(Circulation. 1997;96:3745-3760.)
© 1997 American Heart Association, Inc.
Articles |
Myocardial Contrast Echocardiography
15 Years of Research and Development
From the Cardiovascular Division, University of Virginia School of Medicine, Charlottesville, Va.
Correspondence to Sanjiv Kaul, MD, Cardiovascular Division, Box 158, Medical Center, University of Virginia, Charlottesville, VA 22908. E-mail sk{at}virginia.edu
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Introduction |
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 Top Introduction Technical IssuesAcute Myocardial InfarctionDetection of CADApplications in the Operating...Quantification of Myocardial...Work in ProgressSummaryReferences |
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"An untroubled mind, no longer seeking to consider what is right and what is wrong; A mind beyond judgements, watches and understands."
The Buddha (translated from the Dhammapada)
The purpose of this article is to describe our personal experience in translating observations made in the experimental laboratory using MCE into the clinical setting. It is not intended to be an exhaustive review of MCE, for which readers are referred elsewhere.1 2 3 The work of others in MCE and related subjects will be mentioned only when it has influenced our own work. Our bench-to-bedside experience with MCE over the past 15 years will be discussed under these six broad categories: (a) technical issues; (b) AMI, (c) detection of CAD, (d) applications in the operating room, (e) quantification of myocardial perfusion, and (f) work in progress.
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Technical Issues |
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TopIntroductionTechnical IssuesAcute Myocardial InfarctionDetection of CADApplications in the Operating...Quantification of Myocardial...Work in ProgressSummaryReferences |
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Historically, it has not been possible to directly assess myocardial perfusion with echocardiography. Its clinical focus has involved the evaluation of cardiac chamber size and function, valve morphology and kinetics, pericardial space and great vessels, and intracavitary blood flow velocities. Yet, echocardiography is highly suited for the evaluation of myocardial perfusion for the following reasons: (a) It has very good spatial resolution (<1 mm in the axial direction), which is far superior to that offered by SPECT and positron emission tomography, although not as good as magnetic resonance imaging and ultrafast cine computed tomography; (b) its temporal resolution is excellent (30 to 120 Hz) and exceeds that of other commonly used imaging technologies; (c) for an imaging modality, it is inexpensive and has low overhead costs; (d) it is an integral tool in the day-to-day activities of clinical cardiologists, who can obtain advanced training in its use without needing to learn an entirely new technology.
The study of myocardial perfusion with echocardiography involves the intravascular injection of tracers that can scatter ultrasound.4 Because the compressibility of a particle is the most important determinant of its scattering cross section,5 microbubbles are the most ideal tracers. We have used these bubbles to assess myocardial perfusion in both the spatial and the temporal domain. We have shown that their relative concentrations in different regions of the myocardium reflect the relative MBV in those regions, which is the volume of blood within the myocardial microvasculature.6 Since a large portion of the myocardial microvasculature consists of capillaries,7 MCE actually offers the potential to evaluate tissue perfusion at the level where oxygen transfer to the myocytes occurs.8 MCE can, therefore, provide insights into the functional status of the myocardial microvasculature. The spatial resolution of echocardiography also allows the evaluation of the transmural distribution of abnormal perfusion.
Our initial observations with MCE were made using direct
coronary injections of a mixture of hand-agitated Renografin-76
and saline4 in dogs.9 10 11 These microbubbles
provided adequate information on the spatial distribution of myocardial
perfusion (Fig 1
), but their large size
(>10 µm) precluded their clinical use. Subsequently, with the
development of sonication,12 small bubbles were formed
when air in liquid media was exposed to high-energy ultrasound. We
found that microbubble solutions produced by the sonication of
Renografin-76 were safe in humans when injected directly into the
coronary arteries.13 Because bubbles made by
sonication of most liquid media have a very short
half-life,12 they are unable to opacify the LV cavity
after a venous injection. The sonication of 5% human serum
albumin solutions, however, resulted in microbubbles with a
thin (15 nm) shell consisting of denatured albumin formed by
the heat from the sonication process.14 These bubbles were
relatively stable and had a long shelf life. They cleared the
pulmonary microcirculation after venous injection because of
their small size (mean of 4.3 µm) and opacified the LV
cavity.15 This approach was successfully applied to the
commercial production of Albunex, the first
echocardiographic contrast agent approved by the US
Food and Drug Administration for LV cavity opacification from a venous
injection.15
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Because of our interest in myocardial perfusion, we tested the effect of direct intracoronary injections of sonicated albumin microbubbles on left heart and systemic hemodynamics, as well as MBF. Unlike iodinated contrast agents,16 albumin is iso-osmolar and possesses no calcium chelating properties. Unlike these agents, therefore, it does not produce hemodynamic effects after direct intracoronary injections. Importantly, the introduction of microbubbles in albumin does not cause any additional hemodynamic effects.17 18 This effect of albumin microbubbles is secondary to their intravascular rheology, which we found to be similar to that of red blood cells.19 As expected, no obstruction of the microvasculature was observed.
Like other first-generation contrast agents, Albunex contains air,
which is highly diffusible and leaks out of the shell after the bubbles
are exposed to blood.20 Because the scattering cross
section of a bubble is related to the 6th power of its
radius,2 even a small reduction in its size results in a
large decrement in its scattering cross section. Thus, this agent does
not always result in LV cavity opacification after a venous
injection,15 particularly when the duration of its contact
with blood is longer than usual, such as in low-output states.
Second-generation bubbles contain high-molecular-weight gases that are
not easily diffusible.20 These agents invariably produce
LV cavity opacification. Most of these agents consist of preformed
bubbles, and we have found no adverse effects on systemic
hemodynamics, resting MBF, or pulmonary gas
exchange with their use.21 22 23 The venous agents tested in
our laboratory are listed in the
Table.
