CA2806927A1 - Sequential activation rf electrode set for renal nerve ablation - Google Patents

Abstract

A catheter includes a flexible shaft having a length sufficient to access a patient's renal artery. A treatment element at the distal end of the shaft is dimensioned for deployment within the renal artery. The treatment element comprises a radially expandable structure configured to maintain positioning within the renal artery. A multiplicity of electrodes are spaced apart on the treatment element and configured for switchable activation and deactivation in a predetermined sequence to generate overlapping zones of heating directed at perivascular nerves of the renal artery. The overlapping heating zones comprise a distal zone associated with relatively high current densities at a distance from the treatment element sufficient to ablate the perivascular renal nerves and a proximal zone associated with current densities lower than those of the distal zone and insufficient to cause thermal injury to tissue of the renal artery adjacent the treatment element.

Description

SEQUENTIAL ACTIVATION RF ELECTRODE SET
FOR RENAL NERVE ABLATION

SUMMARY
Embodiments of the disclosure are generally directed to apparatuses and methods for ablating target tissue of the body. Embodiments of the disclosure are directed to apparatuses and methods for ablating innervated renal vasculature, such as the renal artery and renal ganglia.
According to various embodiments, an apparatus includes a catheter comprising a flexible shaft having a proximal end and a distal end. A treatment element is provided at the distal end of the shaft. A positioning arrangement is provided at the distal end of the shaft and configured to maintain positioning of the treatment element relative to target tissue at a treatment site during ablation.
A multiplicity of electrodes defining an electrode set are arranged relative to one another at the treatment element. The set of electrodes is configured for switchable activation and deactivation in a predetermined sequence to generate overlapping zones of heating directed at the target tissue.
In some embodiments, the zones of heating overlap to define a distal zone associated with substantially continuous ohmic heating at a distance from the treatment element sufficient to ablate target tissue, and a proximal zone associated with intermittent ohmic heating that results in no or negligible thermal injury to tissue at the treatment site adjacent the treatment element. Preferably, the proximal zone has fewer overlapping current paths than the distal zone.
In other embodiments, heating within the proximal zone is lower than a temperature required to cause coagulative necrosis of tissue at the treatment site adjacent the treatment element. For example, and in accordance with further embodiments, heating within the proximal zone is insufficient to raise a temperature of tissue adjacent the treatment element to above about 50 C.
In some embodiments, the zones of heating overlap to define a distal zone associated with relatively high current densities at a distance from the treatment element sufficient to ablate the target tissue and a proximal zone associated with current densities lower than those of the distal zone that cause no or negligible thermal injury to tissue at the treatment site adjacent the treatment element.
In other embodiments, at least some of the plurality of heating zones have spatially separated origins at the treatment element based on activation and deactivation of the set of electrodes. Each of the heating zones comprises a distal zone of substantially continuous ohmic heating at a distance from the treatment element sufficient to ablate the target tissue. Each of the heating zones further comprises a proximal zone of intermittent ohmic heating proximate the treatment element that causes no or negligible thermal injury to tissue at the treatment site adjacent the treatment element.
In accordance with various embodiments, an apparatus includes a catheter comprising a flexible shaft having a proximal end, a distal end, and a length sufficient to access a patient's renal artery relative to a percutaneous location. A
treatment element is provided at the distal end of the shaft and dimensioned for deployment within the renal artery. The treatment element comprises an expandable structure configured to maintain positioning of the treatment element within the renal artery.
A multiplicity of electrodes defining an electrode set are arranged relative to one another at the treatment element. The set of electrodes is configured for switchable activation and deactivation in a predetermined sequence to generate overlapping zones of heating directed at perivascular nerves of the renal artery. The zones of heating overlap to define a distal zone associated with relatively high current densities at a distance from the treatment element sufficient to ablate the perivascular renal nerves and a proximal zone associated with current densities lower than those of the distal zone that cause no or insignificant thermal injury to tissue of the renal artery adjacent the treatment element.
An electrical conductor arrangement extends along the shaft of the catheter and is coupled to the set of electrodes. A temperature sensor arrangement is provided at the treatment element and coupled to the electrical conductor arrangement. The temperature sensor arrangement is configured to sense a temperature of the set of electrodes.
According to further embodiments, methods can be implemented for maintaining a position of a treatment element relative to target tissue at a treatment site of the body during ablation. The treatment element preferably includes a multiplicity of electrodes defining an electrode set and arranged relative to one another at the treatment element.
The methods also involve switchably activating and deactivating the electrodes in a predetermined sequence to generate overlapping zones of heating directed at the target tissue.
In some embodiments, the zones of heating overlap to define a distal zone associated with relatively high current densities at a distance from the treatment element sufficient to ablate the target tissue and a proximal zone associated with current densities lower than those of the distal zone that cause no or negligible thermal injury to tissue at the treatment site adjacent the treatment element.
In other embodiments, at least some of the heating zones have spatially separated origins at the treatment element based on activation and deactivation of the set of electrodes. Each of the heating zones comprises a distal zone of substantially continuous ohmic heating at a distance from the treatment element and sufficient to ablate the target tissue, and a proximal zone of intermittent ohmic heating proximate the treatment element that causes no or negligible thermal injury to tissue at the treatment site adjacent the treatment element.
These and other features can be understood in view of the following detailed discussion and the accompanying drawings.

BRIEF DESCRIPTION OF THE DRAWINGS
Figure 1 is an illustration of a right kidney and renal vasculature including a renal artery branching laterally from the abdominal aorta;
Figures 2A and 2B illustrate sympathetic innervation of the renal artery;
Figure 3A illustrates various tissue layers of the wall of the renal artery;
Figures 3B and 3C illustrate a portion of a renal nerve;
Figure 4A illustrates a catheter comprising a treatment element which supports a multiplicity of RF electrodes arranged in one or more electrode sets in accordance with various embodiments;
Figure 4B is a cross section of a shaft of the catheter shown in Figure 4A in accordance with various embodiments;
Figure 5 schematically illustrates overlapping areas of heating from each separate RF electrode of an electrode set situated on a treatment element of a catheter, the overlapping heating areas including a zone of greatest heating for nerve ablation and a cooler zone at the artery wall in accordance with various embodiments;

Figure 6 shows a representative set of electrodes of an electrode set situated in a spaced-apart relationship on a portion of an expandable structure of a catheter in accordance with various embodiments;
Figure 7 is a block diagram showing a multiplicity of electrodes and temperature sensors situated on a portion of an expandable structure, and various components of an external control system in accordance with various embodiments; and Figure 8 shows a representative RF renal therapy apparatus in accordance with various embodiments of the disclosure.

