System and method for subclavian periarterial denervation

Abstract

A method of treating a heart disease in a subject includes percutaneously introducing a catheter into the vasculature of the subject. The catheter may include a neuromodulation element. A neuromodulation element may be positioned on the expansion element. A neuromodulation element of the catheter may be positioned in a subclavian artery of a subject. The catheter may be used to electrically stimulate at least one of a dorsal subclavian loop or a ventral subclavian loop. The method may include confirming stimulation to a dorsal subclavian loop and / or a ventral subclavian loop by monitoring cardiac parameters. After the stimulation to the dorsal subclavian loop and / or the ventral subclavian loop is confirmed, ablation energy can be provided to the dorsal subclavian loop and / or the ventral subclavian loop.

Description

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS

[0002] This application claims the benefit of U.S. Provisional Application No. 63 / 367,578, filed on July 1, 2022, and U.S. Provisional Application No. 63 / 430,614, filed on December 6, 2022, the entire disclosure of each of which is incorporated herein by reference. Technical Field

[0003] The present disclosure relates generally to systems and methods for facilitating modulation (e.g., denervation, ablation), and in some embodiments more specifically to systems and methods for facilitating therapeutic modulation of a subject's left and / or right subclavian periarterial nerves to treat heart disease (e.g., atrial fibrillation). Background Art

[0004] Ventricular arrhythmias cause more than 80,000 deaths per year in the UK and more than 150,000 deaths per year in the US, the vast majority of which are related to coronary heart disease and / or heart failure, but the associated morbidity and cost burden far exceeds these figures. Cardiovascular disease accounts for £12 billion of direct medical expenditure in the UK and an estimated $378 billion of direct and indirect costs per year in the US, with heart failure and related arrhythmia care being the main drivers of expenditure. Atrial fibrillation (AF) is a common and significant medical problem that affects approximately 3% of the population. In the US, the prevalence of AF is estimated to increase from approximately 5.2 million in 2010 to approximately 12.1 million in 2030. Patients with AF are at increased risk of death (for both men and women), with an age-adjusted mortality rate of 6.5 deaths per 100,000 population. AF is associated with increased risk factors for other cardiovascular diseases, including heart failure, myocardial infarction, sudden cardiac death, diabetes, gastrointestinal bleeding, and stroke. Summary of the invention

[0005] Arrhythmias are caused by heterogeneity in the myocardium but are exacerbated by dynamic changes in sympathetic (adrenergic) and parasympathetic (cholinergic) signaling. In heart disease, higher sympathetic signaling is generated by the brainstem and reaches the heart via the thoracic sympathetic nerves. Most denervation surgeries (stellate ganglionectomy) are performed by the surgeon identifying the location of the ganglion and empirically removing the thoracic (T1-T4) level of the sympathetic ganglia because they are the most accessible nerves. This surgery is associated with side effects that affect the patient's quality of life.

[0006] The nerves that surround the blood vessels that supply blood to the arm (the subclavian artery) are called subclavianansae, connecting two paravertebral sympathetic ganglia on the same side of the body, forming a highly selective sympathetic innervation pathway to the heart. Therefore, targeting one or both subclavianansae for ablation is a new mechanism for selectively modulating the sympathetic innervation of the heart. Energy is applied to stimulate these nerves non-therapeutically, and by monitoring changes in the heart's condition indicated by cardiac parameters (e.g., heart rate, etc.), it can be confirmed that the nerves leading to the heart have been affected by the application of energy. Energy can then be applied chronically to ablate or destroy the affected nerves, which has a beneficial effect on the heart to reduce cardiac electrical heterogeneity and reduce the further development of pathological diseases. There are posterior (dorsal) and anterior (ventral) subclavian loops around the left and right subclavian arteries, and the user can selectively target stimulation and ablation of any of the four nerves to any degree desired to achieve different effects. The stimulation is not therapeutic, but is used to determine the location of therapeutic ablation.

[0007] In some embodiments, a method of treating atrial fibrillation in a subject comprises percutaneously introducing a catheter into the vasculature of the subject. The catheter comprises a neuromodulator. The method further comprises positioning the neuromodulator in the left subclavian artery of the subject, electrically stimulating the left dorsal subclavian loop, confirming the stimulation of the left dorsal subclavian loop by monitoring a first cardiac parameter, and after confirming the stimulation of the left dorsal subclavian loop, providing ablative energy to the left dorsal subclavian loop; electrically stimulating the left ventral subclavian loop, confirming the stimulation of the left ventral subclavian loop by monitoring a second cardiac parameter, and after confirming the stimulation of the left ventral subclavian loop, providing ablative energy to the left ventral subclavian loop; ablative energy; placing a neuromodulator in the right subclavian artery of the subject, electrically stimulating the right dorsal subclavian loop, confirming the stimulation of the right dorsal subclavian loop by monitoring a third cardiac parameter, and after confirming the stimulation of the right dorsal subclavian loop, providing ablative energy to the right dorsal subclavian loop; electrically stimulating the right ventral subclavian loop, confirming the stimulation of the right ventral subclavian loop by monitoring a fourth cardiac parameter, and after confirming the stimulation of the right ventral subclavian loop, providing ablative energy to the right ventral subclavian loop. In some embodiments, an ablative temperature can be delivered so as to heat the target tissue to between 40-80 degrees Celsius and for a time of 20 to 240 seconds. Cooling can optionally be provided to non-target tissue, however, in some embodiments, cooling is not required. In some embodiments, after stimulating the left ventral subclavian haptic and the left dorsal subclavian haptic, ablative energy is provided to the left ventral subclavian haptic and the left dorsal subclavian haptic simultaneously. In some embodiments, after stimulating the right ventral subclavian haptic and the right dorsal subclavian haptic, ablative energy is provided to the right ventral subclavian haptic and the right dorsal subclavian haptic simultaneously.

[0008] The first cardiac parameter may be different from at least one of the second cardiac parameter, the third cardiac parameter, or the fourth cardiac parameter. The second cardiac parameter may be different from at least one of the first cardiac parameter, the third cardiac parameter, or the fourth cardiac parameter. The third cardiac parameter may be different from at least one of the first cardiac parameter, the second cardiac parameter, or the fourth cardiac parameter. The fourth cardiac parameter may be different from at least one of the first cardiac parameter, the second cardiac parameter, or the third cardiac parameter. The first cardiac parameter may be the same as at least one of the second cardiac parameter, the third cardiac parameter, or the fourth cardiac parameter. The second cardiac parameter may be the same as at least one of the first cardiac parameter, the third cardiac parameter, or the fourth cardiac parameter. The third cardiac parameter may be the same as at least one of the first cardiac parameter, the second cardiac parameter, or the fourth cardiac parameter. The fourth cardiac parameter may be the same as at least one of the first cardiac parameter, the second cardiac parameter, or the third cardiac parameter.

[0009] At least one of the first cardiac parameter, the second cardiac parameter, the third cardiac parameter, or the fourth cardiac parameter may include arterial micro-blood pressure changes, whether AF is induced, whether arrhythmia is induced, whether a change in cardiac cycle length is induced, a repetitive recovery curve, right atrial ERP, left atrial ERP, dERP, heart rate, IACT, or at least one of a unipolar electrogram from a multipolar catheter under steady-state RV pacing or short DI after steady-state RV pacing. The method may further include, after providing ablation energy, re-stimulating the subclavian loop, and if the cardiac parameters confirm stimulation, further providing ablation energy to the subclavian loop. The method may include repeating re-stimulation and providing further ablation energy until the cardiac parameters do not confirm stimulation. The catheter may include an expansion element on which the neuromodulator is located. The expansion element may be an expansion element that dilates a blood vessel.

[0010] In some embodiments, a method of treating a heart disease in a subject comprises percutaneously introducing a catheter into the vasculature of the subject. The catheter comprises a neuromodulator. The method further comprises positioning the neuromodulator in a subclavian artery of the subject, electrically stimulating a dorsal subclavian loop, confirming the stimulation of the dorsal subclavian loop by monitoring a cardiac parameter, and providing ablative energy to the dorsal subclavian loop after confirming the stimulation of the dorsal subclavian loop; electrically stimulating a ventral subclavian loop, confirming the stimulation of the ventral subclavian loop by monitoring a second cardiac parameter, and providing ablative energy to the ventral subclavian loop after confirming the stimulation of the ventral subclavian loop. In some embodiments, after electrically stimulating the dorsal subclavian loop and the ventral subclavian loop and confirming the stimulation, providing ablative energy to the dorsal subclavian loop and the ventral subclavian loop simultaneously.

[0011] The first cardiac parameter may be different from the second cardiac parameter. The first cardiac parameter may be the same as the second cardiac parameter. At least one of the first cardiac parameter or the second cardiac parameter may include at least one of arterial micro-blood pressure changes, whether AF is induced, whether arrhythmia is induced, whether cardiac cycle length changes are induced, repetitive recovery curves, right atrial ERP, left atrial ERP, dERP, heart rate, IACT, or a unipolar electrogram from a multipolar catheter in the case of short DI under steady-state RV pacing or after steady-state RV pacing.

[0012] The method may further include, after providing the ablative energy, restimulating the subclavian haptic and, if the cardiac parameters confirm the stimulation, further providing ablative energy to the subclavian haptic. The method may include repeating restimulation and providing further ablative energy until the cardiac parameters no longer confirm the stimulation. The catheter may include an expansion element on which the neuromodulation element is located. The method may further include expanding the expansion element an amount to dilate the vasculature.

[0013] In some embodiments, a method of treating a heart disease in a subject comprises percutaneously introducing a catheter into the vasculature of the subject. The catheter comprises a neuromodulatory element. The method further comprises positioning the neuromodulatory element in a subclavian artery of the subject, electrically stimulating at least one of a dorsal subclavian loop or a ventral subclavian loop, confirming the stimulation of the dorsal subclavian loop and / or the ventral subclavian loop by monitoring cardiac parameters, and after confirming the stimulation of the dorsal subclavian loop and / or the ventral subclavian loop, providing ablative energy to the dorsal subclavian loop and / or the ventral subclavian loop. The method may comprise providing ablative energy to the dorsal subclavian loop and the ventral subclavian loop simultaneously after electrically stimulating the dorsal subclavian loop and the ventral subclavian loop and / or confirming the stimulation of the dorsal subclavian loop and the ventral subclavian loop by monitoring cardiac parameters.

[0014] The method may further include, after providing the ablative energy, restimulating the subclavian haptic and, if the cardiac parameters confirm the stimulation, providing further ablative energy to the subclavian haptic. The method may include repeating restimulating and providing further ablative energy until the cardiac parameters no longer confirm the stimulation.

[0015] Percutaneously introducing the catheter into the vasculature may include inserting the catheter into the femoral artery of the subject. Percutaneously introducing the catheter into the vasculature may include inserting the catheter into the radial artery of the subject. Percutaneously introducing the catheter into the vasculature may include inserting the catheter into the carotid artery of the subject. Percutaneously introducing the catheter into the vasculature may include inserting the catheter into the femoral vein of the subject. At least one of positioning the neuromodulatory element in the left subclavian artery or positioning the neuromodulatory element in the right left subclavian artery may include passing from the venous vasculature to the arterial vasculature.

[0016] In some embodiments, a method of treating a cardiac condition in a subject comprises positioning a neuromodulatory element in a subclavian artery of the subject, electrically stimulating at least one of a dorsal subclavian haptic or a ventral subclavian haptic, confirming stimulation of the dorsal subclavian haptic and / or the ventral subclavian haptic by monitoring cardiac parameters, and upon confirming stimulation of the dorsal subclavian haptic and / or the ventral subclavian haptic, providing ablative energy to the dorsal subclavian haptic and / or the ventral subclavian haptic. In some embodiments, ablative energy is provided to the dorsal subclavian haptic and the ventral subclavian haptic simultaneously.

[0017] The ablative energy may include radiofrequency ablative energy. The ablative energy may include cryogenic ablative energy. The electrical stimulation may include using an electrode combination of the neuromodulator. Providing the ablative energy may include using the same electrode combination of the neuromodulator.

[0018] The heart disease may include atrial fibrillation. The heart disease may include a refractory arrhythmia. The method may further include assessing whether sympathetic drive drives the refractory arrhythmia. The heart disease may include ventricular tachycardia. The heart disease may include ventricular fibrillation. The heart disease may include congestive heart failure. The heart disease may include atrial flutter.

[0019] In some embodiments, a catheter for treating a heart disease in a subject includes or alternatively consists essentially of an elongated element configured to be positioned in at least one of a left subclavian artery or a right subclavian artery. A distal portion of the elongated element includes a first neuromodulation element configured to stimulate at least one of a dorsal subclavian haptic or a ventral subclavian haptic, a second neuromodulation element configured to ablate at least one of the dorsal subclavian haptic or the ventral subclavian haptic, and a distal protection device located distal to the first neuromodulation element and the second neuromodulation element.

[0020] The first neuromodulatory element may include a first plurality of electrodes coupled to a first plurality of struts. The first neuromodulatory element may include a first plurality of electrodes coupled to a first ring. The first neuromodulatory element may include a first plurality of electrodes coupled to a first spiral. The second neuromodulatory element may include a first plurality of electrodes or a second plurality of electrodes coupled to a second plurality of struts. The second neuromodulatory element may include a first plurality of electrodes or a second plurality of electrodes coupled to a second ring. The second neuromodulatory element may include a first plurality of electrodes or a second plurality of electrodes coupled to a second spiral. At least one of the plurality of electrodes may include a triangular base including a tip configured to press into a vessel wall. At least one electrode may further include a plurality of electrode protrusions located on different sides of the tip of the triangular base. The catheter may further include an expansion element. The first and second neuromodulatory elements may be positioned on the expansion element.

