J. ELECTROCARDIOLOGY 10 (4), 1977, 321-330
The Diagnostic Inadequacy of Exercise Testing in Critical Left Coronary Artery Disease BY GERALD
G. TIMMIS, M.D., F.A.C.C.,* SEYMOUR GORDON, RENATO G. RAMOS, M.D. AND V. GANGADHARAN,
SUMMARY
M.D., F.A.C.C.,* M.D.
dysfunction in either group. Five of 15 pat i e n t s with n e g a t i v e GXT (18% of e n t i r e group) achieved 85% or more PMR. Eleven of this group achieved a r a t e o f more t h a n 110/rain. Although the substantial incidence of false n e g a t i v e exercise tests in m u l t i p l e vessel coronary artery disease is well known, its frequency in "critical" LCA stenoses has not previously been emphasized.
Coronary cinearteriograms were consecutively reviewed to identify "critical" (75% or more stenosis) left coronary a r t e r y (LCA) disease in patients who had previously been electrocardiographically monitored during s u b m a x i m a l stress by e r g o m e t r y (GXT). There were 26 such patients with lesions of the left main coronary artery or its equivalent (proximal left anterior descending and left circumflex branches), and two of the left anterior descending proximal to the large septal perforator. A positive GXT was identified by ST depression of I mm or more persisting for 0.08 sec. Exercise was terminated when symptoms, exhaustion, a threatening response (4ram or more ST depression) or 85% predicted maximal rate (PMR) occurred. There were 13 (46%) positive and 15 (54%) negative GXTs. Three of the positive group and five negative responders had a previous myocardial infarction which was located anteriorly in two and three cases respectively (P = NS). Asynergy was observed in seven patients in each group and was anterior in location in four and six patients respectively (P = NS). There was no significant difference in the incidence of impaired contractility or in cardiodynamic evidence of left ventricular
There is general agreement t h a t severe left coronary artery disease, especially t h a t involving the left m a i n stem (LMC), frequently cannot be clinically predicted before arteriographic study. 1-3 On the other hand, electrocardiographic monitoring during and after exercise is reported to reliably identify critical or high risk LCA disease, defined as severe stenosis involving the LMC, the proximal left anterior descending coronary artery (LAD) or combined involvement of the LAD and circumflex coronary arteries (LCX) proxi m a l to t h e i r first major bifurcations. 1,4'5 Nevertheless, despite these claims, neither the sensitivity nor specificity of such testing exhibit a consistently acceptable correlation with the results of coronary arteriography 6 (Table I). In a review of 611 patients who were submaximally stress, 36% with anatomic evidence of coronary a r t e r y disease failed to achieve a pathologic threshold ST segment depression of 0.75 mm. ~'7 In a recent report of 88 patients with three vessel disease with 70% or greater stenosis who achieved 85% of predicted maximal rate (PMR), 24% had false negative treadmill tests. In the same study, 13% of 31 patients with lei~ m a i n coronary stenosis had false negative tests, s DeMots et al 2 recently reported more t h a n a 25% incidence of negative responders (five of nineteen)
From William Beaumont Hospital, Royal Oak, Michigan. *Directors, Division of Cardiovascular Diseases. Presented in part at the 48th Scientific Session of the American Heart Association, Nov. 17-20, 1975. Reprint requests to: Gerald C. Timmis, M.D., Division of Cardiovascular Diseases, William Beaumont Hospital, 3601 W. 13 Mile Rd., Royal Oak, MI 48072. 321
322
TIMMIS ET AL
TABLE I Review of Diagnostic Sensitivity and Specificity of Stress Testing in Coronary Heart Disease AUTHORS Demany et a124 Hulgren et a~25 Mason et a126
NUMBER OF PROTOCOL ST CRITERIA BASELINESENSITIVITY SPECIFICITY MINIMUM (mm) ECG (%) (%) STENOSIS PATIENTS TEST RATE (% diam) (% PMR) 55 84
Kassebaum et a127 Roitman et a128 Cohn et a129 McConahay et a132
Ascoop et a133 Martin et a134
Bartel et al 8 Linhart et a135 Teieholz et a131
DM DM & GXT GXT 90
GXT
85
100 110 100
GXT DM DM
90
96 91 100
DM OM GXT DM GXT
332 57 61 59
GXT GXT GXT DM
Max Max
85 Max Max
90.5 90.75 1.0 ~ 0.5 ~> 1.o ~ 1.0 ~ 0.5 ~ 0.5 90.75 1.0 ~ 1.0 90.5 ~ 1.0 90.75 0.5 ~ 1.0 ~ 1.0 ~ 1.0 0.5
43 63 Normal 88 84 78 Normal 74 71 73 Abnormal 86* No previous 63t MI 42 35 59 33 62~ 68 84 AMI (136/332) 65§ Normal 85 Abnormal 76 Normal 32¶
70 100 69 83 89 97 97 82 73 83
50 50 50
91 100 94 93 89 78 57
50 50 50 50 50
50 50 50 75 50
70
75
* 64%, 86%, 93%, per 1, 2, & 3 vessels t 37%, 67%, 76%, per 1, 2, & 3 vessels 35%, 67%, 86%, per I, 2, & 3 vessels § 40%, 66%, 76%, per 1, 2, & 3 vessels ¶ Normotensive patients 14%, 31%, 67%, per 1, 2, & 3 vessels PMR = predicted maximal rate; D.M. = double Masters' two-step test; GXT = graded exercise test; MI & AMI = myocardial myocardial infarction
to stress e l e c t r o c a r d i o g r a p h y (ergometer) who h a d a 50% or g r e a t e r r e d u c t i o n of left m a i n c o r o n a r y d i a m e t e r ( e q u i v a l e n t to a 75% reduction of lumen). The d e p e n d a b i l i t y of a d a t a base including history, physical e x a m i n a t i o n a n d stress elect r o c a r d i o g r a p h y in i d e n t i f y i n g critical LCA disease m u s t be specifically defined because of t h e p a r t i c u l a r l y u n f a v o r a b l e prognosis of such lesions. 1,2'9-12 O u r s t u d y looks f u r t h e r into t h e s e n s i t i v i t y of one of t h e s e p a r a m e t e r s , exercise e l e c t r o c a r d i o g r a p h y , in i d e n t i f y i n g this subset of patients.
MATERIALS AND METHODS Patients with a technically adequate submaximal graded exercise test (GXT) were included in
this study when subsequent arteriography documented high risk LCA disease. This was defined as 70% or greater narrowing of the LMC, the LAD, proximal to the first large septal perforator, or combined stenosis of 70% or greater of the LAD proximal to the second diagonal and LCX proximal to the obtuse marginal branch. Cheitlin et al 4 have referred to the latter as a left main equivalent lesion (LME). Patients having had previous cardiac surgery and other types of heart disease such as rheumatic valvular involvement, congential heart disease, and cardiomyopathies were excluded from this study. Chest pain syndromes were classified according to New York Heart Association criteria (Class I-IV). Pre-stress electrocardiograms (ECGs) were designated normal or abnormal depending on the presence or absence of repolarization (ST-T) changes, conduction system disease, hypertrophy, or evidence of previous myocardial infarction. J. ELECTROCARDIOLOGY, VOL. 10, NO. 4, 1977
E X E R C I S E T E S T I N G IN S E V E R E LCAD
ECG DATA EX,.ClSE
.EST A-ll~l
I
~:
_
. . . . .
___:
':" ' " " ! ~ ' NEGATIVE J: f~'~;, r~" ~i f~'~ (0.1mV.J;O O.O8sec) I[..
r.
' ii:,:: '
L ,.
I I I _
B C
NEGATIVE
0.1mV.. 0.08 sec
Slope ~ lmV/sec)
~![i:: i I I ~I I ! [ ::i ::~i !I:: !] !~ili!!!~i~i![iiiTil ! ]i !ii
POSITIVE ,,~
~ii I inii'ii'iii;iii"
~.-
~ i.i ]
(~O.JmV~O.08 sec~ ~,.~- ~.,from Baseline ST,
il; ill, i!i
POSITIVE (0"4mV'°O'O8sec)
iill =='~ E~
rl,,',l ,,,I ,,,I
~ i,l: i,:~]:: !1 ~
;.... ....
,:.~POSITIVE
~ :' !
{O.5mV.O.O8se¢)
~::::
Fig. 1. Examples of variable responses to submaximal stress testing.