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For many years, we used regular echocardiographic equipment with high-frequency transducers for our experimental work. We obtained adequate myocardial opacification with intracoronary, aortic root, and left atrial injections of microbubbles. We could also opacify the myocardium from right heart injections of Albunex using highly concentrated solutions not suitable for clinical use.24 When the second-generation contrast agents were injected intravenously at the recommended doses, myocardial opacification was not visually striking, although changes in myocardial video intensity could be quantified. Since <5% of the stroke volume enters the coronary circulation at rest, we postulated that the primary reason for suboptimal myocardial opacification was the poor signal-to-noise ratio.
We therefore developed image-processing algorithms to display and
measure video intensity from images produced by venous injections of
ultrasound contrast agents. These algorithms are particularly helpful
because the human eye is very poor at differentiating levels of gray
but very adept at discriminating between hues of color. The following
steps are involved in our approach to image processing: separate
alignment and averaging of a few (3 to 6) pre-contrast and contrast
enhanced images; realignment of the averaged pre-contrast and contrast
enhanced images before the former are subtracted from the latter; and
rescaling of the digitally subtracted image over a dynamic range of 256
gray-level values before colors are assigned to these values. The
highest gray level within the myocardium is assigned the
color white with progressively lower gray levels assigned colors of
yellow, orange, and red. Gray-level values of 
10 are considered to
represent noise and are not assigned a color.25
Relative video intensity measurements can then be made directly from
these color-coded images.
About the same time that the new ultrasound contrast agents were being developed, nonlinear scattering properties of microbubbles were reported.26 Because ultrasound creates bands of compression and rarefaction of the medium through which it travels, bubbles exposed to ultrasound also alternately contract and expand equally (or linearly). If ultrasound of a specific frequency (resonant frequency, which depends on bubble size and shell thickness, among other variables) is used, the oscillations of the bubbles could become nonlinear, and result in the production of signals that contain not only the frequency to which the bubbles were originally exposed (the fundamental frequency) but also harmonics of those frequencies.26 27 Since harmonic signals emanate primarily from bubbles, the signal-to-noise ratio is much higher.28
By serendipity, the resonant frequencies for bubbles small enough to transit the pulmonary capillaries (<6 to 7 µm) are in the range of frequencies used clinically in adults (<3 MHz). To take advantage of the improved signal-to-noise ratio during harmonic imaging, transducers have been designed to transmit ultrasound at a particular frequency (say, 1.67 MHz) and receive at twice this frequency (in this case, 3.3 MHz). Even with harmonic imaging, however, the increase in myocardial opacification during venous injections of microbubbles was minimal. The value of harmonic imaging was truly recognized, however, when an increase in myocardial opacification from venous injection of microbubbles was reported from a chance observation when ultrasound was resumed after it had been accidentally suspended for a short period.29
We demonstrated that the lack of contrast effect during real-time
(continuous) imaging was related to bubble destruction caused by
ultrasound.30 Fig 2
illustrates video intensity produced by a second-generation microbubble
(FS-069, which is similar to Albunex, except that instead of air alone
it also contains perfluoropropane) suspended in saline, constantly
mixed, and imaged continuously. The video intensity gradually declined
(filled squares) and Coulter counter measurements demonstrated a marked
decrease in both microbubble size and concentration. When ultrasound
was paused for 30 seconds (arrow) in a similar experiment (open
squares), no change in video intensity was noted during that pause
immediately after resumption of ultrasound. These data indicate that no
bubbles were destroyed during the cessation of ultrasound.
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The implications of these findings in the in vivo setting are as follows: during a pause of ultrasound transmission, microbubbles in the pulmonary circulation and LV cavity, which have not been destroyed by ultrasound, enter the coronary microcirculation. Pausing ultrasound transmission results in greater opacification by permitting the myocardial sample being insonified by the ultrasound beam (whose thickness is approximately 0.5 cm) to become replenished with these new bubbles. If flow is high (in centimeters times seconds-1), then replenishment will occur even when imaging is performed in real time. This is the reason why larger myocardial vessels, such as septal perforators, are seen with continuous harmonic imaging while the rest of the myocardium does not show any opacification. If flow is slow (in millimeters times seconds-1), as occurs in capillaries (average resting flow <0.1 cm · s-1), then beam replenishment will take several cycles to complete. Imaging in real time will not produce much opacification because bubbles are destroyed very soon after they reenter the beam. At normal resting flows, therefore, the best myocardial opacification is seen when imaging is performed once every few (5 to 8) cardiac cycles, when the entire beam is replenished by microbubbles.
The exact mechanism of bubble destruction is not known. It could occur from nonlinear oscillations produced by a resonant frequency or simply by the acoustic power of ultrasound itself. Since acoustic emissions resulting from bubble destruction contain many frequencies, a signal will be recorded when imaging is performed at any of these frequencies, including the harmonic frequency. Irrespective of the mechanism behind the production of harmonic signals from microbubbles, since normal myocardium has little harmonic properties, the signal-to-noise ratio during MCE is significantly greater with harmonic compared to fundamental imaging (where the signal includes backscatter from both bubbles and tissue).28 Furthermore, because ultrasound causes microbubble destruction, decreasing their exposure to ultrasound with intermittent imaging results in better myocardial opacification as discussed above.29 Consequently, intermittent harmonic imaging is currently the best approach for obtaining optimal myocardial opacification after venous injection of microbubbles.29 30 It is also likely that continuous infusion of microbubbles during intermittent harmonic imaging will prove to be the ideal method for assessing myocardial perfusion with MCE in the clinical setting.
