U.S. patent application number 13/361542 was filed with the patent office on 2012-08-02 for apparatuses for renal neuromodulation.
This patent application is currently assigned to Ardian, Inc.. Invention is credited to Benjamin J. Clark, Mark Deem, Denise Demarais, Mark Gelfand, Hanson Gifford, III, Howard R. Levin, Douglas Sutton.
Application Number | 20120197252 13/361542 |
Document ID | / |
Family ID | 36148656 |
Filed Date | 2012-08-02 |
United States Patent
Application |
20120197252 |
Kind Code |
A1 |
Deem; Mark ; et al. |
August 2, 2012 |
APPARATUSES FOR RENAL NEUROMODULATION
Abstract
Methods and apparatus are provided for renal neuromodulation
using a pulsed electric field to effectuate electroporation or
electrofusion. It is expected that renal neuromodulation (e.g.,
denervation) may, among other things, reduce expansion of an acute
myocardial infarction, reduce or prevent the onset of morphological
changes that are affiliated with congestive heart failure, and/or
be efficacious in the treatment of end stage renal disease.
Embodiments of the present invention are configured for
extravascular delivery of pulsed electric fields to achieve such
neuromodulation.
Inventors: |
Deem; Mark; (Mountain View,
CA) ; Demarais; Denise; (Los Gatos, CA) ;
Sutton; Douglas; (Pacifica, CA) ; Gifford, III;
Hanson; (Woodside, CA) ; Levin; Howard R.;
(Teaneck, NJ) ; Gelfand; Mark; (New York, NY)
; Clark; Benjamin J.; (Redwood City, CA) |
Assignee: |
Ardian, Inc.
Menlo Park
CA
|
Family ID: |
36148656 |
Appl. No.: |
13/361542 |
Filed: |
January 30, 2012 |
Related U.S. Patent Documents
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Application
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Filing Date |
Patent Number |
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11189563 |
Jul 25, 2005 |
8145316 |
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13361542 |
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11129765 |
May 13, 2005 |
7653438 |
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11189563 |
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10900199 |
Jul 28, 2004 |
6978174 |
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11129765 |
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10408665 |
Apr 8, 2003 |
7162303 |
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10900199 |
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60616254 |
Oct 5, 2004 |
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60624793 |
Nov 2, 2004 |
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60370190 |
Apr 8, 2002 |
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60415575 |
Oct 3, 2002 |
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60442970 |
Jan 29, 2003 |
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Current U.S.
Class: |
606/41 |
Current CPC
Class: |
A61B 2018/00791
20130101; A61B 2018/00982 20130101; A61N 1/36117 20130101; A61B
2018/00404 20130101; A61B 2018/00434 20130101; A61N 1/0551
20130101; A61N 5/00 20130101; A61N 1/36007 20130101; A61B
2018/00577 20130101; A61N 1/36017 20130101; A61N 1/327 20130101;
A61N 1/36128 20130101; A61B 2018/00702 20130101; A61B 2018/1435
20130101; A61B 2018/00613 20130101; A61B 2018/00511 20130101; A61B
18/1492 20130101; A61B 2018/00875 20130101; A61N 1/32 20130101;
A61B 2018/00779 20130101; A61B 2018/00267 20130101 |
Class at
Publication: |
606/41 |
International
Class: |
A61B 18/14 20060101
A61B018/14 |
Claims
1. An apparatus for renal neuromodulation, the apparatus
comprising: an electric field generator; and an electrode
configured for extravascular placement proximate a renal nerve in a
patient, wherein the electrode is electrically coupled to the
electric field generator, and wherein the electrode is configured
to deliver an electric field to the renal nerve while the electrode
is located proximate the renal nerve.
2. The apparatus of claim 1, wherein the electrode is configured
for placement adjacent to a renal vasculature.
3. The apparatus of claim 2, wherein the electrode is configured
for percutaneous placement adjacent to the renal vasculature.
4. The apparatus of claim 2, wherein the electrode is configured to
be arranged in (a) a reduced delivery configuration for placement
adjacent to the renal vasculature and (b) an expanded treatment
configuration for delivering the electric field to the renal
nerve.
5. The apparatus of claim 4, wherein the electrode is configured to
at least partially encircle the renal vasculature in the expanded
treatment configuration.
6. The apparatus of claim 1, wherein the electrode is configured to
at least partially encircle a renal artery of the patient.
7. The apparatus of claim 2, wherein the electrode is configured
for placement in an annular space between renal fascia and renal
vasculature.
8. The apparatus of claim 2, wherein the apparatus is configured to
orient a longitudinal portion of the electric field with a
longitudinal dimension of at least one of the renal nerve and the
renal vasculature.
9. The apparatus of claim 1, wherein the electrode comprises a
bipolar electrode pair.
10. The apparatus of claim 1, wherein the electrode comprises an
active electrode, and wherein the apparatus further comprises a
ground electrode located remote the renal nerve, such that the
active electrode is configured to deliver the electric field to the
renal nerve in a monopolar fashion.
11. The apparatus of claim 10, wherein the ground electrode is
configured for exterior attachment to the patient.
12. The apparatus of claim 1, wherein the electric field generator
is configured to produce a pulsed electric field that induces
irreversible electroporation in the renal nerve.
13. The apparatus of claim 1, wherein the electric field generator
is configured to produce a pulsed electric field that induces
electrofusion in the renal nerve.
14. The apparatus of claim 1, wherein the electrode and the
electric field generator are further configured to deliver a
stimulation electric field to the renal nerve.
15. The apparatus of claim 1, wherein the apparatus comprises an
element for monitoring the response of at least one physiological
parameter to stimulation of the renal nerve.
16. The apparatus of claim 15, wherein the element is chosen from
the group consisting of ultrasound sensors, electrodes,
thermocouples, pressure sensors, imaging modalities, electrical
impedence sensors and combinations thereof.
17. The apparatus of claim 1, wherein the electrode is chosen from
the group consisting of basket-shaped electrodes, cup-shaped
electrodes, spiral electrodes, helical electrodes, ring electrodes,
cuff electrodes, fan-shaped electrodes, space-occupying electrodes,
undulating electrodes, sinusoidal electrodes, coil electrodes, wire
electrodes, arcuate electrodes, concave electrodes, curved
electrodes, ribbon electrodes, braid electrodes, composite
electrodes, expandable electrodes and combinations thereof.
18. The apparatus of claim 1, wherein the apparatus further
comprises an infusion element configured to create a working space
to facilitate placement of the electrode.
19. The apparatus of claim 1 further comprising an implanted
subcutaneous element electrically coupled to the electrode via
tunneled leads.
20. The apparatus of claim 19, wherein the implanted subcutaneous
element comprises a subcutaneous electrical contact, the apparatus
further comprising a transcutaneous probe electrically coupled to
the electric field generator and configured for reversible
placement across skin of the patient for electrically coupling the
transcutaneous probe to the subcutaneous electrical contact.
21. The apparatus of claim 19, wherein the implanted subcutaneous
element comprises a transcutaneous energy transfer receiving
element, the apparatus further comprising a transcutaneous energy
transfer transmission element electrically coupled to the pulse
electric field generator and configured to non-invasively transmit
energy transcutaneously to the receiving element.
22. The apparatus of claim 19, wherein the implanted subcutaneous
element comprises the electric field generator.
23. The apparatus of claim 22, wherein the implanted subcutaneous
element further comprises an energy storage device electrically
coupled to the electric field generator.
24. The apparatus of claim 23, wherein the energy storage device is
configured for recharging.
25. The apparatus of claim 24 further comprising an external
charger configured to transcutaneously recharge the energy storage
device.
26. The apparatus of claim 23, wherein the implanted subcutaneous
element further comprises a controller.
27. The apparatus of claim 26, wherein the controller further
comprises a programmable controller.
28. The apparatus of claim 27 further comprising an external
programmer configured to transcutaneously program the
controller.
29. The apparatus of claim 1 further comprising a probe configured
for percutaneous insertion in proximity to the renal nerve under
guidance.
30. The apparatus of claim 29, wherein the guidance comprises
guidance chosen from the group consisting of visual, computed
tomographic, radiographic, ultrasonic, angiographic, laparoscopic
and combinations thereof.
31. The apparatus of claim 29, wherein the probe is electrically
coupled to the electric field generator, and wherein the electrode
is attached to the probe.
32. The apparatus of claim 29, wherein the electrode is configured
for extravascular placement through the probe proximate the renal
nerve.
33. The apparatus of claim 29, wherein the probe is chosen from the
group consisting of needles, trocars and combinations thereof.
34. The apparatus of claim 29 further comprising a catheter
configured for advancement through the probe, wherein the electrode
is attached to the catheter.
35-57. (canceled)
58. An apparatus for renal neuromodulation, the apparatus
comprising: an electric field generator; and a device configured
for percutaneous placement under Computed Tomography-guidance at an
extravascular location within a patient proximate to a sympathetic
neural path associated with renal function, wherein the device
comprises an electrode electrically coupled to the electric field
generator for delivering a pulsed electric field to the sympathetic
neural path while the device is at the extravascular location.
59. (canceled)
60. The apparatus of claim 1, wherein the apparatus further
comprises a mechanical element configured to create a working space
to facilitate placement of the electrode.
61. The apparatus of claim 1, wherein the electrode further
comprises at least three electrodes.
62. The apparatus of claim 61, wherein at least one of the
electrodes is configured for monitoring.
63-65. (canceled)
Description
CROSS-REFERENCE TO RELATED APPLICATIONS
[0001] This application is a continuation of U.S. patent
application Ser. No. 11/189,563, filed on Jul. 25, 2005, which is a
Continuation-In-Part of U.S. application patent Ser. No.
11/129,765, filed on May 13, 2005, now U.S. Pat. No. 7,653,483,
which claims benefit from the filing dates of U.S. provisional
patent application Ser. No. 60/616,254, filed Oct. 5, 2004; and
Ser. No. 60/624,793, filed Nov. 2, 2004; all of which are
incorporated herein by reference in their entireties. Furthermore,
U.S. patent application Ser. No. 11/189,563 is also a
Continuation-In-Part of U.S. application patent Ser. No. 10/900,199
filed Jul. 28, 2004, now U.S. Pat. No. 6,978,174, and U.S.
application patent Ser. No. 10/408,665, filed Apr. 8, 2003, now
U.S. Pat. No. 7,162,303; both of which claim the benefit of the
filing dates of U.S. provisional patent application Ser. No.
60/370,190, filed Apr. 8, 2002; Ser. No. 60/415,575, filed Oct. 3,
2002; and Ser. No. 60/442,970, filed Jan. 29, 2003; and all of
which are incorporated herein by reference in their entireties.
INCORPORATION BY REFERENCE
[0002] All publications and patent applications mentioned in this
specification are herein incorporated by reference to the same
extent as if each individual publication or patent application was
specifically and individually' indicated to be incorporated by
reference.
TECHNICAL FIELD
[0003] The present invention relates to methods and apparatus for
renal neuromodulation. More particularly, the present invention
relates to methods and apparatus for achieving renal
neuromodulation via a pulsed electric field and/or electroporation
or electrofusion.
