PULMONARY HYPERTENSION TREATMENT METHOD AND/OR SYSTEM

RELATED APPLICATION/S

This application claims the benefit of priority under 35 USC § 119(e) of U.S. Provisional Patent Application No. 62/473,545 filed 20 March 2017, Provisional Patent Application No. 62/473,532 filed 20 March 2017 and Provisional Patent Application No. 62/473,512 filed 20 March 2017 the contents of which are incorporated herein by reference in their entirety.

This application is related to a PCT application entitled "PULMONARY HYPERTENSION TREATMENT" of the same applicant, filed on the same filing date as this application.

This application is related to PCT application no. PCT/IL2018/050316 of the same applicant, filed on the same filing date as this application.

FIELD AND BACKGROUND OF THE INVENTION

The present invention, in some embodiments thereof, relates to hypertension treatment and, more particularly, but not exclusively, to treatment of pulmonary hypertension and associated conditions.

U.S. Patent Application Publication No. US20130204068 to Gnanashanmugam et al. teaches "A method is described for decreasing activity of at least one sympathetic nerve, nerve fiber or neuron innervating at least one blood vessel in the pulmonary vasculature of a patient to ameliorate pulmonary hypertension. In one embodiment, the method may involve advancing an intravascular treatment device to a target location in a target blood vessel within the pulmonary vasculature of the patient and using the treatment device to decrease activity of at least one sympathetic nerve, nerve fiber or neuron innervating the target blood vessel at or near the target location to ameliorate pulmonary hypertension".

SUMMARY OF THE INVENTION

Some examples of some embodiments of the invention are listed below: Example 1. A method of treating pulmonary hypertension comprising:

introducing a catheter device comprising one or more energy emitting transceivers into the pulmonary artery lumen; positioning said one or more transceivers within the left, right and/or main pulmonary artery at a location which is in between a first bifurcation of the left pulmonary artery and a first bifurcation of the right pulmonary artery; and

thermally damaging nerve tissue by emitting energy having parameters selected to damage nerves only within a distance window of between 0.2 mm and 20 mm from the intimal aspect of the pulmonary artery wall when said one or more transceivers are positioned at said location.

Example 2. The method according to example 1, wherein said energy parameters comprise an intensity high enough to raise a temperature of said nerve tissue by at least 10°C.

Example 3. The method according to example 1, wherein said energy parameters comprise an intensity high enough to raise the blood temperature by between 5-9°C.

Example 4. The method according to example 1, wherein said energy parameters comprise an intensity high enough to heat said nerve tissue at a rate higher than a cooling rate of said nerve tissue due to perfusion in a tissue volume including said nerve tissue.

Example 5. The method according to example 1, wherein said energy parameters are selected taking into account one or both of self-heat generation in said tissue volume and heat absorption in said tissue volume.

Example 6. The method according to example 1, wherein said energy comprises unfocused ultrasound energy.

Example 7. The method according to example 6, wherein parameters of said unfocused ultrasound energy are selected so that only nerve tissue found within coverage of the emitted energy beam is affected, while non-target tissue within the beam coverage is substantially unaffected.

Example 8. The method according to example 6, wherein parameters of said unfocused ultrasound energy are selected so as to avoid thermal damage to non-target tissue including one or more of connective tissue, adipose tissue, lymph nodes. Example 9. The method according to example 1, wherein said thermally damaging comprises thermally damaging nerves only within a distance window of between 4-10 mm from the intimal aspect of the pulmonary artery wall. Example 10. The method according to example 1, wherein said thermally damaging comprises thermally damaging nerves only within a distance window of between 0.5-5 mm from the intimal aspect of the pulmonary artery wall.

Example 11. The method according to example 1, wherein thermally damaging nerve tissue comprises thermally damaging one or more nerve plexuses extending along at least a longitudinal segment of the left, right and/or main pulmonary artery.

Example 12. The method according to example 1, wherein said energy parameters are selected so as to reduce thermal damage to the intima and media layers of the artery wall. Example 13. The method according to example 12, wherein said energy parameters are selected so as not to affect a structure of said intima and media layers of the artery wall.

Example 14. The method according to example 12, wherein reducing thermal damage comprises reducing thrombus or aneurysm formation. Example 15. The method according to example 12, wherein reducing thermal damage comprises thermal damage to a level that cannot be observed in MRI and/or an angiogram obtained post treatment.

Example 16. The method according to example 12, wherein said energy parameters are selected as ones that would demonstrate safety in pre-clinical studies and demonstrate efficacy using TxA2 model.

Example 17. The method according to example 1, comprising positioning said one or more transceivers within said left or right pulmonary artery at a distance of less than 10 cm from a central longitudinal axis of the main pulmonary artery. Example 18. The method according to example 17, wherein a distance of said one or more transceivers relative to the artery wall is set by a distancing device.

Example 19. The method according to example 1, comprising repeating said positioning and thermally damaging at between 6-16 treatment locations along the long axis of the left, right and/or main pulmonary artery.

Example 20. The method according to example 19, wherein a number of said treatment locations is selected to so as to: reduce at least one of: Right atrial pressure (RAP), Right ventricle pressures (RVP), Systolic pulmonary artery pressure (sPAP), Mean pulmonary artery pressures (mPAP), Pulmonary vascular resistance (PVR), NT-pro-BNP and/or increase at least one of: Cardiac output (CO), Cardiac Index (CI), Ejection Fraction (EF), Pulmonary distensability, Exercise tolerance - 6 minutes walking distance (6MWD), Quality of life as assessed by questionnaire, cardiopulmonary exercise testing and V02 max. Example 21. The method according to example 19, wherein a distance between adjacent treatment locations, as measured along the long axis of the artery, ranges between 0.1 cm to 2 cm.

Example 22. The method according to example 1, wherein said positioning comprises positioning said one or more transceivers at a distance from the internal surface of the left, right and/or main pulmonary artery during said thermally damaging.

Example 23. The method according to example 1, wherein said positioning comprises positioning said one or more transceivers in the left pulmonary artery at a distance of between 0- 2 cm from the bifurcation of the left pulmonary artery and the main pulmonary artery.

Example 24. The method according to example 1, wherein the locations are set per a specific patient anatomy according to pre-defined set boundaries determined using one or more of an angiogram, CT and MRI. Example 25. The method according to example 1, wherein said positioning comprises positioning said one or more transceivers at a predetermined distance from a point of maximal curvature of the inferior wall of the left pulmonary artery. Example 26. The method according to example 1, wherein said thermally damaging comprises heating a nerve at two or more locations along an axon or a bundle of axons of said nerve.

Example 27. The method according to example 1, wherein said catheter device comprises three transceivers configured to be actuated simultaneously to treat 3 spaced apart locations arranged circumferentially with respect to the artery lumen.

Example 28. The method according to example 27, comprising actuating only one or two of said three transceivers to prevent damage to non-targeted tissue. Example 29. The method according to example 27, comprising automatically detecting if one or more of said transceivers are directed towards non-targeted tissue, and deactivating those transceivers.

Example 30. The method according to example 1, comprising targeting nerves of which at least at least 60% in volume are sympathetic nerves.

Example 31. The method according to example 1, wherein said energy comprises unfocused ultrasound energy having the following parameters: an intensity between 40[W/cm ^A 2- 60[W/cm ^A 2], a frequency between 10[MHz]-12[MHz] and an excitation duration between 30 [sec] to 50 [sec].

Example 32. The method according to example 1, wherein said positioning comprises expanding a distancing device and avoiding movement of the catheter once the distancing device has been expanded. Example 33. The method according to example 1, wherein during said thermally damaging movement of said catheter device is avoided.

Example 34. The method according to example 1, comprising administering a systemic anticoagulant to the patient prior to said introducing of said catheter device. Example 35. The method according to example 1, comprising monitoring activated clotting time during treatment and stopping treatment of the activated clotting time is shorter than 275 seconds. Example 36. The method according to example 1, wherein during said thermally damaging, said catheter device moves in a lateral movement within said left, right and/or main pulmonary artery while keeping said one or more transceivers at a distance from the internal surface of said artery. Example 37. The method according to example 36, wherein said lateral movement is up to a distance of 5 cm.

Example 38. The method according to example 1, wherein said energy parameters are selected to so as to: reduce at least one of: Right atrial pressure (RAP), Right ventricle pressures (RVP), Systolic pulmonary artery pressure (sPAP), Mean pulmonary artery pressures (mPAP), Pulmonary vascular resistance (PVR), NT-pro-BNP and/or increase at least one of: Cardiac output (CO), Cardiac Index (CI), Ejection Fraction (EF), Pulmonary distensability, Exercise tolerance - 6 minutes walking distance (6MWD), Quality of life as assessed by questionnaire, cardiopulmonary exercise testing and V02 max. Example 39. A method of reducing thermal damage to a vessel wall during denervation treatment comprising:

introducing, into a vessel in which fluid exists, a catheter device comprising one or more transceivers suitable for emitting unfocused ultrasound;

emitting ultrasound energy at an intensity of at least 10[W/cm ^A 2] to cause an acoustic streaming effect in said fluid which cools said vessel wall at a rate sufficient to prevent thermal damage to the intima and media layers of the vessel wall.

Example 40. The method according to example 39, wherein said acoustic streaming effect is strong enough to reduce a temperature of an intimal aspect of said vessel wall by at least 3 °C. Example 41. The method according to example 39, wherein said streaming effect cools a surface of said transceiver. Example 42. A method for selecting patients for a pulmonary artery denervation treatment, comprising:

obtaining a drug regimen of pulmonary hypertension patients;

selecting pulmonary hypertension patients receiving one or more anti-coagulation drugs based on said drug regimen;

treating said selected pulmonary hypertension patients by positioning one or more ultrasound transceivers within the left, right and/or main pulmonary artery of said selected patients and thermally damaging nerve tissue by energy emitted from said one or more ultrasound transceivers. Example 43. The method of example 42, wherein said one or more anti-coagulation drugs comprise one or more of Acenocoumarol, heparin, warfarin (Coumadin), rivaroxaban (Xarelto), dabigatran (Pradaxa), apixaban (Eliquis), edoxaban (Savaysa), enoxaparin (Lovenox), and/or fondaparinux (Arixtra). Example 44. The method of example 42 comprising, administering an anti-coagulation drug during said treating to maintain ACT values higher than 270 seconds.

Example 45. A system for delivery of a nerve denervation treatment, comprising:

an ultrasonic device shaped and sized to be insertable into a pulmonary artery, comprising at least one ultrasonic transceiver configured to generate non-focused ultrasonic energy;

a memory configured to store at least one activation parameter of said ultrasonic device;

a control circuitry electrically connected to said ultrasonic device and said memory, wherein said control circuitry signals said ultrasonic device to generate non-focused ultrasonic energy with intensity in a range of 40-70 W/cm ^A 2 based on said at least one activation parameter stored in said memory.

Example 46. The system of example 45, comprising at least one interface electrically connected to said control circuitry and configured to generate a human detectable indication. Example 47. The system of example 46, wherein said control circuitry signals said interface to generate said human detectable indication when said ultrasonic device generates said non- focused ultrasonic energy during a time period which exceeds 50 seconds. Example 48. The system of example 46, wherein said interface is configured to receive at least one input signal related to at least one position of said ultrasonic device within said pulmonary artery, and wherein said control circuitry is configured to store said at least one position in said memory based on said received input signal. Example 49. The use of an anti-coagulation drug during a denervation treatment, comprising: administering an anti-coagulation drug to a patient to reach ACT values higher than 270 seconds; treating said patient by delivering a denervation treatment from a catheter positioned within the pulmonary arterial system. Example 50. The use according to example 49, wherein said anti-coagulation drug comprises Heparin.

According to an aspect of some embodiments of the invention, there is provided a method of treating pulmonary hypertension comprising: introducing a catheter device comprising one or more energy emitting transceivers into the pulmonary artery lumen; positioning the one or more transceivers within the left, right and/or main pulmonary artery at a location which is in between the first bifurcation of the left pulmonary artery and the first bifurcation of the right pulmonary artery; and thermally damaging nerve tissue by emitting energy having parameters selected to damage nerves only within a distance window of between 0.2 mm and 20 mm from the intimal aspect of the pulmonary artery wall when the one or more transceivers are positioned at the location.

In some embodiments, the energy parameters comprise an intensity high enough to raise a temperature of the nerve tissue by at least 10°C.

In some embodiments, the energy parameters comprise an intensity high enough to raise the blood temperature by between 5-9°C.

In some embodiments, the energy parameters comprise an intensity high enough to heat the nerve tissue at a rate higher than a cooling rate of the nerve tissue due to perfusion in a tissue volume including the nerve tissue.

In some embodiments, the energy parameters are selected taking into account one or both of self-heat generation in the tissue volume and heat absorption in the tissue volume.

In some embodiments, the energy comprises unfocused ultrasound energy. In some embodiments, parameters of the unfocused ultrasound energy are selected so that only nerve tissue found within coverage of the emitted energy beam is affected, while non-target tissue within the beam coverage is substantially unaffected.

In some embodiments, parameters of the unfocused ultrasound energy are selected so as to avoid thermal damage to non-target tissue including one or more of connective tissue, adipose tissue, lymph nodes.

In some embodiments, thermally damaging comprises thermally damaging nerves only within a distance window of between 4-10 mm from the intimal aspect of the pulmonary artery wall.

In some embodiments, thermally damaging comprises thermally damaging nerves only within a distance window of between 0.5-5 mm from the intimal aspect of the pulmonary artery wall.

In some embodiments, thermally damaging nerve tissue comprises thermally damaging one or more nerve plexuses extending along at least a longitudinal segment of the left, right and/or main pulmonary artery.

In some embodiments, the energy parameters are selected so as to reduce thermal damage to the intima and media layers of the artery wall.

In some embodiments, the energy parameters are selected so as not to affect a structure of the intima and media layers of the artery wall.

In some embodiments, reducing thermal damage comprises reducing thrombus or aneurysm formation

In some embodiments, reducing thermal damage comprises thermal damage to a level that cannot be observed in MRI and/or an angiogram obtained post treatment

In some embodiments, the energy parameters are selected as ones that would demonstrate safety in pre-clinical studies and demonstrate efficacy using TxA2 model.

In some embodiments, the method comprises positioning the one or more transceivers within the left or right pulmonary artery at a distance of less than 10 cm from a central longitudinal axis of the main pulmonary artery.

In some embodiments, a distance of the one or more transceivers relative to the artery wall is set by a distancing device.

In some embodiments, the method comprises repeating the steps of positioning and thermally damaging at between 2-8 treatment locations along the long axis of the left, right and/or main pulmonary artery. In some embodiments, a number of the treatment locations is selected to so as to: reduce at least one of: Right atrial pressure (RAP), Right ventricle pressures (RVP), Systolic pulmonary artery pressure (sPAP), Mean pulmonary artery pressures (mPAP), Pulmonary vascular resistance (PVR), NT-pro-BNP and/or increase at least one of: Cardiac output (CO), Cardiac Index (CI), Ejection Fraction (EF), Pulmonary distensability, Exercise tolerance - 6 minutes walking distance (6MWD), Quality of life as assessed by questionnaire, cardiopulmonary exercise testing and V02 max.

In some embodiments, a distance between adjacent treatment locations, as measured along the long axis of the artery, ranges between 0.1 cm to 2 cm.

In some embodiments, positioning comprises positioning the one or more transceivers in the main pulmonary artery at distance of at least 1 cm from the pulmonary valve.

In some embodiments, positioning comprises positioning the one or more transceivers in the left pulmonary artery at a distance of between 0-2 cm from the bifurcation of the left pulmonary artery and the main pulmonary artery.

In some embodiments, wherein the locations are set per a specific patient anatomy according to pre-defined set boundaries determined using one or more of an angiogram, CT and MRI.

In some embodiments, positioning comprises directing the one or more transceivers towards an inner curvature of the left or right pulmonary artery.

In some embodiments, positioning comprises positioning the one or more transceivers at a predetermined distance from a point of maximal curvature of the inferior wall of the left pulmonary artery.

In some embodiments, the method comprises producing thermal damage having a teardrop cross section profile, in which a bulbous portion of the teardrop faces the direction of the artery wall and a pointed end of the teardrop faces away from the artery wall.

In some embodiments, thermally damaging comprises causing a damage sufficient to prevent a nerve from reconnecting or regenerating.

In some embodiments, thermally damaging comprises heating the nerve at two or more locations along an axon or a bundle of axons of the nerve.

In some embodiments, thermally damaging comprises causing damage to at least a part of a nerve which produces, stores and/or transports norepinephrine or other neurotransmitters.

In some embodiments, the catheter device comprises three transceivers configured to be actuated simultaneously to treat 3 spaced apart locations arranged circumferentially with respect to the artery lumen. In some embodiments, the method comprises actuating only one or two of the three transceivers to prevent damage to non-targeted tissue.

In some embodiments, the method comprises automatically detecting if one or more of the transceivers are directed towards non-targeted tissue, and deactivating those transceivers.

In some embodiments, the method comprises targeting nerves of which at least at least

60% in volume are sympathetic nerves.

In some embodiments, the energy comprises unfocused ultrasound energy having the following parameters: an intensity between 30[W/cm ^A 2-70[W/cm ^A 2], a frequency between 8[MHz]- 13 [MHz] and an excitation duration between 30 [sec] to 50 [sec].

In some embodiments, the method comprises controlling operation of the catheter device via a console.

In some embodiments, positioning comprises expanding a distancing device and avoiding movement of the catheter once the distancing device has been expanded.

In some embodiments, during the thermally damaging movement of the catheter device is avoided.

In some embodiments, the method comprises administering a systemic anticoagulant to the patient prior to the introducing of the catheter device.

In some embodiments, the method comprises monitoring activated clotting time during treatment and stopping treatment of the activated clotting time is shorter than 250 seconds.

In some embodiments, the method comprises injecting contrast agent before, during and/or following treatment.

In some embodiments, the method comprises immediately ceasing energy emission in case one or more of the following conditions are present: coughing, arrhythmia, breathing disorders, pain.

In some embodiments, treatment is ceased when a predefined change in hemodynamic measures is detected.

In some embodiments, the method comprises repeating the positioning and emitting if a predefined change in hemodynamic measures has not yet been obtained.

In some embodiments, prior to the introducing, the method comprises telescopically introducing a guiding catheter over a second guiding catheter to the treatment location.

In some embodiments, energy parameters are selected to so as to: reduce at least one of: Right atrial pressure (RAP), Right ventricle pressures (RVP), Systolic pulmonary artery pressure (sPAP), Mean pulmonary artery pressures (mPAP), Pulmonary vascular resistance (PVR), NT- pro-BNP and/or increase at least one of: Cardiac output (CO), Cardiac Index (CI), Ejection Fraction (EF), Pulmonary distensability, Exercise tolerance - 6 minutes walking distance (6MWD), Quality of life as assessed by questionnaire, cardiopulmonary exercise testing and V02 max.

According to an aspect of some embodiments of the invention, there is provided a method of reducing thermal damage to a vessel wall during denervation treatment comprising: introducing, into a vessel in which fluid exists, a catheter device comprising one or more transceivers suitable for emitting unfocused ultrasound; emitting ultrasound energy at an intensity of at least 10[W/cm ^A 2] to cause an acoustic streaming effect in the fluid which cools the vessel wall at a rate sufficient to prevent thermal damage to the intima and media layers of the vessel wall.

In some embodiments, the acoustic streaming effect is strong enough to reduce a temperature of an intimal aspect of the vessel wall by at least 3 °C

In some embodiments, the streaming effect cools a surface of the transceiver.

In some embodiments, the acoustic streaming effect is strong enough to provide cooling during periods in which fluid flow through the vessel is reduced.

In some embodiments, the periods of reduced flow include reduced flow due to heart pulsation.

In some embodiments, the fluid is static.

According to an aspect of some embodiments of the invention, there is provided a method for pulmonary artery denervation, comprising: mapping nerves innervating the pulmonary artery; using the mapping, selecting target nerves according to one or both of a distance of the nerve from the pulmonary artery lumen and a cross sectional area of the nerve; and emitting energy suitable to thermally damage the target nerves.

In some embodiments, a number of target nerves is selected to be sufficient to reduce pulmonary vascular resistance levels by at least 10%-25% as compared to pulmonary vascular resistance levels measured before treatment.

According to an aspect of some embodiments of the invention, there is provided a method of treating pulmonary hypertension, comprising: selecting patients diagnosed with pulmonary hypertension; rejecting patients belonging to one or more of the following groups: patients who are pregnant, nursing or planning pregnancy; patients with implantable cardiac pacemakers, ICDs and/or neuro stimulators; patients with a known sensitivity to heparin and/or any of its substitutes; patients diagnosed with a clotting disorder and/or thrombocytopenia; patients diagnosed with a blood and/or bleeding disorder; patients with an anatomy that may interfere with the procedure, for example, an anatomy associated with the venous access site, right heart, pulmonary arteries and/or lungs; patients with a pulmonary artery aneurism; and treating the remaining patients.

According to an aspect of some embodiments of the invention, there is provided a kit for treating pulmonary hypertension, comprising: a package comprising: an intravascular catheter device comprising one or more ultrasonic transceivers; and instructions for use indicating the following exclusion criteria: patients who are pregnant, nursing or planning pregnancy; patients with implantable cardiac pacemakers, ICDs and/or neuro stimulators; patients with a known sensitivity to heparin and/or any of its substitutes; patients diagnosed with a clotting disorder and/or thrombocytopenia; patients diagnosed with a blood and/or bleeding disorder; patients with an anatomy that may interfere with the procedure, for example, an anatomy associated with the venous access site, right heart, pulmonary arteries and/or lungs; patients with a pulmonary artery aneurism.

According to an aspect of some embodiments there is provided method for selectively modifying nerve activity without causing substantial damage to non-targeted tissue, comprising: introducing a catheter device comprising one or more ultrasonic transceivers to the pulmonary artery lumen; receiving, using the one or more ultrasonic transceivers, echo signals reflected from the non-targeted tissue following emission of ultrasound energy by the one or more ultrasonic transceivers; analyzing the received echo signals to identify at least one of a type and location of the non-targeted tissue relative to the one or more ultrasonic transceivers; and emitting ultrasound energy from the one or more ultrasonic transceivers in accordance with the analyzing, to modify nerve activity without substantially damaging the identified non-targeted tissue. In some embodiments, the method further comprises selecting at least one of a location of the transceivers, an orientation of the transceivers, and a denervation treatment profile according to the analyzing. In some embodiments, the non-targeted tissue comprises one or more of: lung, trachea, vagus, lymph, bronchi. In some embodiments, analyzing comprises determining a distance between the non-targeted tissue and the one or more transceivers.

In some embodiments, analyzing comprises identifying targeted tissue. In some embodiments, emitting comprises targeting nerve tissue at a distance ranging between 0.5 mm to 10 mm from an inner wall of the artery lumen. In some embodiments, ultrasound energy is non- focused energy applied at an intensity sufficient to cause at least semi-permanent nerve modification to targeted tissue. In some embodiments, the method further comprises diagnosing the patient with one or more of pulmonary hypertension, asthma and/or COPD, and selecting a denervation treatment profile in accordance with the diagnosing. In some embodiments, the method further comprises collecting feedback and modifying the emitting based on the feedback by measuring one or more physiological parameters before and after the emitting. In some embodiments, one or more physiological parameters include one or more of heart rate, pulmonary artery diameter, bronchi diameter, cardiac output, respiratory rate, lung volumes _, arterial constriction, pulmonary artery pressure, blood flow, artery stiffness. In some embodiments, the pulmonary artery diameter is estimated by analyzing echo signals reflected by walls of the artery and received by the one or more ultrasonic transceivers. In some embodiments, measuring comprises stimulating the sympathetic nervous system, and measuring the physiological parameter in response to the stimulation.

