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Hemodynamic abnormalities in patients with coronary artery disease and their relationship to intermittent ischemic episodes
Hemodynamic
a&normalities
coronary artery disease to intermittent ischemic
in patienfs
and their episodes
wit
relationshi
Nom Goldschlager, M.D. F. Joan Sakai, M.D. Keith E. Cohn, M.D. Arthur Seizer, 4cf.D. San Francisco, Calif.
T
he clinical signs of cardiac failure commonly occurring in the course of ischemic heart disease have usually been ascribed to myocardial damage produced by infarction, mitral incompetence, or ventricular aneurysm .1-4 In recent years, it has been demonstrated that milder forms of cardiac failure can be found in patients with ischemic heart disease even in the absence of myocardial infarction or mitral insufficiency; the cardiac dysfunction is manifested only as abnormalities in hemodynamic performance, without symptoms or signs of circulatory congestion. Such hemodynamic malfunction most often occurs during spontaneous or exercise-induced angina1 attacks, but has also been observed in patients without symptoms of myocardial ischemia at the time of study.5-n The purpose of this report is to examine further such latent forms of cardiac failure in ischemic heart disease. An attempt is made to correlate the extent of coronary artery disease as assessed by selective
coronary cineangiography with degree of hemodynamic dysfunction and occurrence of exercise-induced electrocardiographic changes. Methods One hundred twenty-two patients referred to the cardiology unit for evaluation of ischemic heart disease and. possible myocardial revascularization procedures were studied. All patients had intermittent chest pain or discomfort; in many cases, the pain was intractable to medical management. I’atients in overt heart failure, not considered surgical candidates, generally do not undergo coronary angiography and were, therefore, not included in this report. Also excluded were patients with coronary artery disease and coexisting valvular lesions, regardless of etiology, and patients with significant systemic hypertension (diastolic blood pressure >95 mm. Hg). All patients were in normal sinus rhythm at the time of the study.
From
the Cardiology Unit, Presbyterian Ilospital, Pacific Medical Center. and the Heart Research Institute, The Institute of Medical Sciences, San Francisco, Calif. Snooorted bv Grants Nos. HE-05498. HE-06311. and FR-00241 from the National Institutes of Health, Bethesda, Md. ~-I_ Received f&publication Jan. 22, 1970. Reprint requests to: Arthur Seizer, M.D., Cardiopulmonary Laboratory. Pacific Medical Center, Clay and Webster Streets. San Francisco. Calif. 94115.
610
American Heart Journal
November, 1970
Yd 6‘0,No. 5, pp. 61ff
-618
Volume 80 Nzcmber 5
Coronary artery disease and ischemic episodes
Each patient underwent hemodynamic study, at rest and during exercise, and selective coronary cineangiography. The majority of patients (87 of 122) also had electrocardiographically monitored stress tests. Changes in the RS-T segment of the electrocardiogram (ECG) were evaluated during a multistage motor-driven treadmill test; in this procedure, the treadmill speed and grade are increased every 3 minut’es to produce progressive increment in exercise load. The test was continued until either the appearance of ischemic ST-T changes (flat or downward sloping S-T dlepression greater than 1 mm.) or attainment of a heart rate approaching that consiclered maximal for a given age.r2 On occasion, severe chest discomfort, arrhythmia, or fatigue necessitated premature discontinuation of the test. Patients not subjected to treadmill testing were those in whom severe angina1 symptoms developed on minimal exertion or those in whom serial ECG changes occurred during hospital stay. Hemodynamic studies were performed in all patients by means of a right heart catheterization at rest and during 4 minutes Iof supine leg exercise on a bicycle ergometer. Cardiac outputs were measured by the direct Fick method. Depending on the work load, increase in oxygen consump tion of 2 to 3 times the basal value was generally achieved during this exercise. Angina1 pain and/or ischemic ST-T-wave changes occurred infrequently in our patients at this level of exercise; in only one patient was exercise terminated prematurely. Patients requiring nitroglycerin in order to complete their exercise hemodynamic study were excluded from this report. Resting hemodynamic measurements were considered abnormal if the indirect left atria1 pressure (pulmonary artery wedge pressure), considered to represent left ventricular end-diastolic pressure, was greater than 42 mm. Hg and/or the cardiac index less than 2.5 L. per minute per square meter. Response to exercise was considered abnormal when the wedge pressure rose beyond 16 mm. Hg and/or the cardiac output rose less than 550 ml. per minute for a rise in oxygen consumption of 100
611
ml. per minute. The degree of hemodynamic abnormality was further subdivided into mild (wedge pressure less than 2.5 mm. Hg at rest or during exercise) and gross (wedge pressure of 2.5 mm. Hg or greater at rest or during exercise). These values, while appearing inordinately high, served to weigh hemodynamic performance in favor of the patients. In this way, relationships between cardiac function and degree of coronary disease would be more meaningful. Selective coronary arteriography was performed employing the transfemoral percutaneous technique of Judkins.i3 Cineangiograms using 76 per cent Renografin taken at 60 frames per second on 3.5 mm. film were obtained in anteroposterior and left and right anterior oblique projections. All radiographic studies were reviewed by two independent observers. Obstruction in the 3 main coronary arteries was considered significant only if lumen size were reduced by 50 per cent or more; data obtained in patients not having this degree of vascular occlusion are not presented in this report. The extent of coronary artery disease was determined by the number of major vessels involved, regardless of whether the disease process was localized or diffuse. An obstructing lesion in the left main coronary artery was considered to represent twovessel disease. The patients were grouped according to the number of coronary arteries involved by significant disease. Statistical analysis relating the extent of coronary disease, treadmill test response, and hemodynamic findings were performed using the chi-square method. Also evaluated were the effects of age, duration of angina, electrocardiographically proved myocardial infarction, and cardiomegaly as visualized on conventional chest radiographs. Results
Patients were grouped according to the extent of obstructive coronary artery disease. There were 29 patients with singlevessel disease (Group I), 34 patients with disease in two major vessels (Group II), and 59 patients with three-vessel disease (Group III). The results of our investigation (Tables I to III, Figs. 1 to 3) show
612
Goldschlager et a2.
