WO2008070413A2

WO2008070413A2 - Methods for treating heart arrhythmia

Info

Publication number: WO2008070413A2
Application number: PCT/US2007/084705
Authority: WO
Inventors: Denise Demarais; Hanson Gifford Iii
Original assignee: Ardian, Inc.
Priority date: 2006-11-14
Filing date: 2007-11-14
Publication date: 2008-06-12
Also published as: US10130792B2; US20110257564A1; US20150157398A1; US9326817B2; US20160279384A1; US8948865B2; US20100174282A1; US20140107539A1; WO2008070413A3; US8620423B2; US20070129761A1

Abstract

Methods and apparatus are provided for treatment of heart arrhythmia via renal neuromodulation. Such neuromodulation may effectuate irreversible electroporation or electrofusion, ablation, necrosis and/or inducement of apoptosis, alteration of gene expression, action potential attenuation or blockade, changes in cytokine up-regulation and other conditions in target neural fibers. In some embodiments, such neuromodulation is achieved through application of an electric field. In some embodiments, such neuromodulation is achieved through application of neuromodulatory agents, of thermal energy and/or of high intensity focused ultrasound. In some embodiments, such neuromodulation is performed in a bilateral fashion.

Description

METHODS FOR TREATING HEART ARRHYTHMIA

REFERENCE TO RELATED APPLICATIONS

The present application claims priority to each of the following co-pending United States patent applications:

(1) U.S. Patent Application No. 11/599,882, filed November 14, 2006.

(2) U.S. Patent Application No. 10/408,665, filed on April 8, 2003 (published as United States Patent Publication 2003/0216792 on November 20, 2003), which claims the benefit of U.S. Provisional Patent Application Nos. 60/442,970, filed January 29, 2003; 60/415,575, filed October 3, 2002; and 60/370,190, filed April 8, 2002.

(3) U.S. Patent Application No. 11/133,925, filed on May 20, 2005, which is a continuation of U.S. Patent Application No. 10/900,199, filed on July 28, 2004 (now U.S. Patent No. 6,978,174), which is a continuation-in-part of U.S. Patent Application No. 10/408,665, filed on April 8, 2003.

(4) U.S. Patent Application No. 11/189,563, filed July 25, 2005, which is a continuation-in-part of U.S. Patent Application No. 11/129,765, filed on May 13, 2005, which claims the benefit of U.S. Provisional Patent Application Nos. 60/616,254, filed October 5, 2004; and 60/624,793, filed November 2, 2004.

(5) U.S. Patent Application No. 11/266,993, filed on November 4, 2005.

(6) U.S. Patent Application No. 11/363,867, filed February 27, 2006, which (a) claims the benefit of U.S. Provisional Application No. 60/813,589, filed on December 29, 2005 (originally filed as U.S. Application No. 11/324,188), and (b) is a continuation-in-part of each of U.S. Patent Application No. 11/189,563, filed on July 25, 2005, and U.S. Patent Application No. 11/266,933, filed on November 4, 2005.

(7) U.S. Patent Application No. 11/504,117 filed on August 14, 2006.

All of the foregoing applications, publication and patent are incorporated herein by reference in their entireties. INCORPORATION BY REFERENCE

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

TECHNICAL FIELD

The present invention relates to methods and apparatus for neuromodulation. In some embodiments, the present invention relates to methods and apparatus for treating heart arrhythmia, such as atrial fibrillation.

BACKGROUND

Heart arrhythmia are conditions affecting the electrical system of the heart, causing irregular heart rhythms. Arrhythmia may originate in the atria or the ventricles of the heart, and they may induce tachycardia (fast heart rate) or bradycardia (slow heart rate). Atrial tachycardia include atrial fibrillation, atrial flutter, supraventricular tachycardia and Wolff-Parkinson-White syndrome. The irregular heart rhythm experienced during atrial fibrillation or other heart arrhythmia may reduce the volume of blood pumped by the heart and/or may put a patient at an elevated risk for stroke. Ventricular tachycardia include ventricular tachycardia, ventricular fibrillation and long QT syndrome. Bradycardia include sick sinus and conduction block. Pre-existing heart conditions, such as high blood pressure, valvular disease, coronary artery disease and cardiomyopathy, may trigger heart arrhythmia by lowering blood supply to the heart, damaging heart tissue and/or other mechanisms.

Bradycardia may, for example, be treated with a pacemaker. Medical practitioners commonly treat tachycardia, such as atrial fibrillation, via electrical cardioversion with an external defibrillator. An implantable cardioverter defibrillator additionally or alternatively may be utilized. Medical practitioners also may utilize antiarrhythmics to control the patient's heart rhythm. Furthermore, they may recommend that a patient take anti-coagulants, such as warfarin or aspirin, to thin the blood and reduce a risk of blood clot formation. Serious tachycardia may be treated via ablation of targeted regions of the heart that impede aberrant electrical signals via a band of scar tissue. Patients who have undergone such ablation procedures may require a pacemaker to maintain a regular heart rhythm.

The kidneys may play a role in atrial fibrillation, as well as other heart arrhythmia or other cardio-renal diseases. Numerous academic studies have noted an increase in sympathetic nerve activity during atrial fibrillation. The functions of the kidneys can be summarized under three broad categories: (a) filtering blood and excreting waste products generated by the body's metabolism; (b) regulating salt, water, electrolyte and acid-base balance; and (c) secreting hormones to maintain vital organ blood flow. Without properly functioning kidneys, a patient may suffer water retention, reduced urine flow and an accumulation of waste toxins in the blood and body.

Applicants have previously described methods and apparatus for treating renal and/or cardio-renal disorders by applying energy or neuromodulatory agents, either directly or indirectly, to neural fibers that contribute to renal function. Such energy may, for example, comprise a monopolar or bipolar electric field, a thermal or non-thermal electric field, a pulsed or continuous electric field, a stimulation electric field, a beam of high intensity focused ultrasound, a thermal cooling energy and/or a thermal heating energy. See, for example, Applicants' co-pending United States Patent Application Serial Nos. 11/129,765, filed on May 13, 2005; 11/189,563, filed on July 25, 2005; 11/363,867, filed on February 27, 2006; 11/368,836, filed on March 6, 2006; and 11/504,117, filed on August 14, 2006. Additional methods and apparatus for achieving renal neuromodulation, e.g., via localized drug delivery (such as by a drug pump or infusion catheter) or via use of a stimulation electric field, etc, are described, for example, in co-owned and co-pending United States patent application Serial No. 10/408,665, filed April 8, 2003, as well as United States Patent No. 6,978,174.

