential array of electrodes and a distal end of a catheter connected to a recessed connecting hub of the occlusion apparatus.

[0139] FIG. 5 illustrates a non-uniform e-field applied by a device of the invention to the wall of the LAA

[0140] FIG. 6 illustrates an arrangement of electrodes for measuring electrical impedance along a circumferential section of the wall of the LAA.

[0141] FIG. 7 illustrates an arrangement of electrodes for measuring electrical impedance radially across a section of the wall of the LAA.

[0142] FIG. 8 is a block diagram illustrating the use of the device of the invention to occlude the LAA by pulsed field ablation.

[0143] FIG. 9 is an illustration of an occlusion apparatus having an array of electrodes deployed in the LAA and the use of the electrodes to determine the electrical impedance of circumferential sections of the LAA.

[0144] FIG. 10 is an illustration of an occlusion apparatus having an array of electrodes deployed in the LAA and the use of the electrodes to determine the electrical impedance radially across the wall of the LAA at eight positions around the wall of the LAA.

DETAILED DESCRIPTION OF THE INVENTION

[0145] All publications, patents, patent applications and other references mentioned herein are hereby incorporated by reference in their entireties for all purposes as if each individual publication, patent or patent application were specifically and individually indicated to be incorporated by reference and the content thereof recited in full.

Definitions and General Preferences

[0146] Where used herein and unless specifically indicated otherwise, the following terms are intended to have the following meanings in addition to any broader (or narrower) meanings the terms might enjoy in the art:

[0147] Unless otherwise required by context, the use herein of the singular is to be read to include the plural and vice versa. The term a or an used in relation to an entity is to be read to refer to one or more of that entity. As such, the terms a (or an), one or more, and at least one are used interchangeably herein.

[0148] As used herein, the term comprise, or variations thereof such as comprises or comprising, are to be read to indicate the inclusion of any recited integer (e.g. a feature, element, characteristic, property, method/process step or limitation) or group of integers (e.g. features, element, characteristics, properties, method/process steps or limitations) but not the exclusion of any other integer or group of integers. Thus, as used herein the term comprising is inclusive or open-ended and does not exclude additional, unrecited integers or method/process steps.

[0149] As used herein, the term disease is used to define any abnormal condition that impairs physiological function and is associated with specific symptoms. The term is used broadly to encompass any disorder, illness, abnormality, pathology, sickness, condition or syndrome in which physiological function is impaired irrespective of the nature of the aetiology (or indeed whether the aetiological basis for the disease is established). It therefore encompasses conditions arising from infection, trauma, injury, surgery, radiological ablation, age, poisoning or nutritional deficiencies.

[0150] As used herein, the term treatment or treating refers to an intervention (e.g. the administration of a PFA treatment to a subject) which cures, ameliorates or lessens the symptoms of a disease or removes (or lessens the impact of) its cause(s). In this case, the term is used synonymously with the term therapy.

[0151] Additionally, the terms treatment or treating refers to an intervention (e.g. the administration of a PFA treatment to a subject) which prevents or delays the onset or progression of a disease or reduces (or eradicates) its incidence within a treated population. In this case, the term treatment is used synonymously with the term prophylaxis.

[0152] In the context of treatment and effective amounts as defined above, the term subject (which is to be read to include individual, animal, patient or mammal where context permits) defines any subject, particularly a mammalian subject, for whom treatment is indicated. Mammalian subjects include, but are not limited to, humans, domestic animals, farm animals, zoo animals, sport animals, pet animals such as dogs, cats, guinea pigs, rabbits, rats, mice, horses, camels, bison, cattle, cows; primates such as apes, monkeys, orangutans, and chimpanzees; canids such as dogs and wolves; felids such as cats, lions, and tigers; equids such as horses, donkeys, and zebras; food animals such as cows, pigs, and sheep; ungulates such as deer and giraffes; and rodents such as mice, rats, hamsters and guinea pigs. In preferred embodiments, the subject is a human. As used herein, the term equine refers to mammals of the family Equidae, which includes horses, donkeys, asses, kiang and zebra.