BACKGROUND
[0004] Congestive Heart Failure ("CHF") is a condition that occurs
when the heart becomes damaged and reduces blood flow to the organs
of the body. If blood flow decreases sufficiently, kidney function
becomes impaired and results in fluid retention, abnormal hormone
secretions and increased constriction of blood vessels. These
results increase the workload of the heart and further decrease the
capacity of the heart to pump blood through the kidney and
circulatory system.
[0005] This reduced capacity further reduces blood flow to the
kidney. It is believed that progressively decreasing perfusion of
the kidney is a principal non-cardiac cause perpetuating the
downward spiral of CHF. Moreover, the fluid overload and associated
clinical symptoms resulting from these physiologic changes are
predominant causes for excessive hospital admissions, terrible
quality of life and overwhelming costs to the health care system
due to CHF.
[0006] While many different diseases may initially damage the
heart, once present, CHF is split into two types: Chronic CHF and
Acute (or Decompensated-Chronic) CHF. Chronic Congestive Heart
Failure is a longer term, slowly progressive, degenerative disease.
Over years, chronic congestive heart failure leads to cardiac
insufficiency. Chronic CHF is clinically categorized by the
patient's ability to exercise or perform normal activities of daily
living (such as defined by the New York Heart Association
Functional Class). Chronic CHF patients are usually managed on an
outpatient basis, typically with drugs.
[0007] Chronic CHF patients may experience an abrupt, severe
deterioration in heart function, termed 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 deteriorations can occur when extra stress
(such as an infection or excessive fluid overload) significantly
increases the workload on the heart in a stable chronic CHF
patient. In contrast to the stepwise downward progression of
chronic CHF, a patient suffering acute CHF may deteriorate from
even the earliest stages of CHF to severe hernodynamic collapse. In
addition, Acute CHF can occur within hours or days following an
Acute Myocardial Infarction ("AMI"), which is a sudden,
irreversible injury to the heart muscle, commonly referred to as a
heart attack.
[0008] As mentioned, the kidneys play a significant role in the
progression of CHF, as well as in Chronic Renal Failure ("CRF"),
End-Stage Renal Disease ("ESRD"), hypertension (pathologically high
blood pressure) and other cardio-renal diseases. The functions of
the kidney can be summarized under three broad categories:
filtering blood and excreting waste products generated by the
body's metabolism; regulating salt, water, electrolyte and
acid-base balance; and secreting hormones to maintain vital organ
blood flow. Without properly functioning kidneys, a patient will
suffer water retention, reduced urine flow and an accumulation of
waste toxins in the blood and body. These conditions resulting from
reduced renal function or renal failure (kidney failure) are
believed to increase the workload of the heart. In a CHF patient,
renal failure will cause the heart to further deteriorate as the
water build-up and blood toxins accumulate due to the poorly
functioning kidneys and, in turn, cause the heart further harm.
[0009] The primary functional unit of the kidneys that is involved
in urine formation is called the "nephron." Each kidney consists of
about one million nephrons. The nephron is made up of a glomerulus
and its tubules, which can be separated into a number of sections:
the proximal tubule, the medullary loop (loop of Henle), and the
distal tubule. Each nephron is surrounded by different types of
cells that have the ability to secrete several substances and
hormones (such as renin and erythropoietin). Urine is formed as a
result of a complex process starting with the filtration of plasma
water from blood into the glomerulus. The walls of the glomerulus
are freely permeable to water and small molecules but almost
impermeable to proteins and large molecules. Thus, in a healthy
kidney, the filtrate is virtually free of protein and has no
cellular elements. The filtered fluid that eventually becomes urine
flows through the tubules. The final chemical composition of the
urine is determined by the secretion into, and re-absorption of
substances from, the urine required to maintain homeostasis.
[0010] Receiving about 20% of cardiac output, the two kidneys
filter about 125 ml of plasma water per minute. Filtration occurs
because of a pressure gradient across the glomerular membrane. The
pressure in the arteries of the kidney pushes plasma water into the
glomerulus causing filtration. To keep the Glomerulur Filtration
Rate ("GFR") relatively constant, pressure in the glomerulus is
held constant by the constriction or dilatation of the afferent and
efferent arterioles, the muscular walled vessels leading to and
from each glomerulus.
[0011] In a CHF patient, the heart will progressively fail, and
blood flow and pressure will drop in the patient's circulatory
system. During acute heart failure, short-term compensations serve
to maintain perfusion to critical organs, notably the brain and the
heart that cannot survive prolonged reduction in blood flow.
However, these same responses that initially aid survival during
acute heart failure become deleterious during chronic heart
failure.
[0012] A combination of complex mechanisms contribute to
deleterious fluid overload in CHF. As the heart fails and blood
pressure drops, the kidneys cannot function and become impaired due
to insufficient blood pressure for perfusion. This impairment in
renal function ultimately leads to the decrease in urine output.
Without sufficient urine output, the body retains fluids, and the
resulting fluid overload causes peripheral edema (swelling of the
legs), shortness of breath (due to fluid in the lungs), and fluid
retention in the abdomen, among other undesirable conditions in the
patient.
[0013] In addition, the decrease in cardiac output leads to reduced
renal blood flow, increased neurohormonal stimulus, and release of
the hormone renin from the juxtaglomerular apparatus of the kidney.
This results in avid retention of sodium and, thus, volume
expansion. Increased renin results in the formation of angiotensin,
a potent vasoconstrictor. Heart failure and the resulting reduction
in blood pressure also reduce the blood flow and perfusion pressure
through organs in the body other than the kidneys. As they suffer
reduced blood pressure, these organs may become hypoxic, resulting
in a metabolic acidosis that reduces the effectiveness of
pharmacological therapy and increases a risk of sudden death.
[0014] This spiral of deterioration that physicians observe in
heart failure patients is believed to be mediated, at least in
part, by activation of a subtle interaction between heart function
and kidney function, known as the renin-angiotensin system.
Disturbances in the heart's pumping function results in decreased
cardiac output and diminished blood flow. The kidneys respond to
the diminished blood flow as though the total blood volume was
decreased, when in fact the measured volume is normal or even
increased. This leads to fluid retention by the kidneys and
formation of edema, thereby causing the fluid overload and
increased stress on the heart
[0015] Systemically, CHF is associated with an abnormally elevated
peripheral vascular resistance and is dominated by alterations of
the circulation resulting from an intense disturbance of
sympathetic nervous system function. Increased activity of the
sympathetic nervous system promotes a downward vicious cycle of
increased arterial vasoconstriction (increased resistance of
vessels to blood flow) followed by a further reduction of cardiac
output, causing even more diminished blood flow to the vital
organs.
[0016] In CHF via the previously explained mechanism of
vasoconstriction, the heart and circulatory system dramatically
reduce blood flow to the kidneys. During CHF, the kidneys receive a
command from higher neural centers via neural pathways and hormonal
messengers to retain fluid and sodium in the body. In response to
stress on the heart, the neural centers command the kidneys to
reduce their filtering functions. While in the short term, these
commands can be beneficial, if these commands continue over hours
and days they can jeopardize the person's life or make the person
dependent on artificial kidney for life by causing the kidneys to
cease functioning
[0017] When the kidneys do not fully filter the blood, a huge
amount of fluid is retained in the body, which results in bloating
(fluid retention in tissues) and increases the workload of the
heart. Fluid can penetrate into the lungs, and the patient becomes
short of breath. This odd and self-destructive phenomenon is most
likely explained by the effects of normal compensatory mechanisms
of the body that improperly perceive the chronically low blood
pressure of CHF as a sign of temporary disturbance, such as
bleeding.
[0018] In an acute situation, the body tries to protect its most
vital organs, the brain and the heart, from the hazards of oxygen
deprivation. Commands are issued via neural and hormonal pathways
and messengers. These commands are directed toward the goal of
maintaining blood pressure to the brain and heart, which are
treated by the body as the most vital organs. The brain and heart
cannot sustain low perfusion for any substantial period of time. A
stroke or a cardiac arrest will result if the blood pressure to
these organs is reduced to unacceptable levels. Other organs, such
as the kidneys, can withstand somewhat longer periods of ischemia
without suffering long-term damage. Accordingly, the body
sacrifices blood supply to these other organs in favor of the brain
and the heart.
[0019] The hemodynamic impairment resulting from CHF activates
several neurohormonal systems, such as the renin-angiotensin and
aldosterone system, sympatho-adrenal system and vasopressin
release. As the kidneys suffer from increased renal
vasoconstriction, the GFR drops, and the sodium load in the
circulatory system increases. Simultaneously, more renin is
liberated from the juxtaglomerular of the kidney. The combined
effects of reduced kidney functioning include reduced glomerular
sodium load, an aldosterone-mediated increase in tubular
reabsorption of sodium, and retention in the body of sodium and
water. These effects lead to several signs and symptoms of the CHF
condition, including an enlarged heart, increased systolic wall
stress, an increased myocardial oxygen demand, and the formation of
edema on the basis of fluid and sodium retention in the kidney.
Accordingly, sustained reduction in renal blood flow and
vasoconstriction is directly responsible for causing the fluid
retention associated with CHF.
[0020] CHF is progressive, and as of now, not curable. The
limitations of drug therapy and its inability to reverse or even
arrest the deterioration of CHF patients are clear. Surgical
therapies are effective in some cases, but limited to the end-stage
patient population because of the associated risk and cost.
Furthermore, the dramatic role played by kidneys in the
deterioration of CHF patients is not adequately addressed by
current surgical therapies.
[0021] The autonomic nervous system is recognized as an important
pathway for control signals that are responsible for the regulation
of body functions critical for maintaining vascular fluid balance
and blood pressure. The autonomic nervous system conducts
information in the form of signals from the body's biologic sensors
such as baroreceptors (responding to pressure and volume of blood)
and chemoreceptors (responding to chemical composition of blood) to
the central nervous system via its sensory fibers. It also conducts
command signals from the central nervous system that control the
various innervated components of the vascular system via its motor
fibers.
[0022] Experience with human kidney transplantation provided early
evidence of the role of the nervous system in kidney function. It
was noted that after transplant, when all the kidney nerves were
totally severed, the kidney increased the excretion 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 the denervation acted on a kidney
similar to a diuretic medication. Later the "denervation diuresis"
was found to be associated with vasodilatation of the renal
arterial system that led to increased blood flow through the
kidney. This observation was confirmed by the observation in
animals that reducing blood pressure supplying the kidneys reversed
the "denervation diuresis."
[0023] It was also observed that after several months passed after
the transplant surgery in successful cases, the "denervation
diuresis" in transplant recipients stopped and the kidney function
returned to normal. Originally, it was believed that the "renal
diuresis" was a transient phenomenon and that the nerves conducting
signals from the central nervous system to the kidney were not
essential to kidney function. Later discoveries suggested that the
renal nerves had a profound ability to regenerate and that the
reversal of "denervation diuresis" could be attributed to the
growth of new nerve fibers supplying the kidneys with necessary
stimuli.
[0024] Another body of research focused on the role of the neural
control of secretion of the hormone renin by the kidney. As was
discussed previously, renin is a hormone responsible for the
"vicious cycle" of vasoconstriction and water and sodium retention
in heart failure patients. It was demonstrated that an increase or
decrease in renal sympathetic nerve activity produced parallel
increases and decreases in the renin secretion rate by the kidney,
respectively.