[0021] In some embodiments, a catheter for treating a heart disease in a subject comprises or alternatively consists essentially of an elongated element configured to be positioned in at least one of a left subclavian artery or a right subclavian artery, a distal portion of the elongated element comprising a neuromodulation element configured to stimulate at least one of a dorsal subclavian haptic or a ventral subclavian haptic, and configured to ablate at least one of a dorsal subclavian haptic or a ventral subclavian haptic, and a distal protection device located distal to the neuromodulation element.

[0022] The neuromodulatory element may include a plurality of electrodes coupled to a plurality of struts. The neuromodulatory element may include a plurality of electrodes coupled to a ring. The neuromodulatory element may include a plurality of electrodes coupled to a helix. At least one of the plurality of electrodes may include a triangular base including a tip configured to press into a vessel wall. At least one electrode may further include a plurality of electrode protrusions located on different sides of the tip of the triangular base. The catheter may further include an expansion element. The neuromodulatory element may be positioned on the expansion element.

[0023] In some embodiments, a method of treating a subject includes stimulating specific electrodes of a neuromodulatory device, providing the results to an interface computer configured to perform real-time data analysis and overlaying anatomical images with the responses to the stimulation, including marking the location with the greatest response, and performing ablation at that location.

[0024] The method may further include restimulating after ablation to verify the effectiveness of the ablation. The method may further include, if the ablation is ineffective, further ablation. The method may include repeating verification and further ablation until the ablation is effective.

[0025] In some embodiments, a method of treating a subject experiencing a refractory arrhythmia comprises stabilizing the subject, assessing the cause of the refractory arrhythmia, assessing whether sympathetic drive is driving the refractory arrhythmia, coordinating an assessment for an arrhythmogenic lesion if sympathetic drive is not driving the refractory arrhythmia, and performing a subclavian loop ablation if sympathetic drive is driving the refractory arrhythmia.

[0026] Assessing whether sympathetic drive is driving the refractory arrhythmia may include gradually initiating epidural anesthesia. Assessing whether sympathetic drive is driving the refractory arrhythmia may include shutting down the subject's implantable cardioverter-defibrillator.

[0027] In some embodiments, a method of treating a cardiac disease in a subject comprises positioning a neuromodulatory element in a subclavian artery of the subject and providing ablative energy to a dorsal subclavian haptic and / or a ventral subclavian haptic.

[0028] Providing ablative energy may include selectively providing ablative energy. Selectively providing ablative energy may include non-therapeutic stimulation to determine the location of the dorsal subclavian loop and / or the ventral subclavian loop. Selectively providing ablative energy may include imaging the subclavian artery to determine the possible location of the dorsal subclavian loop and / or the ventral subclavian loop. Providing ablative energy includes providing ablative energy around the subclavian artery.

[0029] In some embodiments, a method of treating a subject includes positioning a neuromodulatory element of a catheter in a subclavian artery of the subject. The neuromodulatory element may include an array of electrodes spaced circumferentially about the circumference of the catheter and longitudinally along the length of the catheter. The method may include stimulating specific electrodes of the electrode array, providing the results to an interface computer configured to perform real-time data analysis; and overlaying an anatomical image with a response to the stimulation, including marking a location with a maximum response; and performing ablation at the marked location.

[0030] The method may further include restimulating after ablation to verify the effectiveness of the ablation. If the ablation is ineffective, the method may include further ablation. The method may include repeating restimulation and further ablation until the ablation is verified to be effective. The neuromodulatory element may be positioned on the expansion element. The method may include expanding the expansion element by a certain amount to dilate the subclavian artery.

[0031] In some embodiments, a catheter for treating a heart disease in a subject may include an elongated element configured to be positioned in at least one of a left subclavian artery or a right subclavian artery. A distal portion of the elongated element may include a neuromodulatory element configured to stimulate at least one of a dorsal subclavian haptic or a ventral subclavian haptic and configured to ablate at least one of a dorsal subclavian haptic or a ventral subclavian haptic. The neuromodulatory element of the catheter is configured to be positioned in a subclavian artery of the subject. The neuromodulatory element includes an array of electrodes spaced circumferentially about the circumference of the catheter and longitudinally along the length of the catheter.

[0032] The neuromodulatory element may include a plurality of electrodes coupled to a plurality of struts. The neuromodulatory element may include a plurality of electrodes coupled to a ring. The neuromodulatory element may include a plurality of electrodes coupled to a helix. At least one of the plurality of electrodes may include a triangular base including a tip configured to press into a vessel wall. The catheter may include an expansion element. The expansion element may include a balloon.

[0033] In some embodiments, a method for treating heart disease in a subject comprises percutaneously introducing a catheter into the subject's vasculature, wherein the catheter comprises a neuromodulatory element; positioning the neuromodulatory element in a subclavian artery of the subject; electrically stimulating at least one of a dorsal subclavian loop or a ventral subclavian loop, and confirming the stimulation of the dorsal subclavian loop and / or the ventral subclavian loop by monitoring biomarkers, wherein the biomarkers comprise at least one of an inotropic biomarker, a chronotropic biomarker, a conduction biomarker, a comfort biomarker, or an inflammatory biomarker; and providing ablative energy to the dorsal subclavian loop and / or the ventral subclavian loop after confirming stimulation of the dorsal subclavian loop and / or the ventral subclavian loop.

[0034] The method may further include re-stimulating the subclavian loop after providing the ablation energy, and if the biomarker confirms the stimulation, further providing ablation energy to the subclavian loop. The method may include repeating the re-stimulation and providing further ablation energy until the biomarker no longer confirms the stimulation. The biomarker may include at least one of the growth pressure (dP / dt), arterial blood pressure (systolic, diastolic, average), pulse pressure change, systemic blood pressure increase, or left ventricular growth pressure (dP / dt). The biomarker may include at least one of the heart rate change (change in the R_R or Q_Q interval on the surface ECG), heart rate increase (RR interval shortening), or change in the length of the basic cycle on the intracardiac electrocardiogram. The biomarker may include a variable conduction biomarker. The catheter may include a balloon, and the neuromodulatory element may be positioned on the balloon. The method may include inflating the balloon catheter by a certain amount to expand the subject's vasculature.

[0035] In some embodiments, a method for treating a heart disease in a subject includes positioning a neuromodulatory element on an expandable element in a subclavian artery of the subject; expanding the expandable element; electrically stimulating at least one of a dorsal subclavian loop or a ventral subclavian loop; confirming stimulation of the dorsal subclavian loop and / or the ventral subclavian loop by monitoring cardiac parameters; and upon confirming stimulation of the dorsal subclavian loop and / or the ventral subclavian loop, providing ablative energy to the dorsal subclavian loop and / or the ventral subclavian loop.

[0036] The ablation energy may include radiofrequency ablation energy. The ablation energy may include cryogenic ablation energy. The method may include electrical stimulation using an electrode combination of the neuromodulation element, and wherein providing the ablation energy includes using the same electrode combination of the neuromodulation element. The cardiac disease may include atrial fibrillation. The cardiac disease may include a refractory arrhythmia.

[0037] In some embodiments, a catheter for treating heart disease in a subject includes a slender element configured to be positioned in at least one of a left subclavian artery or a right subclavian artery, wherein a distal portion of the slender element includes: an expansion element; a neuromodulation element positioned on the expansion element and configured to stimulate at least one of the dorsal subclavian haptic or the ventral subclavian haptic, and configured to ablate at least one of the dorsal subclavian haptic or the ventral subclavian haptic, the neuromodulation element of the catheter being positioned in the subclavian artery of the subject, the neuromodulation element comprising an array of electrodes spaced circumferentially about the circumference of the catheter and longitudinally along the length of the catheter.

[0038] The neuromodulation element may include a plurality of electrodes coupled to the plurality of struts. The neuromodulation element may include a plurality of electrodes coupled to a ring. At least one of the plurality of electrodes may include a triangular base including a tip configured to press into a vessel wall.

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

[0040] In some embodiments, a tissue treatment system comprises, consists essentially of, or consists of one or more features described herein.

[0041] In some embodiments, a method of ablating a subclavian haptic comprises, consists essentially of, or consists of one or more features described herein. BRIEF DESCRIPTION OF THE DRAWINGS

[0042] The following drawings are for illustration purposes only and show non-limiting embodiments. Features in different drawings may be combined in several embodiments.

[0043] Figure 1 is a schematic diagram showing an example of the sympathetic nerve bundles innervating the heart.

[0044] Figure 2A is a schematic diagram of an example method of modulating the nerve surrounding the left subclavian artery.

[0045] Figure 2B is a schematic diagram of an example method of modulating the nerve surrounding the right subclavian artery.

[0046] Figure 3 is a schematic diagram of an example system for regulating nerves.

[0047] Figure 4 is a schematic diagram of an example neuromodulatory element.

[0048] Figure 5 is a schematic diagram of another example neuromodulatory element.

[0049] Figure 6 is a schematic diagram of another example neuromodulatory element.

[0050] Figure 7 is a schematic diagram of another example neuromodulatory element.

[0051] Figure 8 is another example of a neuromodulatory element in a blood vessel.

[0052] Fig. 9 are end or cross-sectional schematics of examples of neuromodulatory elements in blood vessels.

[0053] Fig.10 is a schematic diagram of another example neuromodulatory element.

[0054] Fig.11 An end view of an example catheter in a blood vessel is schematically shown.

[0055] Fig.12 is a flow chart of an example method 1100 of treating a subject.

[0056] Fig.13 is based on Fig.12 The method can be shown by examples provided by a computer.

[0057] Fig.14A Another example neuromodulator is schematically shown in a side view in a constricted blood vessel.

[0058] Fig. 14B Another example neuromodulatory element is schematically shown in a side view in a dilated blood vessel.

[0059] Fig.15A yes Fig.14A -B is a cross-sectional view of an example neuromodulator in a constricted blood vessel.

[0060] Fig. 15B yes Fig.14A -B is a cross-sectional view of an example neuromodulator in a dilated blood vessel.

[0061] Fig.16 is a flow chart of another example method of treating a subject. DETAILED DESCRIPTION

[0062] Most arrhythmic events are caused by myocardial infarction (MI) due to coronary artery disease, but heart failure of any cause can result in a strong arrhythmogenic tendency. Treatments for myocardial infarction (such as primary angioplasty and stenting) are effective in restoring blood flow but can result in significant residual myocardial damage. A common denominator among patients with myocardial damage is an underlying elevation in sympathetic signaling, which further increases stress on the cardiovascular system. This deleterious cascade can lead to heart failure and arrhythmias. Beta-blockers mitigate the effects of elevated sympathetic tone and are the mainstay of arrhythmia prevention and are key agents in the treatment of heart failure. However, these drugs are not completely effective and have severe systemic side effects at the high doses required for therapeutic efficacy.

[0063] Implantable cardioverter-defibrillators (ICDs) are implanted to suppress sudden cardiac death from ventricular arrhythmias. These devices monitor cardiac rhythm and provide immediate electrical defibrillation when tachyarrhythmias are detected, thus providing an insurance pathway as a reactive therapy. However, ICDs are associated with major iatrogenic morbidity: generator and lead replacements occur throughout the patient’s life, life-threatening device infections are common, and inappropriate shocks that are extremely painful and can even cause skin burns are frequent (1 in 20 patients). The vast majority of ICDs are implanted as primary prevention devices (e.g., in the presence of an arrhythmia), yet in these patients, even a small reduction in arrhythmia risk can reverse the risk / benefit profile of the ICD. Multiple clinical trials and meta-analyses have demonstrated the prevalence of inappropriate shocks from ICDs. Although most patients are implanted for primary prevention, algorithms do not predict arrhythmias well, and patients receive inappropriate shocks (shocks when an inappropriate or life-threatening arrhythmia is not present). There is also emerging evidence in the literature that the cumulative increase in the number of shocks can lead to further electrical instability in the heart, which can trigger additional arrhythmias and hospitalize patients for inappropriate shocks with symptoms ranging from extreme discomfort (pain to skin burns) to death. For these patients who continue to have arrhythmias despite the implantation of an ICD, a thoracic epidural can be performed to relieve pain and stratify patients for possible stellate ganglionectomy. Stellate ganglionectomy or stellate ganglion denervation addresses the problem of elevated sympathetic signaling (caused by cardiac disease) that is mediated by direct neural pathways that emanate from the heart to brainstem regions and then return to the heart via extracardiac, intrathoracic neural bundles such as the paraspinal sympathetic chain and its associated nerves (eg, subclavian loop) and may provide a sensible biologic target for reducing life-threatening arrhythmias and worsening of heart failure. The limited treatment strategies for primary heart failure and secondary arrhythmias leave many patients with few options during disease progression. Although catheter ablation of ventricular arrhythmias is effective in some patients, it is a very complex procedure and does not alter the underlying pathology. Many patients considered at risk for ventricular arrhythmias, with or without an implanted device (ICD), undergo a stepwise escalation of medication titration before proceeding to ICD implantation.

[0064] In terms of atrial arrhythmias, the most common arrhythmia, atrial fibrillation, is caused by an imbalance in the nerve supply to different anatomical structures of the atria (composed of cardiac and vascular tissues with fat pads in between). The current treatment strategy is through electrophysiological procedures, which directly map the most heterogeneous areas of the atria and then disconnect / electrically isolate these areas from the rest of the atria. All of these procedures target intracardiac structures, which cannot completely avoid arrhythmias. A considerable proportion of patients will have recurring arrhythmias, so experimental procedures such as fat pad ablation or ganglion plexus ablation on the surface of the heart are required. The nerve supply to these intracardiac structures comes from the sympathetic and parasympathetic nerve bundles outside the heart, among which the sympathetic nerves cause significant heterogeneity, which induces atrial fibrillation. The operator performing the ganglion plexus ablation does not know whether the ablation of all neural tissues was successful at the time of the operation.

