U.S. patent application number 14/792401 was filed with the patent office on 2015-12-31 for cardiac neuromodulation and methods of using same.
This patent application is currently assigned to The Board of Regents of the University of Oklahoma. The applicant listed for this patent is The Board of Regents of the University of Oklahoma. Invention is credited to Jeffrey L. Ardell, John A. Armour, Michael J.L. DeJongste, Robert D. Foreman, Bengt G.S. Linderoth.
Application Number | 20150374995 14/792401 |
Document ID | / |
Family ID | 27403510 |
Filed Date | 2015-12-31 |
United States Patent
Application |
20150374995 |
Kind Code |
A1 |
Foreman; Robert D. ; et
al. |
December 31, 2015 |
CARDIAC NEUROMODULATION AND METHODS OF USING SAME
Abstract
The present invention relates in general to methodologies for
the treatment quenching preconditioning and communication between
the intrinsic cardiac nervous system and an electrical stimulus. In
particular, the present invention utilizes spinal cord stimulation
to alter and/or affect the intrinsic cardiac nervous system and
thereby protect the myocytes, stabilize myocardial electrical
instability and/or alleviate or diminish cardiac pathologies.
Inventors: |
Foreman; Robert D.; (Edmond,
OK) ; Ardell; Jeffrey L.; (Johnson City, TN) ;
Armour; John A.; (Halifax, CA) ; DeJongste; Michael
J.L.; (CK Haren, NL) ; Linderoth; Bengt G.S.;
(Solna, SE) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
The Board of Regents of the University of Oklahoma |
Norman |
OK |
US |
|
|
Assignee: |
The Board of Regents of the
University of Oklahoma
Norman
OK
|
Family ID: |
27403510 |
Appl. No.: |
14/792401 |
Filed: |
July 6, 2015 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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12952653 |
Nov 23, 2010 |
9072901 |
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14792401 |
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11287094 |
Nov 23, 2005 |
7860563 |
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12952653 |
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11266558 |
Nov 3, 2005 |
7769441 |
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11287094 |
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10128787 |
Apr 22, 2002 |
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11266558 |
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60295028 |
May 31, 2001 |
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60291681 |
May 17, 2001 |
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60285176 |
Apr 20, 2001 |
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Current U.S.
Class: |
607/117 |
Current CPC
Class: |
A61N 1/0551 20130101;
A61N 1/36114 20130101; A61N 1/36117 20130101 |
International
Class: |
A61N 1/36 20060101
A61N001/36; A61N 1/05 20060101 A61N001/05 |
Claims
1. A method of treating sequelae of myocardial ischemia in a
patient comprising: identifying a patient suffering from or that is
susceptible to myocardial ischemia; implanting a stimulation device
into the patient to electrically stimulate the spinal cord, wherein
the stimulation device comprises a plurality of electrodes and a
generator in which at least one electrode is placed near the spinal
cord; activating the stimulation device to deliver electrical
stimulation to the spinal cord to suppress intrinsic cardiac nerve
activity thereby treating sequelae of myocardial ischemia.
Description
CROSS-REFERENCE TO RELATED APPLICATIONS/INCORPORATION BY REFERENCE
STATEMENT
[0001] This application is a continuation of U.S. Ser. No.
12/952,653, filed on Nov. 23, 2010; which is a divisional of U.S.
Ser. No. 11/287,094, filed on Nov. 23, 2005, now U.S. Pat. No.
7,860,563, issued on Dec. 28, 2010; which is a continuation of U.S.
Ser. No. 11/266,558, filed on Nov. 3, 2005, now U.S. Pat. No.
7,769,441, issued on Aug. 3, 2010; which is a continuation of U.S.
Ser. No. 10/128,787, filed on Apr. 22, 2002, now abandoned; which
claims priority under 35 U.S.C. .sctn.119(e) of U.S. Provisional
Application Ser. No. 60/295,028, filed on May 31, 2001; U.S.
Provisional Application Ser. No. 60/291,681, filed on May 17, 2001;
and U.S. Provisional Application Ser. No. 60/285,176, filed on Apr.
20, 2001. The entire contents of each of the above-referenced
patents and patent applications are hereby expressly incorporated
herein by reference.
BACKGROUND OF THE INVENTION
1. Field of the Invention
[0002] The present invention relates in general to methodologies
for the treatment quenching preconditioning and communication
between the intrinsic cardiac nervous system and an electrical
stimulus. In particular, the present invention utilizes spinal cord
stimulation to alter and/or affect the intrinsic cardiac nervous
system and thereby protect the myocytes, stabilize myocardial
electrical instability and/or alleviate or diminish cardiac
pathologies.
BRIEF DESCRIPTION OF THE FIELD OF THE INVENTION
[0003] Recently, the emergence of novel views of the anatomic
pathways and neural mechanisms involved in the regional control of
the heart have led to the presently claimed and disclosed intrinsic
cardiac nervous system modalities and treatments. In fact, it has
been determined that a level of processing occurs that permits
independent intrinsic cardiac as well as intrathoracic extracardiac
and central spinal integration of afferent and efferent autonomic
influences, and local neural coordination without necessarily
involving the higher brain centers. This knowledge has led to the
development of the presently claimed and disclosed invention(s).
Lathrop and Spooner [24] have postulated that a "hierarchy of
control mechanisms among these different elements, and that they
interact as a system of autonomous efferent feedback loops rather
than simply as relay stations subservient to central command."
Indeed, disruption of neuronal circuitry leads to numerous cardiac
pathologies. Neuronal interactions that occur within this circuitry
or hierarchy modulate different regions of both healthy and
diseased hearts. Thus, the knowledge of this circuitry and
methodologies of modulating this circuitry (as disclosed and
claimed herein) have allowed for the development and treatment of
cardiac pathologies using novel therapeutic approaches to
ameliorate specific cardiac pathologies.
[0004] Regional control of cardiac function is dependent upon the
coordination of activity generated by neurons within intrathoracic
autonomic ganglia and the central nervous system. The hierarchy of
nested feedback loops therein provides precise beat-to-beat control
of regional cardiac function. Contrary to classical teaching,
studies undertaken and disclosed in the present specification
utilizing electrophysiological and neuropharmacological techniques
applied from the level of whole organ to that of neurons recorded
in vitro indicate that intrathoracic autonomic ganglia act in a
manner greater than simple relay stations for autonomic efferent
neuronal control of the heart. It has been determined that within
this hierarchy of intrathoracic ganglia and nerve interconnections,
complex processing takes place that involves spatial and temporal
summation of sensory inputs, preganglionic inputs from central
neurons and intrathoracic ganglionic reflexes activated by local
cardiopulmonary sensory inputs. The activity of neurons within
intrathoracic autonomic ganglia is likewise modulated by
circulating hormones, chief among them being circulating
catecholamines and angiotensin II.
[0005] The progressive development of cardiac disease is associated
with maladaptation of these neurohumoral control mechanisms. Recent
data indicate that conventional therapy of cardiac diseases such as
myocardial ischemia and heart failure exert their beneficial
effects not only on cardiomyocytes directly, but indirectly via the
intrinsic cardiac nervous system. The presently disclosed and
claimed inventions of the complex processing that occurs within the
intrathoracic nervous system, as well as between peripheral and
central neurons, will provide a basis for understanding the role
that the cardiac nervous system plays in regulating not only the
normal heart, but the diseased heart. Information derived from
research and experimentation of this complex neuronal hierarchy
provides for novel therapeutic approaches for the effective
treatment of cardiac dysfunction including protection of cardiac
myocytes and stabilization of myocardial electrical activity by
targeting various populations of neurons regulating regional
cardiac behavior.
[0006] Varying elements within the cardiac neuronal hierarchy exert
more influence over regional cardiac function than has been
traditionally understood. For example, it is now well recognized
that the cardiac nervous system is fundamental to the management of
heart failure. As such, this nervous system represents a novel and
previously unrecognized target for the treatment of heart failure.
Control of regional cardiac function is dependent upon intrinsic
properties of the cardiac electrical and mechanical tissues as
modulated by neural inputs arising from neurons in the
intrathoracic autonomic ganglia, spinal cord and brainstem.
Disruptions in neural inputs to the heart or alterations in the
cardiac interstitial milieu can be associated with deleterious
cardiac structural remodeling and, as a consequence, cardiac
dysfunction. In the most extreme case, this becomes evident in
congestive heart failure. Excessive activation of the intrathoracic
cardiac efferent nervous system, as with myocardial ischemia, can
evoke ventricular dysrhythmias involving changes within the cardiac
nervous system in addition to alterations in cardiomyocyte ion
channel function. Maladaptation of neurohumoral control mechanisms
can likewise adversely remodel the cardiac extracellular
matrix.
[0007] The conventional treatment for reducing the frequency and
intensity of angina pectoris resulting from myocardial ischemia is
anti-ischemic therapy. These therapies are usually based upon
restoring the balance between myocardial oxygen supply and
myocardial oxygen demand. Pharmacological agents and
revascularization procedures (CABG and PTCA) are conventional
treatments for such disease states. Yet there are a significant
number of patients that do not experience adequate relief of their
anginal symptoms with these treatments or are poor candidates for
these therapies. Thus, alternative approaches utilizing direct
electrical activation of neural elements within the spinal cord
have been devised, with the resultant modulation of the
intrathoracic neurohumoral milieu thereby eliciting anti-ischemic,
antiarryhtymic, and anti-anginal effects.
[0008] A disturbance of the fine balance within the whole cardiac
neuraxis can result in dramatic changes in cardiac efferent
neuronal outflow. Experimental studies have been performed to
demonstrate that pathological processes can change the integrative
behavior of the cardiac neuraxis. These changes occur when cardiac
sensory neurites are activated intensely and for long periods, as
when cardiac tissue becomes damaged during regional ventricular
ischemia. On the other hand, central processing of cardiac sensory
output may become deranged leading to conflicting signals that
interfere with the maintenance of cardiac function. This has led to
the proposed scheme that the hierarchy of cardiac neurons interacts
effectively if there is an appropriate balance therein.
[0009] Under normal, physiological conditions stimuli applied to
the heart do not elicit marked changes in cardiac efferent neuronal
activity because central neurons can suppress excessive cardiac
sensory information processing. Information has been obtained to
support the conclusion that, in the hierarchy of cardiac control,
activation of spinal neuronal circuits modulates the intrathoracic
cardiac nervous system. Experimental studies have shown that
activation of the dorsal columns at the T1-T2 segments
significantly reduces the activity generated by the intrinsic
cardiac neurons in their basal conditions as well as when activated
in the presence of focal ventricular ischemia induced by occluding
the left coronary artery. Not only does dorsal column activation
modulate the intrinsic cardiac nervous system, but it also modifies
the activity of spinal neurons within the T3-T4 segments. In
addition, experimental evidence indicates that the central nervous
system maintains a tonic inhibitory influence over intrathoracic
cardiopulmonary-cardiac reflexes. One of the present inventors has
also shown that reflexes mediated through the middle cervical
ganglion are increased after decentralization. Based on this
evidence, it is postulated that disease processes change the
balance between the central and peripheral neuronal processing of
cardiac sensory information. Thus, use of electrical currents to
activate spinal neuronal circuits can reverse or halt disease
processes of the heart preconditioning the heart--i.e., applying
electrical activation prior to disease--also is contemplated as a
means to pro-actively treat a patient with high susceptibility to
cardiac pathologies including arrhythmias.
[0010] Within the hierarchy for cardiac control, neurons of the
upper cervical segments modulate information processing in the
spinal neurons of the upper thoracic segments. In human studies,
spinal cord stimulation of the C1-C2 spinal segments relieved the
pain symptoms in patients with chronic refractory angina pectoris.
Experimental studies in support of the presently claimed and
disclosed invention have shown that spinal cord activation of the
upper cervical segments of the spinal cord suppressed the activity
of spinal neurons in T3-T4 segments. Furthermore, chemical
stimulation with glutamate of cells in the C1-C2 segments also
reduced upper thoracic spinal neuronal activity. The upper cervical
region is intriguing because it is positioned between supraspinal
nuclei and spinal circuitry. Neurons in C1-C2 could serve as a
filter, an integrator, or as a relay for afferent information,
since these neurons receive inputs from vagal afferents from the
heart.
[0011] Very little information has been published to address
underlying mechanisms explaining how central and peripheral cardiac
neurons process cardiac sensory information and interact in the
maintenance of adequate cardiac output. The presently claimed and
disclosed invention shows that disease processes change the balance
between the central and peripheral neuronal processing so involved.
For instance, when the activity generated by cardiac sensory
neurons becomes excessive (such as during focal ventricular
ischemia), cardiac function is profoundly affected, cardiac myocyte
protection is reduced and arrhythmias are increased. A disturbance
of the fine balance within the whole cardiac neuraxis results in
dramatic changes in cardiac efferent neuronal outflow. Over the
past 30 years, the anatomy and function of the peripheral cardiac
nervous system has been studied, focusing during the last decade on
its intrinsic cardiac component. The classical view of the
autonomic nervous system presumes that its intrinsic cardiac
component acts solely as a parasympathetic efferent neuronal relay
station in which medullary preganglionic neurons synapse with
parasympathetic efferent postganglionic neurons therein. In such a
concept, the latter neurons project to end effectors on the heart
with little or no integrative capabilities occurring therein.
Similarly, intrathoracic extracardiac sympathetic ganglia have been
thought to act solely as efferent relay stations for sympathetic
efferent projections to the heart. As the presently claimed and
disclosed invention shows, neural control of regional cardiac
function resides in the network of nested feedback loops made up of
the intrinsic cardiac nervous system, extracardiac intrathoracic
autonomic ganglia, the spinal cord and brainstem. Within this
hierarchy, the intrinsic cardiac nervous system functions as a
distributive processor at the level of the target organ. Thus, the
intrinsic cardiac nervous system plays an important role in the
functioning of the heart and in its diseased pathologies. This
novel information thereafter leads to numerous methodologies (some
of which are claimed and disclosed herein for the treatment,
preconditioning and/or quenching of disease pathologies through the
use of spinal cord stimulation.
[0012] Experimental studies have also shown that pathological
processes can change the integrative behavior of the cardiac
neuraxis. These changes occur when populations of cardiac sensory
neurites are activated intensely and for long periods of time when
local cardiac tissue becomes damaged during, for instance, regional
ventricular ischemia. Thus, under normal, physiological conditions
stimuli applied to the heart do not elicit marked changes in
cardiac efferent neuronal activity because central neurons suppress
cardiac sensory information processing. On the other hand, central
processing of cardiac sensory output may become deranged during
excessive inputs leading to conflicting signals that interfere with
the maintenance of cardiac function. This has led to the novel
concept that the hierarchy of cardiac neurons interact effectively
if there is an appropriate balance therein. Fundamental to this
hierarchy is its component on the target organ--the intrinsic
cardiac nervous system and its influence on the heart.
[0013] Consistent coherence of activity generated by differing
populations of neurons is indicative of principal and direct
synaptic interconnections between them or, conversely, the sharing
by such neurons of common inputs. Such relationships have been
identified among medullary and spinal cord sympathetic efferent
preganglionic neurons, as well as among different populations of
sympathetic efferent preganglionic neurons. Different populations
of neurons, distributed spatially within the intrinsic cardiac
nervous system, respond to cardiac perturbations in a coordinate
fashion. If neurons in one part of this neuronal network respond to
inputs from a single region of the heart, such as the
mechanosensory neurites associated with a right ventricular ventral
papillary muscle, then the potential for imbalance within the
different populations of neurons regulating various cardiac regions
might occur and, thus, its neurons display little coherence of
activity. In other words, relatively low levels of specific inputs
on a spatial scale to the intrinsic cardiac nervous system result
in low coherence among its various neuronal components. On the
other hand, excessive input to this spatially distributed nervous
system would destabilize it, leading to cardiac arrhythmia
formation, etc.
[0014] Thus it is an object of the present invention to use the
identification of the intrinsic cardiac nervous system along with
the experimental data and results to provide methodologies
utilizing spinal cord stimulation for the (1) treatment of cardiac
disease pathologies; (2) communication between an external point
and the intrinsic cardiac nervous system; (3) preconditioning of
the intrinsic cardiac nervous system in order to promote a
protective effect against cardiac disease pathologies; and (4)
quenching aberrant neuronal activity occurring within the intrinsic
cardiac nervous system.
[0015] This and numerous other objects of the present invention
will be appreciated in light of the present specification,
drawings, and claims.
SUMMARY OF THE INVENTION
[0016] The presently claimed and disclosed invention encompasses
the concept of an intrinsic cardiac nervous system and the ability
to stimulate this intrinsic cardiac nervous through the use of SCS
or DCA. The stimulation of this intrinsic cardiac nervous system
results in the ability to easily and with minimal invasiveness,
treat cardiac pathologies either pre-, during, or post-symptom.
[0017] The presently claimed and disclosed invention provides a
method for protecting cardiac function and reducing the impact of
ischemia on the heart. This methodology includes the steps of: (1)
providing a stimulator capable of generating a predetermined
electrical signal; (2) placing the stimulator adjacent a neural
structure capable of carrying the predetermined electrical signal
from the neural structure to the intrinsic cardiac nervous system;
and (3) activating the stimulator for a predetermined period of
time to generate the predetermined electrical signal to protect
cardiac function and reduce the impact of ischemia on the heart. In
an alternate embodiment of this method, the neural structure is a
spinal cord.
[0018] The presently claimed and disclosed invention further
provides a method for treating an animal having a cardiac pathology
by protecting cardiac function and reducing the impact of ischemia
on the heart. This methodology includes the steps of: (1) providing
a stimulator capable of generating a predetermined electrical
signal; (2) placing the stimulator adjacent a neural structure
capable of carrying the predetermined electrical signal from the
neural structure to at least one of the intrinsic cardiac nervous
system and the heart; and (3) activating the stimulator for a
predetermined period of time to generate the predetermined
electrical signal to modulate at least one of the intrinsic cardiac
nervous system and the heart, and thereby protecting at least one
of the intrinsic cardiac nervous system and the heart to treat the
cardiac pathology. I an alternate embodiment of this methodology,
the neural structure is a spinal cord.
[0019] The presently claimed and disclosed invention also provides
a method for electrically communicating with at least one of an
intrinsic cardiac nervous system and a heart. This methodology
includes the steps of: (1) providing a stimulator capable of
generating a predetermined electrical signal; (2) placing the
stimulator adjacent a neural structure capable of carrying the
predetermined electrical signal from the neural structure to at
least one of the intrinsic cardiac nervous system and the heart;
and (3) activating the stimulator for a predetermined period of
time to generate the predetermined electrical signal to communicate
with at least one of the intrinsic cardiac nervous system and the
heart. In an alternate embodiment of this methodology, the neural
structure is a spinal cord.
[0020] Additionally, the presently claimed and disclosed invention
encompasses a method of modulating electrical neuronal and humoral
responses of at least one of an intrinsic cardiac nervous system
and a heart. This methodology includes the steps of: (1) providing
a stimulator capable of generating a predetermined electrical
signal; (2) placing the stimulator adjacent a neural structure
capable of carrying the predetermined electrical signal from the
neural structure to at least one of the intrinsic cardiac nervous
system and the heart; and (3) activating the stimulator for a
predetermined period of time to thereby generate the predetermined
electrical signal to modulate the electrical neuronal and humoral
response of at least of the intrinsic cardiac nervous system and
the heart. In an alternate embodiment of this methodology, the
neural structure is a spinal cord.
[0021] Furthermore, the presently claimed and disclosed invention
also calls for a method of activating spinal cord neurons to induce
a conformational change in an intrinsic cardiac nervous system.
This methodology includes the steps of: (1) providing a stimulator
capable of generating a predetermined electrical signal; (2)
placing the stimulator adjacent a spinal cord to carry the
predetermined electrical signal from the spinal cord to an
intrinsic cardiac nervous system; and (3) activating the stimulator
for a predetermined period of time to thereby generate the
predetermined electrical signal to thereby activate spinal cord
neurons in proximity of the stimulator so as to induce a
conformational change in the intrinsic cardiac nervous system. In
an alternate embodiment of this methodology, the neural structure
is a spinal cord.
[0022] The presently claimed and disclosed invention also provides
for a method for the prolonged activation of spinal cord neurons to
induce a conformational change in an intrinsic cardiac nervous
system. This methodology includes the steps of: (1) providing a
stimulator capable of generating a predetermined electrical signal;
(2) placing the stimulator adjacent a spinal cord to carry the
predetermined electrical signal from the spinal cord to an
intrinsic cardiac nervous system; and (3) activating the stimulator
for a predetermined period of time to thereby generate the
predetermined electrical signal to thereby activate spinal cord
neurons in proximity of the stimulator so as to induce a
conformational change in the intrinsic cardiac nervous system
wherein the activation effects persist for a period of time
extending beyond the activation of the stimulator. In an alternate
embodiment of this methodology, the neural structure is a spinal
cord.
[0023] Additionally, the presently claimed and disclosed invention
includes a method for transiently nullifying neuronal activation of
an intrinsic cardiac nervous system by myocardial ischemia. This
methodology includes the steps of: (1) providing a stimulator
capable of generating a predetermined electrical signal; (2)
placing the stimulator adjacent a neural structure capable of
carrying the predetermined electrical signal from the neural
structure to the intrinsic cardiac nervous system; and (3)
activating the stimulator for a predetermined period of time to
thereby generate the predetermined electrical signal to transiently
nullify neuronal activation of an intrinsic cardiac nervous system
by myocardial ischemia. In an alternate embodiment of this
methodology, the neural structure is a spinal cord.
[0024] The presently claimed and disclosed invention also provides
for a method for prolonged nullification of neuronal activation of
an intrinsic cardiac nervous system by myocardial ischemia. This
methodology includes the steps of: (1) providing a stimulator
capable of generating a predetermined electrical signal; (2)
placing the stimulator adjacent a neural structure capable of
carrying the predetermined electrical signal from the neural
structure to the intrinsic cardiac nervous system; and (3)
activating the stimulator for a predetermined period of time to
thereby generate the predetermined electrical signal to nullify the
neuronal activation of the intrinsic cardiac nervous system by
myocardial ischemia for a prolonged period of time extending beyond
stimulator activation. In an alternate embodiment the neural
structure is a spinal cord.
[0025] The presently claimed and disclosed invention also includes
a method for transiently suppressing neuronal activation of an
intrinsic cardiac nervous system by myocardial ischemia. This
methodology includes the steps of: (1) providing a stimulator
capable of generating a predetermined electrical signal; (2)
placing the stimulator adjacent a neural structure capable of
carrying the predetermined electrical signal from the neural
structure to the intrinsic cardiac nervous system; and (3)
activating the stimulator for a predetermined period of time to
thereby generate the predetermined electrical signal to transiently
suppress the neuronal activation of the intrinsic cardiac nervous
system by myocardial ischemia. In an alternate embodiment of the
present methodology, the neural structure is a spinal cord.
[0026] The presently claimed and disclosed invention includes a
method for prolonged suppression of neuronal activation of an
intrinsic cardiac nervous system by myocardial ischemia. This
methodology includes the steps of: (1) providing a stimulator
capable of generating a predetermined electrical signal; (2)
placing the stimulator adjacent a neural structure capable of
carrying the predetermined electrical signal from the neural
structure to the intrinsic cardiac nervous system; and (3)
activating the stimulator for a predetermined period of time to
thereby generate the predetermined electrical signal to suppress
the neuronal activation of the intrinsic cardiac nervous system by
myocardial ischemia for a prolonged period of time extending beyond
stimulator activation. In an alternate embodiment of this
methodology, the neural structure is a spinal cord.
BRIEF DESCRIPTION OF THE SEVERAL VIEWS OF THE DRAWINGS
[0027] The patent or application file contains at least one drawing
executed in color. Copies of this patent or patent application
publication with color drawings will be provided by the Office upon
request and payment of the necessary fee.
[0028] FIG. 1 is a schematic of the neural interactions occurring
within the intrathoracic autonomic ganglia and between the
peripheral networks and the central nervous system. Within the
intrinsic cardiac ganglia are included sympathetic (Sympath) and
parasympathetic (Parasym) efferent neurons, local circuit neurons
(LCN) and afferent neurons. Contained within the extracardiac
intrathoracic ganglia are sympathetic efferent neurons, local
circuit neurons and afferent neurons. These intrinsic cardiac and
extracardiac networks form separate and distinct nested feedback
loops that act in concert with CNS feedback loops involving the
spinal cord and medulla to regulate cardiac function on a beat to
beat basis. These nerve networks are also influenced by circulating
humoral factors including catecholamines (catechol) and angiotensin
II (ANG II). Aff., afferent; DRG, dorsal root ganglia; G.sub.s,
stimulatory guanine nucleotide binding protein; G.sub.i, inhibitory
guanine nucleotide binding protein; AC, adenylate cyclase;
.beta..sub.1--beta-1 adrenergic receptor; M.sub.2--muscarinic
receptor.
[0029] FIG. 2 shows chronotropic (ECG), inotropic (LVP, Left vent.
pressure) and neuronal responses recorded simultaneously in atrial
(right atrial ganglionated plexus; RAGP) and ventricular (cranial
medial ganglionated plexus; CMVGP) intrinsic cardiac neurons before
and during transient occlusion of the left anterior descending
coronary artery. Note the enhanced activity in both ganglionated
plexi, with the ventricular ganglionated plexus being more
affected.
[0030] FIG. 3 is a graphical representation of the change in
intrinsic cardiac neuronal activity induced by transient occlusion
of the left anterior descending artery (CAO) and/or dorsal cord
activation (DCA) at 90% Motor Threshold.
[0031] FIG. 4 is a graphical representation of long-term effects
(memory) on intrinsic cardiac neuronal activity induced by
short-term DCA. Following bilateral transection of the ansae
subclavia, DCA no longer affected activity within the intrinsic
cardiac nervous system.
[0032] FIG. 5 shows activity generated by two different populations
of intrinsic cardiac neurons contained within the right atrial
ganglionated plexus. Arrow indicates application of veratridine to
the epicardium of the left ventricle. At baseline, note the cycling
of activity with a periodicity of 20 seconds. In the unstressed
condition, this bursting is usually associated with increased
coordination of activity between the two populations of neurons
(see bottom trace). When an afferent stress is imposed to the ICN,
as with application of epicardial veratridine, activity increased
in both sites and the coherence of activity generated by these two
populations of neurons approached unity.
[0033] FIG. 6 shows that chronic myocardial ischemia is induced by
placement of an ameroid constrictor on the left circumflex (LCx)
artery 4 weeks previously (panel A). Under basal conditions,
electrograms display slight ST segment displacement (panel B).
Transient rapid ventricular pacing (240/min for 1 min), used to
increase myocardial O.sub.2 demand, precipitates ischemic episodes.
In the first beats following rapid pacing, ST segment displacement
is inhomogeneously augmented in the LCx territory. Marked ST
segment depression (-2 to -6 mV) occurs in some areas, whereas ST
elevation (+2 to +15 mV) develops in others (panel C). ST segment
changes were also induced by ANG II when administered to RAGP
neurons via the right coronary artery proximal to branching of the
SA node artery (40 g/min for 2 min). Note that the ST changes,
induced by ANG II, occurred at the apical margin of the plaque
electrode, i.e., at the periphery of the LCx territory (Panel D).
In contrast, the changes induced by transient rapid pacing occurred
at a more central location in the LCx territory (panel C).
[0034] FIG. 7 shows ST segment changes were induced by angiotensin
II (ANG II) administered to RAGP neurons via the right coronary
artery proximal to branching of the SA node artery (40 .mu.g/min
for 2 min). Note that the ST changes occurred at the apical margin
of the plaque electrode (panel B). Thus, the ST segment changes are
caused by direct or indirect activation of ganglionated plexus
neurons that project efferent axons to the specific ventricular
areas in which the changes occurred. Moreover, the ANG II effects
are attenuated by DCA (panel C), showing that such ventricular
events can be influenced by interactions between intrinsic cardiac
and spinal neurons.
[0035] FIGS. 8A-8C show ISF, aorta and coronary sinus
norepinephrine (NE) and epinephrine (EPI) levels in response to
stellate stimulation (4 Hz), angiotensin II (ANG II) infusion (100
.mu.M, 1 ml/min) into the blood supply for the Right Atrial
Ganglionated Plexus (RAGP) and Dorsal Cord Activation (DCA, 50 Hz,
200 .mu.sec, 90% motor threshold). ISF fluids were sampled using
the microdialysis techniques summarized in Aim 3.
[0036] FIG. 9 shows the effects of acetylcholine (ACh) on canine
intrinsic cardiac neurons obtained from sham control (CONTROL) and
from hearts where all extracardiac nerve connections to the heart
were interrupted 3 weeks previously (DCX). The horizontal bar under
the traces indicates application of a 10 ms pulse of ACh (1 mM)
from the tip of a pipette placed near the ganglion. A, CONTROL. ACh
depolarized a control intrinsic cardiac neuron, evoking a short
burst of APs at the start of depolarization. DCX. ACh depolarized
the chronically decentralized neuron more than the control one,
evoking a longer lasting burst of APs. During the repolarization
phase, the membrane potential began to oscillate with APs being
discharged on oscillatory peaks. B. Hexamethonium (100 .mu.M for 5
min in perfusate) reduced the amplitude of ACh-induced
depolarization relative to the control state; no APs were
generated. DCX. Hexamethonium reduced the amplitude of ACh-induced
depolarization; AP discharge was facilitated during plateau phase
of response. The bursting of activity is reflective of the enhanced
muscarinic receptor-mediated responses of these neurons.
[0037] FIG. 10 shows inhibition of ACh-evoked responses by
substance P (SP). Top trace shows intracellular recording from an
intracardiac neuron and bottom marks indicate times when 28 ms
puffs of ACh (10 mM) were given by local pressure injection. Local
application of ACh evoked action potentials. These ACh evoked
potentials were blocked during bath application of 10 .mu.M
substance P (see horizontal bar).
[0038] FIG. 11 shows photomicrographs showing CGRP-immunoreactive
nerve fibers in a dog intracardiac ganglion (panel A) and PGP
9.5-immunoreactive nerve fibers in dog sinoatrial node (panel B).
The chromogen was VIP in A and diaminobenzadine in B (both from
Vector). Both panels are at the same magnification. Scale bar=50
.mu.m.
[0039] FIG. 12 shows enhancement of the activity generated by a
canine nodose ganglion afferent neuron following application of the
long acting adenosine agonist CPA (via a 1 cm.times.1 cm pledget)
to the ventral left ventricular epicardium (between panels A &
B). Monitored cardiac variables were not affected by this
intervention. Panel B was obtained 1 minute after terminating CPA
application.
[0040] FIG. 13 shows simultaneous recordings of activity generated
by intrinsic cardiac (above) and intrathoracic extracardiac (left
middle cervical ganglion-LMCG) neurons concomitant with left
ventricular sensory inputs induced by epicardial application of
veratridine. The right hand panels denote XY plots of each activity
versus pressure. Note that enhancement of their ventricular sensory
inputs depicted in panel B activated one population while
suppressing the other. Activities occurred during specific phases
of the cardiac cycle (XY plots).
[0041] FIG. 14 shows examples of two different pairs of spinal
neurons in the T3 spinal segment. Aa is background activity
recorded from deeper (Unit 1; lamina V-VII) and superficial (Unit
2; lamina I-II) neurons. Ab is the cross-correlogram of the
background activity. Central peaks centered around 0 delay
represent the action potentials that occur from one neuron shortly
before (negative delays) or after an action potential occurs in the
other neuron. Ba is activity from superficial (Unit 1; lamina I-II)
and deeper (Unit 2; lamina V-VII) neurons evoked by an injection of
bradykinin into the pericardial sac. Bb is the cross-correlogram of
the evoked activity. The upper tracings are discharge rate in
impulses/sec (imp/s) and lower tracings (Unit) are the raw records
of the extracellular action potentials. The arrows represent the
injection (upward) and removal of bradykinin. The characteristics
of the cross-correlograms were similar to those described by
Sandkuhler et al.
[0042] FIG. 15 shows responses of a T3 spinal neuron to visceral
and somatic stimulation. A&B: responses of the cell to saline
(A) and to intrapericardial injections of algogenic chemicals
before (A) and after (B) the spinal cord was transected at the C7
segment. C: responses of brushing hair (Br) and pinching (Pi) the
skin in the somatic field represented by the ellipse on the rat
figurine. D: the black dot marks the location of the recording site
for this cell.
[0043] FIG. 16 shows response of T3 deeper spinal neuron to
occlusion of the left coronary artery (CAO). The top trace is the
rate of cell discharges in impulses/sec (imp/s). The second trace
shows the raw tracing of the individual extracellular action
potentials (Cell Activity). The third trace is blood pressure in
mmHg. The horizontal bar represents the stimulus period for CAO.
The occlusion was sustained for one minute.
[0044] FIG. 17 shows intrapericardial infusion of algogenic
chemicals caused intense c-fos immunoreactivity in the nuclei of
T3-T4 neurons (arrows) in the marginal zone (left photo) and
central gray region (right photo; cc--central canal).
[0045] FIG. 18 shows distribution of c-fos immunoreactive (IR)
neurons/100 .mu.m in the C1 spinal segment following
(A)--unoperated control, (B)--Vagal crush, (C)--Vagal stimulation.
Following stimulation of the vagus, c-fos IR neurons (black dots)
were abundant in the medial marginal zone and substantia
gelatinosa. C-fos IR neurons also were located throughout the
nucleus proprius, along the marginal zone, in the ventral horn, and
central gray region.
[0046] FIG. 19 shows responses of T3 cell to chemical stimulation
of glutamate before and after rostral C1 spinal transection. The
responses were evoked by intrapericardial injections of bradykinin
(BK). Saline was used as the control. Pledgets of glutamate placed
on the C1-C2 dorsal spinal cord (B) decreased the discharge rate of
the cell for the three minute period it was applied. The background
activity recovered after glutamate was removed. After the rostral
C1 cut, BK still increased the discharge rate of the thoracic STT
cell (D) although the BK response characteristics changed. The
presence of glutamate attenuated this response (E). The increased
rate of discharge to BK injections was again observed when
glutamate was removed (F). In each panel, action potentials were
recorded on a rate histogram.
[0047] FIG. 20 shows anterogradely labeled fibers (arrows) with
PHAL were abundant in the T3-T4 central gray region (area X;
photograph on right; cc=central canal). The lateral portion of the
central gray region contains the intermediomedial (IMM) cell
nucleus where some preganglionic sympathetic neuronal cell bodies
reside. Abundant PHAL immunoreactive fibers also were found in the
superficial dorsal horn and nucleus proprius (photograph on left)
in the T3-T4 segments.
[0048] FIG. 21 shows effects of vagal afferent stimulation on the
background activity and evoked activity of a T3 neuron before
ibotenic acid was placed on the dorsal C1-C2 spinal cord.
Electrical stimulation of the left cervical vagus (A: LCVS; {30 V,
0.1 ms} ipsilateral to the cell) right cervical vagus (B; RCVS;
contralateral) at different frequencies. Vagal stimulation reduced
the discharge rate of the evoked response to noxious stimulation of
the cardiac afferents intrapericardial injections of bradykinin
(C). IA; ibotenic acid. The short horizontal bars represent the
period of vagal stimulation, the long horizontal bar represents the
bradykinin injection and the numbers indicate the frequencies
tested.
[0049] FIG. 22 shows vehicle (A) or ibotenic acid (B) was placed
via pledget on the dorsal surface of the C1-C2 spinal segments for
2 hrs. After 14-16 hrs, rats were perfused with fixative and the
medulla, C1-2, C3-5 segments were processed for annexin
fluorescence histochemistry. Photomicrographs are from the C1
dorsal horn and the gray matter is outlined. Very little annexin
staining was observed in control tissue sections (A) or in the
medulla and C3-5 segments from ibotenic acid treated rats. White
arrows point to unlabeled (black) cells in the dorsal horn. In rats
treated with ibotenic acid (B), many annexin positive (white) cells
were observed (arrows). Annexin binding indicates cells with energy
impairment and/or undergoing apotosis. Annexin belongs to a family
of proteins that bind acidic phospholipids, particularly
phosphotidylserine (PS). PS is assymetically distributed in the
cell membrane by the enzyme, aminophospholipid translocase.
