Detection of coronary artery disease in aortic stenosis by exercise gated nuclear angiography

VALVULAR HEART DISEASE

Detection of Coronary Artery Disease in Aortic Stenosis by Exercise Gated Nuclear Angiography JULIO C. MILANES, MD, JACK PALDI, MD, MARIO ROMERO, MD, DAVID GOODWlN, MD, and HERBERT N. HULTGREN, MD

Because the clinical diagnosis of coronary artery disease (CAD) in the presence of aortic stenosis (AS) is difficult, the value of exercise gated nuclear angiography in detecting CAD in 33 patients with AS was assessed. Exercise left ventricular (LV) ejection fraction (EF) and wall motion analysis were evaluated after symptom-limited supine cycle ergometer exercise. Sixteen patients had severe AS (valve area 0.8 cm 2 or less). Thirteen had significant associated CAD (50 % or greater reduction in luminal diameter of 1 major coronary artery). Twenty patients had normal coronary arteriograms. All 10 patients with mild to moderate AS and normal coronary arteries had normal nuclear studies. Patients with CAD, regardless of the severity of AS, had a decrease in LVEF during exercise (12 of 13 patients)

and regional wall motion abnormalities (11 of 13 patients). Abnormal exercise gated nuclear ventriculographic studies occurred in the absence of CAD in 10 of 20 patients, and all had severe AS (mean aortic valve area 0.8 cm 2 or less, range 0.4 to 0.8). Ten had an abnormal LVEF response to exercise and 7 had exercise-induced abnormal wall motion. These findings suggest that the presence of an abnormal LVEF, whether in conjunction with an abnormal wall motion analysis, is indicative of further invasive evaluation; conversely, in those patients with a normal response of LVEF and normal wall motion during exertion, invasive studies may be safely deferred.

Coronary artery disease (CAD) is a common finding in elderly patients with aortic stenosis (AS). The reported prevalence rate varies between 24 and 61%. 1-4 The diagnosis of CAD associated with AS is difficult without coronary arteriography. The presence of angina is unreliable because it may occur in AS without CAD. 2,4 The absence of angina does not exclude CAD. 2,4 Ischemic ST. changes during exercise are similarly nondiagnostic. 5 Because CAD influences the operative results in AS, 3 coronary bypass grafting is currently done in combination with valve replacement when significant CAD is present. For these reasons, coronary arteriography is an important part of the evaluation of patients with AS. In most institutions, routine coror ary arteriography is performed in patients older than age 40 with symptomatic AS. The availability of a reliable noninvasive method to detect CAD in elderly patients with AS would

reduce the need for coronary arteriography in the 40 to 75% of patients who have normal coronary arteries. Exercise gated radionuclide ventriculography, a valuable method of detecting CAD,6, 7 has not been systematically evaluated in patients with AS. Therefore, the following study has been carried out to determine the value of this method in detecting CAD in the presence of AS.

(Am J Cardiol 1984;54:787-791)

Methods Patients: Thirty-three men were studied. The mean age was 64 years (range 42 to 88). All had been referred for evaluation of aortic valve disease. All had clinical and phonocardiographic signs of pure AS. Typical exertional angina was present in 18 patients, whereas 15 had no chest pain. Nine

patients fulfilled the electrocardiographic criteria for left ventricular (LV) hypertrophy, s In 7 patients, electrocardiographic signs of prior myocardial infarction were present. Thirteen patients showed arteriographic evidence of significant CAD, defined as 50% or greater reduction in luminal diameter of a major coronary artery, and 20 had normal coronary arteries. Invasive studies revealed pure or predominant AS in all 33 patients. Nine patients had mild AS with slight aortic regurgitation. Sixteen had severe AS (aortic valve area 0.8 cm2 or less). Seventeen patients with mild to moderate AS had valve areas more than 0.8 cm2 (Table I). Evidence of significant aortic regurgitation, mitral valve disease, history of ex-

From Stanford University School of Medicine, Stanford, California, and the Cardiology Service of Palo Alto Veterans Administration Medical Center, Palo Alto, California. This study was supported by Veterans Administration research funds. Manuscript received November 25, 1983; revised manuscript received June 8, 1984, accepted June 11, 1984. Address for reprints: Herbert N. Huitgren, MD, Palo Alto Veterans Administration Medical Center, Cardiology Service (111-C), 3801 Miranda Avenue, Palo Alto, California 94304.