[0065] The connection point for pathologically upregulated cardiac sympathetic signaling is from the thoracic sympathetic chain ganglia in the upper thoracic spine. In most cases of severe arrhythmias, increased sympathetic signaling is the primary cause of atrial and ventricular arrhythmias. Increased or decreased sympathetic signaling plays an important role in regulating the inotropy, conduction, relaxation, and chronotropy of the heart. In addition, the regulation of the activation-recovery interval or refractory period of the heart is well described in the literature from both preclinical studies and human studies. Therefore, patients with cardiac disease (such as those with long QT syndrome) who have underlying sympathetic hyperinnervation are considered candidates for surgical removal of the stellate ganglion (stellate ganglionectomy / stellate ganglion denervation). Cardiac surgeons have performed the highly invasive stellate ganglionectomy / stellate ganglion denervation (denervation of the heart by removal of the stellate ganglion) to treat life-threatening arrhythmias with good results. For example, these surgeries can reduce the arrhythmia burden in patients with long QT syndrome. For patients presenting with refractory ventricular arrhythmias, the only effective treatment is thoracic epidural anesthesia to block sympathetic nerve communication followed by stellate nerve resection using video-assisted thoracoscopic surgery. However, these stellate nerve resection / stellate nerve lowering procedures are highly invasive, require general anesthesia and highly specialized surgical skills and / or robotic equipment, and carry high surgical risks in patients with advanced heart disease. Despite advances in technology such as video-assisted thoracoscopic surgery, only select surgeons in select centers perform this procedure, and it is currently reserved for refractory patients as a “last resort” therapy.

[0066] While stellate ganglionectomy is effective in reducing arrhythmias by more than 90%, patients experience a wide range of postoperative complications. Because the stellate ganglion controls the sympathetic innervation of the arms, shoulders, and upper back, surgeons must remove the stellate ganglion, a highly delicate segment, by visual inspection. Surgeons perform stellate ganglionectomy by naked eye surgery, as the axial, thoracic, and cardiac fibers cannot be appreciated during surgery due to the lack of clearly discernible margins. Due to this empirical and highly subjective procedure, many patients experience symptoms of nerve damage, which results in increased pain sensation (hyperalgesia) and asymmetric sweating function (hyperhidrosis / anhidrosis) in the affected upper limb. In addition, the required robotic surgery is very complex, resulting in increased healthcare costs and reduced access to surgery.

[0067] In the pathophysiology of arrhythmias, there can be important interactions between the heart and the autonomic nervous system (ANS). Dysregulation of the ANS has been shown to play an important role in the development of arrhythmias. The role of the ANS in the development and maintenance of AF is related to autonomic imbalance. Modulation of autonomic signaling has great promise in reducing (e.g., preventing) and treating arrhythmias (e.g., vagus nerve stimulation clinical trials). The cardiac autonomic nervous system is complex and offers many easily accessible, minimally invasive targets. The use of autonomic modulation to treat AF may include potential therapeutic targets such as the autonomic ganglionic 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 (e.g., stellate ganglion block / sympathectomy) may have off-target side effects, while others do not directly affect the reduction of sympathetic signaling. Anesthetic blockade of the stellate ganglion is reversible, and patients develop symptoms of neurological damage several months later, so it is only used as a palliative treatment in extreme cases. In animal models, extracardiac nerve activity in the left stellate ganglion is enhanced before the onset of paroxysmal atrial tachycardia or atrial fibrillation (AT / AF). Stimulation of the stellate ganglion increases sinus rate and predisposes to atrial arrhythmias. Unilateral temporary stellate ganglion block prolongs the atrial effective refractory period (ERP), reduces the rate of AF induction, and / or shortens the duration of AF. Renal denervation can significantly improve the freedom from AF compared with standard pulmonary vein isolation alone.

[0068] Therapies that selectively target the cardiac sympathetic neuron supply using percutaneous intravascular devices could provide users (e.g., cardiologists) with the ability to provide effective, safe, and permanent neuromodulatory therapy to subjects at risk for arrhythmias, even as an adjunct to a primary catheter procedure. Synergies between pathophysiological mechanisms suggest that this could be a novel therapeutic approach for patients with heart failure, particularly those who cannot tolerate beta-blockers.

[0069] Cardiac dysfunction promotes increased sensory signals to the brainstem, which in turn upregulate compensatory inotropic mechanisms, which can be pathogenic in the early stages of the disease. In the setting of reduced pump function due to ischemic heart disease, cardiac sympathetic signals are enhanced in the early stages to maintain cardiac output and adequate oxygen delivery to the extremities. As the disease progresses, these sympathetic responses are amplified, leading to cardiac pathology. This pathology results in the following responses: myocardial replacement fibrosis and increased cardiac sympathetic sprouting. While the former is a maladaptive response to stress, increased sympathetic sprouting is initially an adaptive response that leads to increased heterogeneity over time. The fibrotic myocardium acts as a shunt, while areas of sympathetic sprouting act as accelerated pathways. This is an ideal substrate for the development of arrhythmias. The cardiac ANS has a major influence on cardiac electrophysiology and arrhythmias. This influence is diverse: different types of arrhythmias have different autonomic triggers. As knowledge of identifying these specific triggers grows, appropriate treatment modalities through neuromodulation can be employed accordingly.

[0070] Figure 11 is a schematic diagram showing an example of the innervation of the cardiac sympathetic nerve bundle. The subclavian artery 102 is surrounded by a dorsal subclavian loop 104 and a ventral subclavian loop 106. The subclavian loops 104 and 106 are nerve cords that form a loop around the subclavian artery downward and connect the inferior cervical ganglion and the middle cervical ganglion (also known as the C8 and T1 layers of the paravertebral sympathetic chain). The vagus nerve 108 is also shown. Arrow 110 indicates that the nerve shown extends toward the heart. In most human bodies, the C8 / T1 layers of the sympathetic chain (stellate ganglion) are significantly fused or slightly separated, providing nerve supply to the muscles of the shoulder, arm and heart. The role of the subclavian loops 104 and 106 is to transport the sympathetic nerves that specifically innervate the heart to the heart and directly connect the heart to the T1 segment. Sympathetic nerves flow to the heart through the stellate ganglion, which receives sympathetic input from the middle cervical ganglion via two separate nerve bundles, the dorsal subclavian loop 104 and the ventral subclavian loop 106. These two nerves pass above and below the subclavian artery 102, and they carry sympathetic efferent (motor) neurons that increase heart rate (chronotropic), contraction force (inotropic), relaxation force (inotropic), and conduction velocity (inotropic). Fibers that efferent through the subclavian loop originate from the T1-T4 thoracic sympathetic chain ganglia, and these fibers travel from the ventral crest of the spinal cord to T4, to T3, to T2, to T1, converge toward T1, and then converge at the middle cervical ganglion (C8-T1) through the subclavian loops 104, 106, and finally reach the heart. Afferent fibers appear to bypass the subclavian loops 104, 106 and go directly to the C8 ganglion. Surgical denervation for the treatment of arrhythmias relies on the removal of the entire T4 to half of the C8 / T1 complex (removal of the four ganglion cell bodies and their interganglionic bundles, without affecting the subclavian loops 104, 106 due to the complexity of performing the procedure around the subclavian artery 102).

[0071] The preganglionic fibers associated with the heart that arise from the thoracic cord pass upward along the paravertebral chain through the T1-T2 region, some of which synapse with postganglionic neurons in the stellate neurons, while others project to more distal internal thoracic ganglia (middle cervical ganglion, mediastinal ganglion, and internal ganglion) through the subclavian loop 104, 106, where they intermingle with parasympathetic vagal fibers. Therefore, the subclavian loop 104, 106 and the T1-T2 region of the paravertebral chain are the connection points for sympathetic afferent projections to the heart. Based on structural and functional considerations, both sites are potential targets for cardiac neuromodulation.

[0072] Preclinical studies in dogs and more recently in pigs have demonstrated that stimulation of the subclavian loops 104 and 106 produces reproducible increases in heart rate, contractility, and conduction velocity, and decreases in relaxation force. Denervation of the subclavian loops 104 and 106 followed by stimulation of the proximal (C8) stellate ganglion resulted in no change in cardiac index, confirming a nodal intervention point for cardiac sympathetic communication. Due to their close relationship to size and anatomy, the subclavian loops 104 and 106 can be modulated via catheterization of the subclavian artery 102. Modulation of the subclavian loops 104 and 106 increases heart rate and contractility while increasing conduction velocity. Denervation of the subclavian loops 104 and 106 followed by stimulation of the stellate ganglion resulted in no change in cardiac index, confirming a nodal intervention point for cardiac sympathetic communication.

[0073] Subclavian artery percutaneous catheterization can be used to target the subclavian loops 104 and 106 to map the innervation along the subclavian artery 102, detect the presence of nerves 104 and 106, and selectively ablate nerves 104 and 106 through the subclavian artery. This is a cost-effective alternative to robotic surgery.

[0074] Figure 2A is a schematic diagram of an example method of modulating nerves 204 and 206 surrounding a left subclavian artery 202. Figure 2A Shown Figure 1 222 and its branch vessels. The abdominal aorta branches from the aorta 222 to the right subclavian artery 203 and the right common carotid artery 225, the former supplying blood to the right arm and the latter supplying blood to the cerebral vessels. The left common carotid artery 224, which supplies blood to the cerebral vessels, branches directly from the aorta 222. The left subclavian artery 202, which supplies blood to the left arm, also branches directly from the aorta 222. The aorta 222 descends to the lower body, branches to the left renal artery 226 and the right renal artery 227, and then branches to the left iliac artery 228 and the right iliac artery 229. The left subclavian artery 202 is surrounded by the dorsal subclavian loop 204 and the ventral subclavian loop 206. The right subclavian artery 203 is surrounded by the dorsal subclavian loop 205 and the ventral subclavian loop 207. The vagus nerve 208 is also shown.

[0075] Figure 2A The positioning of catheter 230 is schematically shown for neuromodulation of nerves 204 and 206. Figure 2AAs shown, the catheter 230 has been navigated from an access point in the lower body (such as the right femoral artery) to the left subclavian artery 202 (e.g., a position in the left subclavian artery 202 surrounded by the dorsal subclavian loop 204 and the ventral subclavian loop 206). The catheter 230 can be introduced over a guidewire, introduced through a guide catheter, directly navigated, and / or other navigation methods. Other vascular access points can also be used. For example, the right femoral artery, the left or right radial artery, the carotid artery, etc. can be accessed, and the catheter 230 can be passed through these blood vessels to the left subclavian artery 202. In other examples, a venous vessel can be accessed, and the catheter 230 can be passed from the venous vessel to the arterial vessel (e.g., through the foramen ovale, dialysis fistula, etc.).

[0076] The distal portion of the catheter 230 includes a neuromodulatory element 232. For example, the neuromodulatory element 232 may include one or more of the following modulation means: a cryogenic element, a radiofrequency element, an ultrasound element, a laser element, a heat transfer element, a chemical transfer element, a microwave element, an electrical element, a pressure element, an acoustic element, a vibration element, a mechanical stretching element, and / or the like.

[0077] Once the neuromodulator 232 is positioned in the left subclavian artery 202, a signal can be applied to the neuromodulator (e.g., using an appropriate energy level for stimulation and surgical safety) to locate the nerves of the subclavian loops 204 and 206 for subclavian loop stimulation (SAS), which is non-therapeutic. In some embodiments, stimulation is directed away from therapy, for example because stimulation can cause side effects, such as inducing arrhythmias. Before, during, and / or after SAS, inotropy, chronotropy, and / or inotropy can be measured to determine whether the subclavian loops 204 and 206 are stimulated, for example compared to baseline (resting), vagal stimulation, and / or induced AF. SAS can be determined by cardiac hemodynamics, electrophysiological measurements, and or induced atrial tachycardia.

[0078] In some embodiments, the vagus nerve 108 may also or alternatively undergo vagus nerve stimulation (VNS). For example, an electrode catheter may be placed in the internal jugular vein (IJV) and energy may be delivered to the vagus nerve 108 (e.g., an amplitude of 0.5 to 1 V / kg, a frequency of 30 Hz, a pulse width of 50 μs, and a duration of 30 seconds). The output threshold may be determined to reduce the heart rate by 10-20%. The arterial trajectories may be recorded to determine the effect on the arterial pressure waveform.

[0079] Skin electrodes may be placed before, during, and / or after surgery to monitor diaphragmatic electromyography. The procedure may be performed under general anesthesia in a sterile environment, and appropriate therapeutic agents, such as heparin, may be administered as needed. Percutaneous access to sites such as the femoral vein, femoral artery, or radial artery may be performed under ultrasound guidance. Arterial access is not routinely used for AF ablation. In some embodiments, an arterial line may be placed for monitoring arterial pressure.

[0080] Baseline measurements prior to SAS / VNS may include, for example, baseline arterial trace, electrocardiogram, heart rate, right atrial and / or left atrial ERP, difference in ERP between left and right atria (dERP), heart rate, interatrial conduction time (IACT), and / or unipolar electrograms at baseline, during steady-state right ventricular (RV) pacing at 20-30% above basal heart rate, and / or recovery curves for RV steady-state pacing and short diastolic intervals (S1-S2).

