Stress testing: Clinical application and predictive capacity

Stress Testing: M.

Clinical H. Ellestad.

Application

Bernard

M. Cooke,

T

HIS article presents a conceptual review of the “state of the art” as pertains to the clinical application of exercise stress testing. We will provide data insofar as possible on the physiologic basis for the findings now utilized in the day-to-day application of this important diagnostic tool. It is of interest that a number of exercise tests designed to evaluate aerobic capacity were popular in the 1920s and 193Os, during which the heart rate and blood pressure were carefully recorded and compared to the normal response. After a number of workers demonstrated that ST segment changes correlated with ischemia, Master’ and those who followed his lead abandoned their interest in the total cardiovascular response to exercise and focused on the ischemic ST segment to the exclusion of all else. Only in the late 1950s following the lead of Bruce,’ were efforts again made to use the stress test as an attempt to evaluate as many exercise parameters as possible in order to derive an overall evaluation of the patient’s function. This treatise will emphasize this approach. It is our contention that the tendency to concentrate on ST changes to the exclusion of many other parameters now known to be of importance in the evaluation of patients during an exercise test should be abandoned. Many of the articles deprecating the value of exercise testing were written by authors with this type of tunnel vision.3 Much of the voluminous cardiovascular literature of the past few decades has been oriented towards assessment of cardiac function. Most of the early studies, though well conceived and well executed, involved making correlations and observations with the subjects at rest. It became obvious that such studies were insufficient in many instances, since the hemodynamics of exercise alter many parameters quite drastically. Consequently, observations made during rest were discovered to be not necessarily applicable during periods of physical activity. Despite certain limitations, exercise stress testing has become an invaluable tool for diagnosing the presence as well as extent of coronary artery disease. Although only electrocardiographic abberations have been extensively used

Progress

m Cardiovascular

Diseases,

Vol. XXI,

No. 6 (May/June),

Jr.,

and Predictive and

Capacity

Paul S. Greenberg

in the past, it has become apparent that assessment of hemodynamic and symptomatic data may be equally as useful. The currently accepted indications and contraindications for stress testing are presented in Tables 1 and 2, respectively. SAFETY

OF

STRESS

TESTING

Rochimis and Blackburn, in a 197 1 survey of 73 centers, noted a mortality rate of 1/ 10,000 or 0.01%. They also noted an 0.04% incidence of arrhythmias and prolonged chest pain necessitating hospital admission. Stuart and Ellestad in an unpublished study of 1400 centers found the death rate to be l/20,000 or 0.005%. The arrhythmia complication rate was 4.78/10,000, the infarction rate was 3.6/10,000, and the total complication rate was 8.86/10,000. We believe the improvement in the reported complication rates indicates an increase in the understanding of exercise physiology as well as added awareness of the potential dangers and the necessary safeguards. Thus, the risks appear to be acceptable and indicate that the stress test is a safe procedure. STRESS

TESTING

PROTOCOLS

The cardiovascular system may be stressed by use of either dynamic or isometric exercise. In addition, a combination of both types may be utilized. Because the work load is more easily measured with dynamic exercise, it is by far the most widely used method. Although both maximal and submaximal dynamic exercises are in use, the former has gained much popularity in recent years. Mitchell and Blomqvis? have shown that at maximal exercise, the measured oxygen consumption reaches a plateau and fails to increase despite

From the Section of Cardiology and Division oj Clinical Physiology, Memorial Hospital Medical Center. Long Beach, Cal$. Reprint requesrs should be addressed to M. H. Ellestad. M.D., Section of Cardiology and Divison of Clinical Physiology, Memorial Hospital Medical Center, 2801 Atlantic Avenue, Long Beach, Calij 90801. 0 1979 by Grune & Stratton, Inc.

1979

431

ELLESTAD,

432

Table

1.

1. Evaluation of coronary 2. Determination and aerobic 3. Determination postinfarction 4.

rehabilitation Evaluation

Indications

for Stress

of the patient with artery disease.

symptoms

of the patient’s

exercise

physical

patient

program

5. Evaluation of the asymptomatic with risk factors for coronary

work

capacity

patient disease.

of arrhythmias.

7. Evaluation arrhythmias,

of therapeutic drug regimens angina, or ischemia. patients

to aid in the

and to detect

6. Evaluation

8. To stimulate modification.

suggestive

capacity. of a patient’s physical IimitatIons and as an aid in the design of a exercise program. of the post by-pass

rehabilitation ischemia.

