U.S. patent application number 10/882645 was filed with the patent office on 2006-01-05 for method and system for the prediction of cardiac arrhythmias.
Invention is credited to Peng-Sheng Chen.
Application Number | 20060004413 10/882645 |
Document ID | / |
Family ID | 35515025 |
Filed Date | 2006-01-05 |
United States Patent
Application |
20060004413 |
Kind Code |
A1 |
Chen; Peng-Sheng |
January 5, 2006 |
Method and system for the prediction of cardiac arrhythmias
Abstract
Methods and systems are provided for determining an increased
likelihood of the occurrence of a cardiac arrhythmia in a patient.
The methods and systems comprise monitoring the sympathetic neural
discharges of a patient from the left stellate ganglion, the
thoracic ganglia, or both, and detecting increases in the
sympathetic neural discharges. The methods and systems may further
comprise delivering anti-arrhythmic therapy to the patient in
response to a detected increase in the sympathetic neural
discharge, such as delivering one or more pharmacological agents;
stimulating myocardial hyperinnervation in the sinus node and right
ventricle of the heart of the patient; and applying cardiac pacing,
cardioversion or defibrillation shocks. Pharmacologic agents which
may be used in connection with the delivery of anti-arrhythmic
therapy include those which are known to exert anti-arrhythmic
effect and anti-convulsant agents, such as phenyloin,
carbamazepine, valproate, and phenobarbitone.
Inventors: |
Chen; Peng-Sheng; (La
Canada, CA) |
Correspondence
Address: |
JONES DAY
555 SOUTH FLOWER STREET FIFTIETH FLOOR
LOS ANGELES
CA
90071
US
|
Family ID: |
35515025 |
Appl. No.: |
10/882645 |
Filed: |
June 30, 2004 |
Current U.S.
Class: |
607/3 ; 600/515;
607/4 |
Current CPC
Class: |
A61N 1/39622 20170801;
A61N 1/37258 20130101; A61N 1/36585 20130101; A61B 5/24 20210101;
A61N 1/3962 20130101 |
Class at
Publication: |
607/003 ;
607/004; 600/515 |
International
Class: |
A61N 1/362 20060101
A61N001/362; A61B 5/0402 20060101 A61B005/0402 |
Goverment Interests
GOVERNMENT INTEREST
[0001] This invention was made in part with government support
under Grant R01 HL66389, awarded by the National Institutes of
Health. The government has certain rights to this invention.
Claims
1. A method for determining an increased likelihood of the
occurrence of a cardiac arrhythmia in a patient, the method
comprising: monitoring the sympathetic neural discharges of the
patient from the left stellate ganglion or the thoracic ganglia;
and detecting an increase in the sympathetic neural discharges.
2. The method of claim 1 wherein the step of monitoring the
sympathetic neural discharges comprises implanting an electrode on
the left stellate ganglion in the patient, wherein the electrode
senses the electrical activity of the left stellate ganglion.
3. The method of claim 2 wherein the increase in the sympathetic
neural discharges is determined by an increase in the amplitude or
frequency of the sensed electrical activity beyond defined
values.
4. The method of claim 2 wherein the increase in the sympathetic
neural discharges is determined by comparing the sensed electrical
activity and the normal electrical activity of the patient.
5. The method of claim 1 further comprising producing an output
signal in response to a detected increase in the sympathetic neural
discharges.
6. The method of claim 5 wherein the output signal is an audible
sound.
7. The method of claim 5 wherein the output signal is a command
signal.
8. The method of claim 7 further comprising the step of delivering
anti-arrhythmic therapy in response to the command signal, the
anti-arrhythmic therapy selected from any one or more of the group
consisting of: delivering one or more pharmacological agents;
stimulating myocardial hyperinnervation in the sinus node and right
ventricle of the heart of the patient; and applying cardiac pacing,
cardioversion or defibrillation shocks.
9. The method of claim 8 wherein the one or more pharmacological
agents is an anti-convulsant agent.
10. The method of claim 9 wherein the anti-convulsant agent is
selected from the group consisting of: phenyloin, carbamazepine,
valproate, and phenobarbitone.
11. A system for determining an increased likelihood of the
occurrence of a cardiac arrhythmia in a patient, the system
comprising: a sensor for acquiring data relating to the sympathetic
neural discharges of a patient from the left stellate ganglion or
the thoracic ganglia; a processor for receiving the data acquired
from the sensor, wherein the processor analyzes the data and
determines if there is an increase in the sympathetic neural
discharge; and an output unit for generating an output signal in
response to a determined increase in the sympathetic neural
discharge.
