usefulness of thallium-201 scintigraphy in predicting the development of angina pectoris in...

Usefulness of Thallium-201 Scintigraphy in Predicting the Development of Angina Pectoris in Hypertensive Patients with Left Ventricular

Hypertrophy Julio F. Tubau, MD, Jadwiga Szlachcic, MD, Milton Hollenberg, MD, and Barry M. Massie, MD

Hypertension and left ventricular (LV) hypertrophy are imlependent risk factors for the development of coronary artery disease. To determine whether patients at higher risk for coronary artery disease can be identified, 40 asymptomatic hypertensive men with LV hypertrophy were prospectively studied using exercise thallium-201 scintigraphy and exercise radionuclide angiography. Endpoints indicative of coronary artery disease were defined as the subsequent development of typical angina pectoris, which occurred in 8 patients during a median follow-up of 36 months, or myocardial infarction, which did not occur. The exercise electrocardiogram was interpreted by standard ST-segment criteria and by a computerized treadmill exercise score. Abnormal ST-segment responses were present in 16 of the 40 hypertensive8 (40%), whereas the treadmill score was positive in 8 of those same 40 patients (20%). Sclntigraphii perfusion defects assessed both visually and semiquantitatively were observed in 8 of 40 (20%) patients. An abnormal ejection fraction response to exercise was present in 40% (16 of 40) of patients, and 3 of 40 (7.5%) developed new wall motion abnormalities &ring exercise. Six of 8 patients with either perfusion defects or abnormal treadmill score developed typical angina during follow-up. All 5 patients with concordant positive exercise scintigrams and treadmill score developed chest pain during follow-up and had coronary artery disease confirmed by coronary angiography. However, only 7 of 16 (44%) patients with positive ST changes or abnormal ejection fraction responses during exercise developed chest pain during follow-up. In contrast, of 32 patients with negative scintigrams only 2 developed atypical chest pain syndromes, and significant coronary artery disease was excluded by angiography in 1 patient. Thus, both thallium-201 scintigraphy and treadmill score accurately detect coronary artery disease in asymptomatic hypertensive patients with LV hypertrophy and predict the future development of angina symptoms.

(Am J Cardiol 1989;64:45-49)

A ntihypertensive therapy has reduced the morbidity and mortality from most complications of hypertensive cardiovascular disease.‘s2 However,

the frequency of events related to coronary artery disease has not been consistently diminished by various antihypertensive therapies in numerous large, multicen- ter trials.1-8 Although a number of potential explana- tions exist for this unexpected result, 1 possibility is that relatively short-term therapy may be of limited benefit in patients who, although asymptomatic, already have physiologically significant coronary artery disease. These trials have not attempted to identify such patients and little information is available concerning their prev- alence within the hypertensive population.

The Framingham Study has demonstrated dramati- cally that left ventricular (LV) hypertrophy is an inde- pendent risk factor for coronary events9J0 and there is evidence, both in animals and in humans, of abnormalities of coronary flow reserve in LV hypertrophy. l l Thus, hypertensive patients with LV hypertrophy represent a particularly high risk group for ischemic events. How- ever, because of the nonspecific nature of electrocardiographic repolarization changes in LV hypertrophy, it re- mains uncertain whether patients with asymptomatic coronary disease can be identified. The present study assessed the incidence and prognostic significance of exercise-induced electrocardiographic and scintigraphic abnormalities suggestive of myocardial ischemia in a cohort of asymptomatic hypertensive patients with LV hypertrophy.

METHODS Patient= Seventy-eight asymptomatic hypertensive

patients were selected by chart review from our hypertension clinic. Forty-two male patients with essential hypertension and electrocardiographic (Romhilt-Estes criteria, n = 16) and/or echocardiographic (posterior wall thickness 11 .l cm, n = 35) evidence of LV hypertrophy were studied. Their mean age was 58 f 10 years (range 38 to 70). The patients were free of other significant medical diseases and were able to exercise without limi-

From the Department of Medicine and the Cardiovascular Research Institute, University of California, and the Veterans Administration Medical Center, San Francisco, California. Manuscript received Janu- ary 9, 1989; revised manuscript received and accepted April 19, 1989.