Testing

to conform

residual

over age 40

for

to risk-factor

continued exercise. Consequently, the use of maximal exercise tests would be expected to provide more accurate data on physical performance capacity. Perhaps equally as important. there would be fewer false negative results. There are many multistage tests presently in use that are carried to a symptom-limited or maximal workload level. Each has both advantages and disadvantages depending on the type of patient being tested. Whereas a protocol with a very gradual increase in workload may be appropriate for a young well conditioned patient, it may be unsuitable for an elderly patient whose musculoskeletal system becomes fatigued before he reaches his maximal O2 consumption. It is apparent then that in order to obtain the maximal amount of information from the stress test, the protocol may need to be altered somewhat to fit the clinical situation. Treadmill protocols, utilizing progressive and continuous increases in workload, are currently Table

2.

Contraindications

to Stress

Tasting

70% symptom-limited test prior 2. Acute myocarditis or pericarditis.

to discharge.

3. 4. 5.

Symptomatology suggestive of unstable Rapid atrial arrhythmias. Advanced atrioventricular block (second

6. 7.

degree). Uncompensated congestive heart fallwe. Acute noncardiac illnesses (e.g.. hyperthyroidism. infection, pulmonary disease).

8. 9.

Aortic stenosis (relative contraindication). Known left main coronary artery disease contraindication).

angma. or third

(relative

AND

GREENBERG

the most popular in the United States. Although there are many types currently in use, each one allows the patient to arrive at about the same place in terms of work performed and heart rate response’ (Fig. I). Regardless of the type of protocol selected, data must be available on the normal heart rate responses so that deviations from the expected response can be appreciated. Noting such deviations may permit the physician to assess the degree of physical conditioning, variations in cardiac performance as might result from a decreased stroke volume, or the existence of autonomic abnormalities that reportedly may occur in coronary patients.’ The bicycle stress test, which is very popular in Europe, has the advantage of allowing one to obtain more stable ECGs and more accurate blood pressure measurements. Whereas the treadmill test is observer controlled, the bicycle stress test allows the subject to regulate the workload. Therefore, the treadmill may yield more reproducible results. In addition, the maximal oxygen consumption is about 10% greater with the treadmill as compared to bicycle stress testing.’ SENSITIVITY,

SPECIFICITY,

PREDICTIVE

VALUE

Sensitivity, specificity, and predictive value are important terms to understand if one is to have a clear picture of the value of stress testing for the detection of coronary disease. An understanding of the limitations and factors that influence these variables is also important. Sensitivity is the ability of the stress test to correctly identify patients with disease from a group of patients known to have disease. It tells how reliable the test is in identifying disease. Sensitivity

1. Acute myocardial infarction. However, many centers are routinely subjecting patients to a submaximal

COOKE,

=

True positives True positives + False negatives

Specificity is the ability of the stress test to correctly identify those patients who are “normal” or who do not have significant coronary disease. It tells how reliable a negative test is in identifying the absence of disease. Specificity is defined by the formula: True negatives Specificity = True negatives + False positives Predictability of a test is the likelihood of disease being present if the test is positive. It is defined as:

STRESS

TESTING:

APPLICATION

AND

PREDICTIVE

CAPACITY

433

50 45; 40E ,” 35\ E - 300” ’

66 -0 BALKE -*BRUCE ---0 ELLESTAD ---. ASTRAND

2520-

0

3

6

I6 TE:T

D”Rd:IDN

&tW

Predictability =

True positives True positives -t False positives

Rifkin and Hood’ showed by application of the Bayesian theorem of analysis to stress testing that the predictive value varies with the prevalence of disease in the population being studied. The greater the number of patients with coronary disease in the population, the greater the predictive value of the stress test. Others have also made this observation.“3’0,” Zohman and Kattus” and Fortuin and Weiss’ have noted that sensitivity and specificity will vary as the population composition is varied. Populations where there are a large number of women or any population group with a low risk of disease,” have a large number of false positive responses and reduced predictive value and specificity for the stress test.*-” ST segment depression is not specific for coronary disease, since there are many causes for these changes. Many false positive responses are due to a myocardial abnormality of an apparent nonischemic variety. Ischemia can result from causes other than coronary atherosclerotic disease, such as anemia, aortic stenosis, coronary artery spasm, severe hypertension,‘* left ventricular hypertrophy,” and stress tests involving a sudden strenuous work load.20 ST segment depression in left ventricular hypertrophy, hypertension, and patients subjected to sudden vigorous exercise is probably caused by an unfavorable change in the subendocardial supply-demand ratio. Metabolic conditions can also result in false

Fig. 1. Comparison of the maximal 0, consumption and metabolic equivalent of four commonly used stress test protocols. All essentially have the same end point. (Reproduced by permission of American Heart Journal 92:39-46. 1976.)