that of the total series of 122 patients, 75 (61 per cent) had hernodynamic malfunction either at rest or during exercise, and 51 of 87 patients completing treadmill exercise (57 per cent) had positive tests. The majority of patients with positive
treadmill tests (39 of 51, or 76 per Cent) were found to have hernodynamic dysfunction at catheterization. The frequency of positive treadmill tests clearly rose with increasing severity of coronary artery disease (Table I, Fig. 1).
Table I. Summary of results in groups studied Treadmill*
I
Hemodynamic
data
1 Electrocardiogramt
-. Groufi
-
’
Rest Positive
A(%‘,)
Normal
N%b)
I
7(39%) 12(43%) 32(78%)
34 59
Curdionregaly MI
NC%‘,)
I
In=29 II n= III n=
Exercise
Negative
11051%) 16(57%) 902%)
Abbreviations: N = normal; A = abnormal; MI = myocardial infarction. *As not all patients underwent treadmill testing, the numbers in each group do not add up to the total number results are not given in the table. $The remainder of the ECG’s in each group had nondiagnostic ST-T changes.
in that group.
Equivocal
Table II. Mean hemodynamic data in 122 patients” I Mean hge ___---
Group
In=29 X111=34 !IIn=59
50 46 52
CI (L./min./M?)
SI (c.c./min./M.2) ____I--_____-~~
R
E
R
2.9k 0.53 3.1,0.86 2.7F 0.56
4.3F 0.85 4.3Fl.O 3.7? 0.89
PAM
(A-W, w. %) ,!
E
R
j
422 10 475 12 4.11F 0.55 37+11 44+11 4.18C0.94 401 9 39f I1 4.501 0.72
E
1
coronary
Relation of myocardial ,infarction arteries significantly obstructed
prior
Normal ECG myocardial
R
j
.y,:T-i--
7.35, 1.6 152~ 3 26rt 10 lo+ 2 16_+ 8 7.76k1.6 1423 27&H 1123 22_+11 8.092 1.5 17* 5 35+ 11 9F 4 24i 10
Abbreviations: CI = cardiac index; SI = stroke index; (A-V)02 = arteriovenous oxyge~l difference; pressure; PAW = pulmonary artery wedge pressure; R = rest; E = exercise. *Means and standard deviations.
Table III.
PAW (mm. Hd
(mm. Hd
PAM = pulmonary
to 1zemodynamic performance
without infarction
Prior
artery
and wmber
myocardial
infarction
Hemodynamics Normal Group Group Group
I II III
10 5 2
Abnormal 4 3 13
Normal 2 7 2
I
Abnormal 1 7 10
mean
of
Coronary artery disease and ischemic episodes
‘The incidence of hemodynamic dysfunction was also seen to be closely associated with the extent of coronary vascular disease (Table I, Fig. 2). Forty-eight per cent of the 73 patients with hemodynamic abnormalities had mild degrees of dysfunction (elevation of the pulmonary artery wedge pressure to 2.5 mm. Hg or less at rest or during exercise) and 52 per cent had gross abnormalities (wedge pressure rising above 2.5 mm. Hg). Although cardiac malfunction occurred more commonly in patients with two- and three-vessel obstruction, the degree of dysfunction (mild versus gross) was less closely related to extent of coronary disease than was incidence of dysfunction. Group I. Single-vessel disease. Of the 29 patients in this group, 22 male and 7 female, the mean age was 50 (range 35 to 65). Fourteen had a normal EGG and 3 had electrocardiographically proved myocardial infarction, all involving the inferior wall (Table I). Two patients without prior infarction had minimal cardiomegaly; neither had evidence of impaired cardiac performance. The majority of patients undergoing treadmill testing had a negative test (61 per cent); 39 per cent had positive
Negative@## Positive
_20-
0 __I GROUP
1
GROUP
2
GROUP
613
3
Fig. 1. Bar graphs representing the percentage of patients in each group with norma and abnormal treadmill stress tests. The frequency of positive tests increases with the number of coronary vessels significantly obstructed.
%
Normal
1001
f&@
Abnormal
_
80-
o-
R GROUP
E 1
R GROUP
Fig. 2. Bar graphs representing the percentage of patients dynamic performance at rest and during exercise. There and the number of vessels significantly obstructed.
E
in each is clearly
E
R
2
GROUP
group with a relationship
3
normal and between
abnormal cardiac
hemofunction
664
Goldschluger ef al.
C.I.,
llminiM2
_I_ GROUP
2
GROUP
3
7’or * .
6.0
J
2.0
.
i P.A.W.,
R mm
E Hg
*=No GROUP
0
Prior
M.I.
O= Prior
M.I.
2
t
I
.
30 c 5
I
.. . . . ..e
I
. . . ..moo :::::o %Y .
