ES2361460T3 - APPLIANCE FOR RENAL NEUROMODULATION. - Google Patents

Abstract

Apparatus for renal neuromodulation, the apparatus comprising: an electric field generator (100); and a catheter (150) comprising at least one electrode (212) electrically connected to the electric field generator; wherein the catheter is configured for percutaneous placement within the renal vasculature in a patient for the application of an electric field to the renal nerves while the device is located proximal to the renal vasculature in which the catheter further comprises a section Expandable helical configured to position the catheter in contact with an inner surface of a wall of a vessel of the renal vasculature, in which the at least one electrode is in an expandable helical section and in which the passage of the helix of the section Expandable helical is variable to minimize circumferential overlap of adjacent treatment areas.

Description

Technical field

The present invention relates to equipment for renal neuromodulation. More particularly, the present invention relates to equipment for achieving renal neuromodulation by means of an electric field of pulses and / or electroporation or electrofusion.

Background

Congestive heart failure ("CHF") is a condition that occurs when the heart becomes damaged and reduces blood flow to the body's organs. If blood flow decreases sufficiently, kidney function becomes impaired and results in fluid retention, abnormal hormonal secretions and an increase in blood vessel constriction. These results increase the cardiac workload and further decrease the ability of the heart to pump blood through the kidney and the circulatory system.

This reduced capacity further reduces blood flow to the kidney, which in turn further reduces the capacity of the heart. It is believed that the progressively decreasing perfusion of the kidney is a major non-cardiac cause that perpetuates the decreasing spiral of CHF. Moreover, fluid overload and associated clinical symptoms resulting from these physiological changes are the predominant causes of excessive hospital admissions, a terrible quality of life and unstoppable costs for the health care system due to CHF.

While many different diseases can initially damage the heart, once it is present, CHF is divided into two types: Chronic CHF and Acute CHF (or chronic decompensated). Chronic congestive heart failure is a long-term, slowly progressive degenerative disease. Over the years, chronic congestive heart failure leads to heart failure. Chronic CHF is classified clinically by the ability of patients to exercise or perform normal activities of daily living (as defined by the New York Heart Association Functional Class). Patients with chronic CHF are usually managed on an outpatient basis, typically with drugs.

Patients with chronic CHF may experience abrupt, severe impairment of cardiac function, called acute congestive heart failure, resulting in the inability of the heart to maintain sufficient blood flow and pressure to keep vital organs of the body alive. These acute CHF impairments can occur when extra stress (such as an infection or excessive fluid overload) significantly increases the cardiac workload in a patient with stable chronic CHF. Unlike gradual progression in chronic CHF stages, a patient suffering from acute CHF can deteriorate from even the earliest stages of CHF to severe hemodynamic collapse. In addition, Acute CHF may occur after a few hours or days after an Acute Myocardial Infarction ("AMI"), which is a sudden, irreversible damage to the heart muscle, commonly referred to as a heart attack.

As mentioned, the kidneys play a significant role in the progression of CHF, as well as in Chronic Renal Failure (“CRF”), the Final Stage of Renal Disease (“ESRD”), hypertension (pathologically blood hypertension) and other cardio-renal diseases. The functions of the kidney can be summarized in three broad categories: blood filtration and excretion of waste products generated by the body's metabolism; regulation of sodium or sodium balance, water, electrolytes and acid-base balance; and hormone secretion to maintain the blood flow of vital organs. Without proper kidney function, a patient will suffer water retention, reduced urinary flow and accumulation of waste toxins in the body's blood. These conditions resulting from reduced renal function or renal failure (kidney failure) are believed to increase the work of the heart. In a patient with CHF, renal failure will cause the heart to deteriorate further as the accumulation of water and toxins in the blood increases due to malfunctioning kidneys and, in turn, produce additional damage to the heart.

The main functional unit of the kidneys that is involved in the formation of urine are called "nephrons." Each kidney consists of approximately one million nephrons. The nephron is composed of glomeruli and their tubules, which can be separated into a number of sections: proximal tubule, medullary loop (Henle's loop) and the distal tubule. Each nephron is surrounded by different types of cells that have the ability to secrete various substances and hormones (such as renin and erythropoietin). Urine is formed as a result of a complex process that begins with the filtration of water from the blood plasma in the glomeruli. The walls of the glomeruli are freely permeable to water and small molecules but almost impervious to proteins and large molecules. Therefore, in a healthy kidney, the filtrate is virtually protein free and has no cellular elements. The filtered fluid that eventually converts to urine flows through the tubules. The final chemical composition of the urine is determined by the secretion in, and the reabsorption of substances from, the urine required to maintain homeostasis.

Receiving approximately 20% of cardiac output, the two kidneys filter approximately 125 ml of plasma water per minute. Filtering takes place due to a pressure gradient across the glomerular membrane. The pressure in the arteries of the kidney pushes the plasma water into the glomeruli producing filtration. To keep the glomerular filtration rate (“GFR”) relatively constant, the pressure in the glomeruli is maintained constant by the constriction or dilation of the afferent and efferent arterioles, the vessels with muscular walls that lead to and from each glomerulus.

In a patient with CHF, the heart will progressively fail and blood flow and pressure will fall into the patient's circulatory system. During an acute heart failure, short-term compensations serve to maintain perfusion to critical organs, mainly the brain and the heart that cannot survive a prolonged reduction in blood flow. However, these same responses that initially help survive during acute heart failure become harmful during chronic heart failure.

A combination of complex mechanisms contributes to a harmful fluid overload in CHF. When the heart fails and blood pressure drops, the kidneys cannot function and are affected due to insufficient blood pressure for perfusion. This affectation in renal function ultimately leads to a decrease in urine production. Without sufficient urine output, the body retains fluids and the resulting fluid overload produces peripheral edema (swelling of the legs), respiratory distress (due to fluids in the lungs) and fluid retention in the abdomen, among other undesirable conditions in the patient.

In addition, the decrease in cardiac output leads to reduced renal blood flow, an increased neurohormonal stimulus and a release of the renin hormone from the juxtaglomerular apparatus of the kidney. That results in an avid sodium retention and, therefore, volume expansion. The increase in renin results in the formation of angiotensin, a potent vasoconstrictor. Heart failure and the resulting reduction in blood pressure also reduce blood flow and perfusion pressure through organs in the body other than the kidneys. When they suffer a reduced blood pressure, these organs can become hypoxic, resulting in a metabolic acidosis that reduces the effectiveness of drug therapy and increases a risk of sudden death.

This spiral of deterioration observed by doctors in patients with heart failure is believed to be mediated, at least in part, by the activation of a slight interaction between cardiac function and renal function, known as the renin-angiotensin system. Disturbances in the pumping function of the heart result in decreased cardiac output and decreased blood flow. The kidneys respond to decreased blood flow as if the total blood volume had decreased, when in fact the measured volume is normal or even increased. This leads to a retention of fluids by the kidneys and the formation of edema, resulting in an overload of fluids and an increase in stress in the heart.

Systematically, it is associated with CHF with abnormally high peripheral vascular resistance and is controlled by circulation disorders resulting from an intense disturbance of sympathetic nervous system function. The increased activity of the sympathetic nervous system promotes a decreasing vicious circle of increase in arterial vasoconstriction (increased resistance of blood vessels to the blood vessel) followed by an additional reduction in cardiac output, causing even more decreased blood flow to the organs vital.

In CHF, through the previously explained mechanisms of vasoconstriction, the heart and the circulatory system dramatically reduce blood flow to the kidneys. During CHF, the kidneys receive an order from the higher neural centers through the nerve pathways and hormonal messengers to retain fluid and sodium in the body. In response to stress in the heart, the neural centers instruct the kidneys to reduce their filtering functions. While in the short term, these orders can be beneficial, if these orders continue for hours and days they can harm the person's life or make the person dependent on an artificial kidney to live by causing the kidneys to cease functioning.

When the kidneys do not completely filter the blood, a huge amount of fluid is retained in the body, resulting in a strain (retention of fluid in the tissues) and an increase in the workload of the heart. The fluid can penetrate the lungs of the patient who has difficulty breathing. This rare and self-destructive phenomenon is most commonly explained by the effects of the normal compensatory mechanism of the body that inappropriately perceives the low chronic blood pressure of CHF as a sign of temporary disturbance, similar to bleeding.

In an acute situation, the body tries to protect its most vital organs, the brain and the heart, from the dangers of lack of oxygen. Orders are sent through the neural and hormonal pathways and messengers. These commands are directed towards the goal of maintaining blood pressure in the brain and heart, which are treated by the body as the most vital organs. The brain and the heart cannot sustain a low perfusion for a substantial period of time. An attack or cardiac arrest will result if blood pressure to those organs is reduced to unacceptable levels. Other organs, such as the kidneys, can withstand somehow longer periods of ischemia without suffering long-term damage. Consequently, the body sacrifices the blood supply to these other organs in favor of the brain and the heart.

The hemodynamic problem resulting from CHF activates several neurohormonal systems, such as reninaangiotensin and aldosterone system, sympathetic-adrenal system and vasopressin release. When the kidneys suffer from increased renal vasoconstriction, the GFR falls and the sodium load in the circulatory system increases. Simultaneously, more renin is released from the juxtaglomerular kidney. The combined effects of reduced renal function include a reduced glomerular sodium load and an aldosterone-mediated increase in tubular reabsorption of sodium and retention in the body of sodium and water. These effects lead to various signs and symptoms of the CHF situation, including an enlarged heart, increased systolic wall tension and an increased demand for myocardial oxygen and the formation of edema based on fluid and sodium retention in the kidneys Consequently, a sustained reduction in renal blood flow and a vasoconstriction is directly responsible for producing fluid retention associated with CHF.