[0153] Implantable occlusion apparatus means an apparatus configured for implantation in a body lumen, especially implantation in the heart at least partially or fully within the left atrial appendage, and upon actuation to at least partially or fully fluidically occlude the body lumen. The occlusion apparatus is typically detachably connected to a delivery catheter which delivers the occlusion apparatus to the target site, and typically remains attached during occlusion, sensing and energy delivery treatments and in one embodiment is generally detached after the energy delivery treatment and removed from the body leaving the occlusion apparatus implanted in the body lumen. Occlusion may be complete occlusion (closing) of the body lumen or partial occlusion (narrowing of the body lumen or near complete occlusion). The occlusion apparatus typically comprises a body that is expansible from a contracted delivery configuration to an expanded deployed configuration. The body may take many forms, for example a wireframe structure formed from a braided or meshed material. Examples of expandable wireframe structures suitable for transluminal delivery are known in the literature and described in, for example, WO01/87168, U.S. Pat. No. 6,652,548, US2004/219028, U.S. Pat. Nos. 6,454,775, 4,909,789, 5,573,530, WO2013/109756. Other forms of bodies suitable for use with the present invention include plate or saucer shaped scaffolds, or stents. In one embodiment, the body is formed from a metal, for example a shape-memory metal such as nitinol. The body may have any shape suitable for the purpose of the invention, for example cylindrical, discoid or spheroid. In one preferred embodiment, the apparatus comprises a cylindrical body, for example a cylindrical cage body. In one embodiment, the body comprises a tissue energising module. In one embodiment, the ablation device comprises an array of electrodes, typically a circumferential array. In one embodiment, the array of electrodes are configured to deliver pulsed field ablation to the tissue. In one embodiment, a distal face of the radially expansible body comprises a covering configured to promote epithelial cell proliferation. In one embodiment, the body comprises a stepped radial force stiffness profile from distal to proximal device. In one embodiment, the body comprises a metal mesh cage scaffold. In one embodiment, a coupling between the body and the catheter member is located distally to the left atrial facing side of the body. In one embodiment, the body in a deployed configuration has a radial diameter at least 10% greater than the radial diameter of the left atrial appendage at a point of deployment. In one embodiment, the furthermost distal part is configured to be atraumatic to cardiac tissue. In one embodiment, the body comprises a braided mesh scaffold that in one embodiment is conducive to collagen infiltration on thermal energy delivery to promote increased anti migration resistance. Examples of an implantable occlusion apparatus for use in a body lumen especially the LAA are described in WO2018/185256, WO2018/185255 and WO2020/074738.

[0154] Body lumen means a cavity in the body, and may be an elongated cavity such as a vessel (i.e. an artery, vein, lymph vessel, urethra, ureter, sinus, auditory canal, nasal cavity, bronchus) or an annular space in the heart such as the left atrial appendage, left ventricular outflow tract, the aortic valve, the mitral valve, mitral valve continuity, or heart valve or valve opening.

[0155] Detachably attached means that the device is configured such that the occlusion apparatus is attached to the elongated delivery catheter during delivery and can be released after deployment and treatment whereby the occlusion apparatus is implanted in the heart and the elongated delivery catheter can be withdrawn leaving the occlusion apparatus in-situ. Typically, the device includes a control mechanism for remotely detaching the occlusion apparatus or radially expansible element from the elongated catheter member. Typically, an actuation switch for the control mechanism is disposed on the control handle.

[0156] Transluminal delivery means delivery of the occlusion apparatus to a target site (for example the heart) heart through a body lumen, for example delivery through an artery or vein. In one embodiment, the device of the invention is advanced through an artery or vein to deliver the occlusion apparatus to the left atrium of the heart and at least partially in the LAA. In one embodiment, the device is delivered such that the distal part is disposed within the LAA and the proximal part is disposed in the left atrium just outside the LAA. In one embodiment, the device is delivered such that the distal part is disposed within the LAA and the proximal part is disposed in the left atrium abutting a mouth of the LAA. In one embodiment, the device is delivered such that both the distal and proximal parts are disposed within the LAA.

