U.S. patent application number 10/304025 was filed with the patent office on 2003-06-19 for method and apparatus for demand injury in stimulating angiogenesis.
This patent application is currently assigned to Scimed Life Systems, Inc.. Invention is credited to Chee, U. Hiram, Mueller, Richard L..
Application Number | 20030114872 10/304025 |
Document ID | / |
Family ID | 22591212 |
Filed Date | 2003-06-19 |
United States Patent
Application |
20030114872 |
Kind Code |
A1 |
Mueller, Richard L. ; et
al. |
June 19, 2003 |
Method and apparatus for demand injury in stimulating
angiogenesis
Abstract
Various methods and devices for treating a patient who has lost,
or is at risk of losing cardiac function by cardiac ischemia are
disclosed. Treatment includes first imaging a patient's heart, or a
portion thereof, to identify underperfused regions of cardiac
muscle, and a source of oxygenated blood that is proximate to the
underperfused region. Between the underperfused regions and the
oxygenated blood source, a target area is selected where thermal or
mechanical injury is introduced, and optionally reintroduced, to
convert initial capillary blush, resulting from the injury,
Inventors: |
Mueller, Richard L.; (Byron,
CA) ; Chee, U. Hiram; (Santa Cruz, CA) |
Correspondence
Address: |
PENNIE AND EDMONDS
1155 AVENUE OF THE AMERICAS
NEW YORK
NY
100362711
|
Assignee: |
Scimed Life Systems, Inc.
|
Family ID: |
22591212 |
Appl. No.: |
10/304025 |
Filed: |
November 25, 2002 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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10304025 |
Nov 25, 2002 |
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09706016 |
Nov 3, 2000 |
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6524324 |
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60163704 |
Nov 5, 1999 |
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Current U.S.
Class: |
606/167 |
Current CPC
Class: |
A61B 17/3207 20130101;
A61B 2090/374 20160201; A61B 17/320783 20130101; A61B 17/3478
20130101; A61B 2018/00392 20130101; A61B 17/3203 20130101; A61B
2017/00247 20130101; A61B 90/37 20160201; A61B 2017/22077
20130101 |
Class at
Publication: |
606/167 |
International
Class: |
A61B 017/32 |
Claims
It is claimed:
1. A method of treating a patient at risk of loss of cardiac
function by cardiac ischemia, comprising (a) imaging the patient's
heart, or a portion thereof, to identify (i) an underperfused
region of cardiac muscle, (ii) a source of oxygenated blood that is
proximate a boundary of the underperfused region, and (ii) a target
area that includes said underperfused region boundary and a tissue
expanse lying between said oxygenated blood supply and said
boundary; and (b) at each of a plurality of sites throughout the
target area, applying a tool effective to produce an annulus of
injury about a core of healthy cells in the myocardial layer of the
heart.
2. The method of claim 1, wherein the diameter of core of healthy
tissue in the myocardial layer has a dimension of between about 1-4
mm.
3. The method of claim 1, wherein step (b) is carried out with a
cutting tool that has a distal tissue-piercing end, and an annular
cutting edge, by cutting through the epicardial or endocardial
region of heart, to a depth of 1-4 mm into the underlying
myocardium.
4. The method of claim 1, wherein step (b) is carried out with a
cutting tool that has a distal tissue-piercing end, and a plurality
of retractable cutting elements arrayed about said end, where the
cutting elements can be retracted for insertion of the cutting tool
into said target site, and deployed once in the target site.
5. The method of claim 1, wherein step (b) is carried out with a
macerating tool that has (i) a distal tissue-piercing conical end
piece defining a plurality of fluid-dispensing openings, and (ii) a
fluid-injection conduit communicating with the end piece, wherein
fluid supplied to the conduit under pressure, when the tool is
positioned in the myocardium of the heart, is effective to produce
tissue maceration in the vicinity of the end-piece openings.
6. A tool for use in stimulating angiogenesis in a patient's heart,
comprising a tapered tissue-piercing portion adapted to pierce a
selected target site in the heart, injury producing elements that
are disposed or can be deployed in a 1-4 mm inner-diameter annulus
about the tissue piercing portion, and a handle operatively
connected to the tissue-piercing portion and injury-producing
elements, for use in (i) placing the tissue-piercing portion at a
selected target site outside the heart (ii) inserting said portion
into the site, to a depth which disposes the injury-producing
elements within the upper 1-3 mm of the myocardium, and (iii)
manipulating the tool to effect an annulus of tissue injury within
the myocardium.
7. The tool of claim 6, wherein the injury-producing elements
include a serrated annulus disposed about the tissue-piercing
portion.
8. The tool of claim 6, wherein the injury-producing elements
include a plurality of blades that are retractable into said
handle, during initial piercing at the target site, and extendable
within the site.
9. The tool of claim 6, wherein the tissue-piercing portion is a
conical end piece and said injury-producing elements include (i) a
plurality of fluid-dispensing openings formed in said end piece,
and a fluid-conduit mounted on said handle and communicating with
said openings, wherein fluid introduced under pressure through said
conduit is effective to macerate myocardial tissue when the tool is
placed at a target site.
Description
[0001] This application claims priority of U.S. Provisional Patent
Application Serial No. 60/163,704 filed on Nov. 5, 1999, herein
incorporated in its entirety by reference.
FIELD OF THE INVENTION
[0002] The present invention relates to methods and devices for
treating a patient at risk of loss of cardiac function by cardiac
ischemia.
REFERENCES
[0003] The following references are cited in this application,
either as references pertinent to the Background of the Invention,
or to methods or materials described in the Detailed Description of
the Invention.
BACKGROUND OF THE INVENTION
[0004] Heart disorders are a common cause of death in developed
countries. They also impair the quality of life of millions of
people and restrict activity by causing pain, breathlessness,
fatigue, fainting spells and anxiety. The major cause of heart
disease in developed countries is impaired or inadequate blood
supply. The coronary arteries may become narrowed due to
arteriosclerosis and part of the heart muscle is deprived of oxygen
and other nutrients. The resulting ischemia or blockage can lead to
angina pectoris, a pain in the chest, arms or jaw due to lack of
oxygen to the heart's myocardium, infarction or tissue necrosis in
myocardial tissue. Alternatively, and particularly with age, the
extent of vascularization of the heart may diminish, leaving the
heart undersupplied with oxygen even in the absence of significant
arteriosclerosis.
[0005] Coronary-artery blockage can be relieved in a number of
ways. Drug therapy, including nitrates, beta-blockers, and
peripheral vasodilator drugs (to dilate the arteries) or
thrombolytic drugs (to dissolve clots) can be very effective. If
drug treatment fails, transluminal angioplasty is often
indicated--the narrowed part of the artery, clogged with
atherosclerotic plaque or other deposits, can be stretched apart by
passing a balloon to the site and gently inflating it a certain
degree. In the event drug therapy is ineffective or angioplasty is
too risky (introduction of a balloon in an occluded artery can
cause portions of the arteriosclerotic material to become dislodged
which may cause a total blockage at a point downstream of the
subject occlusion, thereby requiring emergency procedures), the
procedure known as coronary artery bypass grafting (CABG) is the
most common and successful major heart operation performed, with
over 500,000 procedures done annually in America alone. A length of
vein is removed from another part of the body. The section of vein
is first sewn to the aorta and then sewn onto a coronary artery at
a place such that oxygenated blood can flow directly into the
heart. CABG typically is performed in an open chest surgical
procedure, although recent advances suggest minimally invasive
surgery (MIS) techniques may also be used.