[0081] Measurements during and / or after SAS / VNS may include, for example, changes in arterial micro-blood pressure, whether AF is induced, whether arrhythmia is induced, whether changes in cardiac cycle length are induced, repetitive recovery curves, right atrial and / or left atrial ERP, dERP, heart rate, IACT and / or unipolar electrograms of multipolar catheters during RV steady-state pacing and / or short DI after RV steady-state pacing. The monitored parameters may vary based on the nerves. For example, the cardiac parameters monitored when stimulating the dorsal subclavian loop 204 may be different from the cardiac parameters monitored when stimulating the ventral subclavian loop 206, because it is expected that modulation of these nerves may have different effects on the heart. The monitored parameters may also vary based on the lateral position. For example, the cardiac parameters monitored when stimulating the left dorsal subclavian loop 204 may be different from the cardiac parameters monitored when stimulating the right dorsal subclavian loop 206 ( Figure 2B ), as modulation of these nerves may be expected to have different effects on the heart. The cardiac parameters monitored when stimulating each subclavian loop can be tailored. In some embodiments, the cardiac parameters monitored when stimulating all subclavian loops are the same. In some embodiments, the cardiac parameters monitored when stimulating some subclavian loops are the same, while the cardiac parameters monitored when stimulating other subclavian loops are different. For example, the cardiac parameters monitored when stimulating the left and right dorsal subclavian loops may be the same, the cardiac parameters monitored when stimulating the left and right ventral subclavian loops may be the same, but the cardiac parameters monitored when stimulating the right dorsal subclavian loop may be different from the cardiac parameters monitored when stimulating the left ventral subclavian loop. For example, the cardiac parameters monitored when the left ventral subclavian loop is stimulated may be the same as the cardiac parameters monitored when the right dorsal subclavian loop is stimulated, but the cardiac parameters monitored when the left ventral subclavian loop is stimulated may be different from the cardiac parameters monitored when the right dorsal subclavian loop is stimulated.

[0082] Reference again Figure 2AOnce the neuromodulator 232 is positioned in the left subclavian artery 202, non-therapeutic stimulation can be applied to the dorsal subclavian loop 204 and / or the ventral subclavian loop 206 by achieving a targeted increase in cardiac function. For example, an increase in heart rate (e.g., an increase of about 5% to about 30% (e.g., about 5%, about 10%, about 15%, about 20%, about 25%, about 30%, ranges between these values, etc.)) can indicate that the sympathetic nervous system is stimulated. For another example, an increase in a cardiac parameter (e.g., an increase in heart rate (shortened RR interval), an increase in systemic blood pressure, an increase in left ventricular contractility, an increase in ventricular growth pressure (dP / dt), a shortening of the PR interval and QT interval, a shortening of the effective refractory period / activation recovery interval of the atria and / or ventricles, an induction of atrial tachyarrhythmias or ventricular tachyarrhythmias - which can be stopped by cardioversion or electrical shock, and combinations thereof, etc.) can indicate that the sympathetic nervous system is stimulated. Once the location of the subclavian haptics 204 and 206 is determined by non-therapeutic stimulation, the neuromodulator 232 can be used to therapeutically ablate or denervate the subclavian haptics 204 and 206. In some embodiments, the neuromodulator 232 includes multiple modes (e.g., a first mode for stimulating the subclavian haptics 204 and 206 and a second mode for ablating the subclavian haptics 204 and 206). For example, the neuromodulator 232 may include an electrode array configured to provide electrical stimulation and a different electrode array configured to provide radiofrequency ablation. For example, the neuromodulator 232 may include an electrode array configured to provide electrical stimulation and a cryogenic ablation device. In some embodiments, the neuromodulator 232 includes a single mode (e.g., configured to stimulate the subclavian haptics 204 and 206 based on a first set of stimulation parameters, and configured to ablate the subclavian haptics 204 and 206 based on a second set of ablation parameters). For example, the neuromodulatory element 232 can include an electrode array configured to provide electrical stimulation (e.g., in bipolar mode, one or more electrodes act as cathodes and one or more electrodes act as anodes) and configured to provide radiofrequency ablation (e.g., using one or more electrodes in monopolar mode). Ablation of the subclavian loops 204 and 206, rather than just stimulation, can produce long-term effects. For clarity, ablation signals are destructive signals that are irreversible in the short term (e.g., the nerves have the potential to regrow after many years). Ablation is performed selectively using a percutaneous catheter 230, rather than surgical resection. In some embodiments, the ablations described herein preferably do not target the stellate ganglion. Ablation is preferably performed from within the subclavian artery, rather than, for example, due to entering the paraspinal groove.

[0083] The dorsal subclavian loop 204 and the ventral subclavian loop 206 can be stimulated and / or ablated separately. A possible advantage of this approach is the ability to map and discretely locate nerves, visualized by biomarker changes superimposed on anatomical maps, such as CARTO mapping. In some embodiments, less than 360° of tissue surrounding the left subclavian artery is ablated. For example, this is in stark contrast to renal denervation, which aims to completely ablate all tissue surrounding the renal artery, and stent resection, which removes all nerves surrounding the subclavian artery. Compared to more thorough ablation, more specific ablation of only the dorsal subclavian loop 204 and / or the ventral subclavian loop 206 can reduce side effects (e.g., sensory disturbances (such as hypoalgesia) and / or abnormal urination movements) because ablation targets the nerves that supply the heart and avoids nerves and other tissues associated with the head, neck, and other parts of the body. In some embodiments, the dorsal subclavian haptic 204 and the ventral subclavian haptic 206 can be stimulated at the same time or simultaneously and / or ablated at the same time or simultaneously. For example, in some embodiments, the dorsal subclavian haptic 204 and the ventral subclavian haptic 206 are stimulated separately, but ablated at the same time (or a portion of the same time) or simultaneously. A possible advantage of this approach is that the nerves can be mapped and discretely located, but the dorsal subclavian haptic 204 and the ventral subclavian haptic 206 are ablated at the same time, thereby reducing the treatment time.

[0084] Figure 2B 203. The method can be similar or identical to the method for modulating nerves 204 and 206, except that catheter 230 (which can be a catheter 230) is provided. Figure 2A The same catheter shown and described or a different catheter) has been positioned in the right subclavian artery 203 (e.g., a location in the right subclavian artery 203 surrounded by the dorsal subclavian loop 204 and the ventral subclavian loop 206). Figure 2BAs shown, the catheter 230 has been navigated from an access point in the lower body (such as the right femoral artery) to the right subclavian artery 203. The catheter 230 can be introduced through a guidewire, introduced through a guide catheter, directly navigated, and / or other navigation methods. In some embodiments where the same catheter 230 is used for treatment around the left subclavian artery 202 and the right subclavian artery 203 at the same time, the catheter 230 can be repositioned without withdrawing the catheter 230 from the body. For example, a first guidewire can be navigated to the left subclavian artery 202 and the catheter 230 can be introduced over the first guidewire. During treatment around the left subclavian artery 202, the first guidewire can remain in place, partially retracted, or fully retracted. Once the treatment around the left subclavian artery 202 is completed, the first guidewire can be advanced and navigated to the right subclavian artery 203. If the first guidewire is fully retracted, the first guidewire or the second guidewire can be advanced through the catheter 230. The catheter 230 can be advanced over the first guidewire or the second guidewire repositioned in the right subclavian artery 203. The right subclavian artery 203 may be treated before the left subclavian artery 202, or vice versa.

[0085] If two catheters 230 are used, treatment of the right subclavian artery 203 and the left subclavian artery 202 can be performed at least partially simultaneously. For example, a first catheter 230 can extend from the right radial artery access point to the right subclavian artery 203, and a second catheter 230 can extend from the left radial artery access point to the left subclavian artery 202. The first and second catheters can be similar or different (e.g., including different sizes, different neuromodulation elements 232, etc.).

[0086] In some embodiments, the subclavian haptic ablation is unilateral (only the left dorsal subclavian haptic 204 and / or the left ventral subclavian haptic 206, or only the right dorsal subclavian haptic 205 and / or the right ventral subclavian haptic 207). In some embodiments, the subclavian haptic ablation is bilateral (the left dorsal subclavian haptic 204 and / or the left ventral subclavian haptic 206, and the right dorsal subclavian haptic 205 and / or the right ventral subclavian haptic 207). This provides at least four degrees of freedom to adjust the treatment for a specific outcome and / or subject. As with the left subclavian artery 202, in some embodiments, the right dorsal subclavian haptic 205 and the right ventral subclavian haptic 207 can be stimulated and / or ablated at the same time or simultaneously. For example, in some embodiments, the right dorsal subclavian loop 205 and the right ventral subclavian loop 207 can be stimulated separately, but ablated at the same time (or part of the same time) or simultaneously. A possible advantage of this approach is that while ablating the right dorsal subclavian loop 205 and the right ventral subclavian loop 207 simultaneously, the nerves can be mapped and discretely located, thereby reducing treatment time.

[0087] Figure 3is a schematic diagram of an example system 300 for regulating nerves. The system 300 includes a catheter 230 (which includes a neuromodulatory element 232) and a signal generator 302. The signal generator can be an external signal generator, an internal signal generator (e.g., the signal generator 302 can be powered from the outside via inductive coupling), or a signal generator in which components are separated between the internal and external. The signal generator 302 can include wired or wireless communication (e.g., configured to communicate with the neuromodulatory element 232, a hospital system, a computer, a handheld device (such as a mobile phone or tablet computer, etc.)). The system 300 can also include a control system / controller 301, which can include a processor for controlling one or more operations of the system 300 described herein, a display 303 for displaying information described herein, and a computer interface 305 that can be used to input information to the control system / controller 301.

[0088] If neuromodulatory element 232 includes electrodes, signal generator 302 may generate electrical signals configured as non-therapeutic SAS. For example, non-therapeutic SAS may include monopolar, bipolar, or multipolar stimulation using a pulse width between about 0.05 milliseconds (ms) and 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 therebetween, etc.), at a frequency between about 0.1 Hertz (Hz) and 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 these values, etc.), and an amplitude between about 0.1 milliamperes (mA) and 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 these values, etc.). The signal may include a charge balanced wave, a symmetrical wave, and / or an asymmetrical wave (e.g., using a 2:1 charging pulse width or an active first phase with a passive charging phase), with a duration based on the capacitance coupled to ground. The duty cycle may depend on hysteresis or the cardiac system (e.g., stimulation-induced RR shortening). The stimulation duration may be less than 1 second or greater than 30 seconds. The recovery time may be a few seconds or a few minutes, after which the stimulation may be repeated as needed.

[0089] Signal generator 302 may also or alternatively generate a signal configured for ablation. Tissue denervation occurs above 50° C. The subclavian loop may be ablated in a variety of ways, including, for example, radio frequency (RF), high power short duration radio frequency RF (HPSD RF), cryoablation (CB), microwave, high intensity focused ultrasound (HIFU), electroporation, combinations thereof, and the like. The RF energy for producing RF ablation can be generated at a frequency between about 50 (kilohertz) kHz and about 1500 kHz (e.g., 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 1000 kHz, about 1500 kHz, ranges between these values, etc.) and within a specific time window, such as between about 15 s and about 90 s (e.g., 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 these values, etc.), using a power of about 10 watts (W) to about 60 W (e.g., about 10 W, about 20 W, about 30 W, about 40 W, about 50 W, about 60 W, ranges between these values, etc.). Most lesions are caused by conductive heat, which is inversely proportional to the distance from the electrode tip. HPSD RF uses higher power and shorter duration. For example, HPSD RF can use a power between about 50W and about 90W (e.g., about 50W, about 90W, a range between these values, etc.) and a duration between about 4s and about 15s (e.g., about 4s, about 15s, a range between these values, etc.). The principle of high-power short-duration ablation is intended to change the balance between resistive and conductive energy transfer and increase the durability of tissue damage. Before the advent of RF ablation, direct current ablation or DC ablation mainly caused cell damage through electroporation or thermal damage. Electroporation can be applied with energy greater than about 200 joules (J) and lasts for several milliseconds. CB involves three stages of tissue damage. The first stage occurs during the delivery of CB, which is called the freeze-thaw stage. When the temperature drops below -15°C, tiny extracellular ice is formed, and then when the temperature drops below -40°C, intracellular ice is formed and causes local tissue damage. Upon thawing, ice crystals fuse with microthrombi and platelets aggregate. This is followed by a hemorrhagic-inflammatory phase with local tissue inflammation and edema, and finally a replacement-fibrotic phase with the formation of a fibrotic scar. The signal generator can make all of these settings and timings as needed to achieve complete ablation and denervation of the subclavian loop. CB can be used in the subclavian artery to ablate the subclavian loop using tissue cooling and the Joule-Thompson effect and the circulation of noble inert gases such as argon, helium, etc. The cryoprobe can be used with circulating cryogens.

[0090] Figure 4is a schematic diagram of an example neuromodulator 400. Neuromodulator 400 is located at the distal end of catheter 402, which may also be referred to as an elongated member. Neuromodulator 400 includes a plurality of struts 404 and a plurality of electrodes 406 coupled to struts 404. The term strut should not be limited to the material remaining after cutting from a tube, but may also include filaments braided together, strips of material joined together (e.g., at the proximal and distal ends), tubular members, combinations thereof, and the like. Electrodes 406 may be coupled directly to struts 404 (e.g., such as Figure 4 ), or may be part of an electrode assembly coupled to support 404. The combination of electrodes 406 may be used to electrically stimulate the subclavian loop. Figure 4 406. For example, one or more electrodes 406 may be used as an anode, and one or more electrodes 406 may be used as a cathode. If electrical stimulation demonstrates neural capture, the same electrode 406 combination and different parameters may be used to ablate the nerve.