‘.o ::: 0
01 R
E
10
Fig. 3. Scattergram ence in hemodynamic
. :: 0%
20 c
of cardiac indices and pulmonary performance in patients with
stress tests (Table I, Fig. 1). Twenty-eight of 29 patients (97 per cent) had normal resting hemodynamic measurements; 69 per cent (20 out of 29) remained normal during exercise (Tables I and II, Fig. 2). The single patient with abnormal resting hemodynamic measurements had obstructive disease in the left anterior descending artery, without evidence of myocardial infarction, and mild systemic hypertension. Two of the 3 patients who had had prior
E artery wedge pressures in 122 patients. or without prior myocardial infarction.
There
is no differ-
myocardial infarcts had normal exercise hemodynamics (Fig. 3). Of the 9 patients (31 per cent) with abnormal exercise hemodynamic data, no relation was found between cardiac performance, specific artery occluded, normal or abnormal resting ECG, or results of treadmill tests. In summary, the majority (97 per cent) of patients with single-vessel disease had normal resting hemodynamic measurements, two thirds had a negative treadmill
VoZume 80
Numbr’r5
Coronary artery disease and ischemic episodes
test and two thirds had normal hemodynamic studies during exercise. Group II. Two-vessel disease. There were 34 patients in this group; 32 were men. The mean age was 46 (range 33 to 61). Fourteen had had prior myocardial infarctions and in 13 the inferior wall was involvled. Four had cardiomegaly and, in contrast to Group I, there was evidence of cardiac malfunction in all of these. Twelve of 28 patients (43 per cent) undergoing treadmill exercise had positive tests, (Table I, Fig. 1). Resting hemodynamic data were normal in 88 per cent of the group (30 of 34) but 15 of 34 (44 per cent) became abnormal during exercise (Tables I and II, Fig. 2). Despite the larger number of Group II patients with hem’odynamic abnormalities, there was no statistically significant difference in degree or frequency of hemodynamic dysfunction either at rest or during exercise between Groups I and II. Of the 4 patients who had abnormal resting hemodynamic measurements, the left circumflex and right coronary arteries were obstructed in 2, the main left coronary in one, and the left anterior descending and right coronary arteries in one; this last patient had a subsequently demonstrated left ventricular aneurysm but had no clinkal signs of congestive heart failure at the time of study. Two of these 4 patients had had prior infarctions, both involving the inferior wall, and both had cardiomegaly on chest x-ray. Of the 15 patients with abnormal hemodynamic response to exercise, 3 had an entirely normal ECG and 7 had sustained infarction. However, of the total of 14 patients with prior infarction, 7 had normal catheterization data (Table III, Fig. 3). Thus, although prior myocardial infarct may be associated with impaired cardiac function, as it was in 50 per cent of the patients in this group, this is by no means always the case. In summary, the majority (88 per cent) of the patients with two-vessel disease had normal resting hemodynamic measurements, about one half had positive treadmill tests, and about one half had abnormal hemodynamic response to exercise. Group III. Three-vessel disease. There
615
were 59 patients in this group; 52 were men. The mean age was 52 (range 36 to 64). Cardiomegaly was present in 11 patients; 4 had sustained infarction, and only one had no evidence of impaired cardiac performance. Thirty-two of 41 patients in whom treadmill testing was done (78 per cent) had positive tests (Table I, Fig. l), representing a significantly higher incidence of abnormal stress tests with respect to Groups I and II (p
The object of this study was to investigate the relationship between the extent of anatomic involvement of the coronary arterial tree, overt evidence of myocardial
416
Goidschlager et al,
&hernia as indicated by a positive treadmill test, and the presence of hemodynamic abnormalities. Previous studies5-8J0J1have demonstrated that reversible left ventricular failure occurs frequently during attacks of angina pectoris in patients with coronary disease; furthermore, impaired cardiac performance has also been shown to occur at times other than during actual cardiac pain. 6,7 In view of the foregoing observations, it seemed warranted to inquire into the possibility that the cardiac dysfunction found in such patients is related to the extent of coronary vascular disease. To our knowledge, this relationship has not been previously investigated. Our series of patients dealt with only a specific segment of the total population of patients with coronary artery disease, namely, patients with angina pectoris; excluded were patients with clinical evidence of cardiac failure and patients who were asymptomatic, as well as patients with hypertension or coexisting valvular disease. There are obvious limitations in the design of a study which attempts to analyze the 3 factors under consideration. None of these factors can be quantitated. The designation of obstructive coronary artery disease as single-, two-, and three-vessel involvement implies increasing degrees of occlusive disease in very crude terms, for neither the true functional severity of the stenosis nor the influence of collateral circulatory adjustment can be properly taken into account. Treadmill test data, reported only as either positive or negative, express all-or-none results; in addition, equivocal tests, though of possible significance, must be ignored. Finally, hemodynamic performance has been arbitrarily classified as normal and abnormal, despite the realization that there is overlap between the two. Nevertheless, it was hoped that by studying a large enough group of patients, trends might be demonstrated which would throw additional light on the natural history of ischemic heart disease. The results of our study show a definite relationship between the degree oi coronary vessel involvement and cardiac malfunction. It is seen that in milder vessel involvement (Group I), as a rule, no hemo-
