Contrast Perfusion Echocardiography: Distribution and Reproducibility of Myocardial Contrast Enhancement

in Coronary Artery Disease

BRIAN GRIFFIN, MB, ADAM D. TIMMIS, MD, and EDGAR SOWTON, MD

A qualitative assessment was undertaken of the echocardiographic distribution of myocardial con- trast enhancement after selective intracoronary in- jections of 2 ml of hand-agitated Urografin@ solution. The reproducibility and duration of contrast en- hancement has also been examined. Forty-five con- trast injections were given, 36 into the left and 6 into the right coronary arteries and 3 into bypass grafts of 26 patients undergoing diagnostic atteriog- raphy. Myocardial contrast enhancement occurred in 91% of cases. Although contrast enhancement appeared within the expected area of distribution of the artery infused, in no case was enhancement ho- mogeneous. In 4 patients (1 of whom had under- gone coronary bypass surgery), contrast enhance- ment also appeared in areas remote from the expected perfusion territory, in each case due to well established collateral supply seen angiographi- tally. The contrast effect persisted for 71 f 26 sec-

onds. Repeat injection in 5 patients (using identical echocardiographic windows) confirmed the repro- ducibility of the technique. No patient had symptoms related to the injections, although transient left ven- tricular wall motion abnormalities were observed in 3 cases. High-grade coronary stenoses did not af- fect distribution of myocardial contrast enhance- ment, although coronary occlusions produced well defined deficits. Thus, selective intracoronary injec- tions of hand-agitated echocardiographic contrast medium produce regional myocardial enhancement, which probably reflects the perfusion territory of the artery. The technique is safe and reproducible in hu- man subjects. Nevertheless, because regional en- hancement after selective coronary injections is not homogeneous, analysis of enhancement deficits is unlikely to provide a clinically useful means of eval- uating the functional significance of coronary steno- ses. (Am J Cardiol 1967;60:536-543)

I njection of microbubble contrast solution into the coronary arteries enhances the echogenic properties of the myocardium .lJ This technique has yielded no important adverse effects in animal studies,3 and re- cently its safety in humans was reported.4,5 Animal studies indicate that the area of contrast enhancement reflects the perfusion territory of the artery injected and correlates closely with the area at risk of infarction after occlusion of the artery.6-8 Human studies have been restricted to patients with normal coronary arte- ries,4,5 those undergoing coronary angioplastyg and those undergoing coronary bypass surgery.lO We per- formed contrast perfusion echocardiography in pa-

From the Department of Cardiology, Guy’s Hospital, London, England. Manuscript received January 23, 1987; revised manu- script received May 19,1987, accepted May 24, 1987.

Address for reprints: Brian Griffin, MB, Department of Car- diology, Guy’s Hospital, St. Thomas’ Street, London SE1 SRT, England.

tients undergoing diagnostic coronary arteriography in order to evaluate the regional distribution of contrast enhancement and the effects of coronary stenoses and occlusions on contrast enhancement. The duration and reproducibility of contrast enhancement was also examined.

Methods Patients: Twenty-eight patients (22 men, 6 women),

aged 55 f 9 years, were studied during diagnostic coro- nary arteriography. These patients constituted a non- consecutive series with suspected coronary artery dis- ease studied over 15 weeks. Exclusion criteria were unstable angina or chest pain requiring medication during catheterization. Patients in whom adequate ul- trasound signals could not be recorded were also ex- cluded. Patient characteristics are listed in Table I. All but 6 of the patients had coronary artery disease, in- volving 1 vessel in 11 cases and multiple vessels in 11 cases. Coronary occlusions were demonstrated in 7

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September 1, 1987 THE AMERICAN JOURNAL OF CARDIOLOGY Volume 60 539

TABLE I Patient Characteristics and Distribution of yocardial Contrast Enhancement

Coronary Disease (% Diameter Stenosis)