[0006] Another method of improving myocardial blood supply is
called transmyocardial revascularization (TMR), the creation of
channels from the epicardial to the endocardial portions of the
heart. Initially, the procedure used needles to perform "myocardial
acupuncture," and has been experimented with at least as early as
the 1930s and used clinically since the 1960s, see Deckelbaum. L.
I., Cardiovascular Applications of Laser Technology, Lasers in
Surgery and Medicine 15:315-341 (1994). This procedure has been
likened to transforming the human heart into one resembling that of
a reptile. In the reptile heart, perfusion occurs via communicating
channels between the left ventricle and the coronary arteries.
Frazier, O. H., Myocardial Revascularization with
Laser--Preliminary Findings, Circulation, 1995; 92 [suppl
II:II-58-11-65]. There is evidence of these communicating channels
in the developing human embryo. In the human heart, myocardial
microanatomy involves the presence of myocardial sinusoids. These
sinusoidal communications vary in size and structure, but represent
a network of direct arterial-luminal, arterial-arterial,
arterial-venous, and venous-luminal connections. The needle
technique was not continued because the channels did not remain
open, replaced by the use of laser energy to accomplish TMR.
[0007] Drug therapies with angiogenic growth factors may expedite
and/or augment collateral artery development. To accomplish these
needs, drug transfer devices for delivering precise amounts of
these drugs can enhance this healing process. Surgeons who deal
with minimally invasive surgical techniques, and interventional
cardiologists who deal with percutaneous approaches, need devices
for drug delivery procedures. The drugs used in modern medical
technology are often quite expensive, potentially mixing and/or
handling sensitive, and it is a new challenge to make these drugs
or other compounds readily available for precise, predetermined
delivery during these advanced or other procedures.
SUMMARY OF THE INVENTION
[0008] The invention includes, in one aspect, a method of treating
a patient at risk of loss of cardiac function by cardiac ischemia.
The method is practiced by first imaging the patient's heart, or a
portion thereof, to identify (i) an underperfused region of cardiac
muscle, (ii) a source of oxygenated blood that is proximate a
boundary of the underperfused region, and (iii) a target area that
includes the underperfused region boundary and a tissue expanse
lying between the oxygenated blood supply and the boundary.
Applying a tool at each of a plurality of sites throughout the
target area to produce an annulus of injury about a core of healthy
cells in the myocardial layer of the heart.
[0009] The underperfused region is an at risk region of cardiac
muscle which is insufficiently perfused to handle heightened
activity or is likely to be near term at risk of underperfusion due
to the progression of nearby disease and cannot be treated by the
full restoration of normal coronary flow.
[0010] Usually, patients will enter this treatment regiment by
appearing for intermittent angina (intermittent identifies that
demand for arterial growth and arterial maturation is not reliably
turned on) through drug or exercise stress testing where cardiac
reserve appears less than optimal or when a routine treatment such
as bypass, angioplasty or stents is unable to restore normalized
blood flow, and in the judgment of the cardiologist or surgeon is
at risk due to lack of reserve capacity. The imaging step to
identify the area at risk and nearby source of oxygenated blood
(target) may be carried out by monitoring blood flow in the heart
by myocardial perfusion imaging by single-photon emission computed
tomography (SPECT), positron-emission tomography (PET), echo-planar
imaging, MRI, or angiogram.
[0011] The source of oxygenated blood in the method may be one in
which arteries less than about 1 mm branch into surrounding
arterioles, and in which the arterioles with inner-lumen diameters
between about 50-200 microns are plentiful, and the sites are
spaced from one another at spacing of between 0.5 to 1 cm.
Alternatively, or in addition, the underperfused region may be a
myocardial region of either of the patient's ventricles, and the
source of oxygenated blood, the interior of the underperfused heart
ventricle region. Here the target area includes the region of
ventricle endocardium underlying the underperfused region.
[0012] A stimulus may also be introduced at each of the target-area
sites in the form of a growth factor, such as basic or acidic
fibroblast growth factor-1 (FGF-2, FGF-1), vascular endothelial
growth factor (VEGF), platelet-derived growth factor (PDGF),
insulin-like growth factor-1 (IGF-1), or combinations of two or
more of these growth factors. The growth factor may be introduced
in the form of a recombinant protein carried in a pharmaceutically
acceptable medium, a vector containing the coding sequence for the
growth factor and a control region effective to promote
transcription of the coding region in patient myocardial cells,
and/or in the form of a myocardial or cardiac myoblast cells which
have been transformed with a gene encoding the growth factor. The
manner of introducing the growth factor may be by (i) injecting the
protein, vector of cells directly into myocardial tissue at each
site, (ii) drawing the protein or vector into myocardial tissue at
each site by iontophoresis from a reservoir placed against the
site, (iii) forming a channel in the myocardium at each site, and
placing the protein, vector or cells into the channel, or (iv)
bombarding each site with a biolistic particle containing or coated
with the protein, vector or cells. For example, an angiogenic
stimulus would be used without adjunctive biological triggering
when the target area is predetermined at the patient evaluation and
diagnosis stage to have sufficient pre-existing tissue demand for
oxygen in the form of significant angina (Canadian Heart Class 4)
or when the physician has predetermined that the patient can
exercise post treatment to provide dependable tissue demand for
arteriole growth beyond the pre-existing patient reserve
capacity.
[0013] In another aspect, the invention involves a tool for use in
stimulating angiogenesis in a patient's heart. The tool comprises a
tapered tissue-piercing portion adapted to pierce a selected target
site in the heart, and injury producing elements that are disposed
or can be deployed in a 1-4 mm inner-diameter annulus about the
tissue piercing portion. A handle is operatively connected to the
tissue-piercing portion and injury-producing elements, for use in
(i) placing the tissue-piercing portion at a selected target site
outside the heart (ii) inserting the portion into the site, to a
depth which disposes the injury-producing elements within the upper
1-3 mm of the myocardium, and (iii) manipulating the tool to effect
an annulus of tissue injury within the myocardium.
[0014] These and other and features of the invention will become
more fully apparent when the following detailed description of the
invention is read in conjunction with the accompanying
drawings.