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NUCLEARANGIOGRAPHY IN AORTIC STENOSIS

TABLE I

Summary of Radionuclide, H e modynamic and Coronary Angiographic Findings % Luminal Obstruction

Pt.

Age (yr)

Symptoms

A LVEF °

RWMA

AVG (mm Hg)

AVA (cm 2)

AR

LM

LAD

Cx

RC

0 0 0 0 0 0 70 0 0 0 0 0 0

50 70 80 70 70 90 80 90 0 0 90 50 70

90 80 100 100 80 80 80 100 50 0 70 0 60

0 0 100 90 100 100 100 100 90 90 70 100 80

Aortic Stenosis With Coronary Artery Disease (n = 13)

1 2 3 4 5 6 7 8 9 10 11 12 13

61 70 66 70 60 71 75 64 62 60 63 65 62

A AD A AD S D A ADS No A A D A

--3 --4 --41 --8 -13 --4 --3 0 --4 -11 -10 --3 --7

14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33

55 63 58 50 46 63 52 64 53 78 69 42 60 69 88 73 42 68 58 78

No No No No No No DA D DA No DA A DA A DA DA DA D D D

-t-5 +5 -I-15 -I-11 +14 -I-7 + 12 +6 +10 +15 --8 +3 -I-4 --9 --5 --7 --13 --4 --2 --6

+ + + + + + 0 (d) + 0 (d) + + + +

10 39 28 20 36 28 31 22 41 47 40 47 65

1.8 1.5 1.4 1.1 1.1 0.9 0.9 0.6 0.6 0.6 0.6 0.5 0.5

1 1 0 0 0 0 0 0 1 0 0 0 0

Aortic Stenosis Without Coronary Artery Disease (n = 20)

0 0 0 0 0 0 0 0 0 0 + 0 0 + 0 (d) 0 + + 0 (d) 0 (d)

5 5 10 11 23 22 33 47 32 49 45 80 56 36 50 115 103 140

1.8 1.8 1.8 1.8 1.1 1.1 1.0 0.9 0.9 0.9 0.8 0.7 0.6 0.6 0.5 0.5 0.4 0.4 0.4 (s) 0.4 (s)

2 2 0 0 0 0 0 2 0 0 0 0 0 0 0 2 2 0 1 0

" Percent change in left ventricular ejection fraction during exercise (-t- = increase; -- = decrease). A = angina; AR = aortic regurgitation, graded 0-4; AVA = aortic valve area; AVG = transaortic value gradient; Cx = circumflex; (d) = diffuse; D = dyspnea; LAD = left anterior descending artery; LM = left main coronary artery; A LVEF = percent change in left ventricular ejection fraction during exercise; No = no symptoms; RC = right coronary artery; RWMA = regional wall motion abnormalities; (s) = measured at surgery; S = syncope.

ertional syncope, inability to perform cycle ergometer exercise and congestive heart failure were reasons for exclusion from the study. Standard informed consent forms were signed. Cardiac catheterization: All patients underwent left- and right-sided cardiac catheterization studies including selective coronary arteriography performed with the Judkins technique. Additionally, LV cineangiography was carried out in 26 patients. Transaortic valve pressure gradients were measured by retrograde catheterization of the left ventricle. Cardiac output was determined by the Fick method, and the aortic valve area was calculated by Gorlin's hydraulic formula. 9 The presence or absence of aortic regurgitation was evaluated in all patients by aortic root angiography. The resuits of each study were arrived at by an independent consensus of 2 angiographers who were unaware of the results of the nuclear studies. Exercise gated radionuclide ventriculography: This study was performed using electrocardiogram-synchronized blood pool imaging of technetium-99m-labeled red blood cells. Images were obtained in the 45 ° left anterior oblique projection using a portable multicrystal gamma camera, equipped with a general-purpose collimator (Ohio series 420, Technicare Corporation), interfaced to a computer dedicated to the acquisition and processing of nuclear medicine data (Simis 3 Informatek States, Inc.). In this procedure, 25 mCi of the radioisotope was administered intravenously before exercise. The patients exercised in the supine position on an electrically

