Note: Descriptions are shown in the official language in which they were submitted.
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A SYSTEM AND METHOD FOR MANAGING DETRIMENTAL CARDIAC
REMODELING
CROSS REFERENCE TO RELATED APPLICATIONS
[0001 ] This application claims priority under 35 U.S.C. 119(e) from
provisional application
number 60/575,121 filed May 28, 2004. The 60/575,121 provisional application
is incorporated
by reference herein, in its entirety, for all purposes. This application is a
continuation in part of
of U.S. patent application 10/053,750 filed January 21, 2002, pending, which
is a continuation
of U.S. patent application no. 09/690,947, filed October 18, 2000, now U.S.
Patent no.
6,341,235, which is a continuation-in-part of U.S. patent application no.
09/008,636 filed
January 16, 1998, now U.S. Patent no. 6,136,019, which is a continuation-in-
part of U.S. patent
application no. 08/699,552, filed August 19, 1996, now U.S. Patent no.
5,871,506. The
10/053,750, 09/690,947, 09/008,636, and 08/699,552 applications are all
incorporated by
reference herein, in their entirety, for all purposes.
BACKGROUND
[0002] This application is generally related treatment of the heart, and more
particularly to
managing and preventing detrimental cardiac remodeling following myocardial
infarction.
Remodeling of the heart is a harmful physical change in the heart that occurs
with heart failure,
heart attack, and heart disease. Remodeling is characterized by enlargement of
the heart and
thinning of the heart walls. For example, after a heart attack, while the
normal heart muscle
responds normally to excitatory pulses. tissue that is damaged by the heart
attack does not
respond or responds in a slower than normal rate to excitatory pulses. The
healthy tissue
.however, continuing to function normally, places increased stress on the
damaged and
marginalized tissue, thereby "stretching" it. The stretching increases the
volume of blood held
by the heart resulting in a short term increased blood output via a Frank-
Sterling mechanism. In
this way, the heart muscle behaves something like a rubber band - the more it
is stretched, the
more "snap" the heart generates. However, if cardiac muscle is overstretched,
or if the heart is
stretched repetitively over a long period of time, it eventually loses its
"snap" and becomes
flaccid (a fonn of remodeling). Remodeling progresses in stages. Following a
heart attack or as
a consequence of heart disease, the heart becomes rounder and larger. Heart
muscle cells die and
the heart as a pump gets weaker. If the remodeling is allowed to progress, the
heart's main
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pumping chamber - the left ventricle - enlarges and changes shape, getting
rounder. The heart
also undergoes changes at the cell level.
[0003] The heart is divided into the right side and the left side. The right
side, comprising the
right atrium and ventricle, collects and pumps de-oxygenated blood to the
lungs to pick up
oxygen. The left side, comprising the left atrium and ventricle, collects and
pumps oxygenated
blood to the body. Oxygen-poor blood returning from the body enters the right
atrium through
the vena cava. The right atrium contracts, pushing blood through the tricuspid
valve and into the
right ventricle. The right ventricle contracts to pump blood througli the
pulmonic valve and into
the pulmonary artery, which connects to the lungs. The blood picks up oxygen
in the lungs and
then travels back to the heart through the pulmonary veins. The pulmonary
veins empty into the
left atrium, which contracts to push oxygenated blood into the left ventricle.
The left ventricle
contracts, pushing the blood through the aortic valve and into the aorta,
which connects to the
rest of the body. Coronary arteries extending from the aorta provide the heart
blood.
[0004] The heart's own pacemaker is located in the atrium and is responsible
for initiation of the
heartbeat. The heartbeat begins with activation of atrial tissue in the
pacemaker region (i.e., the
sinoatrial or "SA" node), followed by cell-to-cell spread of excitation
throughout the atrium.
The only normal link of excitable tissue connecting the atria to the
ventricles is the
atrioventricular (AV) node located at the boundary between the atria and the
ventricles.
Propagation takes place at a slow velocity, but at the ventricular end the
bundle of His (i.e., the
electrical conduction pathway located in the ventricular septum) and the
bundle braides carry the
excitation to many sites in the right and left ventricle at a relatively high
velocity of 1-2 m/s.
The slow conduction in the AV junction results in a delay of around 0.1
seconds between atrial
and ventricular excitation. This timing facilitates terminal filling of the
ventricles from atrial
contraction prior to ventricular contraction. After the slowing of the AV
node, the bundle of His
separates into two bundle branches (left and right) propagating along each
side of the septum.
The bundles ramify into Purlcinje fibers that diverge to the inner sides of
the ventricular walls.
This insures the propagation of excitatory pulses within the ventricular
conduction system
proceeds at a relative high speed wlien compared to the propagation through
the AV node.
[0005] The syndrome of "heart failure" is a common course for the progression
of many forms
of heart disease. Heart failure may be considered to be the condition in which
an abnormality of
cardiac function is responsible for the inability of the heart to pump blood
at a rate
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commensurate with the requirements of the metabolizing tissues, or can do so
only at an
abnormally elevated filling pressure. Typically, the elevated filling
pressures result in dilatation
of the left ventricular chamber. Etiologies that can lead to this form of
failure include idiopathic
cardiomyopathy, viral cardiomyopathy, and ischemic cardiomyopathy.
[0006] Heart failure is a chronic condition that affects over five million
Americans, and is the
most common reason for hospitalization among elderly persons. Contrary to its
name, heart
failure is not a heart attack. Neither does the heart suddenly stop beating.
Heart failure means
that the heart is failing to pump enough blood to meet the body's needs. It
often occurs in
patients whose hearts have been weakened or damaged by a heart attack or other
conditions. As
the heart continues to fail, patients may experience breathlessness, fluid
build-up in the limbs
and severe fatigue. Delays in response of the septum to excitatory pulse may
cause contractions
that are not simultaneous and therefore the ventricular contraction pattern is
non-concentric. In
this mode, the heart is beating inefficiently. .