CHF is progressive, and so far, not curable. The limitations of drug therapy and its inability to reverse or even stop the deterioration of patients with CHF are clear. Surgical therapies are effective in some cases, but limited to the population of patients in the final stage due to the risk and the associated cost. Additionally, the dramatic role played by the kidneys in the deterioration of patients with CHF is not adequately focused by current surgical therapies.

The autonomic nervous system is recognized as an important pathway for control signals that are responsible for the regulation of critical bodily functions to maintain vascular fluid balance and blood pressure. The autonomic nervous system conducts information in the form of signals from the body's biological sensors such as baroreceptors (which respond to blood pressure and volume) and chemoreceptors (which respond to the chemical composition of blood) to the nervous system central through its sensory fibers. It also directs command signals from the central nervous system that control the various innervated components of the vascular system through its motor fibers.

The experience with human kidney transplantation provided first evidence of the role of the nervous system in kidney function. It was observed that after the transplant, when all the nerves of the kidney are completely cut, the kidney increased the secretion of water and sodium. This phenomenon was also observed in animals when the renal nerves were cut or chemically destroyed. The phenomenon was called "denervation diuresis" since denervation acted on a kidney in a manner similar to a diuretic medication. Subsequently, it was discovered that "denervation diuresis" was associated with vasodilation of the renal arterial system that led to increased blood flow through the kidney. This phenomenon was confirmed by the observation in animals that by reducing the blood pressure that is supplied to the kidneys, the "denervation diuresis" was reversed.

It was also observed that after several months after transplant surgery in successful cases, the "denervation diuresis" in the transplanted recipients was stopped and the renal function returned to normal. Originally, it was believed that "renal diuresis" was a transient phenomenon and that the nerves that carry signals from the central nervous system to the kidney were not essential for kidney function. Later discoveries suggested that the renal nerves had a profound capacity to regenerate and that the reversal of "denervation diuresis" could be attributed to the growth of new nerve fibers that gave the kidneys the necessary stimuli.

Another research nucleus focused on the role of neural control of the secretion of the renin hormone by the kidney. As previously explained, renin is a hormone responsible for the "vicious circle" of vasoconstriction and the retention of water and sodium in patients with heart failure. It was shown that an increase

or decrease in renal sympathetic nerve activity produced parallel increases and decreases, respectively, in the rate of renin secretion by the kidney.

In summary, it is known from clinical experiences in the broad field of animal research that an increase in renal sympathetic nerve activity leads to vasoconstriction of the blood vessels that feed the kidney, a decrease in renal blood flow, a decrease in the elimination of water and sodium from the body and an increase in the secretion of renin. It is also known that the reduction of sympathetic renal nerve activity, for example, through denervation, can reverse these processes.

It has been established in animal models that the condition of cardiac failure results in an abnormally elevated sympathetic stimulation of the kidney. This phenomenon was followed back to the sensory nerves that carry the signals from the baroreceptors to the central nervous system. Baroreceptors are present in different locations of the vascular system. There are powerful relationships between baroreceptors in the carotid arteries (which feed the brain with arterial blood) and sympathetic nerve stimuli to the kidneys. When arterial blood pressure dropped suddenly in experimental animals with heart failure, sympathetic tone increased. However, the baroreceptor reflex is probably not solely responsible for the high renal nerve activity in patients with chronic CHF. If they are exposed to a reduced level of blood pressure for a long time, the baroreceptors usually "replenish", that is, they return to their basic level of activity, until a new disturbance is introduced. Therefore, it is believed that in patients with chronic CHF, the components of the autonomic nervous system responsible for blood pressure control and neural control of kidney function become abnormal. The exact mechanisms that produce this abnormality are not fully understood, but its effect on the overall situation of patients with CHF is profoundly negative.

The Final Stage of Renal Dysfunction is another condition at least partially controlled by renal neural activity. There has been a dramatic increase in patients with ESRD due to diabetic nephropathy, chronic glomerulonephritis and uncontrolled hypertension. Chronic renal failure progresses slowly towards ESRD. The CRF represents a critical period in the evolution of the ESRD. The signs and symptoms of CRF are initially minor, but over the course of 2-5 years, they become progressive and irreversible. While some progress has been made to combat progression towards, and the complications of, ESRD, the clinical benefits of existing interventions remain limited.

It has been known for several decades that kidney diseases of different etiology (hypotension, infection, trauma, autoimmune disease, etc.) can lead to CRF syndrome characterized by systemic hypertension, proteinuria (excess of filtered blood protein in the urine ) and a progressive fall in the GFR resulting in the ESRD. These observations suggest that CRF progresses through a common pathway of mechanisms and that therapeutic interventions that inhibit this common pathway can be successful in stopping the rate of progression of CRF regardless of the cause of onset.

To begin the vicious cycle of CRF, an initial damage to the kidney causes a loss of some nephrons. To maintain normal GFR, there is an activation of renal and systemic compensatory mechanisms that result in a state of hyperfiltration in the remaining nephrons. Eventually, however, the increased number of "overloaded" nephrons damaged by hyperfiltration are lost. At some point, a sufficient number of nephrons is lost so that a normal GFR can no longer be maintained. These pathological changes of CRF cause the worsening of systemic hypertension, and therefore high glomerular pressure and increased hyperfiltration. Hyperfiltration and increased glomerular permeability in the CRF cause a high increase in blood proteins, through the glomeruli and into the renal tubules. This protein is directly toxic to the tubules and leads to additional losses of nephrons, increasing the rate of progression of the CRF. This vicious circle of the CRF continues while the GFR falls with loss of additional nephrons leading to additional hyperfiltration and finally to the ESRD that requires dialysis. Clinically, hypertension and excess protein filtration have been shown to be two main determining factors in the rate of progression of CRF towards ESRD.

Although previously known clinically, it was not until the 1980s that the physiological link between hypertension, proteinuria, loss of nephrons and CRF was identified. In the 1990s, the role of sympathetic nervous system activity was clarified. Afferent signals that arrive from the damaged kidneys due to the activation of mechanoreceptors and chemoreceptors stimulate areas of the brain responsible for blood pressure control. In response, the brain increases sympathetic stimulation at the systemic level, resulting in increased blood pressure primarily through vasoconstriction of blood vessels. When high sympathetic stimulation reaches the kidneys through efferent sympathetic nerve fibers, it produces major detrimental effects in two ways. The kidneys are damaged by direct renal toxicity from the release of sympathetic neurotransmitters (such as norepinephrine) in the kidneys independent of hypertension. Additionally, the renin secretion that activates Angiotensin II is increased, which increases systemic vasoconstriction and aggravates hypertension.

Over time, damage to the kidneys leads to an additional increase in afferent sympathetic signals from the kidneys to the brain. The elevated Angiotensin II further facilitates the internal renal release of neurotransmitters. The feedback loop is therefore closed, which accelerates the deterioration of the kidneys.

In view of the foregoing, it would be desirable to provide procedures and apparatus for the treatment of congestive heart failure, kidney disease, hypertension and / or other cardio-renal diseases through neuromodulation and / or renal denervation.

Summary

The present invention provides apparatus for renal neuromodulation (eg, denervation) using a pulsating electric field (PEF). Several aspects of the invention are applicable to pulsing electric fields to effect electroporation and / or electrofusion in renal nerves, in other neural fibers that contribute to renal neural function or in other neural features. Several embodiments of the invention are intravascular devices for inducing renal neuromodulation. The apparatus and procedures described herein may use any suitable parameter of the signal or electric field that achieves a neuromodulation, including denervation and / or otherwise create an electroporation and / or electrofusion effect. For example, the electrical signal can incorporate a pulsating electric field of nanoseconds (nsPEF) and / or a PEF to effect electroporation. A specific embodiment comprises the application of a first electroporation treatment by PEF followed by a second electroporation treatment by nsPEF to induce apoptosis in any cell that remains intact after PEF treatment, or vice versa. An alternative embodiment comprises the fusion of nerve cells by applying a PEF in a manner that is expected to reduce or eliminate the ability of nerves to conduct electrical impulses. When the procedures and apparatus are applied to the renal nerves and / or other neural fibers that contribute to renal neural function, the present inventors believe that urine production will increase and / or blood pressure will be controlled in a manner that will prevent or treat CHF, hypertension, diseases of the renal system and other renal abnormalities.

Several aspects and particular embodiments can achieve such results by selecting the appropriate parameters for PEF and / or nsPEF. The parameters of the pulsing electric field may include, but are not limited to, the field strength, the pulse width, the pulse shape, the number of pulses and / or the interval between pulses (for example the duty cycle). Suitable field strengths include, for example, intensities of up to about 10,000 V / cm. Suitable pulse widths include, for example, widths of up to about 1 second. Suitable forms of the pulse waveform include, for example, alternating current waveforms, sine waves, cosenoid waves, sine and cosine wave combinations, direct current waveforms, alternating current waveforms continuously displaced, radiofrequency waveforms, square waves, trapezoidal waves, exponentially decreasing waves, combinations thereof, etc. Suitable pulse numbers include, for example, at least one pulse. Suitable intervals between pulses include, for example, intervals of less than about 10 seconds. Any combination of these parameters can be used as desired. These parameters are provided for purposes of illustration and should not be considered limiting in any way. Additional parameters and alternative waveforms will be apparent.

Various embodiments are directed to percutaneous intravascular systems to provide long-lasting denervation to minimize the expansion of acute myocardial infarction ("AMI") and to help prevent the occurrence of morphological changes that are associated with congestive heart failure. For example, one embodiment of the invention comprises the treatment of a patient by infarction, for example, by coronary angioplasty and / or stent placement, and the performance of a procedure of renal denervation by intra-arterial pulsating electric field under fluoroscopic guidance. Alternatively, PEF therapy could be applied in a separate session as soon as the AMI has stabilized. Renal neuromodulation can also be used as a complementary therapy for renal surgical processes. In these embodiments, the anticipated increase in urine production and / or blood pressure control provided by renal PEF therapy is expected to reduce the burden on the heart to inhibit the expansion of the infarction and prevent CHF.