Graded exercise tests (GXTs) were performed following a 12-hour fast (including medications) in a manner similar to that described by Goldbarg et al TMand Borer et aP 4 A~er a standard 12-lead ECG was obtained in the sitting position before and after 30 sec of hyperventilation, leads V4-V6 were oscilloscopically monitored and recorded at 1 min. intervals during and for at least 6 min. after exercise. The exercise lead system was that of the standard diagnostic configuration. The precordial leads referred to were of the routine unipolar variety. The position of the limb leads, however, was adjusted to reduce noise and artifact. Thus, the arm lead electrodes were placed over the acromion processes and the leg lead electrodes over the anterior extreme of the iliac crests. The subjects working on a variably loaded bicycle ergometer* were instructed to pedal at a frequency of 50 rpm/min. Following a warm-up at 150 kpm/mint for 1.5 min, men began cycling at a load of 600 kpm/min and women at 300 kpm/min, the load increasing thereafter at 3 min intervals, usually in 300 and 150 *Elema Schonander, Model #450, type AM 368. tkpm = kilopond-meter, the energy required to lift a 1 kilogram mass 1 meter against the gravitational force at sea level (approximately equivalent to 1/6 watt). J. ELECTROCARDIOLOGY, VOL. 10, NO. 4, 1977
323
kpm increments for men and women, respectively. Stress was terminated when symptoms, exhaustion, a threatening response (4mm+ ST segment depression), or 85% PMR 1~ were observed. There were no m a j o r a r r h y t h m i a s or h y p o t e n s i v e episodes during exercise. A response was interpreted as positive when 0.1 mV ST segment depression of horizontal or downsloping configuration was observed for at least 0.08 seconds beyond the j point. Upsloping ST segment depression was excluded unless depression of 0.1 mV at 0.08 sec beyond the j point was decreasing at a rate less than 1.0 mV/sec. (Figure 1). 1~19 A positive submaximal stress test may be identified by changes other than ST segment shifts. Thus, chronotropic incompetence, 19 changes in blood pressure, the appearance of gallop rhythms and murmurs as well as the development of arrhythmias may reflect ischemia, ls'19 Of all these indicators of a positive response, only ST segment shifts have been correlated with any statistical precision to angiographically documented coronary heart disease. Therefore, only this parameter will be further considered in this report. Coronary arteriography was performed using the Sones technique. 2° The left ventricle was studied angiographically in a 40 degree RAO projection recorded on 35 mm film at 60 frames/sec. Estimates were made of size, contractility and ejection fraction. These have been reported to correlate well with objective measurements thereof (R = 0.92). 21 Abnormal contracting segments were identified as described by Herman and Gorlin. 22'23 Left ventricular performance was assessed during cardiac catheterization by following parameters in the basal state and in the fourth minute of isometric stress:** dp/dt, LVEDP, the ratio of dp/dt and LVEDP (dp/dt/LVEDP): left ventricular minute work (LVW), and the ratio of the change in LVW to the change in LVEDP during exercise (ALVW/ALVEDP). No attempt was made to quantitatively equate isometric exercise in the catheter laboratory to the kinetic exercise ofergometry. The former was employed only to evaluate pump and muscle function more accurately than would be ** one-third of maximum handgrip capacity, Stoelting dynamometer.
DISABILITY
(NYHA)
x 2 (+vs-) Trr : p = NS "l~T:p = NS
1-1
+GXT
-GXT
Fig. 2. D i s t r i b u t i o n of the degree of cardiovascular disability in positive and negative responders to submaximal stress testing. Disability refers to the severity of angina.
324
TIMMIS ET AL
BASELINE X 2
possible in the basal state alone. The term sensitivity was defined as the quotient of true positive tests divided by the sum of true positive and false negative tests. Specificity was defined as the quotient of true negative tests divided by the sum of true negative and false positive tests. Both were multiplied by 100 and expressed as a percentage. The latter applies only to reviewed data and is not germane to our study. Differences in frequency of discrete variables were analyzed by the Chi square test. All other data were assessed by Student's T test.
ECG
( + v s - )
Normal: paNS Ant. Inj. : paNS Post. Inj. : p=N$
+GXT
ant. Ml: p:NS
Post, M I: p : N S Other*: P=NS
-GXT
RESULTS
*Abnorm=l
Conduction,
We c o n s e c u t i v e l y i d e n t i f i e d 28 p a t i e n t s w i t h critical LCA disease who previously h a d i n t e r p r e t a b l e GXTs. The vast m a j o r i t y (25) were males. All were s y m p t o m a t i c (angina), the m a j o r i t y s e v e r e l y so. T h u s , t h e r e were 11 p a t i e n t s in class II, 13 in class III and four in class IV (NYHA). In t h e t o t a l group t h e r e were 13 (46%) positive a n d 15 (54%) n e g a t i v e r e s p o n d e r s to GXT. T h e r e was no significant difference in t h e degree of disability b e t w e e n t h e two groups (Fig. 2). Electrocardiographic data. Abnormal resting ECGs w e r e observed in t e n p a t i e n t s in e a c h group (77% a n d 67% of positive a n d n e g a t i v e responders, respectively). I n j u r y or i n f a r c t i o n p a t t e r n s w e r e observed in t e n of 13 positives a n d e i g h t of 15 n e g a t i v e s . A n t e r i o r i n j u r y p a t t e r n s w e r e twice as f r e q u e n t in positive responders, a l t h o u g h a n t e r i o r infarction patt e r n s were e q u a l l y d i s t r i b u t e d (Fig. 3). T h e r e was one case w i t h s e v e r e left v e n t r i c u l a r h y p e r t r o p h y a n d a n o t h e r w i t h a n incomplete r i g h t b u n d l e b r a n c h b l o c k p a t t e r n in t h e
Hypertrophy
Fig. 3. Baseline electrocardiographic data in positive and negative responders to submaximal stress testing. Ant. inj. and AI = anterior injury. Post. inj. and PI = posterior injury. AMI & Ant. MI = anterior myocardial infarction. PMI & post MI = posterior myocardial infarction. See text.
TABLE II Anatomic Distribution of Left Coronary Artery Disease
CORONARY ARTERY
PATIENTS
LEFT MAIN 50% : PLUS 70% LAD ON LME 3 80-90%: 2 LEFT ANTERIOR DESCENDING (Pre-Perforator) LEFT MAIN EQUIVALENT
5
2 21
TOTAL
28
TABLE III Cardiodynamic Variables in Positive and Negative Responders to GXT
dp/dt (ram Hg/sec)
GXT +
Basal mean S.D. N.* t. P Exercise mean S.D. N.* t.
LVEDP (mm Hg) --
+
(dp/dt)/LVEDP (sec -1)
--
+
--
Work (kg. M/rain) +
--
1435 • 1565 330 550 13 13 0.7797 NS
13.1
13.4
129.7
135.4
11.0
5.7
5.7
63.6
87.0
5.7
13
12
1564 367 13
17.5
1826 526 10 1.4111
13
12 0.1490 NS
16.6 7.1 13 11 0:2938 6.6
13
0.1889 NS 103.7 48.9 13 1.0911
A Work A LVEDP +
--
11.0 6.2
11 0.3644 NS
134.7
13.4
13.3
1.5
86.4
5.4
6.3
4.3
10
13
11 0.0391
0.9 1.4
13
11 0.4174
LVEDP = Left ventricular end-diastolic pressure;S.D. = standard deviation; N. = number (variations measurable data; GXT = graded exercise test J. ELECTROCARDIOLOGY, VOL. 10, NO. 4, 1977
EXERCISE TESTING IN SEVERE LCAD
325
ASYNERGY ×2 (+vs-)
+GXT / , ~ A
t
: p=NS : p~NS : p~NS : p~NS
NORMAL
Hypokinesis Akynesis Dyskinesis ABNORMAL
:
p~NS
TOTAL
x 2 (+vs--) Hypokinesis Akynesis Dyskinesis
: p=NS : p~NS : pENS
ABNORMAL
:
p~NS
Fig. 4. Localization and severity of abnormal contracting segments in positive and negative responders to submaximal stress testing.
CONTRA CTILITY x 2 (+vs - ) N:p=NS ~, : p = N S
+GXT
~4':p=NS
-GXT
~ 4,: p =NS
,~&~
N
(s)
(6) Fig. 5. Comparison of myocardial contractility in positive and negative responders. Single, double and triple arrows refer to mild, moderate and severe depression of left ventricular contractility.
MAXIMUM HEART R A T E / G X T 109 8
t--'--I + G X T = 1 3 1 + _ 2 0 I
! -GXT=128
+-20
P =NS
I,- 6 Z
-I-
=144+_7
-GXT
(D U.I
=145+_13
+GXT
7
5
a. 4
I
90--110
111--130
131--50 HEART
151RATE
J. ELECTROCARDIOLOGY, VOL. 10, NO. 4, 1977
I
I
85% P M R
Fig. 6. Distribution of heart rates achieved during exercise in positive and negative responders to s u b m a x i m a l stress.
326
T I M M I S ET A L
GXT T I M E
MAXIMUM +GXT
I
I-GXT
I
- - 5 , 2 + 2 . 4
p=NS
+GXT-
792
+234
GXT
782
+
I
4~
4-
iiiiiiii
!