Address for reprints: Julio F. Tubau, MD, Veterans Administration Medical Center (111 -C), 4150 Clement Street, San Francisco, Califor- nia 94121.

THE AMERICAN JOURNAL OF CARDIOLOGY JULY 1. 1989 45

6ClNTlGRAPHlC PREDICTION GF ANGtNA IN HYPERTENSIGN

tations due to noncardiovascular endpoints. None of them had angina symptoms or electrocardiographic evidence of myocardial infarction, or left bundle branch block. However, additional risk factors were common- 85% smoked, 30% had known family history of coronary artery disease and 25% had cholesterol values >240 mg/dl.

Patients were either untreated or had all their medi- cations discontinued for at least 4 weeks before exercise testing. Patients were included in the study if their supine diastolic blood pressure without therapy was between 95 and 124 mm Hg on at least 2 consecutive visits 1 week apart. Written informed consent was obtained from all patients. One patient was excluded after developing angina during the exercise test and recalling similar symptoms on previous occasions. A second patient was excluded because of a thallium defect at rest and an earlier hospitalization consistent with a non-Q- wave myocardial infarction. Thus, only 40 patients were retained for follow-up.

Eehocardiography: The two-dimensional-guided M- mode echocardiograms were performed using standard techniques.‘* Measurements of LV dimensions, posteri- or wall thickness and ventricular septal thickness were made on 3 to 5 consecutive cardiac cycles and averaged. The LV mass was calculated using the formula vali- dated by Devereux et all3 and the LV mass index was calculated by dividing mass by body surface area. All echocardiograms were read by 2 experienced readers.

Exercise testing and scinttwaphy: Exercise testing was performed on a treadmill using the standard Bruce protocol.14 Fatigue or exhaustion was used as an end- point. A full 1Zlead electrocardiogram was recorded with the patient at rest and at the termination of the study. The leads Vi, Vs and aVF were simultaneously and continuously monitored during exercise and recovery.

The exercise electrocardiograms were interpreted by 2 approaches. First, standard criteria were used to clas- sify the results of tests as positive if there was at least 1 mm of additional horizontal or downsloping ST-seg-

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46 THE AMERICAN JOURNAL OF CARDIOLOGY VOLUME 64

ment depression at 80 ms after the J point compared with the baseline values at rest. Second, we used a treadmill exercise score developed in our institution and previously described.15 To derive this score, plots of J- point deviation and ST-segment slope versus time for the leads V5 and aVF generated by the Marquette exercise system are algebraically summed and divided by the exercise duration and the percentage of maximal predicted heart rate. This value is further normalized by the R-wave amplitude using a “normal” reference value for each lead. Based on our previous work, a treadmill score of -13 was used as the distinction between normal and abnormal.16 This approach has provided ac- ceptable results in patients with LV hypertrophy and has improved the diagnostic accuracy of exercise testing in an asymptomatic population.15316 At peak exercise, 2.5 mCi of thallium-201 were injected intravenously. Exercise was continued for another 45 to 60 seconds. Imaging was commenced within 10 minutes after com- pletion of exercise, using either a 7-pinhole tomography or single-photon emission computed tomography from data generated by a rotating camera. Scintigraphy was repeated after 3 hours to obtain “redistribution” im- ages. The scintigrams were interpreted both visually and semiquantitatively by 2 blinded observers.17

On a separate day at least 1 week apart, exercise radionuclide angiography was performed using a protocol described in detail elsewhere.18 Briefly, equilibrium blood pool scintigrams were performed at rest and during supine bicycle exercise after in vivo red cell labelling with technetium-99m pertechnetate. The exercise protocol consisted of 3-minute stages, starting with no exter- nal load and with subsequent 200 kpm/min increments. Scintigraphy was accomplished during the last 2 minutes of each stage. The ejection fraction was derived using standard methods and calculated from the back- ground-corrected LV counts following the equation: ejection fraction = end-diastolic counts - end-systolic counts/end-diastolic counts. An abnormal response to exercise was defined as an increase of <5 units with exercise or decrease when the resting ejection fraction was >70%. All studies were also visually assessed by 2

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observers for the development of new segmental wall motion abnormalities.

