From the Cardiovascular Division, University of Virginia School of
Medicine, Charlottesville, Virginia.
Correspondence to Sanjiv Kaul, MD, Cardiovascular Division, Box 158, Medical Center, University of Virginia, Charlottesville, VA 22908. E-mail sk{at}virginia.edu
In
patients with AMI who have undergone attempted reperfusion, two
questions need to be answered. The first, and the most obvious, is
whether the myocardium has been successfully reperfused.
The second, and perhaps equally important, is how much of the
myocardium has been salvaged, and how much can still
potentially be salvaged? To answer these questions, one must have the
tools to accurately assess myocardial perfusion and infarct size. The
ultimate indicator of tissue perfusion is capillary flow, whereas that
of myocardial infarction is myocyte necrosis. The farther we deviate
from a direct assessment of these indicators, the more imprecise we
become. The Figure
Although the presence of a wall motion abnormality is valuable for
the diagnosis of prior infarction and resting or inducible
ischemia,1 it is of limited value in
patients with AMI who have recently undergone reperfusion therapy. In
these patients, a wall motion abnormality is likely to be present
whether or not reperfusion has been successful. Regional function will
be normal only if the period of ischemia was very short
(minutes), which is uncommon in the clinical setting. The degree of
wall thickening also does not reflect the transmural extent of
myocardial necrosis because dysfunction may be present in the
noninfarcted reperfused tissue.1 For the same
reason, the circumferential extent of a wall motion abnormality also
does not reflect infarct size. Thus, only when the wall motion
abnormality is localized to a small region of the
myocardium is a sizable infarction
excluded.1
The ECG is a useful clinical tool in the diagnosis of acute
ischemic syndromes. Its role in determining the success of
reperfusion or the extent of myocardial salvage, however, is less
valuable.2 3 While resolution of ST-segment
elevation can be helpful in determining successful reperfusion,
particularly if associated with amelioration of chest pain, occurrence
of ventricular arrhythmias, or a rapid rise in
cardiac enzymes,4 the absence of ST-segment
resolution does not exclude the occurrence of reperfusion. Albeit at a
slower pace, ST-segment elevation also eventually resolves in AMI even
in the absence of reperfusion. Likewise, the presence of Q waves on the
ECG correlates poorly with the transmurality of infarction after
successful reperfusion.
There are also limitations of using coronary angiography for
determining the success of reperfusion. Although TIMI grades 1 and 2
flow are known to indicate poor tissue perfusion, TIMI grade 3 flow has
generally been thought to represent successful
reperfusion.5 Studies using MCE have, however,
shown that about one sixth to one fourth of all patients with TIMI
grade 3 flow have poor tissue perfusion.6 7 The
best approach to determine the success of myocardial reperfusion is
therefore to assess capillary flow. Of the currently available and
developing techniques capable of assessing capillary flow, MCE has
demonstrated the most promise because it uses microbubbles, which are
pure intravascular tracers.6 7
With MCE, the low-reflow or the no-reflow phenomenon is commonly seen
after attempted reperfusion.6 7 The proximate
cause of this finding is thought to be capillary obstruction by
leukocytes and/or tissue edema, and it is associated with myocardial
tissue necrosis and cell injury.8 9 There is
controversy regarding the temporal relation between the microvascular
abnormalities and myocyte injury. It is believed that either the
microvascular phenomenon is a consequence of cell
death10 or it precedes cell death and may even
cause it.11 Determining which of these mechanisms
is operative is of more than academic interest. In the former case, any
attempts at altering microvascular function after reflow are unlikely
to alter patient outcome. In the latter case, pharmacological or other
interventions aimed at improving endothelial and other
microvascular functions could potentially salvage additional
myocardium and reduce infarct size. Recent studies using
MCE have reported that the low-reflow phenomenon can be partially
reversed by the intracoronary injection of
verapamil or the intravenous administration of
nicorandil and that this reversal is associated with improved regional
function and outcome.12 13 Although preliminary,
these exciting results create a potentially new treatment strategy for
patients with AMI who have undergone reperfusion therapy.
Because of reactive hyperemia, however, caution needs to be
exercised in the interpretation of MCE data immediately after attempted
reperfusion. Depending on the extent of the hyperemic response
(which is determined by the amount of microvascular damage and the
severity of residual stenosis), the low-reflow phenomenon can
be underestimated by MCE or any other method used to assess
MBF.14 The microvasculature in normal tissue has
flow reserve in excess of that in the infarcted tissue. Therefore, when
a coronary vasodilator is administered, the increase in MBF
caused by reactive hyperemia within the infarcted tissue is
less than that caused by the vasodilator in normal tissue. The region
of relative hypoperfusion in the presence of a coronary
vasodilator has consequently been shown to accurately reflect infarct
size after early reperfusion.14 Additionally,
although resting MBF in the infarct bed fluctuates wildly within the
first few hours after reflow, the flow reserve within the bed remains
remarkably stable and could be used as an indicator of the integrity of
the myocardial microvasculature.14 This may be
another reason to use coronary vasodilators after attempted
reperfusion. The safety of these agents in the early stages of AMI,
however, needs to be demonstrated.