Following energy impairment, PS distributes to the outer cell
leaflet and annexin binding illustrates cells with PS on the
outside of the cell.
[0050] FIG. 23 shows responses of T3 cell to intrapericardial
injections of bradykinin (BK) before and after dorsal cord
activation. Electrical stimulation (250 uA, 0.25 us and 50 Hz) of
the ipsilateral (A) or contralateral (B) C1-C2 dorsal columns
applied prior to intrapericardial injections of BK markedly reduced
the evoked responses. C: dorsal cord activation during the evoked
response to BK also reduced the cell activity. Horizontal lines are
the period of the stimulus.
[0051] FIG. 24 shows epicardial conduction mapping across the
anterior myocardial infarction in a susceptible dog (panel a) and a
resistant dog (panel b) with normal left ventricular function. The
longest time for epicardial electrical activation was about 80
milliseconds in susceptible dogs. This is in contrast to resistant
dogs in which the longest time for epicardial activation was about
40 milliseconds.
[0052] FIG. 25 shows stratification of ventricular fibrillation
risk in a susceptible dog. Left panel illustrates induction of
ventricular fibrillation during exercise and myocardial ischemia
test. As shown in right panel, susceptible dogs are characterized
by a tachycardic response to acute myocardial ischemia that is
uncontrolled and leads to VF. Resistant dogs have an increase in
heart rate within 15 seconds of coronary occlusion, but have strong
vagal reflexes that reduce heart rate within 30 seconds of the
occlusion as illustrated in the right panel.
[0053] FIG. 26 shows the heart rate slowing in response to systemic
hypertension (phenylephrine induced) quantifies baroreflex
sensitivity.
[0054] FIG. 27 shows chronotropic response to graded increases in
treadmill exercise. Once heart rate reaches 210 beats per minute
the circumflex occluder is inflated for 2 minutes, the first minute
the dogs continue to run on the treadmill and the treadmill is
stopped for the last minute. While concurrent DCA minimally
affected heart rate responses in the resistant dog (right panel),
in the susceptible dog DCA reduced the heart rate during the
ischemic period (left panel).
[0055] FIG. 28 shows heart rate variability was computed from 25
minutes of continuous resting ECG with spectral densities computed
using a fast Fourier transformation. High frequency variation in
heart rate is thought to predominantly arise from vagal input to
the SA node, while lower frequency bands (VLF, LF) are thought to
arise predominantly from sympathetic activity. DCA effects were
examined on two different days following 4 days of stimulation
lasting for 4 hours.
[0056] FIG. 29 shows dorsal cord activation increased the standard
deviation of the RR intervals in both resistant and susceptible
dogs, again suggesting that cardiac autonomic neuronal activity
shifted toward efferent vagal control. Standard deviation of the RR
interval values below 100 milliseconds predicts high risk for
ventricular fibrillation during exercise and ischemia.
[0057] FIG. 30 shows percent change is ISF NE and EPI in response
to sole coronary artery occlusion (CAO, solid lines) and CAO in the
presence of DCA (CAO+DCA, dotted lines). Left panels show data from
normally perfused left ventricular regions. Right panels show data
from the ischemic zone. Time 0 is pre-occlusion baseline; CAO is on
for 15 min.
[0058] FIG. 31 shows effects of DCA on induction of ventricular
fibrillation (VF) associated with 15 min coronary artery occlusion
and reperfusion. Arrows indicate time point for onset of VF. With
coronary artery occlusion, VF was induced in 50% of the animals;
when VF occurred, it was within 6 min of reperfusion onset. With
pre-existing DCA, coronary artery occlusion induced VF in only 1 of
9 animals (1 min post DCA; 7 min post-occlusion).
[0059] FIG. 32 shows examples of the activity generated by a pair
of superficial spinal neurons in the T3 spinal segment. Aa is basal
activity recorded simultaneously from the neuron pair with intact
neuraxis and Ba is basal activity after vagotomy. With the neuraxis
intact, the cross-correlogram of the basal activity between these
two neurons showed a central peak centered around 0 delay and a
second smaller peak occurred approximately 150 ms after the central
peak. Following bilateral vagotomy, the central peak was reduced
and the secondary peak eliminated. Upper tracings represent
discharge rate (impulses/sec; imp/s) and lower tracings (Unit)
extracellular action potentials.
[0060] FIG. 33 shows responses of a T3 spinal neuron to an
electrically induced premature ventricular contraction. The extra
stimulus was delivered at the arrow in the top trace. This stimulus
produced a premature ventricular contraction that was followed by a
compensatory contraction (CC in middle trace). The 2.sup.nd arrow
in the top trace points out the burst of neuronal activity
following the extra stimulus that was associated with the
potentiated beat. The arrow in the bottom trace indicates
electrical activity associated with the electrical stimulus. The
ECG was recorded from lead II.
[0061] FIG. 34 shows the average neuronal activity data derived
from all animals during each of the five protocols utilized in this
study. When SCS was applied alone (A) neuronal activity was
suppressed, a change which persisted for a short time after
terminating the SCS (SCS off). (B) Coronary artery occlusion (CAO)
enhanced neuronal activity. (C) SCS suppressed neuronal activity
before, during and after coronary artery occlusion. Data obtained
for the other protocols (SCS and CAO) are presented in panels D and
E. * Represents data which was significantly different from control
values (P<0.05).
[0062] FIG. 35 shows the initiation of coronary artery occlusion
(arrow below) resulting in an increase in the activity generated by
right atrial neurons (individual units identified by action
potentials greater than the small atrial electrogram artifacts).
From above down are the ECG, aortic pressure (AP), left ventricular
chamber pressure (LVP) and neuronal activity. Horizontal timing
bar=30 s.
[0063] FIG. 36 shows the influence of SCS on the ECG, left
ventricular chamber pressure (LVP=145 mmHg) and intrinsic cardiac
neuronal activity (lowest line) before and during coronary artery
occlusion. (A) Multiple neurons generated action potentials,
represented by their differing heights, at a rate of 132 impulses
per minute (ipm) during control states. (B) Once SCS was initiated
(note stimulus artifacts in the neuronal tracing), neuronal
activity decreased to 34 imps/min (no activity generated during the
record). ECG alterations were induced thereby. (C) Neuronal
activity continued at the rate (39 imp) in the presence of SCS even
though coronary artery occlusion had been maintained for over 1.5
min.
[0064] FIG. 37 shows the transmural blood flow (ml/min/g) to LV
ischemic (closed spheres) and non-ischemic (closed squares) zones
for each of the three baseline control conditions (C1, C2, and C3)
and during the successive interventions of 5-min spinal cord
stimulation (SCS), 4-min occlusion of the LAD occlusion commencing
1 min into SCS (SCS-CO). Transmural blood flow within the ischemic
zone is significantly lower (* p=0.02) during both CO, and SCS-CO
(p=NS between these two interventions) compared to base line.
[0065] FIG. 38 shows pressure-volume (P-V) loops for the left
ventricle; P-V loops obtained under basal conditions are shown in
panels (A), (C) and (E) (i.e., baseline steady-state resting
conditions). P-V loops obtained during SCS at 90% motor threshold
(B), 4 min of LAD occlusion (D), and concurrent SCS and LAD
occlusion (F) are also shown.
[0066] FIG. 39 shows a graphical representation of the two
protocols in each group of five dogs. Note that 1.5 h was allowed
to lapse between each intervention in either protocol.
[0067] FIG. 40 shows the effects of coronary artery occlusion on
the activity generate by intrinsic cardiac neurons in one animal.
Following occlusion of the left anterior descending coronary artery
(beginning at arrow below), the activity generated by right atrial
neurons (lowest line) increased (right-hand panel). Heart rate was
unaffected by this intervention, while left ventricular chamber
systolic pressure (LVP) increased a little. The time between panels
represents 1.5 min.
[0068] FIG. 41 shows the activity generated by intrinsic cardiac
neurons in one animal during control states (panel A, lowest line)
decreased when the dorsal aspect of the spinal cord was stimulated
(panel B). The suppressor effects of SCS persisted during coronary
artery occlusion (panel C). The electrical stimuli delivered during
SCS are represented in panels B and C by regular, low
signal-to-noise artifacts (note that atrial electrical artifact is
recorded during each cardiac cycle as a low signal during the p
wave of the ECG). The suppression of spontaneous activity generated
by intrinsic cardiac neurons persisted after discontinuing SCS
(panel E represents neuronal activity recorded 5 min post-SCS and 6
min post-LAD occlusion; panel D represents basal activity at same
time scale obtained before commencing these interventions).
ECG=electrocardiogram; AP=aortic pressure; LVP=left ventricular
chamber pressure.
[0069] FIG. 42 shows representative ECG records obtained from one
animal during control states (A), as well as a few minutes after
beginning coronary artery occlusion in the presence of spinal cord
stimulation (B) and at the end of occlusion while SCS was
maintained (C). Note that ST segment alterations occurred
throughout the period of ischaemia.
[0070] FIG. 43 shows the average neuronal activity recorded in all
animals before, during and after dorsal spinal cord stimulation
(SCS) delivered in the presence of coronary artery occlusion
(occlusion). Note that SCS reduced neuronal activity soon after its
application began. SCS also prevented enhancement in intrinsic
cardiac neuronal activity normally associated with coronary artery
occlusion (cf. Table V). Neuronal activity remained reduced for 17
min after terminating SCS despite the induction of myocardial
ischaemia. These data were collected during application of the
first SCS in protocol 2.
[0071] FIG. 44 is a flow chart illustrating the steps of the method
of treating sequelae of myocardial ischemia in a patient discussed
herein.
DETAILED DESCRIPTION OF THE INVENTION
[0072] Before explaining at least one embodiment of the invention
in detail, it is to be understood that the invention is not limited
in its application to the details of construction and the
arrangements of the components set forth in the following
description of illustrated in the drawings. The invention is
capable of other embodiments or of being practiced or carried out
in various ways. Also, it is to be understood that the phraseology
and terminology employed herein is for purpose of description and
should not be regarded as limiting.
[0073] The intrinsic cardiac nervous system has been classically
considered to contain only parasympathetic efferent postganglionic
neurons that receive inputs from medullary parasympathetic efferent
preganglionic neurons. As such, intrinsic cardiac ganglia have been
viewed as simple relay stations and major autonomic neuronal
control of the heart was believed to reside solely in the brainstem
and spinal cord. However, the data supporting the presently claimed
and disclosed invention indicate that centripetal as well as
centrifugal processing occurs within the mammalian intrathoracic
nervous system (i.e., the intrinsic cardiac nervous system). This
involves afferent neurons, local circuit neurons (i.e., neurons
that interconnect neurons within one ganglion and neurons in
different intrathoracic ganglia), as well as sympathetic and
parasympathetic efferent postganglionic neurons.
[0074] The intrinsic cardiac nervous system consists of multiple
aggregates of neurons and associated neural interconnections,
localized to discrete atrial and ventricular regions. Among these
distinct ganglionated plexi, preferential control of specific
cardiac functions has been identified. For example, right atrial
ganglionated plexus neurons have been associated with primary, but
not exclusive, control of SA nodal function and inferior vena
cava-inferior atrial ganglionated plexus neurons primarily, but not
exclusively, with control of AV nodal function. One population of
intrinsic cardiac neurons, the parasympathetic postganglionic ones,
receives direct input from medullary parasympathetic preganglionic
neurons. Another population, adrenergic efferent ones [8,9],
receives input from more centrally located neurons in intrathoracic
ganglia and the spinal cord. The fact that ventricular sensory
neurites continue to influence the activity generated by neurons on
the heart following chronic decentralization of the intrinsic
cardiac nervous system indicates that the somata of afferent
neurons, some of which project axons to central neurons, are
located within the intrinsic cardiac nervous system. This concept
has received anatomical confirmation. Functional data also indicate
that the intrinsic cardiac nervous system contains local circuit
neurons interconnecting intrinsic cardiac afferent with efferent
neurons.
[0075] Sub-populations of right atrial neurons that receive
afferent inputs from sensory neurites in both ventricles are
responsive to local mechanical stimuli and the nitric oxide donor
nitroprusside. Neurons in at least one ganglionated plexus locus
were activated by epicardial application of veratridine,
bradykinin, the .beta.1-adrenoceptor agonist prenaterol or the
excitatory amino acid glutamate. Epicardial application of
angiotensin II, the selective .beta..sub.2-adrenoceptor agonist
terbutaline or selective .alpha..sub.1- or
.alpha..sub.2-adrenoceptor agonists elicited inconsistent neuronal
responses. The activity generated by both populations of atrial
neurons studied over 5 minute periods during basal states displayed
periodic coupled behavior (cross correlation coefficients of
activities that reached, on average, 0.88.+-.0.03; range 0.71-1)
for 15-30 seconds periods of time. These periods of coupled
activity occurred every 30-50 second during basal states, as well
as when neuronal activity was enhanced by chemical activation of
their ventricular sensory inputs. It has been observed that neurons
throughout one intrinsic cardiac ganglionated plexus receive inputs
from mechano- and chemo-sensory neurites located in both
ventricles. That such neurons respond to multiple chemical stimuli,
including those liberated from adjacent adrenergic efferent nerve
terminals, indicates the complexity of the integrative processing
of information that occurs within the intrinsic cardiac nervous
system. Thus, the interdependent activity displayed by populations
of neurons in different regions of one intrinsic cardiac
ganglionated plexus, responding as they do to multiple cardiac
sensory inputs, forms the basis for integrated regional cardiac
control.
[0076] Recent anatomical and functional data indicate the presence
of the multiple neuronal subtypes within intrathoracic extracardiac
and intrinsic cardiac ganglia. Within this neuronal hierarchy, the
intrinsic cardiac nervous system functions as a distributive
processor at the level of the target organ. The redundancy of
function and non-coupled behavior displayed by neurons in
intrathoracic extracardiac and intrinsic cardiac ganglia minimizes
the dependency for such control on a single population of
peripheral autonomic neurons. In this regard, network interactions
that occur within the intrinsic cardiac nervous system to integrate
parasympathetic and sympathetic efferent outflow to the heart do so
in coordination with intrathoracic extracardiac neurons that
process afferent information from multiple sites in the heart
during each cardiac cycle. As no consistent coherence of activity
generated has been identified among neurons in intrinsic cardiac
and intrathoracic extracardiac ganglia, different populations of
neurons, distributed spatially within the intrathoracic cardiac
nervous system, respond to cardiac perturbations in a coordinate
fashion. If neurons in one part of this neuronal network respond
solely to inputs from a single region of the heart, such as the
mechanosensory neurites associated with a right ventricular ventral
papillary muscle, then the potential for imbalance within the
different populations of neurons regulating various cardiac regions
might occur. A relatively low level of inputs on a spatial scale to
the intrinsic cardiac nervous system would result in low coherence
among its components. In contrast, excessive input to this
spatially distributed nervous system would destabilize it, leading
to cardiac arrhythmia formation, etc.
[0077] Regional control of cardiac function is dependent upon the
coordination of activity generated by neurons within intrathoracic
autonomic ganglia and the central nervous system. The hierarchy of
nested feedback loops therein provides precise beat-to-beat control
of regional cardiac function. Contrary to classical teaching,
intrathoracic autonomic ganglia act as more than simple relay
stations for autonomic efferent neuronal control of the heart.
Within the hierarchy of intrathoracic ganglia and nerve
interconnections, complex processing takes place that involves
spatial and temporal summation of sensory inputs, preganglionic
inputs from central neurons and intrathoracic ganglionic reflexes
activated by local cardiopulmonary sensory inputs. The activity of
neurons within intrathoracic autonomic ganglia is likewise
modulated by circulating hormones, chief among them being
circulating catecholamines and angiotensin II.
[0078] The progressive development of cardiac disease is associated
with maladaptation of these neurohumoral control mechanisms.
Differences exist in autonomic control of the heart before any
overt cardiovascular disease occurs and such differences critically
influence the outcome at the time of ischemic heart disease onset.
Differential remodeling of the cardiac neuron hierarchy (central
and peripheral) for reflex control of the heart occurs in animals
susceptible verses resistant to development of ventricular
fibrillation during the evolution of chronic myocardial
ischemia/infarction. Understanding neuronal
reorganization/remodeling that occurs within the peripheral
autonomic nervous system and the interactions that occur between
this neural remodeling and the remodeling of the myocardium leads
to the novel approaches as presently disclosed and claimed for
anti-arrhythmia therapy and also to therapies directed at ischemic
heart disease and protection of the heart.
[0079] With respect to neural control of the heart, the
intrathoracic ganglia and their interconnections form the final
common pathway for autonomic modulation of cardiac function. Data
summarized and presented herein indicates in support of the
presently claimed and disclosed invention that intrathoracic
autonomic ganglia contain a heterogeneous population of cell types
including afferent, efferent and local circuit neurons. Yet, as a
group, the intrathoracic reflexes mediated within these peripheral
autonomic ganglia function in a coordinated fashion with central
neurons located in the spinal cord, brainstem and supraspinal
regions to regulate cardiac output on a beat to beat basis.
[0080] Afferent Neurons
[0081] Cardiac Afferent Neurons.
[0082] Sensory afferent neurons provide the autonomic nervous
system with information about blood pressure, blood volume, blood
gases as well as the mechanical and chemical milieu of the heart.
For sensory inputs from cardiopulmonary regions, the nodose and
dorsal root ganglia are classically recognized as providing sensory
inputs to the brainstem and spinal cord respectively. Data
indicates that intrathoracic extracardiac (i.e., stellate and
middle cervical ganglia) and intrinsic cardiac ganglia also contain
afferent neurons whose sensory neurites lie variously within the
heart, lungs and great thoracic vessels. Additional sensory inputs
for the control of cardiac autonomic neurons arise from
baroreceptors and chemoreceptors located along the aortic arch,
carotid sinus and carotid bodies as well as from other afferent
neural elements within the CNS, especially the hypothalamus.
[0083] Nodose Ganglia Afferent Neurons.
[0084] The nodose receive cardiac afferent inputs from sensory
neurites located in atrial and ventricular tissues. These sensory
neurites preferentially sense chemical stimuli, with a few
responding to mechanical stimuli or both modalities. The response
characteristics to induced stimuli are likewise divergent with
mechanical stimuli exerting short-lived effects, while the
augmentation in activity elicited by chemical stimuli far outlasts
the applied stimulus. While inputs from these receptors contribute
to overall cardiovascular regulation, they are not normally
perceived.
[0085] Dorsal Root Ganglia (DRG) Afferent Neurons.
[0086] The cell bodies of DRG afferent neurons, receiving input
from cardiac sensory neurites, are located in C.sub.6-T.sub.6
dorsal root ganglia. The sensory neurites of most of these afferent
neurons transduce chemical and mechanical stimuli. The inputs from
this subpopulation of cardiac afferent neurons subserve normal
cardiovascular regulation, as well as nociception when excessively
activated.
[0087] Intrathoracic Afferent Neurons.
[0088] Functional and anatomical data indicate that intrathoracic
autonomic ganglia contain afferent soma. The sensory neurites
associated with these afferent neurons are variously located in
atrial, ventricular, major vascular and pulmonary tissues. Most are
responsive to mechanical and chemical stimuli. These afferent
neurons continue to influence intrathoracic efferent postganglionic
outflows to the heart even after long-term decentralization of
intrathoracic ganglia. Such intrathoracic afferent neurons provide
inputs to the intrathoracic short-loop feedback control circuits
that involve intrinsic cardiac and intrathoracic extracardiac
neurons. These intrathoracic neural circuits, acting in concert
with CNS mediated reflexes, dynamically control regional cardiac
function throughout each cardiac cycle to maintain electrical
stability of the heart and protect the myocytes.
[0089] Aortic and Carotid Artery Baroreflexes.
[0090] Stretch receptors, sensitive to changes in vessel size, are
found on thoracic and cervical arteries, being concentrated on the
aortic arch and the carotid sinus. They provide inputs to neurons
within the medulla and spinal cord proportional to systemic
arterial blood pressure. Inputs from these sensory neurites course
centrally in the IX and X cranial nerves to synapse with neurons
located in the nucleus of the medullary solitary tract. Via
multi-synaptic connections, these afferent inputs modulate the
activity of cardiac parasympathetic efferent preganglionic neurons
located primarily in the nucleus ambiguus. They also influence
sympathetic efferent neuronal outflow to the heart via brainstem
projections to the intermediolateral (IML) region of the spinal
cord. The baroreflex so involved represents a negative feedback
system that modulates cardiac function and peripheral vascular tone
in response to everyday stressors.
[0091] Efferent Neurons
[0092] Sympathetic Efferent Neurons.
[0093] The somata of sympathetic preganglionic efferent
preganglionic neurons which regulate the heart are located within
the intermediolateral (IML) cell column of the spinal cord,
projecting axons via the rami T1-T5 to synapse with sympathetic
postganglionic neurons contained within various intrathoracic
extracardiac and intrinsic cardiac ganglia. Activation of these
sympathetic efferent projections augments heart rate, changes
patterns and speed of impulse conduction through the electrical
system of the heart and increases contractile force in atrial and
ventricular tissues. Sympathetic efferent postganglionic somata
that project axons to various cardiac effector tissues are
localized in intrathoracic extracardiac and intrinsic cardiac
ganglia. Classically, the somata of sympathetic efferent
postganglionic neurons that innervate the heart have been thought
to be restricted to the stellate ganglia. However, cardiac
sympathetic efferent postganglionic soma have also been identified
in thoracic middle cervical, mediastinal and intrinsic cardiac
ganglia. A subpopulation of intrinsic cardiac neurons express the
catecholaminergic phenotype, these neurons thus contain the
necessary enzymes to convert L-DOPA to dopamine and norepinephrine.
The intrinsic cardiac nervous system also contains a separate
population of small intensely fluorescent (SIF) cells that display
tyrosine hydrolyase immunoreactivity. Some of these projects to
adjacent principal intrinsic cardiac neurons.
[0094] Parasympathetic Efferent Neurons.
[0095] The somata of cardiac parasympathetic efferent preganglionic
neurons within the brainstem are located primarily within the
nucleus ambiguous, with lesser numbers being located in the dorsal
motor nucleus and regions in between. Axons from these
preganglionic soma projects via the X cranial nerve to synapse with
parasympathetic efferent postganglionic neurons located within
various intrinsic cardiac ganglia (see hereinafter below).
Activation of parasympathetic efferent neurons depresses heart
rate, slows the speed of impulse conduction through the heart,
induces major suppression of atrial muscle contractile force and
evokes negative inotropic effects on ventricular contractile
force.
[0096] Local Circuit Neurons
[0097] A subpopulation of neurons contained within extracardiac and
intrinsic cardiac intrathoracic autonomic ganglia function to
interconnect neurons within individual ganglia and between neurons
in separate intrathoracic ganglia; these are called local circuit
neurons. Preliminary data indicate that these neurons are involved
in processing of afferent information to coordinate sympathetic and
parasympathetic efferent outflows to cardiac effector sites.
Interactions within this neuron population form the substrate for
generation of the basal activity within peripheral autonomic
ganglia, especially when intrathoracic ganglia are disconnected
from the influence of central neurons.
[0098] Organization of the Intrinsic Cardiac Nervous System
[0099] The cardiac nervous system consists of distinct ganglia
clusters that function in an interdependent manner to modulate
regional cardiac function. To date, eight separate ganglia clusters
have been identified within the canine intrinsic nervous system,
five associated with atrial tissues and three with ventricular
tissue.
[0100] The five atrial ganglionated plexuses include: 1) the right
atrial ganglionated plexus localized in fatty tissue on the ventral
surface of the common right pulmonary vein complex; 2) the inferior
vena cava-inferior atrial ganglionated plexus located on the
inferior right atrium adjacent to the inferior vena cava; 3) the
dorsal atrial ganglionated plexus located on the dorsal surface of
the atria between the common pulmonary veins, immediately caudal to
the right pulmonary artery; 4) the ventral left atrial ganglionated
plexus contained within fat on the caudal-ventral aspect of the
left atrium adjacent to the AV groove; and 5) the posterior atrial
ganglionated plexus.
[0101] The three major ventricular ganglionated plexi are: 1) the
right lateral ventricular ganglionated plexus located adjacent to
the origin of the right marginal artery; 2) the left lateral
ventricular ganglionated plexus located adjacent to the origin of
the left marginal artery; and 3) the cranial medial ventricular
ganglionated plexus located in fatty tissues surrounding the base
of the aorta and main pulmonary artery. Of these eight clusters of
ganglia, functions have been primarily ascribed to five of them:
neurons in the right atrial and posterior atrial ganglionated
plexus have been shown to exert preferential control over the
sinoatrial node; those in inferior vena cava-inferior atrial
ganglia exert predominant control over inferior atrial and
atrioventricular conductile tissues. Neurons in dorsal atrial and
cranial medial ventricular ganglia are principal modulators of
contractile tissue.
[0102] Neurohumoral Interactions Contributing to Cardiac
Control
[0103] FIG. 1 is a graphical representation of the neurohumoral
interactions involved in control of cardiac function. Data
indicates that a hierarchy of peripheral autonomic neurons
functions interdependently via nested feedback loops to regulate
cardiac function on a beat-to-beat basis. FIG. 1, therefore,
summarizes the concept of neural control of the heart as mediated
by intrathoracic extracardiac and intracardiac neurons which are
continuously influenced by descending projections from higher
centers in the spinal cord, brainstem, and suprabulbar regions.
Each successive synaptic relay point within this autonomic outflow,
from the brainstem to the heart, is in turn influenced by afferent
feedback from various cardiopulmonary and vascular afferent
receptors. Accumulating evidence suggests that there may be at
least four functionally distinct neuronal types within the
intrinsic cardiac nerve plexus; parasympathetic postganglionic
efferent neurons, local circuit neurons, adrenergic postganglionic
efferent neurons and afferent neurons. Local circuit and cardiac
afferent neurons also lie within intrathoracic extracardiac
ganglia, along with the sympathetic postganglionic neurons.
[0104] With respect to intrathoracic autonomic ganglia, cholinergic
and adrenergic efferent neurons in these ganglia represent the
output elements that project axons to cardiac electrical and
mechanical tissues. Local circuit neurons interconnect adjacent
neurons within one ganglion or link neurons in separate clusters of
intrathoracic ganglia. These interneurons are involved in
coordination of neuronal activity within these peripheral autonomic
ganglia, thereby providing the underlying inputs necessary for the
maintenance of basal autonomic neuronal discharge. Intrathoracic
afferent neurons provide mechanosensitive and chemosensitive inputs
from cardiopulmonary regions directly to intrinsic cardiac and
extracardiac neurons, forming the basis of the intrathoracic neural
feedback system. Superimposed on activities generated by neurons in
peripheral autonomic ganglia are efferent inputs from preganglionic
neurons in the brainstem and spinal cord that together exert tonic
influences on regional cardiac tone. CNS preganglionic inputs are,
in turn, influenced by inputs from higher centers in the central
nervous system and by afferent feedback from central and peripheral
sensory afferent neurons.
[0105] Interactions Among Peripheral Autonomic Neurons
[0106] Cardiac performance is modulated by both sympathetic and
parasympathetic efferent neuronal inputs. The induced change in any
regional cardiac function ultimately depends upon the intrinsic
characteristics of the cardiac end-effector being innervated, the
level of efferent activity from the CNS to the periphery and
interactions occurring within peripheral autonomic ganglia and at
the respective cardiac end-effectors.
[0107] Interactions at the Organ Level.
[0108] Anatomical and functional studies indicate that sympathetic
and parasympathetic efferent postganglionic nerve endings lie in
close proximity to each other in the target tissues. Interactions
among sympathetic and parasympathetic efferent projections to the
heart involve pre- and postjunctional mechanisms at the
end-effectors in cardiac tissue. Postjunctional interactions
involve differential modulation of adenylate cyclase via G-protein
coupled receptor systems (FIG. 1). Catecholamines, released from
sympathetic efferent projections or derived from the circulation,
influence myocardial tissues by binding primarily to .beta..sub.1
and .beta..sub.2-adrenoceptors. Myocardial .beta. adrenergic
receptors are coupled to and stimulate adenylate cyclase via
stimulatory guanine nucleotide binding protein (G.sub.s).
Acetylcholine, released from parasympathetic efferent
postganglionic neurons, binds to cardiomyocyte M.sub.2 muscarinic
receptors which, in turn, are coupled to and inhibit adenylate
cyclase via inhibitory guanine nucleotide binding protein
(G.sub.i). The interactions between these two receptor-coupled
systems at the adenylate cyclase level ultimately determine the
rate of formation of cAMP and thereby myocyte second messenger
function. The neural interactions that occur at cardiac
end-effectors involve primarily modulation of neurotransmitter
release from pre-junctional synaptic terminals. Neural release of
the principal mediators norepinephrine and acetylcholine, along
with the co-release of various neuropeptides (e.g. NPY and VIP) act
on specific receptors associated with sympathetic or
parasympathetic efferent axon terminals. These mechanisms act to
modulate subsequent neurotransmitter release.
[0109] Interactions within the ICN.
[0110] Various lines of evidence indicate that peripheral sites
that are separate from the end-effectors contribute to mediating
sympathetic-parasympathetic interactions for the control of
regional cardiac function. Stimulating parasympathetic and/or
sympathetic efferent projections to the heart activates
subpopulations of intrinsic cardiac neurons. These extrinsic
autonomic projections converge on separate aggregates of intrinsic
cardiac neurons, each of which exhibit preferential control over
regional cardiac function. With respect to control of chronotropic
function, surgical disruption of the right atrial ganglionated
plexus eliminates direct vagal projections to the sinoatrial node.
Sympathetic efferent neuronal control of chronotropic function and
the vagal inhibition of the sinus tachycardia produced by cardiac
sympathetic efferent neurons are maintained. These residual
sympathetic-parasympathetic efferent neuronal interactions occur at
the level of the heart and are prejunctional to the sinoatrial
node. As shown herein, these residual interactions occur within the
intrinsic cardiac nervous system. Whether such intraganglionic
autonomic interactions play correspondingly roles in modulation of
dromotropic and inotropic function has yet to be determined.
[0111] Intraganglionic interactions within the intrinsic cardiac
nervous system depend in large part on common shared afferent
inputs and/or interconnections mediated via local circuit neurons.
In order to evaluate these interactions, separate populations of
neurons were recorded in the ventral right atrial ganglionated
plexus (RAGP) in basal states and during discrete mechanical and
chemical stimuli of ventricular neurites. In basal states, the
coherence of activity generated by the two populations of RAGP
neurons fluctuated with a periodicity of 30-50 s and with an
average peak coherence of 0.88.+-.0.03. Coherence was increased in
conjunction with the enhanced neuronal activity evoked during
exposure of ventricular sensory inputs to mechanical and chemical
(nitroprusside, veratridine, bradykinin, adrenergic agonists or
glutamate) stimuli. The interdependent activity displayed by the
population of neurons in different regions of one intrinsic cardiac
ganglionated plexus, depending as they do on multiple cardiac
sensory inputs, forms the basis for coordination of regional
cardiac function within the intrinsic cardiac nervous system.
[0112] Interactions within the Intrathoracic Nervous System.
[0113] Coordination of autonomic outflows from intrathoracic
neurons to cardiomyocytes depends to a large extent on sharing of
inputs from higher centers along with interactions among and
between various peripheral ganglia. Interactions within and between
intrathoracic ganglia involve local circuit neurons (see herein
above). Activities generated by neurons in intrinsic cardiac
ganglia demonstrate no consistent short-term relationship to
neurons in extracardiac ganglia. However, the sharing of
cardiopulmonary afferent information acting through both
intrathoracic and brain stem/spinal cord feedback loops permits an
overall coordination of effector control. Together, these nested
feedback control systems allow for a redundancy in neural control
of the heart while at the same time maintaining the flexibility to
differentially modulate regional cardiac function.
[0114] Electrophysiology of Intrinsic Cardiac Ganglia
[0115] In Vivo Studies.
[0116] Cardiac neurons generate spontaneous activity in situ,
frequently exhibiting activity that is temporally related to the
cardiac or respiratory cycles. Of the neurons that displayed
cardiac-related activity, many are affected by mechano- or
chemosensory inputs from the heart. Trains of electrical stimuli
delivered to axons in the T1-T5 ventral roots activate a
substantial population of stellate and middle cervical neurons.
These data indicate a convergence of preganglionic inputs onto the
extracardiac postganglionic soma, reflective of a functional
amplification of such sensory input. In contrast, trains of
electrical stimuli delivered to the vagosympathetic trunks or
stellate ganglia activate a much smaller population of intrinsic
cardiac neurons. Moreover, few intrinsic cardiac neurons are
activated after a fixed latency when extracardiac efferent neurons
that innervate the heart are stimulated electrically, a finding
indicative of monosynaptic interconnections to such neurons. These
data indicate that, in contradistinction to extracardiac ganglia,
substantial spatial and temporal summation of inputs are required
to modify the activity generated by neurons on the heart. Intrinsic
cardiac neurons generate low level activity in such a state
consistent with a nerve network that functions as a "low pass
filter", thereby minimizing the potential for imbalances within
autonomic efferent neuronal inputs to the heart, a process which by
itself could be arrhythmogenic.
[0117] In Vitro Studies.
[0118] Intrinsic cardiac ganglia contain a heterogeneous population
of neurons. An intracellular recording from isolated whole mount
aggregates of intrinsic cardiac ganglia indicates that complex
neural interactions occur within the heart. Studies on aggregates
of intrinsic cardiac ganglia derived from different species further
indicate that the resting membrane potentials of these neurons is
approximately -60 mV, with relatively low input resistances and
thresholds for the generation of action potential being
approximately 20 mV more positive than the resting membrane
potential. These properties are consistent with neurons functioning
with low excitability. No evidence for ramp-like pacemaker
activities has been found within mammalian intrinsic cardiac
neurons in vitro. Thus spontaneous activity generated by such
neurons in vivo likely reflects underlying cell-cell interactions.
For orthodromic stimulation there is substantial dispersion in time
of the evoked excitatory postsynaptic potentials (EPSP's) generated
by a given intrinsic cardiac neuron, indicative of polysynaptic
inputs to neurons within the intrinsic cardiac nervous system.
After the generation of action potentials, prolonged after
hyperpolarizations are produced by these cells, an additional
factor which limits the excitability of intrinsic cardiac neurons
in situ. Chronic disruptions of nerve inputs to these ganglia evoke
changes in membrane properties which may result in increased
excitability within the ganglionated plexus.
[0119] Intracellular recordings from isolated aggregates of
intrinsic cardiac ganglia have identified both cholinergic and
non-cholinergic synaptic mechanisms coexisting within intrinsic
cardiac ganglia. In rats and pigs only fast excitatory postsynaptic
potentials are displayed by intrinsic cardiac neurons in response
to orthodromic stimulation of closely adjacent intraganglionic
axons. These postsynaptic potentials are substantially attenuated,
but not completely eliminated, by nicotinic cholinergic blockade.
In the dog, orthodromic stimulation of presynaptic fibers in these
nerves elicits fast and slow postsynaptic potentials within
intrinsic cardiac neurons. Fast excitatory postsynaptic potentials
are mediated by cholinergic nicotinic receptors, while the slow
excitatory and slow inhibitory potentials are mediated by
cholinergic muscarinic receptors. In the pig direct application of
norepinephrine modifies the properties of about 25% of identified
intrinsic cardiac neurons. These data indicate that intrinsic
cardiac neurons possess muscarinic cholinergic, nicotinic
cholinergic as well as adrenergic receptors. As detailed
hereinafter, many other putative neurotransmitters likewise modify
electrical events of intrinsic cardiac neurons. These
neurochemicals may play important roles in the modulation of
intrinsic cardiac neuronal activity.
