U.S. patent application number 14/019466 was filed with the patent office on 2014-01-02 for devices and methods for predicting and preventing restenosis.
The applicant listed for this patent is John F. BLACK, Xuanmin HE, Michael H. ROSENTHAL, John B. SIMPSON. Invention is credited to John F. BLACK, Xuanmin HE, Michael H. ROSENTHAL, John B. SIMPSON.
Application Number | 20140005534 14/019466 |
Document ID | / |
Family ID | 44146169 |
Filed Date | 2014-01-02 |
United States Patent
Application |
20140005534 |
Kind Code |
A1 |
HE; Xuanmin ; et
al. |
January 2, 2014 |
DEVICES AND METHODS FOR PREDICTING AND PREVENTING RESTENOSIS
Abstract
The present invention relates to methods and devices for
predicting restenosis, and for treating atherosclerosis to prevent
or reduce the incidence of restenosis. Methods of predicting
restenosis in a stenosed peripheral artery may include quantitative
histology of the vessel. For example, a method of treating a
stenosed artery (and particularly a peripheral artery) may include
the steps of determining a level of hypercellularity and one or
more of the lipid-richness and extent of inflammatory cell
inclusion in the tissue. An index of restenosis based on the
hypercellularity and lipid richness and/or extent of inflammatory
cell inclusion in the tissue may be determined. Systems for
treating or preventing restenosis may include one or more imaging
modalities for imaging tissue regions and determining the level of
hypercellularity and one or more of the degree of lipid-richness
and the extent of inflammatory cell inclusion in the tissue
region.
Inventors: |
HE; Xuanmin; (Sunnyvale,
CA) ; SIMPSON; John B.; (Woodside, CA) ;
ROSENTHAL; Michael H.; (San Carlos, CA) ; BLACK; John
F.; (San Mateo, CA) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
HE; Xuanmin
SIMPSON; John B.
ROSENTHAL; Michael H.
BLACK; John F. |
Sunnyvale
Woodside
San Carlos
San Mateo |
CA
CA
CA
CA |
US
US
US
US |
|
|
Family ID: |
44146169 |
Appl. No.: |
14/019466 |
Filed: |
September 5, 2013 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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12963536 |
Dec 8, 2010 |
8548571 |
|
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14019466 |
|
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61267811 |
Dec 8, 2009 |
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Current U.S.
Class: |
600/425 ;
600/407; 600/431; 606/108 |
Current CPC
Class: |
A61B 5/02007 20130101;
A61B 5/0066 20130101; A61M 31/005 20130101; A61B 5/4836 20130101;
A61F 2/06 20130101; G06T 2207/30101 20130101; A61B 5/0084 20130101;
A61B 5/0036 20180801; G06T 2207/10068 20130101; A61B 17/22
20130101; G06T 7/0012 20130101 |
Class at
Publication: |
600/425 ;
600/407; 600/431; 606/108 |
International
Class: |
A61B 5/02 20060101
A61B005/02; A61B 17/22 20060101 A61B017/22; A61F 2/06 20060101
A61F002/06; A61B 5/00 20060101 A61B005/00; A61M 31/00 20060101
A61M031/00 |
Claims
1. A device for treating atherosclerosis and prevent restenosis,
the device comprising: an imaging catheter having a sensor
configured to image a portion of an artery; a processor configured
to receive images of the artery from the sensor processor and to
detect regions of hypercellularity in the artery based on the
received images, and further configured to detect regions of either
or both: lipid-rich tissue and inflammatory cells in the artery
from the received images; and a display configured to display a
modified view of the artery indicating hypercellularity and one or
both of lipid-rich tissue and inflammatory cells in the artery.
2. The device of claim 1, wherein the imaging catheter is an
atherectomy catheter.
3. The device of claim 1, wherein the imaging catheter is an OCT
imaging catheter and the sensor comprises an OCT imaging
sensor.
4. The device of claim 1, wherein the processor and display are
configured to operate in real or near-real time.
5. The device of claim 1, wherein the processor comprises detection
logic configured to detect the regions of hypercellularity and
either or both: lipid-rich tissue and inflammatory cells in the
artery from the received images.
6. The device of claim 1, wherein the display is configured to
highlight region of overlap indicating both hypercellularity and
either or both: lipid-rich tissue and inflammatory cells in the
artery on the modified view of the artery.
7. The device of claim 1, wherein the processor further comprises
index logic configured to determine an index of restenosis based on
the degree of hypercellularity and either or both: the degree of
lipid-rich tissue and the degree of inflammatory cells in the
artery from a region of the artery in the received images.
8. The device of claim 7, wherein the index logic determines the
index of restenosis based on the degree of hypercellularity, the
degree of lipid-rich tissue and the degree of inflammatory cells
from the region of the artery.
9. The device of claim 7, wherein the display is configured to
display the index of restenosis for the region.
10. The device of claim 7, wherein the display is configured to
overlay an indicator of the index of restenosis for the region over
a view including the region of the artery.
11. A system for indicating an enhanced risk of restenosis in an
arterial tissue, the system comprising: an imaging modality
configured to image a region of arterial tissue; and a processor
configured to receive the image of the region of arterial tissue
from the imaging modality and to determine a measure of
hypercellularity and further configured to determine one or both
of: a measure of how lipid-rich the tissue region is and a measure
of how many inflammatory cells there are associated with the tissue
region; and index logic configured to determine an index of
restenosis for the tissue region based on the measure of
hypercellularlity and one or both of the measures of how lipid-rich
the first tissue region is and the measure of how many inflammatory
cells are associated with the first tissue region.
12. The system of claim 11, further comprising an output configured
to output the index of restenosis.
13. The system of claim 11, further wherein the index logic is
configured to determine an index of restenosis based on the measure
of hypercellularlity, the measure of how lipid-rich the first
tissue region is, and the measure of how many inflammatory cells
are associated with the first tissue region.
14. A method of determining an enhanced risk of restenosis in an
arterial tissue, the method comprising: determining a measure of
hypercellularity in a first arterial tissue region; determining one
or both of: a measure of how lipid-rich the first tissue region is
and a measure of how many inflammatory cells there are associated
with the first tissue region; determining an index of restenosis
for the first tissue region based on the measure of
hypercellularlity and one or both of the measures of how lipid-rich
the first tissue region is and the measure of how many inflammatory
cells are associated with the first tissue region; and presenting
the index of restenosis for the first tissue region.