braked bicycle ergometer with the torso immobilized. Exercise was continued to a level that produced dyspnea, fatigue, angina, arrhythmia, 2 mm or more of downsloping or horizontal ST depression, or any combination of these factors. Cuff blood pressures and the electrocardiogram were monitored throughout the exercise. After a 3-minute warm-up period of cycling at a load of 200 kpm/min without symptoms, the work load was increased by 100 kpm/min every 3 minutes until any of the aforementioned end point factors appeared. After the tracer had equilibrated in the blood pool, recordings at rest and exercise were made. A cumulative representative cardiac cycle was reconstructed in a set of 16 images, digitized as 64 X 64 frames by means of electrocardiographic gating using a minute-by-minute recalculated RR reference, -I-20% RR window, and a 56-s/min acquisition. After smoothing and nonlinear background subtraction, the automatic region of interest determinations were performed. Wall motion images included routine regional phase, amplitude, stroke volume, isocontour mapping and ejection fraction displayed in 16 shades/color 5-color format. Quantitative measurements of LV ejection fraction (EF) were calculated by the computer from the background of corrected cumulative representative cardiac cycle counts in each level of exercise achieved by the patient. Radionuclide ventriculographic images and numerical data were interpreted by 2 observers who had no knowledge of the clinical, electrocardiographic or angiographic findings. A

October 1, 1984

TABLE II

Data on Patients Studied

TABLE III

CAD (n = 13)

Variables

n

THE AMERICAN JOURNAL OF CARDIOLOGY Volume 54

No CAD (n = 20)

%

n

%

7 4 8 4

35 ° 20 40 20

Difference in Left Ventricular Ejection Fraction Between Patients With and Patients Without Coronary Artery Disease Groups

Incidence of Angina and ECG Findings Angina Prior infarct (ECG) abnormal Exercise ST depression LVH (by ECGs)

9 2 7 6

69 15 54 46

Variables

CAD (n = 13)

No CAD (n = 20)

p Value

LVEF rest LVEF exercise

43 4- 15 36 4- 12

50 -I- 14 53 4- 18

NS <0.01

CAD (n = 13)

No CAD AVA < 0 . 8 cm 2 (n = 10)

43 4- 15 34 4- 12

41 4- 19 42 4- 15

CAD (n = 13)

No CAD AVA >0.8 cm 2 (n = 10)

43 4- 15 34 4- 12

50 4- 10 63 4- 10

No CAD AVA

No CAD AVA

--<0.8 cm 2

~ 0 . 8 cm 2

(n = lO)

(n = lO)

41 4- 19 42:1:15

54 4- 10 63 4- 10

Age, Double Product and Hemodynamic Measurements Age (yr) Double product~ TAVG (mm Hg) AVA (cm 2)

64 4- 5 161 4- 37 33 4- 14

61 4- 13 180 4- 59 47 4- 42

0.90 4- 0.4

0.96 4- 0.4

LVEF rest LVEF exercise

* p = <0.05. Exercise double product = heart rate × systolic blood pressure/100. All values are presented as mean 4- standard deviation. AVA = aortic valve area; CAD = coronary artery disease; ECG = electrocardiogram; LVH = left ventricular hypertrophy; TAVG = transaortic valve gradient.

LVEF rest LVEF exercise

normal LVEF response was defined as a 5% or greater increment during exercise. Normally, regional wall motion increases symmetrically with exercise as detected by an increase in the color scale from blue to red. Any color change in the opposite direction was considered to be abnormal, if present in at least 2 functional images at 2 consecutive exercise levels. Statistical analysis: All data are presented as mean 4- 1 standard deviation. Comparisons between groups were determined by the chi-square equivalent and 2-sample t test for differences in proportions and means, respectively.1°,11The paired t test was used to assess intragroup changes of LVEF from rest to maximal exercise.12Differences in LVEF response intergroup was calculated by the t test for differences between 2 means. 11A difference of p -<0.05 was considered statistically significant.

