U.S. patent application number 15/200950 was filed with the patent office on 2017-01-05 for system and method of assessing endothelial function.
The applicant listed for this patent is Everist Genomics, Inc.. Invention is credited to Thomas Stephen Everist, Peter F. Lenehan.
Application Number | 20170000355 15/200950 |
Document ID | / |
Family ID | 57609260 |
Filed Date | 2017-01-05 |
United States Patent
Application |
20170000355 |
Kind Code |
A1 |
Lenehan; Peter F. ; et
al. |
January 5, 2017 |
SYSTEM AND METHOD OF ASSESSING ENDOTHELIAL FUNCTION
Abstract
A medical diagnostic system and method for assessing endothelial
function comprise adjusting a reactive hyperemia indicator,
measured in response to a stimulus, based on an anthropomorphic
and/or demographic variable. The adjusted reactive hyperemia
indicator provides a more accurate reflection of endothelial
function and can be communicated to a clinician.
Inventors: |
Lenehan; Peter F.; (Chelsea,
MI) ; Everist; Thomas Stephen; (Denver, CO) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
Everist Genomics, Inc. |
Ann Arbor |
MI |
US |
|
|
Family ID: |
57609260 |
Appl. No.: |
15/200950 |
Filed: |
July 1, 2016 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
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62187793 |
Jul 1, 2015 |
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Current U.S.
Class: |
1/1 |
Current CPC
Class: |
A61B 8/488 20130101;
A61B 5/14551 20130101; A61B 5/14542 20130101; A61B 5/6824 20130101;
A61B 5/7239 20130101; A61B 5/0537 20130101; A61B 5/02225 20130101;
A61B 5/4836 20130101; A61B 8/06 20130101; A61B 5/02055 20130101;
A61B 8/0891 20130101; A61B 5/1495 20130101; A61B 5/02116 20130101;
A61B 5/02141 20130101; A61B 5/02007 20130101 |
International
Class: |
A61B 5/02 20060101
A61B005/02; A61B 8/08 20060101 A61B008/08; A61B 5/0205 20060101
A61B005/0205; A61B 5/0295 20060101 A61B005/0295; A61B 5/00 20060101
A61B005/00 |
Claims
1. A method for assessing endothelial function in a mammal, the
method comprising: applying a stimulus to generate reactive
hyperemia; measuring a reactive hyperemia indicator; adjusting the
reactive hyperemia indicator based on an anthropomorphic and/or
demographic variable to arrive at an endothelial function
indicator; and communicating the endothelial function indicator to
a clinician.
2. The method of claim 1, wherein the anthropomorphic or
demographic variable comprises a lean body mass of the mammal.
3. The method of claim 1, wherein the reactive hyperemia indicator
comprises at least one of a hemodynamic parameter or a
temperature.
4. The method of claim 3, wherein the hemodynamic parameter
comprises at least one of a volume; a pressure; an amplitude, a
frequency, or a shape of a plethysmographic wave form; a blood
vessel diameter; peripheral arterial tone changes; or any
derivative thereof.
5. The method of claim 3, wherein the temperature comprises a
fingertip temperature.
6. The method of claim 1, wherein the reactive hyperemia indicator
comprises a percentage of flow-mediated dilation.
7. The method of claim 6, wherein measuring the percentage of
flow-mediated dilation comprises assessing a change in arterial
volume of a limb segment of the mammal.
8. The method of claim 7, wherein assessing the change in arterial
volume of the limb segment comprises: determining amplitudes of
component pulse waves of detected volume pulse waves of the limb
segment detected during a baseline period prior to applying the
stimulus to determine a baseline arterial volume; determining
amplitudes of component pulse waves of detected volume pulse waves
of the limb segment detected during a time period after the
stimulus has been applied to determine a post-stimulus arterial
volume; and determining relative change in arterial volume of the
limb segment based on the difference between the baseline arterial
volume and the post-stimulus arterial volume.
9. The method of claim 8, wherein the component pulse wave is an
early systolic component.
10. The method of claim 6, wherein adjusting the reactive hyperemia
indicator comprises approximating a measure of reactive hyperemia
based on brachial artery ultrasound imaging.
11. The method of claim 1, wherein the adjusting step further
comprises using an algorithm to adjust the reactive hyperemia
indicator based upon (i) a lean body mass of the mammal and (ii) at
least one of a pulse pressure and a mean arterial pressure of the
mammal.
12. The method of claim 11, wherein the pulse pressure and the mean
arterial pressure are determined prior to measuring the reactive
hyperemia indicator.
13. The method of claim 11, wherein the adjusting step further
comprises using the algorithm to adjust the reactive hyperemia
indicator based upon the pulse pressure and the mean arterial
pressure, and wherein the pulse pressure and the mean arterial
pressure are differentially weighted in the algorithm.
14. The method of claim 13, wherein the greater the lean body mass,
the more the mean arterial pressure is weighted in the
algorithm.
15. The method of claim 13, wherein the smaller the lean body mass,
the more the pulse pressure is weighted in the algorithm.
16. The method of claim 1, wherein the applied stimulus comprises
at least one of a mechanical stimulation, a thermal stimulation, a
chemical stimulation, an electrical stimulation, a neurological
stimulation, a mental stimulation, or a physical exercise
stimulation.
17. The method of claim 1, wherein the applied stimulus comprises
an inflated cuff disposed on a limb segment of the mammal, the
inflated cuff imparting a supra-systolic pressure for a time period
sufficient to induce reactive hyperemia upon release of the
supra-systolic pressure.
18. A system for assessing endothelial function in a mammal, the
system comprising: a means for applying a stimulus to generate
reactive hyperemia; a means for measuring a reactive hyperemia
indicator; a means for adjusting the reactive hyperemia indicator
based on an anthropomorphic or demographic variable to arrive at an
endothelial function indicator; and a means for communicating the
endothelial function indicator to a clinician.
19. The system of claim 18, wherein the anthropomorphic or
demographic variable comprises a lean body mass of the mammal.
20. The system of claim 18, wherein the reactive hyperemia
indicator comprises at least one of a hemodynamic parameter or a
temperature.
21. The system of claim 20, wherein the hemodynamic parameter
comprises at least one of a volume; a pressure; an amplitude, a
frequency, or a shape of a plethysmographic wave form; a blood
vessel diameter; peripheral arterial tone changes; or any
derivative thereof.
22. The system of claim 20, wherein the temperature comprises a
fingertip temperature.
23. The system of claim 18, wherein the reactive hyperemia
indicator comprises a percentage of flow-mediated dilation.
24. The system of claim 23, wherein a means for measuring the
reactive hyperemia indicator comprises a means for assessing a
change in arterial volume of a limb segment of the mammal.
25. The system of claim 24, wherein a means for assessing the
change in arterial volume of the limb segment comprises: a means
for determining amplitudes of component pulse waves of detected
volume pulse waves of the limb segment detected during a baseline
period prior to applying the stimulus to determine a baseline
arterial volume; a means for determining amplitudes of component
pulse waves of detected volume pulse waves of the limb segment
detected during a time period after the stimulus has been applied
to determine a post-stimulus arterial volume; and a means for
determining relative change in arterial volume of the limb segment
based on the difference between the baseline arterial volume and
the post-stimulus arterial volume.
26. The system of claim 25, wherein the component pulse wave is an
early systolic component.
27. The system of claim 23, wherein a means for adjusting the
reactive hyperemia indicator comprises a means for approximating a
measure of reactive hyperemia based on brachial artery ultrasound
imaging.
28. The system of claim 18, wherein the means for adjusting further
comprises a means for using an algorithm to adjust the reactive
hyperemia indicator based upon (i) a lean body mass of the mammal
and (ii) at least one of a pulse pressure and a mean arterial
pressure of the mammal.
29. The system of claim 28, wherein the pulse pressure and the mean
arterial pressure are determined prior to measuring the reactive
hyperemia indicator.
30. The system of claim 28, wherein the means for adjusting further
comprises a means for using the algorithm to adjust the reactive
hyperemia indicator based upon the pulse pressure and the mean
arterial pressure, and wherein the pulse pressure and the mean
arterial pressure are differentially weighted in the algorithm.