dynamic abnormalities are present; it is also apparent that such abnormalities become increasingly frequent in pa.tients with more extensive coronary artery involvement. Thus, patients in Group II showed a higher (but not statistically significantly so) incidence of abnormal exercise hemodynamics, while the frequency of such abnormalities became highly significant in Group III. Hemodynamic abnormalities were present at rest, as well as during exercise, in a significantly greater number of cases in Group III as compared with the other two groups. It is assumed that the principle physiological disturbance in this series of patients is intermittent myocardial ischemia. Proof of ischemia, given by a positive treadmill test, was found with greater frequency in patients with more extensive occlusive coronary disease. There were several patients in Group I in whom the clinical impression suggested to us that the chest pain was noncardiac in origin and, therefore, unrelated to the occlusive lesion in a single coronary artery. However, it was also recognized that many patients with negative treadmill tests undoubtedly also have ischemic episodes at times, and this was reflected in hemodynamic dysfunction at cardiac catheterization. Hemodynamic abnormalities were found in 73 of the 122 patients in this series: 54 of these (77 per cent) had no evidence of prior myocardial infarction, 40 (82 per cent) had no radiographically demonstrable cardiomegaly (Table Ij, and none had significant hypertension. The data, therefore, suggest that the relationship noted between the incidence of abnormal hemodynamic performance and the degree of coronary artery involvement is not causally related to previous myocardial infarction or coexisting hypertension. It is, therefore, justifiable to postulate that the intermittent ischemia in itself may produce cardiac dysfunction,‘* and is more likely to do so with increasing degrees of coronary vascular obstructive disease. Two possibilities are suggested in the consideration of the mechanism by which intermittent myocardial ischemia leads to ventricular malfunction. The first is the development of scattered areas of myo-
Coronary artery disease and ischemic episodes
cardiall fibrosisi which might affect myocardiayl function either directly or by reducing ventricular compliance. Such pathological changes would be expected to be related to the extent of coronary artery disease, but direct investigation of this possibility is obviously precluded in patients. The second possibility, and the one that seems more plausible to us, is that myocardial performance may be impaired in the presence of subclinical ischemia; that is, ischemia not detectable by available criteria, such as chest pain or abnormalities of ventricular repolarization. This is supported by our observation that most of the hemodynamic dysfunction occurring in our patients during supine exercise was only rarely of sufficient degree to produce either angina1 pain or electrocardiographic changes of overt ischemia. Additional support :is given by our finding that prior myocardial infarction, despite the associated area of fibrosis attendant upon it, was associated with no greater incidence of hemodynamic dysfunction that was absence of prior infarction. It therefore appears likely that subclinical degrees of ischemia exist, and it is entirely possible that episodes of this sort may alter myocardial performance in the same direction as do overt ischemic attacks. The data also suggest that in patients recovered from myocardial infarction who continue to suffer angina1 pain and who are not in congestive heart failure, it is the intermittent ischernic attacks rather than the prior infarct per se that are more directly related to im:paired ventricular performance. The results of our study therefore indicate that two- and three-vessel coronary artery disease unfavorably affects myocardial function as evidenced by the large number of patients with hemodynamic abnormalities at rest and/or during exercise. It is suggested that this may be related to repeated ischemic insults, clinically overt or covert, and that this factor plays an important roIe in evaluating the natural history of ischemic heart disease.
normalities found in patients with angina pectoris and the extent of coronary artery disease. Studies were made of 122 patients with anginal-syndrome. Coronary arteriograms, hemodynamic studies at rest and during exercise were used and, in the majority (87 patients), treadmill stress tests were performed. On the basis of coronary angiograms, the patients were classified into 3 groups: single-vessel disease (29 patients), two-vessel disease (34 patients) f and three-vessel disease (59 patients). In patients with single-vessel disease, resting hemodynamics were normal in all but one; exercise hemodynamic measurements remained normal in 69 per cent, and treadmill testing was negative in 61 per cent. In patient with two-vessel disease, 30 out of 34 had normal resting dynamics, 44 per cent showed abnormal hemodynamic response to exercise, and 43 per cent had positive treadmill tests. In patients with three-vessel disease, 40 per cent had hemodynamic abnormalities at rest, 83 per cent performed abnormally during exercise, and 78 per cent had positive treadmill tests; the frequency of abnormalities in all these parameters was significantly higher in these patients than in those with disease in one or two coronary arteries. Seventy-two of the 101 patients with hemodynamic abnormalities had neither cardiomegaly nor prior myocardial infarction. The results of the study are interpreted to indicate that repeated ischemic episodes may impair myocardial performance, and that such impairment occurs even at times when overt evidence of ischemia is not present. Such myocardial dysfunction is related to the extent of coronary artery disease, more so than to prior myocardial infarction in the type of patients studied. The fact that impaired myocardial function may occur in the absence of prior myocardial infarction must be taken into consideration in the natural history of coronary artery disease. The authors wish to assistance of Mr. Arnold the statistical analyses.
acknowledge the expert Baranco, who performed
REFERENCES
Summury
The purpose of this study was to clarify -the relationship between hemodynamic ab-
617
1.
Chapman, C. B., and Fraser, R. S.: Studies on the effect of exercise on cardiovascular function. III. Cardiovascular response to exercise in
618
2.
3.
4. 5.
6.
7.
Golds&lager et al.
patients with healed myocardial infarction, Circulation 9:347, 19.54. Parker, J. O., West, R. O., and DiGiorgi, S.: The hemodynamic response to exercise in patients with healed myocardial infarction without angina, Circulation 36~734, 1967. Malmcrona, R., Cramer, G., and Varnauskas, E.: Hemodynamic data during rest and exercise for patients who have or have not been able to retain their occupation after myocardial infarction, Acta Med. &and. 174557, 1963. Klein, M. D., Herman, M. V., and Goriin, R.: A hemodynamic study of left ventricular aneurysm, Circulation 35:614, 1967. Parker, J. O., DiGiorgi, S., and West, R. 0.: A hemodynamic study of acute coronary insufficiency precipitated by exercise, Amer. J. Cardiol. 17~470, 1966. Malmborg, R. 0.: A clinical and hemodynamic analysis of factors limiting the cardiac performance in patients with coronary heart disease, Acta Med. Stand. 177(Suppl. 426):1, 196.5. Messer, J. V., Levine, H. J., Wagman, R. J., and Gorlin, R.: Effect of exercise on cardiac performance in human subjects with coronary artery disease, Circulation 28:404, 1963.
