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“Silent” myocardial ischemia during and after exercise testing in patients with coronary artery disease
“Silent” myocardial ischemia during and aher exercisd testing in patients with coronary artery disease* H. Eugene Lindsey, Jr., M.D. Peter F. Cohn, M.D. Boston, Mass.
During exercise testing, subjective symptoms of chest pain can often be related to objective evidence of myocardial ischemia when ST segment depression or elevation appears on the ECG.’ F’requently, however, individuals with coronary artery disease have ischemic ECG responses to exercise testing without experiencing angina or it+ equivalents,*-’ indicating that there may be “silent” or asymptomatic myocardial &hernia just as there may be “silent” myocardial infarction.3 Because the clinical and kngiographical features of asymptomatic and symptomatic myocardial &hernia have not been compared in detail in previous exercise studies, we studied the subjective as well as the objective responses to exercise testing in a group of patients with exercise-induced ischemic ST changes in whom coronary artery disease was demonstrated by angiography. Methods Patient selection. In evaluating the phenomenon of “silent” myocardial ischemia, we studied the exercise responses of 232 consecutive patients (tested between 1972 and 74) with chest pain syndromes who were free of concomitant valvular, per&z&dial, or congenital heart disease. One hundred eighty-four patients had angiographitally determined coronary artery disease and 48 From the Cardiovascular Division, Department of Medicine, Peter Bent Brigham Hospibl and Harvard Medical School, Boston, Mass. Supported by United States Public Health Service Grants No. HL 11306 and HL-7049. Received for publication Oct. 14, 1976. Accepted for publication Nov. 12, 1976. Reprint requests: Peter F. Cohn, M.D., Cardiovascular Division, Peter Bent Brigham Hospital, 721 Huntington Ave., Boston, Mass. 02115. *Presented at the Forty-eighth Annual Scientific sessions of the American Heart Association,‘Anaheim, California, November, 1976.
0002-8703/78/0495-0441$00.70/O
0 1978 The
C. V. Mosby
Co.
had normal coronary arteriograms. Because of the difficulty in relating the presence or absence of chest pain to myocardial ischemia during a negative exercise test, we were most interested in the patient who had an abnormal or positive exercise test. As expected from prior studies,” only about 20 per cent of the patients with normal coronary arteriograms had a positive exercise test, a number (11). too small for meaningful analysis. Therefore, the present report concerns only the subgroup of 122 consecutive patients with coronary artery disease and an abnormal ECG response to exercise testing. These 122 consecutive patients all had clinically stable co& nary artery disease (defined for this study as > 75 per cent stenosis in the d&meter of one or more of the three coronary arteries or their major branches) and neither left bundle branch block nor other disorders which might affect interpretation of the post-exercise ECG’ such as alcoholism, thyroid disease, valvular or pericardial heart disease, or electrolyte abnormalities. Patients were queried (and their medical recorda examined) to determine whether they had a history of typical angina pectoris or a prior myocardial infarction, or manifested signs of clinical congestive heart failyre, hypertexision (blood pressure > 140/90 at any time) or hyperglycemia (fasting or two hour postprandial blqod sugar > 120 mg. per cent), or were taking a digitalis preparation or propranolol. Patients who were on propranolol had their medication held for 24 to 36 hours prior to exercise testing. Exercise testing. Each patient was evaluated by one or more exercise tests on the day prior to angiography. The exercise protocol consisted of a double two-step test, for which the end point was chest pain (or its usual equivalent in each
American Heart Journal
441
Lindsey
and
Cohn
CLINICAL DATA I 5 5oyr
*40yr
Fig. 1. Sax distribution, exercise testing.
age, and history
of typical
patient) or completion of the test. Standard 1% lead ECGs were recorded with patients in the supine position before, immediately after, and three, five, and eight minutes after the test. A two-step test was considered positive if there was new or additional J point depression I 0.5 mm. with a flat or depressed ST segment in any lead for at least 80 milliseconds immediately after and up to 8 minutes post-exercise.’ If the test was negative or equivocal, a bicycle ergometer test was performed after a 30 to 60 minute rest period. Patients were exercised with a bicycle ergometer at an initial work load of 300 k.p.m. and this load was increased every three minutes by 150 k.p.m. until 85 per cent of the maximum predicted heart rate was reached or symptoms forced the patient to stop. Lead V, was monitored during the exercise test and recorded at minute intervals, and the standard 12-lead ECG was recorded at the same time intervals as the two-step test. A bicycle test was considered positive if the ST segment depression was 2 1.0 mm. during or up to 8 minutes post-exercise.’ During and after the test, patients were queried as to the presence of chest, arm or jaw pain, pressure, tightness, or discomfort as well as fatigue or dyspnea. Coronary angiography. Coronary angiograms were recorded on 16 mm. tine film in multiple projections using the Sones or Judkins technique. They were interpreted by consensus of two or more members of the senior cardiology staff, usually without prior knowledge of whether the exercise test resulted in pain or not.