DESCRIPTION
In general, when using RF electrode(s) placed in the renal artery for ablation of perivascular renal nerves for treatment of hypertension, the highest current density and thus the greatest heating is typically adjacent to the electrode typically situated within the lumen of the renal artery. In order to achieve tissue temperatures for effective ablation of the renal nerves, the renal artery is also injured. Active cooling can be provided but requires a larger catheter and a more complex system.
Embodiments of the disclosure are directed to improved RF ablation catheters, systems, and methods. Apparatuses disclosed herein are directed to an improved ablation catheter and system that uses electrical current. Embodiments of the disclosure are directed to apparatuses and methods for ablating perivascular renal nerves for the treatment of hypertension.
Hypertension is a chronic medical condition in which the blood pressure is elevated. Persistent hypertension is a significant risk factor associated with a variety of adverse medical conditions, including heart attacks, heart failure, arterial aneurysms, and strokes. Persistent hypertension is a leading cause of chronic renal failure.
Hyperactivity of the sympathetic nervous system serving the kidneys is associated with hypertension and its progression. Deactivation of nerves in the kidneys via renal denervation can reduce blood pressure, and may be a viable treatment option for many patients with hypertension who do not respond to conventional drugs.
The kidneys are instrumental in a number of body processes, including blood filtration, regulation of fluid balance, blood pressure control, electrolyte balance, and hormone production. One primary function of the kidneys is to remove toxins, mineral salts, and water from the blood to form urine. The kidneys receive about 20-25% of cardiac output through the renal arteries that branch left and right from the abdominal aorta, entering each kidney at the concave surface of the kidneys, the renal hilum.
Blood flows into the kidneys through the renal artery and the afferent arteriole, entering the filtration portion of the kidney, the renal corpuscle. The renal corpuscle is composed of the glomerulus, a thicket of capillaries, surrounded by a fluid-filled, cup-like sac called Bowman's capsule. Solutes in the blood are filtered through the very thin capillary walls of the glomerulus due to the pressure gradient that exists between the blood in the capillaries and the fluid in the Bowman's capsule. The pressure gradient is controlled by the contraction or dilation of the arterioles. After filtration occurs, the filtered blood moves through the efferent arteriole and the peritubular capillaries, converging in the interlobular veins, and finally exiting the kidney through the renal vein.
Particles and fluid filtered from the blood move from the Bowman's capsule through a number of tubules to a collecting duct. Urine is formed in the collecting duct and then exits through the ureter and bladder. The tubules are surrounded by the peritubular capillaries (containing the filtered blood). As the filtrate moves through the tubules and toward the collecting duct, nutrients, water, and electrolytes, such as sodium and chloride, are reabsorbed into the blood.
The kidneys are innervated by the renal plexus which emanates primarily from the aorticorenal ganglion. Renal ganglia are formed by the nerves of the renal plexus as the nerves follow along the course of the renal artery and into the kidney. The renal nerves are part of the autonomic nervous system which includes sympathetic and parasympathetic components. The sympathetic nervous system is known to be the system that provides the bodies "fight or flight" response, whereas the parasympathetic nervous system provides the "rest and digest" response. Stimulation of sympathetic nerve activity triggers the sympathetic response which causes the kidneys to increase production of hormones that increase vasoconstriction and fluid retention. This process is referred to as the renin-angiotensin-aldosterone-system (RAAS) response to increased renal sympathetic nerve activity.
In response to a reduction in blood volume, the kidneys secrete renin, which stimulates the production of angiotensin. Angiotensin causes blood vessels to constrict, resulting in increased blood pressure, and also stimulates the secretion of the hormone aldosterone from the adrenal cortex. Aldosterone causes the tubules of the kidneys to increase the reabsorption of sodium and water, which increases the volume of fluid in the body and blood pressure.
Congestive heart failure (CHF) is a condition that has been linked to kidney function. CHF occurs when the heart is unable to pump blood effectively throughout the body. When blood flow drops, renal function degrades because of insufficient perfusion of the blood within the renal corpuscles. The decreased blood flow to the kidneys triggers an increase in sympathetic nervous system activity (i.e., the RAAS becomes too active) that causes the kidneys to secrete hormones that increase fluid retention and vasorestriction. Fluid retention and vasorestriction in turn increases the peripheral resistance of the circulatory system, placing an even greater load on the heart, which diminishes blood flow further. If the deterioration in cardiac and renal functioning continues, eventually the body becomes overwhelmed, and an episode of heart failure decompensation occurs, often leading to hospitalization of the patient.
Figure 1 is an illustration of a right kidney 10 and renal vasculature including a renal artery 12 branching laterally from the abdominal aorta 20. In Figure 1, only the right kidney 10 is shown for purposes of simplicity of explanation, but reference will be made herein to both right and left kidneys and associated renal vasculature and nervous system structures, all of which are contemplated within the context of embodiments of the disclosure. The renal artery 12 is purposefully shown to be disproportionately larger than the right kidney 10 and abdominal aorta 20 in order to facilitate discussion of various features and embodiments of the present disclosure.
The right and left kidneys are supplied with blood from the right and left renal arteries that branch from respective right and left lateral surfaces of the abdominal aorta 20. Each of the right and left renal arteries is directed across the crus of the diaphragm, so as to form nearly a right angle with the abdominal aorta 20. The right and left renal arteries extend generally from the abdominal aorta 20 to respective renal sinuses proximate the hilum 17 of the kidneys, and branch into segmental arteries and then interlobular arteries within the kidney 10. The interlobular arteries radiate outward, penetrating the renal capsule and extending through the renal columns between the renal pyramids. Typically, the kidneys receive about 20% of total cardiac output which, for normal persons, represents about 1200 mL of blood flow through the kidneys per minute.
The primary function of the kidneys is to maintain water and electrolyte balance for the body by controlling the production and concentration of urine. In producing urine, the kidneys excrete wastes such as urea and ammonium. The kidneys also control reabsorption of glucose and amino acids, and are important in the production of hormones including vitamin D, renin and erythropoietin.
An important secondary function of the kidneys is to control metabolic homeostasis of the body. Controlling hemostatic functions include regulating electrolytes, acid-base balance, and blood pressure. For example, the kidneys are responsible for regulating blood volume and pressure by adjusting volume of water lost in the urine and releasing erythropoietin and renin, for example. The kidneys also regulate plasma ion concentrations (e.g., sodium, potassium, chloride ions, and calcium ion levels) by controlling the quantities lost in the urine and the synthesis of calcitrol.
Other hemostatic functions controlled by the kidneys include stabilizing blood pH by controlling loss of hydrogen and bicarbonate ions in the urine, conserving valuable nutrients by preventing their excretion, and assisting the liver with detoxification.
Also shown in Figure 1 is the right suprarenal gland 11, commonly referred to as the right adrenal gland. The suprarenal gland 11 is a star-shaped endocrine gland that rests on top of the kidney 10. The primary function of the suprarenal glands (left and right) is to regulate the stress response of the body through the synthesis of corticosteroids and catecholamines, including cortisol and adrenaline (epinephrine), respectively.

