U.S. patent application number 15/884797 was filed with the patent office on 2018-08-02 for enhancing left ventricular relaxation through neuromodulation.
This patent application is currently assigned to NeuroTronik IP Holding (Jersey) Limited. The applicant listed for this patent is NeuroTronik IP Holding (Jersey) Limited. Invention is credited to Michael Cuchiara, Stephen C Masson.
Application Number | 20180214697 15/884797 |
Document ID | / |
Family ID | 62977010 |
Filed Date | 2018-08-02 |
United States Patent
Application |
20180214697 |
Kind Code |
A1 |
Cuchiara; Michael ; et
al. |
August 2, 2018 |
ENHANCING LEFT VENTRICULAR RELAXATION THROUGH NEUROMODULATION
Abstract
Neuromodulation is used to enhance left ventricular relaxation.
An exemplary neuromodulation system includes a therapy element
positionable in proximity to at least one nerve fiber, and a
stimulator configured to energize the therapy element to delivery
therapy to the at least one nerve fiber such that left ventricular
relaxation and left ventricular contractility are contemporaneously
enhanced.
Inventors: |
Cuchiara; Michael; (Durham,
NC) ; Masson; Stephen C; (Raleigh, NC) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
NeuroTronik IP Holding (Jersey) Limited |
St. Helier |
|
JE |
|
|
Assignee: |
NeuroTronik IP Holding (Jersey)
Limited
St. Helier
JE
|
Family ID: |
62977010 |
Appl. No.: |
15/884797 |
Filed: |
January 31, 2018 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
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62452354 |
Jan 31, 2017 |
|
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Current U.S.
Class: |
1/1 |
Current CPC
Class: |
A61N 1/36171 20130101;
A61M 1/125 20140204; A61N 1/0551 20130101; A61N 1/36157 20130101;
A61M 2205/054 20130101; A61M 1/122 20140204; A61N 1/36175 20130101;
A61N 1/36114 20130101; A61N 1/36139 20130101; A61N 1/36153
20130101; A61N 1/36185 20130101 |
International
Class: |
A61N 1/36 20060101
A61N001/36; A61N 1/05 20060101 A61N001/05; A61M 1/12 20060101
A61M001/12 |
Claims
1-23. (canceled)
24. A method of treating a patient having a left ventricular
contractility (LVC) and a left ventricular relaxation (LVR),
comprising: using a mechanical circulatory support device to
increase cardiac output or aid in unloading the heart; and while
using the mechanical circulatory support device, delivering
neuromodulation therapy to contemporaneously enhance LVC and
LVR.
25. The method of claim 24, wherein the neuromodulation therapy
includes: using at least one therapy element to neuromodulate at
least one parasympathetic nerve fiber to increase LVR and to
neuromodulate at least one sympathetic nerve fiber to increase
LVC.
26. The method of claim 24, wherein the neuromodulation therapy is
delivered to contemporaneously enhance LVC and LVR such that the
ratio of the percentage increase of LVC to the percentage increase
of LVR is within a predetermined range.
27. The method of claim 26, wherein the predetermined range is
0.5-1.5.
28. The method of claim 26, wherein the predetermined range is
0.8-1.2.
29. The method of claim 26, wherein the predetermined range is
approximately 1.0.
30. The method of claim 24, wherein the step of delivering
neuromodulation therapy includes positioning at least one therapy
element in an intravascular location and neuromodulating an
extravascular nerve fiber using the therapy element.
31. The method of claim 30, wherein the intravascular location is
selected from the group of blood vessels consisting of the superior
vena cava, left brachiocephalic vein and right brachiocephalic
vein.
32. The method of claim 30, wherein the intravascular location is
selected from the group of blood vessels consisting of the superior
vena cava, left brachiocephalic vein, lower internal jugular vein,
right brachiocephalic vein, azygos vein or azygos arch.
33. The method of claim 25, wherein the steps of neuromodulating
the parasympathetic and sympathetic nerve fibers are performed
contemporaneously.
34. The method of claim 25, wherein the steps of neuromodulating
the parasympathetic and sympathetic nerve fibers are performed at
different times.
35. The method of claim 24, wherein the enhancement of LVR is
determined by determining the increase in a value selected from
left ventricular dP/dt min in diastole, arterial blood pressure
(ABP) in diastole, tau in diastole, mitral valve deceleration time,
mitral valve velocity time interval or end diastolic pressure
volume relationship (EDPVR) from prior to initiation of
neuromodulation to after initiation of neuromodulation.
36. The method of claim 24, wherein the enhancement of LVC is
determined by determining the increase in the value selected from
left ventricular dP/dt max in systole, ABP in systole, from prior
to initiation of neuromodulation to after initiation of
neuromodulation.