Various embodiments of intravascular pulsing electric field systems described herein may denervate or reduce the activity of the renal nerve supply immediately post-infarction, or at any later time, without leaving aside a permanent implant in the patient. These embodiments hope to increase urine production and / or blood pressure control over a period of several months during which the patient's heart can heal. If it is determined that a repeated and / or chronic neuromodulation would be beneficial after this healing period, the renal PEF treatment can be repeated as necessary.

In addition to the effective treatment of AMI, various embodiments of systems described herein are also expected to treat CHF, hypertension, renal failure and other renal or cardio-renal diseases influenced or affected by an increased renal sympathetic nervous activity. . For example, the systems can be used to treat CHF at any time by advancing the PEF system to a treatment site by means of a vascular structure and then applying a PEF therapy at the treatment site. This can, for example, modify a level of fluid discharge.

The embodiments of the intravascular PEF systems described herein can be used in a manner similar to angioplasty or electrophysiology catheters that are well known in the art. For example, arterial access can be achieved through a standard Seldinger technique, and an arterial sheath can be optionally placed to provide access to the catheter. A guidewire can be advanced through the vascular system and into the patient's renal artery, and then the intravascular PEF may be advanced over the guidewire and / or through the sheath within the renal artery. The sheath may be optionally placed before inserting the PEF catheter or advancing together with the PEF catheter so that the sheath partially or completely covers the catheter. Alternatively, the PEF catheter can be advanced directly through the vasculature without the use of a guidewire and / or inserted and advanced into the vasculature without a sheath.

In addition to an arterial placement, the PEF system can be placed inside a vein. The venous access can, for example, be achieved through a jugular approach. The PEF system can be used, for example, within the renal artery, within the renal vein or within both the artery and the renal vein to facilitate more complete denervation.

After positioning the PEF catheter inside the vessel at a desired location with respect to the target neurons, it stabilizes inside the vessel (for example, leaning against the vessel walls) and energy is applied to the target nerve or neurons. In one variation, constant RF energy is applied to the target to create a non-thermal nerve block, reduce neural signaling or otherwise modulate neural activity. Alternatively or additionally, refrigeration, cryogenics, thermal RF, thermal or non-thermal microwaves, focused or non-focused ultrasound, continuous thermal or non-thermal current as well as any combination thereof can be used to reduce or otherwise control the signaling neural.

In yet other embodiments of the invention, other non-renal neural structures could be focused from within the arterial or venous ducts in addition to or in place of the renal neural structures. For example, a PEF catheter can be navigated through the aorta or vena cava and carried in opposition to several neural structures to treat other conditions or increase the treatment of renal-cardiac conditions. For example, the nervous bodies of the lumbar sympathetic chain can be accessed and modulated, blocked

or removed, etc., in this way.

Several embodiments of PEF systems may completely block or denervate the target neural structures or PEF systems may modulate renal nerve activity in another way. Unlike a complete neural block such as denervation, other neuromodulations produce a non-complete change in the level of renal nerve activity between the kidney (s) and the rest of the body. Consequently, the variation of the pulsating electric field parameters will produce different effects on nerve activity.

In one embodiment of an intravascular pulsating electric field system, the device includes one or more electrodes that are configured to make physical contact with an objective region of a renal vasculature for the application of a pulsating electric field. For example, the device comprises a catheter having an expandable helical section and one or more electrodes in the helical section. The catheter can be placed in a renal vasculature while in a low profile configuration. The expandable section can then be expanded to make contact with the inner surface of the vessel wall. Alternatively, the catheter may have one or more expandable helical electrodes. For example, a first and a second expandable electrode can be placed within the vessel at a desired distance from each other to provide an active electrode and a return electrode. Expandable electrodes can comprise shape memory materials, inflatable balls, expandable meshes, link systems and other types of devices that can be expanded in a controlled manner. Expandable link systems include expandable baskets, which have a plurality of shape memory cables or slotted hypotubes and / or expandable rings. Additionally, the expandable electrodes may be contact tip electrodes disposed along a part of a catheter balloon.

Other embodiments of the pulsating electric field systems include electrodes that do not physically contact the vessel wall. RF energy, both traditional thermal energy and relatively non-thermal pulsing RF, are examples of pulsing electrical fields that can be conducted within the tissues to be treated from a short distance apart from the tissue itself. Other types of pulsating electric fields can also be used in situations where the electrodes do not physically make contact with the vessel wall. As such, the pulsating electric fields can be applied directly to the nerve by means of physical contact between the electrode contacts and the vessel wall or other tissues or the pulsating electric fields can be applied indirectly to the nerve by making physical contact with the contact electrodes. The wall of the glass. The term "nerve contact" accordingly includes the physical contact of an element of the system with the nerve and / or the tissue near the nerve and also the electrical contact only without physical contact of the nerve or tissue. To indirectly apply the pulsating electric field, the device has a centering element configured to position the electrodes in a central region of the vessel or otherwise separate the electrodes from the vessel wall. The centering element may include, for example, a balloon or an expandable basket. One or more electrodes can be placed on a central axis of the centering element - both longitudinally aligned with the element and located on either side of the element. When a balloon catheter is used, the inflated balloon can act as an impedance increase insulator to orient or direct a pulsating electric field along a desired path of electrical flow. As will be apparent, alternative insulators can be used.

In another embodiment of the system, a combination of apparatus includes an intravascular catheter having a first electrode configured to physically contact the vessel wall and a second electrode configured to be located within the vessel but separated from the vessel wall. For example, an expandable helical electrode can be used in combination with a centrally arranged electrode to provide a pair of bipolar electrodes.

In yet another embodiment, a radial position of one or more electrodes can be dynamically altered relative to a vessel wall to focus the pulsating electric field applied by the electrode (s). In yet another variation, the electrodes can be configured for partial or complete passage through the vessel wall. For example, the electrode (s) can be placed inside the renal vein. And then pass through the wall of the renal vein into the perivascular space so that at least partially they surround the artery and / or renal vein before the application of a pulsating electric field.

The bipolar embodiments of the present invention can be configured for dynamic movement or operation in relation to the separation between the active and grounding electrodes to achieve treatment over a desired distance, volume or other dimension. For example, a plurality of electrodes may be arranged so that a bipolar pair of electrodes can be moved longitudinally relative to each other to adjust the separation distance between the electrodes and / or to alter the location of the treatment. A specific embodiment includes a first electrode coupled to a catheter and a second mobile electrode that can be moved through a lumen of the catheter. In alternative embodiments, an electrode can be attached to a catheter and a second electrode can be attached to an extraluminally applied device so that the first and second electrode can be relatively resituated with each other to alter a separation distance between the electrodes. Such embodiments may facilitate the treatment of a variety of renal vascular anatomies.

Any of the embodiments of the present invention described herein may optionally be configured for the infusion of agents into the treatment area before, during or after the application of energy. Infused agents can be selected to improve or modify the neuromodulatory effect of energy application. Agents can also temporarily protect or displace non-target cells and / or facilitate visualization.

Several embodiments of the present invention may comprise detectors or other elements that facilitate identification or locations for the treatment and / or measure or confirm the success of the treatment. For example, the system can be configured to also apply stimulation waveforms and monitor physiological parameters that are known to respond to renal nerve stimulation. Based on the results of the monitored parameters, the system can determine the location of the renal nerves and / or if denervation has taken place. Detectors for monitoring such physiological responses include, for example, Doppler elements, thermocouples, pressure sensors and image management modalities (for example, fluoroscopy, intravascular ultrasound, etc.). Alternatively, electroporation can be monitored directly using, for example, Electric Impedance Tomography ("EIT") or other electrical impedance measurements. Other additional monitoring techniques and elements will be evident. Such a detector or detectors can be integrated with PEF systems or they can be separate elements.

Other specific embodiments include electrodes configured to align the electric field with the longest dimension of the target cells. For example, nerve cells tend to be elongated structures with lengths that greatly exceed their lateral dimensions (for example, diameter). By aligning an electric field so that directional field propagation preferentially affects the longitudinal aspects of the cell rather than the lateral aspects of the cell, it is expected that lower field intensities can be used to kill or disable the target cells. This is expected to preserve the life of the battery or implantable devices, reduce side effects on adjacent structures and otherwise improve the ability to modulate the neural activity of the target cells.

Other embodiments of the invention are directed to applications in which the longitudinal dimensions of the cells and the tissues superimposed or underlying the nerve are transverse (for example, orthogonal or at an angle of another shape) with respect to the longitudinal direction of the cells nervous Another aspect of these embodiments is to align the directionality of the PEF so that the field aligns with the longer dimensions of the target cells and the shorter dimensions of the non-target cells. More specifically, arterial smooth muscle cells are typically elongated cells that surround the arterial circumference in a generally spiral orientation so that their longer dimensions are circumferential rather than run longitudinally along the artery. The nerves of the renal plexus, on the other hand, run along the outside of the artery usually in the longitudinal direction of the artery. Therefore, the application of a PEF and which is generally aligned with the longitudinal direction of the artery is expected to preferentially cause electroporation in the target nerve cells without affecting at least some of the non-target arterial smooth muscle cells to some degree. . This may allow preferential denervation of nerve cells (target cells) in the adventitia or periarterial region from an intravascular device without affecting the smooth muscle cells of the vessel to an undesirable extent.

Brief description of the drawings

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

Figure 1 is a schematic view illustrating the human renal anatomy.

Figure 2 is a schematic detail view showing the location of the renal nerves relative to the renal artery.

Figures 3A and 3B are schematic side and end views, respectively, illustrating a direction of an electric current flow to selectively affect the renal nerves.

Figure 4 is a schematic side view, partially in section, of an intravascular catheter having a plurality of electrodes according to an embodiment of the invention.