[0025] In summary, it is known from clinical experience and the
large body of animal research that an increase in renal sympathetic
nerve activity leads to vasoconstriction of blood vessels supplying
the kidney, decreased renal blood flow, decreased removal of water
and sodium from the body, and increased renin secretion. It is also
known that reduction of sympathetic renal nerve activity, e.g., via
denervation, may reverse these processes.
[0026] It has been established in animal models that the heart
failure condition results in abnormally high sympathetic
stimulation of the kidney. This phenomenon was traced back to the
sensory nerves conducting signals from baroreceptors to the central
nervous system. Baroreceptors are present in the different
locations of the vascular system. Powerful relationships exist
between baroreceptors in the carotid arteries (supplying the brain
with arterial blood) and sympathetic nervous stimulus to the
kidneys. When arterial blood pressure was suddenly reduced in
experimental animals with heart failure, sympathetic tone
increased. Nevertheless, the normal baroreflex likely is not solely
responsible for elevated renal nerve activity in chronic CHF
patients. If exposed to a reduced level of arterial pressure for a
prolonged time, baroreceptors normally "reset," i.e., return to a
baseline level of activity, until a new disturbance is introduced.
Therefore, it is believed that in chronic CHF patients, the
components of the autonomic-nervous system responsible for the
control of blood pressure and the neural control of the kidney
function become abnormal. The exact mechanisms that cause this
abnormality are not fully understood, but its effects on the
overall condition of the CHF patients are profoundly negative.
[0027] End-Stage Renal Disease 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 slowly progresses to ESRD. CRF
represents a critical period in the evolution of ESRD. The signs
and symptoms of CRF are initially minor, but over the course of 2-5
years, become progressive and irreversible. While some progress has
been made in combating the progression to, and complications of,
ESRD, the clinical benefits of existing interventions remain
limited.
[0028] It has been known for several decades that renal diseases of
diverse etiology (hypotension, infection, trauma, autoimmune
disease, etc.) can lead to the syndrome of CRF characterized by
systemic hypertension, proteinuria (excess protein filtered from
the blood into the urine) and a progressive decline in GFR
ultimately resulting in ESRD. These observations suggest that CRF
progresses via a common pathway of mechanisms and that therapeutic
interventions inhibiting this common pathway may be successful in
slowing the rate of progression of CRF irrespective of the
initiating cause.
[0029] To start the vicious cycle of CRF, an initial insult to the
kidney causes loss of some nephrons. To maintain normal GFR, there
is an activation of compensatory renal and systemic mechanisms
resulting in a state of hyperfiltration in the remaining nephrons.
Eventually, however, the increasing numbers of nephrons
"overworked" and damaged by hyperfiltration are lost. At some
point, a sufficient number of nephrons are lost so that normal GFR
can no longer be maintained. These pathologic changes of CRF
produce worsening systemic hypertension, thus high glomerular
pressure and increased hyperfiltration. Increased glomerular
hyperfiltration and permeability in CRF pushes an increased amount
of protein from the blood, across the glomerulus and into the renal
tubules. This protein is directly toxic to the tubules and leads to
further loss of nephrons, increasing the rate of progression of
CRF. This vicious cycle of CRF continues as the GFR drops with loss
of additional nephrons leading to further hyperfiltration and
eventually to ESRD requiring dialysis. Clinically, hypertension and
excess protein filtration have been shown to be two major
determining factors in the rate of progression of CRF to ESRD.
[0030] Though previously clinically known, it was not until the
1980s that the physiologic link between hypertension, proteinuria,
nephron loss and CRF was identified. In the 1990s the role of
sympathetic nervous system activity was elucidated. Afferent
signals arising 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 on the systemic level, resulting
in increased blood pressure primarily through vasoconstriction of
blood vessels. When elevated sympathetic stimulation reaches the
kidney via the efferent sympathetic nerve fibers, it produces major
deleterious effects in two forms. The kidneys are damaged by direct
renal toxicity from the release of sympathetic neurotransmitters
(such as norepinephrine) in the kidneys independent of the
hypertension. Furthermore, secretion of renin that activates
Angiotensin II is increased, which increases systemic
vasoconstriction and exacerbates hypertension.
[0031] Over time, damage to the kidneys leads to a further increase
of afferent sympathetic signals from the kidney to the brain.
Elevated Angiotensin II further facilitates internal renal release
of neurotransmitters. The feedback loop is therefore closed, which
accelerates deterioration of the kidneys.
[0032] In view of the foregoing, it would be desirable to provide
methods and apparatus for the treatment of congestive heart
failure, renal disease, hypertension and/or other cardio-renal
diseases via renal neuromodulation and/or denervation.
SUMMARY
[0033] The present invention provides methods and apparatus for
renal neuromodulation (e.g., denervation) using a pulsed electric
field (PEF). Several aspects of the invention apply a pulsed
electric field to effectuate electroporation and/or electrofusion
in renal nerves, other neural fibers that contribute to renal
neural function, or other neural features. Several embodiments of
the invention are extravascular devices for inducing renal
neuromodulation. The apparatus and methods described herein may
utilize any suitable electrical signal or field parameters that
achieve neuromodulation, including denervation, and/or otherwise
create an electroporative and/or electrofusion effect. For example,
the electrical signal may incorporate a nanosecond pulsed electric
field (nsPEF) and/or a PEF for effectuating electroporation. One
specific embodiment comprises applying a first course of PEF
electroporation followed by a second course of nsPEF
electroporation to induce apoptosis in any cells left intact after
the PEF treatment, or vice versa. An alternative embodiment
comprises fusing nerve cells by applying a PEF in a manner that is
expected to reduce or eliminate the ability of the nerves to
conduct electrical impulses. When the methods and apparatus are
applied to renal nerves and/or other neural fibers that contribute
to renal neural functions, the inventors of the present invention
believe that urine output will increase, renin levels will
decrease, urinary sodium excretion will increase and/or blood
pressure will be controlled in a manner that will prevent or treat
CHF, hypertension, renal system diseases, and other renal
anomalies.
[0034] Several aspects of particular embodiments can achieve such
results by selecting suitable parameters for the PEFs and/or
nsPEFs. Pulsed electric field parameters can include, but are not
limited to, field strength, pulse width, the shape of the pulse,
the number of pulses and/or the interval between pulses (e.g., duty
cycle). Suitable field strengths include, for example, strengths of
up to about 10,000 Vlcm. Suitable pulse widths include, for
example, widths of up to about 1 second. Suitable shapes of the
pulse waveform include, for example, AC waveforms, sinusoidal
waves, cosine waves, combinations of sine and cosine waves, DC
waveforms, DC-shifted AC waveforms, RF waveforms, square waves,
trapezoidal waves, exponentially-decaying waves, combinations
thereof, etc. Suitable numbers of pulses include, for example, at
least one pulse. Suitable pulse intervals include, for example,
intervals less than about 10 seconds. Any combination of these
parameters may be utilized as desired. These parameters are
provided for the sake of illustration and should in no way be
considered limiting. Additional and alternative waveform parameters
will be apparent.
[0035] Several embodiments are directed to extravascular systems
for providing longlasting denervation to minimize acute myocardial
infarct ("AMI") expansion and for helping to prevent the onset of
morphological changes that are affiliated with congestive heart
failure. For example, one embodiment of the invention comprises
treating a patient for an infarction, e.g., via coronary
angioplasty and/or stenting, and performing an extravascular pulsed
electric field renal denervation procedure under, for example,
Computed Tomography ("CT") guidance. PEF therapy can, for example,
be delivered in a separate session soon after the AMI has been
stabilized. Renal neuromodulation also may be used as an adjunctive
therapy to renal surgical procedures. In these embodiments, the
anticipated increase in urine output, decrease in renin levels,
increase in urinary sodium excretion and/or control of blood
pressure provided by the renal PEF therapy is expected to reduce
the load on the heart to inhibit expansion of the infarct and
prevent CHF.
[0036] Several embodiments of extravascular pulsed electric field
systems described herein may denervate or reduce the activity of
the renal nervous supply immediately post-infarct, or at any time
thereafter, without leaving behind a permanent implant in the
patient. These embodiments are expected to increase urine output,
decrease renin levels, increase urinary sodium excretion and/or
control blood pressure for a period of several months during which
the patient's heart can heal. If it is determined that repeat
and/or chronic neuromodulation would be beneficial after this
period of healing, renal PEF treatment can be repeated as needed
and/or a permanent implant may be provided.
[0037] In addition to efficaciously treating AMI, several
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 increased renal sympathetic
nervous activity. For example, the systems may be used to treat CHF
at any time by extravascularly advancing the PEF system to a
treatment site, for example, under CT-guidance. Once properly
positioned, a PEF therapy may be delivered to the treatment site.
This may, for example, modify a level of fluid offload.
[0038] The use of PEF therapy for the treatment of CHF,
hypertension, end-stage renal disease and other cardio-renal
diseases is described in detail hereinafter in several different
extravascular system embodiments. The systems can be introduced
into the area of the renal neural tissue under, for example, CT,
ultrasonic, angiographic or laparoscopic guidance, or the systems
can be surgically implanted using a combination of these or other
techniques. The various elements of the system may be placed in a
single operative session, or in two or more staged sessions. For
instance, a percutaneous therapy might be conducted under CT or
CTI/angiographic guidance. For a partially or fully implantable
system, a combination of CT, angiographic or laparoscopic
implantation of leads and nerve contact elements might be paired
with a surgical implantation of the subcutaneous contact element or
control unit. The systems may be employed unilaterally or
bilaterally as desired for the intended clinical effect. The
systems can be used to modulate efferent or afferent nerve signals,
as well as combinations of efferent and afferent signals.
[0039] In one variation, PEF therapy is delivered at a treatment
site to create a nonthermal nerve block, reduce neural signaling,
or otherwise modulate neural activity. Alternatively or
additionally, cooling, cryogenic, pulsed RF, thermal RF, thermal or
nonthermal microwave, focused or unfocused ultrasound, thermal or
non-thermal DC, as well as any combination thereof, may be employed
to reduce or otherwise control neural signaling.
[0040] Several embodiments of the PEF systems may completely block
or denervate the target neural structures, or the PEF systems may
otherwise modulate the renal nervous activity. As opposed to a full
neural blockade such as denervation, other neuromodulation produces
a less-than-complete change in the level of renal nervous activity
between the kidney(s) and the rest of the body. Accordingly,
varying the pulsed electric field parameters will produce different
effects on the nervous activity.
[0041] Any of the embodiments of the present invention described
herein optionally may be configured for infusing agents into the
treatment area before, during or after energy application. The
infused agents may create a working space for introduction of PEF
system elements, such as electrodes. Additionally or alternatively,
the infused agents may be selected to enhance or modify the
neuromodulatory effect of the energy application. The agents also
may protect or temporarily displace non-target cells, and/or
facilitate visualization.