442
angina
in patients
with
and without
angina
during
or after
Left ventriculography. Left ventriculograms were obtained in the right anterior oblique projection using multi-holed catheters and power injections of 40 to 50 ml. of 76 per cent meglumine sodium diazitroate. Volumes and ejection fractions were calculated by standard area-length methods utilized in our laboratory and reported in detail previously.R Results Frequency of angina in patients with positive exercisd’ tests. Seventy-eight of the 122 patients
with positive exercise tests experienced angina or its usual equivalents. Forty-four patients had no such symptoms, but 12 of these 44 pain-free patients had other symptoms which forced them to stop their tests. Three stopped because of shortness of breath and nine stopped because of generalized fatigue. The remaining 32 patients stopped only because they had completed the two-step test or achieved 85 per cent of their predicted heart rate on the bicycle test. Comparison angina.
of subgroups
with
and
without
1. Age and sex distribution (Fig. 1). Seventythree per cent of the patients with pain were males compared to 64 per cent of the patients without pain (pNS). Mean age in the patients with pain was 49 + 4 (S.E.M.) years and 47 -+ 3 years in the non-pain group (pNS).* The percent*Statistical significance determined were by chi-square tests.
by t test;
April,
all
other
comparisons
1978, Vol. 95, No. 4
Silent myocardial
Fig. 2. Frequency of congestive heart failure hyperglycemia in the two subgroups of patients.
(CZZF),
ages of patients in the < 40 and > 50 age groups were also similar. 2. Prior history of typical angina (Fig. 1). When the two subgroups were compared, there was no statistically significant difference (91 per cent vs. 80 per cent) in the frequency of a history of typical angina pectoris (exertion-related chest discomfort promptly relieved by rest and/or nitroglycerin). Further analysis of the pain patterns indicated that there were similar numbers of NYHA Class III and Class IV patients in each subgroup. 3. Clinical congestive heart failure (Fig. 2). In each subgroup, there were statistically similar numbers of patients with overt clinical congestive heart failure (14 per cent vs. 9 per cent). 4. Hypertension (Fig. 2). There were similar percentages of patients in each group with blood pressure higher than 140/90 mm. Hg or a prior history of treated hypertension (27 per cent vs. 36 per cent). 5. Prior history of myocardial infarction (Fig. 2). Prior transmural or non-transmural myocardial infarction (by history of ECG and/or cardiac enzyme evolution) was a common finding in this study but the frequency was statistically similar in each group of patients (59 per cent vs. 73 per cent). 6. Hyperglycemia (Fig. 2). The frequency of hyperglycemia and/or treated diabetes mellitus was similar in each group (17 per cent vs. 20 per cent).
American
Heart Journal
hypertension
(#BP),
myocardial
ischemia with exercise
infarction
MI),
and
7. Drug therapy (Fig. 3). Relatively small but almost equal numbers of patients were taking digitalis preparations prior to the study (18 per cent vs. 16 per cent). As noted earlier, propranolol was held for 24 to 36 hours prior to the exercise test and angiography. Forty-seven per cent of the patients with pain were taking this drug compared to 36 per cent of the pain-free group (PM).
8. Resting ECG (Fig. 4). The frequency of normal control ECGs, ECGs with minor ST-T abnormalities, and ECGs diagnostic of prior transmural myocardial infarction were almost identical in the group with chest pain on exercise testing compared to the group without pain. 9. Angiographic findings (Fig. 5). Multivessel disease was a frequent finding in these patients (83 .per cent vs. 75 per cent, pNS), as was the frequency of collateral vessels (62 per cent vs. 70 per cent, pNS). Impaired left ventricular function (defined as an ejection fraction less than .50)” was less common, but was found with nearly equal frequency in both subgroups (24 per cent vs. 30 per cent, pNS). 10. Exercise tests (Fig. 6). Exercise tests were analyzed to determine ‘the maximum heart rate and the extent of the ischemic response. There were nearly equal numbers of patients in each group who had heart rates greater than 120 recorded during or immediately after exercise (50 per cent vs. 43 per cent), suggesting equivalent degrees of stress. The frequency of strongly posi-