15. The method of claim 14, wherein the step of determining an
index of restenosis comprises determining the index of restenosis
for the first tissue region based on the measure of
hypercellularlity and the measure of how lipid-rich the first
tissue region is and the measure of how many inflammatory cells are
associated with the first tissue region.
16. The method of claim 14, wherein the step of presenting
comprises displaying an image of the first tissue region with a
visual indicator of the index of restenosis.
17. The method of claim 14, further comprising imaging the first
tissue region with an imaging modality configured to detect
hypercellularity.
18. The method of claim 14, further comprising imaging the first
tissue region with an imaging modality configured to detect
lipid-rich regions.
19. The method of claim 14, wherein the step of determining a
measure of hypercellularity comprises imaging the first region with
optical coherence tomography.
20. The method of claim 14, wherein the step of determining a
measure of hypercellularity comprises counting or estimating the
amount of satellite-to-spindle-shaped smooth muscle cells within
stroma.
21. The method of claim 14, wherein the step of determining a
measure of how lipid-rich the first tissue region is comprises
estimating the amount or degree of amorphous material containing
cholesterol crystals, loosely aggregated necrotic debris and foam
cells.
22. The method of claim 14, wherein the step of determining a
measure of how many inflammatory cells are associated with the
first tissue region comprises counting or estimating clusters of
macrophages and lymphocytes.
23. The method of claim 14, further comprising treating the tissue
with a marker, dye, or indicator.
24. The method of claim 14, further comprising inserting a stent
adjacent to the first arterial tissue region when the index of
restenosis indicates a greater likelihood of restenosis.
25. The method of claim 14, further comprising removing the first
tissue region from a patient.
26. A method of preventing restenosis in an arterial tissue, the
method comprising: determining an index of restenosis for a first
arterial tissue region based on a measure of hypercellularlity of
the first arterial tissue region and one or both of a measure of
how lipid-rich the first arterial tissue region is and a measure of
how many inflammatory cells are associated with the first arterial
tissue region; and inserting a stent adjacent to the first arterial
tissue region when the index of restenosis indicates a greater
likelihood of restenosis.
27. The method of claim 26, further comprising removing tissue from
the first arterial tissue region.
28. The method of claim 26, wherein the step of determining an
index comprises imaging the first arterial tissue region in real or
near-real time.
Description
CROSS REFERENCE TO RELATED APPLICATIONS
[0001] This application is a continuation of U.S. patent
application Ser. No. 12/963,536, filed on Dec. 8, 2010, titled
"DEVICES AND METHODS FOR PREDICTING AND PREVENTING RESTENOSIS," now
Patent Publication No. 2011-0263836-A1, which claims priority to
U.S. Provisional Patent Application No. 61/267,811, filed on Dec.
8, 2009, titled "DEVICES AND METHODS FOR PREDICTING AND PREVENTING
RESTENOSIS", each of which is herein incorporated by reference in
its entirety.
INCORPORATION BY REFERENCE
[0002] All publications and patent applications mentioned in this
specification are herein incorporated by reference in their
entirety to the same extent as if each individual publication or
patent application was specifically and individually indicated to
be incorporated by reference.
BACKGROUND
[0003] Atherosclerosis is an artery disease believed to arise from
endothelial malfunction, accumulation of lipid materials in the
intima of artery, inflammatory cell infiltration and reaction,
artery wall structure damage, smooth muscle cell proliferation and
fibrosis change. These factors may result in artery stenosis and
ischemia of supplied organs and severe clinical consequences, such
as heart attack in coronary artery stenosis, claudication and
critical limb ischemia in occlusive peripheral vascular
disease.
[0004] Atherosclerosis may be treated by atherectomy (e.g., removal
of stenosed tissue). For example, directional atherectomy may use a
catheter-based system to excise and retrieve plaque tissue for the
transluminal treatment of coronary and peripheral atherosclerotic
artery disease. The excision and collection of plaque tissue in
directional atherectomy not only leaves behind a large and smooth
lumen at the treated artery segment, but may also provide plaque
tissue for histopathological analysis and new insights into the
mechanism of atherosclerotic progress and variable therapy
response.
[0005] Atherosclerotic stenoses in coronary and peripheral arteries
vary widely in presentation and severity. In peripheral arteries
the disease is under-diagnosed and under-treated, amputation rate
in the US is staggering at 200,000 per year and recurrence rates
following peripheral interventions (atherectomy, angioplasty and
stenting) are still high. Peripheral stent fracture and failure of
drug eluding stents in the periphery remains a big problem. The
Baim-Kuntz coronary model of "bigger is better" has been difficult
to apply to peripheral vessels because of the diffuse nature of the
disease and the large atherosclerotic burden. A high capacity
atherectomy system with on-board real-time imaging to guide plaque
resection could potentially overcome the disadvantages in current
devices and allow the Baim-Kuntz model to be applied to the
peripheral vascular space for the first time.
[0006] As mentioned above it is well recognized that peripheral
plaque burden is large in comparison to coronary lesions. Current
atherectomy systems leave up to 60% of the atheroma atheroma in the
vessel as confirmed by intra-vascular ultra-sound (IVUS). A new
image guided atherectomy (IGA) system with greater capacity for
tissue management may be better able to safely achieve maximal
luminal gain with minimal barotraumas. To achieve this improved
acute outcome, a new cutter design combined with imaging near the
cutter edge may be used. The method and devices described herein
may help guide treatment with such a device, or even in devices
that do not include cutting components and/or on-board imaging.
[0007] Despite high procedure success rates, excellent initial
patency rate, and low complications, post-intervention restenosis
often limits plaque excision methods from becoming a more routine
and effective resvasculization procedure for the treatment of
coronary and peripheral atherosclerotic artery disease. Thus, there
is a need to understand the mechanism of restenosis, and to
determine new approaches for preventing and treating
post-intervention restenosis.
[0008] Although there have been other attempts to
histopathologically analyze excised atherosclerotic plaque tissue,
the results have generally proven unsatisfactory. For example, the
relationship between plaque histopathological components and
subsequent restenosis in atherosclerotic lesions treated with
directional atherectomy device has been controversial. Such plaque
histopathological studies and evaluations have been mostly based
only on the qualitative presence or absence of different plaque
components. Quantitative histological analysis may provide more
detail information to help understand the mechanism of restenosis.
