U.S. patent application number 10/867237 was filed with the patent office on 2004-11-18 for ultrasound imaging.
Invention is credited to Eriksen, Morten, Frigstad, Sigmund, Ostensen, Jonny, Rongved, Pal.
Application Number | 20040230122 10/867237 |
Document ID | / |
Family ID | 26312461 |
Filed Date | 2004-11-18 |
United States Patent
Application |
20040230122 |
Kind Code |
A1 |
Eriksen, Morten ; et
al. |
November 18, 2004 |
Ultrasound imaging
Abstract
A combined preparation comprising: i) an ultrasound contrast
agent capable of accumulation in tissue microvasculature; and ii) a
pharmacologically effective amount of a vasodilator drug may be
used in perfusion imaging, especially of the myocardium. The
contrast agent accumulates in tissue in concentrations related to
the regional rate of tissue perfusion, and the vasodilator drug
enhances distinction between normally perfused and underperfused
tissue.
Inventors: |
Eriksen, Morten; (Oslo,
NO) ; Ostensen, Jonny; (Oslo, NO) ; Frigstad,
Sigmund; (Trondheim, NO) ; Rongved, Pal;
(Oslo, NO) |
Correspondence
Address: |
Li Cai
Amersham Health, Inc.
101 Carnegie Center
Princeton
NJ
08540
US
|
Family ID: |
26312461 |
Appl. No.: |
10/867237 |
Filed: |
June 14, 2004 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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10867237 |
Jun 14, 2004 |
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09553048 |
Apr 20, 2000 |
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09553048 |
Apr 20, 2000 |
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PCT/GB98/03155 |
Oct 21, 1998 |
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60084879 |
May 8, 1998 |
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60071710 |
Jan 16, 1998 |
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Current U.S.
Class: |
600/458 ;
424/9.51 |
Current CPC
Class: |
A61K 49/223
20130101 |
Class at
Publication: |
600/458 ;
424/009.51 |
International
Class: |
A61B 008/14 |
Foreign Application Data
Date |
Code |
Application Number |
Oct 21, 1997 |
GB |
9722224.4 |
Apr 28, 1998 |
GB |
9809099.6 |
Claims
What is claimed is:
1-10. (Canceled)
11. A combined preparation for use as a contrast agent in
ultrasound perfusion imaging, said preparation comprising: i) an
ultrasound contrast agent which following injection into the
vascular system of a human or non-human animal subject will
accumulate in tissue microvasculature of said subject at
concentrations dependent on regional rates of perfusion within said
tissue; and ii) a vasodilatation-inducing amount of a vasodilator
drug.
12. A preparation as claimed in claim 11 wherein said vasodilator
is a substance which is endogenous to said subject.
13. A preparation as claimed in claim 12 wherein said vasodilator
drug is adenosine.
14. A preparation as claimed in claim 11 wherein said ultrasound
contrast agent comprises a phase shift colloid.
15. A preparation as claimed claim 11 wherein said ultrasound
contrast agent comprises a targetable ultrasound contrast agent
having affinity for sites and/or structures within tissue
microvasculature.
16. A preparation as claimed in claim 15 wherein said ultrasound
contrast agent comprises at least one vector having affinity for
normal or activated endothelial cells.
17. A preparation as claimed in claim 15 wherein said ultrasound
contrast agent comprises at least one protein or peptide which
binds to cell-surface proteoglycans.
18. A method of generating enhanced perfusion images of a human or
non-human animal subject which comprises the steps of: i) injecting
into the vascular system of said subject an ultrasound contrast
agent which following injection will accumulate in tissue
microvasculature of said subject at concentrations dependent on
regional rates of perfusion within said tissue; ii) coadministering
a vasodilatation-inducing amount of a vasodilator drug; and iii)
generating an ultrasound image representing perfusion of a target
organ or tissue.
19. A method as claimed in claim 18 wherein images representative
of myocardial perfusion are generated.
20. A preparation as claimed in claim 12 wherein said ultrasound
contrast agent comprises a phase shift colloid.
21. A preparation as claimed in claim 13 wherein said ultrasound
contrast agent comprises a phase shift colloid.
22. A preparation as claimed in claim 12 wherein said ultrasound
contrast agent comprises a targetable ultrasound contrast agent
having affinity for sites and/or structures within tissue
microvasculature.