12. The system of claim 11 wherein the sensor is an electrode that
is implanted on the left stellate ganglion of the patient and
wherein the electrode senses the electrical activity of the left
stellate ganglion.
13. The system of claim 12 wherein the processor determines that an
increase in the sympathetic neural discharge has occurred by an
increase in the amplitude or frequency of the sensed electrical
activity beyond defined values.
14. The system of claim 12 wherein the processor determines that an
increase in the sympathetic neural discharge has occurred by
comparing the sensed electrical activity and the normal electrical
activity of the left stellate ganglion.
15. The system of claim 11 wherein the output signal is an audible
sound.
16. The system of claim 11 wherein the output signal is a command
signal.
17. The system of claim 16 further comprising an anti-arrhythmia
delivery module for delivering anti-arrhythmic therapy in response
to the command signal, the anti-arrhythmic therapy selected from
any one or more of the group consisting of: delivering one or more
pharmacological agents; stimulating myocardial hyperinnervation in
the sinus node and right ventricle of the heart of the patient; and
applying cardiac pacing, and cardioversion or defibrillation
shocks.
18. The system of claim 17 wherein the one or more pharmacological
agents is an anti-convulsant agent.
19. The system of claim 18 wherein the anti-convulsant agent is
selected from the group consisting of: phenyloin, carbamazepine,
valproate, and phenobarbitone.
20. A cardiac arrhythmia prediction system comprising: means for
monitoring the sympathetic neural discharges of a patient from the
left stellate ganglion or the thoracic ganglia; means for
determining an increase in the sympathetic neural discharge; and
means for producing an output signal in response to a determined
increase in the sympathetic neural discharge.
21. The system of claim 20 wherein the means for monitoring
sympathetic neural discharges comprises sensing the electrical
activity of the left stellate ganglion.
22. The system of claim 21 wherein the means for determining an
increase in the sympathetic neural discharges comprises comparing
the sensed electrical activity of the left stellate ganglion and
the normal electrical activity of the left stellate ganglion.
23. The system of claim 21 wherein the increase in the sympathetic
neural discharge is determined by detecting an increase in the
amplitude or frequency of the sensed electrical activity beyond
defined values.
24. The system of claim 20 wherein the output signal is an audible
sound.
25. The system of claim 20 wherein the output signal is a command
signal.
26. The system of claim 25 further comprising means for delivering
anti-arrhythmic therapy in response to the command signal, the
anti-arrhythmic therapy selected from any one or more of the group
consisting of: delivering one or more pharmacological agents;
stimulating myocardial hyperinnervation in the sinus node and right
ventricle of the heart of the patient; and applying cardiac pacing,
cardioversion or defibrillation shocks.
27. The system of claim 26 wherein the one or more pharmacological
agents is an anti-convulsant agent.
28. The system of claim 27 wherein the anti-convulsant agent is
selected from the group consisting of: phenyloin, carbamazepine,
valproate, and phenobarbitone.
Description
FIELD OF THE INVENTION
[0002] The invention generally relates to a methods and systems for
the prediction of cardiac arrhythmias of the type that can result
in sudden cardiac death.
BACKGROUND OF THE INVENTION
[0003] Sudden cardiac death (SCD) is a major public health problem
that accounts for more than half of all cardiovascular deaths. SCD
takes the lives of approximately 450,000 people in the United
States each year, more than lung cancer, breast cancer, stroke, and
AIDS combined. Most cases of SCD are due to ventricular arrhythmias
and there is often an element of underlying ischemic heart disease.
Ventricular tachycardia (VT) and ventricular fibrillation (VF) are
different types of ventricular arrhythmias. VT is an abnormally
fast ventricular heart rhythm which is, by itself, typically not
fatal. VF is a chaotic ventricular heart rhythm which produces
little or no net blood flow from the heart, such that there is
little or not net blood flow to the brain and other organs. VF, if
not terminated, results in death. Patient groups most at risk of
ventricular arrhythmias leading to SCD include those with an acute
or chronic myocardial infarction. Accordingly, deaths from SCDs may
be lowered by preventing the specific heart rhythm disturbances
(ventricular arrhythmias) associated with it.
