Denervation system and method around the subclavian artery

Abstract

A method for treating a heart disease in a subject includes the step of percutaneously introducing a catheter into the vascular system of the subject. The catheter comprises a neuromodulation element. The neuromodulation element can be positioned on an expansion element. The neuromodulation element of the catheter can be positioned within the left subclavian artery of the subject. At least one of a dorsal subclavian snare or a ventral subclavian snare can be electrically stimulated using the catheter. The method includes the step of confirming the stimulation of the dorsal subclavian snare and / or the ventral subclavian snare by monitoring cardiac parameters. After confirming the stimulation of the dorsal subclavian snare and / or the ventral subclavian snare, ablation energy can be applied to the dorsal subclavian snare and / or the ventral subclavian snare.

Description

Technical Field

[0001] Reference to Related Applications This application claims the benefit of U.S. Provisional Patent Application No. 63 / 367,578, filed on July 1, 2022, and U.S. Provisional Patent Application No. 63 / 430,614, filed on December 6, 2022, which are hereby incorporated by reference in their entirety.

[0002] The present disclosure generally relates to systems and methods for facilitating regulation (e.g., denervation, ablation), and more particularly, in some embodiments, to systems and methods for facilitating therapeutic regulation of nerves around the left and / or right subclavian arteries of a subject to treat heart disease (e.g., atrial fibrillation).

Background Art

[0003] Ventricular arrhythmia is a cause of death for 80,000 people annually in the UK and 150,000 people annually in the US. The majority of ventricular arrhythmias are associated with coronary heart disease and / or heart failure, but the associated mortality and cost burden far exceed these numbers. Cardiovascular disease accounts for £12 billion in direct medical costs annually in the UK and an estimated £378 billion in direct and indirect costs annually in the US, and heart failure and related arrhythmia treatment are major factors in expenditure. Atrial fibrillation (AF) is a common and serious medical problem affecting approximately 3% of the population. The number of AF patients in the US is estimated to have increased from approximately 5.2 million in 2010 to approximately 12.1 million in 2030. Individuals with AF, both men and women, have an increased risk of death, and the age-adjusted mortality rate due to AF is 6.5 per 100,000. AF is associated with an increased risk of other cardiovascular pathologies, particularly heart failure, myocardial infarction, as well as sudden cardiac death, diabetes, gastrointestinal bleeding, and stroke, among several other pathologies.

Summary of the Invention

Means for Solving the Problems

[0004] Arrhythmias are due to heterogeneity accumulated within the heart muscle, but are worsened by dynamic changes in sympathetic (adrenergic) signaling and parasympathetic (cholinergic) signaling. In heart disease, there is higher sympathetic signaling originating from the brainstem and reaching the heart via the thoracic sympathetic nerves. In most surgical denervation procedures (stellate ganglionectomy), the surgeon identifies the ganglion and removes the thoracic ganglion (T1 - T4) levels of the sympathetic ganglion based on experience. This is because the thoracic ganglion levels are the most accessible nerves. This procedure is accompanied by side effects that affect the patient's quality of life.

[0005] The nerves surrounding the blood vessel (subclavian artery) that sends blood to the arm, called the subclavian snare, connect two paravertebral sympathetic ganglia on the same side of the body, thereby forming a highly selective access route for sympathetic innervation of the heart. Therefore, targeting one or both sides of the subclavian snare for ablation is a novel mechanism for selectively regulating sympathetic innervation of the heart. When energy is applied to non - therapeutically stimulate these nerves, it can be confirmed that the nerves sending signals to the heart are affected by the applied energy, as indicated by changes in cardiac pathology monitored by cardiac parameters (such as heart rate). Subsequently, energy can be applied to ablate or destroy the affected nerves over a longer period, which has a beneficial effect on the heart, reducing cardiac electrical heterogeneity and alleviating further pathological disease progression. There are posterior (dorsal) and anterior (ventral) subclavian snares around the left and right subclavian arteries, and the user can selectively target any of these four for ablation to any desired degree with different effects. The stimulation is not therapeutic and is used to identify the location of therapeutic ablation.

[0006] In some embodiments, a method of treating atrial fibrillation in a subject includes the step of percutaneously introducing a catheter into the subject's vasculature. The catheter comprises a neuromodulation element. The method includes positioning the neuromodulation element within the subject's left subclavian artery, electrically stimulating the left dorsal subclavian ganglion, confirming the stimulation of the left dorsal subclavian ganglion by monitoring a first cardiac parameter, applying ablation energy to the left dorsal subclavian ganglion after confirming the stimulation of the left dorsal subclavian ganglion, electrically stimulating the left ventral subclavian ganglion, confirming the stimulation of the left ventral subclavian ganglion by monitoring a second cardiac parameter, applying ablation energy to the left ventral subclavian ganglion after confirming the stimulation of the left ventral subclavian ganglion, positioning the neuromodulation element within the subject's right subclavian artery, electrically stimulating the right dorsal subclavian ganglion, confirming the stimulation of the right dorsal subclavian ganglion by monitoring a third cardiac parameter, applying ablation energy to the right dorsal subclavian ganglion after confirming the stimulation of the right dorsal subclavian ganglion, electrically stimulating the right ventral subclavian ganglion, confirming the stimulation of the right ventral subclavian ganglion by monitoring a fourth cardiac parameter, and applying ablation energy to the right ventral subclavian ganglion after confirming the stimulation of the right ventral subclavian ganglion. In some embodiments, the temperature for ablation is applied such that the target tissue is heated to 40°C to 80°C and may be applied over a period of 20 seconds to 240 seconds. Cooling of non-target tissue is optionally performed, but in some embodiments, cooling is not required. In some embodiments, after stimulation of the left ventral subclavian ganglion and the left dorsal subclavian ganglion, the left ventral subclavian ganglion and the left dorsal subclavian ganglion receive ablation energy simultaneously. In some embodiments, after stimulation of the right ventral subclavian ganglion and the right dorsal subclavian ganglion, the right ventral subclavian ganglion and the right dorsal subclavian ganglion receive ablation energy simultaneously.

[0007] The first heart parameter may be different from at least one of the second heart parameter, the third heart parameter, or the fourth heart parameter. The second heart parameter may be different from at least one of the first heart parameter, the third heart parameter, or the fourth heart parameter. The third heart parameter may be different from at least one of the first heart parameter, the second heart parameter, or the fourth heart parameter. The fourth heart parameter may be different from at least one of the first heart parameter, the second heart parameter, or the third heart parameter. The first heart parameter may be the same as at least one of the second heart parameter, the third heart parameter, or the fourth heart parameter. The second heart parameter may be the same as at least one of the first heart parameter, the third heart parameter, or the fourth heart parameter. The third heart parameter may be the same as at least one of the first heart parameter, the second heart parameter, or the fourth heart parameter. The fourth heart parameter may be the same as at least one of the first heart parameter, the second heart parameter, or the third heart parameter.

[0008] At least one of the first cardiac parameter, the second cardiac parameter, the third cardiac parameter, or the fourth cardiac parameter may include at least one of an arterial trace blood pressure change, whether AF is induced, whether an arrhythmia is induced, whether a change in cardiac cycle length is induced, a restitution curve, right atrial ERP, left atrial ERP, dERP, heart rate, IACT, or a unipolar electrogram from a multipolar catheter under steady state RV pacing or a unipolar electrogram from a multipolar catheter having a short DI after steady state RV pacing. The method may further include re-stimulating the subclavian fossa after applying ablation energy and, if the cardiac parameter confirms the stimulation, applying additional ablation energy to the subclavian fossa. The method may include repeating the re-stimulation and applying additional ablation energy until the cardiac parameter no longer confirms the stimulation. The catheter may include an expansion element in which a neuromodulation element is positioned. The expansion element may be an element that expands to dilate the vasculature.

[0009] In some embodiments, a method of treating a cardiac disorder in a subject includes percutaneously introducing a catheter into the subject's vasculature. The catheter comprises a neuromodulation element. The method further includes positioning the neuromodulation element within the subject's subclavian artery, electrically stimulating the dorsal subclavian fossa, confirming the stimulation of the dorsal subclavian fossa by monitoring a cardiac parameter, applying ablation energy to the dorsal subclavian fossa after confirming the stimulation of the dorsal subclavian fossa, electrically stimulating the ventral subclavian fossa, confirming the stimulation of the ventral subclavian fossa by monitoring a second cardiac parameter, and applying ablation energy to the ventral subclavian fossa after confirming the stimulation of the ventral subclavian fossa. In some embodiments, after electrically stimulating the dorsal subclavian fossa and the ventral subclavian fossa to confirm the stimulation of the dorsal subclavian fossa and the ventral subclavian fossa, ablation energy is applied to the dorsal subclavian fossa and the ventral subclavian fossa simultaneously.

[0010] The first heart parameter may be different from the second heart parameter. The first heart parameter may be the same as the second parameter. At least one of the first heart parameter or the second heart parameter may include at least one of arterial trace blood pressure change, whether AF is induced, whether arrhythmia is induced, whether a change in cardiac cycle length is induced, a recovery curve, right atrial ERP, left atrial ERP, dERP, heart rate, IACT, or a unipolar electrogram from a multipolar catheter under steady-state RV pacing or a unipolar electrogram from a multipolar catheter having a short DI after steady-state RV pacing.

[0011] This method may further include re-stimulating the subclavian snare after applying ablation energy and, if the heart parameter confirms the stimulation, applying additional ablation energy to the subclavian snare. This method may include repeating the re-stimulation and applying additional ablation energy until the heart parameter no longer confirms the stimulation. The catheter may include an expansion element in which the neuromodulation element is positioned. This method may further include expanding the expansion element by an amount that expands the vasculature.

[0012] In some embodiments, a method of treating a subject's heart disease includes the step of percutaneously introducing a catheter into the subject's vascular system. The catheter comprises a neuromodulation element. The method further includes positioning the neuromodulation element within the subject's left subclavian artery, electrically stimulating at least one of the dorsal subclavian ganglion or the ventral subclavian ganglion, confirming the stimulation of the dorsal subclavian ganglion and / or the ventral subclavian ganglion by monitoring cardiac parameters, and applying ablation energy to the dorsal subclavian ganglion and / or the ventral subclavian ganglion after confirming the stimulation of the dorsal subclavian ganglion and / or the ventral subclavian ganglion. The method may further include applying ablation energy simultaneously to the dorsal subclavian ganglion and the ventral subclavian ganglion after electrically stimulating the dorsal subclavian ganglion and / or the ventral subclavian ganglion and / or confirming the stimulation of the dorsal subclavian ganglion and / or the ventral subclavian ganglion by monitoring cardiac parameters.

[0013] The method may further include restimulating the subclavian ganglion after applying ablation energy and applying additional ablation energy to the subclavian ganglion if the cardiac parameters confirm the stimulation. The method may further include repeating the restimulation and applying additional ablation energy until the cardiac parameters no longer confirm the stimulation.

[0014] The step of percutaneously introducing a catheter into the vascular system may include inserting the catheter into the subject's femoral artery. The step of percutaneously introducing a catheter into the vascular system may include inserting the catheter into the subject's radial artery. The step of percutaneously introducing a catheter into the vascular system may include inserting the catheter into the subject's carotid artery. The step of percutaneously introducing a catheter into the vascular system may include inserting the catheter into the subject's femoral vein. At least one of the step of positioning the neuromodulation element within the left subclavian artery or the step of positioning the neuromodulation element within the right subclavian artery may include crossing from the venous vascular system to the arterial vascular system.

[0015] In some embodiments, a method of treating a cardiac disorder in a subject includes positioning a neuromodulation element within the subject's subclavian artery, electrically stimulating at least one of a dorsal subclavian ganglion or a ventral subclavian ganglion, verifying the stimulation of the dorsal subclavian ganglion and / or the ventral subclavian ganglion by monitoring cardiac parameters, and, after verifying the stimulation of the dorsal subclavian ganglion and / or the ventral subclavian ganglion, applying ablation energy to the dorsal subclavian ganglion and / or the ventral subclavian ganglion. In some embodiments, the ablation energy is applied to the dorsal subclavian ganglion and the ventral subclavian ganglion simultaneously.

[0016] The ablation energy can include radiofrequency ablation energy. The ablation energy can include cryoablation energy. The step of electrically stimulating can include using a combination of electrodes of the neuromodulation element. The step of applying ablation energy can include using the same combination of electrodes of the neuromodulation element.