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Acute Myocardial Infarction |
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TopIntroductionTechnical IssuesAcute Myocardial InfarctionDetection of CADApplications in the Operating...Quantification of Myocardial...Work in ProgressSummaryReferences |
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Our first applications of MCE were in the setting of AMI where a substantial portion of the microvasculature is hypoperfused. We showed that MCE could be used in vivo to accurately define risk area (Fig 1
)
in real time, something that was heretofore not possible. Our interest
at that time was to assess serial changes in myocardial perfusion
during coronary occlusion and to determine the effect of the
duration of coronary occlusion on the risk area/infarct size
ratios.31 We also wanted to understand the influence of
the size of the risk area on clinical measurements such as regional and
global LV function, as well as systemic hemodynamics in
the setting of AMI. We found that because of compensatory mechanisms,
these variables did not become abnormal until risk area involved a
very sizeable portion of the LV.31 It was previously demonstrated in dogs that within 30 to 45 minutes after coronary occlusion, necrosis is initiated in the subendocardium and progresses transmurally over time.32 33 It was shown that the ultimate extent of necrosis was related to both the duration of occlusion and the residual MBF within the risk area.32 33 The former message was heard clearly in the clinical world. Accordingly, the duration between the onset of symptoms and the restoration of infarct-related artery patency became of utmost importance, forming the basis for emergent reperfusion during AMI. Unfortunately, the second message was lost—that is, necrosis would not be severe if adequate residual MBF was present within the risk area.32 33
We demonstrated the ability of MCE to measure spatial changes in collateral perfusion caused by altering the collateral driving pressure.34 We also noted myocardial opacification in regions remote from those receiving grafts in patients undergoing CABG surgery when microbubbles were injected into the cross-clamped aortic root.35 This finding implied the presence of collateral perfusion. Additionally, we found extensive collateral perfusion on MCE in patients with both recent36 and old37 infarction in the presence of an occluded infarct-related artery. Interestingly, a poor correlation was noted between the extent of myocardial opacification from collateral vessels and the angiographic collateral score.35 36 37
On the basis of these observations, we hypothesized that, although
collateral-derived MBF may not be adequate for normal myocardial
systolic function distal to an occluded vessel, it may be
enough to maintain viability for prolonged periods after
coronary occlusion. We argued that providing
anterograde coronary flow to such
myocardium would result in improvement of regional function
over time. We studied patients with recent (2 days to 5 weeks) AMI and
an occluded infarct-related artery.38 These patients were
referred for definition of their coronary anatomy and
not because of postinfarction angina. We injected microbubbles directly
into the left main and the right coronary arteries. We then
attempted to open the infarct-related artery by angioplasty with
success in about 80% of cases. Fig 3
illustrates a parasternal LV short-axis view in a patient with a recent
inferior AMI who exhibited moderate hypokinesia of that
region. Fig 3A shows opacification of the entire LV
myocardium from a left main injection prior to angioplasty.
After successful angioplasty of the occluded RCA, microbubbles were
injected directly into it to define its vascular bed (B). It is obvious
that this region was supplied by left-to-right collaterals during RCA
occlusion (A). Coronary angiography showed poor collaterals in
this patient. Assessment of collateral perfusion is more accurate with
MCE than with coronary angiography because the latter can
define only vessels >100 µm in size, while most collateral
channels are much smaller.39
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In this study, nearly 80% of the patients exhibiting adequate collateral perfusion within the infarct bed by MCE demonstrated an improvement in regional systolic function 1 month after anterograde flow was restored.38 Importantly, as long as there was adequate collateral perfusion within the infarct zone (involving >50% of the bed), function improved even when anterograde flow was established days to weeks after AMI.38 These data indicate that, in addition to the duration of coronary occlusion, the spatial extent of residual myocardial perfusion is also a major determinant of infarct size. Thus, myocardial regions that suffer an infarction but are not immediately reperfused are still likely to be viable if they have adequate collateral flow. Conversely, if not revascularized, these regions are likely to undergo repeated episodes of ischemia with its multiple sequelae. We believe that our findings provide the physiological basis for the "open artery hypothesis" and explain why patients with open infarct-related arteries post-AMI have a better prognosis than those with occluded arteries.
It was also known for many years that despite reflow, adequate amounts of tissue perfusion may not be achieved (the "low reflow" or the "no reflow" phenomenon) because of microvascular disruption, plugging by debris, or myocardial edema.40 41 This phenomenon is localized only within the infarct and indicates the presence of severe necrosis, which was successfully demonstrated in a canine model of coronary occlusion and reperfusion using MCE.42 A great deal of interest was, however, generated when this same finding was first described in patients with AMI who underwent MCE in the cardiac catheterization laboratory immediately after patency of the infarct-related artery was restored.43 In one fourth of the patients, tissue perfusion was not seen despite good angiographic results. It was shown that patients exhibiting the "no reflow" phenomenon had worse regional and global function 1 month later compared to those who did not show this phenomenon.43
We were invited to write an editorial in response to the article. We emphasized the importance of assessing microvascular rather than epicardial coronary flow in patients after reperfusion, since the presence of "flow" in the epicardial coronary artery was not indicative of actual nutrient perfusion.44 We also raised the concern that infarct size may be underestimated by MCE immediately after reflow because of the possibility of reactive hyperemia. We suggested that the best time to assess microvascular perfusion may be after reactive hyperemia had abated (12 to 24 hours later).44 It was previously shown that despite reactive hyperemia, microvascular reserve within the infarct bed was diminished consequent to functional if not anatomic damage to the microvasculature.41 45 We therefore indicated that if it were necessary to determine infarct size immediately after reperfusion, MCE should be performed in the presence of a coronary vasodilator.44 We postulated that since the microvasculature in noninfarcted tissue is normal, the response to hyperemia in the normal bed would be greater than that within the infarct bed. Consequently, despite an increase in the absolute MBF in the infarct bed, MBF in that bed would appear to be less compared with the normal bed during exogenous hyperemia.
To prove these hypotheses, we studied dogs undergoing 2 to 6 hours of
LAD occlusion followed by 3 hours of reperfusion.46 Fig 4 illustrates radiolabeled
microsphere–derived MBF data obtained from the infarct bed
during reflow after the values were normalized to those of the remote
noninfarcted bed. Wide variations and fluctuations are seen in MBF to
the infarct bed in individual dogs during reflow (A). Because of
reactive hyperemia, the average MBF within the infarct bed is
similar to that in the normal bed despite considerable microvascular
damage in the infarct bed (B). Importantly, abnormal MBF reserve within
the infarct bed (compared with the normal bed) is unmasked by infusion
of dipyridamole. Fig 5
illustrates color-coded MCE images at different points in time after
establishment of reflow. Figs 5A & 5B (45 minutes and 3 hours after
reperfusion) shows small areas of "no reflow," while in reality the
infarct size is much larger (D). In the presence of
dipyridamole, however, since all gray-level values are
scaled to the highest value (in the normal bed in this case), the
perfusion defect within the infarct bed appears more extensive (C) and
accurately reflects infarct size.46
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Abnormal MBF reserve in the infarct bed in the above study was measured 3 hours after reflow. We have demonstrated that similar information can be obtained immediately (15 minutes in this case) after reflow.47 We also showed that although basal MBF to the infarct bed varies widely between 15 minutes and 3 hours after reflow, the abnormality in microvascular MBF reserve is remarkably consistent at both periods.47 Thus, the assessment of microvascular reserve any time after reflow should provide an accurate assessment of infarct size irrespective of the degree of reactive hyperemia and the unpredictable fluctuations in basal MBF.