positive responses. Glucose ingestion has been shown by Riley et al. to be such a factor.” Hypokalemia is also an occasional cause.“’ There are a large number of drugs that can produce ST segment depression,‘3m’5 such as diuretics, phenothiazines, lithium, antihypertensives, and digitalis. Resting ST segment abnormalities can be a problem. Linhart and Turnoff” noted that when the resting tracing was abnormal and the patient was not on a medication known 1.0 influence repolarization, ST depression of 1 mm more than the baseline depression correlated well with the presence of disease. Stress testing in patients with resting abnormalities when the patient is taking cardiac medication was of no value. Kansal et al. found the sensitivity for I mm of added ST depression in patients with baseline resting ST depression to be 92% while the specificity was 75%.” Conduction defects in the resting tracing can cause ST segment changes during stress testing. Vasoregulatory asthenia further complicates matters. The ST changes in this syndrome are thought to be due to increased sympathetic tone.2,4 Cardiomyopathies, the click murmur syndrome, valvular heart disease, asymmetric septal hypertrophy, and syndrome X can all cause a false positive response. Eliminating those patients suspected of having any of the above factors by clinical suspicion can enhance the specificity by reducing the false positive ST responses. Sensitivity is influenced by a variety of factors. Cummings” showed that the maximal stress test is more sensitive than the submaximal

ELLESTAD,

434

test carried to 85% of the maximal predicted heart rate. The number and position of leads used is also an important factor. Chaitman et a1.19showed that using 1 I leads increased sensitivity to 76%, while sensitivity for a single CM, lead was 68%. The difference in specificity was only 6%. Chaitman found the optimum system to be 14 leads, including CMS, CC,, CL, and the standard ECG leads excluding AVR. The sensitivity for this system was 88%) with a specificity of 82%. For practical purposes, a 3-lead system employing CC,, CM,, and CL is adequate with a sensitivity of 79% and a specificity of 82%‘. Chaitman found CM, and CC, to be the most sensitive single leads. Liberalizing the criteria for a positive test will enhance sensitivity but it will also reduce specificity. McConahay et al.“’ showed that using $ mm versus I mm of ST depression produced more false positive responses, while increasing sensitivity. False negative tests can also be associated with nitrates or propranolol therapy and prior infarction.‘” Nitrates and propranolol obscure the ischemic response. Infarction may shift the ST vector or an aneurysm may mask it with its ST elevation. Sensitivity can be enhanced by eliminating certain recognizable causes of false negative responses. ST segment depression used as the sole parameter for predicting the presence or absence of coronary disease is an oversimplification and will result in false responses. The use of additional parameters, such as the occurrence of typical angina1 pain during the stress test, blood pressure and heart rate response, age, sex, and achieved workload enables one to increase the sensitivity and specificity of the stress test. These factors will be discussed in detail below. Ellestad et al.,” using a multivariate analysis, were able to reduce the false positive ST responses by 65%) by the use of other variables with ST segment change. It is possible that at some time in the future. sensitivity and specificity will be optimized by using some formulation that gives appropriate weight to all the influencing variables listed above. Table 3 lists the sensitivity, specificity, and predictive values for a series of 15 studies based on ST segment depression alone.“,25,3’ 43 The coronary angiogram was the standard used to determine the presence or absence of coronary

Table

3.

Correlation

COOKE,

of Exercise

AND

ECG With

GREENBERG

Coronary

Arteriography

-

Sensltlvlty 1%) ___~

Ritchle

45

Lewis

50

Bailey

(Many

SVD)

Speclflclty (%I

Predlctlve Value (%I

-

38

McGowan

80

Martin

62

50 89

91

Goldschlager

64

93

95

Froellcher

61 65

92 92

95

79

64

Mason

78

89

0

Kasserbaum

54

97

96

Roltman

80

88

92

Ascoop

59

94

89

K&man

62

89

91

Froellcher

77

Bartel Botwnick

et al.

Average R Wave Average In the

63.6%

85%

90%

68%

84%

84%

-

depresslon

sensltwty compared

literature.

Note

speclficlty. to R-wave the

72

and change

slmllar!ty

predtctlve for a series

in values

value

for

ST

of 15 studies

for ST and

R-wave

change.

disease. It should be noted that these studies were carried out at centers where the prevalence of disease is high since patients are referred for evaluation. The average sensitivity is 64% average specificity 85%. and average predictive value 90%. If it were possible to do angiograms on large numbers of asymptomatic patients, the sensitivity would definitely be reduced. CORRELATES

OF

ST

SEGMENT

DEPRESSION

Inadequate myocardial oxygenation may be manifested in a variety of ways. As previously noted, these manifestations may be conveniently grouped into three categories electrocardiographic, hemodynamic, and symptomatic. Hemodynamic aberrations include inappropriate blood pressure or heart rate responses to exercise, while symptomatic manifestations include most notably chest pain. The most commonly used criteria for determining the presence of myocardial hypoxia involve electrocardiographic changes. Whereas the onset of arrhythmias or conduction defects with exercise are undoubtedly of diagnostic and prognostic significance, ST segment depression is probably more reliable as a sign of myocardial hypoxia. Although the exact sequence of events resulting in ST depression is still problematical in

STRESS

TESTING:

APPLICATION

AND

PREDICTIVE

CAPACITY

some areas, the following explanation is currently well accepted. With decreasing coronary blood flow (CBF) and OZ availability, the affected myocardial cells begin to “leak” potassium, resulting in increased potassium ion (K +) extracellularly and decreased K + intracellularly. Since the electrical potential of the cell is proportional to the ratio of K+ inside to K-t outside the cell, these cells become partially depolarized during diastole. Accumulation of K+ outside the cell is also known to cause a shortening of the action potential relative to cells with a normal extracellular Kt concentration. These two situations-the diastolic depolarization and the shortening of the action potential of ischemic cells-produce a potential difference between these cells and surrounding normally oxygenated cells. Normally, all myocardial cells are essentially at the same level of electrical depolarization during diastole and thus no potential difference exists across the ventricular wall. In the abnormal situation discussed above, a potential difference does exist, and the flow of current resulting would be expected to cause ST segment deflections. The very nature of the coronary circulation. along with the greater wall tension of the inner myocardial layers, render these deeper layers (especially the subendocardium) more susceptible to ischemia whenever the supplydemand balance is altered. Consequently, the earliest ischemia-produced abnormalities in potassium ion flux are to be noted in the deeper myocardial layers or subendocardium. The resultant potential difference produces a diastolic current from endocardium to epicardium, displacing the T-Q segment upward, which on conventional ECG is recognizable and manifested as ST segment depression (Fig. 2). A frequently overlooked consequence of myocardial hypoxia is its effect on ventricular compliance. The sequence of events can probably be viewed as follows. The reduction in available oxygen, most severe in the subendocardial regions, leads to a reduction in high-energy phosphates. There is a consequent impairment of the Ca+ + pump, which requires energy in order to return this ion to the sarcoplasmic reticulum. With the resultant accumulation of calcium ion intracellularly, there is incomplete relaxation of the sarcomeres.This stiffening, termed reduced

E

Fig. 2. Depicted is the cause of ST segment shifts with ischemia. Subendocerdial ischemia resulting from stress gives en upward shift of the TQ segment or baseline. which on conventional ECG is seen as ST depression.

compliance, causes an elevation in the ventricular end-diastolic pressure.The elevated diastolic cavitary pressure results in an even greater degree of wall tension and transmural pressure further complicating an already perilous situation. CRITERIA FOR ASSESSMENT STRESS TEST RESULTS

OF

Electrocardiographic

Magnitude of ST Segment Depression The specificity of stress testing can be improved by employing more stringent standards for ST depression (e.g., using 2 mm depression rather than I mm,) since false positive results are significantly decreased. Recently, a correlation between the degree of ST depression and extent of disease has been suggested. A long-term follow-up by Robb and Marks,44 who analyzed the results of Master’s double two-step stresstests in 2224 male insurance applicants, revealed that mortality increased as the amount of ST depressioninduced by stress increased. They concluded that “the severity of CAD and the prognosis are closely related to the amount of ischemic ST segment depression induced by exercise.” Ellestad and

ELLESTAD.

436

COOKE.

Time of Onset of ST Depression More severe coronary obstructions would be expected to produce myocardial ischemia at an earlier stage of exercise or lower workload. Therefore, the onset of ST depression would occur earlier than would be the case with less significant obstruction. Indeed, both epidemiologic and angiographic correlative studies tend to confirm this. Ellestad and Wan’ found an increased incidence of future coronary events (progression of angina, myocardial infarction, and death) in subjects with earlier onset of ST depression on the treadmill. A follow-up of 2700 subjects after maximal treadmill stress testing reveals an incidence of combined coronary events of 15%) per year in those who developed ST depression by 3 min. This was in marked contrast to the 8% and 4% annual incidence observed in those whose ST depression did not develop until 5 and 7 mitt, respectively. Angiographic data that tend to support this finding have been provided by Goldschlager and Associates? They evaluated 269 patients with

60

Fig.

% EVENTS

nary

40

2690 NEG.

937

319

3 MIN.

60

EX.

345

GREENBERG

finding of markedly depressed ST segments in patients with left main disease. It is reasonable to assume that the magnitude of ST segment depression correlates with the amount of myocardium involved and the degree to which this myocardium is made ischemic by exercise. The excellent correlation between arteriographically extensive and/or “critically” located lesions and marked ST depression lend support lo such an assumption.