DESCRIPTION OF THE DRAWINGS
[0015] FIG. 1 is a simplified view of a human heart;
[0016] FIGS. 2A and 2B show cross-sectional (2A) and plan (2B)
views of a ventricle wall a human heart, in an underperfused region
of the wall, and corresponding generally to the region of line 2-2
in FIG. 1;
[0017] FIGS. 3A and 3B illustrate the development of capillary
blush in an underperfused region of a heart ventricle wall (3A) and
subsequent development of arterioles with sustained demand (3B),
where the source of blood supply is a coronary arterial supply;
FIGS. 4A and 4B illustrate the distribution of growth-factor
stimulus introduced in a target area of an underperfused region of
a heart for achieving substantially uniform distribution of a
growth factor (4A), and for achieving a higher short-term growth
factor effect close to the blood supply, and a longer-term
growth-factor effect close to the underperfused region;
[0018] FIGS. 5A-5D illustrate various methods of producing an
injury stimulus to a target-area of adjacent an underperfused heart
region, including a mechanical "coring" injury (5A), a mechanical
wire injury (5B), a laser-induced channel injury (5C), and a
combination of a mechanical wire injury and growth factor
stimuli;
[0019] FIGS. 6A and 6B illustrate the development of capillary
blush in an underperfused region of a heart ventricle wall (6A) and
subsequent development of arterioles that occurs with sustained
demand (6B); where the source of blood supply is the interior
chamber of the heart left ventricle;
[0020] FIGS. 7A and 7B illustrate coring tools constructed in
accordance with embodiments of the invention;
[0021] FIGS. 8A-8C illustrate various states of a
coring/drug-delivery tool constructed in accordance with another
embodiment of the invention;
[0022] FIGS. 9A and 9B illustrate different types of
myocardial-slice injuries producible by the coring/drug-delivery
tool of FIGS. 8A-8C;
[0023] FIG. 10 illustrates how a wire tool is introduced into a
target-area site in the heart, in accordance with one embodiment of
the invention;
[0024] FIG. 11 shows how the wire tool can be controlled from an
external chest site;
[0025] FIG. 12 illustrates the mechanics of vascularization that is
produced by a sustained-injury from the FIG. 10 tool;
[0026] FIG. 13 shows details of a portion of the wire tool in FIG.
10;
[0027] FIG. 14 is a perspective view of a cutting tool constructed
according to one embodiment of the invention;
[0028] FIG. 15 illustrates the placement of the tool of FIG. 14 in
producing a channel injury to a ventricle endocardial wall
surface;
[0029] FIG. 16 shows an exercise monitoring device for use in
monitoring and tracking heart-rate exercise, in creating a
sustained demand to an underperfused region of the heart; and
[0030] FIG. 17 illustrates the operation of the exercise-monitoring
tool in FIG. 16.
DETAILED DESCRIPTION OF THE INVENTION
[0031] I. Treatment Method
[0032] FIG. 1 is a simplified view of a human heart 20. The
interior of the heart is divided into right and left halves by a
thick central muscular wall 22 known as a septum. On the right
side, the upper chamber is known as the right atrium, indicated at
24. Deoxygenated blood from the rest of the body arrives in the
right atrium via the vena cava, and is pumped across a one-way
valve 28 known as the tricuspid valve into the lower right chamber
known as the right ventricle, indicated at 30. From there the blood
circulates to the lungs through the pulmonary valve via the
pulmonary artery where it is oxygenated by circulation through the
alveoli of the lungs (not shown). The blood returns via the
pulmonary veins to the left atrium, shown at 34 and flows through a
second valve, known as the mitral valve, into the left ventricle,
indicated at 38, where it is pumped via the aorta 32 to the rest of
the body.
[0033] With reference to FIGS. 2A and 2B, which show a wall portion
40 of the heart left ventricle corresponding to view line 2-2 in
FIG. 1, much of the heart consists of a special type of muscle
called myocardium, indicated at 42. The myocardium requires a
constant supply of oxygen and nutrients to allow it to contract and
pump blood throughout the vasculature. The inner surfaces of the
chambers of the heart are lined with a smooth membrane 44, the
endocardium, and the entire heart is enclosed in a tough,
membranous bag 46, known as the pericardium or pericardial sac.
[0034] Though the heart supplies blood to all other parts of the
body, the heart itself has relatively little communication with the
oxygenated blood supply. Thus, the two coronary arteries, the left
coronary artery and the right coronary artery, arise from the aorta
and encircle the heart muscle on either side "like a crown" to
supply the heart itself with blood. Coronary arteries are shown at
48 in FIGS. 2A and 2B, and the arterioles branching from these
arteries, at 50. The arteries and arterioles are largely confined
to the epicardium 45 and adjacent regions of the myocardium. The
arterioles, in turn, feed a capillary bed within the three
heart-wall layers. A venous capillary system in the same layers
returns blood from the coronary arteries to the coronary veins, the
coronary sinus, and the right atrium.
[0035] A. Supply-and-Demand Model
[0036] The present invention provides methods and devices for
treating a patient at risk of loss of cardiac function by cardiac
ischemia. The methods are designed to increase blood flow or
circulation from a source of oxygenated blood in the heart to a
region that is underperfused--that is, a region that is receiving
less oxygenated blood than that optimally required by the heart
under a moderate load or stress. As a consequence of this
underperfusion, or ischemia, the patient is at risk of, or has
already suffered some loss of, cardiac muscle used in normal heart
functioning. If the patient at risk has already suffered some loss
of heart muscle, the region of lost muscle is referred to as a
nonviable muscle, indicative of a cardiac infarction.
[0037] In practicing the treatment method, one first images the
patient's heart, to identify (i) an underperfused region of cardiac
muscle, (ii) a source of oxygenated blood that is proximate a
boundary of the underperfused region, and (iii) a target area that
includes the underperfused-region boundary and a tissue expanse
lying between the oxygenated blood supply and said boundary. The
imaging may also be used to identify (iv) the degree or magnitude
of high grade tissue demand for oxygenated blood that is naturally
occurring in the underperfused region and based on this assessment
if a biological trigger will be added.
[0038] The imaging step is illustrated in FIGS. 2A and 2B,
illustrating a portion of a heart ventricle wall 40 as described
above. The figures show an underperfused region 54 in the
myocardium of a ventricle wall. The underperfused region contains
at least some viable, but hibernating muscle (i) whose functioning
can be improved by increased blood supply to the region, and/or
(ii) which is at high risk of suffering future injury due to the
advanced state and expected progression of disease (iii) which in
the physician's judgment is not ideal for an expected safe full
normal blood flow restoration procedure such as balloon
angioplasty. It is possible that some portions of the underperfused
region will contain non-viable cells for which improved blood
supply will not affect the cell status. The underperfused region is
preferably identified in lateral surface dimensions, and to the
extent possible, in sectional dimension, to produce a lateral or
volumetric image of the underperfused regions.
[0039] The source of oxygenated blood will typically be the
arterial supply of blood localized in the pericardial, epicardial
and outer myocardial layers of the heart, adjacent the
underperfused region. Ideally, the source will be one in which an
area of dense arteries less than about 1 mm branch into surrounding
arterioles, and in which the arterioles with inner-lumen diameters
between about 50-200 microns are plentiful. FIGS. 2A and 2B
illustrate an artery 48 branching into arterioles 50 that form a
suitable source of oxygenated blood.
[0040] In another embodiment of the invention, discussed below, the
source of oxygenated blood is the interior of a ventricle chamber,
where the method is practiced in a manner to promote blood supply
between the interior of the chamber, across the endocardium, to the
myocardial layer.