[0007] When the heart is working properly, both of its lower chambers
(ventricles) pump at the
same time and in sync with the pumping of the two upper chambers (atria). Up
to 40 percent of
heart failure patients, however, have disturbances in the conduction of
electrical impulses to the
ventricles (e.g., bundle branch block or intraventricular conduction delay).
As a result, the left
and right ventricles are activated at different times. When this happens, the
walls of the left
ventricle (the chamber responsible for pumping blood throughout the body) do
not contract
simultaneously, reducing the heart's efficiency as a pump. The heart typically
responds by
beating faster and dilating. This results in a vicious cycle of further
dilation, constriction of the
vessels in the body, salt and water retention, and further worsening of heart
failure. These
conduction delays do not respond to antiarrhythmics or other drugs.
[0008] Patients who have heart failure may be candidates to receive a
pacemalcer. A
biventricular pacemaker is a type of implantable pacemaker designed to treat
heart failure. A
biventricular pacemaker can help synchronize the lower chambers by sending
electrical signals
simultaneously to the left ventricle and to the right ventricle. By
stimulating both ventricles
(biventricular pacing), the pacemaker makes the walls of the right and left
ventricles pump
together again. The heart is thus resynchronized, pumping more efficiently
while causing less
wear and tear on the heart muscle itself. This is why biventricular pacing is
also referred to as
cardiac resynchronization therapy (CRT).
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[0009] For patients who suffer from heart failure, remodeling of the heart may
occur.
Remodeling associated with heart failure is characterized by enlargement of
the heart's left
ventricle. In addition, the left ventricle walls become thinner. There is an
increased use of
oxygen, greater degree of mitral valve regurgitation, and decreased ejection
fraction.
Remodeling sets off a "domino effect" of further damage to heart cells and
more severe heart
disease. Biventricular pacing of the present invention can potentially reverse
the process. This
beneficial effect on the heart is called "reverse remodeling." Typical
biventricular pacemakers
use cathodal pulses of 2.5 volts in the atrium and 5 volts in the ventricle.
HEART ATTACK
[0010] A heart attack is an event that results in permanent heart damage or
death. It is also
known as a myocardial infarction, because part of the heart muscle
(myocardiuin) may literally
die (infarct). A heart attack occurs when one of the coronary arteries becomes
severely or totally
blocked, usually by a blood clot. When the heart muscle does not receive the
oxygenated blood
that it needs, it will begin to die. The severity of a heart attack usually
depends on how much of
the heart muscle is injured or dies during the heart attack.
[0011] Although a heart attack is usually the result of a number of chronic
heart conditions (e.g.,
coronary artery disease), the trigger for a heart attack is often a blood clot
that has blocked the
flow of blood through a coronary artery. If the artery has already been
narrowed by fatty plaque
(a disease called atherosclerosis), the blood clot may be large enough to
block the blood flow
severely or completely. The victim may experience an episode of cardiac
ischemia, which is a
condition in which the heart is not getting enough oxygenated blood. This is
often accompanied
by angina (a type of chest pain, pressure or discomfort), although silent
ischemia shows no signs
at all. Severe or lengthy episodes of cardiac ischemia can trigger a heart
attack. Depending upon
the severity of both the attack and of the subsequent scarring, a heart attack
can lead to the
following:
= Heart failure, a chronic condition in which at least one chamber of the
heart is not pumping
well enough to meet the body's demands.
= Electrical instability of the heart, which can cause a potentially dangerous
abnormal heart
rhythm (arrhythmia).
= Cardiac arrest, in which the heart stops beating altogether, resulting in
sudden cardiac death
in the absence of immediate medical attention.
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= Cardiogenic shock, a condition in which damaged heart muscle cannot pump
normally and
enters a shock-like state that is often fatal.
= Death.
[0012] Whether or not the heart muscle will continue to function after a heart
attack depends on
how much of it was damaged or how much of it died before the patient could get
medical
treatment. The location of the damage in the heart muscle is also iinportant.
Because different
coronary arteries supply different areas of the heart, the severity of the
damage will depend upon
the degree to which the artery was blocked and the amount and area of the
heart muscle that
depended on that blocked artery.
[0013] As previously noted, tissue that is damaged by the heart attack does
not respond or
responds a slower than normal rate to excitatory pulses. The healthy tissue
operates normally,
but as a consequence places increased stress on this marginalized tissue,
thereby "stretching" it.
It is desirable to treat a heart attack so as to minimize the likelihood of
continued detrimental
remodeling. This can be accomplished by reducing the contraction strength of
healthy cardiac
tissues, by increasing the contraction strength of marginalize cardiac tissue,
or by implementing
a coinbination of both therapies.
HEART DISEASE AND ARRHYTHMIA
[0014] Disease affecting the AV junction may result in interference with
normal AV conduction.
This is described by different degrees of block. In first-degree block the
effect is simply slowed
conduction, in second-degree block there is a periodic dropped beat, but in
third-degree block no
signal reaches the ventricles. This latter condition is also referred to as
complete heart block. In
this case the ventricles are completely decoupled from the atria. Whereas the
atrial heart rate is
still determined at the AV node, the ventricles are paced by ectopic
ventricular sites. Since under
normal conditions the ventricles are driven by the atria, the latent
ventricular pacemakers must
have a lower rate. Consequently, in complete heart block the ventricles beat
at a low rate
(bradycardia). Even this condition may not require medical attention, but if
the heart rate is too
low, a condition known as Stokes-Adams syndrome, the situation becomes life-
threatening. The
prognosis in the case of complete heart block and Stokes-Adams is 50%
mortality within one
year. In this case the implantation of an artificial pacemaker is mandatory.