443
Lindsey
and
Cohn
lOO-
80 -
ff
60-
2 if 40sp 20 -
0 Fig. 3. Use of digitalis study.
and propranolol
by the patients
in the
tive exercise tests (greater than 2 mm. ST segment depression in any lead) was 42 per cent vs. 41 per cent. In addition, the lead location of the most positive response was also similar in time both groups, as was the post-exercise interval in which the maximum ST depression developed. Finally, the numbers of patients tested by only the double two-step test versus those with additional bicycle ergometry was similar in each group, with 64 per cent of the patients with pain having only a double two-step test compared to 70 per cent of the pain-free group. In addition to the above analyses, various and hyperglycombinations such as hypertension cemia were also compared, with no significant differences noted between the two groups. Discussion
The present report concerns a group of 122 patients with coronary artery disease and an abnormal ECG response to exercise testing, and examines their subjective response to presumed myocardial &hernia. In this study, clinical and angiographic findings in the 78 patients with angina1 pain or its equivalents during or after a positive exercise test were compared to the 44 patients without such symptoms. The two subgroups in the present study were shown to be similar statistically in selected aspects of their clinical histories, resting ECGs, technical aspects of exercise testing, exercise test results, extent of diseaseby angiography, and left ventricular function. A majority of the patients in both groups
had a history of angina that could be described as typical, but this occurred as frequently and with the same severity in both subgroups. Similarly, patients with myocardial infarction by history and by resting ECG were found with similar frequency in both groups, and the group without chest pain was not comprised primarily of those patients whose marker for coronary artery disease had been a myocardial infarction rather than angina. Since diabetes mellitus and hypertension have a higher-than-expected incidence in patients with clinically unrecognized myocardial infarction,” one might ascribe differences in the frequency of pain-free exercise tests to differences in the numbers of the hyperglycemic and hypertensive patients in the two groups, but no such differences were found. The resting ECGs were also examined in the two groups. Although the presence of prior ST-T abnormalities might be expected to cause some difficulties in interpreting post-exercise changes and possibly result in false positive (as well as false negative) results, patients with ST-T abnormalities were equally distributed between the two groups. Drug therapy might also contribute to problems in interpreting ECG changes’ as well as modifying the subjective response to ischemia, yet similar numbers of patients in each group had been on propranolol or digitalis preparations prior to hospitalization, and propranolol was routinely held in this group of clinically stable patients for 24 to 36 hours prior to exercise studies. Analysis of the exercise test results shows that patients with pain did not have more strongly ischemic responsesthan patients without pain, nor did the latter group have a reduced prevalence of lower exercise or post-exercise heart rates, which would have suggested a less stressful test. The lead location of the most positive response was similar in both groups. Also, there were similar numbers of patients in each group tested by both bicycle ergometry and two-step tests so that the mechanisms of testing should not have affected the results. The frequencies of multivessel diseaseand collateral circulation were the same in both groups, and impaired ventricular function (decreased ejection fraction or clinical heart failure) was not related statistically to either the presence or absence of pain with exercise. Various combinations of clinical and angiographic parameters were also compared in the two groups and again no significant differences were found.
April,
1978, Vol. 95, No. 4
Silent myocardial
6s9 w
Fig.
Ah
4. Frequency = nonspecific
of
ECG abnormalities;
findings at rest in the two subgroups MI = myocardial infarction.
The conclusion that o the subjective recognition of ischemic pain d entiated the patients to be justified by the in these two groups see clinical, ECG, and angio phic parameters that were examined, but seve qualifications should has been reported to be considered. First, dys three of the 44 be an angina1 equival of shortness of pain-free patients did eir exercise test. breath when they stop in the symptomatic Inclusion of these patie subgroup did not result ny significant differn of another nine ences, nor would incl reason for stopping patients with fatigue as the test. We are still left h 32 patients (or 26% overt symptoms-asof the total group) with istories. Second, it is suming the veracity of th s been exercised on a possible that had all pat more rigorous exercise pr 01, more would have experienced symptoms. difference probably would not have been ed, however, since Bartel and’ associates,‘o g graded treadmill tests, reported 17% pa e coronary patients with positive tests. Third did not conduct pain threshold tests to determ if our pain-free group actually had a higher than rmal pain threshold. Fourth, patients may experienced truly unusual angina1 equival ithout either they re of them. Finally, or the investigators bein during exercise blood pressure deter were not available in m patients and thus differences in pressu cts between the two groups could n
American Heart Journal
ischemia with exercise
PAW NO PAIN
of patients.
WNL = normal;
ST
cations notwithstanding, our results and those of the Duke University series”’ (as well as the studies dealing only with asymptomatic individuals?‘) indicate that a considerable number of patients with coronary disease may have ECG evidence of exercise-induced myocardial ischemia without angina or its usual equivalents. These studies, plus those employing ambulatory ECG monitoring to detect ischemic heart disease,” suggest that in some patients the angina1 warning system (resulting from a combination of humoral, neural, and psychologic factor+) is temporarily or permanently “defective.” The presence of such a “defective” warning system may help to explain why the initial manifestation of coronary artery disease in some individuals is myocardial infarction or sudden death, and why identification of such individuals before the occurrence of a morbid event can be difficult.‘” Summary
Although many patients with coronary artery disease (CAD) have a positive exercise test without pain, the frequency and significance of this “silent” &hernia is unclear. Therefore, we studied 122 consecutive clinically stable patients with angiographicall,y defined CAD (> 75 per cent luminal stenosis) and a positive exercise test. Seventy-eight patients had pain or angina1 equivalent during or after a positive exercise test; 44 did not, including 32 (26 per cent) with no symptoms at all. Patients were evaluated as to age, sex,
445
Lindsey
and
Cohn
Fig. 5. Frequency of multivessel disease (MVD), subgroups of patients. EF = ejection fraction.