a. Cohen, L. s., Elliott, w, c., Roiett, E. L., ad Gorlin, R.: Hemoclynamic studies during angina pectoris, Circulation 31:409, 1967. 9. Muller, O., and R@vik, K.: Hemodynamic consequences of coronary heart disease, with observations during angina1 pain and on the effect of nitroglycerine, Brit. Heart J” 20:302, 19.58. 10. Roughgarden, J. W., and Newman, E. V.: Circulatory changes during the pain angina pectoris, Amer. J. Med. 41:935, 1966. 11. Roughgarden, J. W.: Circulatory changes associated with spontaneous angina pectoris, Amer. J. Med. 4X:947, 1966. 12. Lester, M., Sheffield, L. T., Trammell, P., and Reeves, T. J.: The effect of age and athletic training on the maximal heart rate during muscular exercise, AMER. HEART J. 76:370, 1968. 13. Judkins, M. : Selective coronary arteriography, Part I: A percutaneous transfemoral technic, RadioIogy 89:815, 1967. 14. Edwards, J. E.: What is myocardial infarction, Circulation 4O(Suppl. IV):5, 1969.
a&normalities
coronary artery disease to intermittent ischemic
in patienfs
and their episodes
wit
relationshi
Nom Goldschlager, M.D. F. Joan Sakai, M.D. Keith E. Cohn, M.D. Arthur Seizer, 4cf.D. San Francisco, Calif.
T
he clinical signs of cardiac failure commonly occurring in the course of ischemic heart disease have usually been ascribed to myocardial damage produced by infarction, mitral incompetence, or ventricular aneurysm .1-4 In recent years, it has been demonstrated that milder forms of cardiac failure can be found in patients with ischemic heart disease even in the absence of myocardial infarction or mitral insufficiency; the cardiac dysfunction is manifested only as abnormalities in hemodynamic performance, without symptoms or signs of circulatory congestion. Such hemodynamic malfunction most often occurs during spontaneous or exercise-induced angina1 attacks, but has also been observed in patients without symptoms of myocardial ischemia at the time of study.5-n The purpose of this report is to examine further such latent forms of cardiac failure in ischemic heart disease. An attempt is made to correlate the extent of coronary artery disease as assessed by selective
coronary cineangiography with degree of hemodynamic dysfunction and occurrence of exercise-induced electrocardiographic changes. Methods One hundred twenty-two patients referred to the cardiology unit for evaluation of ischemic heart disease and. possible myocardial revascularization procedures were studied. All patients had intermittent chest pain or discomfort; in many cases, the pain was intractable to medical management. I’atients in overt heart failure, not considered surgical candidates, generally do not undergo coronary angiography and were, therefore, not included in this report. Also excluded were patients with coronary artery disease and coexisting valvular lesions, regardless of etiology, and patients with significant systemic hypertension (diastolic blood pressure >95 mm. Hg). All patients were in normal sinus rhythm at the time of the study.
From
the Cardiology Unit, Presbyterian Ilospital, Pacific Medical Center. and the Heart Research Institute, The Institute of Medical Sciences, San Francisco, Calif. Snooorted bv Grants Nos. HE-05498. HE-06311. and FR-00241 from the National Institutes of Health, Bethesda, Md. ~-I_ Received f&publication Jan. 22, 1970. Reprint requests to: Arthur Seizer, M.D., Cardiopulmonary Laboratory. Pacific Medical Center, Clay and Webster Streets. San Francisco. Calif. 94115.
610
American Heart Journal
November, 1970
Yd 6‘0,No. 5, pp. 61ff
-618
Volume 80 Nzcmber 5
Coronary artery disease and ischemic episodes
Each patient underwent hemodynamic study, at rest and during exercise, and selective coronary cineangiography. The majority of patients (87 of 122) also had electrocardiographically monitored stress tests. Changes in the RS-T segment of the electrocardiogram (ECG) were evaluated during a multistage motor-driven treadmill test; in this procedure, the treadmill speed and grade are increased every 3 minut’es to produce progressive increment in exercise load. The test was continued until either the appearance of ischemic ST-T changes (flat or downward sloping S-T dlepression greater than 1 mm.) or attainment of a heart rate approaching that consiclered maximal for a given age.r2 On occasion, severe chest discomfort, arrhythmia, or fatigue necessitated premature discontinuation of the test. Patients not subjected to treadmill testing were those in whom severe angina1 symptoms developed on minimal exertion or those in whom serial ECG changes occurred during hospital stay. Hemodynamic studies were performed in all patients by means of a right heart catheterization at rest and during 4 minutes Iof supine leg exercise on a bicycle ergometer. Cardiac outputs were measured by the direct Fick method. Depending on the work load, increase in oxygen consump tion of 2 to 3 times the basal value was generally achieved during this exercise. Angina1 pain and/or ischemic ST-T-wave changes occurred infrequently in our patients at this level of exercise; in only one patient was exercise terminated prematurely. Patients requiring nitroglycerin in order to complete their exercise hemodynamic study were excluded from this report. Resting hemodynamic measurements were considered abnormal if the indirect left atria1 pressure (pulmonary artery wedge pressure), considered to represent left ventricular end-diastolic pressure, was greater than 42 mm. Hg and/or the cardiac index less than 2.5 L. per minute per square meter. Response to exercise was considered abnormal when the wedge pressure rose beyond 16 mm. Hg and/or the cardiac output rose less than 550 ml. per minute for a rise in oxygen consumption of 100