23. A preparation as claimed in claim 13 wherein said ultrasound
contrast agent comprises a targetable ultrasound contrast agent
having affinity for sites and/or structures within tissue
microvasculature.
24. A preparation as claimed in claim 11 wherein said ultrasound
contrast agent comprises: i) an injectable aqueous medium having
gas dispersed therein, said dispersed gas having affinity for sites
and/or structures within tissue microvasculature; and ii) a
composition comprising a diffusible component, said diffisible
component being separate from said dispersed gas and being capable,
following administration of said contrast agent to said subject, of
diffusion in vivo into said dispersed gas so as to promote
controllable growth and temporary retention of said dispersed gas
within tissue microvasculature in said subject.
Description
[0001] This invention relates to ultrasound imaging, more
particularly to use of ultrasound imaging in visualising tissue
perfusion, i.e. blood flow per unit of tissue mass, in particular
cardiac perfusion.
[0002] It is well known that contrast agents comprising dispersions
of gas microbubbles are particularly efficient backscatterers of
ultrasound by virtue of the low density and ease of compressibility
of the microbubbles. Such microbubble dispersions, if appropriately
stabilised, may permit highly effective ultrasound visualisation
of, for example, the vascular system and tissue microvasculature,
often at advantageously low doses.
[0003] Measurements of tissue perfusion are of importance in, for
example, tumour detection, tumour tissue typically having different
vascularity from healthy tissue, and studies of the myocardium,
e.g. to evaluate the blood supply thereto. Whilst contrast agent
detection using current ultrasound imaging techniques may provide
information as to whether particular organs or regions thereof are
perfused or not, it does not readily permit quantification of
levels of perfusion. Such information, which is useful in assessing
whether a patient is at risk owing to low perfusion and so may
benefit from preventative methods and/or treatment, must currently
be obtained using radioisotopic imaging techniques such as
scintigraphy, positron emission tomography or single photon
emission computed tomography. These techniques all involve
injection of radioactive substances, with potential safety risks
for both the patient and medical staff, and use of expensive
imaging equipment; this inevitably prohibits their widespread
use.
[0004] It is known from radionucleide cardiac imaging that patients
may be subjected to physical or pharmacological stress in order to
enhance the distinction, and thus the difference in imaging
intensities, between normally perfused myocardium and any
myocardial regions supplied by stenotic arteries. Such stress
induces vasodilatation and increased blood flow in healthy
myocardial tissue, whereas blood flow in underperfused tissue
supplied by a stenotic artery is substantially unchanged since the
capacity for arteriolar vasodilatation is already exhausted by
inherent autoregulation seeking to increase the restricted blood
flow.
[0005] The application of stress as physical exercise or
pharmacologically by administration of adrenergic agonists may
cause discomfort such as chest pains in patient groups potentially
suffering from heart disease, and it is therefore preferable to
enhance the perfusion of healthy tissue by administration of a
vasodilating drug.
[0006] The present invention is based on the finding that
ultrasound contrast agents capable of accumulation in tissue
microvasculature may be used in perfusion imaging, especially of
the myocardium, when coadministered with a pharmacologically
effective amount of a vasodilating drug. Because such contrast
agents will accumulate in tissue in concentrations related to the
regional rate of tissue perfusion, ultrasound imaging modalities
such as conventional or harmonic B-mode imaging where the display
is derived from return signal intensities will provide images which
may be interpreted as perfusion maps in which the displayed signal
intensity is a function of local perfusion. This is in contrast to
images obtained using free-flowing contrast agents, where the
regional concentration of contrast agent and corresponding return
signal intensity depend on the actual blood content rather than the
rate of perfusion of local tissue.
[0007] A disadvantage of existing radionucleide cardiac imaging
techniques is that the uptake of radionucleide tracers such as
thallium 201 and technetium sestamibi is limited by low contact
time between tracer and tissue and so may require maintenance of
vasodilatation for the whole period of blood pool distribution for
the tracer (e.g. 4-6 minutes for thallium scintigraphy) to ensure
optimum effect. Accumulative ultrasound contrast agents used in
accordance with the present invention, on the other hand, do not
suffer such diffusion or transport limitations and, especially
where accumulation occurs through a process of physical entrapment,
may undergo highly efficient retention in tissue microvasculature.
The period of vasodilatation needed to achieve cardiac or other
perfusion imaging in accordance with the invention may therefore be
short, for example less than one minute; this will reduce the
duration of any possible discomfort caused to patients by
administration of vasodilator drugs.