The current methods of evaluating infarct size are indirect and do not
provide a complete assessment of the pathophysiology of AMI. For
example, even if cardiac enzymes do provide an accurate estimate of
infarct size,4 they do so without reference to
the risk area. A transmural infarct within a small risk area has
different implications than a similarly sized infarct within a large
risk area. A transmural infarct will expand and can result in
significant left ventricular dilation and heart
failure.15 Being buttressed by normal tissue, a
nontransmural infarct is less likely to result in these sequelae.
Perhaps in the former situation, ACE inhibitors are most
helpful, and they may not even be necessary in the latter situation.
Cardiac enzyme determinations and the ECG cannot be used reliably to
address these important pathophysiological
questions.
After reperfusion, although loss and damage of capillaries within an
infarct zone (no reflow) can provide an estimation of infarct size by
MCE, this assessment is still indirect. A more direct delineation of
infarct size could ensue from examination of myocardial tissue itself.
It is in this regard that the article by Mujsilovic and
colleagues16 in this issue of
Circulation is of interest. This article is an example in
which experimental data provide a biological basis for clinical
findings. These authors have shown that wavelet image decomposition of
ultrasound images can be used to separate necrotic from nonnecrotic
tissue, although the emphasis of the article has been incorrectly
placed on the detection of successful reperfusion. Because timely
reperfusion is associated with less infarction, the method can by
inference define patients with successful reperfusion. On the basis of
the present discussion, however, MCE would be a better method to
determine the success of reperfusion.
Texture analysis has been used in
echocardiography for almost 2 decades and is based
on alterations in myocardial tissue structure and composition caused by
disease. The most obvious example in coronary artery disease is
the thin, highly echogenic muscle occasionally seen in patients with
old infarction. Changes that are visually less obvious can be
documented by use of measurements of acoustic
intensity17 and cyclic variation in integrated
backscatter18 or by higher-order statistical
analysis of backscatter.19 These
procedures, however, have not entered the mainstream of
echocardiography because they are not robust enough
for routine clinical use. The acoustic properties of tissue on
transthoracic echocardiography are
affected as much by intervening tissue and lungs as by the disease
process itself. The methods are also tedious and time-consuming, making
them less attractive for routine clinical use.
We have observed increases in tissue echogenicity in patients with
recent (weeks to months) myocardial infarction on harmonic imaging,
which is not obvious on routine fundamental imaging. This increase in
echogenicity can be a source of error for MCE because the entire
myocardium may appear opacified after a venous injection of
microbubbles, giving an impression that there is normal and
homogeneous perfusion in all myocardial segments. Only on
examination of the precontrast image does it become apparent that the
video intensity is already increased in the infarct bed before
administration of microbubbles. That the video intensity does not
change in the infarct bed after microbubble injection to the same
degree as within the normal bed becomes apparent on image subtraction
and color coding or on quantification of myocardial video intensities.
The reason for increased signals from infarcted tissue on harmonic
imaging could be related to greater nonlinearity in acoustic properties
of abnormal versus normal tissue20 and/or a
higher signal-to-noise ratio.21 Tissue
characterization with harmonic imaging therefore appears promising in
determining infarct size when the injury is days to weeks old and
changes in the composition and structure of the extracellular matrix
have occurred. Whether similar information can be obtained immediately
after reflow needs to be investigated. Furthermore, the superiority of
tissue characterization for measuring infarct size over the more easily
available information regarding zones with no reflow or low reflow will
need to be demonstrated before it is to become accepted as a clinical
tool.
Given that we may now have tools that can assess both tissue perfusion
and infarct size with echocardiography, how can
these be used in patients with AMI? First, it is important to define
the risk area in a patient with AMI. If the risk area is small because
of occlusion of a small artery or abundant collateral flow, initial
treatment can be conservative. If the risk area is moderate to large,
thrombolysis or mechanical reperfusion should be
immediately instituted. Myocardial perfusion should be reassessed
immediately thereafter. If after attempted thrombolysis
the size of the risk area is unchanged, it denotes unsuccessful
reperfusion, and a case for rescue coronary angioplasty could
be made in selected patients.