Encompassing the kidneys 10, suprarenal glands 11, renal vessels 12, and adjacent perirenal fat is the renal fascia, e.g., Gerota's fascia, (not shown), which is a fascial pouch derived from extraperitoneal connective tissue.
The autonomic nervous system of the body controls involuntary actions of the smooth muscles in blood vessels, the digestive system, heart, and glands. The autonomic nervous system is divided into the sympathetic nervous system and the parasympathetic nervous system. In general terms, the parasympathetic nervous system prepares the body for rest by lowering heart rate, lowering blood pressure, and stimulating digestion. The sympathetic nervous system effectuates the body's fight-or-flight response by increasing heart rate, increasing blood pressure, and increasing metabolism.
In the autonomic nervous system, fibers originating from the central nervous system and extending to the various ganglia are referred to as preganglionic fibers, while those extending from the ganglia to the effector organ are referred to as postganglionic fibers. Activation of the sympathetic nervous system is effected through the release of adrenaline (epinephrine) and to a lesser extent norepinephrine from the suprarenal glands 11. This release of adrenaline is triggered by the neurotransmitter acetylcholine released from preganglionic sympathetic nerves.
The kidneys and ureters (not shown) are innervated by the renal nerves 14.
Figures 1 and 2A-2B illustrate sympathetic innervation of the renal vasculature, primarily innervation of the renal artery 12. The primary functions of sympathetic innervation of the renal vasculature include regulation of renal blood flow and pressure, stimulation of renin release, and direct stimulation of water and sodium ion reabsorption.
Most of the nerves innervating the renal vasculature are sympathetic postganglionic fibers arising from the superior mesenteric ganglion 26. The renal nerves 14 extend generally axially along the renal arteries 12, enter the kidneys 10 at the hilum 17, follow the branches of the renal arteries 12 within the kidney 10, and extend to individual nephrons. Other renal ganglia, such as the renal ganglia 24, superior mesenteric ganglion 26, the left and right aorticorenal ganglia 22, and celiac ganglia 28 also innervate the renal vasculature. The celiac ganglion 28 is joined by the greater thoracic splanchnic nerve (greater TSN). The aorticorenal ganglia 26 is joined by the lesser thoracic splanchnic nerve (lesser TSN) and innervates the greater part of the renal plexus.
Sympathetic signals to the kidney 10 are communicated via innervated renal vasculature that originates primarily at spinal segments T10-T12 and Li.
Parasympathetic signals originate primarily at spinal segments S2-S4 and from the medulla oblongata of the lower brain. Sympathetic nerve traffic travels through the sympathetic trunk ganglia, where some may synapse, while others synapse at the aorticorenal ganglion 22 (via the lesser thoracic splanchnic nerve, i.e., lesser TSN) and the renal ganglion 24 (via the least thoracic splanchnic nerve, i.e., least TSN). The postsynaptic sympathetic signals then travel along nerves 14 of the renal artery 12 to the kidney 10. Presynaptic parasympathetic signals travel to sites near the kidney 10 before they synapse on or near the kidney 10.
With particular reference to Figure 2A, the renal artery 12, as with most arteries and arterioles, is lined with smooth muscle 34 that controls the diameter of the renal artery lumen 13. Smooth muscle, in general, is an involuntary non-striated muscle found within the media layer of large and small arteries and veins, as well as various organs. The glomeruli of the kidneys, for example, contain a smooth muscle-like cell called the mesangial cell. Smooth muscle is fundamentally different from skeletal muscle and cardiac muscle in terms of structure, function, excitation-contraction coupling, and mechanism of contraction.
Smooth muscle cells can be stimulated to contract or relax by the autonomic nervous system, but can also react on stimuli from neighboring cells and in response to hormones and blood borne electrolytes and agents (e.g., vasodilators or vasoconstrictors).
Specialized smooth muscle cells within the afferent arteriole of the juxtaglomerular apparatus of kidney 10, for example, produces renin which activates the angiotension II
system.
The renal nerves 14 innervate the smooth muscle 34 of the renal artery wall 15 and extend lengthwise in a generally axial or longitudinal manner along the renal artery wall 15. The smooth muscle 34 surrounds the renal artery circumferentially, and extends lengthwise in a direction generally transverse to the longitudinal orientation of the renal nerves 14, as is depicted in Figure 2B.
The smooth muscle 34 of the renal artery 12 is under involuntary control of the autonomic nervous system. An increase in sympathetic activity, for example, tends to contract the smooth muscle 34, which reduces the diameter of the renal artery lumen 13 and decreases blood perfusion. A decrease in sympathetic activity tends to cause the smooth muscle 34 to relax, resulting in vessel dilation and an increase in the renal artery lumen diameter and blood perfusion. Conversely, increased parasympathetic activity tends to relax the smooth muscle 34, while decreased parasympathetic activity tends to cause smooth muscle contraction.
Figure 3A shows a segment of a longitudinal cross-section through a renal artery, and illustrates various tissue layers of the wall 15 of the renal artery 12.
The innermost layer of the renal artery 12 is the endothelium 30, which is the innermost layer of the intima 32 and is supported by an internal elastic membrane. The endothelium 30 is a single layer of cells that contacts the blood flowing though the vessel lumen 13.
Endothelium cells are typically polygonal, oval, or fusiform, and have very distinct round or oval nuclei. Cells of the endothelium 30 are involved in several vascular functions, including control of blood pressure by way of vasoconstriction and vasodilation, blood clotting, and acting as a barrier layer between contents within the lumen 13 and surrounding tissue, such as the membrane of the intima 32 separating the intima 32 from the media 34, and the adventitia 36. The membrane or maceration of the intima 32 is a fine, transparent, colorless structure which is highly elastic, and commonly has a longitudinal corrugated pattern.
Adjacent the intima 32 is the media 33, which is the middle layer of the renal artery 12. The media is made up of smooth muscle 34 and elastic tissue. The media 33 can be readily identified by its color and by the transverse arrangement of its fibers. More particularly, the media 33 consists principally of bundles of smooth muscle fibers 34 arranged in a thin plate-like manner or lamellae and disposed circularly around the arterial wall 15. The outermost layer of the renal artery wall 15 is the adventitia 36, which is made up of connective tissue. The adventitia 36 includes fibroblast cells 38 that play an important role in wound healing.
A perivascular region 37 is shown adjacent and peripheral to the adventitia 36 of the renal artery wall 15. A renal nerve 14 is shown proximate the adventitia 36 and passing through a portion of the perivascular region 37. The renal nerve 14 is shown extending substantially longitudinally along the outer wall 15 of the renal artery 12. The main trunk of the renal nerves 14 generally lies in or on the adventitia 36 of the renal artery 12, often passing through the perivascular region 37, with certain branches coursing into the media 33 to enervate the renal artery smooth muscle 34.
Embodiments of the disclosure may be implemented to provide varying degrees of denervation therapy to innervated renal vasculature. For example, embodiments of the disclosure may provide for control of the extent and relative permanency of renal nerve impulse transmission interruption achieved by denervation therapy delivered using a treatment apparatus of the disclosure. The extent and relative permanency of renal nerve injury may be tailored to achieve a desired reduction in sympathetic nerve activity (including a partial or complete block) and to achieve a desired degree of permanency (including temporary or irreversible injury).
Returning to Figures 3B and 3C, the portion of the renal nerve 14 shown in Figures 3B and 3C includes bundles 14a of nerve fibers 14b each comprising axons or dendrites that originate or terminate on cell bodies or neurons located in ganglia or on the spinal cord, or in the brain. Supporting tissue structures 14c of the nerve 14 include the endoneurium (surrounding nerve axon fibers), perineurium (surrounds fiber groups to form a fascicle), and epineurium (binds fascicles into nerves), which serve to separate and support nerve fibers 14b and bundles 14a. In particular, the endoneurium, also referred to as the endoneurium tube or tubule, is a layer of delicate connective tissue that encloses the myelin sheath of a nerve fiber 14b within a fasciculus.
Major components of a neuron include the soma, which is the central part of the neuron that includes the nucleus, cellular extensions called dendrites, and axons, which are cable-like projections that carry nerve signals. The axon terminal contains synapses, which are specialized structures where neurotransmitter chemicals are released in order to communicate with target tissues. The axons of many neurons of the peripheral nervous system are sheathed in myelin, which is formed by a type of glial cell known as Schwann cells. The myelinating Schwann cells are wrapped around the axon, leaving the axolemma relatively uncovered at regularly spaced nodes, called nodes of Ranvier.
Myelination of axons enables an especially rapid mode of electrical impulse propagation called saltation.
In some embodiments, a treatment apparatus of the disclosure may be implemented to deliver denervation therapy that causes transient and reversible injury to renal nerve fibers 14b. In other embodiments, a treatment apparatus of the disclosure may be implemented to deliver denervation therapy that causes more severe injury to renal nerve fibers 14b, which may be reversible if the therapy is terminated in a timely manner. In preferred embodiments, a treatment apparatus of the disclosure may be implemented to deliver denervation therapy that causes severe and irreversible injury to renal nerve fibers 14b, resulting in permanent cessation of renal sympathetic nerve activity. For example, a treatment apparatus may be implemented to deliver a denervation therapy that disrupts nerve fiber morphology to a degree sufficient to physically separate the endoneurium tube of the nerve fiber 14b, which can prevent regeneration and re-innervation processes.
By way of example, and in accordance with Seddon's classification as is known in the art, a treatment apparatus of the disclosure may be implemented to deliver a denervation therapy that interrupts conduction of nerve impulses along the renal nerve fibers 14b by imparting damage to the renal nerve fibers 14b consistent with neruapraxia.
Neurapraxia describes nerve damage in which there is no disruption of the nerve fiber 14b or its sheath. In this case, there is an interruption in conduction of the nerve impulse down the nerve fiber, with recovery taking place within hours to months without true regeneration, as Wallerian degeneration does not occur. Wallerian degeneration refers to a process in which the part of the axon separated from the neuron's cell nucleus degenerates.
This process is also known as anterograde degeneration. Neurapraxia is the mildest form of nerve injury that may be imparted to renal nerve fibers 14b by use of a treatment apparatus according to embodiments of the disclosure.
A treatment apparatus may be implemented to interrupt conduction of nerve impulses along the renal nerve fibers 14b by imparting damage to the renal nerve fibers consistent with axonotmesis. Axonotmesis involves loss of the relative continuity of the axon of a nerve fiber and its covering of myelin, but preservation of the connective tissue framework of the nerve fiber. In this case, the encapsulating support tissue 14c of the nerve fiber 14b are preserved. Because axonal continuity is lost, Wallerian degeneration occurs. Recovery from axonotmesis occurs only through regeneration of the axons, a process requiring time on the order of several weeks or months. Electrically, the nerve fiber 14b shows rapid and complete degeneration. Regeneration and re-innervation may occur as long as the endoneural tubes are intact.