[0015] Another condition, known as the sick sinus syndrome, is also one for
which the artificial
pacemaker is the treatment of choice. In these conditions, the bradycardia
results from the atrial
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rate being abnormally low. Thus, even though the AV junction is normal, the
ventricles are
driven at too low a rate.
[0016] A wide variety of arrhythmias can occur after acute myocardial
infarction.
Supraventricular tachyarrhytlunias, including sinus tachycardia, atrial
fibrillation, and atrial
flutter, are relatively common and generally not life-threatening. Ventricular
arrhythmias have a
high incidence: premature ventricular beats occur in up to 90% of patients,
ventricular
tachycardias in up to 40% of patients, and ventricular fibrillation in up to
5%. Ventricular
fibrillation is most common in the first 24 to 48 hours after myocardial
infarction and is life-
threatening. Although nonsustained ventricular tachycardia is of prognostic
significance in the
postinfarction period, it is not certain if therapy will alter prognosis.
Conduction abnormalities
and bradyarrhythmias, also frequent complications of acute myocardial
infarction, require
pacing therapy when symptomatic.
[0017] Temporary pacing is typically used first. If symptoms persist, a
permanent pacemalcer
may be needed. A pacemaker is an artificial device to electrically assist in
pacing the heart so
that the heart may pump blood more effectively. Implantable electronic devices
have been
developed to treat both abnormally slow heart rates (bradycardias) and
excessively rapid heart
rates (tachycardias). The job of the pacemaker is to maintain a safe heart
rate by delivering to
the pumping chainbers appropriately timed electrical impulses that replace the
heart's normal
rhythmic pulses. The device designed to perform this life-sustaining role
consists of a power
source the size of a silver dollar (containing the battery), and control
circuits, wires or "leads"
that connect the power source to the chambers of the heart. The leads are
typically placed in
contact with the right atrium or the right ventricle, or both. They allow the
pacemaker to sense
and stimulate in various combinations, depending on where the pacing is
required.
[0018] Absent a diagnosis of arrhythmia, anti-arrhythmic pacing is not
typically used as a
treatment for myocardial infarction victims.
[0019] Whether a myocardial infarction leads to heart failure depends to a
large extent on how
the remaining normal heart muscle behaves. The process of ventricular
dilatation (remodeling)
is generally the result of chronic volume overload or specific damage to the
myocardium. In a
normal heart that is exposed to long term increased cardiac output
requirements, for example,
that of an athlete, there is an adaptive process of slight ventricular
dilation and muscle myocyte
hypertrophy. In this way, the heart fully compensates for the increased
cardiac output
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requirements. With damage to the myocardium or chronic volume overload,
however, there are
increased requirements put on the contracting myocardium to such a level that
this compensated
state is never achieved and the heart continues to dilate.
[0020] The basic problem with a large dilated left ventricle is that there is
a significant increase
in wall tension and/or stress both during diastolic filling and during
systolic contraction. In a
normal heart, the adaptation (or remodeling) of muscle hypertrophy
(thickening) and ventricular
dilatation maintain a fairly constant wall tension for systolic contraction.
However, in a failing
heart, the ongoing dilatation is greater than the hypertrophy and the result
is a rising wall tension
requirement for systolic contraction. This is felt to be an ongoing insult to
the muscle myocyte
resulting in further muscle damage. The increase in wall stress is also true
for diastolic filling.
Additionally, because of the lack of cardiac output, there is generally a rise
in ventricular filling
pressure from several physiologic mechanisms. Moreover, in diastole there are
both a diameter
increase and a pressure increase over normal, both contributing to higher wall
stress levels. The
increase in diastolic wall stress is felt to be the primary contributor to
ongoing dilatation of the
chamber.
[0021 ] Inadequate pumping of blood into the arterial system by the heart is
sometimes referred
to as "forward failure," with "backward failure" referring to the resulting
elevated pressures in
the lungs and systemic veins leading to congestion. Backward failure is the
natural consequence
of forward failure as blood in the pulmonary and venous systems fails to be
pumped out.
Forward failure can be caused by impaired contractility of the ventricles or
by an increased
afterload (i.e., the forces resisting ejection of blood) due to, for example,
systemic hypertension
or valvular dysfunction. One physiological compensatory mechanism that acts to
increase
cardiac output is due to backward failure which increases the diastolic
filling pressure of the
ventricles and thereby increases the preload (i.e., the degree to which the
ventricles are stretched
by the volume of blood in the ventricles at the end of diastole). An increase
in preload causes an
increase in stroke volume during systole, a phenomena known as the Frank-
Starling principle.
Thus, heart failure can be at least partially compensated by this mechanism
but at the expense of
possible pulmonary and/or systemic congestion.
[0022] When the ventricles are stretched due to the increased preload over a
period of time, the
ventricles become dilated. The enlargement of the ventricular volume causes
increased
ventricular wall stress at a given systolic pressure. Along with the increased
pressure-volume
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work done by the ventricle, this acts as a stimulus for hypertrophy of the
ventricular
myocardium leading to alterations in cellular structure, a process referred to
as ventricular
remodeling.
[0023] Hypertrophy can increase systolic pressures but also decreases the
compliance of the
ventricles and hence increases diastolic filling pressure to result in even
more congestion. It also
has been shown that the sustained stresses causing hypertrophy may induce
apoptosis (i.e.,
programmed cell death) of cardiac muscle cells and eventual wall thinning
which causes further
deterioration in cardiac function. Thus, although ventricular dilation and
hypertrophy may at
first be compensatory and increase cardiac output, the process ultimately
results in both systolic
and diastolic dysfunction. It has been shown that the extent of ventricular
remodeling is
positively correlated with increased mortality in CHF patients.