[0041] The oxygenated blood supply that is identified is proximate
to a boundary or boundary portion 56 (FIG. 2A) of the underperfused
region. This boundary represents the initial portion of the
underperfused region which will receive increased blood supply as a
vascular network from the blood supply to the underperfused region
is formed. In the drawing, the boundary represents the 20-40% of
the total underperfused region that is closest to the identified
supply of oxygenated blood. Although more of the region may be
included in the boundary, there may be little gain in increased
vascularization of the underperfused region, until the boundary
region itself can be initially vascularized, assuring sufficient
blood cells in reserve for later new growth distribution. Thus, the
method may involve an initial treatment to vascularize the boundary
of the underperfused region, and subsequently using the new
vascular supply as the source of oxygenated blood for extending the
vascular network deeper into the underperfused region, that is,
into the region below the initial boundary portion shown in FIG.
2A.
[0042] The area between the identified source of oxygenated blood
and the underperfused region, including the boundary portion of the
underperfused region, and the tissue expanse 58 between the
underperfused region and the source of oxygenated blood, is
identified from the imaging step as a target area 60 (typically a
volumetric region) at which the stimulus for angiogenesis is to be
introduced, as will be described. Within this target area, the user
will identify a plurality of sites, such as indicated at 62, at
which a stimulus will be applied. The sites in the target area have
a preferred site-to-site spacing of between about 0.5 to 1 cm.
[0043] A variety of tools are available for imaging the heart, and
localizing regions of subnormal blood circulation. One such tool
involves monitoring blood flow in the heart by myocardial perfusion
imaging (MPI) by single-photon emission computed tomography (SPECT)
positron-emission tomography (PET), echo-planar imaging or
angiography. These techniques are described in the literature
(e.g., Amanullah, Mannting, Golub, Hansen, Toma, Dietlein, Sand,
Marwick, Yang, Inuoe, and Nishimura).
[0044] Alternatively, or in addition, the patient's heart can be
imaged by magnetic resonance imaging (MRI), including myocardial
perfusion imaging by dynamic contrast MRI. Pertinent methods have
been detailed in the literature (e.g., Furber, Lauerma, and
Sechtem). Thallium scintigraphy is yet another imaging method
technique available (e.g., Machecourt).
[0045] In addition an assessment is made to determine the
pre-existing level of tissue demand for oxygenated blood. The heart
has naturally occurring angiogenesis when disease progression
occurs slowly so the high stress/exercise demand periods requiring
blood flow do not exceed the compromised supply. By way of example
a Class 4 Angina (measure of chest pain and class 4 is usually
indicative of near constant pain) would be a good indicator of high
level demand for new capillary growth. When high grade angina is
not present patients will typically receive an exercise or chemical
stress test where cardiac reserve can be quantified. Physicians may
also use their own predictive skills when finding a high grade,
non-symptomatic untreatable distal coronary artery blockage. When
high grade demand is not present it can be added by using a
biologic trigger as described herein. When general health permits
demand can be increased with exercise.
[0046] Once the target-area and sites within this area have been
identified, a stimulus effective to stimulate angiogenesis in the
myocardial tissue from the source of the oxygenated blood to the
underperfused region is introduced at each of the target sites. As
will be discussed in detail below, the stimulus may be an
angiogenic growth factor that is introduced either as a
growth-factor protein, a vector capable of transfecting myocardial
cells, to produce the desired protein growth factor, or cells which
have been transfected in vitro to contain the desired to growth
factor. Alternatively, the stimulus may be a biological trigger,
such as a tissue injury produced by a mechanical, laser,
electrical, radio frequency, chemical, thermal, or ultrasonic
injury. The stimuli introduced may be in the form of a combination
of growth factor and injury.
[0047] FIGS. 3A and 3B illustrate the supply/demand model of
vascularization on 15 which the present method is based. The model
has four components: (i) a supply or source of oxygenated blood;
(ii) a localized underperfused region which represents a demand for
increased oxygenation, (iii) localized stimuli applied to a target
area between the source of blood and underperfused region, to
induce a capillary blush in the target area, and (iv) a sustained
demand for oxygen in the underperfused region which is effective to
convert the capillary blush to a stable and effective arteriole
vasculature supplying the underperfused region from the source of
oxygenated blood.
[0048] The initial angiogenic event is a capillary blush, such as
indicated at 64 in FIG. 3A. This blush is made up of a fine network
of capillaries, and typically is formed within 3-15 days after the
initial angiogenic stimulus. The formation of the initial capillary
blush requires a poor supply of oxygenated blood, and an angiogenic
stimulus, but not necessarily a demand for increased
vascularization. Without a sustained demand, or without a
continuous introduction of stimulus, the capillary blush will begin
to fade within several weeks, and eventually the heart will return
to its pre-treatment conditions.
[0049] In accordance with the invention, an effective, and
long-term vascular network from the source of oxygenated blood to
the underperfused region is created by maintaining a sustained
oxygen demand (or creating conditions of a natural sustained
demand), until the capillary blush matures into a network of
arterioles, such as indicated at 66 in FIG. 3B, which are supplied
by the source of oxygenated blood, and which extend into the target
area, to supply oxygenated blood to the previously underperfused
region.
[0050] Thus, the treatment method has three key features: (i) the
identification of a target site between an area of oxygenated blood
supply and an underperfused region, (ii) the introduction of
angiogenic stimuli in this area, to create a capillary blush in the
area, and (iii) conditions of a sustained demand, produced either
naturally or artificially, that cause the capillary blush to
develop into a mature vasculature between the areas of supply and
demand.
[0051] B. Stimulating Angiogenesis by Growth Factor
[0052] In one general embodiment of the invention, the stimulus
introduced into the target-area sites is a growth factor effective
to induce angiogenesis in the myocardial sites where it is
introduced, including area surrounding the sites. Exemplary growth
factors include basic and acidic fibroblast growth factor (FGF-2
and FGF-1, respectively), vascular endothelial growth factor
(VEGF), platelet-derived growth factor (PDGF), insulin-like growth
factor-1 (IGF-1), angiopoietin-1, angiopoietin-2, and combinations
of two or more of these growth factors, including as angiopoietin-1
in combination with VEGF. Typical growth-factor doses, such as
those given for VEGF (Murayama) or FGF-2 (Hasegawa), can be found
in the literature. The growth factor introduced may be in the form
of (a) a protein, typically made by recombinant methods, (b) a
vector containing the coding region for the growth factor under the
control of suitable human regulatory elements, or (c) myocardial
cells which have been transfected in vitro to express the selected
growth factor. Alternatively, the growth factor may be introduced
through special cells, such as bone-marrow-derived endothelial
progenitor cells (EPCs), that may contribute to neovascularization,
introduced either alone or in combination with growth factors, such
as VEGF, known to mobilize EPCs.
[0053] The growth factor may be introduced by a variety of means
including (i) injecting the protein, vector, or transformed
myocardial cells directly into myocardial tissue at each
target-area site, (ii) drawing the protein or vector into
myocardial tissue at each site by iontophoresis from a reservoir
placed against the site, (iii) forming a channel in the myocardium
at each site, and placing the protein, vector or cells into the
channel, and (iv) bombarding each site with a biolistic particle
containing or coated with the protein, vector or cells.