[0017] The cardiac disorder can include atrial fibrillation. The cardiac disorder can include refractory arrhythmia. The method can further evaluate whether sympathetic drive is causing the refractory arrhythmia. The cardiac disorder can include ventricular tachycardia. The cardiac disorder can include ventricular fibrillation. The cardiac disorder can include congestive heart failure. The cardiac disorder can include atrial flutter.

[0018] In some embodiments, a catheter for treating a cardiac disorder in a subject comprises an elongate element configured to be positioned in at least one of the left subclavian artery or the right subclavian artery, or alternatively, consists essentially of this elongate element. The distal portion of the elongate element comprises a first neuromodulation element configured to stimulate at least one of a dorsal subclavian ganglion or a ventral subclavian ganglion, a second neuromodulation element configured to ablate at least one of a dorsal subclavian ganglion or a ventral subclavian ganglion, and a distal protection device distal to the distal sides of the first neuromodulation element and the second neuromodulation element.

[0019] The first neuromodulation element may comprise a first plurality of electrodes coupled to a first plurality of struts. The first neuromodulation element may comprise a first plurality of electrodes coupled to a first loop. The first neuromodulation element may comprise a first plurality of electrodes coupled to a first corkscrew. The second neuromodulation element may comprise a first plurality of electrodes, or a second plurality of electrodes coupled to a second plurality of struts. The second neuromodulation element may comprise a first plurality of electrodes, or a second plurality of electrodes coupled to a second loop. The second neuromodulation element may comprise a first plurality of electrodes, or a second plurality of electrodes coupled to a second corkscrew. At least one of the plurality of electrodes may comprise a triangular base including a tip configured to be pushed into the vessel wall. At least one electrode may comprise a plurality of electrode bumps on different sides of the tip of the triangular base. The catheter may further comprise an expansion element. The first and second neuromodulation elements may be positioned on the expansion element.

[0020] In some embodiments, a catheter for treating a heart disease in a subject comprises, or consists essentially of, an elongate element configured to be positioned in at least one of the left or right subclavian arteries. The distal portion of the elongate element comprises a neuromodulation element configured to stimulate at least one of the dorsal subclavian ganglion or the ventral subclavian ganglion and configured to ablate at least one of the dorsal subclavian ganglion or the ventral subclavian ganglion, and a distal protection device distal to the neuromodulation element.

[0021] The neuromodulation element may comprise a plurality of electrodes coupled to a plurality of struts. The neuromodulation element may comprise a plurality of electrodes coupled to a loop. The neuromodulation element may comprise a plurality of electrodes coupled to a corkscrew. At least one of the plurality of electrodes may comprise a triangular base including a tip configured to be pushed into the vessel wall. At least one electrode may comprise a plurality of electrodes on different sides of the tip of the triangular base. The catheter may further comprise an expansion element. The neuromodulation element may be positioned on the expansion element.

[0022] In some embodiments, a method of treating a subject comprises stimulating a particular electrode of a neuromodulation device and providing the results to an interface computer, the interface computer being configured to perform real-time data analysis and overlay the response to the stimulation on an anatomical image, including marking the location having the maximum response, and performing ablation at those locations.

[0023] The method may further comprise, after ablation, verifying the effectiveness of the ablation by restimulation. The method may further comprise performing additional ablation if the ablation was not effective. The method may comprise repeating the verification and additional ablation until the ablation is effective.

[0024] In some embodiments, a method of treating a subject presenting with refractory arrhythmia comprises stabilizing the subject, evaluating the cause of the refractory arrhythmia, evaluating whether sympathetic drive is causing the refractory arrhythmia, adjusting the evaluation of the arrhythmia focus if sympathetic drive is not causing the refractory arrhythmia, and performing a subclavian crush ablation procedure if sympathetic drive is causing the refractory arrhythmia.

[0025] The step of evaluating whether sympathetic drive is causing the refractory arrhythmia may comprise injecting an epidural anesthetic. The step of evaluating whether sympathetic drive is causing the refractory arrhythmia may comprise turning off the subject's implantable defibrillator.

[0026] In some embodiments, a method of treating a heart disease in a subject comprises positioning a neuromodulation element within the subject's subclavian artery and applying ablation energy to a dorsal subclavian crush and / or a ventral subclavian crush.

[0027] The step of applying ablation energy may include the step of selectively applying ablation energy. The step of selectively applying ablation energy may include the step of non-therapeutically stimulating to determine the position of the dorsal subclavian fossa and / or the ventral subclavian fossa. The step of selectively applying ablation energy may include the step of imaging the subclavian artery to determine the likely positions of the dorsal subclavian fossa and / or the ventral subclavian fossa. The step of applying ablation energy includes the step of applying ablation energy over the entire circumference of the subclavian artery.

[0028] In some embodiments, a method of treating a subject includes positioning a neuromodulation element of a catheter within the subject's subclavian artery. The neuromodulation element may comprise an array of electrodes circumferentially spaced along the circumference of the catheter and longitudinally spaced along the length of the catheter. The method includes stimulating a particular one of the array of electrodes and providing the results to an interface computer configured to overlay a response to the stimulation onto an anatomical image by performing real-time data analysis and marking the position having the maximum response. The method may include performing ablation at those positions.

[0029] The method may further include re-stimulating after ablation to verify the effectiveness of the ablation. The method may include performing further ablation if the ablation was not effective. The method may include repeatedly re-stimulating and performing further ablation until it is verified that the ablation is effective. The neuromodulation element may be positioned on an expansion element. The method may include expanding the expansion element by an amount that expands the subclavian artery.

[0030] In some embodiments, a catheter for treating a heart disease in a subject may include an elongate element configured to be positioned in at least one of the left or right subclavian artery. The distal portion of the elongate element may comprise a neuromodulation element configured to stimulate at least one of the dorsal subclavian fossa or the ventral subclavian fossa and configured to ablate at least one of the dorsal subclavian fossa or the ventral subclavian fossa. The neuromodulation element of the catheter is configured to be positioned within the subject's subclavian artery. The neuromodulation element may comprise an array of electrodes circumferentially spaced along the circumference of the catheter and longitudinally spaced along the length of the catheter.

[0031] The neuromodulation element may comprise a plurality of electrodes coupled to a plurality of struts. The neuromodulation element may comprise a plurality of electrodes coupled to a loop. The neuromodulation element may comprise a plurality of electrodes coupled to a corkscrew. At least one of the plurality of electrodes may comprise a triangular base including a tip configured to be pressed into the vessel wall. The catheter may comprise an expansion element. The expansion element may comprise a balloon.

[0032] In some embodiments, a method of treating a heart disease in a subject comprises the steps of percutaneously introducing a catheter into the subject's vasculature, the catheter comprising a neuromodulation element; positioning the neuromodulation element within the subject's subclavian artery; electrically stimulating at least one of the dorsal subclavian fossa or the ventral subclavian fossa; confirming the stimulation of the dorsal subclavian fossa and / or the ventral subclavian fossa by monitoring a biomarker, the biomarker including at least one of an inotropic biomarker, a dromotropic biomarker, a lusitropic biomarker, or an inflammatory biomarker; and after confirming the stimulation of the dorsal subclavian fossa and / or the ventral subclavian fossa, applying ablation energy to the dorsal subclavian fossa and / or the ventral subclavian fossa.

[0033] This method may further include, after applying ablation energy, restimulating the subclavian fossa and, if a biomarker confirms the stimulation, applying additional ablation energy to the subclavian fossa. This method may include repeating the restimulation and applying additional ablation energy until the biomarker no longer confirms the stimulation. The biomarker may include at least one of generated pressure (dP / dt), arterial blood pressure (systolic, diastolic, mean), change in pulse pressure, increase in systemic blood pressure, or increase in left ventricular generated pressure (dP / dt). The biomarker may include at least one of a change in heart rate (R_R or Q_Q interval on surface ECG), an increase in heart rate (shortened R-R interval), or a change in the basic cycle length on an intracardiac electrocardiogram. The biomarker may include a conduction change biomarker. The catheter may include a balloon, and the neuromodulation element may be positioned on the balloon. This method may include expanding the balloon catheter by an amount that dilates the subject's vasculature.

[0034] In some embodiments, a method of treating a heart disease in a subject includes positioning a neuromodulation element positioned on an expansion element within the subject's subclavian artery, expanding the expansion element, electrically stimulating at least one of a dorsal subclavian fossa or a ventral subclavian fossa, confirming the stimulation of the dorsal subclavian fossa and / or the ventral subclavian fossa by monitoring cardiac parameters, and after confirming the stimulation of the dorsal subclavian fossa and / or the ventral subclavian fossa, applying ablation energy to the dorsal subclavian fossa and / or the ventral subclavian fossa.

[0035] The ablation energy may include radiofrequency ablation energy. The ablation energy may include cryoablation energy. This method includes applying electrical stimulation using a combination of electrodes of the neuromodulation element, and the step of applying ablation energy may include using the same combination of electrodes of the neuromodulation element. The heart disease may include atrial fibrillation. The heart disease may include refractory arrhythmia.

[0036] In some embodiments, a catheter for treating a heart disease in a subject comprises an elongate element configured to be positioned in at least one of the left subclavian artery or the right subclavian artery, a distal portion of the elongate element comprising an expansion element and a neuromodulation element positioned on the expansion element and configured to stimulate at least one of the dorsal subclavian snare or the ventral subclavian snare and to cauterize at least one of the dorsal subclavian snare or the ventral subclavian snare, the neuromodulation element of the catheter being positioned within the subclavian artery of the subject, the neuromodulation element comprising an array of electrodes circumferentially spaced along the circumference of the catheter and longitudinally spaced along the length of the catheter.

[0037] The neuromodulation element may comprise a plurality of electrodes coupled to a plurality of struts. The neuromodulation element may comprise a plurality of electrodes coupled to a loop. At least one of the plurality of electrodes may comprise a triangular base including a tip configured to be pushed into the vessel wall.

[0038] In some embodiments, a treatment system comprises, consists essentially of, or consists of one or more of the features described herein.

[0039] In some embodiments, a tissue treatment system comprises, consists essentially of, or consists of one or more of the features described herein.

[0040] In some embodiments, a method of cauterizing a subclavian snare comprises, consists essentially of, or consists of one or more of the features described herein.

[0041] The following drawings are for illustrative purposes only and show non-limiting embodiments. Features found in different drawings may be combined in some embodiments. BRIEF DESCRIPTION OF THE DRAWINGS

[0042]

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DETAILED DESCRIPTION OF THE INVENTION

[0043] Most arrhythmic events are caused by myocardial infarction (MI) due to coronary artery disease, but heart failure from any cause provides a potent predisposition to developing arrhythmias. Treatments for myocardial infarction, such as primary angioplasty and stent placement, may be effective in restoring blood flow but can result in significant residual myocardial damage. A common finding among patients with myocardial damage is enhanced sympathetic signaling that serves to increase the stress on the cardiovascular system. This harmful cascade induces heart failure and arrhythmias. Beta blockers can mitigate the effects of increased sympathetic tone and are a mainstay of arrhythmia prevention and an important treatment for heart failure. However, these agents are of incomplete efficacy and have significant systemic side effects at the high doses required to achieve a therapeutic effect.

[0044] An implantable cardioverter defibrillator (ICD) can be implanted to suppress sudden cardiac death caused by ventricular arrhythmias. These devices monitor the heart rate rhythm and provide direct electrical defibrillation when tachyarrhythmias are detected, thereby providing an assured path as a reactive therapy. However, ICDs are associated with iatrogenic mortality, patients have their cardiac activity interrupted by replacement of the generator and leads, device infections that threaten life are common, inappropriate shocks with strong pain occur frequently (1 in 20 patients), and in some cases skin burns may occur. The overwhelming majority of ICDs are implanted as primary prevention devices (for example, in case of arrhythmias), but in these patients, when the arrhythmia risk is moderately reduced, the risk / benefit profile of the ICD is reversed. Multiple clinical trials and meta-analyses have shown that inappropriate shocks by ICDs are frequent. Most patients have an ICD implanted for primary prevention, but the algorithm fails to accurately predict arrhythmias, and as a result, patients receive inappropriate shocks (shocks applied when it is not appropriate or when there is no life-threatening arrhythmia). As shocks accumulate, they lead to further electrical instability in the heart that causes more arrhythmias, and there is also emerging literature evidence demonstrating that inappropriate shocks can lead to hospitalization for symptoms ranging from extreme discomfort (from pain to skin burns) to death. In these patients who present with arrhythmias despite ICD implantation, thoracic epidural analgesia is administered for pain relief and to classify the patients who are most likely to undergo stellate ganglionectomy. Stellate ganglionectomy or stellate ganglion central denervation procedures can address enhanced sympathetic signaling (caused by heart disease) that originates from the heart and reaches the brainstem region via extracardiac, intrathoracic neural pathways (such as the paravertebral sympathetic chain and its associated nerves (e.g., the subclavian snare)) and returns to the heart via direct neural pathways, providing a tangible biological target and reducing the progression of life-threatening arrhythmias and heart failure. The limited treatment strategies available for early heart failure and secondary arrhythmias offer few options to many patients while the disease progresses.Catheter ablation of ventricular arrhythmias is effective in some patients but is a very complex procedure and does not correct the underlying lesion. In many patients who are considered at risk for ventricular arrhythmias, pharmacologic titration can be performed stepwise, with or without using a device (ICD) implant, followed by ICD implantation.