[0024] Over the past several years, numerous randomized clinical trials have
been completed
that show that two classes of drugs can significantly improve the overall
survival of patients
who have signs of impending heart failure (either low left ventricular
ejection fraction or
increased ventricular dilation). These drugs are the beta blockers and the ACE
inhibitors. Beta-
blockers work by bloclcing the effect of adrenaline on the heart, and have
been noted to have
numerous beneficial effects in several types of heart disease. Beta blockers
reduce the risk of
angina in patients with coronary artery disease, significantly improve the
survival of patients
with heart failure, significantly reduce the risk of sudden death in patients
after heart attacks,
and appear to delay or prevent the remodeling seen in the left ventricle after
heart attacks.
However, patients with severe asthma or otller lung disease simply cannot
safely take these
drugs.
[0025] ACE inhibitors block angiotensin converting enzyme, and thereby produce
numerous
salutary effects on the cardiovascular system. This class of drugs
significantly improves long-
term survival among survivors of acute myocardial infarction, and in addition
reduces the
incidence of heart failure (apparently by preventing or delaying remodeling),
recurrent heart
attacks, stroke, and sudden death.
[0026] While the use of drugs may be beneficial, following a myocardial
infarction the
undamaged area of the heart is still required to work harder and the tissue
damaged by the
infarction remains unhealed.
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[0027] What would be truly useful is to provide alternative methods of
treating heart failure and
post myocadial infarction conditions that will reduce or prevent adverse
remodeling and allow
damaged tissue to heal. Such alternative methods would be provided in lieu of,
or in concert
with, conventional pharmaceutical therapies and with new tissue-regeneration
therapies.
SUMMARY
[0028] An embodiment of the present invention provides a method for treating
the heart
following a myocardial infarction (MI). Electrical stimulation is provided to
selected portions
of the heart without regard to whether a diagnosis of arrhythmia has been
made. Stimulation
may be in the form of excitatory or non-excitatory pulses using cathodal,
anodal, and biphasic
waveforms. The portions of the heart selected for stimulation are determined
selected based on
the type of stimulation to be administered and the extent of the damage
sustained by the cardiac
tissue. In an exemplary embodiment, only health cardiac tissue is stimulated.
[0029] In an alternative exemplary embodiment of the present invention,
marginalized heart
tissue can also be stimulated so that the heart beats in a more balanced
fashion.
[0030] In an exemplary embodiment, biphasic, biventricular stimulation is
directed to
undamaged areas of the heart to enhance the muscular contraction of the
healthy tissue thereby
allowing the heart to achieve normal or near-normal functioning. The enhanced
muscular
contraction of the stimulated portion of the heart reduces uneven heart
loading and prevents or
reduces the adverse forms of remodeling of the heart following a myocardial
infarction. The
biphasic, biventricular stimulation of the exemplary embodiment of the present
invention
co>,nprises continuous application of both cathodal and anodal pulses
simultaneously to the right
and left ventricles through electrodes that contact undamaged portions of the
heart.
[0031 ] In an embodiment of the present invention, unlike pacing that is used
to control
arrhythmias, the non-excitatory biphasic stimulation is not applied to the
heart in response to
sensing a cardiac signal indicative of an arrhythmia. Rather, the non-
excitatory biphasic
stimulation is applied continuously to allow the heart to compensate for the
cardiac tissue
affected by a MI while avoiding undesirable forms of remodeling. Optionally,
the application of
the biphasic stimulation is timed to coincide with an initialization of a
depolarization wave as
determined by cardiac sensors.
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[0032] Additionally, the stimulation of the exemplary embodiment may be
combined with stem
cell implantation at sites where the cardiac tissue has been damaged. The stem
cell therapy
regenerates damaged cardiac tissue so that over time, the stimulation therapy
may be terminated.
[0033] In this exemplary embodiment of the present invention, the prevention
of adverse
remodeling stems from a nuinber of inechanisms. The effect of bi-ventricular
pacing provides
increased inotropic effect while at the same time reducing oxygen demand and
consumption by
the heart, and by reducing and equalizing the wall tension, in effect reducing
the tendency to
stretch damaged areas of the heart. Also, the stimulus for stem cell
implantation and proper
orientation depends on proper wall tension and electrical activity over the
damaged area. These
conditions are properly established by this treatment. Additionally, the
exposure of the damaged
cardiac tissue to an electrical current can directly heal damaged areas. This
is similar to the use
of currents of proper polarity to heal other tissues such as fractures of bone
and skin incisions.
[0034] As will be appreciated by those skilled in the art, the description of
exemplary
embodiments is not limiting. While biphasic, bi-ventricular stimulation is
described herein,
other waveforms and stimulation sites may be employed to reduce the workload
on the
undamaged cardiac tissue and to thereby allow the heart to reverse or avoid
the undesirable
remodeling. Additionally, therapies may utilize excitatory or non-excitatory
pulses. As
previously noted, tissue that is damage by the heart attack does not respond
or responds a slower
than normal rate to excitatory pulses. The healthy tissue places increased
stress on this
marginalized tissue, thereby "stretching" it. It is desirable to treat a heart
attack so as to
minimize the likelihood of continued detrimental remodeling. This can be
accomplished by
reducing the contraction strength of healthy cardiac tissues, by increasing
the contraction
strength of marginalize cardiac tissue, or by implementing a combination of
both therapies.
[0035] It is therefore an aspect of the present invention to promote the
healing of cardiac tissue
affected by a MI.
[0036] It is another aspect of the present invention to increase cardiac
output of cardiac tissue
not affected by a MI through more coordinated cardiac contraction leading to
greater stroke
volume with less cardiac worlc required.
[0037] It is yet another aspect of the present invention to stimulate
marginalized areas of cardiac
tissue so that they contract to some extent leading to more balanced operation
of the heart post-
MI.
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[0038] It is still another aspect of the present invention to apply a
combination of stimulation to
tissue that is damaged and to tissue that is undamaged by an MI to promote
balanced
functioning of cardiac tissue post-MI.