[0004] Different treatment options exist for SCD. The most common
treatment includes implantable cardiac defibrillators (ICD) and
drug therapy. ICDs have been available in the United States since
the mid-1980s and have a well-documented success rate in decreasing
the rate of death of patients at high risk for SCD. A major trial
conducted by the U.S. National Institutes of Health (the
Anti-arrhythmics Versus Implantable Defibrillator or AVID trial)
compared therapy with the best available anti-arrhythmic drugs with
ICD therapy for patients with spontaneous ventricular tachycardia
or ventricular fibrillation. The overall death rate in the ICD
patient group was found to be 39% lower than the death rate of
patients treated with anti-arrhythmic drugs after only 18 months
mean follow-up.
[0005] An ICD has two basic components: the ICD generator and the
lead system for pacing and shock delivery to which it is connected.
An ICD generator contains sensing circuits, memory storage,
capacitors, voltage enhancers, a telemetry module, and a control
microprocessor. Advances in miniaturization and complexity in all
of these components have permitted a tremendous reduction in size
of the generator itself despite increased functionality, such as
added programming options, anti-tachycardia pacing, single- and
dual-chamber rate-responsive pacing for bradycardia, biphasic
defibrillation waveforms, enhanced arrhythmia detection features,
and innovations in lead systems.
[0006] Current ICD technology, however, provides for the detection
and recognition of an arrhythmia based on the sensed heart rate
once it has already started. This leaves very little time to
protect the individual from death resulting from SCD. Although
there have been several attempts at developing new technology for
predicting the onset of a cardiac arrhythmia, many of these methods
and systems appear to rely primarily on events occurring within the
heart, such as sensed heart rate and electrocardiography (ECG). For
example, U.S. Pat. No. 6,308,094 discloses a method and device for
predicting cardiac arrhythmias by gathering and processing
electrocardiographic data, such as intervals between heart beats
(RR-series) or other heart signals, to predict the occurrence of a
cardiac arrhythmia. U.S. Pat. No. 6,516,219 discloses a method and
apparatus for forecasting arrhythmia based on real-time intact
intracardiac electrograms.
SUMMARY OF INVENTION
[0007] Methods and systems are provided for determining an
increased likelihood of the occurrence of a cardiac arrhythmia in a
patient. The methods and systems disclosed herein generally
comprise monitoring the sympathetic neural discharges of a patient
from the left stellate ganglion, the thoracic ganglia, and/or any
other sympathetic nerve identified as having an influence over the
heart rate of a patient. Other sympathetic nerves suitable for use
in connection with the prediction of cardiac arrhythmias may be
determined by analyzing simultaneous recordings of the neural
discharges and the heart rate, as disclosed in the examples
contained herein.
[0008] In one embodiment, the sympathetic neural discharges may be
monitored by a sensor or electrode that is implanted in the left
stellate ganglion of the patient. The electrode may directly sense
electrical activity of the left stellate ganglion and transmit this
data to a processor. The processor may then analyze the data
acquired from the electrode and, upon the determination that the
sympathetic neural discharges have increased beyond a defined
value, produce an output signal indicating the likely onset of an
arrhythmia.
[0009] In another embodiment, an increase in the sympathetic neural
discharge in the patient may be determined by comparing the
parameters for the sensed and normal sympathetic neural discharges
in the patient. In yet another embodiment, an increase in the
sympathetic neural discharge may be determined by detecting
increases in the amplitude and frequency of the sensed sympathetic
neural discharge beyond defined values, such as the sensed
electrical activity of the left stellate ganglion and/or the
thoracic ganglia.
[0010] The defined value represents a value above or beyond which
is indicative of an impending arrhythmic condition of the heart and
may be determined with reference to the normal baseline sympathetic
neural discharge. For example, a two-fold or greater increase in
the amplitude of the sensed sympathetic neural discharge from the
normal baseline amplitude of sympathetic neural discharge may be
used as a suitable defined value. A second defined value reflecting
the frequency of the sympathetic neural discharge above or beyond
which is indicative of an impeding arrhythmic condition of the
heart may similarly be provided. The defined values may be a preset
or user-defined programmable value.
[0011] An output signal may be generated in response to a
determined increase in the sympathetic neural discharge. In one
embodiment, the output signal may be an audible sound, a
radio-transmitted signal, or any other type of signal that would
alert the patient or physician to the possibility of an impending
arrhythmia. In another embodiment, the output signal may be an
analog or digital command signal directing the delivery of
anti-arrhythmic therapy.