[0120] In summary, intrathoracic autonomic ganglia do not function
as obligatory synaptic stations for autonomic efferent neuronal
input to the heart. Instead, they are capable of complex signal
integration involving afferent, local circuit as well as
parasympathetic and sympathetic efferent neurons. While the
physiological properties of extracardiac autonomic ganglia tend to
amplify CNS and afferent feedback inputs, those of the intrinsic
cardiac nervous system act to limit cardiac excitability. As such,
the final common pathway of cardiac control--the intrinsic cardiac
nervous system--appears to function as a "low pass" filter to
minimize transient neuronal imbalances arising from separate
sympathetic and parasympathetic efferent neuronal inputs to the
heart. In conjunction with this local afferent feedback mechanism,
neurons in intrathoracic ganglia also mediate local cardio-cardiac
reflexes at sites separate from those on the heart and the CNS. The
synaptic events underlying such intraganglionic interactions
involve multiple neurotransmitters that interact with various
neuronal receptors to exert rapid acting neuronal membrane
conductance and/or longer-term modulation of synapses within the
intrinsic cardiac nervous system.
[0121] Synaptic Mechanisms Associated with Neurons in Intrathoracic
Autonomic Ganglia
[0122] Cholinergic Mechanisms.
[0123] Synaptic transmission in autonomic ganglia principally
involves the release of acetylcholine by presynaptic terminals and
subsequent binding of that neurotransmitter to nicotinic
cholinergic receptors on postganglionic neurons. In mammals this
synaptic junction is not obligatory, indicating that a significant
convergence of inputs may be necessary to evoke postganglionic
neuronal activity. Thus the potential for synaptic integration
exists within intrathoracic autonomic ganglia. Nicotinic and
muscarinic cholinergic receptors have been associated with
intrathoracic autonomic neurons. Furthermore, blockade of nicotinic
receptors attenuates, but does not eliminate, activity generated by
the intrinsic cardiac neurons. Muscarinic blockade attenuates
excitatory and inhibitory synaptic function within intrinsic
cardiac ganglia as well. These sets of data indicate that
acetylcholine exerts both mediator and modulator effects at
synapses within intrathoracic autonomic ganglia.
[0124] Application of nicotine to intrathoracic autonomic neurons
can alter their activity and induce concomitant changes in regional
cardiac function, whether the neurons are located in extracardiac
or intrinsic cardiac ganglia. Nicotinic activation of intrinsic
cardiac neurons evokes a biphasic cardiac response, with initial
suppression in regional cardiac function being followed by
augmentation. Acute decentralization of intrathoracic ganglia from
the CNS attenuates, but does not eliminate, such effects. In time,
following chronic decentralization of intrathoracic ganglia
including those on the heart as with cardiac transplantation,
peripheral nerve networks remodel to sustain cardiac function. For
cholinergic receptor systems, the remodeling primarily involves
augmentation of excitatory influences mediated by muscarinic
receptors.
[0125] Non-Cholinergic Mechanisms.
[0126] Blockade of nicotinic cholinergic receptors attenuates, but
does not eliminate, the activity generated by neurons within the
intrathoracic autonomic ganglia. These data indicate that
non-nicotinic putative neurotransmitters act as mediators for
synaptic transmission within the intrathoracic neuronal system.
Anatomical and physiological studies have identified multiple
putative neurotransmitters in association with the mammalian
intrinsic cardiac ganglia which include purinergic agonists,
catecholamines, angiotensin II, calcitonin gene-related peptide,
neuropeptide Y, substance P, neurokinins, endothelin and vasoactive
intestinal peptide. Many of these putative neurochemicals arise
from neurons whose cell bodies are located in stellate, middle
cervical or mediastinal ganglia, while others may be synthesized by
neurons intrinsic to the heart. Direct application of various
neurotransmitters adjacent to neurons in intrinsic cardiac ganglia
modifies the activities they generated, often resulting in
concomitant changes in cardiac pacemaker and/or contractile
behavior.
[0127] Intrinsic cardiac ganglia contain a heterogeneous population
of neurons that utilize cholinergic and non-cholinergic synapses to
control intraganglionic, interganglionic and nerve effector organ
cell activities. Some of these neurotransmitters subserve short
duration synaptic actions (e.g., acetylcholine) while others
modulate pre- and/or post-synaptic function over longer periods of
time (e.g., neuropeptide Y).
[0128] Neural Remodeling in the Heart Associated with Myocardial
Ischemia
[0129] Myocardial ischemia and infarction can induce substantial
changes in the intrathoracic nerve networks and their reflex
control of regional cardiac function. Chen and co-workers [(41; 42;
122)] have recently proposed the sprouting hypothesis of sudden
cardiac death: namely, "Myocardial Ischemia results in nerve
injury, followed by sympathetic nerve sprouting and regional
myocardial hyperinnervation. The coupling between augmented
sympathetic nerve sprouting with electrical remodeled myocardium
results in VT, VF and SCD." The results of these studies and others
have indicated that the evolution of cardiac pathologies may be
associated with a heterogeneous distribution of efferent
projections to cardiac end-effectors. Myocardial ischemia may also
alter the neurochemical profile of that innervation; e.g.,
expression of vasoactive intestinal polypeptide and calcitonin
gene-related peptide are enhanced in sympathetic neurons after
myocardial infarction. Finally, the evolution of cardiac pathology
can be associated with disruptions of the intrinsic cardiac nervous
system and its ability to process afferent information. Such
changes compromise the abilities of the peripheral nerve networks
to maintain homogeneity for reflex control of regional cardiac
function. This neural remodeling, when coupled with the
ischemic-induced heterogeneous electrical remodeling of cardiac
myocytes, creates a synergistic substrate for arrhythmias and
sudden cardiac death.
[0130] Interactions Between CNS and Intrathoracic Neuronal
Networks: Implications for Treatment of Myocardial Ischemia and
Angina Pectoris
[0131] Myocardial ischemia reflects an imbalance in the supply:
demand balance within the heart with resultant activation of
cardiac afferent neurons and, as a consequence, the perception of
symptoms (i.e., angina pectoris). In addition to such nociceptive
responses, activating cardiac afferent neurons can elicit autonomic
and somatic reflexes. Pharmacological, surgical and angioplasty
therapies are commonly used to improve symptoms and cardiac
function in patients exhibiting angina pectoris. While these
treatments are usually successful, some patients still suffer from
cardiac pain following these procedures. Recently, epidural
stimulation of the spinal cord (SCS or Dorsal Cord Activation, DCA)
has been suggested as an alternative to bypass surgery in high-risk
patients. With DCA, high frequency, low intensity electrical
stimuli are delivered to the dorsal aspect of the T1-T3 segments of
the thoracic spinal cord. This therapy decreases the frequency and
intensity of anginal episodes. DCA reduces the magnitude and
duration of ST segment alteration during exercise stress in
patients with cardiac disease, improves myocardial lactate
metabolism and increases workload tolerance. The mechanisms whereby
this mode of therapy produces such beneficial effects are, to date,
poorly understood and although used extensively in Europe, are not
a standard of practice within the United States.
[0132] Since intrathoracic cardiac neurons have been found to play
important modulatory roles in cardiac regulation, the use of DCA
and its effects on the activity generated by intrinsic cardiac
neurons has been studied and is at least one component of the
presently claimed and disclosed invention. Transient cardiac
ventricular ischemia increases the activities generated by
intrathoracic ganglia, including those on the heart. Excessive
focal activation of intrathoracic neural circuits can induce
cardiac dysrhythmias, even in normally perfused hearts. DCA results
in an immediate suppression in intrinsic cardiac neuronal activity.
A neuro-suppressor effect imposed in the intrinsic cardiac nervous
system occurs whether DCA is applied immediately before, during or
after coronary artery occlusion (FIGS. 2 and 3). Furthermore, the
suppression of intrinsic cardiac neuronal activity persists even
after cessation of DCA (FIG. 4). That transection of the ansae
subclavia eliminated these effects indicates that they primarily
involve the sympathetic nervous system.
[0133] The synaptic mechanisms and specific pathways mediating
these responses likely involve both sympathetic afferent and
efferent neurons. Dorsal cord activation excites sensory afferent
fibers antidromically such that endorphins or neuropeptides such as
calcitonin gene-related peptide or substance P are locally released
in the intrinsic cardiac ganglia and myocardium. Opiates and
neuropeptides can also influence intrinsic cardiac neurons (see
hereinabove). Spinal cord stimulation also suppresses intrinsic
cardiac adrenergic as well as local circuit neurons as the result
of altered sympathetic efferent preganglionic neuronal activity. It
is also known that activation of sympathetic efferent preganglionic
axons suppresses many intrathoracic reflexes that are involved in
cardiac regulation. Thus these neuro-suppressor effects appear to
be due, in part, to activation of inhibitory synapses within
intrathoracic ganglia. Recent clinical experience with DCA
highlights the dynamic interactions that can occur between central
and intrathoracic neurons, demonstrating the potential for
effective clinical treatment of cardiac pathology via modulation of
the intrathoracic nervous system or the intrinsic cardiac nervous
system.
[0134] Coordination of Activities within and Between Ganglia of the
Intrinsic Cardiac Nervous System
[0135] FIGS. 2-4 summarize the induced changes in intrinsic cardiac
nerve activity produced by transient coronary artery occlusion
(CAO) and their modulation by descending projections from the T1-T3
segments of the spinal cord. Note the augmentation in activity
within the atrial and ventricular neurons (FIG. 2) produced by CAO
is attenuated by electrical stimulation of the dorsal aspects of
the T1-T3 segments of the spinal cord (FIG. 3, DCA; Dorsal Cord
Activation). The suppression of activity induced by DCA on the
intrinsic cardiac neuronal activity is maintained long after the
termination of spinal cord stimulation (FIG. 4).
[0136] As shown in FIG. 5, activity generated by two different
populations of intrinsic cardiac neurons contained within the right
atrial ganglionated plexus. Arrow indicates application of
veratridine to the epicardium of the left ventricle. At baseline,
note the cycling of activity with a periodicity of 20 seconds. In
the unstressed condition, this bursting is usually associated with
increased coordination of activity between the two populations of
neurons (see bottom trace). When an afferent stress is imposed to
the ICN, as with application of epicardial veratridine, activity
increased in both sites and the coherence of activity generated by
these two populations of neurons approached unity.
[0137] Functional Remodeling of the Intrinsic Cardiac Nervous
System in Response to Chronic Myocardial Ischemia
[0138] FIGS. 6 and 7 summarize the changes induced in baseline
electrophysiology and in the neural control of cardiac electrical
function in response to chronic myocardial ischemia produced by
chronic placement of an ameroid constrictor on the left circumflex
artery. This constrictor produces a progressive occlusion of the
artery with induction of collateral blood vessels and does not
produce muscle necrosis or scar formation.
[0139] Differential Control of Neurotransmitter Release within the
Cardiac Interstitium
[0140] Exogenous administration of ANG II into the blood supply for
the right atrial ganglionated plexus increased NE concentration in
the cardiac interstitial fluid (ISF) to the same extent as achieved
during electrical stimulation of the stellate ganglia (FIG. 8A) in
the anesthetized dog. LV dP/dt correlated with ISF NE release.
However, NE spillover into the coronary sinus occurred only during
sympathetic efferent neuronal stimulation (FIG. 8C). ISF EPI levels
increased moderately with stellate stimulation and to levels equal
to NE release with ANG II stimulation. This differential release of
catecholamines from cardiac nerves occurred in spite of a 40-fold
higher NE compared to EPI content in the dog LV myocardium
(237.+-.33 vs. 6.4.+-.1.0 ng/g). Neither stellate nor ANG II
stimulation evoked EPI spillover into the coronary sinus. Dorsal
cord activation (FIG. 8B) evoked a release of EPI into the ISF
equivalent to stellate stimulation, but with only a modest increase
in ISF NE. These data illustrate the potential for differential
neural release of catecholamines within the heart depending on how
efferent outflows are activated and underscore the importance of
simultaneous measurements of ISF and transcardiac release in
evaluation of the neural control of regional cardiac function.
[0141] Electrophysiological Properties of In Vitro Cardiac
Ganglia
[0142] Disruption of nerve projections to or within the intrinsic
cardiac nervous (ICN) system is associated with alterations in the
passive and active properties of the cardiac neurons. chronic
interruption of the extrinsic nerve inputs to the ICN has been
shown to produce changes in membrane properties that lead to
increased network excitability within this ganglionated plexus.
Intrinsic cardiac neurons remain responsive to cholinergic synaptic
inputs. The cholinergic receptor systems are differentially
affected by disruption of nerve inputs to the ICN, with muscarinic
responsiveness being enhanced (FIG. 9). Non-cholinergic
neurotransmitters can modulate the activity of these neurons. FIG.
10 illustrates the interaction between acetylcholine and the
peptide, substance P.
[0143] Quantification of the Innervation Profile for the Canine
Heart
[0144] Data indicate that the progression of cardiac disease is
associated with myocyte and neural remodeling. The neural
remodeling likely includes degenerative and regenerative aspects.
The net result is the potential for heterogeneous innervation to
various regions of the heart. Chen et al. have therefore proposed
the "nerve sprouting hypothesis of sudden cardiac death". As
illustrated in FIG. 11 by using immunohistochemical techniques,
characterization of innervation density (panel B) and types of
fibers (panel A) within ganglia and cardiac tissues has been
accomplished.
[0145] Interactions within the intrinsic cardiac nervous system
depend in large part on common shared afferent inputs and/or
interconnections mediated via local circuit neurons. The degree of
coordination between aggregates of intrinsic cardiac neurons is
influenced by proximity and the activation state of afferent
inputs. In basal states, the degree of coherence of activity within
a single cardiac ganglia waxes and wanes with a periodicity of
approximately 20-30 sec. In response to enhanced neuronal activity,
evoked during activation of their associated sensory inputs, that
coherence increases. For neurons contained within different
intrinsic cardiac ganglia, lesser degrees of coherence of basal
activity between them, but this coherence increases during
stimulation of afferent inputs owing to common shared inputs
between them.
[0146] There are two distinct classes of sensory input affecting
ICN activity: a phasic input, whose influence is short-lived and
subserves rapid feedback processes within the ICN and a dynamic
input whose influence is determined by the context/history of its
activation and whose influence on ICN activity is long-lived.
Mechano-sensitive neurites subserve the phasic inputs and
chemo-sensitive neurites subserve the neural "memory".
[0147] Myocardial ischemia and infarction induce substantial
changes in the intrathoracic nerve networks and their reflex
control of regional cardiac function including protection and
stabilization of electrical activity of the heart. Chronic
myocardial ischemia induces a heterogeneous distribution of
efferent projections to cardiac end-effectors. Heterogeneous
distribution of sympathetic fibers to the left ventricle results in
similar heterogeneous release of catecholamines into the
interstitial space during stimulation of the efferent nerves.
Myocardial ischemia alters the neurochemical profile of that
innervation, with differential increases in neuropeptide content
within subsets of neurons contained within the intrinsic cardiac
nervous system. The evolution of cardiac pathology is associated
with disruptions of the intrinsic cardiac nervous system and its
ability to process afferent information and such changes are more
evident in the CMVPG than the RAGP intrinsic cardiac ganglia.
Animals that exhibit indices of higher vagal tone (higher
baroreflex sensitivity and higher heart rate variability)
demonstrate lesser degrees of ischemic-induced neural
remodeling.
[0148] DCA can exert long-term modulation of the activities within
the intrinsic cardiac nervous system. While initial studies
indicate that catecholamines are released in response to DCA, it is
anticipated that DCA also will activate sensory afferent fibers
antidromically such that endorphins or neuropeptides such as
calcitonin gene-related peptide or substance P are locally released
in the intrinsic cardiac ganglia and myocardium. Opiates and
neuropeptides can also influence the intrinsic cardiac neurons. DCA
also suppresses intrinsic cardiac adrenergic as well as local
circuit neurons via altered sympathetic efferent preganglionic
neuronal input. Activation of sympathetic efferent preganglionic
axons suppresses many intrathoracic reflexes that are involved in
cardiac regulation. Thus these neuro-suppressor effects may be due,
in part, to activation of inhibitory synapses within intrinsic
ganglia.
[0149] Heterogeneous alterations within the intrinsic cardiac
ganglia or at the end-terminus of the autonomic innervation to the
ischemic myocardium are major contributors to the increased
incidence of sudden cardiac death in patients with coronary artery
disease. Chronic DCA ameliorates ischemia-induced remodeling within
the intrinsic cardiac nervous system and thereby reduces the
heterogeneous neural substrate that predisposes the susceptible
animals to ventricular arrhythmias and sudden cardiac death.
[0150] Control of regional cardiac electrical and mechanical
function is dependent upon varied neural inputs from intrathoracic
autonomic ganglia, the spinal cord and brainstem, as well as by
circulating neurohumoral agents. Neural control of the heart is
dependent upon the coordination of activity generated by neurons
within intrathoracic autonomic ganglia and the CNS. The hierarchy
of nested feedback loops therein provides precise beat-to-beat
control over regional cardiac function. Within the hierarchy of
intrathoracic ganglia and nerve interconnections, complex
processing takes place that involves the summation of preganglionic
inputs from central neurons with those derived from cardiopulmonary
sensory inputs.
[0151] Excessive activation of the intrathoracic cardiac efferent
nervous system can provoke cardiac arrhythmias, as can myocardial
ischemia. These maladaptations likely involve changes within the
cardiac nervous system in addition to alterations in cardiomyocyte
function. Differential adaptations of cardiomyocyte ion channels
(e.g., IK and ICa) and intercellular connections during the
progression of cardiac disease have been termed "electrical
remodeling." Recent data indicates that neurohumoral control
mechanisms likewise reorganize during progression into certain
cardiac diseases and are referred to as "neurohumoral
remodeling."
[0152] Changes in autonomic outflow accompany and influence the
progression of cardiac disease. Sympathetic efferent neuronal
activation contributes to sudden cardiac death in patients with
ischemic as well as non-ischemic heart disease. The ATRAMI study
demonstrates that baroreflex sensitivity and heart rate variability
predict risk for cardiovascular mortality and myocardial
infarction. Electrical stimulation of vagal efferent neurons
suppresses the tendency to ventricular fibrillation formation in
dogs with depressed vagal reflex activity as measured by baroreflex
sensitivity. Yet, pharmacological agents that increase vagal
efferent neuronal tone, such as a low-dose scopolamine, do not
confer similar degrees of protection.
[0153] The mechanism(s) whereby activation of sympathetic efferent
neurons and/or withdrawal of parasympathetic efferent neuronal tone
increase the risk for sudden death are not clear. However,
post-infarction heterogeneous remodeling of cardiac innervation,
including extracardiac sympathetic and intrinsic cardiac efferent
neural elements, likely contributes to the resultant cardiac
electrical instability. The present claimed and disclosed
invention, as disclosed herein, outlines the evolution of neural
remodeling associated with chronic myocardial ischemia and
infarction and thus provides a stepping off point for the
development of treatments for cardiac pathologies utilizing SCS or
DCA.
[0154] After decades of progress, improvement in the management of
cardiac arrhythmias appears to have leveled off. The problem of
sudden cardiac death occurring as the result of an initial
arrhythmic event has not been addressed (except perhaps through
palliative public health strategies which include public access
defibrillators, PAD). This state of affairs is due, in part, to the
fact that key pieces of information regarding cardiac arrhythmia
formation are still missing, including the ability to identify the
apparently normal individual at risk before an event occurs. While
changes in myocardial electrical events have been well
characterized in the diseased heart, information concerning the
complex neuronal organization regulating cardiac rhythm remains
limited. The comprehensive presently claimed and disclosed
invention which includes the knowledge of the complex processing
which occurs within the intrathoracic nervous system, as well as
between peripheral and central cardiovascular neurons, provides a
basis for understanding the role that the cardiac nervous system
plays in regulating the electrical behavior of not only the normal
heart, but the diseased heart as well, thus providing for novel
therapeutic approaches for the effective treatment of cardiac
arrhythmias, sudden cardiac death or syncope of cardiac origin by
targeting discrete populations of neurons regulating regional
cardiac behavior.
[0155] Control of regional cardiac function is dependent upon
properties intrinsic to cardiac electrical and mechanical tissues
as modulated by neuronal reflexes arising at the level of the
intrinsic cardiac and intrathoracic extracardiac nervous systems,
in addition to well-known spinal cord and brainstem reflexes. The
proper function of this cardiac neuronal hierarchy is ultimately
dependent on ongoing cardiovascular sensory and spinal cord
neuronal inputs. The synergism of function within the cardiac
autonomic hierarchy and cardiac myocytes results in a finely
balanced, rapidly responsive control system that is continuously
being upgraded to maintain adequate cardiac output. As outlined
hereinabove, the intrinsic cardiac ganglia form the principal final
common pathway for autonomic modulation of regional cardiac
function. Maintenance of cardiac output depends not only on the
Frank-Starling mechanism and circulating catecholamines, but also
on inputs from this nervous system. Disruptions of the sensory
inputs to the hierarchy of autonomic neurons regulating the heart
due to alterations in the mechanical and/or chemical milieu of the
heart can be associated with compromised control of the heart.
[0156] Anatomy and Function of the Intrathoracic Cardiac Nervous
System (Intrinsic Cardiac Nervous System)
[0157] Divergent populations of cardiac neurons within different
intrathoracic ganglia interact on an ongoing basis to maintain
adequate cardiac output, requiring little ongoing input from spinal
cord neurons. neurons in this hierarchy interact to regulate normal
cardiac function on a beat-to-beat basis. The development of novel
strategies to manage cardiac disease necessitates not only a
thorough understanding of the processing of information arising
from cardiac and major intrathoracic vascular sensory neurites, but
also inputs from central neurons. Neurons in the spinal control
exert preferential control over such intrathoracic neuronal
processing of cardiac sensory information.
[0158] Human studies have shown that stimulation of the dorsal
T1-T2 segments of the spinal cord suppresses angina pectoris
(sensory information arising from the heart) without masking
awareness of acute myocardial ischemic episodes. The mechanisms
whereby activation of the dorsal aspect of the cranial thoracic
spinal cord produces improved cardiac function and reduces symptoms
of the ischemic myocardium are not currently understood. The
experiments and resulting data from the presently claimed and
disclosed invention show that the anti-anginal and cardiac
stabilization effects of such spinal cord modulation are mediated
via stabilization of the intrathoracic nervous system, especially
its intrinsic cardiac component. Neural control of cardiac function
resides in the network of nested feedback loops made up of the
intrinsic cardiac nervous system, extracardiac intrathoracic
autonomic ganglia, the spinal cord and brainstem. Within this
hierarchy, the intrinsic cardiac nervous system functions as a
distributive processor at the level of the target organ. The
redundancy of function and non-coupled behavior displayed by
neurons in intrathoracic extracardiac and intrinsic cardiac ganglia
minimizes the dependency for such control on a single population of
peripheral autonomic neurons. On the other hand, network
interactions occurring within the intrinsic cardiac nervous system
integrate parasympathetic and sympathetic efferent outflow with
cardiovascular afferent feedback to modify cardiac rate and
regional contractile force throughout each cardiac cycle. Thus,
neural control of cardiac function resides in the network of nested
feedback loops made up of the intrinsic cardiac nervous system as
well as the extracardiac intrathoracic nervous system, spinal cord
and brainstem (FIG. 1).
[0159] The redundancy of function and non-coupled behavior
displayed by neurons in intrathoracic extracardiac and intrinsic
cardiac ganglia minimizes the dependency for such control on a
single population of peripheral autonomic neurons. Furthermore,
network interactions occurring within the intrinsic cardiac nervous
system integrate parasympathetic and sympathetic efferent outflow
with afferent feedback to modify cardiac rate and regional
contractile force throughout each cardiac cycle.
[0160] The Intrinsic Cardiac Nervous System
[0161] The intrinsic cardiac nervous system has been classically
considered to contain only parasympathetic efferent postganglionic
neurons that receive inputs from medullary parasympathetic efferent
preganglionic neurons. As such, intrinsic cardiac ganglia are
viewed as simple relay stations and major autonomic neuronal
control of the heart is purported to reside solely in the brainstem
and spinal cord. However, current data indicates that centripetal
as well as centrifugal processing occurs within the mammalian
intrathoracic nervous system. This involves afferent neurons, local
circuit neurons (i.e., neurons that interconnect neurons within one
ganglion and neurons in different intrathoracic ganglia), as well
as sympathetic and parasympathetic efferent postganglionic neurons.
The divergent populations of neurons within the intrinsic cardiac
nervous are influenced by spinal cord neurons on an ongoing basis
in the maintenance of adequate cardiac output. FIG. 1 provides an
outline for the putative types of neurons and their
interconnectivity within the cardiac neuronal hierarchy.
[0162] The development of novel therapeutic strategies to manage
abnormal cardiac states necessitates a thorough understanding of
not only of the processing of information arising from sensory
neurites in various regions of the heart and great thoracic
vessels, but how spinal control neurons exert preferential control
over the intrathoracic cardiac nervous system with particular
reference to its target organ. Similarly, intrathoracic
extracardiac sympathetic ganglia have been thought to act solely as
efferent relay stations for sympathetic efferent projections to the
heart. However, recent anatomical and functional data indicate the
presence of the multiple neuronal subtypes within the intrinsic
cardiac nervous system. The intrathoracic nervous system, including
its intrinsic cardiac component, is made up of different neuronal
subtypes. These include afferent, local circuit as well as
adrenergic and cholinergic efferent postganglionic neurons. These
neurons form the intrathoracic component of the central and
peripheral neuronal feedback loops that regulate regional
cardiodynamics on a beat-to-beat basis.
[0163] The intrinsic cardiac nervous system consists of multiple
aggregates of neurons and associated neural interconnections,
localized to discrete atrial and ventricular regions. Among these
distinct ganglionated plexuses, preferential control of specific
cardiac functions has been identified. For example, right atrial
ganglionated plexus (RAGP) neurons have been associated with
primary, but not exclusive, control of SA nodal function and
inferior vena cava-inferior atrial ganglionated plexus neurons
primarily, but not exclusively, with control of AV nodal function.
One population of intrinsic cardiac neurons, the parasympathetic
postganglionic ones, receives direct inputs from medullary
parasympathetic preganglionic neurons. Another population,
adrenergic efferent ones, receives inputs from more centrally
located neurons in intrathoracic ganglia and the spinal cord. That
ventricular sensory neurites continue to influence the activity
generated by neurons on the heart following chronic
decentralization of the intrinsic cardiac nervous system has been
interpreted as indicating that the somata of afferent neurons are
located within the intrinsic cardiac nervous system, some of which
project axons to central neurons. This latter concept has received
anatomical confirmation. Intrinsic local circuit neurons
interconnect cardiac afferent to efferent neurons that innervate
each region of the heart.
[0164] The Intrathoracic Extracardiac Nervous System
[0165] Neurons in intrathoracic ganglia, including those on the
heart, receive constant inputs not only from spinal cord neurons,
but also from cardiac afferent neurons to modulate cardiac efferent
neurons. The activity generated by most intrinsic cardiac neurons
increases markedly in the presence of focal ventricular ischemia.
Furthermore, excessive activation of limited populations of
intrinsic cardiac neurons induces cardiac dysrhythmias that lead to
ventricular fibrillation, even in normally perfused hearts.
Therapies that act to stabilize such heterogeneous evoked
activities within cardiac reflex control circuits have obvious
clinical importance. Proper information exchange among the
intrathoracic components of the cardiac nervous system act in
concert to stabilize the electrical and mechanical behavior of the
heart, particularly in the presence of focal ventricular ischemia.
Thus, use of SCS or DCA is a means to stabilize the heart prior or
post ischemia. An object of the present invention is to provide
such treatment methodologies.
[0166] Consistent coherence of activity generated by differing
populations of neurons is indicative of principal, direct synaptic
interconnections between them or, conversely, the sharing by such
neurons of common inputs. Such relationships have been identified
among medullary and spinal cord sympathetic efferent preganglionic
neurons, as well as among different populations of sympathetic
efferent preganglionic neurons. Different populations of neurons,
distributed spatially within the intrathoracic cardiac nervous
system, respond to cardiac perturbations in a coordinate fashion.
If neurons in one part of this neuronal network respond to inputs
from a single region of the heart, such as the mechanosensory
neurites associated with a right ventricular ventral papillary
muscle, then the potential for imbalance within the different
populations of neurons regulating various cardiac regions might
occur and, thus, its neurons would display little coherence of
activity. In other words, relatively low levels of specific inputs
on a spatial scale to the intrathoracic cardiac nervous system
would result in low coherence among its various neuronal
components. On the other hand, excessive input to this spatially
distributed nervous system would destabilize it, leading to cardiac
arrhythmia formation, etc.
[0167] Interactions Among Intrathoracic Extracardiac and Intrinsic
Cardiac Neurons
[0168] One must know how neurons in intrinsic cardiac versus
intrathoracic extracardiac ganglia interact to regulate regional
contractile function in order to understand not only the complexity
of cardiac control, but also how the cardiac neuroaxis can be
targeted therapeutically to manage specific cardiac disease
entities. Over the past 30 years studies of the anatomy and
function of the peripheral cardiac nervous system have taken place,
focusing during the last decade on its intrinsic cardiac component.
The classical view of the autonomic nervous system presumes that
its intrinsic cardiac component comprises a parasympathetic
efferent neuronal relay station in which medullary preganglionic
neurons synapse with parasympathetic efferent postganglionic
neurons therein. In such a concept, the latter neurons project to
end effectors on the heart with little or no integrative
capabilities occurring therein. Similarly, intrathoracic
paravertebral ganglia have been thought to represent synaptic
stations for sympathetic efferent postganglionic neurons
controlling the heart.
[0169] The intrinsic cardiac nervous system functions, according to
the presently claimed and disclosed invention, as a distributive
processor at the level of the target organ. The redundancy of
function and non-coupled behavior displayed by neurons within
intrathoracic extracardiac and intrinsic cardiac ganglia minimizes
the dependency for such control on a single population of
peripheral autonomic neurons. In that regard, network interactions
occurring at the level of the heart integrate parasympathetic and
sympathetic efferent inputs with local afferent feedback to modify
cardiac rate and regional contractile force throughout each cardiac
cycle. A recent editorial by David Lathrop and Pete Spooner of the
NIH highlights the potential clinical relevance of altered
processing of information by these populations of neurons such that
a lack of coordination of data exchange within the cardiac neuronal
axis may lead to the genesis of cardiac arrhythmias. Hence the
importance of determining how neurons in intrathoracic extracardiac
and intrinsic cardiac ganglia interact in the maintenance of
adequate cardiac output.
[0170] The different populations of neurons distributed spatially
within the intrathoracic cardiac nervous system respond to cardiac
perturbations in a complex fashion. Neurons in intrathoracic
extracardiac ganglia do not respond to cardiac perturbations in a
fashion similar to that displayed by intrinsic cardiac ones.
Consistent coherence of activity generated by differing populations
of neurons has been identified among medullary and spinal cord
sympathetic efferent preganglionic neurons, as well as among
different populations of sympathetic efferent preganglionic
neurons. A relatively low level of inputs on a spatial scale to one
population of intrathoracic cardiac neurons results in low
coherence among its components. In contrast, excessive input to
this spatially distributed nervous system destabilizes it, leading
for instance to cardiac arrhythmia formation. Since neurons in one
part of the intrathoracic neuronal network respond solely to inputs
from a single region of the heart, such as from mechanosensory
neurites in a right ventricular ventral papillary muscle, then the
potential for imbalance within the different populations of neurons
in various levels of the intrathoracic neuronal hierarchy
arises.
[0171] Ultimately, the outflows of efferent neuronal signals to the
various regions of the heart depend to a large extent on the direct
or indirect inputs they receive from cardiac and major
intrathoracic vascular sensory neurites in addition to pulmonary
mechanosensory neurites. The redundancy of function and non-coupled
behavior displayed by neurons in intrathoracic extracardiac and
intrinsic cardiac ganglia minimizes the dependency for regional
cardiac control on a single population of intrathoracic neurons.
This may be particularly relevant with respect to supporting the
output of the ischemic heart. In that regard, network interactions
occurring among intrathoracic extracardiac and intrinsic cardiac
neurons secondary to inputs from cardiovascular afferent neurons
involve local circuit neurons feeding information foreword to
cardiac parasympathetic and sympathetic efferent neurons. These
network interactions are under the constant influence of spinal
cord neurons
[0172] Cardiac Afferent Neurons
[0173] Overview of Cardiac Sensory Neuronal Transduction.
[0174] It has been known for some time that cardiac sensory
neurites (nerve endings) are associated with somata located in
ganglia relatively distant from the heart, nodose and dorsal root
ganglia. It has recently become evident that cardiac sensory
neurites are also associated with somata located in intrathoracic
ganglia, including those on the heart. The relative distance
between these sensory neurites and their associated somata
represents a major determinant of their function. The somata of
many cardiac afferent neurons located near to or on the target
organ display high frequency (phasic) activity that directly
affects target organ efferent neurons (TABLE I). In this manner,
high fidelity information content can exert rapid control over
efferent neurons adjacent to or on the heart that modulate regional
contractility. In contrast, cardiac afferent neuronal somata
located relatively distant from their sensory neurites (i.e., in
nodose or dorsal root ganglia) are, of necessity, involved in
longer latency influences on second order neurons in the cardiac
neuroaxis. These relatively distant cardiac afferent neurons, as
such, are involved in relatively long latency cardio-cardiac
reflexes, being spatially removed from the target organ they
display memory. A division of cardiac sensory neuronal function
into two broad, functional categories can be based on spatially
derived cardiac sensory transduction (TABLE I). It should be noted
that some cardiac sensory neurons within dorsal root ganglia
generate high frequency phasic activity, particularly when their
sensory neurites are exposed to increasing concentrations of local
chemicals.
TABLE-US-00001 TABLE I Cardiac afferent neuronal function Fast
responding afferent Slow responding afferent neurons neurons
Mechanosensory specific Multimodal (mechanical/chemical) Activity
related to local Not responsive to mechanical events instantaneous
events High frequency, phasic (non- Tonic, low frequency tonic)
activity activity High fidelity signals Noisy signals that limit
resolution Noise free transduction Requires noise for signal
transduction Limited memory Memory capability (affected by past
events) Soma located primarily on or Soma primarily in ganglia Near
the heart distant from the heart Primarily inputs to short
Primarily inputs to longer control control loops Loops
[0175] That two broad categories of cardiac afferent neurons exist
(TABLE I) indicates unique transduction capabilities such that
cardiac information provided to second order cardiac neuroaxis
neurons depends not only on the location of their sensory neurites,
but on the location of their somata. The sensory information
transduced by fast responding cardiac afferent neurons, impinging
as it does directly on cardiac motor neurons, is one of the primary
determinants of the input function to cardiac efferent neurons that
coordinate regional cardiac behavior. Fast responding cardiac
sensory neurons normally generate relatively high frequency (10-100
Hz) activity patterns reflective of regional cardiodynamics. Slow
responding cardiac afferent neurons generally transduce alterations
primarily in the local chemical milieu and, thus, by their nature
are generally not responsive to regional alterations that occur on
a short time scale. During physiological states, they generate
tonic activity at lower frequencies (0.1-1 Hz).
[0176] The sensory neurites associated with intrinsic afferent
neuronal somata are located in atrial and ventricular tissues, as
well as the adventitia of major coronary arteries. The sensory
neurites associated with the somata of afferent neurons in
intrathoracic extracardiac ganglia are concentrated in the same
cardiac regions, in addition to being found around the origins of
vena cava and on the thoracic aorta. Cardiovascular afferent
neurons within the thorax provide feed-forward information to
efferent neurons in intrathoracic ganglia, some via local circuit
neurons. Those in the nodose ganglion influence medullary nucleus
tractus solatarius neurons, while those in dorsal root ganglia
influence spinal cord neurons. As discussed hereinabove, the varied
transduction properties displayed by cardiac afferent neurons in
nodose, dorsal root and intrathoracic ganglia reflect to a
considerable extent the anatomical location of their somata, i.e.,
the distance between their somata and associated sensory neurites.
Cardiac afferent neurons with somata close to or on the heart
influence cardiac efferent neurons to initiate short-loop reflexes
with short latencies of activation while those located in nodose
ganglia initiate longer latency reflexes. That is why cardiac
afferent neurons in intrathoracic ganglia display different
transduction capabilities than those in dorsal root and nodose
ganglia.