[0045] In the case of atrial arrhythmias, atrial fibrillation, the most common arrhythmia, is caused by an imbalance in innervation to the atrial heterotopic structure (composed of the contact of cardiac and vascular tissues with adipose bodies scattered) that promotes arrhythmias. Current treatment strategies are electrophysiological procedures that directly map the most heterogeneous regions of the atria and disconnect / electrically isolate these regions from the rest of the atria. All of these procedures target intracardiac structures that cannot completely eliminate the arrhythmia. In a significant proportion of patients, the arrhythmia recurs and experimental procedures such as adipose body ablation or cardiac plexus ablation are performed on the surface of the heart. These intracardiac structures receive innervation from extracardiac sympathetic and parasympathetic pathways, and the sympathetic nerves create significant heterogeneity that promotes atrial fibrillation. The surgeon performing cardiac plexus ablation may not always be able to recognize that ablation of all nerve tissue has been successful during the procedure.

[0046] The nexus points for the supranormal control of cardiac sympathetic nerve signaling are derived from the thoracic sympathetic ganglion at the upper thoracic level. In the most severe cases of cardiac arrhythmias, enhanced sympathetic nerve signaling is the major cause of arrhythmia induction in both the atria and ventricles. The enhancement or attenuation of sympathetic nerve signaling plays an important role in regulating the inotropic, dromotropic, lusitropic, and chronotropic properties of the heart. In addition, the regulation of cardiac excitatory recovery intervals or refractory periods has been duly shown in both preclinical trials and human studies in the literature. As a result, cardiac disease conditions such as those in patients with long QT syndrome with underlying sympathetic overdrive are considered candidates for surgical removal of the stellate ganglion (stellate ganglionectomy or central denervation of the stellate ganglion). To treat life-threatening arrhythmias, invasive stellate ganglionectomy or central denervation of the stellate ganglion (cardiac denervation by resection of the stellate ganglion) has been performed by cardiac surgeons with good results. For example, these procedures can reduce the arrhythmia burden in patients with long QT syndrome. In patients presenting with refractory ventricular arrhythmias, the only effective treatment was to perform thoracic epidural anesthesia to block sympathetic connections and then surgically remove the stellate ganglion using video-assisted thoracoscopy. However, these stellate ganglionectomy or stellate ganglion central denervation procedures are highly invasive, require general anesthesia as well as highly specialized surgical skills and / or robotic equipment, and are associated with an increased risk of treatment in the patient population with advanced heart disease. Despite technological advancements such as video-assisted thoracoscopy, only selected surgeons perform this procedure at certain facilities, and currently, this procedure is only performed on refractory patients as a "last resort" therapy.

[0047] Stellate ganglionectomy may be effective in reducing arrhythmia to more than 90%, but patients suffer from a very wide variety of postoperative complications. The surgeon needs to remove the stellate ganglion by visual inspection, which requires great care as the stellate ganglion controls sympathetic innervation to the arm, shoulder, and upper back. Since there are no clear identifiable stumps during surgery that can be confirmed to understand the relationship between axons, pectoral muscle fibers, and myocardial fibers, the surgeon performs stellate ganglionectomy by open surgery. As a result of this very subjective procedure based on this experience, many patients present signs of nerve branch ligation injury, which causes increased pain sensation (hyperalgesia) and asymmetric sweating motor function (hyperhidrosis / anhidrosis) of the affected upper limb. Furthermore, the required robotic surgery is a very complex attempt, driving up medical costs and reducing access.

[0048] There can be an important interaction between the heart and the autonomic nervous system (ANS) in the pathophysiology of arrhythmia. Disorders of the ANS have been proven to play an important role in cardiac arrhythmogenicity. The role of the ABS in the initiation and maintenance of AF is related to autonomic imbalance. The regulation of autonomic signaling is promising for the reduction (e.g., prevention) and treatment (e.g., vagus nerve stimulation clinical trials) of arrhythmia. The cardiac autonomic nervous system has a complex structure and provides many easily accessible and minimally invasive targets. The use of autonomic regulation for the treatment of AF may include potential targets for therapies such as cardiac autonomic plexus, renal denervation, stellate ganglion block, vagus nerve stimulation (e.g., low-level vagus nerve stimulation), tragus stimulation, renal denervation, spinal cord stimulation, baroreceptor activation, and cardiac sympathetic denervation. Some targets such as stellate ganglion block / stellate ganglionectomy may have off-target side effects, while other targets do not directly affect the attenuation of sympathetic signaling. The anesthetic block of the stellate ganglion is reversible, and patients experience signs of nerve branch ligation injury after several months, and the anesthetic block of the stellate ganglion is provided only as a treatment for symptom relief in extreme cases. In paroxysmal atrial tachycardia or atrial fibrillation (AT / AF) in animal models, an increase in exogenous cardiac nerve activity is clearly shown in the left stellate ganglion. Stimulation of the stellate ganglion increases sinus rhythm and increases the predisposition to atrial arrhythmia. Unilateral temporary stellate ganglion block prolongs atrial effective refractory period (ERP), reduces AF inducibility, and / or shortens AF duration. Renal denervation can significantly increase freedom from AF compared to standard pulmonary vein isolation alone.

[0049] Therapies that selectively target cardiac sympathetic innervation using percutaneous intravascular devices can give users (e.g., cardiac surgeons) the ability to provide effective, safe, and permanent neuromodulatory treatment for arrhythmia-prone subjects, and in some cases as a primary catheterization procedure. The synergistic effect between pathophysiological mechanisms indicates that this may be useful as a new treatment angle for heart failure patients, especially those who cannot tolerate beta blockade.

[0050] Cardiac dysfunction increases sensory signal transmission to the brainstem, thereby upregulating the compensatory inotropic mechanism, which can be pathogenic in the early stages of the disease. In the case of ischemic heart disease leading to reduced pump function, cardiac sympathetic nerve signaling is enhanced in the early stages to maintain cardiac output and adequate oxygenation of the extremities. As the disease progresses, these sympathetic responses are amplified, thereby inducing cardiac pathological characteristics. These pathological characteristics induce the following reactions, namely, replacement fibrosis of the myocardium and an increase in sympathetic nerves sprouting in the heart. First, there is a maladaptive response to stress, although sympathetic nerve sprouting is initially an adaptive response and becomes more heterogeneous over time. The fibrotic myocardium acts as a detour, and sympathetic nerve sprouting acts as a speed pathway. This is an ideal substrate for the progression of cardiac arrhythmias. The cardiac ANS has a significant impact on cardiac electrophysiological properties and arrhythmogenicity. This impact is diverse, and different types of arrhythmias have different autonomic triggers. As knowledge increases in the identification of those specific triggers, appropriate treatment modalities can be applied via neuromodulation accordingly.

[0051] Figure 1 is a schematic diagram showing exemplary innervation of the sympathetic pathway to the heart. The subclavian artery 102 is surrounded by the dorsal subclavian snare 104 and the ventral subclavian snare 106. The subclavian snares 104, 106 are nerve cords that form a loop around the subclavian artery and connect the inferior cervical ganglion and the middle cervical ganglion (also called the C8 and T1 levels of the paravertebral sympathetic chain). The vagus nerve 108 is also shown. Arrow 110 indicates that the illustrated nerves extend toward the heart. The C8 / T1 level of the sympathetic chain (stellate ganglion) is predominantly fused or slightly separated in most human subjects and provides innervation to the muscles of the shoulder, arm, and heart. The subclavian snares 104, 106 specify the sympathetic communication pathway that exclusively distributes nerves between the heart and serves to directly connect the heart to the T1 segment. The pathway of the sympathetic communication to the heart occurs through two discrete nerve pathways, i.e., via the stellate ganglion that receives sympathetic input from the middle cervical ganglion via the dorsal subclavian snare 104 and the ventral subclavian snare 106. These two nerves pass above and below the subclavian artery 102 and transmit within the nerve the sympathetic efferent (dynamic) neurons that increase heart rate (chronotropy), contractility (inotropy), relaxation (myocardial relaxation), and conduction velocity (dromotropy). The origin of the efferent fibers passing through the subclavian snare is the T1 to T4 thoracic sympathetic chain ganglia, which converge toward T1 as they proceed from the anterior branches of the spine to T4, T3, T2, T1, and then converge to the middle cervical ganglion (C8 - T1) through the subclavian snares 104, 106 and then proceed to the heart. The afferent fibers appear to bypass the subclavian snares 104, 106 and proceed directly to the C8 ganglion. Surgical denervation for the treatment of arrhythmias depends on removing from the entire T4 to one - half of the C8 / T1 complex (removing four ganglion cell bodies and their interganglionic ducts without affecting the subclavian snares 104, 106 due to the procedural complexity in operating around the subclavian artery 102).

[0052] The cardiac-related preganglionic fibers ascending from the thoracic cord traverse the paravertebral chain through the T1 - T2 region. Some fibers synapse with postganglionic neurons in the stellate ganglion, and other fibers project through the subclavian snares 104, 106 to more distal intrathoracic ganglia (middle cervical ganglion, mediastinal ganglion, and intrinsic ganglia) and mix with sympathetic vagal fibers. Thus, the subclavian snares 104, 106 and the T1 - T2 region of the paravertebral chain are nexus points for sympathetic communication to the afferent projections of the heart. Based on the examination of structure and function, both sites are potential targets for cardiac neuromodulation.

[0053] Preliminary experiments in dogs and more recently in pigs have shown that stimulation of the subclavian snares 104, 106 reproducibly increases heart rate, contractility, and conduction velocity and decreases relaxation. Denervation of the subclavian snares 104, 106 followed by stimulation of the stellate ganglion at the proximal end (C8) does not change the cardiac index, confirming the nodal intervention point of cardiac sympathetic communication. Due to the close anatomical correlation of size and biological structure, the subclavian snares 104, 106 can be regulated via percutaneous catheterization of the subclavian artery 102. Regulation of the subclavian snares 104, 106 reproducibly increases heart rate and contractility and, on the other hand, increases conduction velocity. Denervation of the subclavian snares 104, 106 followed by stimulation of the stellate ganglion does not change the cardiac index, confirming the nodal intervention point of cardiac sympathetic communication.

[0054] The subclavian snares 104, 106 can be targeted using percutaneous catheterization of the subclavian artery, mapping the nerves along the length of the subclavian artery 102, detecting the presence of the nerves 104, 106, and selectively ablating the nerves 104, 106 through the subclavian artery. This is a cost - effective alternative to robotic surgery.

[0055] Figure 2A is a schematic diagram of an exemplary method for adjusting nerves 204, 206 around the left subclavian artery 202. Figure 2A shows additional biological structures of FIG. 1, including the aorta 222 and its branch vessels. The brachiocephalic artery branches from the aorta 222 into the right subclavian artery 203 that supplies blood to the right arm and the right common carotid artery 225 that supplies blood to the cerebrovascular system. The left common carotid artery 224 that supplies blood to the cerebrovascular system branches directly from the aorta 222. The left subclavian artery 202 that supplies blood to the left arm also branches directly from the aorta 222. The aorta 222 descends toward the lower body, branches into the left renal artery 226 and the right renal artery 227, and then branches into the left iliac artery 228 and the right iliac artery 229. The left subclavian artery 202 is surrounded by the dorsal subclavian snare 204 and the ventral subclavian snare 206. The right subclavian artery 203 is surrounded by the dorsal subclavian snare 205 and the ventral subclavian snare 207. The vagus nerve 208 is also shown.

[0056] Figure 2A schematically shows a catheter 230 positioned to perform neuromodulation of nerves 204, 206. As shown in Figure 2A, the catheter 230 is guided from an access site in the lower body, such as the right femoral artery, to a position within the left subclavian artery 202 (the left subclavian artery 202 surrounded by the dorsal subclavian snare 204 and the ventral subclavian snare 206). The catheter 230 can be sent above the guide wire, through the guide catheter, directly guided, and / or guided by other guiding methods. Other vascular access sites are also possible. For example, access can be made to the right femoral artery, left or right radial access, carotid artery, etc., and then the catheter 230 can be sent through such a vascular system to the left subclavian artery 202. In an additional example, the venous vascular system can be accessed and the catheter 230 can cross from the venous vascular system to the arterial vascular system (e.g., through a patent foramen ovale, dialysis fistula, etc.).