[0054] Methods for injecting pharmaceutical agents into myocardial
tissue are known in the art, e.g., as detailed U.S. Pat. Nos.
5,685,853 and 5,661,133. One preferred device is the drug-delivery
module disclosed in U.S. patent application Ser. No. 09/080,892,
filed Sep. 24, 1998, which is incorporated herein by reference.
Briefly, this device allows successive regulated introduction of a
metered amount of a drug agent into a cardiac site, for example, as
an attachment to an endoscope. The drug-delivery device may also be
equipped with a sensing device, such as the ultrasound device
disclosed in U.S. patent application Ser. No. 08/852,977, filed May
7, 1997, also incorporated herein by reference, which provides the
user with information about the distance of the injection head from
the surface of the heart.
[0055] Ionotophoretic administration of a growth factor protein or
vector may be carried out by placing embedding the protein in a
porous electrode, placing the electrode against the pericardial
wall corresponding to one of the target sites, and applying a
current across the electrode. The counter-electrode may be any
attached to any external site on the patient.
[0056] A variety of tools are available for forming transmyocardial
channels, e.g., by laser ablation, ultrasound, mechanical means, or
the like, and these tools may be combined with suitable delivery
tools for introducing into the channels, the selected protein,
vector, or transformed cells. One suitable drug delivery device
that employs laser ablation for drug delivery is disclosed in U.S.
Pat. No. 5,925,012, which is incorporated herein by reference.
[0057] For biolistic introduction of growth-factor protein, vectors
or transformed cells are known, the agent to be delivered is
introduced into a high-pressure stream of fluid, e.g., air or
water, and directed against the pericardial surface of the heart.
Alternatively, the device may be designed to puncture the
pericardium, and introduce the material in a high-pressure stream
directly into the myocardial layer.
[0058] Methods for producing human growth factors are known, e.g.,
by recombinant production are known, as are vectors suitable for
transforming human cells to achieve expression of selected growth
factors (refs). Myocardial cells transformed in vitro with
angiogenic growth factors, and injected into myocardial tissue have
also been reported (refs).
[0059] The growth factor may be introduced in free, that is,
solution or suspension form, encapsulated within suitable carriers,
such as liposomes or biodegradable particles. Gold particles
suitable for biolistics are well known, as are methods for
introducing projectile particles into tissue (refs).
[0060] The introducing step may be carried out in a manner that
achieves a desired spatial or temporal pattern of growth factors at
the target-area sites. The pattern shown in FIG. 4A is a uniform
spatial and temporal pattern in which the growth factor is equally
accessible at roughly equal concentrations at each site, such as
site 70, where the drug in free form is represented by dots in the
figure, and the sectional view is like that in FIGS. 2A, 3A and 3B,
where similar numbers represent similar anatomical features. With
this pattern, substantially each site with the target area is
exposed over the same time period to the same concentration of
growth factor. This pattern of growth factor results in a capillary
blush that has a relatively short duration, e.g., a period of a few
weeks, without a sustained demand for oxygen at the underperfused
region.
[0061] The pattern of growth factor shown in FIG. 4B is designed to
produce a temporal gradient of angiogenic factor that produces a
relatively high, short-term concentration of the agent closest to
the oxygen supply, where capillary blush is initiated, and a
longer-term release of growth factor progressing toward the
underperfused region. The temporal gradient is produced by
introducing into the sites closest to the blood supply, such as
sites 72, a freely usable form of growth factor, e.g., the growth
factor protein in solution form. At sites intermediate the blood
supply and underperfused region, such as sites 74, the growth
factor is packaged in a controlled release form, such as in a
biodegradable particle, or in a form of a transforming vector, that
functions to meter growth factor from the site over a relatively
long period, e.g., 1-4 weeks. At sites close to or within the
boundary of the underperfused region, such as indicated at 76, the
growth factor is contained in an even slower-release form, e.g.,
for growth-factor release or production for a 1-3 month period of
longer. This temporal distribution of growth factor allows for
initial formation of capillary blush near the source of oxygenated
blood supply, followed by angiogenesis at progressively deeper
levels in the myocardium.
[0062] C. Stimulating Angiogenesis by Injury
[0063] In another general embodiment of the treatment method, the
angiogenic stimulus is provided by a biologic trigger, an injury to
the myocardial tissue, either alone or in combination with an
angiogenic growth factor. Heart-muscle injury is known to produce a
sequence of biochemical responses that ultimately lead to
angiogenesis. This sequence generally involves a hypoxic condition
following injury, leading to build up of lactic acid in the injured
area, which stimulates macrophage infiltration into the injury
site, stimulation of angiogenic factors by the macrophages and, in
response to the growth factors, epithelial cell proliferation
leading to capillary formation.
[0064] One feature of injury as an angiogenic stimulus is that the
injury may also contribute to the sustained demand for oxygen
necessary for stable vasculature development in the target area and
underperfused region. That is, until the injury is resolved, the
body will attempt to supply the injury area with increased blood
supply as part of the response to injury. The ideal injury is a
recurrent injury, and/or one slow to resolve, but at the same time,
is resolved with a minimum of scarring, which is the body's way of
resolving an area of cells destroyed by the injury and where the
degree of surrounding inflammatory and angiogenic effect is
maximized or compliments the co-delivered angiogenic compound. For
example a more thermal injury is slower healing and might
compliment a time release gell-based angiogenic drug co-placement,
while a more abrasive/inflammatory injury might compliment a short
lived gene or protein construct.
[0065] FIGS. 5A-5D illustrates several types of injuries suitable
as angiogenic stimuli in the present invention. In each of these
cross-sectional figures, anatomical features corresponding to those
described in FIGS. 2A, 3A and 3B have the same figure numbers as in
those figures. The injury illustrated in FIG. 5A is a novel coring
injury, such as injury 80, that results in a core or island 82 of
healthy cells surrounded by an annulus 84 of injured cells at each
target-area site, such as site 86. The injury is made in a way that
leaves a relatively narrow channel injury 87, in the epicardium,
about 2-3 mm in depth, and the annular injury about 2-3 mm in depth
in the myocardial layer, at the target site 86. The core injury
minimizes the total amount of destroyed cells in the myocardium,
while leaving a large injury area that will become vascularized,
both within and outside the core, and an injury that may be
relatively slow to resolve. The coring injury can also be made from
the ventricle starting at the endocardium. Additional details of a
coring device used to produce such an injury and its method of use
are given in Section II below.
[0066] FIG. 5B illustrates a mechanical injury produced by a wire
device, such as device 88. The wire device, which is described in
greater detail in Section III below, includes a wire 90 having a
series of barbs or cutters, such as barbs 92, along its length.