Figure 5 is a schematic side view, partially in section, of an intravascular device having a pair of expanding helical electrodes arranged at a desired distance from each other in accordance with another embodiment of the invention.

Figure 6 is a schematic side view, partially in section, of an intravascular device having a first expandable balloon electrode, and a second electrode of a catheter shaft according to another embodiment of the invention.

Figure 7 is a schematic side view, partially in section, of an intravascular device having a first expanding electrode applied through the lumen of a catheter and a second complementary electrode carried by the catheter according to another embodiment of the invention.

Figure 8 is a schematic side view, partially in section, of an intravascular device having an expandable basket and a plurality of electrodes in the basket according to another embodiment of the invention.

Figure 9 is a schematic detail view of the apparatus of Figure 8 illustrating an embodiment of the electrodes according to another embodiment of the invention.

Figure 10 is a schematic side view, partially in section, of an intravascular device having expandable ring electrodes to make contact with the vessel wall and an optional insulating element according to another embodiment of the invention.

Figures 11A-11C are schematic detail views of embodiments of different windings for the ring electrodes of Figure 10.

Figure 12 is a schematic side view, partially in section, of an intravascular device having ring electrodes of Figure 10 with the windings shown in Figures 11A-11C.

Figure 13 is a schematic side view, partially in section, of an intravascular device having a ring electrode and a light-applied electrode in accordance with another embodiment of the invention.

Figure 14 is a schematic side view, partially in section, of an intravascular device having a balloon catheter and expandable tip contact electrodes disposed proximally and distally of the balloon according to another embodiment of the invention.

Figure 15 is a schematic side view and an intravascular device having a balloon catheter and electrodes disposed proximally and distally of the balloon according to another embodiment of the invention.

Figures 16A and 16B are schematic side views, partially in section, illustrating steps of a method of using the apparatus of Figure 15 according to an embodiment of the invention.

Figure 17 is a schematic side view of an intravascular device having a balloon catheter and a plurality of dynamically operable electrodes according to another embodiment of the invention.

Figure 18 is a schematic side view of an intravascular device having a distal electrode deployed through a lumen of the balloon catheter according to another embodiment of the invention.

Figures 19A and 19B are side views, partially in section, illustrating methods of using intravascular devices shown in Figure 18 to modulate renal neural activity in patients with various renal vasculatures.

Figure 20 is a side view, partially in section, illustrating an intravascular device having a plurality of electrodes disposed along the axis of, and in line with, a centering element according to another embodiment of the invention.

Figure 21 is a side view, partially in section, illustrating an intravascular device having electrodes configured for radially and dynamically repositioning to facilitate focusing of a pulsating electric field according to another embodiment of the invention.

Figure 22 is a side view, partially in section, of an intravascular device having an infusion / aspiration catheter according to another embodiment of the invention.

Figures 23A-23C are, respectively, a side view, partially in section, and cross-sectional views along section lines AA of Figure 23A, illustrating a method of using an intravascular device according to a embodiment of the invention configured for the passage of the electrode (s) at least partially through the vessel wall.

Figures 24A and 24B are side views, partially in section, illustrating an intravascular device having detectors for measuring or monitoring the efficacy of the treatment according to another embodiment of the invention.

Detailed description

A. Overview

The present invention relates to an apparatus for renal neuromodulation and / or other neuromodulation. More particularly, the present invention relates to methods and apparatus for renal neuromodulation using a pulsating electric field to effect electroporation or electrofusion. As used herein, electroporation and electropermeabilization are methods of manipulating the cell membrane or intracellular devices. For example, short pulses of high energy produce pores to open cell membranes. The degree of porosity in the cell membrane (for example, size and number of the pores) and the duration of the pores (for example temporary or permanent) are a function of the field strength, the pulse width, the duty cycle, of field orientation, cell type and other parameters. In general, the pores will generally close spontaneously upon termination or lower field intensity or shorter pulse width (defined herein as "reversible electroporation"). Each type of cell has a critical threshold above which the pores do not close so that the formation of the pores is no longer reversible; This result is defined as "irreversible electroporation", "irreversible breakage" or "irreversible damage". At this point, cell membrane tears and / or irreversible chemical imbalances caused by high porosity occur. Such high porosity may be the result of a single large hole and / or a plurality of smaller holes. Certain types of electroporation energy parameters also suitable for use in renal neuromodulation are high voltage pulses with a duration in the range of microseconds (pulsating electric fields of nanoseconds, or nsPEF), which can leave the cell membrane intact, but alter the intracellular devices or functions of the cell in ways that cause death or cell disorder. Certain applications of nsPEF have been shown to produce cell death by inducing apoptosis, or programmed cell death, rather than acute cell death. Also, the term "understanding" is used throughout the document to indicate that it includes at least the feature listed so that no larger number of the same feature and / or features of additional types are discarded.

Several embodiments of the present invention provide intravascular devices for inducing renal neuromodulation such as a temporary change in the objective nerves that dissipates over time, continuous control over renal function and / or denervation. The apparatus and procedures described herein can use any suitable electrical field or signal parameter, for example, any electrical field, which will achieve the desired neuromodulation (for example, electroporation effect). To better understand the structures of intravascular devices and the procedures for using these devices for neuromodulation, it is useful to understand renal anatomy in humans.

B. Selected embodiments of neuromodulation procedures

Referring now to Figure 1, the human renal anatomy includes the kidneys K to which oxygenated blood is supplied 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 through the RV renal veins and the IVC inferior vena cava. Figure 2 illustrates a part of the renal anatomy in greater detail. More specifically, the renal anatomy also includes the RN renal nerves that extend longitudinally along the longitudinal dimension L of the renal artery RA in general within the adventitia of the artery. The renal artery RA has smooth muscle cells SMC that surround the spiral of the arterial circumference around the angular axis θ of the artery, that is, around the circumference of the artery. The smooth muscle cells of the renal artery consequently have a longitudinal or longer dimension that extends transversely (i.e., not in parallel) with the longitudinal dimension of the renal artery. Misalignment of the longitudinal dimensions of the renal nerves and smooth muscle cells is defined as "cellular misalignment."

With reference to Figure 3, cellular misalignment of renal nerves and smooth muscle cells can be used to selectively affect renal nerve cells with reduced effect on smooth muscle cells. More specifically, because longer cells require less energy to exceed the irreversibility threshold of electroporation, several embodiments of electrodes of the present invention are configured to align at least a portion of an electric field generated by the electrodes with or near of the longest dimensions of the cells to be affected. In specific embodiments, the intravascular device has electrodes configured to create an electric field aligned with or near the longitudinal dimension of the renal artery RA to affect the renal nerves RN. By aligning an electric field so that the field preferentially affects the longitudinal aspect of the cell rather than the diametral or radial aspect of the cell, lower field intensities can be used to necrotize cells. As mentioned earlier, this is expected to reduce power consumption and mitigate the effects on non-target cells in the electric field.

Similarly, the longitudinal or longer dimensions of the tissues that line or underlie the target nerve are orthogonal or off-axis in another way (eg, transverse) with respect to the longer dimensions of nerve cells. Therefore, in addition to aligning the PEF with the longitudinal or longer dimensions of the target cells, the PEF can propagate along the lateral or shorter dimensions of the non-target cells (ie so that the PEF propagates to the less partially out of alignment with non-target SMC smooth muscle cells). Therefore, as seen in Figure 3, the application of a PEF with propagation lines Li generally aligned with the longitudinal dimension L of the renal artery RA is expected to preferably produce electroporation, electrofusion, denervation or other neuromodulation in the target RN renal nerve cells without unduly affecting non-target arterial SMC smooth muscle cells. The pulsating electric field can propagate in a simple plane along the longitudinal axis of the renal artery or it can propagate in the longitudinal direction along any angular segment θ through the range of 0º-360º.

The embodiments shown in Figure 3 may have particular applications with the intravascular apparatus of the present invention. For example, a PEF catheter placed within the renal artery can propagate an electric field that has a longitudinal part that aligns to run with the longitudinal dimension of the artery in the region of the renal nerves RN and the smooth muscle cell SMC of the vessel wall so that the artery wall remains at least substantially intact while the outer nerve cells are destroyed.

C. Implementation of additional systems and procedures for neuromodulation

Figure 4 shows an embodiment of a pulsating electric field apparatus 200 according to the present invention that includes one or more electrodes configured to physically contact a target region within the renal vasculature and apply a pulsating electric field through a Vasculature wall. The apparatus 200 is shown within a renal artery RA of the patient, but can be placed in other intravascular locations (for example, the renal vein). This embodiment of the apparatus 200 comprises an intravascular catheter 210 having a proximal section 211a, a distal section 211b, and a plurality of distal electrodes 212 in the distal section 211b. The proximal section 211a generally has an electrical connector for coupling the catheter 210 to a pulse generator in the distal section 211b which in this embodiment has a helical configuration. The apparatus 200 is electrically connected to a pulsating electric field generator 100 located near and external to the patient; the electrodes 212 are electrically connected to the generator through the catheter 210. The generator 100 can be used with any embodiment of the present invention described later for the application of a PEF with the desired field parameters. It should be understood that the electrodes of the embodiments described hereinbelow can be connected to the generator, even if the generator is not explicitly shown or described with each variation.

The helical distal section 211b of the catheter 210 is configured to juxtapose the vessel wall and bring the electrodes 212 in close proximity to the extravascular neural structures. The pitch of the propeller can be varied to provide a longer treatment zone or to minimize circumferential overlap of adjacent treatment zones to reduce a risk of stenosis formation. This step change can be achieved by combining a plurality of catheters of different passages to form catheter 210 or by adjusting the passage of catheter 210 through the use of internal tension wires, adjustment spindles inserted into the catheter, shaping sheaths placed on the catheter, or by other means suitable for changing the passage either in situ or before the introduction into the body.