In the last two studies discussed above, reflow was established in the absence of any residual stenosis, which is usually not the case in patients with AMI unless angioplasty is also performed in conjunction with or instead of thrombolysis. There are two confounding issues when a stenosis is present. First, if it is critical and does not permit reactive hyperemia to occur, then the infarct size could be accurately measured immediately after reflow is established. Although such a situation may occasionally exist, the residual stenosis is usually not critical after the thrombus has resolved and, therefore, various degrees of reactive hyperemia may still be present. Second, if exogenous hyperemia is induced in the presence of a stenosis, then the entire infarct bed should demonstrate relative hypoperfusion compared with beds not supplied by stenotic vessels or by vessels with less stenosis. MCE during exogenous hyperemia could, therefore, conceivably overestimate infarct size.
We have demonstrated that although perfusion is reduced to the entire
bed distal to a stenosis, there is still marked
heterogeneity in the microvascular reserve within the
infarct bed.48 The area with the most diminished reserve
corresponds to the necrotic area and can be easily discriminated from
other areas within the infarct bed. Fig 6A depicts an MCE perfusion defect in the
LCx bed immediately after reflow, prior to an infusion of
dobutamine, where infarct size (D) is underestimated. After
infusion of dobutamine, infarct size is accurately
estimated (B). Dobutamine causes coronary
hyperemia by increasing myocardial oxygen consumption. Fig 6C
illustrates an MCE perfusion defect in the presence of
dobutamine, after the placement of a stenosis.
Although the intensity of colors is less in the entire LCx bed because
of reduced reserve in that bed caused by the stenosis,
infarcted areas can still be separated from noninfarcted ones because
of the marked disparity in MBF reserve within these regions in the same
bed.
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We have shown in humans that if MCE is performed after reactive
hyperemia has abated (at least 1 day after establishment of
reflow), the extent of adequate microvascular perfusion within the
infarct zone indicates the extent of myocellular
integrity.49 50 Fig 7 shows
MCE images from a patient with an anteroapical AMI who had previously
received thrombolytic therapy. Angiography of the large
wraparound LAD showed "excellent flow." Microbubbles were then
injected into the left main coronary artery. No opacification
is seen in the apex, and patchy opacification is noted in the middle
and apical portions of the anterior interventricular
septum. Only the basal interventricular septum demonstrates
adequate perfusion in this apical 4-chamber view. In this study of
patients who had patent infarct-related arteries without flow-limiting
stenoses at rest (<80% luminal diameter narrowing), regional
function 1 month later correlated inversely with the spatial extent of
microvascular perfusion at the time of the original
examination.49 50 Dysfunctional regions with extensive
myocardial opacification showed near-normal function 1 month later,
while those with no opacification or that limited to very small regions
showed the most dysfunction. Areas where the spatial extent of
microvascular perfusion was intermediate showed intermediate function 1
month later. Thus, MCE provides optimal assessment of viability in
patients with AMI undergoing reperfusion therapy after
hyperemia has abated.
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As described above, our early experience with MCE in both the
experimental and clinical settings involved direct coronary
arterial, aortic, or left atrial51 injections
of microbubbles. With the advent of second-generation contrast agents
and intermittent harmonic imaging, it has become possible to obtain
similar results in animals and humans using venous injections of
microbubbles. Fig 8 illustrates MCE
images obtained in a dog undergoing LCx occlusion and reperfusion where
1 mL of FS-069 was injected intravenously. Data were
acquired using intermittent (once every systole) harmonic imaging. Fig 8A depicts the baseline image prior to coronary occlusion.
Other than some posterior wall attenuation caused by the presence of
contrast in the LV cavity, myocardial opacification is
homogeneous. Fig 8B shows an image after proximal LCx
occlusion where a large transmural defect is seen, indicating the
location and spatial extent of the risk area. Following reflow and
during dipyridamole infusion, injection of microbubbles
reveals opacification of the previously occluded bed (C). The perfusion
pattern, however, is not homogeneous, with very little
opacification seen in the central portion of the bed. The location and
topography of this defect closely mimic that of the actual infarct
(D).
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The clinical implications of these findings are obvious, particularly in patients presenting to the emergency department. Only one third of those with ongoing AMI have diagnostic ECGs at the time of presentation to the emergency department.52 53 The majority of patients admitted to a hospital bed do not have AMI and may not even have CAD. Defining the presence or absence of a risk area could be very useful in such patients. The size of the risk area could also be important in determining management strategies. Documentation of normal myocardial perfusion and normal microvascular reserve could rule out not only acute ischemia but also CAD. The success of attempted reperfusion could be documented as could the residual infarct size, which could be used for risk stratification and long-term management.