::::::::::::
:::.~:~:i
•: . : . : . . . •: . : . : . . .
.:.:,:.: .:.:.:.:
:i :i :i :';
:i:i:i:i
,~
::i:i:i.~ :.::: ••:.:.:.:
:i.~ .~:! .:.:.:.: .:.:.:.:
o. 2
ii!iiiiiiii
!iii!i!i
•• ,.,..:.. ......,...
.:.:.:.: ~.:.:.:
Z
3-
268
p=NS
/
b (/) I-. Z u.I k.-
GXT LOAD
-- 4.9+1.6
::i:~::::::
:i:i:i:i
2-
0 0
2.0
2.1 - 4 . 0
4.1
b.O
5.1-8.0
8.1
450
;:i::::::::
:i:i:i:i
::i:i:i:i . .
:": .:": . :"~: :...
.
.
.
.
600
.
.
.
.
750
MINUTES
LOAD
900
1050
(kpm)
Fig. 7. Comparison of the duration of exercise in positive and negative responders to submaximal stress.
Fig. 8. Comparison of maximal loads achieved in positive and negative responders to submaximal stress.
negative group. No such cases were observed in the positive groups. Ten patients previously had a double Master's two-step test. Only one of these was positive. The results of this and seven negative studies were concorda n t with subsequent GXTs. Anatomy. There were five patients with a 50% or greater reduction of LMC diameter. Three of these five had co-existent stenoses of the LME type or of the preperforator LAD exceeding 70% reduction in diameter. The remaining two had 80% and 90% reduction of LMC diameter, respectively. The former had co-existent extensive three vessel disease. The latter uncharacteristically demonstrated hemodynamically significant involvement of the LMC alone. There were 21 patients with LME. All had at least 90% narrowing of at least one of the two vessels and eight had total occlusion of at least one. Two patients had proximal LAD stenoses of 80% or more (Table 2). Left ventrieular function. There were no sign i f i c a n t differences b e t w e e n positive a n d negative GXT responders in any of the systolic or diastolic parameters of ventricular function either basally or in the fourth minute of isometric exercise (Table 3). There was a n exercise-associated reduction of dp/dt/ LVEDP in positives t h a t was not observed in negative responders. This suggested more severe myocardial impairment in the former. On the other hand, a 2 point muscle function curve (ALVW/ALVEDP) d i s c o r d a n t l y reflected a more favorable response of LV funct i o n to e x e r c i s e in p o s i t i v e r e s p o n d e r s . Asynergy was identified in seven of 13 (54%) positive and seven of 15 (47%) negative responders to GXT. Hypokinesis, akinesis, and dyskinesis were equally distributed between the two groups (Fig. 4). Generalized impair-
m e n t of myocardial c o n t r a c t i l i t y was also equally distributed (Fig. 5). Thus, seven of 13 (54%) positive responders a n d nine of 15 (60%) n e g a t i v e r e s p o n d e r s d e m o n s t r a t e d decreased contractility. GXT rate, d u r a t i o n and load. Significant group differences in exercise rates were not observed. Moreover, the n u m b e r achieving 85% PMR was equal in both groups. The group average rates achieved during exercise were v i r t u a l l y identical (Fig. 6). Exercise times of negative responders were slightly greater t h a n those of positives, but insignificantly so (Fig. 7). The distribution of work loads achieved in each group was heterogeneous. The mean values, however, were essentially the same for each group (Fig. 8). Drug therapy. A greater number of negative responders were m a i n t a i n e d on vasodilators and propranolol (Fig. 9). However, it is em-
DRUG
THERAPY X ~ (+ VS-)
Digitalis Diuretics Propranolol Vasodilators None
+GXT 8
I
I
--
GXT
m
0
/
/
/ J
o/"
: p=
NS
: p=
NS
: p=
NS
: p = NS : p =
NS
.oO"
Fig. 9. Comparison of drug therapy in positive and negative responders to submaximal stress. See text. J. ELECTROCARDIOLOGY, VOL. 10, NO. 4, 1977
EXERCISE TESTING IN SEVERE LCAD
phasized t h a t both were d i s c o n t i n u e d 12 hours prior to the performance of GXT. Propranolol was rarely utilized in doses exceeding 160 mg/day. The most striking individual drug difference was in the number of patients taking digitalis. The duration of abstinence from this drug would probably result in inc o n s e q u e n t i a l c h a n g e s in chronic s e r u m levels. However, digitalis was t a k e n by only one positive responder (his ST segment depression was 0.15 mV greater than that observed in baseline study, which revealed a pattern consistent with anterolateral subendocardial injury or drug effect). The configuration of ST segment depression in this case was of the classically horizontal configuration. Moreover, 85% P M R in this case was well exceeded (160/149). Collaterals. No significant difference between the two groups was observed. Seven of 13 (54%) with a positive GXT and eight of 15 (53%) with a negative response were observed to have collaterals. This involved the LAD in five of 13 positives and five of 15 negatives and the LCX in five of 13 positives and three of 15 negatives. Thus, collaterals failed to explain the high incidence of negative responders in this study.
DISCUSSION The importance of accurately defining the sensitivity of exercise testing is compounded by our failure to discriminate clinically high risk coronary artery disease, as represented by the subjects herein, from more benign disease which m a y p r e s e n t in clinically identical fashion. 1-3'5 This study and others confirm that there are appreciable n u m b e r s of pat i e n t s w i t h c o r o n a r y h e a r t d i s e a s e of documented severity in whom stress inducible ECG abnormalities are not observed in spite of relatively intense levels of exercise. 6 The importance of identifying coronary heart dise a s e c a n n o t be o v e r e m p h a s i z e d e v e n in asymptomatic patients. The marginal precision of exercise electrocardiography in this regard has been amply attested to in numerous reports, s'24-29,31-35 The c l a i m t h a t an ~'adequately" performed submaximal or maximal GXT, wherein 85% or more of P M R has been achieved, sensitively identified coronary heart disease, especially that subset studied in this report, 4 is questionable. Admittedly, if all the subjects in our series had been able to achieve this benchmark of exercise, our positive yield may well have been higher. Nevertheless, a false negative response was observed in 18% of our group achieving this target rate (5 of 28). It is additionally germane to recognize that many patients, by virtue of their infirmities, suboptimal fitness or motivation to cooperate, cannot be so tested. J. ELECTROCARDIOLOGY, VOL. 10, NO. 4, 1977
327
The majority of patients in this study with a negative GXT were able to achieve a heart rate in excess of ll0/min. Cohn et al, using a double Master's protocol, demonstrated that 86% of such patients with 75% or greater stenosis d e m o n s t r a t e d a positive response (equal or greater to 0.05 mV). 29 Because of the demonstrated relationship of heart rate and myocardial oxygen consumption, 3° one probably cannot explain the d i s p a r i t y b e t w e e n t h e i r s t u d y a n d o u r s on t h e b a s i s of methodologic differences relating to single versus multiple load testing. More likely the difference is explicable by the relationship between sensitivity and the accepted threshold of ST segment depression, as has been well demonstrated. 26'27'32-~5 As opposed to the initial study by Cohn et al, this same group subsequently reported only 68% sensitivity for one to three vessel coronary heart disease in normotensives with a normal baseline ECG. Thus, a double Master II step test was positive in 19 of their 28 patients achieving a heart rate of at least 110 beats/min. However, when all their patients with coronary heart disease w e r e c o n s i d e r e d , w h e t h e r or n o t t h e y achieved a rate of 110 or more, the exercise test was positive in only 32% (19 of 59 patients). 31 The clinical u s e f u l n e s s of r e d u c i n g the threshold depth of pathologic ST segment depression (to increase sensitivity) has been seriously questioned by Martin and M c C o n a h a y , 34 who d e m o n s t r a t e d an increased incidence of false positive responses from 11% at 0.1 mV to 22% at 0.075 mV and 43% at 0.05 mV. This would be particularly troublesome in women where the incidence of a positive GXT (Bruce protocol) is as high as 67% with normal coronaries (or less than 50% reduction of vessel diameter). 36 Confining precordial exploration to V4-Vs would unlikely yield more t h a n 10% false negatives. 37 One would expect t h a t t h e s e leads would detect ST segment and T wave changes with an anterolateral vector. Stressinduced ST-T shifts on this axis were anticipated in our subjects with LCA disease. This m a y be an erroneous assumption, however, in light of the inability of submaximal stress testing to accurately predict the location of coronary artery disease. 5 The question of medication influencing the results of this study is not an easy one to answer, although all drugs were discontinued 12 hours prior to the performance of GXT. Rep o r t s of p r o p r a n o l o l ' s effect on exercisei n d u c e d ST s e g m e n t c h a n g e s h a v e b e e n c o n t r o v e r s i a l . 3s'4° N e v e r t h e l e s s , t h e eardiodynamics and energetics of propranolol effects are such that one would expect a dissociation between the metabolic demands of the heart, 41 and therein a blunting effect on the
328
TIMMIS ET AL
diagnostic sensitivity of exercise electrocardiography. Residual effects of propranolol, however, should have negligibly influenced our study in light of its half life of three to six hours. 3s Moreover, there was no significant difference in the number of positive and negative responders on this drug. Three of the five positive responders n e a r l y achieved t h e i r target rate of 85% PMR and one of the five exceeded it. Similarly, two of the negative responders exceeded 85% P M R and a n o t h e r three developed more than 90% of their target heart rate. A sixth patient achieved 85% of his target rate. Thus, while the question of propranolol effect is bothersome, its chronotropic effect in negative responders was at most marginal. The duration of activity of virtually all vasodilators is such that their influence on the results of a GXT would be inconsequential with our protocol. Digitalis is troublesome from the standpoint of false positives but recent studies have indicated that even in "ischemic responders" to GXT a true positive can be identified by .2 mV depression over that noted in the baseline s t u d y s and false positive changes by their t e n d e n c y to r e s o l v e as 85% P M R is approached. 42 The t h r u s t of our report should not be influenced by digitalis since, although its effect would be clearly operative 12 to 24 hours after the last dose, it would unlikely produce false negative results. Potassiumdepleting agents which were rarely used by our negative responders are also more likely to cause false positive than negative results. 43 L i n h a r t and Turnoff, 35 in studying 50 patients with baseline ECG abnormalities who were also on drug therapy, reported 15 false negative responders to GXT of 33 with coronary heart disease, but identified no false n e g a t i v e s in p a t i e n t s on digitalis or propranolol and only one on a diuretic. 85 There were 9 of 26 false negatives in their study on various combinations of drugs as well as phenothiazines, quinidine and alpha methyldopa. 35 The association of myocardial infarction with false negative responses to GXT is well recognized. 14'35'4° We considered not only previous m y o c a r d i a l infarction b u t also t h e influence of injury patterns, myocardial contractility and asynergy on the response to GXT. For example, occult ST segment elevation arising from asynergic myocardial segments (a frequently recognized ST segment shift with dyskinesis) m a y have cancelled out ST segment depression that m a y otherwise have appeared in V4-V~. However, no significant difference in any of these variables between positive and negative responders was observed. The hemodynamic assessment of myocardial function also failed to identify differences between groups.