37. The method of claim 24, wherein the mechanical circulatory
support device is selected from the group of mechanical circulatory
support devices consisting of blood pumps, ventricular assist
devices, percutaneous ventricular assist devices, and intra-aortic
balloon pumps.
38. The method of claim 26, wherein the neuromodulation therapy is
delivered by a neuromodulation system, and wherein the method
further includes receiving by the neuromodulation system LVR input
corresponding to a measure of LVR and LVC input corresponding to a
measure of LVC, the neuromodulation system automatically adjusting
at least one neuromodulation parameter such that the ratio of the
enhancement of LVC to the enhancement of LVR is within the
predetermined range.
39. A system for treating a patient having a left ventricular
contractility (LVC) and a left ventricular relaxation (LVR),
comprising: a mechanical circulatory support device positionable to
enhance circulation of blood in the patient to increase cardiac
output or aid in unloading the heart; and a neuromodulation system
for enhancing left ventricular relaxation (LVR) and left
ventricular contractility (LVC), the neuromodulation system
comprising at least one neuromodulation therapy element adapted for
positioning in proximity to at least one nerve fiber and a
stimulator configured to energize said at least one therapy element
to deliver therapy to the at least one nerve fiber, such that the
LVR and LVC are contemporaneously enhanced.
40. The system of claim 39, wherein the neuromodulation system
includes wherein neuromodulation therapy element is adapted for
positioning within a blood vessel and the stimulator is configured
to energize said at least one therapy element within the blood
vessel to deliver therapy to said at least one nerve fiber disposed
external to the blood vessel, such that the LVR and LVC are
contemporaneously enhanced.
41. The system of claim 39 wherein the stimulator is configured to
energize the therapy element such that the ratio of the enhancement
of LVC to the enhancement of LVR is within a predetermined
range.
42. The system of claim 39, further including at least one sensor
adapted to deliver LVR input to the system corresponding to a
measure of LVR and to deliver LVC input to the system corresponding
to a measure of LVC.
43. The system of claim 42 wherein the system is configured to
determine the enhancement of LVR by comparing the measure of LVR
from prior to initiation of neuromodulation to said selected
measure after initiation of neuromodulation, and to determine the
enhancement of LVR by comparing the measure of LVR from prior to
initiation of neuromodulation to said selected measure after
initiation of neuromodulation.
44. The system of claim 43, wherein the measure of LVR is selected
from the set of measures consisting of left ventricular dP/dt min
in diastole, arterial blood pressure (ABP) in diastole, tau in
diastole, mitral valve deceleration time or mitral valve velocity
time interval.
45. The system of claim 43, wherein the measure of LVC is selected
from the set of measures consisting of left ventricular dP/dt max
in systole, ABP in systole, increases in stroke volume without
changes in pre-load (i.e. left ventricular end diastolic pressure),
afterload (i.e. systemic vascular resistance) or end systolic
pressure volume relationship (ESPVR).
46. The system of claim 43 wherein the system is configured to
automatically adjust at least one neuromodulation parameter such
that the ratio of the enhancement of LVC to the enhancement of LVR
is within a predetermined range.
47. The system of claim 46, wherein the therapy elements are
electrodes and the neuromodulation parameter adjusted by the system
is at least one of electrical currents, voltages, and pulse widths,
pulse frequency, charge density, effective electrode surface area,
effective electrode spacing, and electrode combinations
energized.
48. The system of claim 41, wherein the predetermined range is
0.5-1.5.
49. The system of claim 41, wherein the predetermined range is
0.8-1.2.
50. The system of claim 41, wherein the predetermined range is
approximately 1.0.
51. The system of claim 39, wherein the mechanical circulatory
support device is selected from the group of mechanical circulatory
support devices consisting of blood pumps, ventricular assist
devices, percutaneous ventricular assist devices, and intra-aortic
balloon pumps.
52. The system of claim 42, wherein said at least one sensor is
positioned on a portion of the mechanical circulatory support
device that during use is disposed within the circulatory
system.
53. The system of claim 39, wherein the neuromodulation system
includes: a parasympathetic therapy element intravascularly
positionable to neuromodulate at least one parasympathetic nerve
fiber to increase LVR; and a sympathetic therapy element
intravascularly positionable to neuromodulate at least one
sympathetic nerve fiber to increase LVC.
54-65. (canceled)
Description
[0001] This application claims the benefit of U.S. Provisional
Application No. 62/452,354, filed Jan. 31, 2017
TECHNICAL FIELD OF THE INVENTION
[0002] The present application generally relates to systems and
methods for neuromodulation.