[0157] Cover: Typically, the implantable occlusion apparatus has a proximal cover which is impermeable to blood and that may include a re-closable aperture, for example an overlapping flap of material. The re-closable aperture may be configured to allow a distal end of the catheter through the aperture while preventing blood flow through the aperture. The occlusion apparatus may include a connecting hub distal of the cover, and configured for coupling with a distal end of the catheter. The cover may be configured to act as a scaffold for in-vivo endothelialisation. The cover may be formed from a woven mesh material.

[0158] Covering/cover configured to act as a scaffold for in-vivo endothelialisation means a material that is use promotes epithelialisation of the distal or proximal body. In one embodiment, the covering is a membrane that comprises agents that promote epithelial cell proliferation. Examples include growth factors such as fibroblast growth factor, transforming growth factor, epidermal growth factor and platelet derived growth factor, cells such as endothelial cells or endothelial progenitor cells, and biological material such as tissue or tissue components. Examples of tissue components include endothelial tissue, extracellular matrix, sub-mucosa, dura mater, pericardium, endocardium, serosa, peritoneum, and basement membrane tissue. In one embodiment, the covering is porous. In one embodiment, the covering is a biocompatible scaffold formed from biological material. In one embodiment, the covering is a porous scaffold formed from a biological material such as collagen. In one embodiment, the covering is a lyophilised scaffold.

[0159] Tissue energising module as used herein refers to an array of electrodes disposed on the implantable occlusion apparatus (e.g. a radially expansible body) configured for electrical coupling with the electrical controller. The electrodes are generally individually coupled with the controller to allow electrode specific energising of the electrode. They array of electrodes is generally arranged on the implantable occlusion apparatus in a circumferential arrangement and configured to contact the wall of the body lumen in a circumferential pattern when the apparatus is deployed. The electrodes are configured to deliver energy, generally PFA, circumferentially around the wall of the body lumen. The electrodes may also function as sensors to detect an electrical parameter of the tissue of the wall of the body lumen, for example electrical impedance or electrical activity (voltage). The electrodes may be configured to measure an electrical parameter radially across the wall of the body lumen, or circumferentially along a section of the circumference of the wall of the body lumen. Generally, measuring an electrical parameter such as electrical impedance radially across the wall of the body lumen employs an electrode of the array of electrodes and an earth or ground pad placed on the patient's body, often the leg. Measuring an electrical parameter such as electrical impedance circumferentially along a section of the body lumen employs two electrodes where one electrode functions as an energising electrode and the other functions as a detecting electrode. The electrical parameter such as electrical impedance may be measured at one frequency or over a range of frequencies.

[0160] Independently energise as applied to the device means that at least a plurality of the electrodes may be energised differently to apply a non-uniform energy (e.g. PFA) treatment to the body lumen. Thus, the present invention solves the technical problem of the prior art systems by individually energising the elements or pairs of elements so as to enable some elements to be energised with greater ablative power than others to create a non-uniform tissue ablation circumferentially around the wall of the LAA, tuned to the specific anatomy of the subject. The device is configured to tune the energy delivery to the tissue ablative elements based on tissue electrical parameter data determined at a plurality of locations around the circumference of the body lumen. The power of the treatment of tissue may be varied, for example in the case of PFA by varying the applied current or applied voltage. The device of the invention may be configured to energise the electrodes during a PFA treatment simultaneously or at different time points. The or each electrode may be energised at one frequency, or energised at different frequencies.

[0161] Electrical parameter profile describes a plurality of electrical parameter measurements taken at different locations along the circumference of the wall of the body lumen. It represents a body lumen specific fingerprint comprising electrical parameter measurements and can be used to tune the energy (e.g. PFA) treatment to avoid damage to tissue during energy treatment. The electrical parameter is generally electrical impedance, although other electrical parameters such as electrical activity may be employed. The electrical parameter profile is determined at a part of the wall of the body lumen where the electrodes are disposed. For example, where the device is configured to have electrodes positioned at 0, 90, 180 and 270 around the circumference of the wall of the body lumen, the electrical parameter profile may be a compilation of the values of electrical impedance at these across the four sections defined by these electrodes. A processor may be configured to receive the electrical impedance values, compile an electrical parameter profile, and generate output characteristics for the controller based on the electrical parameter profile. Generating the electrical parameter profile may comprise comparing each electrical parameter measurement with a reference electrical parameter measurement. In cases where the tissue electrical impedance measurements are not the same, the processor will be configured to modify the output characteristics of the controller to energise the electrodes unevenly and generate a non-uniform e-field around the wall of the body lumen, where areas of tissue with higher impedance will be treated by energy (e.g. PFA) of lower power and areas of tissue with lower impedance will be treated by energy (e.g. PFA) of higher power. This help avoid over-treatment of areas of tissue of high electrical impedance and helps reduce or avoids damage to adjacent structures and nerves due to over-treatment.