It has been contended that exercise testing with a variably loaded bicycle ergometer is inferior t o treadmill testing. However, only small differences in maximal cardiac output and oxygen consumption exist when bicycle and treadmill exercise are c o m p a r e d Y The decrease in oxygen u p t a k e elicited during cycling is small, usually about 10%, and not likely to be of clinical significance. 44 Indeed, bicycle e x e r c i s e h a s b e e n c l a i m e d to be perhaps more stressful than treadmill exertion because cycling evokes higher heart rates and blood pressure at a given workload. 37 On the other hand, ergometry produces a type of stress which for most patients is probably less facile than walking. This could conceivably account for p r e m a t u r e t e r m i n a t i o n of t h e GXT in some patients. It m u s t be emphasized that the clinician frequently cannot enjoy the academic luxury of prolonged therapeutic abstinence preparatory to GXT. He cannot exclude patients who a r e u n l i k e l y to a c h i e v e t h e o p t i m u m threshold of physical effort or study only those whose myocardial integrity is such that the sensitivity and specificity of GXT is unimpaired. Indeed, less t h a n 50% of 343 cases with two and three vessel disease in the Duke University study achieved 85% PMR. s It is unrealistic to withhold exercise testing from those in whom various conditions exist which m a y weigh unfavorably on the precision of this diagnostic study. It is within this context that the results of our s t u d y are reported. These are diagnostic shortcomings that characterize exercise electrocardiography as clinically utilized on a daily basis. With this perspective, one clearly recognizes that exercise testing falls short of the precision characteristic of hemodynamic, ventriculographic and coronary arteriographic studies, especially as these are performed with the excellence and safety characteristic of those institutions with adequate caseloads. In conclusion, our data underscores the too frequent inadequacy of exercise testing rather than its insensitivity, although the latter is also suboptimal in critical left coronary artery disease. REFERENCES 1. COHEN, M V AND GORLIN, R: Main left coronary artery disease; Clinical experience from 1964-1974. Circulation 52:275, 1975 2. DEMOTS, H, BONCHEK,L I, ROSCH,J, ANDERSON, R P, STARR,A ANDRAHIMTOOLA,S H: Left main coronary artery disease: Risks of angiography, importance of coexisting disease of other coronary arteries and effects of revascularization. Am J Cardiol 38:136, 1975 3. HARRELL, R R, OBERMAN, A, RUSSEL, R O, KOUCHOUKOS,N T, HOLT,J H ANDRACKLEY,C E: Left main coronary disease: Predictability J. ELECTROCARDIOLOGY, VOL. 10, NO. 4, 1977
EXERCISE TESTING IN SEVERE LCAD
4.
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6.
7. 8.
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15.
16. 17.
18. 19.
and s u r v i v a l in medical v e r s u s surgical groups. Circulation 50, Suppl III-35, 1974 CHEITLIN, M D, DAVIA, J E, DECASTRO, C M, BARROWE A AND ANDERSON,W T: Correlation of "critical" left coronary artery lesions with positive submaximal exercise tests in patients with chest pain. Am Heart J 89:305, 1975 KAPLAN, M A, HARRIS, C N, ARONOW, W S, PARKER, D P AND ELLESTAD,M H: Inability of the submaximal treadmill stress test to predict the location of coronary disease. Circulation 47:250, 1973 REDWOOD, D R AND EPSTEIN, S E: Uses and limitations of stress testing in the evaluation of ischemic heart disease. Circulation 46:1115, 1972 BRUCE,R A: Values and limitations of exercise electrocardiography. Circulation 50:1, 1974 BARTEL,A G, BEHAR,V S, PETER, R H, ORGAIN, E S AND KONG, Y: Graded exercise stress tests in angiographically documented coronary artery disease. Circulation 49:348, 1974 CROCHET,D, PETITCLERC,R AND CAMPEAU, L: Left main coronary artery stenosis: Significance of degree of obstruction, associated involvement of other coronary arteries and of status of left ventricular contraction as related to surgery (147 cases). Circulation 50:Suppl III-111, 1974 TALANO, J V, SCANLON, P J, KHAN, M, MEADOWS, W R, LOEB, H S, PIFARRE, R AND GUNNAR, R M: Influence of surgery on survival in 145 patients with left main coronary disease. Circulation 50:Suppl III-110, 1974 LIM, J S, PROUDFIT,W L AND SONES, F M, JR: Left m a i n coronary a r t e r i a l obstruction: Long-term follow-up of 141 nonsurgical cases. Am J Cardiol 36:131, 1975 BRYMER,J R, BUTER,T H, WALTON, J A, JR ANDWILLIS,P W, Ill: A natural history study of the prognostic role of coronary arteriography. Am Heart J 88:139, 1974 GOLDBARG,A N, MORAN,J R ANDRESNEKOV, L: Multistage electrocardiographic exercise tests: Principles and clinical application. Am J Cardiol 24:84, 1970 BORER, J S, BRENSIKE, J R, REDWOOD, D R, ITSCOITZ, S B, PASSAMANI, E R, STONE,N J, RICHARDSON, J M, LEVY,R I ANDEPSTEIN,S E: Limitations of the electrocardiographic response to exercise in predicting coronaryartery disease. New Engl J Med 293:367, 1975 SHEFFIELD,L T, HOLT, J H AND REEVES, T J: Exercise graded by heart rate in electrocardiographic testing for angina pectoris. Circulation 32:622, 1965 SHEFFIELD,L T, ROTTMAN,D AND REEVES T J: Submaximal exercise testing. J S C Med Assoc 65 (Suppl 1-18, 1969) MCHENRY, P L, PHILLIPS,J R AND KNOEBEL, S B: C o r r e l a t i o n of c o m p u t e r - q u a n t i t a t e d treadmill exercise electrocardiogram with arteriographic location of coronary artery disease. Am J Cardiol 30:747, 1972 LINHART,J W AND TURNOFF, H B: Pitfalls in diagnostic and functional evaluation using exercise testing. Chest 65:364, 1974 STUART,R J, JR AND ELLESTAD,M H: Upsloping S-T segments in stress testing: A 6 year
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20. 21.