BACKGROUND
[0003] U.S. Pat. No. 9,067,071 (the '071 patent), U.S. application
Ser. No. 14/642,699, filed Mar. 9, 2015 (the "699 application"),
U.S. application Ser. No. 14/801,560, filed Jul. 16, 2015 (the
"'560 application"), U.S. application Ser. No. 14/820,536, filed
Aug. 6, 2015 (the "'536 application"), and U.S. application Ser.
No. 15/098,237, filed Apr. 13, 2016 describe systems which may be
used for hemodynamic control in the acute hospital care setting, by
transvascularly directing therapeutic stimulus to parasympathetic
nerves and/or sympathetic cardiac nerves using one or more
therapeutic elements (e.g. electrodes or electrode arrays)
positioned in the neighboring vasculature. Each of the
above-referenced applications is incorporated herein by
reference.
[0004] In accordance with a method described in the '071 patent,
autonomic imbalance in a patient may be treated by energizing a
first therapeutic element disposed in the vasculature to deliver
therapy to a parasympathetic nerve fiber such as a vagus nerve and
energizing a second therapeutic element disposed in the vasculature
to deliver therapy to a cardiac sympathetic nerve fiber. Delivery
of the parasympathetic and sympathetic therapy decreases the
patient's heart rate (through the delivery of therapy to the
parasympathetic nerves) while at the same time elevating or
maintaining the blood pressure (through the delivery of therapy to
the cardiac sympathetic nerves) of the patient in treatment of
heart failure. For treatment of acute heart failure syndromes, the
neuromodulation therapy may be used to lower heart rate and
increase cardiac contractility.
[0005] The '071 patent describes a neuromodulation system having a
parasympathetic therapy element adapted for positioning within a
blood vessel, a sympathetic therapy element adapted for positioning
with the blood vessel; and a stimulator configured to energize the
parasympathetic therapy element to deliver parasympathetic therapy
to a parasympathetic nerve fiber disposed external to the blood
vessel and to energize the sympathetic therapy element within the
blood vessel to deliver sympathetic therapy to a sympathetic nerve
fiber disposed external to the blood vessel. In other methods of
transvascular nerve capture, including some described in the '699
and '560 applications, therapy may be delivered using multiple
therapeutic elements positioned in different blood vessels. For
example, one therapeutic element may be positionable within a first
blood vessel to capture a first nervous system target outside the
first blood vessel, and the other may be positionable in a second,
different, blood vessel to capture a second nervous system target
outside the second blood vessel.
[0006] A neuromodulation system used for the therapy may include an
external pulse generator/stimulator that is positioned outside the
patient's body. The therapeutic elements may be carried by one or
more percutaneous catheters that are coupled to the external pulse
generator. In other embodiments an implantable stimulator may
instead be used, in which case the therapeutic elements may be
disposed on leads electrically coupled to the implantable
stimulator/pulse generator. The stimulator/pulse generator is
configured to energize the therapeutic elements to transvascularly
capture the target nerve fibers.
[0007] Left ventricular contractility ("LV contractility" or "LVC")
is the strength and vigor with which the left ventricle of the
heart contracts during systole. The greater the contractility the
greater the stroke volume of blood per contraction of the heart.
Since cardiac output ("CO") is the product of stroke volume and
heart rate, greater contractility of the left ventricle correlates
to greater cardiac output ("CO").
[0008] Left ventricular relaxation ("LV relaxation" or "LVR") is
the relaxation of the muscle of the left ventricle during diastole.
Rapid relaxation of the left ventricle is important for proper
functioning of the heart. It helps to draw blood into the ventricle
and allows more complete filling of the left ventricle. Slow LVR
can cause congestion and thus increased pressure in the pulmonary
circuit, and insufficient filling of the left ventricle. Some
medical conditions, such as heart failure with preserved ejection
fraction, can result in a reduction of LVR. Some treatments may
cause an increase in contractility without causing a corresponding
increase in relaxation. For example, heart failure patients are
often treated using administration of inotropes, a treatment that
increases contractility with the goal of increasing cardiac output,
but because they do not cause a corresponding increase in
relaxation, the left ventricle may not be able to fill adequately
and cardiac output can remain compromised.
BRIEF DESCRIPTION OF THE DRAWINGS
[0009] FIG. 1 shows a first embodiment of a neuromodulation
system;
[0010] FIG. 2 shows a second embodiment of a neuromodulation
system;
[0011] FIG. 3 shows the neuromodulation system of FIG. 1 in use as
a combined therapy with a percutaneous blood pump in the left
ventricle.
DETAILED DESCRIPTION
[0012] This application describes the use of neuromodulation to
enhance, to a similar degree, contractility of the left ventricle
in systole, and relaxation of the left ventricle in diastole. This
application also describes the use of neuromodulation to enhance
LVR, a therapy that may be combined with other therapies that
enhance LVC, such as administration of inotropes.