[0042] Several embodiments of the present invention may comprise
detectors or other elements that facilitate identification of
locations for treatment and/or that measure or confirm the success
of treatment. For example, temporary nerve-block agents, such as
lidocaine, bupivacaine or the like, might be infused through a
percutaneous needle injection or through an infusion port built
into a partially or fully implantable system to ensure proper
location of neural contact elements prior to delivering PEF
therapy. Alternatively or additionally, the system can be
configured to also deliver stimulation waveforms and monitor
physiological parameters known to respond to stimulation of the
renal nerves. Based on the results of the monitored parameters, the
system can determine the location of renal nerves and/or whether
denervation has occurred. Detectors for monitoring of such
physiological responses include, for example, Doppler elements,
thermocouples, pressure sensors, and imaging modalities (e.g.,
fluoroscopy, intravascular ultrasound, etc.). Alternatively,
electroporation may be monitored directly using, for example,
Electrical Impedance Tomography ("EIT") or other electrical
impedance measurements or sensors. Additional monitoring techniques
and elements will be apparent. Such detector(s) may be integrated
with the PEF systems or they may be separate elements.
[0043] In some embodiments, stimulation of the nerve plexus may be
utilized to determine whether repeat therapy is required. For
example, stimulation may be used to elicit a pain response from the
renal nerves. If the patient senses this stimulation, then it is
apparent that nerve conduction has returned, and repeat therapy is
warranted. This method optionally may be built into any of the
systems described hereinafter--percutaneous, partially implantable
or fully implantable.
[0044] Still other specific embodiments include electrodes
configured to align the electric field with the longer dimension of
the target cells. For instance, nerve cells tend to be elongate
structures with lengths that greatly exceed their lateral
dimensions (e.g., diameter). By aligning an electric field so that
the directionality of field propagation preferentially affects the
longitudinal aspect of the cell rather than the lateral aspect of
the cell, it is expected that lower field strengths can be used to
kill or disable target cells. This is expected to conserve the
battery life of implantable devices, reduce collateral effects on
adjacent structures, and otherwise enhance the ability to modulate
the neural activity of target cells.
[0045] Other embodiments of the invention are directed to
applications in which the longitudinal dimensions of cells in
tissues overlying or underlying the nerve are transverse (e.g.,
orthogonal or otherwise at an angle) with respect to the
longitudinal direction of the nerve cells. Another aspect of these
embodiments is to align the directionality of the PEF such 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 elongate cells which
surround the arterial circumference in a generally spiraling
orientation so that their longer dimensions are circumferential
rather than running longitudinally along the artery. Nerves of the
renal plexus, on the other hand, run along the outside of the
artery generally in the longitudinal direction of the artery.
Therefore, applying a PEF 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 the
same degree. This may enable preferential denervation of nerve
cells (target cells) in the adventitia or periarterial region
without affecting the smooth muscle cells of the vessel to an
undesirable extent.
[0046] It should be understood that the PEF systems described in
this application are not necessarily required to make physical
contact with the tissue or neural fibers to be treated. Electrical
energy, such as thermal RF energy and non-thermal pulsed RF, may be
conducted to tissue to be treated from a short distance away from
the tissue itself. Thus, it may be appreciated that "nerve contact"
comprises both physical contact of a system element with the nerve,
as well as electrical contact alone without physical contact, or as
a combination of the two.
[0047] In one embodiment of an extravascular pulsed electric field
system, a laparoscopic or percutaneous system is utilized. For
example, a percutaneous probe may be inserted in proximity to the
track of the renal neural supply along the renal artery or vein
and/or within the Gerota's fascia, under, e.g., CT or radiographic
guidance. Once properly positioned, pulsed electric field therapy
may be applied to target neural fibers via the probe, after which
the probe may be removed from the patient to conclude the
procedure.
[0048] It is expected that such therapy would reduce or alleviate
clinical symptoms of CHF, hypertension, renal disease and/or other
cardio-renal diseases, for several months (e.g., potentially up to
six months or more). This time period might be sufficient to allow
the body to heal, for example, this period might reduce a risk of
CHF onset after an acute myocardial infarction, thereby alleviating
a need for subsequent re-treatment. Alternatively, as symptoms
reoccur, or at regularly scheduled intervals, the patient might
return to the physician or self-administer a repeat therapy. As
another alternative, repeat therapy might be fully automated.
[0049] The need for a repeat therapy optionally might be predicted
by monitoring of physiologic parameters, for example, by monitoring
specific neurohormones (plasma renin levels, etc.) that are
indicative of increased sympathetic nervous activity.
Alternatively, provocative maneuvers known to increase sympathetic
nervous activity, such as head-out water immersion testing, may be
conducted to determine the need for repeat therapy.
[0050] In addition or as an alternative to laparoscopic or
percutaneous PEF systems, partially implantable PEF systems may be
utilized. For example, an external control box may connect through
or across the patient's skin to a subcutaneous element. Leads may
be tunneled from the subcutaneous element to a nerve cuff or a
nerve contact element in proximity to Gerota's fascia, the renal
artery, vein and/or hilum. PEF therapy may be conducted from the
external control box across or through the skin to the subcutaneous
element and to the nerve cuff or nerve contact element to modulate
neural fibers that contribute to renal function.
[0051] The PEF may be transmitted across or through the skin via
direct methods, such as needles or trocars, or via indirect methods
such as transcutaneous energy transfer ("TET") systems. TET systems
are used clinically to recharge batteries in rechargeable
implantable stimulation or pacing devices, left ventricular assist
devices, etc. In one TET embodiment of the present invention, the
subcutaneous system may have a receiving coil to gather transmitted
energy, a capacitor or temporary storage device to collect the
charge, control electronics to create a waveform, as well as leads
and nerve electrode(s) to deliver the energy waveform to the renal
nerves.
[0052] In another TET embodiment, a PEF signal itself may be
transmitted telemetrically through the skin to a subcutaneous
receiving element. Passive leads connecting the subcutaneous
receiving element to nerve electrodes may conduct the signal to the
nerves for treatment, thereby eliminating a need for a receiving
battery or capacitor, as well as signal processing circuitry, in
the implanted portion of the PEF system.
[0053] In other partially implanted embodiments, the implanted
subcutaneous elements may be entirely passive. The subcutaneous
elements may include an implantable electrical connector that is
easily accessible via a simple needle, leads to the nerve
electrodes, and the nerve electrodes themselves. The implanted
system might also incorporate an infusion lumen to allow drugs to
be introduced from a subcutaneous port to the treatment area. A
control box, a lead and a transcutaneous needle or trocar
electrical connector may be disposed external to the patient.
[0054] In addition or as an alternative to non-implanted PEF
systems, or partially implantable PEF systems, fully implantable
PEF systems may be utilized. An implantable control housing
containing signal generation circuitry and energy supply circuitry
may be attached to leads which are tunneled to a renal nerve cuff
or renal nerve contact electrodes. Power may be provided by a
battery included with the implantable housing. The battery may, for
example, require surgical replacement after a period of months or
years, or may be rechargeable via a TET system. When therapy is
required, a PEF signal is applied to the nerves using the contact
electrodes, with the control housing serving as the return
electrode.
[0055] The need for repeat therapy may be tested by the implantable
system. For example, a lower-frequency stimulation signal may be
applied to the nerves periodically by the system. When the nerve
has returned toward baseline function, the test signal would be
felt by the patient, and the system then would be instructed to
apply another course of PEF therapy. This repeat treatment
optionally might be patient or physician initiated. If the patient
feels the test signal, the patient or physician might operate the
implantable system via electronic telemetry, magnetic switching or
other means to apply the required therapeutic PEF.
[0056] Alternatively, the system could be programmed in an
open-loop fashion to apply another PEF treatment periodically, for
example, once every six months. In still another embodiment,
monitoring methods that assess parameters or symptoms of the
patient's clinical status may be used to determine the need for
repeat therapy.
[0057] The nerve contact elements of any of the percutaneous,
partially implantable or fully implantable systems may comprise a
variety of embodiments. For instance, the implanted elements might
be in the form of a cuff, basket, cupped contact, fan-shaped
contact, space-filling contact, spiral contact or the like.
Implantable nerve contact elements may incorporate elements that
facilitate anchoring and/or tissue in-growth. For instance, fabric
or implantable materials such as Dacron or ePTFE might be
incorporated into the design of the contact elements to facilitate
in-growth into areas of the device that would help anchor the
system in place, but repel tissue in-growth in undesired areas,
such as the electrical contacts. Similarly, coatings, material
treatments, drug coatings or drug elution might be used alone or in
combination to facilitate or retard tissue in-growth into various
segments of the implanted system as desired.
BRIEF DESCRIPTION OF THE DRAWINGS
[0058] Several embodiments of the present invention will be
apparent upon consideration of the following detailed description,
taken in conjunction with the accompanying drawings, in which like
reference characters refer to like parts throughout, and in
which:
[0059] FIG. 1 is a schematic view illustrating human renal
anatomy.
[0060] FIG. 2 is a schematic detail view showing the location of
the renal nerves relative to the renal artery.
[0061] FIGS. 3A and 3B are schematic side- and end-views,
respectively, illustrating a direction of electrical current flow
for selectively affecting renal nerves.
[0062] FIG. 4 is a schematic view illustrating a percutaneous or
laparoscopic method and apparatus for renal neuromodulation.
[0063] FIG. 5 is a schematic view illustrating another percutaneous
or laparoscopic method and apparatus for renal neuromodulation
comprising a spreading electrode for at least partially surrounding
renal vasculature.
[0064] FIG. 6 is a schematic view illustrating a percutaneous or
laparoscopic method and apparatus for renal neuromodulation
comprising a spiral electrode configured to surround renal
vasculature.
[0065] FIG. 7 is a schematic view illustrating a percutaneous or
laparoscopic method and apparatus for renal neuromodulation
comprising a ring electrode configured to at least partially
surround renal vasculature.
[0066] FIG. 8 is a schematic view illustrating another percutaneous
or laparoscopic method and apparatus for renal neuromodulation
comprising a spreading electrode configured for positioning near
the renal hilum.
[0067] FIG. 9 is a schematic view illustrating a percutaneous or
laparoscopic method and apparatus for renal neuromodulation
comprising a space-occupying electrode configured for positioning
near the renal hilum.
[0068] FIG. 10 is a schematic view illustrating a percutaneous or
laparoscopic method and apparatus for accessing Gerota's
fascia.
[0069] FIGS. 11A and 11B are schematic views illustrating methods
and apparatus for mechanically anchoring a delivery system or
electrode within Gerota's fascia.
[0070] FIG. 12 is a schematic view illustrating a method and
apparatus for positioning electrodes along a patient's renal artery
within an annular space between the artery and Gerota's fascia in
order to achieve renal neuromodulation.
[0071] FIGS. 13A-13C are schematic detail views of various
embodiments of the electrodes of FIG. 12.
[0072] FIGS. 14A-14C are schematic views and a detail view
illustrating another method and apparatus for positioning
electrodes along the patient's renal artery.
[0073] FIGS. 15A and 158 are a schematic view and a detail view
illustrating yet another method and apparatus for positioning
electrodes.
[0074] FIG. 16 is a schematic view illustrating still another
method and apparatus for positioning electrodes along the patient's
renal artery.
[0075] FIGS. 17A and 17B are schematic views illustrating another
method and apparatus for positioning electrodes along the patient's
renal artery.
[0076] FIG. 18 is a schematic view illustrating a method and
apparatus for positioning implantable electrodes along the
patient's renal artery.
[0077] FIGS. 19A and 19B are schematic views illustrating methods
and apparatus for renal neuromodulation via partially implantable
systems.