[0012] Anti-arrhythmic therapy suitable for use in connection with
the methods and systems are known in the art and may include any
one or a combination of the following: delivering one or more
pharmacological agents; stimulating myocardial hyperinnervation in
the sinus node and right ventricle of the heart of the patient; and
applying cardiac pacing, cardioversion or defibrillation shocks, to
name a few.
[0013] Pharmacologic agents which may be used in connection with
the delivery of anti-arrhythmic therapy include those which are
known to exert anti-arrhythmic effect, such as sodium channel
blockers, .beta.-blockers, potassium channel blockers, such as
amiodarone and solatol, and calcium channel blockers, such as
verapamil and diltiazem. Other suitable pharmacologic agents
include anti-convulsant agents, including but not limited to
phenyloin, carbamazepine, valproate, and phenobarbitone, to name a
few.
[0014] The methods and systems described herein may be incorporated
into any number of implantable medical devices including, but not
limited to, implantable cardiac rhythm management systems such as
pacemakers, cardioverters, defibrillators, and the like. The
present methods and systems may also be incorporated in external
unimplanted devices of the same sort, as well as in external
monitors, programmers and recorders.
[0015] The above and other objects, features and advantages will
become apparent to those skilled in the art from the following
description of the preferred embodiments.
BRIEF DESCRIPTION OF THE DRAWINGS
[0016] FIG. 1 is a perspective view of a nanoelectrode array.
[0017] FIG. 2 is a magnified view of an individual nanoelectrode
tip.
[0018] FIG. 3 depicts simultaneous recordings of rabbit renal
sympathetic neural discharges by wire electrode and nanoelectrode
and electrocardiograph (ECG) recordings in the rabbit subject over
a time span of 2 seconds. FIG. 3A shows the bursts of renal
sympathetic neural discharges and signal and FIG. 3B shows
suppression of renal sympathetic neural discharges by intravenous
bolus dose of xylazine and ketamine.
[0019] FIG. 4 depicts simultaneous ECG and sympathetic neural
discharge recordings of an ambulatory canine subject two weeks
after implantation of the nanoelectrode to the left stellate
ganglion. A burst of sympathetic neural discharges preceded the
onset of accelerated atrial rate by approximately 0.2 seconds. The
arrows indicate cross-talk from the surface ECG, which shared the
same ground as the nanoelectrode.
[0020] FIG. 5 depicts three separate simultaneous recordings of ECG
and sympathetic neural discharges recorded from a nanoelectrode
implanted at the left stellate ganglion of a canine subject over a
time span of 28 seconds. The onset of increased sympathetic neural
discharges is designated by (a) through (h) and is followed by
increased heart rate.
[0021] FIG. 6 depicts three separate simultaneous recordings of
heart rate and sympathetic neural discharges over a one hour
period.
[0022] FIG. 7 shows the simultaneous 60 second recordings of (A)
ECG, (B) the heart rate in beats per second, (C) the integrated
sympathetic neural discharges, (D) the raw nerve signals and (E)
the sonogram (frequency in the Y-axis and power in shades of
grey).
[0023] FIG. 8 shows the cross-correlation between sympathetic
neural discharges and heart rate over a one hour period.
[0024] FIG. 9 shows the continuous tracings of heart rate and
sympathetic neural discharges over a 24 hour period for a canine
subject. Phenyloin was injected at 9:45 a.m. and the tracings
following that time show the effects of phenyloin injection on the
heart rate and the sympathetic neural discharges of the canine
subject.
DESCRIPTION OF THE PREFERRED EMBODIMENTS
[0025] Methods and systems are disclosed for determining an
increased likelihood of the occurrence of a cardiac arrhythmia in a
patient. The methods and systems disclosed herein comprise
monitoring the sympathetic neural discharges of a patient;
determining an increase in the sympathetic neural discharges in the
patient beyond defined values; and producing an output signal upon
a determined increase in the sympathetic neural discharges in the
patient. In one embodiment, the output signal may be an audible
sound, a radio-transmitted signal, or any other type of signal that
would alert the patient or physician to the possibility of an
impending arrhythmia. In another embodiment, the output signal may
be a command signal directing the delivery of anti-arrhythmic
therapy.