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329
follow up: Correlation in 248 angiograms. Circulation 50: Suppl III-8, 1974 SONES, F M AND SHIREY, E K: Cine coronary arteriography. Mod Concepts Cardiovasc Dis 31:735, 1962 CHAITMAN, B R, DEMOTS, H, BRISTOW, J D, ROSCH, J AND RAHIMTOOLA,S H: Objective and subjective analysis of left ventricular angiograms. Circulation 52:420, 1975 HERMAN, M V, HEINLE, R A, KLEIN, M D AND GORLIN, R: Localized disorders in myocardial contraction: Asynergy and its role in congestive heart failure. New Engl J Med 277:222, 1967 HERMAN, M V AND GORLIN, R: Implications of left v e n t r i c u l a r a s y n e r g y . Am J Cardiol 23:538, 1969 DEMANY, M A, TAMBE, A AND ZIMMERMAN, H A: Correlation between coronary arteriography and the postexercise electrocardiogram. Am J Cardiol 19:526, 1967 HULTGREN, H, CALCIANO, A, PLATT, F AND ABRAMS, H: A clinical evaluation of coronary arteriography. Am J Med 42:228, 1967 MASON,R E, LIKAR,I, BIERN,R O ANDROSS,R S: Multiple-lead exercise electrocardiography: Experience in 107 normal subjects and 67 patients with angina pectoris, and comparison with coronary cinearteriography in 84 patients. Circulation 36:517, 1967 KASSEBAUM,D G, SUTHERLAND,K I ANDJUDKINS, M P: A comparison of hypoxemia and exercise electrocardiographyin coronary artery disease: Diagnostic precision of the methods correlated with coronary angiography. Am Heart J 75:759, 1968 ROITMAN,D, JONES, W B ANDSHEFFIELD,L T: Comparison of submaximal exerciseECG test with coronary cineangiogram. Ann Intern Med 72:641, 1970 COHN, P F, VOKONAS, P S, HERMAN, M V AND GORLIN R: Postexercise electrocardiogram in patients with abnormal resting electrocardiograms. Circulation 43:648, 1971 NELSON, R R, GOBEL, F L, JORGENSON, C R, WANG, K, WANG, Y AND TAYLOR, H L: Hemodynamic predictors of myocardial oxygen consumption during static and dynamic exercise. Circulation 50:1179, 1974 TEICHHOLZ,L E, COHN, P E AND GORLIN, R: The omnicardiogram: New approach to detection of heart disease in patients with a normal r e s t i n g e l e c t r o c a r d i o g r a m . Am J Cardiol 35:531, 1975 MCCONAHAY, D R, MCCALLISTER, B D AND SMITH, R E: Postexercise electrocardiography: Correlations with coronary arteriography and left ventricular hemodynamics. Am J Cardiol 28:1, 1971 AscooP, C A, SIMOONS, M L, EGMOND, W G AND BRUSCHKEA V G: Exercise test, history, and serum lipid levels in patients with chest pain and normal electrocardiogram at rest: Comparison to findings at coronary arteriography. Am Heart J 82:609, 1971 MARTIN,C M AND MCCONAHAY, D R: Maximal treadmill exercise electrocardiography: Correlations with coronary arteriography and cardiac hemodynamics. Circulation 46:956, 1972
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35. LINHART, J W AND TURNOFF, H B: Maximum treadmill exercise test in patients with abnormal control electrocardiogram. Circulation 49:667, 1974 36. SKETCH, M H, MOHIUDDIN, S M, LYNCH, J D, ZENCKA, A E AND RUNCO, V: Significant sex differences in the correlation of electrocardiographic exercise testing and coronary arteriograms. Am J Cardiol 36:169, 1975 37. ROSING, D R, REICHEK, N AND PERLOFF, J K: The exercise test as a diagnostic and therapeutic aid. Am Heart J 87:584, 1974 38. NIEW, A S AND SHAND, D G: Clinical pharmacology of propranolol. Circulation 52.'6, 1975 39. GIANELLY,R E, TREISTER, B L AND HARRISON, D C: The effect of propranolol on exerciseinduced ischemic S-T segment depression. Am J Cardiol 24:161, 1969 40. FURBERG, C: Adrenergic beta blockade and
41.
42.
43.
44.
electrocardiographic ST-T changes. Acta Med Scand Suppl 472:119, 1967 JORGENSEN,C R, WANG, K, WANG, Y, GOBEL, F L, NELSON, R R AND TAYLOR, H: Effect of propranolol on myocardial oxygen consumption and its hemodynamic correlates during upright exercise. Circulation 48:1173, 1973 ADAIR, R F, HELLERSTEIN, H K AND WHITE, L W: Digoxin induced exercise ECG changes in young men: ST-T walk through phenomenon above 80% max h e a r t rate. Circulation 46: Suppl II-11, 1972 KATTUS, A A: Exercise electrocardiography: Recognition of the ischemic response, false positive and negative patterns. Am J Cardiol 33:721, 1974 BLOMQVIST, C G: Use of exercise testing for diagnostic and functional evaluation of patients with arteriosclerotic heart disease. Circulation 44:1120, 1971
J. ELECTROCARDIOLOGY, VOL. 10, NO. 4, 1977
The Diagnostic Inadequacy of Exercise Testing in Critical Left Coronary Artery Disease BY GERALD
G. TIMMIS, M.D., F.A.C.C.,* SEYMOUR GORDON, RENATO G. RAMOS, M.D. AND V. GANGADHARAN,
SUMMARY
M.D., F.A.C.C.,* M.D.
dysfunction in either group. Five of 15 pat i e n t s with n e g a t i v e GXT (18% of e n t i r e group) achieved 85% or more PMR. Eleven of this group achieved a r a t e o f more t h a n 110/rain. Although the substantial incidence of false n e g a t i v e exercise tests in m u l t i p l e vessel coronary artery disease is well known, its frequency in "critical" LCA stenoses has not previously been emphasized.
Coronary cinearteriograms were consecutively reviewed to identify "critical" (75% or more stenosis) left coronary a r t e r y (LCA) disease in patients who had previously been electrocardiographically monitored during s u b m a x i m a l stress by e r g o m e t r y (GXT). There were 26 such patients with lesions of the left main coronary artery or its equivalent (proximal left anterior descending and left circumflex branches), and two of the left anterior descending proximal to the large septal perforator. A positive GXT was identified by ST depression of I mm or more persisting for 0.08 sec. Exercise was terminated when symptoms, exhaustion, a threatening response (4ram or more ST depression) or 85% predicted maximal rate (PMR) occurred. There were 13 (46%) positive and 15 (54%) negative GXTs. Three of the positive group and five negative responders had a previous myocardial infarction which was located anteriorly in two and three cases respectively (P = NS). Asynergy was observed in seven patients in each group and was anterior in location in four and six patients respectively (P = NS). There was no significant difference in the incidence of impaired contractility or in cardiodynamic evidence of left ventricular
There is general agreement t h a t severe left coronary artery disease, especially t h a t involving the left m a i n stem (LMC), frequently cannot be clinically predicted before arteriographic study. 1-3 On the other hand, electrocardiographic monitoring during and after exercise is reported to reliably identify critical or high risk LCA disease, defined as severe stenosis involving the LMC, the proximal left anterior descending coronary artery (LAD) or combined involvement of the LAD and circumflex coronary arteries (LCX) proxi m a l to t h e i r first major bifurcations. 1,4'5 Nevertheless, despite these claims, neither the sensitivity nor specificity of such testing exhibit a consistently acceptable correlation with the results of coronary arteriography 6 (Table I). In a review of 611 patients who were submaximally stress, 36% with anatomic evidence of coronary a r t e r y disease failed to achieve a pathologic threshold ST segment depression of 0.75 mm. ~'7 In a recent report of 88 patients with three vessel disease with 70% or greater stenosis who achieved 85% of predicted maximal rate (PMR), 24% had false negative treadmill tests. In the same study, 13% of 31 patients with lei~ m a i n coronary stenosis had false negative tests, s DeMots et al 2 recently reported more t h a n a 25% incidence of negative responders (five of nineteen)
From William Beaumont Hospital, Royal Oak, Michigan. *Directors, Division of Cardiovascular Diseases. Presented in part at the 48th Scientific Session of the American Heart Association, Nov. 17-20, 1975. Reprint requests to: Gerald C. Timmis, M.D., Division of Cardiovascular Diseases, William Beaumont Hospital, 3601 W. 13 Mile Rd., Royal Oak, MI 48072. 321
322
TIMMIS ET AL
TABLE I Review of Diagnostic Sensitivity and Specificity of Stress Testing in Coronary Heart Disease AUTHORS Demany et a124 Hulgren et a~25 Mason et a126
NUMBER OF PROTOCOL ST CRITERIA BASELINESENSITIVITY SPECIFICITY MINIMUM (mm) ECG (%) (%) STENOSIS PATIENTS TEST RATE (% diam) (% PMR) 55 84
Kassebaum et a127 Roitman et a128 Cohn et a129 McConahay et a132
Ascoop et a133 Martin et a134
Bartel et al 8 Linhart et a135 Teieholz et a131
DM DM & GXT GXT 90
GXT
85
100 110 100
GXT DM DM
90
96 91 100
DM OM GXT DM GXT
332 57 61 59
GXT GXT GXT DM
Max Max
85 Max Max
90.5 90.75 1.0 ~ 0.5 ~> 1.o ~ 1.0 ~ 0.5 ~ 0.5 90.75 1.0 ~ 1.0 90.5 ~ 1.0 90.75 0.5 ~ 1.0 ~ 1.0 ~ 1.0 0.5
43 63 Normal 88 84 78 Normal 74 71 73 Abnormal 86* No previous 63t MI 42 35 59 33 62~ 68 84 AMI (136/332) 65§ Normal 85 Abnormal 76 Normal 32¶
70 100 69 83 89 97 97 82 73 83
50 50 50
91 100 94 93 89 78 57
50 50 50 50 50
50 50 50 75 50
70
75
* 64%, 86%, 93%, per 1, 2, & 3 vessels t 37%, 67%, 76%, per 1, 2, & 3 vessels 35%, 67%, 86%, per I, 2, & 3 vessels § 40%, 66%, 76%, per 1, 2, & 3 vessels ¶ Normotensive patients 14%, 31%, 67%, per 1, 2, & 3 vessels PMR = predicted maximal rate; D.M. = double Masters' two-step test; GXT = graded exercise test; MI & AMI = myocardial myocardial infarction
to stress e l e c t r o c a r d i o g r a p h y (ergometer) who h a d a 50% or g r e a t e r r e d u c t i o n of left m a i n c o r o n a r y d i a m e t e r ( e q u i v a l e n t to a 75% reduction of lumen). The d e p e n d a b i l i t y of a d a t a base including history, physical e x a m i n a t i o n a n d stress elect r o c a r d i o g r a p h y in i d e n t i f y i n g critical LCA disease m u s t be specifically defined because of t h e p a r t i c u l a r l y u n f a v o r a b l e prognosis of such lesions. 1,2'9-12 O u r s t u d y looks f u r t h e r into t h e s e n s i t i v i t y of one of t h e s e p a r a m e t e r s , exercise e l e c t r o c a r d i o g r a p h y , in i d e n t i f y i n g this subset of patients.