[0078] FIG. 20 is a schematic view illustrating a method and
apparatus for renal neuromodulation via a fully implantable
system.
[0079] FIGS. 21A and 21B are schematic views illustrating a method
and apparatus for positioning electrodes relative to a renal neural
structure in accordance with another embodiment of the
invention.
[0080] FIGS. 22A and 22B are schematic views illustrating a method
and apparatus for positioning electrodes relative to a patient's
renal neural structure in accordance with still another embodiment
of the invention.
[0081] FIG. 23 is a schematic view illustrating a method and
apparatus for positioning electrodes relative to a patient's renal
neural structure in accordance with yet another embodiment of the
invention.
DETAILED DESCRIPTION
A. Overview
[0082] The present invention relates to methods and apparatus for
renal neuromodulation and/or other neuromodulation. More
particularly, the present invention relates to methods and
apparatus for renal neuromodulation using a pulsed electric field
to effectuate electroporation or electrofusion. As used herein,
electroporation and electropermeabilization are methods of
manipulating the cell membrane or intracellular apparatus. For
example, short high-energy pulses cause pores to open in cell
membranes. The extent of porosity in the cell membrane (e.g., size
and number of pores) and the duration of the pores (e.g., temporary
or permanent) are a function of the field strength, pulse width,
duty cycle, field orientation, cell type and other parameters. In
general, pores will generally close spontaneously upon termination
of lower strength fields or shorter pulse widths (herein defined as
"reversible electroporation"). Each cell type has a critical
threshold above which pores do not close such that pore formation
is no longer reversible; this result is defined as "irreversible
electroporation," "irreversible breakdown" or "irreversible
damage." At this point, the cell membrane ruptures and/or
irreversible chemical imbalances caused by the high porosity occur.
Such high porosity can be the result of a single large hole and/or
a plurality of smaller holes. Certain types of electroporation
energy parameters also appropriate for use in renal neuromodulation
are high voltage pulses with a duration in the sub-microsecond
range (nanosecond pulsed electric fields, or nsPEF) which may leave
the cellular membrane intact, but alter the intracellular apparatus
or function of the cell in ways which cause cell death or
disruption. Certain applications of nsPEF have been shown to cause
cell death by inducing apoptosis, or programmed cell death, rather
than acute cell death. Also, the term "comprising" is used
throughout to mean including at least the recited feature such that
any greater number of the same feature and/or additional types
features are not precluded.
[0083] Several embodiments of the present invention provide
extravascular devices or systems for inducing renal
neuromodulation, such as a temporary change in target nerves that
dissipates over time, continuous control over neural function,
and/or denervation. The apparatus and methods described herein may
utilize any suitable electrical signal or field parameters, e.g.,
any electric field, that will achieve the desired neuromodulation
(e.g., electroporative effect). To better understand the structures
of the extravascular devices and the methods of using these devices
for neuromodulation, it is useful to understand the renal anatomy
in humans.
B. Selected Embodiments of Methods for Neuromodulation
[0084] With reference now to FIG. 1, the human renal anatomy
includes kidneys K that are supplied with oxygenated blood by renal
arteries RA, which are connected to the heart by the abdominal
aorta AA. Deoxygenated blood flows from the kidneys to the heart
via renal veins RV and the inferior vena cava IVC. FIG. 2
illustrates a portion of the renal anatomy in greater detail. More
specifically, the renal anatomy also includes renal nerves RN
extending longitudinally along the lengthwise dimension L of renal
artery RA generally within the adventitia of the artery. The renal
artery RA has smooth muscle cells SMC that surround the arterial
circumference and spiral around the angular axis .theta. of the
artery. The smooth muscle cells of the renal artery accordingly
have a lengthwise or longer dimension extending transverse (i.e.,
non-parallel) to the lengthwise dimension of the renal artery. The
misalignment of the lengthwise dimensions of the renal nerves and
the smooth muscle cells is defined as "cellular misalignment."
[0085] Referring to FIG. 3, the cellular misalignment of the renal
nerves and the smooth muscle cells may be exploited to selectively
affect renal nerve cells with reduced effect on smooth muscle
cells. More specifically, because larger cells require 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 the longer dimensions of the cells to be
affected. In specific embodiments, the extravascular device has
electrodes configured to create an electrical field aligned with or
near the lengthwise dimension L of the renal artery RA to affect
renal nerves RN. By aligning an electric field so that the field
preferentially affects the lengthwise aspect of the cell rather
than the diametric or radial aspect of the cell, lower field
strengths may be used to necrose cells. As mentioned above, this is
expected to reduce power consumption and mitigate effects on
non-target cells in the electric field.
[0086] Similarly, the lengthwise or longer dimensions of tissues
overlying or underlying the target nerve are orthogonal or
otherwise off-axis (e.g., transverse) with respect to the longer
dimensions of the nerve cells. Thus, in addition to aligning the
PEF with the lengthwise or longer dimensions of the target cells,
the PEF may propagate along the lateral or shorter dimensions of
the non-target cells (i.e., such that the PEF propagates at least
partially out of alignment with non-target smooth muscle cells
SMC). Therefore, as seen in FIG. 3, applying a PEF with propagation
lines Li generally aligned with the longitudinal dimension L of the
renal artery RA is expected to preferentially cause
electroporation, electrofusion, denervation or other
neuromodulation in cells of the target renal nerves RN without
unduly affecting the non-target arterial smooth muscle cells SMC.
The pulsed electric field may propagate in a single plane along the
longitudinal axis of the renal artery, or may propagate in the
longitudinal direction along any angular segment 9 through a range
of 0''-360''.
[0087] Embodiments of the method shown in FIG. 3 may have
particular application with the extravascular methods and apparatus
of the present invention. For instance, a PEF system placed
exterior to the renal artery may propagate an electric field having
a longitudinal portion that is aligned to run with the longitudinal
dimension of the artery in the region of the renal nerves RN and
the smooth muscle cell SMC of the vessel wall so that the wall of
the artery remains at least substantially intact while the outer
nerve cells are destroyed.
C. Embodiments of Systems and Additional Methods for
Neuromodulation
[0088] FIG. 4 shows one embodiment of an extravascular pulsed
electric field apparatus 200 in accordance with the present
invention that includes one or more electrodes configured to
deliver a pulsed electric field to renal neural fibers to achieve
renal neuromodulation. Apparatus 200 comprises a laparoscopic or
percutaneous PEF system having -probe 210 configured for insertion
in proximity to the track of the renal neural supply along the
renal artery or vein or hilum and/or within Gerota's fascia under,
e.g., CT or radiographic guidance. The proximal section of probe
210 generally has an electrical connector to couple the probe to
pulse generator 100, and the distal section has at least one
electrode 212.
[0089] Pulsed electric field generator 100 is located external to
the patient, and the electrode(s) 212 are electrically coupled to
the generator via probe 210 and wires 211. The generator 100, as
well as any of the electrode embodiments described herein, may be
utilized with any embodiment of the present invention described
hereinafter for delivery of a PEF with desired field parameters. It
should be understood that electrodes of embodiments described
hereinafter may be electronically connected to the generator, even
if the generator is not explicitly shown or described with each
embodiment.
[0090] The electrode(s) 212 can be individual electrodes, a common
but segmented electrode, or a common and continuous electrode. A
common but segmented electrode may, for example, be formed by
providing a slotted tube fitted onto the electrode, or by
electrically connecting a series of individual electrodes.
Individual electrodes or groups of electrodes 212 may be configured
to provide a bipolar signal. Electrodes 212 may be dynamically
assignable to facilitate monopolar and/or bipolar energy delivery
between any of the electrodes and/or between any of the electrodes
and external ground pad 214. Ground pad 214 may, for example, be
attached externally to the patient's skin, e.g., to the patient's
leg or flank.
[0091] As seen in FIG. 4, electrode 212 may comprise a single
electrode that is used in conjunction with separate patient ground
pad 214 located external to the patient and coupled to generator
100 for monopolar use. Probe 210 optionally may comprise a
conductive material that is insulated in regions other than its
distal tip, thereby forming distal tip electrode 212.
Alternatively, electrode 212 may, for example, be delivered through
a lumen of probe 210. Probe 210 and electrode 212 may be of the
standard needle or trocar-type used clinically for pulsed RF nerve
block, such as those sold by Valleylab (a division of Tyco
Healthcare Group LP) of Boulder, Colo. Alternatively, apparatus 200
may comprise a flexible and/or custom-designed probe for the renal
application described herein.
[0092] In FIG. 4, percutaneous probe 210 has been advanced through
percutaneous access site P into proximity within renal artery RA.
Once properly positioned, pulsed electric field therapy may be
applied to target neural fibers across electrode 212 and ground pad
214. After treatment, apparatus 200 may be removed from the patient
to conclude the procedure.
[0093] It is expected that such therapy will alleviate clinical
symptoms of CHF, hypertension, renal disease and/or other
cardio-renal diseases for a period of months, potentially up to six
months or more. This time period might be sufficient to allow the
body to heal, for example, this period might reduce the risk of CHF
onset after an acute myocardial infarction, thereby alleviating a
need for subsequent re-treatment. Alternatively, as symptoms
reoccur, or at regularly scheduled intervals, the patient might
return to the physician for a repeat therapy.
[0094] The need for a repeat therapy optionally might be predicted
by monitoring of physiologic parameters, for example, by monitoring
specific neurohormones (plasma renin levels, etc.) that are
indicative of increased sympathetic nervous activity.
Alternatively, provocative maneuvers known to increase sympathetic
nervous activity, such as head-out water immersion testing, may be
conducted to determine the need for repeat therapy.
[0095] In some embodiments, apparatus 200 may comprise a probe
having an introducer with an expandable distal segment having one
or more electrodes. After insertion in proximity to target neural
fibers, the distal segment may be opened or expanded into an
expanded configuration. In one embodiment, this expanded
configuration would follow a contour of the renal artery and/or
vein to treat a number of neural fibers with a single application
of PEF therapy. For example, in the expanded configuration, the
distal segment may partially or completely encircle the renal
artery and/or vein. In another embodiment, the expanded
configuration may facilitate mechanical dissection, for example, to
expand Gerota's fascia and create a working space for placement of
the electrodes and/or for delivery of PEF therapy. The distal
segment optionally may be translated independently of the probe or
introducer.
[0096] When utilized as an electrode, the distal segment may, for
example, be extended out of an introducer placed near the treatment
area. The conducting distal segment maybe advanced out of the
sheath until a desired amount of renal neural tissue is contacted;
and then PEF therapy may be delivered via the distal segment
electrode. Alternatively, the conducting distal segment may be
allowed to reform or expand into a spiral of one or more loops, a
random space-occupying shape, or another suitable configuration.
Mesh, braid, or conductive gels or liquids could be employed in a
similar manner.
[0097] FIG. 5 illustrates another embodiment of apparatus 200
comprising an expandable distal segment. In FIG. 5, apparatus 200
comprises introducer probe 220 and electrode element 230 with a
distal segment 232 that may be expandable. Probe 220 may, for
example, comprise a standard, needle or trocar. Electrode element
230 is proximally coupled to generator 100 and is configured for
advancement through probe 220. Distal segment 232 of the electrode
element may be delivered to a treatment site in a closed or
contracted configuration within probe 220 and then opened or
.expanded to a treatment configuration at or near the treatment
site. For example, the distal segment 232 can be expanded by
advancing segment 232 out of probe 220 and/or by retracting the
probe relative to the distal segment. The embodiment of the distal
segment 232 shown in FIG. 5 comprises a basket or cup-shaped
element in a deployed configuration 234 for delivering treatment.