[0091] Figure 5 5 is a schematic diagram of another example neuromodulator 500. Neuromodulator 500 is positioned at the distal end of catheter 502. Neuromodulator 500 includes a ring 504 and a plurality of electrodes 506 coupled to ring 504. The term ring should not be limited to circular or arcuate members, but may also include spiral, partially arcuate members, combinations thereof, etc. Electrodes 506 may be directly coupled to ring 504 (e.g., Figure 5 504 ), or may be part of an electrode assembly coupled to ring 504. A separate neuromodulatory element may be used for SAS prior to ablation. In some embodiments, cryogenic energy may be used for stimulation during initial cooling, which may be very localized and of short duration. Once the location of the target tissue is determined, cryogenic energy may be applied to electrode 506 to ablate the tissue surrounding ring 504.

[0092] Figure 6 6 is a schematic diagram of another example neuromodulation element 600. Neuromodulation element 600 is positioned at the distal end of catheter 602. Similar to neuromodulation element 500, neuromodulation element 600 includes a ring 504 and a plurality of electrodes 506 coupled to ring 504, the electrodes being configured to apply cryogenic energy to ablate tissue surrounding ring 504. Neuromodulation element further includes a second ring 604 and a second plurality of electrodes 606. Electrodes 606 may be coupled directly to ring 604 (e.g., Figure 6604 ), or may be part of an electrode assembly coupled to the ring 604. A combination of electrodes 606 may be used to electrically stimulate the subclavian loop. For example, one or more electrodes 606 may be used as an anode, and one or more electrodes 606 may be used as a cathode. If electrical stimulation demonstrates nerve capture, the corresponding combination of electrodes 506 may be used to ablate the nerve with cryogenic energy. The rings 504 and 604 are so close together that even if there is a slight offset from the location of the captured nerve, the ablation location is not negatively affected by the small distance. In some embodiments, the distance between the rings is between about 0 mm (e.g., contact) and about 3 mm (e.g., about 0 mm, about 0.5 mm, about 1 mm, about 1.5 mm, about 2 mm, about 2.5 mm, about 3 mm, a range between these values, etc.). In some embodiments, after the target tissue location is determined using the ring 604, the catheter 602 is advanced distally between the rings 504 and 604 at a known distance so that the ablation electrode 506 is in the same position as the stimulation electrode 606. For example, the handle of catheter 602 may include a slider in the channel that, when advanced distally, may advance catheter 602 and / or neuromodulation element 600 distally by the distance.

[0093] Figure 7 is a schematic diagram of another example neuromodulator 700. Neuromodulator 700 is positioned at the distal end of catheter 702. As with neuromodulator 400, neuromodulator 700 includes a plurality of struts 404 and a plurality of electrodes 406 coupled to the struts, which are configured to apply SAS. Similar to neuromodulator 500, neuromodulator 700 includes a ring 504 and a plurality of electrodes 506 coupled to the ring 504, which are configured to apply cryogenic energy to ablate tissue surrounding the ring 504. The combination of electrodes 406 can be used to electrically stimulate the subclavian loop. If the electrical stimulation demonstrates neural capture, the ring 504 can be moved longitudinally and / or rotationally into position so that the cryogenic energy applied to the selected electrode 506 can ablate the tissue. For example, catheter 702 may include a tether 708 configured to longitudinally move and / or rotationally position the ring 504, thereby positioning the electrode 506.

[0094] Figure 8 800 is a schematic diagram of another example neuromodulation element 800 in a blood vessel 808 (e.g., an artery such as the subclavian artery). Neuromodulation element 800 is positioned at a distal portion of catheter 802. Neuromodulation element 800 includes a helix or spiral 804 and a plurality of electrodes 806 coupled to helix 804. Electrodes 806 can be coupled directly to helix 804 (e.g., Figure 8 ), or may be part of an electrode assembly coupled to helix 804. Helix 804 may be configured to dilate the wall of artery 808 (e.g., as Figure 8804 ), for example, to reduce the distance between the electrode 806 in the artery 808 and the associated nerve to provide additional targeting, and / or to provide isolation. Prior to ablation, SAS may be performed using a separate neuromodulation element. Once the location of the target tissue is determined, energy may be applied to the electrode 806 to ablate the tissue surrounding the spiral 804.

[0095] Fig. 9 9 is a schematic diagram of an end or cross-sectional view of an example neuromodulation element 900 in a blood vessel 902 (e.g., an artery such as the subclavian artery). Figure 4-8 The stimulation and / or ablation element described herein or any other stimulation and / or ablation element is compatible. The neuromodulation element 900 includes a trunk 904 and a plurality of electrodes 906 coupled to the trunk 904. The trunk 904 may include, for example, struts, loops, spirals, etc. The electrode 906 includes a triangular base 908. 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 protrusions 910 (e.g., located on each side of the tip), for example, to disperse energy and / or push the electrode 906 into tissue contact.

[0096] Fig.10 1 is a schematic diagram of another example neuromodulation element 1000. Neuromodulation element 1000 is positioned at a distal portion of a catheter 1002, which may also be referred to as an elongated element. Neuromodulation element 1000 may include stimulation and / or ablation elements 1004 (e.g., as described herein). Figure 4-9 The neuromodulator 1000 may include a distal protection device 1006. For example, the distal protection device 1006 may include, for example, a filter having a distal-facing port configured to capture blood clots, thrombi, emboli, and / or any other material that may be generated during SAS and / or ablation, which preferably should not flow into the arm or other parts of the subject. The neuromodulator 1000, like other neuromodulators described herein, preferably does not block blood flow in several embodiments.

[0097] Fig.11An end view of an example catheter 1100 in a blood vessel (e.g., a subclavian artery 1102) is schematically shown. The catheter 1100 can be, for example, catheters 230, 400, 500, 600, 700, 800, 900, 1000, and 1400 (discussed below). The central spline of the catheter 1100 opens in the subclavian artery 1102 in response to operator adjustment of the catheter controller to expose electrode contacts 1104 that extend radially outward and maintain approximation to the wall of the subclavian artery 1102. This approximation determines the ability to stimulate the lumen 1103 of the subclavian artery 1102 at selected electrode contacts 1104 to determine the location of the dorsal subclavian loop 1106 and the ventral subclavian loop 1108. This information is then fed into a computer which integrates the location information, channels / electrodes stimulated, biomarker analysis, and overlays the measured biomarker changes onto the anatomical structure of the subclavian artery 1102, as shown, and divided by region. This overlay informs the operator of the location of the maximum response to the SAS, and thus the direction of the ablation energy, and allows for rechecking the success of the ablation by repeating the SAS stimulation. This process can be repeated multiple times until successful ablation of all subclavian loops 1106 and 1108 nerves is achieved and the operator is satisfied.

[0098] Fig.12 12 is a flow chart of an example method 1200 for treating a subject. At box 1202, specific electrodes are stimulated to provide non-therapeutic stimulation. At box 1204, the results are input into a computer interface (e.g., automatic, manual, semi-automatic). At box 1206, real-time data analysis is performed on the results. At box 1208, the computer overlays an anatomical image (e.g., a schematic diagram, a real ultrasound image, a combination thereof, etc.) with the response to the nerve stimulation. At box 1210, the point of maximum response marked with an asterisk or other indicator is ablated. At box 1212, the specific electrodes are re-stimulated to check for efficacy. For example, if the stimulation continues to produce a change in a cardiac parameter, it indicates that the stimulated nerve was not adequately ablated.

[0099] Fig.13 is based on Fig.12 1200. The subclavian artery 1302 is depicted as being divided into eight radial segments 1304. The segments 1304 may be asymmetric (e.g., Fig.13 ), for example, based on the expected, known and / or detected location of the subclavian artery. Segment 1304 may be asymmetric. Fig.13Eight segments 1304 are shown, but more or fewer segments 1304 may be used (e.g., depending on the number of electrodes). The computer places a first asterisk 1306 at a location believed to include the dorsal subclavian haptic and a second asterisk 1308 at a location believed to include the ventral subclavian haptic. The percentage displayed in a segment 1304 is the likelihood of ablation of that segment 1304 including the subclavian haptic. The segments 1304 may also be color coded.

[0100] Fig.11 , Fig.12 and Fig.13 Embodiments of methods and systems are shown that can identify the subclavian loop along the circumference of the subclavian artery. In addition to identifying the anterior and posterior subclavian loops along the circumference, catheter 1100 (e.g., which can be catheter 230, 400, 500, 600, 700, 800, 900, 1000) can also be provided with electrodes along the circumference and the length of the catheter. For example, in one embodiment, 5 to 20 electrodes are used. In this configuration, Fig.11 , Fig.12 and Fig.13 The method and system may be configured to identify the subclavian loop along the length of the subclavian artery. For example, when the central spline of the catheter 1100 opens in the subclavian artery 1102 in response to the operator's adjustment of the catheter control, the electrode contacts 1104 are exposed, which are radially deployed and longitudinally distributed along the length of the subclavian artery 1102. In addition to the circumference, the above-mentioned superposition may also include a superposition of the length of the subclavian artery 1102, thereby dividing the subclavian artery 1302 into radial segments 1304 (e.g., 8) and longitudinal segments (e.g., 2 to 8 longitudinal segments). These longitudinal segments can be marked, described and incorporated into the algorithm as described above. For example, in one embodiment, the catheter 1100 can be, for example, catheters 230, 400, 500, 600, 700, 800, 900, 1000, 1400 (discussed below). The central splines of the catheter 1100 open in the subclavian artery 1102 in response to operator adjustments on the catheter controls to expose electrode contacts 1104 that extend radially outward and also along the length of the subclavian artery 1302 (e.g., as shown in FIG. 1 ). Fig.14A1400 in the figure) and maintains proximity to the wall of the subclavian artery 1102. This proximity determines the ability to stimulate the lumen 1103 of the subclavian artery 1102 along the radial and length directions of the artery at the selected electrode contact 1104 to determine the location of the dorsal subclavian loop 1106 and the ventral subclavian loop 1108. This information is then input into a computer, which integrates the position information, the stimulated channel / electrode, and the biomarker analysis, and superimposes the measured biomarker changes on the anatomical structure of the represented subclavian artery 1102 and divides it into regions that can extend along the radial and length directions of the artery. Through superposition, the operator can understand the location of the greatest response to the SAS, thereby determining the direction of the ablation energy and rechecking the success of the ablation by repeatedly stimulating the SAS. This process can be repeated multiple times until successful ablation of all subclavian loops 1106 and 1108 nerves is achieved and the operator is satisfied.

[0101] As mentioned above, Fig.12 12 is a flow chart of an example method 1200 for treating a subject. At box 1202, specific electrodes are stimulated to provide non-therapeutic stimulation. At box 1204, the results are input into a computer interface (e.g., automatic, manual, semi-automatic). At box 1206, real-time data analysis of the results is performed. At box 1208, the computer overlays an anatomical image (e.g., a schematic diagram, a real ultrasound image, a combination thereof, etc.) with the response to nerve stimulation. The anatomical image may include radial positions / segments at more than one location along the length of the artery. At box 1210, the point of maximum response marked with an asterisk or other indicator is ablated. At box 1212, the specific electrodes are re-stimulated to check for efficacy. For example, if stimulation continues to cause changes in cardiac parameters, it indicates that the stimulated nerve was not adequately ablated. In one embodiment, the catheter 230, 400, 500, 600, 700, 800, 900, 1000, 1400 can also be moved to different locations along the length of the artery, and one or more of the above operations can be repeated to collect more information at different locations along the length of the artery. This process can be repeated at one or more different locations.

[0102] As mentioned above, Fig.13 is based on Fig.12 An example display may be provided by a computer of method 1200. In embodiments where there is more than one radial position / segment along the length of the artery, the depiction of the subclavian artery 1302 is divided into eight radial segments 1304 and may provide a display similar to Fig.13Additional images may be provided to represent radial segments at different locations along the length of the artery. In some embodiments, the length of the artery being tested may extend from the periosteum or opening of the subclavian artery to the portion of the artery where it begins to bend toward the arm. In some embodiments, this length of the artery may be divided into equal or unequal longitudinal segments, and in some embodiments may be divided into 5, 6, 7, 8, 9, or 10 equal or unequal longitudinal segments. In some embodiments, fewer or more segments may also be used. In some embodiments, the length of the artery being tested may be between about 1 and 5 centimeters. Segments 1304 may be asymmetrical (e.g., such as Fig.13 ), for example based on an expected, known and / or detected location of the subclavian loop. Segment 1304 may be asymmetric. Fig.13 Eight segments 1304 are shown, but more or fewer segments 1304 may be used (e.g., depending on the number of electrodes). As described above, in addition to illustrating radial segments, multiple images may be provided, such as Fig.13 to illustrate data collected at different locations along the length of the artery. Each image can provide a visual indicator indicating the location along the length of the artery. Additionally, in one embodiment, a three-dimensional representation of radial segments at more than one location along the length of the artery can also be provided on the display screen. In one embodiment, a table or chart can also be provided to display the information. Additionally, in some embodiments, ultrasound can be used to visualize the location of the stellate ganglion and the subclavian artery. For example, in some embodiments, a marker can be placed on the patient, such as a skin marker visible under fluoroscopy. The marker can be used to identify the peripheral boundaries of the artery.

[0103] In the embodiments described herein, the lesion or ablation pattern formed by the electrode can have a variety of shapes, such as, for example, circular, annular, cigar-shaped, linear, donut-shaped, elliptical and / or spherical. In some embodiments, the lesion width can be between 5 and 15 mm and the depth can be between 2 and 10 mm.