Although we have not yet received US Food and Drug Administration
approval to study patients with AMI, we have been able to study those
with chronic CAD, including some with old infarction, using the same
techniques as those in the animal studies discussed above. One such
study was performed in the United Kingdom in collaboration with
colleagues at the Northwick Park Hospital in Harrow.54 Fig 9 illustrates examples of resting MCE
perfusion defects from 2 patients, which correspond to those on resting
99mTc-sestamibi-SPECT. Whereas these data are preliminary,
they are very encouraging and indicate that at least post-AMI, MCE has
the same potential to assess myocardial viability as other commonly
used imaging modalities.54
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Detection of CAD |
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TopIntroductionTechnical IssuesAcute Myocardial InfarctionDetection of CADApplications in the Operating...Quantification of Myocardial...Work in ProgressSummaryReferences |
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Despite the presence of coronary stenoses, resting MBF is normal in the majority of stable patients with CAD who have not had a previous myocardial infarction. MBF is maintained distal to a stenosis by autoregulation. As the stenosis severity increases, <300-µm arterioles distal to it dilate in order to maintain resting MBF as close to normal as possible.55 When autoregulation is exhausted (usually at
85% luminal diameter
narrowing), resting MBF begins to decline, particularly if collateral
flow is low or absent. A sudden decrease in resting MBF can manifest as
an acute ischemic syndrome, while a more gradual decrease can
result in congestive heart failure with or without chest pain. In
either case, resting perfusion and function are abnormal. For the majority of patients with CAD (those with <85% luminal diameter narrowing of the coronary arteries), resting perfusion is normal and the detection of CAD depends on unmasking abnormal MBF reserve within regions supplied by stenotic vessels. Since microvessels in these regions have already used some of their reserve to maintain normal resting MBF, MBF cannot increase during stress to the same extent as in other regions with greater microvascular reserve such as those supplied by lesser stenosis or no stenosis. The resulting perfusion mismatch can be detected on myocardial perfusion imaging, which forms the physiological basis for many imaging modalities for the detection of CAD.56 57
We have shown that in the case of MCE, the relative concentration of
microbubbles in the myocardium reflects relative
MBV.6 It is generally assumed that during exogenously
induced hyperemia, MBV is equally maximized in regions supplied
by stenosed and nonstenosed arteries. It has been demonstrated,
however, that both MBF and MBV distal to a stenosis are less
than in the normal bed.8 58 59 Fig 10 illustrates color-coded MCE images
obtained after a venous injection of 0.4 mL of a second-generation
contrast agent (AFO150, containing air and perfluorohexane) during
exogenous hyperemia. The posterior-wall attenuation seen in
these images can be minimized or abolished with use of continuous
infusions (where the infusion rate can be optimized) rather than a
bolus injection. The images are obtained at baseline (A) and in the
presence of mild (B) and moderate (C) stenoses of the LAD. The
relative video intensities in the anterior wall reflect the relative
flow mismatch to the stenosed compared with the normal bed, which in
turn reflects the severity of the stenosis. Because changes in
MBF and MBV are coupled during hyperemia, the measurement of
MBV ratios from different myocardial beds provides an indirect
assessment of the ratios of MBF to those beds.23 56 60 The
spatial distribution of a perfusion defect on MCE during
hyperemia also corresponds closely with that of relative
hypoperfusion measured by radiolabeled
microspheres.59 60 This information can be
obtained from coronary artery,62 aortic
root,63 left atrial,59 or venous
injections.23 60 It is important to realize, however, that
video intensity reflects MBF only in the presence of a stenosis
and that also only during hyperemia. This relation between
video intensity and MBF is not seen in most other situations.
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Fig 11 is an example of a reversible
defect in the lateral wall on MCE in a patient with CAD that
corresponds to a similar defect on 99mTc-sestamibi-SPECT.
These images were obtained using 0.5-mL venous injections of FS-069
during rest and dipyridamole-induced coronary
hyperemia.54 Although preliminary, these results
indicate an important potential role for MCE in the detection and risk
stratification of CAD in ways similar to other myocardial perfusion
imaging techniques.57
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Applications in the Operating Room |
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TopIntroductionTechnical IssuesAcute Myocardial InfarctionDetection of CADApplications in the Operating...Quantification of Myocardial...Work in ProgressSummaryReferences |
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There is no reliable method to assess myocardial perfusion on-line in the operating room. For instance, cardioplegia delivered through a cross-clamped aorta may not reach myocardial regions subtended by severe stenoses. Unlike regions receiving adequate perfusion with cardioplegia, these may not undergo cardiac arrest and may, therefore, suffer ischemic insult. After proving that MCE can define regions of reduced cardioplegia delivery in canine models,64 65 we translated our experience to humans undergoing CABG surgery. We showed that MCE can assist the surgeon in determining the adequacy of anterograde cardioplegia delivery in patients with severe CAD, and hence guide the appropriate sequence of graft placement.66 Fig 12
is an example of images obtained
from a patient undergoing CABG surgery for multivessel CAD where
microbubbles were injected during cardioplegia delivery via the side
arm of a catheter placed in the cross-clamped aorta. The presence of
perfusion is seen only in the anterior wall, while the entire posterior
myocardium appears hypoperfused (A). Thus, if left
unprotected, the posterior myocardium could undergo severe
ischemic damage during bypass surgery. The surgeon placed a
graft first to a dominant RCA and then anastomosed it to the aorta.
When microbubbles were reinjected into the cross-clamped aorta during
the second run of cardioplegia, the entire myocardium
showed excellent opacification (B). These results show that in addition
to determining the strategy for myocardial protection, the surgeon can
also determine the success of graft placement on-line.66
Any technical problems with anastomoses can be ascertained and attended
to intraoperatively.64
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Cardioplegia may also be delivered retrogradely, particularly in
patients with severe multivessel disease, where it reaches the
myocardium unhindered, and during valve surgery, where it
can be delivered periodically without interrupting surgery. It is
usually administered through a catheter placed in the coronary
sinus with an occlusive balloon that prevents it from regurgitating
into the right atrium. This balloon can, however, occlude one of the
veins draining into the coronary sinus and prevent cardioplegia
delivery to that region, with resulting ischemic damage. Fig 13 from one of our canine experiments
shows that similar to the situation with anterograde
cardioplegia delivery, MCE can also be used to characterize the
distribution of retrogradely delivered cardioplegia. The regions with
no perfusion on retrograde cardioplegia delivery also show severe
reduction in MBF by radiolabeled microspheres.67
Thus, MCE can be used to assist coronary sinus balloon
placement during retrograde cardioplegia delivery.