A treatment apparatus may be implemented to interrupt conduction of nerve impulses along the renal nerve fibers 14b by imparting damage to the renal nerve fibers 14b consistent with neurotmesis. Neurotmesis, according to Seddon's classification, is the most serious nerve injury in the scheme. In this type of injury, both the nerve fiber 14b and the nerve sheath are disrupted. While partial recovery may occur, complete recovery is not possible. Neurotmesis involves loss of continuity of the axon and the encapsulating connective tissue 14c, resulting in a complete loss of autonomic function, in the case of renal nerve fibers 14b. If the nerve fiber 14b has been completely divided, axonal regeneration causes a neuroma to form in the proximal stump.
A more stratified classification of neurotmesis nerve damage may be found by reference to the Sunderland System as is known in the art. The Sunderland System defines five degrees of nerve damage, the first two of which correspond closely with neurapraxia and axonotmesis of Seddon's classification. The latter three Sunderland System classifications describe different levels of neurotmesis nerve damage.
The first and second degrees of nerve injury in the Sunderland system are analogous to Seddon's neurapraxia and axonotmesis, respectively. Third degree nerve injury, according to the Sunderland System, involves disruption of the endoneurium, with the epineurium and perineurium remaining intact. Recovery may range from poor to complete depending on the degree of intrafascicular fibrosis. A fourth degree nerve injury involves interruption of all neural and supporting elements, with the epineurium remaining intact. The nerve is usually enlarged. Fifth degree nerve injury involves complete transection of the nerve fiber 14b with loss of continuity.
Embodiments of the disclosure are directed to apparatuses and methods that provide an improved way of reducing injury to the renal artery during ablation of the renal nerves. Various embodiments are directed to apparatuses and methods for reducing injury to other tissues and structures of the body when ablating nearby target tissue. Examples of such other body tissues, structures, and target tissue include organs, tumors, diseased tissue, and vasculature of the heart, such as pulmonary veins or electrically active target cardiac tissue for treatment of cardiac rhythm pathologies.
Embodiments of the disclosure are directed to apparatuses and methods for ablation of perivascular renal nerves for treatment of hypertension, using electrical current.
As previously discussed, when using an RF electrode placed in the renal artery, the highest current density and thus the area of greatest heating and injury is typically adjacent to the electrode. Embodiments of the disclosure provide for sufficient ablation of target nerves while reducing injury to the renal artery by moving the current among a set of nearby RF
electrodes.
According to various embodiments, when one electrode is activated, the artery wall section adjacent to the other electrodes can cool. The current is switched to a different electrode in the set, allowing the artery wall section adjacent to the first electrode to cool.
The current spreads out somewhat in the perivascular tissue, so that the regions heated by activating each electrode in the set overlap, preventing cooling of the target tissue.
Referring now to Figures 4A, there is illustrated a catheter 100 which includes a multiplicity of sequentially activatable RF electrodes for ablating target tissue of a treatment site. Figure 4A is a simplified schematic representation provided for purposes of explanation. It is understood that an inner lumen through the balloon 102 can be used for guidewire passage while maintaining balloon inflation, and that the guidewire hole 111 is a schematic representation of the distal end of this inner lumen.
According to some embodiments, the catheter 100 includes a flexible shaft 104 having a proximal end and a distal end. A treatment element 101 is provided at the distal end of the shaft 104. A positioning arrangement 102 is provided at the distal end of the shaft 204 and configured to maintain positioning of the treatment element 101 relative to target tissue at a treatment site during ablation. The positioning arrangement preferably includes a radially expandable structure 103, such as a balloon or a mesh structure. In the embodiment shown in Figure 4A, the treatment arrangement 101 and the positioning arrangement 102 are collocated on a common structure (e.g., expandable structure 103). In other embodiments, the treatment arrangement 101 and the positioning arrangement 102 can be situated on separate structures of the catheter 100.
According to some embodiments, the shaft 104 of the catheter 100 has a length sufficient to access a patient's renal artery 12 relative to a percutaneous location. The treatment element 101 provided at the distal end of the shaft 204 is dimensioned for deployment within the renal artery 12. The treatment element 101 comprises a radially expandable structure 103 configured to maintain positioning of the treatment element 101 within the renal artery 12, such as a balloon or mesh structure.
Figure 4B shows a cross section of the shaft 104 of the catheter 100 of Figure 4A, which includes an electrode conductor lumen 113a, a sensor conductor lumen 113b, a guide wire lumen 111, a supply lumen 106, and a return lumen 108. The supply and return lumens 106, 108 respectively deliver and remove a pressurizing fluid to and from the balloon 102 during inflation and deflation operations.
The electrode and sensor conductor lumens 113a, 113b may each include a layer of electrically insulating material and/or the conductors disposed therein may each include an insulating layer. In various embodiments, each of the electrodes 120 of a given electrode set 119 is connected to an electrical conductor arrangement 110 of the catheter 100 via individual electrical conductors that extend through the electrode conductor lumen 113a.
A temperature sensor arrangement 121 is shown in Figure 4A and includes a multiplicity of temperature sensors 123 distributed within the electrode set 119. The temperature sensor arrangement 121 is configured to sense a temperature at or proximate the set 119 of electrodes 120. Each of the temperature sensors 123 of a given temperature sensor arrangement 121 is connected to the electrical conductor arrangement 110 of the catheter 100 via individual electrical conductors that extend through the sensor conductor lumen 113b. The electrical conductor arrangement 110 extends along the shaft 104 to a proximal end of the catheter 100.
It is noted that each electrode 120 need not have an associated temperature sensor 123, and that one, two or a few (i.e., a number less than the number of electrodes 120) temperature sensors 123 may be deployed for an electrode set 119. In some embodiments, for example, temperatures sensing is not used, in view of the local cooling at the electrode-tissue interface provided by the time activation and spatial location arrangements of the set 119 of electrodes 120.
The guide wire lumen 111 is dimensioned to receive a guide wire or other elongated navigation assist member that can by used by the clinician to facilitate delivery of the balloon 102 into a desired treatment location, such as a renal artery.
In the configuration shown in Figure 4A, the guide wire lumen 111 defines an open lumen of the balloon 102, which allows for advancement of a guide wire therethrough for navigating the balloon 102 to the renal artery, for example. After the guide wire is positioned within the renal artery, the balloon catheter 100 is advanced along the guide wire and delivered to the lumen of the renal artery using an over-the-wire delivery technique.
As is shown in Figures 4A and 5, a multiplicity of electrodes 120 define an electrode set 119 and are arranged relative to one another at the treatment element 101.
The electrodes 120 of the electrode set 119 are configured for switchable activation and deactivation in a predetermined sequence to generate overlapping zones of heating 240 directed at the target tissue. For example, individual electrodes within an electrode set can be energized in a predetermined sequence, or multiple electrodes within a set can be energized simultaneously, such as electrodes 1 and 3, followed by 2 and 4, and so forth.
Energizing of electrodes can partially overlap in time. Specific electrodes can be energized using different electrical waveforms to enhance target tissue heating while reducing artery wall injury. Figure 5 schematically illustrates overlapping areas of heating from each separate RF electrode 120, and a zone of greatest heating for nerve ablation, and a cooler zone at the artery wall.
It is noted that in Figure 5, shaded cones are used to schematically represent zones of higher current density. It is understood that actual field and current lines are more complicated and are dependent on a number of factors, including impedance of the various tissues and the location of the return electrode(s) (e.g., an external skin pad or a second electrode if a bipolar arrangement is used).
Figure 5 illustrates an area of less overlapping current paths on the artery wall which would be cooler due to intermittent heating, and an area of more continuous current and greater heating in the target tissue a short distance away. For example, The zones of heating 240 in Figure 5 overlap to define a distal zone 250, associated with relatively high current densities at a distance from the treatment element 101 sufficient to ablate the target tissue, and a proximal zone 260, associated with current densities lower than those of the distal zone that cause no or negligible thermal injury to tissue at the treatment site adjacent the treatment element 101.
The current densities associated with the proximal zone of heating 260 are preferably lower than a current density required to cause coagulative necrosis of tissue at the treatment site adjacent the treatment element 101. For example, the current densities associated with the proximal zone of heating 260 are preferably insufficient to cause heating of tissue adjacent the treatment element 101 to a temperature above about 50 C.
The current densities associated with the distal zone of heating 250, in contrast, are preferably sufficient to cause heating of the target tissue to a temperature of at least about 55 C.
In accordance with various embodiments, at least some of the heating zones 240 have spatially separated origins at the treatment element 101 based on selective activation and deactivation of the set 119 of electrodes 120. Each of the heating zones comprises a distal zone 250 of substantially continuous ohmic heating at a distance from the treatment element 101 and sufficient to ablate the target tissue. Each of the heating zones 240 also comprises a proximal zone 260 of intermittent ohmic heating proximate the treatment element 101 that causes no or insubstantial thermal injury to tissue at the treatment site adjacent the treatment element 101.
According to some embodiments, the electrodes 120 of the electrode set 119 are configured for switchable activation and deactivation in a predetermined sequence to generate overlapping zones of heating 240 directed at perivascular nerves of the renal artery 12. The zones of heating 240 overlap to define a distal zone 250 associated with relatively high current densities at a distance from the treatment element 101 sufficient to ablate the perivascular renal nerves, and a proximal zone 260 associated with current densities lower than those of the distal zone 250 that cause no or insubstantial thermal injury to tissue of the renal artery 12 adjacent the treatment element 101.
In various embodiments, the time activation arrangement and spatial location arrangement of the set 119 of electrodes 120 can be selected to spare substantial portions of the renal artery wall, even if renal artery tissue located immediately adjacent the electrodes 120 is subject to thermal injury. Accordingly, only an insignificant percentage of renal artery tissue (i.e., that small percentage of renal artery tissue located immediately adjacent the electrodes 120) is subject to possible thermally injury during ablation.