[0039] It is still another aspect of the present invention to reduce the
adverse forms of
remodeling of the heart following a MI.
[0040] It is yet another aspect of the present invention to continuously
stimulate selection
portions of the heart not affected by a MI using stimulation pulses.
[0041] It is a further aspect of the present invention to promote the healing
of cardiac tissue
affected by a MI using stem cells.
[0042] It is another aspect of the present invention to maintain wall tension
in the heart at
acceptable levels in patients suffering from heart disease.
[0043] It is a further aspect of the present invention to promote normalizing
of wall stresses
thereby promoting the implantation of stem cells in damages tissue.
[0044] These and other aspects of the present invention will be apparent from
the general and
detailed description that follows.
[0045] According to an embodiment of the present invention, an apparatus for
minimizing
cardiac remodeling of a non-arrhythmic patient comprises a heart stimulation
device, a left
ventricular electrode group, and a right ventricular electrode group. The left
ventricular
electrode group comprises LV electrodes attached to the left ventricle at
increasing distances
from the AV node. The right ventricular electrode group comprises RV
electrodes attached to
the left ventricle at increasing distances from the AV node. The heart
stimulation device is
adapted to stimulate healthy and compromised areas of cardiac tissue.
[0046] The heart stimulation device attaches to the LV and RV electrodes and
generates a timing
signal coincident with a refractory period. In response to the timing signal,
the heart stimulation
device sends pulses to the LV and RV electrodes sequenced such that an initial
pulse arrives at
an LV electrode and at an RV electrode nearest the AV junction and subsequent
pulses arrive at
an LR and at an RV electrode progressively further from the AV junction.
[0047] In an embodiment of the present invention, the pulse is excitatory. In
another
embodiment of the present invention, the pulse is non-excitatory. In yet
another embodiment of
the present invention, the pulse is biphaisic.
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[0048] According to an embodiment of the present invention, the biphasic pulse
comprises a first
stimulation phase having a first phase polarity, a first phase amplitude, a
first phase shape, and a
first phase duration, so as to precondition the myocardium to accept
subsequent stimulation. The
biphasic pulse further comprises a a second stimulation phase having a second
phase polarity, a
second phase amplitude that is larger in absolute value than the first phase
amplitude, a second
phase shape, and a second phase duration. In an embodiment of the present
invention, the first
phase polarity is positive, and the second phase polarity is negative. In yet
another embodiment
of the present invention, the first phase amplitude is at a maximum
subthreshold amplitude.
[0049] In an embodiment of the present invention, stem cells are deposited on
the cardiac tissue.
In one embodiment of the present invention, the LV and RV electrodes are
located so as to
electrically stimulate the compromised area of cardiac tissue on wliich stem
cells have been
deposited. In an alternate embodiment of the present invention, the LV and RV
electrodes are
located so as to preclude electrical stimulation of the compromised area of
cardiac tissue on
which stem cells have been deposited.
[0050] According to an embodiment of the present invention, an apparatus for
minimizing
cardiac remodeling of a non-arrhythmic patient comprises a heart stimulation
device, a left
ventricular electrode group, a right ventricular electrode group, and a
sensor. The sensor senses
excitation of a heart chamber.
[0051] The left ventricular electrode group comprises LV electrodes attached
to the left ventricle
at increasing distances from the AV node. The right ventricular electrode
group comprises RV
electrodes attached to the left ventricle at increasing distances from the AV
node. The heart
stimulation device is adapted to stimulate healthy and compromised areas of
cardiac tissue.
[0052] The heart stimulation device attaches to the LV and RV electrodes and
the sensor. In
response to a signal from the sensor, the heart stimulation device sends
pulses to the LV and RV
electrodes sequenced such that an initial pulse arrives at an LV electrode and
at an RV electrode
nearest the AV junction and subsequent pulses arrive at an LR and at an RV
electrode
progressively further from the AV junction.
[0053] In an embodiment of the present invention, the pulse is excitatory. In
another
embodiment of the present invention, the pulse is non-excitatory. In yet
another embodiment of
the present invention, the pulse is biphaisic.
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[0054] According to an embodiment of the present invention, the biphasic pulse
comprises a first
stimulation phase having a first phase polarity, a first phase amplitude, a
first phase shape, and a
first phase duration, so as to precondition the myocardium to accept
subsequent stimulation. The
biphasic pulse further comprises a second stimulation phase having a second
phase polarity, a
second phase amplitude that is larger in absolute value than the first phase
amplitude, a second
phase shape, and a second phase duration. In an embodiment of the present
invention, the first
phase polarity is positive, and the second phase polarity is negative. In yet
another embodiment
of the present invention, the first phase amplitude is at a maximum
subthreshold amplitude.
[0055] In an embodiment of the present invention, stem cells are deposited on
the cardiac tissue.
In one embodiment of the present invention, the LV and RV electrodes are
located so as to
electrically stimulate the compromised area of cardiac tissue on which stem
cells have been
deposited. In an alternate embodiment of the present invention, the LV and RV
electrodes are
located so as to preclude electrical stimulation of the compromised area of
cardiac tissue on
which stem cells have been deposited.
[0056] An embodiment of the present invention provides a method for minimizing
cardiac
remodeling of a non-arrhythmic patient. Stem cells are administered to a
myocardial infarct
(MI) area of a patient. Biphasic bi-ventricular stimulation is continuously
administered to
cardiac tissue outside of the MI area.
[0057] According to an embodiment of the present invention, the biphasic pulse
comprises a first
stimulation phase having a first phase polarity, a first phase amplitude, a
first phase shape, and a
first phase duration, so as to precondition the myocardiuin to accept
subsequent stimulation. The
biphasic pulse further comprises a a second stimulation phase having a second
phase polarity, a
second phase amplitude that is larger in absolute value than the first phase
amplitude, a second
phase shape, and a second phase duration. In an embodiment of the present
invention, the first
phase polarity is positive, and the second phase polarity is negative. In yet
another embodiment
of the present invention, the first phase amplitude is at a maximum
subthreshold amplitude.