[0104] A variety of methods can be used to ablate the subclavian loop, such as radio frequency (RF), high-power short-duration radio frequency (HPSDRF), cryoablation (CB), microwave, ultrasound, high-intensity focused ultrasound (HIFU), electroporation, steam, laser, heat, alcohol or other or other chemicals, cryotherapy or a combination thereof, etc. Ablation can be reversible or irreversible. The RF energy for producing RF ablation can be generated at a frequency between about 50 (kilohertz) kHz and about 1500 kHz (e.g., 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 1000 kHz, about 1500 kHz, ranges between these values, etc.) and within a specific time window, such as between about 15 s and about 90 s (e.g., 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 these values, etc.), using a power of about 10 watts (W) to about 60 W (e.g., about 10 W, about 20 W, about 30 W, about 40 W, about 50 W, about 60 W, ranges between these values, etc.). Most lesions are caused by conductive heat, which is inversely proportional to the distance from the electrode tip. HPSD RF uses higher power and shorter duration. For example, HPSD RF can use a power between about 50W and about 90W (e.g., about 50W, about 90W, a range between these values, etc.) and a duration between about 4s and about 15s (e.g., about 4s, about 15s, a range between these values, etc.). The principle of high-power short-duration ablation is intended to change the balance between resistive and conductive energy transfer and increase the durability of tissue damage. Before the advent of RF ablation, direct current ablation or DC ablation mainly caused cell damage through electroporation or thermal damage. Electroporation can be applied with energy greater than about 200 joules (J) and lasts for several milliseconds. CB involves three stages of tissue damage. The first stage occurs during the delivery of CB, which is called the freeze-thaw stage. When the temperature drops below -15°C, tiny extracellular ice is formed, and then when the temperature drops below -40°C, intracellular ice is formed and causes local tissue damage. Upon thawing, ice crystals fuse with microthrombi and platelets aggregate. This is followed by a hemorrhagic-inflammatory phase with local tissue inflammation and edema, and finally a replacement-fibrotic phase with the formation of a fibrotic scar. The signal generator can make all of these settings and timings as needed to achieve complete ablation and denervation of the subclavian loop. CB can be used in the subclavian artery to ablate the subclavian loop using tissue cooling and the Joule-Thompson effect and the circulation of noble inert gases such as argon, helium, etc. The cryoprobe can be used with circulating cryogens.

[0105] Fig.14A-B and 15A-B show embodiments of methods and systems that can measure expansion or dilation of the subclavian artery. Catheter 1400 (e.g., catheters 230, 400, 500, 600, 700, 800, 900, 1000, 1100), also referred to as an elongated element, can include an expansion element 1404 that can be expanded or contracted by an operator adjusting the catheter (e.g., by adding or removing water or gas, or other mechanical means). In the illustrated embodiments, the expansion element can be formed in various ways to provide radial expansion of the surface of the expansion element. In some embodiments, the expansion element can include a balloon that can be filled with a filling medium. In some embodiments, the expansion element can be mechanically expanded by using a self-expanding stent or connecting rod. In embodiments utilizing a balloon, the filling of the expansion element 1404 can cause the expansion element 1404 to push against the inner wall of the artery 1402, causing the artery 1402 to dilate. The contraction of the expansion element 1404 can cause the artery 1402 to shrink to its original size. As described above, catheter 1400 may also include a neuromodulatory element 1401, which may be in the form of electrodes 1406 along the length and / or circumference of catheter 1400, including electrodes 1406 along the length and circumference of the outer surface of expansion element 1404, which may form an array and be referred to as an electrode 1406 array. The operator may decide whether to fill or shrink the expansion element 1404, and to what extent, based on various parameters measured by electrodes 1406. These parameters include, but are not limited to, vessel diameter, proximity of catheter 1400 to the relevant nerve, and tissue compliance. These expansion measurements may be used for radial and longitudinal segments of the arterial wall.

[0106] Fig.14A A side view of a catheter / elongated member 1400 is schematically shown, wherein an expansion member 1404 includes a neuromodulation member 1401 positioned on the expansion member 1404, and wherein the expansion member 1404 is in a partially expanded configuration within an artery 1402. The expansion member 1404 can be designed such that in its partially expanded configuration, an electrode 1406 of the neuromodulation member contacts the inner wall of the artery 1402. Fig. 14B A schematic side view of catheter 1400 is shown with expansion element 1404 in a second, more fully expanded configuration within artery 1402, causing dilation of artery 1402. The inner diameter and / or amount of dilation of artery 1402 may be determined by catheter 1400 (e.g., via electrodes and / or sensors located on diametrically opposite sides of expansion element 1404).

[0107] As the expansion element 1406 expands and the artery 1402 dilates, the distance between the electrode 1406 and the associated nerve 1410 can decrease, resulting in a decrease in the stimulation threshold measured by the electrode. In this way, the stimulation threshold measured by the electrode 1406 can be used to determine the distance between the electrode 1406 and the associated nerve 1410. A smaller distance between the electrode 1406 and the associated nerve 1410 can advantageously minimize the required ablation energy and allow for a more targeted application of the ablation energy. In addition to utilizing the stimulation threshold, the biomarker measurements described herein can also be used to identify movement of the electrode 1406 close to the associated nerve 1410. As described above, these measurements can also be made along radial and longitudinal segments of the arterial wall.

[0108] In some embodiments, impedance spectroscopy measurements taken by the electrode 1406 can be used to estimate tissue compliance. This has the advantage of ensuring that the blood vessel is not over-dilated and / or damaged when the balloon member (also referred to as the balloon) 1404 is inflated in an attempt to increase the proximity of the electrode 1406 to the associated nerve 1410. For example, in some embodiments, if the impedance crosses (exceeds and / or falls below) a threshold at a given frequency, a signal and / or alarm can be provided to the user to stop the expansion of the expansion element 1406 to avoid over-dilation or damage to the blood vessel. In an embodiment, if the impedance crosses (exceeds and / or falls below) a threshold at a given frequency, the system can automatically stop the expansion or reduce the expansion of the expansion element 1406 to avoid over-dilation or damage to the blood vessel. Impedance spectroscopy measurements can be used to estimate the impedance of the fluid and or tissue surrounding the electrode. As the expansion element expands, the fluid / tissue contacting the electrode changes, and the impedance changes accordingly. In addition, when the thickness of the tissue changes as the expansion element expands, the impedance also changes. Using impedance spectroscopy at a specific frequency or multiple different frequencies can provide feedback to the system. In some embodiments, the feedback can indicate how evenly the electrode is in contact with the circumference of the vessel. In other embodiments, the feedback can provide information about how much blood is in contact with the electrode. In yet another embodiment, the feedback from the impedance spectrometer can provide the approximate location of the nerve target, because the impedance on those electrodes closest to the nerve will change compared to the electrodes just contacting the smooth muscle, especially when the expandable member is expanded.

[0109] Fig.15A A cross-sectional view of expansion element 1404 in a partially expanded configuration within artery 1402 is shown. Fig. 15B A cross-sectional view of expansion element 1404 is shown within artery 1402 in a second, more expanded configuration, causing artery 1402 to dilate.

[0110] In some embodiments, a customized system for treating the subclavian loop includes one or more of the following features. The lumen of the subclavian artery is assumed to be circular and can be segmented like a clock face. The dorsal subclavian loop can be between about 7:00 and about 11:00, the ventral subclavian loop can be between about 2:00 and about 5:00, and the electrodes can be concentrated at these locations. In addition, as described above, the electrodes can also be distributed along the length of the catheter so that the lumen of the subclavian artery can be segmented along the length in addition to being segmented circumferentially. In some embodiments, the catheter can be moved longitudinally along the length of the subclavian artery lumen to produce longitudinal segmentation and / or produce additional longitudinal segmentation, and / or the catheter can be rotated to produce radial segmentation and / or produce additional radial segmentation. In some arrangements, a combination of radial and longitudinal segmentation can form a grid. Non-therapeutic stimulation along the length and / or circumference of the artery can accurately locate the loop, which provides ablation locations along the length and / or circumference. After ablation, the loop can be re-stimulated to verify whether the ablation was successful. For example, biomarkers of sympathetic nerve simulation may include (i) inotropic biomarkers, such as, for example, growth pressure (dP / dt), arterial blood pressure (systolic, diastolic, mean), pulse pressure change, increase in systemic blood pressure, increase in left ventricular growth pressure (dP / dt); (ii) chronotropic biomarkers, such as, for example, heart rate change (change in R_R or Q_Q interval on surface electrocardiogram), increase in heart rate (shortening of RR interval), change in basal cycle length on intracardiac electrogram; (iii) inotropic conduction biomarkers, such as, for example, change in PR interval (indicator of change in heart rate and AV conduction time), change in QT interval (indicator of change in ventricular excitation, increase in denervation / ablation activation recovery interval (measured by intracardiac electrogram in EP laboratory), change in QT variability, change in T peak-T end interval, denervation branch (iv) biomarkers of change, such as, for example, negative differentiation function of growth pressure, and changes in the slope of the pressure-volume loop base; (v) biomarkers of inflammation, such as, for example, reduction in inflammatory markers - changes in CRP (blood and tissue), local tissue TNFα levels, reduction in inflammasome levels, changes in leukotrienes and prostaglandins levels or their precursors, and reduction in 3-nitrotyrosine levels in myocardium or tissue biopsy. For some biomarkers, ablation may produce an effect that is opposite to baseline, such as a slight decrease in basal heart rate, a mild decrease in arterial pressure, little change in left ventricular contractility, and / or a prolonged effective refractory period. If restimulation testing does not produce the same changes in biomarkers of sympathetic stimulation, then the ablation was successful.Thus, in some applications, the position of the catheter 1110 within the subclavian artery is first confirmed, stimulation is then performed to determine the loop, followed by determination of cardiac biomarkers, and then a denervation procedure (e.g., ablation) is performed on the loop. Once the denervation procedure is complete, the results can be confirmed by re-applying stimulation and demonstrating that the biomarkers no longer change with stimulation. Denervation (e.g., ablation) can be partial or complete and can be reversible or permanent.

[0111] In some embodiments, the controller 301 can use a machine learning algorithm that can be used to set and / or automatically adjust the stimulation applied by the catheter and / or analyze the cardiac parameters and / or biomarkers being monitored. In some embodiments, the machine learning algorithm can adjust the stimulation parameters (power, duration, amplitude) based on the cardiac parameters and / or biomarkers being monitored and / or in combination with the cardiac parameters and / or biomarkers being monitored after ablation of the target nerve. In some embodiments, the training result of the machine learning algorithm is to determine typical positions, stimulation parameters, ablation parameters, cardiac parameters and / or biomarkers.

[0112] In certain embodiments, a catheter, e.g., catheters 230, 400, 500, 600, 700, 800, 900, 1000, 1400 (discussed below), can be driven by a robotic control system and / or have automatic or semi-automatic control capabilities. For example, in certain embodiments, the longitudinal movement and / or rotation of the catheter can be controlled by a robot with linear and / or rotary actuators. Bending and expansion of the distal end of the catheter can also be controlled by the robotic system. In one example embodiment, the movement and motion of the catheter can be automatically controlled by a robotic system to collect the above data along the radial and longitudinal divisions of the artery. Once the information is collected, the robotic system can automatically or semi-automatically move the neuromodulatory element to a designated or target area to perform the ablation described herein.

[0113] Fig.16 16 is a flow chart of another example method 1600 for treating a subject. At box 1602, a subject presents with a refractory arrhythmia. At box 1604, the subject is stabilized and the cause of the refractory arrhythmia is evaluated. At box 1606, any ICD is turned off and an epidural is administered to assess whether sympathetic drive is driving the arrhythmia. If sympathetic drive is not driving the arrhythmia, an arrhythmogenic lesion is assessed at box 1608 by an electrophysiology laboratory (EP lab). If sympathetic drive is driving the arrhythmia, a subclavian loop ablation is performed at box 1610 (e.g., as described herein).

[0114] The present disclosure relates to neuromodulation and ablation of the subclavian loop of a subject to treat heart disease. Heart disease can refer to ventricular arrhythmias, atrial fibrillation, ventricular tachycardia, ventricular fibrillation, congestive heart failure and atrial flutter. In addition, the method and system for neuromodulation (such as ablation) of the subclavian loop of a subject can also be used to treat other conditions or diseases. For example, aspects of the present disclosure are to recognize that stellate ganglion block or denervation, or subclavian loop ablation can also affect hemodynamic function. In some applications, activation of sympathetic nerves using pharmacological agonists or neural stimulation can change heart rate, contractility, conduction and relaxation. In one embodiment, targeted sympathetic denervation / dispersion or blocking can lead to improvements in cardiac diastolic properties. Specifically, in some embodiments, the compliance of the left ventricle can be improved, thereby reducing afterload. This improvement in compliance can have a positive impact on the increase in stroke volume and subsequent cardiac output. Thus, stellate nerve blockade using neuromodulation (such as the ablation method proposed herein) can result in improvements in indices of diastolic function as measured by end-systolic transventricular wall stress, changes in peripheral vascular resistance, increases in end-diastolic volume, and increases in stroke volume and / or cardiac output. This can occur with or without measurable changes in heart rate due to direct sympathetic nerve effects on the myocardium, independent of varicoceptive effects.

[0115] Ablation can also be performed without stimulation before and / or after ablation. For example, ablation can be performed around the subclavian artery, including the locations of the dorsal and ventral subclavian loops. As another example, ablation can be performed at an expected location in the subclavian loop. For example, the longitudinal and / or radial position of the neuromodulatory element can be visualized (e.g., using fluoroscopy, ultrasound, etc.), and electrodes can be selected for ablation energy. For example, the longitudinal and / or radial position of the neuromodulatory element, whose electrodes can be selectively positioned to correspond to the expected subclavian loop location, can be visualized (e.g., using fluoroscopy, ultrasound, etc.), and all electrodes can be selected for ablation energy. Stimulation can only be performed after ablation to verify the effectiveness of the ablation.