[0013] Use of neuromodulation to enhance LVR causes the left
ventricle to relax more quickly in diastole and has several
benefits: [0014] more rapid relaxation of the LV increases the rate
at which blood is drawn through the mitral valve into the left
ventricle ("LV"), decreasing congestion in the pulmonary circuit
more effectively or more quickly, and reducing pressure in the
pulmonary circuit. [0015] more rapid relaxation of the LV causes
more rapid filling of the LV, and consequently results in an
increase in the volume of blood that fills the LV (compared with
the volume that can be achieved without the enhanced relaxation
achieved from the neuromodulation therapy); [0016] enhanced
myocardial energetics--or an increase in the efficiency at which
the tissue of the heart utilizes oxygen. In contrast, conventional
heart failure treatments involving administration of inotropes to
the patient will increase contractility but do not increase
relaxation to a similar extent. Conventional heart failure
treatments involving administration of inotropes that result in
poor contractility relaxation balance have the disadvantage that
they increase the amount of oxygen consumed by the myocardial
tissue. Therefore, neuromodulation that can increase contractility
(and thus CO) while augmenting relaxation to a similar degree also
enhances myocardial energetics.
[0017] The impact of therapy on LVR is assessed by looking at a
measure of LV relaxation, such as any of the following values:
[0018] dP/dt min of LV pressure (LVP) drop in early diastole;
[0019] tau (time constant of LV isovolumetric relaxation in
diastole); [0020] arterial blood pressure (ABP) dP/dt min in early
diastole; or [0021] ABP tau (time constant of ABP isovolumetric
relaxation in diastole); or [0022] mitral valve deceleration time
or mitral valve velocity time interval, determined using Doppler
echocardiography. [0023] The end diastolic pressure volume
relationship (EDPVR)
[0024] The impact of therapy on LVC is assessed by looking at a
measure of LV contractility, such as: [0025] dP/dt max of LV
pressure rise in early systole; [0026] the value of LV stroke
volume with a fixed pre-load (i.e. left ventricular end diastolic
pressure) [0027] the value of stroke volume with a fixed afterload
(i.e. systemic vascular resistance) [0028] the end systolic
pressure volume relationship (ESPVR)
[0029] The embodiments below describe neuromodulation systems for
enhancing LVR, or LVR and LVC, alone or in combination with other
therapies such as mechanical hemodynamic support or pharmaceutical
interventions.
First Embodiment: LV Relaxation Enhancement System
[0030] In a first embodiment, neuromodulation is used to deliver a
therapy that enhances LVR. The neuromodulation may be carried out
using one or more therapy elements positioned in intravascular
sites, such as in venous blood vessels superior to the heart, with
the therapy elements used to neuromodulate extravascular nerve
fibers to achieve LVR enhancement. Suitable sites for the therapy
elements include those described in U.S. patent application Ser.
Nos. 14/642,699 and 14/801,560 or U.S. Pat. No. 9,067,071, such as
the superior vena cava, left brachiocephalic vein, lower internal
jugular vein, right brachiocephalic vein, azygos vein or azygos
arch. Placement of therapy elements such as electrodes against the
posterior portions of these blood vessels can be particularly
advantageous for allowing capture of nerve fibers for LVR
enhancement.
[0031] In general, an exemplary neuromodulation system 100 for
enhancing LVR in accordance with the first embodiment may include,
as shown in FIG. 1, one or more parasympathetic therapy elements 10
and a stimulator 12. The parasympathetic therapy element 10 is
adapted to be positioned where it can (when energized) capture a
parasympathetic nerve fiber, such as a cardiac branch of the vagus
nerve or the main vagus nerve. The stimulator 12 is operable to
energize the parasympathetic therapy element to deliver
parasympathetic therapy to the parasympathetic nerve fiber so as to
increase LV relaxation in diastole.
[0032] Preferred embodiments have therapy elements configured to be
positioned within a blood vessel and energizeable to capture target
nerve fibers outside the vessel, but alternative therapy elements
include those configured to be positioned in locations other than
blood vessels. Examples include electrodes that are positioned in
direct contact with the nerve fibers or elsewhere in the
extravascular space.
[0033] The therapy elements may be electrodes or electrode arrays,
although it is contemplated that other forms of therapeutic
elements (including, but not limited to, ultrasound, thermal, or
optical elements) may instead be used. The therapy elements are
preferably positioned on a flexible percutaneous catheter that
includes an expandable support 14 for biasing the therapy elements
(electrodes) into contact with the interior surface of the blood
vessel. This optimizes conduction of neuromodulation energy from
the electrodes to the target nerve fibers outside the vasculature.