Age W NYHA Pt & Sex Class LAD LC Right Graft Collaterals Dominance

Artery Echo LV Injected Window Enhancement

1 55F

2” 41M 3 5OF 4 54M 5 55F 6 40M 7 51M 8 54M 9 63M

10 58M

11 41M 12 56M 13 59M 14 64M 15 55M 16” 50M

17” 78F

18 60M 19 37M 20 47M 21” 55F

22” 55M

23 44M 24 55F 25 64M

26 62M 27 63M 28 73M

2

2 2 2 2 2 2 3 3 2

3 2 3 3 3 3

3

3 2 3 3

3

2 3 3

2 3 3

N

N N N N N N 95 70 50

90 N 70 N 95 90

90

100 100 100

N

90

N N

N N N 60 N N N N N N N 60 N N 85 90 50 60

90 N N N N N 80 100 N N N N

60 N

N N N N N 100 N 95

100 100

95 60 90 85 00 100 95 70 80

90 95 95

N 100 N N N N

Right

Right Right Right Right LC Right LC Right -I- LC Right

Right Rlght Right Right Right LC

LC LC

RCA

Right Right Right Right

LAD RCA Right

LAD Right RCA Right LAD Right

RCA Right Right

LCA X 2 Right LCA X 2 LCA LCA LCA LCA X 2 LCA LCA LCA LCA Right LCA LCA LCA LCA RCA LCA X 2 Right LCA X 2 LC G LCA LCA LCA LCA X 2 Right LCA X 2 LAD G

LC G LCA X 2 LCA LCA f Right

LCA X 2 LCA LCA

PSAlLA PSA PSA PSA LA A4C PSAILA A4C LA A4C PSA PSA A4C PSA PSA A4C PSA PSA PSA A46 A4C PSA A4C A4C PSA PSA PSA PSA PSA PSAILA PSA A4C

A4G PSA/LA A4C PSA

AS, A, L IS, I AS, A, L AS, A s, 1 s, L AS, A, L, I s, L s, 1 s, L AS: A, L IS, I s, L AS, A, L AS, A, L s, L IS, I AS, A, I

s: ; L L L L Global

IS, I AS, A, I AS, A, I L AS, A, L Global s, L S Global s, L AS, A, L

“Reproducibility study. A = anterior wall; AS = anteroseptal; A4C = apical 4-chamber; G = graft; I = inferior wall; IS = inferoseptal; L = lateral wall; LA = long axis; LAD = left

anterior descending; LC = left circumflex: LV = left ventricular: N = normal coronary artery: S = septum.

patients, and 6 patients had well developed collateral flow. Two patients had undergone coronary artery by- pass grafting.

Protocol: Patients gave informed consent for inclu- sion in this study, which had been approved by the hospital ethical committee. Coronary arteriography was performed from the brachial artery using Sones or Amplatz catheters. On completion of diagnostic arteri- ography, echocardiographic contrast material was in- jected into either the left (n = 36) or the right (n = 6) coronary arteries or into bypass grafts (n = 3). An echo- cardiogram was recorded continuously, before, during and for 2 minutes after the contrast injection, without adjustment of the gain setting. Different protocols were applied in small groups of patients in order to determine the distribution, reproducibility and dura- tion of contrast enhancement. Thus, in 5 patients both coronary arteries received an injection. In 5 patients repeat contrast injections into the same coronary ar- tery (using identical ultrasound windows] were per-

formed to evaluate reproducibility. In another 5 pa- tients M-mode echocardiograms were recorded to measure duration of contrast enhancement, In 4 pa- tients 2 contrast injections into a single coronary artefy were performed to examine the distribution of en- hancement using different ultrasound windows,

Echocardiographic contrast medium: The contrast medium was a 50% solution of Urografinm and normal saline solution, hand-agitated using a 3-way stopcock and two IO-ml syringes. Up to 1 ml of air was intro- duced and the contrast solution was rapidly injected back and forth between both syringes for 2 to 3 min- utes. Excess air and visible bubbles were manually expelled from the system. Two milliliters of contrast medium were used for each coronary injection.

Echocardiography: A Hewlett-Packard 2-D and M-mode scanner was used. For right coronary artery injections a parasternal short-axis view [at papillary muscle level) was used in all cases except 1. For left coronary artery injections a combination of parnstcr-

540 CONTRAST PERFUSION ECHOCARDIOGRAPHY

nal short-axis, parasternal long-axis and apical 4- chamber views were used. Two-dimensional images were recorded on videotape and the M-mode images on heat sensitive paper at 5 mm/s.

Analysis of contrast effect: All videotape and M- mode recordings were analyzed by 2 experienced echocardiographers. The degree of contrast enhance- ment was graded arbitrarily as none, moderate, good or excellent. Distribution of myocardial contrast en- hancement on the a-dimensional images was deter- mined by consensus. Duration of contrast enhance- ment was measured on the M-mode recordings and was defined as the time taken for myocardial contrast to return to the baseline level. Although the endpoint of this exponential function was hard to determine, interobserver variability on multiple assessments nev- er exceeded 8 seconds. During analysis of the contrast effect, the observers were blinded to the results of coronary arteriography.