MATERIALS AND METHODS Patients with a technically adequate submaximal graded exercise test (GXT) were included in
this study when subsequent arteriography documented high risk LCA disease. This was defined as 70% or greater narrowing of the LMC, the LAD, proximal to the first large septal perforator, or combined stenosis of 70% or greater of the LAD proximal to the second diagonal and LCX proximal to the obtuse marginal branch. Cheitlin et al 4 have referred to the latter as a left main equivalent lesion (LME). Patients having had previous cardiac surgery and other types of heart disease such as rheumatic valvular involvement, congential heart disease, and cardiomyopathies were excluded from this study. Chest pain syndromes were classified according to New York Heart Association criteria (Class I-IV). Pre-stress electrocardiograms (ECGs) were designated normal or abnormal depending on the presence or absence of repolarization (ST-T) changes, conduction system disease, hypertrophy, or evidence of previous myocardial infarction. J. ELECTROCARDIOLOGY, VOL. 10, NO. 4, 1977
E X E R C I S E T E S T I N G IN S E V E R E LCAD
ECG DATA EX,.ClSE
.EST A-ll~l
I
~:
_
. . . . .
___:
':" ' " " ! ~ ' NEGATIVE J: f~'~;, r~" ~i f~'~ (0.1mV.J;O O.O8sec) I[..
r.
' ii:,:: '
L ,.
I I I _
B C
NEGATIVE
0.1mV.. 0.08 sec
Slope ~ lmV/sec)
~![i:: i I I ~I I ! [ ::i ::~i !I:: !] !~ili!!!~i~i![iiiTil ! ]i !ii
POSITIVE ,,~
~ii I inii'ii'iii;iii"
~.-
~ i.i ]
(~O.JmV~O.08 sec~ ~,.~- ~.,from Baseline ST,
il; ill, i!i
POSITIVE (0"4mV'°O'O8sec)
iill =='~ E~
rl,,',l ,,,I ,,,I
~ i,l: i,:~]:: !1 ~
;.... ....
,:.~POSITIVE
~ :' !
{O.5mV.O.O8se¢)
~::::
Fig. 1. Examples of variable responses to submaximal stress testing.
Graded exercise tests (GXTs) were performed following a 12-hour fast (including medications) in a manner similar to that described by Goldbarg et al TMand Borer et aP 4 A~er a standard 12-lead ECG was obtained in the sitting position before and after 30 sec of hyperventilation, leads V4-V6 were oscilloscopically monitored and recorded at 1 min. intervals during and for at least 6 min. after exercise. The exercise lead system was that of the standard diagnostic configuration. The precordial leads referred to were of the routine unipolar variety. The position of the limb leads, however, was adjusted to reduce noise and artifact. Thus, the arm lead electrodes were placed over the acromion processes and the leg lead electrodes over the anterior extreme of the iliac crests. The subjects working on a variably loaded bicycle ergometer* were instructed to pedal at a frequency of 50 rpm/min. Following a warm-up at 150 kpm/mint for 1.5 min, men began cycling at a load of 600 kpm/min and women at 300 kpm/min, the load increasing thereafter at 3 min intervals, usually in 300 and 150 *Elema Schonander, Model #450, type AM 368. tkpm = kilopond-meter, the energy required to lift a 1 kilogram mass 1 meter against the gravitational force at sea level (approximately equivalent to 1/6 watt). J. ELECTROCARDIOLOGY, VOL. 10, NO. 4, 1977
323
kpm increments for men and women, respectively. Stress was terminated when symptoms, exhaustion, a threatening response (4mm+ ST segment depression), or 85% PMR 1~ were observed. There were no m a j o r a r r h y t h m i a s or h y p o t e n s i v e episodes during exercise. A response was interpreted as positive when 0.1 mV ST segment depression of horizontal or downsloping configuration was observed for at least 0.08 seconds beyond the j point. Upsloping ST segment depression was excluded unless depression of 0.1 mV at 0.08 sec beyond the j point was decreasing at a rate less than 1.0 mV/sec. (Figure 1). 1~19 A positive submaximal stress test may be identified by changes other than ST segment shifts. Thus, chronotropic incompetence, 19 changes in blood pressure, the appearance of gallop rhythms and murmurs as well as the development of arrhythmias may reflect ischemia, ls'19 Of all these indicators of a positive response, only ST segment shifts have been correlated with any statistical precision to angiographically documented coronary heart disease. Therefore, only this parameter will be further considered in this report. Coronary arteriography was performed using the Sones technique. 2° The left ventricle was studied angiographically in a 40 degree RAO projection recorded on 35 mm film at 60 frames/sec. Estimates were made of size, contractility and ejection fraction. These have been reported to correlate well with objective measurements thereof (R = 0.92). 21 Abnormal contracting segments were identified as described by Herman and Gorlin. 22'23 Left ventricular performance was assessed during cardiac catheterization by following parameters in the basal state and in the fourth minute of isometric stress:** dp/dt, LVEDP, the ratio of dp/dt and LVEDP (dp/dt/LVEDP): left ventricular minute work (LVW), and the ratio of the change in LVW to the change in LVEDP during exercise (ALVW/ALVEDP). No attempt was made to quantitatively equate isometric exercise in the catheter laboratory to the kinetic exercise ofergometry. The former was employed only to evaluate pump and muscle function more accurately than would be ** one-third of maximum handgrip capacity, Stoelting dynamometer.
DISABILITY
(NYHA)
x 2 (+vs-) Trr : p = NS "l~T:p = NS
1-1
+GXT
-GXT
Fig. 2. D i s t r i b u t i o n of the degree of cardiovascular disability in positive and negative responders to submaximal stress testing. Disability refers to the severity of angina.
324
TIMMIS ET AL
BASELINE X 2
possible in the basal state alone. The term sensitivity was defined as the quotient of true positive tests divided by the sum of true positive and false negative tests. Specificity was defined as the quotient of true negative tests divided by the sum of true negative and false positive tests. Both were multiplied by 100 and expressed as a percentage. The latter applies only to reviewed data and is not germane to our study. Differences in frequency of discrete variables were analyzed by the Chi square test. All other data were assessed by Student's T test.