The energy or neuromodulatory agents may be delivered to the neural fibers that contribute to renal function from apparatus positioned intravascular^, extravascularly, intra-to-extravascularly or a combination thereof. Furthermore, the energy or neuromodulatory agents may be delivered to neural fibers innervating a single kidney, or they may be delivered bilaterally to neural fibers innervating both kidneys. In some embodiments, the energy may initiate denervation or other renal neuromodulation substantially athermally at least in part via irreversible electroporation or via electrofusion. In other embodiments, the energy may thermally induce the denervation or other renal neuromodulation via ablation or other mechanisms. Renal neuromodulation may reduce renal sympathetic nerve activity.

In view of the foregoing, it would be desirable to provide novel methods and apparatus for treating heart arrhythmia.

BRIEF DESCRIPTION OF THE DRAWINGS

Several embodiments of the present invention will be apparent upon consideration of the following detailed description, taken in conjunction with the accompanying drawings, in which like reference characters refer to like parts throughout, and in which:

Figure 1 is a schematic view illustrating human renal anatomy.

Figure 2A-2C are schematic isometric and end views showing the location of the renal nerves relative to the renal artery, and illustrating orienting of an electric field for selectively affecting the renal nerves.

Figures 3A and 3B are schematic diagrams illustrating, respectively, steps in the treatment of heart arrhythmia via modulation of renal neural fibers, and potential mechanisms by which renal neuromodulation may treat arrhythmia.

Figure 4 is a schematic side view, partially in section, illustrating an example of an extravascular method and apparatus for renal neuromodulation.

Figures 5A-5D are schematic side views, partially in section, illustrating examples of intravascular and intra-to-extravascular methods and apparatus for renal neuromodulation.

Figures 6A-6H are schematic side views, partially in section, illustrating methods of achieving bilateral renal neuromodulation utilizing apparatus of the present invention, illustratively utilizing the apparatus of Figure 5A.

Figures 7A and 7B are schematic side views, partially in section, illustrating methods of achieving concurrent bilateral renal neuromodulation utilizing embodiments of the apparatus of Figure 5A. Figure 8 is a schematic side view, partially in section, illustrating methods of achieving concurrent bilateral renal neuromodulation utilizing an alternative embodiment of the apparatus of Figure 4.

Figure 9 is a schematic view illustrating an example of methods and apparatus for achieving renal neuromodulation via fully implanted apparatus.

DETAILED DESCRIPTION

A. Overview

The present invention provides methods and apparatus for treating heart arrhythmia via modulation of neural fibers that contribute to renal function. The neuromodulation may be achieved, for example, via (a) a monopolar or bipolar electric field, (b) a thermal or a non-thermal electric field, (c) a continuous or a pulsed electric field, (d) a stimulation electric field, (e) localized drug delivery, (f) a high intensity focused ultrasound field or beam, (g) thermal techniques, (h) substantially athermal techniques, and/or (i) combinations thereof. Such neuromodulation may, for example, effectuate irreversible electroporation or electrofusion, ablation, necrosis and/or inducement of apoptosis, alteration of gene expression, action potential blockade or attenuation, changes in cytokine up-regulation and other conditions in target neural fibers. Heart arrhythmia that potentially may be treated by the present invention include, but are not limited to, atrial arrhythmia, ventricular arrhythmia, tachycardia, bradycardia, atrial tachycardia, atrial fibrillation, atrial flutter, supraventricular tachycardia, Wolff-Parkinson-White syndrome, ventricular tachycardia, ventricular fibrillation, long QT syndrome, sick sinus, conduction block and combinations thereof.

When the neuromodulatory methods and apparatus are applied to renal nerves and/or other neural fibers that contribute to renal neural functions, it is expected that the neuromodulation can directly or indirectly increase urine output, decrease plasma renin levels, decrease tissue (e.g., kidney) and/or urine catecholamines (e.g., norepinephrine), increase urinary sodium excretion, and/or control blood pressure. Furthermore, the neuromodulatory effects may reduce renal sympathetic nerve activity, which may reduce the load on the heart and/or may provide a systemic reduction in sympathetic tone to reduce the patient's susceptibility to heart arrhythmia, such as atrial fibrillation. Applicants believe that these or other changes may prevent or treat heart arrhythmiaor a host of other renal or cardio-renal conditions, such as congestive heart failure, hypertension, acute myocardial infarction, end-stage renal disease, contrast nephropathy, other renal system diseases, and/or other renal or cardio-renal anomalies. The methods and apparatus described herein could be used to modulate efferent or afferent nerve signals, as well as combinations of efferent and afferent nerve signals.

In several embodiments, bilateral renal neuromodulation is effectuated by modulating neural fibers that contribute to renal function of both the right and left kidneys. Bilateral renal neuromodulation may provide enhanced therapeutic effect in some patients compared to unilateral renal neuromodulation (i.e. modulation of neural fibers innervating a single kidney). In some bilateral embodiments, concurrent modulation of neural fibers that contribute to both right and left renal function may be achieved. In other bilateral embodiments, the modulation of the right and left neural fibers may be sequential. Bilateral or unilateral renal neuromodulation may be continuous or intermittent, as desired.

When utilizing an electric field to achieve desired neuromodulation, the electric field parameters may be altered and combined in any combination, as desired. Such parameters can include, but are not limited to, voltage, field strength, power, pulse width, pulse duration, the shape of the pulse, the number of pulses and/or the interval between pulses (e.g., duty cycle), etc. For example, suitable field strengths can be up to about 10,000 V/cm, and the field may be continuous or pulsed. When pulsed, suitable pulse widths can be of any desired length, for example, up to about 1 second. Suitable shapes of the electrical waveform include, for example, AC waveforms, sinusoidal waves, cosine waves, combinations of sine and cosine waves, DC waveforms, DC-shifted AC waveforms, RF waveforms, square waves, trapezoidal waves, exponentially-decaying waves, or other combinations of wave shapes. When pulsed, the field may include at least one pulse, and in many applications the field includes a plurality of pulses. Suitable pulse intervals include, for example, intervals less than about 10 seconds. These parameters are provided as suitable examples and in no way should be considered limiting. The electric field (or other energy modality or neuromodulatory agent) may achieve desired neuromodulation thermally or substantially athermally. To better understand the structures of the devices described herein, and the methods of using such devices, for renal neuromodulation in the treatment of heart arrhythmia, it is instructive to examine the renal anatomy in humans.

