limitations of Dipyridamole-Echocardiography in Effort Angina Pectoris

ALBERT0 MARGONATO, MD, SERGIO CHIERCHIA, MD, DOMENICO CIANFLONE, MD, GILLIAN SMITH, BSc, FILIPPO CREA, MD, GRAHAM J. DAVIES, MRCP,

AlTILl MASERI, FRCP, and RODNEY A. FOALE, MRCP

The sensitivity of dipyridamole-2-dimensional (2-D) echocardiography was assessed for detection and localization of ischemia in 21 patients with severe chronic stable angina pectoris, a clearly positive ex- ercise stress test response and multivessel coronary atherosclerosfs. Regional wall motion during dipyrkt- amole infusion (0.6 mg/kg intravenously over 4 minutes) was compared wfth control and recovery by 2 blinded observers in consensus. Transient re- gional wail motion abnormalities were observed in 11 patients. Angina and ST-segment changes occurred in 9 of these 11 patients with positive responses, but in none of those who showed no transient abnormality of regfonai wail motion. Locai- ization of regional wail motion abnormafiiies corre- lated well with angiographic severity of coronary ie- sions. Endocardiai area contraction, evaluated by a computerized system, was reduced significantly af-

ter dipyridamoie administration in patients with a posttiveresponse(from51f10%to35f11%, p <O.OOl), whereas it did not change significantly in the others (from 43 f 6% to 42 f 6%). in the 11 patients with a positive response, coronary re- serve assessed by exercise testing (modified Bruce protocol) was more impaired than in those with a negative response (time to 1 mm of ST depression 177 f 146 seconds and 472 f 179 seconds, re- spectively, p <O.Ol). in patients with severe angina and muftivessei coronary artery disease, dipyrida- mole-2-D echocardiography appears to identify the vessel in which flow reserve is most limited. Ai- though this information may be valuable, indications for the test are restricted to patients with severely limited exercise capacity.

(Am J Cardioi 1967;59:225-230)

T ransient abnormalities of myocardial contractile function are usually the earliest and most evident signs of acute myocardial ischemia.l Use of 2-dimensional (2-D] echocardiography has been proposed to increase the specificity of exercise testing in patients with coro- nary artery disease (CAD).2J Although this technique theoretically represents a simple diagnostic tool for detecting regional wall motion abnormalities in pa- tients with acute myocardial ischemia, its use is limited because of movement artifacts, which prevent record- ing of good-quality images in as many as !XWO of pa-

225

From the Cardiovascular Research Unit, Royal Postgraduate Medical School, Hammersmith Hospital, London, England, and Clinica Medica VII, Istituto S Raffaele, Milan, Italy. Manuscript received April 20,1986; revised manuscript received September l&1986, accepted September 18,1986.

Address for reprints: Albert0 Margonato, MD, Cardiovascu- lar Research Unit, Royal Postgraduate Medical School, Ham- mersmith Hospital, Du Cane Road, London Wl2 OHS, England.

The ability of dipyridamole to induce acute myo- cardial ischemia in patients with CAD has long been known,5v6 and dipyridamole has been used in conjunc- tion with perfusion studies for noninvasive detection of CAD.7-8 We assessed the diagnostic value of 2-D echocardiography during dipyridamole administra- tion for detecting and localizing myocardial ischemia. We studied 26 patients with severe chronic stable angi- na, significant CAD and a clearly positive exercise electrocardiographic (ECG) response at low or moder- ately low workloads. The aims of the study were to establish the frequency of positive responses, to corre- late the results of the test with the patients’ effort toler- ance and to investigate the relation between transient regional wall motion abnormalities induced by dipy- ridamole and the degree of impairment of coronary flow reserve and the location of CAD.

tients.4 Therefore, alternative means of provoking acute myocardial ischemia are needed that can be used as alternatives to exercise in conjunction with 2-D echocardiography.