According to an aspect of some embodiments there is provided a method for selectively targeting nerve tissue, comprising: introducing a catheter comprising one or more ultrasonic transceivers to the pulmonary artery lumen; selecting to damage only nerves that are not coated by myelin; emitting ultrasound energy at a frequency, intensity and duration sufficient to damage only nerves that are not coated by myelin, by producing a predetermined temperature profile in the treated tissue, the temperature profile ranging between 47-57 degrees C. In some embodiments, the method comprises modifying at least one of the frequency, intensity and duration of the energy to produce a temperature profile ranging between 58-70 degrees C in the treated tissue, to selectively damage both myelin coated nerves and non-coated nerves. In some embodiments, the method further comprises assessing a bronchial reaction to the emitting as feedback to the targeting, and modifying at least one of the frequency, intensity and duration of the energy in accordance with the bronchial reaction. In some embodiments, the method comprises positioning the one or more ultrasonic transceivers away from a wall of the pulmonary artery lumen to allow blood to flow between the transceivers and the wall.

According to an aspect of some embodiments there is provided an ultrasonic catheter for selectively targeting nerve tissue from a pulmonary artery lumen, comprising: a head configured at a distal end of the catheter, the head comprising one or more ultrasonic transceivers, the transceivers configured to emit non-focused ultrasound energy; a controller configured to select one or more of frequency, intensity and duration of the non-focused ultrasound energy emitted by the transceivers to selectively damage only nerves that are not coated by myelin. In some embodiments, the controller is configured to select one or more of the frequency, intensity and duration of the non-focused ultrasound energy emitted by the transceivers to selectively damage both myelin coated nerves and non-coated nerves.

According to an aspect of some embodiments there is provided an ultrasonic catheter device comprising: an elongated shaft; a head configured at a distal portion of the shaft, the head comprising a plurality of leaflets expandable in a radially outward direction relative to the shaft, each of the leaflets comprised of a rod-like element bendable into an elbow shaped configuration; and a plurality of ultrasonic transceivers, each transceiver mounted onto one of the expandable leaflets. In some embodiments, each of the transceivers comprises an energy emitting surface and an opposing surface, the opposing surface coupled to the leaflet to position the energy emitting surface to face a central direction. In some embodiments, a distal tip of the shaft is retractable for expanding the leaflets relative to the shaft and advanceable for contracting the leaflets closer to the shaft. In some embodiments, the transceiver is mounted onto the leaflet at the elbow shaped bend of the leaflet.

According to an aspect of some embodiments there is provided an ultrasonic catheter device for modifying nerve activity from an air filled lumen, comprising: a head comprising one or more ultrasonic transceivers, the transceivers configured to emit energy having parameters suitable to modify nerve tissue in target tissue; a balloon arrangement in which fluid is circulated, the balloon arrangement comprising at least an inner balloon, surrounding the transceivers, and an outer balloon, surrounding the inner balloon, wherein cold fluid is circulated in the inner balloon for cooling the one or more transceivers, and warm fluid is circulated in the outer balloon for enhancing a thermal heating effect of energy emitted by the transceivers, to effectively increase a depth of the produced ultrasonic field in the target tissue. In some embodiments, cold fluid and the warm fluid are the same fluid, the cold fluid heated as a result of cooling the transceivers and circulated as the warm fluid to enhance the thermal heating effect of the emitted energy. In some embodiments, the balloon arrangement comprises two or more balloons which when inflated cover only portions of the head, and do not surround the head circumferentially. In some embodiments, emitting surfaces of the one or more transceivers are exposed in between the balloons. In some embodiments, the balloon arrangement is configured to push the one or more transceivers away from a wall of the lumen when inflated. In some embodiments, the air filled lumen is the trachea.

According to an aspect of some embodiments there is provided a method for modifying nerve activity, comprising introducing a catheter device comprising at least one ultrasonic transceiver to the aorta; engaging the celiac artery ostium using an elongated tool extending from the catheter; and emitting ultrasound energy to modify nerve activity of the celiac ganglion. In some embodiments, the method comprises selecting a position of the at least one transceiver in the aorta in accordance with a location of the celiac artery ostium. In some embodiments, the method comprises positioning and orienting the at least one transceiver relative to the celiac artery ostium using the elongated tool. According to an aspect of some embodiments there is provided a kit for modifying nerve activity of the celiac ganglion, comprising a catheter comprising at least one ultrasonic transceiver; an elongated tool extendible from the catheter, the tool long enough to engage the celiac artery ostium, the tool comprising a curvature suitable to direct the ultrasonic transceiver towards the celiac artery ostium when the tool engages the ostium. In some embodiments, the elongated tool comprises a rod insertable through a cannulated shaft of the catheter and extendible from a distal opening of the catheter shaft.

According to an aspect of some embodiments there is provided an ultrasonic catheter system for modifying nerve activity, comprising a catheter comprising a head at its distal end, the head comprising one or more ultrasonic emitters, the emitters configured to emit energy suitable for modifying nerve activity; a tool usable with the catheter, the tool comprising: a supporting section; an emitter-positioning section configured distally to the supporting section; wherein the catheter is cannulated to be advanced over the tool into a blood vessel, until the emitters are axially aligned with the emitter positioning section of the tool; wherein the tool is shaped and sized such that the supporting section leans against a vessel wall opposite the wall to be treated, setting a location of the emitter positioning section at a predetermined radial distance from the vessel wall to be treated.

In some embodiments, the tool comprises a sigmoid shaped curvature, so that when the tool is within the blood vessel, the emitter-positioning section is located away from a central longitudinal axis of the vessel, at an angle to the longitudinal axis. In some embodiments, an arrangement of the emitters on the catheter head is selected so that when the head is advanced over the emitter-positioning section, an emitting surface of at least one of the emitters faces the vessel wall to be treated. In some embodiments, at least one of advancement of the catheter over the tool, and axial rotation of the tool when the catheter is positioned over it provide for treating the blood vessel circumferentially. In some embodiments, the tool is a guide wire, the guide wire comprising a spiral shape, the spiral having a cross sectional diameter which is no more than 10% smaller than a cross sectional diameter of the lumen. In some embodiments, the tool is a guide wire the guide wire comprising a Z shape, tracing a jagged path between the opposite walls of the body lumen so that when the guide wire is rotated, at least the one or more emitters are maintained at the predetermined radial distance from the lumen wall. In some embodiments, the catheter is positionable over the tool such that the head is proximal to at least one of the supporting section, and the emitter-positioning section.

According to an aspect of some embodiments there is provided an ultrasonic catheter for modifying nerve activity from within a blood vessel, comprising a shaft comprising at least one curved portion; a head configured at a distal end of the shaft, the head comprising one or more ultrasonic emitters, the emitters configured to emit energy suitable for modifying nerve activity; wherein the curved portion of the shaft comprises a sigmoid-shape curvature which pushes the head away from one wall of the blood vessel and in proximity to an opposite wall of the blood vessel. In some embodiments, the sigmoid shaped shaft portion distances the head away from a central longitudinal axis of the vessel, at an angle to the longitudinal axis. In some embodiments, an arrangement of the emitters on the catheter head is selected so that an emitting surface of at least one of the emitters faces the vessel wall to be treated. In some embodiments, axial rotation of the catheter provides for treating the blood vessel circumferentially. In some embodiments, the sigmoid shaped shaft portion comprises a cross sectional diameter which is no more than 10% smaller than a cross sectional diameter of the blood vessel.

According to an aspect of some embodiments there is provided a method for advancing an ultrasonic catheter within a body lumen while keeping at least emitters of the catheter at a predetermined radial distance range from the walls of the body lumen, comprising delivering a catheter comprising one or more ultrasonic emitters over a guide wire into a body lumen, the guide wire comprising a curvature selected in accordance with a cross sectional profile of the body lumen; advancing the catheter over the guide wire within the lumen, while the emitters are maintained within the predetermined radial distance range from a wall of the body lumen. In some embodiments, the radial distance range is between 1 mm from the wall of the body lumen, and 1 mm from a central longitudinal axis of the body lumen. In some embodiments, the cross sectional profile comprises a diameter of the body lumen, and the curvature of the guide wire comprises a diameter at least 5% shorter than the lumen diameter. In some embodiments, the catheter is advanced over the guide wire to a position in which the emitters are located proximally to the curvature of the guide wire. In some embodiments, the catheter comprises a single ultrasonic emitter, and wherein the method further comprises rotating the guide wire to treat the body lumen circumferentially.

According to an aspect of some embodiments there is provided an ultrasonic catheter structured to reduce movement of a distal portion of the catheter when at least a proximal portion of the catheter is subjected to movement resulting from heart pulsation, comprising a head configured at a distal end of the catheter, the head comprising one or more ultrasonic emitters configured to emit energy to modify nerve activity; a shaft comprising at least one axial decoupling at a distance of no more than 10 cm away from the head. In some embodiments, the axial decoupling is provided by a coil configured to dampen movement of the head when a proximal portion of the catheter is moved due to heart pulsation. In some embodiments, the catheter is sized for insertion into the pulmonary artery, the distance between the head and the axial decoupling selected so that when the head is positioned within the pulmonary artery, the axial decoupling is between the heart and the catheter head.

According to an aspect of some embodiments there is provided a method for treating pulmonary hypertension, comprising inserting a catheter comprising one or more ultrasonic emitters into the pulmonary artery; emitting non-focused ultrasound energy to thermally damage nerve tissue; measuring pulmonary arterial pressure; modifying the emitting in accordance with the pulmonary arterial pressure. In some embodiments, the catheter is equipped with one or more pressure sensors, and the measuring of pulmonary arterial pressure is performed using the one or more pressure sensors. In some embodiments, the method further comprises measuring one or more of cardiac output, systemic pressure. In some embodiments, emitting is performed at a distance of at least 1 mm from the wall of the pulmonary artery, allowing blood to flow between the emitter and the wall.

According to an aspect of some embodiments there is provided a method for modifying nerve activity from within the pulmonary artery, comprising introducing a catheter comprising an ultrasonic emitter into the pulmonary artery; emitting ultrasound energy having parameters suitable for thermally damaging nerve tissue; axially rotating the catheter to emit the energy circumferentially towards the walls of the artery.

Unless otherwise defined, all technical and/or scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which the invention pertains. Although methods and materials similar or equivalent to those described herein can be used in the practice or testing of embodiments of the invention, exemplary methods and/or materials are described below. In case of conflict, the patent specification, including definitions, will control. In addition, the materials, methods, and examples are illustrative only and are not intended to be necessarily limiting.

Implementation of the method and/or system of embodiments of the invention can involve performing or completing selected tasks manually, automatically, or a combination thereof. Moreover, according to actual instrumentation and equipment of embodiments of the method and/or system of the invention, several selected tasks could be implemented by hardware, by software or by firmware or by a combination thereof using an operating system.

For example, hardware for performing selected tasks according to embodiments of the invention could be implemented as a chip or a circuit. As software, selected tasks according to embodiments of the invention could be implemented as a plurality of software instructions being executed by a computer using any suitable operating system. In an exemplary embodiment of the invention, one or more tasks according to exemplary embodiments of method and/or system as described herein are performed by a data processor, such as a computing platform for executing a plurality of instructions. Optionally, the data processor includes a volatile memory for storing instructions and/or data and/or a non- volatile storage, for example, a magnetic hard-disk and/or removable media, for storing instructions and/or data. Optionally, a network connection is provided as well. A display and/or a user input device such as a keyboard or mouse are optionally provided as well.

BRIEF DESCRIPTION OF THE SEVERAL VIEWS OF THE DRAWINGS

Some embodiments of the invention are herein described, by way of example only, with reference to the accompanying drawings and images. With specific reference now to the drawings in detail, it is stressed that the particulars shown are by way of example and for purposes of illustrative discussion of embodiments of the invention. In this regard, the description taken with the drawings makes apparent to those skilled in the art how embodiments of the invention may be practiced.

In the drawings:

FIG. 1 is a flowchart of a method for treating nerves by positioning an ultrasonic device in the pulmonary artery, according to some embodiments of the invention;

FIG. 2A is a schematic illustration of neural networks and organs in the vicinity of a pulmonary artery, in a human thorax;

FIG. 2B is a block diagram of a system for treating nerve tissue, according to some embodiments of the invention;

FIGs. 3A-B illustrate an ultrasonic device positioned within a pulmonary artery, according to some embodiments of the invention;

FIGs. 4A-B illustrate an ultrasonic catheter device, according to some embodiments of the invention;

FIGs. 5A-B illustrate an ultrasonic device used with a distancing device, according to some embodiments of the invention;

FIGs. 6A-B are a flowchart of various aspects of selective treatment (6A), and a schematic graph of selectively treating different types of nerve tissue (6B), according to some embodiments of the invention;

FIG. 7 is a flowchart of an exemplary feedback loop associated with a denervation procedure, according to some embodiments of the invention; FIG. 8 illustrates an exemplary catheterization path to a pulmonary artery treatment zone selected in accordance with efficacy and safety considerations, according to some embodiments of the invention;

FIG. 9 illustrates an ultrasonic catheter device positioned within the left pulmonary artery, according to some embodiments of the invention;

FIG. 10 illustrates a cross section of the artery schematically illustrating a plurality of unfocused ultrasonic energy beams emitted by the catheter device, according to some embodiments of the invention;

FIG. 11 is a flowchart of a general method for treating pulmonary hypertension by thermally damaging nerves at a selected distance from the pulmonary artery lumen, according to some embodiments of the invention;

FIGs. 12A-G are images presenting introducing and positioning of an ultrasonic catheter for example as described herein in the pulmonary artery, according to some embodiments of the invention;

FIGs. 13A-C are computational simulations of a thermal effect on the tissue following exposure to various ultrasonic intensities, according to some embodiments of the invention;

FIG. 13D is a cross sectional image of thermal necrosis in bovine liver tissue in response to denervation treatment;

FIGs. 14A-C are histopathology images of a thermal effect obtained by ultrasound energy delivery in the pulmonary artery of swine models, according to some embodiments of the invention;

FIGs. 15A-B are graphs of mPAP levels: FIG. 15A presents differences in mPAP levels between the control group and treated group following administering of TxA2; FIG. 15B presents results of mPAP levels measured over time, before and after denervation treatment, according to some embodiments of the invention;

FIGs. 16 A- J and FIGs. 17A-D are histopathology images showing some long term effects of ultrasound energy delivery in the pulmonary artery of swine models, according to some embodiments of the invention;

FIGs. 18A-C are tables summarizing results of nerve mapping for determining a location and/or distribution of pulmonary artery nerves, in accordance with some embodiments of the inventions;

FIGs. 19A-F graphically present an analysis of nerves innervating the pulmonary artery, performed in accordance with some embodiments of the invention; FIGs. 20A-B schematically define anatomical limits for performing denervation, according to some embodiments of the invention;

FIGs. 21A-C are examples of single and multiple treatment locations along the pulmonary artery, according to some embodiments of the invention;

FIG. 22 schematically illustrates an acoustic streaming effect produced in response to energy emission in the artery, in accordance with some embodiments;

FIG. 23A is a table of scheduled events related to a treatment or a clinical study of the treatment, according to some embodiments of the invention;

FIG. 23B is a flow chart of a treatment or a clinical study of the treatment, according to some embodiments of the invention;

FIG. 24A is an angiogram showing treatment locations in the right and main pulmonary artery, according to some embodiments of the invention;

FIG. 24B is an angiogram showing treatment locations within the left and main pulmonary artery, according to some embodiments of the invention;

FIGs. 25A-25D are a series of column charts demonstrating changes in (A) Mean PAP, (B) Cardiac Index, (C) PVR and (D) RA pressure compared to baseline levels 4 months post treatment, according to some embodiments of the invention;

FIGs. 26A-26C are a series of column charts demonstrating changes in (A) Quality of life, (B) 6MWD, (C) Actimetry compared to baseline levels 4 months post treatment, according to some embodiments of the invention; and

FIG. 27 is a column chart demonstrating changes in PVR compared to baseline levels 4 months post treatment between a group of patients receiving an anti-coagulation treatment and a group of patients that did not receive the anti-coagulation treatment, according to some embodiments of the invention. DESCRIPTION OF SPECIFIC EMBODIMENTS OF THE INVENTION

The present invention, in some embodiments thereof, relates to hypertension treatment and, more particularly, but not exclusively, to treatment of pulmonary hypertension.

A broad aspect of some embodiments relates to positioning an ultrasonic catheter in the pulmonary artery, trachea and/or aorta for targeting and treating nerve tissue by thermally damaging the nerve tissue. In some embodiments, treating comprises emitting ultrasound energy, such as non focused ultrasound, for modifying nerve function. In some embodiments, activity of one or more nerves, nerve segments, nerve plexuses and/or other nerve tissue is reduced or eliminated. In some embodiments, treatment comprises ablating nerve tissue, such as nerve tissue of the pulmonary vasculature, and causing damage sufficient to prevent regeneration of the tissue.

An aspect of some embodiments relates to selectively treating nerve tissue, using at least one ultrasonic transceiver to characterize tissue and using that same transceiver to emit energy for treating targeted tissue. In some embodiments, selective treatment comprises causing damage to selected nerves without causing substantial damage to non- targeted tissue, such as surrounding organs and/or other nerve tissue. In some embodiments, characterizing tissue comprises identifying one or more organs such as the lungs, trachea, lymph, bronchi or others. In some embodiments, organs are identified based on their echo signal reflection. Optionally, the reflected signals are received by the one or more ultrasonic transceivers of the catheter device, and are analyzed to determine the organ type and/or the relative distance of the organ from the lumen from which treatment is applied, such as the pulmonary artery lumen. In some embodiments, the ultrasonic transceivers are activated at a first energy profile to identify and/or characterize tissue, and at a second energy profile to treat tissue. Optionally, non-targeted tissue is identified. Additionally or alternatively, targeted tissue is identified.

In some embodiments, selective treatment comprises differentiating between nerves during treatment, for example by producing a predetermined temperature profile in the treated nerves. Optionally, the predetermined temperature profile is obtained by emission of ultrasound energy at a selected profile, suitable to heat the nerves to a desired temperature or range of temperatures. In an example, differentiating between nerves comprises causing damage only to nerves that are not coated by myelin by producing a first temperature range, and causing damage to both coated and non-coated nerves by producing a second temperature range.

In some embodiments, selective treatment comprises emitting energy for thermally damaging nerve tissue without causing substantial damage to the artery wall. Optionally, damage to the wall is reduced by keeping the one or more ultrasonic transceivers away from the wall, for example by using a distancing device. In some embodiments, selective treatment comprises treating from an artery in which a wall disorder such as thrombus or atheroma exist, while reducing a risk of breakage of the thrombus or atheroma, which may result in emboli and possibly occlude the artery.

Selective treatment is pursued, in some embodiments, by activating one or more transceivers to emit energy towards a selected direction, and/or deactivating one or more transceivers to reduce or prevent emission in one or more other directions.

An aspect of some embodiments relates to feedback based treatment of the pulmonary vasculature. In some embodiments, treatment is continued and/or modified based on one or more measurements of physiological control parameters, including local parameters such as, for example, pulmonary artery diameter, bronchi diameter, and/or systemic parameters, which may be a byproduct of denervation, including, for example, heart rate, respiratory volume, and/or other physiological parameters. In some embodiments, the physiological parameters are measured internally to the body. Additionally or alternatively, the physiological parameters are measured externally to the body. In some embodiments, the ultrasonic catheter is configured to acquire the one or more physiological parameters. In an example, a physiological parameter such as a diameter of the pulmonary artery is estimated by analyzing echo signals reflected by the artery walls and received by the one or more transceivers of the catheter device. In some embodiments, the physiological parameter is acquired by stimulating the nervous system to evoke an observable physiological response and/or a chain of responses, one or more of which are detectable and optionally measureable.

In some embodiments, a measurement of the physiological parameter acquired before treatment is compared to a measurement of the same physiological parameter following treatment, to determine treatment effectiveness. For example, an increase in artery diameter above a certain threshold, measured following treatment, may indicate that the treatment was effective.

In some embodiments, immediate feedback is provided, and treatment is modified and/or ceased based on the feedback. In an example, immediate feedback comprises assessing dilation of the bronchi, which may be observed shortly after denervation. In another example, immediate feedback comprises assessing arterial blood pressure.

An aspect of some embodiments relates to an ultrasonic catheter structure and/or to elements used with the catheter that are suitable for reducing unwanted movement of the catheter, and more specifically movement of at least a distal portion of the catheter when a more proximal portion of the catheter is passed through cardiac vasculature, where it is subjected to movement resulting from heart pulsation. In some embodiments, the catheter is passed through the right ventricle of the heart. In some cases, contraction of the ventricle may cause movement of the catheter shaft, thereby possibly moving the distal head of the catheter, which comprises the one or more transceivers.

In some embodiments, a structure of the catheter shaft is selected to damp movement resulting from heart pulsation, potentially reducing a number of movements and/or a range of movement of at least a distal head of the catheter. In some embodiments, one or more locations along the catheter shaft are structured to provide a full or partial axial decoupling between axial segments of the catheter, for example so that movement of the head at a distal end of the device is least affected by movement of a more proximal portion of the catheter shaft. Additionally or alternatively, the catheter is anchored to a certain location in the artery and/or to other tissue or organs, to prevent or reduce movement of the catheter relative to the tissue, for example during emission of ultrasound. Optionally, a small range of movement is permitted, such as movement to an extent which does not affect targeting. Additionally or alternatively, a "working frame" is provided, and the catheter is maneuvered within the working frame. Additionally or alternatively, movement of the catheter is synchronized with movement of the targeted tissue, for example by anchoring the catheter to a structure that moves in a similar pattern to the targeted tissue.

In some embodiments, at least a head of the catheter, comprising the one or more ultrasonic transceivers, is positioned and/or oriented within the lumen from which treatment is applied at a predetermined location. Optionally, positioning of the catheter and/or directing of the ultrasonic beam is selected based on one or more of: a distance from the tissue to be treated, a distance from the lumen wall, a position along the length of the lumen, parameters of the ultrasonic beam emitted by the transceivers (e.g. beam shape), and/or others. In some embodiments, positioning of the catheter and/or directing of the beam is performed by delivering the catheter over a pre- shaped guide wire, for example a spiral guide wire or a guide wire curved to a substantial Z shape. A potential advantage of the spiral configuration may include setting an advancement path for the catheter in which at any point along the path, at least the catheter head is maintained at a selected distance from the lumen wall, for example in proximity to the lumen wall. Optionally, the catheter is positioned a distance between 0.1mm to 20 mm from the lumen wall. Optionally, the distance is selected in accordance with the intensity applied, for example a distance ranging between 0.1mm to 5 mm, 5 mm-10 mm, 15 mm- 20 mm or intermediate, larger or smaller distance ranges are used with an intensity between 20 W/cm ^A 2 to 80 W/cm ^A 2. In some embodiments, the spiral diameter (i.e. a diameter of a loop) is selected according to the lumen diameter. Additionally or alternatively, the spiral diameter is selected according to the catheter diameter, for example a diameter of the catheter head. In some embodiments, a similar effect to delivering the catheter over a helical structure may be obtained by delivering the catheter over the Z-shaped wire, and rotating the wire. Optionally, the catheter is introduced over the wire to a position in which the catheter head is proximal to the curved portion of the wire. Alternatively, the catheter is introduced over the wire to a position in which the catheter head is distal to the curved portion of the wire. Another potential advantage of the spiral and/or Z- shaped configurations (and/or any other configurations suitable to position the catheter away from the center of the lumen and in proximity to the walls) may include facilitating treating the lumen circumferentially. Optionally, when applying circumferential treatment by delivering the catheter over a curved guide wire, the curvature of the wire can be selected to obtain a certain orientation of the transceivers at the head of the catheter, for example positioning a transceiver such that a longer dimension of the transceiver (for example being a rectangular transceiver) extends at an angle relative to a longitudinal axis of the lumen.