B. Selected Embodiments of Methods for Neuromodulation

With reference now to Figure 1 , the human renal anatomy includes the kidneys K that are supplied with oxygenated blood by the renal arteries RA, which are connected to the heart by the abdominal aorta AA. Deoxygenated blood flows from the kidneys to the heart via the renal veins RV and the inferior vena cava IVC. Figure 2A illustrates a portion of the renal anatomy in greater detail. More specifically, the renal anatomy also includes renal nerves RN extending longitudinally along the lengthwise dimension L of the renal artery RA generally within the adventitia of the artery. The renal artery RA has smooth muscle cells SMC that surround the arterial circumference and spiral around the angular axis θ of the artery. The smooth muscle cells of the renal artery accordingly have a lengthwise or longer dimension extending transverse (i.e., non-parallel) to the lengthwise dimension of the renal artery. The misalignment of the lengthwise dimensions of the renal nerves and the smooth muscle cells is defined as "cellular misalignment."

Referring to Figures 2B and 2C, the cellular misalignment of the renal nerves and the smooth muscle cells may be exploited to selectively affect renal nerve cells with reduced effect on smooth muscle cells. More specifically, because larger cells require a lower electric field strength to exceed the cell membrane irreversibility threshold voltage or energy for irreversible electroporation, embodiments of electrodes of the present invention may be configured to align at least a portion of an electric field generated by the electrodes with or near the longer dimensions of the cells to be affected. In specific embodiments, the device has electrodes configured to create an electrical field aligned with or near the lengthwise dimension L of the renal artery RA to affect renal nerves RN. By aligning an electric field so that the field preferentially aligns with the lengthwise aspect of the cell rather than the diametric or radial aspect of the cell, lower field strengths may be used to affect target neural cells, e.g., to ablate, necrose or fuse the target cells, to induce apoptosis, to alter gene expression, to attenuate or block action potentials, to change cytokine up-regulation and/or to induce other suitable processes. This is expected to reduce total energy delivered by the system and to mitigate effects on non-target cells in the electric field.

Similarly, the lengthwise or longer dimensions of tissues overlying or underlying the target nerve are orthogonal or otherwise off-axis (e.g., transverse) with respect to the longer dimensions of the nerve cells. Thus, in addition to aligning an electric field with the lengthwise or longer dimensions of the target cells, the electric field may propagate along the lateral or shorter dimensions of the non-target cells (i.e., such that the electric field propagates at least partially out of alignment with non-target smooth muscle cells SMC). Therefore, as seen in Figures 2B and 2C, applying an electric field with propagation lines Li generally aligned with the longitudinal dimension L of the renal artery RA may preferentially cause electroporation (e.g., irreversible electroporation), electrofusion or other neuromodulation in cells of the target renal nerves RN without unduly affecting the non-target arterial smooth muscle cells SMC. The electric field may propagate in a single plane along the longitudinal axis of the renal artery, or may propagate in the longitudinal direction along any angular segment θ through a range of 0°-360°.

An electric neuromodulation system placed within and/or in proximity to the wall of the renal artery may propagate an electric field having a longitudinal portion that is aligned to run with the longitudinal dimension of the artery in the region of the renal nerves RN and the smooth muscle cells SMC of the vessel wall so that the wall of the artery remains at least substantially intact while the outer nerve cells are destroyed, fused or otherwise affected. Monitoring elements may be utilized to assess an extent of, e.g., electroporation or temperature change, induced in renal nerves and/or in smooth muscle cells, as well as to adjust electric field parameters to achieve a desired effect.

C. Illustrative Schematic Diagrams of Steps and Potential Mechanisms by which Renal Neuromodulation May Treat Heart Arrhythmia

With reference to Figure 3A, illustrative steps in one embodiment for the treatment of heart arrhythmia, such as atrial fibrillation, via modulation of neural fibers that contribute to renal function are described. An energy delivery element is placed in proximity to the target renal neural fibers. Energy and/or a neuromodulatory agent is then delivered to the target neural fibers via the energy delivery element or an agent delivery element. The energy and/or the neuromodulatory agent treats the heart arrhythmia. As shown by dotted line in Figure 3A, the effects of the energy delivery optionally may be monitored (e.g., via a thermocouple or other sensor), and monitoring data optionally may be utilized in a feedback loop to adjust the energy delivery to treat the heart arrhythmia.

As seen in Figure 3B, the neuromodulatory effects induced by the apparatus and methods of the present invention may reduce renal and/or systemic sympathetic nerve activity. A reduction in renal sympathetic activation may induce hormonal changes that reduce renin secretion, which inhibits Angiotensin conversion and reduces production of Aldosterone. These hormonal responses, coupled with direct neuronal controls, may increase sodium excretion, which in turn may increase fluid offload. These events may reduce the pre-load on the heart. Furthermore, the neurohormonal changes may reduce peripheral vascular resistance, which may reduce after-load on the heart. The reduction in load on the heart may be used in the treatment of heart arrhythmia, such as atrial fibrillation. Meanwhile, a reduction in systemic sympathetic tone may reduce the patient's susceptibility to the heart arrhythmia.

Applicants believe that these or other changes might prevent or treat heart arrhythmia or a host of other renal or cardio-renal conditions, such as heart failure, hypertension, acute myocardial infarction, end-stage renal disease, contrast nephropathy, other renal system diseases, and/or other renal or cardio-renal anomalies for a period of months, potentially up to six months or more. This time period may be sufficient to allow the body to heal, thereby alleviating a need for subsequent re- treatment. Alternatively, as symptoms reoccur, or at regularly scheduled intervals, the patient may return to the physician for a repeat therapy. The methods and apparatus described herein could be used to modulate efferent or afferent nerve signals, as well as combinations of efferent and afferent nerve signals. D. Illustrative Embodiments of Systems and Additional Methods for Neuromodulation

With reference to Figures 4 and 5, examples of systems and methods for renal neuromodulation are described. Figure 4 shows one embodiment of an extravascular electric field apparatus 200 that includes one or more electrodes configured to deliver an electric field to renal neural fibers to achieve renal neuromodulation. The apparatus of Figure 4 is configured for temporary extravascular placement; however, it should be understood that partially or completely implantable extravascular apparatus additionally or alternatively may be utilized. Applicants have previously described extravascular electric field ("e-field") systems, for example, in co-pending U.S. patent application Serial No. 11/189,563, filed July 25, 2005.