Herein we describe a method of describing and quantifying various
atherosclerotic plaque elements, and devices for applying this
analysis. Furthermore, we herein identify specific factors and
parameters that correlate with angiographic restenosis rates in
coronary atherosclerotic patients treated by directional
atherectomy.
[0009] We have discovered that histopathological analysis of
atherosclerotic artery tissue from patients with cardiovascular
disease may be used to predict incidence of restenosis in the
artery. More particularly, restenosis of may be predicted based on
the histopathological analysis of atherosclerotic tissue (including
excised fragments from atherectomy procedures) in patients with
atherosclerotic artery disease. The histopathological analysis
applied may be quantitative; furthermore, quantitative estimates
and ranges are provided which may correlate to restenosis.
Applications of the quantitative histological parameters and ranges
of values of these parameters are also described.
SUMMARY OF THE INVENTION
[0010] The present invention relates to methods and devices for
predicting restenosis, and for treating atherosclerosis to prevent
or reduce the incidence of restenosis.
[0011] In particular, described herein are methods of predicting
restenosis in a stenosed peripheral artery based on the
quantitative histology of the vessel. For example, a method of
treating a stenosed artery (and particularly a peripheral artery)
may include the steps of determining a level of hypercellularity,
and providing a predictive index of restenosis based on the level
of hypercellularity and/or the level of lipid-rich tissue, and/or
the level of inflammatory cells in the tissue. Each of these
factors may be examined individually, or they may be combined.
[0012] These factors (e.g., hypercellularity, lipid-rich regions,
inflammatory cells) may be provided as a quantitative and/or
qualitative index. For example, hypercellularity may be provided as
a percentage of total tissue or a percentage of hypercellularity,
or the level of hypercellularity may be used to provide an
indicator of "low/medium/high" or the like. An index indicating the
likelihood of restenosis (either quantitatively or qualitatively)
may be provided by combining one or more of these factors. These
factors may also be combined with other factors, such as
post-interventional minimal lumen diameter (MLD) to provide a more
robust indicator of
[0013] Also described herein are systems and devices for treating
or assisting in the treatment of stenosis by providing an
indication of the hypercellularity, lipid-rich regions and/or
inflammatory cells in an artery, and particularly a peripheral
artery. Systems including visualization methods such as
catheter-based imaging systems using Optical Coherence Tomography
(OCT) are of particular interest. Systems may also be configured
for predicting or indicating if restenosis is to occur. Systems or
devices may be configured to show hypercellularity and/or
lipid-rich tissue and/or inflammatory cells in an arterial tissue.
The systems may be configured to present quantitative or
qualitative estimates in real-time.
[0014] In some variations devices for treating atherosclerosis may
be configured for real-time or near real-time imaging of tissue so
that the artery may be treated while imaging the tissue. In
general, these devices may be used with one more catheters for
imaging and treating the tissue.
[0015] For example, described herein are devices for treating
atherosclerosis and prevent restenosis. In some variations the
devices include: an imaging catheter having a sensor configured to
image a portion of an artery; a processor configured to receive
images of the artery from the sensor processor and to detect
regions of hypercellularity in the artery based on the received
images, and further configured to detect regions of either or both:
lipid-rich tissue and inflammatory cells in the artery from the
received images; and a display configured to display a modified
view of the artery indicating hypercellularity and one or both of
lipid-rich tissue and inflammatory cells in the artery.
[0016] The device imaging catheter may be any appropriate catheter,
including an atherectomy catheter. Steerable catheters, and
catheters having more than one imaging modality may be included (or
catheters having one imaging modality). For example, the imaging
catheter may be an OCT imaging catheter and the sensor comprises an
OCT imaging sensor.
[0017] The device (or systems) may include any appropriate
processor or processors for taking and analyzing images of the
arterial tissue or regions of the artery. A processor may be a
dedicated or general purpose processor. The processor may be
configured in part as a controller for controlling operation of the
various components of the system. In some variations a separate
controller may be used. The controller may control operation of the
analysis and/or the display of images and the resulting identified
tissue regions (e.g., showing regions at high risk for restenosis
on a display). As mentioned, in some variations, the processor and
display are configured to operate in real or near-real time.
[0018] The processor (or processors) may include logic for
analyzing and/or controlling the system. For example a device or
system may include detection logic configured to detect regions of
hypercellularity and either or both: lipid-rich tissue and
inflammatory cells in the artery from the received images. The
detection logic may be further configured to estimate, measure or
count a degree of hypercellularity and one or both of
lipid-richness and/or the amount of inflammatory cells (e.g.,
macrophages, lymphocytes, etc.) in the tissue region. The device or
system may also include index logic for calculating an index that
combined (and/or weights) the measures, counts, or estimates of
hypercellularity and one or both of lipid-richness and/or the
amount of inflammatory cells (e.g., macrophages, lymphocytes, etc.)
in the tissue region. In some variation the index logic may be
included with the detection logic, or vice-versa.
[0019] The display may be a visual display, such as monitor,
screen, projection, or the like. The display may be configured to
highlight one or more regions of overlap indicating both
hypercellularity and either or both: lipid-rich tissue and
inflammatory cells in the artery on the modified view of the
artery. In some variations the display may overlay an image of the
artery or a region of the artery with an indication of the
likelihood of restenosis, and my include markers indicating the
relative location of the catheter or another device such as an
atherectomy catheter or the cutting region of an atherectomy
catheter. The indicator of the likelihood of restenosis may be a
color (e.g., color intensity or color-coding) or numeric (0 to 100,
0 to 10, 0.00 to 1.00, etc.) or percentage indicator.
[0020] As mentioned, the processor further may also include index
logic configured to determine an index of restenosis based on the
degree of hypercellularity and either or both: the degree of
lipid-rich tissue and the degree of inflammatory cells in the
artery from a region of the artery in the received images. In some
variations, the index logic determines the index of restenosis
based on the degree of hypercellularity, the degree of lipid-rich
tissue and the degree of inflammatory cells from the region of the
artery. In variations in which an index of restenosis is
determined, the system may display the index of restenosis for the
region. For example, the device display may be configured to
overlay an indicator of the index of restenosis for the region over
a view including the region of the artery.