[0057] The additional portion of the catheter 230 includes a neuromodulation element 232. For example, the neuromodulation element 232 can include one or more of the following means for modulation, namely, a cryogenic element, a radio frequency element, an ultrasonic element, a laser element, a heat delivery element, a drug delivery element, a microwave element, an electrical element, a pressure element, an acoustic element, a vibration element, a mechanical elongation element, etc.

[0058] After the neuromodulation element 232 is positioned within the left subclavian artery 202, a signal can be applied to the neuromodulation element (e.g., using an appropriate energy level for the safety of stimulation and treatment) to identify the nerves of the subclavian snares 204, 206 for non-therapeutic subclavian snare (SAS) stimulation. In some embodiments, for example, the stimulation is taught not to be treated because it causes side effects such as inducing arrhythmias. Before, during, and / or after SAS, inotropism, chronotropism, and / or dromotropism can be measured to determine whether the subclavian snares 204, 206 have been stimulated, for example, compared to baseline (resting), vagus nerve stimulation, and / or induction of AF. SAS can be determined by cardiac hemodynamics, electrophysiological measurements, and / or inducible atrial tachyarrhythmias.

[0059] In some embodiments, additionally or alternatively, the vagus nerve 108 can be stimulated by vagus nerve stimulation (VNS). For example, an electrode catheter can be positioned within the internal jugular vein (IJV) to deliver energy to the vagus nerve 108 (e.g., at an amplitude of 0.5 V / kg to 1 V / kg, a frequency of 30 Hz, and a pulse width of 50 μs for 30 seconds). The output threshold can be determined to achieve a 10% to 20% reduction in heart rate. An arterial trace can be recorded to determine the arterial pressure waveform.

[0060] Skin electrodes can be placed to monitor diaphragmatic electromyogram before, during, and / or after the procedure. The procedure can be performed under general anesthesia in a sterile field, and appropriate therapeutic agents such as heparin can be administered as needed. Percutaneous access can be made to sites such as the femoral vein, femoral artery, or radial artery under ultrasound guidance. Arterial access is not always performed for AF ablation. In some embodiments, an arterial pathway can be placed to monitor arterial pressure.

[0061] For baseline measurements before SAS / VNS, for example, baseline arterial trace, electrocardiogram, heart rate, right and / or left atrial ERP, difference in ERP between the left and right atria (dERP), heart rate, interatrial conduction time (IACT), and / or unipolar electrogram at baseline, unipolar electrogram during steady-state right ventricular (RV) pacing at a heart rate 20% - 30% above the basal heart rate, and / or a recovery curve with RV steady-state pacing and apical diastolic interval (S1 - S2) can be included.

[0062] Measurements during and / or after SAS / VNS can include, for example, arterial trace blood pressure changes, whether AF is induced, whether arrhythmias are induced, whether changes in cardiac cycle length are induced, recovery curves, right and / or left atrial ERP, dERP, heart rate, IACT, and / or unipolar electrograms from a multipolar catheter under steady-state RV pacing and / or unipolar electrograms from a multipolar catheter with an apical diastolic interval after steady-state RV pacing. The parameters to be monitored can be changed based on the nerves. For example, the cardiac parameters monitored when stimulating the dorsal subclavian snare 204 may be different from the cardiac parameters monitored when stimulating the ventral subclavian snare 206. The reason is that the regulation of those nerves can be expected to have different effects on the heart. Additionally or alternatively, the parameters to be monitored can vary based on the side of the subject. For example, the cardiac parameters monitored when stimulating the left dorsal subclavian snare 204 may be different from the cardiac parameters monitored when stimulating the right dorsal subclavian snare 205 (Figure 2B). The reason is that the regulation of those nerves can be expected to have different effects on the heart. The cardiac parameters monitored when stimulating each subclavian snare can be adjusted. In some embodiments, the cardiac parameters monitored when stimulating all subclavian snares are the same. In some embodiments, the cardiac parameters monitored when stimulating some of the subclavian snares are the same, and the cardiac parameters monitored when stimulating other subclavian snares are different. For example, the cardiac parameters monitored when stimulating the left and right dorsal subclavian snares can be the same, and the cardiac parameters monitored when stimulating the left and right ventral subclavian snares can be the same, but the cardiac parameters monitored when stimulating the right dorsal subclavian snare can be different from the cardiac parameters monitored when stimulating the left ventral subclavian snare. In another example, the cardiac parameters monitored when stimulating the left ventral subclavian snare can be the same, and the cardiac parameters monitored when stimulating the right dorsal subclavian snare can be the same, but the cardiac parameters monitored when stimulating the left ventral subclavian snare can be different from the cardiac parameters monitored when stimulating the right dorsal subclavian snare.

[0063] Referring again to FIG. 2A, after the neuromodulation element 232 is positioned within the left subclavian artery 202, non-therapeutic stimulation can be applied to identify the dorsal subclavian snare 204 and / or the ventral subclavian snare 206 by achieving a targeted increase in cardiac function. For example, an increase in heart rate (e.g., an increase from about 5% to about 30% (e.g., about 5%, about 10%, about 15%, about 20%, about 25%, about 30%, ranges between such values, etc.)) can indicate that the sympathetic nervous system is being stimulated. In another example, an increase in cardiac parameters (e.g., an increase in heart rate (shortening of the R-R interval), an increase in systemic blood pressure, an improvement in left ventricular contractility, ventricular generated pressure (dP / dt), shortening of the P-R interval and the Q-T interval, shortening of the effective refractory period / recovery interval of the atria and / or ventricles, induction of atrial tachyarrhythmia or ventricular tachyarrhythmia that can be terminated by electrical defibrillation or electrical shock, combinations thereof, etc.) can indicate that the sympathetic nervous system is being stimulated. After the subclavian snares 204, 206 are identified by non-therapeutic stimulation, the neuromodulation element 232 can be used to therapeutically ablate or denervate the subclavian snares 204, 206. In some embodiments, the neuromodulation element 232 includes a plurality of modalities (e.g., a first modality for stimulating the subclavian snares 204, 206 and a second modality for ablating the subclavian snares 204, 206). For example, the neuromodulation element 232 can include an array of electrodes configured to provide electrical stimulation and a different array of electrodes configured to perform radiofrequency ablation. For example, the neuromodulation element 232 can include an array of electrodes configured to provide electrical stimulation and a cryoablation device. In some embodiments, the neuromodulation element 232 includes a single modality (e.g., a modality configured to stimulate the subclavian snares 204, 206 based on a first set of stimulation parameters and configured to ablate the subclavian snares 204, 206 based on a second set of ablation parameters).For example, the neuromodulation element 232 can include an array of electrodes configured to provide electrical stimulation (e.g., in a bipolar mode where one or more electrodes function as cathodes and one or more electrodes function as anodes) and configured to perform radiofrequency ablation (e.g., using one or more electrodes in a monopolar mode). Ablation, as opposed to mere stimulation of the subclavian snares 204, 206, can provide long-term effects. For clarity, the ablation signal is a destructive signal and is short-term irreversible (e.g., nerves may grow back years later). Ablation is selective by using a percutaneous catheter 230 and is not a surgical stellate ganglionectomy. The ablation described herein preferably does not target the stellate ganglion in some embodiments. The ablation is preferably performed from within the subclavian artery and is not, for example, due to access to the paravertebral groove.

[0064] The dorsal subclavian snare 204 and the ventral subclavian snare 206 can be stimulated and / or ablated separately. A possible advantage of this technique is that it enables nerve mapping and discrete identification, and changes in biomarkers can be overlaid on anatomical mapping such as CARTO mapping and visualized. In some embodiments, less than 360° of tissue around the left subclavian artery is ablated. This is in contrast to, for example, renal denervation aimed at completely ablating all of the tissue around the renal artery and stellate ganglionectomy that removes all of the nerves around the subclavian artery. More specific ablation of the dorsal subclavian snare 204 and / or the ventral subclavian snare 206 can reduce side effects (sensory disturbances such as hyperalgesia), and / or can target cardiac distributive nerves and compare hyperhidrosis to more complete ablation by avoiding other tissues associated with the head, neck, and other body parts. In some embodiments, the dorsal subclavian snare 204 and the ventral subclavian snare 206 can be stimulated at the same time or simultaneously, and / or can be ablated at the same time or simultaneously. For example, in some embodiments, the dorsal subclavian snare 204 and the ventral subclavian snare 206 are stimulated separately but ablated at the same time (or part of the same time) or simultaneously. A possible advantage of this technique is that it enables nerve mapping and discrete identification, but simultaneous ablation of the dorsal subclavian snare 204 and the ventral subclavian snare 206 is used to shorten the treatment time.

[0065] Figure 2B is a schematic diagram of an exemplary method for regulating nerves 205, 207 around the right subclavian artery 203. This method can be the same catheter or a different catheter as the catheter shown in and described with respect to Figure 2A, catheter 230, which is positioned within the right subclavian artery 203 (e.g., a position within the right subclavian artery 203 surrounded by the dorsal subclavian snare 204 and the ventral subclavian snare 206), except that it is similar or the same as the method for regulating nerves 204, 206. As shown in Figure 2B, catheter 230 is guided from an access site in the lower back, such as the right femoral artery, to the right subclavian artery 203. Catheter 230 can be advanced over a guidewire, through a guiding catheter, and / or guided by other guiding methods. In some embodiments where the same catheter 230 is used for treatment around both the left subclavian artery 202 and the right subclavian artery 203, catheter 230 can be repositioned without withdrawing the catheter 230 from the body. For example, a first guidewire can be guided to the left subclavian artery 202, and catheter 230 can be advanced over the first guidewire. The first guidewire can remain at a predetermined position around the left subclavian artery 202 during treatment. After treatment around the left subclavian artery 202 is completed, the first guidewire can be advanced and guided to the right subclavian artery 203. When the first guidewire is fully retracted, a first guidewire or a second guidewire can be advanced through catheter 230. Catheter 230 can be advanced above the repositioned first guidewire or second guidewire within the right subclavian artery 203. The right subclavian artery 203 can be treated before the left subclavian artery 202, or the left subclavian artery 202 can be treated before the right subclavian artery 203.

[0066] When two catheters 230 are used, treatment of the right subclavian artery 203 and the left subclavian artery 202 can be at least partially simultaneous. For example, a first catheter 230 can extend from a right radial access point to the right subclavian artery 203, and a second catheter 230 can extend from a left radial access point to the left subclavian artery 202. The first catheter and the second catheter can be the same or different (e.g., having different sizes, different neuromodulation elements 232, etc.).

[0067] In some embodiments, subclavian snares ablation is performed on only one side (only the left dorsal subclavian snare 204 and / or the left ventral subclavian snare 206, or only the right dorsal subclavian snare 205 and / or the right ventral subclavian snare 207). In some embodiments, subclavian snares ablation is performed on both sides (the left dorsal subclavian snare 204 and / or the left ventral subclavian snare 206, and the right dorsal subclavian snare 205 and / or the right ventral subclavian snare 207). This provides at least four degrees of freedom for adjusting the treatment for a particular outcome and / or subject. Similar to the left subclavian artery 202, in some embodiments, the right dorsal subclavian snare 205 and the right ventral subclavian snare 207 can be stimulated at the same time or simultaneously, and / or ablated at the same time or simultaneously. For example, in some embodiments, the right dorsal subclavian snare 205 and the right ventral subclavian snare 207 are stimulated separately, but can be ablated at the same time (or part of the same time) or simultaneously. A possible advantage of this approach is that it allows for nerve mapping and discrete identification, while simultaneous ablation of the right dorsal subclavian snare 205 and the right ventral subclavian snare 207 is used to shorten the treatment time.

[0068] FIG. 3 is a schematic diagram of an exemplary system 300 for modulating a nerve. The system 300 includes a catheter 230 that includes a nerve modulation element 232 and a signal generator 302. The signal generator 302 may be an external signal generator, an internal signal generator (e.g., the signal generator 302 may be powered externally via inductive coupling), or a signal generator having components divided between internal and external. The signal generator 302 may include wired or wireless communication (e.g., wired or wireless communication configured to communicate with the nerve modulation element 232, a hospital system, a computer, a telephone, or a handheld device such as a tablet). The system 300 may also include a control system / controller 301 that can include a processor for controlling one or more operations of the system 300 as described herein, a display 303 for displaying information as described herein, and a computer interface 305 that can be used to input information to the control system / controller 301.