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Quantification of Myocardial Perfusion |
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TopIntroductionTechnical IssuesAcute Myocardial InfarctionDetection of CADApplications in the Operating...Quantification of Myocardial...Work in ProgressSummaryReferences |
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The purpose of quantifying myocardial perfusion is to determine whether myocytes are being adequately oxygenated. A comprehensive assessment of perfusion, therefore, requires the measurement of both oxygen delivery to and oxygen consumption by myocytes. Furthermore, these measurements must be interpreted on the basis of energy requirements of myocytes in a specific pathophysiological state; otherwise, the results of these measurements can be easily misinterpreted.
A commonly used laboratory assessment of oxygen delivery is made by measuring MBF. Given that the oxygen-carrying capacity of blood (hemoglobin saturation and oxygen dissociation kinetics of hemoglobin) and myoglobin are constant, the quantitative assessment of MBF provides a reasonable assessment of oxygen delivery. Unfortunately, neither oxygen consumption nor myocyte energy requirements are reflected by MBF itself. However, because MBF to normal tissue is determined by myocardial oxygen demand (oxygen consumption based on energy requirements)68 under physiological conditions, measurement of MBF has been considered to offer a reasonable and valuable assessment of myocardial perfusion. This assessment may, however, not be optimal in abnormal situations.
As already stated, unlike other tracers used for imaging that can enter
the extravascular space or are actively transported into myocytes, we
have shown that microbubbles remain entirely within the intravascular
space.19 21 Fig 14
illustrates a branching arteriole in a hamster cheek-pouch preparation
viewed under high-powered microscopy (A) where we compared the
intravascular rheology of fluorescein-labeled red blood
cells (B) with that of similarly labeled sonicated albumin
microbubbles (C). The arteriovenous transit times, branch point flux,
mean velocity, and velocity profiles of the microbubbles were found to
be very similar to those of red blood cells. Importantly, obstruction
or adhesion of the microbubbles within the microcirculation was not
seen.19 In other studies we demonstrated that the
intravascular rheology of Albunex corresponded to those of radiolabeled
red blood cells in both the beating canine69 and
human70 hearts.
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We have shown that MCE can be used to quantify myocardial flow of cardioplegia delivered both anterogradely and retrogradely.65 71 The time-to-peak-contrast effect correlates well with flow in both situations. During anterograde cardioplegia delivery, because of lack of arteriovenous or arterio-lumenal connections, >99% of 11-µm radiolabeled microspheres delivered into the cross-clamped aortic root are entrapped in arterioles of that size. All flow that enters the coronary arteries travels through these arterioles and capillaries to the venules and coronary sinus. Consequently, we found that anterogradely injected radiolabeled microspheres provide accurate measurements of cardioplegic flow to all levels of the myocardial microvasculature.71 In contradistinction, we found that after retrograde delivery, radiolabeled microspheres consistently underestimate flow to 11-µm myocardial veins because they are lost through thebesian veins even before they can reach these vessels. We also found that cardioplegia loss occurs through thebesian veins even distal to the site of microsphere entrapment, making radiolabeled microspheres even more inaccurate for measuring myocardial flow. MCE, however, provides an accurate estimation of retrograde cardioplegia flow, because the transit of microbubbles through the myocardium is registered from the moment of entry into the myocardium, regardless of whether they transit the capillaries to exit via the aorta or through thebesian veins prior to reaching the capillaries.71
When an indicator is injected as a bolus directly into a
coronary artery, the input function can be likened to a delta
function. As the bolus spreads through the coronary
circulation, its mean transit rate through the myocardium
reflects the MBF/CBV relation. We have shown that for the same input
function, when CBV is held constant, the mean myocardial transit rate
of microbubbles corresponds to MBF;69 72 when MBF is held
constant, it corresponds to CBV.73 Fig 15 illustrates the relation between
microbubble and red blood cell transit rates in a canine experiment
where we held CBV constant and mechanically altered MBF.69
The input function to the coronary artery (volume,
concentration, and injection rate of both microbubbles and red blood
cells) was held constant.
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Since arteriolar dilation maintains constant resting MBF in the
presence of coronary stenoses, we hypothesized that
measurement of CBV (total volume of blood in the small coronary
arteries, arterioles, capillaries, venules, and veins) distal to a
stenosis should provide an assessment of its severity. Thus,
for the same input function, transit rates of microbubbles injected
directly into a coronary artery should decrease with more
severe stenoses despite normal resting MBF. Fig 16 illustrates the relation between
stenosis severity (represented by the perfusion
pressure distal to it) and mean microbubble transit
rates.73 The following are evident: MBF to the bed
supplied by the stenosed vessel remains constant until the distal
coronary pressure decreases to approximately 45 to 54
mm Hg; beyond these pressures, MBF declines precipitously with small
reductions in the distal coronary pressure. The mean
microbubble transit rate decreases with reductions in the
coronary perfusion pressure, but reaches a plateau when the
latter declines to between 45 and 74 mm Hg, after which it
decreases further with reduction in MBF.
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One possible explanation of the plateau effect in the microbubble transit rate at moderate levels of stenosis is that, although the microvessels distal to the stenosis continue to dilate with increasing severity of coronary stenosis, their net volume of distribution does not increase, keeping the mean microbubble transit rate constant. A constant volume of distribution of the microbubbles can occur if the degree of vasodilation is counterbalanced by a decrease in the perfusion bed size, which is what we found.73 We noted that the perfusion bed size decreases with a reduction in distal coronary pressure even before MBF is reduced. An approximately 20% decrease in perfusion bed size was noted with a decrease in perfusion pressure of about 50% and no change in MBF. As previously noted by us,74 the decrease in perfusion bed size was more precipitous when MBF decreased. Thus, the perfusion bed of a coronary artery changes dynamically depending on pressures within the coronary arteries supplying anterograde and collateral MBF.