An aspect of some embodiments relates to an anatomical treatment zone for positioning an energy emitter (such as an ultrasonic transceiver) of a denervating catheter such that the emitter is positioned to treat a selected target tissue volume while damage to non-targeted tissue types and/or non-targeted organs is reduced.

In some embodiments, the selected treatment zone provides for targeting a tissue volume comprising a high nerve content as compared to other tissue volumes, while reducing a risk of damage to non-targeted tissue (such as adipose tissue, connective tissue) and/or to nearby organs (such as the aorta, vagus, esophagus and/or other organs). A potential advantage of positioning the catheter at the selected treatment zone may include optimizing a tradeoff between denervation efficacy and treatment safety, such as avoiding damage to non-targeted tissue. Other optimization methods may include treating the most efficient treatment location. The described location was found to be the most efficient due to highest nerve density, and also considered a safe location to treat.

In some embodiments, the anatomical treatment zone comprises an ostial and/or near- ostial area within the lumen of the left pulmonary artery, in the vicinity of the bifurcation in which the main pulmonary trunk splits into the left pulmonary artery and the right pulmonary artery. In some embodiments, the anatomical treatment zone is located at a distance of less than 50mm, 40mm, 30 mm, less than 20 mm, less than 10 mm or intermediate, longer or shorter distances from a central longitudinal axis of the main trunk of the pulmonary artery. Additionally or alternatively, the anatomical treatment zone is situated at an axial distance (measured along the length of the left pulmonary artery) between 5-50 mm, 0-10 mm, 10-30 mm or intermediate, longer or shorter distance ranges from the artery ostium. Additionally or alternatively, the anatomical treatment zone is situated at a distance of less than 10 mm, less than 7 mm, less than 3 mm from the point of maximal curvature of the left pulmonary artery. Additionally or alternatively, the anatomical treatment zone is situated within the range of the first 1/5, 1/4, 1/3 or intermediate, longer or shorter sections of the total length of the left pulmonary artery, measured for example between the long axis of the main pulmonary trunk to the lateral bifurcation of the left pulmonary artery, where it splits into two or more branches, each extending towards one of the lobes of the left lung. The ostium here refers to the bifurcation point that is mutual to the main trunk, the left and the right pulmonary arteries. In some embodiments the ostium point is first located by fluoroscopy prior to deciding the treatment zone.

In some embodiments, the anatomical treatment zone does not include the right pulmonary artery. A potential advantage of not treating from within the right pulmonary artery may include reducing potential damage (e.g. thermal damage) to the aorta, which ascends with the main pulmonary trunk and arches around the right pulmonary artery, and/or to reduce potential damage to the vagus nerve, which extends dorsally to the right pulmonary artery. Alternatively, the anatomical treatment zone comprises the right pulmonary artery.

In some embodiments, treatment is applied from the anatomical treatment zone to treat a selected target tissue volume. In some embodiments, the selected target tissue volume comprises one or more nerve plexuses situated to the left of the left pulmonary artery. In some embodiments, the selected target tissue volume is located laterally, posteriorly and/or anteriorly to the left pulmonary artery. In some embodiments, the selected target tissue volume is located within a distance range of 0.2-30mm from a point of maximal curvature of the left pulmonary artery. Additionally or alternatively, the selected target tissue volume is located laterally to the main trunk of the pulmonary artery, inferior to the left pulmonary artery.

In some embodiments, unfocused ultrasound energy having parameters (e.g intensity, frequency, beam shape, duration and/or other parameters) suitable to thermally damage nerve tissue is emitted. Additionally or alternatively, other forms of energy suitable to thermally damage nerve tissue are applied, such as RF (monopolar or bipolar), ultrasound, light heat, cold radiation, microwave radiation, phototherapy,magnetic therapy, electro magnetical radiation, electrotherapy, cryotherapy, plasma therapy, mechanical manipulation, kinetic therapy, nuclear therapy, elastic and hydrodynamic energy. In some embodiments, parameters of the applied energy are selected in accordance with the anatomical treatment location, based on the type(s) and/or quantity and/or distribution of tissue that exist within the targeted volume. Optionally, selective treatment is performed, in which only a part of the tissue and/or a certain type of tissue within the target volume such as nerve tissue is affected by the emitted energy, while other tissue remains substantially unharmed. In an example, the applied energy parameters are selected to produce a temperature profile in the target tissue which thermally damages nerve tissue, but does not have a substantial effect (e.g. necrosis, denaturation) on non-targeted tissue within the target volume.

In some embodiments, energy is emitted towards a circumferential region of the left pulmonary artery. Optionally, the one or more transceivers are activated and/or rotated during and/or between treatment sessions to cover different circumferential sections. In some embodiments, a line of electrodes/ ultrasonic transceivers are aligned along the circumference of the artery and only the ones facing to target zone are activated. This may be potentially advantages to increasing safety.

In some embodiments, when emitting energy from the selected anatomical treatment zone towards the selected target tissue volume, a separation angle of at least 20 degrees, at least 30 degrees, at least 60 degrees or intermediate, larger or smaller angle is formed between the emitted energy beam and non-targeted organs. A potential advantage of emitting energy such that a separation angle is formed between the non-targeted organs and the emitted beam may include increasing treatment safety, as even if the beam is emitted at an offset angle from the selected angle, at least to some extent, non-targeted tissue will remain substantially unharmed.

In some embodiments, a structure of the catheter is designed to provide for positioning the one or more energy emitters (e.g ultrasonic transceivers) within the anatomical treatment zone, for example by the catheter comprising a shaft that is shaped and/or deformable to a curvature that matches the curvature of the left pulmonary artery.

An aspect of some embodiments relates to a synergy between the denervating catheter and the anatomy of the selected treatment zone and/or the anatomy of a delivery path of the catheter. In some embodiments, the physician utilizes the anatomy to direct the catheter to a selected treatment location, such as within the anatomical treatment zone described herein. In some embodiments, the anatomy naturally "assists" in directing the catheter to the selected location, for example by defining boundaries which force the catheter to the selected location.

In some embodiments, a shaft of the catheter is shaped in a manner in which at least some portions of the shaft lean and/or anchor against walls of a lumen through which the catheter is introduced to the selected treatment location, for example a lumen of the pulmonary artery trunk and/or a lumen of the right and/or left pulmonary arteries, to provide for positioning a head of the catheter at a selected treatment zone. In an example, the catheter shaft is arched, allowing a more proximal portion of the shaft to lean against a right wall of the pulmonary artery trunk to thereby position a more distal portion of the catheter which includes the energy emitting head within a treatment zone located in the ostial left pulmonary artery section.

In some embodiments, a path through which catheter is introduced to the treatment zone follows the natural path of blood flow. Optionally, the flow of blood assists in directing the catheter to the selected treatment location, for example by using an inflatable balloon tip and/or sail tip providing for flow-directed floatation of the catheter to the selected location. An aspect of some embodiments relates to denervating nerve tissue within a predefined distance window from the pulmonary artery wall. In some embodiments, the distance ranges between, for example, 0.2-20 mm, 0.2-10 mm, 4 mm-9 mm, 1 - 6 mm or intermediate, larger or smaller distance ranges relative to the intimal aspect of the artery wall. In some embodiments, a position of the catheter along the artery and suitable energy parameters are selected together in order to target nerve tissue within the predefined distance window. In some embodiments, one or more transceivers of the catheter are positioned within the left, right and/or main pulmonary artery within a limited area, in which the first bifurcation of the right pulmonary artery sets a border line and a first bifurcation of the left pulmonary artery sets a second border line. In some embodiments, an angiogram and/or CT and/MRI images acquired before and/or during treatment are used for determining border line locations.

In some embodiments, the transceivers are positioned such that a tissue volume covered by the beam of emitted energy encompasses mostly nerves innervating the pulmonary artery. Optionally, the volume is selected such that nerves innervating other organs are avoided or their presence is insignificant. Optionally, at least 50%, at least 60%, at least 70%, at least 80% by volume of nerve tissue within the tissue volume covered by the beam includes sympathetic nerves.

In some embodiments, energy parameters are selected using a computational model that takes into account one or more of metabolic heat generation in tissue, heat absorption characteristics of the tissue, heat conductivity, metabolic flow in the tissue, tissue density, acoustic absorption, volumetric blood perfusion in the tissue, cell sensitivity to heat, cell sensitivity to mechanical or acoustical damage and/or other tissue parameters. In some embodiments, the model is constructed according to a finite element analysis which assists in determining a temperature distribution profile in the tissue, in space and/or time. Optionally, the finite element analysis takes into account a solution of the bioheat equation under selected conditions.

In some embodiments, the energy parameters are selected so that energy deposited in the tissue outside the artery is sufficient to thermally damage nerves within the distance window. In some embodiments, the emitted beam is selective in the sense that nerve tissue within the beam coverage is thermally damaged, while other, non-target tissue within the beam coverage (such as adipose tissue, lymph and/or other non-target tissue) remains substantially undamaged. In some embodiments, the tissue specific damage has a higher affinity to nerve tissue surrounded by fatty tissue, due to the low heat conductivity of the fatty tissue. Optionally, due to acoustic absorption and/or thermal sensitivity properties that are higher than acoustic absorption and/or thermal sensitivity properties of other tissue, such as lymph tissue, fibrous tissue, or connective tissue, the acoustic energy affects the nerve tissue most.

In some embodiments, cooling as a result of blood flow through the pulmonary artery and/or cooling as a result of perfusion in the tissue reduces or prevents thermal damage to the intima and media layers of the artery wall, so that a significant thermal effect starts only at a distance away from the wall.

In some embodiments, treatment is performed at a plurality of locations situated along a long axis of the left, right and/or main pulmonary artery, for example between 2-8 locations within each of the left, right and main artery. Optionally, a distance between adjacent treatment locations ranges between 0.1 to 2 cm, between 0.5- 1 cm, between 1-2 cm or intermediate, longer or shorter distances. In some embodiments, energy is emitted at plurality of locations to damage a nerve (or a bundle of nerves) at a plurality of sections along the length of the nerve. For example, a nerve may be damaged at an initial section of the axon and at a distal section of the axon (e.g. at or near the synapse), impairing also an intermediate section of the axon as a result. In some embodiments, the extent of thermal damage is high enough to prevent from the nerve from reconnecting and/or regenerating for at least a time period following treatment (for example at least 1 month, 3 months, 6 months, 1 year following treatment). In some embodiments, nerve portions that transport, store and/or produce neurotransmitters are damaged. In some embodiments, the thermal damage is manifested as coagulation, vacuolation and/or nuclei pyknosis of the targeted nerve. In some embodiments, the thermal damage results in tissue fibrosis and optionally in formation of remodeled scar tissue.

In some embodiments, a temperature distribution profile of the thermal damage produced depends on tissue homogeneity. Optionally, in homogenous tissue, a cross section profile of thermal damage takes the form of a teardrop.

An aspect of some embodiments relates to reducing thermal damage to the pulmonary artery wall by taking advantage of a streaming effect produced in response to emission of ultrasound. In some embodiments, ultrasound emitted at a frequency of between 8-13 MHz, 5-10 MHz, 10-20 MHz or intermediate, higher or lower frequency ranges and an intensity of between 20-100 W/cm ^A 2, 30-70 W/cm ^A 2, 35-65 W/cm ^A 2, or intermediate, higher or lower intensity ranges produces fluid circulation in which fluid is caused to flow from the transceiver surface towards the artery wall, thereby dissipating heat away from the transceiver and, in turn, from the artery wall. In some embodiments, even if fluid (e.g. blood) in the artery is static or the flow is reduced (e.g. due to pulsation, such as during diastole) the acoustic streaming effect produced by emission of ultrasound energy sufficiently cools the artery wall, preventing at least the intima and media of the artery wall from thermal damage. In some embodiments, cooling provided by the streaming effect is sufficient to dissipate at least 10%, at least 20%, at least 40% or intermediate, higher or lower percentage of the power of the emitted energy. In some embodiments, cooling provided by the streaming effect is sufficient to reduce a temperature of the intima to a temperature of 42°C or lower.

An aspect of some embodiments relates to targeting nerves according to mapping of the nerves. In some embodiments, nerves are selected as target according to one or both of a distance of the nerve from the artery lumen and a cross sectional area of the nerve. In some embodiments, a number of target nerves is selected to reduce one or more of: mPAP, pulmonary vascular resistance, contractibility, and/or systemic pressure levels in the pulmonary artery as compared to mPAP levels measured before treatment. In some embodiments, right heart ejection fraction is increased. Generally, the number of target nerves may be selected to improve (e.g. increase or decrease a level of) any parameter associated with pulmonary hypertension.

It is noted that various conditions may be treated using the methods and/or devices described herein, including, for example, one or more of pulmonary hypertension, pulmonary arterial hypertension (PAH), asthma, chronic obstructive pulmonary disease (COPD), mesothelioma, heart failure, atrial fibrillation, sleep apnea, insulin resistance and/or other conditions directly or indirectly associated with nerve activity.

Throughout the application, when the term "pulmonary artery" is used, the term may refer to one or more of the pulmonary artery trunk, the right pulmonary artery, the left pulmonary artery, and/or the bifurcation area of the pulmonary artery. In some embodiments, a catheter structure and/or a treatment protocol are selected based on an anatomy of the pulmonary artery region intended for treatment. For example, when treating the pulmonary artery trunk, in which the cross sectional area is relatively large (comprising a diameter which is about 1.5 times a diameter of the right or left pulmonary arteries), it may be desirable to position the catheter head closer to the lumen wall as compared to, for example, when treating in an artery region of smaller cross sectional area. Optionally, when treating an artery region having a relatively large cross sectional area, higher intensities are applied. In some embodiments, a high intensity is applied to compensate for undesired movement of the catheter within the large artery region. Optionally, by directing energy at a high intensity towards a large volume or cross section of tissue, the energy spreads over the large volume, thereby reducing the actual intensity of energy that effectively reaches the various tissue locations within the large volume.

An aspect of some embodiments relates to selecting PAH patients for a denervation treatment based on the drug regimen of the patients. In some embodiments, PAH patients receiving anti-coagulation drugs are selected for the denervation treatment. In some embodiments, the denervation treatment is delivered from within the pulmonary arterial system, optionally using ultrasonic energy, for example non-focused ultrasonic energy. In some embodiments, patients receiving Acenocoumarol and/or warfarin (Coumadin) are selected for the denervation treatment. Alternatively or additionally, patients receiving one or more of heparin, rivaroxaban (Xarelto), dabigatran (Pradaxa), apixaban (Eliquis), edoxaban (Savaysa), enoxaparin (Lovenox), and/or fondaparinux (Arixtra), are selected for denervation treatment.

An aspect of some embodiments relates to maintaining ACT values higher than 270 seconds during a denervation treatment. In some embodiments, the denervation treatment is delivered from within the pulmonary arterial system, optionally using ultrasonic energy, for example non-focused ultrasonic energy. In some embodiments, an anti-coagulation drug, for example Heparin is administered to patients undergoing the denervation treatment for maintaining ACT values higher than 270 seconds, for example 270 seconds, 275 seconds, 280 seconds or any intermediate, smaller or larger value. In some embodiments, ACT values higher than 270 seconds are maintained before, during and/or after the denervation treatment.

Before explaining at least one embodiment of the invention in detail, it is to be understood that the invention is not necessarily limited in its application to the details of construction and the arrangement of the components and/or methods set forth in the following description and/or illustrated in the drawings and/or the Examples. The invention is capable of other embodiments or of being practiced or carried out in various ways.

A general method for treating nerves using an intravascular catheter in the pulmonary artery

Referring now to the drawings, Figure 1 is a flowchart of a method for treating nerves, according to some embodiments of the invention.

In some embodiments, a patient is diagnosed with a respiratory condition such as one or more of pulmonary hypertension (including, for example, pulmonary arterial hypertension), asthma, and/or chronic obstructive pulmonary disease (COPD) (101). In some cases, a decision is made, such as by a physician, to treat the condition (103).

In some embodiments, an intravascular ultrasonic catheter device is introduced to the pulmonary artery (105), to treat one or more sympathetic nerves which innervate the pulmonary vasculature. In some embodiments, the catheter device is configured to emit ultrasound energy having parameters suitable for treating the nerves, for example as further described herein. In some embodiments, treating comprises modifying nerve activity, for example reducing the activity of one or more nerves. In some cases, treating comprises thermally damaging the nerves, to reduce or eliminate their function. In some embodiments, treatment comprises ablating nerves and causing enough damage to prevent the nerves from regenerating.

In some embodiments, treatment includes applying the ultrasonic treatment, in addition to administrating pharmaceutical treatment (e.g. medication such as diuretics, beta blockers, ACE inhibitors or other). Alternatively, the ultrasonic treatment alone is provided.

In some cases, the device is introduced to the body in a percutaneous procedure. In some embodiments, the device is passed through the right atrium, into the right ventricle, and advanced into the main pulmonary artery. In some cases, the device is further advanced into the left pulmonary artery and/or the right pulmonary artery (107). In some cases, the device is positioned in the vicinity of the bifurcation.

In some embodiments, positioning of the device within the vessel involves anchoring the device. In some embodiments, positioning of the device involves stabilizing the device, for example reducing movement of the device resulting from the flow of blood within the artery, and/or reducing movement of the device resulting from muscular contraction such as heart contraction, for example in cases in which the catheter is passed through the heart. Optionally, if treatment is performed in the vicinity of the bifurcation, the device is anchored against turbulent flow at the bifurcation. In an example, the head of the catheter is held in place in the bifurcation area by an anchoring element, such as a curved rod or a spring coil which is coupled to a more proximal portion of the catheter, and extends into the left and/or right pulmonary arteries to anchor the more proximal of the catheter to the smaller artery region, thereby reducing or preventing movement of the more distal portion of the catheter comprising the head.

In some embodiments, positioning of the device involves distancing one or more emitting elements of the catheter away from the wall of the artery lumen. In some embodiments, positioning of the device is selected in accordance with heart pulsation, for example by locating the catheter in an area in which it is least subjected to movement.

In some embodiments, since the pulmonary artery (for example at the main pulmonary artery section) comprises a relatively larger artery diameter, for example ranging between 15mm to 40mm, for example 20 mm, 30 mm, 37 mm, or intermediate, larger or smaller diameters. In some embodiments, a catheter comprising a diameter of between 4F to 11F is used. A potential advantage of treating from within the relatively large pulmonary artery using a catheter with a large head diameter may include increased circumferential coverage of the artery walls, for example as compared to a catheter having a smaller head diameter. In some embodiments, various positioning elements such as a distancing device and/or one or more balloons may be used with the catheter to assist in locating the catheter at a desired location for applying treatment.

In some embodiments, the catheter itself and/or a guide wire used with the catheter (e.g. a guide wire over which the catheter is delivered) is configured to obtain and/or maintain a selected position in the vessel. In some embodiments, the selected position is one in which the one or more transceivers at a distal head of the catheter are positioned adjacent the vessel wall. Additionally or alternatively, the selected position is one in which a maximal coverage of the vessel circumference is obtained, for example by positioning the one or more transducers substantially aligned with the vessel axis. In an example, a shaft of the catheter is mechanically deflectable only in certain directions and/or angles. In another example, a guidewire used with the catheter comprises a predefined curvature, which places the catheter that is delivered over it at a selected location, for example relative to the vessel walls. Optionally, the guide wire comprises memory shape material, such as nitinol.

In some embodiments, treatment is applied to modify the activity of one or more nerves, nerves sections, and/or nerve plexuses (109). In some embodiments, applying treatment comprises emitting ultrasound energy. In some embodiments, non-focused ultrasound is applied. Optionally, treatment is applied in pulses.

In some embodiments, treatment parameters are selected to produce an ultrasonic field which is effective to modify nerves within a certain distance range from the lumen wall, for example a distance of up to 5 mm, up to 8.5 mm, up to 10 mm or intermediate, larger or smaller distances from the artery wall. Optionally, parameters are selected such as not cause damage to the vessel wall tissue.

In some embodiments, emitting is performed from a minimal radial distance away from the artery wall, such as at least 1 mm from the wall, allowing a sufficient amount of blood to flow between the transceiver and the wall, potentially cooling the transceiver and/or reducing a risk of thermal damage to the vessel wall.

Exemplary treatment parameters usable when treating nerves from a pulmonary artery location may include one or more of an intensity of at least 35 W/cm ^A 2, at least 40 W/cm ^A 2, at least 45 W/cm ^A 2, at least 55W/cm ^A 2, at least 65 W/cm ^A 2 or intermediate, higher or lower intensities, a frequency ranging between 10 MHz to 20 MHz, such as 12 MHz, 15 MHz, 18 MHz or intermediate, higher or lower frequencies, and/or a waveform which is sinusoidal. It is noted that other parameters may be used, including various intensity and/or frequency ranges, and/or various waveforms such as squared or triangular. In some embodiments, an effect of the treatment is assessed (111). In some embodiments, immediate feedback is provided, such as by observing physical changes to the bronchi, for example as further described herein. In some embodiments, treatment is applied and/or modified based on feedback. In some embodiments, obtaining feedback comprises assessing a condition of the artery, such as by processing of echo signals received by the device. In an example, a diameter of the artery, for example at one or more treatment locations, is estimated. Optionally, vasodilation or constriction of the artery are assessed using the diameter estimation.

In some embodiments, the device is moved to a different location (113) along the pulmonary artery, for example in attempt to target other nerve tissue. In some embodiments, one or more of steps 109-113 are repeated. In some embodiments, treatment is applied at a plurality of locations, for example a first location in the main pulmonary artery, before the bifurcation, a second location in the vicinity of the bifurcation, and a third location within the right and/or left branches of the artery. Typically, the device is positioned within the pulmonary vasculature, and does not enter the lungs.

Examples of targeted nerve tissue

Figure 2A is a schematic illustration of neural networks and organs in the vicinity of a pulmonary artery, in a human thorax. Some of the organs are shown only in part, to enable viewing adjacent organs. The illustration shows the layout of nerves and nerve plexuses, which may be treated by an apparatus for example as described herein. In some embodiments, the targeted nerves may include one or more of, for example, the left coronary plexus 201 and/or the right coronary plexus 203, surrounding the main pulmonary artery 205; the right atrial plexus 207 and/or the left atrial plexus 209; the right pulmonary plexus 211, surrounding the right pulmonary artery 213; and the left pulmonary plexus 215, surrounding the left pulmonary artery 217.