Analysis of coronary arteriograms: Coronary arte- riograms were analyzed by 2 observers. The presence of collaterals was noted. During analysis the observers were blinded to the results of the echo contrast study.

Monitoring of adverse effects: All patients re- ceived continuous electrocardiographic (,ECG) (lead I) and echocardiographic monitoring during the echo- cardiographic contrast injections. Appearance of new echocardiographic wall motion abnormalities after contrast injection was noted. ECG changes and symp- toms related to the injections were also noted.

Results Intracoronary injection of echo contrast medium

produced no subjective adverse effects or abnormali- ties in any patient. Transient wall motion abnormali-

RCA Injection t

FIGURE 1. Duration of myocardial contrast enhancement (M-mode echocardiograms). After left and right coronary artery (LCA and RCA) injections, contrast enhancement is seen in the septum and inferior wall, respectively. Arrow marks the time of the injec- tions. Recordings were continued until contrast enhancement disappeared.

ties were seen in 3 patients in the expected distribution of the artery infused and were associated with a dense contrast effect. In each case contrast washout and re- covery of dyskinesia occurred within 90 seconds.

Quality of contrast enhancement Forty-five con- trast injections were performed in 28 patients. Myo- cardial contrast enhancement was seen after 41 of these injections (91%). The quality of contrast en- hancement was not notably different for left and right coronary injections, although the number of right coro- nary injections was small. Four injections failed to show contrast effect. This was probably the result of poor-quality echo contrast medium in 3 cases; repeat injections produced normal contrast enhancement. In 1 case failure of contrast enhancement occurred prob- ably because the right coronary artery that received the injection was small and nondominant.

Duration of contrast enhancement (Fig. 1): Dura- tion of contrast enhancement was measured in 5 patients, all of whom had significant disease in the coronary artery assessed. Myocardial contrast en- hancement persisted for 71 f 26 seconds [range 36 to 1201.

Reproducibility of contrast enhancement (Fig. 2): Of the 5 patients in whom reproducibility studies were performed, imaging was performed from the paraster- nal short-axis window in 4 and apical 4-chamber win- dow in 1 patient during 2 consecutive left coronary injections separated by 5 minutes. The distribution of contrast was qualitatively reproducible in each case.

Distribution of contrast enhancement: Distribu- tion of contrast enhancement was largely dependent on the coronary artery that received the injection. Oth-

First lniection

Second InjectIon

FIGURE 2. Reproducibility study (parasternal short-axis view). The left coronary artery (LCA) received injections on 2 separate occa- sions. The distribution of myocardial enhancement shown in the righf panels was reproducible, involving the anterior and lateral walls of the left ventricle and the papillary muscles. Attenuated enhancement of the inferior wail is also seen. The inferior septum, however, did not show contrast enhancement on either occasion.

September 1, 1987 THE ANlERlCAN JOURNAL OF CARDIOLOGY Volume 60 541

er factors that influenced distribution were coronary artery occlusions and collateral flow.

In general, right coronary artery injections en- hanced the inferior septum and the inferior wall and left coronary artery injections enhanced the remain- der of the left ventricle (Fig 31. Nevertheless, after left coronary injections, lateral wall enhancement (seen only on parasternal short-axis and apical a-chamber views] was relatively attenuated in 16 cases (52%] and did not occur at all in 3 patients, only 1 of whom had an occluded circumflex artery. Injections into the left cor- onary artery produced attenuated inferior wall en- hancement (seen only on parasternal short-axis and long-axis views) in 6 patients (33%), none of whom had obvious collateralization of this area on the angiogram. In none of the patients was regional contrast enhance- ment homogeneous after selective injection into the right or left coronary artery.

In 4 of 5 patients who had contrast injections into both the left and right coronary arteries in turn, en- hancement of the entire left ventricular myocardium occurred. One patient showed no enhancement of the lateral wall. Extensive contrast enhancement also oc- curred after left coronary artery injections in 4 patients in whom the right coronary artery was totally or subto- tally occluded but well collateralized (Fig. 4).