[0069] When the neuromodulation element 232 includes an electrode, the signal generator 302 can generate an electrical signal configured for non-therapeutic SAS. For example, non-therapeutic SAS can include monopolar, bipolar, or multipolar stimulation using a pulse width of about 0.05 milliseconds (ms) to about 3 ms (e.g., about 0.05 ms, about 0.1 ms, about 0.25 ms, about 0.5 ms, about 0.75 ms, about 1 ms, about 1.5 ms, about 2 ms, about 2.5 ms, about 3 ms, ranges between such values, etc.), a frequency of about 0.1 Hertz (Hz) to about 150 Hz (e.g., about 0.1 Hz, about 1 Hz, about 5 Hz, about 10 Hz, about 25 Hz, about 50 Hz, about 75 Hz, about 100 Hz, about 125 Hz, about 150 Hz, ranges between such values, etc.), and about 0.1 milliamperes (mA) to about 30 mA (e.g., about 0.1 mA, about 1 mA, about 2.5 mA, about 5 mA, about 10 mA, about 15 mA, about 20 mA, about 25 mA, about 30 mA, ranges between such values, etc.). The signal can include charge balanced waves, symmetric waves, and / or asymmetric waves having a duration based on a capacitance coupled to ground, (e.g., a 2:1 recharge pulse width or using an active first phase with a passive recharge phase). The duty cycle can depend on hysteresis or the cardiac system (e.g., R-R shortening induced by stimulation). The duration of the stimulation can be less than 1 second or greater than 30 seconds. The recovery time can be in seconds or minutes, after which the stimulation can be repeated as needed.

[0070] Additionally or alternatively, signal generator 302 can generate signals configured for ablation. Denervation of tissue is performed at temperatures above 50°C. For ablation of the subclavian fossa, various modalities can be used, including, for example, radio frequency (RF), high-power short-duration RF (HPSD RF), cryoablation (CB), microwave, high-intensity focused ultrasound (HIFU), electroporation, combinations thereof, and the like. The RF energy for performing RF ablation can be generated by using power in the range of about 10 watts (W) to about 60 W (for example, about 10 W, about 20 W, about 30 W, about 40 W, about 50 W, about 60 W, ranges between such values, etc.) over a specific time window of about 15 s to about 90 s (for example, about 15 s, about 20 s, about 30 s, about 40 s, about 50 s, about 60 s, about 75 s, about 90 s, ranges between such values, etc.) at frequencies of about 50 (kilohertz) kHz to about 1,500 kHz (for example, about 500 kHz, about 100 kHz, about 250 kHz, about 350 kHz, about 400 kHz, about 450 kHz, about 500 kHz, about 600 kHz, about 750 kHz, about 1,000 kHz, about 1,500 kHz, ranges between such values, etc.). Most of the lesion occurs as a result of conduction heat, which is inversely proportional to the distance from the tip of the electrode. HPSD RF uses higher power and shorter durations. For example, HPSD RF can use power in the range of about 50 W to about 90 W (for example, about 50 W, about 90 W, ranges between such values, etc.) and a duration of about 4 s to about 15 s (for example, about 4 s, about 15 s, ranges between such values, etc.). The principle of high-power short-duration ablation is to change the balance between resistive energy transfer and conductive energy transfer and to strive to improve the durability of tissue damage. Before RF ablation was developed, direct current or DC ablation mainly caused cell damage by electroporation or thermal injury. Electroporation can be applied by applying energy higher than about 200 joules (J) over several milliseconds. CB involves three phases of tissue damage. During CB, a first phase occurs, which is called the freeze-thaw phase. When the temperature drops below -15°C, microscopic extracellular freezing occurs, and then when the temperature drops below 40°C, intracellular freezing occurs, resulting in local tissue damage.When thawing occurs, melting of ice crystals with microthrombi and platelet aggregation takes place. Subsequently, a hemorrhage-inflammation phase with local tissue inflammation and edema disease occurs, and finally, a replacement fibrosis phase occurs, forming a fibrous scar. The signal generator can accommodate all of these settings and timings necessary for complete ablation and denervation of the subclavian snare. CB can be used within the subclavian artery to ablate the subclavian snare by using tissue cooling and the Joule-Thomson effect and circulating a noble gas such as argon or helium. A cryoprobe can be used while circulating a cryogen.

[0071] Figure 4 is a schematic diagram of an exemplary nerve modulation element 400. The nerve modulation element 400 is positioned at the distal portion of a catheter 402. The catheter 402 may also be referred to as an elongate element. The nerve modulation element 400 comprises a plurality of struts 404 and a plurality of electrodes 406 coupled to the struts 404. The term strut should not be limited to the material remaining after cutting from a tube and may include woven filaments, strips of joined material (such as at proximal and distal ends), tubular elements, combinations thereof, and the like. The electrodes 406 may be directly coupled to the struts 404 (as schematically shown in FIG. 4) or may be part of an electrode assembly coupled to the struts 404. A combination of the electrodes 406 can be used to apply electrical stimulation to the subclavian snare. A plurality of electrodes (such as shown in FIG. 4) may be referred to as an array of electrodes 406. For example, one or more of the electrodes 406 may be referred to as anodes and one or more of the electrodes 406 may be referred to as cathodes. If the electrical stimulation indicates nerve capture, the same combination of electrodes 406 can be used with different parameters.

[0072] FIG. 5 is a schematic view of another exemplary nerve modulation element 500. The nerve modulation element 500 is positioned at the distal portion of the catheter 502. The nerve modulation element 500 includes a loop 504 and a plurality of electrodes 506 coupled to the loop 504. The term loop should not be limited to circular or arcuate members and may include spiral members, partially arcuate members, combinations thereof, and the like. The electrodes 506 may be directly coupled to the loop 504 (e.g., as schematically shown in FIG. 5) or may be part of an electrode assembly coupled to the loop 504. A separate nerve modulation element may be used for the SAS prior to ablation. In some embodiments, it is possible to apply a stimulus using cryogenic energy during initial cooling, and this stimulus can be very local and short in duration. After the location of the target tissue is identified, cryogenic energy can be applied to the electrodes 506 to ablate the tissue around the loop 504.

[0073] FIG. 6 is a schematic diagram of another exemplary nerve modulation element 600. The nerve modulation element 600 is positioned at the distal portion of a catheter 602. Similar to the nerve modulation element 500, the nerve modulation element 600 includes a loop 504 and a plurality of electrodes 506, the plurality of electrodes 506 being coupled to the loop 504 and configured to apply cryogenic energy to ablate tissue surrounding the loop 504. The nerve modulation element further includes a second loop 604 and a second plurality of electrodes 606. The electrodes 606 can be directly coupled to the loop 604 (as schematically shown in FIG. 6, for example) or can be part of an electrode assembly coupled to the loop 604. A combination of the electrodes 606 can be used to apply electrical stimulation to the brachial plexus. For example, one or more of the electrodes 606 can be used as an anode and one or more of the electrodes 606 can be used as a cathode. If the electrical stimulation indicates nerve capture, a corresponding combination of the electrodes 506 can be used to ablate the nerve using cryogenic energy. The loops 504, 604 are positioned close to each other such that a short distance does not adversely affect the ablation location even if the ablation location is slightly displaced from the location of the captured nerve. In some embodiments, the distance between the loops is from about 0 mm (e.g., in contact) to about 3 mm (such as about 0 mm, about 0.5 mm, about 1 mm, about 1.5 mm, about 2 mm, about 2.5 mm, about 3 mm, ranges between such values, etc.). In some embodiments, after identifying the location of the target tissue using the loop 604, the catheter 602 is advanced distally by a known distance between the loops 504, 604, whereby the ablation electrode 506 is at the same location as the stimulation electrode 606. For example, the handle of the catheter 602 can include a slider within a channel, and the slider, when advanced distally, advances the catheter 602 and / or the nerve modulation element 600 distally by this distance.

[0074] FIG. 7 is a schematic diagram of another exemplary nerve modulation element 700. The nerve modulation element 700 is positioned at the distal portion of a catheter 702. Similar to the nerve modulation element 400, the nerve modulation element 700 includes a plurality of struts 404 and a plurality of electrodes 406, and the plurality of electrodes 406 are coupled to the struts and configured to apply SAS. Similar to the nerve modulation element 500, the nerve modulation element 700 includes a loop 504 and a plurality of electrodes 506, and the plurality of electrodes 506 are coupled to the loop 504 and configured to apply cryogenic energy to ablate tissue around the loop 504. A combination of the electrodes 406 can be used to apply electrical stimulation to the subclavian snare. If the electrical stimulation indicates nerve capture, the loop 504 can be moved longitudinally to a predetermined position and / or rotated to a predetermined position so that the cryogenic energy applied to the selected electrodes 506 can ablate the tissue. The catheter 702 can include, for example, a tether 708 configured to move the loop 504 longitudinally, thereby moving the electrodes 506 longitudinally and / or rotating to orient the loop 504, thereby orienting the electrodes 506.

[0075] FIG. 8 is a schematic diagram of another exemplary nerve modulation element 800 within a blood vessel 808 (e.g., an artery such as the subclavian artery). The nerve modulation element 800 is positioned at the distal portion of a catheter 802. The nerve modulation element 800 includes a corkscrew or helix 804 and a plurality of electrodes 806 coupled to the corkscrew 804. The electrodes 806 can be directly coupled to the corkscrew 804 (e.g., as schematically shown in FIG. 8) or can be part of an electrode assembly coupled to the corkscrew 804. The corkscrew 804 can be configured to expand the wall of the artery 808 to shorten the distance between the electrodes 806 and the target nerve within the artery 808 for additional targeting and / or isolation. A separate nerve modulation element can be used for SAS prior to ablation. After the location of the target tissue is identified, energy can be applied to the electrodes 806 to ablate the tissue around the corkscrew 804.

[0076] FIG. 9 is a schematic end view or cross-sectional view of an exemplary nerve modulation element 900 within a blood vessel 902 (e.g., an artery such as the subclavian artery). The nerve modulation element 900 may be adapted to the stimulation and / or ablation elements described herein with respect to FIGS. 4-8 or any other stimulation and / or ablation elements. The nerve modulation element 900 includes a backbone 904 and a plurality of electrodes 906 coupled to the backbone 904. The backbone 904 may include, for example, struts, loops, corkscrews, and the like. The electrode 906 includes a base 908 having a triangular shape. The shape of the base 908 is configured to push the tip of the electrode 906 into the vessel wall. The electrode 906 optionally further includes one or more electrode bumps 910 (e.g., electrode bumps 910 located on each side of the tip) for diffusing energy and / or pushing the electrode 906 into contact with tissue.

[0077] FIG. 10 is a schematic view of another exemplary nerve modulation element 1000. The nerve modulation element 1000 is positioned at the distal portion of a catheter 1002, which may also be referred to as an elongate element. The nerve modulation element 1000 may include a stimulation and / or ablation element 1004 (e.g., as described herein with respect to FIGS. 4-9) or any other stimulation and / or ablation element. For example, the catheter may include a plurality of spokes including electrode pads that cover specific radial positions (e.g., 2 o'clock to 3 o'clock, 3 o'clock to 4 o'clock, etc. with respect to the face of a clock). These radial positions can enable selective stimulation of the subclavian snare. The nerve modulation element 1000 further includes a distal protection device 1006. The distal protection device 1006 may include, for example, a filter having a distal facing port configured to receive clots, thrombi, emboli, and / or any other material that may form during SAS and / or ablation and preferably should not flow into the subject's arm or other area. The nerve modulation element 1000, like the other nerve modulation elements described herein, preferably does not occlude blood flow in some embodiments.

[0078] FIG. 11 schematically shows an end view of an exemplary catheter 1100 within a blood vessel (e.g., subclavian artery 1102). The catheter 1100 may be, for example, catheters 230, 400, 500, 600, 700, 800, 900, 1000, and 1400 (described below). In response to the surgeon adjusting the catheter control device, the central spline of the catheter 1100 opens within the subclavian artery 1102, exposing the electrode contacts 1104, and the electrode contacts 1104 radially expand and remain in a position close to the wall of the subclavian artery 1102. This close position determines the ability of the electrode contacts 1104, which were selected to determine the positions of the dorsal subclavian snare 1106 and the ventral subclavian snare 1108, to stimulate the lumen 1103 of the subclavian artery 1102. This information is then sent to a computer, which integrates the position information, stimulated channels / electrodes, biomarker analysis, and superimposes biomarker changes over the measured biological structure of the subclavian artery 1102 separated into respective regions. This overlay conveys to the surgeon the position of the maximum response to the SAS, thereby indicating where to send the ablation energy and enabling reexamination of whether ablation is successful using iterative SAS stimulation. This process can be repeated many times until successful ablation of all subclavian snares 1106, 1108 nerves is achieved and is considered sufficient by the surgeon.