31. The system of claim 30, wherein the greater the lean body mass,
the more the mean arterial pressure is weighted in the
algorithm.
32. The system of claim 30, wherein the smaller the lean body mass,
the more the pulse pressure is weighted in the algorithm.
33. The system of claim 18, wherein the applied stimulus comprises
at least one of a mechanical stimulation, a thermal stimulation, a
chemical stimulation, an electrical stimulation, a neurological
stimulation, a mental stimulation, or a physical exercise
stimulation.
34. The system of claim 18, wherein the applied stimulus comprises
an inflated cuff disposed on a limb segment of the mammal, the
inflated cuff imparting a supra-systolic pressure for a time period
sufficient to induce reactive hyperemia upon release of the
supra-systolic pressure.
35. A non-transitory machine-readable medium encoded with
instructions, that when executed by one or more processors, cause
the processor to carry out a process for assessing endothelial
function in a mammal, the process comprising: applying a stimulus
to generate reactive hyperemia; measuring a reactive hyperemia
indicator; adjusting the reactive hyperemia indicator based on an
anthropomorphic or demographic variable to arrive at an endothelial
function indicator; and communicating the endothelial function
indicator to a clinician.
Description
CROSS-REFERENCE TO RELATED APPLICATIONS
[0001] This application claims priority to U.S. provisional patent
application No. 62/187,793 titled "SYSTEM AND METHOD OF ASSESSING
ENDOTHELIAL FUNCTION," filed 1 Jul. 2015, which is hereby
incorporated by reference as though fully set forth herein. This
application is related to U.S. application Ser. No. 12/483,930,
filed 12 Jun. 2009 (the '980 application), now U.S. Pat. No.
8,057,400 B2, issued 15 Nov. 2011 (the '400 patent). The '980
application and the '400 patent are both hereby incorporated by
reference as though fully set forth herein.
FIELD
[0002] The present invention relates generally to assessing
endothelial function in a mammal.
BACKGROUND
[0003] Cardiovascular disease is a leading cause of morbidity and
mortality. It has been shown that the early stages of
cardiovascular disease can be diagnosed by assessing the ability of
the arteries to dilate in response to an increase in blood flow.
The degree of arterial dilation in response to an increased blood
flow correlates with the severity of cardiovascular disease.
[0004] Endothelial cells constitute the innermost lining of blood
vessels and produce nitric oxide, which is the predominant
vasodilator in the arterial system. An increase in blood flow
results in increased shear stress at the surface of endothelial
cells and initiates a signaling pathway that results in
phosphorylation and activation of nitric oxide synthase, and
increased production of nitric oxide. In addition to acting as a
potent vasodilator, endothelium-derived nitric oxide inhibits many
of the initiating steps in the pathogenesis of atherosclerotic
cardiovascular disease, including low-density lipoprotein uptake,
white cell adhesion to the vessel wall, vascular smooth muscle
proliferation, and platelet adhesion and aggregation.
[0005] Brachial artery flow-mediated dilation serves as a measure
of the bioavailability of endothelium-derived nitric oxide in
patients, and it has been used extensively in large clinical
studies to non-invasively detect systemic endothelial
dysfunction.
[0006] Several invasive and non-invasive techniques have been
developed to evaluate endothelial function. Invasive techniques,
which involve intra-coronary or intra-brachial infusions of
vasoactive agents, are considered to be the most accurate for the
detection of endothelial dysfunction. Due to their highly invasive
nature, the use of such techniques is limited and has led to the
development of several non-invasive techniques. The ultrasound
imaging of the brachial artery is the most commonly employed
non-invasive technique for the assessment of the vasodilatory
response. See, for example, Mary C. Corretti et al. J. Am. Coll.
Cardiol. 2002; 39:257-265, which is incorporated herein by
reference in its entirety. It utilizes continuous electrocardiogram
(EKG) gated two-dimensional ultrasound imaging on the brachial
artery before and after induction of arterial dilation by
five-minute cuff occlusion of the arm. The ultrasound imaging
technique is mostly used to assess (1) the changes in the diameter
of the brachial artery induced by administration of vasoactive
drugs; and (2) flow-mediated dilation, which follows an occlusion
of the brachial artery via inflating a cuff around the limb. Once
the cuff is released, the blood flow causes shear stress on the
endothelium, which, in turn, produces vasoactive substances that
induce arterial dilation. The increase in the diameter of the
brachial artery in healthy people is higher than that in patients
with endothelial dysfunction. However, even in healthy people, the
magnitude of the arterial dilation is not sufficient to be reliably
determined by the ultrasound imaging technique. A trained and
experienced operator is essential in obtaining meaningful data with
the ultrasound imaging technique. This difficulty limits the
testing of arterial dilation with the ultrasound imaging technique
to specialized vascular laboratories.
[0007] Most of the existing techniques do not quantify the amount
of stimulus delivered to the endothelium nor do they account for
other sources of nitric oxide such as the nitric oxide transported
and released by the blood cells in response to hypoxemia induced by
the temporary occlusion of the brachial artery. It has been shown
that these factors can significantly affect the amount of
flow-mediated dilation and, therefore, inject additional
variability into the test results obtained with equipment that does
not account for such factors.
[0008] U.S. Pat. No. 6,152,881 (to Rains et. al.), which is
incorporated herein by reference in its entirety, describes a
method of assessing endothelial dysfunction by determining changes
in arterial volume based on measured blood pressure using a
pressure cuff. The pressure cuff is held near diastolic pressure
for about ten minutes after an artery occlusion until the artery
returns to its normal state. The measured pressure during this time
is used to determine the endothelial function of the patient. The
extended period of applying cuff pressure to the limb affects
circulation, which in turn impacts the measurements.
[0009] U.S. Pat. No. 7,390,303 (to Dafni), which is incorporated
herein by reference in its entirety, describes a method of
assessing arterial dilation and endothelial function, in which the
relative changes in the cross sectional area of a limb artery are
assessed using a bio-impedance technique to monitor cross-sectional
area of a conduit artery. Measurements of bio-impedance are
difficult to perform. Since bio-impedance measurements involve
applying electrical to the skin of the patient, such measurements
are poorly tolerated by patients due to skin irritation. Further,
the measured signals vary greatly.
[0010] U.S. Pat. No. 7,074,193 (to Satoh et al.) and U.S. Pat. No.
7,291,113 (to Satoh et al.), which are incorporated herein by
reference in their entirety, describe a method and apparatus for
extracting components from a measured pulse wave of blood pressure
using a fourth order derivative and an n-th order derivative,
respectively.
[0011] A clinical need exists for a system and method that are
inexpensive, easy to perform, non-invasive, well tolerated by
patients, and provide an indication of the ability arteries to
respond to an increase in blood flow.
SUMMARY
[0012] Methods and diagnostic systems provide for assessing changes
in arterial volume of a limb segment of a mammal and for assessing
endothelial function of a mammal. In one aspect, a diagnostic
system determines amplitudes of component pulse waves of detected
volume pulse waves of a limb segment detected during a baseline
period to determine a baseline arterial volume of the limb segment.
The diagnostic system determines amplitudes of component pulse
waves of detected volume pulse waves of the limb segment detected
during a time period after a stimulus has been applied to the
mammal to induce a period of change in the arterial volume of the
limb segment. The diagnostic system determines relative change in
arterial volume of the limb segment during the time period after
the stimulus relative to the arterial volume of the limb during the
baseline period from the amplitudes of the component pulse waves of
the detected volume pulse waves at baseline and after the
stimulus.
[0013] In another aspect, the diagnostic system determines relative
change in arterial volume by comparing the amplitudes of the
component pulse waves of volume pulse waves at baseline and after
the stimulus.
[0014] In another aspect, the component pulse wave is an early
systolic component. In another aspect, the diagnostic system
determines relative change in arterial volume by comparing maximum
amplitudes of the early systolic components of the volume pulse
waves during the baseline period and maximum amplitudes of the
early systolic components of the volume pulse waves after the
stimulus.
[0015] In another aspect, the diagnostic system monitors the limb
segment to detect the detected volume pulse waves of the limb
segment during the baseline period, and monitors the limb segment
to detect the detected volume pulse waves of the limb segment
during an after-stimulus period.