[0116] Pharmacological therapy

[0117] In several embodiments, the neuromodulation therapies described herein may be used to replace pharmacological (drug) therapies. However, in other embodiments, drug therapies may be used in combination with the neuromodulation therapies described herein, but at a reduced frequency or dosage, thereby reducing undesirable side effects. For example, a drug (or combination of drugs), when used in combination with the neuromodulation therapies described herein, may shorten the overall duration of medication, reduce the number of medications per day / week / month, and / or reduce the dosage of medication. In addition to reducing undesirable pharmacological side effects, this may also reduce addiction or dependence. The neuromodulation described herein may also be used to reduce or otherwise discontinue pain medications and other medications in a subject.

[0118] Certain experiments describe the use of drugs, such as to induce certain physiological conditions before, during, and / or after stimulation and / or ablation. The devices and methods described herein can be used without the use of drugs (e.g., without the use of drugs that induce certain physiological conditions). For example, anesthetics and other drugs that enable 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 to be drugs.

[0119] The above description and examples are only used to illustrate the concepts of the present invention and are not restrictive. Each disclosed aspect and example of the present disclosure may be considered alone or in combination with other aspects, examples and variations of the present disclosure. In addition, unless otherwise stated, any step of the disclosed method is not limited to any specific order of execution. Reasonable modifications to the disclosed examples that incorporate the spirit and substance of the present disclosure are within the scope of the present disclosure. In addition, all references cited herein are incorporated by reference in their entirety. The titles used herein are for organizational purposes only and should not be used to improperly limit the scope of the claims or implementation methods.

[0120] Although the methods and devices described herein may have various modifications and alternative forms, specific examples thereof have been shown in the accompanying 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, they cover all reasonable modifications, equivalents, and alternative forms that fall within the spirit and scope of the various examples described and the appended claims. In addition, any specific features, aspects, methods, attributes, characteristics, qualities, properties, elements, or the like related to the examples disclosed herein may be used in all other examples described herein. None of the methods disclosed herein need to be performed in the order described. According to different examples, one or more behaviors, events, or functions in the algorithms, methods, or processes described herein may be performed in different orders, or may be added, merged, or completely omitted (e.g., not all described behaviors or events are necessary for the practice of the algorithm). Algorithms, modules, blocks, steps, boxes, elements, features, etc. may be stored in machine-readable memory. In some instances, behaviors or events may be executed concurrently, such as by multithreading, interrupt processing, or multiple processors or processor cores or other parallel architectures, rather than sequentially. In addition, any element, feature, block, frame or step, or any group of elements, features, blocks, frames or steps, is not necessary or indispensable for each instance. In addition, all possible combinations, sub-combinations and rearrangements of systems, methods, features, elements, modules, blocks, frames, etc. are within the scope of the present disclosure. Unless otherwise specifically stated, or otherwise understood according to the context used, the use of sequential or time-sequential language such as "then", "next", "after", "subsequently" is generally for the convenience of text, rather than for limiting the order of the operations performed. Therefore, some instances can be performed using the order of operations described herein, while other instances can be performed in different orders of operations.

[0121] Various illustrative logic blocks, boxes, modules, processes, methods, and algorithms associated with the examples disclosed herein can be implemented as electronic hardware, computer software, or a combination of the two. In order to clearly illustrate this interchangeability of hardware and software, various illustrative components, modules, modules, operations, and steps have been generally described above from a functional perspective. Whether these functions are implemented in the form of hardware or software depends on the specific application and the design constraints on the entire system. For each specific application, the functions can be implemented in different ways, but such implementation decisions should not be interpreted as departing from the scope of the present disclosure.

[0122] The various illustrative logical blocks and modules associated with the examples disclosed herein may 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 thereof, to perform the functions described herein. A general purpose processor may be a microprocessor, but in the alternative, the processor may also be a controller, a microcontroller or a state machine, a combination thereof, or a similar device. The processor may also be implemented as a combination of computing devices, such as a combination of a DSP and a microprocessor, a plurality of microprocessors, a combination of one or more microprocessors and a DSP core, or any other such configuration.

[0123] The blocks, operations or steps of the methods, processes or algorithms described in the examples disclosed herein may be directly embodied in hardware, or in software modules executed by a processor, or in a combination of the two. The software module may be present in a RAM memory, a flash memory, a ROM memory, an EPROM memory, an EEPROM memory, a register, a hard disk, a removable disk, an optical disk (such as a CD-ROM or a DVD), or any other form of volatile or non-volatile computer-readable storage medium known in the art. The storage medium may be connected to the processor so that the processor can read information from the storage medium and write information to the storage medium. Alternatively, the storage medium may be integrated with the processor. The processor and the storage medium may be installed in an ASIC. The ASIC may be located in a user terminal. Alternatively, the processor and the storage medium may be present in a user terminal as discrete components.

[0124] Conditional language used herein, such as "can", "might", "may", "eg", etc., unless otherwise specifically stated or understood otherwise in the context of use, is generally intended to express that some instances include certain features, elements, and / or states, while other instances do not include these features, elements, and / or states. Therefore, such conditional language does not generally mean that features, elements, blocks, and / or states are required for one or more instances, or that one or more instances necessarily include logic for determining whether these features, elements, and / or states are included in any particular instance or whether to be performed in any particular instance with or without author input or prompting.

[0125] The methods disclosed herein may include certain actions taken by a practitioner; however, the methods may also include any third-party instructions for these actions, whether explicit or implicit. For example, an operation such as "stimulating a nerve" includes "instructing stimulation of a nerve."

[0126] The ranges disclosed herein also include any and all overlaps, sub-ranges, and combinations thereof. Language such as "up to", "at least", "greater than", "less than", "between" includes the stated numbers. Numbers beginning with words such as "about" or "approximately" include the stated numbers and should be interpreted according to the specific circumstances (e.g., as accurately as possible in the specific circumstances, such as ±5%, ±10%, ±15%, etc.). For example, "about 1mm" includes "1mm". Phrases beginning with words such as "substantially" include the stated phrases and should be interpreted according to the specific circumstances (e.g., as reasonably as possible in the specific circumstances). For example, "substantially parallel" includes "parallel". Unless otherwise stated, all measurements are performed under standard conditions, including temperature and pressure. The phrase "at least one of" is intended to require at least one item in the list that follows, rather than one of each item in the list that follows. For example, “at least one of A, B, and C” may include A, B, C, A and B, A and C, B and C, or A, B and C.

[0127] Unless otherwise defined, all technical terms used herein have the same meaning as those generally understood by those of ordinary skill in the art to which the present disclosure relates. The singular forms "a", "an" and "the" used herein also include plural forms, unless the context clearly states otherwise. As used herein, the terms "comprises" and / or "comprising" may indicate the presence of the features, steps, operations, elements, components and / or groups, but do not exclude the presence or addition of one or more other features, steps, operations, elements, components and / or groups. As used herein, the term "and / or" may include any and all combinations of one or more related listed items. The terms "first", "second" and the like used herein should not limit the elements described by these terms. These terms are only used to distinguish one element from another. Therefore, the "first" element discussed below may also be referred to as the "second" element without departing from the teachings of the present disclosure. Unless otherwise specifically stated, the order of operations (or actions / steps) is not limited to the order shown in the claims or figures.

[0128] As used herein, the term "neuromodulation" may refer to an electrical signal delivered to a nervous tissue as a therapy. In some cases, the nervous tissue may include at least a portion of a sympathetic chain. For example, the sympathetic chain may refer to a lumbar sympathetic chain. As used herein, the term "sympathetic nervous system" may refer to a portion of the autonomic nervous system that activates a "fight or flight" response (usually increasing heart rate, dilating pupils, dilating bronchi, inhibiting digestion, constricting blood vessels, increasing cardiac output, and raising blood pressure, etc.), which prepares for intense physical activity. As used herein, the term "electrical signal" may refer to a voltage or current that varies over time. For example, an electrical signal may be represented by a waveform (a graphical representation of a current or voltage that varies over time). As used herein, the term "electrode contact" may refer to a material that is a conductor through which an electric current enters or leaves. At least a portion of the material may be a biocompatible material. As used herein, the terms "subject" and "patient" are used interchangeably and refer to any warm-blooded organism, including but not limited to humans, pigs, rats, mice, dogs, cats, goats, sheep, horses, monkeys, apes, rabbits, cows, etc.

Claims

1. A method for treating heart disease in a subject, the method comprising: percutaneously introducing a catheter into the vasculature of the subject, wherein the catheter comprises a neuromodulatory element; positioning the neuromodulatory element in a left subclavian artery of the subject; Electrical stimulation of the left dorsal subclavian loop; confirming stimulation of the left dorsal subclavian loop by monitoring a first cardiac parameter; After confirming stimulation of the left dorsal subclavian loop, providing ablative energy to the left dorsal subclavian loop; Electrical stimulation of the left ventral subclavian loop; confirming stimulation of the left ventral subclavian loop by monitoring a second cardiac parameter; After confirming the stimulation of the left ventral subclavian loop, providing ablative energy to the left ventral subclavian loop; positioning the neuromodulatory element in a right subclavian artery of the subject; Electrical stimulation of the right dorsal subclavian loop; confirming stimulation of the right dorsal subclavian loop by monitoring a third cardiac parameter; After confirming stimulation of the right dorsal subclavian loop, providing ablative energy to the right dorsal subclavian loop; Electrical stimulation of the right ventral subclavian loop; confirming stimulation of the right ventral subclavian loop by monitoring a fourth cardiac parameter; and After confirming stimulation of the right ventral subclavian loop, ablation energy is provided to the right ventral subclavian loop.

2. The method of claim 1, wherein the first cardiac parameter is different from at least one of the second cardiac parameter, the third cardiac parameter, or the fourth cardiac parameter.

3. The method of claim 2, wherein the second cardiac parameter is different from at least one of the first cardiac parameter, the third cardiac parameter, or the fourth cardiac parameter.

4. The method of claim 3, wherein the third cardiac parameter is different from at least one of the first cardiac parameter, the second cardiac parameter, or the fourth cardiac parameter.

5. The method of claim 4, wherein the fourth cardiac parameter is different from at least one of the first cardiac parameter, the second cardiac parameter, or the third cardiac parameter.

6. The method of claim 1, wherein the first cardiac parameter is the same as at least one of the second cardiac parameter, the third cardiac parameter, or the fourth cardiac parameter.

7. The method of claim 1, wherein the second cardiac parameter is the same as at least one of the first cardiac parameter, the third cardiac parameter, or the fourth cardiac parameter.

8. The method of claim 1, wherein the third cardiac parameter is the same as at least one of the first cardiac parameter, the second cardiac parameter, or the fourth cardiac parameter.

9. The method of claim 1, wherein the fourth cardiac parameter is the same as at least one of the first cardiac parameter, the second cardiac parameter, or the third cardiac parameter.

10. The method according to any one of claims 1 to 9, wherein at least one of the first cardiac parameter, the second cardiac parameter, the third cardiac parameter or the fourth cardiac parameter comprises at least one of arterial micro-blood pressure changes, whether AF is induced, whether arrhythmia is induced, whether cardiac cycle length changes are induced, a repetitive recovery curve, right atrial ERP, left atrial ERP, dERP, heart rate, IACT, or a multipolar catheter unipolar electrogram of short DI under or after steady-state RV pacing.

11. The method of any one of claims 1 to 9, further comprising re-stimulating the subclavian haptic after providing ablative energy, and providing further ablative energy to the subclavian haptic if cardiac parameters confirm stimulation.

12. The method of claim 11, comprising repeating said restimulation and providing further ablation energy until said cardiac parameters no longer confirm stimulation.

13. The method of any one of claims 1 to 9, wherein the catheter comprises an expansion element, the neuromodulation element being positioned on the expansion element.

14. The method of claim 13, comprising expanding the expansion element to dilate the vasculature.

15. A method of treating heart disease in a subject, the method comprising: positioning a neuromodulatory element in a subclavian artery of the subject; electrically stimulating at least one of the dorsal subclavian loop or the ventral subclavian loop; confirming stimulation of the dorsal subclavian loop and / or the ventral subclavian loop by monitoring cardiac parameters; and After confirming stimulation of the dorsal subclavian haptic and / or the ventral subclavian haptic, ablative energy is provided to the dorsal subclavian haptic and / or the ventral subclavian haptic.

16. The method of claim 15, wherein the ablation energy comprises radiofrequency ablation energy. The method of claim 15 , wherein the ablative energy comprises cryogenic ablative energy.

18. The method of claim 15, wherein electrically stimulating comprises using a combination of electrodes of the neuromodulation element, and wherein providing ablative energy comprises using the same combination of electrodes of the neuromodulation element.

19. The method of claim 15, further comprising assessing whether sympathetic nerve drive drives a refractory arrhythmia.

20. The method of any one of claims 15 to 19, wherein the heart disease comprises atrial fibrillation.

21. The method of any one of claims 15 to 19, wherein the cardiac disease comprises a refractory arrhythmia or a ventricular arrhythmia.

22. A catheter for treating a heart condition in a subject, the catheter comprising: An elongated member configured to be positioned in at least one of a left subclavian artery or a right subclavian artery, wherein a distal portion of the elongated member comprises: Expansion element, A neuromodulatory element positioned on the expansion element and configured to stimulate at least one of the dorsal subclavian haptic or the ventral subclavian haptic and configured to ablate at least one of the dorsal subclavian haptic or the ventral subclavian haptic, the neuromodulatory element of the catheter being in the subclavian artery of the subject, the neuromodulatory element comprising an array of electrodes spaced circumferentially about the circumference of the catheter and longitudinally along the length of the catheter.