[0058] In an embodiment of the present invention, stem cells are deposited on
the cardiac tissue.
In one embodiment of the present invention, the LV and RV electrodes are
located so as to
electrically stimulate the compromised area of cardiac tissue on which stem
cells have been
deposited. In an alternate embodiment of the present invention, the LV and RV
electrodes are
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located so as to preclude electrical stimulation of the compromised area of
cardiac tissue on
which stem cells have been deposited.
[0059] According to an embodiment of the present invention, an apparatus for
minimizing
cardiac remodeling of a non-arrhytlimic patient comprises a heart stimulation
device, a left
ventricular electrode group, a right ventricular electrode group, and a
sensor. The sensor senses
excitation of a heart chamber.
[0060] The left ventricular electrode group comprises LV electrodes attached
to the left ventricle
at increasing distances from the AV node. The right ventricular electrode
group comprises RV
electrodes attached to the left ventricle at increasing distances from the AV
node. The heart
stimulation device is adapted to stimulate healthy and compromised areas of
cardiac tissue. A
compromised area of the heart has stem cells deposited thereon.
[0061 ] The heart stimulation device attaches to the LV and RV electrodes and
the sensor. In
response to a signal from the sensor, the heart stimulation device sends
pulses to the LV and RV
electrodes sequenced such that an initial pulse arrives at an LV electrode and
at an RV electrode
nearest the AV junction and subsequent pulses arrive at an LR and at an RV
electrode
progressively further from the AV junction.
[0062] In an embodiment of the present invention, stem cells are deposited on
the cardiac tissue.
In one embodiment of the present invention, the LV and RV electrodes are
located so as to
electrically stimulate the compromised area of cardiac tissue on which stem
cells have been
deposited. In an alternate embodiment of the present invention, the LV and RV
electrodes are
located so as to preclude electrical stimulation of the compromised area of
cardiac tissue on
which stem cells have been deposited.
DESCRIPTION OF THE FIGURES
[0063] Figure 1 illustrates a heart with multiple ventricular electrodes that
are connected to
external surfaces of the ventricles, and include a separate electrode set each
for the right and left
ventricles according to embodiments of the present invention.
[0064] Figure 2 is a schematic representation of a leading anodal biphasic
stimulation according
to an embodiment of the present invention.
[0065] Figure 3 is a schematic representation of a leading anodal stimulation
of low level and
long duration, followed by cathodal stimulation according to an embodiment of
the present
invention.
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[0066] Figure 4 is a schematic representation of leading anodal stimulation of
ramped low level
and long duration, followed by cathodal stimulation according to an embodiment
of the present
invention.
[0067] Figure 5 is a schematic representation of leading anodal stimulation of
low level and
short duration administered in a series, followed by cathodal stimulation
according to an
embodiment of the present invention.
DETAILED DESCRIPTION
[0068] An embodiment of the present invention provides a method for treating
the heart
following a myocardial infarction (MI). Electrical stimulation is provided to
selected portions of
the heart without regard to whether a diagnosis of any arrhythmia has been
given. Stimulation
may be in the form of excitatory or non-excitatory pulses using cathodal,
anodal, and biphasic
waveforms. The portions of the heart selected for stimulation are selected
based on the type of
stimulation to be administered and the extent of the damage sustained by the
cardiac tissue. In
an exemplary embodiment, only healthy cardiac tissue is stimulated.
[0069] In an exeinplary embodiment of the present invention, biphasic,
biventricular stimulation
is directed to undamaged areas of the heart to enhance the muscular
contraction of the healthy
tissue thereby allowing the heart to achieve normal or near-normal
functioning. The enhanced
muscular contraction of the stimulated portion of the heart reduces heart
loading and prevents or
reduces the adverse forms of remodeling of the heart following a myocardial
infarction. The
biphasic, biventricular stimulation coinprises continuous application of both
cathodal and anodal
pulses simultaneously to the right and left ventricles through electrodes that
contact undamaged
portions of the heart.
[0070] In an embodiment of the present invention, unlike pacing that is used
to control
arrhythmias, the biphasic stimulation is not applied to the heart in response
to sensing a cardiac
signal indicative of an arrhythmia. Rather, the biphasic stimulation is
applied continuously to
allow the heart to compensate for the cardiac tissue affected by a MI while
avoiding undesirable
forms of remodeling. Optionally, the application of the biphasic stimulation
is timed to coincide
with the beginning of a depolarization wave as determined by cardiac sensors.
[0071] Additionally, the biphasic stimulation of the exemplary embodiment is
combined with
stem cell implantation at sites where the cardiac tissue has been damaged. The
stem cell therapy
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regenerates damaged cardiac tissue so that over time, the biphasic stimulation
therapy may be
terminated.
[0072] Referring to Figure 1, a diagram of the heart illustrates the four
chambers: right atrium
(RA), left atrium (LA), right ventricle (RV), and left ventricle (LV).
Electrode lead 201,
connected to RV electrode group 201A comprising individual electrodes 202,
204, 206, 208 and
210, is shown with the individual electrodes connected to multiple points on
the external
surfaces of the right ventricle. Electrode lead 301, connected to LV electrode
group 301A
comprising individual electrodes 302, 304, 306, 308 and 310, is shown with the
individual
electrodes connected to multiple points on the external surfaces of the left
ventricle. While RV
electrode group 201A and LV electrode group 301A are illustrated with five
electrodes per
group, this is not meant as a limitation. Other group sizes may be used
without departing from
the scope of the present invention.