[0162] Independently energise the electrodes in a pattern synergistic with the tissue parameter profile means that the device is configured to individually energise the electrodes or pairs of electrodes so as to enable some electrodes to be energised with greater ablative power than others to create a non-uniform tissue ablation circumferentially around the wall of the LAA, tuned to the specific anatomy of the subject. The device is configured to tune the energy delivery to the tissue ablative electrodes based on tissue electrical parameter data determined at a plurality of locations around the circumference of the body lumen. Thus, the device can energise electrodes in the array so as to generate a uniform or non-uniform e-field depending on the electrical parameter profile of the body lumen. Thus, where the electrical parameter measurements are equal around the circumference of the wall of the LAA, the device is configured to energise the electrodes around the wall of the body lumen with equal or similar energy. Likewise, where the electrical parameter measurements are unequal around the circumference of the wall of the LAA, the device is configured to independently energise the electrodes around the wall of the body lumen unequally, to generate a non-uniform e-field which is higher in some areas (e.g. areas of low tissue impedance) and lower in other areas (e.g. areas of high tissue impedance). Generally a processor is employed to independently energise the electrodes in a pattern synergistic with the tissue parameter profile, and the processor may be configured to receive electrical parameter measurements, generate a body lumen specific electrical parameter profile, and energise the electrodes in a pattern synergistic with the tissue parameter profile.

[0163] Electrical controller refers to a pulsed field energy delivery generator that comprises or can be operably coupled to an electrical power source and is operatively coupled to the plurality of electrodes and configured to energise the electrodes, typically in a pulsed field ablation modality. In one preferred aspect, the controller comprises a signal generator configured for generating a pulse waveform. In any embodiment, the signal generator is configured to deliver at least one train of PFA energy to an electrode. In any embodiment, the signal generator is configured to deliver a train of energy of at least 20 pulses to an electrode. In any embodiment, the signal generator is configured to deliver at least one train of energy comprising an inter-phase delay of between 0 s and 100 s. In any embodiment, the signal generator is configured to deliver a train of energy comprising an inter-pulse delay of 1 to 100 s, and typically at least 5 s. In any embodiment, the signal generator is configured to deliver a train of energy comprising a pulse width of 100 ns-100 s. In any embodiment, the signal generator is configured to deliver at least one train of PFA energy having a voltage amplitude between 100V and 5000V. In any embodiment, the signal generator is configured to deliver pulses in monophasic or biphasic form. The electrical controller is operably coupled to some or all of the electrodes (or electrode pairs) in the array in a manner allowing electrode pairs to be energised independently. The electrical controller may a comprise a plurality of electrode channels, and optionally a routing channel. Such an electrical controller is described in US2020230403. Electrical controllers for generating pulsed field ablative energy are described in EP3399933, US2020046423, WO2019157359 and US2020139114. Fraczek et al. describes the use of two electrodes or four electrodes to measure electrical impedance in tissue.

[0164] Atrial fibrillation or AF is a common cardiac rhythm disorder affecting an estimated 6 million patients in the United States alone. AF is the second leading cause of stroke in the United States and may account for nearly one-third of strokes in the elderly. In greater than 90% of cases where a blood clot (thrombus) is found in the AF patient, the clot develops in the left atrial appendage (LAA) of the heart. The irregular heartbeat in AF causes blood to pool in the left atrial appendage, because clotting occurs when blood is stagnant, clots or thrombi may form in the LAA. These blood clots may dislodge from the left atrial appendage and may enter the cranial circulation causing a stroke, the coronary circulation causing a myocardial infarction, the peripheral circulation causing limb ischemia, as well as other vascular beds. The term includes all forms of atrial fibrillation, including paroxysmal (intermittent) AF and persistent and longstanding persistent AF (PLPAF).