In some embodiments, damage to nerves such as the laryngeal nerve 219 and/or the vagus nerves such as the left vagus nerve 221 is reduced or prevented. Alternatively, in some cases, pulmonary branches of the vagus nerve are treated, for example to modify bronchi activity. Exemplary system

Figure 2B illustrates a system for providing nerve treatment, according to some embodiments of the invention.

According to some exemplary embodiments, system 240 comprises an ultrasonic device 242 shaped and sized to be introduced into the main, the left and/or the right pulmonary arteries. In some embodiments, the ultrasonic device comprises one or more ultrasound transceivers configured to generate ultrasound energy, optionally non-focused ultrasound energy, for example to nerve targets located at the wall of the pulmonary artery or in a distance from the pulmonary artery. In some embodiments, the ultrasonic device 242 comprises at least one distancing element or device, optionally surrounding the at least one ultrasonic transceiver. In some embodiments, the at least one distancing element prevents direct contact between an external surface of the ultrasonic transceiver and the inner surface of the pulmonary artery, dor example during the delivery of the non-focused ultrasonic energy.

According to some exemplary embodiments, the ultrasonic device moves within the pulmonary artery when delivering the non-focused ultrasound energy, optionally without contacting the internal surface of the pulmonary artery with the external surface of the transceiver. In some embodiments, the ultrasonic device 242 is configured to laterally move within the pulmonary artery. In some embodiments, the ultrasonic device 242 is configures to laterally move up to a distance of 5 cm within the pulmonary artery, for example 1 mm, 2 mm, 4 mm or any intermediate, smaller or larger value, optionally while ultrasonic energy is generated by the one or more ultrasound transceivers.

According to some exemplary embodiments, the ultrasonic device 242 comprises at least one marker for determining the position of at least part of the ultrasonic device within the pulmonary artery.

According to some exemplary embodiments, the system comprises a control unit 244, electrically connected to the ultrasonic device 242. In some embodiments, the control unit 244 comprises a control circuitry 248 electrically connected to a memory 250 within the control unit. In some embodiments, the memory 250 is configured to store log files of the system, for example the number of treatment locations, treatment parameters, for example energy intensity, energy frequency and duration optionally in each treatment location. In some embodiments, the memory 250 is configured to store at least one treatment protocol or parameters thereof. In some embodiments, the memory 250 is configured to store at least one treatment plan which comprises at least one planned treatment location within the pulmonary arterial system, for example 2 treatment locations, 3 treatment locations, 6 treatment locations, 4 treatment locations, 10 treatment locations, 16 treatment locations or any intermediate, smaller or larger number of treatment locations within the pulmonary arterial system. Alternatively or additionally, the memory 250 stores at least one treatment location within the pulmonary arterial system where a denervation treatment was delivered by the ultrasonic device. In some embodiments, the treatment locations comprises 4 to 18 treatment locations within the pulmonary arterial system, for example 4, 6, 10, 12 or any intermediate, smaller or larger number of treatment locations within the pulmonary arterial system. In some embodiments, the pulmonary arterial system comprises the main pulmonary artery, the left pulmonary artery and the right pulmonary artery.

According to some exemplary embodiments, the control circuitry 248 is electrically connected to the ultrasonic device 242. In some embodiments, the control circuitry signals the ultrasonic device to generate ultrasonic energy according to at least one activation parameter stored in the memory 250. In some embodiments, the at least one activation parameter comprises ultrasonic energy intensity, ultrasonic energy frequency and/or energy application duration.

According to some exemplary embodiments, the control circuitry 248 signals the ultrasonic device to generate ultrasonic energy with an intensity in a range of 45[W/cm ^A 2]- 70[W/cm ^A 2], for example 45 [W/cm ^A 2], 27[W/cm ^A 2], 55[W/cm ^A 2] or any intermediate, smaller or larger intensity value.

According to some exemplary embodiments, the control circuitry signals said ultrasonic device to generate ultrasonic energy with a frequency in a range of 10-14 [MHz], for example 10[MHz], 1 l[MHz], 12[MHz] or any intermediate, smaller or larger value.

According to some exemplary embodiments, the control circuitry signals said ultrasonic device to generate ultrasonic energy for a time duration in a range of 30-50 seconds, for example 30 seconds, 35 seconds, 40 seconds or any intermediate, smaller or larger time duration.

According to some exemplary embodiments, the control unit 244 comprises an interface 246, electrically connected to the control circuitry 248. In some embodiments, the interface 246 is configured to generate at least one human-detectable indication to a user of the system 240. In some embodiments, the interface 246 comprises a screen, for example for delivery of a visible indication to the user, for example an image or a picture showing the ultrasonic device 242 within the pulmonary arterial system. Alternatively or additionally, the interface 246 comprises at least one sound-producing element, for generating at least one sound indication to a user of the system. In some embodiments, the interface 246 is configured to receive at least one input signal from a device connected to the control unit, for example an imaging device. In some embodiments, the imaging device comprises an x-ray device or any other imaging device used for determining the position of the ultrasonic device within the body. Alternatively or additionally, the interface 246 comprises at least one input element, for example a keyboard, a microphone, an activation and/or a selection button, for receiving at least one input signal from a user of the system.

According to some exemplary embodiments, the control circuitry 248 signals the interface 246 to generate an indication when the ultrasonic device is positioned in a pre- determined treatment location within the pulmonary artery, for example based on pre-determined treatment locations stored in the memory 250. In some embodiments, the control circuitry signals the interface 246 to generate an indication when ultrasonic energy is generated by the ultrasonic device 242 and/or when the generation of the ultrasonic energy is stopped. In some embodiments, the control circuitry 248 signals the interface 246 to generate an indication when the ultrasonic energy parameters, for example intensity, frequency and/or duration, are within a desired range of values.

According to some exemplary embodiments, the control circuitry 248 signals the interface 246 to generate a human detectable indication when the ultrasonic energy is generated during a time period which exceeds 40 seconds, for example when the time period exceeds 40 seconds, 45 seconds, 50 seconds, 60 seconds or any intermediate, smaller or larger time period. In some embodiments, the interface 246 receives an input signal related to a position of the ultrasonic device 246 within the main, left and/or right pulmonary arteries. In some embodiments, the control circuitry 248 stores the position of the ultrasonic device 246 in the memory 250. In some embodiments, the control circuitry 248 signals the interface 246 to activate an imaging device electrically connected to interface 246 during the generation of the ultrasonic energy, for example to determine the location of the ultrasonic device 246.

Position and operation of an ultrasonic catheter inside the pulmonary artery

Figures 3A-B illustrate an ultrasonic device positioned within a pulmonary artery, according to some embodiments of the invention. In some embodiments, device 301 is delivered to the pulmonary artery, for example to the right pulmonary artery 321, as shown in this example.

In some embodiments, device 301 is introduced to the artery with the aid of a guiding sheath or catheter 303. In some embodiments, a size of the catheter ranges between 4-12 Fr, such as a 4 Fr, 6 Fr, 8 Fr.

In some embodiments, device 301 comprises one or more ultrasonic transceivers 305, adapted for emitting and/or receiving ultrasound energy. In some embodiments, an ultrasonic field 307 produced by the one more transceivers is effective to modulate nerve activity to a depth 309 of, for example, up to 10 mm, up to 8 mm, up to 6 mm, up to 12 mm, or intermediate, larger or smaller ranges from the artery wall 311.

In some cases, for example in patients diagnosed with pulmonary arterial hypertension, a thickness of wall 311, for example a thickness of a medial layer of the wall, increases. In some cases, the thickness may increase in 1-3 mm. In a situation in which the artery wall is characterized by increased thickness, relative to a normal wall, emission of unfocused ultrasound which is effective to travel a relatively large distance may be advantageous.

In some embodiments, device 301 comprises one or more transceivers facing a single direction. Alternatively, device 301 comprises a plurality of transceivers, such as 2, 3, 4, 6, 8, or intermediate, larger or smaller number, facing various directions. Optionally, the transceivers are arranged circumferentially. In some embodiments, for example when the device is unidirectional, the device is rotated axially within artery lumen 315, such as to treat circumferential segments of the artery.

In some cases, the device is centered with respect to artery lumen 315, for example as shown in Figure 3 A. Alternatively, the device is positioned closer to one of the artery's walls, for example as shown in Figure 3B.

In some embodiments, device 301 is equipped with a distancing device 313, for example as further described herein. In some embodiments, the distancing device pushes the device away from artery wall 311. Optionally, the distancing device pushes transceiver 305 away from wall 311, for example away from an innermost layer of the wall such as the intima, to a distance 317 (as shown in Figure 3B) ranging between 1mm to 10mm, such as 3 mm, 5 mm, 7 mm or intermediate, longer or shorter distances.

A potential advantage of keeping at least transceiver 305 away from the wall may include reducing a risk of damage to the wall, for example a risk of thermal damage caused by overheating of the tissue. In some embodiments, enough blood is allowed to flow between the transceiver and the artery wall, to cool the wall. Another potential advantage may include reducing a risk of damage to the transceiver, for example damage caused by material such as organic material charring over the transceiver surface.

In some cases, thrombi, atherosclerotic atheroma and/or other wall related disorders 319 exist in the artery. In such a case, a distance between device 301 which is located within lumen 315 and the surrounding nerves 325 which are intended to be treated is effectively increased. By producing an ultrasonic field with a relatively large effective range, an interfering effect of the wall disorder with the transfer of energy may be overcome.

In some cases, as ultrasound energy is expected to be absorbed in the artery tissue more than it is absorbed in the thrombus or atheroma, the energy may pass through the thrombus or atheroma with a minor or no substantial decrease in intensity. A potential advantage of using ultrasound to treat the nerves, for example in comparison to radiofrequency (RF) or laser, may include the transferring of an increased amount of energy through the wall disorder, for ablating nerves located beyond the artery wall. RF or laser energy are expected to be absorbed in the tissue of the wall disorder more than ultrasound energy is absorbed, therefore when using ultrasound energy, a larger amount of energy is expected to reach the nerves intended for treatment.

In some cases, in which a narrowing of the artery is observed, for example due to plaque, the catheter device is used for preventing partial or total occlusion of the artery, for example by targeting nerves associated with constriction of the artery, to prevent spasm and/or cause permanent dilation of the artery which will reduce the risk of the artery being occluded, for example by the plaque.

In some embodiments, the distancing device pushes the catheter away from the wall disorder, reducing a risk damage which may be caused, for example, by breakage of a thrombus or atheroma, which could result in an embolus. A risk of breakage may be reduced by the relatively low energy absorption of the thrombus or atheroma.

In some embodiments, guiding catheter 303 is passed through the right ventricle of the heart. Contraction of the ventricle may cause periodical movement of the catheter, possibly resulting in movement of transceiver 305. In some cases, when applying treatment, it is desirable to stabilize device 301 in position, for example stabilize the device with respect to a longitudinal, axial direction of the artery and/or with respect to a horizontal, cross sectional direction of the artery.

In some embodiments, for example as further described herein, device 301 is anchored with respect to the artery walls and/or with respect to the targeted nerves 325, for example by a positioning element, as further described herein. Optionally, the device is anchored in a constant, fixed position. Alternatively, the anchoring allows for a certain range of axial and/or cross sectional movement of the device, for example axial movement within a distance range smaller than twice a maximal axial spread of the effective field. In some embodiments, the device is anchored in a configuration which provides for the device and the target, such as nerves 325, to move together in a synchronized manner, for example move periodically with heart pulsation. Optionally, the device is equipped with an expandable member, which engages the artery walls when expanded, anchoring at least a portion of the device (such as a distal portion on which the transceivers are mounted) in place (e.g. in a selected cross sectional and/or axial position relative to the artery), allowing the device and artery to move together in a synchronized manner.

Additionally or alternatively to anchoring, for example as further described herein, the device is provided with an axial decoupling, for example in which a segment of a shaft of the device dampens or does not transfer axial forces, to reduce movement of the one or more transceivers 305 resulting from movement of a more proximal portion of guiding catheter 303. Optionally, the axial decoupling is structured to allow sufficient transmission of torque in a distal direction, to enable maneuvering the catheter.

In some embodiments, a "working frame" is constructed, in which the device is oriented and/or positioned relative to the target, such as nerve 325. Optionally, a guiding pattern is used, for example comprising one or more markings which indicate a current and/or desired position of the device. In an example, the markings comprise a dot, arrow or other localized marker which is fitted within a larger marker defining the working frame, for example a marker in the form of a circle. In some embodiments, imaging modalities are used. Optionally, angiography images are marked to indicate a location and/or direction for energy emission. Optionally, the markings are placed to indicate non-targeted tissue, to prevent or reduce emission towards tissue or anatomical structures such as the lungs, the vagus, the trachea, the aorta.

Additionally or alternatively, the device is not anchored but rather positioned at a location in which movement of the device is synchronized with movement of the targeted tissue. In an example, considering that for some targeted tissues movement of the heart moves the targeted tissue, the device is positioned in proximity to the heart.

An ultrasonic catheter structure

Figures 4A-B are isometric drawings of an exemplary catheter head comprising a plurality of ultrasonic transceivers, according to some embodiments of the invention.

In some embodiments, head 401 comprises one or more piezoelectric transceivers such as transceiver 403, configured for emitting and/or receiving ultrasound by comprising a body vibratable at ultrasonic frequencies. In some embodiments, the transceivers are coupled to a chassis 409 of head 401. Optionally, the transceivers are mounted onto one or more external surfaces of chassis 409.

In some embodiments, catheter head 401 is sized to fit within the pulmonary artery, the head having a diameter ranging between, for example, 1.3 mm to 4mm (corresponding with a catheter of between 4-12 F). Optionally, head 401 is sized such that it occupies less than 50%, less than 40%, less than 30% or other percentage of the cross section of the artery, to reduce interference with and/or obstruction of blood flow.

In some embodiments, the plurality of transceivers include three transceivers, for example arranged in a triangular configuration. Alternatively, the head comprises a different number of transceivers, such as 2, 4, 5, 6, 8 or intermediate, larger or smaller number. The transceivers may be arranged in various configurations, such as a squared configuration, a hexagonal configuration, an octagonal configuration, or other polygonal configurations. Optionally, the spatial arrangement of the transceivers is configured such that a periphery of head 401 is reduced to a minimum.

In some embodiments, adjacent transceivers are positioned such that a spacing 411 is formed between them. Optionally, spacing 411 provides an electrical and/or thermal isolation between the adjacent transceivers.

In some embodiments, one or more of the transceivers is adapted for emitting ultrasound. In some embodiments, one or more of the transceivers is adapted for receiving ultrasound. In some embodiments, a single transceiver is adapted for both emitting and receiving ultrasound. Optionally, a portion of the transceiver is adapted for emitting ultrasound, and another portion is adapted for receiving ultrasound.

In some embodiments, the one or more transceivers are adapted for receiving echo signals, such as echo signals reflected by walls of the pulmonary artery.

In some embodiments, the transceivers are arranged circumferentially. Optionally, the irritated energy is suitable for treating a circumferential region of tissue.

In some embodiments, each of the transceivers faces a different direction than the other transceivers. Optionally, each of the transceivers is configured for emitting and/ receiving ultrasound from a different portion of the artery wall. Additionally or alternatively, two or more of the transceivers face the same portion of the artery wall. Optionally, the transceivers are arranged so that each of the transceivers covers a sector of the cross section of the artery, such as a semicircle, a quadrant, a sextant, or a sector having other central angle such as 20 degrees, 40 degrees, 70 degrees.

In some embodiments, for example as shown in this figure, a transceiver is shaped as a rectangle. Exemplary dimensions of a rectangular transceiver include a length 413 ranging between, for example, 3mm to 8mm, and a width 415 ranging between 0.8mm to 2mm. Optionally, all transceivers are uniformly shaped, for example all transceivers are shaped as rectangles. A potential advantage of uniformly shaped transceivers may include producing a symmetric effective field. Optionally, by having a symmetric field, additional safety is provided, for example in cases where an uncontrolled axial rotation of the catheter head occurs within the artery. Another potential advantage may include simplifying the manufacturing process. Alternatively, in some embodiments, each of the transceivers comprises a different shape, for example one transceiver shaped as a rectangle, a second transceiver shaped as a trapezoid, etc. Additionally or alternatively, in some embodiments, all transceivers are uniformly shaped with a shape other than a rectangle, such as a trapezoid, a circle, a triangle, or any other shape. In some embodiments, the transceivers are selected during the assembling of the catheter. Optionally, the transceivers are sorted according to characteristics such as a resonant frequency and/or impedance properties. Optionally, a catheter assembled with pre-sorted transceivers can be operated at a frequency range that is determined according to the resonant frequencies of its transceivers, thereby optionally increasing the efficiency of the catheter.

In some embodiments, the transceivers of a single catheter comprise different resonant frequencies. Optionally, the transceivers are operated independently of one another. Alternatively, two or more of the transceivers are operated together.

In some embodiments, the catheter can be used as a unidirectional catheter, a bidirectional catheter, a triple directional catheter or any multidirectional catheter. Optionally, this is obtained by selectively operating one or more transceivers at an efficiency higher than one or more other transceivers.

In some embodiments, the operating frequency is selected and/or modified so that two opposing transceivers of a catheter (for example transceivers that are furthest apart from each other on a squared shaped catheter) are operated together. The operating frequency may then be modified to sweep between the transceivers and operate a second set of transceivers. A potential advantage of alternating between the transceivers may include reducing overheating of the transceivers, which may occur when a transceiver is activated over time. Optionally, one or more transceivers that are directed towards the target tissue are activated, while one or more transceivers that are directed towards non-target tissue are deactivated.

In some embodiments, the transceivers are operated (e.g. by a controller, for example comprised within a console of the catheter) according to a lookup table. Optionally, the lookup table correlates between an efficiency of each of the transceivers and a certain operating frequency. By operating the transceivers according to the lookup table, various combinations and alternations between the transceivers can be obtained.

In some embodiments, a radially outward facing surface of the one or more transceivers is flat. Additionally or alternatively, one or more transceiver surfaces are concave. Additionally or alternatively, one or more surfaces are convex.

In some embodiments, chassis 409 is formed as an elongated shaft, in this example having a triangular cross section profile. Alternatively, in other embodiments, the chassis may comprise a square profile, a rectangular profile, a circular profile, a hexagonal profile, or an arbitrary profile. Optionally, a cross sectional profile of the chassis corresponds with the transceiver configuration, for example, a triangular configuration of transceivers is mounted (directly or indirectly) onto a triangular chassis. In some embodiments, chassis 409 is cannulated. Optionally, a lumen 417 (as clearly shown, for example, in Figure 4B) within the chassis is dimensioned to receive a guide wire. In some embodiments, lumen 417 is sized to receive a pressure measurement device, for example a guide wire comprising one or more pressure sensors. In some embodiments, lumen 417 is sized and/or shaped to receive a guide wire of a predefined curvature, for example a Z-shaped guide wire.

Optionally, when head 401 is positioned within the artery, blood flow is allowed to pass through the lumen. In some embodiments, substances such as saline, cooling fluid, contrast liquid, medication and/or other fluids are delivered through the lumen of chassis 409. In some embodiments, a collapsed balloon is delivered through the lumen of chassis 409, and delivered through the distal tip of the catheter to be inflated within the artery. Optionally, an inflating substance such as air or saline are passed through the lumen to fill the balloon. In some embodiments, the balloon comprises one or more pressure sensors. Optionally, the one or more sensor are configured on an external wall of the balloon, for example at a distally facing wall, and are used for assessing pressure within the artery.

In some embodiments, a radially outward facing surface of chassis 409 such as facet 419 serves as a platform onto which a PCB and/or one or more transceivers can be mounted.

In some embodiments, chassis 409 is formed of an electrically conductive material. Additionally or alternatively, chassis 409 is formed of a thermally conductive material, for transferring heat away from the transceivers. Optionally, chassis 409 is coated by a thermally and/or electrically conductive material. Exemplary materials include metal such as gold or copper. Optionally, various components of the catheter such as electrical wiring are soldered onto a surface of the chassis, and may thereby reduce the need for soldering pads. Optionally, chassis 409 is rigid enough to prevent deformation of the piezoelectric transceivers that are mounted onto it.

In some embodiments, the facets of chassis 409 are evenly distributed with respect to a longitudinal axis AA' of the chassis. For example, each facet of a triangular chassis is positioned at an equal radial distance from longitudinal axis AA'. Optionally, by mounting the transceivers onto facets such as facet 419 of the chassis, the transceivers are aligned with respect to longitudinal axis AA' and/or with respect to each other. Optionally, a radial distance between each transceiver and axis AA' is equal for all peripherally arranged transceivers. Alternatively, the distance varies for different transceivers. A potential advantage of utilizing a periphery of the catheter head for mounting of components such as the transceivers may include a simpler, more reliable manufacturing and assembly process. In some embodiments, one or more of the transceivers is electrically coupled to a circuit board (not shown in this figure). Optionally, a surface of the PCB opposite the transceiver is mounted onto a chassis 409. Additionally or alternatively, one or more of the transceivers is mounted directly onto chassis 409.

In some embodiments, catheter head 401 is in communication, such as by a wire connection or wireless connection, with an operating console. In some embodiments, the console comprises software for processing the acquired echo signals.

In some embodiments, the console is configured for scanning an impedance of the transceivers and comparing the scanning results to calibrated values, to determine if the catheter is qualified for use.

An intravascular distancing device of a catheter

Figures 5A-B are photos a distancing device 501 of a catheter in a closed configuration (Figure 5 A) and an expanded configuration (Figure 5B), according to some embodiments of the invention. In some embodiments, distancing device 501 is configured for pushing catheter head 503 away from the artery wall 505. In some embodiments, one or more of the transceivers 509 is pushed away from the wall. In some embodiments, distancing device 501 is configured for centering head 503 with respect to the artery wall.

In some embodiments, when device 501 is in the closed configuration, a total diameter of the catheter head 503 including the distancing device threaded onto the head is small enough to provide for insertion and/or removal and/or positioning of the catheter within the artery. For example, the total diameter ranges between 1.3mm to 2.6mm or intermediate, longer or shorter diameters. In some embodiments, a total diameter of head 503 is small enough to enable delivery through a guiding catheter or sheath.

In some embodiments, distancing device 501 is formed in the shape of a slotted cylinder. Optionally, cylinder portions 507 in between the slots form bendable leaflets. In some embodiments, in an expanded configuration, as shown for example in figure 5B, the leaflets are forced into a rounded 'elbow' shaped configuration, pushing the one or more transceivers 509 away from wall 505. Optionally, the transceiver is pushed at least 1 mm, at least 0.5 mm, at least 2 mm or intermediate, large or smaller distances away from the vessel wall.

In some embodiments, leaflets 507 are positioned such that in the open position, they do not interfere with the field of emitted ultrasound, and in the closed position, the leaflets conform into recesses between the transceivers for maintaining a minimal diameter of the catheter.

In some embodiments, in the closed configuration, leaflets 507 cover at least a portion of the transceiver surface and protect it. In some embodiments, a width of a leaflet is small enough to reduce an unwanted thermal effect on the vessel wall. Additionally or alternatively, a width of a leaflet 507 is selected such as to prevent mechanically induced damage such as scratches to the artery wall tissue.