100
lilt z 120
collateral
vessels,
and poor
EXEIKISE TEST DATA r2mm ST&
Fig. 6. The two subgroups are compared for frequency of maximum heart markedly positive post-exercise ECG (> 2 mm. ST segment depression),
446
function
in the two
%MASTERS iiii
80
prior myocardial infarction, congestive failure, hypertension, diabetes mellitus, and digoxin or propranolol therapy-in addition to angina1 symptoms before, during, or after the exercise itself. Extent of CAD, presence of collaterals, and left ventricular ejection fraction were also determined. All exercise tests were evaluated for evidence of ST-T abnormalities or prior infarction on the control ECG as well as peak heart rate during exercise and post-exercise degree of ST segment depression. There were no significant differences between patients with and without exercise-induced pain in regard to any of the clinical and angiographic features noted above,
ventricular
zzw-4
rate > 120 beats/minute and two-step (Master’s)
with exercise, testing.
demonstrating that “silent” myocardial &hernia during or after exercise testing is not uncommon and is not readily attributable to any obvious clinical or catheterization findings. Further studies are necessary to determine if patients with evidence of “silent” myocardial ischemia are especially prone to sudden death. REFERENCES 1.
2.
Bruce, R. A., and Hornsten, T. R.: Exercise stress testing in evaluation of patients with ischemic heart disease, Brag. Cardiovasc. Dis. 11:371, 1969. Kattus, A. K., Jorgensen, C. R., Worden, R. E., and Alvaro, A. B.: ST segment depression with near-maximal exercise in detection of preclinical coronary heart disease, Circulation 44585, 1971.
April,
1978, Vol. 95, No. 4
Silent myocardial ischemia with exercise 3.
4.
5.
6.
7.
Froelicher, V. F., Yanowitz, F. G., Thompson, A. J., and Lancaster, M. C.: The correlation of coronary angiography and the electrocardiographic response to maximal treadmill testing in 76 asymptomatic men, Circulation 48597, 1973. Borer, J. S., Brensike, J. F., Redwood, D. R., Itscoitz, S. B., Passamani, E. R., Stone, N. J., Richardson, J. M., Levy, R. I., and Epstein, S. E.: Limitations of the electrocardiographic response to exercise in predicting coronary artery disease, N. Engl. J. Med. 293:367, 1975. Margolis, J. R., Kannel, W. B., Feinleib, M., Dawber, T. R., and McNamara, P. M.: Clinical features of unrecognized myocardial infarction-silent and asymptomatic, Am. J. Cardiol. 32:1, 1973. Kemp, H. G., Jr., Vokonas, P. S., Cohn, P. F., and Gorlin, R.: The angina1 syndrome associated with normal coronary arteriograms. Report of a six year experience, Am. J. Med. 54:735, 1973. Lepeschkin, E., and Surawicz, B.: Characteristics of truepositive and false-positive results of electrocardiographic two-step teat, N. Engl. J. Med. 258:511, 1958.
Information
8.
9.
10.
11.
12. 13.
Cohn, P. F., Gorlin, R., Adams, D. F., Chahine, R. A., Vokonas, P. S., and Herman, M. V.: Comparison of biplane and single plane left ventriculograms in patients with coronary artery disease, Am. J. Cardiol. 33:1, 1974. Kennedy, H. L., and Underhill, S. J.: Ischemic ST segment depression and dyspnea, AM. HEART J. 89:544, 1975. Bartel, A. G., Behar, V. S., Peter, R. H., Orgain, E. S., and Kong, Y.: Graded exercise teats in angiographically documented coronary artery disease, Circulation 49:348, 1974. O’Rourke, R. A., Ross, J. R., Jr.: Ambulatory electrocardiographic monitoring to detect ischemic heart disease, Ann. Intern. Med. 81:695, 1974. Gorlin, R.: Pathophysiology of cardiac pain, Circulation 32:138, 1965. Cohn, P. F.: Severe, asymptomatic coronary artery disease: A diagncetic, prognostic and therapeutic puzzle, Am. J. Med. 82:565, 1977.
for authors
Most of the provisions of the Copyright Act of 1976 became effective on January 1,1978. Therefore, all manuscripts must be accompanied by the following statement, signed by each author: “The undersigned author(s) transfers all copyright ownership of the manuscript entitled (title of article) to The C. V. Mosby Company in the event the work is published. The author(s) warrants that the article is original, is not under consideration by another journal, and has not been previously published.” Authors will be consulted, when possible, regarding republication of their material.