The distal segment 232 preferably self-expands to the treatment
configuration. The apparatus 200 can further include one or more
electrodes 233 coupled to distal segment 232.
[0098] As seen in FIG. 5, distal segment 232 partially or
completely encircles or surrounds renal artery RA in the deployed
configuration 234. PEF therapy delivered through electrode element
230 to electrodes 233 in a bipolar or monopolar fashion may achieve
a more thorough or complete renal neuromodulation than a PEF
therapy delivered from electrodes along only one side of the artery
or at an electrode at a single point along the artery. Electrode
element 230 optionally may be electrically isolated from probe 220
such that the probe and electrodes 233 form two parts of a bipolar
system in which the probe 220 is a return electrode.
[0099] With reference to FIG. 6, distal segment 232 alternatively
may comprise a spiral element 236 in the treatment configuration.
The distal segment may, for example, be pre-formed into a spiral
configuration. The spiral might be straightened through a number of
different mechanisms (e.g., positioning within probe 220, pull
wires to actuate segment 232 between straight and spiraled, a
shape-memory material, etc.) for insertion into proximity, e.g.,
with the renal vasculature. Once near a target vessel, the spiral
may be actuated or allowed to reform in order to more fully
encircle the vessel, thereby facilitating treatment of a greater
number of neural fibers with a single application of PEF
therapy.
[0100] The spiral or helical element 236 of distal segment 232 is
configured to appose the vessel wall and bring electrode(s) 233
into close proximity to renal neural structures. The pitch of the
helix can be varied to provide a longer treatment zone or to
minimize circumferential overlap of adjacent treatments zones,
e.g., in order to reduce a risk of stenosis formation. This pitch
change can be achieved, for example, via (a) a heatset, (b)
combining a plurality of segments of different pitches to form
segment 232, (c) adjusting the pitch of segment 232 through the use
of internal pull wires, (d) adjusting mandrels inserted into the
segment, (e) shaping sheaths placed over the segment, or (f) any
other suitable means for changing the pitch either in-situ or
before introduction into the body.
[0101] As with previous embodiments, the electrode(s) 233 along the
length of distal segment 232 can 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 into or placed over the helix of distal
segment 232. Individual electrodes or groups of electrodes 233 may
be configured to provide a bipolar signal, or any configuration of
the electrodes may be used together at a common potential in
conjunction with a separate external patient ground for monopolar
use. Electrodes 233 may be dynamically assignable to facilitate
monopolar and/or bipolar energy delivery between any of the
electrodes and/or between any of the electrodes and an external
ground. Distal segment 232 optionally may be insulated on a side
facing away from the renal artery such that at least portions of
the side of the segment configured to face the renal artery are
exposed to form electrode(s) 233.
[0102] Distal segment 232 of electrode element 230 may be delivered
in proximity to renal artery RA in a low profile delivery
configuration within probe 220. Once positioned in proximity to the
artery, distal segment 232 may self-expand or may be expanded
actively, e.g., via a pull wire or a balloon, into the spiral
configuration 236 about the wall of the artery. The distal segment
may, for example, be guided around the vessel, e.g., via steering
and blunt dissection, and activated to take on the tighter-pitch
coil of the spiral configuration 236. Alternatively or
additionally, the distal segment might be advanced relative to
probe 220 and snaked around the artery via its predisposition to
assume the spiral configuration. Positioning the distal segment
within Gerota's fascia might facilitate placement of distal segment
232 around the artery.
[0103] Once properly positioned, a pulsed electric field then may
be generated by the PEF generator 100, transferred through
electrode element 230 to electrodes 233, and delivered via the
electrodes to renal nerves located along the artery. In many
applications, the electrodes are arranged so that the pulsed
electric field is aligned with the longitudinal dimension of the
artery to modulate the neural activity along the renal nerves
(e.g., denervation). This may be achieved, for example, via
irreversible electroporation, electrofusion and/or inducement of
apoptosis in the nerve cells.
[0104] Referring to FIG. 7, another percutaneous or laparoscopic
method and apparatus for renal neuromodulation is described. In
FIG. 7, distal segment 232 of electrode element 230 of apparatus
200 comprises electrode 233 having ring or cuff configuration 238.
The ring electrode may partially surround renal artery RA, as
shown. Electrode 233 optionally may comprise retractable pin 239
for closing the ring to more fully or completely encircle the
artery once the electrode has been placed about the artery. A PEF
therapy may be delivered via the electrode to achieve renal
neuromodulation. As an alternative to laparoscopic placement, ring
electrode 238 optionally may be surgically placed.
[0105] FIG. 8 illustrates another percutaneous or laparoscopic
method and apparatus for renal neuromodulation comprising a
spreading electrode configured for positioning near the renal
hilum. As seen in FIG. 8, distal segment 232 of electrode element
230 may comprise fan-shaped member 240 having a plurality of
fingers that may be collapsed or constrained within probe 220
during percutaneous introduction to, and/or retraction from, a
treatment site. One or more electrodes 233 may be positioned along
the fingers of the distal segment. Once in the area of the renal
vasculature and/or renal hilum HI the fan may be extended, or probe
220 may be retracted, to deploy distal segment 232. The fingers,
for example, spread out to cover a larger treatment area along the
vasculature or renal hilum that facilitates treatment of a greater
number of target neural fibers and/or creates a working space for
subsequent introduction of electrodes 233.
[0106] In FIG. 8, a distal region of probe 220 is positioned in
proximity to renal hilum HI and the fan-shaped distal segment 232
has been expanded to the deployed configuration. PEF therapy then
may be delivered via electrodes 233 to neural fibers in that region
for renal neuromodulation.
[0107] With reference to FIG. 9, distal segment 232 alternatively
may comprise a tufted element 242 having one or more strands with
electrodes 233. Distal segment 232 may be positioned in proximity
to renal hilum H within probe 220, and then the tufted element 242
can be expanded to a space-occupying configuration. Electrodes 233
then may deliver PEF therapy to renal nerves.
[0108] With reference to FIG. 10, probe 220 optionally may pierce
fascia F (e.g. Gerota's fascia) that surrounds kidney K and/or
renal artery RA. Distal segment 232 may be advanced through probe
220 between the fascia and renal structures, such as hilum H and
artery RA. This may position electrodes 233 into closer proximity
with target renal neural structures. For example, when distal
segment 232 comprises the fan-shaped member 240 of FIG. 8 or the
tufted element 242 of FIG. 9, expansion of the distal segment
within fascia F may place electrodes 233 into proximity with more
target renal neural structures and/or may create a working space
for delivery of one or more electrodes 233 or of conducting gels or
liquids, etc.
[0109] Referring to FIGS. 11A and 118, methods and apparatus for
mechanically anchoring probe 220, distal segment 232 of electrode
element 230, and/or electrode(s) 233 within fascia F are described.
FIGS. 11A and 11B illustrate mechanical anchoring element 250 in
combination with distal segment 232 of electrode element 230, but
this should in no way be construed as limiting because the
apparatus 200 does not need to include the anchoring element 250.
In embodiments with the anchoring element, distal segment 232 may
be expandable or non-expansile.
[0110] In the embodiment of FIG. 11A, distal segment 232 comprises
anchoring element 250 having collar 252 disposed about the distal
segment. Self-expanding wire loops 254 of the anchoring element
extend from the collar. The loops 254 may be collapsed against the
shaft of distal segment 232 while the distal segment is disposed
within probe 220 (as illustrated in dotted profile in FIG. 11A).
Probe 220 may pierce the fascia near a treatment site, thereby
positioning a distal tip of the probe within the fascia. The probe
then may be retracted relative to electrode element 230 (and/or the
electrode element may be advanced relative to the probe) to
position distal segment 232 distal of the probe. The loops 254
self-expand in a manner that mechanically anchors distal segment
232 within the fascia. Alternatively, anchoring element 250 may be
actively expanded, e.g., in a mechanical fashion.
[0111] The loops 254 optionally may be covered with an elastic
polymer, such as silicone, CFlex, urethane, etc., such that the
anchoring element 250 at least partially seals an entry site into
fascia F. This may facilitate immediate infusion of fluids through
probe 220 or electrode element 230 without leakage or with reduced
leakage. Additionally or alternatively, when electrode element 230
is configured for longer-term implantation, anchoring element 250
may be covered in a porous material, such as a polyester fabric or
mesh, that allows or promotes tissue in-growth. Tissue in-growth
may enhance the anchoring providing by element 250 for maintaining
the position of distal segment 232 and/or electrode(s) 233. Tissue
in-growth may also enhance sealing at the entry site into the
fascia.
[0112] In the embodiment of FIG. 11B, distal segment 232 is cut in
the longitudinal direction to create a series of flaps 256 around
the catheter that form an alternative anchoring element 250.
Pull-wire 258 may, for example, extend along the exterior of
electrode element 230 or may be disposed within a lumen of the
electrode element, and is coupled to distal segment 232 distal of
flaps 256. Once distal segment 232 is positioned within fascia F,
pull-wire 258 is moved proximally to extend the flaps 256 and
anchor the distal segment within the fascia. Alternatively, other
expandable members incorporating wires, baskets, meshes, braids or
the like may be mechanically expanded to provide anchoring.
[0113] With anchoring element 250 expanded, an infusate optionally
may be infused through slits 256. Furthermore, as with the
embodiment of FIG. 11A, anchoring element 250 of FIG. 11B
optionally may be covered with an elastic polymer covering to
create a gasket for sealing the entry site into the fascia. In such
a configuration, infusion holes may be provided distal of the
anchoring element. Alternatively, a proximal portion of the slit
section of anchoring element 250 may be covered with the elastic
polymer, while a distal portion remains uncovered, for example, to
facilitate infusion through slits 256. In another embodiment,
anchoring element 250 of FIG. 11B may comprise a porous material to
facilitate tissue in-growth, as described previously. As with the
elastic polymer, the porous material optionally may cover only a
portion of the anchoring element to facilitate, for example, both
tissue in-growth and infusion.
[0114] FIG. 12 shows a method and apparatus for renal
neuromodulation in which electrodes are positioned along a
patient's renal vasculature within an annular space between the
vasculature and the surrounding fascia. The electrodes may be
positioned in proximity to the renal artery and/or the renal vein
by guiding a needle within fascia F using, for example, Computed
Tomography ("CT") guidance. The needle may comprise introducer
probe 220, or the probe may be advanced over and exchanged for the
needle after placement of the needle within the fascia.
[0115] When the probe 220 is within the Gerota's fascia, the
electrode element 230 is delivered through the probe in close
proximity to renal vasculature (e.g., the renal artery RA). The
electrode element optionally may be advanced along the length of
the artery toward the patient's aorta to bluntly dissect a space
for the electrode element as the electrode element is advanced. The
electrode element 230 may comprise a catheter, and electrodes 233
coupled to the electrode element 230 may deliver PEF therapy or
other types of therapy to renal neural structures located along the
renal artery. Bipolar or monopolar electrode(s) may be provided as
desired.