226 DIPYRIDAMOLE-ECHOCARDIOGRAPHY IN EFFORT ANGINA

Methods Patients: Twenty-six patients with angina pectoris

(24 men, 2 women, mean age 56 f 9 years, range 29 to 69) were admitted for elective evaluation and treat- ment. All had a typical history of exertional angina and a positive exercise stress test response as defined by standard ECG diagnostic criteria (at least 1 mm of ST depression, rectilinear or downsloping). Although in all patients angina was usually associated with physi- cal exertion, emotions or other conditions known to increase myocardial oxygen demand, 15 also reported occasional episodes of rest pain. However, none had noted a change in severity, duration or precipitating factors of angina in the last 3 months. Patients with concomitant valvular or congenital heart disease, pre- vious cardiac surgery, recent myocardial infarction or unstable angina were excluded. All patients gave in- formed consent.

Exercise testing: Exercise stress tests were per- formed in the fasting state in the morning on a motor- driven treadmill using the modified Bruce protocol.g Three ECG leads were monitored throughout the test, while 1%lead electrocardiograms and blood pressure (cuff sphygmomanometer) were recorded during con- trol, at l-minute intervals during exercise and for 10 minutes after exercise. ST-segment derived variables were analyzed on line in the 3 monitored leads by a computerized system (CASE Marquette) and plotted, along with the heart rate (HR) and HR-blood pressure (BP] product, against time in a trend format.

Cardiac catheterization: Selective coronary arteri- ography and left ventriculography were performed us- ing the Judkins technique. Left ventricular angiogra- phy was performed in the 45’ right anterior oblique position while the left and right coronary arteries were studied in multiple projections. All angiograms were reviewed blindly by 2 independent observers and cor- onary stenoses were expressed as percent diameter reduction. Furthermore, a severity score for CAD was attributed to every patient according to the method of Gensini.*O

Study protocol: No medications other than sublin- gual nitroglycerin were administered on the 3 days preceding the test. No smoking, tea or coffee were allowed on the day of the test. Aminophylline and isosorbide dinitrate for intravenous use were avail- able. Dipyridamole was infused through an antecubi- tal vein at a dose of 0.6 mg/kg over 4 minutes.

Twelve ECG leads (V, and VB were displaced by 1 intercostal space because of the parasternal echocar- diographic window used) were recorded continuously on a 14-channel ink recorder (Mingograph 14, Elema- Schonander). Standard lead I was also monitored con- tinuously on the echo display.

A high-resolution, ultrasound, phased-array system (PASS “C” General Electric) was used for the study. The suitability and technical quality of the ultrasound images were assessed for each patient before the test. Particular attention was paid to obtaining good-quality short-axis images of the left ventricle from the left parasternal transducer position. Continuous short-axis images of the left ventricle were recorded on video-

tape for 5 minutes before, during and for 20 minutes after dipyridamole infusion. For each patient, serial images were obtained at the level of the mitral valve at proximal, mid- and distal papillary muscle level and at the cardiac apex. The best quality echo image from papillary muscle level or below was then selected to follow the course of wall motion change, although at approximately l-minute intervals other short-axis pro- jections were briefly scanned to ascertain whether wall motion changes were present.

Echocardiographic analysis: Echocardiograms were evaluated blindly by 2 experienced observers. For the levels studied, the left ventricle was empirical- ly divided into 5 segments (posterior, inferior, septal, anterior and lateral) using a modification of the meth- od described by Weymanll (Fig. 1). For each segment wall motion was subjectively defined as normal, hypo- kinetic, akinetic or dyskinetic.zp3 The ECG lead dis- played on the monitor was covered during the analy sis of echocardiographic data. Echocardiograms were also evaluated by a commercially available computer- ized system (Microsonics, Mod 886-lAE), which allows a resolution of 0.004 cm/pixel for studies performed using a l&cm depth. With this standard system, analog video signals are transferred into the computer bulk memory after digital conversion. To improve image quality, in particular for better defini- tion of the endocardial edge, digital averaging of ECG- gated frames was performed (Fig. 2). In patients with a positive response, 10 seconds of ECG-gated end-dia- stolic and end-systolic frames were averaged during control and at peak change. In patients with a negative test, frames were acquired in the basal state and 500 seconds after infusion. This interval was longer than the maximum observed for development of regional wall motion abnormalities in patients with positive responses and shorter than that required for recovery. The papillary muscle plane was selected for comput- erized analysis because in all positive patients regional wall motion abnormalities were present at this level (Table I].