[0021] Also described herein are systems for indicating an enhanced
risk of restenosis in an arterial tissue. For example, a system may
include: an imaging modality configured to image a region of
arterial tissue; and a processor configured to receive the image of
the region of arterial tissue from the imaging modality and to
determine a measure of hypercellularity and further configured to
determine one or both of: a measure of how lipid-rich the tissue
region is and a measure of how many inflammatory cells there are
associated with the tissue region; and index logic configured to
determine an index of restenosis for the tissue region based on the
measure of hypercellularlity and one or both of the measures of how
lipid-rich the first tissue region is and the measure of how many
inflammatory cells are associated with the first tissue region. The
system may also include an output configured to output the index of
restenosis.
[0022] As mentioned above, in some variations of the system, the
index logic is configured to determine an index of restenosis based
on the measure of hypercellularlity, the measure of how lipid-rich
the first tissue region is, and the measure of how many
inflammatory cells are associated with the first tissue region.
[0023] Methods of treating atherosclerosis based on an estimate of
the risk of restenosis as described herein are also provided. Also
taught are methods, devices and systems for determining an enhanced
risk of restenosis in an arterial tissue, as well as methods,
devices and systems for treating and/or preventing restenosis in an
arterial tissue.
[0024] For example, described herein are methods of determining an
enhanced risk of restenosis in an arterial tissue. In some
variations, these methods include the steps of: determining a
measure of hypercellularity in a first arterial tissue region;
determining one or both of: a measure of how lipid-rich the first
tissue region is and a measure of how many inflammatory cells there
are associated with the first tissue region; determining an index
of restenosis for the first tissue region based on the measure of
hypercellularlity and one or both of the measures of how lipid-rich
the first tissue region is and the measure of how many inflammatory
cells are associated with the first tissue region; and presenting
the index of restenosis for the first tissue region.
[0025] The step of determining an index of restenosis may include
determining the index of restenosis for the first tissue region
based on the measure of hypercellularlity and the measure of how
lipid-rich the first tissue region is and the measure of how many
inflammatory cells are associated with the first tissue region.
[0026] The step of presenting may include displaying an image of
the first tissue region with a visual indicator of the index of
restenosis. In some variations, the method further includes imaging
the first tissue region with an imaging modality configured to
detect hypercellularity and/or imaging the first tissue region with
an imaging modality configured to detect lipid-rich regions. In any
of the devices, system and methods described herein, a measure of
hypercellularity may be determined using an imaging modality such
as optical coherence tomography to image the arterial tissue or a
region (e.g., the "first region") of the tissue.
[0027] The step of determining a measure of hypercellularity may
include counting or estimating the amount of
satellite-to-spindle-shaped smooth muscle cells within stroma. In
general, determining a measure, estimate or count of
hypercellularity may include determining the density of cells
(e.g., muscle cells) within the stroma or a region of stroma (e.g.,
fibrotic stroma rich in proteoglycan materials). The step of
determining a measure of how lipid-rich a tissue region is may
comprise estimating the amount or degree of amorphous material
containing cholesterol crystals, loosely aggregated necrotic debris
and foam cells. The step of determining a measure of how many
inflammatory cells are associated with the first tissue region may
include counting or estimating clusters of macrophages and
lymphocytes.
[0028] In any of the devices, systems and methods described herein,
the arterial tissue may be treated with a marker, dye, or
indicator, which may help in determining a measure/estimate/count
of the degree of hypercellularity, lipid-richness and/or presence
of inflammatory cells.
[0029] In some variations, the methods described herein may also
include the step of inserting a stent adjacent to the first
arterial tissue region when the index of restenosis indicates a
greater likelihood of restenosis. Other treatment methods may be
used as well. For example, tissue (additional tissue in some cases)
may be excited, the arterial region treated locally with one or
more drugs or therapies (e.g., ablated, heat-treated, etc.), or the
like.
[0030] In some variations of the methods described herein, tissue
(e.g., an arterial tissue region) may be removed from the patient
before or during the procedure, including before or during the
estimation of hypercellularity, lipid-richness or the presence of
inflammatory cells. In some variations it is the removed tissue
that is examined; in other variations in is the tissue left behind
that is examined; while in still other variations both tissues are
examined.
[0031] Also described herein are methods of preventing restenosis
in an arterial tissue. For example, a method of preventing
restenosis may include: determining an index of restenosis for a
first arterial tissue region based on a measure of
hypercellularlity of the first arterial tissue region and one or
both of a measure of how lipid-rich the first arterial tissue
region is and a measure of how many inflammatory cells are
associated with the first arterial tissue region; and inserting a
stent adjacent to the first arterial tissue region when the index
of restenosis indicates a greater likelihood of restenosis. As
mentioned above, in some variations other methods of treating the
artery may be used in addition to, or in place of, the insertion of
a stent.
[0032] The method may further include removing of tissue from the
first arterial tissue region, either before (to analyze) or after
(to treat). In some variations, the step of determining an index
comprises imaging the first arterial tissue region in real or
near-real time.
BRIEF DESCRIPTION OF THE DRAWINGS
[0033] FIG. 1 illustrates hypercellular tissue.
[0034] FIG. 2 shows an example of fibrocellular tissue.
[0035] FIG. 3 shows an example of fibrous tissue.
[0036] FIG. 4 shows an example of a lipid-rich region of
tissue.
[0037] FIG. 5 illustrates a region of tissue containing
inflammatory cells.
[0038] FIG. 6 shows a thrombus.
[0039] FIG. 7 shows an example of a hemorrhage.
[0040] FIG. 8 illustrates the media portion of arterial tissue.
[0041] FIG. 9 shows a portion of adventitia tissue.
[0042] FIG. 10 shows an example of a total section area.
[0043] FIG. 11 is a diagram schematically illustrating one method
of determining the risk of restenosis.
[0044] FIG. 12 schematically illustrates one variation of a system
for determining the risk of restenosis as described herein.
DETAILED DESCRIPTION OF THE INVENTION
[0045] Section I, below, describes the key observation that
quantitative histology may be used to predict rates of restenosis
in patients undergoing atherectomy. In particular, certain levels
of hypercellularity may indicate restenosis. The degree of
lipid-rich tissue, as well as the level of inflammatory cells in
the tissue may also be combined (individually or together) with the
level of hypercellularity or other factor to provide an indication
(which may be provided as an index) of the likelihood of
restenosis. Section II describes how these observations may be
applied.