The electrodes 212 along the length of the passage may be individual electrodes, a common but segmented electrode, or a common and continuous electrode. A common and continuous electrode may, for example, comprise a conductive coil formed inside or placed on a helical part of the catheter 210. A common but segmented electrode can, for example, be formed by providing a grooved tube fitted on or within the helical part of the catheter, or by electrical connection of a series of individual electrodes.

Individual electrodes or groups of electrodes 212 may be configured to provide a bipolar signal, or all or a subset of the electrodes may be used in conjunction with a separate external patient ground for monopolar use (the ground mat may, for example , be placed on the patient's leg). The electrodes 212 can be dynamically assigned to facilitate the application of monopolar and / or bipolar energy between any of the electrodes and / or between any of the electrodes and an external ground.

The catheter 210 can be applied to a renal artery RA in a low profile application configuration within a sheath 150. Once positioned within the artery, the catheter can be self-expanding or actively expanded, for example, by means of a tension wire or a ball in contact with an inner wall of the artery. A pulsating electric field can then be generated by a PEF generator 100, transferred through catheter 210 to electrodes 212 and applied through electrodes 212 through the artery wall. In many applications, the electrodes are arranged so that the pulsating electric field aligns with the longitudinal dimension of the artery to modulate neural activity along the renal nerves (eg, denervation). This can be achieved, for example, by irreversible electroporation, electrofusion and / or induction of apoptosis in nerve cells.

Figure 5 illustrates an apparatus 220 for neural modulation according to another embodiment of the invention. The apparatus 220 includes a pair of catheters 222a and 222b having expandable distal sections 223a and 223b with helical electrodes 224a and 224b, respectively. The helical electrodes 224a and 224b are separated from each other by a desired distance within the patient's renal vasculature. Electrodes 224a-b can be activated in a bipolar manner so that one electrode is an active electrode and the other is a return electrode. The distance between the electrodes can be altered as desired to change the field strength and / or the length of the nerve segment modulated by the electrodes. The expandable helical electrodes may comprise memory properties so as to facilitate self-expansion, for example, after passing through the sheath 150,

or the electrodes can be actively expanded in contact with the vessel wall, for example, by an inflatable balloon or by tension wires, etc. The catheters 222a-b are preferably electrically isolated in areas other than the distal propellers of the electrodes 224a-b.

Figure 6 illustrates an apparatus 230 comprising a balloon catheter 232 having an expandable balloon 234, a helical electrode 236 disposed on the balloon 234 and an axis electrode 238 on the axis of the catheter 232. The axis electrode 238 can be locate proximal to the expandable balloon 284 as shown, or the axis electrode 268 can be located distal to the expandable balloon 284.

When the apparatus 230 is applied to a target vessel, for example within the renal artery RA, the expandable balloon 234 and the helical electrode 236 are arranged in a low profile application configuration. As seen in Figure 6, once the apparatus has been positioned as desired, the expandable balloon 234 can be inflated to place the helical electrode 236 in physical contact with the vessel wall. In this embodiment, the shaft electrode 238 does not physically contact the vessel wall.

It is known in the art both of the application of thermal RF energy and in the application of relatively non-thermal pulsing RF energy, that energy can be directed to the tissue to be treated from a short distance separated from the tissue itself. Therefore, it can be seen that "contact with the nerve" comprises both physical contact of an element of the system with a nerve, and electrical contact only without physical contact or a combination of the two. A centering element can be optionally provided to place the electrodes in a central region of the vessel. The centering element may comprise, for example, an expandable balloon, such as a balloon 234 of the apparatus 230 or an expandable basket as described later herein. One or more electrodes can be placed on a central axis of the centering element - either longitudinally aligned with the element or located on one or both sides of the element - as is the electrode of the axis 238 of the apparatus 230. When a device is used Balloon catheter like catheter 232, the inflated balloon can act as an insulator for increasing impedance to direct the pulsating electric field along a desired electrical flow path. As will be apparent, alternative insulators can be used.

As seen in Figure 6, when the helical electrode 236 physically makes contact with the wall of the renal artery RA, the generator 100 can generate a PEF so that the current passes between the helical electrode 236 and the axis electrode 238 in A bipolar way. The PEF travels between the electrodes along the Li lines that generally extend along the longitudinal dimension of the artery. The balloon 234 isolates locally and / or increases the impedance within the patient's vessel so that the PEF travels through the vessel wall between the helical and shaft electrodes. This will focus energy to improve denervation and / or other neuromodulation of the patient's renal nerves, for example, through irreversible electroporation.

Figure 7 illustrates an apparatus 240 similar to those shown in Figures 4-6 in accordance with another embodiment of the invention. The apparatus 240 comprises a balloon catheter 242 having an expandable balloon 244 and an axis electrode 246 located proximal to the expandable balloon 244. The apparatus 240 further comprises an expandable helical electrode 248 configured for application through a lumen of guidewire. 243 of catheter 242. The helical electrode 248 shown in Figure 7 is self-expanding.

As seen in Figure 7, after positioning the catheter 242 in the target vessel (for example in the renal artery RA), the balloon 244 is inflated until it makes contact with the vessel wall to keep the axis electrode 246 in a desired location within the vessel and to isolate or increase the impedance inside the vessel. The balloon 244 is generally configured to also center the axis electrode 236 inside the vessel or otherwise separate the axis electrode from the vessel wall at a desired distance. After inflation of balloon 234, helical electrode 248 is pushed through lumen 243 until helical electrode 248 extends beyond the axis of the catheter; electrode 248 then expands or moves in another way within the helical configuration to physically make contact with the vessel wall. A bipolar pulsing electric field can then be applied between the helical electrode 248 and the axis electrode 226 along the lines Li. For example, the helical electrode 248 may comprise the active electrode and the axis electrode 246 may comprise the return electrode, or vice versa.

Referring now to Figure 8, the apparatus comprising an expandable basket having a plurality of electrodes that can be expanded in contact with the vessel wall is described. The apparatus 250 comprises the catheter 252 having a distal and expandable basket 25 4 formed by a plurality of uprights or circumferential elements. A plurality of electrodes 256 are formed along the elements of the basket 254. Each element of the basket illustratively comprises a pair of bipolar electrodes configured to make contact with a wall of the renal artery RA or other desired blood vessel .

The basket 254 can be manufactured, for example, from a plurality of threads or tapes with shape memory, such as Nitinol, steel spring or elgiloy cables or tapes, which form the elements of the basket 253. When the elements of the basket comprises tapes, the tapes can be moved so that the area of contact with the vessel wall is increased. The elements of the basket 223 are coupled to the catheter 253 at the proximal and distal connections 255a and 255b, respectively. In such a configuration, the basket can be collapsed for application within the sheath 150 and can be self-expanding in contact with the artery wall after removal of the sheath. The proximal and / or distal connection 255 may optionally be configured to travel along the axis of catheter 252 at a specified or unspecified distance to facilitate the expansion and collapse of the basket.

The basket 254 can alternatively be formed from a granulated and / or laser cut hypotube. In such a configuration, the catheter 252 may, for example, comprise inner and outer shafts that move relatively together. The distal connection 255b of the basket 254 can be coupled to the inner shaft and the proximal connection 255a of the basket can be coupled to the outer shaft. The basket 254 can be expanded from a collapsed application configuration to be deployed in the configuration of Figure 8 by approaching the inner and outer axes of the catheter 252, thereby approaching the proximal and distal connections 255 of the basket and expanding the basket In the same way, the basket can be collapsed by separating the inner and outer axes of the catheter.

As seen in Figure 9, the individual electrodes can be arranged along the uprights or elements of the basket 253. In one embodiment, the upright is formed from conductive material coated with a dielectric material and electrodes 256 are they can form by removing regions of the dielectric coating. The insulation can optionally be removed only along a radially outer surface of the element so that electrodes 256 remain insulated on their radially inner surfaces; It is expected that this will direct the flow of current outward into the vessel wall.

In addition, or as an alternative, to the fixing technique of Figure 9, the electrodes can be fixed to the inner surface, outer surface or embedded within the uprights or elements of the basket 254. The elements placed along each Upright or element may comprise individual electrodes, a segmented but common electrode, or a common and continuous electrode. The individual electrodes or groups of electrodes can be configured to provide a bipolar signal or all or a subset of the electrodes can be operated together with an external patient ground for monopolar use.

An advantage of having electrodes 256 in contact with the vessel wall, as shown in the embodiment of Figure 8, is that it can reduce the need for an insulating element, such as an expandable balloon, to achieve renal denervation or Another neuromodulation However, it should be understood that such an insulation element can be applied and, for example, expanded within the basket. Additionally, having the electrodes in contact with the wall can provide an improved field geometry, that is, it can provide an electric field more aligned with the longitudinal axis of the vessel. Such contact electrodes can also facilitate the stimulation of the renal nerves before, during or after neuromodulation to better position the catheter 252 before treatment or to monitor the effectiveness of the treatment.

In a variation of the apparatus 250, the electrodes 256 can be arranged along the central axis of the catheter 252, and the basket 254 can simply center the electrodes inside the vessel to facilitate a more precise application of the energy through the walls of the glass. This configuration may be well suited for a precise selection of the vascular or extra vascular tissue target, such as the renal nerves surrounding the renal artery. Properly sized, the basket or other centering element for the artery provides a known distance between the centered electrodes and the artery wall that can be used to direct and / or focus the electric field as desired. This configuration can be used in focused ultrasound or high intensity microwave applications, but can also be adapted for use with any other energy mode as desired.