611
ml. per minute. The degree of hemodynamic abnormality was further subdivided into mild (wedge pressure less than 2.5 mm. Hg at rest or during exercise) and gross (wedge pressure of 2.5 mm. Hg or greater at rest or during exercise). These values, while appearing inordinately high, served to weigh hemodynamic performance in favor of the patients. In this way, relationships between cardiac function and degree of coronary disease would be more meaningful. Selective coronary arteriography was performed employing the transfemoral percutaneous technique of Judkins.i3 Cineangiograms using 76 per cent Renografin taken at 60 frames per second on 3.5 mm. film were obtained in anteroposterior and left and right anterior oblique projections. All radiographic studies were reviewed by two independent observers. Obstruction in the 3 main coronary arteries was considered significant only if lumen size were reduced by 50 per cent or more; data obtained in patients not having this degree of vascular occlusion are not presented in this report. The extent of coronary artery disease was determined by the number of major vessels involved, regardless of whether the disease process was localized or diffuse. An obstructing lesion in the left main coronary artery was considered to represent twovessel disease. The patients were grouped according to the number of coronary arteries involved by significant disease. Statistical analysis relating the extent of coronary disease, treadmill test response, and hemodynamic findings were performed using the chi-square method. Also evaluated were the effects of age, duration of angina, electrocardiographically proved myocardial infarction, and cardiomegaly as visualized on conventional chest radiographs. Results
Patients were grouped according to the extent of obstructive coronary artery disease. There were 29 patients with singlevessel disease (Group I), 34 patients with disease in two major vessels (Group II), and 59 patients with three-vessel disease (Group III). The results of our investigation (Tables I to III, Figs. 1 to 3) show
612
Goldschlager et a2.
that of the total series of 122 patients, 75 (61 per cent) had hernodynamic malfunction either at rest or during exercise, and 51 of 87 patients completing treadmill exercise (57 per cent) had positive tests. The majority of patients with positive
treadmill tests (39 of 51, or 76 per Cent) were found to have hernodynamic dysfunction at catheterization. The frequency of positive treadmill tests clearly rose with increasing severity of coronary artery disease (Table I, Fig. 1).
Table I. Summary of results in groups studied Treadmill*
I
Hemodynamic
data
1 Electrocardiogramt
-. Groufi
-
’
Rest Positive
A(%‘,)
Normal
N%b)
I
7(39%) 12(43%) 32(78%)
34 59
Curdionregaly MI
NC%‘,)
I
In=29 II n= III n=
Exercise
Negative
11051%) 16(57%) 902%)
Abbreviations: N = normal; A = abnormal; MI = myocardial infarction. *As not all patients underwent treadmill testing, the numbers in each group do not add up to the total number results are not given in the table. $The remainder of the ECG’s in each group had nondiagnostic ST-T changes.
in that group.
Equivocal
Table II. Mean hemodynamic data in 122 patients” I Mean hge ___---
Group
In=29 X111=34 !IIn=59
50 46 52
CI (L./min./M?)
SI (c.c./min./M.2) ____I--_____-~~
R
E
R
2.9k 0.53 3.1,0.86 2.7F 0.56
4.3F 0.85 4.3Fl.O 3.7? 0.89
PAM
(A-W, w. %) ,!
E
R
j
422 10 475 12 4.11F 0.55 37+11 44+11 4.18C0.94 401 9 39f I1 4.501 0.72
E
1
coronary
Relation of myocardial ,infarction arteries significantly obstructed
prior
Normal ECG myocardial
R
j
.y,:T-i--
7.35, 1.6 152~ 3 26rt 10 lo+ 2 16_+ 8 7.76k1.6 1423 27&H 1123 22_+11 8.092 1.5 17* 5 35+ 11 9F 4 24i 10
Abbreviations: CI = cardiac index; SI = stroke index; (A-V)02 = arteriovenous oxyge~l difference; pressure; PAW = pulmonary artery wedge pressure; R = rest; E = exercise. *Means and standard deviations.
Table III.
PAW (mm. Hd
(mm. Hd
PAM = pulmonary
to 1zemodynamic performance
without infarction
Prior
artery
and wmber
myocardial
infarction
Hemodynamics Normal Group Group Group
I II III
10 5 2
Abnormal 4 3 13
Normal 2 7 2
I
Abnormal 1 7 10
mean
of
Coronary artery disease and ischemic episodes
‘The incidence of hemodynamic dysfunction was also seen to be closely associated with the extent of coronary vascular disease (Table I, Fig. 2). Forty-eight per cent of the 73 patients with hemodynamic abnormalities had mild degrees of dysfunction (elevation of the pulmonary artery wedge pressure to 2.5 mm. Hg or less at rest or during exercise) and 52 per cent had gross abnormalities (wedge pressure rising above 2.5 mm. Hg). Although cardiac malfunction occurred more commonly in patients with two- and three-vessel obstruction, the degree of dysfunction (mild versus gross) was less closely related to extent of coronary disease than was incidence of dysfunction. Group I. Single-vessel disease. Of the 29 patients in this group, 22 male and 7 female, the mean age was 50 (range 35 to 65). Fourteen had a normal EGG and 3 had electrocardiographically proved myocardial infarction, all involving the inferior wall (Table I). Two patients without prior infarction had minimal cardiomegaly; neither had evidence of impaired cardiac performance. The majority of patients undergoing treadmill testing had a negative test (61 per cent); 39 per cent had positive
Negative@## Positive
_20-
0 __I GROUP
1
GROUP
2
GROUP
613
3
Fig. 1. Bar graphs representing the percentage of patients in each group with norma and abnormal treadmill stress tests. The frequency of positive tests increases with the number of coronary vessels significantly obstructed.