[0177] Afferent axons arising from cardiac or intrathoracic
vascular sensory neurites vary in diameter (degree of myelination),
according to the location of the cardiopulmonary nerve in which
they course. For instance, most aortic mechanosensory neurites are
associated with Ad axons, most of which are located in the
intrathoracic dorsal cardiopulmonary nerve. Many ventricular
sensory neurites are associated with c class axons. On the other
hand, carotid artery mechanosensory neurites associated with
afferent axons are divisible into the A and C fiber categories,
each population displaying unique transduction properties.
[0178] Function.
[0179] The majority of cardiac sensory neurons, particularly those
located distant from the heart, generate sporadic, low frequency
activity. As the activity generated by the most cardiac afferent
neurons is of low frequency (i.e., 0.01-0.1 Hz), information
content cannot reside in the interspike intervals of activity.
Rather, it resides primarily in their average activity over time
unless their activity becomes entrained to cardiodynamics in the
presence of increased sensory neurite chemical milieu. Information
transduced by multimodal sensory neurites associated with each axon
connected to individual cardiac afferent neuronal somata also
depends on their cardiac spatial distribution. Arrays of atrial
sensory neurites are concentrated in the region of the sino-atrial
node (right atrium) and the dorsal aspects of both atria, others
are scattered throughout the rest of the atria. Ventricular sensory
neurites are concentrated in the outflow tracts of the two
ventricles as well as the right and left ventricular papillary
muscles. Another concentration of sensory neurites is located in
the adventitia on the inner arch of the thoracic aorta.
[0180] Intrathoracic cardiac afferent neurons influence (via
intrathoracic local circuit neurons) cardiac efferent
postganglionic neurons with latencies as short as 40 milliseconds.
Nodose ganglion cardiac afferent neurons influence cardiac
parasympathetic efferent preganglionic neurons in the medulla via
short latency reflexes (75 ms) as well. On the other hand, dorsal
root ganglion cardiac afferent neurons influence sympathetic
efferent postganglionic neurons via longer latency (100-500 ms)
reflexes. Thus, the differing populations of cardiac sensory
neurons located at each level of the cardiac neuroaxis not only
displaying unique transduction characteristics, but subserve
cardio-cardiac reflexes that of necessity differ in latency and
form.
[0181] Nodose Ganglion Afferent Neurons.
[0182] Using neuroanatomical tracing techniques, about 500 somata
associated with cardiac sensory neurites have been identified
throughout the right and left nodose ganglia. Their axons belong to
the A and c classes, as defined by Erlanger and Gasser.
Histochemical evidence indicates that the somata of nodose ganglion
afferent neurons express receptors for a variety of neurochemicals,
including adenosine, bradykinin and substance P receptors. Most of
these cardiac afferent neurons transduce multiple chemicals,
including purinergic agents such as adenosine (FIG. 12). Few nodose
ganglion cardiac sensory neurons solely transduce alterations in
the mechanical milieu of the heart.
[0183] Doral Root Ganglion Afferent Neurons.
[0184] Despite the widely held opinion that the majority of cardiac
afferent neurons are located primarily in left-sided dorsal root
ganglia, anatomic evidence indicates that cardiac afferent neurons
are distributed relatively equally among right and left dorsal root
ganglia from the C6 to the T6 levels of the spinal cord. Afferent
neuronal somata lie scattered predominantly, but not exclusively,
around the centrally located axons in these ganglia. Over 500
cardiac sensory neurons have been identified anatomically in canine
dorsal root ganglia from the T.sub.1 to the T.sub.3 levels of the
spinal cord, ganglia containing up to 50 cardiac afferent neuronal
somata. The axons connecting cardiac sensory neurites with somata
in dorsal root ganglia belong to the Ad or c classes of axons, each
having little bearing on their sensory transduction
capabilities.
[0185] Intrathoracic Extracardiac Ganglion Afferent Neurons.
[0186] Functional evidence indicates the presence of cardiac
sensory neuronal somata in stellate, middle cervical and
mediastinal ganglia. Axons connecting atrial or ventricular
mechanosensory neurites with somata in extracardiac ganglia belong
in the Ad class of axons. Those connecting intrathoracic vascular
mechanosensory neuritis with somata in intrathoracic extracardiac
ganglia belong to Ad class of axons as well. On the other hand,
ventricular endocardial mechanosensory neurites connected with
somata in intrathoracic ganglia belong to c class axons. Cardiac
and aortic chemosensory neurites connected with somata in
intrathoracic ganglia also belong to Ad class axons.
[0187] Intrinsic Cardiac Ganglion Afferent Neurons.
[0188] Unipolar neurons are located throughout atrial and
ventricular intrinsic cardiac ganglionated plexuses. Based on
anatomical and functional data, the somata of some intrinsic
cardiac afferent neurons project axons centrally; the remainder
interacting directly with other intrinsic cardiac neurons exclusive
of central neuronal inputs. Sensory neurites associated with
intrinsic cardiac afferent neurons are located in all four chambers
of the heart (particularly in the cranial aspect of the ventricles)
are multimodal in nature (transduce mechanical and chemical
stimuli). Unfortunately, little is currently known of their
transduction capabilities.
[0189] Cardiac afferent neurons with sensory neurites located
primarily in the atria and the outflow tracts of the ventricles or
major intrathoracic vessels initiate short, intermediate and
relatively long duration cardiovascular-cardiac reflexes, depending
on their multimodal transduction capabilities.
[0190] Intrathoracic Extracardiac and Intrinsic Cardiac Ganglionic
Interactions
[0191] Cardiac sensory input to the multiple nested feedback loops
within the intrathoracic cardiac neuronal axis displaying
redundancy of function and non-coupled behavior within the
different anatomical levels of this hierarchy (FIG. 1) to minimize
dependency of regional cardiac control on a single population of
neurons. The different populations of cardiac afferent neurons,
being capable of transducing multiple stimuli, forms the basis for
integrated control of cardiac efferent neurons affecting regional
cardiac function. Such control resides from the level of target
organ to that of the central nervous system. As mentioned
hereinabove, neurons in intrathoracic extracardiac and intrinsic
cardiac ganglia exhibit differential reflex control over regional
cardiac function that depends in large part on the varied anatomy
and function of afferent neurons providing information about the
cardiac milieu. This concept is based on the observation that
intrathoracic extracardiac and intrinsic cardiac neurons display
redundancy of function and non-coupled behavior (FIG. 13), such
non-coupled behavior minimizing cardiac dependency on a single
population of intrathoracic neurons. Intrathoracic reflexes can
exert considerable influence over regional cardiodynamic behavior
(11).
[0192] Intrathoracic cardiac afferent neurons are multimodal in
nature (i.e., responsive to local mechanical and chemical stimuli),
transducing a host of chemicals that include ion channel modifying
agents (i.e., veratridine; c.f., FIG. 13), .beta.1- or
.beta..sub.2-adrenoceptor agonists, .sub.1- or .sub.2-adrenoceptor
agonists, excitatory amino acids, or peptides (c.f., angiotensin
II, bradykinin or substance P). The activity generated by
populations of intrinsic cardiac local circuit neurons display, as
a consequence of such sensory inputs, periodically occurring
coupled behavior (cross correlation coefficients of activities that
reach, on average, 0.88.+-.0.03; range 0.71-1) for 15-30 seconds
periods of time. This coupled activity occurs every 30-50 seconds
during basal states, as well as when cardiac afferent neuronal
inputs to this neuronal hierarchy increase in response to
alterations in the ventricular chemical milieu.
[0193] On the other hand, neurons in intrathoracic extracardiac
(middle cervical or stellate) and intrinsic cardiac ganglia do not
display such function, despite the fact that neurons in
intrathoracic extracardiac and intrinsic cardiac ganglia receive
inputs from cardiac mechanosensory and chemosensory neurites. That
is due in part because neurons in intrathoracic extracardiac
ganglia receive many inputs mechanosensory neurites located on the
inner arch of the aorta. That some of these neurons are still
influenced by cardiac sensory inputs when decentralized from
central neurons indicates that intrathoracic cardiac afferent
neurons can influence the intrathoracic neuronal hierarchy
independent of central neuronal inputs.
[0194] Neurons in intrathoracic extracardiac and intrinsic cardiac
ganglia exhibit non-coupled behavior, even when they are mutually
entrained to cardiac events by cardiovascular afferent feedback
(FIG. 13). This shows a redundancy of cardioregulatory control
exerted by the different populations of intrathoracic neurons. That
these different populations respond differently to similar cardiac
interventions indicates the selective nature of the feedback
mechanisms extant in different `levels` of the intrathoracic
neuronal hierarchy FIG. 1. This also implies minimal reliance at
any time on one population of peripheral autonomic neurons for the
control of regional cardiac behavior. The selective influence
exerted by each population of intrathoracic (intrinsic and
extrinsic) neurons on regional cardiac function depends in large
part on the nature and content of their inputs from cardiac and
intrathoracic vascular sensory neurites. Since the sensory
information transduced by most cardiac sensory neurons is in the
0.1 Hz range, it is unlikely that meaningful data is represented by
interspike intervals during physiological states as such relatively
low frequency activity is not coherent. The fact that most of the
sensory information they receive is of low frequency content
implies that their responsiveness is dependent primarily on average
activity rather than instant-to-instant activity change (interspike
intervals). Coherent (rhythmic) activity is generated by limited
populations of cardiac sensory neurons such as those in dorsal root
ganglia. Indeed, excessive sensory neuronal input to spinal cord
neurons in the ischemic state may act to destabilize cardiac
neuronal hierarchical control of cardiac electrical behavior.
[0195] Intrathoracic Synapses
[0196] Direct application of neurochemical agonists or selective
antagonists has been used to survey receptor subtypes associated
with neurons within the intrathoracic cardiac nervous system and to
characterize the functional differences of neurons within its
various ganglia. Chemical stimulation of specific intrathoracic
neurons with low doses of chemicals such as nicotine,
neuropeptides, catecholamines, amino acids and purinergic agents
can induce changes in their activity. When neuronal changes so
induced are of sufficient magnitude, alterations in cardiac
pacemaker, conductive and regional contractile function occur. The
cardiac responses so induced reflect activation of specific
populations of neurons in intrathoracic extracardiac or intrinsic
cardiac ganglia as similar application of such neurochemicals to
intracardiac axons of passage does not effect neuronal activity or
cardiodynamics. In agreement with that, transection of all
extrinsic neuronal inputs to the intrathoracic nervous system
(acute decentralization) attenuates cardiac responses so elicited.
This data indicates the importance of the connectivity of neurons
within the thorax with central ones in mediating cardio-cardiac
reflexes.
[0197] Cholinergic Mechanisms:
[0198] Synaptic transmission in cardiac autonomic ganglia has been
thought to be principally involved in the release of acetylcholine
by presynaptic terminals and subsequent binding of that
neurotransmitter to nicotinic cholinergic receptors on
postganglionic neurons. In mammals this synaptic junction is not
obligatory, indicating that a significant convergence of inputs may
be necessary to evoke postganglionic activity. Nicotinic and
muscarinic cholinergic agonists and antagonists modify intrinsic
cardiac neurons in vitro and in vivo, as well as neurons in
intrathoracic extracardiac ganglia. Local application of nicotine
to intrinsic cardiac or intrathoracic extracardiac neurons induces
alterations in cardiac rate and regional contractile function.
Activation of intrinsic cardiac neurons with nicotine induces
either augmenter or depressor cardiac effects, depending on the
population of neurons so affected. Blockade of nicotinic receptors
attenuates, but does not eliminate, these cardiac reflexes.
Muscarinic cholinergic blockade attenuates synaptic function within
intrathoracic ganglia, as well, indicating that acetylcholine
exerts both mediator and modulator effects at synaptic junctions
within intrathoracic ganglia.
[0199] Noncholinergic Mechanisms:
[0200] Blockade of nicotinic cholinergic receptors attenuates, but
does not eliminate synaptic transmission within intrathoracic
ganglia indicating that non-nicotinic synapses act as primary
mediators of synaptic transmission within the intrathoracic nervous
system. Anatomical and physiological studies have identified
multiple putative neurotransmitters in association with neuronal
somata in mammalian intrathoracic extracardiac and intrinsic
cardiac ganglia. These chemicals include purinergic agents
(adenosine and ATP), alpha- and beta-adrenergic agonists,
angiotensin II, bradykinin, calcitonin gene-related peptide,
neuropeptide Y, histamine, serotonin, substance P and vasoactive
intestinal peptide as well as excitatory and inhibitory amino
acids. Many of these putative neurotransmitters arise from neurons
whose cell bodies are intrathoracic extracardiac (stellate and
middle cervical) ganglia, while other may be synthesized by neurons
intrinsic to the heart. Direct application of various putative
neurotransmitters adjacent to neurons in intrinsic cardiac or
intrathoracic extracardiac ganglia modifies cardiac pacemaker and
contractile activities. Such responses presumably reflect varied
receptor mediated activation of adjacent neurons and their
associated dendrites since when identical concentrations of these
neurochemicals are applied directly to intracardiac axons of
passage neuronal activity and cardiac indices remain
unaffected.
[0201] Thus, when taken together, synapses interconnecting
intrathoracic afferent, local circuit and efferent neurons utilize
a host of neurochemicals in the regulation of regional
cardiodynamics, even when disconnected from the influence of
central neurons.
[0202] Memory Function within the Intrathoracic Nervous System
[0203] Cardiovascular-cardiac reflexes exert long-term control over
cardiodynamics, including those initiated solely within the
intrathoracic neuronal hierarchy. Intrathoracic cardio-cardiac
reflexes display different latencies of activation in as much as
intrathoracic cardiac afferent neurons influence local circuit
neurons in ganglia at different levels of the thorax (intrinsic
cardiac, mediastinal, middle cervical and stellate ganglia)
following different latencies. The differing populations of cardiac
afferent neurons that initiate these varied intrathoracic reflexes
display unique transduction characteristics that are suited to the
cardio-cardiac reflexes that they sub serve. For instance,
intrathoracic cardio-cardiac reflexes have latencies as short as 40
ms, whereas those involving spinal cord neurons have latencies that
exceed 450 milliseconds. Thus, the relative distance between
cardiac sensory neurites and neuronal somata is a significant
determinant of cardio-cardiac reflex latencies they initiate.
[0204] Inherent in this issue is the fact that intrathoracic
neurons involved have two types of memory: (1) The first type
involves non-computational memory displayed by cardiac chemosensory
neurons, in as much as the previous status of their transduction
behavior is a major determinant of their responsiveness to a
chemical stimulus. The slowly varying, long-term transduction
capabilities exhibited by cardiac chemosensory neurites is
characteristic of passive memory. (2) The second type of memory
displayed in the intrathoracic nervous system is represented by
active processing of sensory inputs from: (i) cardiovascular
afferent neurons and (ii) central efferent preganglionic neurons.
This computational memory resides in the network interactions that
are dependent on intrathoracic local circuit neurons. Their state
dependent memory represents hysteretic computation of
cardiovascular sensory information that, along with inputs from
central neurons, exerts ongoing control over cardiac efferent
neurons. Such computation ability is necessary if a population of
neurons is to simultaneously process information arising from many
sources--an important characteristic of the intrathoracic nervous
system. The presence of such complex information processing within
the intrathoracic autonomic nervous system has led to the discovery
that this nervous system functions as a distributive processor of
centripetal and centrifugal information arising from and going to
the heart that, of necessity, requires state-dependent memory.
[0205] Memory Displayed by Slow Responding Cardiac Afferent
Neurons.
[0206] Most of the cardiac afferent neuronal somata located near or
on the target organ transduce high frequency (phasic) information
directly to target organ efferent neurons that control regional
contractile behavior. In this manner, high fidelity information
content can exert rapid control over cardiac efferent neurons
coordinating regional contractile patterns. On the other hand, the
cardiac sensory neurites located anatomically distant from their
associated somata (i.e., in nodose and dorsal root ganglia) take
longer to influence second order neurons (c.f., neurons in the
CNS). These latter cardiac afferent neurons are involved in
relatively long latency cardio-cardiac reflexes. Presumably because
of that function (lack of necessary short term influences), for the
most part they display relatively long term memory function since
they transduce slowly varying chemical signals. It should be noted
that some intermediary cardiac afferent neurons also generate tonic
activity, only generating high frequency, phasic activity when
exposed to increasing concentrations of chemicals reflective of
their multimodal transduction properties. The passive memory
function displayed by these slow responding cardiac sensory neurons
resides in the state dependent properties of their cardiac
chemosensory neurites. This is also indicative of the fact that
chemical excitation of these afferent neurons remains long after
removal of the stimulus--yet another form of memory.
[0207] Local Circuit Neuronal Memory Function.
[0208] It has been postulated that active memory resides in the
multi-synaptic processing of cardiac sensory information that takes
place within the intrathoracic neuronal hierarchy. This is
particular relevant with respect to the processing of
cardiopulmonary sensory information by intrathoracic local circuit
neurons. It has been determined that memory is displayed by
remodeled intrathoracic local circuit neurons following chronic
removal of their central neuronal inputs. Short duration (10 msec.)
cardiopulmonary sensory inputs to neurons in chronically
decentralized intrathoracic ganglia results in the activation of
local circuit neurons therein for up to 2 seconds. Such data
indicates a memory capacity that lasts for a number of cardiac
cycles subsequent to sensory inputs arising during one cardiac
cycle.
[0209] As there is little direct relationship between sensory
inputs and output in the intrathoracic cardiac nervous system, its
local circuit neurons act to compute state-dependent information on
a beat-to-beat basis. This permits inputs from multiple sources
(peripheral cardiovascular afferent neurons and spinal cord
efferent neurons) to influence restricted cardiac efferent neuronal
outputs to the heart in an efficient manner and over time. Thus,
one function of intrathoracic local circuit neurons is key to
understanding hysteretic information processing (memory) since
their capacity to compute relatively minor sensory input
alterations without adapting out represents an important
characteristic of this neuronal hierarchy. In such a scenario,
local circuit neurons function to reduce `noise` to ensure
restricted (not excessive) output in the presence of multiple
sensory inputs.
[0210] This processing of cardiovascular sensory information by
intrathoracic local circuit neurons accounts for the stability of
the control exerted over regional cardiac function during
relatively prolonged period of time in normal cardiovascular
states. On the one hand, simple state switching among excitatory
versus inhibitory neurons in this population would generate
oscillatory behavior such as occurs among excitatory and inhibitory
neurons in the spinal cord. This would, in fact, lead to
instability of function since computational analysis would become
deranged and noise reduction capabilities would be lost. On the
other, memory function associated with intrathoracic local circuit
neurons, driven by ongoing cardiac sensory inputs, ensures stable
control over cardiac efferent neuronal outputs. For that reason,
hysteretic memory related to the active processing of cardiac
sensory information is important for the ultimate stability of
cardiac efferent neuronal control.
[0211] Current data indicates that passive memory resides in
cardiac sensory transduction and active memory in the processing of
that information by local circuit neurons within the intrathoracic
neuronal hierarchy. Control based memory residing in intrathoracic
extracardiac and intrinsic cardiac local circuit neuronal
interactions, driven as they are by cardiovascular sensory inputs;
it is not a passive process. Neurons in chronically decentralized
intrathoracic ganglia also display hysteretic memory. In the
situation where there is a loss of inputs from central neurons, 100
millisecond long bursts of sensory information (such as arise from
aortic mechanosensory neurites during each cardiac cycle) affect
local circuit neurons for up to 3 seconds after their
discontinuance. That period of time is sufficient for the next five
or six cardiac cycles to be generated.
[0212] Thus, events in one cardiac cycle influence regional cardiac
behavior throughout a few subsequent cardiac cycles via
fed-foreword reflexes residing solely within the intrathoracic
nervous system. By utilizing such fed-foreward reflexes, the
intrinsic cardiac nervous system can be pre-conditioned through the
use of SCS or DCA to thereby "override" quench neuronal signals
which would place the heart into a diseased state. Such
pre-conditioning may take the form of constant SCS or DCA
stimulation; and/or long pulses of SCS or DCA stimulation followed
by short or long resting periods. In this manner the intrinsic
cardiac nervous system is pre-conditioned to resist ischemic
neuronal overloading.
[0213] Focal Ventricular Ischemia
[0214] Myocardial Ischemia.
[0215] The importance of the processing of sensory information
arising from the ischemic myocardium by the intrathoracic cardiac
nervous system in the maintenance of adequate cardiac output is
only now beginning to be appreciated by those of ordinary skill in
the art. One of the major challenges to neurocardiology is
understanding the response characteristics of each component of the
cardiac neuronal hierarchy to myocardial ischemia so that focused
neurocardiological strategies can be devised to stabilize cardiac
function in such a state. For that reason, one of the objects of
the present invention is to remodel the heart using SCS or DCA
stimulation to combat remodeling that occurs within the
intrathoracic cardiac nervous system in the presence of focal
ventricular ischemia. The selective nature of the responses
elicited by each component of the intrathoracic neuronal hierarchy
to myocardial ischemia depends on how each population is affected
by the content of their altered cardiac sensory inputs. Neuronal
interactions in diseased states are relevant given the fact that
pharmacological agents proven for use in treating heart failure
(i.e., beta-adrenoceptor or angiotensin II receptor blocking
agents) target not only cardiomyocytes directly, but also
indirectly by altering their inputs from cardiac efferent neurons
secondary to altering the intrathoracic neuronal interactions.
[0216] Data also indicates that the cardiac neuronal hierarchy
becomes obtunded by a variety of interventions, including multiple
transmural laser `revascularization` therapy or heart failure.
Intrathoracic neuronal function also remodels in the presence of
focal ventricular ischemia. Given the fact that certain populations
of intrathoracic neurons, when activated, can induce ventricular
fibrillation even in the normally perfused heart, therapy directed
at the intrinsic cardiac nervous system, whether pharmacological or
surgical in nature, or through use of SCS or DCA stimulation are of
benefit in managing the ischemic heart and one of its
sequellae--ventricular arrhythmias.
[0217] Activation of the dorsal columns of the cranial thoracic
spinal cord results in a suppression of the activity generated by
neurons not only on the target organ, but also in middle cervical
and stellate ganglia. It is known that neurons in middle cervical
and stellate ganglia are under the constant influence of spinal
cord neurons such that following their decentralization the
activity generated by many of the latter increased upon removal of
such control. Furthermore, removal of spinal cord inputs to the
intrathoracic extracardiac nervous system results in enhancement of
many intrathoracic extracardiac cardio-cardiac reflexes. It has
also been shown that excessive activation of spinal cord neurons
suppresses the intrinsic cardiac nervous system, i.e.,
preconditioning the intrinsic cardiac nervous system.
[0218] Heart failure has been considered to be primarily a
hemodynamic disorder. Only recently has the importance of
neurohumoral mechanisms that act to maintain adequate cardiac
output in the presence of heart failure become appreciated,
particularly with respect to arrhythmia formation. This recognition
and other clinically relevant findings have forced a reappraisal of
neuronal mechanisms involved in regulating the ischemic
myocardium.
[0219] Upper cervical neuronal modulation of upper thoracic cell
activity and interactions within and between upper cervical and
upper thoracic spinal neurons involved in this processing have been
examined. More specifically, these experiments have determined that
different populations of neurons within and between segments of the
spinal cord exhibit coherence and correlation of activity and may,
on occasion, act independently. It has been determined that neurons
in the upper cervical (C1-C2) spinal cord are organized to process
cardiac sensory information and coordinate the interactions between
the C1-C2 and the T3-T4 spinal neurons, to thereby determine
autonomic outflow to the intrinsic cardiac nervous system. Coupling
of neuronal processing fluctuates within and between two cell
populations during increased cardiac sensory stimulation. In the
present application it is shown that chemical activation of upper
cervical neurons modulates the stimulus locked and long lasting
responses of thoracic spinal cord neurons to myocardial algogenic
chemical stimuli. It has also been demonstrated that cardiac
sensory information arising via thoracic sympathetic afferent
activity ascends in the spinal cord via propriospinal neurons to
influence neurons in the upper cervical spinal cord. In addition,
vagal sensory inputs excite neurons in upper cervical spinal
segments. Thus, the upper cervical spinal cord is an area that
processes cardiac sensory information transduced by afferent somata
in nodose and dorsal root ganglia. Based on these experiments and
data, it was determined that, within the hierarchy of control that
regulates cardiac function (FIG. 1), neurons in C1-C2 spinal cord
process cardiac sensory information to coordinate the interactions
within and between C1-C2 and T3-T4 spinal neurons and thereby
determine autonomic outflow to the intrinsic cardiac nervous
system.
[0220] Well-established evidence links the autonomic nervous system
to life-threatening arrhythmias and cardiovascular mortality. The
autonomic imbalance of increased sympathetic activity and reduced
vagal activity increases the likelihood for ventricular
fibrillation during myocardial ischemia. Clinical studies using
various markers of impaired vagal activity support the experimental
evidence that this type of autonomic imbalance increases
cardiovascular risk. Disease processes may change the balance
between the central and peripheral neurons involved in such
regulation. For instance, when the activity generated by cardiac
sensory neurons becomes abnormal, cardiac function can be affected
profoundly. Therefore, a disturbance of the fine balance within the
cardiac neuraxis will produce dramatic changes in cardiac efferent
neuronal outflow. Within the hierarchy of central neurons that
control the heart, complex sensory processing involves spatial and
temporal summation of cardiac sensory inputs to affect central
preganglionic autonomic efferent neurons that modulate autonomic
efferent postganglionic activity, as well as intrathoracic
ganglionic reflexes and the intrinsic cardiac nervous system.
Experimental studies, as discussed herein, show that pathological
processes can change the integrative behavior of the central
cardiac neuraxis. For example, arrhythmias generated by occlusion
of the coronary artery are significantly decreased after
transection of upper thoracic dorsal roots. This observation
indicates that the spinal cord receives and processes information
that is generated during an ischemic episode. Furthermore, spinal
neurons of the upper thoracic segments are sensitive to changes
associated with arrhythmias. These changes can occur when cardiac
sensory neurites are activated intensely and for long periods when
cardiac tissue becomes damaged during regional ventricular
ischemia.
[0221] Information Processing of Spinal Neurons--Single Cell
Analysis
[0222] Sympathetic afferents from the heart convey noxious and
mechanical, presumably innocuous, information via the dorsal roots
primarily in the upper thoracic segments. We herein show that both
centrally projecting as well as non-projecting neurons respond to
noxious stimuli applied to the heart. We also demonstrate that
chemical stimulation of cardiac nociceptors produces either a
stimulus-locked or long lasting evoked response of superficial and
deep spinal neurons of the upper thoracic spinal cord.
[0223] The classical concept of acute cardiac nociception is based
on a serial neuronal system that transmits information from cardiac
afferents to spinal neurons. The transfer of information is
mediated by classical neurotransmitters, such as excitatory amino
acids, that lead to membrane potential changes within a time span
of milliseconds to seconds. Thus, nociceptive stimulation of
cardiac afferents evokes discharge rates of spinal neurons that
increase as long as the nociceptors are stimulated. It is generally
assumed that impulses of spinal neurons responding to cardiac
stimuli constitute a simple renewal process with a very high number
of degrees of freedom. Electrophysiological studies show that
nociceptive responses of spinal neurons are the basis of mean
discharge rates of single neurons. It was further shown that
discharge rates are often correlated in a generally linear manner
to the intensity of noxious stimulation and antinociception is
consequently defined as a reduction in discharge rates of
nociceptive neurons.
[0224] Multiple Cell Analysis
[0225] Under normal, physiological conditions stimuli applied to
the heart do not elicit marked changes in cardiac efferent neuronal
activity because central neurons suppress excessive cardiac sensory
information processing. In the hierarchy of cardiac control,
activation of spinal neuronal circuits modulates the intrathoracic
cardiac nervous system. Activation of the dorsal columns at the
T1-T2 segments significantly reduces the activity generated by the
intrinsic cardiac neurons in their basal conditions as well as when
activated in the presence of focal ventricular ischemia induced by
occluding the left coronary artery. Not only does dorsal column
activation modulate the intrinsic cardiac nervous system, but it
also modifies the activity of spinal neurons within the T3-T4
segments. In addition, the central nervous system maintains a tonic
inhibitory influence over intrathoracic cardiopulmonary-cardiac
reflexes. Reflexes mediated through the middle cervical ganglion
are increased after decentralization. Thus, disease processes
change the balance between the central and peripheral neuronal
processing of cardiac sensory information. For instance, when the
activity generated by cardiac sensory neurons becomes excessive,
e.g., during focal ventricular ischemia, cardiac function can be
profoundly affected. Thus, a disturbance of the fine balance within
the cardiac neuraxis results in dramatic changes in cardiac
efferent neuronal activity. Nests of neural networks in the
hierarchy of cardiac control, therefore, appear to interact
effectively when an appropriate balance is achieved therein.
[0226] Upper Cervical Modulation of the Thoracic Spinal Cord and
Heart
[0227] Within the hierarchy for cardiac control, neurons of the
upper cervical segments modulate information processing in the
spinal neurons of the upper thoracic segments. In human studies,
spinal cord stimulation of the C1-C2 spinal segments relieves pain
symptoms in patients with chronic refractory angina pectoris.
Experimental studies disclosed and discussed herein show that
spinal cord activation of the upper cervical segments of the spinal
cord suppresses the activity of spinal neurons in T3-T4 segments.
Furthermore, chemical stimulation with glutamate of cells in the
C1-C2 segments also reduces upper thoracic spinal neuronal activity
and that chemical stimulation of C1-C2 cells suppresses the
activity of lumbosacral spinal neurons. It is especially important
to note that this suppression of lumbosacral neuronal activity is
sustained even after the spinal cord is transected at the
spinomedullary junction. Glutamate was chosen as the stimulant
because it only activates cell bodies but not the axons passing
through the upper cervical segments.
[0228] Neuroanatomy of High Cervical Neurons
[0229] Little information about descending pathways that originate
from C1-C2 segments is available, but anatomical studies provide
some evidence for a subpopulation of C1-C2 cells that are involved
in propriospinal modulation of spinal sensory neurons. Horseradish
peroxidase (HRP) injection into the thalamus of cats labeled cells
in the lateral cervical nucleus; however, a subpopulation of cells
in the medial part of this nucleus was unlabeled, and axons of
these unlabeled cells appear to descend to caudal spinal segments.
Others in the art have confirmed those descending projections by
injecting HRP in the C8-T5 segments of one monkey and finding
labeled cells in the lateral cervical nucleus and in the C1-C2 gray
matter. Furthermore, another group skilled in the art has shown in
cats that neurons in the medial portion of the lateral cervical
nucleus respond to noxious stimuli. In addition, spinal sensory
neurons in upper cervical segments receive noxious inputs from
large areas of the body and thus, may project to more caudal spinal
segments, as well as to the thalamus. Indeed, it has been proposed
that the lateral spinal nucleus, which extends down the entire
spinal cord, may participate in inhibition of efferent nerve
activity in rats. The data as presently disclosed also shows that
after selective spinal transections in rats supported the concept
that spinal inhibitory effects in sensory neurons utilize upper
cervical segments.
[0230] Spinal Relay for Vagal Inputs
[0231] A very interesting finding is the differential processing of
cardiac vagal afferent information in the cervical and thoracic
spinal cord. Electrical and chemical stimulation of vagal afferent
fibers primarily excites neurons of the C1, C2 segments. It should
be pointed out that these cervical cells also receive input that
was carried to the thoracic spinal cord via the sympathetic
afferents. However, the vagal information elicits larger evoked
responses. In contrast to excitation of upper cervical spinal
neurons, vagal input from the cardiopulmonary region generally
reduces neuronal activity in sensory cells of rats, cats and
monkeys in segments below C3; vagal facilitation of responses to
noxious inputs are reported only at low stimulus intensities.
Antinociceptive effects of vagal stimulation also are found in the
tail-flick response in rats, and vagotomy attenuates
opioid-mediated and stress-induced analgesia.
[0232] Disruption of the C1-C2 neurons with the excitotoxin,
ibotenic acid, eliminates the suppressor effects on thoracic spinal
neurons with vagal stimulation. Vagal suppression of evoked
activity of thoracic spinal neurons resulting from intrapericardial
injections of algogenic chemicals is attenuated or eliminated after
ibotenic acid was placed on the dorsal surface of the C1-C2 spinal
segments.
[0233] Neurons in the upper cervical (C1-C2) and upper thoracic
(T3-T4) spinal cord process cardiac sensory information to
coordinate the interactions within and between these populations of
spinal cord neurons and thereby modulate efferent neurons that
regulate regional cardiac function. Specifically, neurons in C1-C2
spinal cord process cardiac sensory information to coordinate the
interactions within and between C1-C2 and T3-T4 spinal neurons and
thereby determine autonomic outflow to the intrinsic cardiac
nervous system.
[0234] Simultaneous Recordings of Two Neurons
[0235] Different populations of neurons within and between segments
of the spinal cord exhibit coherence and correlation of activity
and may, on occasion, act as independent units. Valuable data was
gathered by recording from two cells simultaneously by using two
microelectrodes. FIG. 14 demonstrates simultaneous recordings of
two cells and particularly indicates the correlation of two cells
in the T3 segment of the spinal cord.
[0236] Noxious Chemical Stimulation of the Heart-Responses of T3-T4
and C1-C2 Neurons.
[0237] A typical example of an upper thoracic cell responding to
somatic and noxious chemical stimulation of the heart is shown in
FIG. 15. The chemical evoked responses also show tonic activity
descending from upper cervical and supraspinal regions. The
evidence of tonic modulation supports the conclusion that there is
a hierarchy of control or modulation from the upper cervical spinal
cord (FIG. 1). Intrapericardial injections of algogenic chemicals
generally increase the activity of T3-T4 spinal neurons, but the
activity appears to decrease in a few cells. Intrapericardial
injections also increased the average activity of 50% of the
C.sub.1-C.sub.2 spinal neurons from 8.1.+-.1.3 imp/s to 21.6.+-.2.6
imp/s. Mechanical stimulation of the somatic fields on the chest
and forelimbs activated afferent fibers that converged onto the
T3-T4 spinal neurons; whereas, the input from somatic afferent
fibers converging onto C1-C2 neurons was from receptive fields in
the neck and jaw regions.
[0238] Cell Response to Coronary Artery Occlusion
[0239] Chemical stimulation of the heart using algogenic chemical
stimulation of cardiac afferents provides a global method for
activating cardiac afferents. The effects of coronary artery
occlusion on upper cervical and upper thoracic cell activity is
included herein because it specifically provides a means of
activating nociceptive afferents in regional areas of the heart and
clearly demonstrates that SCS or DCA stimulation has a
preconditioning or protective effect on the heart thereby dampening
neuronal activity of the intrinsic cardiac nervous system. Such an
effect leads or lends itself to therapeutic SCS or DCA stimulation
of the intrinsic cardiac nervous system to prevent and/or lessen
the effects of cardiac pathologies. FIG. 16 demonstrates that the
left coronary artery can be occluded and thereby produce a response
in a T3 spinal neuron.
[0240] Neurochemistry
[0241] Experiments were performed to show changes in c-fos
expression in the upper thoracic segments in response to activation
of cardiac afferents by injecting algogenic chemicals into the
pericardial sac (FIG. 17). In the resting conditions, very little
c-fos was expressed in the T3-T4 segments and the little c-fos that
was expressed appeared in the more superficial laminae (I-III)
rather than in the deeper laminae, where cells are activated by
stimulation of cardiac afferent fibers. In another experiment, an
intra pericardial infusion of normal saline did not cause any
additional expression of c-fos. These results show that very few
neuronal sites are activated by either the surgical procedures or
the infusion of a solution which does not activate the cardiac
afferent fibers. Heart rate and mean blood pressure did not change
during these infusions. In contrast, the intrapericardial infusion
of algogenic chemicals produced greater c-fos expression in the
supercial laminae and laminae surrounding the central canal V-VII
(FIG. 17). This data simulates a process (angina and the activation
of cardiac nociceptive sympathetic afferent fibers) that most
likely occurs for an extended time period. This data is provided to
demonstrate that these techniques represent a reproducible approach
to simulate cardiac pathologies and that the use of SCS or DCA
stimulation to modulate the intrinsic cardiac nervous system can
significantly impact the progression or effecti of such cardiac
pathologies.