[0016] In another aspect, a diagnostic system applies a stimulus to
generate reactive hyperemia, measures a reactive hyperemia
indicator, adjusts the reactive hyperemia indicator based on an
anthropomorphic or demographic variable to arrive at an endothelial
function indicator, and communicates the endothelial function
indicator to a clinician.
[0017] The features and advantages described in the specification
are not all inclusive and, in particular, many additional features
and advantages will be apparent to one of ordinary skill in the art
in view of the drawings, specification, and claims. Moreover, it
should be noted that the language used in the specification has
been principally selected for readability and instructional
purposes, and may not have been selected to delineate or
circumscribe the inventive subject matter.
BRIEF DESCRIPTION OF THE DRAWINGS
[0018] FIG. 1 is a pictorial diagram illustrating a diagnostic
system in accordance with the present invention.
[0019] FIG. 2 is a block diagram illustrating the diagnostic system
of FIG. 1.
[0020] FIG. 3 is a flow chart illustrating an operation of arterial
volume change assessment of the diagnostic system of FIG. 1.
[0021] FIG. 4 is a timing diagram illustrating pressure applied to
a limb during baseline testing and analysis and after-stimulus
testing and analysis of FIG. 3 with an occlusion providing a
stimulus.
[0022] FIG. 5 is a timing diagram illustrating amplitudes of early
systolic components of pulse waves measured during a baseline
period and an after-stimulus period of FIG. 4.
[0023] FIG. 6 is a graph illustrating correlation between the
normalized increases in amplitudes of early systolic components of
pulse waves of a segment of an arm as measured in some embodiments
and the increases in diameter of the brachial artery measured via
ultrasound imaging of the brachial artery.
[0024] FIG. 7 is a timing diagram illustrating blood flow and
systolic pressure after release of the occlusion in FIG. 4.
[0025] FIGS. 8a and 8b are timing diagrams illustrating, in an
expanded view, measured cuff pressure oscillations of a limb during
one inflation/deflation cycle of FIG. 4 before occlusion and during
one cycle of FIG. 4, respectively, after occlusion of blood vessels
in the limb.
[0026] FIG. 9 is a timing diagram illustrating pressure applied to
the limb during the baseline testing and analysis and
after-stimulus testing and analysis of FIG. 3 with an oral
administration of nitroglycerin providing a stimulus.
[0027] FIG. 10 is a timing diagram illustrating amplitudes of early
systolic components of pulse waves measured during a baseline
period, a stimulus period, and an after-stimulus period of FIG.
9.
[0028] FIG. 11 is a flow chart illustrating one embodiment of the
operation of arterial volume change assessment of FIG. 3.
[0029] FIG. 12 is a flow chart illustrating one embodiment of an
operation of determining amplitude of the arterial volume change
assessments of FIGS. 3 and 11.
[0030] FIG. 13 is a timing diagram illustrating a measured pulse
wave for a healthy person.
[0031] FIG. 14 is a timing diagram illustrating a measured pulse
wave for a patient with cardiovascular disease.
[0032] FIG. 15 is a flow chart illustrating one embodiment of an
operation of determining changes in arterial volume of the
operations of FIGS. 3 and 11.
[0033] FIG. 16 is a flow chart illustrating one embodiment of a
process for adjusting a reactive hyperemia indicator based on
anthropomorphic and/or demographic variables.
DETAILED DESCRIPTION
[0034] A preferred embodiment of the present invention is now
described with reference to the figures where like reference
numbers indicate identical or functionally similar elements. Also
in the figures, the leftmost digits of each reference number
corresponds to the figure in which the reference number is first
used.
[0035] FIG. 1 is a pictorial diagram illustrating a diagnostic
system 100 (also referred to herein as the ANGIODEFENDER system) in
accordance with the present invention. The diagnostic system 100
comprises a diagnostic device 102, a diagnostic computer 104, a
cuff 106, a Doppler transducer 108, and an oxygen saturation
(StO.sub.2) sensor 110.
[0036] As used herein, the volume pulse waves are oscillations in
the blood pressure between the systolic and the diastolic pressures
of arteries. The diagnostic system 100 detects the volume pulse
waves and performs diagnostics for assessing arterial volume
changes of a limb segment based on the detected pulse waves. In
some embodiments, the volume pulse wave includes a composite pulse
wave formed of a superposition of a plurality of component pulse
waves. The component pulse waves partially overlap and the arterial
pulse wave shape or contour is formed by the superposition of the
component pulse waves. The component pulse waves may include, for
example, an incident systolic wave (also called early systolic
wave), a reflected wave (also called late systolic wave), and other
waves. The diagnostic system 100 measures amplitudes of components
of arterial volume pulse waves as a way of monitoring the changes
in arterial volume of the limb segment after a stimulus. While it
may be easier to measure the amplitude of the whole arterial volume
pulse wave, the timing of the component pulse waves shifts
throughout the testing procedure and changes the shape of the pulse
wave. In some embodiments, the diagnostic system 100 measures
amplitude of a physiologically significant component (such as a
component pulse wave) of the volume pulse wave to assess the
changes in arterial volume of the limb segment. The diagnostic
system 100 may use any component pulse wave of the detected volume
pulse wave or portion thereof (such as maximum, inflection point,
or amplitude at a fixed time of the component pulse wave), any
portion of the volume pulse wave (such as maximum, inflection
point, or amplitude at a fixed time of the volume pulse wave), or a
combination thereof for the diagnostics for assessing arterial
volume changes. As an illustrative example, the operation of the
diagnostic system 100 is described herein in terms of the early
systolic wave.
[0037] In use, the cuff 106 is disposed around a limb 120 so that
when the cuff 106 is inflated, the cuff 106 constricts a segment of
the limb 120. It is understood by those skilled in the art that the
measurements of the changes in the arterial volume of a limb
segment described herein are not measuring the volume changes of
only a single artery in the limb 120, but are measuring the volume
changes in substantially all arteries in the segment of the limb
120 that is being constricted. Although the volume changes
measurements and the physiology thereof are described for a single
artery, one skilled in the art will recognize that the invention is
not restricted to a single artery and that the volume changes
measurements are of all or substantially all arteries in the
segment of the limb being measured. The limb 120 may be any limb or
digits thereof, but for the sake of simplicity, the limb 120 is
described as an arm, and the artery that is being evaluated is
described as the brachial artery. In some embodiments, the limb 120
is a leg and the artery is a femoral artery. Although the
diagnostic system 100 is described for use on a human being, the
invention is not so limited. The diagnostic system 100 can be used
on other mammals.
[0038] The diagnostic computer 104 provides control signals to the
diagnostic device 102 and receives information and detected data
from the diagnostic device 102.
[0039] The diagnostic device 102 provides air to and releases air
from the cuff 106 via a tube 112 of the cuff 106. The diagnostic
device 102 may control, detect and monitor the air pressure in the
tube 112. In some embodiments, a gas other than air, or a liquid,
such as water, may be used in the cuff 106, the tube 112, and the
pneumatic module 202 (see FIG. 2). In some embodiments, the cuff
can be an electrically-controlled elastomer or a
mechanically-controlled material.
[0040] Although the diagnostic system 100 is described herein as
applying a pressure via the cuff 106 to the limb 120 to occlude an
artery 122 as a stimulus of the endothelium as blood flows into the
artery 122 after release of the occlusion, other forms of stimuli
may be provided. In various embodiments, the stimulus of the
endothelium comprises a mechanical stimulation, a thermal
stimulation, a chemical stimulation, an electrical stimulation, a
neurological stimulation, a mental stimulation or a stimulation via
physical exercise, or any combination thereof, to induce a change
in arterial volume of the limb segment. The stimuli are well known
and some of them induce formation of nitric oxide by the
endothelial cells lining the walls of the arteries. In some
embodiments, the stimulus to the endothelium can also be delivered
in any way that transiently and locally increases the blood flow
and shear stress at the arterial wall. For instance, this can be
achieved by applying ultrasound waves such that it creates
turbulence inside a major artery. The chemical stimulation may be,
for example, a vasoactive agent, such as an oral administration of
nitroglycerol, or an intra-brachial infusion of acetylcholine.