Importantly high grade [more than 70%) coronary stenoses produced no discernible regional reduction in echo contrast. In 2 patients with left anterior de- scending coronary artery occlusions, however, no con- trast enhancement occurred in the apical-septal region after injections into the left coronary artery, despite normal enhancement of the lateral wall (Fig. 51. Simi- larly, in 1 patient with circumflex occlusion the left coronary injection failed to enhance the lateral wall,

Three bypass graft injections were given during the study. After 2 circumflex graft injections, contrast en- hancement occurred in the lateral wall of the left ven- tricle. In the left anterior descending graft, contrast enhancement occurred not only in the anterior wall and septum, but also in the inferior wall of the left ventricle due to collateralization of an occluded right coronary artery.

Discussion We examined the effects of selective intracoronary

injections of hand-agitated Urografin on the echoden- sity of the left ventricular myocardium. Regional myo- cardial enhancement occurred within the expected territory of distribution of the coronary artery that re- ceived the injection, although enhancement was never homogeneous. No serious adverse effects were noted during or after the procedure.

In this study, 91% of the contrast injections pro- duced myocardial enhancement, which in most cases was judged to be of good or excellent quality. These findings are in accord with those of Santoso et al,4 who reported that 33% of intracoronary contrast injections produced myocardial enhancement of similar qual- ity. The myocardial enhancement corresponds to the known perfusion territory of the artery injected. More- over, when both left and right coronary arteries received injections in turn, global enhancement of

the left ventricular myocardium occurs. Nevertheless, qualitative assessment of contrast enhancement pro- vides only limited information about the functional significance of coronary artery disease. Thus, although coronary occlusions produced regional enhancement deficits, similar deficits were not produced by high- grade coronary stenoses, possibly because none of our patients showed ischemia at the time of the injections.

Other investigators have reported regional en- hancement deficits during contrast echocardiography in patients with nonocclusive coronary artery disease. Lang et al9 noted perfusion deficits in areas subtended by high-grade stenoses before coronary angioplasty. In every case, however, wall motion abnormalities in the same areas were detected on the echocardiogram, in- dicating significant rest ischemia. Presumably, there- fore, the coronary stenoses in this subgroup of patients selected for angioplasty were more severe and pro- duced a greater rest perfusion deficit than those in the present study. Goldman and MindichlO also reported

LCA Injection

RCA Iniectlor

FIGURE 3. Distribution study (parasternal short-axis view). Injec-

tion into the left coronary artery (LCA) produced myocardial en-

.hancement in the anterior wall and inferior wall of the left ventricle,

with attenuated enhancement of the lateral wall. Injection into the

right coronary artery (RCA) produced enhancement of the remaain-

der of the left ventricular myocardium.

542 CONTRAST PERFUSION ECHOCARDIOGRAPHY

LCA Injection (collaterals to RCA1

FIGURE 4. Collateral flow (para- sternal short-axis view). Injection into the left coronary artery (LCA) produced contrast en- hancement of the entire left ven- tricular myocardium due to .well established collateral flow to the right coronary artery (RCA), which was occluded.

Control Contrast

regional myocardial enhancement deficits in patients tion, more complete mixing within the blood pool with nonocclusive coronary artery disease undergoing would occur after left ventricular or aortic root injec- bypass surgery. Again, however, these patients were a tions, leading to more homogeneous myocardial distri- subgroup selected for revascularization in whom coro- bution. Sonication of the contrast medium to yield nary stenoses may have been particularly severe. smaller, more uniform microbubbles may also provide Moreover, because the studies were performed in fi- more homogeneous distribution of tracer.ll Thus, in brillating hearts on cardiopulmonary bypass (using the studies of Goldman and MindichlO and Lang et a1,g aortic root injections of echocardiographic contrast use of aortic root injections and sonicated echo con- cardioplegia], the dynamics of coronary flow and myo- trast medium, respectively, probably contributed to cardial perfusion were different from those in the demonstration of regional enhancement deficits distal beating hearts of our patients. to high-grade coronary stenoses.

A fundamental requirement of perfusion imaging techniques is that the distribution of tracer within the normal heart is homogeneous. Contrast echocardiog- raphy using hand-agitated solutions does not fulfill the requirement. Thus, Santoso et a,14 in their study of patients with normal coronary arteries, found regional attenuation of contrast enhancement in most cases. Similar attenuation was observed in the preset study unrelated to the presence of coronary stenoses. One may speculate that more useful diagnostic information could be obtained by refining the technique. Although there is no satisfactory method of intravenous or right- sided cardiac echocardiographic contrast administra-

An alternative means of improving the diagnostic value of contrast perfusion echocardiography is by analysis of the kinetics of contrast washout from the myocardium. Experimental data reveal a significant correlation between the rate of washout and the de- gree of coronary obstruction.12J3 Application of these methods in patients with coronary artery disease has yet to be validated.