In some embodiments, even when distancing device 501 is expanded, blood is allowed to flow between the artery wall and the one or more transceivers 509. For example, blood may flow through an aperture 511 formed by bending leaflet 507 to the elbow configuration. Optionally, the flow of blood cools down the artery wall.

In some embodiments, distancing device 501 is expanded in multiple steps, for example 2, 3, 4, 5 steps. In an exemplary embodiment, distancing device 501 is first bended such that an angle a ranging between 110-175 is formed by leaflet 507, and in the second step angle a is reduced to, for example, 90-110 degrees, as transceiver 509 is being pushed further away from wall 505.

In some embodiments, distancing device 501 is transferred into an open configuration by retracting distal tip 513 of catheter head 503 in the proximal direction. Optionally, retraction is performed by pulling an internal shaft of the catheter which is connected to tip 513, such as a guide wire shaft, in the proximal direction. Optionally, retraction is performed by pulling on an inner cable coupled to tip 513. In some embodiments, the guide wire shaft and/or the cable are coupled on one end to distal tip 513, and on an opposite end to a handle configured externally to the body. Optionally, the handle comprises a lever for operating the distancing device, for example by remotely pulling on tip 513 to move it in the proximal direction. In some embodiments, a diameter of the proximal end of tip portion 513 is equal to a diameter of the cylinder of distancing device 501, and by retraction of tip 513 force is applied by the tip on the cylinder of distancing device 501, causing leaflets 1307 to bend.

In some embodiments, distancing device 501 comprises a combination of rigid and soft materials, for example layered on top of each other. Optionally, by using a rigid material, the distance between catheter head 503 and wall 505 is maintained. Optionally, by using a soft material, damage to the tissue of wall 505 is reduced or prevented. In some embodiments, distancing device 501 comprises a soft plastic material embedded with fibers such as Nitinol fibers.

Selective treatment

Figure 6A is a flowchart describing a variety of options for selectively treating nerve tissue, according to some embodiments of the invention. It is noted that any of the described options may be used independently and/or together with one or more of the other options described. In some embodiments, selective treatment (601) comprises targeting nerves while damage to non targeted tissue, such as surrounding organs and/or non targeted nerves, is reduced or prevented. In some embodiments, selective treatment comprises targeting a predetermined nerve, nerve segment, and/or nerve plexus. In some embodiments, selective treatment comprises identifying nerves according to their innervating function, and targeting those nerves. In some embodiments, selective treatment comprises modifying energy emission parameters such as intensity, frequency, duration, timing and/or other operational parameters according to the selected target, for example according a size of the target and/or a distance of the targeted nerve(s) from the artery lumen. Optionally, the temperature profile is selected according to desired level of thermal damage and/or according to a location of the targeted nerves with respect to the catheter and/or according to the type of nerve tissue intended for treatment.

In some embodiments, one or more organs are identified before and/or during the procedure (603). Optionally, a location of the organs relative to the artery lumen is identified based on an ultrasonic reflection of an organ. Additionally or alternatively, organs are identified using imaging modalities.

In some embodiments, echo signals reflected by one or more surrounding organs are received by the one or more transceivers of the catheter device. Optionally, the signals are processed, for example by a console in communication with the device, to identify one or more organs which reflected the signals, such as, for example, one or more of the heart, lungs, aorta, and/or trachea. In an example, a distinctive echo signal pattern may be acquired from the trachea, since it is mostly filled with air. A potential advantage of identifying organs may include increasing a safety level of the device, by distinguishing between the organs even though they may be located very close to each other, and orienting the catheter device to emit energy in certain directions, selected with respect to the identified organs so that damage to those organs is reduced. In some embodiments, the identified organs are used as location markers (605). Optionally, a position of the catheter along the artery and/or an angular orientation of the catheter are selected using the location markers. In some embodiments, an operating console of the device is configured to provide, for example to a physician, an indication to activate and/or deactivate emission of ultrasound energy, in accordance with the detected location of one or more identified organs. A potential advantage of treating nerves using location markers, such as identified organs acting as location markers, may include reducing a risk of damage to non- targeted tissue. In an example, air ways such as the trachea are identified based on a relatively strong ultrasonic reflection. In another example, the esophagus is identified based on an echo pattern indicating peristaltic movement. In some embodiments, applying selective treatment includes differentiating between nerves (607). Optionally, differentiating comprises not causing thermal damage to myelin coated nerves (609). The inventors have observed that by selecting a certain temperature profile, for example by denervating using a temperature above, for example, 47 degrees C, yet below, for example, 57 degrees C, thermal damage is caused to nerves that are not coated by myelin, while myelin coated nerves are not damaged. By increasing the temperature, for example to a temperature of 58 degrees C or higher, myelin coated nerves are damaged. Differentiating between myelin coated and non coated nerves may provide an advantage when treating nerves which innervate the lung vasculature. According to Schelegle et al. (Respir Physiol Neurobiol. 2012 May 31; 181(3): 277-285. doi: 10.1016/j.resp.2012.04.003., "Vagal afferents contribute to exacerbated airway responses following ozone and allergen challenge") myelinated fibers initiate bronchodilation. Figure 6B is a schematic graph illustrating selectively treating nerves by modifying a temperature profile. As explained hereinabove, when heating at certain temperature range Tl, for example ranging between 47 -57 degrees C, only non-coated nerves are damaged. When increasing the temperature to a range T2, for example ranging between 58- 70 degrees C, both non-coated nerves and myelin coated nerves are thermally damaged.

In some embodiments, differentiating between nerves comprises identifying the vagus or its branches. A potential advantage of identifying the vagus may include reducing a risk of damaging or affecting the heart, for example due to heating of the vagus which may affect heart rate. Alternatively, the vagus and/or its branches are treated, for example vagal fibers are treated to affect dilation and/or constriction of the bronchi. In some embodiments, the vagus is identified by emission of short bursts of ultrasonic energy, which are capable of exciting the vagus to an extent that substantially does not cause damage to structures that are innervated by the vagus. In some cases, excitation of the vagus affects heart pulsation, and measuring a change in heart rate may provide an indication that the vagus is located within the range of the ultrasonic field emitted by the catheter. Additionally or alternatively, in some embodiments, branches of the vagus such as the recurrent laryngeal nerve are excited by emission of ultrasonic energy, and a response to the stimulation is assessed for identifying whether the vagus and/or one or more of its branches are located within the treatment region.

In some embodiments, for applying selective treatment, an external guiding element is used with the catheter device. Optionally, the external guiding element is positioned externally to the body, for example adjacent the patient's chest. In some embodiments, the guiding element comprises a receiver which receives signals from the catheter device, for example during treatment. Additionally or alternatively, the guiding element is configured to send data to the catheter device, for example to activate or deactivate emission. In some embodiments, the guiding element is in communication with the catheter's operating console. Optionally, the guiding element indicates a current position and/or orientation of the catheter to the console, and treatment is initiated and/or modified and/or ceased based on the indication.

While ultrasound energy, such as non-focused energy, may be specifically advantageous when targeting nerve tissue to modify nerve activity, selective targeting can be performed by using other energy forms and/or methods, such as RF, application of direct heat, and/or other energy forms or methods suitable to thermally affect the targeted nerves.

Feedback

Figure 7 is a flowchart of an exemplary feedback loop associated with a pulmonary denervation procedure, according to some embodiments of the invention. In some embodiments, the treatment is modified according to the feedback, for example treatment parameters such as one or more of intensity, duration, frequency, timing, and/or power may be adjusted based on the feedback.

In some embodiments, immediate feedback is obtained in real time. Optionally, feedback is obtained within time periods in between energy emissions. Additionally or alternatively, feedback is obtained before the catheter device is moved to a different location. Additionally or alternatively, feedback is obtained following an excitation and/or a set of excitations of the one or more transceivers, for example 30 seconds, 1 minute, 15 minutes, 1 hour or intermediate, shorter or longer time periods following excitation. In an example, immediate feedback includes observing a visible effect of treatment on the bronchi, such as bronchodilation or bronchoconstriction, which are expected to occur within a relatively short time period, such as 10-120 sec, for example 15 seconds, 30 seconds, 80 seconds or intermediate, longer or shorter time periods following ablation of the nerves which innervate the bronchi, such as the anterior and/or posterior pulmonary plexuses.

In some embodiments, additionally or alternatively to immediate feedback, long term feedback is obtained. Exemplary physiological parameters that can be assessed to obtain long term feedback for the denervation treatment may include one or more of blood pressure, cardiac output, artery wall thickness, artery flow resistance, lung volume, diastolic pressure, and/or other parameters.

In some embodiments, physiological and/or functional changes to the heart, pulmonary artery and/or bronchus are monitored. Optionally, changes are assessed to indicate the effect of treatment. In some embodiments, one or more physiological parameters are measured. Optionally, the parameters are used as control parameters, for deciding whether to continue the treatment and/or whether to modify the treatment.

For example, when monitoring the heart, a parameter such as heart rate may be measured. When monitoring the pulmonary artery, one or more parameters such the artery diameter, arterial blood pressure, blood flow velocity and/or rate, and/or artery stiffness may be measured and/or estimated. When monitoring the bronchus, parameters such as the bronchus diameter and/or the flow rate of air through may be measured and/or estimated.

In some embodiments, one or more parameters are monitored continuously. In an example, heart rate is measured continuously, and if arrhythmia is detected, energy emission from the device is ceased. Alternatively, a parameter is measured once. Alternatively, a parameter is measured intermittently, for example every 30 seconds, every 2 minutes, every 15 minutes, or intermediate, shorter or longer time intervals.

In some embodiments, measurements obtained from the left and right pulmonary arteries are compared to each other, for example to detect a change in the branch that was treated with respect to the branch that was not treated.

In some embodiments, feedback is acquired by receiving echo signals, such as echo signals reflected by the artery wall, and processing the signals. Optionally, processing comprises estimating a physiological condition of the artery, for example assessing vasoconstriction or vasodilation based on an estimation of the artery diameter.

In some embodiments, feedback is acquired using a sensor, for example a pressure sensor, a flow sensor, and/or a temperature sensor. Optionally, the sensor is coupled to the catheter device. Additionally or alternatively, a sensor is positioned in the artery separately from the catheter. In some embodiments, one or more external sensors are used, such as a sensor adapted for detecting breathing of the patient. In some embodiments, a guide wire comprising one more sensors is delivered through a lumen of the catheter device.

It is noted that where "measurements" or "measuring" are referred to, these may include estimating and/or otherwise indicating a selected parameter.

In some embodiments, one or more physiological parameters are measured (701). In some embodiments, parameters are obtained before treatment. Optionally, the parameters are used as reference (or base line) measurements. In an example, a baseline indication of blood pressure within the pulmonary artery is measured. Optionally, a decision of whether to treat to or not to treat is made based on the measured parameters.

In some embodiments, measuring includes one or more of, for example: - assessing heart function, such as heart rate, for example using electrocardiography. In some cases, a change in heart rate is associated with treatment of the vagus and/or vagal nerves. In some cases, a change in heart rate may include arrhythmia.

- measuring muscle sympathetic nerve activity (MSNA).

- measuring arterial blood pressure and/or other hemodynamic properties, such as mean pulmonary arterial pressure, for example using a "Swan-Ganz" catheter, and/or a pressure sensor mounted onto the catheter device and/or onto a guide wire inserted along with device, for example through a lumen of the device.

-measuring right heart ejection fraction, for example using MRI or ECO ultrasound - measuring artery dimensions, such as diameter, by processing echo signals received by the catheter device and/or by using angiography.

- measuring arterial stiffness, for example by processing of echo signals received on the device to determine a movement pattern of the artery wall.

- measuring arterial resistance to flow, for example by assessing a difference between pulmonary artery pressure and diastolic left ventricle pressure.

-measuring bronchial dimensions, such as diameter, for example by using a balloon. In some embodiments, the balloon is filled with fluid, and a volume of the filled balloon and/or inflation pressure of the balloon is measured for assessing bronchial dimension. Additionally or alternatively, bronchial dimensions are measured using angiography. Additionally or alternatively, dimensions of the bronchus are estimated based on returning echo signals. Optionally, the emitting catheter is located within the pulmonary artery.

-measuring air flow (for example measuring parameters such as flow volume, flow rate). In some embodiments, measuring includes stimulating the sympathetic and/or parasympathetic nervous systems. Optionally, the physiological parameter is a parameter measured in response to the stimulation. In some embodiments, one or more nerves are stimulated to assess their innervating function. Optionally, the nerves that are stimulated are targeted during the treatment. Additionally or alternatively, different nerves than the ones that were stimulated are targeted during treatment.

In some embodiments, stimulating involves one or more of, for example:

- using the ultrasonic catheter device for stimulating the nerves. In some embodiments, the device is configured to apply ultrasound energy having parameters suitable for causing a stimulation effect, which does not thermally damage the nerve tissue. Optionally, parameters such as frequency, power, intensity, temperature range, beam shape, catheter location and/or orientation and/or other parameters are selected to produce a stimulating effect, while reducing or preventing thermal damage to the nerves. Optionally, the selected set of parameters defines a stimulating profile that is different from the treating profile.

- applying pressure onto the artery wall, for example by inflating a balloon, which may cause spasm of the artery.

- blocking or partially blocking the blood flow, for example by inflating a balloon.

Blocking the blood flow may affect the resistance of the artery walls.

- electrically stimulating the nerves. In some embodiments, electrification is provided using one or more electrodes. Optionally, the electrodes are delivered over a balloon which is inflated within the artery. Additionally or alternately, electrification is applied externally.

- heating and/or cooling the trachea which may cause bronchoconstriction.

-injecting one or more substances which have a stimulating effect, for example injecting thromboxane A, which induces constriction of the artery which may thereby increase blood pressure.

-injecting air bubbles which may have a similar constricting effect on the artery.

In some embodiments, optionally based on the measurement, a decision is made whether or not to treat (703). In some cases, the measured parameter may indicate that treatment (or, in some cases, additional treatment) is not required, and the procedure will end (705). Alternatively, treatment is applied (707). Optionally, parameters of the treatment (for example frequency, power, intensity, duration, temperature profile, and/or other parameters) are selected according to the measurement. Optionally, the targeted nerves are selected according to the measurement. Optionally, a location of the catheter in the artery is selected according to the measurement.

In some embodiments, the one or more parameters that were measured before the treatment are measured again after the treatment. In some cases, the parameters are measured following emission of a pulse and/or a set of pulses, for example measured 30 seconds, 1 minute, 15 minutes, 1 hour, 3 hours or intermediate, longer or shorter time periods following emission. Additionally or alternatively, the parameters are measured before moving the catheter to a different location.

In some embodiments, parameters acquired before the treatment are compared to the parameters acquired after the treatment (711). In some cases, a change between the response of the nervous system to stimulation before treatment and the response of the system after treatment is observed. Optionally, a threshold is set for defining if the change is significant and indicates that the treatment was effective. Exemplary thresholds may include: a mean diameter of the artery increasing by at least 5%, a heart rate being slowed down by at least 10%, flow pressure in the artery decreasing by at least 20%.

In some embodiments, a decision is made whether or not to continue treatment (713). Optionally, if the parameter comparison indicates that a desired change was observed, for example a mean diameter of the artery increased, for example by at least 5%, 15%, 20% or intermediate, larger or smaller percentages, the treatment is not continued (705). Alternatively, if the comparison indicates that no or partial effects of the treatment were achieved, the treatment is continued. Optionally, treatment parameters are adjusted according to the observed change.

In the following, an exemplary feedback controlled operation of the catheter is described, in which blood pressure in the pulmonary artery is the physiological control parameter that is measured.

In some embodiments, the pressure is measured using an intravascular pressure sensor. Optionally, devices and methods known in the art are used for assessing the intravascular pressure. Additionally or alternatively, in some embodiments, the catheter device is equipped with a pressure sensor, and pressure is measured by the device.

In some embodiments, flow rate, which depends, at least in part, on the resistance of the artery walls to the flow, is estimated, and the arterial pressure is calculated using the flow rate. Optionally, flow rate is estimated using one or more measurements obtained by the catheter device. In some embodiments, flow rate is calculated using the estimated artery cross section area and the flow velocity. Optionally, the artery cross section is estimated using an artery diameter estimation, which was optionally estimated by analysis of echo signals reflected by the artery walls and received by the catheter. Optionally, blood flow velocity is measured using a Doppler device, and/or by using angiography, and/or by thermodilution. Optionally, the catheter device comprises an integrated flow velocity measurement mechanism.

In some embodiments, once a reference pressure measurement is obtained, a balloon is inflated in the artery to apply pressure on at least a portion of the artery wall. In some cases, the applied pressure stimulates the nerves, activating innervations which may cause, for example, spasm of the artery. In some embodiments, the pressure is measured again, for example immediately after stimulation, to assess to the response of the artery to stimulation.

In some embodiments, treatment is applied. In some embodiments, to gain feedback following treatment, arterial pressure is measured again. Optionally, stimulation using the balloon is repeated, and the pressure measurements obtained following treatment are compared to the pressure measurements obtained before the treatment. If a change in pressure above a certain threshold is observed, for example the pressure is reduced by at least 5%, at least 15%, at least 50%, at least 70% or intermediate, higher or lower percentages, the treatment is completed. If a sufficient change is not observed, treatment may be repeated, and parameters of the treatment may be modified according to the observed change in attempt to increase the efficiency of the next treatment.

In another exemplary feedback controlled operation regime, the bronchus diameter is measured. Optionally, the diameter is measured continuously. Optionally, the diameter is measured using the catheter device. In some embodiments, the device is positioned within the pulmonary artery, and measurements of the bronchus are performed from within the artery. Treatment is then applied, for example with a gradually increasing intensity level, in parallel to monitoring of the bronchus diameter. Optionally, the treatment is modified based on the measured diameter. In some embodiments, treatment is ceased when reaching a certain intensity level, for example an intensity level above which myelin coated fibers are damaged, since damage to myelin coated fibers may cause constriction instead the desired dilation of the bronchus. In some cases, dilation of the bronchus is achieved by damaging the non-myelin coated fibers, which are prone to thermal damage more than the myelin coated fibers.

Figure 8 illustrates a pulmonary artery treatment zone selected in accordance with efficacy and safety considerations, according to some embodiments of the invention. In some embodiments, a denervating catheter is positioned within the treatment zone and directed towards a selected target tissue volume which has been shown by the inventors to provide for effective denervation of the pulmonary artery while reducing damage to non-targeted tissue.

It is noted that treatment zone 2100, as referred to herein, may include one or more points within the area generally marked as 2100, a smaller area contained within area 2100, one or more points along the periphery of area 2100, and/or combinations thereof. An ellipsoid is used herein for clarity purposes, but it is noted that the general treatment area may comprise any other profile, such as an arbitrary profile. Optionally, boundaries of the treatment area are defined by the walls of the pulmonary artery.

In some embodiments, treatment zone 2100 comprises a lumen of the left pulmonary artery 2102, in proximity to the bifurcation 2104 in which the main trunk 2116 of the pulmonary artery splits into the right pulmonary artery 2108, and the left pulmonary artery 2102. In some embodiments, treatment zone 2100 is situated at and/or in proximity to the left pulmonary artery ostium 2110.

In some embodiments, treatment zone 2100 is selected according to the location and/or distribution of nerve tissue 2112 in the surroundings of the artery. In some embodiments, nerves innervating the pulmonary artery extend along the length of the artery. Optionally, treatment zone 2100 is selected according to a density of surrounding nerve tissue, for example selected to target nerve tissue of relatively high density. In some cases, nerve tissue density is higher at artery sections having a diameter larger than other artery sections, for example at the artery ostium, and the treatment zone is selected to target the high-density nerve tissue. In some embodiments, treatment zone 2100 is selected to target posterior and/or anterior nerve plexuses extending along the length of the left pulmonary artery towards the left lung. In some embodiments, the treatment zone is selected to target one or more tissue volumes having a higher nerve tissue content relative to other tissue volumes, for example a tissue volume located laterally to the ostial left pulmonary artery may have a higher nerve tissue content than an area located anteriorly to the ostial pulmonary artery

In some embodiments, treatment zone 2100 is selected to reduce damage (e.g. thermal damage such as necrosis) to non-targeted tissue. In some embodiments, the location is selected to reduce damage to the aorta 2114, which ascends with the main trunk 2116 of the pulmonary artery and arches around the right pulmonary artery 2108. Optionally, to avoid damage to the aorta, or to the nerves near the aorta which are not the target of the denervation, treatment location 2100 does not include the right pulmonary artery 2108. In some embodiments, treatment zone 2100 is selected to reduce damage to the vagus (not shown in this figure), which extends in a superior-inferior direction dorsally to the right pulmonary artery. Optionally, to avoid damage to the vagus, treatment zone 2100 does not include the right pulmonary artery.

Additionally or alternatively, the treatment zone comprises the right pulmonary artery

2108 and/or bifurcation 2104.

In some embodiments, catheter device 2116 is introduced to treatment location 2100 through the vena-cava 2118, the right atrium 2120, the right ventricle 2122, and into the main trunk 2106 of the pulmonary artery, as indicated by the arrows. In some embodiments, a path through which catheter 2116 is introduced to treatment zone 2100 follows the natural path of blood flow. Optionally, the flow of blood assists in directing the catheter to the selected treatment location, for example by using an inflatable balloon tip and/or sail tip providing for flow-directed floatation of the device to the selected location.

In some embodiments, imaging is performed before, during, and/or in between treatment sessions to determine a location for positioning the one or more transceivers 2126 of the catheter, and/or to determine a location of the target tissue volume in the patient being treated.

In some embodiments, catheter 2116 is directed to the treatment zone with the aid of a steering mechanism. Optionally, the steering mechanism extends to a handle of the catheter positioned outside the body, and provides for controlling articulation of a head 2128 configured at a distal end portion of catheter 2116 which comprises the energy emitting elements, such as the one or more ultrasonic transceivers 2126.

In some embodiments, a distancing element such as an inflatable balloon and/or a distancing device comprising one or more leaflets, for example as described herein in Figures 5A-B, are used for positioning head 2128 at a selected location (e.g. relative to the artery walls) and/or at a selected orientation.

In some embodiments, a shaped guide wire is used for directing head 2128 to a selected location and/or orientation.

In some embodiments, a shaft 2124 of catheter 2116 is flexible enough to enable passing the catheter through curves of the vasculature, yet rigid at least to some extent to provide for transfer of torque, axial force and/or other forces in a distal direction to maneuver the catheter to the treatment location. In some embodiments, shaft 2124 comprises one or more sections that are more flexible than others. In some embodiments, the rigidity of shaft 2124 is low enough to reduce pressure that may be applied by the shaft onto the walls of the atrium and/or ventricle, as such pressure may induce arrhythmia and/or otherwise interfere with normal heart function and/or cause damage to the walls.

Figures 9-10 illustrate an ultrasonic catheter device 2200 positioned within a selected treatment zone in the left pulmonary artery 2202 9), and a cross section of the artery along line AA' (10) schematically illustrating a plurality of unfocused ultrasonic energy beams emitted by device 2200, according to some embodiments of the invention.