Expandable "basket" type catheter arrays may be used, as well as
various other electrode and catheter designs known in the art. Some
examples of catheters and electrode configurations that may be used
are described in the applications referenced in the Background.
Although FIG. 1 shows electrodes on only one strut, electrodes may
be positioned on one or more of the struts in the basket
configuration shown in FIG. 1.
[0034] The stimulator 100 may be an external device that is
positioned outside the patient's body, although in modified
embodiments an implantable stimulator may instead be used, in which
case each the percutaneous catheter may be replaced with leads.
[0035] The system may use a control system that can control the
therapy to achieve a desired effect with regard to LV relaxation.
For example, the user might be prompted to input or select from a
menu any of the following target parameters: [0036] the desired
range for the measure of LVR (which measure may be, for example,
the dP/dt min of LVP drop in early diastole, or the dP/dt min of
arterial blood pressure drop in early diastole, or tau, the time
constant for LV isovolumetric relaxation in diastole [0037] the
desired percentage increase (or range of percentage increase) in
the value of the selected measure of LVR relative to the value
prior to initiation of the neuromodulation therapy (e.g. where the
percentage increase is determined by comparing the
pre-neuromodulation dP/dt min of LVP pressure drop in early
diastole, with the dP/dt min of LVP pressure drop in early diastole
during or after the neuromodulation) [0038] the desired percentage
increase (or range of percentage increase) in the value of the rate
of ABP relaxation relative to the rate prior to initiation of the
neuromodulation therapy (like the above example but using the dP/dt
min of ABP drop in early diastole as measured prior to and then
during/after the neuromodulation) [0039] the desired percentage
decrease (or range of percentage decrease) in the value of the time
constant tau relative to the value of the time constant tau prior
to initiation of the neuromodulation therapy [0040] the desired
range for the ratio of the measure of LVC increase (as measured for
example by the dP/dt max of left ventricle pressure rise in early
systole) to the measure of LVR increase
[0041] The first four inputs pertain to enhancement of LVR. The
fifth pertains to enhancement of LVC. In some uses of the first
embodiment, enhancement of LVC may come from the use of inotropes
(discussed at the end of this section). The type measure for LVR
and LVC may be selectable by the user or the system may be
pre-configured to rely on certain measures of LVR and LVC.
[0042] The stimulator 100 may include a control system that
includes a Parasympathetic Control function, a Parasympathetic
Stimulation Output function, an Electrode Switching function.
[0043] The system may include or be used in conjunction with
patient and system feedback elements that sense, measure, or derive
various patient and system conditions and provide this information
to the Parasympathetic Control function. These feedback elements
may include sensors on the therapy catheter (or on separately
placed catheters) such as pressure sensors, flow sensors, thermal
sensors, PO2 sensors, mechanical interacting component, magnetic
components, as well as the therapeutic electrodes and additional
sensing electrodes. In addition, clinical sensors used directly on
the patient such as arterial pressure transducers, heart rate, ECG
electrodes, echocardiographic-based measurements and other
hemodynamic monitors can be utilized and connected to the external
stimulator. An Arterial Blood Pressure Sensor function in the
neuromodulation system's control system can be connected to a
standard arterial line pressure transducer and used to determine BP
and HR. Therapy catheter electrodes or surface ECG electrodes can
be connected to an ECG analyzer function of the control system that
would derive ECG parameters such as HR, P and R-wave timing,
refractory timing, and presence of cardiac arrhythmias, such as
tachycardia or fibrillation, can be utilized as inputs to the
system or for safety monitoring. Other hemodynamic sensors can be
used to sense or derive hemodynamic parameters (such as flow rates,
cardiac output, temperature, PO2 etc. described above) can be used
both for closed-loop control, as well as safety monitoring. A
central venous pressure sensor can provide feedback both on the
therapy catheter's position, as well as hemodynamic feedback that
can be utilized as part of the closed-loop control system.
[0044] The Parasympathetic Output functions generate the
therapeutic stimuli which, in the exemplary embodiment, are
electrical pulses. This output function can generate therapeutic
levels (for example, electrical currents, voltages, and pulse
widths), timing (frequencies, triggers, or gates to other timing
such as ECG events, polarity (as applicable) and other parameters
(e.g. effective electrode surface area and/or spacing as described
in U.S. Ser. No. 15/098,237) to achieve the target parameters. The
Electrode Switching function provides the means to connect the
Parasympathetic Output function to the desired electrodes on the
catheter support so as to capture the target parasympathetic
cardiac nerves fibers. The selection of which connection or
connections to make is determined during the response mapping
procedure, which is like that described in U.S. Pat. No.