[0165] Ischaemic event refers to a restriction in blood supply to a body organ or tissue, resulting in a shortage of oxygen and glucose supply to the affected organ or tissue. The term includes stroke, a blockage of blood supply to a part of the brain caused by a blood clot blocking the blood supply to the brain and the resultant damage to the affected part of the brain, and transient ischaemic events (TIA's), also known as mini-strokes, which are similar to strokes but are transient in nature and generally do not cause lasting damage to the brain. When the restriction in blood supply occurs in the coronary arteries, the ischaemic event is known as a myocardial infarction (MI) or heart attack.

[0166] Electrical impedance refers to the opposition that a volume of tissue presents to an alternating electrical current when a sinusoidal voltage is applied across the volume of tissue. The actual definition of impedance is by Ohm's law, is the ratio of the complex voltage to the complex current

[00001]$\begin{array}{cc}\stackrel{.fwdarw.}{Z}=\frac{\stackrel{.fwdarw.}{V}}{\stackrel{.fwdarw.}{I}}& \left(2.29\right)\end{array}$

[0167] The active method of measurement (which is most likely method of measurement for the invention) are defined as the measure of the ratio of complex voltage to complex current following the above condition stated by Ohm's law.

[00002]$\begin{array}{cc}\stackrel{.fwdarw.}{Z}=.Math.Z.Math.<=\frac{.Math.V.Math.<{}_v}{.Math.I.Math.<{}_i}=\frac{.Math.V.Math.}{.Math.I.Math.}<{}_v-<{}_i& \left(2.3\right)\end{array}$ [0168] Where |Z|, |V|, |I| are the absolute magnitude values of the impedance, voltage and the current and the phase angles are represented by .sub.z, .sub.v, .sub.i respectively. The different kinds of active instruments are:

[0169] An impedance analyser chip or module may be attached to the controller/generator, this module will directly measure the magnitude of voltage and current and associated phase angles and then calculate angle and phase of the impedance. Other methods of measuring electrical impedance in tissue are described in, for example, Fraczek et al. and Sharp et al. (Saudi Journal of Anaesthesia, 2017, 11(1):15) and Kwon et al. (Scientific Reports 9, Article Number 3145 (2109)).

Exemplification

[0170] The invention will now be described with reference to specific Examples. These are merely exemplary and for illustrative purposes only: they are not intended to be limiting in any way to the scope of the monopoly claimed or to the invention described. These examples constitute the best mode currently contemplated for practicing the invention.

[0171] Referring to the drawing, and initially to FIG. 1, these is illustrated a left atrial appendage (LAA) 1 of a human heart shown in sectional view. The wall of LAA has a non-uniform cross section with wall sections 2, 3 and 4 of different thickness.

[0172] Referring to FIG. 2, there is illustrated another LAA 1 shown in sectional view, in which the LAA has circumferential sections 5 and 6 having different electrical impedance characteristics despite having the same wall thickness.

[0173] Referring to FIGS. 3 and 4, a device according to the invention, indicated generally by the reference numeral 10, is illustrated. Referring initially to FIG. 3, the device comprises a tissue energising module 20 disposed on an implantable occlusion apparatus 30, an electrical controller/generator 40 electrically coupled to a power source 50, a processor 60 and memory module 70. The tissue energising module 20 is electrically coupled to the controller 40 by insulated leads (not shown) provided in the lumen of an elongated catheter 80. The processor 60 is electrically coupled to the controller/generator 40 and configured to receive tissue parameter data from the controller and control the output characteristics of the controller when it energises the electrodes in a pulsed field ablation modality.