%
Normal
1001
f&@
Abnormal
_
80-
o-
R GROUP
E 1
R GROUP
Fig. 2. Bar graphs representing the percentage of patients dynamic performance at rest and during exercise. There and the number of vessels significantly obstructed.
E
in each is clearly
E
R
2
GROUP
group with a relationship
3
normal and between
abnormal cardiac
hemofunction
664
Goldschluger ef al.
C.I.,
llminiM2
_I_ GROUP
2
GROUP
3
7’or * .
6.0
J
2.0
.
i P.A.W.,
R mm
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*=No GROUP
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Prior
M.I.
O= Prior
M.I.
2
t
I
.
30 c 5
I
.. . . . ..e
I
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‘.o ::: 0
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Fig. 3. Scattergram ence in hemodynamic
. :: 0%
20 c
of cardiac indices and pulmonary performance in patients with
stress tests (Table I, Fig. 1). Twenty-eight of 29 patients (97 per cent) had normal resting hemodynamic measurements; 69 per cent (20 out of 29) remained normal during exercise (Tables I and II, Fig. 2). The single patient with abnormal resting hemodynamic measurements had obstructive disease in the left anterior descending artery, without evidence of myocardial infarction, and mild systemic hypertension. Two of the 3 patients who had had prior
E artery wedge pressures in 122 patients. or without prior myocardial infarction.
There
is no differ-
myocardial infarcts had normal exercise hemodynamics (Fig. 3). Of the 9 patients (31 per cent) with abnormal exercise hemodynamic data, no relation was found between cardiac performance, specific artery occluded, normal or abnormal resting ECG, or results of treadmill tests. In summary, the majority (97 per cent) of patients with single-vessel disease had normal resting hemodynamic measurements, two thirds had a negative treadmill
VoZume 80
Numbr’r5
Coronary artery disease and ischemic episodes
test and two thirds had normal hemodynamic studies during exercise. Group II. Two-vessel disease. There were 34 patients in this group; 32 were men. The mean age was 46 (range 33 to 61). Fourteen had had prior myocardial infarctions and in 13 the inferior wall was involvled. Four had cardiomegaly and, in contrast to Group I, there was evidence of cardiac malfunction in all of these. Twelve of 28 patients (43 per cent) undergoing treadmill exercise had positive tests, (Table I, Fig. 1). Resting hemodynamic data were normal in 88 per cent of the group (30 of 34) but 15 of 34 (44 per cent) became abnormal during exercise (Tables I and II, Fig. 2). Despite the larger number of Group II patients with hem’odynamic abnormalities, there was no statistically significant difference in degree or frequency of hemodynamic dysfunction either at rest or during exercise between Groups I and II. Of the 4 patients who had abnormal resting hemodynamic measurements, the left circumflex and right coronary arteries were obstructed in 2, the main left coronary in one, and the left anterior descending and right coronary arteries in one; this last patient had a subsequently demonstrated left ventricular aneurysm but had no clinkal signs of congestive heart failure at the time of study. Two of these 4 patients had had prior infarctions, both involving the inferior wall, and both had cardiomegaly on chest x-ray. Of the 15 patients with abnormal hemodynamic response to exercise, 3 had an entirely normal ECG and 7 had sustained infarction. However, of the total of 14 patients with prior infarction, 7 had normal catheterization data (Table III, Fig. 3). Thus, although prior myocardial infarct may be associated with impaired cardiac function, as it was in 50 per cent of the patients in this group, this is by no means always the case. In summary, the majority (88 per cent) of the patients with two-vessel disease had normal resting hemodynamic measurements, about one half had positive treadmill tests, and about one half had abnormal hemodynamic response to exercise. Group III. Three-vessel disease. There
615
were 59 patients in this group; 52 were men. The mean age was 52 (range 36 to 64). Cardiomegaly was present in 11 patients; 4 had sustained infarction, and only one had no evidence of impaired cardiac performance. Thirty-two of 41 patients in whom treadmill testing was done (78 per cent) had positive tests (Table I, Fig. l), representing a significantly higher incidence of abnormal stress tests with respect to Groups I and II (p
The object of this study was to investigate the relationship between the extent of anatomic involvement of the coronary arterial tree, overt evidence of myocardial
416
Goidschlager et al,
&hernia as indicated by a positive treadmill test, and the presence of hemodynamic abnormalities. Previous studies5-8J0J1have demonstrated that reversible left ventricular failure occurs frequently during attacks of angina pectoris in patients with coronary disease; furthermore, impaired cardiac performance has also been shown to occur at times other than during actual cardiac pain. 6,7 In view of the foregoing observations, it seemed warranted to inquire into the possibility that the cardiac dysfunction found in such patients is related to the extent of coronary vascular disease. To our knowledge, this relationship has not been previously investigated. Our series of patients dealt with only a specific segment of the total population of patients with coronary artery disease, namely, patients with angina pectoris; excluded were patients with clinical evidence of cardiac failure and patients who were asymptomatic, as well as patients with hypertension or coexisting valvular disease. There are obvious limitations in the design of a study which attempts to analyze the 3 factors under consideration. None of these factors can be quantitated. The designation of obstructive coronary artery disease as single-, two-, and three-vessel involvement implies increasing degrees of occlusive disease in very crude terms, for neither the true functional severity of the stenosis nor the influence of collateral circulatory adjustment can be properly taken into account. Treadmill test data, reported only as either positive or negative, express all-or-none results; in addition, equivocal tests, though of possible significance, must be ignored. Finally, hemodynamic performance has been arbitrarily classified as normal and abnormal, despite the realization that there is overlap between the two. Nevertheless, it was hoped that by studying a large enough group of patients, trends might be demonstrated which would throw additional light on the natural history of ischemic heart disease. The results of our study show a definite relationship between the degree oi coronary vessel involvement and cardiac malfunction. It is seen that in milder vessel involvement (Group I), as a rule, no hemo-