American Heart Journal
447
During exercise testing, subjective symptoms of chest pain can often be related to objective evidence of myocardial ischemia when ST segment depression or elevation appears on the ECG.’ F’requently, however, individuals with coronary artery disease have ischemic ECG responses to exercise testing without experiencing angina or it+ equivalents,*-’ indicating that there may be “silent” or asymptomatic myocardial &hernia just as there may be “silent” myocardial infarction.3 Because the clinical and kngiographical features of asymptomatic and symptomatic myocardial &hernia have not been compared in detail in previous exercise studies, we studied the subjective as well as the objective responses to exercise testing in a group of patients with exercise-induced ischemic ST changes in whom coronary artery disease was demonstrated by angiography. Methods Patient selection. In evaluating the phenomenon of “silent” myocardial ischemia, we studied the exercise responses of 232 consecutive patients (tested between 1972 and 74) with chest pain syndromes who were free of concomitant valvular, per&z&dial, or congenital heart disease. One hundred eighty-four patients had angiographitally determined coronary artery disease and 48 From the Cardiovascular Division, Department of Medicine, Peter Bent Brigham Hospibl and Harvard Medical School, Boston, Mass. Supported by United States Public Health Service Grants No. HL 11306 and HL-7049. Received for publication Oct. 14, 1976. Accepted for publication Nov. 12, 1976. Reprint requests: Peter F. Cohn, M.D., Cardiovascular Division, Peter Bent Brigham Hospital, 721 Huntington Ave., Boston, Mass. 02115. *Presented at the Forty-eighth Annual Scientific sessions of the American Heart Association,‘Anaheim, California, November, 1976.
0002-8703/78/0495-0441$00.70/O
0 1978 The
C. V. Mosby
Co.
had normal coronary arteriograms. Because of the difficulty in relating the presence or absence of chest pain to myocardial ischemia during a negative exercise test, we were most interested in the patient who had an abnormal or positive exercise test. As expected from prior studies,” only about 20 per cent of the patients with normal coronary arteriograms had a positive exercise test, a number (11). too small for meaningful analysis. Therefore, the present report concerns only the subgroup of 122 consecutive patients with coronary artery disease and an abnormal ECG response to exercise testing. These 122 consecutive patients all had clinically stable co& nary artery disease (defined for this study as > 75 per cent stenosis in the d&meter of one or more of the three coronary arteries or their major branches) and neither left bundle branch block nor other disorders which might affect interpretation of the post-exercise ECG’ such as alcoholism, thyroid disease, valvular or pericardial heart disease, or electrolyte abnormalities. Patients were queried (and their medical recorda examined) to determine whether they had a history of typical angina pectoris or a prior myocardial infarction, or manifested signs of clinical congestive heart failyre, hypertexision (blood pressure > 140/90 at any time) or hyperglycemia (fasting or two hour postprandial blqod sugar > 120 mg. per cent), or were taking a digitalis preparation or propranolol. Patients who were on propranolol had their medication held for 24 to 36 hours prior to exercise testing. Exercise testing. Each patient was evaluated by one or more exercise tests on the day prior to angiography. The exercise protocol consisted of a double two-step test, for which the end point was chest pain (or its usual equivalent in each
American Heart Journal
441
Lindsey
and
Cohn
CLINICAL DATA I 5 5oyr
*40yr
Fig. 1. Sax distribution, exercise testing.
age, and history
of typical
patient) or completion of the test. Standard 1% lead ECGs were recorded with patients in the supine position before, immediately after, and three, five, and eight minutes after the test. A two-step test was considered positive if there was new or additional J point depression I 0.5 mm. with a flat or depressed ST segment in any lead for at least 80 milliseconds immediately after and up to 8 minutes post-exercise.’ If the test was negative or equivocal, a bicycle ergometer test was performed after a 30 to 60 minute rest period. Patients were exercised with a bicycle ergometer at an initial work load of 300 k.p.m. and this load was increased every three minutes by 150 k.p.m. until 85 per cent of the maximum predicted heart rate was reached or symptoms forced the patient to stop. Lead V, was monitored during the exercise test and recorded at minute intervals, and the standard 12-lead ECG was recorded at the same time intervals as the two-step test. A bicycle test was considered positive if the ST segment depression was 2 1.0 mm. during or up to 8 minutes post-exercise.’ During and after the test, patients were queried as to the presence of chest, arm or jaw pain, pressure, tightness, or discomfort as well as fatigue or dyspnea. Coronary angiography. Coronary angiograms were recorded on 16 mm. tine film in multiple projections using the Sones or Judkins technique. They were interpreted by consensus of two or more members of the senior cardiology staff, usually without prior knowledge of whether the exercise test resulted in pain or not.