Section I: Quantitative Histology
[0046] In an initial study, patients with angiographic follow up
data and with a good quality tissue sections for histological
evaluation were used. A total 409 specimens from native, primary
(de novo) coronary artery lesions, and 354 specimens from
restenosis lesion with prior intervention (balloon angioplasty,
directional atherectomy or both) were included for the
analysis.
Tissue Collection, Process and Slide Scan
[0047] Atherosclerotic tissue fragments were removed from the
collection chamber of atherectomy catheter and fixed in 10%
buffered formalin, processed through graded alcohols, and xylene,
and embedded in paraffin. Tissue sections of 4-6 um thick were cut
and stained with hematoxylin and eosin, Masson's trichrome, and
elastic van Gieson stains. The stained slides were scanned into
digital images using a slide scanner, e.g., ScanScope CS (Aperio,
Vista, Calif. 92081).
Characterization of Atherectomy Tissue Specimens
[0048] Various histological elements or components were described
as follow:
[0049] Hypercellular: Hypercellular plaque tissue was characterized
by the presence of numerous satellite-to-spindle shaped smooth
muscles cells within loose-to-mildly fibrotic stroma rich in
proteoglycan materials (see, e.g., FIG. 1).
[0050] Fibrocellular: Fibrocellular plaque tissue was consisted of
moderate amount of connective tissue and intermediate numbers of
smooth muscle cells (FIG. 2).
[0051] Fibrous: Fibrous plaque tissue was defined by presence of
abundant dense connective tissue with sparse cells (FIG. 3).
[0052] Lipid-rich: Lipid rich lesion was defined as an area of
amorphous materials containing cholesterol crystals, loosely
aggregated necrotic debris or collection of foam cells (FIG.
4).
[0053] Inflammatory cells: Inflammatory cell infiltration was
evidence by the presence of clusters of macrophages and lymphocytes
(FIG. 5).
[0054] Thrombus: Thrombus was defined as an organized collection of
fibrin, platelets and red blood cells (FIG. 6).
[0055] Hemorrhage: Hemorrhage was defined as collections of
erythrocytes within plaque matrix that were outside of vasa vasorum
and that resulted in some distortion of the plaque structure (FIG.
7).
[0056] Media: Media was recognized by the presence of internal
elastic membrane and more orderly smooth muscle cells and
connective tissue matrix (FIG. 8).
[0057] Adventitia: Adventitia was defined as a vessel layer
consisted of coarse fibrous connective tissue bundles with
fragments of external elastic membrane, and some times, admixed
small blood vessels or nerves (FIG. 9).
Evaluation and Quantification of Histological Elements
Atherosclerotic Plaque Tissue in Digital Images
[0058] The digital images were reviewed to define different
histological components in the section. ScanScope computer analysis
tools were used to draw boundaries around each tissue fragment and
measure total section area on the digital slide (FIG. 10).
Individual histological component was marked to calculate each
element area (FIG. 1.about.9). The individual component area was
then divided by the total section area to calculate individual
percentage for each component. From these measurements, a
quantitative histological dataset was built to include total
section area, individual component area, and percentage of each
element for every specimen.
Quantitative Histology and its Clinical Relevance
[0059] The quantitative histology data were combined with clinical
and angiographic follow-up information to analyze the relation
between individual histology component and clinical outcome after
directional atherectomy procedure.
Analysis
[0060] Tissue taken from all of the 825 patients (approximately
4000 specimens) was examined as described above. The analysis was
performed without any knowledge of the patient outcomes. As part of
the analysis, the criterion above were used to quantify the areas
of cellular hyperplasia, media, media and adventitia, thrombus and
hemorrhage, lipid and inflammatory cells, unidentified
fibrocellular, and fibrous tissue, by individually inspecting and
drawing the area around each component on over 4000 specimens. The
total section area was measured by computer and these values were
used to calculate the individual percentages for each component. A
summary of the measured components appears in Table 1, below. All
variables ending with mm.sup.2 represent the area measurements in
square mm while variables ending with area are expressed as
percentages of the total section area (for example, for the 825
slides available the square mm of fibrous area (fibareamm2)
averaged 3.18 mm.sup.2 and the total section area (totalsectionmm2)
averaged 9.70 mm.sup.2 so 33.3% of the total section was fibrous
tissue as determined by quantitative histology using this
system.
[0061] These histological results were matched using the DCA
procedure number on the tissue slides with the DCA number on the
follow-up records, and merged. The resultant database was used to
determine if there were any histological predictors for risk of
restenosis in the population combining de novo and restenosis
lesions. The analysis was repeated for patients who had not had a
previous procedure (de novo lesions) and repeated for those
patients who had been previously treated (restenosis lesions).
TABLE-US-00001 TABLE 1 Variable Obs Mean Std. Dev. Min Max fibarea
825 .3331044 .2082072 0 1.2124 fibareamm2 825 3.184831 3.075813 0
21.1463 fibrocellu~a 825 .4207189 1.364847 0 39.33 fibrocellu~2 825
3.557204 2.840935 0 20.8931 hyperarea 825 .1404861 .1890572 0 .8378
hyperareamm2 825 1.492413 2.889506 0 33.7809 lipidinfla~a 825
.0613177 .0835959 0 .6168 lipidinfla~2 825 .6174668 .9705671 0
7.4283 mediaadven~a 825 .0151333 .0513151 0 .7157 mediaadven~2 825
.1342177 .3881693 0 3.4761 mediaadven~m 825 .4599795 1.265656 0
11.9982 mediaarea 825 .0305399 .0611516 0 .5539 mediaareamm2 825
.2798194 .5173945 0 4.3514 medialengt~m 825 1.644731 2.626461 0
18.3675 medialengt~2 825 .1936225 .3852916 0 4.45 thromhemoa~a 825
.0483193 .1023152 0 1 thromhemoa~2 825 .4376082 1.02324 0 8.2718
totalsecti~2 825 9.703561 7.047 .1943 56.0936
[0062] As expected the best predictor of reduced risk of restenosis
was the post interventional minimal lumen diameter (MLD). The
larger the lumen that was achieved at the end of the intervention
the lower the restenosis rate (Baim and Kuntz bigger is better
theory).