[0073] In alternative embodiments, the locations of the individual electrodes
in Figure 1 (202,
204, 206, 208 and 210; and 302, 304, 306, 308 and 310) are selected to avoid
stimulation of
damage cardiac tissue as, for example, tissue damaged as a result of a MI.
[0074] In yet another embodiment of the present invention, pulses are applied
to the electrodes
so as to mimic the normal physiological flow of the normal ventricular
depolarization wave. In
this embodiment, the areas closest to (or at) the A-V node are first
stimulated during a given
beat. In an einbodiment of the present invention, atrial excitation is sensed
(P-Q interval) or
ventricular excitation is sensed (QRS interval) and an external excitatory
pulse is applied to the
first electrode (after an appropriate delay) to coincide with the beginning of
the ventricular
depolarization wave. Subsequent excitatory pulses are directed to areas
progressively further
from the A-V node. Areas intermediate between these two extremes are
appropriately
stimulated on a scaled time basis that, again, mimics the normal intrinsic
conduction paths that
facilitate the most efficient cardiac contraction. In an embodiment of the
present invention, the
pulses are applied to healthy cardiac tissue that is unaffected the MI,
thereby allowing the
damaged tissue to heal and the stimulation voltage to be low.
[0075] This progressive stimulation embodiment requires specific knowledge of
the placement
of each electrode relative to each other electrode, as well as the placement
relative to the
electrical conduction pathways in the heart. Thus, it is appropriate to
contemplate "classes" of
electrodes, in which, for example, electrodes are identified or categorized
according to when
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they are fired. In a simplistic five tier system, e.g., the first tier
electrodes are designated as the
first to be fired (i.e., the electrodes closest to the A-V node), followed
successively (and
temporally progressively according to the normal conducting paths) by the
second, third, fourth,
and fifth tier electrodes, where the fifth tier electrodes would be the last
to be fired, and whose
locations on the ventricle(s) would correspond to the last areas to be
depolarized in the course of
a nonnal ventricular contraction/beat. An even simpler (i.e., two, three or
four) tiered system
may be used, or one more complex (i.e., one with greater than 5 tiers, or with
any other basis of
electrode placement, such as a honeycomb-like array in a particular area with
a known or
suspected pathology as to rhythmicity, reentry, conduction, contractility,
etc. Furthermore,
multiple electrodes within a given tier may be numbered or otherwise
distinctly identified so
that the practitioner may test and use electrodes with respect to known
locations in the heart, for
example, to anticipate and/or bypass an area of electrical blockage. In this
embodiment,
multiple, small electrodes are pulsed with excitatory pulses in a physiologic
sequential fashion.
[0076] In still another embodiment of the present invention, the technique
described above for
stimulating the ventricles is applied to the atria. In this embodiment,
electrodes are
progressively placed from close to the SA node (first to be fired) to close to
the AV node (last to
be fired), mimicking the normal intrinsic conduction paths of the atria.
[0077] Bypassing an area of damaged tissue is also anticipated by the present
invention, and can
be effected by first identifying such areas, for example, by detennining
myocardial resistance
values between electrodes. Electrical pulses then are routed to those
myocardial areas with
appropriately low resistances, following as closely as possible the lines of
conduction of the
normal intrinsic conduction paths. Communication of, and control of,
measurements of
resistance between electrodes, as well as developing a bypass protocol for a
particular patient,
can be effected by an external computer. The external computer can communicate
with the
pacemaker by any convenient method, for exainple, radiotelemetry, direct
coupling (as by
connecting to an external wire from the pacemaker to the surface of the skin
of the patient), etc.
[0078] Figures 2 through 5 depict a range of biphasic stimulation protocols.
These protocols
have been disclosed in United States Patent 5,871,506 to Mower, which is
herein incorporated
by reference in its entirety.
[0079] Figure 2 depicts biphasic electrical stimulation in which a first
stimulation phase
comprising anodal stimulus 202 is administered with amplitude 204 and duration
206. The first
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stimulation phase is followed immediately by a second stimulation phase
comprising cathodal
stimulus 208, which is of equal intensity and duration to those of anodal
stimulus 202.
[0080] Figure 3 depicts biphasic electrical stimulation wherein a first
stimulation phase
comprising low level, long duration anodal stimulation 302 having amplitude
304 and duration
306 is administered. This first stimulation phase is immediately followed by a
second
stimulation phase comprising cathodal stimulation 308 of conventional
intensity and duration.
In an alternative embodiment of the invention, anodal stimulation 302 is at
maximum
subthreshold amplitude. In yet another alternative embodiment of the
invention, anodal
stimulation 302 is less than three volts. In another alternative embodiment of
the invention,
anodal stimulation 302 is a duration of approximately two to eight
milliseconds. In yet another
alternative embodiment of the invention, cathodal stimulation 308 is of a
short duration. In
another alternative embodiment of the invention, cathodal stimulation 308 is
approximately 0.3
to 1.5 milliseconds. In yet another alternative embodiment of the invention,
cathodal
stimulation 308 is of a high amplitude. In another alternative embodiment of
the invention,
cathodal stimulation 308 is in the approximate range of three to twenty volts.
In yet another
alternative embodiment of the present invention, cathodal stimulation 308 is
of a duration less
than 0.3 milliseconds and at a voltage greater than twenty volts. In another
alternative
embodiment, anodal stimulation 302 is administered over 200 milliseconds post
heart beat. In
the manner disclosed by these embodiments, as well as those alterations and
modifications
which may become obvious upon the reading of this specification, a maximum
membrane
potential without activation is achieved in the first phase of stimulation.
[0081] Figure 4 depicts biphasic electrical stimulation wherein a first
stimulation phase
comprising anodal stimulation 402 is administered over period 404 with rising
intensity level
406. The ramp of rising intensity leve1406 may be linear or non-linear, and
the slope may vary.