[0026] The sympathetic neural discharges of a patient may be
monitored by a sensor or electrode that is implanted in the left
stellate ganglion, the thoracic ganglia, and/or any other
sympathetic nerve for which the rate of neural discharge influences
the heart rate in a patient. The sensor or electrode may directly
sense electrical activity of the left stellate ganglion, the
thoracic ganglia or other suitable sympathetic nerve of the patient
and transmit this data to a processor for immediate processing or
to a memory for storage.
[0027] In a preferred embodiment, sympathetic nerve recordings
obtained from the left stellate ganglion, the thoracic ganglia, or
both. Increased neural discharges from the left stellate ganglion
has been observed to precede the onset of cardiac arrhythmias.
Consistent with this observation, partial or complete ablation of
the left stellate ganglion, together with the thoracic ganglia T2
to T4, was demonstrated to be effective in reducing the incidence
of SCD in patients after a first myocardial infarction. Schwartz P
J, et al. Left cardiac sympathetic denervation in the management of
high-risk patients affected by the long-QT syndrome. Circulation.
2004; 109:1926-1833. These findings suggest that the left stellate
ganglion and the thoracic ganglia are important for ventricular
arrhythmogenesis and SCD among high risk patients.
[0028] Indeed, it has previously been found that simulation of the
left stellate ganglion has been found to result in a significant
increase in incidence of ventricular arrhythmias and SCD in canine
subjects. A method for inducing ventricular arrhythmias in an
animal model is disclosed in U.S. Pat. No. 6,351,668, which is
incorporated herein in its entirety. Such an animal model is useful
in collecting data pertinent to predictors of heart arrhythmias and
for testing techniques intended to predict the onset of heart
arrhythmias, the disclosures for which are provided in U.S. Pat.
Nos. 6,353,757 and 6,398,800, which are incorporated herein in
their entirety.
[0029] Previous studies have demonstrated heterogeneous sympathetic
hyperinnervation in the left ventricle in canine models for sudden
cardiac death. Cao J-M, Chen L S, KenKnight B H et al. Nerve
sprouting and sudden cardiac death. Circ. Res. 2000; 86:816-21. In
contrast, stimulation of the right stellate ganglion has been shown
to be anti-arrhythmic. The electrical heterogeneity does not have
significant clinical consequences in normal hearts. However, when
the ion channels in the heart are altered by either genetic
mutations or electrical remodeling after a myocardial infarction
and atrioventricular block, this heterogeneity may be amplified and
cause arrhythmia.
[0030] Accordingly, different sympathetic nerves may exert very
different effects on the heart rate. For example, increased neural
discharges from the left stellate ganglion exert an anti-arrhythmic
effect, whereas increased neural discharges from the right stellate
ganglion is believed to be anti-arrhythmic.
[0031] In one embodiment, the sensor or electrode may be a
nanoelectrode array. As shown in FIG. 1, the nanoelectrode array
(10) comprising a plurality of nanoelectrodes (12). The signals
from the sympathetic neural discharges are received by each of the
nanoelectrodes, combined before digitization and transmitted by a
single electrical wire (14). In a preferred embodiment, each
individual nanoelectrode has a sharp tip of approximately 10 to 50
nm in diameter and is configured to penetrate the epineurium or the
connective tissue sheath that surrounds the sympathetic nerve
bundle without damaging the nerves and surrounding blood vessels.
Akingba A G, Wang D, Chen P-S, Neves H, Montemagno C: Application
of nanoelectrodes in recording biopotentials. Nanotechnology, 2003.
IEEE-NANO 2003; 2:870-874
[0032] FIG. 2 depicts an individual nanoelectrode from the
nanoelectrode array having a diameter of approximately 50 nm. The
tips of the nanoelectrode are placed directly on the left stellate
ganglion to record the sympathetic neural discharges. A
nanoelectrode array provides the benefit of providing increased
surface contact with the nervous tissue and improved
signal-to-noise ratio.
[0033] Data acquired from the sensor or electrode may be filtered
to produce optimal signal-to-noise ratio. The amplitude of a signal
from a sympathetic nerve is typically -35 to +35 .mu.V and the
electrode noise is on average 10 .mu.V for an ideal electrode
resistance between 100 k.OMEGA. and 10 M.OMEGA. at 37.degree. C.
for a bandwidth of 1 kHz. Much of the noise during in vivo
recording results from the interfacial effects between the neuron,
epineurium, electrolyte and the electrode, which is dominated by
the charge transfer resistance and the coupling resistance.
Cross-talk from parasitic capacitances may also result in the
generation of unwanted signals when using conventional electrodes
to record sympathetic neural discharges.