In some embodiments, it may be desirable to include a cooling arrangement that enhances local cooling at the electrode-tissue interface in addition to the cooling provided by the time activation and spatial location arrangements of the set 119 of electrodes 120.
Blood perfusion lumens can be incorporated in or on the treatment element 101 and used to provide cooling for the wall of the renal artery 12 during ablation of the perivascular renal nerves. For example, a cooling lumen arrangement can be configured to shunt blood passing through the renal artery 12 to cool the electrodes supported by the treatment element 101 during ablation.
In some embodiments, the cooling arrangement may constitute longitudinal or spiral channels or flutes built into the treatment element 101. Blood passing through channels or flutes serves to enhance cooling of the wall of the renal artery 12 during ablation. Passive or active cooling mechanisms can synergistically enhance the artery wall protection offered by embodiments of the disclosure.
According to some approaches, experiments can be performed to determine which combinations of activation sequence and power settings prove efficacious, from which a standard activation regimen can be established and used. A simple temperature measurement or electrical measurement (e.g., impedance, current, or voltage sensing or a combination thereof) could be combined with a standard activation regimen for limited customization or adjustment, such as using standard sequence and power ratios and timing, simply scaled in magnitude or time by using the simple temperature or electrical measurement.
Referring now to Figure 6, a representative set 119 of electrodes 120 are shown situated in a spaced-apart relationship on a portion of an expandable structure 103. A
temperature sensor arrangement 121 is situated on the expandable structure 103 in close proximity to the set 119 of electrodes 120. As shown in Figure 6, an individual temperature sensor 123 of the temperature sensor arrangement 121 is situated proximate each of the electrodes 120 of the electrode set 119.
As is shown in Figures 5 and 6, one or more temperature sensors 123, such as thermocouples, are provided at the site of the electrode set 119 to measure the temperature of the electrode set 119. In some embodiments, a temperature sensor 123 is positioned near or at the site of each electrode 120 of the electrode set 123, allowing for precision temperature measurements at individual electrode locations of the ablation electrode arrangement 101.