[0079] FIG. 12 is a flowchart of an exemplary method 1200 for treating a subject. At box 1202, specific electrodes are stimulated to apply a non-therapeutic stimulation. At box 1204, the results are sent (e.g., automatically, manually, semi-automatically) to a computer interface. At box 1206, real-time data analysis is performed on the results. At box 1208, the computer overlays the response to the nerve stimulation on an anatomical image (e.g., a schematic, an actual ultrasound image, a combination thereof, etc.). At box 1210, the point of maximum response marked with an asterisk or some other indicia is cauterized. At box 1212, the specific electrodes are re-stimulated to test effectiveness. For example, if the stimulation continues to change the cardiac parameters, it indicates that the nerve being stimulated has not been sufficiently cauterized.

[0080] FIG. 13 is an exemplary display that may be provided by a computer in accordance with method 1200 of FIG. 12. A diagram of the subclavian artery 1302 is divided into eight radial segments 1304. The segments 1304 may be asymmetric (e.g., as shown in FIG. 13) based on, for example, the expected, known, and / or detected position of the subclavian snare. The segments 1304 may be asymmetric. FIG. 13 shows eight segments 1304, although more or fewer segments 1304 are possible (e.g., depending on the number of electrodes). The computer has placed a first asterisk 1306 at a position thought to include the dorsal subclavian snare and a second asterisk 1308 at a position thought to include the ventral subclavian snare. The percentage displayed in segment 1304 is the likelihood that that segment 1304 contains the subclavian snare to be cauterized. Additionally or alternatively, the segments 1304 may be color-coded.

[0081] Figures 11, 12, and 13 illustrate embodiments of a method and system that enable identification of subclavian snares along the circumference of the subclavian artery. In addition to identifying anterior and posterior snares along the circumference, catheter 1100 (which may be, for example, catheter 230, 400, 500, 600, 700, 800, 900, 1000) can have electrodes along both the circumference and the length of the catheter. For example, in one embodiment, 5 to 20 electrodes are used. In such a configuration, the methods and systems of Figures 11, 12, and 13 can be configured to enable identification of subclavian snares along the length of the subclavian artery. For example, in response to an adjustment by the surgeon to the catheter control device, the central spine of catheter 1100 opens within subclavian artery 1102, exposing electrode contacts 1104, which spread radially and are longitudinally distributed along the length of subclavian artery 1102. The overlays described above can include an overlay of length in addition to the circumference of subclavian artery 1102, whereby subclavian artery 1302 is divided into radial segments 1304 (e.g., 8) and longitudinal segments (e.g., 2 to 8 longitudinal segments). Such longitudinal segments can be marked, illustrated, and incorporated into an algorithm as described above. For example, in one embodiment, catheter 1100 may be, for example, catheter 230, 400, 500, 600, 700, 800, 900, 1000, 1400 (described below). In response to an adjustment by the surgeon to the catheter control device, the central spine of catheter 1100 opens within subclavian artery 1102, exposing electrode contacts 1104, which spread radially and also (as shown for catheter 1400 in Figure 14A) extend along the length of subclavian artery 1302 and remain in a position close to the wall of subclavian artery 1102. This close position determines the ability to stimulate the lumen 1103 of subclavian artery 1102 at selected electrode contacts 1104 in the radial direction and at selected electrode contacts 1104 along the length of the artery to determine the positions of dorsal subclavian snare 1106 and ventral subclavian snare 1108.This information is then sent to a computer which integrates the position information, the stimulated channels / electrodes, and biomarker analysis and overlays the measured biomarker changes over the anatomy of the measured subclavian artery 1102 that can be separated into represented regions and extend radially and along the length of the artery. This overlay communicates to the surgeon the location of the maximum response to the SAS, thereby communicating where to send the ablation energy and enabling re-examination of whether ablation is successful using iterative SAS stimulation. This process can be repeated any number of times until successful ablation of all subclavian snares 1106, 1108 nerves is achieved and is deemed sufficient by the surgeon.

[0082] As noted above, FIG. 12 is a flowchart of an exemplary method 1200 for treating a subject. At block 1202, a particular electrode is stimulated to apply a non-therapeutic stimulus. At block 1204, the results are sent (e.g., automatically, manually, semi-automatically) to a computer interface. At block 1206, real-time data analysis is performed on the results. At block 1208, the computer overlays the response to the nerve stimulation on an anatomical image (e.g., a schematic, an actual ultrasound image, a combination thereof, etc.). This anatomical image can include radial positions / segments along a plurality of positions along the length of the artery. At block 1210, the point of maximum response marked with an asterisk or some other indicia is ablated. At block 1212, the particular electrode is re-stimulated to test effectiveness. For example, if the stimulation continues to change cardiac parameters, it indicates that the nerve being stimulated is not sufficiently ablated. In one embodiment, catheters 230, 400, 500, 600, 700, 800, 900, 1000, 1400 can also be moved to different positions along the length of the artery and one or more of the actions described above can be repeated to gather additional information at different positions along the length of the artery. This process can be repeated at one or more different positions.

[0083] As noted above, FIG. 13 is an exemplary display that can be provided by a computer in accordance with method 1200 of FIG. 12. In an embodiment, for the radial positions / segments along a plurality of positions along the length of the artery, the diagram of the subclavian artery 1302 is divided into eight radial segments 1304, and additional images can be provided as in FIG. 13 to represent the radial segments at different positions along the length of the artery. In some embodiments, the length of the artery where detection is performed can extend from the subclavian artery orifice or opening of the subclavian artery to the portion of the artery that begins to bend towards the arm. In some embodiments, this length of the artery can be divided into equal longitudinal segments or unequal longitudinal segments, and in some embodiments, it can be divided into 5, 6, 7, 8, 9, or 10 equal longitudinal segments or unequal longitudinal segments. In some embodiments, fewer segments or additional segments can also be used. In some embodiments, the length of the artery where detection is performed can be about 1 centimeter to 5 centimeters. The segments 1304 can be asymmetric (e.g., as shown in FIG. 13) based on, for example, the expected, known, and / or detected positions of the subclavian snares. The segments 1304 can be asymmetric. FIG. 13 shows eight segments 1304, but more or fewer segments 1304 are possible (e.g., depending on the number of electrodes). As described above, in addition to showing the radial segments, multiple images such as the image of FIG. 13 can be provided to show the data collected at different positions along the length of the artery. Each image can be provided with a visual indicia indicating the position along the length of the artery. Additionally, in one embodiment, a three-dimensional representation of the radial segments along a plurality of positions along the length of the artery can also be provided on a display. In one embodiment, a table or graph can also be provided to display the information. Additionally, in some embodiments, ultrasound can be used to visualize the positions of the stellate ganglion and the subclavian artery.For example, in some embodiments, markers such as skin markers visible based on fluoroscopy can be positioned on the patient. This marker can be used to identify the peripheral boundary of the artery.

[0084] In the embodiments described herein, the lesions or ablation patterns formed by the electrodes can have various shapes such as, for example, circular, annular, cigar-shaped, linear, donut-shaped, oval, and / or spherical. In some embodiments, the width of the lesion can be from 5 millimeters to 15 millimeters, and the depth can be from 2 millimeters to 10 millimeters.

[0085] For cauterization of the subclavian snare, various modalities can be used, including, for example, radiofrequency (RF), high-power short-duration RF (HPSD RF), cryoablation (CB), microwave, high-intensity focused ultrasound (HIFU), electroporation, water vapor, laser, heat, alcohol or other chemicals, freezing, or combinations thereof, and the cauterization can be either reversible or irreversible. The RF energy for performing RF cauterization can be generated by using power of about 10 watts (W) to about 60 W (for example, about 10 W, about 20 W, about 30 W, about 40 W, about 50 W, about 60 W, ranges between such values, etc.) over a specific time window of about 15 seconds (s) to about 90 s (for example, about 15 s, about 20 s, about 30 s, about 40 s, about 50 s, about 60 s, about 75 s, about 90 s, ranges between such values, etc.) at frequencies of about 50 (kilohertz) kHz to about 1,500 kHz (for example, about 500 kHz, about 100 kHz, about 250 kHz, about 350 kHz, about 400 kHz, about 450 kHz, about 500 kHz, about 600 kHz, about 750 kHz, about 1,000 kHz, about 1,500 kHz, ranges between such values, etc.). Most of the lesion occurs as a result of conductive heat, which is inversely proportional to the distance from the tip of the electrode. HPSD RF uses higher power and shorter duration. For example, HPSD RF can use power of about 50 W to about 90 W (for example, about 50 W, about 90 W, ranges between such values, etc.) and a duration of about 4 s to about 15 s (for example, about 4 s, about 15 s, ranges between such values, etc.). The principle of high-power short-duration cauterization is to change the balance between resistive energy transfer and conductive energy transfer and strive to improve the durability of tissue damage. Before RF cauterization was developed, direct current or DC cauterization mainly caused cell damage by electroporation or thermal injury. Electroporation can be applied by applying energy higher than about 200 joules (J) over several milliseconds. CB is accompanied by three phases of tissue damage. During CB, the first phase occurs, which is called the freeze-thaw phase. When the temperature drops below -15°C, microscopic extracellular freezing occurs, and then when the temperature drops below 40°C, intracellular freezing occurs, resulting in local tissue damage.When thawing occurs, melting of ice crystals with microthrombi and platelet aggregation takes place. Subsequently, a bleeding-inflammation phase with local tissue inflammation and edema disease occurs, and finally, a replacement fibrosis phase occurs, forming a fibrous scar. The signal generator can accommodate all of these settings and timings necessary for complete ablation and denervation of the subclavian snare. CB can be used within the subclavian artery to ablate the subclavian snare by using tissue cooling and the Joule-Thomson effect and circulating a noble gas such as argon or helium. A cryoprobe can be used while circulating a cryogen.

[0086] Figures 14A and 14B and Figures 15A and 15B illustrate embodiments of a method and system that enable measurement of the dilation and expansion of the subclavian artery. A catheter 1400 (which may be, for example, catheters 230, 400, 500, 600, 700, 800, 900, 1000, 1100), which may also be referred to as an elongate element, can include an expansion element 1404 that can be expanded or contracted by an operator (e.g., by addition or removal of water or gas, or by other mechanical means) adjusting the catheter. In the illustrated embodiment, the expansion element can be formed in various ways that allow the surface of the expansion element to expand radially. In some embodiments, the expansion element can comprise a balloon that can be inflated using an inflation medium. In some embodiments, the expansion element can be mechanically expanded by using a self-expanding stent or linkage. In embodiments that utilize a balloon, when the expansion element 1404 is inflated, the expansion element 1404 can be pressed against the inner wall of the artery 1402, causing the artery 1402 to expand. When the expansion element 1404 is deflated, the artery 1402 may be able to contract back to its original size. As described above, the catheter 1400 can also include a neuromodulation element 1401 in the form of electrodes 1406 along both the length and / or circumference of the catheter 1400, including along the length and circumference of the outer surface of the expansion element 1404. The electrodes 1406 can form an array, which may be referred to as an array of electrodes 1406. The operator can determine whether to expand or deflate the expansion element 1404 and to what extent based on various parameters measured by the electrodes 1406. Such parameters include, but are not limited to, the diameter of the blood vessel, the proximity of the catheter 1400 to the nerves of the subject, and tissue compliance. These dilation measurements can be used in the radial and longitudinal segmentation of the arterial wall.

[0087] FIG. 14A schematically shows a side view of a catheter / elongated element 1400, where the expansion element 1404 includes a neuromodulation element 1401 positioned on the expansion element 1404, and the expansion element 1404 is in a partially expanded configuration within the artery 1402. The expansion element 1404 can be designed such that in its partially expanded configuration, the electrodes 1406 of the neuromodulation element contact the wall of the artery 1402. FIG. 14B shows a schematic side view of the catheter 1400, where the expansion element 1404 is in a second, more fully expanded configuration within the artery 1402, expanding the artery 1402. The inner diameter and / or the amount of expansion of the artery 1402 can be determined by the catheter 1400 (e.g., via electrodes and / or sensors located on opposite radial sides of the expansion element 1404).