9,067,071.
[0045] The Parasympathetic Control functions implements the
system's overall function based on user inputs and feedback from
patient sensed or derived hemodynamic parameters. The
Parasympathetic Control function directly governs the therapeutic
output from the Parasympathetic Output function by controlling the
therapeutic levels, timing, polarity, and other parameters. The
Control function is responsible for the closed-loop modulation of
LV relaxation as well as the response mapping function. In one
example, the Parasympathetic Control function implements closed
loop modulation utilizing the user-targeted parameters discussed
above, as well as the feedback from actual LV relaxation (as
measured for example by the rate dP/dt min of LV pressure drop in
early diastole) and, as applicable, LVC (measured for example by
the rate dP/dt max of left ventricle pressure rise in early
systole). Also, in other examples, HR, BP and additional sensed
and/or derived hemodynamic parameters (such as flow rates, cardiac
output, LVP, ABP, tau, and Doppler echocardiographic-based measures
etc. described above) can also be determined by the system and used
to control the therapy.
[0046] The control system elements or functions can be implemented
individually as or any combination of electronic circuitry,
computer subsystems, computer software, mechanical subsystems,
ultrasound subsystems, magnetic subsystems, electromagnetic
subsystems, optical subsystems, and a variety of sensors or
detectors including, but not limited to, electromechanical sensors,
electrochemical sensors, thermal sensors, and infrared sensors. In
each embodiment, the control system elements or functions
communicate with each other by direct physical means (electrically
wired connection, mechanical interaction) or other indirect means
(such as wireless RF, visible light, infrared, sound,
ultrasound).
[0047] In lieu of a control system to control the therapy, the user
can monitor the change in LV pressure while applying the
neuromodulation therapy and fine tune the stimulation parameters
described above to bring the LV relaxation rate to a desired
level.
[0048] The system may be used to neuromodulate or stimulate cardiac
parasympathetic nerve fibers for enhancing LV relaxation and to
optionally decrease or sustain the heart rate. Electrode placement
sites described in the prior patents and applications incorporated
herein (e.g. U.S. Pat. No. 9,067,071 and U.S. patent application
Ser. Nos. 14/642,699 and 14/801,560) may be used for the electrodes
used to target those nerve fibers from within the vasculature.
[0049] The first embodiment may be used as a patient therapy in
combination with administration with inotropes. As one example, the
parasympathetic neuromodulation is administered to reduce heart
rate and improve relaxation in combination with inotropes that
increase heart rate and inadequately increase relaxation. Here the
neuromodulation counteracts the negative effects of inotropes,
namely increased heart rate and the inadequate increase in
relaxation.
Second Embodiment: System for Enhancing LV Contractility and LV
Relaxation
[0050] In a second embodiment, neuromodulation is used to deliver a
therapy that enhances both LVC and LVR to a similar degree. The
neuromodulation may be carried out using one or more therapy
elements positioned in intravascular sites, such as in venous blood
vessels superior to the heart, with the therapy elements used to
neuromodulate extravascular nerve fibers to achieve LVR and LVC
enhancement. Suitable sites for the therapy elements include those
described in described in U.S. patent application Ser. Nos.
14/642,699 and 14/801,560 or U.S. Pat. No. 9,067,071, such as the
superior vena cava, left brachiocephalic vein, lower internal
jugular vein, right brachiocephalic vein, azygos vein or azygos
arch. Placement of therapy elements such as electrodes against the
posterior portions of these blood vessels can be particularly
advantageous for allowing capture of nerve fibers for LVR and LVC
enhancement.
[0051] An example of a system in accordance with the second
embodiment is a system having one or more sympathetic therapy
elements in combination with the parasympathetic therapy element
and the stimulator described as the first embodiment. In the second
embodiment the sympathetic therapy element is adapted to be
positioned where it can, when energized, capture a cardiac
sympathetic nerve fiber. The stimulator is operable to energize the
sympathetic therapy element to deliver energy to the sympathetic
cardiac nerve fiber to increase LVC, leading to increased cardiac
output (CO). As discussed in the '699 and '560 applications
referenced above, neuromodulation systems of the type described in
the Background section may be used to carry out a treatment to
increase LV contractility for increased CO. Neuromodulation therapy
using therapy elements positioned to capture cardiac branches of
the vagus nerve and cardiac sympathetic nerve fibers may be
employed to deliver a therapy having the simultaneous effect of
both increasing LV contractility in systole and increasing LV
relaxation in diastole.
[0052] The sympathetic therapy elements may be on a common support
with the parasympathetic therapy elements. For example, referring
to FIG. 1, both the sympathetic and parasympathetic therapy
elements may be on the support 14. Other configurations will have
the sympathetic and parasympathetic therapy elements on different
supports as shown in FIG. 2, which may optionally be on telescoping
catheter shafts.