A set of electrical conductors 127 is arranged on the expandable structure 103 for establishing electrical connection between each electrode 120 of the electrode set 119 and external electrode activation circuitry. A set of electrical conductors 129 is arranged on the expandable structure 103 for establishing electrical connection between each temperature sensor 123 of the temperature sensor arrangement 121 and external temperature sensor circuitry.
In some embodiments, the electrical conductors 127 and 129 can be formed using a metalized layer in combination with a non-conductive polymer material used to construct the expandable structure 103 (e.g., balloon) and appropriate masking. In other embodiments, the electrical conductors 127 and 129 can be formed using a conductive wire mesh in combination with a non-conductive material or coating and appropriate masking. In further embodiments, the wire mesh structure can be a wire mesh or braid or basket. Depending on the electrical features of a particular implementation, the wire mesh structure can comprise insulated or non-insulated conductive wires, or non-conductive or polymeric structures, or combinations thereof.
In one configuration, a set 119 of eight unipolar electrodes 123 is affixed to an expandable balloon or wire mesh structure 103 to maintain positioning within the renal artery. The set of electrical conductors 127 is connected to external electrode activation circuitry which activates each RF electrode 120 in a sequence to allow cooling of the artery 12, but maintain desired heating in the target tissue. Other numbers of electrodes can be used, such as a set of five electrodes activated in the sequence 1-3-5-2-4 and repeating, or other sequence chosen for maximal artery cooling.
One or more additional sets 119 of electrodes 123 located at other areas on the renal artery wall can be used to ablate different portions of the perivascular renal nerves, or the catheter and/or expandable structure 103 can be moved to a different location and activated again.
According various embodiments, bipolar electrode sets can be used, mixing the locations of activated electrodes 123 to maintain heating of target tissue but allow the artery to heat and cool intermittently to minimize artery injury. A similar approach can be used with other heating mechanisms to generate heat in a sequence of adjacent locations that intersect to create a heated zone to ablate the target tissue and a cooler zone to protect the artery 12. A similar approach can be used to ablate target tissue a short distance away, while protecting tissue closer to the heating device, such as for tumor ablation or BPH
(benign prostatic hypertrophy) treatment.
Figure 7 is a block diagram showing a multiplicity of electrodes and temperature sensors situated on a portion of an expandable structure 103, and various components of an external control system in accordance with various embodiments. In some embodiments, it may be desirable to use more than one electrode set 119 disposed on an expandable structure 103 of a catheter 101. Two, three, or four electrode sets 119 may be situated on the expandable structure 103 at different longitudinal and circumferential locations. For example, four offset electrode sets 119 each covering a different 90 of arc on the expandable structure 103 can be deployed to define a generally spiral shape. By way of further example, three electrode sets 119 each covering a different 120 of arc on the expandable structure 103 can be deployed to define a generally circumferential shape.
The portion of the expandable structure 103 shown in Figure 7 includes a multiplicity of electrode sets 119a-119n, each of which comprises several independently controlled electrodes 120. Each of the electrode sets 119a-119n is electrically coupled to external electrode activation circuitry 320. As discussed previously, each electrode 120 of each electrode set 119a-119n is separately coupled to the external electrode activation circuitry 320.
The portion of the expandable structure 103 shown in Figure 7 also includes a multiplicity of temperature sensor arrays 121a-121n, each of which comprises several independent temperature sensors 123. Each of the temperature sensor arrays 121a-121n is electrically coupled to external temperature measuring circuitry 328. Each temperature sensor 123 of each temperature sensor array 121a-121n is separately coupled to the external temperature measuring circuitry 328.
The external temperature measuring circuitry 328 is coupled to the external electrode activation circuitry 320. Temperature information for each temperature sensor 123 of each temperature sensor array 121a-121n is provided to the external electrode activation circuitry 320 by the external temperature measuring circuitry 328.
The external electrode activation circuitry 320 includes power control 322 and timing control 324.
Based in part on received temperature information, the external electrode activation circuitry 320 controls the activation sequence of, and amount of RF energy supplied to, each electrode 123 of each electrode set 119a-119n.