ECG
( + v s - )
Normal: paNS Ant. Inj. : paNS Post. Inj. : p=N$
+GXT
ant. Ml: p:NS
Post, M I: p : N S Other*: P=NS
-GXT
RESULTS
*Abnorm=l
Conduction,
We c o n s e c u t i v e l y i d e n t i f i e d 28 p a t i e n t s w i t h critical LCA disease who previously h a d i n t e r p r e t a b l e GXTs. The vast m a j o r i t y (25) were males. All were s y m p t o m a t i c (angina), the m a j o r i t y s e v e r e l y so. T h u s , t h e r e were 11 p a t i e n t s in class II, 13 in class III and four in class IV (NYHA). In t h e t o t a l group t h e r e were 13 (46%) positive a n d 15 (54%) n e g a t i v e r e s p o n d e r s to GXT. T h e r e was no significant difference in t h e degree of disability b e t w e e n t h e two groups (Fig. 2). Electrocardiographic data. Abnormal resting ECGs w e r e observed in t e n p a t i e n t s in e a c h group (77% a n d 67% of positive a n d n e g a t i v e responders, respectively). I n j u r y or i n f a r c t i o n p a t t e r n s w e r e observed in t e n of 13 positives a n d e i g h t of 15 n e g a t i v e s . A n t e r i o r i n j u r y p a t t e r n s w e r e twice as f r e q u e n t in positive responders, a l t h o u g h a n t e r i o r infarction patt e r n s were e q u a l l y d i s t r i b u t e d (Fig. 3). T h e r e was one case w i t h s e v e r e left v e n t r i c u l a r h y p e r t r o p h y a n d a n o t h e r w i t h a n incomplete r i g h t b u n d l e b r a n c h b l o c k p a t t e r n in t h e
Hypertrophy
Fig. 3. Baseline electrocardiographic data in positive and negative responders to submaximal stress testing. Ant. inj. and AI = anterior injury. Post. inj. and PI = posterior injury. AMI & Ant. MI = anterior myocardial infarction. PMI & post MI = posterior myocardial infarction. See text.
TABLE II Anatomic Distribution of Left Coronary Artery Disease
CORONARY ARTERY
PATIENTS
LEFT MAIN 50% : PLUS 70% LAD ON LME 3 80-90%: 2 LEFT ANTERIOR DESCENDING (Pre-Perforator) LEFT MAIN EQUIVALENT
5
2 21
TOTAL
28
TABLE III Cardiodynamic Variables in Positive and Negative Responders to GXT
dp/dt (ram Hg/sec)
GXT +
Basal mean S.D. N.* t. P Exercise mean S.D. N.* t.
LVEDP (mm Hg) --
+
(dp/dt)/LVEDP (sec -1)
--
+
--
Work (kg. M/rain) +
--
1435 • 1565 330 550 13 13 0.7797 NS
13.1
13.4
129.7
135.4
11.0
5.7
5.7
63.6
87.0
5.7
13
12
1564 367 13
17.5
1826 526 10 1.4111
13
12 0.1490 NS
16.6 7.1 13 11 0:2938 6.6
13
0.1889 NS 103.7 48.9 13 1.0911
A Work A LVEDP +
--
11.0 6.2
11 0.3644 NS
134.7
13.4
13.3
1.5
86.4
5.4
6.3
4.3
10
13
11 0.0391
0.9 1.4
13
11 0.4174
LVEDP = Left ventricular end-diastolic pressure;S.D. = standard deviation; N. = number (variations measurable data; GXT = graded exercise test J. ELECTROCARDIOLOGY, VOL. 10, NO. 4, 1977
EXERCISE TESTING IN SEVERE LCAD
325
ASYNERGY ×2 (+vs-)
+GXT / , ~ A
t
: p=NS : p~NS : p~NS : p~NS
NORMAL
Hypokinesis Akynesis Dyskinesis ABNORMAL
:
p~NS
TOTAL
x 2 (+vs--) Hypokinesis Akynesis Dyskinesis
: p=NS : p~NS : pENS
ABNORMAL
:
p~NS
Fig. 4. Localization and severity of abnormal contracting segments in positive and negative responders to submaximal stress testing.
CONTRA CTILITY x 2 (+vs - ) N:p=NS ~, : p = N S
+GXT
~4':p=NS
-GXT
~ 4,: p =NS
,~&~
N
(s)
(6) Fig. 5. Comparison of myocardial contractility in positive and negative responders. Single, double and triple arrows refer to mild, moderate and severe depression of left ventricular contractility.
MAXIMUM HEART R A T E / G X T 109 8
t--'--I + G X T = 1 3 1 + _ 2 0 I
! -GXT=128
+-20
P =NS
I,- 6 Z
-I-
=144+_7
-GXT
(D U.I
=145+_13
+GXT
7
5
a. 4
I
90--110
111--130
131--50 HEART
151RATE
J. ELECTROCARDIOLOGY, VOL. 10, NO. 4, 1977
I
I
85% P M R
Fig. 6. Distribution of heart rates achieved during exercise in positive and negative responders to s u b m a x i m a l stress.
326
T I M M I S ET A L
GXT T I M E
MAXIMUM +GXT
I
I-GXT
I
- - 5 , 2 + 2 . 4
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+GXT-
792
+234
GXT
782
+
I
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4-
iiiiiiii
!
::::::::::::
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.:.:,:.: .:.:.:.:
:i :i :i :';
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,~
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o. 2
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.:.:.:.: ~.:.:.:
Z
3-
268
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/
b (/) I-. Z u.I k.-
GXT LOAD
-- 4.9+1.6
::i:~::::::
:i:i:i:i
2-
0 0
2.0
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.
.
.
.
600
.
.
.
.
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LOAD
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Fig. 7. Comparison of the duration of exercise in positive and negative responders to submaximal stress.
Fig. 8. Comparison of maximal loads achieved in positive and negative responders to submaximal stress.
negative group. No such cases were observed in the positive groups. Ten patients previously had a double Master's two-step test. Only one of these was positive. The results of this and seven negative studies were concorda n t with subsequent GXTs. Anatomy. There were five patients with a 50% or greater reduction of LMC diameter. Three of these five had co-existent stenoses of the LME type or of the preperforator LAD exceeding 70% reduction in diameter. The remaining two had 80% and 90% reduction of LMC diameter, respectively. The former had co-existent extensive three vessel disease. The latter uncharacteristically demonstrated hemodynamically significant involvement of the LMC alone. There were 21 patients with LME. All had at least 90% narrowing of at least one of the two vessels and eight had total occlusion of at least one. Two patients had proximal LAD stenoses of 80% or more (Table 2). Left ventrieular function. There were no sign i f i c a n t differences b e t w e e n positive a n d negative GXT responders in any of the systolic or diastolic parameters of ventricular function either basally or in the fourth minute of isometric exercise (Table 3). There was a n exercise-associated reduction of dp/dt/ LVEDP in positives t h a t was not observed in negative responders. This suggested more severe myocardial impairment in the former. On the other hand, a 2 point muscle function curve (ALVW/ALVEDP) d i s c o r d a n t l y reflected a more favorable response of LV funct i o n to e x e r c i s e in p o s i t i v e r e s p o n d e r s . Asynergy was identified in seven of 13 (54%) positive and seven of 15 (47%) negative responders to GXT. Hypokinesis, akinesis, and dyskinesis were equally distributed between the two groups (Fig. 4). Generalized impair-
m e n t of myocardial c o n t r a c t i l i t y was also equally distributed (Fig. 5). Thus, seven of 13 (54%) positive responders a n d nine of 15 (60%) n e g a t i v e r e s p o n d e r s d e m o n s t r a t e d decreased contractility. GXT rate, d u r a t i o n and load. Significant group differences in exercise rates were not observed. Moreover, the n u m b e r achieving 85% PMR was equal in both groups. The group average rates achieved during exercise were v i r t u a l l y identical (Fig. 6). Exercise times of negative responders were slightly greater t h a n those of positives, but insignificantly so (Fig. 7). The distribution of work loads achieved in each group was heterogeneous. The mean values, however, were essentially the same for each group (Fig. 8). Drug therapy. A greater number of negative responders were m a i n t a i n e d on vasodilators and propranolol (Fig. 9). However, it is em-
DRUG
THERAPY X ~ (+ VS-)
Digitalis Diuretics Propranolol Vasodilators None
+GXT 8
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--
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m
0
/
/
/ J
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: p=
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NS
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Fig. 9. Comparison of drug therapy in positive and negative responders to submaximal stress. See text. J. ELECTROCARDIOLOGY, VOL. 10, NO. 4, 1977
EXERCISE TESTING IN SEVERE LCAD
phasized t h a t both were d i s c o n t i n u e d 12 hours prior to the performance of GXT. Propranolol was rarely utilized in doses exceeding 160 mg/day. The most striking individual drug difference was in the number of patients taking digitalis. The duration of abstinence from this drug would probably result in inc o n s e q u e n t i a l c h a n g e s in chronic s e r u m levels. However, digitalis was t a k e n by only one positive responder (his ST segment depression was 0.15 mV greater than that observed in baseline study, which revealed a pattern consistent with anterolateral subendocardial injury or drug effect). The configuration of ST segment depression in this case was of the classically horizontal configuration. Moreover, 85% P M R in this case was well exceeded (160/149). Collaterals. No significant difference between the two groups was observed. Seven of 13 (54%) with a positive GXT and eight of 15 (53%) with a negative response were observed to have collaterals. This involved the LAD in five of 13 positives and five of 15 negatives and the LCX in five of 13 positives and three of 15 negatives. Thus, collaterals failed to explain the high incidence of negative responders in this study.