23. The catheter of claim 22, wherein the neuromodulation element comprises a plurality of electrodes coupled to a plurality of struts.

24. The catheter of claim 22, wherein the neuromodulation element comprises a plurality of electrodes coupled to a ring.

25. The catheter of claim 22, comprising a distal protection device located distal to the neuromodulation element.

26. The catheter of any one of claims 23 to 25, wherein at least one electrode of the plurality of electrodes comprises a triangular base including a tip configured to press into a blood vessel wall.

27. A catheter for treating a cardiac condition in a subject, the catheter comprising: An elongated member configured to be positioned in at least one of a left subclavian artery or a right subclavian artery, wherein a distal portion of the elongated member comprises: A neuromodulatory element configured to stimulate at least one of the dorsal subclavian haptic or the ventral subclavian haptic and configured to ablate at least one of the dorsal subclavian haptic or the ventral subclavian haptic, the neuromodulatory element comprising an array of electrodes spaced circumferentially about the circumference of the catheter and longitudinally along the length of the catheter.

28. The catheter of claim 27, wherein the electrode array comprises a plurality of electrodes coupled to a plurality of struts.

29. The catheter of claim 27, wherein the electrode array comprises a plurality of electrodes coupled to a ring.

30. The catheter of Claim 27, wherein the electrode array comprises a plurality of electrodes coupled to a helix.

31. The catheter of any one of claims 27 to 30, wherein at least one electrode of the electrode array comprises a triangular base including a tip configured to press into a blood vessel wall.

32. The catheter of any one of claims 27 to 30, further comprising an expansion element on which the electrode array is located.

33. The catheter of claim 32, wherein the expansion element comprises a balloon.

34. A method of treating heart disease in a subject, the method comprising: percutaneously introducing a catheter into the vasculature of the subject, wherein the catheter comprises a neuromodulatory element; positioning the neuromodulatory element in a subclavian artery of the subject; electrically stimulating at least one of the dorsal subclavian loop or the ventral subclavian loop; confirming stimulation of the dorsal subclavian loop and / or the ventral subclavian loop by monitoring cardiac parameters; and After confirming stimulation of the dorsal subclavian haptic and / or the ventral subclavian haptic, ablative energy is provided to the dorsal subclavian haptic and / or the ventral subclavian haptic.

35. The method of claim 34, further comprising re-stimulating the subclavian haptic after providing ablative energy, and further providing ablative energy to the subclavian haptic if cardiac parameters confirm stimulation.

36. The method of claim 35, comprising repeating said restimulation and providing further ablation energy until said cardiac parameters no longer confirm stimulation.

37. The method of any one of claims 34 to 36, wherein percutaneously introducing the catheter into the vasculature comprises inserting the catheter into a femoral artery of the subject.

38. The method of any one of claims 34 to 36, wherein percutaneously introducing the catheter into the vasculature comprises inserting the catheter into a radial artery of the subject.

39. The method of any one of claims 34 to 36, wherein percutaneously introducing the catheter into the vasculature comprises inserting the catheter into a carotid artery of the subject.

40. The method of any one of claims 34 to 36, wherein percutaneously introducing the catheter into the vasculature comprises inserting the catheter into a femoral vein of the subject, and at least one of positioning the neuromodulatory element in the left subclavian artery or positioning the neuromodulatory element in the right left subclavian artery comprises traversing from a venous vasculature to an arterial vasculature.

41. A method of treating heart disease in a subject, the method comprising: percutaneously introducing a catheter into the vasculature of the subject, wherein the catheter comprises a neuromodulatory element; positioning the neuromodulatory element in a subclavian artery of the subject; Electrical stimulation of the dorsal subclavian loop; confirming stimulation of the dorsal subclavian loop by monitoring a first cardiac parameter; After confirming stimulation of the dorsal subclavian loop, providing ablative energy to the dorsal subclavian loop; Electrical stimulation of the ventral subclavian loop; confirming stimulation of the ventral subclavian loop by monitoring a second cardiac parameter; and After confirming stimulation of the ventral subclavian loop, ablative energy is provided to the ventral subclavian loop.

42. The method of claim 41, wherein the first cardiac parameter is different from the second cardiac parameter.

43. The method of claim 41, wherein the first cardiac parameter is the same as the second cardiac parameter.

44. The method according to any one of claims 41 to 43, wherein at least one of the first cardiac parameter or the second cardiac parameter comprises at least one of arterial micro-blood pressure changes, whether AF is induced, whether arrhythmia is induced, whether cardiac cycle length changes are induced, repetitive recovery curves, right atrial ERP, left atrial ERP, dERP, heart rate, IACT, or a multipolar catheter unipolar electrogram of short DI under or after steady-state RV pacing.

45. The method of any one of claims 41 to 43, further comprising re-stimulating the subclavian haptic after providing ablative energy, and further providing ablative energy to the subclavian haptic if cardiac parameters confirm stimulation.

46. ​​The method of claim 45, comprising repeating said restimulation and providing further ablation energy until said cardiac parameters no longer confirm stimulation.

47. The method of any one of claims 41 to 43, wherein the catheter comprises an expansion element on which the neuromodulation element is positioned, and optionally The expansion element is expanded an amount to dilate the vasculature.

48. A catheter for treating heart disease in a subject, the catheter comprising: An elongated member configured to be positioned in at least one of a left subclavian artery or a right subclavian artery, wherein a distal portion of the elongated member comprises: a first neuromodulation element configured to stimulate at least one of the dorsal subclavian haptic or the ventral subclavian haptic; a second neuromodulatory element configured to ablate at least one of the dorsal subclavian haptic or the ventral subclavian haptic; and A distal protection device is distal to the first neuromodulation element and the second neuromodulation element.

49. The catheter of claim 48, wherein the first neuromodulation element comprises a first plurality of electrodes coupled directly or indirectly to one or more struts, rings, and / or helices.

50. The catheter of claim 49, wherein at least one electrode of the plurality of electrodes comprises a triangular base comprising a tip configured to press into a vessel wall, in, Optionally, the at least one electrode further comprises a plurality of electrode protrusions located on different sides of the tip of the triangular base.

51. The catheter of any one of claims 48 to 50, wherein the second neuromodulatory element comprises the first plurality of electrodes and a second plurality of electrodes coupled directly or indirectly to a second plurality of struts, rings and / or helices or other elements of similar functionality.

52. The catheter of claim 48, further comprising an expansion element, and wherein the first neuromodulation element and the second neuromodulation element are positioned on the expansion element, wherein the expansion element optionally comprises a balloon.

53. A catheter for treating heart disease in a subject, the catheter comprising: An elongated member configured to be positioned in at least one of a left subclavian artery or a right subclavian artery, wherein a distal portion of the elongated member comprises: a neuromodulatory element configured to stimulate at least one of the dorsal subclavian haptic or the ventral subclavian haptic and configured to ablate at least one of the dorsal subclavian haptic or the ventral subclavian haptic; and A distal protection device is located at the distal end of the neuromodulation element.

54. The catheter of claim 53, wherein the neuromodulatory element comprises a plurality of electrodes coupled directly or indirectly to a plurality of struts, loops and / or helices or other elements of similar functionality.

55. A catheter according to any one of claims 53 to 54, wherein at least one of the plurality of electrodes comprises a triangular base including a tip configured to press into a vessel wall, and optionally comprising a plurality of electrode protrusions located on different sides of the tip of the triangular base.

56. The catheter of claim 55, further comprising an expansion element, and wherein the neuromodulation element is positioned on the expansion element, wherein the expansion element optionally comprises a balloon.

57. A method of treating a subject, the method comprising: Stimulate specific electrodes of the neuromodulation device; The results are provided to an interface computer, the computer being configured to: Perform real-time data analysis; and superimposing a response to the stimulus on the anatomical image, including marking the location where the response is maximal; and Ablation is performed at the location.

58. The method of claim 57, further comprising one or more of the following: After ablation, restimulation is performed to verify the effect of the ablation; If the ablation is ineffective, further ablation is performed, and the verification and further ablation are optionally repeated until the ablation is effective.

59. A method of treating a subject experiencing a refractory cardiac arrhythmia, the method comprising: stabilizing the subject; Evaluate the cause of the refractory arrhythmia; Assess whether sympathetic nerve drive drives the refractory arrhythmias; If sympathetic drive is not driving the refractory arrhythmia, coordinate evaluation for an arrhythmogenic lesion; and If sympathetic drive drives the refractory arrhythmia, subclavian loop ablation is performed.

60. The method of claim 59, wherein assessing whether sympathetic drive is driving the refractory arrhythmia comprises infusing epidural anesthesia and / or wherein assessing whether sympathetic drive is driving the refractory arrhythmia comprises shutting down an implantable cardioverter-defibrillator of the subject.

61. A method of treating heart disease in a subject, the method comprising: positioning a neuromodulatory element in a subclavian artery of the subject; and Ablation energy is delivered to the dorsal subclavian loop and / or the ventral subclavian loop.

62. The method of claim 61, wherein providing the ablation energy comprises selectively providing the ablation energy.

63. The method of claim 62, wherein selectively providing the ablative energy comprises one or more of: non-therapeutic stimulation to determine the location of the dorsal subclavian haptic and / or the ventral subclavian haptic; The subclavian artery is imaged to determine the possible location of the dorsal subclavian loop and / or the ventral subclavian loop.

64. The method of claim 63, wherein providing the ablative energy comprises providing the ablative energy around the subclavian artery.

65. A method of treating a subject, the method comprising: positioning a neuromodulation element of a catheter in a subclavian artery of the subject, the neuromodulation element comprising an array of electrodes spaced circumferentially about a circumference of the catheter and longitudinally along a length of the catheter; stimulating specific electrodes in the electrode array; The results are provided to an interface computer, the computer being configured to: Perform real-time data analysis; and superimposing a response to the stimulus on the anatomical image, including marking the location where the response is maximal; and Ablation is performed at the location.

66. The method of claim 65, further comprising, after ablation, restimulation to verify effectiveness of the ablation, and further ablation if the ablation is ineffective, and optionally comprising repeating restimulation and further ablation until the ablation is verified to be effective.

67. The method of claim 65 or 66, wherein the neuromodulatory element is positioned on an expansion element.

68. The method of claim 67, comprising expanding the expandable element to dilate the subclavian artery.

69. The method of claim 68, comprising taking impedance measurements while the expansion element is expanded.

70. A method of treating heart disease in a subject, the method comprising: percutaneously introducing a catheter into the vasculature of the subject, wherein the catheter comprises a neuromodulatory element; positioning the neuromodulatory element in a subclavian artery of the subject; electrically stimulating at least one of the dorsal subclavian loop or the ventral subclavian loop; confirming stimulation of the dorsal subclavian loop and / or the ventral subclavian loop by monitoring biomarkers, wherein the biomarkers include at least one of an inotropic biomarker, a chronotropic biomarker, a transduction biomarker, a comfort biomarker, or an inflammatory biomarker; After confirming stimulation of the dorsal subclavian haptic and / or the ventral subclavian haptic, ablative energy is provided to the dorsal subclavian haptic and / or the ventral subclavian haptic.

71. The method of claim 70, further comprising re-stimulating the subclavian haptic after providing ablative energy, and further providing ablative energy to the subclavian haptic if the biomarker confirms stimulation.

72. The method of claim 71 comprising repeating said restimulation and providing further ablation energy until said biomarker no longer confirms stimulation.

73. The method of claim 71, wherein the biomarker comprises at least one of increased systolic pressure (dP / dt), arterial blood pressure (systolic, diastolic, mean), pulse pressure variation, increased systemic blood pressure, or increased left ventricular systolic pressure (dP / dt).

74. The method of claim 71, wherein the biomarker comprises at least one of a change in heart rate (a change in the R_R or Q_Q interval on a surface ECG), an increase in heart rate (shortening of the RR interval), or a change in the length of the basal cycle on an intracardiac electrogram.

75. The method of claim 71, wherein the biomarker comprises a rheoconduction biomarker.

76. The method of any one of claims 70 to 75, wherein the catheter comprises a balloon, and wherein the neuromodulation element is positioned on the balloon, and optionally the balloon catheter is inflated an amount to dilate the vasculature of the subject.

77. A method of treating heart disease in a subject, the method comprising: positioning a neuromodulatory element over the expandable element in a subclavian artery of the subject; expanding the expansion element; electrically stimulating at least one of the dorsal subclavian loop or the ventral subclavian loop; confirming stimulation of the dorsal subclavian loop and / or the ventral subclavian loop by monitoring cardiac parameters; and After confirming stimulation of the dorsal subclavian haptic and / or the ventral subclavian haptic, ablative energy is provided to the dorsal subclavian haptic and / or the ventral subclavian haptic.

78. A method according to any of the preceding claims, wherein the ablation or other neuromodulation is performed using radiofrequency, ultrasound, microwaves, steam, laser, heat, alcohol or other chemicals, cryogenics, or a combination thereof, and wherein the ablation is reversible or irreversible.

79. The method of claim 78, wherein the electrical stimulation comprises using a combination of electrodes of the neuromodulation element, and wherein providing ablation energy comprises using the same combination of electrodes of the neuromodulation element.

80. The method of any one of claims 77 to 79, wherein the cardiac disease comprises atrial fibrillation and / or refractory arrhythmias.

81. A signal generator for generating ablative energy according to any one of the preceding claims, having one or more of the features described in the preceding description.

82. A method of regulating and / or ablating the subclavian haptic having one or more of the features described above.

83. A therapeutic system having one or more of the features described above.

84. A tissue treatment system having one or more of the features described above.

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