[0053] Measures that may be used for LVC and LVR include those
described elsewhere in this application. For example, one measure
of LVC that may be used in evaluating the change in LVC is the
value dP/dt max of LVP rise in early systole taken prior to
neuromodulation and after initiation of neuromodulation. One
measure of LVR that may be used in evaluating the change in LVR is
the rate dP/dt min of LVP drop in early diastole taken prior to
neuromodulation and after initiation of neuromodulation.
[0054] The system may use a control system used to control the
therapy to enhance both LVC and LVR. In general, it is desirable
for LVR and LVC to be enhanced to a similar degree so that one is
not be largely out of proportion to the other. The user may thus
give input to the system selecting the ratio of LVC enhancement to
LVR enhancement (each value of enhancement determined as described
above). In a study conducted by the inventors of the present
invention, the parasympathetic and sympathetic neuromodulation
therapy performed using intravascular electrodes simultaneously
increased a patient's LVC by +17% and LVR by +25%, for a ratio of
LVC enhancement to LVR enhancement of 17/25=0.68. In contrast,
administration of the inotrope Dobutamine, in the same patient in
the absence of neuromodulation, increased LVC by 151% and LVR 54%,
for a ratio of 2.8.
[0055] In general, ratios of LVC enhancement to LVR enhancement of
0.5-1.5 are desirable, with ratios of 0.8-1.2 more preferred and
ratios of approximately 1 being most preferred. The magnitude of
the desired ratio of LVC enhancement to LVR enhancement may depend
on the clinical context. For example: [0056] High LVC/LVR
augmentation ratios (>=1.5) are useful in hemodynamic scenarios
where cardiac output is low and more forward flow out of the left
ventricle is preferred over pulmonary congestion relief. These may
include Heart Failure with reduced ejection fraction (HFrEF) where
CO is low, end organ perfusion is compromised, and there is a want
for increased blood pressure. These ratios may also be useful when
weaning from mechanical circulatory support (e.g. a blood pump)
(MCS) or inotrope support. [0057] LVC/LVR augmentation ratios close
to 1 (0.8-1.2) are useful in hemodynamic scenarios where cardiac
output is low, pulmonary congestion is high and both forward flow
and congestion relief are preferred. Many HF patients would benefit
from this. [0058] Low LVC/LVR augmentation ratios (<0.5) are
useful in hemodynamic scenarios where cardiac output is preserved
and perfusion is adequate but pulmonary congestion relief is
desired. These may include Heart failure with preserved ejection
fraction (HFpEF) or in combination with other forward flow
augmentation therapies such as an inotrope or MCS (discussed below
in the section "Combination Therapies").
[0059] The control system of the second embodiment is similar to
that of the first, and so the discussion of the control system
above is incorporated by reference into the present discussion. The
control system of the second embodiment additionally includes a
Sympathetic Control function which generates the sympathetic
therapeutic stimuli, and a Sympathetic Stimulation Output function
that works with the Parasympathetic Control function to implement
the system's overall function based on the user inputs (target
LVC/LVR enhancement ratio) and feedback from patient sensed or
hemodynamic parameters. The Parasympathetic and Sympathetic Control
functions directly govern the therapeutic output from
Parasympathetic and Sympathetic Output functions, respectively, by
controlling the therapeutic levels, timing, polarity etc. The
Control functions are responsible for the closed-loop modulation of
the LVC/LVR enhancement ratio utilizing the user-targeted LVC/LVR
enhancement ratio, as well as the feedback from actual LVC
(measured for example by the rate dP/dt max of left ventricle
pressure rise in early systole) and LVR (as measured for example by
the rate dP/dt min of LV pressure drop in early diastole).
[0060] In lieu of a control system to control the therapy, the user
can monitor the change in LV pressure during systole and diastole
while applying the neuromodulation therapy and fine tune the
stimulation parameters described above to bring the LVC/LVR
enhancement ratio into the desired range.
[0061] The system may be used to deliver therapy of the type
described in incorporated U.S. Pat. No. 9,067,071 to target
sympathetic and parasympathetic nerve fibers to achieve both
increased LVC and increased LVR. In particular, the therapy is
directed to stimulate or neuromodulate cardiac sympathetic nerves
for enhancing LV contractility, and to neuromodulate or stimulate
cardiac parasympathetic nerves for enhancing LV relaxation.