[0242] Effects of Vagal Stimulation on c-Fos Expression in C1-C2
Neurons
[0243] In order to determine whether input from the vagus would
activate C1-C2 neurons, c-fos immunohistochemical studies following
vagal electrical stimulation were performed. Three groups have been
evaluated: unoperated controls, rats with the vagus nerve crushed
for 2 hrs, and rats with the vagus nerve stimulated with the
following parameters: (20 Hz, 30 V, 0.2 ms, 5 min on, 5 min off for
1 hr. Abundant c-fos immunoreactive neurons were found in the
superficial dorsal horn (marginal zone, substantia gelatinosa),
nucleus proprius, central gray region (area X), and ventral horn
(FIG. 18).
[0244] C1 Modulation of Upper Thoracic Cell Activity
[0245] Originally, it was assumed that supraspinal pathways are
necessary for descending inhibitory effects of visceral afferents
on sensory neurons. However, evidence shows that in rats that high
cervical neurons can mediate inhibitory effects of cardiopulmonary
spinal input in lumbar spinothalamic tract (STT) and dorsal horn
(DH) neurons. Thus, it appears that the upper cervical segments
play an important role in the hierarchy that controls the efferent
outflow to the intrathoracic and intrinsic cardiac nervous system.
Based on this knowledge and evidence from previous studies, we
conclude that cell bodies located in the gray matter of C1-C2
spinal segments can modulate nociceptive cardiac-evoked activity of
spinal neurons in the upper thoracic spinal cord. The effects of
glutamate activation of cell bodies in the upper cervical spinal
cord on the activity of cells in the T3-T4 spinal cord evoked by
injections of bradykinin (BK) into the pericardial sac have been
examined. Others have used Glutamate to activate cell bodies in the
cervical spinal cord in the art. Glutamate (1M) was absorbed onto
filter paper pledgets (2.times.2 mm) and was placed on the dorsal
surface of the C1-C2 segments. Saline control pledgets were applied
at the same sites before and after glutamate. Saline did not elicit
any responses.
[0246] Chemical Stimulation of C1-C2 Cells Before and after Rostral
C1 Transection
[0247] The evoked activity of one T3 cell to glutamate is shown
before (panels A-C of FIG. 19) and after rostral C1 (panels D-F of
FIG. 19) transections. These transections demonstrate that
supraspinal pathways are not necessary to elicit the effects from
C1 cell activation. Chemical stimulation of the C1 cell bodies with
glutamate suppresses the evoked responses of the T3 cell to
algogenic chemical stimulation of cardiac afferent fibers. Cells in
the upper cervical segments serve as an important relay in the
hierarchy of cardiac control that modulates the activity of cells
in thoracic segments.
[0248] Neuroanatomy and Immunohistochemistry
[0249] Retrograde tracing was used to detect upper cervical neurons
with propriospinal projections to the lumbosacral spinal segments
in the rat. Termination sites of the upper cervical propriospinal
neurons in the gray matter of the upper thoracic segments are shown
in FIG. 20. Termination sites of the thoracic propriospinal neurons
in the upper cervical segments are also shown in FIG. 21. Using
PHA-L an anterograde study has been performed from the C1-C2
segments in the rat. PHA-L was injected into the C1-C2 segments and
rats survived 12-24 hours. Anterogradely labeled fibers were
identified in the nucleus proprius as far as the upper thoracic
segments. PHAL moves by fast transport, degrades rapidly, and is
picked up by fibers of passage. The results shown in FIG. 20
indicate the feasibility of anterograde tracing from upper cervical
segments.
[0250] Vagal modulation of T3-T4 neurons via the C1-C2 segments
[0251] Electrical Stimulation of the Vagus
[0252] Electrical stimulation of the vagal afferents, in general,
suppresses the activity of the upper thoracic spinal neurons (FIG.
21). Electrical and chemical stimulation of vagal afferents excites
upper cervical spinal neurons.
[0253] Chemical Disruption of the C1-C2 Neurons
[0254] Chemical disruption of the C1-C2 spinal neurons alters the
effects of stimulation of the cardiac afferent input on the
regulation of information processing in the cervical and thoracic
spinal cord. In order to produce chemical disruption of cells,
ibotenic acid was chosen because it is an excitotoxin that has been
used effectively in previous studies. Ibotenic acid is a
structurally rigid glutamate analog that destroys neuronal
perikarya, but spares axons and non-neuronal cells. After ibotenic
acid is injected into a nucleus or applied to the surface of the
spinal cord, the cells in the region are initially excited and then
enter a phase of depolarization block. FIG. 22 shows that ibotenic
acid applied to the dorsal surface of the C1-C2 spinal segments
causes energy impairment and/or apoptosis of cells located beneath
the surface of these segments. The advantage of this methodology is
that the neuronal relays in the C1-C2 segments can be disrupted
without interrupting the axons that pass through this region.
[0255] Vagal Effects after Chemical Disruption of C1-C2 Cell
Bodies
[0256] At least part of the vagal inhibitory effects of the upper
thoracic neurons depends on the C1-C2 relay. Approximately 20 min.
after ibotenic acid was placed on the spinal cord, the inhibitory
effects to vagal stimulation observed in FIG. 22 were eliminated.
These results indicate that at least part of the vagal inhibitory
pathway is dependent on an intact relay in the C1-C2 segments.
[0257] Using high frequency, low intensity electrical stimulation
of the dorsal aspect of the T1-T2 spinal cord, the modulatory
effects on the final common integrator of cardiac function, the
intrinsic cardiac nervous system, have been determined. Dorsal cord
activation by itself decreases basal intrinsic cardiac neuronal
activity by 77%. This suppression of neuronal activity persisted
for 30-45 minutes after terminating the dorsal cord stimulation.
When LAD occlusion was initiated during dorsal cord activation,
neuronal activity remained suppressed. Thus, use of SCS or DCA cord
stimulation to precondition and/or remodel the neuronal activity of
the intrinsic cardiac nervous system has been shown.
[0258] Thus, dorsal cord activation suppresses intrinsic cardiac
neuronal activity in both normally perfused and ischemic hearts and
dorsal cord activation suppresses the activity of upper thoracic
spinothalamic tract neurons evoked by chemical stimulation of
cardiac afferents. Dorsal cord activation or SCS can modulate the
activity of cells in central nervous system and the intrinsic
cardiac nervous system. Dorsal cord activation can be used at
either the thoracic or the cervical levels. The cervical segments
are particularly interesting, because this is a key region for
hierarchical control, and dorsal cord activation of the upper
cervical segments has been used to relieve the symptoms in patients
with chronic refractory angina pectoris. Dorsal cord activation of
the upper cervical segments suppresses the responses of a T3 spinal
neuron evoked by algogenic chemical stimulation of the cardiac
afferents is shown in FIG. 23.
[0259] Chemical stimulation of the upper cervical cell bodies
suppresses upper thoracic cell responses to nociceptive (chemical)
and non-nociceptive (mechanical) input. In contrast, chemical
stimulation of the upper thoracic cell bodies excites the upper
cervical spinal neurons. Furthermore, the responses to nociceptive
and non-nociceptive stimuli are enhanced. Inactivation of the upper
cervical cell bodies eliminates the suppression of spontaneous and
evoked activity of the upper thoracic neurons. In fact, the
nociceptive and non-nociceptive responses are facilitated because
elimination of the upper cervical spinal neurons reduces the tonic
inhibition that continually impinges on the upper thoracic spinal
neurons. Elimination of the upper thoracic cell bodies does not
have an appreciable effect on the spontaneous activity and the
evoked responses of the upper cervical spinal neurons, because
vagal input produces larger responses of the upper cervical neurons
than do the inputs that originate from sympathetic afferents.
[0260] Vagotomy also changes the modulation of spontaneous activity
and nociceptor evoked responses of C1-C2 and T3-T4 spinal neurons.
Inactivation of C1-C2 cell bodies eliminates vagal effects of
chemical and mechanical stimulation on the activity of the upper
thoracic neurons. Vagotomy also eliminates the nociceptive and
non-nociceptive responses of the C1-C2 spinal neurons after
elimination of input from the T3-T4 spinal neurons. C-fos
expression at the upper thoracic segments increases after C1-C2
ablation before and after activation of the vagal afferents,
because the cells of the upper cervical segments tonically suppress
cell activity in the upper thoracic spinal cord. Perturbations
change the correlation characteristics of the pairs of neurons. In
addition, the responses of the individual neurons, which are
recorded simultaneously, change their response characteristics
independently after the interventions are made. The cfos expression
does not change in the cervical segments because of the disruption
of the cells by ibotenic acids that participate in producing the
suppression of thoracic activity. In anterograde tracing studies
with PHAL, a clearer picture of the reciprocal innervation between
the C1-C2 and T3-T4 segments is seen.
[0261] The experiments were designed in order to study the activity
and responses of individual cells (192) as well as pairs (96) of
cells. Results indicate that coronary artery occlusion evokes
responses in the C1-C2 and T3-T4 neurons. That ischemic responses
differ from the algogenic chemical responses because chemical
stimulation provides a global activation of the afferents; whereas,
coronary artery occlusion limits the stimulus to a specific region
of the heart. Since vagal input provided the strongest input to the
C1-C2 neurons and sympathetic afferents provided the excitatory
inputs to T3-T4 neurons, different patterns of activity are
demonstrated. Since activation of the vagus excites C1-C2 cells and
suppresses the activity of T3-T4 cells, vagotomy reduced the
responses of upper cervical neurons but enhances upper thoracic
responses to coronary artery occlusion. Coronary artery occlusions
will increase the number of cells filled with c-fos expression in
both C1-C2 and T3-T4 spinal segments.
[0262] The experiments were also designed to study the activity and
responses of individual cells (384) as well as pairs (192) of cells
to address information processing of the effects of algogenic
chemical stimulation and coronary artery occlusion before and after
the cells of C1-C2 are disrupted using ibotenic acid. Dorsal cord
activation of the T1-T2 or C1-C2 segments suppresses the evoked
T3-T4 cell activity to algogenic chemical stimulation and coronary
artery occlusion. Since disruption of cells with ibotenic acid
reduces or eliminates vagal suppression of the evoked activity of
the T3-T4 cells, inhibitory effects of dorsal cord activation are
reduced or eliminated, because synaptic activity occurs in the same
segments that are stimulated electrically with dorsal cord
activation. Disruption of C1-C2 cells with ibotenic acid might
reduce the effectiveness of T1-T2 dorsal cord activation on the
evoked responses of T3-T4 spinal neurons due to the vasodilator
effects of dorsal cord activation being eliminated when the spinal
cord was transected at least four to six segments rostral to the
site of stimulation. Dorsal cord activation changes the correlation
of cell activity in the pairs of cells. These changes are
responsible for the suppressed activity of the intrinsic cardiac
nerve activity. Dorsal cord activation generates patterns of
activity in the spinal neurons that act to stabilize the activity
generated by the intrinsic cardiac neurons.
[0263] Algogenic chemical stimulation evokes short lasting and long
lasting excitatory as well as inhibitory responses of the C1-C2 and
T3-T4 neurons. If two neurons recorded simultaneously receive
common input from algogenic chemical stimulation of cardiac
afferents, they have more synchronous action potentials than
statistically expected, and their cross-correlation function
correspondingly shows a sharp central peak (i.e., when the mutual
delay is at zero). However, the central peak is widened to a
variable extent when several neuronal connections are interposed
between the locus of common input and the neurons from which the
activity is recorded. There are stronger correlations in pairs of
neurons when one neuron is in the superficial dorsal horn and the
other one is in the deeper dorsal horn. Experiments have shown that
latency to the onset of the evoked response of superficial cell to
algogenic chemical stimulation of cardiac afferents is shorter than
the latency to the onset of the evoked response in a deeper cell.
This difference in the latency suggests that the superficial
neurons serve as an interneuron between the input from the primary
afferents and the activation of the deeper cells. Since vagal input
provided the strongest input to the C1-C2 neurons and the
sympathetic afferents provided the excitatory inputs to the T3-T4
neurons, different patterns of activity have been demonstrated.
Since activation of the vagus excites C1-C2 cells and suppresses
the activity of T3-T4 cells, vagotomy will reduce the responses of
the upper cervical but enhance upper thoracic responses to
nociceptive algogenic chemical stimulation. No effects occurred
using saline controls. With respect to mechanical studies, some of
the cells discharge in response to the premature ventricular
contraction. Some of the bursts occur early in the compensatory
phase, but more commonly the burst is associated with the
potentiated contraction. Cells were analyzed individually and as
pairs. Vagotomy does not prevent responses of the neurons to
chemical stimulation, but most likely modulates some of the
mechanical responses. Chemical stimulation increases the number of
cells filled with c-fos expression in both the upper cervical and
upper thoracic spinal segments. After bilateral vagotomy, a
decreased number of cells with c-fos, but the number of thoracic
spinal cells with c-fos increases because vagal activation of upper
cervical neurons suppresses the activity in thoracic neurons. As
shown in FIG. 18, cells located in specific regions of these
segments were found.
[0264] Chemical stimulation of the upper cervical cell bodies
suppresses upper thoracic cell responses to nociceptive (chemical)
and non-nociceptive (mechanical) input. In contrast, chemical
stimulation of the upper thoracic cell bodies excites the upper
cervical spinal neurons. Furthermore the responses to nociceptive
and non-nociceptive stimuli are enhanced. Inactivation of the upper
cervical cell bodies eliminates the suppression of spontaneous and
evoked activity of the upper thoracic neurons. In fact, the
nociceptive and non-nociceptive responses are facilitated because
elimination of the upper cervical spinal neurons reduces the tonic
inhibition that continually impinges on the upper thoracic spinal
neurons. Elimination of the upper thoracic cell bodies does not
have much effect on the spontaneous activity and the evoked
responses of the upper cervical spinal neurons because vagal input
produces larger responses of the upper cervical neurons than do the
inputs that originate from sympathetic afferents. Vagotomy changes
the modulation of spontaneous activity and nociceptor evoked
responses of C1-C2 and T3-T4 spinal neurons. Inactivation of C1-C2
cell bodies eliminates vagal effects of chemical and mechanical
stimulation on the activity of the upper thoracic neurons. Vagotomy
also eliminates the nociceptive and non-nociceptive responses of
the C1-C2 spinal neurons after elimination of input from the T3-T4
spinal neurons. C-fos expression at the upper thoracic segments
increases after C1-C2 ablation before and after activation of the
vagal afferents, because the cells of the upper cervical segments
tonically suppress cell activity in the upper thoracic spinal cord.
The perturbations change the correlation characteristics of the
pairs of neurons. In addition, the responses of the individual
neurons, but recorded simultaneously, change their response
characteristics independently after the interventions are made. The
cfos expression is not changed in the cervical segments because of
the disruption of the cells by ibotenic acids that participate in
producing the suppression of thoracic activity. Anterograde tracing
studies with PHAL, have shown that a clearer picture of the
reciprocal innervation between the C1-C2 and T3-T4 segments is
obtained.
[0265] Differential remodeling of the peripheral and central
cardiac nervous hierarchy and its nerve-cardiac myocyte junction in
the presence of a healed myocardial infarction specifically as
related to the genesis of ventricular fibrillation occurs. Tests
utilize a well-defined canine model of ventricular fibrillation
that combines three elements relevant to the genesis of malignant
arrhythmias in man: a healed myocardial infarction, acute
myocardial ischemia, and physiologically elevated sympathetic
efferent neuronal activity have shown that differential remodeling
is at least partially responsible for cardiac pathologies. Test
also reveal and demonstrate that SCS or DCA stimulation of the
intrinsic cardiac nervous system has a preconditioning effect
pre-remodeling and a quenching effect post re-modeling. Based on an
"exercise and ischemia test", animals in this model separate into
two groups: 1) animals that develop ventricular fibrillation and
are thereby classified "susceptible" to fibrillation; and 2) dogs
that don't develop sustained ventricular tachycardia/fibrillation
and are thus defined as "resistant". Thus, differential remodeling
of the cardiac neuron hierarchy (central and peripheral) for reflex
control of the heart occurs in susceptible versus resistant
animals.
[0266] Autonomic Nervous System and Sudden Death after Myocardial
Infarction.
[0267] A canine model of lethal ventricular arrhythmias developed
in 1978 has been used to elaborate the mechanisms of sudden death
after myocardial infarction (MI). In this model, animals with a
chronic anterior wall infarction undergo a sub-maximal exercise
stress test, culminating in transient total occlusion of the
circumflex coronary artery for 2 minutes. During that 2-minute
period of transient myocardial ischemia, 40% of the dogs develop
ventricular fibrillation (VF); the remaining animals do not
generate sustained ventricular arrhythmias. This model produces
clinically relevant information by incorporating a healed anterior
MI in the setting of elevated sympathetic efferent neuronal tone
(induced by exercise), coupled with acute, regional myocardial
ischemia distant from the original infarction. This model was
developed to duplicate the clinical situation of a patient with
multi-vessel coronary artery disease who begins sub-maximal
exertion in the convalescent phase of an uncomplicated MI, patients
who then develop transient myocardial ischemia. In the dog model,
those destined to develop VF display persistent tachycardia in
response to transient, acute myocardial ischemia. In contrast, VF
resistant animals have been found to possess active vagal reflexes
that control heart rate during the ischemic event. Thus, this model
produces two distinct groups of animals, based on the occurrence of
VF, that have very different characteristics of autonomic control
of heart rate.
[0268] This model gives rise to the data that non-invasive markers
of cardiac vagal reflexes predict risk for sudden death after
myocardial infarction. This is shown through baroreflex sensitivity
(BRS) data relating a rise in systolic blood pressure to RR
interval slowing was prospectively tested prior to exercise and the
induction of myocardial ischemia to predict outcomes. BRS was
reduced in chronic MI dogs destined to develop VF during exercise
and acute, regional myocardial ischemia. Interestingly, BRS was
lower before MI in dogs that either died after coronary artery
ligation or developed VF within 30 days of acute MI during
exercise. Clinical conformation of these results has been published
and shows that BRS was lower in patients who subsequently died
suddenly after their first myocardial infarction. Results establish
that autonomic markers add critical predictive information to the
sudden death risk profile after MI. Baroreflex sensitivity
measurements provide one index of the cardiac parasympathetic
nervous system. Heart rate variability (HRV) quantifies cardiac
autonomic interactions by measuring the impact of vagally mediated
respiratory sinus arrhythmia via beat-to-beat RR interval
variability derived from resting ECG recordings. It is shown herein
dogs at high risk for sudden death had low variability
measurements, suggesting low tonic vagal input to the heart. Tonic
autonomic activity was influenced significantly by MI and recovered
only in dogs at low risk for sudden death. In contrast, dogs at
high risk for sudden death displayed little recovery during the
first 30 days following MI. This persistent blunting of vagal tone
was associated with a high risk for VF during exercise and
myocardial ischemia. These experiments provide evidence that
autonomic control of heart rate remodels during the progression of
coronary artery disease.
[0269] If depression of vagal efferent neuronal tone to the heart
and, as a consequence, cardiovascular reflexes are important for
the development of lethal ventricular arrhythmias, does
augmentation of cardiac vagal efferent neuronal activity prevent
sudden cardiac death in such a model? This issue was addressed
using the Schwartz and Stone model of sudden death by electrically
stimulating the vagus nerve by means of chronically implanted
electrodes. When the vagosympathetic trunk was electrically
stimulated during exercise initiated at the onset of coronary
artery occlusion, the incidence of VF was prevented in over 80% of
high-risk dogs tested. This effect was largely independent of the
heart rate reduction associated with vagal activation. Furthermore,
augmentation of tonic vagal activity by daily exercise training
prevented VF in 100% of the high-risk dogs, either in the presence
or absence of acute myocardial infarction. Finally, left stellate
ganglionectomy was effective in reducing VF in these high-risk
animals. Thus, abnormal autonomic control of the infarcted heart
associated with sympathetic efferent neuronal dominance and weak
vagal input, results in ventricular electrically instability that
increases the risk for sudden cardiac death.
[0270] Remodeling of the Cardiac Neuronal Hierarchy after
Myocardial Infarction.
[0271] What comprises the cardiac neuronal hierarchy and why is it
important for the management of cardiac arrhythmias in chronically
infracted hearts? Neurons in intrathoracic extracardiac and
intrinsic cardiac ganglia have long been thought to act as simple
efferent information relay stations involving one synapse, for
instance in paravertebral sympathetic ganglia or parasympathetic
ganglia on the heart. Recently, this concept has been extended in
recognition of the fact that cardiovascular afferent information is
also processed within the intrathoracic nervous system, including
its component intrinsic to the heart. Neurons in intrathoracic
ganglia, including those on the heart, receive constant inputs from
spinal cord neurons to modulate their behavior. They also receive
sensory inputs from cardiac afferent neurons on an ongoing basis.
That is why the activity generated by most intrinsic cardiac
neurons increases markedly in the presence increased sensory inputs
arising from the ischemic myocardium. Indeed, excessive activation
of limited populations of intrinsic cardiac neurons induced cardiac
dysrhythmias that lead to ventricular fibrillation. Thus, therapies
that act to stabilize heterogeneous evoked activities within
cardiac reflex control circuits such, as the SCS or DCA stimulation
of the intrinsic cardiac nervous system of the presently claimed
and disclosed invention, has obvious clinical importance.
[0272] Proper information exchange among the intrathoracic
components of the cardiac nervous system act in concert to
stabilize the electrical and mechanical behavior of the heart,
particularly in the presence of focal ventricular ischemia.
Different populations of neurons, distributed spatially within the
intrathoracic cardiac nervous system, respond to cardiac
perturbations in a coordinate fashion. If neurons in one part of
this neuronal axis respond to inputs from a single region of the
heart, such as the mechanosensory neurites associated with a right
ventricular ventral papillary muscle, then the potential for
imbalance within the different populations of neurons regulating
various cardiac regions occurs and, thus, its neurons display
little coherence of activity. On the other hand, relatively low
levels of specific inputs on a spatial scale to the intrathoracic
cardiac nervous system results in low basal coherence among its
various neuronal components, thereby acting to stabilize cardiac
regulation. Alternatively, excessive input to the spatially
distributed intrathoracic nervous system destabilizes cardiac
electrical behavior, leading to cardiac arrhythmia formation.
Intrathoracic extracardiac and intrinsic cardiac neurons receive
tonic inputs not only from cardiac and major intrathoracic vascular
sensory neurites, but also from spinal cord neurons in the
integration of efferent neuronal inputs to the heart.
[0273] Chronic Ventricular Ischemia and the Cardiac Neuronal
Hierarchy
[0274] The infarct matrix is important in determining risk for VF
in the Schwartz and Stone model discussed hereinabove. This is
illustrated by data showing epicardial conduction mapping across
the infarct zone in high and low risk dogs. It has been found that
conduction delays are much more profound across the infarct zone in
high-risk dogs (>85 millisecond) compared with low risk animals
(FIG. 24). High-risk dogs exhibit "mottled" myocardial infarcts
that are electrophysiologically unstable, with electrical
activation waves persisting as long as 85 milliseconds after
epicardial electrical activation terminates. This matrix reflects a
very large surface area for the development and sustaining of
reentrant arrhythmias, which lead to VF in high-risk dogs. When
ventricular function is normal, very fast VT leading to VF arises
from a purely reentrant mechanism. Components that contribute to
development of a mottled infarct include autonomic characteristics
of dogs before MI. Baroreflex sensitivity is lower in dogs destined
to die after MI or develop VF during the exercise and myocardial
ischemia test. Using a marker derived of both baroreflex
sensitivity and spectral analysis of heart rate variability, dogs
at high risk for post-MI sudden death were identified with high
sensitivity and specificity. These findings indicate that innate
differences in cardiac autonomic control that can be identified
before the development of overt cardiac disease may determine
post-MI sudden death. Furthermore, autonomic differences before MI
influence the type of infarct that develops with the LAD ligation
in this model. This underscores the importance of understanding the
hierarchy of autonomic control of the heart and how abnormalities
contribute to the pathophysiology of cardiac disease (FIG. 1).
[0275] The importance of the peripheral cardiac nervous system in
the maintenance of normal cardiac output can be appreciated from
the presently claimed and disclosed invention. The selective nature
of the responses elicited by each component of the intrathoracic
neuronal hierarchy to myocardial ischemia depends on how each
population of peripheral autonomic neurons is affected, as well as
the nature and content of their sensory inputs. That ischemia
sensitive cardiac afferent neurons in nodose and dorsal root
ganglia influence the behavior of central autonomic neurons which,
in turn, modify cardiovascular autonomic efferent preganglionic
neurons represents yet another level of this regulatory
hierarchy.
[0276] Myocardial Ischemia.
[0277] Recent anatomical and functional data indicate the presence
of the multiple neuronal subtypes within intrathoracic extracardiac
and intrinsic cardiac ganglia. Its intrinsic cardiac component
functions as a distributive processor at the level of the target
organ. The redundancy of function and non-coupled behavior
displayed by neurons within intrathoracic extracardiac and
intrinsic cardiac ganglia minimizes the dependency for such control
on a single population of peripheral autonomic neurons. In that
regard, network interactions occurring at the level of the heart
integrate parasympathetic and sympathetic efferent inputs with
local afferent feedback to modify cardiac rate and regional
contractile force throughout each cardiac cycle. A recent editorial
by David Lathrop and Pete Spooner of the NIH highlights the
potential clinical relevance of altered processing of information
by these populations of neurons such that a lack of coordination of
data exchange within the cardiac neuronal axis may lead to the
genesis of cardiac arrhythmias.
[0278] Interactions Among Neurons in the Cardiac Neuronal
Hierarchy.
[0279] The different populations of neurons distributed spatially
within the intrathoracic cardiac nervous system respond to cardiac
perturbations in a complex fashion. For instance, neurons in
intrathoracic extracardiac ganglia do not respond to cardiac
perturbations in a similar fashion as intrinsic cardiac ones.
Consistent coherence of activity generated by differing populations
of neurons has been identified among medullary and spinal cord
sympathetic efferent preganglionic neurons, as well as among
different populations of sympathetic efferent preganglionic
neurons. If neurons in one part of the intrathoracic neuronal
network respond solely to inputs from a single region of the heart,
then the potential for imbalance within the different populations
of neurons in various levels of the intrathoracic neuronal
hierarchy might occur. A relatively low level of inputs on a
spatial scale to populations of intrathoracic cardiac neurons would
result in a low basal coherence among its components and stabilize
that system. In contrast, excessive input to this spatially
distributed nervous system would destabilize it, leading for
instance to cardiac arrhythmia formation.
[0280] Arterial reflexes can become blunted during the evolution of
heart disease. Focal ventricular ischemia is known to alter
cardio-cardiac reflexes. Furthermore, ischemia induced liberation
of chemicals such as adenosine or hydroxyl radicals within the
affected myocardium can suppress ventricular myocyte electrical and
contractile behavior. On the other hand, locally released adenosine
or hydroxyl radicals can influence the cardiac nervous system via
excitation of its afferent neuronal components. Thus, when devising
a therapy to modify the outcome of myocardial ischemia one must
consider not only altered cardiac myocyte behavior, but autonomic
neuronal alterations. A brief summary of some of the issues
concerning autonomic neuronal control of the ischemic myocardium is
presented below, including its importance in one sequellae of
myocardial ischemia--ventricular arrhythmia formation.
[0281] Symptomatology.
[0282] The somata of isolated afferent neurons are sensitive to
adenosine. ATP and, to a lesser extent, adenosine influence sensory
neurites of dorsal root ganglion neurons. The importance of
adenosine in the genesis of cardiac pain became evident when
Christer Sylven and his colleagues administered adenosine into the
blood stream of patients with diseased coronary arteries. Indeed,
the symptoms induced by adenosine in these patients mimicked those
that they experienced during effort. These data are in accord with
the fact that dorsal root ganglion purine cardiac afferent neurons
play an important role in the genesis of pain and that the
ventricular sensory neurites of these neurons become non-responsive
to ischemia in the presence of adenosine receptor blockade.
[0283] Cardiovascular Reflexes Secondary to Myocardial Ischemia.
Alterations in heart rate secondary to ventricular ischemia can be
due, in part, to altered neural control of cardiac pacemaker cells.
Myocardial ischemia can be attended by not only by tachycardia, but
also by bradycardia.
[0284] Most ventricular sensory neurites associated with nodose
ganglion cardiac afferent neurons are sensitive to purinergic
agents. Activation of a sufficient population of nodose ganglion
afferent neurons by exposing their sensory neurites to purinergic
agents can result in the induction of bradycardia via medullary
reflexes. Bradycardia can also be induced when sufficient
populations of intrinsic cardiac neurons projecting axons to
medullary neurons are activated by purinergic agents. In contrast,
activation of cardiac sensory neurites associated with dorsal root
ganglion neurons with adenosine results in the reflex excitation of
sympathetic efferent neurons that innervate the heart. The details
of the various reflex responses induced when specific populations
of cardiac afferent neurons in nodose as opposed to dorsal root
ganglia are modified by local ischemia remain to be fully
elucidated. Coordination of autonomic outflows to the heart depends
to a large extent upon the sharing of inputs from higher centers
concomitant with interactions among neurons in various
intrathoracic ganglia. That sharing of cardiac afferent information
occurs within the intrathoracic and brainstem/spinal cord feedback
loops of FIG. 1 allows for overall coordination of cardiac
function.
[0285] Cardiac Arrhythmias.
[0286] Another sequel of myocardial ischemia is the development of
cardiac arrhythmias. As neurons from the level of the insular
cortex to the intrinsic cardiac nervous system can be involved in
the genesis of cardiac arrhythmias, it is important to recognize
that such neurons can induce untoward cardiac electrical events in
the presence of myocardial ischemia. For instance, activation of a
relatively minor population of intrinsic cardiac neurons in
anesthetized canine preparations by exogenous application of an
alpha- or beta-adrenoceptor agonist, endothelin I or angiotensin II
can induce ventricular dysrhythmias or even fibrillation. DCA and
SCS do reduce or ameliorate these effects.
[0287] Neural Substrates for Arrhythmia Formation in Ischemia.
[0288] The selective nature of the responses elicited by each
component of the cardiac neuronal hierarchy to focal, ventricular
ischemia depends on how each population of neurons within this
autonomic neuronal hierarchy is affected and that depends in large
part on the nature and content of their ventricular sensory inputs.
It also depends, in part, on any alteration in ventricular efferent
postganglionic axon function secondary to their presence within the
ischemic zone.
[0289] Cardiac Afferent Neurons.
[0290] The chemical milieu of the sensory neurites associated with
intrinsic cardiac afferent neurons also change when the blood flow
in a coronary artery is compromised. Locally liberated adenosine,
ATP, oxygen free radicals and peptides can affect the sensory
neurites associated with afferent neuronal somata in nodose, dorsal
root or intrathoracic ganglia. Oxygen free radicals also affect the
functional integrity of ventricular nerves. The quantities of
purinergic agents liberated into the local blood stream and
pericardial fluid, increases during ventricular ischemia, as
peptides or hydrogen peroxide can affect the activity generated by
intrathoracic and central cardiac afferent neurons in an indirect
fashion as chemicals accumulated in myocardial tissues and
pericardial fluid modify their sensory neurites. When coronary
arterial blood flow is restored, during the reperfusion phase
various metabolites that accumulate upstream can influence
intrinsic cardiac neurons and their sensory neurites supplied by
that blood even more.
[0291] That ischemia sensitive cardiac afferent neurons in
relatively distant (nodose and dorsal root) ganglia versus the
somata of cardiac afferent neurons relatively closer to the
affected tissue (intrathoracic extracardiac and intrinsic cardiac
afferent neurons) influence the behavior of cardiac efferent
postganglionic neurons via central and intrathoracic local circuit
neurons represents yet another issue of importance within this
regulatory hierarchy (FIG. 1). Alterations in heart rate secondary
to ventricular ischemia activation of cardiac afferent neurons
results in altered neural control of cardiac pacemaker cells. Thus,
myocardial ischemia can be attended by tachycardia or bradycardia.
Activation of a sufficient population of nodose ganglion afferent
neurons by exposing their sensory neurites to a variety of
chemicals that are liberated by the ischemic myocardium results in
the induction of bradycardia via medullary reflexes. In contrast,
excitation of the cardiac sensory neurites associated with dorsal
root ganglion neurons by chemicals such as adenosine results
induces the reflex excitation of sympathetic efferent neurons that
innervate the heart.
[0292] Intrinsic Cardiac Neurons.
[0293] Intrinsic cardiac neurons are modified by myocardial
ischemia in two fashions: one direct and the other indirect.
Transient occlusion of the coronary arterial blood supply to a
population of intrinsic cardiac neurons directly affects the
function of their somata and/or dendrites. Presumably a lack of
energy substrates normally available to them via their local
arterial blood supply accounts in part for their altered behavior,
as well as the fact that they are bathed by local products of
ischemia such as oxygen free radicals and purinergic agents. Each
major intrinsic cardiac ganglionated plexus on human or dog hearts
is perfused by two or more arterial branches arising from different
major coronary arteries. Intrinsic cardiac neurons and
cardiomyocytes are affected by hypoxia. Myocardial ischemia of
short duration affects not only cardiac myocyte function, but also
the capacity of intrinsic cardiac neurons to respond to their
sensory inputs. Metabolites accumulating locally when the regional
coronary arterial blood supply of intrinsic cardiac neurons is
compromised also influence the somata and dendrites of such neurons
in a direct manner. Thus, regional ventricular ischemia influences
the cardiac neuronal hierarchy in a number of ways, depending on
whether the arterial blood supply affected by the arterial lesion
directly affects the somata and dendrites of somata therein or
indirectly via affecting sensory neurites in the infarct zone.
[0294] Data indicate that adaptations occur within the cardiac
neuronal hierarchy in the presence of acute, focal ventricular
ischemia. The cardiac nervous system remodels during chronic
ischemic/infarction to maintain control over regional cardiac
dynamics.
[0295] Myocardial infarction is induced by ligation of the left
anterior descending coronary artery in an open chest procedure
during surgical anesthesia. The circumflex coronary artery is
instrumented with a pneumatic occluder so that reversible
myocardial ischemia can be induced at a later time. After 30 days
of recovery, dogs have autonomic tests performed including
baroreflex sensitivity (Sleight phenylephrine method) and heart
rate variability (time and frequency domain). Then animals run on a
treadmill using a protocol in which workload (belt speed and
elevation) are increased every 3 minutes. Once heart rate reaches
210 beats per minute the circumflex occluder is inflated for 2
minutes, the first minute the dogs continue to run on the treadmill
and the treadmill is stopped for the last minute. Forty percent of
the post-MI animals develop ventricular fibrillation (VF) during
the 2 minutes of coronary occlusion. The other 60% do not have
sustained ventricular arrhythmias. An example of the arrhythmia
that susceptible dogs develop is illustrated in FIG. 25. This
observation indicates that reflex vagal activation is relatively
weak in susceptible dogs and thus leads to ventricular electrical
instability and even ventricular fibrillation. This indication was
further tested by measuring baroreflex sensitivity during
activation of cardiac vagal fibers by means of high pressure
baroreflex testing. Relating the heart rate slowing in response to
systemic hypertension (phenylephrine induced) quantifies baroreflex
sensitivity (FIG. 26). It was found that baroreflex sensitivity was
depressed in susceptible dogs compared with resistant animals and
the baroreflex was an accurate predictor of the outcome of the
exercise and ischemia test (Table II).
TABLE-US-00002 TABLE II Resistant Susceptible Strong vagal reflexes
Weak vagal reflexes High baroreflex sensitivity Low baroreflex
sensitivity High heart rate variability Low heart rate variability
Transmural scar Mottled scar No late potentials +late
potentials
[0296] These findings were clinically validated in the multicenter
trial called ATRIAMI in which baroreflex sensitivity was found to
be an independent risk factor for post-MI sudden cardiac death.
Subsequently, the indication that weak vagal reflexes was
responsible for susceptible dogs developing VF was tested using
electrical stimuli delivered to vagal efferent preganglionic axons
to augment cardiac vagal control. Vagal stimulation was started at
the time of coronary artery occlusion and continued until the
occluder was released. Vagal stimulation prevented VF in over 80%
of the susceptible dogs. Even during subsequent exercise testing in
which vagal stimulation was coupled with atrial pacing to maintain
heart rate at control levels, VF was prevented in about 50% of the
animals. Therefore, electrical stimulation of cardiac vagal
efferent neurons prevents ventricular electrical instability that
develops during exercise and transient myocardial ischemia in
susceptible dogs.