Measurements were performed blindly by a third experienced observer on averaged end-diastolic and end-systolic images. Endocardial areas of end-systole and end-diastole were drawn on the computer video by an electronic cursor at the echo leading edge and percent changes were calculated (normal values 36 to 64%). Each area was drawn 6 times and its average value was used for analysis.

Statistical analysis: Continuous data are expressed as mean f standard deviation. Paired and unpaired Student t tests were used as appropriate. Significance was derived by statistical tables.

Results Exercise testing: Exercise duration ranged from 66

to 780 seconds (mean 408 f 194) and time to 1 mm of ST depression from 48 to 720 seconds (mean 318 f 218). HR and HR-BP product at 1 mm of ST depression were 117 f 17 beats/min and 17,083 f 3,007 beats/ min X mm Hg, respectively. At peak exercise they were 123 f 18 beats/min and 18,738 f 3,259 beats/min X mm Hg.

February 1, 1987 THE AMERICAN JOURNAL OF CARDIOLOGY Volume 59 227

TABLE I Cllnlcal Echocardlographlc and Electrocardlographlc Findings and Coronary Anatomy In the 21 Study Patlents

Coronary Angiography (% DR) Echo B ST-Segment LV Inf

Patient Hypokinesia Echo D/level Changes (mm) Pain Right LM LAD LC LOM HYPE

Positive

1 Inferior 2 Inferior 3 Inferior 4 Inferior 5 0 6 Inferior 7 Inferior 6 Inferior 9 Inferior

10 0 11 Inferior

Anterior/PM Anterior+lateral/AklPMIA Septal+anterior/PM/A Anterior+lateral/Dk/PM Inferior+posteriorlPM/A Septal/PM/+A Septal-IanteriorlPM Anterior/PM SeptallantllatlDklPM/A Lateral/PM Lateral/PM

1 .qv,-V,) + 1 .5(V,-V,) + 1.7(V,-V,) +

0 0 1 .5(D,-Da-aVF) +

1.2(V,-V,) + 1 S(V,-V,) + 2 w4-Vd +

1 .S(V,-V,) + 0 0

1.2(V,-V,) +

100 100 100

99 100

99 100

I I I

100

0 80+20 0 60 0 90 0 70+90 0 60+50 0 ao+70 0 90+60

90 70+60 0 85+100 0 90 0 60

40 0 0

100 70 90

0 0

100 95f90

0 + 0 + 0 +

90 + 0 0 0 + 0 + 0 + 0 + 0 0

90 +

12 InferiorlAk Unchanged 0 0 100 0 I 60 0 +(AW 13 Inferior Unchanged 0 0 75 0 100+80 0 0 + 14 Inferior Unchanged 0 0 50 0 0 100 0 + 15 Inferior Unchanged 0 0 100 0 0 75 0 + 16 InferiorlAk Unchanged 0 0 100 0 75 0 0 + 17 0 Unchanged 0 0 70 0 90 40 0 0 18 0 Unchanged 0 0 I 0 go+60 0 0 0 19 Inferior Unchanged 0 0 99 0 100 0 0 + 20 Inferior Unchanged 0 0 I 0 50 95 0 + 21 Inferior Unchanged 0 0 100 0 70 90 0 +

A = apex: Ak = akinesia; B = baseline; D = after dipyridamole infusion; Dk = dyskinesia; DR = diameter reduction; typo = hyp&in&a; I = irregularity; klf = inferior; LAD = left anterior descending coronary artery; LC = left circumflex coronary artery; LM = left main coronary artery; LDM = left obtuse marginal Coronary artery: LV = left ventriculographic; PM = papillary muscle level; + = present; 0 = absent,

Hemodynamic response to dipyridamole: After di- pyridamole administration, HR increased from 77 f 12 beats/min to 87 f 12 beats/min (p <O.Ol). Systolic BP decreased from 131 f to 16 mm Hg to 126 f 17 mm Hg (p <O.Ol). HR-BP product increased from 10,047 f 2,143 beats/min X mm Hg to 10,922 f 2,043 beats/min X mm Hg (p <O.Ol). In all patients HR-BP product after dipyridamole administration was lower than at 1 mm of ST depression during exercise testing (Fig. 3).