[0063] For the 825 patients with saved slides, clinical and
follow-up quantitative angiography was available for 692 (83.3%) of
the patients. Using QCA the angiographic restenosis rate was 39.6%
(all pts), 37.5% (de novo pts) and 42.0% (restenosis pts).
[0064] Univariant analysis using Student's t-test showed that there
was an increased incidence of restenosis in de novo lesion
comparing the presence or absence of hypercellular plaque measured
quantitative histology. For de novo patients with hypercellular
plaque present in the histology the restenosis rate was 45% vs. 30%
when hypercellular plaque was absent. P=0.0019. This association
became even more pronounced when lipid and inflammatory cells were
present. In patients with de novo lesions that had both
hypercellular plaque as well as lipid and inflammatory cells the
restenosis rate was 50% compared to 28% when both
lipid/inflammatory cells and hypercellular plaque were not
present.
[0065] Stepwise logistic regression was then used to compare MLD
post intervention to the quantitative histological parameters
seeking to determine if any of the histology findings were
independent predictors of restenosis in the de novo patient
population. MLD post (p=0.000) and hypercellularity expressed as a
% of total section area (p=0.012) were both independent predictors
of restenosis. The % of tissue represented by media/adventitia
(p=0.317), lipid/inflammatory cells (p=0.881), and
thrombus/hemorrhage (p=0.394) were not independent predictors of
restenosis, as indicated in Table 2, below:
[0066] Iteration 0: log likelihood=-250.22451
[0067] Iteration 1: log likelihood=-236.74983
[0068] Iteration 2: log likelihood=-236.45296
[0069] Iteration 3: log likelihood=-236.45208
[0070] Iteration 4: log likelihood=-236.45208
[0071] Logit estimates Number of obs=377 [0072] LR chi2(5)=27.54
[0073] Prob>chi2=0.0000
[0074] Log likelihood=-236.45208 Pseudo R2=0.0550
TABLE-US-00002 TABLE 2 rsatfup Coef. Std. Err. z P > |z| [95%
Conf. Interval] postmm -.6996334 .1745044 -4.01 0.000 -1.041656
-.357611 hyperarea 2.422905 .9602835 2.52 0.012 .5407841 4.305026
Lipidinfla~a -.1721168 1.151897 -0.15 0.881 -2.429794 2.08556
mediaadven~a -2.131326 2.128189 -1.00 0.317 -6.302499 2.039848
thromhemoa~a .8373006 .9829864 0.85 0.394 -1.089317 2.763919 _cons
1.194315 .4874256 2.45 0.014 .238978 2.149651
[0075] When the analysis was repeated for those de novo patients
with both lipid/inflammatory cells and hypercellularity the
predicative value of quantitative histology increased. Step-wise
logistic regression showed the relationship between quantitative
histological evidence of hypercellularity and restenosis at 6-9
month follow-up to be more significant for both MLD post and
hypercellular % area (p=0.001 for both), as illustrated in Table
3.
[0076] Iteration 0: log likelihood=-180.79407
[0077] Iteration 1: log likelihood=-167.91003
[0078] Iteration 2: log likelihood=-167.6878
[0079] Iteration 3: log likelihood=-167.68732
[0080] Logit estimates Number of obs=269 [0081] LR chi2(2)=26.21
[0082] Prob>chi2=0.0000
[0083] Log likelihood=-167.68732 Pseudo R2=0.0725
TABLE-US-00003 TABLE 3 P > rsatfup Coef. Std. Err. z |z| [95%
Conf. Interval] postmm -.6572298 .2050497 -3.21 0.001 -1.05912
-.2553398 hyperarea 4.720442 1.38667 3.40 0.001 2.002619 7.438266
_cons 1.022995 .5513755 1.86 0.064 -.0576811 2.103671
[0084] These findings confirm that MLD post was an independent
predictor of restenosis in the de novo patient population (as
expected). However, the finding that quantitative histology
provides a new parameter as an independent predictor of restenosis
is surprising. When quantitative histology confirms the presence of
both hypercellularity and lipid/inflammatory cells, this
combination is as powerful as MLD post as an independent predictor
of restenosis. Unexpectedly, quantitative histology may provide a
new parameter as an independent predictor of restenosis. Based on
these findings, when quantitative histology confirms the presence
of both hypercellularity and lipid/inflammatory cells, this
combination is as powerful as MLD post as an independent predictor
of restenosis.
[0085] This new finding is not dependent on classical histological
techniques, such as those used above. Using light microscopy and
routine histological staining may take several days and may be of
limited value in helping drive decisions on patient treatment
during an actual procedure. Thus, described briefly in Section II
below are systems for providing real-time tissue characterization
with the resolution approaching that of light microscopy that allow
or provide tailored therapies directed toward the biology of the
lesion. For example, in some variations, Optical Coherence
Tomography may be used, although the general methods and
applications described herein are not limited to any particular
modality.
Section II: Applications
[0086] A system (e.g., a system for treating atherosclerosis) may
be provided that is configured to allow visualization (direct
imaging) or an indicator of one or more of any of the factors
described above. In a particular, a system may be configured to
provide visualization or an indication of hypercellularity,
lipid-rich tissue regions, and/or inflammatory cells. In some
variations the system may provide an index of one or more of these
factors, or a "restenosis index" based on one or more of these
factors. In some variations, the system may provide an image of a
tissue region (e.g., a peripheral vessel) that allows visualization
of one or more of hypercellularity, lipid-rich tissue and/or
inflammatory cells. The system may be configured so that multiple
versions of the same image are displayed that are specific for
showing one or more of these factors. The system may also include
logic that assists the user in identifying or quantifying these
factors.