In some embodiments, catheter 2200 is positioned within the lumen of the left pulmonary artery. In some embodiments, a head 2204 of catheter 2200 comprising the one or more ultrasonic transceivers 2206 is advanced to a location along a long arched axis 2220 of the left pulmonary artery 2202, extending for example (for explanatory purposes) from a central axis 2208 of the main trunk 2210 that pass through a center point 2212 of the substantial V-shape defined by the artery walls at the bifurcation of the main trunk, to the lateral bifurcation 2214 of the left pulmonary artery where the artery splits into two branches 2216 and 2218, one for each lobe of the left lung. In some embodiments, head 2204 is positioned within the range of the first 1/3, 1/5, 1/4 or intermediate, longer or shorter sections of the total length of axis 2220, closer to central axis 2208 of the main trunk. In some embodiments, head 2204 is positioned at a depth of 3, 5, 9, 10 20, 30, 50 mm or intermediate, longer or shorter distances from axis 2208 into the left pulmonary artery.

In some embodiments, head 2204 is positioned within the artery lumen in a manner that distances the one or more transceivers 2206 facing the target tissue volume away from artery wall 2224, for example to a distance 2222 higher than 0.5 mm, higher than 1 mm, higher than 3 mm or intermediate, longer or shorter distances. Optionally, the minimal distance is selected in accordance with the artery diameter.

In some embodiments, the catheter is positioned in the treatment zone such that the one or more transceivers 2206 are positioned at a predetermined distance from a point of maximal curvature of the inferior wall of the left pulmonary artery, for example point A' illustrated herein. Optionally, the distance of the transceiver from the point of maximal curvature ranges between 10-30 mm.

In some embodiments, head 2204 is pushed away from artery wall 2224 by a distancing device, for example as described hereinabove. In some embodiments, distance 2222 is selected to be long enough so as to provide for blood to flow between transceiver 2206 and wall 2224 at an amount sufficient to cool the transceiver and/or cool the intima of the artery to prevent thermal damage to the intima.

In some embodiments, head 2204 is positioned to target tissue 2226 such as nerve tissue beyond artery wall 2224. Optionally, the targeted tissue is situated at a location lateral, posterior and/or anterior to the left pulmonary artery 2202. Optionally, the targeted tissue is situated to the left of the main trunk 2210. In some embodiments, the targeted tissue is located behind an inner intima layer of the artery wall, for example located at and/or behind an outer adventitia layer of the artery wall 2224. In some embodiments, target tissue 2226 is located at within a distance range smaller than 5 mm, 10 mm, 15 mm or intermediate, longer or shorter distances from the outer layer of artery wall 2224. A potential advantage of targeting nerve tissue within a range smaller than 15 mm from the artery wall may include reducing damage to nerve bundles innervating the spine and/or brain which are located more than 20 mm from the artery wall.

In some embodiments, the device is positioned such that the transceiver is placed a relatively long distance from the targeted tissue (e.g. positioned closer to the bifurcation and/or deeper in the LPA for treating tissue such as 2226). Optionally, an orientation of the transceiver is modified in order to target the relatively far tissue. Optionally, higher power is used.

In some embodiments, target tissue 2226 includes only nerve tissue. Additionally or alternatively, target tissue 2226 comprises other types of tissue, such as adipose tissue, connective tissue, lymph nodes and/or other.

In some embodiments, an energy beam 2228 is emitted by the one or more transceivers facing the target tissue 2226. Optionally, the energy is unfocused ultrasound energy. In some embodiments, parameters of the applied energy such as intensity, frequency, a duration of emission and/or other parameters are selected to target one or more selected types of tissue, for example to thermally damage only nerve tissue while having a reduced or no effect on other types of tissue found within the area covered by beam 2228 and/or surrounding area and/or surrounding organs. Alternatively, the targeted tissue comprises tissue other than nerve tissue.

In some embodiments, a shape and/or size of a volume of tissue which is thermally affected by beam 2228 is not constant and may vary between different treatment locations. Optionally, the shape and/or size of the thermally affected volume depend on the responsiveness of the tissue within the targeted area to the applied energy, for example, nerve tissue will be more strongly affected (i.e. thermally damaged) by the applied ultrasonic energy than adipose tissue or connective tissue. In some embodiments, the responsiveness of a certain type of tissue to the applied energy is expressed by a denaturation threshold which may be different (i.e. caused by a higher temperature or a lower temperature) than the denaturation threshold of other tissue.

In some embodiments, at least a part of target tissue volume 2226 is heated to a temperature between 50-80 degrees Celsius, such as 50.5, 55, 60, 65, 70 degrees Celsius or intermediate, higher or lower temperatures. Optionally, nerve damage is caused at a temperature above 47 degrees Celsius, 49 degrees Celsius, 50 degrees Celsius, 53 degrees Celsius, 55 degrees Celsius, 60 degrees Celsius, or intermediate temperatures. In some embodiments, energy is applied to heat the tissue to cause damage sufficient to prevent a nerve from reconnecting or regenerating. Additionally or alternatively, energy is applied to heat the tissue to cause damage sufficient to prevent or reduce the nerve ability to produce norepinephrine or other neurotransmitters .

In some embodiments, treatment is performed within and/or between a variety of exemplary treatment locations 2230, situated along the left pulmonary artery 2202, right pulmonary artery 2232, and/or main trunk 2210.

Figure 10 is a schematic illustration of an artery cross section showing a plurality of beams 2228 emitted by the one or more transceivers 2206 configured on head 2204. In the exemplary configuration shown herein, head 2204 comprises a triangular arrangement of transceivers. Optionally, each transceiver faces a different circumferential section of the artery.

In some embodiments, beam 2228 is substantially trapezoidal. Optionally, a divergence angle β of the beam is between 5-180 degrees, for example 7 degrees, 30 degrees, 60 degrees, 120 degrees, or intermediate, larger or smaller angles. In some embodiments, a divergence angle of the beam depends on the transceiver shape and/or size and/or on the arrangement of the transceivers on head 2204. Optionally, a transceiver comprising a rectangular emitting surface, having a length between 3-10 mm, such as 4 mm, 6 mm, 8 mm or intermediate, longer or shorter lengths, and a width between 0.5- 2 mm such as 1 mm, 1.5 mm or intermediate longer or shorter widths may be especially advantageous when treating in the location for example as shown Figure 9.

In some embodiments, the plurality of transceivers are separately activated, for example only one transceiver at a selected location and/or orientation is activated while others are inactive. Alternatively, more than one transceiver is activated. In some embodiments, an orientation of head 2204 is changed during and/or in between treatment sessions to cover different circumferential sections of the artery. Optionally, parameters of the energy beam such as a depth of the applied field are changed during and/or in between treatment sessions.

In some embodiments, energy is emitted towards a selected circumferential section of the artery, for example towards ¼, 1/3, ½, ¾ of the circumference. In the exemplary treatment location of Figure 9, energy may be emitted in a lateral, posterior and/or anterior direction relative to the ostial left pulmonary artery, towards a circumferential portion covering for example between ¼-l/3 of the artery circumference. In some embodiments, the one or more transceivers are rotated during and/or between treatment sessions to cover different circumferential sections. In an embodiment, treatment is applied circumferentially.

In some embodiments, the catheter is advanced along an axial section of the artery, and treatment is applied at one or more locations along the length of the axial section. A length of an axial section which may be especially advantageous when treating in the selected treatment zone for example as shown in Figure 9 may range between 5-20 mm. A potential advantage of treating an axial section (for example by advancing the catheter head and applying excitations at selected distance intervals from each other) may include increasing the probability of effectively reaching the target tissue. Another potential advantage may include targeting nerve tissue along a length of the nerve, thereby interfering with the innervation ability of the nerve and/or potentially reducing the likelihood of unwanted regrowth of the nerve.

Targeting nerves at a selected distance from the artery lumen

Figure 11 is a flowchart of a general method for treating pulmonary hypertension by thermally damaging nerves at a selected distance from the pulmonary artery lumen, according to some embodiments.

In some embodiments, a patient is diagnosed with pulmonary hypertension (1100).

Pulmonary arterial hypertension is often characterized by progressive remodeling of the pulmonary vasculature and increased pulmonary vascular resistance, often leading to right heart failure. PAH is a life-limiting condition that confers a poor clinical prognosis. Sympathetic activity and neurohormonal activity are increased in patients with PAH: plasma norepinephrine, muscle sympathetic nerve activity (MSNA) and indicators of renin-angiotensin-aldosterone system (RAAS) activity are increased and increased plasma norepinephrine and MSNA are associated with adverse clinical outcome.

In some cases, current therapies improve patient outcomes through modulation of the prostacyclin (PGI2), endothelin (ET) and nitric oxide (NO) pathways. Modulation of the sympathetic and renin-angiotensin-aldosterone systems are established treatments for heart failure and administration of beta-blockers and AEC inhibitors has demonstrated attenuation of disease in experimental models of PAH. Observational studies performed by others reported clinical outcomes of patients with PAH with and without beta-blocker have shown no association with adverse outcomes, however, no positive effect was observed. Of note, an 18 patient clinical trial of bisoprolol in patients with idiopathic PAH showed acceptable drug tolerance and a reduction in heart rate, but decreased cardiac output and reduced 6MWT.

Recent technological advances provide means to target neuronal pathways using for example catheter based radio-frequency, cryotherapy and ultrasound methods. These allow for alteration of electrical conduction, primarily for the treatment of cardiac arrhythmias, providing significant therapeutic benefit. The efficacy of denervation of end-organs such as the kidney for the treatment of heart failure and hypertension is yet to be fully determined.

Pre-clinical studies performed by others have demonstrated that pulmonary artery denervation improves pulmonary hemodynamics in acute and chronic models of pulmonary hypertension. These studies documented the distribution of nerves around the pulmonary arteries and demonstrated reduced sympathetic nerve conduction velocity, demyelination and axon loss following pulmonary artery denervation. The lungs and pulmonary vasculature form and metabolize more than 40% of circulating norepinephrine. As such, decreasing the sympathetic activity in the lungs is a potential target for the treatment of pulmonary arterial hypertension.

Recent studies performed by others have shown that in some cases radio-frequency pulmonary artery denervation improves pulmonary hemodynamics in experimental models and in an early clinical trial, however, in some cases, RF also alters the structure of the pulmonary artery wall. In some cases, the use of radio-frequency for pulmonary artery denervation requires the apposition of an electrode to the luminal aspect of the pulmonary artery. Energy is delivered to the nerves in the adventitia by thermal conduction which may induce widespread thermal necrosis in the intima, media and adventitia. Previous studies in which RF was used for denervation have demonstrated improved pulmonary hemodynamics in acute and chronic models of pulmonary hypertension with reduced sympathetic nerve conduction, local renin-angiotensin system activation, and vascular remodeling. These results suggest that PDN may be beneficial in the treatment of PAH. However, the radiofrequency energy used in these studies was shown to alter the structure of the pulmonary artery media and intima, which may be of long-term consequence.

In some cases, despite recent therapeutic advances, PAH patients continue to experience significant morbidity and mortality. In some cases, the only available cure is lung transplantation.

In methods performed in accordance with some embodiments of this invention, after the patient is diagnosed with pulmonary hypertension, the patient is examined for contraindications, to determine whether they can be treated by pulmonary artery denervation. In some embodiments, contraindications for treatment may include: patients who are pregnant, nursing or planning pregnancy; patients with implantable cardiac pacemakers, ICDs and/or neuro stimulators; patients with a known sensitivity to heparin and/or any of its substitutes; patients diagnosed with a clotting disorder and/or thrombocytopenia; patients diagnosed with a blood and/or bleeding disorder; patients with an anatomy that may interfere with the procedure, for example, an anatomy associated with the venous access site, right heart, pulmonary arteries and/or lungs; patients with a pulmonary artery aneurism; and/or other exclusion criteria.

In some embodiments, if no contraindications exist, a decision is made (e.g. by a physician and/or other clinical personnel) to treat the diagnosed PAH patient by pulmonary artery denervation (1102).

In some embodiments, the denervation treatment is planned with the aid of a computational model (1104) for example as described herein, such as the computational model described in Figures 13A-C. In some embodiments, determining of treatment parameters such as device position, energy intensity, duration, number of activated transceivers, number of treatment sites along the artery and/or other parameters is performed in accordance with one or more of: a distribution of the nerves, nerve size, nerve depth (e.g. relative to the artery lumen), nerve type (e.g. sympathetic or parasympathetic) and/or other parameters. Optionally, the specific anatomy of an individual is assessed for determining treatment parameters. Additionally or alternatively, treatment parameters are selected using a common database and/or lookup table, including data pertaining to the individual and/or data pertaining to a population.

In some embodiments, an intravascular catheter device for example as described hereinabove is introduced to the pulmonary artery lumen, and positioned at the main pulmonary artery, right pulmonary artery and/or left pulmonary artery (1106).

In some embodiments, the device is activated to emit energy effective to thermally damage nerves in the pulmonary artery adventitia, the nerves being located a depth of between 0.2-20 mm, between 1-8 mm, between 4-10 mm, between 3-7 mm, or intermediate, longer or shorter distances from the artery lumen, such as from the intimal aspect of the artery lumen wall (1108).

In some embodiments, the emitted energy comprises high frequency non-focused ultrasound. Emission of high frequency non-focused ultrasound, in accordance with some embodiments, was shown to be capable of delivering energy to nerves in the artery adventitia while sparing the artery wall. In some cases, the heat absorption profile of ultrasonic energy in tissue, combined with the cooling effect of luminal blood flow allows heat to be focused at a specific depth, with limited effect on the tissue found between the ultrasound transceiver(s) and the target tissue. In some embodiments, the intima and media tissues of the artery wall remain substantially undamaged.

In some embodiments, the applied denervation treatment produces focal areas of neo- intima. In some embodiments, the applied denervation treatment produces local areas of fibrosis, affecting connective, adipose and/or nerve tissue. In some embodiments, the applied denervation treatment causes thickening of the epineurium of the targeted nerves.

In some embodiments, one or more energy types different than non-focused ultrasound energy are applied, such as: ultrasound energy including: focused high intensity, low frequency and other forms of ultrasound; radiofrequency energy including: monopolar, bipolar and other forms of radiofrequency energy; cryotherapy, light energy, heat energy, cold radiation, phototherapy, microwave, magnetic, electrical, electromagnetic, kinetic, potential, nuclear, elastic mechanical, chemical, and hydrodynamic energy..

In some embodiments, one or more of the following safety measures are taken before, after and/or during treatment: in some embodiments, the catheter is used for treating a single patient only; in some embodiments, re-sterilization and/or re-use of the catheter are avoided; in some embodiments, the catheter is used only with its compatible console; in some embodiments, care should be taken to avoid applying direct pressure onto the distancing device and/or ultrasonic transducers of the device during preparation; in some embodiments, during treatment, if the distancing device is open, manipulation and/or retraction of the catheter are avoided; in some embodiments, during energy delivery, the catheter is not moved; in some embodiments, for example in cases in which additional electrical devices are used during operation in addition to the catheter, the system is disconnected by unplugging the power cable and/or the catheter is withdrawn; in some embodiments, in case the distancing device malfunctions, the distancing device can be retracted along with the catheter and/or along with the guide sheath; in some cases in which fluoroscopy is performed, care should be taken to avoid excessive exposure of the patient to contrast agents; in some embodiments, before treatment, a patient is provided with a systemic anticoagulant. Optionally, an activated clotting time (ACT) is monitored during treatment. In some cases, an ACT of at least 250 seconds should be maintained. Alternatively, an ACT of at least 270 seconds, for example 270 seconds, 275 seconds, 280 seconds or any intermediate, smaller or larger time duration should be maintained. In some embodiments, use of the catheter and/or console is allowed only for trained, qualified medical personnel (e.g. right heart catheterization experts and/or authorized technicians); in some embodiments, during the procedure, Echocardiography and equipment for diagnosis and immediate therapeutic actions for pericardial tamponade should be made available; in some embodiments, care should be taken to avoid using electro-medical energy sources in the presence of flammable detergents, anesthetics, nitrous oxide (N20), or oxygen that are not controlled in a closed-circuit environment; in some embodiments, use of the system is permitted only following completion of training; in some cases in which tissue dissection or perforation of the pulmonary artery have occurred care should be taken when introducing the catheter; in some embodiments, the catheter and/or other accessories (e.g. distancing device) are to be disposed of according to established hospital protocols of biohazardous waste disposal; in some embodiments, if the device malfunctions, the catheter is returned to the company for analysis; in some embodiments, only predefined intended target areas are treated; in some embodiments, powered and/or automatic contrast injection devices may be used before and/or during the procedure, optionally, specified settings for flow injection and/or contrast agent delivered are taken into consideration; in some embodiments, water ingress into the console should be avoided; in some cases, if the patient suffers from excessive pain during treatment, analgesia and/or sedation should be considered; in some cases, if radiography is used, radiation hazards should be handled.

In some cases, the pulmonary denervation procedure and/or treatment may cause adverse effects such as: heart rhythm disturbances including bradycardia; formation of blood clot and/or embolism, possibly resulting in ischemic events such as myocardial infarction, stroke, hemoptysis; hematoma, bruising, bleeding; vascular complications: arterial spasm, arterial stenosis, arterial dissection, perforation, pulmonary perforation, pseudo-aneurysm, AV-fistula, syncope; complications associated with the contrast agent used during the procedure, e.g., serious allergic reaction or reduced kidney function; pain; infection; nausea or vomiting; fever; death; cardiopulmonary arrest; risks associated with contrast agents, narcotics, anxiolytics, other pain medications and anti-vasospasm agents used during the procedure; Biological Hazards: Risks of infection, toxicity, adverse hematology, allergy, hemorrhage, hemoptysis, pain and pyrogenicity; Damage to the blood vessel wall or other body structures from the delivery of energy, e.g., pulmonary artery stenosis, nerve damage, spasm, aneurysm formation or rupture; unintended/unexpected damage to local anatomical structures such as the cardiac plexus, esophagus, trachea, lung or vagus, leading to bradycardia, tachycardia, partial vocal cord palsy or Haemoptysis; decreased pulmonary function; hypertension; hypo-perfusion. In some embodiments, prophylactic treatment is provided before and/or during and/or following the procedure to reduce or prevent adverse effects for example as listed hereinabove. Optionally, treatment is planned so as to minimize risk to the patient, for example, a patient may be treated by multiple short sessions instead of a long session. Additionally or alternatively, treatment may be limited to the right, left or main pulmonary artery only, and/or limited to specific locations within the artery.

Exemplary Treatment Setup

Figures 12A-G are images presenting introducing and positioning of an ultrasonic catheter for example as described herein in the pulmonary artery, according to some embodiments.

Figures 12A-B are images of a distal portion of the catheter 1200, showing distancing device 1202 in a closed configuration (Figure 12A) and expanded configuration (Figure 12B).

Figure 12C shows the catheter being introduced over a guide wire 1204, in this example over a 0.014" guide wire.

Figure 12D is an angiogram of the right pulmonary artery; Figure 12F is an angiogram of the left pulmonary artery; and Figures 12E and 12G are fluoroscopic images of the catheter being positioned in the right pulmonary artery (Figure 12E), and left pulmonary artery (Figure 12G), according to some embodiments.

In some embodiments, the treating catheter is introduced via jugular vein or femoral vein approach. In some embodiments, the treating catheter is introduced to the pulmonary artery using one or more of the following: via a guiding sheath, via guiding catheter, and/or over a guide wire. In some embodiments, a size of the guiding sheath is 5F, 6F or 7F or intermediate, larger or smaller. In some embodiments, a size of the guiding catheter size is 8F, 9F or 7F, or intermediate, larger or smaller. In some embodiments, a diameter of a guide wire over which the catheter is introduced is 0.014", 0.25", 0.18", or intermediate, larger or smaller diameter. In some embodiments, the usable length of the catheter is between 100cm, 110cm, 120cm 130cm or intermediate, longer or shorter usable length.

An exemplary treatment setup is described as follows: in some embodiments, the method comprises gaining access to the jugular or femoral vein (optionally using standard interventional techniques) and an introducer sheath (e.g. a 8Fr sheath) along with a guide catheter are inserted. In some embodiments, air injection through the guide catheter and/or sheath should be avoided.

In some embodiments, a Y-connector is connected to the guide sheath and/or guide catheter.

In some embodiments, a Swan Ganz catheter is initially introduced into the pulmonary artery, and a plurality of catheters are introduced one after the other over increasing wire size until a final guiding catheter is positioned in the pulmonary trunk.

In some embodiments, prior to insertion of the treating catheter, a diagnostic catheter is introduced and contrast injection is performed to evaluate vasculature anatomy and diagnose abnormalities.

In some embodiments, optionally under fluoroscopic guidance, the guide sheath and/or guide catheter are introduced to a treating position within the pulmonary artery.

In some embodiments, one or more safety mechanisms are employed, for example, energy emission is ceased if a temperature of the transducers is higher than 45 degrees C, higher than 51 degrees, higher than 54 degrees, higher than 58 degrees or intermediate, higher or lower temperature.

In some embodiments, safety measures such monitoring of system blood pressure, monitoring ECG and/or other parameters are taken. Optionally, monitoring is performed continuously during the procedure. In some embodiments, care is taken to avoid and/or diagnose conditions such as arrhythmia and/or perforation of the artery (which may cause tamponade).

In some embodiments, before, during and/or after energy emission, the guide sheath and/or guide catheter and/or treating catheter are flushed with heparinized saline.

In some embodiments, the console will stop treatment if measured electrical parameters of the catheter such as impedance and/or phase and/or frequency have changed from production line settings above a predefined threshold. In some embodiments, the console measures the electrical parameters of the catheter prior to insertion in a sterile zone and a decision is made whether to introduce the catheter into the patient's body or to replace catheter.

In some embodiments, the console prevents treatment in a certain location if a detected distance between the catheter and the artery wall is above and/or below a predefined threshold.

In some embodiments, treatment efficacy is evaluated by the maximum measured temperature of the catheter and/or changes in the electrical parameters of the catheter with respect production line setting. Optionally, a decision is made to introduce a second catheter into the artery. Optionally, a catheter is replaced in case there was a change in its electrical parameters and a second catheter is introduced to the pulmonary artery to complete the treatment.

In some embodiments, as a safety measure, in case of sudden moves of the patient, the console operator stops energy emission. In some embodiments, if the patient is coughing, energy emission is ceased immediately.

Computational model

Figures 13A-C are computational simulations of a thermal effect on the tissue following exposure to various ultrasonic intensities, according to some embodiments.

Some embodiments relate to a computational model for estimating a thermal effect of the emitted energy on the tissue. In some embodiments, the model estimates heat propagation through the tissue. Optionally, a thermal distribution map is obtained.

In some embodiments, the model takes into account one or more of the following parameters: a geometry and/or size of the tissue region of interest; ultrasonic pulse intensity and/or duration; ultrasonic frequency; number of transceivers, the transceiver's physical dimensions and shape; the transceiver's position inside the artery; tissue coefficients such as diffusion coefficient and/or energy attenuation coefficient; a density of the tissue (or portions thereof); a heat capacity of the tissue; a conductivity of the tissue; metabolic heat generation in the tissue, heat absorption of tissue; and/or volumetric blood perfusion.

In some embodiments, the model takes into account self-heat generation in the tissue. In some embodiments, the model takes into account blood perfusion in the tissue.

In some embodiments, the model is carried out using finite element analysis, such as an analysis performed in accordance with the bioheat equation solution. In the exemplary model calculated by the inventors, two-dimensional rectangular elements (of 0.36 mm ^A 2 area each) were selected for simulating surfaces of two ultrasound transceivers from which energy is emitted.