In Figure 4, apparatus 200 comprises a laparoscopic or percutaneous e-field system having a probe 210 configured for insertion in proximity to the track of the renal neural supply along the renal artery or vein or hilum and/or within Gerota's fascia under, e.g., CT or radiographic guidance. At least one electrode 212 is configured for delivery through the probe 210 to a treatment site for delivery of electric field therapy. The electrode(s) 212, for example, may be mounted on a catheter and electrically coupled to a field generator 50 via wires 211. In an alternative embodiment, a distal section of the probe 210 may have one electrode 212, and the probe may have an electrical connector to couple the probe to the field generator 50 for delivering an electric field to the electrode(s) 212.

The electric field generator 50 is located external to the patient. The generator, as well as any of the embodiments of electrodes described herein, may be utilized with any embodiment of the present invention for delivery of an electric field with desired field parameters. It should be understood that embodiments of field delivery electrodes described hereinafter may be electrically connected to the generator even though the generator is not explicitly shown or described with each embodiment.

The electrode(s) 212 can be individual electrodes that are electrically independent of each other, a segmented electrode with commonly connected contacts, or a continuous electrode. A segmented electrode may, for example, be formed by providing a slotted tube fitted onto the electrode, or by electrically connecting a series of individual electrodes. Individual electrodes or groups of electrodes 212 may be configured to provide a bipolar signal. The electrodes 212 may be dynamically assignable to facilitate monopolar and/or bipolar energy delivery between any of the electrodes and/or between any of the electrodes and an external ground pad. Such a ground pad may, for example, be attached externally to the patient's skin, e.g., to the patient's leg or flank. In Figure 4, the electrodes 212 comprise a bipolar electrode pair. The probe 210 and the electrodes 212 may be similar to the standard needle or trocar- type used clinically for pulsed RF nerve block. Alternatively, the apparatus 200 may comprise a flexible and/or custom-designed probe for the renal application described herein.

In Figure 4, the percutaneous probe 210 has been advanced through a percutaneous access site P into proximity with a patient's renal artery RA. The probe pierces the patient's Gerota's fascia F, and the electrodes 212 are advanced into position through the probe and along the annular space between the patient's artery and fascia. Once properly positioned, electric field therapy may be applied to target neural fibers across the bipolar electrodes 212. Such electric field therapy may, for example, at least partially denervate the kidney innervated by the target neural fibers, e.g., through irreversible electroporation of cells of the target neural fibers and/or through thermal damage to the target neural fibers. The electrodes 212 optionally also may be used to monitor the effects of the e-field therapy. After treatment, the apparatus 200 may be removed from the patient to conclude the procedure.

Referring now to Figures 5A-5D, embodiments of intravascular and intra-to- extravascular electric field systems are described. Applicants have previously described intravascular electric field systems, for example, in co-pending U.S. patent application Serial No. 11/129,765, filed May 13, 2005, which has been incorporated herein by reference. Furthermore, applicants have previously described intra-to- extravascular e-field systems, for example, in co-pending U.S. patent application Serial No. 11/324,188 (hereinafter, "the '188 application"), filed December 29, 2005.

The intravascular embodiment of Figure 5A includes an apparatus 300 comprising a catheter 302 having a positioning element 304 (e.g., a balloon, an expandable wire basket, other mechanical expanders, etc.), shaft electrodes 306a and 306b disposed along the shaft of the catheter, and optional radiopaque markers 308 disposed along the shaft of the catheter in the region of the positioning element 304. The electrodes 306a-b, for example, can be arranged such that the electrode 306a is near a proximal end of the positioning element 304 and the electrode 306b is near the distal end of the positioning element 304. The electrodes 306 are electrically coupled to the field generator 50 (see Figure 4), which is disposed external to the patient, for delivery of the electric field therapy.

The positioning element 304 may comprise an impedance-altering element that alters the impedance between electrodes 306a and 306b during the e-field therapy, for example, to better direct the e-field therapy across the vessel wall. This may reduce an applied voltage or a total energy required to achieve desired renal neuromodulation. Applicants have previously described use of an impedance-altering element, for example, in co-pending U.S. patent application Serial No. 11/266,993, filed November 4, 2005. When the positioning element 304 comprises an inflatable balloon, the balloon may serve as both a centering element for the electrodes 306 and as an impedance-altering electrical insulator for directing an electric field delivered across the electrodes, e.g., for directing the electric field into or across the vessel wall for modulation of target neural fibers. Electrical insulation provided by the element 304 may reduce the magnitude of applied voltage or other parameters of the electric field necessary to achieve desired field strength or thermal effects at the target fibers.

The electrodes 306 can be individual electrodes (i.e., independent contacts), a segmented electrode with commonly connected contacts, or a single continuous electrode. Furthermore, the electrodes 306 may be configured to provide a bipolar signal, or the electrodes 306 may be used together or individually in conjunction with a separate patient ground pad for monopolar use. As an alternative or in addition to placement of the electrodes 306 along the central shaft of catheter 302, as in Figure 5A, the electrodes 306 may be attached to the positioning element 304 such that they contact the wall of the renal artery RA. In such a variation, the electrodes may, for example, be affixed to the inside surface, outside surface or at least partially embedded within the wall of the positioning element. The electrodes optionally may be used to monitor the effects of e-field therapy, as described hereinafter. As it may be desirable to reduce or minimize physical contact between the electric field delivery electrodes and the vessel wall during delivery of the e-field therapy, e.g., to reduce the potential for injuring the wall, the electrodes 306 may, for example, comprise a first set of electrodes attached to the shaft of the catheter for delivering the e-field therapy, and the device may further include a second set of electrodes optionally attached to the positioning element 304 for monitoring the effects of e-field therapy delivered via the electrodes 306.

In use, the catheter 302 may be delivered to the renal artery RA as shown, or it may be delivered to a renal vein or to any other vessel in proximity to neural tissue contributing to renal function, in a low profile delivery configuration, for example, through a guide catheter. Once positioned within the renal vasculature, the optional positioning element 304 may be expanded into contact with an interior wall of the vessel. A thermal or non-thermal electric field that is continuous or pulsed is then generated by the field generator 50, transferred through the catheter 302 to the electrodes 306, and delivered via the electrodes 306 across the wall of the artery. The e-field therapy modulates the activity along neural fibers that contribute to renal function, e.g., at least partially denervates the kidney innervated by the neural fibers. This may be achieved, for example, via irreversible electroporation, electrofusion and/or inducement of ablation, necrosis or apoptosis in the nerve cells. In many applications, the electrodes are arranged so that the electric field is aligned with the longitudinal dimension of the renal artery to facilitate modulation of renal nerves with little effect on non-target smooth muscle cells or other cells.