442
angina
in patients
with
and without
angina
during
or after
Left ventriculography. Left ventriculograms were obtained in the right anterior oblique projection using multi-holed catheters and power injections of 40 to 50 ml. of 76 per cent meglumine sodium diazitroate. Volumes and ejection fractions were calculated by standard area-length methods utilized in our laboratory and reported in detail previously.R Results Frequency of angina in patients with positive exercisd’ tests. Seventy-eight of the 122 patients
with positive exercise tests experienced angina or its usual equivalents. Forty-four patients had no such symptoms, but 12 of these 44 pain-free patients had other symptoms which forced them to stop their tests. Three stopped because of shortness of breath and nine stopped because of generalized fatigue. The remaining 32 patients stopped only because they had completed the two-step test or achieved 85 per cent of their predicted heart rate on the bicycle test. Comparison angina.
of subgroups
with
and
without
1. Age and sex distribution (Fig. 1). Seventythree per cent of the patients with pain were males compared to 64 per cent of the patients without pain (pNS). Mean age in the patients with pain was 49 + 4 (S.E.M.) years and 47 -+ 3 years in the non-pain group (pNS).* The percent*Statistical significance determined were by chi-square tests.
by t test;
April,
all
other
comparisons
1978, Vol. 95, No. 4
Silent myocardial
Fig. 2. Frequency of congestive heart failure hyperglycemia in the two subgroups of patients.
(CZZF),
ages of patients in the < 40 and > 50 age groups were also similar. 2. Prior history of typical angina (Fig. 1). When the two subgroups were compared, there was no statistically significant difference (91 per cent vs. 80 per cent) in the frequency of a history of typical angina pectoris (exertion-related chest discomfort promptly relieved by rest and/or nitroglycerin). Further analysis of the pain patterns indicated that there were similar numbers of NYHA Class III and Class IV patients in each subgroup. 3. Clinical congestive heart failure (Fig. 2). In each subgroup, there were statistically similar numbers of patients with overt clinical congestive heart failure (14 per cent vs. 9 per cent). 4. Hypertension (Fig. 2). There were similar percentages of patients in each group with blood pressure higher than 140/90 mm. Hg or a prior history of treated hypertension (27 per cent vs. 36 per cent). 5. Prior history of myocardial infarction (Fig. 2). Prior transmural or non-transmural myocardial infarction (by history of ECG and/or cardiac enzyme evolution) was a common finding in this study but the frequency was statistically similar in each group of patients (59 per cent vs. 73 per cent). 6. Hyperglycemia (Fig. 2). The frequency of hyperglycemia and/or treated diabetes mellitus was similar in each group (17 per cent vs. 20 per cent).
American
Heart Journal
hypertension
(#BP),
myocardial
ischemia with exercise
infarction
MI),
and
7. Drug therapy (Fig. 3). Relatively small but almost equal numbers of patients were taking digitalis preparations prior to the study (18 per cent vs. 16 per cent). As noted earlier, propranolol was held for 24 to 36 hours prior to the exercise test and angiography. Forty-seven per cent of the patients with pain were taking this drug compared to 36 per cent of the pain-free group (PM).
8. Resting ECG (Fig. 4). The frequency of normal control ECGs, ECGs with minor ST-T abnormalities, and ECGs diagnostic of prior transmural myocardial infarction were almost identical in the group with chest pain on exercise testing compared to the group without pain. 9. Angiographic findings (Fig. 5). Multivessel disease was a frequent finding in these patients (83 .per cent vs. 75 per cent, pNS), as was the frequency of collateral vessels (62 per cent vs. 70 per cent, pNS). Impaired left ventricular function (defined as an ejection fraction less than .50)” was less common, but was found with nearly equal frequency in both subgroups (24 per cent vs. 30 per cent, pNS). 10. Exercise tests (Fig. 6). Exercise tests were analyzed to determine ‘the maximum heart rate and the extent of the ischemic response. There were nearly equal numbers of patients in each group who had heart rates greater than 120 recorded during or immediately after exercise (50 per cent vs. 43 per cent), suggesting equivalent degrees of stress. The frequency of strongly posi-