[0034] Wide band pass filter (1 to 3000 Hz) allows recording of
sympathetic neural discharges but also allows for a significant
amount of noise generated by cardiac and respiratory related
movement artifacts. A greater high pass filter setting (30 to 100
Hz) removes some of the noise and achieves a more stable baseline
of the recorded sympathetic neural discharge signals.
[0035] The data acquired from the sensor or nanoelectrode may be
continuously monitored to detect increases in the sympathetic
neural discharges. In one embodiment, an increase in the
sympathetic neural discharges in the patient may be determined by
detecting an increase in the amplitude and frequency of the sensed
sympathetic neural discharges beyond defined values. In another
embodiment, an increase in the sympathetic neural discharges in the
patient may be determined by comparing the parameters for the
sensed sympathetic neural discharges in the patient with the
parameters defined for normal sympathetic neural discharges.
[0036] The defined value represents a value above and beyond which
is indicative of an impending arrhythmic condition of the heart and
may be determined with reference to the normal baseline sympathetic
neural discharge. For example, a two-fold or greater increase in
the amplitude of the sensed sympathetic neural discharge from the
normal baseline amplitude of sympathetic neural discharge may be
used as a suitable defined value. A second defined value with
respect to the frequency of the sympathetic neural discharge may be
similarly provided. The defined values may be a preset or
user-defined programmable value.
[0037] Once an increase in the sympathetic neural discharges has
been determined, an output signal may be generated. In one
embodiment, the output signal may be an audible sound, a
radio-transmitted signal, or any other type of signal that would
alert the patient or physician to the possibility of an impending
arrhythmia. Upon the generation of the output signal, the patient
or physician may then take precautionary or therapeutic measures to
avoid or reduce the likelihood of an impending cardiac
arrhythmia.
[0038] In another embodiment, the output signal may be a command
signal directing the delivery of anti-arrhythmic therapy.
Anti-arrhythmic therapy suitable for use in connection with the
methods and systems are known in the art and may include any one or
a combination of the following: delivering one or more
pharmacological agents; stimulating myocardial hyperinnervation in
the sinus node and right ventricle of the heart of the patient; and
cardiac pacing, cardioversion, or defibrillation shocks. A suitable
drug delivery system for an implantable cardiac device is disclosed
in U.S. Pat. No. 6,361,522, which is incorporated herein in its
entirety.
[0039] Anti-arrhythmic pharmacologic agents may include those which
are known to exert an anti-arrhythmic effect, such as sodium
channel blockers, .beta.-blockers, potassium channel blockers, such
as amiodarone and solatol, and calcium channel blockers, such as
verapamil and diltiazem.
[0040] Other suitable anti-arrhythmic pharmacologic agents include
anti-convulsant agents, such as phenyloin, carbamazepine,
valproate, and phenobarbitone. The left stellate ganglion is
capable of high frequency neuronal discharges and these discharges
directly increase heart rate. Anti-convulsants work by selectively
suppressing high frequency neuronal discharges in the central and
peripheral nervous system. Anti-convulsants are also known to
suppress cardiac sympathetic nerve discharges. Because of the
importance of the autonomic nervous system in arrhythmogenesis,
drugs that prevent the release of adrenergic neurotransmitters may
thereby decrease the sympathetic outflow are useful for controlling
cardiac arrhythmia.
[0041] It has been shown, for example, that phenyloin can also be
used to suppress cardiac arrhythmia induced by digitalis toxicity.
The action of phenyloin is related to use- and frequency-dependent
selective suppression of high-frequency neuronal activity. The
molecular mechanism for this is a voltage-dependent blockade of
membrane sodium channels responsible for the action potential.
Through this action, phenyloin obstructs the positive feedback that
underlies the development of maximal seizure activity.
[0042] Anti-convulsants may block the sympathetic nerve discharges
through two actions. One is frequency-dependent block of sodium
currents and the second is a block of calcium currents. A combined
channel blockade may account for the effects of anticonvulsant
drugs. In addition to epilepsy, anti-convulsants, such as phenyloin
and carbamazepine, are also useful in treating neuropathic pain,
which is characterized by abnormal spontaneous and increased evoked
activity from damaged areas of the peripheral nervous system.