[0041] The diagnostic device 102 provides control signals to and
receives measurement signals from the Doppler transducer 108 and
the oxygen saturation (StO.sub.2) sensor 110. The Doppler
transducer 108 and the oxygen saturation (StO.sub.2) sensor 110 are
used in some embodiments for the purpose of quantifying the amount
of a vasodilatory stimulus, such as a transient occlusion of the
arteries of the limb segment.
[0042] The Doppler transducer 108 is disposed on the limb 120 and
adjacent to the artery 122 in the limb 120 and distal or proximal
from the cuff 106 for measuring blood flow velocity in the artery
122 using a Doppler process. The Doppler transducer 108 may be any
conventional Doppler transducer designed to measure blood flow
velocity in a conduit artery. In some embodiments, the diagnostic
system 100 does not include a Doppler transducer 108.
[0043] The oxygen saturation (StO.sub.2) sensor 110 is disposed on
the limb 120 and distal from the cuff 106 for measuring oxygen
levels in the tissue of the limb to determine the extent to which
hemoglobin in the tissue is saturated with oxygen. The oxygen
saturation (StO.sub.2) sensor 110 may be any conventional StO.sub.2
sensor. In some embodiments, the diagnostic system 100 does not
include an oxygen saturation (StO.sub.2) sensor 110.
[0044] Although the Doppler transducer 108 and the oxygen
saturation sensor 110 are described herein as an apparatus to
quantify the amount of stimulus via occlusion, other apparatus to
quantify the amount of vasoactive stimuli may be provided.
[0045] Although the diagnostic computer 104 is described herein as
performing the control, computation, and analysis of the diagnostic
system 100, the invention is not so limited. The diagnostic device
102 may include a processor or microcontroller for performing any
or all of the operations described herein as being performed by the
diagnostic computer 104.
[0046] Although the diagnostic computer 104 is described herein as
being local to the blood diagnostic device 102, the diagnostic
computer 104 may be coupled to the diagnostic device 102 through a
communication line, system, or network, such as the Internet,
wireless, or landline. For example, the operation of the diagnostic
device 102 may be done near the patient while the diagnostic
computer 104 may remotely process the data.
[0047] FIG. 2 is a block diagram illustrating the diagnostic device
102. The diagnostic device 102 comprises a pneumatic module 202, a
pressure detector 204, a Doppler transducer system 206, an oxygen
saturation (StO.sub.2) sensor system 208, and an interface 210. The
pneumatic module 202 controls pressure in the cuff 106 in response
to control signals from the diagnostic computer 104. The pneumatic
module 202 comprises a pump 222 (e.g., an air pump) for
pressurizing air, a reservoir 224 for storing the pressurized air,
and a pressure controller 226 for controlling the release of air
via the tube 112 into the cuff 106.
[0048] The pressure detector 204 comprises a pressure sensor
electronics system 228 for controlling a pressure sensor 230, which
senses pressure in the cuff 106 via the tube 112. The pressure
sensor 230 detects pressure oscillations in the cuff 106 resulting
from pulse waves in the artery 122. In some embodiments, the
pressure sensor 230 is disposed in the cuff 106 or in the tube 112.
In some embodiments, the pressure sensor 230 is a plethysmography
sensor, such as a reflective photo-plethysmography sensor.
[0049] The interface 210 communicates control signals and
information signals between the diagnostic computer 104 and the
pneumatic module 202, the pressure detector 204, the Doppler
transducer system 206, and the oxygen saturation (StO.sub.2) sensor
system 208. The interface 210 may include a processor or
microcontroller for performing any or all of the operations
described herein.
[0050] The Doppler transducer system 206 communicates with the
Doppler transducer 108 for measuring blood flow velocity in the
artery 122. In some embodiments, the diagnostic computer 104
commands the Doppler transducer system 206 to measure blood flow
velocity through the artery 122 after the cuff pressure has been
released to assess the amount of stimulus delivered via shear
stress to the artery 122.
[0051] In some embodiments, the diagnostic computer 104 may include
test data of blood velocity and may use such test data to quantify
the amount of the post-occlusion stimulus in a patient. The
diagnostic computer 104 may use this data as part of the assessment
of changes in the arterial volume of the limb segment described
herein.
[0052] The oxygen saturation (StO.sub.2) sensor system 208
communicates with the oxygen saturation (StO.sub.2) sensor 110 to
measure oxygen levels in the tissue for determining the extent to
which the hemoglobin in the blood of the tissue is saturated with
oxygen.
[0053] In some embodiments, the diagnostic computer 104 may include
test data of oxygen saturation and may use such test data to
standardize the degree of limb ischemia among the test subjects,
and quantify the amount of the post-occlusion stimulus in a
particular patient. The diagnostic computer 104 may use this data
as part of the assessment of changes in the arterial volume of the
limb segment described herein.
[0054] FIG. 3 is a flow chart illustrating an operation of arterial
volume change assessment of the diagnostic system 100. Before
operating the diagnostic system 100, the cuff 106 is placed around
the limb 120 (e.g., arm) of the patient. The test is started with
an entry on the diagnostic computer 104 in any well known manner
such as keystrokes on a keyboard (not shown) or movement of a
cursor and selection of a screen button via a mouse (not shown). In
response to an initiation of the diagnostic command, the diagnostic
computer 104 assesses changes in the arterial volume of a segment
of the limb 120. The diagnostic computer 104 performs baseline
testing and analysis (block 302) during a baseline period 402 (see
FIG. 4 below). In some embodiments, the diagnostic system 100
detects and analyzes volume pulse waves of a segment of the limb
120 during the baseline period in which no stimulus is applied to
the patient. In some embodiments, the analysis of the volume pulse
waves includes determining amplitudes of the detected volume pulse
waves to calculate a baseline arterial volume of the segment of the
limb 120. One embodiment of the baseline testing is described below
in conjunction with FIG. 4.
[0055] A stimulus is applied to the patient to induce a period of
change in arterial volume of the segment of the limb 120 (block
304) during a stimulus period 404 (see FIG. 4 below). In some
embodiments, the diagnostic computer 104 commands the pneumatic
module 202 to pressurize the cuff 106 to a level sufficient to
occlude the artery 122. In some embodiments, the cuff 106 is
inflated to a pressure above systolic for a period of time
sufficient to induce change in arterial volume of the segment of
the limb 120 after releasing the cuff pressure.
[0056] The diagnostic computer 104 performs after-stimulus testing
and analysis (block 306) during an after-stimulus period 406 (see
FIG. 4 below). In some embodiments, the diagnostic system 100
detects and analyzes volume pulse waves of a segment of the limb
120 after the stimulus, such as a predetermined time after either
starting or terminating the application of the stimulus. In some
embodiments, the analysis of the volume pulse waves includes
determining amplitudes of early systolic components of the detected
volume pulse waves to calculate an after-stimulus arterial volume
of the segment of the limb 120. One embodiment of the
after-stimulus testing is described below in conjunction with FIG.
4. The analyses of blocks 302 and 306 may be performed separately
from the testing and at a later time.
[0057] The diagnostic computer 104 performs an arterial volume
change assessment (block 308). In some embodiments, the diagnostic
computer 104 calculates the relative change in arterial volume of
the limb 120 during the after-stimulus time period 406 (see FIG. 4
relative to the arterial volume of the limb 120 during the baseline
period 402 (see FIG. 4) from the amplitudes of the early systolic
component of volume pulse waves at baseline and after the stimulus.
One embodiment of the arterial volume change assessment is
described below in conjunction with FIG. 15.
[0058] In some embodiments, the assessment of the level of
hypoxemia (or oxygen saturation) can be included in the arterial
volume change assessment (block 308) and achieved by any method
that is compatible with the testing procedure (e.g., based on
non-pulsatile measurements of hypoxemia if a cuff 106 is used to
occlude the artery). In some embodiments, the assessment of
post-occlusion blood velocity or blood shear stress can be included
in the arterial volume change assessment (block 308) and achieved
by any method that is compatible with the testing procedure (e.g.,
based on Doppler measurements).