[0174] Referring to FIG. 4, the implantable occlusion apparatus 30 and tissue energising module 20 are described in more detail. The implantable occlusion apparatus 30 comprises a cylindrical mesh cage 31 with a recessed proximal end 22 and an open distal end 23. A connection hub 24 is provided on the proximal end, distal of a blood-impermeable cover membrane 25 having an aperture (not shown). An array of six electrodes 26 (four are illustrated in the drawing) are provided circumferentially around the wall of the occlusion apparatus at equally spaced apart locations. Each electrode 26 is connected to the connecting hub with a dedicated insulated lead 27. The distal end of the catheter has a connecting hub 51 configured for detachable engagement and electrical coupling with the connecting hub 24. The catheter has six insulated leads (not shown) that electrically connect the contacts of the connecting hub with the controller. When the hubs 24 and 51 are electrically connected, each electrode is electrically connected to the controller with a dedicated electrical lead, allowing each electrode to be independently energised.

[0175] The processor 60 controls the operation of the controller/generator 40 and can modify the output characteristics of the controller to operate in a treatment modality and in a sensing modality. In the sensing modality, the electrical impedance of tissue at a plurality of locations around the circumference of the LAA can be determined. For example, referring to FIG. 5, the electrical impedance of a circumferential section of the wall of the LAA defined between electrodes 26A and 26B can be measured by modifying the controller to create a circuit between these electrodes and the controller, energising one of the electrodes, and detecting voltage and current across the electrodes at a given frequency (or optionally at a plurality of different frequencies). In this manner, the array of electrodes can be employed in a sensing modality to determine the electrical impedance of the tissue of the LAA around the full circumference of the wall of the LAA, and the processor can compile the electrical impedance values into the electrical impedance profile which is specific to the LAA of the subject.

[0176] In a treatment modality, the processor is configured to calculate the pulsed field ablation energy to be applied to an electrode pair (e.g. electrodes 26A and 26B) based on the electrical impedance value for the section of tissue defined by the electrode pair. Thus, for a section of the wall of the LAA where the electrical impedance is determined to be high, the electrode pair bordering the section of the wall will be energised with low PFA power, and for a section of the wall of the LAA where the electrical impedance is determined to be low, the electrode pair bordering the section of the wall will be energised with higher PFA power. In this way, the processor controls the output characteristics of the controller so as to independently energise the electrodes in a pattern synergistic with the tissue parameter profile. In cases where the electrical impedance of the tissue around the wall of the LAA is non-uniform, this results in a non-uniform circumferential e-field being created around the wall of the LAA, illustrated in FIG. 5, where the e-fields 27 generated at the electrodes 26A to D are different in size providing a composite non-uniform e-field having areas of larger e-field located where the electrical impedance of the tissue is low and smaller e-fields at locations where the electrical impedance of the tissue is higher. This helps avoid over treating tissue and consequent damage to adjacent structures such as nerves and blood vessels.

[0177] Referring to FIG. 6, a part of the LAA 1 and tissue energising module comprising electrodes 26A and 26B is shown along with leads 27 electrically coupling the electrodes with the controller 40. In a sensing mode, the controller energises one electrode to pass a current through the tissue for detection by the second electrodes and the current and voltage between the electrodes is determined and use to calculate the electrical impedance circumferentially across the shaded section of tissue.

[0178] Referring to FIG. 7, a part of the LAA 1 and tissue energising module comprising electrodes 26A is shown along with lead 27 electrically coupling the electrode with the controller 40. A ground pad 28 placed remotely to the LAA on the leg of the patient and electrically coupled to the controller 40 is also illustrated. In an alternative sensing mode, the controller energises the electrode to pass a current radially across the tissue for detection by the ground pad and the current and voltage between the electrodes is determined and use to calculate the electrical impedance radially across the shaded section of tissue.

[0179] A method of the invention is described with reference to FIG. 7. In a first step 100, a device of the invention comprising a delivery catheter attached to an implantable occlusion body is advanced into the heart along femoral vein, iliac vein, IVC, right atrium, transeptally to left atrium or alternatively the brachial vein, jugular vein, right atrium, transeptally to left atrium and the occlusion apparatus is positioned in the mouth of the left atrial appendage (LAA). In a second step 110, the occlusion apparatus is radially deployed to close the mouth of the LAA and bring the circumferential array of electrodes into contact with the wall of the LAA. In a third step 120, the processor then actuates the controller to operate in a sensing modality, measuring the electrical impedance of the tissue along a plurality of sections circumferentially around the wall of the LAA, each section being defined by an electrode pair as described above. In a fourth step 130, the processor compiles an electrical impedance profile comprising the electrical impedance measurements around the wall of the LAA. In a fifth step 140, the processor calculates the pulsed field ablation energy to be applied to electrode pairs based on the electrical impedance profile. In a sixth step, the processor controls the output characteristics of the controller to energise each electrode with PFA in a pattern synergistic with the electrical impedance profile.