[0297] One susceptible and one resistant dog were implanted with a
spinal cord stimulator and allowed to recover for 7 days. Control
exercise and ischemia testing and heart rate variability were
studied prior to and during dorsal cord activation (DCA, 50 Hz, 200
.mu.s, 90% motor threshold). The stimulator was activated for 4
hours daily for 4 days; then testing was repeated with the
stimulator on. FIG. 27 shows the chronotropic response to graded
increases in treadmill exercise. Once heart rate reaches 210 beats
per minute the circumflex occluder is inflated for 2 minutes, the
first minute the dogs continue to run on the treadmill and the
treadmill is stopped for the last minute. While concurrent DCA
minimally affected heart rate responses in the resistant dog (right
panel), in the susceptible dog DCA reduced the heart rate during
the ischemic period (left panel).
[0298] Spinal Cord Influences on Neural Control of Chronotropic
Function
[0299] Both spectral analysis (FIG. 28) and time domain analysis
(FIG. 29) of heart rate variability indicate that spinal cord
stimulation via DCA augments parasympathetic nervous system
activity to the heart.
[0300] It is very difficult to predict how central and
intrathoracic autonomic neurons involved in cardiac regulation
remodel to sustain cardiac output in the presence of chronic,
regional ventricular infarction. Data indicate, however, that the
cardiac neuronal hierarchy becomes obtunded by a variety of
interventions, including chronic regional ventricular injury.
[0301] Information Processing within the Intrinsic Cardiac Nervous
System and its Control of Regional Cardiac Function.
[0302] Myocardial ischemia and infarction induce substantial
changes in the intrathoracic nerve networks and their reflex
control of regional cardiac function. Chronic myocardial
infarction/ischemia induces a heterogeneous distribution of
efferent projections to cardiac end-effectors. Myocardial
infarction/ischemia alters the neurochemical profile of that
innervation, with differential increases in neuropeptide content
within subsets of neurons contained within the intrinsic cardiac
nervous system. The evolution of cardiac pathology is associated
with disruptions of the intrinsic cardiac nervous system and its
ability to process afferent information and such changes will be
more evident in the CMVPG than the RAGP intrinsic cardiac ganglia.
Animals that exhibit indices of higher vagal tone (higher
baroreflex sensitivity and higher heart rate variability)
demonstrate lesser degrees of ischemic/infarct-induced neural
remodeling.
[0303] The Functional Connectivity of Intrinsic Cardiac and
Intrathoracic Extracardiac Neurons in Normal and Acutely Ischemic
Hearts.
[0304] Little direct functional interconnectivity exists among
intrinsic cardiac neurons and their intrathoracic extracardiac
counterparts. Independent function as such indicates that little
reliance on one such population normally occurs when regulating
regional cardiac function; i.e., dysfunction of one population
occurs without a major loss of regional cardiac control.
Significant alterations in the cardiac milieu, such as occurs
during acute, focal ventricular ischemia, induces greater coherence
of activity among populations of intrathoracic and intrathoracic
extracardiac neurons.
[0305] Chronic myocardial ischemia induces a heterogeneous
distribution of efferent projections to cardiac end-effectors. We
anticipate that this heterogeneous distribution of sympathetic
fibers to the left ventricle results in similar heterogeneous
release of catecholamines and neuropeptides into the interstitial
space during stimulation of the efferent nerves. Finally, animals
that exhibit indices of higher vagal tone (higher baroreflex
sensitivity and higher heart rate variability) demonstrate lesser
degrees of ischemic/infarct-induced remodeling of the efferent
outflow of the left ventricle.
[0306] Activation of the dorsal columns of the cranial thoracic
spinal cord suppresses the activity generated by neurons not only
on the target organ, but also in middle cervical and stellate
ganglia. It is known that neurons in these ganglia are under the
constant influence of spinal cord neurons such that following their
decentralization their activity increases (i.e., spinal cord
neurons exert tonic suppression of their function). Removal of
spinal cord inputs to the intrathoracic nervous system enhances
many intrathoracic cardio-cardiac reflexes is tied to the principle
and thus excessive activation of spinal cord neurons suppress the
intrinsic cardiac nervous system.
[0307] Heterogeneous alterations within the intrinsic cardiac
ganglia or at the end-terminus of the autonomic innervation to the
ischemic myocardium are major contributors to the increased
incidence of sudden cardiac death in patients with coronary artery
disease. The increased incidence of sudden death often result from
lack of protection of the myocytes and instability of the cardiac
electrical system. Chronic DCA ameliorate ischemia-induced
remodeling within the intrinsic cardiac nervous and thereby reduces
the heterogeneous neural substrate that predisposes the susceptible
animals to ventricular arrhythmias and sudden cardiac death.
[0308] Heart failure has traditionally been considered to be
primarily a hemodynamic disorder. The importance of neurohumoral
mechanisms that act to maintain adequate cardiac output in the
presence of ventricular ischemia is apparent. This recognition has
forced a reappraisal of neuronal mechanisms involved in regulating
the ischemic myocardium leading to the development of the presently
claimed and disclosed invention.
[0309] Spinal cord-peripheral neural interactions and modulation of
peripheral nerve function in the ischemic heart. Dorsal column
activation stabilizes the intrinsic cardiac nervous system in acute
myocardial ischemia experiments were conducted. The purpose of
these experiments was to determine if dorsal column activation
(DCA) induces long-term effects on the intrinsic nervous system,
the final common integrator of cardiac function, particularly in
the presence of myocardial ischemia. Methods: Activity generated by
right atrial neurons was recorded in 10 anesthetized dogs during
basal states, and during 15 min occlusions of the LAD coronary
artery, with and without background DCA. For DCA, dorsal T1-T4
spinal segments were stimulated for 17 min. at 90% of motor
threshold (50 Hz; 0.2 ms duration). For combined effects, the
coronary occlusion commenced 1 min into DCA. Results:
Ischemia-induced excitatory effects on the intrinsic cardiac
nervous system were suppressed (-76%) during DCA and for
approximately 20 min after DCA termination. Conclusions: DCA
suppresses basal activity within the intrinsic cardiac nervous
system and prevents the ischemia-induced activation of these
peripheral neural networks. This stabilization of intrinsic cardiac
neuronal function, induced by higher elements of the neural
hierarchy for cardiac control, is maintained for prolonged periods
post-stimulation and is reflective of the neural memory of these
processes. These long-term effects may partially explain the
prolonged effects patients with angina experience not only during
DCA, but also for a time thereafter.
[0310] Coronary artery occlusion induces differential catecholamine
release in the normal and ischemic myocardium. (FIG. 30, solid
line). The purpose of this study was to determine if transient
coronary occlusion differentially effects norepinephrine (NE) and
epinephrine (EPI) release into the canine ventricular interstitial
space (ISF). Methods: In anesthetized dogs, left ventricular ISF
samples were collected by microdialysis during 15 min occlusions of
the circumflex coronary artery. Results: Coronary artery occlusion
(CAO) induced a biphasic response in ISF catecholamine release,
with ISF EPI increased 400% and ISF NE increased 150% in both the
normal and ischemic myocardium. By 15 min of CAO, ISF
catecholamines returned towards baseline. ISF EPI, and to a lesser
extent NE, increased upon reperfusion. Conclusions: Coronary artery
occlusion evokes a differential release of catecholamines,
primarily reflected in the neuronal release of epinephrine.
Neuronal release of catecholamines into the ISF, associated with
coronary artery occlusion onset and reperfusion, is reflective of
reflex interactions among peripheral and central components of the
cardiac neural hierarchy in response to the ischemic stress.
[0311] Doral column activation stabilizes peripheral adrenergic
function in acute myocardial ischemia. The purpose of this study
was to determine whether DCA modulates NE and EPI release into the
canine ISF in both normal hearts and those exposed to transient
myocardial ischemia. Methods: In anesthetized dogs, left
ventricular ISF samples were collected by microdialysis during
electrical stimulation (50 Hz, 0.2 ms) of the dorsal T1-T4 segments
of the spinal cord at an intensity of 90% of motor threshold with
and without concurrent 15 min occlusions of the circumflex coronary
artery. Results: ISF EPI doubled by 10 min and tripled by 20 min of
DCA (239 to 935 pg/ml, respectively). ISF EPI remained twice
baseline 20 min post-DCA. DCA increased left ventricular NE by 43%
(890 to 1273 pg/ml); ISF NE returned to baseline values 20 min
post-DCA. Heart rate and left ventricular inotropic function were
not affected by DCA. When 15 min CAO was instituted during DCA
(FIG. 30, dotted lines), ischemia induced changes in ISF EPI and NE
were obtunded (FIG. 30, solid lines), both at the onset of
occlusion and during reperfusion. Conclusions: DCA evokes
differential release of catecholamines, primarily reflecting
neuronal release of epinephrine. Evoked release of catecholamines
into the ventricular interstitium persists for a considerable
period of time post-DCA. Pre-existing DCA suppresses the release of
catecholamines by intrathoracic adrenergic neurons reflexly-induced
by transient myocardial ischemia. The long-term DCA effects on
myocardial catecholamine release may account, in part, for the fact
that this form of therapy produces clinical benefit to patients
with angina pectoris not only during its application, but for a
time thereafter.
[0312] Spinal Cord-Peripheral Neuronal Interactions Modify
Myocardial Electrical Stability. Dorsal Column Activation Reduces
Ventricular Fibrillation Accompanying Acute Myocardial
Ischemia.
[0313] The purpose of this study was to determine if the
stabilization of peripheral neural function exerted by DCA reduces
the potential for ventricular fibrillation induction in acute
myocardial ischemia. Methods: Under anesthesia, atrial and
ventricular electrograms were recorded during basal states, and
during 15 min occlusions of the proximal circumflex artery with and
without pre-existing DCA. DCA involved electrical stimulation (50
Hz, 0.2 ms) of the dorsal T1-T4 segments of the spinal cord at an
intensity of 90% of motor threshold for 36 min, with coronary
artery occlusion commencing 15 min into DCA (FIG. 31). Results:
Coronary artery occlusion induced ventricular fibrillation (VF) in
5 of 10 dogs, with VF occurring within 6 min of reperfusion (FIG.
31 arrows). With pre-existing DCA, coronary artery occlusion
induced VF in 1 of 9 dogs, the VF occurring after terminating DCA.
Conclusions: DCA stabilizes efferent neuronal outflows for cardiac
control and obtunds the ischemia-induced reflex activation of
cardiac neural networks. Such stabilization of neural function
reduces the substrate for induction of lethal arrhythmias during
acute myocardial ischemia and, in particular, the subsequent
reperfusion period.
[0314] Dorsal column activation stabilizes ischemic myocardial
electrical dysfunction. The purpose of this study was to determine
whether DCA modulates electrical imbalance within the chronically
ischemic ventricle. Methods: An ameroid constrictor was implanted
around the left circumflex coronary artery to gradually occlude
that vessel. Four weeks later, under general anesthesia multiple
ventricular unipolar electrograms were recorded in the normal and
ischemic left ventricle during basal states and when ANG II (40
.mu.g/min; 1 minute) was administered to right atrial neurons
before and after DCA. Results: ANG II increased the area and
magnitude of regional ST segment changes in the ischemic ventricle.
ANG II induced minimal changes in the electrical behavior of the
normal myocardium. DCA (50 Hz, 0.2 ms, 0.32 mA for 15 min) modified
ischemic indices, even suppressing regional ventricular ST segment
abnormalities previously induced by ANG II. Conclusions: DCA
suppresses ischemia induced ventricular electrical disturbances.
This may occur, in part, via stabilizing intrathoracic adrenergic
neurons that modulate the ischemic ventricle.
[0315] Processing of cardiac sensory information by neurons in the
upper thoracic (T3-T4) spinal cord. Chemical activation of cardiac
receptors differentially affects activity of superficial and deeper
spinal neurons in rats. The purpose of this study was to evaluate
responses of superficial (depth <300 .mu.m) versus deeper
thoracic spinal neurons to chemical stimulation of cardiac afferent
neurons and to determine if descending central neuronal inputs
modulate these effects. Methods: Extracellular potentials of single
T3-T4 neurons were recorded in pentobarbital anesthetized,
paralyzed and ventilated male rats. A catheter was placed in the
pericardial sac to administer 0.2 ml of an algogenic chemical
mixture that contained adenosine (10.sup.-3 M), bradykinin,
histamine, serotonin, and prostaglandin E.sub.2 (10.sup.-5 M).
Results: Intrapericardial chemicals elicited responses in 27% of
the superficial neurons and in 47% of the deeper neurons. All
superficial neurons that responded to cardiac afferents were
excited. Of the deeper neurons, approximately 80% were excited, 15%
were inhibited and 5% showed excitation-inhibition. Spontaneous
activity of superficial neurons with short-lasting excitatory
responses was significantly lower than that of deeper neurons
(P<0.05). After cervical spinal transection, spontaneous
activity generated by superficial and deeper neurons increased
significantly, as did responses to chemical activation of cardiac
afferents neurons. Conclusions: Chemical stimulation of cardiac
afferent neurons excites superficial T3-T4 spinal neurons; deeper
neurons exhibit multiple patterns of responses. These data further
indicate that thoracic spinal neurons that process cardiac
nociceptive information are tonically inhibited by higher center
neurons.
[0316] Descending modulation of thoracic cardiac nociceptive
transmission by upper cervical spinal neurons. The purpose of this
study was to examine effects of stimulating upper cervical spinal
neurons on spontaneous and evoked activity of thoracic spinal
sensory neurons that responded to noxious cardiac stimuli. Methods:
Extracellular potentials of single T3 neurons were recorded in
pentobarbital anesthetized male rats. A catheter was placed in the
pericardial sac to administer bradykinin (10.sup.-5 M, 0.2 ml, 1
min) as a noxious cardiac stimulus and saline as control. A
glutamate pledget (1 M, 1-3 min) was placed on the surface of C1-C2
segments to chemically activate upper cervical spinal neurons.
Results: In 77% of the T3 neurons tested, glutamate at C1-C2
inhibited spontaneous activity and/or excitatory responses to
intrapericardial bradykinin. After transection at the rostral C1
spinal cord, excitatory amino acid (glutamate) excitation of C1-C2
neurons still reduced the spontaneous activity of T3 neurons, as
well as excitatory inputs from cardiac sensory neurons.
Conclusions: Chemical activation of C1-C2 spinal neurons evokes a
descending inhibition in thoracic spinal cord cardiac neurons
during basal states as well as in the presence of noxious cardiac
stimuli. Furthermore, modulation of cranial thoracic neurons by
upper cervical spinal neurons does not require supraspinal
connectivity.
[0317] Interdependence of cardiac sensory information processing by
neurons in the upper thoracic (T3-T4) spinal cord. The purpose of
these studies was to evaluate the coordination of activity among
upper thoracic neurons that process cardiac sensory inputs. To
date, we have evaluated the correlation of spontaneous and evoked
activity of 15 pairs of T3 spinal neurons. Included is FIG. 32 that
demonstrates the ability to simultaneously record the activity
generated by two cells in the T3 segment of the spinal cord, both
before and after their multisynaptic vagal inputs was disrupted. In
this case, vagotomy changed correlation among their function. In
another pair of T3 neurons, their activity recorded simultaneously
demonstrated that they exhibited coordination of activity
approximately 130 ms from time 0, a feature that disappeared after
placing glutamate on the C1-C2 segments of the dorsal spinal cord
(not shown). In that case, background activity was similar before
and after glutamate application. This data indicate that
coordination of activity among T3 neurons can be modified by
cardiac afferent inputs or following activation of descending
pathways. These novel data indicate that different populations of
neurons distributed spatially within and among thoracic and upper
cervical spinal cord segments respond to cardiac sensory inputs in
a coordinate fashion. These results also demonstrate the
contributions that vagal afferent neurons make to the coordination
of activity among cervical and thoracic spinal neurons; their
cardiac component representing an important transducer of
myocardial ischemic events to central neurons.
[0318] Mechanical activation of spinal neurons using programmed
ventricular arrhythmias. Data demonstrating the feasibility of
recording the responses of spinal neurons to premature ventricular
contractions and compensatory beats. To generate these events, an
electrical stimulus was applied through a pair of stainless steel
electrodes that were inserted in the free wall of the left
ventricle. FIG. 33 shows that the T3 deeper spinal neuron responded
with a burst of activity during the compensatory beat. However, the
cell was unresponsive to mechanical events associated with normal
beats. The results demonstrate that we are able to record the
activity of cells in response to the effects of administering an
extra stimulus electrically.
[0319] Without the present specification, one of ordinary skill in
the art would not have appreciated or known to use SCS or DCA
stimulation as a means to (1) electrically influence the intrinsic
cardiac nervous system to protect cardiac myocytes from initial
ischemic damage or from being further damaged during subsequent
ischemic episodes; and (2) preserve the electrical stability of the
intrinsic cardiac nervous system and the heart itself prior,
during, or post an ischemic episode. As such, the presently claimed
and disclosed invention would be non-obvious in light of the prior
art showing the use of SCS stimulation for the treatment of angina.
In fact, those of ordinary skill in the art that SCS alleviated
widely and traditionally believe angina pain by either changing
blood flow within ischemic or non-ischemic myocardium or modifying
left ventricular (LV) pressure-volume dynamics. As the following
experiments show, however, SCS does not alter these blood
parameters--rather, SCS influences and effects the modulation of
neuronal activity within the intrinsic cardiac nervous system.
Thus, use of SCS to treat, modify, protect, and influence neuronal
activity within the intrinsic cardiac nervous system is a novel and
non-obvious approach to the pre- and post-treatment of an ischemic
heart.
[0320] In the first series of experiments, it is shown that (1) SCS
modifies the capacity of the intrinsic cardiac nervous system to
generate electrical activity; (2) SCS suppresses the excitatory
effects that local myocardial ischemia exerts on the neurons of the
intrinsic cardiac nervous system; and (3) SCS does not change heart
indices such as blood pressure. Thus, the underlying principle that
SCS can and does stimulate and provoke an effect in the intrinsic
cardiac nervous system is shown and demonstrated.
[0321] Electrical stimulation of the dorsal aspect of the upper
thoracic spinal cord is used increasingly to treat patients with
severe angina pectoris refractory to conventional therapeutic
strategies. Clinical studies show that spinal cord stimulation
(SCS) is a safe adjunct therapy for cardiac patients, producing
anti-anginal as well as anti-ischemic effects. The effects of SCS
on the final common integrator of cardiac function, the intrinsic
cardiac nervous system, were studied during basal states as well as
during transient (2 min) myocardial ischemia. Activity generated by
intrinsic cardiac neurons was recorded in 9 anesthetized dogs in
the absence and presence of myocardial ischemia before, during and
after stimulating the dorsal T1-T2 segments of the spinal cord at
66 and 90% of motor threshold using epidural bipolar electrodes (50
Hz; 0.2 ms; parameters within the therapeutic range used in
humans). The SCS suppressed activity generated by intrinsic cardiac
neurons. No concomitant change in monitored cardiovascular indices
was detected. Neuronal activity increased during transient
ventricular ischemia (46%), as well as during the early reperfusion
period (68% compared to control). Despite that, activity was
suppressed during both states by SCS.
[0322] Thus, SCS modifies the capacity of intrinsic cardiac neurons
to generate activity. SCS also acts to suppress the excitatory
effects that local myocardial ischemia exerts on such neurons.
Since no significant changes in monitored cardiovascular indices
were observed during SCS, it is concluded that modulation of the
intrinsic cardiac nervous system might contribute to the
therapeutic effects of SCS in patients with angina pectoris.
[0323] Introduction
[0324] Patients who suffer from severe angina pectoris following
coronary artery revascularization or whose clinical status render
them inappropriate candidates for such a procedure can obtain
relief from their angina by spinal cord stimulation (SCS) (Jessurun
et al., 1997; Schoebel et al., 1997). High frequency, low intensity
electrical stimuli delivered to the dorsal aspect of the
T.sub.1-T.sub.2 thoracic spinal cord suppresses the pain associated
with myocardial ischemia without affecting awareness of the
symptoms from a possible myocardial infarction (Anderson et al.,
1994; Eliasson et al., 1996; Hautvast et al., 1998; Sanderson et
al., 1994). Application of SCS does not appear to induce any
adverse effects in patients experiencing transient ischemia of the
myocardium (Sanderson et al., 1992), patients retain their capacity
to sense angina during increased workload (Mannheimer et al.,
1993).
[0325] The effects of SCS have been attributed to improved
myocardial perfusion and/or alterations in the oxygen demand and
supply ratio as reflected in a reduction in stress-induced
alterations in the ST segment of the ECG (Sanderson et al., 1992).
Spinal cord stimulation also improves myocardial lactate metabolism
(Mannheimer et al., 1993). Spinal cord stimulation has recently
been suggested as an adjunct to coronary artery bypass surgery in
high-risk patients (Mannheimer et al., 1998).
[0326] Spinal cord stimulation has been shown to influence
information processing within the central nervous system (Chandler
et al., 1193; Yakhnitsa et al., 1999). This treatment modality has
also been demonstrated to influence peripheral blood flow
(Augustinsson et al., 1995; Augustinsson et al., 1997; Linderoth et
al., 1991; Linderoth et al., 1994; Croom et al., 1997). In order to
understand the mechanisms underlying SCS in cardiac control, we
studied the effects of SCS upon the intrinsic cardiac nervous
system. Intrinsic cardiac neurons receive constant inputs from
spinal cord neurons to regulate regional cardiac function on a
beat-to-beat basis (NAMES). Transient regional ventricular ischemia
markedly increases the activity generated by intrinsic cardiac
neurons (Huang et al., 1993). Furthermore, excessive activation of
limited populations of intrinsic cardiac neurons induces cardiac
dysrhythmias, even in normally perfused hearts (Huang et al.,
1994).
[0327] The experiments and data detailed hereinbelow show that SCS,
applied with clinically employed electrical stimulation parameters,
modifies the activity generated by intrinsic cardiac neurons in
situ. SCS does not change cardiac dynamics. Effects of SCS on
intrinsic cardiac neural activity were characterized during
coronary arterial occlusion as well as during the subsequent
reperfusion period and it was determined that SCS modifies
intrinsic cardiac neuronal function in the presence of myocardial
ischemia. These experiments show that SCS influences the behavior
of intrinsic cardiac neurons markedly, changes that are involved in
the clinically observed effects of SCS during acute myocardial
ischemia.
[0328] Methods
[0329] Animal Preparation
[0330] Experiments performed in the present study were approved by
the Institutional Animal Care and Use Committee of the OUHSC and
followed the guidelines outlined by the International Association
for the Study of Pain and in the NIH Guide for the Care and Use of
Laboratory Animals (National Academy Press, Washington, DC, 1996).
Nine adult male dogs of mixed breed weighing between 15 and 25 kg
were used. Animals were kept under standard laboratory conditions
in a light-cycled environment (12 h/12 h) with free access to water
at all times and to food at regular intervals. For the duration of
the surgery, dogs were first anesthetized with sodium thiopental
(20 mg/kg, i.v.) and maintained with sodium thiopental administered
in boluses (5 mg/kg i.v.) to effect every 5-10 min. Animals were
intubated and then artificially ventilated using a Harvard
respirator (Palm Springs, Calif.). After the surgical preparation
was completed, anesthesia was changed to alpha chloralose. An
initial bolus dose of alpha chloralose (75 mg/kg, i.v.) was
administered, with repeat doses (20 mg/kg) given as required during
the remainder of the experiment. The level of anesthesia was
checked throughout each experiment by observing pupil reaction,
monitoring jaw tension and squeezing a hindpaw to determine if
blood pressure and heart rate changed. This anesthetic regimen has
been demonstrated to produce adequate anesthesia without
suppressing autonomic neural responses (Gagliardi et al., 1988).
Electrodes inserted into the forelimbs and the left hind limb were
connected to an Astro-Med, Inc. (West Warwick, R.I.) model MT 9500
eight channel rectilinear recorder to monitor a modified Lead II
electrocardiogram.
[0331] Implantation of Spinal Cord Stimulation Electrodes
[0332] After induction of anesthesia, animals were placed in the
prone position and the epidural space of the mid-thoracic spinal
column was penetrated percutaneously with a Touhy needle using A-P
fluoroscopy and loss-of-resistance technique, as is routinely done
in the clinic. A four-pole catheter (Medtronic QUAD Plus Model
3888; Medtronic Inc., Minneapolis, Minn.) was introduced through
the cannula and its tip was advanced to the T.sub.1 level of the
spinal column and placed slightly to the left of the midline
(Augustinsson et al., 1995). The two poles of this stimulating lead
chosen for subsequent use (inter-electrode distance of 1.5 cm) were
placed at the level of the T.sub.1 and T.sub.4 vertebrae. Final
placement was aided by delivering electrical current to induce
motor responses using the rostral or caudal poles as cathodes,
respectively. Rostral stimulation just above motor threshold
resulted in proximal forepaw and/or shoulder muscle contractions
while caudal electrode stimulation induced contractions in the
lower trunk. Once the appropriate electrode positions were
obtained, the lead was fixed to the intraspinous ligaments with a
suture surrounding a Silicone protective sleeve. Extension wires
were tunneled subcutaneously to the ventral surface of the animal
where they were connected to a stimulator. Motor responses were
rechecked after the animal had been turned to the supine position
to make sure the electrodes had not moved during this maneuver and
to establish the appropriate stimulus intensities for the
subsequent SCS.
[0333] Cardiac Instrumentation
[0334] After placing the animal on its back, a bilateral
thoracotomy was made in the fifth intercostal space to expose the
heart. The subclavian ansae on both sides of the thorax were
exposed and silk ligatures were placed around them so that each
could be easily sectioned later in the experiments to decentralize
the intrinsic cardiac nervous system. The ventral pericardium was
incised and retracted laterally to expose the heart and the ventral
right atrial deposit of fat containing the ventral component of the
right atrial ganglionated plexus. Neurons in this ganglionated
plexus are representative of those found in the various intrinsic
cardiac ganglionated plexuses (Gagliardi et al., 1988).
[0335] Left atrial chamber pressure was measured via a PE-50
catheter inserted directly into the left atrial chamber via its
appendage. Left ventricular chamber pressure was monitored via a
Cordis (Miami, Fla.) #6 French pigtail catheter, which was inserted
into that chamber through a femoral artery. Systemic arterial
pressure was measured using a Cordis #7 French catheter placed in
the descending aorta via the other femoral artery. These catheters
were attached to Bentley (Irvine, Calif.) Trantec model 800
transducers.
[0336] Neuronal Recording
[0337] Activity generated by ventral right atrial neurons was
recorded in situ, as has been done in previous studies (Gagliardi
et al., 1988). To minimize epicardial motion during each cardiac
beat, a circular ring of stiff wire was placed gently on the fatty
epicardial tissue overlying the ventral surface of the right atrium
containing the right atrial ganglionated plexus. A tungsten
microelectrode (30-40 .mu.m diameter and exposed tip of 1 .mu.m;
impedance of 9-11 M at 1000 Hz), mounted on a micromanipulator, was
lowered into this fat using a microdrive. Exploration was done by
driving the electrode tip through this tissue beginning at the
surface of this fat, penetrating to regions adjacent to cardiac
musculature. Proximity to the atrial musculature was indicated by
increases in the amplitude of the ECG artifact. The indifferent
electrode was attached to mediastinal connective tissue adjacent to
the heart. Signals recorded via the electrode were led to a CWE
BMA-831 differential preamplifier with a high impedance head stage
(bandpass filters set at 300 Hz and 10 kHz), and were processed by
a signal conditioner (bandpass 100 Hz-2 kHz). Signals were
amplified further via a Princeton Applied Research (Princeton,
N.J.) battery driven amplifier (300 Hz-2 kHz) and were displayed on
an Astro-Med, Inc. (West Warwick, R.I.) MT 9500 8 channel
rectilinear recorder along with the cardiovascular variables
described above. Data were stored via a Vetter (Rebesburg, Pa.)
M3000A digital tape system for later analysis. Action potentials
generated by neurons in one site of a right atrial ganglionated
plexus were recorded using extracellular recording electrodes,
individual units being identified by their amplitudes and
configurations. As established previously (Armour et al., 1990),
extracellular action potentials so generated are derived from
somata and/or dendrites rather than axons of passage. Amplitudes of
identified action potentials varied by less than 25 .mu.V over
several minutes. Each potential retained the same configuration
over time. Action potentials recorded in a given locus with the
same configuration and amplitude (.+-.25 .mu.V) were considered to
be generated by a single unit.
[0338] Protocols
[0339] Five different protocols were employed in each animal (cf.
FIG. 34) The order in which each protocol was applied was
randomized among animals.
[0340] Protocol A-Spinal Cord Stimulation
[0341] The parameters used to electrically stimulate the thoracic
spinal cord were similar to those used clinically. Stimuli were
delivered to the dorsal aspect of the thoracic spinal cord via a
Grass model S48 stimulator connected to the quadripolar electrode
via a stimulus isolation unit (Grass model CCU1) via, a constant
current unit (Grass SIU1). With the animal placed in the supine
position for all subsequent experimentation, the current intensity
used to evoke detectable skeletal muscle motor responses was
determined as the motor threshold (MT). Stimuli (50 Hz and 0.2 ms
duration) were delivered at two intensities (66 and 90% of MT). An
intensity of 66% of MT has been shown to recruit low threshold,
rapidly conducting axons (A-beta), whereas higher, intensity
stimuli (90%) activate fast A-delta fibers as well as the other
axonal populations (Croom et al., 1997; Linderoth et al., 1991).
The current measured at MT varied among animals likely because of
the varied anatomy of the thoracic spinal space among animals. The
stimulus intensity was found to vary between 30 and 50 .mu.A when
current was set to 66% of MT. When the stimulus current was 90% of
MT, it varied between 80 and 210 .mu.A among different animals. The
MT was rechecked periodically and remained stable over time in
individual animals. With respect to protocol A, cardiac indices and
intrinsic cardiac neural activity were monitored immediately
before, during and for 30-45 s after 4 ruin of SCS at 90% of MT
(FIG. 34 (A)).
[0342] Protocol B-Regional Ventricular Ischemia
[0343] A silk (3-0) ligature was placed around the left anterior
descending coronary artery and another around the circumflex
coronary artery, approximately 1 cm from their respective origins.
Each ligature was led through a short segment of polyethylene
tubing in order to occlude these arteries later in the experiments
while leaving the arterial blood supply (right coronary and
sino-atrial arteries) patent to the ventral right atrial neurons
that were being investigated. Fur protocol B, cardiac indices and
neuronal activity were monitored before, during and immediately
after occluding the two coronary arteries concurrently for 2 min
(FIG. 34(B)).
[0344] Protocols C, D and E in which SCS and Regional Ventricular
Ischemia were Combined
[0345] The effects of 2 min of myocardial ischemia on intrinsic
cardiac neuronal activity and regional cardiac indices were studied
in the presence of SCS (at 90% of MT for 4 min) applied at
different times during the myocardial ischemia. Protocol C: The
spinal cord was stimulated for 4 min and the 2 min of coronary
artery occlusion began 1 min after the onset of the SCS (in the
middle of the SCS; Foreman FIG. 1C). Protocol D: Spinal cord
stimulation was initiated 1 min after coronary artery occlusion
began (staged occlusion with overlapping stimulation) (FIG. 34(D)).
Protocol E: In this protocol, spinal cord stimulation began
immediately after finishing 2 min of coronary artery occlusion
(FIG. 34(E)). The order in which each of these protocols was
applied was randomized among dogs.
[0346] After all of the protocols described above were completed,
the right and left subclavian ansae were sectioned in five of the
dogs, thereby eliminating spinal cord afferent and efferent
communications with neurons in intrathoracic ganglia. After this
maneuver, the five SCS and transient coronary occlusion protocols
described above were repeated.
[0347] Data Analysis
[0348] Individual action potentials, which maintained their
configurations over time, were analyzed. Activity generated by the
somata and/or dendrites of neurons within the right atrial
ganglionated plexus was averaged during successive 30-s periods
before, during and after each intervention. At the same time, heart
rate, left ventricular wall (intramyocardial) and chamber systolic
pressures were measured, as was aortic pressure. Neuronal activity
and cardiovascular indices recorded immediately before each
intervention and during the steady state response to an
intervention were averaged and presented as means.+-.S.E.M.
Fluctuations in the amplitude of action potentials generated by a
unit varied by less than 50 .mu.V over several minutes, action
potentials retaining the same configurations over time. Thus,
action potentials recorded in a given locus with the same
configuration and amplitude (.+-.50 .mu.V) were considered to be
generated by a single unit. Action potentials with signal-to-noise
ratios greater than 3:1 were analyzed. The threshold for neuronal
activity changes was taken as a change of more than 20% from
baseline values. Neuronal activity responses elicited by each
intervention were evaluated by comparing activity generated
immediately before each intervention with data obtained at the
point of maximum change during the intervention. Data were
expressed as means.+-.S.E.M. Oneway ANOVA and paired t-test with
Bonferroni correction for multiple tests was used for statistical
analysis. A significance value of P<0.05 was used for these
determinations.
[0349] Results
[0350] Identification of Active Sites
[0351] Action potentials were identified in 1-3 loci within the
ventral right atrial ganglionated plexus of each animal. Based on
the different amplitudes and configurations of the recorded action
potentials within these loci, ongoing activity was generated by an
average of 5.1.+-.0.9 (range 3-9) neurons. Identified neurons
generated, on average, 496.+-.112 impulses per minute (ipm) during
control conditions throughout the duration of these experiments.
Multiple neurons at each identified active site generated action
potentials that were altered in a similar fashion by each of the
different interventions tested.
[0352] (Protocol A) Effects of Spinal Cord Stimulation
[0353] Only the effects of SCS employed at 90% of MT are presented
herein since 66% MT elicited minimal changes in the activity
generated by the intrinsic cardiac neurons. The average activity
generated by identified right atrial neurons in all animals (n=9)
fell from 496.+-.112 to 1501.+-.71 ipm (P<0.01) during SCS at
90% MT (FIG. 34(A)). Neuronal activity remained depressed for 10-20
s after SCS ceased (142.+-.61 ipm), returning to control levels by
about 1 min after cessation of stimulation (FIG. 35(A)). SCS did
not change monitored cardiac indices overall. For instance, SCS did
not change heart rate (155.+-.8 vs. 159.+-.8 beats per minute) or
left ventricular chamber systolic 124.+-.8 vs. 131.+-.8 mmHg) and
diastolic pressures. SCS did not change aortic pressure
(124.+-.8/99.+-.6 vs. 122.+-.5/95.+-.4 mmHg).
[0354] FIG. 35. shows initiation of coronary artery occlusion
(arrow below) resulted in an increase in the activity generated by
right atrial neurons (individual units identified by action
potentials greater than the small atrial electrogram artifacts).
From above down are the ECG, aortic pressure (AP), left ventricular
chamber pressure (LVP) and neuronal activity. Horizontal timing
bar=30 s.
[0355] (Protocol B) Effects of Transient Myocardial Ischemia
[0356] When ventricular ischemia was induced by occluding both the
left anterior descending and circumflex coronary arteries for 2 min
in neurally intact preparations, the activity generated by right
atrial neurons increased in each animal (FIG. 35). Neuronal
activity increased, on average, by 46% (370.+-.126 to 539.+-.91
ipm; P<0.01) (FIGS. 35(B) and CC) despite the fact that the
blood supply of identified neurons was unaffected. Neuronal
activity remained elevated immediately after reperfusion began
(621.+-.175 ipm, +68% compared to control values; P<0.05).
Monitored cardiac indices did not change significantly during the 2
min of coronary artery occlusion or during the reperfusion period.
For instance, heart rate was similar at the end of ventricular
ischemia episodes (140.+-.10 beats per minute) as before these
episodes began (142.+-.9 beats per minute). Even though left
ventricular chamber systolic pressure underwent minor reductions in
a few instances, this index remained unchanged overall (121.+-.6
vs. 121.+-.6 mmHg). Left ventricular diastolic pressure and aortic
pressures were also unaffected. No serious dysrhythmias were
induced during the brief periods of coronary artery occlusion.