Wan,’ who also conducted an epidemiologic study, originally failed to demonstrate an increased risk with greater ST depression. However, upon reevaluation of their data, it was found that if the depression was analyzed at lower levels of exercise (or work loads), an increased risk could be demonstrated” (Fig. 3). Studies comparing the magnitude of ST depression with the extent of disease as demonstrated by coronary angiography have also been conducted. These studies, like the epidemiologic ones cited above, suggest a positive correlation between extensiveness of CAD and degree of exercise-induced ST depression.25,“,45%46Typical of the studies was the investigation conducted by Goldman et al.,45 which showed a 69% incidence of 3-vessel disease in patients who exhibited 3 mm or more ST depression compared with only 33% and 13% showing l-2.9 mm and normal responses, respectively. It is well known that proximal lesions of the left anterior descending (LAD) coronary artery or left main vessel have a particularly high risk for future coronary events.‘5.47 Therefore, any consideration of severity of coronary disease must include a discussion of location as well as extent of involvement. In the Goldman study,J5 92% of the patients with 3 mm or more ST depression had proximal LAD lesions, whereas 67% with less than 3 mm depression had such lesions. Bartel et al.” and Cheitlin and associates4’ have demonstrated a high incidence of left main and left main equivalent lesions in patients with markedly depressed ST segments. Kleiner et al.49 confirmed this

N=

AND

409 5 MIN.

69 EX.

221

286

7 MIN.

EX.

3. events

Incidence correlated

of

corowith

the magnitude of ST depression and the timed onset of ST depression. The earlier ST depression occurs, or the greater the magnitude of depression, the higher the incidence of coronary events. Marked ST depression during the first 3 min of exercise causes a high incidence of future events.

STRESS

TESTING:

APPLICATION

AND

PREDICTIVE

CAPACITY

angiographically proven CAD and 141 normal subjects, all of whom had stress tests performed. Of 59 patients developing ischemic changes during the initial 3 min of exercise, 13% had either normal coronary arteries or single-vessel disease. The remainder had either double- or triple-vessel disease with the majority (33 of 59, 56%) having the latter. These authors hasten to point out, however, that many of their patients with double- or triple-vessel disease exercised well past 3 or even 6 min before ischemic changes occurred. Thus, the absence of ST depression during the earlier stages of exercise does not rule out the presence of angiographitally extensive disease. Duration

of ST Depression

The view is widespread that the duration of ST segment depression correlates in some manner with the severity of coronary disease. Goldschlager et al. found that persistenceof ST segment depressionpast 8 min into the recovery period was associated with double- or triplevessel disease in 90% of patients with 64% having the latter. This prolonged depressionwas not predictive of location, with the possible exception of left main disease, where 8 of 15 such patients had ST segmentdepressionbeyond 8 min of recovery. These authors emphasize the following two points. First, whereas persistent depression suggestedmore severe disease,the converse was not the case. In other words, rapid normalization of ischemic ST segmentswas also seen in severe double- or triple-vessel disease.This was true in 58% of the cases.Secondly, definite and uniform criteria for terminating the test must be employed if one is to properly use and interpret these findings of persistent ST depression. Having the patient exercise beyond the intial evidence of ischemia would be expected to prolong the duration of depressedST segments, even in the presence of lesser extents of CAD, and thus negate its predictive value. The criterion used in this study for terminating the test was the appearance of l-2 mm ST depressionof a horizontal or down-sloping configuration. ST Segment

Conjiguration

The electrocardiographic pattern or type of ST segment configuration exhibited with stress

437

testing is of considerable importance in predicting both presence and severity of disease. A recent study by Goldschlager and colleagues’b demonstrated the relationship between ST segment configuration and predictive value. Down-sloping ST segments were found to be highly specific for coronary disease, with only one false positive result in 123 angiographically proven cases. The finding of horizontal ST segmentswas associatedwith a 15% incidence of false positives (9 of 60), whereas the slowly upsloping patterns had a 32% incidence of false positives (I 5 of 47). The severity of CAD also bears a relationship to the ST segment configuration induced with exercise. Over a decade ago, Robb and Marksd4 recognized the higher mortality and worse prognosis in cases with down-sloping ST segment depression as compared with the horizontal pattern. They postulated the former to be due to transmural ischemia, whereas the latter was felt to be secondary to subendocardial involvement only. Although this hypothesis remains unproven, the increased mortality has been confirmed in later studies.36,‘0 Goldschlager et al.3b found the down-sloping responseto be indicative of the greatest severity of disease in terms of the number of diseased vessels.In addition, those patients with left main diseasewere most likely to exhibit this response. They felt the down-sloping pattern was suggestive of profound myocardial ischemia and that this might explain the higher mortality and morbidity found in the longitudinal study of Robb and Marks.““ It is generally agreed that junctional depression with a rapidly upsloping ST segment is a normal phenomenon, although even this has recently been questioned. There is much less agreement concerning the significance of the slowly up-sloping ST segment. The most frequently cited study supporting a role for upsloping ST segmentsin predicting the presence of CAD was conducted by Stuart and Ellestad.‘” These authors emphasized the importance of distinguishing true up-sloping from J-point depression,since the prognostic implications are quite different. A true up-sloping pattern was defined as one in which the ST segment was depressedat least 2 mm below the baseline at 0.08 set from the J point (Fig. 4). Using this

438

ELLESTAD.