[0059] FIG. 4 is a timing diagram illustrating pressure applied to
the limb 120 during the baseline testing and analysis (block 302)
and after-stimulus testing and analysis (block 306) of FIG. 3 with
an occlusion providing a stimulus. Prior to the procedure described
in FIG. 4, a patient's blood pressure is measured to select an
individualized pressure that will be applied to the limb. During
blood pressure measurements, the diagnostic system 100 determines
systolic, diastolic, and mean arterial pressures, which may be done
in a conventional manner. Once the blood pressure measurements are
performed, the individualized pressure applied to the patient's
limb is determined as a percentage of diastolic, or systolic, or
mean arterial pressure. It can also be determined according to a
formula based on the patient's blood pressure. For instance, the
pressure applied to the patient's limb may be computed as the
patient's diastolic pressure minus 10 mm Hg. Standardization of the
pressure applied to each patient allows the comparison of the test
data among patients in whom blood pressures are different.
[0060] As an illustrative example, during a baseline period 402
(e.g., 150 seconds), the diagnostic device 102 measures the resting
arterial volume pulse waves of the brachial artery 122, which are
indicative of the resting diameter of the brachial artery 122.
During the baseline period 402, the diagnostic system 100 commands
the diagnostic device 102 to perform a series of rapid inflations
412 and deflations 414 of the cuff 106, and to collect data from
the pressure sensor 230. (For the sake of clarity, only ten
inflations 412 and ten deflations 414 are shown, but other numbers
may be used. For the sake of clarity only one inflation/deflation
cycle is labeled.) In each cycle, the cuff is rapidly inflated 412
to a pressure, such as the sub-diastolic arterial pressure, and
held inflated 416 for a predetermined time (e.g., 4 to 6 seconds)
and then held deflated 418 for a predetermined time (e.g., 4 to 10
seconds). In some embodiments, the diagnostic computer 104 may
dynamically determine the time of the inflation 416 and the number
of pulses based on the measurements. While the cuff 106 is inflated
416, the diagnostic device 102 detects a plurality of pressure
oscillations (or volume pulse waves).
[0061] After the baseline period 402, the diagnostic device 102
inflates the cuff 106 to a supra-systolic pressure (e.g., systolic
pressure plus 50 mm Hg) to temporarily occlude the artery 122 for
an occlusion period 403 (e.g., about 300 seconds). Concurrent with
the occlusion, the oxygen saturation (StO.sub.2) sensor electronics
208 controls the oxygen saturation (StO.sub.2) sensor 110 to
monitor the level of hypoxemia in the limb distal to the occluding
cuff.
[0062] Thereafter, the diagnostic device 102 rapidly deflates the
cuff 106 (e.g., to a pressure below venous pressure, for instance,
below 10 mm Hg) to allow the blood flow to rush into the limb 120
during a stimulus period 404. The pressure release of the cuff 106
creates a rapid increase in the blood flow in the artery 122, which
generates shear stress on the endothelium of the brachial artery
122. The shear stress stimulates the endothelial cells to produce
nitric oxide (NO), which dilates the artery 122.
[0063] Concurrent with the cuff deflation, the Doppler transducer
electronics 206 controls the Doppler transducer 108 to collect data
for a predetermined time (e.g., 10-180 seconds) during which time
the Doppler transducer 108 measures blood velocity.
[0064] During an after-stimulus period 406, the diagnostic system
100 commands the diagnostic device 102 to perform a series of rapid
inflations 422 and deflations 424 of the cuff 106, and to collect
data from the pressure sensor 230 in a manner similar to that for
the baseline period 402 for a predetermined time (e.g., 1-10
minutes). (For the sake of clarity, only fourteen inflations 422
and fourteen deflations 424 are shown, but other numbers may be
used. For the sake of clarity only one inflation/deflation cycle is
labeled.) In each series, the cuff is rapidly inflated to a
pressure, and held inflated 426 for a predetermined time (e.g., 4
to 6 seconds), and then deflated 428. In some embodiments, the
diagnostic computer 104 may dynamically determine the time of the
inflation 426 and the number of pulses detected based on the
measurements. During this time, the diagnostic computer 104
monitors the dynamics of changes in arterial volume of a limb
segment (a gradual increase in pulse wave amplitude to maximum and
then a gradual decrease in the pulse wave amplitude to return to a
resting state).
[0065] FIG. 5 is a timing diagram illustrating amplitudes of early
systolic components of pulse waves measured during the baseline
period 402 and the after-stimulus period 406 of FIG. 4.
[0066] FIG. 6 is a graph illustrating correlation between the
normalized increases in amplitudes of early systolic components of
volume pulse waves of a segment of an arm as measured in some
embodiments and the increases in diameter of a brachial artery
measured via ultrasound imaging of the brachial artery. Each data
point in the graph corresponds to a different patient. The stimulus
in both methods was a 5-minute occlusion of the brachial artery via
cuff inflation to a supra-systolic pressure. A normalization of the
test results obtained with the present invention accounts for the
fact the diagnostic system 100 assesses the change in the volume of
substantially all arteries in the limb segment, while the
ultrasound imagining visualizes only the main artery.
[0067] FIG. 7 is a timing diagram illustrating blood flow and
systolic pressure after release of the occlusion in FIG. 4 during
the stimulus period 404. A line 701 shows a rapid increase in blood
flow followed by a decrease to normal flow. A line 702 shows the
temporary drop in systolic pressure after the occlusion.
[0068] FIGS. 8a and 8b are timing diagrams illustrating measured
cuff pressure oscillations of the limb 120 during one
inflation/deflation cycle before occlusion (FIG. 8a) and during one
cycle after occlusion (FIG. 8b) of blood vessels in the limb 120 in
an expanded view. During the cuff pressure sequence, data is
collected about the oscillations in the cuff pressure due to the
pulsation of the brachial artery. The changes in the oscillatory
amplitude (or the amplitude of a pulse wave) are related to the
changes in the radius of the brachial artery, and FIG. 8b shows the
pulse wave amplitude after occlusion being larger than the pulse
wave amplitude before occlusion.
[0069] In some embodiments, arterial volume pulse waves are
detected using an external pressure that is applied to the segment
of the limb 120. In some embodiments, the externally applied
pressure varies gradually between near-systolic and near-diastolic.
In some embodiments, the external pressure is applied by initially
applying the external pressure at a pressure near systolic, and
gradually reducing the external pressure to a pressure near
diastolic. In some embodiments, the external pressure is applied by
initially applying the external pressure at a pressure near
diastolic, gradually increasing to a pressure near systolic at a
rate to allow the oscillations to be detected, and then quickly
decreasing the pressure.
[0070] In some embodiments, as shown in FIGS. 4 and 9, an applied
external pressure is cycled between a high level and a low level so
that the arterial volume pulse waves are determined while the
external pressure is at the high level. In some embodiments, the
high level is below diastolic pressure and the low level is below
venous pressure.
[0071] In some embodiments, the high level 416 or 426 is maintained
for no more than 10 seconds in any cycle. In some embodiments, the
low level 418 or 428 is maintained for at least 4 seconds in any
cycle. In some embodiments, the measurements are taken over at
least one cardiac cycle.
[0072] FIG. 9 is a timing diagram illustrating pressure applied to
the limb 120 during the baseline testing and analysis (block 302)
and after-stimulus testing and analysis (block 306) of FIG. 3 with
an oral administration of nitroglycerin providing a stimulus.
Because there is no occlusion period 403, the diagnostic system 100
generates a series of rapid inflations 422 and deflations 424 with
an inflation state 426 and measures the volume pulse waves during
the baseline period 402, the stimulus period 404 and the
after-stimulus period 406.
[0073] FIG. 10 is a timing diagram illustrating amplitudes of early
systolic components of pulse waves measured during the baseline
period 402, the stimulus period 404 and the after-stimulus period
406 of FIG. 9.
[0074] FIG. 11 is a flow chart illustrating one embodiment of the
operation of arterial volume change assessment (block 308 of FIG.
3). In response to an initiation of the diagnostic command from the
user, the diagnostic computer 104 assesses change in the arterial
volume of a segment of the limb 120. The diagnostic device 102
detects volume pulse waves of a segment of the limb during the
baseline period 402, such as described above in conjunction with
FIGS. 4-8 (or FIGS. 9-10, depending on the stimulus) (block 1102).