dynamic abnormalities are present; it is also apparent that such abnormalities become increasingly frequent in pa.tients with more extensive coronary artery involvement. Thus, patients in Group II showed a higher (but not statistically significantly so) incidence of abnormal exercise hemodynamics, while the frequency of such abnormalities became highly significant in Group III. Hemodynamic abnormalities were present at rest, as well as during exercise, in a significantly greater number of cases in Group III as compared with the other two groups. It is assumed that the principle physiological disturbance in this series of patients is intermittent myocardial ischemia. Proof of ischemia, given by a positive treadmill test, was found with greater frequency in patients with more extensive occlusive coronary disease. There were several patients in Group I in whom the clinical impression suggested to us that the chest pain was noncardiac in origin and, therefore, unrelated to the occlusive lesion in a single coronary artery. However, it was also recognized that many patients with negative treadmill tests undoubtedly also have ischemic episodes at times, and this was reflected in hemodynamic dysfunction at cardiac catheterization. Hemodynamic abnormalities were found in 73 of the 122 patients in this series: 54 of these (77 per cent) had no evidence of prior myocardial infarction, 40 (82 per cent) had no radiographically demonstrable cardiomegaly (Table Ij, and none had significant hypertension. The data, therefore, suggest that the relationship noted between the incidence of abnormal hemodynamic performance and the degree of coronary artery involvement is not causally related to previous myocardial infarction or coexisting hypertension. It is, therefore, justifiable to postulate that the intermittent ischemia in itself may produce cardiac dysfunction,‘* and is more likely to do so with increasing degrees of coronary vascular obstructive disease. Two possibilities are suggested in the consideration of the mechanism by which intermittent myocardial ischemia leads to ventricular malfunction. The first is the development of scattered areas of myo-
Coronary artery disease and ischemic episodes
cardiall fibrosisi which might affect myocardiayl function either directly or by reducing ventricular compliance. Such pathological changes would be expected to be related to the extent of coronary artery disease, but direct investigation of this possibility is obviously precluded in patients. The second possibility, and the one that seems more plausible to us, is that myocardial performance may be impaired in the presence of subclinical ischemia; that is, ischemia not detectable by available criteria, such as chest pain or abnormalities of ventricular repolarization. This is supported by our observation that most of the hemodynamic dysfunction occurring in our patients during supine exercise was only rarely of sufficient degree to produce either angina1 pain or electrocardiographic changes of overt ischemia. Additional support :is given by our finding that prior myocardial infarction, despite the associated area of fibrosis attendant upon it, was associated with no greater incidence of hemodynamic dysfunction that was absence of prior infarction. It therefore appears likely that subclinical degrees of ischemia exist, and it is entirely possible that episodes of this sort may alter myocardial performance in the same direction as do overt ischemic attacks. The data also suggest that in patients recovered from myocardial infarction who continue to suffer angina1 pain and who are not in congestive heart failure, it is the intermittent ischernic attacks rather than the prior infarct per se that are more directly related to im:paired ventricular performance. The results of our study therefore indicate that two- and three-vessel coronary artery disease unfavorably affects myocardial function as evidenced by the large number of patients with hemodynamic abnormalities at rest and/or during exercise. It is suggested that this may be related to repeated ischemic insults, clinically overt or covert, and that this factor plays an important roIe in evaluating the natural history of ischemic heart disease.
normalities found in patients with angina pectoris and the extent of coronary artery disease. Studies were made of 122 patients with anginal-syndrome. Coronary arteriograms, hemodynamic studies at rest and during exercise were used and, in the majority (87 patients), treadmill stress tests were performed. On the basis of coronary angiograms, the patients were classified into 3 groups: single-vessel disease (29 patients), two-vessel disease (34 patients) f and three-vessel disease (59 patients). In patients with single-vessel disease, resting hemodynamics were normal in all but one; exercise hemodynamic measurements remained normal in 69 per cent, and treadmill testing was negative in 61 per cent. In patient with two-vessel disease, 30 out of 34 had normal resting dynamics, 44 per cent showed abnormal hemodynamic response to exercise, and 43 per cent had positive treadmill tests. In patients with three-vessel disease, 40 per cent had hemodynamic abnormalities at rest, 83 per cent performed abnormally during exercise, and 78 per cent had positive treadmill tests; the frequency of abnormalities in all these parameters was significantly higher in these patients than in those with disease in one or two coronary arteries. Seventy-two of the 101 patients with hemodynamic abnormalities had neither cardiomegaly nor prior myocardial infarction. The results of the study are interpreted to indicate that repeated ischemic episodes may impair myocardial performance, and that such impairment occurs even at times when overt evidence of ischemia is not present. Such myocardial dysfunction is related to the extent of coronary artery disease, more so than to prior myocardial infarction in the type of patients studied. The fact that impaired myocardial function may occur in the absence of prior myocardial infarction must be taken into consideration in the natural history of coronary artery disease. The authors wish to assistance of Mr. Arnold the statistical analyses.
acknowledge the expert Baranco, who performed
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Summury
The purpose of this study was to clarify -the relationship between hemodynamic ab-
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Golds&lager et al.
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