Although not shown here, the device may have a proximal-end thread
by which the device can be can be extracted from a remote, e.g.,
external body site. To produce the initial angiogenic stimuli, a
wire device is inserted at each preselected target-area site 94 in
the heart. As the heart tissue attempt to resolve the injury, an
initial capillary blush develops in the target area. At periodic
intervals after wire placement at the sites, e.g., typically at
intervals of hours or days with longer intervals possible using
smaller devices and anti-fibrotic coatings, the wire may be
partially extracted, preferably from a remote site, as discussed in
Section III. This pulling drags the wire barbs through the initial
injury site, producing a recurrent injury that sustains the demand
for oxygen within the target site, and thus promotes transformation
of an initial capillary blush into a more stable arteriolar blood
supply to the underperfused region. Over a period of several weeks
or months, the wire devices will have been completely extracted
from the heart, and are thereafter removed from the patients'
body.
[0067] FIG. 5C illustrates an injury produced by an energy beam
source, such as a laser beam. As illustrated, the beam produces
channels, such as channels 96, of vaporized or otherwise destroyed
cells that extend through the epicardium into the myocardium, and
form the angiogenic sites in the target area. The channel
thickness, which is larger than the laser-beam width, is typically
about 1 mm; the channel depth ranges typically between about 4-8
mm, and extends either into or through the myocardial layer. Over
time, the channel fills with clotted blood and it is ultimately
resolved by vascularization in the target area, and scar formation
in the channel areas. Apparatus for producing laser-channel injury
to the heart, in a procedure known as transmyocardial
revascularization (TMR) is described for example, in U.S. Pat. Nos.
5,931,834 and 5,785,702. The present invention differs from known
TMR methods in that the injury channels are placed selectively in a
target-area preselected to bridge the region of myocardium between
a supply of oxygenated blood and an underperfused region. This has
the advantage over the prior art of maximizing the vascularization
effect of the channels, while minimizing the number of channels,
and thus extent of scarring injury to the heart needed to
effectively revascularize an underperfused heart region.
[0068] In each of the injury methods outlined above, the injury can
be combined with added growth-factor stimuli to augment or
accelerate the development of the original capillary blush, or to
augment the development of a mature vasculature in the target area.
For example, in the channel injury illustrated in FIG. 5C, an
angiogenic growth factor may be introduced into the channels, or
introduced into separate sites in the target area. A combined
injury/growth-factor stimuli is illustrated in FIG. 5D, which shows
a target area having injury stimuli produced by wire devices, such
as device 98 at preselected target-area sites, such as site 100,
and sites of growth-factor placement, such as site 102. The growth
factors assist initial capillary blush, and the wire devices are
manipulated, as above, to produce a recurrent-injury demand on the
developing vasculature.
[0069] In a second general embodiment, the source of oxygenated
blood flow for supplying an underperfused myocardial region is the
interior of the heart's left or right ventricle walls. Normally,
blood passing from the interior ventricle chambers into the
myocardium supplies only about 20% of the oxygen needs of the
heart, the other 80% being supplied coronary arteries surrounding
the outside of the heart. In subjects having adequate oxygen supply
to the heart muscles, the relatively non-porous endocardium, which
limits blood flow from the ventricle chambers into the myocardium
serves to hold blood dampen extremes of pressure occurring in the
ventricles. However, in subjects with underperfused regions of
myocardium, it would be useful to make localized wall regions of
the ventricle more porous, to allow direct blood supply from the
ventricle interior to the adjacent undersupplied myocardium.
[0070] This is done, in accordance with this general embodiment, by
using a biological trigger to produce an injury to the ventricle
wall, adjacent the underperfused regions and/or by introducing
growth factors at sites in a target area located between the
underperfused regions and immediately "underlying" endocardium. The
method is illustrated in FIGS. 6A and 6B which show a
cross-sectional ventricle portion 100 of a heart, including a
ventricle chamber 102, an inner endocardial layer 104, a myocardial
layer 106 containing an underperfused region, 108, and an outer
epicardial layer. The target area in the method is a region 112
between the inner wall of the ventricle chamber and the
underperfused region, and includes a boundary 114 in the
underperfused region adjacent the ventricle wall. In practicing the
method, one identifies (i) target area by imaging, as above, and
(ii) a plurality of target-area sites for introducing an angiogenic
stimulus. The sites may be sites such as sites 116, on the inner
ventricle wall, when the angiogenic stimulus is an injury to the
inner wall, and/or sites, such as sites 118, within the ventricle
wall, when the angiogenic stimulus is a growth factor. The growth
factor is introduced at the preselected sites by one of the methods
outlined above. The injury to the inner ventricle wall is
preferably produced by a skiving or channeling tool, which produces
elongate channels, such as channel 120 along the inner ventricle
(endocardial) wall surface. The skiving tool and its application to
the present method are detailed in Section III below.
[0071] FIG. 6A illustrates a network 122 of capillaries that make
up the initial capillary blush in response to the injury and/or
growth-factor stimuli. Over time, and with the continued
stimulation provided by the channel injuries, this capillary blush
will develop into a more stable blood-supply source to the
underperfused region, either by forming more stable arterioles or
through the maintenance of the oxygen demand by the injury.
[0072] The treatment method also contemplates treating an
underperfused region of the heart by combining the treatment
directed at the "outer" boundary of the region, as described with
respect to FIGS. 2-5, with the treatment directed at the "inner"
boundary of the heart, as described with respect to FIG. 6.
[0073] D. Sustaining Demand
[0074] As already noted, the treatment method requires continued
demand for oxygen at the underperfused site to convert the initial
capillary blush into a more stable and effective oxygen supply from
the blood-supply source.
[0075] In one general embodiment, detailed in Section V below, the
demand for oxygen is maintained by stressing the underperfused
region by exercise. Briefly, the patient is equipped with an
exercise monitor that indicates the level and amount of heart
exercise the patient achieves. Typically, the patient should begin
the exercise regimen within 3-8 days following the introduction of
angiogenic stimuli to the heart. The patient is required to achieve
a given exercise level for a period of at least 14 days, and
preferably for a period of 2-3 months, following capillary blush
formation. The amount and level of heart exercise is effective to
stimulate the conversion of capillary blush produced by said step
(b) to arterioles in the target area. The level can be readily
derived from reviewing the result of a patients baseline exercise
stress testing, and developing a heart rate level and time which is
both safe and challenging. The exercise monitor can provide the
safety and record keeping necessary. A pacemaker may be temporarily
or permanently added to exercise the heart.
[0076] In another general embodiment, the sustained demand is
produced by a slow-healing or recurrent biological trigger, such as
outlined above, and also considered in detail in Sections II, III,
and IV below. The demand for oxygenated blood created by the injury
is sustained for a period of at least 2-3 months, following
capillary blush formation.
[0077] II. Method and Device for Mechanical Coring Injury
[0078] FIGS. 7A-7B and 8A-8C illustrate various
coring-injury-producing devices. These devices are designed to
produce various types of coring injuries, such as an injury that
defines a disk-shaped area or carves out a conical portion of
injured cells at a target site surrounded by healthy cells. The
core injury is preferably produced below the surface in the
myocardial layer and in such a manner as to minimize the total
number of destroyed cells in the myocardium, while leaving a
relatively large injury area that will become vascularized and that
may be relatively slow to resolve. Localization of such an injury
requires a tool that has a means of entry into the tissue which is
lower in trauma than the introduction of the injury itself which is
preferably produced about 1-4 mm below the epicardial region in the
underlying myocardial region.