In some embodiments, the diagnostic computer 104 commands the
pneumatic module 202 to pressurize the cuff 106 to a level
sufficient for the pressure detector 204 to detect volume pulse
waves of a segment of the limb 120.
[0075] The diagnostic device 102 determines amplitudes of early
systolic components of the detected volume pulse waves (block
1104). In some embodiments, the diagnostic computer 104 commands
the pressure detector 204 to detect volume pulse waves of the
segment of the limb 120. The diagnostic computer 104 analyzes the
waveforms of the detected volume pulse waves and determines
relevant amplitudes of the volume pulse waves for the baseline
period. In one embodiment, the relevant amplitude of a pulse wave
is the difference between the maximum and the minimum pressures of
the pulse wave. In some embodiments, the relevant amplitude is the
amplitude of the early systolic component. One embodiment for
determining amplitudes of block 1104 is described below in
conjunction with FIG. 12. (Blocks 1102 and 1104 may be used for the
block 302 of FIG. 3).
[0076] The diagnostic device 102 applies a stimulus during the
stimulus period 402 to induce a period of change in arterial volume
of the segment of the limb 120 (block 1106). In some embodiments,
the diagnostic computer 104 commands the pneumatic module 202 to
pressurize the cuff 106 to a level sufficient for occluding the
artery 122. (Block 1106 may be used for the block 306 of FIG. 3;
other examples of stimuli are described above in conjunction with
FIG. 1 and FIGS. 9-10).
[0077] The diagnostic device 102 detects volume pulse waves of the
segment of the limb 120 during the after-stimulus period 406 to
detect change in arterial volume of a limb segment, such as
described above in conjunction with FIGS. 4-8 (block 1108). In some
embodiments, the diagnostic computer 104 commands the pneumatic
module 202 to pressurize the cuff 106 to a level sufficient for the
pressure detector 204 to detect volume pulse waves of a segment of
the limb 120.
[0078] The diagnostic device 102 determines amplitudes of early
systolic components of the detected volume pulse waves after the
stimulus (block 1110). In some embodiments, the diagnostic computer
104 commands the pressure detector 204 to detect volume pulse waves
of the segment of the limb 120. The diagnostic computer 104
analyzes the waveforms of the detected volume pulse waves and
determines relevant amplitudes of the volume pulse waves for the
baseline period. In one embodiment, the relevant amplitude of a
pulse wave is the difference between the maximum and the minimum
pressures of the pulse wave. In some embodiments, the relevant
amplitude is the amplitude of the early systolic component. One
embodiment for determining amplitudes of block 1110 is described
below in conjunction with FIG. 12. (Blocks 1108 and 1110 may be
used for the block 306 of FIG. 3).
[0079] The diagnostic device 102 performs an arterial volume change
assessment (block 1112). In some embodiments, the diagnostic
computer 104 calculates the relative change in arterial volume of
the limb segment 120 during the after-stimulus time period 406
relative to the arterial volume of the limb 120 during the baseline
period 402 from the amplitudes of the early systolic component of
volume pulse waves at baseline and after the stimulus. In some
embodiments, the diagnostic computer 104 calculates the relative
change by comparing the amplitudes of early systolic component of
volume pulse waves at baseline (block 1104) and after the stimulus
(block 1106). (Block 1112 may be used for the block 308 of FIG. 3).
One embodiment of the arterial volume change assessment is
described below in conjunction with FIG. 15.
[0080] FIG. 12 is a flow chart illustrating one embodiment of an
operation of determining amplitude of the arterial volume change
assessments (block 308 of FIG. 3 and block 1112 of FIG. 11). The
diagnostic computer 104 determines the amplitude of the early
systolic component of a volume pulse wave by computing fourth
derivative of the detected volume pulse wave (block 1202). The
diagnostic computer 104 determines a time at which the fourth
derivative crosses the zero-line for the third time (block 1204).
(A third zero-line crossing 1322 of FIG. 13 below and a third
zero-line crossing 1422 of FIG. 14 below.) In some embodiments, the
diagnostic computer 104 may instead determine the second derivative
of the detected volume pulse wave. In some embodiments, the
diagnostic computer 104 may instead determine an inflection point
in the volume pulse wave and use the time of occurrence of the
inflection point. In some embodiments, the diagnostic computer 104
may instead use Fourier transformation of the volume pulse wave to
determine the time of occurrence of the peaks of the pulse
component pulse waves.
[0081] The diagnostic computer 104 determines a pressure value on
the detected volume pulse wave at that time (block 1206). The
diagnostic computer 104 determines a pressure value at the
beginning of the volume pulse wave (block 1208). In some
embodiments, the diagnostic computer 104 determines the pressure
value at the beginning of the volume pulse wave by determining a
minimum during the diastolic component of the pulse wave. The
diagnostic computer 104 assesses the amplitude of the early
systolic component of the volume pulse wave as the difference
between the pressure values (block 1210).
[0082] In some embodiments, the diagnostic computer 104 may compute
other orders of derivatives in block 1202, or not compute a
derivative, but instead determine the inflection point
corresponding to the peak of the early systolic component of the
pulse wave by other methods. In other embodiments, the diagnostic
computer 104 may determine the maximum amplitude of the arterial
volume pulse waves.
[0083] FIG. 13 is a timing diagram illustrating a measured pulse
wave for a healthy person. A pulse wave 1300 includes an early
systolic component 1302 and a late systolic component 1304. (The
pulse wave 1300 may include other component pulse waves, which are
not shown.) The early systolic component 1302 forms an inflection
point 1310 in the pulse wave 1300. Because of the amplitude and the
timing of the late systolic component 1304, the maximum of the
pulse wave 1300 coincides with the peak of the early systolic
component 1310. A line 1320 is a fourth derivative of the pulse
wave 1300 and includes a third zero-line crossing point 1322. The
crossing point 1322 is used to determine the time and amplitude
1312 of the early systolic component.
[0084] During the after-stimulus period, the shape of the arterial
volume pulse wave changes to a pulse wave 1350. The pulse wave 1350
includes an early systolic component 1352 and a late systolic
component 1354. (The pulse wave 1350 may include other component
pulse waves, which are not shown.) The early systolic component
1352 forms an inflection point 1360 in the pulse wave 1350. During
the after stimulus period, the amplitude and the timing of the late
systolic component 1352 change slightly and the maximum 1366 of the
pulse wave 1350 no longer coincides with the peak of the early
systolic component 1360. Yet, the amplitude 1362 of the early
systolic component 1352 and the amplitude (distance 1362 plus the
distance 1364) of the maximum 1366 of the pulse wave 1350 differ
slightly.
[0085] FIG. 14 is a timing diagram illustrating a measured pulse
wave for a patient with cardiovascular disease. A pulse wave 1400
includes an early systolic component 1402 and a late systolic
component 1404. (The pulse wave 1400 may include other component
pulse waves, which are not shown.) The early systolic component
1402 forms an inflection point 1410 in the pulse wave 1400. Because
of the amplitude and the timing of the late systolic component
1404, the maximum of the pulse wave 1400 coincides with the peak of
the early systolic component 1410. A line 1420 is a fourth
derivative of the pulse wave 1400 and includes a third zero-line
crossing point 1422. The crossing point 1422 is used to determine
the time and amplitude 1412 of the early systolic component.
[0086] During the after-stimulus period, the shape of the arterial
volume pulse wave changes to a pulse wave 1450. A pulse wave 1450
includes an early systolic component 1452 and a late systolic
component 1454. (The pulse wave 1450 may include other component
pulse waves, which are not shown.) The early systolic component
1452 forms an inflection point 1460 in the pulse wave 1450. During
the after stimulus period the amplitude and the timing of the late
systolic component change significantly and the maximum 1466 of the
pulse wave 1450 no longer coincides with the peak of the early
systolic component 1460. The amplitude 1462 of the early systolic
component 1452 and the amplitude (distance 1462 plus the distance
1464) of the maximum 1466 of the pulse wave 1450 differ
significantly.