443
Lindsey
and
Cohn
lOO-
80 -
ff
60-
2 if 40sp 20 -
0 Fig. 3. Use of digitalis study.
and propranolol
by the patients
in the
tive exercise tests (greater than 2 mm. ST segment depression in any lead) was 42 per cent vs. 41 per cent. In addition, the lead location of the most positive response was also similar in time both groups, as was the post-exercise interval in which the maximum ST depression developed. Finally, the numbers of patients tested by only the double two-step test versus those with additional bicycle ergometry was similar in each group, with 64 per cent of the patients with pain having only a double two-step test compared to 70 per cent of the pain-free group. In addition to the above analyses, various and hyperglycombinations such as hypertension cemia were also compared, with no significant differences noted between the two groups. Discussion
The present report concerns a group of 122 patients with coronary artery disease and an abnormal ECG response to exercise testing, and examines their subjective response to presumed myocardial &hernia. In this study, clinical and angiographic findings in the 78 patients with angina1 pain or its equivalents during or after a positive exercise test were compared to the 44 patients without such symptoms. The two subgroups in the present study were shown to be similar statistically in selected aspects of their clinical histories, resting ECGs, technical aspects of exercise testing, exercise test results, extent of diseaseby angiography, and left ventricular function. A majority of the patients in both groups
had a history of angina that could be described as typical, but this occurred as frequently and with the same severity in both subgroups. Similarly, patients with myocardial infarction by history and by resting ECG were found with similar frequency in both groups, and the group without chest pain was not comprised primarily of those patients whose marker for coronary artery disease had been a myocardial infarction rather than angina. Since diabetes mellitus and hypertension have a higher-than-expected incidence in patients with clinically unrecognized myocardial infarction,” one might ascribe differences in the frequency of pain-free exercise tests to differences in the numbers of the hyperglycemic and hypertensive patients in the two groups, but no such differences were found. The resting ECGs were also examined in the two groups. Although the presence of prior ST-T abnormalities might be expected to cause some difficulties in interpreting post-exercise changes and possibly result in false positive (as well as false negative) results, patients with ST-T abnormalities were equally distributed between the two groups. Drug therapy might also contribute to problems in interpreting ECG changes’ as well as modifying the subjective response to ischemia, yet similar numbers of patients in each group had been on propranolol or digitalis preparations prior to hospitalization, and propranolol was routinely held in this group of clinically stable patients for 24 to 36 hours prior to exercise studies. Analysis of the exercise test results shows that patients with pain did not have more strongly ischemic responsesthan patients without pain, nor did the latter group have a reduced prevalence of lower exercise or post-exercise heart rates, which would have suggested a less stressful test. The lead location of the most positive response was similar in both groups. Also, there were similar numbers of patients in each group tested by both bicycle ergometry and two-step tests so that the mechanisms of testing should not have affected the results. The frequencies of multivessel diseaseand collateral circulation were the same in both groups, and impaired ventricular function (decreased ejection fraction or clinical heart failure) was not related statistically to either the presence or absence of pain with exercise. Various combinations of clinical and angiographic parameters were also compared in the two groups and again no significant differences were found.
April,
1978, Vol. 95, No. 4
Silent myocardial
6s9 w
Fig.
Ah
4. Frequency = nonspecific
of
ECG abnormalities;
findings at rest in the two subgroups MI = myocardial infarction.
The conclusion that o the subjective recognition of ischemic pain d entiated the patients to be justified by the in these two groups see clinical, ECG, and angio phic parameters that were examined, but seve qualifications should has been reported to be considered. First, dys three of the 44 be an angina1 equival of shortness of pain-free patients did eir exercise test. breath when they stop in the symptomatic Inclusion of these patie subgroup did not result ny significant differn of another nine ences, nor would incl reason for stopping patients with fatigue as the test. We are still left h 32 patients (or 26% overt symptoms-asof the total group) with istories. Second, it is suming the veracity of th s been exercised on a possible that had all pat more rigorous exercise pr 01, more would have experienced symptoms. difference probably would not have been ed, however, since Bartel and’ associates,‘o g graded treadmill tests, reported 17% pa e coronary patients with positive tests. Third did not conduct pain threshold tests to determ if our pain-free group actually had a higher than rmal pain threshold. Fourth, patients may experienced truly unusual angina1 equival ithout either they re of them. Finally, or the investigators bein during exercise blood pressure deter were not available in m patients and thus differences in pressu cts between the two groups could n
American Heart Journal
ischemia with exercise
PAW NO PAIN
of patients.
WNL = normal;
ST
cations notwithstanding, our results and those of the Duke University series”’ (as well as the studies dealing only with asymptomatic individuals?‘) indicate that a considerable number of patients with coronary disease may have ECG evidence of exercise-induced myocardial ischemia without angina or its usual equivalents. These studies, plus those employing ambulatory ECG monitoring to detect ischemic heart disease,” suggest that in some patients the angina1 warning system (resulting from a combination of humoral, neural, and psychologic factor+) is temporarily or permanently “defective.” The presence of such a “defective” warning system may help to explain why the initial manifestation of coronary artery disease in some individuals is myocardial infarction or sudden death, and why identification of such individuals before the occurrence of a morbid event can be difficult.‘” Summary
Although many patients with coronary artery disease (CAD) have a positive exercise test without pain, the frequency and significance of this “silent” &hernia is unclear. Therefore, we studied 122 consecutive clinically stable patients with angiographicall,y defined CAD (> 75 per cent luminal stenosis) and a positive exercise test. Seventy-eight patients had pain or angina1 equivalent during or after a positive exercise test; 44 did not, including 32 (26 per cent) with no symptoms at all. Patients were evaluated as to age, sex,
445
Lindsey
and
Cohn
Fig. 5. Frequency of multivessel disease (MVD), subgroups of patients. EF = ejection fraction.