[0116] With reference to FIGS. 13A-C, various additional
embodiments of electrodes 233 and distal segment 232 of electrode
element 230 are described. In FIG. 13A, electrodes 233 comprise a
pair of bipolar electrode coils disposed about distal segment 232.
In FIG. 136, electrodes 233 comprise a pair of bipolar electrodes
having contoured metal plates disposed on the side of distal
segment 232 facing renal artery RA to face target renal neural
structures. This is expected to preferentially direct PEF therapy
delivered between electrodes 233 towards the renal artery. As seen
in FIG. 13C, distal segment 232 and/or electrodes 233 may comprise
a concave profile so that more surface area of the electrodes is
juxtaposed with the wall of the renal artery. When the pulsed
electric field delivered by electrodes 233 is strong enough,
suitably directed and/or in close enough proximity to target neural
structures, it is expected that the electrodes may achieve a
desired level of renal neuromodulation without fully encircling the
renal artery.
[0117] FIGS. 14A-C show another method and apparatus for
positioning electrodes along the patient's renal artery. In
addition to probe 220 and electrode element 230, apparatus 200 of
FIGS. 14A-C comprises catheter 300. Electrode element 230 is
positioned within catheter 300 and optionally may comprise an
atraumatic tip of the catheter. As seen in FIG. 14A, catheter 300
may be advanced through probe 220 within the annular space between
the fascia F and the renal vasculature shown as renal artery RA.
The catheter and/or the probe optionally may be advanced over a
guidewire. Various agents may be infused through the catheter to
create a working space for advancement of the catheter and/or to
facilitate placement of electrodes 233.
[0118] Once positioned as desired at a treatment site, the catheter
may be retracted relative to the electrode element to expose
electrodes 233 along distal segment 232 of the electrode element,
as in FIG. 140. The electrodes 233 in FIGS. 14A-C may comprise a
bipolar pair of expandable electrodes that may be collapsed for
delivery within catheter 300. The electrodes may, for example, be
fabricated from a self-expanding material, such as spring steel or
Nitinol. Although electrodes 233 illustratively are on a common
electrode element 230, it should be understood that multiple
electrode elements 230 each having one or more electrodes 233 may
be delivered through catheter 300 and positioned as desired along
the renal vasculature.
[0119] In the expanded configuration of FIG. 146, electrodes 233 at
least partially surround or encircle renal artery RA. It is
expected that at least partially encircling the renal artery during
PEF therapy will enhance the efficacy of renal neuromodulation or
denervation. The electrodes may be used to deliver PEF therapy
and/or to stimulate a physiologic response to test or to challenge
an extent of neuromodulation, as well as to apply energy to
disrupt, modulate or block renal nerve function. Various agents may
be infused in the vicinity of electrodes 233 prior to, during or
after energy delivery, for example, to aid in conduction (e.g.,
saline and hypertonic saline), to improve electroporative effect
(e.g., heated solutions) or to provide protection to non-target
cells (e.g., cooling solutions or Poloxamer-188).
[0120] Electrodes 233 may, for example, comprise coils, wires,
ribbons, polymers, braids or composites. Polymers may be used in
combination with conductive materials to direct a pulsed electric
field into and/or along target tissue while insulating surrounding
tissue. With reference to FIG. 14C, distal segment 232 of electrode
element 230 may comprise insulation I that is locally removed or
omitted along an inner surface of electrodes 233 where the
electrodes face or contact renal vasculature.
[0121] Referring now to FIGS. 15A-B, another embodiment of the
apparatus and method of FIGS. 14A-C is described. As seen in FIG.
15A, electrode(s) 233 may comprise an undulating or sinusoidal
configuration that extends along the renal vasculature. The
sinusoidal configuration of electrodes 233 may provide for greater
contact area along the vessel wall than do electrodes 233 of FIGS.
14A-C, while still facilitating sheathing of electrode element 230
within catheter 300 for delivery and/or retrieval. Electrode(s) 233
may comprise a unitary electrode configured for monopolar energy
delivery, or distal segment 232 of electrode element 230 may
comprise insulation that is locally removed or omitted to expose
electrodes 233. Alternatively, as seen in FIG. 15B, the electrodes
may comprise discrete wire coils or other conductive sections
attached to the undulating distal segment 232. Electrodes 233 may
be energized in any combination to form a bipolar electrode
pair.
[0122] FIG. 16 is a schematic view illustrating yet another
embodiment of the method and apparatus of FIGS. 14A-C. In FIG. 16,
catheter 300 comprises multiple lumens 304 through which electrode
elements 230 may be advanced and electrodes 233 may be collapsed
for delivery. When positioned at a treatment site, electrode
elements 230 may be advanced relative to catheter 300 and/or the
catheter 300 may be retracted relative to the electrode elements,
such that electrodes 233 expand to the configuration of FIG. 16 for
at least partially encircling renal vasculature. In FIG. 16,
apparatus 200 illustratively comprises two electrode elements 230,
each having an expandable electrode 233. The two electrodes 233 may
be used as a bipolar electrode pair during PEF therapy. Electrode
elements 230 may be translated independently, such that a
separation distance between electrodes 233 may be altered
dynamically, as desired.
[0123] FIGS. 17A-B show still another embodiment of the method and
apparatus of FIGS. 14A-C. In FIG. 17A, electrode 233 comprises a
panel that may be rolled into scroll for low-profile delivery
within catheter 300. As seen in FIG. 178, the catheter may be
retracted relative to the electrode, and/or the electrode may be
advanced relative to the catheter, such that panel unfurls or
unrolls, preferably in a self-expanding fashion, to partially or
completely encircle renal artery RA. PEF therapy may be delivered
through electrode 233 in a monopolar fashion, or the electrode may
be segmented to facilitate bipolar use. Alternatively, a second
electrode may be delivery in proximity to electrode 233 for bipolar
PEF therapy.
[0124] Any of the electrode embodiments 212 or 233 of FIGS. 5-17B
may be configured for use in a single PEF therapy session, or may
be configured for implantation for application of follow-on PEF
therapy sessions. In implantable embodiments, leads may, for
example, extend from electrodes 212 or 233 to a subcutaneous
element controllable through the skin or to an implantable
controller.
[0125] With reference to FIG. 18, when electrodes 233 are
configured for implantation, distal segment 232 of electrode
element 230 may, for example, be detachable at a treatment site,
such that electrodes 233 are implanted in the annular space between
renal artery RA and fascia F, while a proximal portion of electrode
element 230 is removed from the patient. As seen in FIG. 18,
electrode element 230 may comprise leads 260 for tunneling to a
subcutaneous element or to an implantable controller. The electrode
element further comprises detachment mechanism 270 disposed just
proximal of distal segment 232 for detachment of the distal segment
at the treatment site. Distal segment 232 optionally may comprise
elements configured to promote tissue in-growth in the vicinity of
electrodes 233.
[0126] With reference to FIGS. 19A-20, partially and completely
implantable PEF systems are described. FIGS. 19A-B illustrate
partially implantable systems having a pulsed electric field
generator 100 connected either directly or indirectly to a
subcutaneous element 400 through or across the patient's skin.
Subcutaneous element 400 may be placed, for example, posteriorly,
e.g., in the patient's lower back. In FIGS. 19A-B, the subcutaneous
element 400 is attached to leads 260, and the leads 260 are
electrically coupled to implanted electrodes 233 positioned in
proximity to the renal artery, renal vein, renal hilum, Gerota's
fascia or other suitable structures. Electrodes 233 can be located
bilaterally, i.e., in proximity to both the right and left renal
vasculature, but alternatively may be positioned unilaterally.
Furthermore, multiple electrodes may be positioned in proximity to
either or both kidneys for bipolar PEF therapy, or monopolar
electrodes may be provided and used in combination with a return
electrode, such as external ground pad 214 or a return electrode
integrated with subcutaneous element 400.
[0127] As seen in FIG. 19A, subcutaneous element 400 may comprise a
subcutaneous port 402 having an electrical contact 403 comprising
one or more connecting or docking points for coupling the
electrical contact(s) to generator 100. In a direct method of
transmitting a PEF across the patient's skin, a transcutaneous
needle, trocar, probe or other element 410 that is electrically
coupled to generator 100 pierces the patient's skin and releasably
couples to contact 403. Transcutaneous element 410 conducts PEF
therapy from the generator 100 across or through the patient's skin
to , subcutaneous contact 403 and to electrodes 233 for modulating
neural fibers that contribute to renal function. The implanted
system might also incorporate an infusion lumen to allow drugs to
be introduced from subcutaneous port 402 to the treatment area.
[0128] In addition to direct methods of transmitting PEF signals
across the patient's skin, such as via transcutaneous element 410,
indirect methods alternatively may be utilized, such as
transcutaneous energy transfer ("TET") systems. TET systems are
used clinically to recharge batteries in rechargeable implantable
stimulation or paving devices, left ventricular assist devices,
etc. In the TET embodiment of FIG. 19B, subcutaneous element 400
comprises subcutaneous receiving element 404, and external TET
transmitting element 420 is coupled to generator 100. A PEF signal
may be transmitted telemetrically through the skin from external
transmitting element 420 to subcutaneous receiving element 404.
Passive leads 260 connect the subcutaneous receiving element to
nerve electrodes 233 and may conduct the signal to the nerves for
treatment.
[0129] With reference to FIG. 20, a fully implantable PEF system is
described. In FIG. 20, subcutaneous receiving element 404 is
coupled to a capacitor or other energy storage element 430, such as
a battery, which in turn is coupled to implanted controller 440
that connects via leads 260 to electrodes 233. External
transmitting element 420 is coupled to external charger and
programmer 450 for transmitting energy to the implanted system
and/or to program the implanted system. Charger and programmer 450
need not supply energy in the form of a PEF for transmission across
the patient's skin from external element 420 to receiving element
404. Rather, controller 440 may create a PEF waveform from energy
stored within storage element 430. The controller optionally may
serve as a return electrode for monopolar-type PEF therapy.
[0130] The embodiment of FIG. 20 illustratively is rechargeable
and/or reprogrammable. However, it should be understood that the
fully implanted PEF system alternatively may be neither
rechargeable nor programmable. Rather, the system may be powered
via storage element 430, which, if necessary, may be configured for
surgical replacement after a period of months or years after which
energy stored in the storage element has been depleted.
[0131] When using a percutaneous or implantable PEF system, the
need for repeat therapy, the location for initial therapy and/or
the efficacy of therapy, optionally may be determined by the
system. For example, an implantable system periodically may apply a
lower-frequency stimulation signal to renal nerves; when the nerve
has returned toward baseline function, the test signal would be
felt by the patient, and the system would apply another course of
PEF therapy. This repeat treatment optionally might be patient
initiated: when the patient feels the test signal, the patient
would operate the implantable system via electronic telemetry,
magnetic switching or other means to apply the required therapeutic
PEF.
[0132] As an alternative or in addition to eliciting a pain
response, the responses of physiologic parameters known to be
affected by stimulation of the renal nerves may be monitored. Such
parameters comprise, for example, renin levels, sodium levels,
renal blood flow and blood pressure. When using stimulation to
challenge denervation and monitor treatment efficacy, the known
physiologic responses to stimulation should no longer occur in
response to such stimulation.