In the exemplary model shown, the region of interest in the tissue was defined as comprising five circular concentric layers, corresponding with: the artery lumen (defined herewith as having a 25 mm diameter); the intima (defined herewith as having a thickness of 0.02 mm); the media (defined herewith as having a thickness of 0.94 mm); the adventitia (defined herewith as having a thickness of 0.04 mm) and perivascular tissue. In order to simulate tissue having different internal heat generation and blood perfusion than the treated tissue, a fifth layer simulating soft tissue (defined herewith as having a thickness of 2.3 mm) was added between the adventitia and perivascular tissue. In some embodiments, as can be observed in Figure 13B, the thermal effect is obtained further from the artery the wall due to soft tissue parameters (e.g. perfusion rate, heat conduction) being different than parameters of the surrounding perivascular tissue.

When defining the conditions the inventors assumed a constant blood temperature of 37 degrees Celsius within the pulmonary artery and also at the interface between the artery wall and the blood, owing to the relatively high convection rate in this artery. The initial tissue temperature (prior to energy delivery) was set at 37 degrees Celsius as well. Since in some embodiments the transceiver's width is substantially smaller than its length, the artery cross section was analyzed and a temperature gradient along the long axis of the artery was neglected.

The following is an exemplary construction of the model, according to some embodiments:

The governing heat equation is described by the general Bioheat Equation: ¾ = V - (k(u, f)Vu(f, t))

Where: u is the thermal distribution in time and space, t is the time variant, k is the thermal diffusion coefficient and r is the position vector.

For simplifying the model, the inventors assumed a constant diffusion coefficient per tissue type through time and piecewise constant through space and therefore the differential equation can be reduced to:

ultrasonic

absorption

in tissue

Where T is the temperature profile along space and time, p is the tissue density, CP is the tissue heat capacity, qs is the tissue's metabolic heat generation and qu is the heat absorption in the tissue, which can be described as: q _u = Ie- ^a « ²

Where I is the intensity of the ultrasonic pulse, a is the attenuation coefficient which linearly depends on the frequency (f), and x is the position vector along the ultrasonic beam.

Figure 13 A simulates the thermal effect of non-focused ultrasound energy at various intensities on tissue having no internal (self) heat generation and no perfusion, imitating ex-vivo conditions. This model did not include a perivascular layer. The various intensities applied, corresponding with simulations 1-6 were 25 [W/cm ^A 2], 32 [W/cm ^A 2], 39[W/cm ^A 2], 46 [W/cm ^A 2], 53[W/cm ^A 2], 60 [W/cm ^A 2].

Figure 13B simulates the effect on tissue having internal heat generation as well as tissue perfusion, imitating in-vivo conditions.

In some embodiments, the thermal damage when observed at a cross section takes the form of a teardrop 1300, which can be described for example as an oval with one end pointed. Optionally, in which a bulbous portion of the teardrop faces the artery wall and a pointed end of the teardrop faces away from the artery wall. Optionally, the highest temperature is obtained at a substantial center of the tear drop. Optionally, the temperature decreases gradually towards a periphery of the tear drop. In some embodiments, the temperature ranges between 56 degrees at the most heated tissue (e.g. at the center of the tear drop) and 37 degrees at the least (or non) heated tissue (e.g. at the outermost borders of the tear drop). In some cases, a cross section profile of the thermally damaged area depends on the type of tissue being treated and/or the anatomical structure of the tissue. For example, a tear drop form may occur mostly in homogenous tissue, while in non-homogenous tissue the thermal damage profile may take an arbitrary form. Optionally, when the treated tissue comprises tissue that is sensitive to ultrasound energy (for example nerve tissue), a longitudinal extent 1316 of the damage (i.e. in a radially outwards direction with respect to the artery wall) may be shorter as compared to the longitudinal extent of the thermal damage in other tissue which is less sensitive to ultrasound. In some embodiments, a width 1318 of the thermal damage and/or the longitudinal extent 1316 of the thermal damage are increased when the energy intensity is raised and/or when the pulse duration is increased.

In some embodiments, a shape of the emitting surface of the transceiver affects the shape and/or dimensions of thermal damage, for example, for a rectangular surface, the shorter the width of the surface the more rounded, circular form the thermal damage will take.

In some embodiments, the shape and/or dimensions of thermal damage are affected by parameters of the emitted energy, for example raising the frequency will result in a shorter longitudinal extent 1316 of the damage.

In some embodiments, the temperature distribution in the tissue in response to the applied energy depends on the intensity of the applied energy. In some embodiments, the temperature distribution in the tissue in response to the applied energy depends on the maximal temperature of the applied energy. As can be observed from the simulation of Figure 13B, the luminal aspect of the artery wall 1310 remains substantially unaffected. In some embodiments, the thermal effect starts a distance 1312 away from the vessel wall, such as a distance of at least 0.2 mm, at least 0.7 mm, at least 1 mm, at least 2 mm, at least 4 mm, or intermediate, longer or shorter distances from the vessel wall. In some cases, for example as shown herein, distance 1312 is higher in perfused tissue as compared to the corresponding distance 1314 in non-perfused tissue, such as shown in Figure 13 A.

In some embodiments, for example as demonstrated by the finite element models of Figures 13 A and 13B, an ultrasound transceiver located within the artery lumen is configured to deliver thermal energy to a depth suitable for targeting nerves in the adventitia, without thermally damaging the intima and media of the artery wall. In some embodiments, the emitted ultrasound is effective to thermally damage nerves located at a distance of between 1-10 mm, 4-8 mm, 5-15 mm or intermediate, higher or lower distance ranges relative to the artery lumen.

Figure 13C is a computational simulation of a thermal effect produced by an arrangement of three ultrasound transceivers, disposed for example on a triangular chassis as described hereinabove. In some embodiments, a plurality of thermally damaged regions (e.g. 3 as shown herein) are produced. Optionally, the plurality of regions are distributed circumferentially around the artery. In some embodiments, two or more damage regions are produced simultaneously. Additionally or alternatively, damage regions are produced consecutively. Optionally, a similar thermal damage is produced in all regions. Alternatively, energy parameters and/or device positioning are selected to produce damage regions of different shapes and/or size and/or thermal distributions. In some embodiments, energy parameters and/or device positioning are selected in accordance with respective locations of the targeted nerves, for example selected in accordance with a mapping of the nerves.

Figure 13D is a cross sectional image of thermal necrosis in bovine liver tissue in response to the treatment, obtained in an ex-vivo experiment performed by the inventors for validating the computational model described above.

In the experiment, an ultrasound catheter (TIVUS, Therapeutic Intravascular Ultrasound, SoniVie, IL) was clamped submerged in a static water bath and positioned (using an XYZ manipulator) 8 mm from the bovine liver sample.

In accordance with some embodiments, the catheter was connected to an operating console and activated to emit unfocused ultrasound energy at various intensities.

In some embodiments, for example as shown in Figure 13D, energy delivery resulted in multiple spaced apart, discrete regions of thermal damage 1320 (indicated by the white discoloration of the tissue). In some regions, necrosis and/or denaturation of the tissue was observed. The thermal damage obtained in this experiment matched the predicted computational model, exhibiting a distribution of temperatures higher than 47 Celsius in the tissue region of interest, for the various ultrasound intensities applied, in accordance with some embodiments.

In some embodiments, for example as demonstrated in this static water bath experiment, the intima and media layers were not altered by the emitted energy even without the cooling effect provided by flowing blood (the water in the bath was static). A possible explanation for this is an acoustic streaming phenomena, further described hereinbelow, in which acoustic oscillations produced by the emitted energy cause the static surrounding fluid to flow, resulting in sufficient cooling of the artery wall and/or of the transducer surface.

In some embodiments, for example as demonstrated by the computational and ex-vivo models described herein, thermal energy is delivered to nerves in the pulmonary artery adventitia while only limited energy is delivered to the intima and media.

(The simulations referred to in this figure were obtained using Matlab R2009, MathWorks, Natick, MA, US).

Effects of pulmonary artery denervation

Figures 14A-C are histopathology images of a thermal effect obtained by ultrasound energy delivery in the pulmonary artery of swine models, according to some embodiments.

The inventors investigated the effect of ultrasound when used for denervation of the pulmonary arteries for determining acute and/or chronic effects on the intima, media and adventitial nerves, and the effect on pulmonary artery pressure.

In the study, 15 male domestic swine were examined for histological changes in the pulmonary arteries following ultrasound denervation. Of the 15 subjects, 5 were tested to determine the efficacy of pulmonary artery denervation in a porcine model of pulmonary hypertension and 10 were tested to determine long-term effects of pulmonary artery denervation on the pulmonary nerves, artery wall, and general physiology.

Anesthesia during the denervation treatment was induced by intramuscular injection of Ketamine (10 mg/Kg, Vetoquinol), Xylasin (2 mg/Kg, Ceva Animal Health Pty Ltd) and intravenous Diazepam (lmg/Kg, Teva Pharmaceutical Industries LTD) and maintained with isoflurane (Piramal) 1.5 - 2.5% in 100% 02 via endotracheal tube). Interventional procedures were performed with radiographic guidance (H-5000, Philips).

In the 5 efficacy animals, prior to the study, acute pulmonary hypertension was induced using stable thromboxane A2 (TxA2) agonist (TxA2, D0400, Sigma-Aldrich). TxA2 was infused via a 6F sheath in the right internal jugular vein. The dose of infused TxA2 was increased at 5- minute intervals until maximal mean pulmonary arterial pressure was achieved. Following the withdrawal of TxA2, the mPAP decreased to baseline. Pulmonary artery denervation was then performed prior to administering a second escalating dose of TxA2.

Initial administration of intravenous TxA2 resulted in the development of acute pulmonary hypertension. This was demonstrated by a mean pulmonary artery pressure greater than 40 mmHg in the control group and in the group intended for treatment. TxA2 was administered a second time to both groups, after performing denervation in the treated group.

Hemodynamic measurements were performed on the tested subjects before denervation treatment. Repeated measurements were obtained prior to euthanasia. The measurements included systemic arterial pressure (measured using a 6F pigtail catheter (Cordis) introduced via a 6F sheath in the femoral artery). Pulmonary hemodynamic measurements were measured in the right internal jugular vein using a 7F Swan-Ganz catheter (Edwards) via an 8F sheath (Cordis). Systemic arterial pressure was measured during the procedure, to assess animal's wellbeing. Pulmonary hemodynamics were measured before the procedure and before animal's euthanasia.

Pulmonary artery denervation was performed in accordance with some embodiments using a 6F compatible TIVUS catheter. The catheter was an 0.014", "over the wire" catheter having a usable length of 64.5 cm, in accordance with some embodiments. The catheter comprised of three outward facing ultrasound elements, in accordance with some embodiments, which are configured to emit energy simultaneously. Ultrasound emission by the three elements was controlled by the TIVUS console, in accordance with some embodiments. A three petal distancing mechanism in accordance with some embodiments was deployed to surround the ultrasound elements. Control over gradual expansion of the distancing mechanism was provided via a lever on the catheter handle.

Pulmonary artery denervation was performed in the subjects via the internal jugular vein. For introducing the TIVUS catheter, in accordance with some embodiments, the Swan-Ganz catheter was introduced to the pulmonary artery and a 0.025' exchange length wire (Guideright, St. Jude) was introduced therethrough. Then the Swan-Ganz catheter was retracted and a guiding catheter (RDC (1), Cordis) was introduced over the wire and positioned at the pulmonary artery bifurcation. The 0.025' wire was then replaced by a 0.014' guidewire, and the TrVUS catheter was introduced over the 0.014' guidewire.

The catheter was positioned at a plurality of treatment sites one after the other, including up to 5 treatment sites in each of the right pulmonary artery, left pulmonary artery and the main trunk. The number of treatment sites was selected, according to some embodiments, in accordance with the specific vessel anatomy, such as according to local vessel diameter, curvature, bifurcations and/or other anatomical characteristics of the vessel. Hemodynamic measurements performed following treatment showed that pulmonary artery denervation was effective to reduce pulmonary arterial pressure by more than 25%, in accordance with some embodiments.

Following the second administering of TxA2, a reduction in mPAP was present in the treated group as compared to the pressure measured before treatment (following the initial administering of TxA2). The treated group exhibited lower mPAP levels as compared to the control group. An example of the effect of denervation on mPAP levels is presented in Figures 15A-B. Figure 15 A graphically presents differences in mPAP levels between the control group and treated group following administering of TxA2. (n=5, mean +/- S.E.M, * P <0.05, Mann- Whitney test). Examples of results of mPAP levels measured over time for one of the subjects before and after denervation treatment are graphed in Figure 15B.

For preparing the histology slides shown in Figures 14A-C, pulmonary arteries were excised en-block and preserved in 4% buffered paraformaldehyde at room temperature for 72 hours, then sectioned in the axial plane. Tissue was dehydrated and paraffin embedded with 5 microns sections cut to glass slides. Sections were stained with hematoxylin & Eosin (H&E) and tyrosine hydroxylase (TH) (AB 152, Millipore).

Slides were incubated overnight at 60°C, deparaffinized and rehydrated in tap water. Slides were incubated for 10 min in 3% hydrogen peroxidase, boiled in acidic citrate solution (Invitrogen, 00-500), blocked for 10 min with CAS block (Invitrogen, 008120) and incubated with rabbit anti-tyrosine hydroxylase antibody (1:300, Millipore, AB 152) for 1 hour at room temperature. Slides were rewashed, incubated with HiDef Detection HRP polymer system (Cell Marque, 954D-20) for 20 min. Color was developed with DAB substrate solution (ScyTek, ACK500) followed by 5 min wash in running tap water. Slides were counter stained in Mayer's Hematoxylene, dehydrated, cleared in Xylene, mounted and covered.

Figures 14A-C show the results of histological examination of the pulmonary arteries and adventitia following treatment, demonstrating an acute, localized thermal effect in accordance with some embodiments. The reference letters indicated in the histopathology images indicate the following tissue types: (L - Lymph, N - nerve, A - adipose, C - collagen (unharmed), CC - coagulated collagen, S - smooth muscle cells and VL - vessel lumen)

In Figure 14A thermal necrosis of connective tissue and thermal necrosis of nerves in the pulmonary artery adventitia in accordance with some embodiments are observed. A thermal effect was identified at a distance from the endothelial aspect of the vessel wall, sparing the intima and media, in accordance with some embodiments. Figures 14B and 14C are magnifications of necrotic nerves in the affected area. Thermal necrosis is indicated by coagulation, mainly of collagenous tissue and adipose tissue. Coagulation, vacuolation and nuclei pyknosis were observed in nerves located within the affected regions.

As can further be observed, in accordance with some embodiments the intima, media, and/or local lymph nodes are spared from thermal effect.

Results of the porcine model trial proved to be consistent with previous studies referring to delivery of RF energy for reducing indication of pulmonary hypertension in an acute porcine model. This finding was consistent with the reduced nerve tyrosine hydroxylase (TH) immunostaining demonstrated at 95 days post-procedure, as further described herein.

While the effect of RF energy in the vascular wall was shown by studies performed by others to be limited to 3 -4mm, in chronic histological studies delivery of US energy resulted in structural changes in nerves located 9.5 mm from the artery lumen, suggesting that a potential advantage of denervating using US energy may include delivering energy which is affective to target a greater portion of the nerves innervating the lung.

Long term effects of pulmonary artery denervation

Figures 16 A- J and Figures 17A-D are histopathology images showing some long term effects of ultrasound energy delivery in the pulmonary artery of swine models, according to some embodiments.

Histological samples were obtained from subjects of the above described trial at 14 days,

28 days, and 95 days post-procedure. The markings indicated on the images represent the following tissue types: A - adipose tissue; C - collagenous connective tissue, N - nerve; P - epineurium.

Focal areas of neo-intima were observed in treated arteries following long term surveillance, as shown for example by Figures 16F-H. The existence of neo-intima could be attributed to the presence of a guiding catheter inside the artery. In some cases, mild mechanical injury may be caused to the intima by the guiding catheter, potentially inducing re-growth of the endothelial layer - a neo-intima. In some cases, formation of a neo-intima is an expected result of the catheterization procedure. A similar, general healing phenomena of human vessels is known from coronary and peripheral procedures.

In the results presented herewith, a thickness of the neo-intima layer was measured to be between 150 μιη to 250 μιη. Given the artery diameter, which is about 25 mm, the layer of neo- intima had substantially no effect on artery lumen patency. No changes were observed in the size (e.g. diameter) of the artery lumen (a change in lumen diameter was defined as larger than 5%).

Localized areas of fibrosis affecting connective, adipose and nerve tissue were observed in the artery adventitia at 14 days, 28 days and 95 days post denervation. These areas of fibrosis were found between 0.5-9.5 mm from the intimal aspect of the artery wall.

At 14 days post denervation, the presence of giant cells, eosinophils and neutrophils in the tissue indicated an early inflammatory response. At day 95, inflammation indications were no longer present.

The presence of large orbicular lipid droplets indicated a thermal effect on adipose tissue, for example as shown by Figures 161, 16J showing orbicular adipose droplets at 14 days post treatment (Figure 161) and at 28 days post treatment (Figure 16J). It is noted that a thermal effect of treatment on connective tissue (such as adipose tissue) may have no clinical significance on the effect of denervation treatment, since the size of the necrotic region is small relative to the total area of connective tissue surrounding the treated blood vessel and/or since re-growth of connective tissue replaces the thermally damaged connective tissue. Optionally, the supporting and binding properties of the connective tissue are substantially unaffected.

Fibrosis and thickening of the epineurium were present even at 95 days post denervation, suggesting long-term alteration of the nerve structure. A reduction in tyrosine hydroxylase staining in adventitial nerves at 95 days post denervation, for example as shown in Figures 17B, 17D (as compared to staining of the control group, shown in Figures 17A, 17C) further supported that ultrasonic denervation was effective to damage sympathetic nerves located within the target area, in accordance with some embodiments. As can be observed, the tyrosine hydroxylase staining of the nerves resulted in strong, distinct staining of undamaged nerves, while damaged nerves demonstrated a fused, light colored stain or no staining at all. Histological examination of adjacent structures such as the lungs and aorta showed no thermal effect on these structures, in accordance with some embodiments.

The histological examination showed acute and chronic thermal necrosis to pulmonary adventitial structures. The thermal effect also caused structural alteration of connective tissue (e.g collagen and/or adipose tissue), which, as discussed above, may be insignificant to the effect of denervation. Most prominently, treatment resulted in a desired structural alteration of sympathetic adventitial nerves innervating the pulmonary artery, in accordance with some embodiments. Immediate changes in the tissue were followed by an inflammatory response and tissue fibrosis, with alteration of nerve structure (e.g. alteration of the nerve's biochemical structure), correlating with the results of nerve staining performed at 95 days post denervation and proving a long term effect on the damaged nerves.

No detrimental effect on vessel integrity or animal health was evidenced. A macroscopic assessment showed no damage to the right heart, no pulmonary artery thrombus, and no aneurysm, dissection, perforation or stenosis of pulmonary arteries or the adjacent aorta.

The results of pulmonary artery denervation in accordance with the study described herein showed an acute reduction in mean pulmonary artery pressure in comparison to sham treatment. Denervation treatment, in accordance with some embodiments, was shown to alter the histological structure of pulmonary artery adventitial tissue containing nerves, while sparing the intima and media of the pulmonary artery.

The treated subjects were maintained under surveillance post-procedure. No abnormalities were found in routine blood investigations. The animals were mobile and gained weight in a manner comparable with littermates, showing no signs of pain or discomfort and no cardiac or respiratory difficulties.

Nerve mapping

Figures 18A-C are tables summarizing results of nerve mapping for determining a location and/or distribution of pulmonary artery nerves, in accordance with some embodiments, and Figures 19A-F graphically present an analysis of nerves innervating the pulmonary artery, performed in accordance with some embodiments of the invention.

The inventors studied human cadavers and human histological samples to determine the location and distribution of the pulmonary artery innervation at both a gross anatomical and histological level, for assessing a preferred treatment area in accordance with some embodiments.

For performing a cadaveric examination, the rib cage of 2 fresh cadavers (1 male and 1 female) was lifted to allow inspection of the upper thorax anatomy. Locations of nerves innervating the pulmonary artery, dimensions of the pulmonary artery and distances of major anatomical structures from proposed treatment sites were assessed by gross anatomical inspection.

A macroscopic inspection demonstrated that the pulmonary plexus originates from the vagus nerve and the spinal ganglions. Parasympathetic nerves extending from the vagus nerve were located caudal and anterior to the main PA. Sympathetic nerves extending from the spinal ganglia initially innervating the posterior aspect of main pulmonary artery. Both sympathetic and parasympathetic nerves split to form a plexus surrounding the arteries. The nerve cross sectional area was shown to be larger at the vicinity of the main pulmonary artery, splitting and reducing in cross sectional area as the nerves progress along the left and right pulmonary arteries. Other than intended target nerves (e.g. nerves defining the pulmonary plexus), only the left recurrent laryngeal nerve was present within the treatment area, which was selected in accordance with some embodiments to encompass a 10 mm depth relative to the intimal aspect of the pulmonary artery wall. In some embodiments, a size of the treatment area (e.g. depth relative to the intimal aspect of the pulmonary artery wall) is selected so that it does not encompass nerves innervating organs other than the pulmonary arteries. Optionally, a position and/or location of the catheter within the artery is selected to apply energy to a region encompassing nerves innervating the pulmonary arteries while avoiding other nerves and/or organs.

For performing a histological examination, the hearts, great vessels and surrounding soft tissue were collected post-mortem from two non-PAH patients with the pulmonary arteries attached to the level of the pulmonary hilum. Pulmonary arteries were formalin fixed and paraffin embedded. The pulmonary arteries were sectioned at 3 mm intervals. Each block was cut at 4 microns and mounted onto slides for staining with hematoxylin and eosin (H&E), TH and NF. Histologic sections were subsequently examined by light microscopy for quantification of nerve size, nerve number and nerve distribution.

Histological analysis of the nerve distribution around the main, left and right pulmonary arteries evaluated the number of nerves and the cross sectional area of each nerve using NF staining (staining all nerves) and TH staining (staining sympathetic nerves only).

(The staining methods used herein differ in that NF staining targets neurofilaments inside the nerve which are present in all types of nerves, providing a general indication for the presence of nerves, while TH staining takes part in the catecholamine production process and as such can be found only in sympathetic nerves.)

The histological analysis showed that the number of nerves and an averaged cross sectional area of the nerves present within the slide taken at the main pulmonary artery level was found to be greater than the number of nerves and an averaged cross sectional area of the nerves present within slides taken at the left and right pulmonary artery levels. The minimal distance of nerves from the inner aspect of the artery lumen was 0.7 mm, and the maximum distance was 12 mm. More than 40% of the nerves surrounding the left and right pulmonary arteries were identified at a distance greater than 4mm from the artery lumen (44.7% and 46.2% respectively, for example as demonstrated in section A of the table). The average nerve was 0.11+0.26 mm ^A 2 in cross sectional area at the MPA, 0.06+0.11 mm ^A 2 in the LPA and 0.07+0.14 mm ^A 2 in the RPA. No correlation was found between nerve size (cross sectional area) and a distance of that nerve from the vessel lumen. The majority of the nerves supplying the pulmonary arteries stained positive for TH, demonstrating a predominantly sympathetic innervation (for example as demonstrated in section B of the table). Sympathetic nerves provided the greatest contribution (71%) to the total nerve area, and individual sympathetic nerves were larger than non- sympathetic nerves with an average cross sectional area which is about two folds the averaged cross sectional area of non- sympathetic nerves (0.22+0.3 mm ^A 2 in the MPA, 0.13+0.19 mm ^A 2 in the LPA and 0.16+0.21 mm ^A 2 in the RPA (for example as demonstrated in section C of the table).