[0087] In one example, a system for treating atherectomy includes
one or more visualization modalities that permit visualization one
or more of these factors. For example, an optical coherence
tomography (OCT) imaging modality may be used. OCT may therefore
provide real-time data indicating, for example, multicellularity,
lipid content and/or inflammatory cells. An OCT system may be
configured to use one or more wavelengths of light (or a band or
mixture of wavelengths) that is selective for one or more of these
features. Any of the imaging systems described herein (including
OCT) may be used in conjunction with one or more markers (e.g.,
vital dyes, contrast agents, etc.) to help visualize. In some
variations, the OCT may be used in vivo prior to excising the
tissue. In other variations, the tissue may be examined as (or
shortly after) it is removed from the vessel. Thus, any of the
systems described herein may include an atherectomy device such as
an atherectomy catheter. In some variations, the catheter may be
guided or controlled based in part of the feedback or guidance from
the determination/visualization of one or more of the factors
described herein. For example, regions of the tissue exhibiting
hypercellularity may be excised more completely or aggressively
than other stenotic regions, or may be treated by stenting and/or
the application of a local drug agent.
[0088] Preliminary analysis of human cadaver coronary artery tissue
by OCT compared to a routine light microscopic image of the same
vessel at the same site suggests that OCT may be configured to
distinguish the lipid and fibrous components. OCT variations that
may be used include OCT systems having multiple fibers,
polarization OCT imaging, multiple/selectable wavelength,
birefringence imaging using OCT, combinations of OCT imaging with
ultrasound or other tissue-perturbation techniques, or the like.
For example, OCT may be used to examine the elastic properties of
the tissue which may correspond to the lipid content. Perturbing
(e.g., vibrating) the tissue either directly (mechanically by
pushing against the tissue, including inflating a balloon against a
region of the tissue and imaging it) or using ultrasound (to
vibrate the tissue) may indicate the lipid composition of the
tissue region.
[0089] For example, FIG. 12 shows a schematic diagram of one
variation of a system (which may also be integrated in a device)
for determining the risk of restenosis. In this example, the
system/device includes a catheter 1203 using an OCT imaging
modality 1205, including a lensing region 1205 at the distal end
from which light may exit the side of the catheter for examining a
region of arterial wall. The system also includes a processor 1209
connected 1207 to receive images from the OCT subsystem (not
shown). The processor may be configured to include or execute
detection logic 1213 and/or index logic 1215 to measure, estimate
or otherwise determine the extent of hypercellularity and one or
both of lipid-richness and/or the presence of inflammatory cells.
The system may also include an output 1211, such as a monitor,
display, or the like. The output may display the image of the
arterial wall (or multiple images) as well as display or indicate
regions of hypercellularity and/or regions of high lipid-richness
and/or the inflammatory cells. In some variations the display shows
only region of high-risk for restenosis. The display may be
adjustable, and allowing the threshold to adjust the level of risk
of restenosis (e.g., changing a threshold above or below which
regions of high/low indexes for restenosis are shown).
[0090] Other imaging modalities that may be used with the systems
described herein, either alone or in combination, may include
ultrasound, angiography (e.g., QVA), CT, MRI, SPECT, PET/CT, X-ray,
etc. Virtually any imaging modality may be used, particularly those
that may provide images of vessel regions displaying
hypercellularity, lipid-rich tissue, and/or inflammatory cells.
[0091] Indication of the hypercellularity, lipid rich tissue,
inflammatory cells and/or other factors may be provided in real
time, near-real time, or otherwise during the procedure, as
mentioned above. "Near-real" time may refer to a slight delay
(e.g., time delayed images) compared to strict real time; for
example an image in near-real time may lag by a few seconds or
minutes. In some variations images illustrating the stenosed tissue
regions may be saved for later analysis. In still other versions
the tissue may be removed before the analysis, and correlated with
a particular region, or merely with a particular patient. For
example, an atherectomy device may be used to remove the tissue,
which can then be examined (including by staining, fixation, or
other treatments not typically advocated before removal from the
patient) for these factors.
[0092] Any of the systems described herein may be configured to
provide automated analysis of these factors. For example, a system
for treating atherosclerosis may include logic for analyzing images
of the vessel and determine an index of one or more of
hypercellularity, lipid-rich membrane, and/or inflammatory cells.
An index may be quantitative (e.g., a percentage, or percentage
area, or square or cubic area or density). The index may be
qualitative (e.g., "high", "medium", "low", etc.). An index for the
risk of restenosis may also be provided, based on the predictive
risks described above. For example, an index of restenosis may be
provided based (weighted heavily) on the degree or extent of very
active (e.g., hypercellularity) tissue when there is a significant
increase in lipid-rich tissue and/or inflammatory cells. Thus, in
some variations, the system may include image analysis logic
configured to examine one or more of the features described
above.
[0093] Logic (e.g., indexing or detecting logic) may include
computer-executable code (software), hardware, firmware, or any
combination of these. For example, detection and/or index logic may
be executable on or as part of a computer processor (e.g.,
microprocessor) that is either a general-purpose processor, a
distributed processor, or a dedicated processor (or
processors).
[0094] In some variations the system provides images that are
colored, highlighted, or otherwise marked to indicate regions
displaying some threshold (typically correlating to an enhanced
risk for restenosis) based on one or more of the factors described
herein. Multiple images may be displayed and/or marked, or a single
composite (e.g., "high risk" for restenosis) image may be
provided.
[0095] Also described herein are methods of determining a risk of
restenosis and methods of treating atherosclerosis. FIG. 11
illustrates one variation of a method determining (and treating)
restenosis.
[0096] In general, a method of determining a risk of restenosis as
described herein may include the steps of determining from the
tissues of a vessel if the tissue is hypercellular. The method may
also include determining if the tissue is lipid-rich and/or the
extent of inflammatory cells in the tissue. Determining if the
tissue is hypercellular, lipid-rich and/or the extent of
inflammatory cells may include determining a quantitative measure
of the extent of hypercellularity, lipid-rich tissue and/or the
extent of inflammatory cells. The tissue may be visualized and
these determinations may be made by a visual means, or the
determinations may be made without presenting an image of the
tissue.
[0097] Determining if a tissue is hypercellular may also include
determining the density of cells per unit area, or the density of a
marker for cells (e.g., nuclei, cell membranes, etc.). As mentioned
above, a determination of hypercellular tissue may mean simply
presenting an image of the tissue in a modality that allows
visualization of hypercellular tissue. For example, determining if
a tissue is hypercellular may mean displaying an OCT image taken
with a wavelength or plurality of wavelengths that permit
visualization of hypercellularity (or a birefringent image, a
polarized OCT image, etc.). Regions of relative hypercellularity
may be marked or unmarked on the image. Similarly, determining if a
tissue is lipid-rich may mean simply displaying an image of tissue
that shows the relative lipid-richness of the tissue, which may be
marked or unmarked on the image; determining the extent of
inflammatory cells may mean showing an image of a tissue in which
it is possible to detect inflammatory cells (or one or multiple
types).