LVEF rest LVEF exercise

NS NS

NS <0.0005

NS <0.01

All values are expressed as mean 4- standard deviation. NS = not significant; other abbreviations as in Tables I and II.

patients, a decrease in LVEF or an increase less than 5% was observed. T he cut-off factor between patients with normal and those with abnormal LV E F response to exertion was the aortic valve area. All patients with a normal LVEF response had valve areas greater than 0.8 cm 2, whereas those with an abnormal response had valve areas 0.8 cm 2 or less. Figure 1 illustrates the LVEF during exercise in these 2 subgroups compared with the L V E F response of patients with CAD. Table III shows the p values of resting and maximal exercise LVEF between groups (CAD vs no-CAD), subgroups (no-CAD 0.8 cm 2 or less vs no-CAD greater than 0.8 cm2), and between each subgroup and CAD (no CAD 0.8 cm 2 or less vs CAD, and no CAD greater than 0.8 cm 2 vs CAD). Differences in LVEF between groups are shown in Table III. Exercise regional wall motion abnormalities were observed in 4 patients and diffuse abnormalities during exercise were present in 3 patients. Six patients had critical AS (aortic valve area 0.6 cm 2 or less), whereas 1 had a valve area of 0.8 cm 2. Normal

Results

Aortic stenosis without coronary artery disease: In this group, electrocardiographic signs of myocardial scar, LV hypertrophy, ischemic ST changes during exercise, and double product were similar to patients with CAD (Table II). Patients with CAD had angina more often (69 vs 35%). Hemodynamic measurements of aortic valve area and transaortic valve gradients were also similar. Both groups were comparable in age. Analysis of the L V E F response to exercise revealed a normal increment (5 or greater) in 10 patients. In 10

AS without CAD

AS with CAD

AVA <-0.8cm2

AVA > 0.8 cm2

LVEF 100 % 9~ FIGURE 1. Left ventricular ejection fraction (LVEF) during exercise in patients with aortic stenosis (AS) with and without coronary artery disease (CAD). Two subgroups of patients, classified on the basis of the aortic valve area (AVA), are shown in the group without coronary artery disease. Ex = exercise; SD = standard deviation.

789

n =10

n= 13

n=10

8o 7o 6o ,5o 40 30 2o lO I

Rest

~+SD 50±10 p value < 0.005

E=x 58+9

I

I

Rest

~

41±15

36+15 < 0.01

Rest

~

42±14

34±12 < 0.01

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NUCLEAR ANGIOGRAPHY IN AORTIC STENOSIS

wall motion was observed in 13 patients. Ten of these patients had aortic valve areas greater than 0.8 cm 2 (Fig. 2). The distribution of normal wall motion analysis, diffuse and regional wall motion abnormalities were similar in the group with aortic valve areas 0.8 cm 2 or less (Fig. 2). The combination of an abnormal LVEF during exercise and regional wall motion abnormalities occurred in only 4 patients (20%). Three had aortic valve areas of 0.06 cm 2 or less, and I had a valve area of 0.8 cm 2. The combination of a normal LVEF during exercise and a normal wall motion analysis was found in 10 patients. All had aortic valve areas greater than 0.8 cm 2. Aortic stenosis w i t h coronary artery disease: LVEF decreased during exercise in all but 1 patient. The exception was a patient who bad a fiat response (no difference between resting and maximal exercise LVEF). Regional wall motion abnormalities were present in 11 of 13 patients (83%). Two patients showed a diffuse pattern (Fig. 2). Of these 2 patients, 1 bad left main coronary obstruction with additional 3-vessel disease, and the other had 2-vessel disease associated with a critical aortic valve area of 0.6 cm 2. No patient with CAD, including 7 with aortic valve areas greater than 0.8 cm 2, had normal wall motion analysis. Two patients, excluded from the group, illustrated a limitation and an exception to the results previously presented. One patient had severe, chronic hypertension with an LV hypertrophy pattern on electrocardiography. His presenting complaint was effort angina and dyspnea. He had mild aortic stenosis with an aortic valve area of 1.6 cm 2, a gradient of 20 mm Hg and normal coronary arteries. His EF at rest was 62%, decreasing to 59% during exercise. Exercise-induced regional wall motion abnormalities were present. During exercise the blood pressure was 212/110 mm Hg. Thus, severe hypertension and LV hypertrophy may result in an abnormal exercise gated nuclear angiographic response to exercise in the absence of CAD or severe AS. AS without CAD % Patients I(X 9C 8G 7(] 6G

[•NWMA N DWMA O

AS with CAD

i!i i i i l -;i!i!