[0008] In accordance with one embodiment of the invention there is
provided a combined preparation for use as a contrast agent in
ultrasound perfusion imaging, especially cardiac perfusion imaging,
said preparation comprising:
[0009] i) an ultrasound contrast agent capable of accumulation in
tissue microvasculature, e.g. of the myocardium; and
[0010] ii) a pharmacologically effective amount of a vasodilator
drug.
[0011] According to a further embodiment of the invention there is
provided a method of generating enhanced perfusion images,
especially cardiac perfusion images, of a human or non-human animal
subject which comprises the steps of:
[0012] i) injecting an ultrasound contrast agent capable of
accumulation in tissue microvasculature, e.g. of the myocardium,
into the vascular system of said subject;
[0013] ii) coadministering a pharmacologically effect amount of a
vasodilator drug; and
[0014] iii) generating an ultrasound image representing perfusion
of a target organ or tissue, especially the myocardium.
[0015] Representative vasodilator drugs useful in accordance with
the invention include endogenous/metabolic vasodilators such as
lactic acid, adenosine triphosphate, adenosine diphosphate,
adenosine monophosphate, adenosine, nitric oxide and agents causing
hypercapnia, hypoxia/hypoxemia or hyperemia; phosphodiesterase
inhibitors such as dipyridamole and sildenafil; sympathetic
activity inhibitors such as clonidine and methyldopa; smooth muscle
relaxants such as papaverine, hydralazine, dihydralazine and
nitroprusside; beta receptor agonists such as dopamine, dobutamine,
arbutamine, albuterol, salmeterol and isoproterenol; alpha receptor
antagonists such as doxazosin, terazosin and prazosin; organic
nitrates, such as glyceryl trinitrate, isosorbide dinitrate and
isosorbide mononitrate; angiotensin converting enzyme (ACE)
inhibitors such as benazepril, captopril, enalapril, fosinopril,
lisinopril, quinapril and ramipril; angiotensin II antagonists (or
AT1 receptor antagonists) such as valsartane, losartan and
candesartan; calcium channel blockers such as amlodipine,
nicardipine, nimodipine, felodipine, isradipine, diltiazem,
verapamil and nifedipine; prostaglandins such as alprostadil; and
endothelium-dependent vasodilators.
[0016] In view of the fact that the required vasodilatation may
need only to be short lasting, adenosine is a particularly useful
vasodilating drug, being both an endogenous substance and having a
very short-lasting action as evidenced by a blood pool half-life of
only a few seconds. Vasodilatation will accordingly be most intense
in the heart, since the drug will tend to reach more distal tissues
in less than pharmacologically active concentrations, and may
result in coronary blood flow in healthy myocardial tissue
increasing by more than 400%. It will be appreciated that because
of this short half-life, repeated injection or infusion of
adenosine may be necessary during cardiac imaging in accordance
with the invention; by way of example, an initial administration of
150 .mu.g/kg of adenosine may be made substantially simultaneously
with administration of the contrast agent, followed 10 seconds
later by slow injection of a further 150 .mu.g/kg of adenosine,
e.g. over a period of 20 seconds.
[0017] One category of accumulative contrast agents useful in
accordance with the invention comprise gas-containing contrast
agent preparations which promote controllable and temporary growth
of the gas phase in vivo following administration owing to the
presence of a diffusible component capable of inward diffusion into
the dispersed gas phase to promote temporary growth thereof,
thereby acting as deposited perfusion tracers. Such compositions
therefore comprise:
[0018] i) an injectable aqueous medium having gas dispersed
therein; and
[0019] ii) a composition comprising a diffusible component capable
of diffusion in vivo into said dispersed gas so as at least
transiently to increase the size thereof. Accumulative contrast
agents of this type are extensively described in WO-A-9817324, the
contents of which are incorporated herein by reference.
[0020] The dispersed gas in such a preparation may, for example,
comprise air, nitrogen, oxygen, carbon dioxide, hydrogen, an inert
gas, a sulphur fluoride, selenium hexafluoride, an optionally
halogenated silane, an optionally halogenated low molecular weight
hydrocarbon (e.g. having a molecular weight such that it is
substantially or completely in gaseous form at the normal human
body temperature of 37EC), a ketone, an ester or a mixture of any
of the foregoing. The use of perfluorinated gases, for example
sulphur hexafluoride, perfluorinated ketones, perfluorinated ethers
and perfluorocarbons, including perfluoroalkanes such as a
perfluoropropane, perfluorobutane or perfluoropentane,
perfluoroalkenes and perfluorocycloalkanes, may be particularly
advantageous in view of the recognised high stability in the
bloodstream of microbubbles containing such gases.