[0087] The diagnostic system 100 may use the differences in the
pulse wave characteristics of FIGS. 13-14 to compute arterial
indexes (for instance, the augmentation index) to assess the
cardiovascular status of the patient.
[0088] FIG. 15 is a flow chart illustrating one embodiment of an
operation of determining changes in arterial volume of the
operations of FIGS. 3 and 11. The diagnostic computer 104
determines average pulse wave amplitude per each
inflation/deflation cycle over the measurement period and obtains a
graph such as the graph described above in conjunction with FIG.
5.
[0089] The diagnostic computer 104 calculates an average
(AVG.sub.baseline) of the calculated average amplitudes of the
early systolic components of pulse wave measured during the
baseline 402 (block 1502). For the after-stimulus period 406, the
diagnostic computer 104 calculates a curve that fits the
after-stimulus data of the early systolic components of pulse wave
measured during the after-stimulus 406 (block 1504), using for
example, a fourth-order polynomial function. The diagnostic
computer 104 calculates a maximum (MAX.sub.after) of the fitted
curve of the after-stimulus data (block 1506). The diagnostic
computer 104 calculates a time from the end of the occlusion (or
other stimulus) to the maximum of the fitted curve of the
after-stimulus data (block 1508). The diagnostic computer 104
calculates a relative amplitude change from the baseline to the
maximum of the fitted curve of the after-stimulus data (block
1510).
[0090] The diagnostic computer 104 calculates relative change in
arterial volume .DELTA.V (block 1512) as follows:
.DELTA.V=[(MAX.sub.after-AVG.sub.baseline)/AVG.sub.baseline]
[0091] The diagnostic computer 104 calculates relative change in
arterial radius as follows (block 1512):
.DELTA.R=[(.DELTA.V+1).sup.1/2-1],
The relative change in radius .DELTA.R is defined as follows:
.DELTA.R=[(R.sub.after-R.sub.baseline)/R.sub.baseline],
where R.sub.after is the maximum after-stimulus radius of the
artery and R.sub.baseline is the arterial radius at baseline.
[0092] In some embodiments, the diagnostic computer 104 may compute
an area under the fitted curve for the after-stimulus data, in
addition to or instead of the determination of the maximum of the
fitted curve of block 1506. In some embodiments, the diagnostic
computer 104 determines the area under the curve by integrating the
fitted polynomial function of block 1504 from the time the stimulus
ends to either the time when the measured amplitude returns to the
baseline or to the end of the test. In some embodiments, the
diagnostic computer 104 extrapolates the fitted curve of block 1504
to the time at which the measured amplitude returns to baseline. In
some embodiments, the diagnostic computer 104 computes other
parameters (e.g., the width at half-height) from the fitted curve
of block 1504 to calculate the relative change in arterial
volume.
[0093] The diagnostic computer 104 may provide any or all of the
raw data and processed data to a doctor or clinical researcher via
a display, paper or other manners well known to those skilled in
the art. In some embodiments, the diagnostic computer 104 provides
a doctor processed data such as 1) relative % change in arterial
volume of a limb segment after a stimulus (for example, after 5 min
cuff occlusion, the arterial volume changed by 57%) as a reflection
of the ability of the arteries to dilate in response to the
stimulus; 2) computed relative maximum % change in the radius of
the artery after the stimulus; time to maximum change in arterial
volume (for instance, 72 sec); 4) area under the curve; and 5)
pulse wave characteristics (time difference between the peaks of
early and late systolic waves, augmentation index, etc.) as
indicators of arterial stiffness. In some embodiments, the
diagnostic computer 104 provides a doctor raw data, such as
detected volume pulse waves in each inflation/deflation cycles.
[0094] Although the diagnostic system 100 is described as including
one cuff 106, other numbers of cuffs 106 may be used. In some
embodiments, the diagnostic system 100 includes two cuffs 106. One
cuff 106 is disposed on the limb 120 and occludes the artery 122,
and the other cuff 106 is disposed on the limb 120 distal to the
first cuff 106, and detects the pressure oscillations.
Alternatively, one cuff 106 is disposed on the limb 120 and detects
the pressure in the artery 122, and the other cuff 106 is disposed
on the limb 120 distal to the first cuff 106, and occludes the
artery 122.
[0095] In an embodiment, the diagnostic computer 104 can provide a
percentage of flow-mediated dilation (% FMD), that has been used as
an indicator of endothelial function. The % FMD can be determined
by the diagnostic computer 104 based on the change in arterial
volume post-occlusion vs. pre-occlusion, which, in turn, can be
determined from the percent change in blood pressure post-occlusion
vs. pre-occlusion, as measured by cuff 106 and reflected as pulse
wave amplitude changes by pressure sensor 230 (described above with
respect to FIGS. 1 and 2). This unadjusted % FMD determined by
diagnostic computer 104 will henceforth be referred to as "AD-%
FMD.sub.U" to indicate that it is derived from the ANGIODEFENDER
system described above and in the '400 patent. While AD-% FMD.sub.U
is comparable to % FMD determined using brachial artery ultrasound
imaging (BAUI-% FMD), the gold standard for measuring flow-mediated
dilation, the correlation between AD-% FMD.sub.U and BAUI-%
FMD.sup.1 can be further optimized. Therefore, the present
inventors have developed an algorithm, based on anthropomorphic
and/or demographic factors, for adjusting AD-% FMD.sub.U to better
correlate with BAUI-% FMD. .sup.1 It should be noted that BAUI-%
FMD, as used herein, includes both unadjusted BAUI-% FMD
measurements and BAUI-% FMD measurements that have been adjusted
based on baseline brachial artery size or other allometric factors.
Unadjusted BAUI-% FMD is calculated based on the percent change in
brachial artery diameter post-occlusion vs. pre-occlusion.
[0096] Based on data obtained using the ANGIODEFENDER system in a
29-person clinical pilot study conducted at Yale University in June
through August of 2014, the present inventors initially determined
that segregation of subjects by lean body mass (LBM), followed by
subsequent adjustments to the subjects' AD-% FMD.sub.U based on
mean arterial pressure (MAP) and pulse pressure (PP), yielded
"adjusted AD-% FMD" (hereinafter AD-% FMD.sub.A) values that were
more comparable (based on Deming regression analysis) to BAUI-%
FMD. It was further determined that both steps performed in the
given order--LBM segregation first followed by subsequent MAP/PP
adjustment--were necessary to achieve AD-% FMD.sub.A values that
correlate well with BAUI-% FMD and, therefore, provide an improved
endothelial function indicator.
[0097] FIG. 16 illustrates the initial adjustment process 1600 the
inventors applied to AD-% FMD.sub.U values to obtain AD-% FMD.sub.A
values that more closely approximate BAUI-% FMD. At block 1602,
AD-% FMD.sub.U values were determined using the ANGIODEFENDER
technology. Specifically, AD-% FMD.sub.U values were determined
according to the following equation:
AD - FMD U = [ [ [ PWA MAX - PWA PREOCC PWA PREOCC + 1 ] 1 / 2 - 1
] * [ 100 / C ] PWA MAX : Maximum post - occlusion pulse wave
amplitude ( PWA ) PWA PREOCC : Median pre - occlusion PWA C = 3.4
##EQU00001##
[0098] At step 1604, the AD-% FMD.sub.U values were segregated
based on LBM. LBM was determined according to the following
equation:
LBM (Lean Body Mass; kg)=((100-% BF)/100)*BMI*BSA
% BF (% body fat)=(((Wt/((Ht/100)
2))*1.2)+(Age*0.23)-(Gender*10.8)-5.4) [0099] =weight (kg) [0100]
=height (cm) [0101] Age=years [0102] Gender=male (1); female
(0)
[0102] BMI (Body Mass Index)=Wt/((Ht/100) 2))
BSA (Body Surface Area)=0.007184*(Ht 0.725)*(Wt 0.425))
It should be noted, however, that alternate equations or methods
can be used to calculate LBM, as well as BMI and BSA. It is
believed that segregation based on LBM is important as a first
adjustment step because the cardiovascular system has evolved for
efficient distribution of metabolic substrates, such as oxygen, to
tissue mass with high metabolic potential (e.g. LBM). LBM may be
more reflective of metabolic potential than other body size
variables, such as weight. It should also be noted that in some
embodiments anthropomorphic and/or demographic factors other than
LBM can be used to segregate the AD-% FMD.sub.U values. Examples of
such factors include height, weight, age, gender, BMI, or BSA.