RWMA

4C 3¢ !:::!?i: ::2:::::

2C 1(; AVA > 0,8 cm = n =10

AVA ~ 0.8 cm 2

n=10

n=13

FIGURE 2. Distribution of wall motion abnormalities. Two subgroups of patients, classified on the basis of aortic valve area (AVA), are shown in the group without coronary artery disease (CAD). AS = aortic stenosls; DWMA = diffuse wall motion abnormalities; NWMA = normal wall motion abnormalities; RWMA -- regional wall motion

abnormalities.

Another patient had mild effort angina and an electrocardiographic pattern of a prior inferior myocardial infarction. One year previously, he underwent triple coronary artery bypass surgery for severe 3-vessel disease. The clinical result was excellent. Cardiac catheterization revealed 3 patient grafts with excellent flow and mild aortic stenosis with a valve area of 1.8 cm 2 and a gradient of 15 ram. Nuclear studies revealed an EF of 3%, increasing to 43% on exercise. Exercise resulted in a slight amount of abnormal regional wall motion. Although this patient had severe CAD, adequate myocardial revascularization had probably improved his exercise EF response to normal. Preoperative nuclear studies were not performed. No complications were found among the 33 patients during the exercise test.

Discussion The patient group examined in this study is representative of the usual patient referred for invasive evaluation of AS. Twenty-five of the 33 patients (76%) had symptoms, and the prevalence of associated CAD was similar to other reported series. 2,3 Neither the presence of angina nor ischemic ST depression during exercise were useful in detecting the presence of CAD. Similar results have been reported by other investigators.Z,3-5 This study has shown that LVEF may decrease during exercise in patients with AS and normal coronary arteries. This abnormal response seems to be closely related to the aortic valve area. All patients with a decrease in LVEF during exercise had aortic valve areas 0.8 cm 2 or less, whereas those with a normal response had valve areas greater than 0.8 cm 2. Similar findings were reported by Borer et a113 in analyzing LV function during exercise in patients with severe AS. Eighty-five percent of their patients showed a decrease in LVEF during exercise. All patients in the group with AS and CAD exhibited an abnormal response of LVEF to exercise. A decrease occurred in 12 patients, and I had a fiat response. Thus, the occurrence of a decrease in LVEF during exercise indicates either an aortic valve area 0.8 cm 2 or less or CAD with any degree of valve obstruction. Similar to LVEF changes during exertion, the presence of regional or diffuse wall motion abnormalities among those patients without CAD was related to the aortic valve area. All 7 patients with wall motion abnormalities had aortic valve areas 0.8 cm 2 or less (0.4 to 0.8 cm 2) and a decrease in LVEF during exercise. Normal wall motion analysis occurred in all patients without CAD and aortic valve areas more than 0.8 cm 2. Regional wall motion abnormalities were present in all but 2 patients in the group with CAD. These 2 patients had diffuse wall motion abnormalities; one had left main CAD and 3-vessel disease, and the other patient had critical AS (aortic valve area 0.6 cm2). Both of these factors could explain the appearance of diffuse rather than regional wall motion abnormalities. It is also possible that regional wall motion abnormalities were present in regions of the left ventricle not well visualized