[0088] As the expansion element 1404 expands and the artery 1402 expands, the distance between the electrode 1406 and the target nerve 1410 is reduced, and the stimulation threshold measured by the electrode decreases. This may enable the distance between the electrode 1406 and the target nerve 1410 to be determined using the stimulation threshold measured by the electrode 1406. When the distance between the electrode 1406 and the target nerve 1410 is reduced, advantageously, the amount of ablation energy required can be minimized, and it may be possible to apply the ablation energy more specifically. In addition to utilizing the stimulation threshold, the biomarker measurements described herein can also be used to identify movement of the electrode 1406 closer to the target nerve 1410 of the subject. These measurements can also be made along the radial and longitudinal segmentation of the artery as described above.

[0089] In some embodiments, impedance spectroscopy measurements obtained by electrode 1406 can be used to estimate tissue compliance. This advantageously enables preventing the blood vessel from undergoing excessive dilation and / or damage when balloon member (also referred to as balloon) 1404 is expanded to increase the proximity of electrode 1406 to the nerve 1410 of interest. For example, in some embodiments, if the impedance crosses a threshold for a given frequency (becomes higher than and / or lower than the threshold), a signal and / or an alarm can be provided to the user to stop the expansion of the expansion element 1404 so as not to overly dilate or damage the blood vessel. In one embodiment, if the impedance crosses a threshold for a given frequency (becomes higher than and / or lower than the threshold), the system can automatically stop the expansion of the expansion element 1404 or reduce the expansion so as not to overly dilate or damage the blood vessel. The impedance spectroscopy measurements can be used to estimate the impedance of the fluid and / or tissue around the electrode. When the fluid / tissue in contact with the electrode changes with the expansion of the expansion element, the impedance changes. Additionally, the impedance changes when the thickness of the tissue changes as the expansion of the expansion element increases. Using impedance spectroscopy at a particular frequency or many different frequencies can provide feedback to the system. In some embodiments, the feedback can represent how flat the electrode is in contact with the circumference of the blood vessel. In other embodiments, the feedback can provide information regarding how much blood is in contact with the electrode. In yet another embodiment, the feedback from impedance spectroscopy can provide a general location of the nerve target. The reason is that the impedance changes on the electrode closest to this nerve, especially when the expansion element is expanded, compared to an electrode simply in contact with smooth muscle.

[0090] FIG. 15A shows a cross-sectional view of the expansion element 1404 in a partially expanded configuration within the artery 1402. FIG. 15B shows a cross-sectional view of the expansion element 1404 in a second, more expanded configuration within the artery 1402 and expanding the artery 1402.

[0091] In some embodiments, a system for treating a subclavian snare includes one or more of the following features. It is assumed that the lumen of the subclavian artery can be divided circularly like the face of a clock. The dorsal subclavian snare can be from about 7 o'clock to about 11 o'clock, the ventral subclavian snare can be from about 2 o'clock to about 5 o'clock, and the electrodes can be connected at these positions. Additionally, as described above, the electrodes can also extend along the length of the catheter such that the lumen of the subclavian artery is not only divided along its circumference but also divisible along its length. In some embodiments, the catheter can be moved longitudinally along the length of the luminal subclavian artery to create longitudinal segments and / or additional longitudinal segments, and / or the catheter can be rotated to create radial segments and / or additional radial segments. In some configurations, a combination of radial and longitudinal segments can form a grid. Non-therapeutic stimulation along the length and / or circumference of the artery allows for precise localization of the snare, thereby providing positions for ablation along the length and / or circumference. After ablation, the snare can be restimulated to verify that the ablation was successful.Biomarkers for sympathetic nerve stimulation include, for example, (i) inotropic biomarkers such as, for example, the rate of change of pressure (dP / dt), arterial blood pressure (systolic, diastolic, mean), change in pulse pressure, increase in systemic blood pressure, increase in left ventricular developed pressure (dP / dt), (ii) chronotropic biomarkers such as, for example, change in heart rate (change in R_R or Q_Q interval on surface ECG), increase in heart rate (shortening of R-R interval), change in basic cycle length on intracardiac electrogram, (iii) dromotropic biomarkers such as, for example, PR interval (index of heart rate and change in AV conduction time), change in QT interval (index of change in ventricular excitation, prolongation of recovery interval after denervation / ablation measured using intracardiac electrogram in an EP lab), change in QT variability, change in Tpeak-Tend interval, prolongation of atrial and ventricular refractory periods by denervation / nerve signal blockade, reduction of arrhythmogenicity demonstrated by testing with S1-S2 stimulus pulse trains, improvement in left ventricular contractility, shortening of P-R interval and / or Q-T interval, shortening of atrial and / or ventricular effective refractory period / recovery interval, or induction of atrial tachyarrhythmia and / or ventricular tachyarrhythmia that can be terminated by electrical defibrillation or electrical shock, (iv) lusitropic biomarkers such as, for example, negative derivative of developed pressure, and change in basic slope of pressure-volume loop, (v) hypoinflammatory biomarkers such as, for example, decrease in inflammatory markers, change in CRP (blood and tissue), local tissue TNF alpha level, decrease in inflammation level, change in leukotriene and prostaglandin levels or their precursors, decrease in 3-nitrotyrosine level in myocardial or tissue biopsy. For some biomarkers, ablation may produce the opposite effect at baseline, such as a slight decrease in basal heart rate, a mild decrease in arterial pressure, no change to no change in left ventricular contractility, and / or a long effective refractory period. If the same changes as the biomarkers for sympathetic nerve stimulation do not occur in a restimulation test, it suggests that the ablation was successful. Thus, in some applications, the position of catheter 1110 in the subclavian artery is confirmed, stimulation is performed to identify the target, then cardiac biomarkers are identified, and then denervation of the target (e.g., ablation) is performed.After the nerve treatment is completed, the result can be confirmed by applying the stimulation again and showing that the biomarker no longer changes with the stimulation. The denervation, such as ablation, can be partial or complete, and can be reversible or permanent.

[0092] In some embodiments, the controller 301 can use a machine learning algorithm, which can be used to set and / or automatically adjust the stimulation applied by the catheter and / or to analyze the monitored cardiac parameters and / or biomarkers. In some embodiments, the machine learning algorithm can adjust the stimulation parameters (power, duration, amplitude) as a result of the monitored cardiac parameters and / or biomarkers and / or in combination with the monitored cardiac parameters and / or biomarkers after ablating the targeted nerves. In some embodiments, representative positions, stimulation parameters, ablation parameters, cardiac parameters, and / or biomarkers are determined by training the machine learning algorithm.

[0093] In some embodiments, catheters, such as catheters 230, 400, 500, 600, 700, 800, 900, 1000, 1400 (described below), can be actuated by a robotic control system and / or can have functions that are automatically or semi-automatically controlled. For example, in some embodiments, the longitudinal movement and / or rotation of the catheter can be controlled by a robot using a linear actuator and / or a rotational actuator. The bending and expansion at the distal portion of the catheter can also be controlled by the robotic system. In an exemplary embodiment, the robotic system can automatically control the movement and motion of the catheter to collect data as described above along the radial and longitudinal segments of the artery. After the information is collected, the robotic system can automatically or semi-automatically move the neuromodulation element to the area or targeted area designated to perform ablation as described herein.

[0094] FIG. 16 is a flowchart of another exemplary method 1600 for treating a subject. In block 1602, the subject presents with refractory arrhythmia. In block 1604, the subject is stabilized and the cause of the refractory arrhythmia is evaluated. In block 1606, the ICD is switched off and epidural anesthesia is injected to evaluate whether sympathetic drive is triggering the arrhythmia. If sympathetic drive is not triggering the arrhythmia, in block 1608 the electrophysiology laboratory (EP lab) evaluates for arrhythmia focus. If sympathetic drive is driving the arrhythmia, in block 1610 a subclavian crush ablation procedure (e.g., a subclavian crush ablation procedure as described herein) is performed.

[0095] The present disclosure relates to the neuromodulation and ablation of the subclavian wan of a subject for treating heart diseases. The heart diseases may relate to ventricular arrhythmia, atrial fibrillation, ventricular tachycardia, ventricular fibrillation, congestive heart failure, and atrial flutter. Additionally, other pathologies or diseases can be treated using the methods and systems for describing the neuromodulation (such as ablation) of the subclavian wan of a subject. For example, one aspect of the present disclosure is the recognition that stellate ganglion block or denervation, or subclavian wan ablation may also affect hemodynamic function. In some applications, sympathetic activation with pharmacological antagonists or nerve stimulation may change heart rate, contractility, conduction, and relaxation. In one embodiment, targeted sympathetic denervation / central disinhibition or block can improve the diastolic properties of the heart. Specifically, in some embodiments, any effect in improving the compliance of the left ventricle that promotes afterload reduction is achieved. Such improvement in compliance can have a beneficial effect on stroke volume and as a result increase cardiac output. Thus, in the stellate ganglion block using neuromodulation such as the ablation method proposed herein, the index of diastolic function measured by the change in end-systolic meridional wall stress, the change in peripheral vascular resistance, the increase in end-diastolic volume, and the increase in stroke volume and / or cardiac output is improved. This may or may not occur with a measurable change in heart rate due to the direct sympathetic effect on the myocardium independent of the conduction-changing effect.

[0096] The cauterization may be performed without stimulation before and / or after the cauterization. For example, the cauterization can be performed around the entire subclavian artery, including the locations of the dorsal and ventral subclavian snares. In another example, the cauterization can be performed at the expected location of the subclavian snare. For example, the longitudinal and / or radial positions of the neuromodulation element can be visualized (e.g., using fluoroscopy, ultrasound, etc.), and electrodes for the cauterization energy can be selected. For example, the longitudinal and / or radial positions of the neuromodulation element with electrodes selectively positioned to correspond to the expected subclavian snare location can be visualized (e.g., using fluoroscopy, ultrasound, etc.), and all electrodes for the cauterization energy can be selected. Stimulation can be performed only after the cauterization to verify the effect of the cauterization.

[0097] Drug therapy In some embodiments, the neuromodulation therapy described herein can be used to replace drug (medication) therapy. However, in other embodiments, drug therapy can be used in combination with the neuromodulation therapy described herein, but at a reduced frequency or dosage, so that undesirable side effects are reduced. For example, when a particular drug (or combination of drugs) is combined with the neuromodulation described herein, it is administered for a shorter overall duration, fewer administrations per day / week / month, and / or at a lower dosage. This can not only reduce undesirable drug side effects but also reduce toxicity or dependence. The neuromodulation described herein can be used to gradually reduce the pain of the subject and gradually reduce other medication therapies, or in other cases to wean the subject from pain and other medication therapies.

[0098] Describe certain experiments regarding the application of agents to induce certain physiological states before, during, and / or after stimulation and / or ablation. The devices and methods described herein can be used without agents (e.g., without agents that induce certain physiological states). Anesthesia and other agents that allow, for example, electrode contact placement can be used. Substances released by a subject in response to stimulation (e.g., calcitonin gene-related peptide (CGRP)) are not considered agents.

[0099] The above descriptions and examples are merely described to illustrate the concepts of the present invention and are not intended to be limiting. Each of the disclosed aspects and examples of the present disclosure may be considered individually or in combination with other aspects, examples, and variations of the present disclosure. Additionally, unless otherwise specified, the steps of the methods of the present disclosure are not limited to any particular order of implementation. Reasonable modifications of the disclosed examples that incorporate the spirit and gist of the present disclosure are within the scope of the present disclosure. Further, all references cited herein are incorporated by reference in their entirety. The headings used herein are for the purpose of organization only and should not be used to unduly limit the claims and embodiments.

[0100] While various modifications and alternative forms are possible for the methods and devices described in this specification, specific examples thereof are shown in the drawings and described in detail herein. However, it should be understood that the embodiments are not limited to the specific devices or methods disclosed, but rather are directed to all reasonable modifications, equivalents, and alternatives within the spirit and scope of the various examples described and the appended claims. Further, the disclosure herein of any particular feature, aspect, method, trait, characteristic, quality, attribute, element, etc. related to an example can be used in all other examples described herein. It is not necessary to perform the disclosed methods in the order described. Depending on the example, one or more acts, events, or functions of any of the algorithms, methods, or processes described herein can be performed in a different sequence, can be added, combined, or completely omitted (e.g., not all acts or events described are necessary to perform the algorithm). Algorithms, modules, blocks, steps, boxes, elements, features, etc. can be stored in a machine-readable memory. In some examples, acts or events can be performed simultaneously rather than sequentially, for example, via multithreaded processing, interrupt processing, or multiple processors or processor cores, or on other parallel architectures. Further, no element, feature, block, box, or step, or group of elements, features, blocks, boxes, or steps is necessary or indispensable. Additionally, all possible combinations, subcombinations, and reconfigurations of systems, methods, features, elements, modules, blocks, boxes, etc. are within the scope of this disclosure. The use of sequential or time-ordering language such as "then," "next," "after," "sequentially," etc. is generally intended to facilitate the flow of the text and not to limit the order of the operations performed, unless specifically stated or otherwise understood within the context in which it is used. Thus, while some examples can be implemented using the order of operations described herein, other examples can be implemented according to a different order of operations.