Follow-up: All patients were seen every 3 to 6 months in an outpatient hypertension clinic. All patients received standard antihypertensive therapy according to their primary care provider and no attempts were made by the investigators to modify such treatment. At each follow-up visit, the physician inquired if there had been any chest pain symptoms, which, if present, were classified according to the Canadian Heart Angina Classifi- cation.19 The electrocardiograms were read by 2 of the investigators for the presence of myocardial infarction using the Minnesota code.20 To avoid the influence of the test results on the measured outcome (angina), the results of exercise tests were discussed with the patient only in summary fashion.

Statistical analysis: To assess the predictive value of a test, the predetermined clinical endpoints (development of angina or myocardial infarction) were used as the gold standard. The statistical significance of differences between the predictive value of the tests was determined by using chi-square analysis. Unpaired t tests were used to compare patient characteristics among those who developed angina and those who did not. The differences in the incidence of outcomes at different times of follow-up were assessed by the Mann-Whitney U test. Differences were considered significant at the p <0.05 level. Results are presented as mean f 1 standard deviation.

RESULTS Echocardiography: The mean LV mass index was

122 f 20 g/m2 (range 110 to 198). The mean posterior wall thickness was 1.19 f 0.04 cm, and the mean septal wall thickness was 1.17 f 0.05 cm. No patient had echocardiographic evidence of significant valvular disease or segmental wall motion abnormalities at rest.

Exercise testing: Using standard electrocardiographic criteria, 16 of 40 patients (40%) exhibited >l mm horizontal or downsloping ST-segment depression during exercise or recovery. The treadmill score was abnormal (below -13) in 8 of 40 patients (20%), with abnormal values ranging from -15 to -35. The smaller number of positive test results using the treadmill score reflected the influence of the normalization for R-wave amplitude, exercise duration and heart rate, and the relatively short duration of horizontal ST-segment depression in many patients. Eight of the 40 patients (20%) had reversible thallium-201 scintigraphic defects, whereas none had fixed defects. These abnormalities in- volved the septum in 5, anterior wall in 2, apex in 2 and inferior wall in 3 patients. Three patients had > 1 abnormal region. Five of the 8 patients had abnormal treadmill score values as well, and the remaining 3 had abnormal exercise electrocardiograms by standard criteria.

An abnormal ejection fraction response by radionu- elide angiography was present in 16 of 40 patients (40%). The change in ejection fraction in these patients ranged from +4 to -1 l%, from a mean of 63% at rest to 60% during exercise. However, only 3 of them (7.5%)

developed new segmental wall motion abnormalities during exercise. Each of these 3 had abnormal thallium- 201 scintigrams and an abnormal treadmill score.

Follow-up: All patients were followed at regular in- tervals. The median duration of follow-up was 38 months (range 12 to 50). Eight patients developed defi- nite or possible angina symptoms. No patient developed a myocardial infarction or died. Among the patients with positive thallium-201 scintigrams, 6 developed typical angina requiring antiangina therapy with nitrates and ,&blocking drugs or calcium antagonists. Five of these patients subsequently underwent coronary angiography. All had significant (>75% of luminal diameter) stenoses, with 2, 1 and 2 having 3-, 2- and l-vessel in- volvement, respectively.

In 1 patient only did the results of noninvasive tests trigger a change in management. This patient with a thallium scintigraphic pattern suggestive of 3-vessel or left main coronary artery disease underwent coronary arteriography within 1 month of exercise testing while still asymptomatic. Angiography confirmed 3-vessel disease with 40% stenosis in the left main coronary artery. Despite treatment with fl blockers and calcium antagonists for his hypertension, he subsequently developed typical angina pectoris and, after hospitalization for un- stable angina, underwent coronary bypass surgery. Among the 32 patients with negative thallium-201 scintigrams, 2 developed atypical chest pain for which an ischemic origin could not be excluded. The coronary angiography obtained in 1 patient revealed minor (<50%) 1 -vessel disease.