100
lilt z 120
collateral
vessels,
and poor
EXEIKISE TEST DATA r2mm ST&
Fig. 6. The two subgroups are compared for frequency of maximum heart markedly positive post-exercise ECG (> 2 mm. ST segment depression),
446
function
in the two
%MASTERS iiii
80
prior myocardial infarction, congestive failure, hypertension, diabetes mellitus, and digoxin or propranolol therapy-in addition to angina1 symptoms before, during, or after the exercise itself. Extent of CAD, presence of collaterals, and left ventricular ejection fraction were also determined. All exercise tests were evaluated for evidence of ST-T abnormalities or prior infarction on the control ECG as well as peak heart rate during exercise and post-exercise degree of ST segment depression. There were no significant differences between patients with and without exercise-induced pain in regard to any of the clinical and angiographic features noted above,
ventricular
zzw-4
rate > 120 beats/minute and two-step (Master’s)
with exercise, testing.
demonstrating that “silent” myocardial &hernia during or after exercise testing is not uncommon and is not readily attributable to any obvious clinical or catheterization findings. Further studies are necessary to determine if patients with evidence of “silent” myocardial ischemia are especially prone to sudden death. REFERENCES 1.
2.
Bruce, R. A., and Hornsten, T. R.: Exercise stress testing in evaluation of patients with ischemic heart disease, Brag. Cardiovasc. Dis. 11:371, 1969. Kattus, A. K., Jorgensen, C. R., Worden, R. E., and Alvaro, A. B.: ST segment depression with near-maximal exercise in detection of preclinical coronary heart disease, Circulation 44585, 1971.
April,
1978, Vol. 95, No. 4
Silent myocardial ischemia with exercise 3.
4.
5.
6.
7.
Froelicher, V. F., Yanowitz, F. G., Thompson, A. J., and Lancaster, M. C.: The correlation of coronary angiography and the electrocardiographic response to maximal treadmill testing in 76 asymptomatic men, Circulation 48597, 1973. Borer, J. S., Brensike, J. F., Redwood, D. R., Itscoitz, S. B., Passamani, E. R., Stone, N. J., Richardson, J. M., Levy, R. I., and Epstein, S. E.: Limitations of the electrocardiographic response to exercise in predicting coronary artery disease, N. Engl. J. Med. 293:367, 1975. Margolis, J. R., Kannel, W. B., Feinleib, M., Dawber, T. R., and McNamara, P. M.: Clinical features of unrecognized myocardial infarction-silent and asymptomatic, Am. J. Cardiol. 32:1, 1973. Kemp, H. G., Jr., Vokonas, P. S., Cohn, P. F., and Gorlin, R.: The angina1 syndrome associated with normal coronary arteriograms. Report of a six year experience, Am. J. Med. 54:735, 1973. Lepeschkin, E., and Surawicz, B.: Characteristics of truepositive and false-positive results of electrocardiographic two-step teat, N. Engl. J. Med. 258:511, 1958.
Information
8.
9.
10.
11.
12. 13.
Cohn, P. F., Gorlin, R., Adams, D. F., Chahine, R. A., Vokonas, P. S., and Herman, M. V.: Comparison of biplane and single plane left ventriculograms in patients with coronary artery disease, Am. J. Cardiol. 33:1, 1974. Kennedy, H. L., and Underhill, S. J.: Ischemic ST segment depression and dyspnea, AM. HEART J. 89:544, 1975. Bartel, A. G., Behar, V. S., Peter, R. H., Orgain, E. S., and Kong, Y.: Graded exercise teats in angiographically documented coronary artery disease, Circulation 49:348, 1974. O’Rourke, R. A., Ross, J. R., Jr.: Ambulatory electrocardiographic monitoring to detect ischemic heart disease, Ann. Intern. Med. 81:695, 1974. Gorlin, R.: Pathophysiology of cardiac pain, Circulation 32:138, 1965. Cohn, P. F.: Severe, asymptomatic coronary artery disease: A diagncetic, prognostic and therapeutic puzzle, Am. J. Med. 82:565, 1977.
for authors
Most of the provisions of the Copyright Act of 1976 became effective on January 1,1978. Therefore, all manuscripts must be accompanied by the following statement, signed by each author: “The undersigned author(s) transfers all copyright ownership of the manuscript entitled (title of article) to The C. V. Mosby Company in the event the work is published. The author(s) warrants that the article is original, is not under consideration by another journal, and has not been previously published.” Authors will be consulted, when possible, regarding republication of their material.
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