When utilizing intravascular e-field apparatus to achieve neuromodulation, in addition or as an alternative to central positioning of the electrode(s) within a blood vessel, the electrode(s) optionally may be configured to contact an internal wall of the blood vessel. Wall-contacting electrode(s) may facilitate more efficient transfer of an electric field across the vessel wall to target neural fibers, as compared to centrally- positioned electrode(s). In several embodiments, the wall-contacting electrode(s) may be delivered to the vessel treatment site in a reduced profile configuration, then expanded in vivo to a deployed configuration wherein the electrode(s) contact the vessel wall. In other embodiments, the electrode(s) may also be at least partially contracted to facilitate retrieval of the electrode(s) from the patient's vessel.

Figures 5B and 5C depict an illustrative embodiment of an intravascular apparatus having electrodes configured to contact the interior wall of a vessel. The apparatus of Figures 5B and 5C is an alternative embodiment of the apparatus 300 of Figure 5A wherein the proximal electrode 306a of Figure 5A has been replaced with a wall-contacting electrode 306a'. The wall-contacting electrode can comprise a proximal attachment 312a that connects the electrode to the shaft of the catheter 302 and is electrically coupled to the pulse generator. Extensions 314a extend from the proximal attachment 312a and at least partially extend over a surface of the positioning element 304. The extensions 314a optionally may be selectively insulated such that only a selective portion of the extensions, e.g., the distal tips of the extensions, are electrically active. The electrode 306a' optionally may be fabricated from a slotted tube, such as a stainless steel or shape-memory (e.g., NiTi) slotted tube. Furthermore, all or a portion of the electrode may be gold-plated to improve radiopacity and/or conductivity.

As seen in Figure 5B, the catheter 302 may be delivered over a guidewire G to a treatment site within the patient's vessel with the electrode 306a' positioned in a reduced profile configuration (e.g., contracted configuration). The catheter 302 optionally may be delivered through a guide catheter 303 to facilitate such reduced profile delivery of the wall-contacting electrode. When positioned as desired at a treatment site, the electrode may be expanded into contact with the vessel wall by expanding the positioning element 304 (Figure 5C). A monopolar or bipolar, pulsed or continuous, thermal or athermal electric field then may be delivered across the vessel wall and between the electrodes 306a' and 306b to induce neuromodulation, as discussed previously. The optional positioning element 304 may alter impedance within the blood vessel and more efficiently route the electrical energy across the vessel wall to the target neural fibers.

After delivery of the electric field, the electrode 306a' may be returned to a contracted profile to facilitate removal of the apparatus 300 from the patient. For example, the positioning element 304 may be collapsed (e.g., deflated), and the electrode 306a' may be contracted by withdrawing the catheter 302 within the guide catheter 303. Alternatively, the electrode may be fabricated from a shape-memory material biased to the collapsed configuration, such that the electrode self-collapses upon collapse of the positioning element.

In addition to extravascular and intravascular neuromodulation systems, intra-to- extravascular neuromodulation systems may be provided having, e.g., electrode(s) that are delivered to an intravascular position, then at least partially passed through/across the vessel wall to an extravascular position prior to delivery of e-field therapy. Intra-to- extravascular positioning of the electrode(s) may place the electrode(s) in closer proximity to target neural fibers during the e-field therapy compared to fully intravascular positioning of the electrode(s). With reference to Figure 5D, one embodiment of an intra-to-extravascular ("ITEV") e-field system, described previously in the '188 application, is shown.

ITEV e-field system 320 comprises a catheter 322 having (a) a plurality of proximal electrode lumens terminating at proximal side ports 324, (b) a plurality of distal electrode lumens terminating at distal side ports 326, and (c) a guidewire lumen 323. The catheter 322 preferably comprises an equal number of proximal and distal electrode lumens and side ports. The system 320 also includes proximal needle electrodes 328 that may be advanced through the proximal electrode lumens and the proximal side ports 324, as well as distal needle electrodes 329 that may be advanced through the distal electrode lumens and the distal side ports 326.

Catheter 322 comprises an optional expandable positioning element 330, which may comprise an inflatable balloon or an expandable basket or cage. In use, the positioning element 330 may be expanded prior to deployment of the needle electrodes 328 and 329 in order to center the catheter 322 within the patient's vessel (e.g., within renal artery RA). Centering the catheter 322 is expected to facilitate delivery of all needle electrodes to desired depths within/external to the patient's vessel (e.g., to deliver all of the needle electrodes approximately to the same depth). In Figure 5D, the illustrated positioning element 330 is positioned between the proximal side ports 324 and the distal side ports 326, i.e., between the delivery positions of the proximal and distal electrodes. However, it should be understood that positioning element 330 additionally or alternatively may be positioned at a different location or at multiple locations along the length of the catheter 322 (e.g., at a location proximal of the side ports 324 and/or at a location distal of the side ports 326).

As illustrated in Figure 5D, the catheter 322 may be advanced to a treatment site within the patient's vasculature (e.g., to a treatment site within the patient's renal artery RA) over a guidewire (not shown) via the lumen 323. During intravascular delivery, the electrodes 328 and 329 may be positioned such that their non-insulated and sharpened distal regions are positioned within the proximal and distal lumens, respectively. Once positioned at a treatment site, a medical practitioner may advance the electrodes via their proximal regions that are located external to the patient. Such advancement causes the distal regions of the electrodes 328 and 329 to exit side ports 324 and 326, respectively, and pierce the wall of the patient's vasculature such that the electrodes are positioned extravascularly via an ITEV approach.

The proximal electrodes 328 can be connected to field generator 50 as active electrodes and the distal electrodes 329 can serve as return electrodes. In this manner, the proximal and distal electrodes form bipolar electrode pairs that align the e- field therapy with a longitudinal axis or direction of the patient's vasculature. As will be apparent, the distal electrodes 329 alternatively may comprise the active electrodes and the proximal electrodes 328 may comprise the return electrodes. Furthermore, the proximal and/or the distal electrodes may comprise both active and return electrodes. Any combination of active and distal electrodes may be utilized, as desired.

When the electrodes 328 and 329 are connected to field generator 50 and are positioned extravascularly, and with positioning element 330 optionally expanded, e- field therapy may proceed to achieve desired neuromodulation. After completion of the e-field therapy, the electrodes may be retracted within the proximal and distal lumens, and the positioning element 330 may be collapsed for retrieval. ITEV e-field system 320 then may be removed from the patient to complete the procedure. Additionally or alternatively, the system may be repositioned to provide e-field therapy at another treatment site, for example, to provide bilateral renal neuromodulation.