With reference now to Figure 10, it is expected that the electrodes that form a circumferential contact with the wall of the renal artery can provide a more complete renal denervation or renal neuromodulacon. Figure 10 describes a variation of the present invention comprising ring electrodes. The apparatus 260 comprises the catheter 262 having expandable ring electrodes 264a and 264b configured to make contact with the vessel wall. The electrodes can be fixed to the axis of the catheter 262 by means of the uprights 266 and the catheter 262 can be configured for application in the renal artery RA through the sheath 150 in a low profile configuration. The uprights 266 can be self-expanding or can be actively or mechanically expanded. Catheter 262 comprises a guide wire lumen 263 for advancing on a guide wire. The catheter 262 also comprises an optional inflatable balloon 268 that can act as an insulation or impedance booster element to preferably direct the flow of current that is traveling between the electrodes 264 through the artery wall.

Figures 11A-11C illustrate various embodiments of windings for ring electrodes 264. As shown, the ring electrodes may, for example, be wound in a coil (Figure 11A), zigzag (Figure 11B) or serpentine ( Figure 11C). You can specify the periodicity of the winding as desired. Additionally, the type of winding, the periodicity etc., may vary along the circumference of the electrodes.

With reference to Figure 12, a variation of the apparatus 260 comprising ring electrodes 264 'having a sinusoidal winding in an embodiment of the serpentine winding shown in Figure 11C is described. The uprights 266 are illustratively fixed to the vertices of the sinusoid. The winding of the electrodes 264 'can provide a greater contact area along the wall of the vessel than what the electrodes 264 do, while the wrapping of the apparatus 260 within the sheath 150 for application and removal is still facilitated. .

Figure 13 illustrates another variation of the apparatus 260 comprising a proximal ring electrode 264a, and comprises a distal electrode 270 applied through the lumen of the guide wire 263 of the catheter 262. The distal electrode 270 is not expandable is centered within the vessel by catheter medium 262. The distal electrode 270 may be a standard guidewire that connects to the pulsating electric field generator and is used as an electrode. However, it should be understood that electrode 270 may alternatively be configured for expansion in contact with the vessel wall, for example, it may comprise a ring or helical electrode.

The application of the distal electrode through the lumen of the catheter 262 may reduce an application profile of the apparatus 260 and / or may improve the flexibility of the device. Additionally, the application of the distal electrode through the lumen of the guidewire can serve as a safety feature that ensures that the medical practitioner removes any guidewire disposed within the lumen 263 before the application of a PEF. It also allows the personalization of the length of the treatment, as well as the treatment in lateral branches, as described later in this document.

Ring electrodes 264 and 264 ′ may optionally be electrically isolated along their radially interior surfaces, while their radially outer surfaces that make contact with the vessel wall are exposed. This can reduce a risk of thrombus formation and can also improve or enhance the directionality of the electric field along the longitudinal axis of the vessel. This can also facilitate a reduction in the field voltage necessary to damage the neural fibers. The materials used to at least partially isolate the ring electrodes may comprise, for example, PTFE, ePTFE, FEP, chloroprene, silicone, urethane, Pebax, etc. With reference to Figure 14, another variation of the apparatus 260 is described, in which the ring electrodes have been replaced with tip electrodes 272 arranged at the ends of the uprights 266 for application through the sheath 150 and can be self-expand with the uprights in contact with the vessel wall. In Figure 14, the catheter 262 illustratively comprises four tip electrodes 272 on both sides of the balloon 268. However, it should be understood that any desired number of uprights and tip electrodes around the circumference of the catheter 262 can be provided. .

In Figure 14, the apparatus 260 illustratively comprises four uprights 266 and four tip electrodes 272 on both sides of the balloon 268. By using all electrodes distally arranged 272b as active electrodes and all proximal electrodes 272a as electrodes of Return, or vice versa, the Li lines along which it propagates to the electric field can be aligned with the longitudinal axis of a vessel. The degree to which the Li line overlaps along the axis of rotation of the vessel can be specified by specifying the angular placement and the density of the tip electrodes 272 around the circumference of the catheter, as well as by specifying PEF parameters.

Referring now to Figure 15, another variation of an intravascular PEF catheter is described. The apparatus 280 comprises the catheter 282 having an optional inflatable balloon or centering element 284, shaft electrodes 286a and 286b arranged along the axis of the catheter on both sides of the balloon, as well as optional radiopaque markers 288 arranged along the catheter shaft, illustratively in line with the balloon. Balloon 284 serves both as a centering element for electrodes 266 and as an electrical insulator for the direction of the electric field, as previously described.

The apparatus 280 may be particularly well adapted for achieving a precise selection of the desired arterial or extra arterial tissue target, since the proper sizing of the balloon 284 for the target artery establishes a known distance between the centered electrodes 286 and the wall of the artery that can be used when the PEF parameters are specified. Electrodes 286 may alternatively be fixed to balloon 284 rather than to the central axis of catheter 282 so as to make contact with the artery wall. In such a variation, the electrodes can be fixed to the inner surface, the outer surface or embedded within the wall of the balloon.

The electrodes 286 arranged along the length of the catheter 282 may be individual electrodes, a common but segmented electrode or a common and continuous electrode. Additionally, electrodes 286 can be configured to provide a bipolar signal, or electrodes 286 can be used together or individually in conjunction with a separate grounding of the patient for monopolar use.

Referring now to Figure 16, a method of using the apparatus 280 to achieve renal denervation is described. As seen in Figure 16A, the catheter 282 can be arranged at a desired location within the renal artery RA, the balloon or centering element 284 can be expanded to center the electrodes 286 and optionally provide electrical isolation and can be applied a PEF, for example in a bipolar form between the proximal and distal electrodes 286. It is expected that the PEF will achieve renal denervation and / or neuromodulation along the treatment zone one T1. If it is desired to modulate the neural activity in other parts of the renal artery, the balloon 264 can be deflated at least partially and the catheter can be positioned in a second desired treatment zone T2, as in Figure 16B. The physician may optionally use fluoroscopic imaging or radiopaque markers 288 to orient the catheter 282 at the desired locations for treatment. For example, the medical practitioner may use the markers to ensure a region of overlap O between the treatment zones T1 and T2, as shown.

With reference to Figure 17, a variation of the apparatus 280 is described which comprises a plurality of dynamically controllable electrodes 286 disposed on the proximal side of the balloon 284. In a variation, any one of the proximal electrodes 286a can be energized in a bipolar form with the distal electrode 286b to provide a dynamic control of the longitudinal distance between the active and return electrodes. This alters the size and shape of the treatment area. In another variation, any subset of proximal electrodes 286a can be energized together as the active or return electrodes of a bipolar electric field established between the proximal electrodes and the distal electrodes 286b.

Although the apparatus 280 shown in Figure 17 has three proximal electrodes 286a, it should be understood that the apparatus 280 can have any alternative number of proximal electrodes. Additionally, the apparatus 280 may have a plurality of distal electrodes 286b in addition, or as an alternative, to multiple proximal electrodes. Additionally, one electrode or pair can be coupled to catheter 282 and the other electrode can be applied through the lumen of the catheter, for example, through the lumen of the guidewire. The endoluminally applied catheter and electrode can be repositioned relative to others to alter a separation distance between the electrodes. Such variation may also facilitate the treatment of a variety of renal vascular anatomies.

In the variations of the apparatuses 280 described so far, the distal electrode 286b is coupled to the axis of the catheter 282 distal to the balloon 284. The distal electrode can use a lumen within the catheter 282, for example, for routing a wire of lead that acts as earth. Additionally, the portion of catheter 282 distal to balloon 284 is long enough to accommodate the distal electrode.

Catheters are commonly applied through metallic guide wires and / or conductors. In many interventional therapies that involve catheters, guidewires are not removed during treatment. As the apparatus 280 is configured for the application of a pulsating electric field, if the guide wire is not removed, there may be a risk of electric shock to anyone in contact with the guide wire during the application of the energy. This irrigation can be reduced by the use of polymer coated guide wires.

With reference to Figure 18, another variation of the apparatus 280 is described in which the distal electrode 286b of Figures 16 and 17 has been replaced with a distal electrode 270 configured to be moved through a lumen of the catheter as described previously with respect to Figure 13. As will be apparent, the proximal electrode 286a may alternatively be replaced by the luminously applied electrode, so that electrodes 286b and 270 form a pair of bipolar electrodes. Electrode 270 does not use an additional lumen inside catheter 282, which can reduce the profile. Additionally, the length of the distal balloon catheter does not need to take into account the length of the distal electrode, which can improve flexibility. Additionally, the guidewire must be exchanged for electrode 270 before treatment, which reduces a risk of inadvertent electric shock. In a variation, electrode 270 may optionally be used as a guidewire through catheter 282 is advanced to its position prior to application of the PEF, thereby obviating a need to exchange the guidewire with the electrode. Alternatively, a standard metal guide wire such as electrode 270 can be used simply by connecting the standard guide wire to the pulsating electric field generator. The distal electrode 270 can extend any desired distance beyond the distal end of the catheter 282. This can provide a dynamic alteration of the length of a treatment area. Additionally, this could facilitate the treatment of distal vasculatures of reduced diameter.

With reference to Figure 19, it may be desirable to carry out treatments within one or more vascular branches that extend from a main vessel, for example, to perform treatments within the branches of the renal artery in the vicinity of the renal hilum. Additionally, it may be desirable to perform treatments within abnormal or less common branches of the renal vasculature, which are observed in a minority of patients. As seen in Figure 19A, the distal electrode 270 can be placed on such a branch of the renal artery RA, while the catheter 282 is positioned within the main branch of the artery. As seen in Figure 19B, multiple distal electrodes 270 could be provided and placed in several common or uncommon branches of the renal artery, while the catheter remains in the main arterial branch.

With reference to Figure 20, another variation of the intravascular PEF catheter is described. The apparatus 290 comprises the catheter 292 having a plurality of shaft electrodes 294 arranged in line with the centering element 296. The centering element 296 illustratively comprises an expandable basket, such as the expandable basket 254 previously described of Figure 8. However, it should be understood that the centering element may alternatively comprise a ball or any other centering element. Electrodes 294 can be used in a bipolar or monopolar form.