[0021] The dispersed gas may, for example, be in the form of
microbubbles stabilised (e.g. at least partially encapsulated) by a
coalescence-resistant surface membrane such as gelatin, a
filmogenic protein (e.g. an albumin such as human serum albumin), a
polymer material, a non-polymeric and non-polymerisable
wall-forming material or a surfactant (e.g. a phospholipid,
preferably such that at least 75% of the surfactant material
comprises molecules individually bearing net overall charge, for
example negative charge as in phosphatidylserines,
phosphatidylglycerols, phosphatidylinositols, phoaphatidic acids
and cardiolipins).
[0022] The diffusible component may advantageously be dispersed in
an aqueous carrier liquid in the form of an oil-in-water emulsion
or microemulsion and may, for example, comprise an aliphatic ether
such as diethyl ether; a polycyclic oil or alcohol such as menthol,
camphor or eucalyptol; a heterocyclic compound such as furan or
dioxane; an aliphatic hydrocarbon or cycloaliphatic hydrocarbon,
e.g. containing up to 7 carbon atoms; or halogenated low molecular
weight hydrocarbon, e.g. contaning up to 7 carbon atoms. The use of
perfluorocarbons, e.g. a perfluoroalkane such as perfluoropentane
or perfluorohexane, a perfluoroalkene, a perfluorocycloalkane such
as perfluorodimethylcyclo-bu- tane, or a perfluorinated alcohol may
be advantageous.
[0023] Where the diffusible component is formulated as an emulsion
it may advantageously be stabilised using a phospholipid
surfactant, e.g. as described above in connection with the
stabilisation of gas dispersions.
[0024] The diffusible component may be administered by any
appropriate route, for example cutaneously, subcutaneously,
intramuscularly, intravenously or by inhalation.
[0025] A further class of accumulative ultrasound contrast agent
which may be used in accordance with the invention comprises phase
shift colloids such as are described in WO-A-9416739, the contents
of which are incorporated herein by reference. Such agents comprise
colloidal dispersions of the liquid-in-liquid type in which the
dispersed liquid has a boiling point below the body temperature of
the subject to be imaged, so that it may volatilise to form
expanding gas microbubbles following administration. Representative
examples of such agents include emulsions of volatile hydrocarbons,
particularly perfluorocarbons such as perfluoropentane, for example
stabilised with surfactants such as phospholipids, e.g. as
described above in relation to emulsions of diffusible
components.
[0026] A still further class of accumulative ultrasound contrast
agents which may be used in accordance with the invention comprises
targetable ultrasound contrast agents having affinity for sites
and/or structures within tissue microvasculature. Such targetable
agents will typically comprise (i) a reporter moiety capable of
interacting with ultrasound irradiation to generate a detectable
signal; (ii) one or more vectors having affinity for particular
target sites and/or structures; and (iii) one or more linkers
connecting said reporter and vector(s), in the event that these are
not directly joined.
[0027] Reporters which may be useful in such targetable agents
include any of the gas-containing systems hereinbefore described in
the context of gas-containing ultrasound contrast agent
formulations.
[0028] The targetable agents may, for example, comprise vectors
which have affinity for normal or activated endothelial cells such
that they target the vascular endothelium and become at least
transiently concentrated on the walls of blood vessels. Activation
of endothelium may for example be caused by microbial infections,
infarcts or ischemia. Representative vectors in this context
include ligands for cell adhesion molecules, for instance proteins
or carbohydrate-containing molecules, as well as cell adhesion
molecules themselves where these have corresponding ligands on
endothelial cell surfaces. Examples of cell adhesion molecules
occuring on activated endothelial cell surfaces include integrins,
such as ICAM-1, most of which bind the Arg-Gly-Asp (RGD) amino acid
sequence. Specific cell adhesion molecules may occur, or occur in
elevated amounts, in relation to the formation of thrombi, for
instance blood coagulation factors, e.g. such as Factor XIII, and
glycoproteins such as GP IIb/IIIa on activated blood platelets.