Figure 1 shows the development of angina symptoms over time in patients with positive and negative thallium-201 scintigrams. Thirty of 32 patients (94%) with

Standard ST Treadmill Criteria Score

+ 4

PV + test 44% PV + test 75%

Nuclear Thallium wall motion

APj$$ AP$$j

PV + test 75% PV + test 31%

FIGURE 3. Pdictive value (PV) ot exercise tests for the dedqmml of angina pecteds (AP) at fotbw-up. The 4 mabixes show the my ot positive and negative results fereachtestversuetheillckhe ef angina symptoms at fat- lowup. Rote the greater predkttve vabs et thaUtum dntigra- phy and exe&se treadmiti scere, both 75% accurate in pre- dietingthedevelopment ef angina during follow-up.

THE AMERICAN JOURNAL OF CARDIOLOGY JULY 1, 1989 47

SCINTIGNAPNIC PREDICTION OF ANGINA IN HYPERTENSION

the negative tests were asymptomatic at the end of 42 months of follow-up. In contrast, only 25% of those patients with positive thallium-201 tests remained angina- free (p = 0.003, Mann-Whitney U test).

Because LV hypertrophy is associated with increased coronary morbidity, we examined whether the degree of LV hypertrophy predicted the development of angina. As shown in Figure 2, although patients who developed angina during follow-up tended to have higher LV mass index, the differences were not statistically significant.

Predictive value of mninvasive testing: We assessed the positive predictive value (proportion of patients with positive test results developing clinical coronary artery disease) of each of the 4 testing modalities. Figure 3 shows the predictive value for each teat separately. The predictive value for the standard 1Zlead electrocardiogram during exercise was 7 of 16 (44%), whereas both our treadmill score and thallium-201 scintigraphy provided better predictive values (6 of 8, 75%). Six of 8 patients with positive thallium tests developed angina. Conversely, of 32 patients with negative thallium-201 studies only 2 developed angina symptoms, which meant that the predictive value of a negative teat was 94%. Finally, the predictive value of an abnormal radionuclide angiography was poor (3 1%).

Of note, all 5 patients who had abnormal treadmill scores and thallium-201 scintigrams developed angina during follow-up. In addition, only 1 of 29 patients in whom both of these teat results were normal developed chest pain, which was atypical.

DiSCUSSION Several reports have discouraged widespread testing

of asymptomatic populations to screen for coronary artery disease because of the expected high incidence of false positive results in populations with a low preva- lence of disease.21 Nevertheless, as the probability of coronary artery disease in the population increases, such as in hypertensive patients with LV hypertrophy, the rationale for screening becomes stronger.22*23

However, the exercise electrocardiogram may be misleading in this group, and the accuracy of thallium- 201 scintigraphy has not been determined. Indeed, myocardial ischemia may occur in the absence of significant coronary artery disease in this population.” Conse- quently, even if scintigraphic abnormalities are demonstrated, their predictive value for coronary disease itself may be limited. When designing the present study, we attempted to maximize our chances of obtaining mean- ingful information by selecting older male hypertensives with LV hypertrophy and additional coronary risk factors. We also implemented more accurate quantitative exercise testing modalities which, in previous studies,24*25 had exhibited improved sensitivity and, especial- ly, specificity.