Figure 8 shows a representative RF renal therapy apparatus 300 in accordance with various embodiments of the disclosure. The apparatus 300 illustrated in Figure 8 includes external electrode activation circuitry 320 which comprises power control circuitry 322 and timing control circuitry 324. The external electrode activation circuitry 320, which includes an RF generator, is coupled to temperature measuring circuitry 328 and may be coupled to an optional impedance sensor 326. The catheter 100 includes a shaft 104 that incorporates a lumen arrangement 105 configured for receiving a variety of components, such as conductors, inflation fluids, pharmacological agents, actuator elements, obturators, sensors, or other components as needed or desired.
The RF generator of the external electrode activation circuitry 320 may include a return pad electrode 330 that is configured to comfortably engage the patient's back or other portion of the body near the kidneys. Radiofrequency energy produced by the RF
generator is coupled to the treatment element 101 at the distal end of the catheter 101 by the conductor arrangement 110 disposed in the lumen of the catheter's shaft 104.
Renal denervation therapy using the apparatus shown in Figure 8 is typically performed using one or more electrode sets 119 of the treatment element 101 positioned within the renal artery and the return pad electrode 330 positioned on the patient's back, with the RF generator operating in a monopolar mode. In this implementation, the electrodes 120 of the one or more electrode sets 119 are configured for operation in a unipolar configuration. In other implementations, the electrodes 120 of the one or more electrode sets 119 can be configured for operation in a bipolar configuration, in which case the return electrode pad 330 is not needed.
The radiofrequency energy flows through the one or more electrode sets 119 in accordance with a predetermined activation sequence causing current flow and Joule heating in the adjacent tissue of the renal artery. Sequential activation of the electrodes 120 serves to generate overlapping heating zones as described hereinabove, with each heating zone comprising a distal zone of substantially continuous ohmic heating at a distance from the treatment element 101 sufficient to ablate perivascular renal nerves, and a proximal zone of intermittent ohmic heating proximate the treatment element insufficient to cause thermal injury to the renal artery tissue adjacent the treatment element 101.
In general, when renal artery tissue temperatures rise above about 113 F (50 C), protein is permanently damaged (including those of renal nerve fibers). If heated over about 65 C, collagen denatures and tissue shrinks. If heated over about 65 C
and up to 100 C, cell walls break and oil separates from water. Above about 100 C, tissue desiccates.
According to some embodiments, the electrode activation circuitry 320 is configured to control activation and deactivation of the electrodes 120 of one or more electrode sets 119 in accordance with a predetermined sequence and in response to signals received from temperature measuring circuitry 328. The electrode activation circuitry 320 controls radiofrequency energy delivered to the electrodes 120 so as to maintain the current densities within the distal zone of heating at a level sufficient to cause heating of the target tissue to at least a temperature of 65 C and to maintain the current densities within the proximal zone of heating to a level insufficient to cause heating of tissue adjacent the treatment element to a temperature above 50 C.
Temperature sensors 123 situated at the treatment element 101 provide for continuous monitoring of renal artery tissue temperatures, and RF generator power is automatically adjusted so that the target temperatures are achieved and maintained. An impedance sensor arrangement 326 may be used to measure and monitor electrical impedance during RF denervation therapy, and the power and timing of the RF
generator 320 may be moderated based on the impedance measurements or a combination of impedance and temperature measurements. The size of the ablated area is determined largely by the size, number, and shape of the electrodes 123 at the treatment element 101, the power applied, and the duration of time the energy is applied.
Marker bands 314 can be placed on one or multiple parts of the treatment element 101 to enable visualization during the procedure. Other portions of the catheter 101, such as one or more portions of the shaft 104 (e.g., at the hinge mechanism 356), may include a marker band 314. The marker bands 314 may be solid or split bands of platinum or other radiopaque metal, for example. Radiopaque materials are understood to be materials capable of producing a relatively bright image on a fluoroscopy screen or another imaging technique during a medical procedure. This relatively bright image aids the user in determining specific portions of the catheter 100, such as the tip of the catheter 101, the treatment element 101, and the hinge 356, for example. A braid and/or electrodes of the catheter 100, according to some embodiments, can be radiopaque, and a balloon can be filled with contrast/saline if a balloon is used as part of the expandable structure 103.