Fig. 4. Example of the slow up-sloping type of ST depression. Significant up-sloping depression is 2 m m at 0.08 set from the J-point. lReproduced by permission of

American

Journalof

Cardiology

37:19-22.

1976.)

criterion, they found essentially the same incidence of major two- or three-vessel disease in subjects with the up-sloping pattern as in those with horizontal ST segments. There was also a similar annual incidence of coronary events (death, myocardial infarction, or onset or progression of angina pectoris) among both groups of patients. However, Goldschlager and colleagues’h caution against interpreting slowly up-sloping segments as being indicative of myocardial ischemia, since they found a 32% false positive incidence on correlation with angiographic data. They felt that this pattern is “best considered an ‘equivocal’ response-neither diagnostic of ischemia nor necessarily normal.” They suggest placing its interpretation in context with clinical data in order to maximize its usefulness in exercise stress testing.

ST Segment

Elevation

Occasionally, ST segment elevation rather than ST depressionis induced by exercise. Kroop et al.” noted this phenomenon in 1949 and suggestedthat it was an unusual manifestation of myocardial ischemia. Numerous papers later appeared espousingthe same view.‘2,4h,47 One of the earlier investigations into the significance of exercise-induced ST segment elevation was conducted by Fortuin and Freisinger.” It was

COOKE,

AND

GREENBERG

concluded that this change was produced by severe myocardial ischemia possibly involving the full thickness of the myocardium, inasmuch as 1I of the 12 patients studied had total or near total occlusion of a major coronary artery by angiography. Of note was the fact that 7 of the 12 patients had a history of previous myocardial infarction. They cited work done by Ekmekci and colleague? and used myocardial surface electrodes to show that ST segment elevation was recorded from those electrodes most centrally placed in an area of ischemia, while depression was recorded by the more peripherally located electrodes. Moreover. when the central area was rendered less ischemic, ST segment depression replaced the ST elevation. This and other similar experimental studies5h.57 support the idea that ST elevation represents a more severedegree of myocardial ischemia than doesST depression. Bartel et al.” found that patients with predominantly ST segment elevation were unlikely to have normal coronary artcriograms and consisted mainly of patients with diseaseof three coronary vessels.Although they concluded that there was no association between exerciseinduced ST elevation and the presence of left ventricular (1.V) aneurysms, such an association has been noted in other studies.“‘~” Excrciseinduced ST elevation was seen in 14 of 29 patients (48%) with angiographically dcmonstrated LV aneurysm by Manvi and Ellestad.‘n Elevation in the absence of LV aneurysm was not observed in any of their 243 consecutively studied cases. Eight hundred and forty consecutive treadmill tests were reviewed by Chahine and colleagues” who noted exercise-induced ST elevation in 29 (3.5%). Twenty-five of the 29 (85%) exhibited evidence of previous anterior myocardial infarction on the resting EKG. Angiography revealed critical LAD lesionsin 19 (90%) and 1-V aneurysms in 18 (855%).Consequently, they felt that elevation suggestedthe presenceof severe CAD most commonly with associated LV aneurysm. Since the occurrence of angina pectoris was significantly lessfrequent in those patients with elevation as compared to those with depression, they suggestedthe elevation “might relate more to the presenceof abnormal wall motion rather than to myocardial ischemia per se.“

STRESS

TESTING:

Exercise-Induced

APPLICATION

AND

Ventricular

PREDICTIVE

CAPACITY

Arrhythmias

There has been much disagreement over the clinical significance of exercise-induced premature ventricular depolarization. The importance of ventricular arrhythmias appearing during exercise was assessed by Goldschlager and associates’” who concluded that they indicated subclinical ischemia, signifying a more advanced degree of coronary and left ventricular disease. These investigators felt that severe exerciseinduced ventricular arrhythmias, although not pathonomic, are strongly suggestive of the presence of severe CAD. In a later study by Helfant and co-workershI the presence of exercise-related ectopic ventricular depolarizations was correlated with both exercise-induced ST segment depression and coronary angiography in 60 patients being evaluated for chest pain. A very high incidence of severe ST segment depression with exercise (~2 mm ST depression) was noted in patients with CAD and both ectopic ventricular depolarizations that increased or were precipitated by exercise. Eighteen of the 22 coronary patients with ectopic ventricular depolarization that increased or were precipitated by exercise had extensive disease with significant 2- or 3-vessel stenosis. The patients who had arrhythmias and no ST depression were more likely to be normal or to have a cardiomyopathy without significant coronary obstruction. A recently published epidemiologic study by Udall and Ellestadh’ lends credence to the view that exercise-induced premature ventricular contractions (PVCs) have prognostic significance. The annual incidence of new coronary events (myocardial infarction, angina. cardiac death) was assessed during a 5-yr follow-up of patients referred for treadmill stress testing for evaluation of known or suspected cardiovascular disease. The annual incidence of new coronary events was 1.7% in those without PVCs or ischemic ST changes, 6.4% in those with PVCs alone, 9.5% in patients with only ischemic ST changes, and 1 1.4% in those exhibiting both PVCs and ischemic ST changes with exercise. The authors caution, however, that 83% of their study group had known or suspected heart disease so that their findings are not necessarily applicable to the general population.