[0079] One such cutting tool that may be used to produce a
subsurface coring injury is shown in its distal portion at 126 in
FIG. 7A. The tool has an elongate sleeve 128 which can be guided to
a selected heart target-area site, and which terminates at its
distal end in a cutting surface 130. The sleeve carries a radially
enlarged annulus 132 which limits the depth of penetration of the
tool into the heart muscle.
[0080] Sleeve 128 accommodates a piercing element 134 which can be
moved radially within the sleeve to project its piercing tip beyond
the distal end of the sleeve. In operation, the piercing element is
moved to such a position to function to pierce the epicardial layer
when the tool is being introduced into the heart muscle, at a
selected target-area site in the heart. Once the piercing tip has
entered the myocardium, the sleeve may be advanced into the
myocardium, with a cutting motion applied to the sleeve, to produce
an annular cut through the myocardium tissue, typically about 2-3
mm into the myocardium.
[0081] To remove the tool from the heart, after the subsurface
coring injury is made the sleeve is removed from the heart muscle,
leaving a core injury of the type described in FIG. 5A above.
[0082] FIG. 7B shows a tool that can be used to make a surface
coring injury. Here a blunt-end rod 136 is used instead of the
piercing element 134. This rod is pushed against the tissue core
inside the sleeve as the sleeve is being extracted, to hold the
core in place during tool extraction. Other arrangements can also
be used for holding the tissue core in place while the tool is
extracted.
[0083] FIGS. 8A-8C illustrate the distal end portion of a coring
and drug-delivery tool 138 constructed according to another
embodiment of the invention. As seen, the tool includes a tipped
needle having an axial bore 142 through which a blade 144 is
received and a drug-delivery bore 146 through which a drug solution
or suspension can be delivered from the needle. Blade 144 is an
elongate, flexible metal blade that has a substantial bend at 144a
adjacent its distal end, between a proximal guide segment 142b, and
a distal cutting segment 144c.
[0084] In operation, the needle is introduced through the
pericardium or endocardium into the myocardium at a selected
target-area site where injury and optionally, growth factor is to
be placed. During this introducing step, blade 144 is retracted
into the bore of the needle. As the needle is being inserted a
selected depth into the myocardial tissue, the blade is moved out
of the needle bore. As the bend in the blade passes through the
outer tip of the needle, the tension in the blade causes the distal
segment of the blade to extend away from the axis of the needle, as
illustrated in FIG. 8B, which shows a partial angle bend, and FIG.
8C, which shows a full right angle bend. The needle is then rotated
to produce a conical section in the tissue defined by the distal
blade's movement through a complete rotation.
[0085] When the blade is partially extended as in FIG. 8B, such a
rotation produces a conical core injury 148 such as shown in FIG.
9A, where the epicardial, myocardial, and endocardial layers are
indicated at 150, 152, 154, respectively. After formation of the
conical cut in the myocardial tissue, a growth factor solution of
suspension may be introduced into the injury site under pressure
through bore 146 in the needle. The separated tissue allows the
drug agent to be received in bolus form at the site, where it
distributes about the site of the injury and ultimately is absorbed
into the cells adjacent the injury. In this way, a growth factor
agent can be placed and distributed over a desired area within the
myocardium.
[0086] Likewise, when the cutting blade is extended passed its
bend, and therefore assumes a full right angle in its cutting
segment, as in FIG. 8C, rotation of the needle produces a
substantially planar, circular cut such as indicated at 156, 158,
and 160 in FIG. 9B. The three cuts in FIG. 9B were produces by
making successively shallower circular cuts in the tissue, with
retracting and extending the cutting blade at each new depth in the
myocardium. At each circular cut, drug may be introduced,
essentially filling the circular space cut into the tissue.
[0087] III. Method and Device for Sustained Wire Injury
[0088] Another device for generating an injury in accordance with
the invention is illustrated in FIGS. 10-13. This device is adapted
to be remotely activated at periodic intervals to produce recurrent
mechanical or thermal injury at implantation sites throughout a
target area over a total period sufficient to convert initial
capillary blush induced at the implantation sites into
arterioles.
[0089] One such device 156 comprises an elongate wire 158 formed
with barbs, such as barbs 160, along its length. Device 156
preferably further includes a flexible thread 162, one end of which
is attached to wire 158 and the other end of which engages an
external hook 164.
[0090] Placement of wire 158 is illustrated in FIG. 10. The wire
may be inserted into the subject using a hollow needle 166 which
includes a funnel-shaped guide 168 at its proximal end. The needle
is inserted into the subject so that a portion 170 of the needle
extends through a target area in the myocardium which includes an
underperfused region 172, as shown in FIG. 10. The wire is then
inserted into the hollow portion of the needle, such that when the
needle is removed, the wire is implanted in the target area and
extends through region 172 in close proximity to healthy tissue
174. Multiple wires may be inserted, as shown in FIG. 10.
[0091] After insertion, each wire is periodically retracted a small
amount, in accordance with the principles of the invention. A crank
mechanism 176 in connection with a sleeve 178 that extends through
the chest wall may be used to retract the wire, as shown in FIG.
11. Other suitable mechanisms may also be used.
[0092] At periodic intervals of between 1-7 days, the wire is
retracted an indexed amount of about 1 cm in the direction of arrow
A by moving the crank handle in the direction of arrow B or
otherwise pulling the wire to effect the retraction. These times
and distances are exemplary only; the amount of removal and the
periodic intervals at which the wire is incrementally removed will
vary depending on the healing response curve desired. The result,
as shown at 180 in FIG. 12, is that each indexed (e.g., 1 cm)
retraction creates a new or fresh tearing injury that promotes
angiogenesis.
[0093] The details of the construction of wire 158 are illustrated
in FIG. 13. The wire is preferably between 0.002" to 0.005"
stainless wire and formed of a bioerodable, ferromagnetic material.
The wire preferably has 3-4 barbs spaced along its length
approximately 1 cm apart, with the barbs themselves preferably
being stainless and 0.010 type sharp bumps, although the number of
barbs as well as their size and spacing will depend on the desired
healing response.
[0094] In accordance with the principles of the invention, the wire
is retracted in steps that are matched to a desired healing
response curve. Periodic and discrete retraction of the wire along
a predetermined track or path re-injures the tissue and results in
a timed sequential injury that promotes arterioles to grow along
the track in a more organized pattern, and thus concentrates blood
flow along the track. The device may be shaped in other ways as
well, including conduits for drug additions.
[0095] IV. Method and Device for Endocardial Injury
[0096] FIG. 14 illustrates one embodiment of a tool 184 for use in
producing an injury at selected locations on the inner endocardial
wall of a heart ventricle. As discussed above, the purpose of this
injury is to stimulate angiogenesis that can supply blood from the
ventricle chambers of the heart to underperfused regions in the
ventricle wall.