Referring now to Figure 21, another variation of the invention is described comprising electrodes configured for dynamic radial repositioning of one or more of the electrodes relative to the vessel wall, thereby facilitating an approach to the application of a pulsating electric field by the electrodes. The apparatus 300 comprises the catheter 302 having the electrodes 304 arranged in line with the expandable nested elements. These nested expandable elements comprise an inner expandable element 306 and an outer expandable centering element 308. The electrodes 304 are disposed along the inner expandable element, while the outer expandable centering element is configured to center and stabilize the catheter 302 inside. of the glass. The inner element 306 can be expanded in varying degrees, as desired by the medical practitioner, to dynamically alter the radial positions of the electrodes 304. This dynamic radial repositioning is

it can be used to focus the energy applied by electrodes 304 so that it is applied to the target tissue.

The nested elements 306 and 308 may comprise a balloon-to-balloon arrangement, a basket-to-basket arrangement, some combination of a balloon and a basket or any other expandable nested structure. In Figure 21, the expandable element 306 illustratively comprises an expandable basket, while the outer expandable centering element 308 illustratively comprises an expandable balloon. The electrodes 302 are positioned along the surface of the inner balloon 306.

Any of the variations of the present invention described herein may optionally be configured for the infusion of agents within the treatment area before, during or after the application of energy, for example, to improve or modify the neurodestructive effect or neuromodulatory energy, to protect or temporarily displace non-target cells and / or to facilitate visualization. Additional applications of the infused agents will be apparent. If desired, the response of the cells to the infused agents can be enhanced by reversible initiation or electroporation in the cells in the presence of the infused agent. Infusion may be especially desirable when using a centering element balloon. The infusion may comprise, for example, saline or heparinized saline, protective agents such as Polomaxer-188 or antiproliferative agents. Variations of the present invention may additionally or alternatively be configured for aspiration. For example, infusion points or outlets may be provided on a catheter shaft adjacent to the centering device, the centering device may be porous (for example a "permeable" balloon) or basket uprights that may be made of hollow hypotubes. and grooved or perforated to allow infusion or aspiration.

With reference to Figure 22, a variation of the present invention comprising an infusion / aspiration PEF catheter is described. The apparatus 310 comprises the catheter 312 which has inflatable proximal and distal balloons 314a and 314b, respectively. The proximal axis electrode 316a is disposed between the balloons along the axis of the catheters 312, while the distal electrode 316b is disposed distal to the balloons along the axis of the catheter. One or more infusion or aspiration holes 318 are disposed along the axis of catheter 312 between the balloons in proximity to the proximal electrode 316a.

The apparatus 310 can be used in a variety of ways. In a first use procedure, catheter 312 is disposed within the target vessel, such as the renal artery RA, at a desired location. One or both balloons 314 are inflated and a protective agent or other infusion is infused through the hole (s) 318 between the balloons in proximity to electrode 316a. A suitable PEF is applied for the initiation of a reversible electroporation through electrodes 316 to facilitate the response of non-target cells to infusion within the vessel wall. The application of the protective agent can be improved first by inflating the distal balloon 314b, then the infusion of the protective agent, which displaces the blood, then the inflation of the proximal balloon 314a.

The remaining infusion can optionally be aspirated so that it is not available during the application of the subsequent PEF when irreversible electroporation of nerve cells is initiated. Aspiration can be achieved by at least partially deflating a balloon during aspiration. Alternatively, aspiration with both inflated balloons can be achieved, for example, by saline infusion in conjunction with the aspiration to purge the vessel segment between the inflated balloons. Such a blood purge may reduce a risk of clot or thrombus formation along proximal electrodes 316a during the application of the PEF. Additionally, purging during the application of energy can cool the electrode and / or the artery wall cells. Such cooling of the wall cells could protect the cells against irreversible electroporation damage, possibly reducing the need for infusion of a protective agent.

After the optional infusion and aspiration, a PEF suitable for the initiation of irreversible electroporation can be applied to the target nerve cells through electrodes 316 to denervate or modulate neural activity. In an alternative procedure, infusion of a protective agent can be performed during or after the onset of irreversible electroporation to protect non-target cells. The protective agent can, for example, plug or fill the pores formed in the non-target cells by means of irreversible electroporation.

In another alternative procedure, a cooled heparinized saline solution (i.e. at a lower temperature than the body) can be infused simultaneously and aspirated between the inflated balloons to purge the region between the balloons and decrease the sensitivity of the cells in the vessel wall to electroporation. This is expected to further protect the cells during application of the PEF suitable for the onset of irreversible electroporation. Said optionally purging can be continuous throughout the application of the pulsating electric field. A thermocouple or other temperature sensor can optionally be positioned between the balloons so that an infusion rate of the cooled infusion can be adjusted to maintain a desired temperature. The cooled infusion preferably does not refrigerate the target tissue, for example, the renal nerves. A protective agent, such as Polomaxer-188, can optionally be infused after treatment as an added safety measure.

Alternatively the infusion can be achieved by means of a permeable balloon catheter. Even more, a cryo-balloon catheter that has at least one electrode can be used. The cryo-balloon can be inflated within a segment of the vessel to locally reduce the temperature of the vessel segment, for example, to protect the segment and / or to induce thermal apoptosis of the vessel walls during application of the electric field. The electric field may, for example, comprise a PEF or a non-pulsing thermal electric field, such as a thermal RF field.

With reference to Figure 23, a variation of a PEF catheter configured for the passage of an electrode or electrodes at least partially through the vessel walls is described. For example, the electrode or electrodes can be positioned within the renal vein and then pass through the wall of the renal vein so that they are arranged in the renal fascia or Gerota fascia and near or at least partially around the artery renal. In this way, the electrode or electrodes can be positioned in close proximity to the target renal nerve fibers before the application of the pulsating electric field.

As seen in Figure 23A, the apparatus 320 comprises the catheter 322 having needle openings 324 and a centering element 326, by way of illustration an inflatable balloon. The catheter 322 may also optionally comprise radiopaque markers 328, the needle openings 324 are configured for the passage of needles 330 therethrough, while the needles 330 are configured for the passage of electrodes 340.

The RV renal vein runs parallel to the RA renal artery. An imaging modality, such as intravascular ultrasound, can be used to identify the position of the renal artery in relation to the renal vein. For example, intravascular ultrasound elements can optionally be integrated into catheter 322. Catheter 322 can be positioned within the RV renal vein using well-known percutaneous techniques and centering element 326 can be expanded to stabilize the catheter into the vein. . The needles 330 can then be passed through the catheter 322 and extracted through the needle holes 324 in a manner in which the needles penetrate the wall of the renal vein and enter the renal fascia or fascia of Gerota F. Radiopaque markers 328 can be visualized with fluoroscopy to properly orient needle holes 324 before needle deployment 330.

Electrodes 340 are deployed through needles 330 to at least partially surround the renal artery RA, as in Figures 23A and 23B. The continuous advance of the electrodes can additionally surround the artery, as in Figure 23C. With the electrodes deployed, the stimulus and / or electroporation waveforms by PEF can be applied to denervate or modulate the renal nerves. The needles 330 can be optionally retracted partially or completely before the treatment so that the electrodes 340 surround a greater part of the renal artery. Additionally, a single electrode 340 can be provided and / or operated to provide a monopolar PEF.

An infusion can optionally be infused from needles 330 in fascia F to facilitate the placement of electrodes 340 by creating a space for electrode placement. The infusion may comprise, for example, fluids, heated or cooled fluids, air, CO2, saline, contrast agents, gels, conductive fluids or any other space-occupying material - gas, solid or liquid. Heparinized saline can also be injected. Saline serum or hypertonic saline may improve the conductivity between electrodes 340. Additionally or alternatively, drugs and / or drug delivery elements may be infused or placed into the fascia through the needles.

After treatment, the electrodes 340 can be retracted into the needles 330 and the needles 330 can be retracted into the catheter 322 by means of the needle holes 324. The needles 330 are preferably small enough so that minimal bleeding occurs and Haemostasis is reached clearly quickly. Balloon centering element 326 may optionally remain inflated for some time after removal of needles 330 to block blood flow and facilitate the coagulation process. Alternatively, a balloon catheter can be advanced into the renal vein and inflated after removal of the apparatus 320.

With reference to Figure 24, variations of the invention comprising detectors or other elements for measuring or monitoring the effectiveness of the treatment are described. The variations of the invention can be configured for the application of electrical stimulation fields, in addition to the PEF of denervation or modulation. These stimulation fields can be used to properly position the apparatus for treatment and / or to monitor the effectiveness of the treatment in modulating neural activity. This can be achieved by monitoring the responses to physiological parameters that are known to be affected by renal nerve stimulation. Such parameters comprise, for example, renin levels, sodium levels, renal blood flow and blood pressure. Stimulation can also be used to question denervation for monitoring the effectiveness of treatment: after denervation of the renal nerves, known physiological responses to stimulation should no longer take place in response to such stimulation.

The efferent nerve stimulation waveforms can, for example, comprise frequencies of approximately 1-10 Hz, while the afferent nerve stimulation waveforms can, for example, comprise frequencies of up to approximately 50 Hz. The amplitudes of Waveforms can, for example, vary up to about 50 V, while pulse durations can, for example, vary up to about 20 milliseconds. When nerve stimulation waveforms are applied intravascularly, as in several embodiments of the present invention, field parameters such as frequency, amplitude and pulse duration can be modulated to facilitate the passage of the forms of Wave through the vessel wall for application to the target nerves. Additionally, although the example parameters for the stimulus waveforms have been described, it should be understood that any alternative parameters can be used as desired.

The electrodes used to apply the PEF in any of the variations of the present invention described previously can also be used to apply stimulation waveforms to the renal vasculature. Alternatively, the variations may comprise independent electrodes configured for stimulation. As another alternative, a separate stimulation apparatus can be provided.