October 1, 1984 THE AMERICAN JOURNAL OF CARDIOLOGY Volume 54

in the single 45 ° left anterior oblique view, such as the posterior or inferior wall. Wall motion analysis provides additional information to EF studies. A normal wall motion rules out the presence of CAD, and when a normal increment in LVEF during exertion is also found, the aortic valve area is greater than 0.8 c m 2. Exercise angiography clearly has limitations, and 2 examples are presented in this study. Severe hypertension and LV hypertrophy may result in an abnormal nuclear angiogram in the absence of CAD or AS. In patients with CAD who have had adequate coronary bypass graft surgery, nuclear studies may be normal. The small number of patients in this study limits definitive conclusions. However, the data show that radionuclide ventriculography is a safe, useful noninvasive method for detecting either AS with an aortic valve area 0.8 cm 2 or less or CAD in the presence of any degree of AS. These findings also suggest that the presence of an abnormal LVEF, associated or not with an abnormal wall motion analysis, is a probable indication for invasive evaluation. Invasive studies could probably be postponed in those patients with AS who show a normal exercise LVEF response with normal wall motion during exertion. It is our policy to follow such patients at 6-month intervals to detect a change in or the appearance of symptoms or clinical evidence of progression of disease. The patients in the present study are more representative of patients referred to the invasive laboratory than those referred to a cardiologist for an evaluation of the significance of a systolic murmur in an asymptomatic patient. In the present study, 25 of 33 patients had symptoms, 13 of 33 had CAD, 16 of 33 had severe AS, and therefore, a high percentage had abnormal nuclear studies (23 of 33 [70%]). &symptomatic patients referred for an evaluation of a murmur of AS would be expected to have a higher prevalence of normal nu-

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clear studies, which would permit deferral of invasive evaluation. Additional potential advantages of nuclear studies are: (1) evaluation of ejection fraction and LV function that may obviate LV contrast angiography, and (2) evaluation of the functional significance of coronary lesions detected by arteriography that may permit proper selection of patients for coronary bypass surgery. Further studies are clearly indicated to evaluate these potential advantages. Acknowledgment: We gratefully acknowledge the technical assistance of Teofilo Martinez and Marcia Rose and the secretarial assistance of Gina Bartlow. References 1. BaMa LL, Ralnes D, NaJJarS, Kloschos JM. Clinical, hemodynamic, and coronary angiographlc correlates of angina pectoris in patients with severe aortic valve disease. Br Heart J 1975;37:150-157. 2. Hancock EW. Aortic stenosis, anginapactoris, and coronary artery disease. Am Heart J 1977;93:382-393. 3. Unhart JW, de la Torre A, Rameey I-IW, Wheat MW Jr. The significance of coronary artery disease in aortic valve replacement.J Thorac Cardiovasc Surg 1968;55:811-819. 4. Thompson RH, Ahmed MS, Mitchell AG, Towers MK, Yacoub MR. Angina, aortic stenosis, and coronary heart disease. Clin Cardiol 1979;2:26-32. 5. Aronow WS, Harris CN. Treadmillexercise test in aortic stenosisand mitral stenosis. Chest 1975;68:507-509. 6. Borer JS, Kent KM, Bacharach SL, Green MV, Realog DR, $eldes SF, Epstein SE Johnston GS. Sensitivity, specificity and predictive accuracy of radionuclide cineangiography during exercise in patients w th coronary artery disease. Comparison with exercise electrocardiography.Circulation 1979;60:572-580. 7. Jengo JA, Freeman R, Brlze~dlna M, Mena I. Detection of coronary artery disease: comparison of exercise stress radionuclide angiocardiography and thallium stress perfusion scanning. Am J Cardiol 1980;45:535-541. 8. Romhllt DW, Estes Ell. A point-score system for EKG diagnosis of left ventricle hypertrophy. Am Heart J 1968;75:752-758. 9. Gorlln R, Gorlln SG. Hydraulic formula for calculation of the area of the stenotic mitral valve, other cardiac valves, and central circulatory shunts. Am Heart J 1951;41:1-29. 10. O'Brlen PC, Shampoo MA. Comparingtwo proportions:the relative deviate test and chi-square equivalent. Mayo Clin Proc 1981;56:513-515. 11. O'Brlen PC, ShampOoMA. Comparingtwo samples (the two sample t test). Mayo Clin Proc 1981;56:393-394. 12. O'Brlen PC, Shampoo MA. One sample of paired observations (paired t test). Mayo Clin Proc 1981;56:324-326. 13. Borer JS, Bacharach SL, Green MV, Kent KM, Roslng DR, Seldes SF, Mclntosh CL, Conkle D, Morrow AG, Epstein SE. Left ventricular function in aortic stenosis: response to exercise and effects of operation (abstr). Am J Cardiol 1978;41:382.