Example 1Exemplary PFA Profile

[0180] Signal generator delivers 10 trains of PFA energy to an electrode.

[0181] Each train has 30 pulses

[0182] Inter-phase delay of 100 s.

[0183] Inter-pulse delay of 100 s.

[0184] Pulse width of 100 s.

[0185] Voltage amplitude of 1000 V.

Example 2Treatment of Left Atrial Appendage with Pulsed Field Ablation Employing Circumferential Electrical Impedance Measurements

[0186] Referring to FIG. 9, an occlusion apparatus 30 has an array of eight electrodes a to h circumferentially arranged the wall of the occlusion apparatus. The electrical impedance profile circumferentially across sections of the wall 1 of the left atrial appendage (Sections A to H) is determined by actuating the controller to create electrical circuits between the controller and pairs of electrodes to pass an alternating electrical current at a defined frequency across the respective sections and measure the voltage and/or current drop across the section and calculate electrical impedance of the tissue. The electrical impedance of the tissue sections were determined to be: [0187] Section A (between electrode a and b)low electrical impedance [0188] Section B (between electrode b and c)low electrical impedance [0189] Section C (between electrode c and d)high electrical impedance [0190] Section D (between electrode d and e)low electrical impedance [0191] Section E (between electrode e and f)low electrical impedance [0192] Section F (between electrode f and g)low electrical impedance [0193] Section G (between electrode g and h)high electrical impedance [0194] Section H (between electrode h and i)low electrical impedance

[0195] The electrical impedance values were compiled by the processor into an electrical impedance profile which was used to calculate output characteristics for the controller so as to energise the electrode pairs differentially around the circumference of the LAA, where lower PFA power was applied to sections C and G and higher PFA power was applied to sections A, B, D, E, F and H. This results in a non-uniform e-field generated around the circumference of the LAA helping avoid over-treating areas of the tissue that have low electrical impedance.

Example 3Treatment of Left Atrial Appendage with Pulsed Field Ablation Employing Radial Electrical Impedance Measurements

[0196] Referring to FIG. 10, an occlusion apparatus 30 has an array of eight electrodes a to h circumferentially arranged around the wall of the occlusion apparatus. A ground pad 28 is also shown which in use is attached to the leg of the patient. The electrical impedance profile across radial sections of the wall 1 of the left atrial appendage (Sections A to H) is determined by by actuating the controller to create electrical circuits between the controller and a single of electrode on the occlusion apparatus and the ground pad 28 placed typically on the leg of the subject to pass an alternating electrical current across the respective sections and measure the voltage and/or current drop across the section and calculate electrical impedance of the tissue. The electrical impedance of the tissue sections were determined to be: [0197] Section Ahigh electrical impedance [0198] Section Blow electrical impedance [0199] Section Clow electrical impedance [0200] Section Dlow electrical impedance [0201] Section Ehigh electrical impedance [0202] Section Fhigh electrical impedance [0203] Section Glow electrical impedance [0204] Section Hlow electrical impedance

[0205] The electrical impedance values were compiled by the processor into an electrical impedance profile which was used to calculate output characteristics for the controller so as to energise the electrode pairs differentially around the circumference of the LAA, where lower PFA power was applied to sections defined between electrodes a-b, b-c, f-g and g-h and higher PFA power was applied to sections defined between electrodes c-d, d-e and e-f. This results in a non-uniform e-field generated around the circumference of the LAA helping avoid overheating areas of the tissue that have low electrical impedance.

EQUIVALENTS

[0206] The foregoing description details presently preferred embodiments of the present invention. Numerous modifications and variations in practice thereof are expected to occur to those skilled in the art upon consideration of these descriptions. Those modifications and variations are intended to be encompassed within the claims appended hereto.