This anodal stimulation is immediately followed by a second stimulation phase
comprising
cathodal stimulation 408 of conventional intensity and duration. In an
alternative embodiment
of the invention, anodal stimulation 402 rises to a maximum subthreshold
amplitude. In yet
another alternative embodiment of the invention, anodal stimulation 402 rises
to a maximum
amplitude that is less than three volts. In another alternative embodiment of
the invention,
anodal stimulation 402 is a duration of approximately two to eight
milliseconds. In yet another
alternative embodiment of the invention, cathodal stimulation 408 is of a
short duration. In
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another alternative embodiment of the invention, cathodal stimulation 408 is
approximately 0.3
to 1.5 milliseconds. In yet another alternative embodiment of the invention,
cathodal
stimulation 408 is of a high amplitude. In another alternative embodiment of
the invention,
cathodal stimulation 408 is in the approximate range of three to twenty volts.
In yet another
alternative embodiment of the present invention, cathodal stimulation 408 is
of a duration less
than 0.3 milliseconds and at a voltage greater than twenty volts. In another
alternative
embodiment, anodal stimulation 402 is administered over 200 milliseconds post
heart beat. In
the manner disclosed by these embodiments as well as those alterations and
modifications which
may become obvious upon the reading of this specification, a maximum membrane
potential
without activation is achieved in the first phase of stimulation.
[0082] Figure 5 depicts biphasic electrical stimulation wherein a first
stimulation phase
comprising series 502 of anodal pulses is administered at amplitude 504. In
one embodiment
rest period 506 is of equal duration to stimulation period 508 and is
administered at baseline
amplitude. In an alternative embodiment, rest period 506 is of a differing
duration than
stimulation period 508 and is administered at baseline amplitude. Rest period
506 occurs after
each stimulation period 508 with the exception that a second stimulation phase
comprising
cathodal stimulation 510 of conventional intensity and duration immediately
follows the
completion of series 502. In an alteniative embodiment of the invention, the
total charge
transferred through series 502 of anodal stimulation is at the maximum
subthreshold level. In
yet another alternative embodiment of the invention, the first stimulation
pulse of series 502 is
administered over 200 milliseconds post heart beat. In another alternative
embodiment of the
invention, cathodal stimulation 510 is of a short duration. In yet another
alternative embodiment
of the invention, cathodal stimulation 510 is approximately 0.3 to 1.5
milliseconds. In another
alternative embodiment of the invention, cathodal stimulation 510 is of a high
amplitude. In yet
another alternative embodiment of the invention, cathodal stimulation 510 is
in the approximate
range of three to twenty volts. In another alternative embodiment of the
invention, cathodal
stimulation 510 is of a duration less than 0.3 milliseconds and at a voltage
greater than twenty
volts. The individual pulses of the series of pulses may be square waves, or
they may be of any
other shape, for example, pulses which decay linearly or curvilinearly from an
initial
subthreshold amplitude, to a lower amplitude.
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[0083] In the biphasic stimulation protocol practiced by the present
invention, the magnitude of
the anodal phase does not exceed the maximum subthreshold amplitude. The
anodal phase
serves to precondition the stimulated myocardium, thereby lowering the
excitation threshold
such that a cathodal stimulation of lesser intensity than normal will produce
depolarization
leading to contraction.
[0084] The pacing and subsequent normalizing of wall stresses promotes the
implantation of
stem cells in damages tissue, and guides their proper orientation during the
maturation of the
cells.
[0085] The values of duration and amplitude will depend on factors such as the
placement/position of the particular electrode (including, e.g., whether the
electrode is in purely
muscle tissue versus in specialized conducting or pacemaking tissue), whether
damaged/scarred
tissue is in close vicinity to the electrode, depth of the electrode within
the tissue, local tissue
resistance, presence or absence of any of a large range of local pathologies,
etc. Nonetheless,
typical anodal phase durations often fall within the range from about two
milliseconds to about
eight milliseconds, whereas typical cathodal durations often fall within the
range from about 0.3
millisecond to about 1.5 millisecond. Typical anodal phase amplitudes (most
commonly at the
maximum subthreshold amplitude) often fall within the range from about 0.5
volt to 3.5 volts,
compared to typical cathodal phase amplitudes from about 3 volts to about 20
volts.
[0086] Because the heart is constantly stimulated, the pacing pulses are
applied without the need
for demand sensing. Further, constant consistent pacing diminishes stress on
the heart.
[0087] In another embodiment of the present invention, the damaged tissue is
located and treated
by inserting or applying donor or "stem" cells. Means for inserting and means
for applying stem
cells to damaged cardiac tissue are described in United States Patent
Application No.
60/429,954, entitled "Method and Apparatus for Cell and Electrical Therapy of
Living Tissue",
a utility application for which was filed on November 25, 2003, both of which
applications are
incorporated herein in their entirety for all purposes. In an embodiment of
the present invention,
the damaged tissue is treated and biventricular pacing pulsing is continuously
applied to
functioning portions of the heart. In one embodiment, the pacing sites are
chosen to assure that
the tissue treated with stem cells is not electrically stimulated. In an
alternate embodiment, the
pacing sites are chosen so that the tissue treated with stem cells receives
electrical stimulation
pulses having an amplitude below that required to excite the heart tissue.
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[0088] A system and method for managing detrimental cardiac remodeling
following myocardial
infarction have been disclosed. It will also be understood that the invention
may be embodied in
other specific forms without departing from the scope of the invention
disclosed and that the
examples and embodiments described herein are in all respects illustrative and
not restrictive.
Those skilled in the art of the present invention will recognize that other
embodiments using the
concepts described herein are also possible. Further, any reference to claim
elements in the
singular, for example, using the articles "a," "an," or "the" is not to be
construed as limiting the
element to the singular.
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