DISCUSSION The importance of accurately defining the sensitivity of exercise testing is compounded by our failure to discriminate clinically high risk coronary artery disease, as represented by the subjects herein, from more benign disease which m a y p r e s e n t in clinically identical fashion. 1-3'5 This study and others confirm that there are appreciable n u m b e r s of pat i e n t s w i t h c o r o n a r y h e a r t d i s e a s e of documented severity in whom stress inducible ECG abnormalities are not observed in spite of relatively intense levels of exercise. 6 The importance of identifying coronary heart dise a s e c a n n o t be o v e r e m p h a s i z e d e v e n in asymptomatic patients. The marginal precision of exercise electrocardiography in this regard has been amply attested to in numerous reports, s'24-29,31-35 The c l a i m t h a t an ~'adequately" performed submaximal or maximal GXT, wherein 85% or more of P M R has been achieved, sensitively identified coronary heart disease, especially that subset studied in this report, 4 is questionable. Admittedly, if all the subjects in our series had been able to achieve this benchmark of exercise, our positive yield may well have been higher. Nevertheless, a false negative response was observed in 18% of our group achieving this target rate (5 of 28). It is additionally germane to recognize that many patients, by virtue of their infirmities, suboptimal fitness or motivation to cooperate, cannot be so tested. J. ELECTROCARDIOLOGY, VOL. 10, NO. 4, 1977
327
The majority of patients in this study with a negative GXT were able to achieve a heart rate in excess of ll0/min. Cohn et al, using a double Master's protocol, demonstrated that 86% of such patients with 75% or greater stenosis d e m o n s t r a t e d a positive response (equal or greater to 0.05 mV). 29 Because of the demonstrated relationship of heart rate and myocardial oxygen consumption, 3° one probably cannot explain the d i s p a r i t y b e t w e e n t h e i r s t u d y a n d o u r s on t h e b a s i s of methodologic differences relating to single versus multiple load testing. More likely the difference is explicable by the relationship between sensitivity and the accepted threshold of ST segment depression, as has been well demonstrated. 26'27'32-~5 As opposed to the initial study by Cohn et al, this same group subsequently reported only 68% sensitivity for one to three vessel coronary heart disease in normotensives with a normal baseline ECG. Thus, a double Master II step test was positive in 19 of their 28 patients achieving a heart rate of at least 110 beats/min. However, when all their patients with coronary heart disease w e r e c o n s i d e r e d , w h e t h e r or n o t t h e y achieved a rate of 110 or more, the exercise test was positive in only 32% (19 of 59 patients). 31 The clinical u s e f u l n e s s of r e d u c i n g the threshold depth of pathologic ST segment depression (to increase sensitivity) has been seriously questioned by Martin and M c C o n a h a y , 34 who d e m o n s t r a t e d an increased incidence of false positive responses from 11% at 0.1 mV to 22% at 0.075 mV and 43% at 0.05 mV. This would be particularly troublesome in women where the incidence of a positive GXT (Bruce protocol) is as high as 67% with normal coronaries (or less than 50% reduction of vessel diameter). 36 Confining precordial exploration to V4-Vs would unlikely yield more t h a n 10% false negatives. 37 One would expect t h a t t h e s e leads would detect ST segment and T wave changes with an anterolateral vector. Stressinduced ST-T shifts on this axis were anticipated in our subjects with LCA disease. This m a y be an erroneous assumption, however, in light of the inability of submaximal stress testing to accurately predict the location of coronary artery disease. 5 The question of medication influencing the results of this study is not an easy one to answer, although all drugs were discontinued 12 hours prior to the performance of GXT. Rep o r t s of p r o p r a n o l o l ' s effect on exercisei n d u c e d ST s e g m e n t c h a n g e s h a v e b e e n c o n t r o v e r s i a l . 3s'4° N e v e r t h e l e s s , t h e eardiodynamics and energetics of propranolol effects are such that one would expect a dissociation between the metabolic demands of the heart, 41 and therein a blunting effect on the
328
TIMMIS ET AL
diagnostic sensitivity of exercise electrocardiography. Residual effects of propranolol, however, should have negligibly influenced our study in light of its half life of three to six hours. 3s Moreover, there was no significant difference in the number of positive and negative responders on this drug. Three of the five positive responders n e a r l y achieved t h e i r target rate of 85% PMR and one of the five exceeded it. Similarly, two of the negative responders exceeded 85% P M R and a n o t h e r three developed more than 90% of their target heart rate. A sixth patient achieved 85% of his target rate. Thus, while the question of propranolol effect is bothersome, its chronotropic effect in negative responders was at most marginal. The duration of activity of virtually all vasodilators is such that their influence on the results of a GXT would be inconsequential with our protocol. Digitalis is troublesome from the standpoint of false positives but recent studies have indicated that even in "ischemic responders" to GXT a true positive can be identified by .2 mV depression over that noted in the baseline s t u d y s and false positive changes by their t e n d e n c y to r e s o l v e as 85% P M R is approached. 42 The t h r u s t of our report should not be influenced by digitalis since, although its effect would be clearly operative 12 to 24 hours after the last dose, it would unlikely produce false negative results. Potassiumdepleting agents which were rarely used by our negative responders are also more likely to cause false positive than negative results. 43 L i n h a r t and Turnoff, 35 in studying 50 patients with baseline ECG abnormalities who were also on drug therapy, reported 15 false negative responders to GXT of 33 with coronary heart disease, but identified no false n e g a t i v e s in p a t i e n t s on digitalis or propranolol and only one on a diuretic. 85 There were 9 of 26 false negatives in their study on various combinations of drugs as well as phenothiazines, quinidine and alpha methyldopa. 35 The association of myocardial infarction with false negative responses to GXT is well recognized. 14'35'4° We considered not only previous m y o c a r d i a l infarction b u t also t h e influence of injury patterns, myocardial contractility and asynergy on the response to GXT. For example, occult ST segment elevation arising from asynergic myocardial segments (a frequently recognized ST segment shift with dyskinesis) m a y have cancelled out ST segment depression that m a y otherwise have appeared in V4-V~. However, no significant difference in any of these variables between positive and negative responders was observed. The hemodynamic assessment of myocardial function also failed to identify differences between groups.
It has been contended that exercise testing with a variably loaded bicycle ergometer is inferior t o treadmill testing. However, only small differences in maximal cardiac output and oxygen consumption exist when bicycle and treadmill exercise are c o m p a r e d Y The decrease in oxygen u p t a k e elicited during cycling is small, usually about 10%, and not likely to be of clinical significance. 44 Indeed, bicycle e x e r c i s e h a s b e e n c l a i m e d to be perhaps more stressful than treadmill exertion because cycling evokes higher heart rates and blood pressure at a given workload. 37 On the other hand, ergometry produces a type of stress which for most patients is probably less facile than walking. This could conceivably account for p r e m a t u r e t e r m i n a t i o n of t h e GXT in some patients. It m u s t be emphasized that the clinician frequently cannot enjoy the academic luxury of prolonged therapeutic abstinence preparatory to GXT. He cannot exclude patients who a r e u n l i k e l y to a c h i e v e t h e o p t i m u m threshold of physical effort or study only those whose myocardial integrity is such that the sensitivity and specificity of GXT is unimpaired. Indeed, less t h a n 50% of 343 cases with two and three vessel disease in the Duke University study achieved 85% PMR. s It is unrealistic to withhold exercise testing from those in whom various conditions exist which m a y weigh unfavorably on the precision of this diagnostic study. It is within this context that the results of our s t u d y are reported. These are diagnostic shortcomings that characterize exercise electrocardiography as clinically utilized on a daily basis. With this perspective, one clearly recognizes that exercise testing falls short of the precision characteristic of hemodynamic, ventriculographic and coronary arteriographic studies, especially as these are performed with the excellence and safety characteristic of those institutions with adequate caseloads. In conclusion, our data underscores the too frequent inadequacy of exercise testing rather than its insensitivity, although the latter is also suboptimal in critical left coronary artery disease. REFERENCES 1. COHEN, M V AND GORLIN, R: Main left coronary artery disease; Clinical experience from 1964-1974. Circulation 52:275, 1975 2. DEMOTS, H, BONCHEK,L I, ROSCH,J, ANDERSON, R P, STARR,A ANDRAHIMTOOLA,S H: Left main coronary artery disease: Risks of angiography, importance of coexisting disease of other coronary arteries and effects of revascularization. Am J Cardiol 38:136, 1975 3. HARRELL, R R, OBERMAN, A, RUSSEL, R O, KOUCHOUKOS,N T, HOLT,J H ANDRACKLEY,C E: Left main coronary disease: Predictability J. ELECTROCARDIOLOGY, VOL. 10, NO. 4, 1977
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