Complete or nearly complete myocardial opacification of the infarct
zone after attempted reperfusion would indicate either almost complete
myocardial salvage or an underestimation of infarct size because of
reactive hyperemia. Use of a coronary vasodilator could
resolve this dilemma.14 If a region of reduced
flow is seen within the infarct bed after reperfusion (with or without
a vasodilator), pharmacological therapy aimed toward reversal of
microvascular dysfunction could be
initiated.12 13 MCE could then be repeated to
determine if the zone of reduced perfusion has decreased in size. If
infarction is transmural (based on no reflow on MCE or abnormal
patterns on tissue characterization), ACE inhibitors could
be initiated, regardless of global left ventricular
function. If the infarction is limited to the endocardial one third of
the myocardium, ACE inhibitors may not be
necessary unless there is global left ventricular
dysfunction from remote infarction or other pathologies.
Although all the scenarios described above represent
hypotheses, each appears plausible, given our knowledge of the
pathophysiology of AMI. With the methods described here, these
hypotheses can be tested in small (hundreds rather than tens of
thousands) numbers of patients without mortality as the end point.
Because each patient with AMI is different, the newer methods described
here have the potential to provide unique and valuable information
regarding the reperfused myocardium on a patient-by-patient
basis, which can then be used to individualize and optimize patient
management. Although this editorial has focussed primarily on
echocardiography, the principles discussed could be
applied to other techniques that can image regional myocardial
perfusion and function. The tools are becoming available. It is now
time to apply them.
Selected Abbreviations and Acronyms
Acknowledgments
This work was supported in part by a grant (R01-HL-48890) from
the National Institutes of Health, Bethesda, Md. I would like to thank
Danny Skyba, PhD, for executing the artwork and Ian J. Sarembock, MD,
for his critical review of my comments.
Footnotes
The opinons expressed in this editorial are not necessarily those of the editors or of the American Heart Association.
References
1.
Kaul S. Echocardiography in
coronary artery disease. Curr Probl Cardiol. 1990;15:233–298.[Medline]
[Order article via Infotrieve]
2.
Califf RM, O'Neil W, Stack RS, Aronson L, Mark DB,
Mantell S, George BS, Candela RJ, Kereiakes DJ, Abbottsmith C, Topol
EJ, for TAMI Study Group. Failure of simple clinical measurements to
predict perfusion status after intravenous
thrombolysis. Ann Intern Med. 1988;108:658–662.
3.
Krucoff MW, Croll MA, Pope JE, Granger CB, O'Connor
CM, Sigmon KN, Wagner BL, Ryan JA, Lee KL, Kereiakes DJ, Samaha JK,
Worley ST, Ellis SG, Wall TC, Topol EJ, Califf RM, for the TAMI Study
Group. Continuous 12-lead ST-segment recovery analysis in the
TAMI 7 Study: performance of a noninvasive method for real-time
detection of failed myocardial perfusion. Circulation. 1993;88:437–446.
4.
Tanasijevic MJ, Cannon CP, Wybenga DR, Fischer GA,
Grudzein C, Gibson CM, Winkelman JW, Antman EM, Braunwald E, for the
TIMI 10A Study Investigators. Myoglobin, creatine kinase MB, and
cardiac troponin-I to assess reperfusion after
thrombolysis for acute myocardial infarction: results
from TIMI 10A. Am Heart J. 1997;134:622–630.[Medline]
[Order article via Infotrieve]
5.
Cheseboro JH, Knatterud G, Roberts R, Borer J, Cohen
LS, Dalen J, Dodge HT, Francis CK, Hillis D, Ludbrook P, Markis JE,
Mueller H, Passamani ER, Powers ER, Rao AK, Robertson T, Ross A, Ryan
TJ, Sobel BE, Willerson JT, Williams DO, Zaret BL, Braunwald E.
Thrombolysis in Myocardial Infarction (TIMI) trial, phase
I: comparison between intravenous plasminogen
activator and intravenous streptokinase:
clinical findings through hospital discharge. Circulation. 1987;76:142–154.
6.
Ito H, Okamura A, Iwakura K, Masuyama T, Hori M,
Takiuchi S, Negoro S, Nakatsuchi Y, Taniyama Y, Higashino Y, Fuji K,
Minamino T. Myocardial perfusion patterns related to
thrombolysis in myocardial infarction grades after
coronary angioplasty in patients with acute anterior wall
myocardial infarction. Circulation. 1996;93:1993–1999.
7.
Ragosta M, Camarano GP, Kaul S, Powers E, Sarembock
IJ, Gimple LW. Microvascular integrity indicates myocellular viability
in patients with recent myocardial infarction: new insights using
myocardial contrast echocardiography.
Circulation. 1994;89:2562–2569.