[0043] Anti-arrhythmic therapy may also be administered by
stimulating myocardial hyperinnervation in the sinus node and right
ventricle of the heart of the patient by applying electrical
stimulation to the right stellate ganglion of the patient or by
applying Nerve Growth Factor or other neurotropic substances to the
right stellate ganglion, as disclosed in U.S. Pat. No. 6,487,450,
which is incorporated herein in its entirety.
[0044] The methods disclosed herein may be carried out by a
programmable implantable or external device, including, but not
limited to, implantable cardiac rhythm management systems such as
pacemakers, cardioverters, ICDs, and the like. In one embodiment,
the system may comprise a microprocessor, memory, bidirectional
data bus, a sympathetic nerve activity (SNA) sensing unit, an
output unit and a telemetry interface.
[0045] The microprocessor may communicate with the memory through
the data bus and execute the program stored in the memory. The
microprocessor may include a comparator, such as a summing
amplifier, operation amplifier, or other methods of comparing the
levels of analog voltage signals. Furthermore, if the sensors or
the electrodes produce digital values reflecting the sympathetic
neural discharges, then numerous methods known to one of skill in
the art may be utilized to digitally compare the respective
sympathetic neural discharges.
[0046] The memory may comprise any suitable combination of
read-only memory (ROM) containing the device operating software,
random access memory (RAM) for data storage, and on-board or
off-board cache memory associated with the microprocessor. The data
bus permits communication between the microprocessor, memory, SNA
sensing unit, output unit and the telemetry interface. The
telemetry interface may be used for downloading stored data to an
external programmer and for receiving telemetry from the programmer
to modify programmable parameters and/or change the device
operating software.
[0047] The SNA sensing unit may comprise one or more electrodes or
sensors coupled to sympathetic nerves of the patient, such as the
left stellate ganglion, and interface circuits that receive and
process the sensed signals from the electrodes. Accordingly, the
SNA sensing unit may receive electrical signals from the
sympathetic nerves of the patient, filter those signals, and
convert them into digital data or otherwise make the data available
to the microprocessor.
[0048] Accordingly, in one embodiment, the microprocessor may
instruct the SNA sensing unit to collect data from the sympathetic
nerve, which is then transmitted over bus to the microprocessor for
immediate processing or to the memory for storage and subsequent
processing as appropriate. The microprocessor may then execute the
programming resident in memory to identify increases in the
sympathetic neural discharges of the patient and command the output
unit to produce an output signal in response thereto.
[0049] The methods and systems illustrated with reference to the
drawings and described herein are merely illustrative of the
principles of the invention which may be implemented in alternative
embodiments to achieve other ends than those specifically described
herein. Accordingly, the following examples are set forth for the
purpose of illustration only and are not construed as limitations
on the method disclosed herein.
EXAMPLE 1
Rabbit Renal Sympathetic Nerve Recordings
[0050] A standard wire electrode and a nanoelectrode array was
implanted on the renal sympathetic nerve of a New Zealand white
rabbit. Simultaneous recordings of the ECG and renal sympathetic
neural discharges were obtained. The renal sympathetic neural
discharges was recorded with both a standard wire electrode and a
nanoelectrode array and amplifier. The signals were digitized with
a band pass filter of 30 to 500 Hz and a digitization rate of 1
K/sec.
[0051] FIG. 3 shows the ECG and renal sympathetic neural discharge
recordings obtained from the rabbit. The nanoelectrode recordings
provided a lower baseline noise than the wire electrode and
therefore a higher signal-to-noise ratio. FIG. 3A shows bursts of
renal sympathetic neural discharges, which did not correlate with
changes in the heart rate. FIG. 3B shows the suppression of renal
sympathetic neural discharges by intravenous bolus dose of xylazine
and ketamine.
EXAMPLE 2
Sympathetic Neural Discharges of the Left Stellate Ganglion and
Heart Rate Control
[0052] The relationship between the sympathetic neural discharges
of the left stellate ganglion and the heart rate was investigated
in a normal canine subject. A normal canine subject was
anesthetized with isoflurane and the chest was opened at the third
intercostal space. The left stellate ganglion was identified and a
nanoelectrode was implanted under the fibrous capsule. The fibrous
capsule was then closed with a 4-0 silk suture and additional
sutures were placed on the wire to secure the nanoelectrodes. The
nanoelectrodes were then connected to a DSI transmitter (DSI TL
10M3-D70-EEE, Data Sciences, International) with a band pass filter
of 0.05 to 100 Hz and a digitization rate of 1 K/sec. An additional
bipolar pair of the DSI transmitter was used for ECG recordings
between the right and left chest. All recordings shared a common
ground.