It is expected that e-field therapy, as well as other methods and apparatus of the present invention for neuromodulation (e.g., localized drug delivery, high intensity focused ultrasound, thermal techniques, etc.), whether delivered extravascularly, intravascular^, intra-to-extravascularly or a combination thereof, may, for example, effectuate irreversible electroporation or electrofusion, ablation, necrosis and/or inducement of apoptosis, alteration of gene expression, action potential blockade or attenuation, changes in cytokine up-regulation and other conditions in target neural fibers. In some patients, when such neuromodulatory methods and apparatus are applied to renal nerves and/or other neural fibers that contribute to renal neural functions, applicants believe that the neuromodulatory effects induced by the neuromodulation may increase urine output, decrease plasma renin levels, decrease tissue (e.g., kidney) and/or urine catecholamines (e.g., norepinephrine), increase urinary sodium excretion, and/or control blood pressure.

Neuromodulation in accordance with the present invention optionally is achieved without completely physically severing, i.e., without fully cutting, the target neural fibers. However, it should be understood that such neuromodulation may functionally sever the neural fibers, even though the fibers may not be completely physically severed. Apparatus and methods described herein illustratively are configured for percutaneous use. Such percutaneous use may be endoluminal, laparoscopic, a combination thereof, etc.

Although the embodiments of Figures 4 and 5 illustratively comprise bipolar apparatus, it should be understood that monopolar apparatus alternatively may be utilized. For example, an active monopolar electrode may be positioned intravascularly, extravascularly or intra-to-extravascularly in proximity to target neural fibers that contribute to renal function. A return electrode ground pad may be attached to the exterior of the patient. Finally, e-field therapy may be delivered between the in vivo monopolar electrode and the ground pad to effectuate desired renal neuromodulation. Monopolar apparatus additionally may be utilized for bilateral renal neuromodulation.

Furthermore, although the embodiments of Figures 4 and 5 illustratively comprise e-field neuromodulation apparatus, it should be understood that alternative energy modalities may be utilized to achieve desired neuromodulation. For example, thermal energy, high intensity focused ultrasound and/or a neuromodulatory agent may be delivered intravascularly, extravascularly, intra-to-extravascularly, or a combination thereof to achieve the desired neuromodulation.

It may be desirable to achieve bilateral renal neuromodulation. Bilateral neuromodulation may enhance the therapeutic effect in some patients as compared to renal neuromodulation performed unilaterally, i.e., as compared to renal neuromodulation performed on neural tissue innervating a single kidney. For example, bilateral renal neuromodulation may further reduce clinical symptoms of heart arrhythmia, and/or of congestive heart failure, hypertension, acute myocardial infarction, contrast nephropathy, renal disease and/or other cardio-renal diseases. Figures 6A-6H illustrate stages of a method for bilateral renal neuromodulation utilizing the intravascular apparatus of Figure 5A. However, it should be understood that such bilateral neuromodulation alternatively may be achieved utilizing the extravascular apparatus of Figure 4, utilizing the intra-to-extravascular apparatus of Figure 5D, or utilizing any alternative intravascular apparatus, extravascular apparatus, intra-to- extravascular apparatus (including monopolar apparatus) or combination thereof.

As seen in Figures 6A and 6E, a guide catheter GC and a guidewire G may be advanced into position within, or in proximity to, either the patient's left renal artery LRA or right renal artery RRA. In Figure 6A, the guidewire illustratively has been positioned in the right renal artery RRA, but it should be understood that the order of bilateral renal neuromodulation illustrated in Figures 6A-6H alternatively may be reversed. Additionally or alternatively, bilateral renal neuromodulation may be performed concurrently on both right and left neural fibers that contribute to renal function, as in Figures 7-9, rather than sequentially, as in Figures 6.

With the guidewire and the guide catheter positioned in the right renal artery, the catheter 302 of the apparatus 300 may be advanced over the guidewire and through the guide catheter into position within the artery. As seen in Figure 6B, the optional positioning element 304 of the catheter 302 is in a reduced delivery configuration during delivery of the catheter to the renal artery. In Figure 6C, once the catheter is properly positioned for e-field therapy, the element 304 optionally may be expanded into contact with the vessel wall, and the guidewire G may be retracted from the treatment zone, e.g., may be removed from the patient or may be positioned more proximally within the patient's aorta.

Expansion of element 304 may center or otherwise position the electrodes 306 within the vessel and/or may alter impedance between the electrodes. With apparatus 300 positioned and deployed as desired, e-field therapy may be delivered, e.g., in a bipolar fashion across the electrodes 306 to achieve renal neuromodulation in neural fibers that contribute to right renal function, e.g., to at least partially achieve renal denervation of the right kidney. As illustrated by propagation lines Li, the electric field may be aligned with a longitudinal dimension of the renal artery RA and may pass across the vessel wall. The alignment and propagation path of the electric field is expected to preferentially modulate cells of the target renal nerves without unduly affecting non-target arterial smooth muscle cells. As seen in Figure 6D, after completion of the e-field therapy, the element 304 may be collapsed back to the reduced delivery profile, and the catheter 302 may be retracted from the right renal artery RRA, for example, to a position in the guide catheter GC within the patient's abdominal aorta. Likewise, the guide catheter GC may be retracted to a position within the patient's aorta. The retracted guide catheter may be repositioned, e.g., rotated, such that its distal outlet is generally aligned with the left renal artery LRA. The guidewire G then may be re-advanced through the catheter 302 and the guide catheter GC to a position within the left renal artery LRA, as shown in Figure 6E (as will be apparent, the order of advancement of the guidewire and the guide catheter optionally may be reversed when accessing either renal artery).

Next, the catheter 302 may be re-advanced over the guidewire and through the guide catheter into position within the left renal artery, as shown in Figure 6F. In Figure 6G, once the catheter is properly positioned for e-field therapy, the element 304 optionally may be expanded into contact with the vessel wall, and the guidewire G may be retracted to a position proximal of the treatment site. Electric field therapy then may be delivered in a bipolar fashion across the electrodes 306, for example, along propagation lines Li, to achieve renal neuromodulation in neural fibers that contribute to left renal function, e.g., to at least partially achieve renal denervation of the left kidney. As seen in Figure 6H, after completion of the bilateral e-field therapy, the element 304 may be collapsed back to the reduced delivery profile, and the catheter 302, as well as the guidewire G and the guide catheter GC, may be removed from the patient to complete the bilateral renal neuromodulation procedure.