Echocardiographic findings: In 3 patients the test was not performed because of an unsuitable echocar- diographic window. In 2 others the results of the test could not be evaluated because of extensive dyskine- sia on the control 2-D echocardiogram. Details of the

Mitral Valve Papillary Muscles Apex

FIGURE 1. Segmental dlvlslon of the left ventricle at the 3 levels studied. l.eff, mitral valve: center, papillary muscles; right, apex. 1 = Inferior wall; 2 = septum; 3 = anterior wall; 4 = lateral wall; 5 = posterior wall.

FIGURE 2. Unprocessed and computer-averaged end-systolic frame of the left ventricle (papillary muscle level) In patient 10.

echocardiographic and ECG findings observed during dipyridamole infusion in the remaining 21 patients are reported in Table I. Seventeen patients had previous myocardial infarctions, all limited to the inferior wall. In all, inferior akinesia was present both in the basal echocardiogram and in the ventriculography.

There was 100% agreement between the 2 inde- pendent observers evaluating the echocardiographic studies on the presence and location of transient re-

228 DIPYRIDAMOLE-ECHOCARDIOGRAPHY IN EFFORT ANGINA

gional wall motion abnormalities. Transient regional wall motion abnormalities occurred in 11 of 21 patients 163 f 77 seconds (range 66 to 330) after the beginning of infusion, whereas no transient changes in left ven- tricular wall motion were detected in 10. Regional wall motion abnormalities were present as hypokinesia in 8 patients, akinesia in 1 patient and dyskinesia in 2.

The correlation between transient regional wall motion abnormalities and angiographic location and severity of coronary lesions was good (Table I). In pa- tients 1, 2.3, 7 and 8, who had only 1 significant lesion besides an occluded artery tributary of an infarcted area, transient regional wall motion abnormalities ap- peared only in the region perfused by the stenosed vessel. In patients 5, 6, 10 and 11, who had 2 critical lesions, transient regional wall motion abnormalities were detected only in the area supplied by the artery with the higher severity score. In patients 4 and 9, who had 2 significant lesions, regional wall motion abnor- malities appeared in both regions perfused by the dis- eased vessels.

During the test, 9 patients with a positive response had both angina and at least 1 mm of ST-segment depression on the electrocardiogram and in 2 no ECG changes or pain occurred despite definite changes in left ventricular wall motion, ECG changes and angina always occurred later than regional wall motion ab- normalities (301 f 99 seconds [range 91 to 4201 and 358

f 99 seconds [range 220 to 5501, respectively, after the beginning of dipyridamole infusion). Pain was promptly relieved in all 9 patients by intravenous ad- ministration of 125 mg of aminophylline. No patients without evidence for regional wall motion abnormali- ties during the test had pain or ECG changes. One patient had nausea during the test.

Computerized area contraction analysis: Within patients, the variability in endocardial area calcula- tions was negligible, with a mean percent difference (difference among measurements expressed as per- centage of the mean value) of 0.443 f 0.361%.

In all patients in whom transient regional wall mo- tion abnormalities were identified by subjective visual analysis, percent change in endocardial area from diastole to systole decreased at peak ischemia [basal 51 f lo%, ischemia 35 f 11%. p <O.OOl) (Fig. 4 and 5). Conversely, no significant changes were observed in patients with a negative response [basal 43 f 6%, dipy- ridamole 42 f 8%, difference not significant) (Fig. 5).

Relation between the response to dipyridamole, electrocardiogram during the test, clinical and angio- graphic findings: Several variables were significantly different between patients with a positive or a nega- tive response (Table II]. In the former the history of angina was longer, rest pain was more frequent (10 vs 5 patients, p <0.05, Fisher’s exact test], CAD was usually

Dipyridamole Positive

iI

Dipyridamole Negative

FIGURE 3. Heart rate-blood pressure product (RPP) at baseline, after dipyrldamole administration and at 1 mm of ST depression during exercise test in patients wlth positive or negative response to

FIGURE 4. Computer-averaged frames of the lefl ventricle (at paptl- lary muscles level) in patient 10. Top, control end-diastole; cenfer, control end-systole; bottom, end-systole at dipyridamole-Induced tschemla. After dipyridamole administration the end-systolic cavity is dilated and the anterior wall is hypokinetlc. the drug.