[0101] Various illustrative logical blocks, boxes, modules, processes, methods, and algorithms described in connection with the embodiments disclosed herein can be implemented as electronic hardware, computer software, or combinations of both. To clearly illustrate such interchangeability of hardware and software, various illustrative components, blocks, modules, operations, and steps have been described above generally in terms of their functionality. Whether such functionality is implemented as hardware or software depends upon the particular application and design constraints imposed on the overall system. The described functionality can be implemented in various ways for each particular application, but such implementation decisions should not be interpreted as causing a departure from the scope of the present disclosure.

[0102] Various illustrative logical blocks and modules described in connection with the embodiments disclosed herein can be implemented or executed by a machine, such as a general-purpose processor, a digital signal processor (DSP), an application specific integrated circuit (ASIC), a field programmable gate array (FPGA) or other programmable logic device, discrete gate or transistor logic, discrete hardware components, or any combination of the above elements designed to perform the functions described herein. A general-purpose processor may be a microprocessor, but in the alternative, the processor may be any conventional processor, controller, microcontroller, or state machine, combinations thereof, etc. The processor may also be implemented as a combination of computing devices, e.g., a combination of a DSP and a microprocessor, a plurality of microprocessors, one or more microprocessors in conjunction with a DSP core, or any other such configuration.

[0103] The blocks, operations, or steps of the methods, processes, or algorithms described in connection with the embodiments disclosed herein can be embodied directly in hardware, in software modules executed by a processor, or in a combination of the two. The software modules can be present in RAM memory, flash memory, ROM memory, EPROM memory, EEPROM memory, registers, a hard disk, a removable disk, an optical disk (e.g., CD-ROM or DVD), or any other form of volatile or non-volatile computer-readable storage medium known in the art. The storage medium can be coupled to the processor, whereby the processor can read information from, and write information to, the storage medium. Alternatively, the storage medium may be integral to the processor. The processor and the storage medium can be present in an ASIC. The ASIC can be present in a user terminal. Alternatively, the processor and the storage medium can be present as discrete components within the user terminal.

[0104] In particular, conditional language, such as “can,” “may,” “might,” “for example,” used herein, unless specifically stated otherwise or otherwise understood within the context in which it is used, generally is intended to convey that some examples include a particular feature, element, and / or state, while other examples do not. Thus, such conditional language is generally not intended to imply that a feature, element, block, and / or state is in any way required for one or more embodiments or that one or more embodiments necessarily include logic for determining whether these features, elements, blocks, and / or states are included in or implemented in any particular embodiment, whether or not there is author input or prompting.

[0105] The methods disclosed herein may include certain actions taken by a physician, but these methods may also include, whether explicitly or implicitly, instructions by a third party for those actions. For example, an action such as "stimulating a nerve" includes "instructing the stimulation of a nerve".

[0106] The ranges disclosed herein also encompass any overlaps, sub-ranges, and combinations thereof. Terms such as "up to", "at least", "greater than", "less than", "between", etc. include the recited numbers. Numbers preceded by terms such as "about" or "substantially" include the recited numbers and should be interpreted based on the context (e.g., should be interpreted accurately to the extent that there is no problem in that context. For example, ±5%, ±10%, ±15%, etc.). For example, "about 1 mm" includes "1 mm". Phrases preceded by terms such as "substantially" include the recited phrases and should be interpreted based on the context (e.g., should be interpreted to the greatest extent possible within a reasonable range in that context). For example, "substantially parallel" includes "parallel". Unless otherwise specified, all measurements are made under standard conditions including temperature and pressure. The phrase "at least one" is intended to require at least one item from the subsequent list, rather than each item of one type in the subsequent list. For example, "at least one of A, B, and C" can include A, B, C, A and B, B and C, or A, B, and C.

[0107] Unless otherwise defined, all technical terms used in this specification have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure pertains. As used in this specification, the singular forms "a", "an", and "the" may also include the plural unless the context clearly dictates otherwise. The terms "comprises" and / or "comprising" as used in this specification can specify the presence of the stated features, steps, operations, elements, components, and / or groups, but do not preclude the presence or addition of other features, steps, operations, elements, components, and / or groups. The term "and / or" as used in this specification can include any combination of one or more of the related listed items. The terms such as "first", "second", etc. used in this specification should not limit the elements described by these terms. These terms are only used to distinguish one element from another. Thus, the "first" element described below can also be referred to as the "second" element without departing from the teachings of this disclosure. The order of operations (or acts / steps) is not limited to the order presented in the claims or figures unless otherwise indicated.

[0108] As used herein, the term "neuromodulation" may refer to an electrical signal delivered as a treatment to neural tissue. In some examples, the neural tissue may include at least a portion of the sympathetic chain. For example, the sympathetic chain may refer to the cervical sympathetic chain. As used herein, the term "sympathetic nervous system" may refer to the part of the autonomic nervous system that activates the "fight or flight" response (commonly accelerating the heart rate, dilating the pupils, expanding the bronchi, suppressing digestion, constricting blood vessels, increasing cardiac output, raising blood pressure, etc.), which prepares the body for intense physical activity. As used herein, the term "electrical signal" may refer to a time-varying voltage or current. As an example, an electrical signal can be represented by a waveform (a graphical representation of the change in current or voltage over time). As used herein, the term "electrode contact" may refer to a material that acts as a conductor for the ingress and egress of electricity. At least a portion of this material may be a biocompatible material. As used herein, the terms "subject" or "patient" may be used interchangeably and may refer to warm-blooded organisms including, but not limited to, humans, pigs, rats, mice, dogs, cats, goats, sheep, horses, monkeys, rabbits, cows, etc.

Explanation of Signs

[0109] 102 Subclavian artery 104 Dorsal subclavian snare, nerve 106 Ventral subclavian snare, nerve 108 Vagus nerve 110 Arrow 202 Left subclavian artery 203 Right subclavian artery 204 Left dorsal subclavian snare, nerve 205 Right dorsal subclavian snare, nerve 206 Left ventral subclavian snare 207 Right ventral subclavian snare 208 Vagus nerve 222 Aorta 224 Left common carotid artery 225 Right common carotid artery 226 Left renal artery 227 Right renal artery 228 Left iliac artery 229 Right iliac artery 230 First catheter, second catheter, percutaneous catheter 232 Neuroregulatory element 300 System 301 Control system / controller 302 Signal generator 303 Display 305 Computer interface 400 Neuroregulatory element 402 Catheter 404 Strut 406 Electrode 500 Neuroregulatory element 502 Catheter 504 Loop 506 Ablation electrode 600 Neuroregulatory element 602 Catheter 604 Second loop 606 Stimulation electrode 700 Neuroregulatory element 702 Catheter 708 Tether 800 Neuroregulatory element 802 Catheter 804 Corkscrew 806 Electrode 808 Artery, blood vessel 900 Neuroregulatory element 902 Blood vessel 904 Backbone 906 Electrode 908 Base 910 Electrode bump 1000 Neuroregulatory element 1004 Stimulation and / or ablation element 1006 Distal protection device 1100 Catheter 1102 Subclavian artery 1103 Lumen 1104 Electrode contact 1106 Subclavian dorsal snare 1108 Subclavian ventral snare 1110 Catheter 1200 Method 1302 Subclavian artery 1304 Radial segment 1306 First asterisk 1308 Second asterisk 1400 Catheter, elongate element 1401 Neuromodulation element 1402 Artery 1404 Expanding element 1406 Electrode 1410 Target nerve 1600 Method

Claims

1. A dual stimulation and cauterization catheter system, wherein the dual stimulation and cauterization catheter system is A slender element configured to be positioned in the subclavian artery, The neuromodulatory element located in the distal portion of the elongated element, Equipped with, The aforementioned neural modulatory element is configured to receive a first signal from a signal generator in order to electrically stimulate the subclavian loop. Based on the first signal, the neural modulator is configured to stimulate the subclavian loop. The aforementioned neuromodulatory element is configured to receive a second signal from the signal generator in order to cauterize the subclavian loop. A catheter system in which, based on the second signal, the neuromodulatory element is configured to cauterize the subclavian loop.

2. The catheter system according to claim 1, wherein the nerve modulating element comprises at least one electrode configured to provide both the stimulation and the cauterization.

3. The catheter system according to claim 1, wherein the nerve modulatory element comprises an array of electrodes spaced apart in the circumferential direction along the circumference of the nerve modulatory element.

4. The catheter system according to claim 3, wherein the electrode array is spaced apart longitudinally along the length of the neuromodulatory element.

5. A dual stimulation and cauterization catheter system, wherein the dual stimulation and cauterization catheter system is A catheter configured to be introduced into the vascular system of a patient, comprising a neuromodulatory element configured to be positioned in the subclavian artery of the patient, It is a processor, To provide non-therapeutic electrical stimulation to the subclavian loop and to obtain data on the subject's response to the applied non-therapeutic stimulation, the signal generator is controlled to transmit a first signal to the neuromodulatory element. Based on the patient's response, the signal generator is controlled to transmit a second signal to the neuromodulatory element in order to electrically cauterize the subclavian loop. A processor configured in such a way, A catheter system equipped with the following features.

6. The catheter system according to claim 5, wherein the processor is further configured to control the signal generator to transmit the first signal in order to restimulate the subclavian loop.

7. The catheter system according to claim 6, wherein the processor is further configured to control the signal generator to transmit the second signal to further cauterize the subclavian trap based on the patient's response to the restimulation.

8. The catheter system according to claim 5, wherein the data is cardiac parameters.

9. The catheter system according to claim 8, wherein the cardiac parameters include at least one of arterial trace blood pressure changes, whether AF is induced, whether arrhythmia is induced, whether changes in cardiac cycle length are induced, repeated recovery curves, right atrial ERP, left atrial ERP, dERP, heart rate, IACT, or a unipolar electrograph from a multipolar catheter under steady-state RV pacing or a unipolar electrograph from a multipolar catheter having a short DI after steady-state RV pacing.

10. The catheter system according to claim 8, further comprising a monitor for the cardiac parameters of the patient.

11. An interface computer, Perform real-time data analysis, The catheter system according to claim 5, further comprising an interface computer configured to overlay the response to the stimulus onto an anatomical image, including marking the location having the greatest response.

12. The catheter system according to any one of claims 1 to 11, wherein the nerve modulating element comprises a plurality of struts.

13. The catheter system according to any one of claims 1 to 11, wherein the nerve modulating element comprises a loop.

14. The catheter system according to any one of claims 1 to 11, wherein the nerve modulating element comprises a corkscrew or a helix.

15. The catheter system according to any one of claims 1 to 11, wherein the nerve modulating element comprises an expansion element.

16. The catheter system according to claim 15, wherein the expansion element is configured to expand or contract in accordance with the adjustments of the surgeon.

17. The first signal is transmitted to a neuromodulatory element in order to electrically stimulate the subclavian loop, The second signal is transmitted in order to electrically cauterize the subclavian trap. A catheter system according to any one of claims 1 to 11, comprising the signal generator configured as described above.

18. A dual stimulation and cauterization catheter system, wherein the dual stimulation and cauterization catheter system is Elongated elements, A neuromodulatory element located in the distal portion of the elongated element, comprising an array of electrodes, Equipped with, The aforementioned neural modulatory element is configured to receive a first signal from a signal generator in order to electrically stimulate target tissue. Based on the first signal, the neuromodulatory element is configured to stimulate the target tissue. The neuromodulatory element is configured to receive a second signal from the signal generator in order to ablate the target tissue. Based on the second signal, the neuromodulatory element is configured to cauterize the target tissue. The catheter system is configured such that the nerve modulating element provides both the stimulation and the cauterization.

19. The catheter system according to claim 18, wherein the target tissue includes a subclavian loop.

20. The catheter system according to claim 18, wherein the nerve modulating element comprises at least one electrode configured to provide both the stimulation and the cauterization.

21. The catheter system according to claim 18, wherein the nerve modulatory element comprises an array of electrodes spaced apart in the circumferential direction along the circumference of the nerve modulatory element.

22. The catheter system according to claim 21, wherein the electrode array is spaced apart longitudinally along the length of the neuromodulatory element.

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