From the above discussion it is clear that the measurement of mean
microbubble transit rate provides important quantitative insights into
the MBF/CBV relation. However, it requires a direct coronary
injection of microbubbles, which is impractical in the routine clinical
environment. Measurement of transit rates is not possible with a venous
injection because the input function to the myocardium
(caused by bolus spread and mixing as it transits the right heart,
lungs, and left heart) is wider than its transfer function. As shown in
Fig 17A, the width of the output
function measured from the myocardial time-intensity plot is very
similar to that of the input function irrespective of the myocardial
transfer function.60 Minor changes that may be present
are not measurable by MCE. Even if these changes were measurable,
because of the threshold effect of ultrasound systems (where
microbubbles are detected only above a certain concentration), the
myocardial time-intensity curve appears narrower than that from the LV
cavity (Fig 17B), making it mathematically impossible to deconvolve the
input from the output function.6 Consequently, myocardial
transit rates cannot be used to measure the MBF/CBV relation after
bolus venous injections of microbubbles.
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i=0.1) than myocardial transfer function rate constants
(
We have recently shown that the destruction of microbubbles by
ultrasound can be used to measure MBF during a constant venous infusion
of microbubbles.75 Microbubbles can be destroyed with
ultrasound, and their reappearance rate in the myocardium
can be measured. This rate represents the mean myocardial
microbubble velocity. The relative concentration of microbubbles in
different myocardial beds during steady state represents
relative capillary density or the sum of their cross-sectional area in
those beds. Fig 18 is a diagrammatic
representation of this concept. If we assume that bubbles
within the ultrasound field are destroyed in a single pulse so that no
video intensity is detectable, then the time available for other
influxing bubbles to travel any distance within the thickness
(elevation) of an ultrasound beam will be determined by the pulsing
interval of ultrasound (the interval between formation of two images),
as well as the mean microbubble velocity. Within a given range,
microbubble concentration and video intensity are linearly related (Fig 17C).6 At any pulsing interval, therefore, video intensity
within the beam will be proportional to the distance traveled by the
microbubbles within the beam. For the same microbubble velocity, video
intensity will increase with increasing pulsing intervals until a
specific pulsing interval is reached where the microbubbles have just
enough time to fill the entire beam thickness as depicted in Fig 18E.
When the pulsing interval exceeds this time, the video intensity will
remain constant and reflect the relative concentration of microbubbles
in tissue. Fig 19A illustrates the
expected pulsing interval versus video intensity curve if microbubble
destruction were homogeneous within the ultrasound
beam.75 In reality, because of inhomogeneous
bubble destruction within the beam and the
heterogeneity of flow dispersion within the
microvasculature, the curve looks like the one depicted in Fig 19B. The
rate of video intensity increase, determined by fitting an exponential
function to the curve, reflects the mean myocardial microbubble
velocity.
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indicates the pulsing interval at which bubbles just fill the beam
thickness as shown in Fig 18E
For this approach, a constant infusion of microbubbles is used. Once
steady state is reached, the imaging protocol consists of changing the
pulsing interval. The "imaging" trigger is set to end systole,
while the "bubble destruction" signal is set to different intervals
prior to the "imaging" trigger, and no ultrasound is transmitted
between these two pulses. Although both triggers result in MCE images,
video intensity measurements are made only from the images captured by
the second trigger. Fig 20A to 20D
depicts images obtained at a constant LAD flow of 20
mL · min-1 and different pulsing intervals using
MRX-115, which is a second-generation microbubble containing a mixture
of air and perfluoropropane within a phospholipid shell.75
At the shortest pulsing interval, contrast cannot be seen in the
anterior wall, indicating that the interval is too short to allow
replenishment of measurable amounts of microbubbles within the beam
after their destruction by the first pulse. The myocardial video
intensity increases progressively with increasing pulsing intervals and
appears to plateau at a pulsing interval of >15 seconds. Initial
opacification of the LCx bed is seen at a higher pulsing interval than
that of the LAD bed and its rate of rise is also slower, indicating a
lower microbubble velocity in that bed.
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Another important point can be noted from Fig 20. Data were acquired at
very low LAD flow (approximately one half to one third of baseline
flow). In a chronic setting, this flow may result in the
"hibernating" myocardium. Casual examination of
myocardial perfusion (say, in real time) would show no myocardial
opacification in this region, because the myocardial microbubble
velocity is much slower than the imaging rate. The "late"
appearance (several seconds) of microbubbles during continuous
infusion, however, attests to presence of myocardial flow, albeit low.
Furthermore, the homogeneous opacification in the entire
LAD bed also attests to normal capillary architecture. A combination of
these findings should be a strong predictor of myocardial viability.
Animal studies are currently under way in our laboratory to test this
hypothesis.
Fig 21A illustrates the
background-subtracted video intensity data and the fitted functions
from the LAD bed at different coronary flows in a single dog.
The increase in flow is paralleled by an increase in microbubble
velocity (rate of rise of video intensity). Fig 21B shows the excellent
relation between the rate of rise of video intensity derived from the
exponential function and flow rate in the same dog whose data also are
shown in Fig 21A.75 To obtain the curves shown in Fig 21A, long pulsing intervals were used that encompassed several cardiac
cycles. Thus, the rate constant derived from these curves
represents average microbubble velocity over several seconds.
It therefore does not matter at which point in the cardiac cycle the
"imaging" trigger is placed. We prefer end systole because of the
ability to place larger regions of interest and derive better
signal-to-noise ratios.76 Contamination from signals in
the LV cavity and specular endocardial and epicardial targets is also
less likely to occur in these images. The larger myocardial area
interrogated in end systole also offers the ability to discriminate
microbubble velocities and MBV at different myocardial depths.
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Work in Progress |
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TopIntroductionTechnical IssuesAcute Myocardial InfarctionDetection of CADApplications in the Operating...Quantification of Myocardial...Work in ProgressSummaryReferences |
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Since we can measure changes in CBV with a bolus injection and microbubble velocity and MBV during continuous infusion, we can better understand the sites of microvascular flow regulation. For instance, CBV increases with intracoronary injection of adenosine without any change in myocardial video intensity during continuous infusion of microbubbles. Thus, it is clear that adenosine causes dilation of arterioles outside the myocardium without causing any changes in MBV.75 In comparison, with phenylephrine, we note increases in both CBV and myocardial video intensity, which indicates that MBV also increases in association with an increase in MBF. In this manner, the sites of action of various coronary vasodilators can be assessed.