During the early reperfusion phase, minor S-T segment elevation and
terminal QRS slurring was evident in each animal.
[0357] SCS Modulated Responses to Transient Myocardial Ischemia
[0358] Neuronal activity was not enhanced by coronary artery
occlusion induced in the presence of SCS, irrespective of whether
SCS was applied during (FIGS. 34 c and 34(D)) or immediately after
(Foreman FIG. 1E) the ischemic period. Monitored cardiovascular
variables did not change significantly when the combined coronary
artery occlusion and SCS protocols were instituted.
[0359] (Protocol C) Occlusion in the Middle of Stimulation
[0360] When the 2-min period of myocardial ischemia occurred in the
middle of the SCS (1 min after SCS began), the neurosuppressor
effects of SCS persisted during the ischemic period (FIG. 36). For
instance, intrinsic cardiac neuronal activity was reduced from that
of control states (511.+-.197 ipm) during SCS (169.+-.99 ipm,
P<0.01 compared to control), neuronal activity remaining
suppressed when the stimulation occurred in conjunction with the
occlusion (164.+-.74, P<0.01 compared to control; FIG. 34-C).
Suppression of neuronal activity persisted after terminating the
occlusion while the SCS was maintained (166.+-.84 ipm, P<0.01
compared to control). Only after discontinuing the SCS did neuronal
activity gradually return to control values.
[0361] (Protocol D) Occlusion Overlapped by Stimulation
[0362] During this protocol (FIG. 34(D)), the activity generated by
intrinsic cardiac neuronal activity was enhanced by 42% (388.+-.155
to 555.+-.211 ipm; P<0.01) during the initial coronary artery
occlusion period. When SCS was applied 1 min after the occlusion
began, neuronal activity was suppressed by 46% (activity of
211.+-.134 ipm) even though the myocardial ischemia persisted (Fig.
CC-C). In this protocol, neuronal activity remained suppressed
during the reperfusion period (227.+-.134 ipm) while the SCS
persisted neuronal activity returned to control values only after
SCS ceased (394.+-.142 ipm).
[0363] FIG. 36 shows the influence of SCS on the ECG, left
ventricular chamber pressure (LVP=145 mmHg) and intrinsic cardiac
neuronal activity (lowest line) before and during coronary artery
occlusion. (A) Multiple neurons generated action potentials,
represented by their differing heights, at a rate of 132 impulses
per minute (ipm) during control states. (B) Once SCS was initiated
(note stimulus artifacts in the neuronal tracing), neuronal
activity decreased to 34 imps/min (no activity generated during the
record). ECG alterations were induced thereby. (C) Neuronal
activity continued at that rate (39 ipm) in the presence of SCS
even though coronary artery occlusion had been maintained for over
1.5 min.
[0364] (Protocol E) Occlusion Followed by Stimulation
[0365] In this protocol (FIG. 34(E)), coronary artery occlusion
alone enhanced neuronal activity (403.+-.150 to 701.+-.315 ipm;
P<0.01). When SCS was started immediately following termination
of 2 min of coronary occlusion (that is during the early
reperfusion period), neuronal activity fell to 173.+-.295 ipm
(P<0.01 compared to the ischemia period). Neuronal activity
remained suppressed throughout this stimulation period, being
244.+-.98 ipm (P<0.01 compared to control values) after 4 min of
SCS. This is in distinct contrast to the finding that neuronal
activity remained elevated (.about.70% of control values) during
the early reperfusion period immediately after SCS was terminated
(FIG. 34(B)).
[0366] Acute Decentralization
[0367] After all of the experimental protocols described above were
completed, the spinal cord was stimulated in 5 animals at 90% of MT
before and after sectioning the right and left ventral and dorsal
subclavian ansae. After surgically disconnecting intrinsic cardiac
neurons from the spinal cord neurons, ongoing neuronal activity
decreased from 378.+-.34 to 162.+-.72 ipm (P<0.01). SCS did not
modify the activity generated by identified intrinsic cardiac
neurons thereafter (162.+-.72 vs. 147.+-.61 ipm); nor did SCS
affect recorded cardiac indices.
DISCUSSION
[0368] Results of the present experiments demonstrate that the
activity generated by intrinsic cardiac neurons is modulated when
the dorsal aspect of the thoracic spinal is stimulated
electrically. That suppression of the ongoing activity generated by
intrinsic cardiac neurons induced by SCS persisted for at least 30
s following termination of 4 min of SCS shows that the effects of
this intervention last beyond the stimulation period. Interruption
of afferent and efferent nerves traveling in the subclavian ansae
eliminated the suppressor effects that SCS exerted on intrinsic
cardiac neurons. These data show that the influence of spinal cord
neurons on the intrinsic cardiac nervous system occur primarily via
axons coursing in the intrathoracic sympathetic nervous system.
[0369] Based on results obtained when SCS was applied to the
lumbosacral spinal cord, both sympathetic afferent and efferent
fibers contribute to the suppression of intrinsic cardiac activity
so identified. Four minutes of SCS at 66% of MT was much less
effective in suppressing neuronal activity than when the spinal
cord was stimulated at 90% of MT. Spinal cord stimulation at 90% MT
antidromically activates sensory afferent fibers that release
calcitonin gene-related peptide (CGRP) from their afferent
terminals, an action that may be dependent on the presence of
nitric oxide; such local release of CGRP from sensory afferent
nerve terminals produces vasodilation of the rat hind paw (Croom et
al., 1997). It is known that endorphins are released into the
coronary circulation of humans during SCS (Eliasson et al., 1991).
The release of neuropeptides by antidromic activation of sensory
neurites (Croom et al., 1997) acts to change the activity generated
by intrinsic cardiac neurons (Armour et al., 1993).
[0370] Activation of sympathetic efferent preganglionic axons
suppresses many intrathoracic reflexes that are involved in cardiac
regulation (Armour et al., 1985) as well as the activity generated
by populations of neurons within intrathoracic extracardiac
(Armour, 1986) and intrinsic cardiac (NAMES) ganglia, thereby
reducing the capacity of intrathoracic sympathetic efferent neurons
to influence cardiodynamics (Butler et al., 1988). This effect may
in part be due to activating inhibitory synapses within
intrathoracic ganglia, including those on the heart such as occurs
when intracranial pressure raises (Murphy et al., 1995). Such
suppression of neuronal activity has been demonstrated in
sympathetic efferent neurons controlling the peripheral vasculature
as well (Linderoth et al., 1991; Linderoth, Fedorcsak et al.,
1991).
[0371] As has been shown previously (Huang et al., 1993), the
activity generated by right atrial neurons increased in the
presence of regional ventricular ischemia (FIG. 35), remaining
elevated during the early reperfusion phase (FIG. 34(B)). This
information and knowledge has clinical relevance since excessive
activation of limited populations of intrinsic cardiac neurons can
lead to the induction of ventricular arrhythmias (Huang et al.,
1994) or even ventricular fibrillation (Armour, 1999). Application
of SCS before and during the induction of transient coronary artery
occlusion prevented ischemia-induced changes in neuronal activity
(FIG. 36), including that identified during the reperfusion period
(FIG. 34(C)). In other words, although intrinsic cardiac neuronal
activity was enhanced during regional ventricular ischemia, SCS
returned intrinsic cardiac neuronal activity to base line levels
during these ischemic episodes. It is important to note that the
two coronary arteries that were occluded did not supply arterial
blood to identified right atrial ventral neurons (Huang et al.,
1993). The transient periods of regional ventricular ischemia were
of short enough duration to induce minor or no alterations in
recorded cardiac variables. Thus, the effects of transient coronary
artery occlusion on intrinsic cardiac neuronal activity are the
result of altered inputs to intrinsic cardiac neurons arising from
distant ischemia-sensitive afferent neurites. SCS was effective in
reducing such inputs. These neurosuppressor effects occurred
whether SCS was applied immediately before or during coronary
artery occlusion, or during the early reperfusion phase (FIG. 34).
These data support the notion that SCS suppresses intrinsic cardiac
neurons responsiveness to regional ventricular ischemia as well as
during the subsequent reperfusion period.
[0372] The data obtained in this study are in accord with clinical
findings indicating that improvement of cardiac function and
symptoms can occur when SCS is applied to patients with angina
pectoris (deJongste et al., 1994). Since modification of the
intrinsic cardiac nervous system can lead to alterations in
ventricular regional flow (Kingma et al., 1994), perhaps some of
the responses elicited by SCS involved subtle changes in the
redistribution of coronary artery blood flow given that no
detectable changes in cardiodynamics were identified with the
methods used in these experiments. Thus, the effects that SCS
induces in a clinical setting reside, in part, in the capacity of
such therapy to stabilize this final common regulator, even in the
presence of ventricular ischemia. Since the intrinsic cardiac
nervous system receives inputs arising from cardiac sensory
nenrites as well as from central neurons (Murphy et al., 1995), SCS
may exert multiple effects on this local neuronal circuitry.
Heterogeneous activation of intrinsic cardiac neurons destabilizes
cardiac neuronal regulation that, in turn, leads to the genesis of
ventricular tachydysrhythmias (Huang et al., 1994). Data obtained
in the present experiments indicated that SCS reduces the
excitability of intrinsic cardiac neurons, even in the presence of
ventricular ischemia and, as such, may help to stabilize cardiac
function.
[0373] In summary, electrical stimulation of the thoracic spinal
cord influences the function of the final common neuronal regulator
of cardiac function, the intrinsic cardiac nervous system, even in
the presence of myocardial ischemic challenge. Thus, SCS acts in
part to protect the heart from some of the deleterious consequences
resulting from myocardial ischemia via altering the function of the
intrinsic cardiac nervous system.
[0374] As stated previously, electrical stimulation of the dorsal
aspect of the upper thoracic spinal cord is used to treat patients
with angina pectoris refractory to conventional therapeutic
strategies. The purpose of the following described experiments was
to determine whether spinal cord stimulation SCS in dogs affects
regional myocardial blood flow and left-ventricular LV function
before and during transient obstruction of the left anterior
descending coronary artery LAD. In anesthetized dogs, regional
myocardial blood flow distribution was determined using
radiolabeled microspheres and left-ventricular function was
measured by impedance-derived pressure-volume loops. SCS was
accomplished by stimulating the dorsal T1-T2 segments of the spinal
cord using epidural bipolar electrodes at 90% of motor threshold MT
50 Hz, 0.2-ms duration. Effects of 5-min SCS were assessed under
basal conditions and during 4-min occlusion of the LAD.
[0375] In summary, SCS alone evoked no change in regional
myocardial blood flow or cardiovascular indices. Transient LAD
occlusion significantly diminished blood flow within ischemic, but
not in non-ischemic myocardial tissue. Left ventricular
pressure-volume loops were shifted rightward during LAD occlusion.
Cardiac indices were altered similarly during LAD occlusion and
concurrent SCS. Thus, SCS does not influence the distribution of
blood flow within the non-ischemic or ischemic myocardium. Nor does
it modify LV pressure-volume dynamics in the anesthetized
experimental preparation.
[0376] Introduction
[0377] The majority of patients with angina pectoris secondary to
coronary artery disease can be adequately controlled with
medication and revascularization procedures. However, a subset of
patients exists with chronic angina that is refractory to these
standard treatment strategies. Neuromodulation therapy has been
advocated as an adjunct therapy for patients with chronic
refractory angina pectoris (DeJongste, Hautvast et al., 1994;
Mannheimer et al., 1985) or even as an alternative to coronary
artery bypass grafting CABG in high-risk patients (Mannheimer et
al., 1998) to improve the clinical response to ischemia. With
regard to safety concerns, electrical stimulation of the dorsal
aspect of the spinal cord SCS does not mask anginal symptoms
elicited during acute myocardial infarction (Anderson et al., 1994;
Sanderson et al., 1994). Furthermore, SCS appears to have
anti-ischemic properties as demonstrated during exercise stress
testing (DeJongste, Hautvast et al., 1994; Sanderson et al., 1994;
Hautvast et al., 1994), ambulatory ECG monitoring (DeJongste et
al., 1994; Hautvast et al., 1997), and rapid right atrial pacing
(Mannheimer et al, 1993; Sanderson et al., 1994).
[0378] Chauhan et al. 1994 showed that the velocity of coronary
arterial blood flow of patients with either CAD measured in the
left main artery with stenosis >50% in the right coronary artery
or syndrome X changed when transcutaneous electrical nerve
stimulation TENS; 150 Hz at 300 ms, 10-60 mA is applied for 5 min.
In agreement with that, other reports indicate that SCS can
increase myocardial blood flow in low-flow regions, possibly
related to recruitment of coronary collateral vessels and a
decrease in flow in normally perfused myocardium (Mobilia et al.,
1998). Other contrary studies indicate, however, that SCS does not
improve blood flow within the ischemic myocardium of patients with
significant coronary artery disease or syndrome X even though it
reduces ST-segment alterations (De Landesheere et al., 1992;
Sanderson et al., 1996; Jessurun et al., 1998; Norrsell et al.,
1998). Furthermore, at least one study has indicated that SCS does
not alter total coronary blood flow in patients undergoing
dipyramidole stress testing (Hautvast et al., 1996).
[0379] In light of these divergent clinical findings, examination
of the influence of SCS on the distribution of regional myocardial
blood flow utilizing radiolabeled microsphere technique (Baer et
al., 1984) and LV chamber dynamics utilizing the conductance
catheter technique (Baan et al., 1984) in canine hearts was
undertaken. As has been indicated in the previously discussed
experiments hereinabove, SCS does not alter cardiac indices
(Foreman et al., 2000). Thus, the effects of altered cardiac
workload on regional ventricular flow elicited during SCS were
expected to be minimal. For that reason, the effects of SCS on the
distribution of blood flow in the acutely ischemic myocardium were
also examined. The duration of ischemic period was brief in order
that cardiac indices return to normal values after terminating
regional myocardial ischemia. The results obtained from these
disclosed experiments indicate that SCS does not affect regional
myocardial blood supply or LV dynamics in the normally perfused
myocardium. Furthermore, SCS does not alter blood flow within a
ventricular ischemic zone; nor does it affect the ischemia-induced
rightward shift of the LV pressure-volume relationship.
[0380] Materials and Methods
[0381] Animal Preparation
[0382] The experiments performed in the present study were
performed in accordance with the Guide to the Care and Use of
Experimental Animals set up by the Canadian Council on Animal Care
and under the regulations of the Animal Care Committee at Laval
University. Adult mongrel dogs of either sex, weighing between 20
and 25 kg, were used. Dogs were tranquilized with diazepam 1 mg/kg,
i.v. and fentanyl 20 mg/kg, i.v. and then anesthetized with sodium
pentobarbital 25 mg/kg, i.v. Noxious stimuli were applied
occasionally to a paw throughout the experiments to ascertain the
adequacy of the anesthesia. Repeat doses of pentobarbital 5 mg/kg,
i.v. were administered throughout the experiments as required. Dogs
were intubated and mechanically ventilated with a mixture of oxygen
25% and room air 75%, maintaining an end-expiratory pressure of 5-7
cm H.sub.2O to prevent atelectasis. Respiratory rate and tidal
volume were adjusted to maintain arterial blood gases within
physiological values. Body temperature was monitored and kept
between 37.58 C and 38.58 C by a water-jacketed Micro-Temp heating
unit Zimmer, Dover, Ohio, USA.
[0383] Spinal Cord Stimulation
[0384] Implantation of the Spinal Cord Stimulation Electrodes
[0385] After the animal was placed in the prone position, the
epidural space was entered with a Touhy needle via a small skin
incision in the lower thoracic region. A four-pole lead Medtronic
QUAD Plus Model 3888; Medtronic, Minneapolis, Minn. was advanced
rostrally in the epidural space to the upper thoracic level under
anterior-posterior fluoroscopy and positioned slightly to the left
of midline according to current clinical practice (DeJongste et
al., 1994). The most cranial pole of the lead was positioned at the
T1 level. Electrical current was delivered via the rostral and
caudal poles to verify their functional positioning. Increasing
stimulus intensity via the rostral pole as cathode to motor
threshold intensity MT-induced muscle contractions in the proximal
forepaw and shoulder. Stimulation with the caudal pole as cathode
at MT activated thoracic paravertebral muscles, resulting in a
twisting movement of the trunk. When a satisfactory electrode
position was obtained, the lead, protected by a silicon sleeve, was
fixed to the interspinous ligament and then connected to an
external stimulator.
[0386] Threshold Determination for Spinal Cord Stimulation
[0387] The animal was shifted to the decubitus position for the
remainder of the experiment and MT was then reestablished. SCS was
delivered via the indwelling electrode connected to a Grass S48
Stimulator Grass Instruments, Quincy, Mass., USA via a stimulus
isolation unit Grass SIU 5B and a constant current generator
GrassrCCU1A. The parameters used to stimulate the spinal cord were
50 Hz and 0.2-ms duration; these values are the same as those used
previously to reduce neuronal activity of intrinsic cardiac neurons
in anesthetized dogs (Foreman et al., 2000). Stimulation intensity
was 90% of that evoking a motor response and corresponds to the
maximum used in patients (Chandler et al., 1993; Anderson et al.,
1994). The current intensity used for SCS at 90% of MT, varied
between 0.16 and 0.72 mA mean: 0.44 mA among animals. The most
rostral and caudal poles were chosen as cathode and anode,
respectively, so that the entire spinal cord area used for angina
therapy in humans would be stimulated.
[0388] CardioVascular Instrumentation
[0389] Both femoral arteries and the right femoral vein were
exposed and cannulated with 8F vascular introducers. Cordis, Miami,
Fla., USA. A 7F 12-electrode conductance catheter with Pigtail and
vascular port Cordis, Roden, The Netherlands was advanced into the
LV chamber via the left femoral artery. Pressure transducers were
connected to the vascular port of the conductance catheter and to a
fluid-filled catheter Cordis a4 placed in the descending aorta. A
femoral vein catheter was used for periodic drug injections and for
fluid replacement therapy physiological saline. Surface needle
electrodes were positioned to record a standard lead II
electrocardiogram. Analog data were displayed on an Astro Med model
MT-9500 polygraph and stored directly on a computer hard disk at a
sampling rate of 333 samples/channel using the AxoScope data
acquisition software Axon Instruments, Foster City, Calif., USA.
Total LV pressure-volume loops were determined from changes in the
electrical impedance measured by the summed volumes using a signal
conditioner-processor Leycom Model Sigma-5, Oegstgeest, The
Netherlands, as described previously (Baan et al., 1984). A
computer analysis system Conduct-PC, Cardiodynamics, Leiden, The
Netherlands was used to assess LV pressure-volume loops.
[0390] Placement of Coronary Artery Occluder
[0391] Under fluoroscopy, a modified right Judkins catheter 8F,
Cordis, USA was advanced to the left coronary ostium. Thereafter, a
balloon catheter was advanced into the left anterior descending LAD
coronary artery. The position of the balloon catheter was verified
by injection of contrast medium Hexabrix 320, Malinckrodt Medical,
Pointe-Claire, CAN into the left main coronary artery, visualized
in the left anterior oblique position. A baseline coronary artery
angiogram was obtained to confirm positioning of the balloon in the
ventral descending coronary artery about 2 cm from its origin.
[0392] Experimental Protocol
[0393] Surgical preparation and angiographic balloon catheter
placement were followed by a 30-min stabilization period. Regional
blood flow and LV dynamics were obtained at: 1 baseline C1; 2
during 5-min SCS; 3 return to steady-state conditions C2; 4 4 min
of LAD occlusion CO; 5 return to steady-state conditions C3; and 6
5-min SCS during which time blood flow in the LAD was stopped for 4
minutes. The experimental protocol was always begun with
interventions 1 and 2 since the initial goal was to assess the
effects of SCS on myocardial blood supply and LV dynamics. SCS and
coronary occlusion were performed twice in each animal. Four dogs
underwent the following protocol sequence baseline-SCS;
baseline-LAD occlusion; baseline-SCS/LAD occlusion. In another four
dogs, the protocol sequence was altered baseline-SCS;
baseline-SCS/LAD occlusion; baseline-LAD occlusion. Blood flow in
the LAD was totally obstructed by inflating the angiocatheter
balloon ns8 to a pressure of 8 atm Inde-flator Plus 20, ACS,
Tomecula, Calif., USA for 4 min. Completeness of coronary
obstruction was confirmed by injection of contrast medium under
fluoroscopy. At least 10 min elapsed between each intervention to
stabilize the experimental preparation. The time during which the
coronary artery was occluded 4 min was of sufficient duration to
alter regional dynamics cf., the pressure-volume relationship, yet
result in a return to control values upon restoration of coronary
artery blood flow.
[0394] Measurement of Regional Myocardial Blood Flow
[0395] Regional blood flow distribution was determined using the
radioactive microsphere technique (Baer et al., 1984). Six
different radiolabeled microspheres Sn, Sr, Nb, Sc, Ce, In, each
with a diameter of 15 mm, were obtained from NEN Boston, Mass.,
USA. Immediately prior to injection, the microsphere suspension was
agitated in a vortex mixer for 2 min. Each injection comprised
1.6-3=106 microspheres administered into the LV chamber as a bolus
over 15-20 s and flushed with 15 ml of warmed saline. For each
microsphere injection, a timed collection of arterial blood was
performed with a Masterflex infusion/withdrawal pump Fisher,
Montreal, CAN from the right femoral artery catheter at a constant
rate of 7.5 ml/min beginning 10 s before microsphere injection and
continuing for 2 min. Myocardial blood flow was evaluated in all
dogs at six different time points: 1 during baseline state before
any intervention had commenced control, 2 during the final 2 min of
the 5-min SCS period, 3 baseline control a2 i.e., 10 min after
return to baseline conditions, 4 at the midpoint of coronary
occlusion, 5 baseline control a3, i.e., 10 min after return to
baseline conditions, and 6 during the final 2 min of the 5-min SCS
plus 4-min coronary occlusion period.
[0396] Anatomic Risk Zone Analysis
[0397] At the end of each study, the angiographic balloon catheter
was re-inflated; contrast medium was injected to verify that the
balloon was positioned in the same location used earlier to induce
regional myocardial ischemia. Monastral blue dye 5 ml was injected
directly into the coronary artery distal to the occlusion site to
identify the ischemic zone. During deep pentobarbital sodium
anesthesia, cardiac arrest was induced by intravenous injection of
saturated potassium chloride. The heart and left kidney were
excised rapidly from the body, rinsed in saline at room temperature
and then fixed in 10% buffered formaldehyde. For blood flow
analysis, the right ventricle was removed and the LV including
interventricular septum was cut into 6-mm slices from apex to base
parallel to the atrioventricular groove. Four transverse myocardial
sections beginning with the second most apical slice were employed
for blood flow analysis. The LV was divided into anterior ischemic
and posterior non-ischemic segments and further subdivided into
endocardial, midmyocardial and epicardial portions. The outlines of
each LV slice, cavity area and the area at risk, i.e., containing
blue dye were traced onto acetate sheets.
[0398] Planimetry with Sigma Scan software; SPSS, California, USA
was performed on these using a digitizing tablet Summagraphics II
Plus interfaced with a personal computer to determine respective
surface areas. The results so obtained were expressed as the area
at risk indexed to total left-ventricular mass. Regional blood flow
was also assessed in 4 kidney slices excluding the most polar slice
that were further subdivided into medulla and cortex regions.
Radioactivity in all tissue and blood reference samples was
measured in a gamma-well scintillation counter Cobra. II, Canberra
Packard Instruments, Montreal, CAN with standard window settings.
Tissue counts were corrected for background, decay and isotope
spillover; regional blood flow ml/min/g was calculated using the
PCGERDA computer software Packard Instruments and expressed in
MI/min/g.
[0399] Data Analysis
[0400] Heart rate, arterial pressure, LV pressure and LV
pressure-volume loops were evaluated on a beat-to-beat basis and
averaged for 30 s prior to and during each intervention.
Comparisons of cardiac hemodynamics and distribution of myocardial
blood flow during different experimental conditions was performed
using analysis of variance ANOVA with repeated measures. When a
significant effect of treatment was obtained, pair wise comparisons
were made using Scheffe's post-hoc test. All statistical procedures
were performed using the SAS statistical software package SAS,
Cary, N.C., USA; a pF0.05 was considered significant.
[0401] Results
[0402] Ten dogs entered into the study; two dogs, one during AD
occlusion and one during LAD occlusion with con-current SCS went
into intractable ventricular fibrillation and were excluded from
the data analysis.
[0403] CardioVascular Variables
[0404] Heart rate, LV end-systolic and end-diastolic pressures and
mean aortic pressure did not change during SCS. Table III LV stroke
volume and ejection fraction were likewise unaffected by SCS.
Monitored cardiovascular indices did not change significantly
during 4 min of LAD occlusion Table III.
TABLE-US-00003 TABLE III Summary of cardiac hemodynamics HR
LVP.sub.sys LVP.sub.dias PaoM RPP ESV EDV SV C1 107 .+-. 12 71 .+-.
3 2 .+-. 1 64 .+-. 4 7.29 .+-. 0.80 33.8 .+-. 2.7 39.7 .+-. 2.6 7.7
.+-. 1.1 CS 110 .+-. 12 72 .+-. 4 1 .+-. 1 63 .+-. 4 7.60 .+-. 0.83
33.3 .+-. 2.3 39.5 .+-. 2.7 7.8 .+-. 2.1 C2 103 .+-. 16 70 .+-. 2 1
.+-. 1 64 .+-. 3 7.10 .+-. 1.05 29.7 .+-. 2.3 37.5 .+-. 3.3 8.9
.+-. 1.3 CO 122 .+-. 12 69 .+-. 4 3 .+-. 1 58 .+-. 4 8.08 .+-. 0.97
35.4 .+-. 2.2 40.1 .+-. 2.7 6.7 .+-. 1.4 C3 110 .+-. 10 70 .+-. 4 3
.+-. 1 63 .+-. 3 7.32 .+-. 0.66 29.4 .+-. 2.9 35.5 .+-. 4.6 8.0
.+-. 2.0 SCS-CO 128 .+-. 13 70 .+-. 5 2 .+-. 1 58 .+-. 3 8.62 .+-.
0.89 35.3 .+-. 2.5 39.8 .+-. 2.8 6.9 .+-. 1.4 Recovery 113 .+-. 11
74 .+-. 4 1 .+-. 1 67 .+-. 3 8.22 .+-. 1.01 29.9 .+-. 2.1 35.6 .+-.
2.9 8.2 .+-. 1.3 Data are means .+-. S.E.M. HR = heart rate
(beats/min); LVPsys, LVPdias = systolic/diastolic pressure (mmHg);
PaoM = mean aortic pressure (mmHg); RPP = heart rate-arterial
pressure product (beats/min .times. mm Hg .times. 10.sup.-3); ESV =
end-systolic volume (ml); EDV = end-diastolic volume (ml); SV =
stroke volume (ml/s); CO = coronary occlusion; SCS = spinal cord
stimulation.
[0405] The decrease in LV chamber systolic and diastolic pressures
was not significant presumably due to the short duration of the
individual ischemic periods. Although the heart rate/LV pressure
product, an index of myocardial oxygen demand, increased slightly
during acute ischemia, this index did not change significantly due
to large standard deviations from mean values data were not
normalized. Ventricular dynamics were not significantly altered
with acute LAD occlusion and concurrent SCS. Cardiac hemodynamics
at the end of the experimental protocol, i.e., recovery-10 min
after the final intervention was comparable to baseline values.
[0406] Regional Myocardial Blood Flow Distribution
[0407] The overall anatomic risk zone represented 21.2"5.3% mean"1
S.D. of total LV volume. Distribution of ventricular blood flow
determined by radiolabeled microspheres showed that average blood
flow levels decreased significantly within the ischemic zone during
LAD occlusion 0.9"0.1 to 0.2"0.1 ml/min/g p-0.02. Blood flow levels
were not significantly affected in the non-ischemic LV wall, the
right ventricle or kidneys during LAD occlusion Table IV.
[0408] Table IV Summary of Blood Flow Changes
[0409] Data are means.+-.S.E.M. Data are expressed in ml/min/g wet
weight. Abbreviations are indicated in
TABLE-US-00004 TABLE III C1 SCS C2 CO C3 SCS-CO Ischemia zone
Endocardium 1.00 .+-. 0.016 1.02 .+-. 0.08 1.02 .+-. 0.27 0.24 .+-.
0.06 1.53 .+-. 0.43 0.28 .+-. 0.09 Mid- 0.80 .+-. 0.15 0.76 .+-.
0.12 0.84 .+-. 0.25 0.24 .+-. 0.06 1.29 .+-. 0.29 0.29 .+-. 0.06
myocardium Epicardium 0.82 .+-. 0.18 0.75 .+-. 0.10 0.90 .+-. 0.20
0.28 .+-. 0.08 1.10 .+-. 0.27 0.24 .+-. 0.06 Non- ischemic Zone
Endocardium 1.07 .+-. 1.12 1.07 .+-. 0.1 1.14 .+-. 0.25 1.05 .+-.
0.20 1.67 .+-. 0.39 1.04 .+-. 0.17 Mid- 0.91 .+-. 0.11 0.95 .+-.
0.11 1.10 .+-. 0.14 0.93 .+-. 0.18 1.32 .+-. 0.36 0.94 .+-. 0.19
myocardium Epicardium 0.72 .+-. 0.09 0.84 .+-. 0.13 0.84 .+-. 0.13
0.82 .+-. 0.18 1.05 .+-. 0.29 0.77 .+-. 0.13 Right 0.54 .+-. 0.07
0.856 .+-. 0.08 0.70 .+-. 0.12 0.78 .+-. 0.14 0.78 .+-. 0.14 0.44
.+-. 0.07 ventricle Kidney Inner 0.29 .+-. 0.03 0.31 .+-. 0.04 0.30
.+-. 0.06 0.49 .+-. 0.10 0.49 .+-. 0.10 0.60 .+-. 0.07 (medulla)
Outer 3.46 .+-. 0.36 3.49 .+-. 0.23 4.60 .+-. 1.05 4.88 .+-. 1.15
4.88 .+-. 1.15 3.24 .+-. 0.42 (cortex)
[0410] During application of SCS concomitant with LAD occlusion,
the level of blood flow reduction in the ischemic zone was similar
to that which occurred during LAD occlusion alone Table IV and FIG.
37 SCS did not affect transmural blood flow distribution within the
LV-free wall or the intraventricular septum (FIG. 37), or total
ventricular flows. Neither did SCS affect regional blood flow in
the kidneys Table IV.
[0411] Pressure-Volume Relations
[0412] The LV pressure-volume loops did not change during SCS FIGS.
38(A) and (B). The LV pressure-volume loops changed immediately
after the onset of LAD occlusion. The LV volumes shifted rightward,
while similar peak FIG. 37. Transmural blood flow ml/min/g to LV
ischemic closed spheres and non-ischemic closed squares zones for
each of the three baseline control conditions C1, C2 and C3 and
during the successive interventions of 5-min spinal cord
stimulation SCS, 4-min occlusion of the LAD CO, and concurrent
5-min SCS plus 4 min LAD occlusion commencing 1 min into SCS
SCS-CO. Transmural blood flow within the ischemic zone is
significantly lower ps0.02 during both CO, and SCS-CO psNS between
these two interventions compared to baseline systolic pressures
were generated FIGS. 38(C) and (D). LV stroke volume and ejection
fraction was reduced almost 30% compared to baseline values during
the periods of local ventricular ischemia. Corresponding changes in
LV pressure-volume loops were observed when the LAD was occluded
concurrent with SCS FIGS. 38(E) and (F). LV stroke volume and
ejection fraction was similarly diminished. Thus, SCS did not
improve overall ventricular dynamics in the presence of local
myocardial ischemia.
DISCUSSION
[0413] Neuromodulation therapy is utilized to alleviate angina of
cardiac origin. In order to investigate the underlying mechanisms
for such therapy, we studied the potential influence of SCS on
myocardial blood flow and LV dynamics in the normal canine heart.
The results of this study demonstrate that electrical stimulation
of the upper thoracic spinal cord does not alter either transmural
distribution of blood flow within the myocardial wall or overall LV
dynamics. As has been found in the past (Foreman et. al., 2000),
transient focal myocardial ischemia did not alter left-ventricular
chamber systolic or diastolic pressures significantly Table III. On
the other hand, the LV pressure-volume loop was shifted rightward
during transient occlusion of the LAD indicative of volume changes
FIG. 38. Changes in LV volumes were accompanied by a significant
decline in the LV ejection fraction, synonymous with altered
contractile function elicited by acute coronary artery occlusion
(Paulus et al., 1985; Sasayama et al., 1985; Applegate, 1991). As
expected, transmural blood flow was also reduced in the ischemic
zone. Application of SCS during this ischemic challenge did not
further alter regional myocardial blood flow. Neither did SCS
affect the rightward shift of LV pressure-volume loops induced
during the ischemic challenge.
[0414] Limitations of Study
[0415] The radioactive microsphere technique for determination of
regional blood flow distribution has the advantage that
microspheres are trapped during the first pass through an organ
with no detectable recirculation; however, the number of
microspheres that can be safely injected without affecting cardiac
hemodynamics is finite. Baer et al. (1984) estimated that injection
of 18-27 million microspheres nine different radiolabels of 2-3
million spheres each into the left atrium had little influence on
distribution of blood flow during normal coronary autoregulation or
vasodilatation. In the present study systolic LV pressure and mean
aortic pressure remained constant during and after microsphere
injections; this indicates that these dogs were hemodynamically
stable during the respective experimental protocols. It is known
that radioactive microspheres have the inherent limitation that
regional blood flow changes less than 10% of baseline are not
readily detectable. Thus, minor changes in regional blood flow
distributions between myocardial regions might not be detected.
Regardless, the lack of change in measured cardiac indices during
SCS suggests that the primary determinant of regional myocardial
blood flow and cardiac work was not altered thereby. Coronary
vascular resistance or conductance was not calculated in the
present study since we did not include measurements of
extravascular compressive forces or critical closing pressure; in a
recent study from our laboratory we document that during
autoregulation the entire coronary pressure-flow relation can shift
in relation to changes in LV pressure and volume Rouleau et. al.,
1999. Under steady-state conditions in the present study the
endocardialrepicardial blood flow ratio was similar not during
ischemia; as such, distribution of blood flow was maintained across
the LV wall.
[0416] Major differences exist between the present study and some
clinical studies; we used SCS, while Chauhan et al., (1994), who
reported an increase in blood flow in the contralateral coronary
artery, used TENS. In addition, SCS at 90% motor threshold in the
anesthetized canine represents an intensity used clinically when
patients anticipate more strenuous activities. Normally,
stimulation intensities between 60% and 66% of paresthesia
threshold are adequate to reduce anginal pain.
[0417] Clinical Implications of SCS
[0418] Pain-reducing properties of neuromodulation resulting from
SCS are based on the gate theory of pain (Melzack and Wall, 1965).
This theory proposes that stimulation of large afferent fibers
conducting innocuous information reduce the nociceptive effects of
the small afferent fibers on the activity of spinal neurons.
Neuromodulation is known to stimulate neurons in the dorsal horn
(Melzack and Wall, 1965; Chandler et al., 1993) and higher centers
(Hautvast et al., 1997; Yakhnitsa et al., 1999). Recently we
documented that the activity generated by intrinsic cardiac neurons
is also suppressed by SCS, even during acute myocardial ischemic
challenges (Foreman et al., 2000).
[0419] The present results are in agreement with the majority of
previous clinical studies that indicate a lack of effect of SCS on
overall coronary blood flow (De Landesheere et al., 1992; Hautvast
et al., 1996; Sanderson et al., 1996; Norrsell et al., 1998). SCS
was applied for 5 min in our study, while in most clinical studies
it is maintained for much longer time periods. It is unlikely that
the duration of SCS stimulation determines the effects that this
intervention exerts on coronary artery blood flow (Chauhan et al.,
1994). The present study was performed in canine hearts that
underwent brief periods of regional ventricular ischemia. In
clinical studies carried out among patients with stable angina,
electrical or pharmacological i.e., dipyramidole induction of
cardiac stress in the presence of neuromodulation has been shown to
exert no influence on their coronary blood flow (Hautvast et al.,
1996; Norrsell et al., 1998). In the present study, the canine
coronary vasculature was considered to be normal in contrast to
these clinical investigations in which coronary artery blood flow
was assessed in patients with underlying coronary vessel disease.