Electrode placement sites described in the prior patents and
applications incorporated herein (e.g. U.S. Pat. No. 9,067,071 and
U.S. patent application Ser. Nos. 14/642,699 and 14/801,560) may be
used for the electrodes used to target those nerve fibers from
within the vasculature. Thus, electrodes may be positioned in a
common blood vessel (e.g. left brachiocephalic vein), and
neuromodulation therapy delivered to enhance both LV relaxation and
LV contractility to similar order of magnitude thus achieving a
sympathovagal balance that favors similar increases in
contractility and relaxation. Alternatively, electrodes used to
capture cardiac sympathetic nerves and electrodes used to capture
cardiac parasympathetic nerves may deliver therapy from within
separate blood vessels. The electrodes used for the sympathetic and
parasympathetic nerve capture may be energized simultaneously or at
different times (e.g. alternated).
[0062] Combination Therapies
[0063] Examples of therapeutic interventions using the disclosed
systems in combination with other therapies will next be
described.
[0064] Combination of LVR Enhancement and Mechanical Circulatory
Support In a first type of combination therapy, neuromodulation of
parasympathetic nerve fibers may be used to enhance relaxation in
patients who are not undergoing neuromodulation of cardiac
sympathetic nerve fibers. For example, neuromodulation using
intravascular therapy elements to enhance relaxation using the
system of FIG. 1 may be used in combination with other therapies
directed towards increasing CO. Exemplary therapies that may be
combined with the disclosed method for enhancing relaxation
including use of hemodynamic support devices that increase the
volume of blood moving through the heart in order to increase
cardiac output CO. Such devices include percutaneous ventricular
assist devices (PVAD), ventricular assist devices (VAD) or
intra-aortic balloon pumps (IABP) for increasing CO. See for
example FIG. 3, which shows neuromodulation therapy element 14 in
the left brachiocephalic vein for use in capturing a
parasympathetic nerve fiber to enhance LV relaxation, together with
a PVAD 18. Where mechanical circulatory support devices are
described herein, sensors used to determine the measures of LVR and
LVC may optionally be positioned on the support devices themselves.
For example, a sensor on a PVAD device disposed within the heart as
shown in FIG. 3 may include a sensor positioned within the left
ventricle. This sensor can be used to determine left ventricular
pressure to aid in the determination of dP/dt min in diastole and
dP/dt max in systole as described above.
[0065] Combination of LVR and HR Decrease and Mechanical
Circulatory Support In a modification of the prior example,
neuromodulation of parasympathetic nerve fibers is used to both
decrease heart rate and improve relaxation in patients who are not
undergoing neuromodulation of cardiac sympathetic nerve fibers. For
example, neuromodulation to reduce heart rate and improve
relaxation may be used in combination with other therapies directed
towards unloading and resting the heart to more fully unload or
rest the heart. Such devices include percutaneous ventricular
assist devices (PVAD), ventricular assist devices (VAD) or
intra-aortic balloon pumps (IABP) for more fully unloading and
resting the heart. See for example FIG. 3, which shows
neuromodulation therapy element 14 in the left brachiocephalic vein
for use in capturing a parasympathetic nerve fiber to enhance LV
relaxation and lowering the heart rate, together with a PVAD
18.
[0066] A blood pump (i.e. PVAD or IABP) mechanically rests the
heart, but it does not alter heart rate which is the other main
determinant of oxygen consumption. By combining a therapy that
mechanically unloads the heart with therapy that reduces heart rate
and improved relaxation ("neuromechanically unloading") the heart
can be rested and unloaded more fully than can be achieved using a
catheter-mounted pump alone. Small percutaneously placed pumps such
as PVAD or IABP pumps achieve a relatively small amount of
unloading or resting compared with larger surgically placed pumps.
Combining the use of catheter-mounted pumps with the disclosed
neuromodulation can result in neuromechanical unloading sufficient
to allow a small catheter pump to be used when a large surgical
pump would otherwise have been needed to more fully rest and unload
the heart.
[0067] Other Combinations
[0068] In general, neuromodulation systems of the type referred to
in the patents and applications incorporated here may be used in
combination with other therapies intended for cardiac effect. In
addition to those described in the preceding paragraph, other
examples include: [0069] parasympathetic neuromodulation to enhance
parasympathetic tone, in combination with catheter-mounted pumps
for increasing CO [0070] sympathetic with or without
parasympathetic neuromodulation to enhance cardiac output, in
combination with beta blockers in order to further lower heart rate
and further improve myocardial energetics. [0071] parasympathetic
neuromodulation to reduce arrhythmias in combination with inotropes
that increase arrhythmias (improving or counteracting the negative
effects of inotropes, which are increased arrhythmias, increased
heart rate and the inadequate increase in relaxation).
[0072] All patents and patent applications referred to herein,
including for purposes of priority, are incorporated herein by
references for all purposes.
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