439

In fact, most studies involving asymptomatic subjects being tested routinely appear to refute any relationship of exercise-induced PVCs and increased risk of coronary events. Lamb and Hiss63 as well as Gooch64 concluded that PVCs induced with exercise were of no clinical significance among healthy subjects. McHenry and co-workershS found a similar incidence of PVCs developing with exercise among a group of policemen with known or suspected cardiac disease and another group who were considered to be without heart disease. Therefore, exerciserelated PVCs were not helpful in differentiating the two groups. Froehlicher et aLhh found a high incidence (35%) of PVCs during stress testing among 1390 active duty airmen and, after an average follow-up period of 6.3 yr, no increased coronary risk could be demonstrated in this population except when there was associated ST segment depression. The consensus opinion regarding the significance of exercise-related ventricular arrhythmias can be summarized as follows: (1) Among subjects being tested routinely who are apparently healthy, the presence of PVCs is of little or no prognostic significance unless associated ST segment depression is present. (2) Subjects with both exercise-induced ventricular arrhythmias and significant ST depression are likely to have severe coronary artery disease. Whereas it was initially believed that ectopic ventricular beats that disappear with exercise are more benign than those that either persist or increase in frequency, it is now well appreciated that many CAD patients have a decrease in ventricular ectopic acitivity as the heart rate increases with exercise.60 “.” Although both regional myocardial ischemia and increased sympathetic activity have been proposed as possible mechanisms of production of such arrhythmias, the answer has remained speculative.“9.60 The abolition or decrease in frequency of resting ventricular extrasystoles by exercise therefore does not provide reassurance that they are “benign,” nor does it indicate the absence of significant coronary occlusive disease. Hemodynamic Inappropriate

Blood Pressure

Response

Only recently has adequate emphasis been placed on hemodynamic data obtained during

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exercise stress testing. The use of such parameters as blood pressure and heart rate response has been found to increase the predictive value of the test significantly. There is also good evidence that the severity of coronary artery disease might also be predicted more accurately by their use. Many epidemiologic data have been accumulated over the past few years supporting the view that maximal systolic blood pressure achieved on stress testing has prognostic value for future coronary events. Irving et al.“’ found the annual rate of sudden cardiac death varied inversely with the maximal systolic blood pressure achieved during stress testing. The annual rate of sudden cardiac death was 97.9 per 1000 men if the maximal systolic pressure was less than 140 mm Hg, 25.3 if the response was between 140 and 199, and 6.6 if it was 200 mm Hg or more. These authors even went so far as to state that in a cohort of men with clinical CAD, the maximal systolic pressure is a “better predictor of mortality than ST depression and arrhythmias, the traditional predictors of exercise testing.” Using multivariate analysis in a follow-up of 1852 men with CAD, Bruce and associates69 showed the maximal systolic blood pressure achieved was among the best predictors of cardiovascular mortality. Angiographic correlative studies have also suggested a relationship between appropriateness of blood pressure response to exercise and the presence and extent of coronary artery disease. Thomson and Keleman” found angiographically severe coronary disease in all 15 patients studied after developing hypotension during treadmill-induced angina pectoris. They felt this hypotension was a sign of acute, ischemia-induced left ventricular power failure, “a sign not seen unless a large amount of left ventricular muscle was rendered ischemic by the testing process.” A normal blood pressure response was restored following bypass surgery, which relieved angina and abolished the ST segment depression in six patients. These investigators believed this was good evidence to support their hypothesis. In a multivariate analysis study of 215 subjects with hemodynamic, angiographic and clinical data, Ellestad and colleagues” found the maximal systolic blood pressure achieved to be the second most useful finding

COOKE,

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(after ST segment depression) in correctly classifying the stress test. This was the case in both men and women. Maximal heart rate ranked first among men, whereas the ST segment configuration was most useful among women. One study that apparently is at variance with the above investigations should be mentioned here. Baker et al.” doubt the reliability of exercise-induced hypotension as a sign of severe coronary artery disease. Twenty-five patients with exertional hypotension were compared to 50 without this finding. There was no significant difference in the incidence of I-, 2-, and 3-vessel disease, ventricular dysfunction, mean left ventricular end-diastolic pressure (LVEDP), and mean cardiac index between both groups. It was concluded that hypotension occurred more frequently in females and was not associated with CAD. They also felt that “the development of hypotension during treadmill testing does not identify a group of patients with a higher incidence or greater severity of coronary artery disease, or increased myocardial dysfunction.” The consensus opinion at this time is that exertional hypotension manifested at low workloads in coronary patients portends a grave prognosis and is usually associated with severe diseasc.7n.7?,” Failure of the systolic blood pressure to rise appropriately also probably is prognostically significant. The importance of an inappropriate blood pressure response in subjects without other evidence of coronary heart disease is still quite controversial. Further studies arc needed to clarify the possible role of this paramcter in predicting the presence of coronary artery disease in patients without ST depression.