[0098] In some variations, the determination steps described may
include adding a marker, dye, or indicator of the factor to be
evaluated (e.g., cellularity, lipid content, inflammatory cell,
etc.). The determining step may also include perturbing the tissue
so that the factor to be evaluated may be more readily determined
using a particular methodology that benefits from this perturbation
(e.g., by changing the temperature of the tissue, by vibrating the
tissue, by irradiating the tissue, etc.).
[0099] For example, in FIG. 11, the method includes the steps of
imaging a region of arterial tissue (e.g., arterial wall tissue or
a depth through a region of arterial wall) 1100. This region is
then examined to determine the extent of hypercellularity (e.g.,
estimating/counting/measuring the extent of hypercellularity) 1102.
The same region is examined to determine either: (1) the extent of
lipid-richness 1106; (2) the presence of inflammatory cells 1108;
or (3) both 1104. From these estimates (1102 and 1108, 1105 or
1104) an index reflecting the likelihood of restenosis may be
determined 1110. Optionally, if the risk of restenosis in this
region of the artery (e.g., the region adjacent to the tissue
examined) is sufficiently high, then the tissue may be treated to
prevent restenosis or to mitigate the effects of restenosis 1112.
As described herein, the magnitude of the index of restenosis may
be used to predict the likelihood of restenosis. For example, one
or more thresholds (e.g., confidence intervals) may be determined
for comparison to the index to predict restenosis. These confidence
intervals and/or thresholds may be determined experimentally (e.g.,
from population studies) or theoretically, e.g., extrapolated from
data such as that shown herein.
[0100] Methods of determining a risk of restenosis may also include
determining an index of restenosis based on the determination of
one or more of the factors mentioned herein, including
hypercellularity, lipid content, and/or inflammatory cells. In some
variations the index may be presented for the patient as a whole (a
global index) or for specific regions mapped to the patients
anatomy (e.g., within the vessels). Thus, a method of determining a
risk of restenosis may be present as an image or series of images
of the subject's vessel lumen, indicating regions of greater and/or
lesser risk. Any of the imaging modalities described herein may be
used in the determining steps mentioned above.
[0101] In some variations, the methods of determining the risk of
restenosis may also include the step of inserting a device
configured to help determine the risk of restenosis (e.g., a
catheter, probe, etc.) within the vessel. Alternatively, in some
variations, the method may include determining the risk
non-invasively, using one or more imaging modalities from outside
of a patient.
[0102] As mentioned, any of the methods described herein typically
include the step of determining if a tissue (e.g., peripheral
vascular tissue) is one or more of hypercellular, lipid-rich and/or
includes inflammatory cells. Any of these determining steps may
also include determining the extent to which the tissue is
hypercellular, lipid-rich and/or includes in inflammatory cells.
For example, a measure of hypercellular, lipid-richness and/or
density of inflammatory cells may be compared to a standard or
metric for these factors, based on the experimental data described
above. The measure may be +/-some percentage of a threshold value
(e.g., within +/-1%, 2%, 3%, 5%, 10%, 15%, 20%, 25%, 30%, 50%, etc.
of a threshold value indicated from the experimental data).
[0103] A method of treating atherosclerosis typically includes the
step of determining if a tissue (e.g., peripheral vascular tissue)
is one or more of hypercellular, lipid-rich and/or includes
inflammatory cells as mentioned above. This (these) determining
steps may include any of the variations described above. The method
of treating atherosclerosis may also include the step of removing
tissue from the vessel. This removing step may be performed before,
during or after the determining step(s).
[0104] In some variations, the method of treating atherosclerosis
also includes the step of treating regions of the vessel that have
a higher risk for restenosis (as suggested by the determination of
one or more of hypercellularity, lipid richness and/or inflammatory
cells) more aggressively than regions of lower risk. For example,
regions of de novo atherectomy lesions having a higher
hypercellularity and/or risk of restenosis may be treated with a
drug eluting stent while atherectomy alone or atherectomy with a
bare metal stent could be advised for less cellular lesions.
[0105] In some variations, the method of treating atherosclerosis
may include the step of providing a pharmacological agent if it is
determined that the subject is at greater risk for restenosis. For
example, based on a subject's overall risk of restenosis, the
subject may be given anticoagulants (e.g., clopidogrel (Plavix),
etc.), or drugs that prevent excessive cell division (e.g., within
the lumen), or the like.
[0106] The data describe above may also be interpreted to suggest
that good results may be achieved by getting the best possible
luminal gain with any intervention (atherectomy, stent, etc.) even
to the extent of resecting media and adventitia with atherectomy,
as long as the vessel is not perforated. Media and adventitia in
the quantitative histology was not associated with an increased
risk of restenosis, and a trend toward reduced restenosis was seen
when media was present (p=0.107) in the extracted tissue. These
data may support the concept that the cellularity of a de novo
lesion is an important predictor or restenosis intervention. Thus
any of the methods described herein that could maximize luminal
gain, avoid perforation, and characterize the underlying tissue
would be very desirable to reduce restenosis, either locally (e.g.,
at regions of greater risk for restenosis or in patients at higher
risk) or globally. Overall a determination of the risk of
restenosis may be useful to help guide the aggressiveness of the
treatment.
[0107] The examples and illustrations included herein show, by way
of illustration and not of limitation, specific embodiments in
which the subject matter may be practiced. Other embodiments may be
utilized and derived there from, such that structural and logical
substitutions and changes may be made without departing from the
scope of this disclosure. Such embodiments of the inventive subject
matter may be referred to herein individually or collectively by
the term "invention" merely for convenience and without intending
to voluntarily limit the scope of this application to any single
invention or inventive concept, if more than one is in fact
disclosed. Thus, although specific embodiments have been
illustrated and described herein, any arrangement calculated to
achieve the same purpose may be substituted for the specific
embodiments shown. This disclosure is intended to cover any and all
adaptations or variations of various embodiments. Combinations of
the above embodiments, and other embodiments not specifically
described herein, will be apparent to those of skill in the art
upon reviewing the above description.
* * * * *