As discussed previously, bilateral renal neuromodulation optionally may be performed concurrently on fibers that contribute to both right and left renal function. Figures 7A and 7B illustrate embodiments of apparatus 300 for performing concurrent bilateral renal neuromodulation. In the embodiment of Figure 7A, apparatus 300 comprises dual e-field therapy catheters 302, as well as dual guidewires G and guide catheters GC. One catheter 302 is positioned within the right renal artery RRA, and the other catheter 302 is positioned within the left renal artery LRA. With catheters 302 positioned in both the right and left renal arteries, e-field therapy may be delivered concurrently by the catheters 302 to achieve concurrent bilateral renal neuromodulation, illustratively via an intravascular approach. In one example, separate arteriotomy sites may be made in the patient's right and left femoral arteries for percutaneous delivery of the two catheters 302. Alternatively, both catheters 302 may be delivered through a single femoral access site, either through dual guide catheters or through a single guide catheter. Figure 7B illustrates an example of apparatus 300 for concurrent bilateral renal neuromodulation utilizing a single arteriotomy access site. In the example of Figure 7B, both catheters 302 are delivered through a custom bifurcated guide catheter GC having a bifurcated distal region for concurrently delivering the catheters 302 to the right and left renal arteries. Concurrent (or sequential) bilateral e-field therapy then may proceed.

Figure 8 illustrates additional methods and apparatus for concurrent bilateral renal neuromodulation. In Figure 8, an embodiment of extravascular apparatus 200 comprising dual probes 210 and electrodes 212. The electrodes have been positioned in the vicinity of both the left renal artery LRA and the right renal artery RRA. Electric field therapy may be delivered concurrently by the electrodes 212 to achieve concurrent bilateral renal neuromodulation, illustratively via an extravascular approach.

As will be apparent, intra-to-extravascular apparatus alternatively may be utilized for bilateral renal neuromodulation. Such bilateral renal neuromodulation may be performed sequentially, concurrently or a combination thereof. For example, ITEV e- field system 320 of Figure 5D may be utilized for bilateral renal neuromodulation.

Additional methods and apparatus for achieving renal neuromodulation, e.g., via localized drug delivery (such as by a drug pump or infusion catheter) or via use of a stimulation electric field, etc, also may utilized. Examples of such methods and apparatus have been described previously, for example, in co-owned and co-pending United States patent application Serial No. 10/408,665, filed April 8, 2003, and in United States Patent No. 6,978,174, both of which have been incorporated herein by reference.

Figure 9 shows one example of methods and apparatus for achieving renal neuromodulation (illustratively bilateral) via fully implanted apparatus. In Figure 9, an element 400 has been implanted within the patient. Conduits 402a and 402b are connected to the element 400 and extend to the vicinity of the right renal artery RRA and the left renal artery LRA, respectively. The element 400 generates or contains a neuromodulatory therapy capable of modulating neural fibers that contribute to renal function, and the conduits 402 deliver the therapy to the vicinity of the renal arteries. Delivering the therapy through the conduits 402a and 402b may achieve bilateral renal neuromodulation. Such therapy delivery may be conducted concurrently or sequentially, as well as continuously or intermittently, as desired, in order to provide concurrent or sequential, continuous or intermittent, renal neuromodulation, respectively.

In one embodiment, the element 400 comprises an implantable neurostimulator or a pacemaker-type device, and the conduits 402 comprise electrical leads that are coupled to the neurostimulator for delivery of an electric field, such as a pulsed or continuous electric field, a stimulation electric field, a thermal or non-thermal electric field, to the target neural fibers. In another embodiment, the element 400 comprises an implantable drug pump, and the conduits 402 comprise drug delivery catheters for delivery of neuromodulator/ agent(s) or drug(s) from the pump to the target neural fibers. In yet another alternative embodiment, electrical techniques may be combined with delivery of neuromodulatory agent(s) to achieve desired renal neuromodulation.

In an alternative embodiment of the apparatus of Figure 9, conduits 402a and 402b may only temporarily be positioned at a desired location, e.g., for acute delivery of the neuromodulatory therapy, e.g., from an external field generator or from an external drug reservoir, such as a syringe. Such temporary positioning may comprise, for example, intravascular, extravascular and/or intra-to-extravascular placement of the catheters.

Although preferred illustrative variations of the present invention are described above, it will be apparent to those skilled in the art that various changes and modifications may be made thereto without departing from the invention. It is intended in the appended claims to cover all such changes and modifications that fall within the true spirit and scope of the invention.

Claims

CLAIMSI/We claim:

1. A method for treating heart arrhythmia, the method comprising: introducing a modulation instrument proximate a neural fiber that contributes to renal function of a kidney of a patient; and delivering energy and/or a neuromodulatory agent to the neural fiber via the modulation instrument in order to modulate a function of the neural fiber, thereby systemically reducing sympathetic tone in the patient.

2. The method of claim 1 , wherein delivering energy further comprises delivering an electric field.

3. The method of claim 2, wherein delivering the electric field further comprises delivering a pulsed electric field.

4. The method of claim 2, wherein delivering the electric field further comprises delivering a continuous electric field.

5. The method of claim 1 , wherein delivering a neuromodulatory agent further comprises delivering a drug to the neural fiber.

6. The method of claim 1 , wherein modulating the function of the neural fiber further comprises at least partially denervating the kidney.

7. The method of claim 1 , wherein modulating the function of the neural fiber further comprises inducing an effect in the neural fiber chosen from the group consisting of irreversible electroporation, electrofusion, ablation, necrosis, apoptosis, gene expression alteration, cytokine up-regulation alteration, and combinations thereof.

8. The method of claim 1 , wherein delivering energy further comprises delivering thermal energy.

9. The method of claim 1 , wherein delivering energy further comprises delivering high intensity focused ultrasound.

10. The method of claim 1 , wherein systemically reducing sympathetic tone in the patient further comprises decreasing a load on a heart of the patient.

11. A method for treating heart arrhythmia, the method comprising: introducing a modulation instrument proximate a neural fiber that contributes to renal function of a kidney of a patient; and delivering energy and/or a neuromodulator/ agent to the neural fiber via the modulation instrument in order to modulate a function of the neural fiber, thereby decreasing a load on a heart of the patient.

12. The method of claim 11 , wherein delivering energy further comprises delivering an electric field.

13. The method of claim 12, wherein delivering the electric field further comprises delivering a pulsed electric field.

14. The method of claim 12, wherein delivering the electric field further comprises delivering a continuous electric field.

15. The method of claim 11 , wherein delivering the neuromodulatory agent further comprises delivering a drug to the neural fiber.