February 1, 1987 THE AMERICAN JOURNAL OF CARDIOLOGY Volume 59 229

TABLE II Characteristics of Patients with a Positive or Negatlve Response to Dipyridamole-Two-Dimensional Echocardiography Test

Age (YO Sex

Duration of Type of EX. Time to 1 mm No. of CAD Severity

Angina (mo) Angina Duration (set) ST Change (set) Stenosed Vessels Score

Dipyridamole positive 54 f 6 lOM,lF 60.2 f 33’ 1E 320 f 164’ 177 f 148’ 7 pts-2 61.4 f 25 (n = 11) 10E + R 4 pt.+-3

Dipyridamole negative 53 f 10 10M 19.8 f 11 5E 505 f 183 472 f 179 8 pts-2 47.1 f 20 (n = 10) 5E + R 2 pts-3

*p <O.Ol vs dipyridamole negative patients. CAD = coronary artery disease; E = exercise: R = rest.

more severe and exercise duration was significantly shorter. Furthermore, time to 1 mm of ST depression during exercise testing was 177 f 148 seconds, com- pared with 472 f 179 seconds in patients with a nega- tive response (p <O.Ol) (Fig. 6). The hemodynamic re- sponse to dipyridamole was similar in the 2 groups. In particular, the HR-BP product after the drug increased significantly in the 2 groups but was much lower than that at 1 mm of ST depression during exercise testing (Fig. 3).

Discussion Of the 26 patients selected for the study, 5 had to be

excluded either because of the unsuitability for echo- cardiographic studies or presence of diffuse resting regional wall motion abnormalities. These figures compare favorably with those achieved using exercise echocardiography, where as much as 50% of the pa- tients had to be excluded.4

Infusion of dipyridamole caused transient myocar- dial ischemia, regional wall motion abnormalities and global impairment of left ventricular function, as shown by changes in endocardial area contraction in 11 of 21 patients. The correlation between patient’s

- : 10 I

p=O.ool 0 I

Baseline Dipyridamole

Positive

I I NS

1 I Baseline Dipyridamole

Negative FIGURE 5. Percent endocardial area contraction at baseline and after dipyridamole administration in patients with a positive or neg- ative response to the drug.

clinical presentation, results of exercise testing and dipyridamole-2-D echocardiography clearly indicate that the test response is more likely to be positive in patients with very severe limitation of coronary flow reserve. For the 11 patients with a positive response to dipyridamole, exercise duration was 320 f 164 sec- onds, significantly lower than that in nonresponders (505 f 183 seconds, p <0.02). Also, the severity score for CAD was higher, although not significantly, in the former. It appears, therefore, that only patients with severely limited coronary flow reserve and exercise capacity are likely to respond to dipyridamole. This is not surprising, considering the mechanism of dipyrid- amole-induced ischemia, which requires that multiple severe stenoses be present.lz

The 52% sensitivity of dipyridamole 2-D echocar- diography found in our study is lower than that for dipyridamole-thallium-201 scintigraphy for detection

800 -

O-

p<O.Ol r 1

0 l

l

: l

f

l

t

ee l

i

Dipyridamoie Dipyridamole +

FIGURE 6. Time to 1 mm of ST-segment depression during exercise test without treatment in patient with positive or negative response to dipyridamole infuslon.

230 DIPYRIDAMOLE-ECHOCARDIOGRAPHY IN EFFORT ANGINA

of coronary stenoses. 7-B However, dipyridamole-thal- hum-201 scintigraphy does not require ischemia as an endpoint because it provides only relative information on the increase in coronary flow after vasodilatation in different regions of the heart. Since even relatively mild coronary stenoses (e.g., 40%) can cause an imag- ing defect on the perfusion scan, in patients with mul- tivessel CAD, it may be difficult to obtain information about the vessel whose flow reserve is most reduced and is likely to cause ischemic episodes.

multivessel CAD, dipyridamole-2-D echocardiogra- phy appears to identify the vessel whose flow reserve is most impaired. Although this information may be valuable, the indications for the test are restricted to patients with severely limited exercise capacity.

Acknowledgment: We thank Bharti Kava and Pat Tierney for secretarial assistance and Jean Powell for drawing the figures.