[0053] FIG. 4 shows the relationship between the sympathetic neural
discharges of the left stellate ganglion from the ambulatory canine
subject. Bursts of sympathetic neural discharges preceded the onset
of an accelerated atrial rate by approximately 200 ms. The arrow
points to cross-talk from the surface ECG, which shared the same
ground as the nanoelectrode.
[0054] FIG. 5 shows three separate segments of ECG and sympathetic
neural discharge recordings of the canine subject two weeks after
implantation, demonstrating the strong correlation between elevated
sympathetic neural discharge and increased heart rate. The increase
in the activation of sympathetic neural discharges activation at
the time indicated by (a) on the recording was followed by heart
rate acceleration, as shown in the corresponding ECG recording.
Again, the increase in the amplitude of the sympathetic neural
discharges at time (b) was again followed by increased heart rate.
Burst increases of sympathetic neural discharges at times (c)
through (h) were again each followed by short run of increased
atrial rate. This demonstrates that increased sympathetic neural
discharges is causally related to increased heart rate.
[0055] FIG. 6 shows the correlation between heart rate and
sympathetic neural discharges in the same canine subject. Heart
rate (HR) was plotted on the first row and the raw sympathetic
neural discharge recording was plotted on the second row. FIGS. 6A,
B and C depict simultaneous ECG and sympathetic neural discharge
recordings over a one hour period and further demonstrate the
correlation between increased sympathetic neural discharges and
increased heart rate.
[0056] FIG. 7 shows a correlation between heart rate and the
integrated sympathetic neural discharges. Panel A depicts the ECG
recording; panel B depicts the heart rate in beats per minute;
panel C depicts the integrated nerve recording and panel D depicts
the raw nerve signal and panel E depicts the sonogram. The
frequency of the sonogram in panel E is provided in the Y axis and
the power is indicated by the gray shading. A correlation is
observed between the heart rate and integrated nerve signal and
between the heart rate and the sonogram.
[0057] The cross-correlation between the sympathetic neural
discharges and the heart rate over an hour is depicted in FIG. 8.
The onset of heart rate changes were defined by the S wave of the
QRS complex. The peak correlation occurred at -580 ms, indicating
that the increased sympathetic neural discharges is followed within
580 ms by an increased heart rate. The P waves occurred
approximately 180 ms before the S wave on the QRS complex.
Therefore, the increase in the sympathetic neural discharges
occurred approximately 400 ms before the onset of the P wave.
EXAMPLE 3
Effects of Anti-Convulsants on SNA
[0058] Anti-convulsant drugs may exert an anti-arrhythmic effect by
suppressing the high frequency sympathetic nerve discharges from
the left stellate ganglion. Phenyloin (Dilantin.RTM.) is one of the
most commonly used anti-convulsants and has been shown to suppress
the sympathetic neural discharges in ambulatory dogs within the
therapeutic range of 10-20 mg/L.
[0059] After confirming the successful recording of sympathetic
neural discharges from the canine subject, 400 mg (approximately 18
mg/kg) of phenyloin was administered intravenously to the canine
subject. FIG. 9 shows the continuous tracings of heart rate and
sympathetic neural discharges over a 24 hour period for a canine
subject. Phenyloin was injected at 9:45 a.m. and the tracings
following that time show the effects of phenyloin injection on the
heart rate and the sympathetic neural discharges of the canine
subject.
[0060] The serum concentration of the canine subject two hours
after the initial injection was 12.9 mg/L, which was within the
therapeutic range of 10-20 mg/L. The results showed that
sympathetic neural discharges appeared to decrease significantly
3-12 hours after the initial injection. There was an increase in
the sympathetic neural discharges observed roughly 20 hours after
the initial injection, which may represent a rebound sympathetic
neural discharges hyper-activation.
[0061] An oral dose of phenyloin was also administered to the
canine subject (800 mg single dose, or roughly 30 mg/kg) after
serum levels from the initial injection of phenyloin dropped to
zero. The serum level 2 hours after the oral dose was 2.2 mg/L,
which is sub-therapeutic. At this dose, there were little changes
in the sympathetic neural discharges. These data show that a
therapeutic dose of phenyloin can suppress sympathetic neural
discharges from the left stellate ganglion and that a
sub-therapeutic dose has little effect. The data also suggest that
a dose-response relationship may be present.
* * * * *