[0097] Tool 184 generally includes a handle 186 by which the
operator guides and operates the tool, an elongate, rigid handle
extension 188, and a cutter element 190 formed at the distal end of
the handle extension. The cutter element has a curved shape, as
shown, allowing the element to be placed firmly against the curved
wall portion of a ventricle chamber during operation, after (i) the
cutter element is introduced through the heart muscle into the
ventricle chamber, and (ii) the handle is manipulated to draw the
cutter element against a ventricle wall surface.
[0098] The cutter element has a recessed segment 192 along which a
cutter blade 194 is movable in guide tracks (not shown) under the
influence of a cable 196 attached to the blade and a motor 198
housed in handle 186. Control of blade motion is through a switch
200 which activates the motor. A cutter retreat lever 202 is used
to reset the blade to its distal cutting position.
[0099] In operation, and with additional reference to FIG. 15, the
tool is moved through a previously installed introducer sleeve 204
having a deformable seal that prevents blood flow from the
ventricle chamber. The tool is placed inside the ventricle wall,
indicated at 206, and placed against a wall region adjacent an
underperfused region. The cutter blade is now activated to form a
shallow channel injury 208 in the ventricle wall, as illustrated in
FIG. 15. The tool is dimensioned to produce a channel of about 1-5
mm, preferably 2-3 mm in width and 0.5-2 mm, preferably about 1 mm,
in depth. After each cut, the tool is moved to form an another cut
in an adjacent target area, until the plurality of cuts
corresponding to the region of the underperfused region are made.
The channels are typically about 1-3 cm long, and spaced about 0.5
to 1 cm apart. apart. After the cutting operation, the tool is
withdrawn, then the introducer sleeve is removed.
[0100] The tool may be adapted to produce a variety of
ventricle-wall injuries, such as needle injury, coring injury, or
laser injury by replacing the movable cutter blade with other
injury-producing elements. For example, in the case of a needle
injury, the cutter blade may be replaced by a movable needle
housing through which a needle can be selectively extended, e.g.,
by a suitable control in the handle, at spaced intervals along the
track of the cutter segment. Likewise, a coring element designed to
produce a myocardial coring injury, such as detailed in Section III
above, may be used. In addition, or alternatively, the tool may be
equipped with a needle or biolistic element for introducing growth
factor at selected sites in the selected target area between the
ventricle wall and the underperfused region. The injury and/or
growth-factor stimuli introduced by the tool functions initially to
stimulate angiogenesis in the region between the endocardial wall
and the underperfused region, serving, in effect, to make the
endocardium more porous to blood flow from the ventricle chamber to
an adjacent region in need of more oxygen. The capillaries forming
a capillary bed in response to the stimuli function as one-way
blood-cell carriers, through the vaso-action motion of capillaries.
Thus, the heart becomes leakier, but only in the desired
endocardium-to-myocardium direction. With sustained injury, such as
is produced by a channel injury or laser injury, the continued
angiogenic stimulus leads to the formation of an arteriole or more
robust capillary bed feeding the underperfused region from the
ventricle wall. Alternatively, the initial stimulus can be followed
by an exercise regimen, as described in Section V, to place a
sustained demand on the growing vasculature.
[0101] This embodiment of the treatment method may be carried out
in conjunction with other aspects of the invention that treat the
underperfused region from the "epicardial" side of the
underperfused region, or independently. An advantage of the
combined methods is that the region in need of greater oxygen
supply is revascularized from both sides of the heart wall. A
second advantage is that the sustained demand placed on the region,
such as by exercise, will contribute to vascularization being
created on both inner and out sides of the underperfused
region.
[0102] V. Method and Device for Sustained Stimulus by Exercise
[0103] In addition to long-term or recurrent injury, the oxygen
demand within the underperfused region can be sustained by
requiring the patient to achieve a desired level of exercise, as
measured by an elevated heart rate, e.g., a 50-100% increase in
heart rate over the resting rate, for a selected daily period,
typically at least 1/2 hour. per day. The exercise regimen should
begin at least by week 4 following the initial angiogenic stimuli,
and be continued at least through week 15-16 following the initial
stimuli. The desired end point is conversion of capillary blush to
a more robust arteriole system, and the transformation of
vasculature can be followed by imaging techniques noted above.
[0104] If desired, a pacemaker may be added to stimulate the heart
at regular exercise intervals.
[0105] The monitoring and tracking components of the device are
illustrated in FIG. 16. The device here takes the form of a
wrist-worn device 210 having against-the-skin electrodes 212, 214,
for detecting pulse rate. Other devices can be designed, for
example to be strapped around the chest of the wearer, with
against-the-skin electrodes being located at the chest region over
the heart. The front face of the device includes a display window
216 and a switch 218 which sends an "activate" signal to the
device, when the user initiates each daily exercise program.
[0106] The operation of the device is illustrated in FIG. 17, which
is a flow diagram of the logic steps carried out by the device.
Initially, when the device is strapped in place, the user allows
the device to measure an average resting pulse, indicated by
function 220, which provides a baseline of heart rate. By
activating the device for exercise measurement, indicated by
functions 222 and 224, the device is set to begin monitoring and
timing the extent and duration of heart exercise over a given
exercise period. The device monitors the heart rate and indicates
to the user when an adequate rise in heart rate has been achieved,
as indicated by function 226. Once the elevated heart-heart
threshold is reached, the device begins measuring the duration of
the period of elevated heart rate, indicated by function 228, and
displays both heart rate and duration date to the user. When an
integrated, elevated heart rate/duration threshold is reached,
indicating a sufficient heart exercise for that day, the device so
signals the user, as indicated by function 230. The daily exercise
data is stored in a suitable storage device 232 that keeps track of
the (i) days when heart-rate exercise was measured, (ii) the
integrated elevated heart rate/duration value on each exercise day,
and the total days remaining in the exercise regimen, and this data
can be supplied to the user on demand, e.g., at the beginning of
each daily exercise.
[0107] At the end of the exercise regimen, the user may be examined
to confirm formation of arteriole blood supply to the underperfused
region. Alternatively, the patient will be able to report
improvement in vascularization of the heart through such measures
as increased exercise tolerance, quality of life, or relief from
cardiac insufficiency symptoms, such as resting or exercise-induced
chest pain.
[0108] From the foregoing, it can be appreciated how various
objects and features of the invention are met. In particular, the
present invention addresses the problem: how can an underperfused
region of the heart, and therefore a region at risk or infarct and
muscle loss, be efficiently resupplied with an adequate supply of
oxygen with a minimum of anatomical damage to the heart.
[0109] Although the prior-art recognized the ability of angiogenic
stimuli, including both growth factors and injury, to stimulate
angiogenesis in the heart, the present invention extends this
solution in two key respects. First, by imaging the heart to
identify and localize the underperfused region, and localizing this
region with respect to the adjacent supply of oxygenated blood, the
sites of angiogenic stimulus can be localized to optimally extend
from the source of oxygenated blood to ward the site of demand (the
underperfused region). This significantly enhances of the
efficiency of capillary blush formation. Secondly, by applying a
sustained demand to the region where capillary blush has occurred,
the initial capillary formation is assured of developing into a
stable and robust vascular supply to the underperfused region.
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