Our findings suggest that standard exercise electrocardiography may not be suitable for predicting the development of symptomatic coronary artery disease during follow-up in these patients. This is not surprising because of the high incidence of false positive results in

48 THE AMERICAN JOURNAL OF CARDIOLOGY VOLUME 64

asymptomatic patients and in those with LV hypertrophy.21v22-25 The treadmill score showed fewer positive results; a high proportion of patients so tested subsequently developed significant coronary disease. Similar- ly, thallium-201 scintigraphic abnormalities were predictive for the development of angina symptoms. As might be expected from predictions made based on the Bayes theorem,24 concordant positive results, which occurred in 5 patients, were highly predictive for the development of angina symptoms and objective evidence of significant disease was confirmed by coronary angiography in all of them. Among the 29 patients with both concordant negative treadmill scores and thallium- 201 scintigrams, only 1 developed symptoms that were atypical for angina and declined coronary angiography during the follow-up.

The radionuclide ejection fraction response to exercise was not helpful, reflecting both its poor specificity in unselected populations25 and the fact that a reduced ejection fraction response to exercise may be an early manifestation of hypertensive heart disease.25v26 Con- versely, the incidence of new wall motion abnormalities-which is very specific for coronary artery disease-was low, indicating that this finding lacks sensitivity in asymptomatic patients.

Few studies are available in asymptomatic patients with abnormal exercise electrocardiograms. Hickman and Froelicher et a121,27 reported that 28% (22 of 78) of such patients developed overt signs of coronary artery disease at a mean follow-up of 36 months. Interestingly, in 73% (16 of 22) the initial event was angina and 45% of patients with cardiac outcomes had 13 risk factors for coronary artery disease. Likewise, McHenry et a128 reported a 34% (21 of 61) incidence of cardiac events at a mean follow-up of 12.7 years in a similar group of patients. Again, angina represented 86% (18 of 21) of these events and was more frequent in these patients (3 1 vs l%, p <O.OOOl) compared with those with normal exercise electrocardiogram results. The incidence of myocardial infarctions and sudden death was similar in both groups. In these studies, the predictive value of an abnormal exercise electrocardiogram was 28 to 34%, which was similar to our findings (44%).

Thallium-201 scintigraphy and exercise electrocardiography provide valuable prognostic information concerning the development of future coronary events in populations with known coronary artery disease or post- myocardial infarction.29y30 The presence of hypertension does not seem to affect the incidence of thallium abnormalities in symptomatic hypertensives with high probability of coronary artery disease, but it has been found to be increased in patients with atypical symptoms and low probability (<25%) of coronary artery disease.31 However, only a minority of these patients underwent angiography and no follow-up data were reported. Less information is available about the usefulness of thallium scintigraphy in asymptomatic populations. A recent study conducted in an unselected asymptomatic population found the predictive value of a positive thallium- 201 scintigram to be 50%, whereas the prognostic value of exercise electrocardiography in this setting was less.32

Only Dunn and Pringle33 have addressed a question similar to that examined by the present study. These investigators studied asymptomatic hypertensive patients with electrocardiograms consistent with LV hypertrophy with “strain” pattern. They observed a 44% incidence of positive thallium-201 scintigrams and a 33% incidence of coronary artery disease by angiogra- ph.

Our findings indicate that methodology is available to screen a particularly high risk group of hypertensive patients with LV hypertrophy. Patients with concordant tests can be classified as highly likely or highly unlikely to have physiologically significant coronary disease and to develop symptomatic coronary disease in a short peri- od of time. The interpretation of discordant tests re- mains to be determined, although we would favor the thallium-201 scintigraphy because of its better specificity.

The failure to demonstrate a reduction of coronary events in several large hypertension trials may reflect the inclusion of patients with significant but asymptomatic coronary artery disease. Therefore, noninvasive screening in future trials could provide the necessary information to interpret these results. Alternatively, iden- tification of patient groups at high risk for coronary events might help in the design of prospective studies addressing the physiologic significance and progression rate of coronary artery disease, as well as therapeutic interventions aimed to reduce coronary event rates. However, if this strategy predicts the development of angina but not that of myocardial infarction or cardiac death, it may be necessary to study an even larger number of patients to ascertain the possible benefits of such an approach.

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THE AMERICAN JOURNAL OF CARDIOLOGY JULY 1. 1989 49

usefulness of thallium-201 scintigraphy in predicting the development of angina pectoris in...

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