One way to use stimulation to identify the renal nerves is to stimulate the nerves so that renal blood flow is affected - or would be affected if the renal nerves had not been denervated or modulated. Stimulation acts to reduce renal blood flow and this response can be attenuated or suppressed with denervation. Therefore, pre-neural modulation stimulation would be expected to reduce blood flow, while stimulation after neural modulation is expected to reduce blood flow to the same degree as when stimulation parameters and locations similar to that of previous neural modulation. This phenomenon can be used to quantify a degree of renal neuromodulation. Variations of the present invention may comprise elements for monitoring renal blood flow or for monitoring any of the other physiological parameters known to be affected by renal stimulation.

In Figure 24A, a variation of the apparatus 280 of Figure 16 is described which has an element for monitoring renal blood flow. A guidewire 350 having an ultrasonic Doppler sensor 252 has been advanced through catheter lumen 282 for monitoring blood flow within the renal artery RA. The Doppler 352 ultrasonic sensor is configured to measure the speed of flow through the artery. A flow rate can be calculated according to the formula:

Q = V A (1)

in which Q is equal to the flow rate, V is equal to the flow rate and A is equal to the cross-sectional area. A baseline of the renal blood flow can be determined by means of the measurements of the sensor 352 prior to the application of a stimulus waveform, then a stimulus can be applied between the electrodes 286, preferably with the balloon 284 deflated. The alteration of the renal blood flow or the lack thereof can be monitored from the baseline with the sensor 352 to identify the optimal locations for neuromodulation and / or denervation of the renal nerves.

Figure 24B illustrates a variation of the apparatus of Figure 24A, in which the ultrasonic Doppler sensor 352 is coupled to the catheter shaft 282. The sensor 352 is provided illustratively proximal to the balloon 284, but it should be understood that the sensor is may alternatively be distal to the ball.

In addition, or as an alternative to intravascular monitoring of renal blood flow by means of Doppler ultrasound, such monitoring can optionally be performed from outside the patient by visualizing renal blood flow through the skin (for example, using a transducer ultrasonic). In another variation, one or more of the intravascular pressure transducers can be used to detect local changes in pressure that may be indicative of renal blood flow. As another alternative, blood velocity can be determined, for example, by means of thermodilution by measuring the time delay in which a variation in intravascular temperature travels between points with a known separation distance.

For example, a thermocouple can be incorporated into, or provided in the vicinity of, each electrode 286 and cooled fluid or saline can be infused (ie, at a lower temperature than that of the body) proximally to the thermocouples. The time delay in which the temperature decrease between the thermocouples can be recorded is quantified to quantify the flow characteristic (s). You can determine a baseline estimate of the

or the characteristics of the flow of interest prior to the stimulation of the renal nerves and can be compared with a second estimate of the characteristic (s) determined after the stimulation.

Commercially available devices can optionally be used to monitor the treatment. Such devices include, for example, SmartWire ™, FloWire and WaveWire devices available from Volcanos Therapeutics Inc., of Rancho Cordova, CA, as well as the PressureWire device available from RADI Medical Systems AB in Uppsala, Sweden. Additional commercially available devices will be apparent. A degree of electroporation can be directly or additionally monitored using the Electric Impedance Tomography ("EIT") or other electrical impedance measurements such as an electrical impedance index.

Although the preferred illustrative variations of the present invention have been described above, it will be apparent to those skilled in the art that various changes and modifications can be made thereto without departing from the invention. For example, although variations have been described primarily for use in combination with pulsing electric fields, it should be understood that any other desired electric field can be applied. It is intended in the appended claims to cover all such changes and modifications within the scope of the invention.

Claims (40)

1. Apparatus for renal neuromodulation, including the apparatus: an electric field generator (100); Y a catheter (150) comprising at least one electrode (212) electrically connected to the electric field generator; in which the catheter is configured for percutaneous placement within the renal vasculature in a patient for the application of an electric field to the renal nerves while the device is located proximal to the renal vasculature wherein the catheter further comprises an expandable helical section configured to position the catheter in contact with an inner surface of a wall of a vessel of the renal vasculature, wherein the at least one electrode is in an expandable helical section and wherein the pitch of the helix of the expandable helical section is variable to minimize circumferential overlap of adjacent treatment areas.

2.

The apparatus of claim 1, wherein

At least one electrode is configured to apply an electric field to the renal nerve while the device is at least partially located within the renal vasculature.

3.

The apparatus of claim 1, wherein the at least one electrode is configured to apply an electric field to a renal nerve while the device is located at least partially within the renal vasculature to reduce neural signaling.

Four.

The apparatus of claim 1, wherein the electric field generator comprises a pulsating electric field generator configured to produce a pulsating electric field that induces irreversible electroporation in a renal nerve.

5.

The apparatus of claim 3, wherein the catheter is configured to be arranged in a reduced application configuration for movement within the renal vasculature.

6.

The apparatus of claim 3, wherein the electrode is configured to physically contact a wall of the renal vasculature.

7.

The apparatus of claim 6, wherein the at least one electrode is selected from the group consisting of expandable helical electrodes, expandable ring electrodes, expandable contact tip electrodes and combinations thereof.

8.

The apparatus of claim 3, wherein the catheter further comprises an expandable centering element configured to physically contact the wall of the renal vasculature.

9.

The apparatus of claim 8, wherein the expandable centering element comprises an inflatable balloon.

10.

The apparatus of claim 8, wherein the at least one electrode is located in the expandable centering element and is configured to physically contact the wall of the renal vasculature.

eleven.

The apparatus of claim 8, wherein the catheter further comprises an axis and the electrode is located along the axis of the device.

12.

The apparatus of claim 11, wherein the catheter further comprises an axis longitudinally aligned with the centering element and the electrode is located on the axis.

13.

The apparatus of claim 8, wherein the at least one electrode comprises a first electrode located proximal to the centering element and a second electrode located distal to the centering element and wherein the first and second electrodes are a pair of electrodes bipolar

14.

The apparatus of claim 8, wherein the centering element is configured to electrically isolate a segment of the renal vasculature and direct the electric field towards the renal nerve.

fifteen.

The apparatus of claim 3, wherein the catheter comprises a guide wire lumen and wherein the at least one electrode is a first electrode and a second electrode configured for movement through the lumen of the guide wire of the catheter.

16.

The apparatus of claim 15, wherein the second electrode is electrically connected to the generator

electric field and is configured for use in a bipolar form with the first electrode.

17.

The apparatus of claim 1, wherein the at least one electrode comprises a first electrode and the catheter further comprises a second electrode for defining a pair of bipolar electrodes.

18.

The apparatus of claim 1, wherein the at least one electrode comprises a first dynamically controllable electrode and the catheter further comprises a plurality of additional dynamically controllable electrodes that are electrically connected to the electric field generator.

19.

The apparatus of claim 1, wherein the at least one electrode and the electric field generator are further configured to apply an electrical stimulation field.

twenty.

The apparatus of claim 1, wherein the catheter is configured to radially control the electrode relative to a wall of the renal vasculature.

twenty-one.

The apparatus of claim 1, wherein the electric field generator is configured to produce a pulsating electric field that induces electrofusion in a renal nerve.

22

The apparatus of claim 3, wherein the at least one electrode is configured for partial or complete passage through a wall of the renal vasculature.

2. 3.

The apparatus of claim 22, wherein the at least one electrode is configured to at least partially surround a renal artery of the patient following its passage through a wall of the renal vasculature.

24.

The apparatus of claim 1 further comprising an infusion element configured to infuse agents through the wall of the renal musculature.

25.

The apparatus of claim 24, wherein the infusion element comprises a diffusion balloon catheter.

26.

The apparatus of claim 1, wherein the at least one electrode comprises an active electrode and a return electrode that together define a bipolar pair of electrodes, wherein at least one of between the active electrode and the return electrode is Configure for its dynamic movement and vary a distance of longitudinal separation between the active and return electrodes of the bipolar pair of electrodes.

27.

The apparatus of claim 1, wherein the catheter is configured for infusion or aspiration.

28.

The apparatus of claim 1, wherein the catheter comprises an element for monitoring the response of at least one physiological parameter to the thermal treatment of a renal nerve.

29.

The apparatus of claim 28, wherein the element is chosen from the group consisting of Doppler ultrasonic sensors, thermocouples, pressure sensors and combinations thereof.

30

The apparatus of claim 1, wherein the catheter is configured to orient a longitudinal part of the electric field with a longitudinal dimension of at least one of the renal nerves and the renal vasculature.

31.

The apparatus of claim 1, wherein the at least one electrode comprises an active electrode and a grounding electrode configured for external fixation to the patient, so that the active electrode is configured to apply the electric field to the renal nerve in a monopolar shape

32

The apparatus of claim 15, wherein the second electrode comprises a guidewire.

33.

The apparatus of claim 1, wherein the electric field generator is configured to generate a thermal electric field.

3. 4.

The apparatus of claim 33, wherein the thermal electric field produces at least a partial renal denervation.

35

The apparatus of claim 33, wherein the thermal electric field produces at least a partial removal of at least one renal nerve.

36.

The apparatus of claim 1, wherein the electric field generator is configured to generate a thermal RF field that produces at least partially renal denervation.

37.

The apparatus of claim 1, wherein the electric field generator is configured to generate an electric field that causes the ablation of at least one renal nerve.

38.

The apparatus of claim 1 further comprising a controller for the control of the electric field generator for applying the electrical energy to at least one electrode, wherein the controller is programmed with instructions for the control of the electric field generator.

39.

The apparatus of claim 3, wherein the catheter comprises a proximal section and a distal section, wherein the electric field generator is electrically connected to the proximal section and at least one electrode is connected to the distal section.

40

The apparatus of claim 39, wherein the catheter further comprises a thermocouple for temperature monitoring.