Thrombi may be targeted by platelet binding peptides such as
PLYKKIIKKLLES, NDGDFEEIPEEYLQ and GPRG. Atherosclerotic plaques may
be targeted by specific peptides such as YRALVDTLK,
YAKFRETLEDTRDRMY and RALVDTEFKVKQEAGAK. Damaged vessel walls may
expose targetable myocyte-specific molecules. Angiogenesis may
cause elevation of receptors to VEGF and tumours may be targeted by
cholecystokinin, alpha-melanocyte-stimulating hormone, heat stable
enterotoxin 1, vasoactive intestinal peptide,
.alpha..sub.v.beta..sub.3 (vitronectin receptor), uPAR (urokinase
plasminogen activator receptor), oncofetal fibronectin, synthetic
alpha-M2 peptide from the third heavy chain complementarity
determining region and analogues thereof. Further references to
this technology, e.g. in targeting to fibrin, thrombi and
atherosclerotic areas are found in publications by Alkanonyuksel, H
et al. in J. Pharm. Sci. (1966) 85 (5), 486-490; J. Am. Coll.
Cardiol. (1996) 27 (2) Supl A, 298A; and Circulation, 68 Sci.
Sessions; Anaheim, 13-16 Nov. 1995.
[0029] Other vectors which may be used include proteins and
peptides which bind to cell-surface proteoglycans. Such
proteoglycans, which are complexes of proteins and sulphated
polysaccharides, are found on most cells, including endothelial
cells, and contribute to the negative surface charge exhibited by
all eukaryotic cells. This charge may be exploited in accordance
with this embodiment of the invention by using vectors which will
interact electrostatically with the endothelial surface, for
example vectors comprising cationic lipids.
[0030] Linking of a reporter unit to a desired vector or vectors
may be achieved by covalent or non-covalent means, usually
involving interaction with one or more functional groups located on
the reporter and/or the vector(s). Examples of chemically reactive
functional groups which may be employed for this purpose include
amino, hydroxyl, sulfhydryl, carboxyl and carbonyl groups, as well
as carbohydate groups, vicinal diols, thioethers, 2-aminoalcohols,
2-aminothiols, guanidinyl, imidazolyl and phenolic groups. Covalent
coupling of reporter and vector(s) may therefore be effected using
linking agents containing reactive moieties capable of reaction
with such functional groups, e.g. as is well known in the art.
[0031] Various vectors and linking agents which it may be useful to
adopt in targetable ultrasound contrast agents in accordance with
this embodiment of the invention are disclosed in EP-A-0727225 and
WO-A-9640285. Suitable vectors, linkers etc. may also be selected
from the wide range of known vectors and linking groups summarised
in WO-A-9818495, WO-A-9818498, WO-A-9818500 and WO-A-9818501. The
contents of all these documents are incorporated herein by
reference.
[0032] Representative ultrasound imaging techniques which may be
useful in accordance with the invention include fundamental B-mode
imaging; harmonic B-mode imaging including reception of
sub-harmonics and the second and higher harmonics; tissue Doppler
imaging, optionally including selective reception of fundamental,
harmonic or sub-harmonic echo frequencies; colour Doppler imaging,
optionally including selective reception of fundamental, harmonic
or sub-harmonic echo frequencies; power Doppler imaging, optionally
including selective reception of fundamental, harmonic or
sub-harmonic echo frequencies; power or colour Doppler imaging
utilising loss of correlation or apparent Doppler shifts caused by
changes in the acoustical properties of contrast agent microbubbles
such as may be caused by spontaneous or ultrasound-induced
destruction, fragmentation, growth or coalescense; pulse inversion
imaging, optionally including selective reception of fundamental,
harmonic or sub-harmonic echo frequencies, and also including
techniques wherein the number of pulses emitted in each direction
exceeds two; pulse inversion imaging utilising loss of correlation
caused by changes in the acoustical properties of contrast agent
microbubbles such as may be caused by spontaneous or
ultrasound-induced destruction, fragmentation, growth or
coalescense; pulse pre-distortion imaging, e.g. as described in
1997 IEEE Ultrasonics Symposium, pp. 1567-1570; and ultrasound
imaging techniques based on comparison of echoes obtained with
different emission output amplitudes or waveform shapes in order to
detect non-linear effects caused by the presence of gas
bubbles.
[0033] The following non-limitative examples serve to illustrate
the invention.