The primary determinant of blood flow in the normal myocardium is
regional myocardial metabolic demand, the latter being very
dependent on LV dynamics (Hoffman, 1987). Hemodynamic alterations
are accompanied by changes in distribution of blood flow patterns
across the LV wall (Dole and Bishop, 1982; Messina et al., 1985).
For that reason, it is important to note that the periods of
regional ventricular ischemia induced in these experiments were of
short enough duration to induce minor, if any change in
left-ventricular pressure Table III. It is also important to point
out that the hemodynamic results obtained in the canine model may
not directly apply to other animal models with different coronary
collateral vascular function. However, intrinsic cardiac neuronal
results derived from the canine model appear to be applicable to
the porcine model and even to humans undergoing bypass surgery.
Thus, the effects of regional ventricular ischemia on the intrinsic
cardiac nervous system depend more on the location of the neurons
and the site of ventricular injury than on species investigated.
The ischemic area i.e., anatomic risk zone that was produced in
these experiments was significant, being 21.2"5.3% mean"1 S.D. of
the total ventricular volume.
[0420] Ventricular ischemic zones of this magnitude are sufficient
to induce fatal ventricular arrhythmias (Vegh et al., 1991; Curtis
et al., 1989). In the study reported by Vegh et al. (1991), hearts
were preconditioned by repeated episodes of rapid ventricular
pacing; this resulted in significant cardioprotection against
ischemia-induced ventricular arrhythmias. Whether SCS triggered a
preconditioning response in the present experimental model is
debatable. The lack of heart rate or hemodynamic effect, reflected
by the similarity of the myocardial oxygen demand and myocardial
blood flow data indicates that SCS may not have induced a
preconditioning response. In addition, we did not observe an
increase in coronary collateral flow within the ischemic
myocardium. Whether preconditioning increases coronary collateral
blood flow within the ischemic zone in dogs remains unclear. In the
present study, ischemic zone size was not influenced by SCS. These
data are in accord with the fact that SCS did not affect the LV
pressure-volume relationships in addition to arterial perfusion of
ventricular tissue. We cannot completely exclude the possibility
that SCS redistributes blood flow between adjacent myocardial
regions via the coronary collateral circulation since the
microsphere technique may not reliably detect changes in blood flow
at this level. Rather, these data suggest that the anti-anginal
effects of SCS are induced by mechanisms other than changes in
regional myocardial blood flow or
LV Dynamics
Summary and Conclusions
[0421] Data obtained in the present study document the fact that
SCS does not affect either total myocardial blood flow or blood
flow distribution across the LV wall. Neither does SCS affect the
distribution of blood within the ischemic myocardium, nor that
between ischemic and non-ischemic zones.
[0422] Additional studies hereinafter disclosed herein, demonstrate
that (1) ischemia causes neuronal activation; (2) SCS or DCA
stimulation nullifies or quenches such ischemia induced activated
neurons; and (3) nullification and/or such quenching or suppressor
effects on such activated neurons occur (i) prior, (ii) during, and
(iii) after the cessation of SCS or DCA stimulation. Thus, SCS or
DCA effectively directs the intrinsic nervous system in such a
manner as to have an immediate and lasting effect on the activity
of myocardial neurons and the intrinsic cardiac nervous system in
general.
[0423] As mentioned previously, it is known currently that
electrical excitation of the dorsal aspect of the rostral thoracic
spinal cord imparts long-term therapeutic benefits to patients with
angina pectoris. What is not known and is being claimed and
disclosed in the present application, is that spinal cord
stimulation induces short-term suppressor effects on the intrinsic
cardiac nervous system. The results of the following tests show
that spinal cord stimulation (SCS) induces long-term effects on the
intrinsic nervous system, particularly in the presence of
myocardial ischemia.
[0424] The activity generated by right atrial neurons was recorded
in 10 anesthetized dogs during basal states, during prolonged (15
min) occlusion of the left anterior descending coronary artery, and
during the subsequent reperfusion phase. Neuronal activity and
cardiovascular indices were also monitored when the dorsal T1-T4
segments of the spinal cord were stimulated electrically (50 Hz;
0.2 ms) at an intensity 90% of motor threshold (mean 0.32 mA) for
17 min. SCS was performed before, during and after 15-min periods
of regional ventricular ischemia. Occlusion of a major coronary
artery, one that did not perfuse investigated neurons, resulted in
their excitation. Ischemia-induced neuronal excitatory effects were
suppressed (>76% from baseline) by SCS. SCS suppression of
intrinsic cardiac neuronal activity persisted during the subsequent
reperfusion period; after terminating 17 min of SCS, at least 20
min elapsed before intrinsic cardiac neuronal activity returned to
baseline values. It is concluded that populations of intrinsic
cardiac neurons are activated by inputs arising from the ischemic
myocardium. Ischemia-induced activation of these neurons is
nullified by SCS. The neuronal suppressor effects that SCS induces
persist not only during reperfusion, but also for an extended
period of time thereafter.
[0425] Introduction
[0426] High frequency, low intensity electrical stimulation of the
dorsal aspect of the T1-T2 spinal cord alleviates angina pectoris
in patients suffering from ischaemic heart disease (Eliasson et
al., 1996; Mannheimer et al., 1993; Sanderson et al., 1992). The
therapeutic effects of spinal cord stimulation on angina (SCS) can
persist for hours after its termination (Jessurun et al., 1999).
Accumulating evidence demonstrates that SCS is a safe anti-anginal
treatment modality that does not result in increased frequency of
arrhythmia formation (DeJongste et al., 1994; Eliasson et al.,
1996; Hautvast et al., 1998; Mannheimer et al., 1998). However, the
mechanisms whereby SCS produces its long-term effects remain
unknown. Clinical studies have led to the hypothesis that SCS
exerts its anti-anginal effects principally by altering the
ventricular oxygen supply/demand ratio (Mannheimer et al., 1993;
Sanderson et al., 1992). Mannheimer et al. (1993) suggested that
SCS reduces cardiac metabolism, thereby reducing oxygen demand and,
consequently, the myocardial lactate production within the ischemic
myocardium. In this regard, Hautvast et al. (1998) proposed that
SCS redistributes myocardial blood flow from normal to ischaemic
regions of the heart. However, in the canine model, SCS does not
alter cardiac chronotropism or inotropism (as shown in the
experiments above), suggesting that oxygen demand is minimally
affected by such an intervention. Furthermore, SCS does not alter
blood flow distribution within either the normal or ischaemic
canine myocardium (also shown above).
[0427] As we show, the effects of SCS reflect changes within the
CNS and/or changes in neurohumoral control of the heart. SCS
modulates impulse transmission within the spinothalamic tracts of
the spinal cord without blocking afferent neuronal signals arising
from the ischaemic myocardium (Chandler et al., 1993). It also
alters intrinsic cardiac neuronal function (show hereinabove). The
intrinsic cardiac nervous system represents the final common
regulator of regional cardiac function (Armour, 1991; Ardell,
2000). Its neurons are under the constant influence of central
neurons, including those in the spinal cord (Gagliardi et al.,
1988). Regional myocardial ischaemia results in the heterogeneous
activation of the intrinsic cardiac nervous system (Armour et al.,
1998). When sub-populations of intrinsic cardiac neurons become
excessively activated, the cardiac electrophysiological
consequences, such as the occurrence of ventricular tachycardia or
ventricular fibrillation, may be devastating (Armour, 1991).
Stabilization of the intrathoracic intrinsic cardiac nervous
system, especially in the presence of myocardial ischaemia
ameliorate the potential for cardiac electrical instability. Such a
system is shown and demonstrated in the experiments outlined in the
present application.
[0428] Short duration SCS (4 min) transiently suppresses the
activity generated by intrinsic cardiac neurons (shown
hereinabove). In a clinical setting, the anti-anginal effects of
SCS persist long after its termination (Jessurun et al., 1999). The
following experiments were devised to evaluate the effects of
prolonged (17 min) SCS on the intrinsic cardiac nervous system in
normally perfused and ischaemic hearts. These experiments were also
designed to evaluate whether the neurohormonal effects that SCS
imparts on the intrinsic cardiac nervous system persist not only
throughout its application, but also for a time thereafter.
[0429] Materials and Methods
[0430] Animal Preparation
[0431] The Institutional Animal Care and Use Committee of Dalhousie
University approved the experiments performed in the following
experiments. These experiments followed the guidelines outlined by
the International Association for the Study of Pain as well as the
NIH Guide for the Care and Use of Laboratory Animals (National
Academy Press, Washington, DC, 1996). Ten adult dogs of mixed
breed, weighing between 12.5 and 26 kg (mean 19.6 kg), were used
for this study. The animals were kept under standard laboratory
conditions in a light-cycled environment (12 h/12 h) with free
access to water at all times and to food at regular intervals.
[0432] Dogs were anesthetized in a standard manner by first
administering a bolus dose of sodium thiopental (20 mg kg.sup.-1,
i.v.). Anesthesia was maintained throughout the surgery period by
means of bolus doses of thiopental (5 mg kg.sup.-1, i.v.)
administered to effect every 5-10 min. Animals were intubated and
then artificially ventilated using a Bird Mark VII respirator with
100% O.sub.2. After completing the surgery, anesthesia was changed
to alpha chloralose by first administering a dose of alpha
chloralose (75 mg kg.sup.-1, i.v.). Thereafter, repeat doses of
alpha chloralose (20 mg kg.sup.-1, i.v.) were administered, as
required, during the remainder of the experiments.
[0433] The level of anesthesia was checked throughout each
experiment by observing pupil reaction as well as monitoring jaw
tension, heart rate and blood pressure, and by periodically
checking for the withdrawal reflex by squeezing a paw. Since each
bolus of alpha chloralose suppressed neuronal activity for a few
minutes after its administration, these doses were administered
between the interventions performed in each protocol. This
anesthetic regimen produces adequate anesthesia without
inordinately suppressing peripheral autonomic neural activity.
Electrodes were inserted in the forelimbs and the left hind limb
and connected to an Astro-Med (West Warwick, R.I.) model MT 9500
eight-channel rectilinear recorder to monitor a Lead II
electrocardiogram throughout the experiments. In addition, a
12-lead electrocardiogram (ECG) strip-chart recorder (Nihon Ohden
Cardiofax V model BME 7707) was employed to obtain standard lead
electrocardiograms during control states and at 5-min intervals
during each intervention. Heart rate and the duration of the PQ, QR
and QTc intervals were analyzed during control states as well as 1,
5, 10 and 15 min after occlusions began in the absence or presence
of SCS. In addition, alterations in the morphology of ST-T segments
and arrhythmia formation were assessed.
[0434] Implantation of Spinal Cord Stimulation Electrodes
[0435] After induction of anesthesia, animals were placed in the
prone position. The epidural space of the mid-thoracic spinal
column was penetrated percutaneously with a Toughy needle (15 F). A
Toughy needle has a slight angle at its tip to ease penetration
between vertebral processes. Using the loss-of-resistance technique
as is routinely done in a clinical setting, the tip of the Toughy
needle was slowly advanced until it entered the epidural space, as
visualized via A-P fluoroscopy. Once the inner cannula was removed
from the Toughy needle, a four-pole catheter electrode (Medtronic
QUAD Plus Model 3888; Medtronic, Minneapolis, Minn.) was introduced
through the needle such that its tip could be advanced to the T1
level of the spinal column, as determined by fluoroscopy. The tip
of this electrode was positioned slightly to the left of the
midline, as is done in a clinical setting (Linderoth and Foreman,
1999). The rostral and caudal poles of the stimulating electrode
chosen for subsequent use (inter-electrode distance of 1.5 cm) were
located at the levels of the T1 and T4 vertebrae. Correct placement
of the stimulating electrodes was confirmed by delivering
electrical current to induce motor responses using the rostral or
caudal poles as cathodes, respectively.
[0436] The rostral cathode (T1 level) and caudal anode (T4 level)
of the quadripolar electrode were connected to a Grass S88
stimulator via a constant current stimulus isolation unit (Grass
model CCU1 and Grass SIU5). Stimuli, delivered at 50 Hz and 0.2-ms
duration, were monitored on an oscilloscope to determine the amount
of current delivered. Rostral stimulation above motor threshold
resulted in proximal forepaw or shoulder muscle fasciculations (or
both), while caudal electrode stimulation induced contractions in
the thoracic trunk. When the appropriate electrode position was
confirmed, the electrode lead was covered by a Teflon protective
sleeve and fixed to adjacent interspinous ligaments with a suture.
Extension wires attached to the electrode leads were connected to
the Grass constant current stimulator (see hereinabove). Motor
responses were rechecked after the animal had been placed in the
supine position to ensure that the electrodes had not moved during
that maneuver.
[0437] Cardiac Instrumentation
[0438] After placing the animal on its back, a bilateral
thoracotomy was made in the fifth intercostal space. The ventral
pericardium was incised and retracted laterally to expose the heart
and the ventral right atrial deposit of fat containing the ventral
component of the right atrial ganglionated plexus. We investigated
the activity generated by neurons in the right atrial ganglionated
plexus because not only are they representative of those found in
other atrial and in ventricular ganglionated plexuses (Armour,
1991), but they do not receive their arterial blood supply from the
left ventral descending coronary artery (Huang et al., 1993). The
regional arterial blood supply of these neurons and other cardiac
tissues is unaffected by spinal cord stimulation (Kingma et al., in
press). Thus, the blood supply of identified neurons was not
affected in a significant manner by the procedures described
below.
[0439] Left ventricular chamber pressure was monitored via a Cordis
(Miami, Fla.) #7 French pigtail catheter that was inserted into the
chamber via one femoral artery. Systemic arterial pressure was
measured using a Cordis #6 French catheter placed in the descending
aorta via the other femoral artery. These catheters were attached
to Bentley (Irvine, Calif.) Trantec model 800 transducers.
[0440] Neuronal Recording
[0441] To minimize epicardial motion during each cardiac beat, a
circular ring of stiff wire was placed gently on the fatty
epicardial tissue overlying the ventral surface of the right atrium
containing the right atrial ganglionated plexus (Gagliardi et al.,
1988). A tungsten microelectrode (10-mm shank diameter; exposed tip
of 1 mm; impedance of 9-11 MV at 1000 Hz) mounted on a
micromanipulator was lowered into this fat using a microdrive. The
indifferent electrode was attached to mediastinal connective tissue
adjacent to the heart. The electrode tip explored this tissue at
depths ranging from the surface of the fat to regions adjacent to
cardiac musculature. Proximity to the atrial musculature was
indicated by increases in the amplitude of the ECG artifact.
Signals generated by the somata and/or proximal dendrites of
intrinsic atrial neurons were differentially amplified by a
Princeton Applied Research model 113 amplifier with bandpass
filters set at 300 Hz to 10 kHz and an amplification range of
100-500.times.. The output of this amplifier, further amplified
(50-200.times.) and filtered (bandwidth 100 Hz-2 kHz) by means of
optically isolated amplifiers (Applied Microelectronics Institute,
Halifax, NS, Canada), was led to a Nicolet model 207 oscilloscope
and to a Grass AM8 Audio Monitor. Signals were displayed on an
Astro-Med MT 9500 eight-channel rectilinear recorder along with the
cardiovascular variables described above. All data were stored via
a Vetter (Rebesburg, Pa.) M3000A digital tape system for later
analysis. Action potentials generated by neurons in a site in the
right atrial ganglionated plexus were recorded.
[0442] Individual units being identified by their amplitudes and
configurations. The amplitudes of the identified action potentials
varied by less than 10-50 .mu.V over several hours; individual
action potential retained the same configuration over time. Somata
and/or dendrites rather than axons of passage generate individual
action potentials so identified. Action potentials recorded at a
given locus that displayed the same configuration and amplitude
were considered to be generated by a single unit. When multiple
action potentials were identified at an active site, action
potentials generate by individual units were discriminated by means
of a window discriminator (Hartley Instrumentation Development
Laboratories, Baylor College of Medicine, Houston, Tex.).
[0443] Induction of Coronary Artery Occlusion
[0444] A silk (3-0) ligature was placed around the left anterior
descending (LAD) coronary artery approximately 1.5 cm from its
origin, distal to its first diagonal branch. If a relatively large
number of collateral arterial branches from the apex or lateral
wall were evident, ligatures were also placed around these vessels.
These ligatures were led through short segments of polyethylene
tubing in order to occlude these arteries later in the experiments.
Since the arterial blood supply of investigated right atrial
neurons arises from major branches of the right and distal
circumflex coronary arteries, their blood supply remained patent
during these coronary artery occlusions.
[0445] Spinal Cord Stimulation (SCS)
[0446] With the animal placed in the supine position, the intensity
of the current delivered via the bipolar electrode was increased
until a detectable skeletal muscle motor response was evident, as
described above. This current intensity corresponds to the
threshold for motor activity induction (MT). An intensity of 90% of
MT was used for all subsequent stimuli as it recruits A-delta
fibers and other axon populations (Linderoth and Foreman, 1999).
This stimulus intensity corresponds to parameters used clinically
to stimulate the thoracic spinal cord (Linderoth and Foreman,
1999). The stimulus intensity at 90% MT varied between 0.09 and
0.63 mA (mean 0.32 mA) among animals studied. Presumably the
variation in current intensity at 90% MT among animals reflected
slight differences in electrode position with respect to the dorsal
surface of the thoracic cord. The MT was checked periodically and
found to remain constant over time in individual animals.
[0447] Protocols
[0448] Two separate protocols were applied to each of five animals,
the order of their application being randomized among the 10
animals. These were devised to evaluate the long-term effects of
successive 15-min periods of coronary artery occlusion performed
with or without concurrent SCS. Electrical stimuli were delivered
to the dorsal aspect of the thoracic spinal cord for 17-min
periods. Protocol #1 began with two 15-min periods of coronary
artery occlusion, with a 1.5-h interval elapsing between occlusions
(FIG. 39, top panels). The coronary artery occlusion was repeated
in these five animals in order to determine the reproducibility of
ischaemia-induced changes in ECG morphology and intrinsic cardiac
neuronal activity. After an additional 1.5-h recovery phase, 17 min
of SCS (90% MT) was performed during which time a 15-min period of
coronary artery occlusion was instigated 1 min after SCS began.
This was followed by a 1-h period during which time neuronal
activity was quantified. Thereafter, veratridine was applied to
epicardial loci (see hereinbelow).
[0449] Protocol #2 was employed in the other five animals. In
protocol #2, the effects of 17 min of SCS combined with 15 min of
coronary artery occlusion were studied first. The coronary
occlusion was initiated 1 min after beginning SCS (FIG. 34, bottom
panels). After waiting for 1.5 h, a 15-min period of coronary
artery occlusion was performed alone. After waiting another 1.5 h,
the combined SCS and coronary artery occlusion was performed again.
Protocol #2 was performed to verify the reproducibility of effects
induced by SCS in the presence of ventricular ischaemia. This
protocol was followed by a 1-h recovery period after which time
veratridine was applied to epicardial loci.
[0450] Epicardial Application of Veratridine
[0451] Veratridine is a selective modifier of Na+ channels that
excites sensory neurites associated with cardiac afferent neurons
without inducing tachyphylaxis (Thompson et al., 2000). This agent
(obtained from Sigma, St. Louis, Mo., USA) was dissolved in
physiological Tyrode solution to make a 7.5 .mu.M solution. Gauze
squares (1.times.1 cm) soaked with veratridine (0.5 ml) were
applied for 60-100 s to discrete epicardial loci on the right
ventricular conus and the ventral surface of the left ventricle at
the end of each experiment (n=10 dogs). In four animals, the
effects that epicardial application of veratridine exerted on the
intrinsic cardiac nervous system was also tested before the
protocols described above had been performed. After removing the
applied gauze, the epicardial region was flushed with normal saline
for at least 30 s. Gauze squares soaked with room temperature
normal saline were also applied to identify epicardial sensory
fields in order to determine whether neuronal responses elicited by
chemical application were due to vehicle effects or the mechanical
effects elicited by gauze squares.
[0452] Data Analysis
[0453] Individual action potentials generated by the somata or
dendrites of neurons within the right atrial ganglionated plexus
were averaged over 30-s periods of time prior to and during each
intervention. Average heart rate, left ventricular chamber systolic
pressure and aortic pressure were determined concomitantly. Changes
in ECG morphology induced by the protocols were assessed. When the
coronary artery occlusion was performed alone, data were assessed
during baseline conditions and 14 min after the occlusion began
(occlusion period), as well as starting 15 s after reperfusion
began (reperfusion period). When the occlusions were performed in
the presence of SCS, cardiac indices and neuronal activity were
assessed at five time points: (1) control period; (2) 30 s after
SCS began; (3) 12 min after coronary artery occlusion began, in the
presence of SCS; (4) after terminating the occlusion while the SCS
persisted; and (5) within 30-60 s of terminating the SCS. Data are
expressed as means.+-.S.E.M. One-way ANOVA and paired t-test, with
Bonferroni correction for multiple tests, were employed to examine
grouped responses elicited during occlusion of a coronary artery
alone (first occlusion) or when SCS and occlusions were performed
in each protocol. Values of P<0.05 were used to determine
significance.
[0454] Results
[0455] Identification of Active Sites
[0456] Action potentials with signal-to-noise ratios greater than
3:1 were identified in 2-3 loci within the ventral right atrial
ganglionated plexus of each animal. Based on the different
amplitudes and configurations of action potentials recorded at one
site per animal, an average of 3.2.+-.0.5 (range 2-6) neurons
generated spontaneous activity at investigated sites during control
states. Neuronal activity during basal states was usually sporadic
in nature. During basal states, a few spontaneous active neurons
were identified in active loci of most animals (FIG. 40), while in
a few animals, a number of neurons generated spontaneous activity
(FIG. 41(D)). The neuron aggregates identified in one active locus
in each of the 10 investigated dogs generated, on average,
34.1.+-.3.4 to 48.2.+-.6.5 impulses/min (Table V).
TABLE-US-00005 TABLE V Heart rate (HR), left ventricular chamber
systolic pressure (LVP), aortic systolic and diastolic pressures
(AP) and the activity generated by right atrial neurons recorded
before (control) and during coronary artery occlusion (CAO), as
well as during early reperfusion (reperfusion). These indices were
also recorded when occlusion occurred during spinal cord
stimulation. Intervention HR LVP Neuronal activity (n = 10 dogs)
(bpm) (mmHg) AP (mmHg) (impulses/min) Control 134 .+-. 2 134 .+-. 5
138 .+-. 5/99 .+-. 5 34.1 .noteq. 3.4 CAO 134 .+-. 2 136 .+-. 5 140
.+-. 5/99 .+-. 5 62.2 .noteq. 9.5* Reperfusion 134 .+-. 2 136 .+-.
5 138 .+-. 5/99 .+-. 5 66.0 .noteq. 13.3* Control 130 .+-. 3 137
.+-. 4 141 .+-. 5/99 .+-. 5 48.2 .noteq. 6.5 SCS 130 .+-. 3 137
.+-. 4 141 .+-. 5/99 .+-. 6 15.1 .noteq. 3.1* SCS + CAO 128 .+-. 3
139 .+-. 4 141 .+-. 5/98 .+-. 6 13.5 .noteq. 2.4* SCS + 130 .+-. 3
137 .+-. 4 141 .+-. 5/99 .+-. 5 15.2 .noteq. 3.3* reperfusion
Control 131 .+-. 4 134 .+-. 5 141 .+-. 5/99 .+-. 5 46.8 .noteq.
10.2
[0457] Effects of Transient Myocardial Ischaemia
[0458] Monitored cardiac indices did not change significantly
overall during coronary artery occlusion or the reperfusion period,
except when cardiac arrhythmias occurred. For instance, heart rate
was 134.+-.2 beats/min (bpm) before occlusion and 130.+-.3,
134.+-.3, 132.+-.2 and 134.+-.2 bpm after 1, 5, 10 and 15 min of
ischaemia, respectively. S-T segment alterations and terminal QRS
slurring was evident in the ECG pattern of each animal during
ischaemic episodes (FIG. 42). The ST segments remained altered
(elevated or depressed by 1.0.+-.0.2 mm) during the first 2-5 min
of reperfusion. ECG patterns returned to baseline values within 20
min of reestablishing coronary artery blood flow. Short bursts of
ventricular arrhythmias occurred in most animals during coronary
artery occlusion. In two animals, ventricular fibrillation
developed during or immediately after the first coronary artery
occlusion. In those instances, the hearts were successfully
defibrillated and, after 1 h, the protocol was continued. These
animals did not exhibit any unusual alterations in monitored
indices throughout during the rest of the protocols. The data
obtained during these short bouts of arrhythmias or fibrillation
was excluded from the study.
[0459] Overall, these electrophysiological data substantiate the
substantial ischaemia insult that was induced by 15-min periods of
left anterior descending coronary artery (LAD) occlusion. When the
LAD was occluded in either protocol in the absence of SCS, the
activity generated by right atrial neurons (FIG. 40). Effects of
coronary artery occlusion on the activity generated by intrinsic
cardiac neurons in one animal. Following occlusion of the left
anterior descending coronary artery (beginning at arrow below), the
activity generated by right atrial neurons (lowest line) increased
(right-hand panel). Heart rate was unaffected by this intervention,
while left ventricular chamber systolic pressure (LVP) increased a
little. The time between panels represents 1.5 min. increased by
82% (FIG. 40; Table V). Neuronal excitation persisted through the
period of occlusion. During protocol #1, the two successive 15-min
periods of coronary artery occlusion separated by 1.5 h of recovery
induced similar neuronal excitation. Twelve minutes after
initiating the first LAD occlusion, neuronal activity was 69%
greater than identified in normally perfused states (31.7.+-.6.9 to
53.5.+-.10.2 impulses/min; P<0.01). During the second period of
coronary artery occlusion, neuronal activity increased by 95%
(28.3.+-.4.1 to 55.1.+-.8.9 impulses/min; P<0.01). Neuronal
activity began to increase within 30-45 s after coronary artery
occlusion began. This occurred despite the fact that coronary
artery occlusion did not interfere with the arterial blood supply
to identified right atrial neurons as it arose from the right and
distal circumflex coronary arteries. Furthermore, neuronal activity
remained elevated not only throughout the period of occlusion but
during the early reperfusion period following reestablishing
coronary artery flow. Five to ten minutes after reestablishment of
coronary artery flow, neuronal activity began to diminish, reaching
steady state values within 15 min.
[0460] FIG. 41 shows the activity generated by intrinsic cardiac
neurons in one animal during control states (panel A, lowest line)
decreased when the dorsal aspect of the spinal cord was stimulated
(panel B). The suppressor effects of SCS persisted during coronary
artery occlusion (panel C). The electrical stimuli delivered during
SCS are represented in panels B and C by regular, low
signal-to-noise artifacts (note that atrial electrical artifact is
recorded during each cardiac cycle as a low signal during the p
wave of the ECG). The suppression of spontaneous activity generated
by intrinsic cardiac neurons persisted after discontinuing SCS
(panel E represents neuronal activity recorded 5 min post-SCS and 6
min post-LAD occlusion; panel D represents basal activity at same
time scale obtained before commencing these interventions).
ECG=electrocardiogram; AP=aortic pressure; LVP=left ventricular
chamber pressure.
[0461] Table V shows heart rate (HR), left ventricular chamber
systolic pressure (LVP), aortic systolic and diastolic pressures
(AP) and the activity generated by right atrial neurons recorded
before (control) and during coronary artery occlusion (CAO), as
well as during early reperfusion (reperfusion). These indices were
also recorded when occlusion occurred during spinal cord
stimulation.
[0462] Effects of Spinal Cord Stimulation in the Presence of
Myocardial Ischaemia
[0463] During normal coronary artery perfusion, SCS did not alter
the ECG or monitored cardiac indices (Table V). The activity
generated by identified right atrial neurons was reduced from
48.2.+-.6.5 to 23.+-.2.5 impulses/min within 30 s of applying
electrical current to the dorsal aspect of the rostral thoracic
spinal cord in hearts with normal coronary arterial blood supply
(FIG. 43). After the coronary artery occlusion had been maintained
for 1 min in the presence of SCS (2 min after beginning SCS), right
atrial neuronal activity was reduced to 15.1.+-.3.1 impulses/min.
Thus, SCS suppressed the activity generated by intrinsic cardiac
neurons not only in normally perfused hearts (FIG. 41(B)), but also
in the presence of regional ventricular ischaemia (FIG. 41(C)).
Furthermore, the neuronal suppressor effects of SCS persisted
throughout the ischaemic periods. Monitored cardiovascular indices
did not change overall when SCS was applied during coronary artery
occlusion. Ischaemia-induced alterations in ECG patterns also
remained throughout the period when SCS was applied concomitant
with the occlusions. Neuronal activity gradually increased after
discontinuing SCS such that by 20 to 25 min after terminating SCS,
neuronal activity was similar statistically to that recorded during
basal conditions. It increased a little thereafter (FIG. 43).
[0464] Epicardial Application of Veratridine
[0465] The activity generated by right atrial neurons increased
when veratridine was applied topically to their ventricular sensory
inputs. Veratridine-induced excitation of intrinsic cardiac neurons
was studied both before and after application of SCS in four
animals. In those cases, veratridine enhanced intrinsic cardiac
neuronal activity by 124% (40.5.+-.26.7; P<0.05) before
application of SCS and by only 39% (11.8.+-.2.5 to 16.5.+-.4.6
impulses/min; no significant difference) after its application.
When veratridine was applied to their ventricular sensory inputs
after completing the protocols in all 10 dogs (following SCS and
regional ventricular ischaemia), intrinsic cardiac neuronal
activity increased by only 58% (25.6.+-.5.7 to 40.6.+-.12.5
impulses/min; P<0.05).
[0466] Figure II shows representative ECG records obtained from one
animal during control states (A), as well as a few minutes after
beginning coronary artery occlusion in the presence of spinal cord
stimulation (B) and at the end of occlusion while SCS was
maintained (C). Note that ST segment alterations occurred
throughout the period of ischaemia.
DISCUSSION
[0467] The results obtained from the experiments conducted in the
present study not only confirm that spinal cord neurons can
modulate the intrinsic cardiac nervous system (as discussed
hereinabove), but they demonstrate that such modulation persists
unabated throughout 17-min periods of stimulating the dorsal
thoracic spinal cord. They also indicate that spinal cord neurons
continue to exert their suppressor effects on the intrinsic cardiac
nervous system long after their activation terminates. Furthermore,
these data indicate that spinal cord neurons reorganize information
processing within the intrinsic cardiac nervous system arising from
the ischaemic myocardium, including during the reperfusion
post-ischaemic phase. Finally, as indicated by the neural responses
evoked by veratridine application to the ventricular epicardium,
the stabilizing influence that SCS exerts on the intrinsic cardiac
nervous system extends to intrinsic cardiac reflex responses evoked
by activating cardiac sensory neurites associated with afferent
neurons within the cardiac neuroaxis.
[0468] Given that bilateral transection of the ansae subclavia
abolishes the neuro-suppressor effects that SCS imparts upon the
intrinsic cardiac nervous system (as discussed hereinabove), it
appears that the sympathetic nervous system is involved in the
effects of SCS on the intrinsic cardiac nervous system. Activation
of spinal cord neurons may inhibit intrinsic cardiac local circuit
neurons in a manner similar to that which occurs when they receive
increasing inputs from sympathetic efferent preganglionic neurons
(Murphy et al., 1995). Based on the results obtained during
application of SCS to the lumbosacral spinal cord (Linderoth and
Foreman, 1999), sympathetic afferent as well as efferent axons may
contribute to the suppressor effects that SCS exerts on the
intrinsic cardiac nervous system.
[0469] Activation of sympathetic efferent preganglionic axons
attenuates the activity generated by sub-populations of neurons
within intrathoracic ganglia, including those on the heart (Armour,
1991; Murphy et al., 1995). Supramaximal stimulation of sympathetic
efferent preganglionic neurons also leads to a rapid reduction in
the capacity of intrathoracic sympathetic efferent neurons to
influence cardiodynamics (Butler et al., 1988). It has been
proposed that such suppressor effects are most likely due to
inhibitory synapses within intrathoracic ganglia, including those
on the heart (Armour, 1991). In accord with that, spinal cord
neurons, when activated, suppress the activity generated by
intrinsic cardiac neurons.
[0470] It is known that the activity generated by many intrinsic
cardiac neurons increases secondary to transient ventricular
ischaemia (Armour et al., 1998). Right atrial neurons are supplied
by arterial blood in the sinoatrial artery arising from the right
coronary artery and distal branches of the circumflex coronary
artery (Huang et al., 1993). Since occlusion of the left anterior
descending coronary artery does not compromise the arterial blood
supply of investigated right atrial neurons (Huang et al., 1993),
the effects that regional ventricular ischaemia exerted on
investigated neurons were primarily the result of ischaemia-induced
enhancement of ventricular sensory neurite inputs to identified
neurons rather than any direct effects of ischaemia on identified
somata and/or dendrites (Armour, 1991). Intrinsic cardiac neuronal
activity remained elevated throughout the 15-min periods of
regional ventricular ischaemia when performed in the absence of
SCS. That these regional coronary artery occlusions affected the ST
segments of the ECG presumably is reflective of the underlying
myocardial ischaemia so induced. The processing of cardiac sensory
information within the intrinsic cardiac nervous system was
affected by SCS, as indicated by changed neuronal responsiveness to
chemical (veratridine) activation of their ventricular sensory
inputs.
[0471] Given the fact that the capacity of veratridine to affect
sensory neurites associated with cardiac afferent neuron exhibits
no tachyphylaxis (Thompson et al., 2000), the changed transduction
properties of ventricular sensory inputs to the intrinsic cardiac
nervous system is due, in part, to remodeling of the intrinsic
cardiac nervous system subsequent to SCS. It should be noted that
in clinical studies, the sensory effects that SCS imparts persist
long after the stimulation has stopped. Patients with refractory
angina pectoris continue to experience decreased episodes of pain
after terminating SCS (Jessurun et al., 1999). Furthermore, the
allodynia associated with neuropathic pain can be reduced for as
long as 1 h after terminating SCS (Stiller et al., 1996).
Application of SCS immediately prior to onset of LAD occlusion did
not blunt the evolution of ischaemic-induced changes in the ECG. It
is unlikely that the results obtained by SCS in a clinical setting
can be ascribed to alterations in hemodynamics (Hautvast et al.,
1998; Linderoth and Foreman, 1999) or coronary artery blood flow
(as discussed hereinabove). This is because SCS exerts its primary
effects on the intrinsic cardiac nervous system that, in turn, may
influence control over regional cardiac electrical or mechanical
events. These data indicate that activation of spinal cord neurons
induces a conformational change in the intrinsic cardiac nervous
system that persists for a considerable period of time after
terminating such activation. This remodeling of the intrinsic
cardiac nervous system can override excitatory inputs to it arising
from the ischaemic myocardium. Thus, thoracic spinal cord neurons
act to stabilize the intrinsic cardiac nervous system in the
presence of ventricular ischaemia and during reperfusion. The
prolonged salutary effects that SCS imparts to some patients long
after it is discontinued are due, in part, to remodeling of the
cardiac nervous system.
[0472] Thus it should be apparent that there has been provided in
accordance with the present invention a detailed description,
examples and data showing the SCS or DCA stimulation directly
impacts the intrinsic cardiac nervous system and that such an
impact can be used to modify, treat, modulate, suppress, and/or
quench the neuronal activity of the intrinsic cardiac nervous
system and in turn protect cardiac myocytes and preserve the
electrical stability of the intrinsic cardiac nervous system and
the heart itself, that fully satisfies the objectives and
advantages set forth above. Although the invention has been
described in conjunction with specific embodiments thereof, it is
evident that many alternatives, modifications, and variations will
be apparent to those skilled in the art. Accordingly, it is
intended to embrace all such alternatives, modifications, and
variations that fall within the spirit and broad scope of the
appended claims.
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