As used in this study, therefore, contrast perfusion echocardiography provided only limited information about the severity of coronary artery disease by identi- fying enhancement deficits only in patients with arte- rial occlusions. Collateral flow demonstrated angio- graphically, however, was reliably identified, and in every case produced myocardial enhancement remote from the expected distribution of the coronary artery that received the injection. This technique therefore provides useful information about the extent and im- portance of collateral flow in patients with coronary occlusions.

Anteroseptal Infarct - LCA Injection

FIGURE 5. Coronary occlusion (apical 4-chamber view). The left anterior descending coronary artery is occluded and subtends a large apical aneurysm. Thus, after injection into the left coronary artery (LCA), contrast enhancement occurs only in the proximal septum and the lateral wall.

As did other investigators,4T5 we found contrast per- fusion echocardiography to be safe. Nevertheless, transient left ventricular wall motion abnormalities were occasionally seen after contrast injections. This almost certainly was related to passage of relative- ly large microbubbles through the capillary circula- tionll-an adverse affect that may be avoided by use of the sonicated contrast material.14

Our study confirms the feasibility of contrast perfu- sion echocardiography in patients undergoing diag- nostic coronary arteriography and suggests that the technique is safe and reproducible. Myocardial con- trast enhancement occurs in the expected distribution of the coronary artery infused and identifies collateral flow to remote myocardial regions. Nevertheless, our

September 1, 1987 THE AMERICAN JOURNAL OF CARDIOLOGY Volume 60 543

qualitative analysis provides no information about the functional significance of coronary stenosis. Indeed, unless the technique can be refined to produce a more homogeneous distribution of tracer, information of this type is unlikely to be forthcoming. Quantitative analy- ses of the kinetics of contrast washout may provide an alternative means of evaluating the functional signifi- cance of coronary stenoses. Preliminary animal stud- ies are promising, but further work is necessary to test the validity of these quantiative methods in patients with coronary artery disease.

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5. Moore CA, Smucker ML, Kaul S. Myocardial contrast echocardiography in humans: 1. Safety-a comparison with routine coronary arteriography. JACC 1986;8:1066-2072. 6. Kaul S, Pandian NC, Okada RD, Pohost GM, Weyman RE. Contrast echo- cardiography in acute myocardial ischemia. I. In vivo determination of total’ Jeft ventricular “area at risk.” IACC 1984;4:1272-1282, 7. Kaul S, Gillam LD, Weyman AE. Contrast echocardiography in acute myocardial ischemia. II. The effect of site of injection of contrast agent on the estimation of area at risk for necrosis after coronary occlusion. [ACC 1985;6:825-830. 8. Kemper AJ, Force T, Perkins L, Gilfoil M, Parisi AF. In vivo prediction of the treatment extent of experimental acute myocardial infarction using con- trast echocardiography. [ACC 1986;8:143-149. 9. Lang RM, Feinstein SB, Feldman T, Neunaan A, Kok GC, Borow KM. Contrast echocardiography for evaluation of myocardial perfusion: effects of coronary angioplasty. fACC 1986;8:232-235. 10. Goldman ME, Mindich BP. Intraoperative cardioplegic contrast echocar- diography for assessing myocardial perfusion during open heart surgery. [ACC 1984:4:1029-1034, 11. Feinstein SB, Ten Cate FJ, Zwehl W, Ong K, Maurel G, Tei C, Shah PM, Meerbaum S, Corday E. Two dimensional contrast echocardiography. I. In vitro development and quantitative analysis of echo contrast agents. IACC 1984;3:14-20. 12. Ten Cate FJ, Drury K, Meerbaum S, Noordsy J, Feinstein S, Shah PM, Corday E. Myocardial contrast two-dimensional echocardiography: experi- mental examination at different coronary flow levels. /ACC 1984;3:1291-1226. 13. Tei 0, Kendo S, Meerbaum S, Ong K, Maurer G, Wood F, Sakamahi T, Shimoura K, Corday E, Shah PM. Correlation of myocardial echo contrast disappearance rate (“washout”) and severity of experimental coronary steno- sis. TACC 1984;3:39-46. 14. Feinstein SB, Shark PM, Bing RJ, Meerbaum S, Corday E, Chang BL, Santillan G, Fujibayashi Y. Microbubble dynamics visualized in the intact capillary circulation. IACC 1984;4:595-600.