[0103] In the initial adjustment process 1600, 35 kilograms (kg)
was used as the threshold value by which to segregate LBM
measurements. Thus, at block 1606A, subjects with LBM of 35 kg or
greater were separated, and at block 1606B, subjects with LBM of
less than 35 kg were separated.
[0104] At block 1608A, the AD-% FMD.sub.U of subjects with LBM
greater than or equal to 35 kg was divided by MAP.sup.2 to arrive
at the AD-% FMD.sub.A. At block 1608B, the AD-% FMD.sub.U of
subjects with LBM less than 35 kg was divided by PP.sup.2 to arrive
at the AD-% FMD.sub.A. Both MAP and PP can be determined by the
diagnostic system 100 during baseline testing, prior to
occlusion.
[0105] In an embodiment, the steps and equations of process 1600
can all be combined into a single equation in which LBM segregation
is taken into account. In one embodiment, the equation is as
follows:
AD-% FMD.sub.A=[Int+{(10.sup.7*AD-% FMD.sub.U)/(Xpp*(U*PPrz)
z)+(1-Xmap)*([k*MAP] w))}]/slope
where:
Int=y-intercept of a least-squares regression line of
{(10.sup.7*AD-% FMD.sub.U)/(Xpp*([j*PP] z)+(1-Xmap)*([k*MAP] w))}
vs BAUI-% FMD
Xpp=ae [-be (-c*(D.sub.PP-LBM))]
Xmap=ae [-be (-c*(D.sub.MAP-LBM))]
slope=slope of a least-squares regression line of {(10.sup.7*AD-%
FMD.sub.U)/(Xpp*([j*PP] z)+(1-Xmap)*([k*MAP] w))} vs BAUI-% FMD
[0106] Constants: j, z, k, w, a, b, c, Dpp, Dmap [0107] [constant]
[value]=`constant` raised to the power designated by the `value`,
in base 10 [constant]e [value]=`constant` raised to the power
designated by the `value`, in base e In an example, the constant j
is equal to about 4.4, the constant k is equal to about 0.5, the
constant z is equal to about 3.2, the constant w is equal to about
4.5, the constant a is equal to about 1, the constant b is equal to
about 2, and the constant c is equal to about 0.8. In an example,
Dpp is equal to about 31.9, Dmap is equal to about 33.4, slope is
equal to about 0.7 and Int is equal to about 2.6.
[0108] In the above equation, MAP and PP are weighted
differentially based on LBM. The greater the LBM, the more heavily
MAP is weighted in the equation. Conversely, the smaller the LBM,
the more heavily the PP is weighted in the equation.
[0109] In an embodiment, AD-% FMD.sub.A can be calculated by a
processor (not shown) located within diagnostic computer 104. In an
alternative embodiment, raw data (e.g., LBM, MAP, PP, AD-%
FMD.sub.U, and BAUI-% FMD) from the diagnostic computer 104 can be
communicated, via wired or wireless means, to an external processor
(not shown) configured to calculate AD-% FMD.sub.A The diagnostic
computer 104 can further be configured to communicate the AD-%
FMD.sub.A to a clinician (e.g., a doctor, a nurse, a healthcare
worker, or a clinical researcher).
[0110] While the above equation for AD-% FMD.sub.A requires AD-%
FMD.sub.U as an input value, other measures of reactive hyperemia
can be used in place of AD-% FMD.sub.U. For example, other
hemodynamic parameters can be used to measure reactive hyperemia
after a stimulus has been applied to a subject. Some examples of
such hemodynamic parameters include a blood volume; a blood
pressure; an amplitude, frequency, or shape of a plethysmographic
wave; a blood vessel diameter; peripheral arterial tone changes; or
any derivative thereof. These hemodynamic parameters that serve as
indicators of reactive hyperemia can be adjusted, similar to AD-%
FMD.sub.U.
[0111] In addition, temperature can be used as a measure of
reactive hyperemia. A change in the temperature of a digit (e.g., a
fingertip) post-stimulus vs. pre-stimulus is an indication of
reactive hyperemia and can therefore be adjusted according the
above equation, similar to AD-% FMD.sub.U. A change in fingertip
temperature can be detected by a temperature sensor (not shown)
communicatively linked to the diagnostic device 102 and/or the
diagnostic computer 104.
[0112] Reference in the specification to "some embodiments" means
that a particular feature, structure, or characteristic described
in connection with the embodiments is included in at least one
embodiment of the invention. The appearances of the phrase "in some
embodiments" in various places in the specification are not
necessarily all referring to the same embodiment.
[0113] Some portions of the detailed description that follows are
presented in terms of algorithms and symbolic representations of
operations on data bits within a computer memory. These algorithmic
descriptions and representations are the means used by those
skilled in the data processing arts to most effectively convey the
substance of their work to others skilled in the art. An algorithm
is here, and generally, conceived to be a self-consistent sequence
of steps (instructions) leading to a desired result. The steps are
those requiring physical manipulations of physical quantities.
Usually, though not necessarily, these quantities take the form of
electrical, magnetic or optical signals capable of being stored,
transferred, combined, compared and otherwise manipulated. It is
convenient at times, principally for reasons of common usage, to
refer to these signals as bits, values, elements, symbols,
characters, terms, numbers, or the like. Furthermore, it is also
convenient at times, to refer to certain arrangements of steps
requiring physical manipulations of physical quantities as modules
or code devices, without loss of generality.
[0114] However, all of these and similar terms are to be associated
with the appropriate physical quantities and are merely convenient
labels applied to these quantities. Unless specifically stated
otherwise as apparent from the following discussion, it is
appreciated that throughout the description, discussions utilizing
terms such as "processing" or "computing" or "calculating" or
"determining" or "displaying" or "determining" or the like, refer
to the action and processes of a computer system, or similar
electronic computing device, that manipulates and transforms data
represented as physical (electronic) quantities within the computer
system memories or registers or other such information storage,
transmission or display devices.
[0115] Certain aspects of the present invention include process
steps and instructions described herein in the form of an
algorithm. It should be noted that the process steps and
instructions of the present invention could be embodied in
software, firmware or hardware, and when embodied in software,
could be downloaded to reside on and be operated from different
platforms used by a variety of operating systems.
[0116] The present invention also relates to an apparatus for
performing the operations herein. This apparatus may be specially
constructed for the required purposes, or it may comprise a
general-purpose computer selectively activated or reconfigured by a
computer program stored in the computer. Such a computer program
may be stored in a computer readable storage medium, such as, but
is not limited to, any type of disk including floppy disks, optical
disks, CD-ROMs, magnetic-optical disks, read-only memories (ROMs),
random access memories (RAMs), EPROMs, EEPROMs, magnetic or optical
cards, application specific integrated circuits (ASICs), or any
type of media suitable for storing electronic instructions, and
each coupled to a computer system bus. Furthermore, the computers
referred to in the specification may include a single processor or
may be architectures employing multiple processor designs for
increased computing capability.
[0117] The algorithms and displays presented herein are not
inherently related to any particular computer or other apparatus.
Various general-purpose systems may also be used with programs in
accordance with the teachings herein, or it may prove convenient to
construct more specialized apparatus to perform the required method
steps. The required structure for a variety of these systems will
appear from the description below. In addition, the present
invention is not described with reference to any particular
programming language. It will be appreciated that a variety of
programming languages may be used to implement the teachings of the
present invention as described herein, and any references below to
specific languages are provided for disclosure of enablement and
best mode of the present invention.
[0118] Any numerical values or ranges presented herein include a
range of +100% to -50% when proceeded by terms like "about" or
"approximately."
[0119] While particular embodiments and applications of the present
invention have been illustrated and described herein, it is to be
understood that the invention is not limited to the precise
construction and components disclosed herein and that various
modifications, changes, and variations may be made in the
arrangement, operation, and details of the methods and apparatuses
of the present invention without departing from the spirit and
scope of the invention as it is defined in the appended claims.
* * * * *