We are also using this new approach to measure transmural changes in MBV and microbubble velocities. Our previous attempts at measuring transmural differences in myocardial perfusion in the absence of vascular damage to the endocardium were not successful using conventional MCE.77 In the past, we measured video intensity only after a bolus injection, which may not have indicated the true pathophysiological basis of endocardial MBF reductions. We are also using this new approach to understand the mechanisms and relevance of phasic changes in MBV and MBF that occur during the cardiac cycle, and relate these to similar changes in flow in the coronary arteries and veins. We intend to use knowledge gained in these areas to understand not only flow control in the human myocardium but also regulation of flow to other organ systems accessible to ultrasound, such as the kidney, liver, skeletal muscle, and skin. The ability to noninvasively and repeatedly measure perfusion to these organs holds great promise in the understanding of control of regional perfusion under normal conditions and in different diseases (including malignant tumors).
During our experience with MCE in the operating room, we found that sonicated albumin microbubbles adhere to the endothelium during crystalloid cardioplegia delivery unlike the situation with the blood-perfused heart.65 71 78 We also observed that when whole blood was added to the crystalloid cardioplegic solution, this adherence was reduced, and none was noted when the cardioplegia hematocrit was greater than 24%.79 The exact mechanism of microbubble adherence is not currently understood. We believe that microbubble adherence reflects reversible endothelial dysfunction, perhaps at the level of the lumenal glycocalyx. When we reperfused the myocardium of patients undergoing cardioplegic arrest during bypass surgery with venous rather than arterial blood, we found microbubble transit rates to be faster with the former.80 It is possible that reperfusion with venous blood results in less endothelial glycocalyx damage than with arterial blood due to an attenuated release of oxygen free radicals in the former setting. These results are preliminary but open the possibility to study reperfusion after bypass surgery and also to address issues pertaining to organ preservation for transplantation.
We found that microbubbles adhere to endothelial cells that are also structurally damaged on electron microscopy.81 We studied the effect of radiofrequency catheter ablation on the myocardial microvasculature. It was found that regions with necrosis caused by the heat did not show any opacification. Regions with normal perfusion and no vascular damage showed rapid bubble washout. However, regions in between necrotic and normal tissue showed persistent microbubble adherence. No changes in routine histopathology were noted in these regions, but ultrastructural alterations in endothelial cells were demonstrated on electron microscopy.81 These findings also support the notion that MCE has the potential to evaluate microvascular endothelial function in vivo.
Because they can be destroyed by ultrasound, microbubbles could be used for local and efficient drug and gene delivery. Their destruction and the subsequent release of drugs at specific target sites could reduce systemic side effects of chemotherapeutic and other agents. Microbubbles can be labeled with antibodies in order to adhere to specific sites and locations such as fibrinogen, which will facilitate the diagnosis of venous and arterial thrombi. Destruction of microbubbles containing small amounts of potent thrombolytic agents at the site of a thrombus could hasten lysis without systemic bleeding. Similarly, thrombogenic materials can be inserted into these bubbles, which can then be destroyed in tumors to "choke" their vascular supply and cause necrosis. Other interesting applications are also being considered.
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Summary |
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TopIntroductionTechnical IssuesAcute Myocardial InfarctionDetection of CADApplications in the Operating...Quantification of Myocardial...Work in ProgressSummaryReferences |
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It has taken 15 years to move MCE from bench to bedside. In the meantime, we have gained important and fascinating insights into human coronary pathophysiology. We have also learned that any functional differences in myocardial perfusion between humans with chronic CAD and acute canine models are only quantitative. Despite structural differences in their coronary systems, clinically important qualitative differences do not exist at the functional level. We can, therefore, continue to learn a great deal about coronary pathophysiology from canines that is pertinent to humans.
We have also gained new knowledge regarding microbubble and ultrasound interactions. Developments based on this knowledge are accelerating in the fields of ultrasound physics and engineering with newer and better clinical systems being manufactured. We are beginning to launch multicenter studies using venous contrast agents and intermittent harmonic imaging to assess myocardial perfusion at rest and during exogenous hyperemia in patients with known and suspected CAD, including those with AMI. It is possible in the future that contrast echocardiography will become the leading tool for assessing organ perfusion in humans. The work in progress relating to endothelial function–, site-, and pathology-specific microbubble adherence, and local drug delivery are exciting. If all goes well, we may be able to report on these advances 15 years from now!
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Selected Abbreviations and Acronyms |
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Acknowledgments |
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This work was supported in part by grants (K08-HL01833, R29-HL38345, and R01-HL48890) from the National Institutes of Health, Bethesda, Md, and from grants-in-aid from the American Heart Association, Dallas, Tex and its Virginia Affiliate, Glen Allen, Va. I was also an Established Investigator of the American Heart Association. I would like to thank Kevin Wei, MD, for a critical review of the manuscript. In this study, I have represented the work of many colleagues and postdoctoral fellows with whom I have had the good fortune and privilege to work over the past 15 years. The true acknowledgment of their work is in the references cited. Our more recent partnerships with companies developing ultrasound contrast agents and those manufacturing ultrasound systems have also been valuable not only in their support of the work (grants-in-aid or equipment grants) but also in the scientific exchange with their research and development teams. None of this work would have been possible without the National Institutes of Health and the American Heart Association, which support the core activities of our laboratory, and for which I am forever indebted. I was fortunate to train with two excellent mentors, Pravin M. Shah, MD, who got me interested in echocardiography, and Arthur E. Weyman, who tried his best to make me a scientist, something at which I am still working. I am most grateful to George A. Beller, MD, for creating a vibrant intellectual environment in the Cardiovascular Division at the University of Virginia and protecting the Division from the recent vagaries of medical economics, so that we can continue to do research without distractions. The magic of Charlottesville also contributes to a state of mind that can occasionally look beyond!
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References |
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