Mapping of the nerves was performed by determining a location, a cross sectional area and a distance of the nerve from the artery lumen, for producing a distribution map, in accordance with some embodiments. Consecutives slides were projected on a Cartesian map to form a 2D representation of nerve distribution, for example as shown in Figures 19A-C, presenting a distribution of the nerves in the vicinity of the main pulmonary artery (Figure 19A); right pulmonary artery (Figure 19B) and the left pulmonary artery (19C). A cross sectional area of each of the nerves is represented by the size of the circle indicating that nerve. Figures 19D-F present cumulative cross sectional areas of both sympathetic nerves and all nerves (i.e. including sympathetic and parasympathetic nerves) at the various distances from the artery lumen, for the main pulmonary artery (Figure 19D), right pulmonary artery (Figure 19E) and left pulmonary artery (19F) respectively.

In some embodiments, nerves are selected as a target according to one or more parameters such as a location of the nerve (e.g. a distance of the nerve from the artery wall), a cross sectional area of the nerve, a type of the nerve, a length of the nerve and/or other parameters. Optionally, a nerve is selected as target based on its individual effect on artery dilation of the artery.

In some embodiments, the number of targeted nerves is selected to be sufficient to cause a reduction in pulmonary pressures such as the systolic PAP (pulmonary artery pressure) and the mean PAP, RAP (right artery pressure), or PVR (pulmonary vascular resistance) levels as compared to pressure levels measured before treatment. In some embodiments, the number of targeted nerves is selected to be sufficient to reduce the pulmonary vascular resistance levels by 10% -25% or intermediate, higher or smaller percentage relative to vascular resistance levels measured before treatment. In some embodiments, the number of targeted nerves is selected to be sufficient to improve right heart function, for example as demonstrated by a rise in ejection fraction levels, a rise in cardiac output and/or a higher cardiac index. Optionally, at least 1%, at least 5%, at least 10% or intermediate, larger or smaller portion of the nerves innervating the pulmonary artery are targeted in order to obtain such reduction in the pulmonary pressure levels and/or to significantly improve right heart function.

In some embodiments, denervation treatment for example as described herein results in a reduction of one or more of the following parameters: Right atrial pressure (RAP), Right ventricle pressures (RVP), Systolic pulmonary artery pressure (sPAP), Mean pulmonary artery pressures (mPAP), Pulmonary vascular resistance (PVR), NT-pro-BNP. In some embodiments, denervation treatment for example as described herein results in an increase in one or more of the following parameters: Cardiac output (CO), Cardiac Index (CI), Ejection Fraction (EF), Pulmonary distensibility, Exercise tolerance - 6 minutes walking distance (6MWD), Quality of life as assessed by questionnaire, cardiopulmonary exercise testing and V02 max.

In some embodiments, a desired reduction in pulmonary artery pressure levels is matched to a predefined number of nerves for targeting. In some embodiments, a desired reduction in pulmonary artery pressure levels is matched to specific, predefined locations of nerves for targeting. In some embodiments, the system is configured to receive as input a desired result (e.g. a reduction of mPAP level by at least 10%) and to automatically match a treatment setup suitable to obtain such result, for example a treatment setup defining an amount and/or location of nerves that for targeting, energy parameters to be used, a duration of treatment and/or other parameters for carrying out suitable treatment. Optionally, the setup parameters are selected according to a lookup table.

Treatment locations

Figures 20A-B schematically define anatomical limits for performing denervation, according to some embodiments.

In some embodiments, treatment is performed by positioning the device at one or more locations along the main pulmonary artery, left pulmonary artery and right pulmonary artery. Figure 20A schematically illustrates border lines defining a region in which the device can be positioned to effectively target nerves innervating the artery, according to some embodiments. In this example, a first border line 3000 is set adjacent a first bifurcation 3002 of the right pulmonary artery; a second border line 3004 is set adjacent a first bifurcation 3006 of the left pulmonary artery; and a third border line 3008 is set at the main pulmonary artery, optionally adjacent (such as superior to) the pulmonary valve 3010.

Optionally, for the right pulmonary artery, a treatment location be limited to up to 5 cm, up to 4 cm, up to 2.5 cm or intermediate, longer or shorter distances distally from the main bifurcation 3016 (i.e. in the direction of bifurcation 3002). Optionally, for the left pulmonary artery, a treatment location should be limited to up to 1 cm, up to 0.5 cm, up to 1.5 cm or intermediate, longer or shorter distances distally from the main bifurcation 3016 (i.e. in the direction of bifurcation 3006.

Figure 20B schematically illustrates border lines for positioning the device within the left pulmonary artery, according to some embodiments. In this example, a lateral border line 3012 is set adjacent bifurcation 3006, and a medial border 3014 is set at a distance 3016 from the lateral border, for example 1 cm from the lateral border, 0.5 cm from the lateral border, 1.5 cm from the lateral border, 2 cm from the lateral border or intermediate, longer or shorter distances from the lateral border.

Figures 21A-C are examples of single and multiple treatment locations along the pulmonary artery, according to some embodiments.

Figure 21 A illustrates a single treatment location 3100, in which the device is positioned adjacent bifurcation 3102 of the left pulmonary artery; Figure 21B illustrates two treatment locations 3104 and 3106. A distance 3105 between adjacent treatment locations (measured along the long axis of the artery) may include, for example, 0.1 cm, 0.2 cm, 0.5 cm, 1 cm, 2 cm, 4 cm or intermediate, longer or shorter distances; Figure 21C illustrates a plurality of treatment locations along the main, left and right pulmonary arteries.

In some embodiments, the number of treatment locations is selected in accordance with one or more of: an axial length of the artery; a diameter of the artery; a location of the targeted nerves; a density of the targeted nerves. In some embodiments, the number of locations is selected to be sufficient to effectively target a nerve along a length of the nerve. Optionally, the targeted length is selected to be sufficient to reduce or eliminate the nerve's function.

In some embodiments, at each treatment location, the one or more transceivers of the device are activated to apply a set of excitations, for example between 2-8 excitations, 1-20 excitations, 1-5 excitations or intermediate, larger or smaller number of excitations. Optionally, at each excitation, the emitted energy beam 3108 is effective to cover an area of between 12-30 cm ^A 2, 10-20 cm ^A 2, 15-25 cm ^A 2 or intermediate, smaller or larger surface areas. In some embodiments, a shape of the area covered by the beam and/or the beam orientation are controlled by selectively positioning the catheter, for example taking into account anatomical structures in a vicinity of the beam. In some embodiments, only nerves found within the area covered by the beam are thermally damaged, while other, non-neural tissue within the area covered by the beam remains substantially undamaged.

In some embodiments, in the left pulmonary artery, the number of treatment locations should be no more than 2, for example so as to reduce or prevent damage to the close by recurrent laryngeal nerve. In some embodiments, adjacent treatment locations are selected to be far enough from each other so as to avoid overlap of the targeted areas. Alternatively, some overlap is allowed or even desired, for example for intensifying the treatment effect (e.g. producing a higher level of thermal damage and/or for treating a larger area, for example due to autonomic natural movement of the tissue).

In some embodiments, the catheter is stabilized at each treatment location, for example using the distancing device and/or using a guide wire over which the catheter was delivered and/or using the guiding catheter. Optionally, at least some movement of the catheter is allowed during applying of treatment, for example natural movement due to pulsation.

In some embodiments, when maneuvering the catheter between different treatment sites, the distancing device is collapsed so as not to interfere with movement along the artery. Optionally, the distancing device is expanded again at the subsequent treatment site. Optionally, in case of damage or failure of the distancing device, the distancing device can be disengaged from the catheter and retracted separately.

In some embodiments, a duration of treatment at each site ranges between, for example,

10-80 seconds, such as 20 seconds, 40 seconds, 70 seconds or intermediate, shorter or longer time periods.

In some embodiments, the applied ultrasound intensity ranges between, for example, 30- 70 W/cm ^A 2, such as 40W/cm ^A 2, 50 W/cm ^A 2, 60W/cm ^A 2 or intermediate, higher or lower intensities.

Optionally, different sets of treatment parameters (such as intensity, duration, frequency and other parameters) are used at different treatment locations. Alternatively, a constant set of parameters is maintained throughout treatment.

Figure 22 schematically illustrates an acoustic streaming effect produced in response to energy emission in the artery, in accordance with some embodiments.

In some embodiments, transceiver 3200 is positioned facing the artery wall 3202. In some embodiments, emission of ultrasound energy having certain parameters produces an acoustic streaming effect in which fluid (e.g. blood) flows from the planar transceiver surface 3203 towards and against the artery wall 3202, for example as illustrated by waves 3204.

In some embodiments, energy parameters such as intensity and frequency are selected to be high enough for producing a streaming effect which is significant enough to provide for cooling of the artery wall and/or of the transducer surface by the motion of fluid. Exemplary parameters may include intensity above 20 W/cm ^A 2, and/or a frequency above 5 MHz. Optionally, by raising the applied intensity, a velocity of the flow is increased. In some embodiments, a distance 3206 is selected to provide for a volume of fluid to exist between transceiver surface 3203 and wall 3202. In some embodiments, the transceiver is positioned such that its surface 3203 is located at a distance of least 0.5 cm away from the wall, at least 1 cm away from the wall, at least 1.5 cm away from the wall or intermediate, longer or shorter distances.

In some embodiments, by emitting ultrasound energy having parameters for example as described hereinabove, the resulting acoustic streaming effect is strong enough so that even when treatment is performed in static fluid (e.g. as described in the static bath experiment of Figure 13D), the artery wall 3202 and/or the transducer surface 3203 are cooled down, reducing or preventing unwanted thermal damage to the artery wall 3202 and/or to intervening tissue between the artery wall and the targeted nerves. In some embodiments, treatment in temporary and/or permanent static fluid conditions and/or in situations in which flow is reduced can be achieved owing to the streaming effect. Such situations may include a reduction in flow due to heart pulsation (during diastole), breathing, artificial restriction of flow and/or other situations in which flow is reduced, stopped, and/or otherwise restricted.

In some embodiments, the extent of cooling enabled by the streaming effect is proportional to the intensity of the applied energy- the higher the energy, the higher the velocity of the flow velocity that carries heat away.

In some embodiments, when treatment is performed in flowing fluid (e.g. natural flow of blood through the artery), the streaming effect may enhance the cooling provided by the natural flow, reducing damage to the artery wall and/or transducer surface. Optionally, the streaming effect causes a reduction in the temperature of the fluid. When the fluid is blood, the streaming effect may reduce blood coagulation, due to one or both of motion of the fluid and/or due to cooling of the blood.

Following is a description of an experiment which validates and shows the effectiveness of a denervation treatment in accordance with some embodiments of the invention. In addition, it is noted that a treatment in accordance with some embodiments of the invention may follow some or all of the experimental protocol, for example, as described below. Noting, that various parts of the protocol used in the experiment may be omitted and/or parameters changed, for example, as noted below.

Validation experiment

Reference is now made to Figures 23 A and 23B, depicting scheduled events of a validation treatment following some embodiments of the invention. In the experiment, 14 patients suffering from pulmonary artery hypertension were selected for the denervation treatment. In the experiment, patients diagnosed with one or more of idiopathic, connective tissue disease PAH, Anorexogen induced or heritable PAH, functional class III who have stable PAH on a stable drug regimen of two pulmonary arterial hypertension specific medications other than parenteral prostanoids, were selected for the denervation treatment. In the experiment, patients diagnosed with PAH that receive one or more anticoagulation drugs, for example Acenocoumarol (Sintrom), heparin, warfarin (Coumadin), rivaroxaban (Xarelto), dabigatran (Pradaxa), apixaban (Eliquis), edoxaban (Savaysa), enoxaparin (Lovenox), and/or fondaparinux (Arixtra) were selected for the denervation treatment. In some embodiments of the inventions, patients are selected using one or more of these criteria.

In the experiment, patients with a PAH diagnosis, optionally confirmed by hemodynamic evaluation, showing one or more of the following parameter values were selected for the treatment:

1. Mean pulmonary artery pressure (mPAP) >25 mmHg at rest

2. Pulmonary capillary wedge pressure (PCWP) or left ventricular end diastolic pressure (LVEDP) <15 mmHg

3. Pulmonary vascular resistance (PVR) at rest >3 Wood units

4. Not meeting the criteria for a positive vasodilator response (fall in mPAP > 10 mmHg to < 40 mmHg).

In some exemplary embodiments of the invention, one or more of these parameters is used with values within the indicated ranges or in other ranges of values.

In the experiment, patients diagnosed with PAH with ACT values of at least 275 seconds, exhibited better treatment results compared to PAH patients with ACT values lower than 275 seconds. In the experiment, ACT values were maintained in at least 275 seconds, during the denervation treatment by administration of heparin. In some exemplary embodiments of the invention, Heparin or any other anti-coagulation drug is administered to the patients, for example to maintain ACT values higher than 270.

In the experiment, a clinical condition of the patients was monitored following the treatment. In the experiment, at least one parameter of the clinical condition was monitored at one or more of the following time points post treatment: 1 week, 2 weeks, 1 month, 4 months, 8 months and/or 12 months following the denervation treatment. In some exemplary embodiments of the invention, other monitoring schedules may be used, for example 24 hours, 48 hours, 4 days or any other time period following the denervation treatment. In the experiment, the at least one monitored clinical parameter comprised heart activity, for example monitored by performing ECG at 1, 4, 8 and/or 12 months following the treatment.

In the experiment, the at least one monitored clinical parameter comprised levels of NT- pro BNP evaluated at 1, 4, 8, and/or 12 months following the denervation treatment.

In the experiment, the at least one monitored clinical parameter comprised 6-minute walking distance (6MWD) evaluated at 1, 8, and 12 months following the denervation treatment.

In the experiment, the activity of patients was monitored, for example using an actigraphy device, at 4, 8, 12 months following the denervation treatment.

In the experiment, the monitored clinical parameter comprised pulmonary hemodynamic parameters, evaluated at 12 months following the denervation treatment.

In the experiment, the at least one monitored clinical parameter comprised arterial vs venous catecholamine concentration, evaluated at 4 and 12 months following the denervation treatment.

In the experiment, the at least one monitored clinical parameter comprised hemodynamic response to inhaled Nitric Oxide (NO) including mPAP and/or PVR, evaluated at 4 and 12 months following the denervation treatment.

In the experiment, the at least one monitored clinical parameter comprised MRI/CT angiography parameters, evaluated at 1 and 12 months following the treatment.

In the experiment, the quality of life is evaluated, for example using one or more quality of life questionnaires at 8 and 12 months following the treatment.

In some exemplary embodiments of the invention, one or more of the clinical parameters is evaluated in a time range of 1 day- 12 months, for example 1 day-7 days following the treatment, 7 days to 1 month following the treatment, 1 month- 12 months following the treatment or any other intermediate, narrower or wider range. In some exemplary embodiments of the invention, the time point for the evaluation of the clinical parameter, for example one or more of the clinical parameters evaluated in the experiment is selected based on the healing of the tissue, and/or based on the remodeling process of the heart. In some exemplary embodiments of the invention, one or more of the clinical parameters is evaluated by the patient in his home and/or by an expert, for example a physician, a technician or a nurse in a clinic.

In the experiment, as shown in Figures 24A and 24B a denervation treatment was applied at 10 treatment locations within the pulmonary arteries.

In some exemplary embodiments of the invention, the number of treatment locations within the pulmonary arteries is selected based on the anatomy of one or more of the pulmonary arteries and/or the distance from a selected nerve. Alternatively or additionally, the number of treatment locations is selected based on the size of the "working frame", as described herein.

In the experiment, the ultrasound catheter was inserted through the main pulmonary artery into the right pulmonary artery until reaching the first bifurcation within the right pulmonary artery. In the experiment, a first denervation treatment was delivered at the distal most treatment location which is close to the first bifurcation. Then, the ultrasound catheter was retracted and delivered a denervation treatment in 5 more treatment locations within the right and/or the main pulmonary artery.

In the next step, as shown in Figure 24B the ultrasound catheter was re-inserted through the main pulmonary artery into the left pulmonary artery, and delivered a denervation treatment at 4 treatment locations within the left pulmonary artery and the main pulmonary artery. The treatment locations within the left and main pulmonary arteries were axially spaced apart and do not overlap with the treatment locations within the right and main pulmonary arteries. To reach the different non-overlapping treatment locations, the catheter was maneuvered when inserted into the main and left pulmonary artery. In some exemplary embodiments of the invention, the catheter is maneuvered, for example by rotation and/or axial movement within the pulmonary arterial system, for example to reach non-overlapping treatment locations

In the experiment, the energy emitted by the ultrasound catheter at any one of the treatment locations was an unfocused ultrasound energy having the following parameters: an intensity between 45[W/cm ^A 2]-50[W/cm ^A 2]. In addition, the energy frequency was between l l[MHz]-12[MHz]. In the experiment the energy excitation duration was between 30 [sec] to 40 [sec]. In the experiment, the catheter had a length of 120 cm.

In some exemplary embodiments of the invention, the energy intensity is in a range of 45[W/cm ^A 2]-70[W/cm ^A 2], for example 45[W/cm ^A 2], 50[W/cm ^A 2], 55[W/cm ^A 2] or any intermediate, smaller or larger value. In some exemplary embodiments of the inventions, a high energy intensity is selected, for example to increase the penetration of the ultrasonic energy to selected deeper tissues, without affecting other tissues, for example adjacent tissues. In some exemplary embodiments of the invention, the energy frequency is in a range of 10[MHz]- 14[MHz], for example 10[MHz], l l[MHz], 12[MHz], 14[MHz] or any intermediate, smaller or larger value. In some exemplary embodiments of the invention, the energy excitation duration is between 30 [sec] to 50 [sec], for example 30 [sec], 40 [sec], 50 [sec] or any intermediate, smaller or larger value. In some exemplary embodiments of the invention, at least some of the activation parameters are determined based on one or more of the anatomy of the patients, the number of treatment locations within the right, main and left pulmonary arteries, and/or the distance between the target nerve and a treatment location.

Following the treatment, as shown in Figures 25A-25D and in Figures 26A-26C improvement of clinical parameters in the treated patients was observed.

In the treated patients, as shown in Figure 25A mPAP values were reduced in an average of about 14% compared to baseline levels, 4 months following the denervation treatment. In addition, cardiac index values, as shown in Figure 25B were increased in an average of about 2% compared to baseline levels, 4 months following the denervation treatment. PVR values measured 4 months following the treatment, as shown in Figure 25C were reduced in an average of about 15% compared to baseline levels. RA pressure values measured 4 months following the treatment, as shown in Figure 25D were reduced in an average of about 20% compared to baseline values.

In the experiment, quality of life was scored 4 months following the treatment, as shown in Figure 26A, and showed a marked increase compared to baseline levels. In addition, 6MWD values were also measured 4 months following the treatment and showed an increase in an average of about 21% compared to baseline values. Actimetry values were also measured 4 months following the treatment, as shown in Figure 26C and showed an increase in about 12% compared to baseline levels.

An additional analysis was performed 4 months following the treatment, comparing changes in PVR levels between patients that received anti-coagulation medication as part of their drug regimen, for example Warfarin (Coumadin) and/or Acenocoumarol (Sintrom) and patients that did not receive anti-coagulation drugs. As shown in Figure 27 PVR levels decreased in patients receiving the anti-coagulation drugs compared to baseline levels, 4 months following treatment and compared to patients not receiving any anti-coagulation drugs.

As shown in Figure 27, a denervation treatment in patients receiving one or more anticoagulation drugs can provide clinical benefits.

Based on the results of the validation experiment, PAH patients receiving one or more anti-coagulation drugs, for example Acenocoumarol (Sintrom), heparin, warfarin (Coumadin), rivaroxaban (Xarelto), dabigatran (Pradaxa), apixaban (Eliquis), edoxaban (Savaysa), enoxaparin (Lovenox), and/or fondaparinux (Arixtra) are selected for the denervation treatment in some exemplary embodiments of the invention. The terms "comprises", "comprising", "includes", "including", "having" and their conjugates mean "including but not limited to".

The term "consisting of means "including and limited to".

The term "consisting essentially of" means that the composition, method or structure may include additional ingredients, steps and/or parts, but only if the additional ingredients, steps and/or parts do not materially alter the basic and novel characteristics of the claimed composition, method or structure.

As used herein, the singular form "a", "an" and "the" include plural references unless the context clearly dictates otherwise. For example, the term "a compound" or "at least one compound" may include a plurality of compounds, including mixtures thereof.

Throughout this application, various embodiments of this invention may be presented in a range format. It should be understood that the description in range format is merely for convenience and brevity and should not be construed as an inflexible limitation on the scope of the invention. Accordingly, the description of a range should be considered to have specifically disclosed all the possible subranges as well as individual numerical values within that range. For example, description of a range such as from 1 to 6 should be considered to have specifically disclosed subranges such as from 1 to 3, from 1 to 4, from 1 to 5, from 2 to 4, from 2 to 6, from 3 to 6 etc., as well as individual numbers within that range, for example, 1, 2, 3, 4, 5, and 6. This applies regardless of the breadth of the range.

Whenever a numerical range is indicated herein, it is meant to include any cited numeral

(fractional or integral) within the indicated range. The phrases "ranging/ranges between" a first indicate number and a second indicate number and "ranging/ranges from" a first indicate number "to" a second indicate number are used herein interchangeably and are meant to include the first and second indicated numbers and all the fractional and integral numerals therebetween.

As used herein the term "method" refers to manners, means, techniques and procedures for accomplishing a given task including, but not limited to, those manners, means, techniques and procedures either known to, or readily developed from known manners, means, techniques and procedures by practitioners of the chemical, pharmacological, biological, biochemical and medical arts.

As used herein, the term "treating" includes abrogating, substantially inhibiting, slowing or reversing the progression of a condition, substantially ameliorating clinical or aesthetical symptoms of a condition or substantially preventing the appearance of clinical or aesthetical symptoms of a condition. It is appreciated that certain features of the invention, which are, for clarity, described in the context of separate embodiments, may also be provided in combination in a single embodiment. Conversely, various features of the invention, which are, for brevity, described in the context of a single embodiment, may also be provided separately or in any suitable subcombination or as suitable in any other described embodiment of the invention. Certain features described in the context of various embodiments are not to be considered essential features of those embodiments, unless the embodiment is inoperative without those elements.

Although the invention has been described in conjunction with specific embodiments thereof, it is evident that many alternatives, modifications and variations will be apparent to those skilled in the art. Accordingly, it is intended to embrace all such alternatives, modifications and variations that fall within the spirit and broad scope of the appended claims.

All publications, patents and patent applications mentioned in this specification are herein incorporated in their entirety by reference into the specification, to the same extent as if each individual publication, patent or patent application was specifically and individually indicated to be incorporated herein by reference. In addition, citation or identification of any reference in this application shall not be construed as an admission that such reference is available as prior art to the present invention. To the extent that section headings are used, they should not be construed as necessarily limiting.