8.
Kloner RA, Ganote CE, Jennings RB. The `no-reflow'
phenomenon after temporary coronary occlusion in the
dog. J Clin Invest. 1974;54:1496–1508.
9.
Johnson WB, Malone SA, Pantely GA, Anselone CG,
Bristow JD. No reflow and extent of infarction during maximal
vasodilation in the porcine heart. Circulation. 1988;78:462–472.
10.
Kloner RA, Rude RE, Carlson N, Maroko PR, DeBoer LW,
Braunwald E. Ultrastructural evidence of microvascular damage and
myocardial cell injury after coronary artery occlusion: which
comes first? Circulation. 1980;62:945–952.
11.
Tillmanns H, Leinberger H, Neumann FJ, Steinhausen M,
Parekh N, Zimmerman R, Dussel R, Kuebler W. Myocardial microcirculation
in the beating heart: in vivo microscopic studies. In: Spaan JAE,
Bruschke AVG, Gittenberger-de Groot AC, eds. Coronary
Circulation. Dordrecht, Netherlands: Martin Nijhoff Publishers;
1987:88–94.
12.
Taniyama Y, Ito H, Iwakura K, Masuyama T, Hori M,
Takiuchi S, Nishikawa N, Higashino Y, Fuji K, Minamino T. Beneficial
effect of intracoronary verapamil on microvascular
and myocardial salvage in patients with acute myocardial infarction.
J Am Coll Cardiol. 1997;30:1193–1199.[Abstract]
13.
Taniyama Y, Ito H, Iwakura K, Higashino Y, Fuji K.
Intravenous nicorandil augments microvascular and
myocardial salvage and reduces complications in patients with acute
myocardial infarction. Circulation. 1997;96(suppl I):I-748.
Abstract.
14.
Villanueva FS, Camarano G, Ismail S, Goodman NC,
Sklenar J, Kaul S. Coronary reserve abnormalities during
post-infarct reperfusion: implications for the timing of myocardial
contrast echocardiography to assess myocardial
viability. Circulation. 1996;94:748–754.
15.
Kaul S. There may be more to myocardial viability than
meets the eye! Circulation. 1995;92:2790–2793.
16.
Neskovic AN, Mojsilovic A, Javanovic T, Vasiljevic J,
Popovic M, Marinkovic J, Bojic M, Popovic AD. Myocardial tissue
characterization after acute myocardial infarction using wavelet image
decomposition: a novel approach for the detection of successful
reperfusion in the early postinfarction period. Circulation. 1998;98:634–641.
17.
Picano E, Faletra F, Marini C, Paterni M, Donzi GB,
Lombardi M, Campolo L, Gigli G, Landini L, Pezzano A, Distante A.
Increased echo density of transiently asynergic myocardium
in humans: a novel echocardiographic sign of myocardial
ischemia. J Am Coll Cardiol. 1993;21:199–207.[Abstract]
18.
Vandenberg BF, Stuhlmuller JE, Rath L, Kerber RE,
Collins SM, Melton HE, Skorton DJ. Diagnosis of recent myocardial
infarction with quantitative backscatter imaging: preliminary studies.
J Am Soc Echocardiogr. 1991;4:10–18.[Medline]
[Order article via Infotrieve]
19.
Saeian K, Rhyne TL, Segar KB. Ultrasonic tissue
characterization for diagnosis of acute myocardial infarction in the
coronary care unit. Am J Cardiol. 1994;74:1211–1215.[Medline]
[Order article via Infotrieve]
20.
Christopher T. Finite amplitude distortion-based
inhomogenous pulse echo ultrasonic imaging. IEEE Trans
Ultrasonics, Ferroelectrics, Frequency Control. 1977;44:125–139.
21.
Burns PN, Powers JE, Simpson DH, Uhlendorf V, Fritzsche
T. Harmonic imaging: principles and preliminary results. Clin
Radiol. 1996;51(suppl I):I-50–I-55.
© 1998 American Heart Association, Inc.
Editorials
Assessing the Myocardium After Attempted Reperfusion
Should We Bother?
Key Words: Editorials • myocardium • echocardiography • microcirculation • myocardial infarction
depicts the findings generally used
in the clinical setting to determine whether reperfusion has actually
occurred and the extent of myocardial salvage achieved.
View larger version (21K):
[in a new window]
Figure 1. Figure depicts the findings generally used in the clinical
setting to determine whether reperfusion has actually occurred and the
extent of myocardial salvage achieved.
AMI
=
acute myocardial infarction
MBF
=
myocardial blood flow
MCE
=
myocardial contrast echocardiography
TIMI
=
Thrombolysis in Myocardial Infarction
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