PREPARATION 1
a) Perfluorobutane Gas Dispersion
[0034] Hydrogenated phosphatidylserine (100 mg) in a 2% solution of
propylene glycol in purified water (20 ml) was heated to 80EC for 5
minutes and the resulting dispersion was allowed to cool to room
temperature overnight. 1 ml portions were transferred to 2 ml
vials, the headspace above each portion was flushed with
perfluorobutane gas, and the vials were shaken for 45 seconds using
an Espe CapMix7 mixer for dental materials, yielding milky white
microbubble dispersions with a volume median diameter of 5.0 .mu.m,
measured using a Coulter Counter (all Coulter Counter measurements
were made at room temperature using an instrument fitted with a 50
.mu.m aperture and having a measuring range 1-30 .mu.m; Isoton II
was used as electrolyte).
b) Dispersion of Lyophilised Perfluorobutane Gas Dispersion
[0035] A sample of the milky white dispersion prepared as in (a)
above was washed three times by centrifugation and removal of the
infranatant, whereafter an equal volume of 10% sucrose solution was
added. The resulting dispersion was lyophilised and then
redispersed in distilled water just prior to use.
PREPARATION 2
Perfluoromethylcyclobutane Emulsion
[0036] Hydrogenated phosphatidylserine (100 mg) in purified water
(20 ml) was heated to 80EC for 5 minutes and the resulting
dispersion was cooled to 0EC overnight. 1 ml of the dispersion was
transferred to a 2 ml vial, to which was added 100 .mu.l of
perfluorodimethylcyclobutane (>97% 1,1-isomer, balance being
1,2- and 1,3-isomers). The vial was then shaken for 75 seconds
using a CapMix7 to yield an emulsion of diffusible component which
was stored at 0EC when not in use.
EXAMPLE 1
In vivo Imaging of Dog Heart with Perfluorobutane Gas Dispersion
and Perfluorodimethyl-cyclobutane Emulsion and Coadministered
Adenosine
[0037] An occluding snare was placed around a major branch of the
left anterior descending coronary artery of an open-chest 22 kg dog
and an ultrasound transit time flowmeter was placed immediately
downstream of the occluder, which was then adjusted to produce a
steady 25% flow reduction from about 14 to 10 ml/min. The contents
of three syringes, respectively containing (i) an amount of a
perfluorobutane microbubble dispersion prepared as in Preparation 1
corresponding to 4.4 .mu.l of gas content, (ii) an amount of the
perfluorodimethylcyclobutane emulsion from Preparation 2
corresponding to 33 .mu.l of the dispersed
perfluorodimethylcyclobutane phase, and (iii) 3.0 mg adenosine
dissolved in 0.9% saline, were then intravenously injected as a
simultaneous bolus; commencing 10 seconds later a further 3.0 mg of
adenosine dissolved in 0.9% saline was injected slowly over 20
seconds. Imaging of the left ventricle of the heart was performed
using an ATL HDI-3000 scanner with a P5-3 probe; continuous
ultrasonication at maximum power was applied for 1 minute to induce
microbubble growth, whereafter the myocardium was examined using
B-mode imaging. A clearly evident difference in gray scale levels
could be seen between stenotic areas (brighter than baseline
recordings) and normal areas (very much brighter than baseline
recordings).
EXAMPLE 2-[COMPARATIVE]
[0038] The procedure of Example 1 was repeated, but without
injection of adenosine. The differences in contrast intensity
between areas supplied by normal and stenotic arteries were now
only barely visible; the main difference from Example 1 was that
the brightness of normal areas was reduced to a level closer to
that of the regions supplied by the stenotic artery.
EXAMPLE 3
Imaging with Contrast Acent Under Dobutamine Stress
[0039] Example 1 was repeated except that a continuous infusion of
dobutamine at a rate of 15 .mu.g/kg/min was administered in place
of adenosine. After a stable dobutamine effect consisting of an
increase in heart rate from the normal 100 beats per minute to 150
beats per minute was obtained, the microbubble dispersion and the
emulsion were intravenously injected from two syringes as a
simultaneous bolus. Infusion of dobutamine was continued for
another 2 minutes after the contrast agent injection. Towards the
end of this period, a distinct pattern of myocardial contrast
enhancement was seen, clearly depicting the areas supplied from the
stenotic artery as darker than the normal myocardium. In addition,
a myocardial contractility deficit consisting of a pronounced wall
thinning was observed in the areas supplied by the stenotic
artery.
* * * * *