16. The method of claim 11 , wherein modulating the function of the neural fiber further comprises at least partially denervating the kidney.

17. The method of claim 11 , wherein modulating the function of the neural fiber further comprises inducing an effect in the neural fiber chosen from the group consisting of irreversible electroporation, electrofusion, ablation, necrosis, apoptosis, gene expression alteration, cytokine up-regulation alteration, and combinations thereof.

18. The method of claim 11 , wherein delivering the energy further comprises delivering thermal energy.

19. The method of claim 11 , wherein delivering the energy further comprises delivering high intensity focused ultrasound.

20. The method of claim 11 , wherein decreasing the load on the heart of the patient further comprises systemically reducing sympathetic tone in the patient.

21. A method for treating heart arrhythmia, the method comprising: introducing a modulation instrument proximate a neural fiber that contributes to renal function of a kidney of the patient; and delivering energy and/or a neuromoduiatory agent to the neural fiber via the modulation instrument in order to modulate a function of the neural fiber, wherein introducing the modulation instrument further comprises percutaneously introducing the modulation instrument.

22. The method of claim 21 , wherein percutaneously introducing the modulation instrument further comprises introducing the modulation instrument via a laparoscopic approach.

23. The method of claim 21 , wherein percutaneously introducing the modulation instrument further comprises introducing the modulation instrument via an endoluminal approach.

24. The method of claim 21 , wherein delivering energy further comprises delivering an electric field.

25. The method of claim 24, delivering the electric field further comprises delivering a pulsed electric field.

26. The method of claim 24, wherein delivering the electric field further comprises delivering a stimulation electric field.

27. The method of claim 21 , wherein delivering a neuromodulatory agent further comprises delivering a drug.

28. The method of claim 21 , wherein modulating the function of the neural fiber further comprises at least partially denervating the kidney.

29. The method of claim 21 , wherein modulating the function of the neural fiber further comprises inducing an effect in the neural fiber chosen from the group consisting of irreversible electroporation, electrofusion, ablation, necrosis, apoptosis, gene expression alteration, cytokine up-regulation alteration, and combinations thereof.

30. The method of claim 21 , wherein delivering energy further comprises delivering thermal energy.

31. The method of claim 21 , wherein delivering energy further comprises delivering high intensity focused ultrasound.

32. The method of claim 21 , wherein modulating the function of the neural fiber further comprises decreasing a load on a heart of the patient.

33. The method of claim 21 , wherein modulating the function of the neural fiber further comprises systemically reducing sympathetic tone in the patient.

34. A method for reducing a load on a heart of a patient, the method comprising: introducing a modulation instrument proximate a neural fiber that contributes to renal function of a kidney of the patient; and delivering energy or a neuromodulatory agent to the neural fiber via the modulation instrument in order to modulate a function of the neural fiber.

35. The method of claim 34, wherein reducing the load on the heart of the patient further comprises treating heart arrhythmia.

36. The method of claim 34, wherein modulating the function of the neural fiber further comprises at least partially denervating the kidney.

37. The method of claim 34, wherein modulating the function of the neural fiber further comprises inducing an effect in the neural fiber chosen from the group consisting of irreversible electroporation, electrofusion, ablation, necrosis, apoptosis, gene expression alteration, cytokine up-regulation alteration, and combinations thereof.

38. The method of claim 34, wherein reducing the load on the heart of the patient further comprises systemically reducing sympathetic tone in the patient.

39. A method for systemically reducing sympathetic tone in a patient, the method comprising: introducing a modulation instrument proximate a neural fiber that contributes to renal function of a kidney of the patient; and delivering energy or a neuromodulatory agent to the neural fiber via the modulation instrument in order to modulate a function of the neural fiber.

40. The method of claim 39, wherein systemically reducing sympathetic tone in the patient further comprises treating heart arrhythmia.

41. The method of claim 39, wherein modulating the function of the neural fiber further comprises at least partially denervating the kidney.

42. The method of claim 39, wherein modulating the function of the neural fiber further comprises inducing an effect in the neural fiber chosen from the group consisting of irreversible electroporation, electrofusion, ablation, necrosis, apoptosis, gene expression alteration, cytokine up-regulation alteration, and combinations thereof.

43. The method of claim 39, wherein systemically reducing systemic sympathetic tone in the patient further comprises reducing a load on a heart of the patient.

44. The method of claim 1, wherein treating heart arrhythmia further comprises treating heart arrhythmia chosen from the group consisting of atrial arrhythmia, ventricular arrhythmia, tachycardia, bradycardia, atrial tachycardia, atrial fibrillation, atrial flutter, supraventricular tachycardia, Wolff-Parkinson-White syndrome, ventricular tachycardia, ventricular fibrillation, long QT syndrome, sick sinus, conduction block and combinations thereof.

45. The method of claim 11 , wherein treating heart arrhythmia further comprises treating heart arrhythmia chosen from the group consisting of atrial arrhythmia, ventricular arrhythmia, tachycardia, bradycardia, atrial tachycardia, atrial fibrillation, atrial flutter, supraventricular tachycardia, Wolff-Parkinson-White syndrome, ventricular tachycardia, ventricular fibrillation, long QT syndrome, sick sinus, conduction block and combinations thereof.

46. The method of claim 21 , wherein treating heart arrhythmia further comprises treating heart arrhythmia chosen from the group consisting of atrial arrhythmia, ventricular arrhythmia, tachycardia, bradycardia, atrial tachycardia, atrial fibrillation, atrial flutter, supraventricular tachycardia, Wolff-Parkinson-White syndrome, ventricular tachycardia, ventricular fibrillation, long QT syndrome, sick sinus, conduction block and combinations thereof.

47. The method of claim 34, wherein treating heart arrhythmia further comprises treating heart arrhythmia chosen from the group consisting of atrial arrhythmia, ventricular arrhythmia, tachycardia, bradycardia, atrial tachycardia, atrial fibrillation, atrial flutter, supraventricular tachycardia, Wolff-Parkinson-White syndrome, ventricular tachycardia, ventricular fibrillation, long QT syndrome, sick sinus, conduction block and combinations thereof.

48. The method of claim 39, wherein treating heart arrhythmia further comprises treating heart arrhythmia chosen from the group consisting of atrial arrhythmia, ventricular arrhythmia, tachycardia, bradycardia, atrial tachycardia, atrial fibrillation, atrial flutter, supraventricular tachycardia, Wolff-Parkinson-White syndrome, ventricular tachycardia, ventricular fibrillation, long QT syndrome, sick sinus, conduction block and combinations thereof.