Various embodiments disclosed herein are generally described in the context of ablation of perivascular renal nerves for control of hypertension. It is understood, however, that embodiments of the disclosure have applicability in other contexts, such as performing ablation from within other vessels of the body, including other arteries, veins, and vasculature (e.g., cardiac and urinary vasculature and vessels), and other tissues of the body, including various organs.
It is to be understood that even though numerous characteristics of various embodiments have been set forth in the foregoing description, together with details of the structure and function of various embodiments, this detailed description is illustrative only, and changes may be made in detail, especially in matters of structure and arrangements of parts illustrated by the various embodiments to the full extent indicated by the broad general meaning of the terms in which the appended claims are expressed.

Claims (15)

1. An apparatus, comprising:
a catheter comprising a flexible shaft having a proximal end and a distal end;

a treatment element provided at the distal end of the shaft;
a positioning arrangement provided at the distal end of the shaft and configured to maintain positioning of the treatment element relative to target tissue at a treatment site during ablation;a plurality of electrodes defining an electrode set and arranged relative to one another at the treatment element, the set of electrodes configured for switchable activation and deactivation in a predetermined sequence to generate a plurality of overlapping zones of heating directed at the target tissue;
the zones of heating overlapping to define a distal zone associated with high heat generation at a distance from the treatment element sufficient to ablate the target tissue and a proximal zone associated with low heat generation lower than that of the distal zone that causes no or negligible thermal injury to tissue at the treatment site adjacent the treatment element; and an electrical conductor arrangement extending along the shaft and coupled to the set of electrodes.

2. The apparatus according to claim 1, wherein:
the distal zone is associated with substantially continuous ohmic heating; and the proximal zone is associate with intermittent ohmic heating.

3. The apparatus according to claim 1, wherein the proximal zone has fewer overlapping current paths than the distal zone.

4. The apparatus according to claim 1, wherein at least some of the plurality of heating zones have spatially separated origins at the treatment element based on activation and deactivation of the set of electrodes.

5. The apparatus according to claim 1, wherein heating within the proximal zone is lower than a temperature required to cause coagulative necrosis of tissue at the treatment site adjacent the treatment element.

6. The apparatus according to claim 1, wherein heating within the proximal zone is insufficient to raise a temperature of tissue adjacent the treatment element to above about 50°C.

7. The apparatus according to claim 1, wherein the plurality of electrodes defining the electrode set are arranged in a circumferential pattern or a spiral pattern.

8. The apparatus according to claim 1, wherein the treatment element comprises a cooling arrangement configured to provide cooling at an electrode-tissue interface defined between the treatment element and tissue adjacent the treatment element.

9. The apparatus according to claim 1, wherein the positioning arrangement comprises a balloon or an expandable mesh structure.

10. The apparatus according to claim 1, wherein the treatment arrangement and the positioning arrangement are collocated on a common structure.

11. The apparatus according to claim 1, wherein:
the treatment element and the positioning arrangement are dimensioned for deployment within a renal artery; and the target tissue comprises perivascular renal nerve tissue at or adjacent the renal artery.

12. The apparatus according to claim 1, wherein the treatment element is configured to treat target tissue of an organ, a vessel, a tumor, or diseased tissue.

13. The apparatus according to claim 1, wherein the treatment element is configured for pulmonary vein ablation.

14. The apparatus according to any of the preceding claims, comprising a temperature sensor arrangement provided at the treatment element and coupled to the electrical conductor arrangement, the temperature sensor arrangement configured to sense a temperature of at least some electrodes of the set of electrodes.

15. The apparatus according to claim 14, comprising a high frequency AC
generator coupled to the electrical conductor arrangement, wherein the generator is configured to control activation and deactivation of the electrodes in accordance with the predetermined sequence and in response to signals received from the temperature sensor arrangement, the generator controlling high frequency AC energy delivery to the electrodes so as to generate heat within the distal zone sufficient to cause heating of the target tissue to at least a temperature of about 55°C and to limit heating within the proximal zone to temperatures that cause no or negligible thermal injury to tissue adjacent the treatment element.