The advantages of combining 2-D echocardiogra- phy with dipyridamole infusion are obvious. The test requires as an endpoint, ischemic regional wall motion abnormalities. Correlations between coronary anato- my and its consequences on regional contractility can be attempted and information on which vessels are more likely to be responsible for patient’s symptoms can be obtained. In patients with multivessel CAD this information could prove valuable for both prognosis and treatment, as it is difficult to assess the severity of CAD purely on angiographic grounds.ls It is well known that this type of information cannot be gathered by the location of the ECG changes. In fact, although patients with a positive response to dipyridamole developed regional wall motion abnormalities in dif- ferent areas, most had ST-segment depression in the anterolateral leads. However, ST-segment changes in- duced by dipyridamole consistently involved the same leads showing ST depression during exercise test. This suggests a good correlation between the 2 stimuli in provoking ischemia in the same areas of the myocardium.

References

The discrepancy between our findings and those reported by Picano et a1,14 who found a higher sensitiv- ity of dipyridamole-2-D echocardiography than exer- cise stress testing for diagnosis of CAD, are probably related to different criteria for selecting the patient population and to the fact that in their study, coronary arteriography was used as an endpoint. In our study, all patients were selected on the basis of a positive response to exercise testing and documented CAD.

1. Amsterdam EA. Function of the hypoxic myocardium. experimental and clinical aspects. Am J Cardiol X17$32:461-468. 2. Mason SJ, Wiss JL. Weisfeldt M, Garrison JB, Fortuin NJ. Exercise echocar- diography: detection of wall motion abnormalities during ischemia. Circulo- tion 1979:59:50-59. 3. Wann LS. Faris JV, Childress RW. Dillon JC. Weyman AE, Feigenbaum H. Exercise cross-sectional echocardiography in ischemic heart disease. Circu- lation 1979:60:1300-1308. 4. Foale RA. Diagnostic use of cross-sectional echocardiogrophy in transient myocardial ischemia. In: Maseri A, ed. Hammersmith Cardiology Workshop Series. Vol. 2. New York: Raven Press, 1965;59-64. 5. Kinsella D, Troup W. McGregor M. Studies with a new coronary vasodila- tor drug: Persantine. Am Heart J 1962;63:146-151. 6. Feldman RL, Nichols WW, Pepine CJ. Conti CR. Acute effect of intrave- nous dipyridamole on regional coronary hemodynamics and metabolism. Circulation 198X64333-344. 7. Albro PC. Gould KL. Westcott HRI. Hamilton GW, Ritchie IL, Williams DL. Noninvasive assessment of corona~stenoses by myocardiai imaging during pharmcologicol coronary vasodilatation. III. Clinical trial. Am J Cordiol 1976;42:751-760. 8.losepbson MA, Brown BG, Hect HS. Hopkins S. Pierce CD, Petersen RB. Noninvasive detection and localization of coronary stenoses in patients: com- parison of resting dipyridamole and exercise thallium 201 myocardial perfu- sion imaninn. Am Heart J 1962:103:1006-1016. 9. Bruce RAY Kusumi F. Hosmer D. Maximal oxygen intake and nomographic assessment of functional aerobic impairment in cardiovascular disease. Am Heart J 1973;65:546-562. 10. Gensini GG. Coronary arteriography. In: Braunwald E, ed. Heart Disease. A Textbook of Cardiovascular Medicine. 2nd ed. Philadelphia WB Saunders, 1984:304-350. 11. Weyman AE. A modified segmental system for describing left ventricular function. In: Wevman AE ed. Cross-Sectional Echocardiography. Philadel- phia: Lea b Febiger, 1982:493-496. 12. Becker LL. Conditions for vasodilotor-induced coronary steal in experi- mental myocardial ischemia. Circulation 1977;57:1103-1110. 13. White CW, Wright CB. Doty DB. Hiratza LF, Eastham CL, Harrison DG. Marcus ML. Does visual interpretation of the coronary angiogram predict the phvsiologic importance of a coronary stenosis? N Engl J Med 1964;310:619- szi. -

In conclusion, in patients with severe angina and 14. Picano E, Distante A, Manini M, Morales MA, Lattanzi F, L’Abbate A. Dipyridamole-echocordiography test in effort ongina pectoris. Am J Cardiol 1985:36:452-456,