[0133] Efferent nerve stimulation waveforms may, for example,
comprise frequencies of about 1-10 Hz, while afferent nerve
stimulation waveforms may, for example, comprise frequencies of up
to about 50 Hz. Waveform amplitudes may, for example, range up to
about 50V1 while pulse durations may, for example, range up to
about 20 milliseconds. Although exemplary parameters for
stimulation waveforms have been described, it should be understood
that any alternative parameters may be utilized as desired.
[0134] The electrodes used to deliver PEFs in any of the previously
described variations of the present invention also may be used to
deliver stimulation waveforms to the renal vasculature.
Alternatively, the variations may comprise independent electrodes
configured for stimulation. As another alternative, a separate
stimulation apparatus may be provided.
[0135] As mentioned, one way to use stimulation to identify renal
nerves is to stimulate the nerves such that renal blood flow is
affected--or would be affected if the renal nerves had not been
denervated or modulated. As stimulation acts to reduce renal blood
flow, this response may be attenuated or abolished with
denervation. Thus, stimulation prior to neural modulation would be
expected to reduce blood flow, while stimulation after neural
modulation would not be expected to reduce blood flow to the same
degree when utilizing similar stimulation parameters and
location(s) as prior to neural modulation. This phenomenon may be
utilized to quantify an extent of renal neuromodulation.
[0136] Embodiments 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.
Renal blood flow optionally may be visualized through the skin
(e.g., using an ultrasound transducer). An extent of
electroporation additionally or alternatively may be monitored
directly using Electrical Impedance Tomography ("EIT") or other
electrical impedance measurements or sensors, such as an electrical
impedance index.
[0137] In addition or as an alternative to stimulation, other
monitoring methods which check for measures of the patient's
clinical status may be used to determine the need for repeat
therapy. These monitoring methods could be completely or partially
implantable, or they could be external measurements which
communicate telemetrically with implantable elements. For instance,
an implantable pressure sensor of the kind known in the field
(e.g., sensors developed by CardioMEMS of Atlanta, Ga.) could
measure right atrial pressure. Increasing right atrial pressure is
a sign of fluid overload and improper CHF management. If an
increase in right atrial pressure is detected by the sensor, a
signal might be sent to controller 440 and another PEF treatment
would delivered. Similarly, arterial pressure might be monitored
and/or used as a control signal in other disease conditions, such
as the treatment of high blood pressure. Alternatively, invasive or
non-invasive measures of cardiac output might be utilized.
Non-invasive measures include, for example, thoracic electrical
bioimpedance.
[0138] In yet another embodiment, weight fluctuation is correlated
with percentage body fat to determine a need for repeat therapy. It
is known that increasing patient weight, especially in the absence
of an increase in percent body fat, is a sign of increasing volume
overload. Thus, the patient's weight and percentage body fat may be
monitored, e.g., via a specially-designed scale that compares the
weight gain to percentage body fat. If it is determined that weight
gain is due fluid overload, the scale or other monitoring
element(s) could signal controller 440, e.g., telemetrically, to
apply another PEF treatment.
[0139] When using partially or completely implantable PEF systems,
a thermocouple, other temperature or impedance monitoring elements,
or other sensors, might be incorporated into subcutaneous elements
400. External elements of the PEF system might be designed to
connect with and/or receive information from the sensor elements.
For example, in one embodiment, transcutaneous element 410 connects
to subcutaneous electrical contact 403 of port 402 and can deliver
stimulation signals to interrogate target neural tissue to
determine a need, or parameters, for therapy, as well as to
determine impedance of the nerve and nerve electrodes.
Additionally, a separate connector to mate with a sensor lead may
be extended through or alongside transcutaneous element 410 to
contact a corresponding subcutaneous sensor lead.
[0140] Alternatively, subcutaneous electrical contact 403 may have
multiple target zones placed next to one another, but electrically
isolated from one another. A lead extending from an external
controller, e.g., external generator 100, would split into several
individual transcutaneous needles, or individual needle points
coupled within a larger probe, which are inserted through the skin
to independently contact their respective subcutaneous target
zones. For example, energy delivery, impedance measurement,
interrogative stimulation and temperature each might have its own
respective target zone arranged on the subcutaneous system.
Diagnostic electronics within the external controller optionally
may be designed to ensure that the correct needle is in contact
with each corresponding subcutaneous target zone.
[0141] Elements may be incorporated into the implanted elements of
PEF systems to facilitate anchoring and/or tissue in-growth. For
instance, fabric or implantable materials, such as Dacron or ePTFE,
might be incorporated into the design of the subcutaneous elements
400 to facilitate in-growth into areas of the elements that would
facilitate anchoring of the elements in place, while optionally
repelling tissue in-growth in undesired areas, such as along
electrodes 233. Similarly, coatings, material treatments, drug
coatings or drug elution might be used alone or in combination to
facilitate or retard tissue in-growth into various elements of the
implanted PEF system, as desired.
[0142] Any of the embodiments of the present invention described
herein optionally may be configured for infusion of agents into the
treatment area before, during or after energy application, for
example, to create a working space to facilitate electrode
placement, to enhance or modify the neurodestructive or
neuromodulatory effect of applied energy, to protect or temporarily
displace non-target cells, and/or to facilitate visualization.
Additional applications for infused agents will be apparent. If
desired, uptake of infused agents by cells may be enhanced via
initiation of reversible electroporation in the cells in the
presence of the infused agents. The infusate may comprise, for
example, fluids (e.g., heated or chilled fluids), air, CO2, saline,
heparinized saline, hypertonic saline, contrast agents, gels,
conductive materials, space-occupying materials (gas, solid or
liquid), protective agents, such as Poloxamer-188,
anti-proliferative agents, or other drugs and/or drug delivery
elements. Variations of the present invention additionally or
alternatively may be configured for aspiration.
[0143] FIGS. 21A and 21B illustrate another embodiment of the
apparatus 200 in accordance with the invention. Referring to FIG.
21A, the apparatus 200 includes the probe 220 and a catheter 300
received within the probe 220. The catheter 300 includes an
anchoring mechanism 251 having a first collar 280, a second collar
282 located distally relative to the first collar 280, and an
expandable member 284 connected to the first and second collars 280
and 282. The expandable member 284 can be a braid, mesh, woven
member or other device that expands as the distance between the
first and second collars 280 and 282 is reduced. The expandable
member 284 can include polyesters, Nitinol, elgiloy, stainless
steel, composites and/or other suitable materials. The collars 280
and 282, and/or the expandable member 284, may be at least
partially covered in an expandable polymer to form a seal with the
patient. The apparatus 200 can further include a plurality of
electrodes 230 located at the expandable member 284 and/or the
first or second collars 280 or 282.
[0144] The anchoring mechanism 250 operates by moving at least one
of the collars 280 and 282 toward the other to reduce the distance
between the collars. For example, the first collar 280 can be
slidable along the catheter 300, and the second collar 282 can be
fixed to the catheter 300. Referring to FIG. 21B, the expandable
member 284 can be expanded by pulling back on the catheter 300 to
engage the proximal collar 280 with the distal end of the probe
220. As the catheter 300 is withdrawn proximally relative to the
probe 220, the distal end of the probe 220 drives the first collar
280 toward the second collar 282 to move the anchoring mechanism
251 from a collapsed position shown in FIG. 21A to an expanded
configuration illustrated in FIG. 218. Alternatively, the apparatus
200 can include an actuator that can be advanced distally to drive
the first collar 280 toward the second collar 282. The actuator,
for example, can be a coaxial sleeve around the catheter 300 that
may be operated from the proximal end of the probe 220.
[0145] FIGS. 22A and 22B illustrate another embodiment of the
apparatus 200 in accordance with the invention. In this embodiment,
the apparatus 200 includes a probe 220 and a catheter 300 that
moves through the probe 220 as described above with reference to
FIGS. 11A-B. The apparatus 200 of this embodiment further includes
an anchoring mechanism 253 having a first collar 281, a second
collar 283 located distally along the catheter 300 relative to the
first collar 281, and an expandable member 285 attached to the
first and second collars 281 and 283. In one embodiment, the first
collar 281 is slidably movable along the catheter 300, and the
second collar 283 is fixed to the catheter 300. Alternatively, the
first collar 281 can be fixed to the catheter 300 and the second
collar 283 can be movable along the catheter 300. The expandable
member 285 is a self-contracting member that is actively stretched
into a collapsed configuration to be contained within the probe 220
for delivery to the desired treatment site in the patient. FIG. 22A
illustrates the expandable member 285 stretched into an elongated
state to be constrained within the probe 220. Referring to FIG.
22B, the apparatus 200 is deployed in the patient by moving the
probe 220 proximally relative to the catheter 300 and/or moving the
catheter 300 distally relative to the probe 220 until the
expandable member 285 is outside of the probe 220. Once the
expandable member 285 is outside of the probe 220, the expandable
member 285 draws the movable collar toward the fixed collar to
allow the expandable member 285 to expand outwardly relative to the
radius of the catheter shaft 300.
[0146] The expandable member 285 can be a spring formed from a
polyester, stainless steel, composites or other suitable materials
with sufficient elasticity to inherently move into the expanded
configuration shown in FIG. 228. Alternatively, the expandable
member can be formed from a shaped memory metal, such as Nitinol or
elgiloy, that moves from the collapsed configuration illustrated in
FIG. 22A to the expanded configuration illustrated in FIG. 226 at a
given temperature. In either embodiment the apparatus 200 can
further include electrodes (not shown) located along the expandable
member for delivering the pulsed electric field to the renal nerve
or other structure related to renallcardio activity.
[0147] FIG. 23 illustrates yet another embodiment of a method and
apparatus for positioning an electrode relative to a renal
structure to deliver a PEF for neuromodulation. In this embodiment,
the apparatus includes a first percutaneous member 510, a second
percutaneous member 520, an electrode assembly 530, and a retriever
540. The first percutaneous member 510 can be a first trocar
through which the electrode assembly 530 is delivered to the renal
artery RA or other renal structure, and the second percutaneous
member 520 can be a second trocar through which the retriever 540
is delivered to the general region of the electrode assembly 530.
In the embodiment shown in FIG. 23, the electrode assembly 530
includes an electrode 532, and the retriever 540 is a snare
configured to capture the electrode assembly. In operation, the
first percutaneous member 510 is inserted into the patient and the
electrode assembly 530 is passed through the first percutaneous
member 510 until the electrode 532 is at or near a desired location
relative to the renal structure. The second percutaneous member 520
is also inserted into the patient so that the retriever 540 can
engage the electrode assembly 530. The retriever 540 can be used to
hold the electrode 532 at the desired location during delivery of a
PEF to the patient and/or to remove the electrode assembly 530
after delivering the PEF.
[0148] Although preferred illustrative variations of the present
invention are described above, it will be apparent to those skilled
in the art that various changes and modifications may be made
thereto without departing from the invention. For example, although
the variations primarily have been described for use in combination
with pulsed electric fields, it should be understood that any other
electric field may be delivered as desired. It is intended in the
appended claims to cover all such changes and modifications that
fall within the true spirit and scope of the invention.
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