Inappropriate

Heart

Rate Responsr

Numerous investigators have noted a correlation between the achieved heart rate during stress testing and the presence or absence of coronary artery disease.That such a relationship might exist was initially suggestedby Hinkle and associates7”in 1972. They concluded a 7-yr prospective study of 301 middle-aged men and found a significantly increased risk of sudden cardiac death in those whoseheart rates failed to rise as expected during a day’s activities or who had a low peak heart rate responseto standard exercise (Fig. 5).

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441

200 160 160 170 160 150

Fig. 5. Chronotropic incompetence or inappropriate heart rate response. The dotted area is the normal heart rate range during exercise and recovery for a given individual. The dark line shows the response for an individual with chronotropic incompetence. Note the failure of the heart rate to increase to the normal range. Such a response is correlated with increased coronary events and the presence of disease.

AGE 51-60 MALE H.P. l-22-74

66 50

R

1

2

3

Bruce et al.” noted that impairment of the heart rate response correlates well with impaired left ventricular function. Linhart and colleagues” studied 24 patients with angiographitally proven CAD and 74 normal subjects. They found that although the two groups had similar resting heart rates, the average maximum heart

4EXEFhE’

7

6

6

10

MIN.

1

2

3

4 3 RECOVERY

6

7

6

rate achieved during exercise in patients with CAD was significantly less than that achieved by those without CAD. Ellestad and Wan’ found a significantly large percentage of those patients with an inadequate heart rate response (heart rate below the 95% confidence limit for any given workload for age

--

I INCIDENCE OF CORONARY EVENTS IN ALL PATIENTS WITH ST SEGMENT DEPRESSION

N =

YEARS

525

339

257

199

142

N = 250

153

105

74

1

2

3

4

85 NO PAIN

49

58

41

29

5

6

Incidence of coronary events in patients with ST depression comparing the Fig. 6. absence. Note the twofold increase in coronary events when pain occurred. (Reproduced of Cardiology 41:227-232, 1978.)

PAIN

presence of pain by permission

1

7 during the of American

test to its Journal

442

and sex) to exercise developed a new coronary event despite having no ischemic ST segment changes. Further investigation in our laboratory has revealed that a high proportion of those patients had poor LV function and severe 3-vessel disease. Thirty percent had experienced a previous myocardial infarction. McNeer et al.” showed that failure of the heart rate to increase to greater than l2O/min with exercise identified a group of patients at high risk for future coronary events. At the same time, patients achieving a heart rate of 160/min or greater were at low risk for the development of a future coronary event. Symptomatic Angina1 Pain During Testing The usefulness of chest pain in predicting presence and severity of coronary disease has been confirmed in several studies utilizing both epidemiologic and angiographic correlative data. Cole and Ellestad’” conducted a 7-yr follow-up study of 1402 patients with a positive maximal treadmill stress test. The incidence of development of subsequent coronary events was approximately twice as great in those with associated angina during testing as compared to those with ST depression alone (Fig. 6). The incidence of coronary events was also much greater among those experiencing pain at lighter workloads as contrasted with those having onset of pain later during the test. Angiography was performed in 295 patients, and the sensitivity of the test using ST segment criteria alone was 64Yo. The sensitivity rate was increased to 85% if angina during testing accompanied the ST depression. Bartel et al.>” have noted a similar increase in sensitivity, reporting an increase from 65%) to 89%‘. Weiner and co-workers7u found the presence of significant angina1 chest pain without ischemic ECG changes to be nearly as predictive of multivessel coronary disease as ischemic ECG changes alone. The incidence of multivessel disease in the former patients was 72% and 76% in the latter. If both chest pain and ischemic ECG changes were noted, the incidence of multivessel disease was 93%. The authors therefore concluded that (I ) angina1 chest pain during stress testing predicts the presence and extent of CAD more accurately than does the absence, and (2) the presence of chest pain even without

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ECG changes during stress testing appears to be as predictive as ECG changes alone. R-Wave Amplitude

Changes in Stress Testing

In an attempt to improve the reliability of stress testing, R-wave changes with exercise have been measured and compared with angiography. Brody. in the mid-1950s. postulated that R-wave amplitude would vary with left ventricular volume changes because of the radial orientation of the electromotive forces of the left ventricle. He noted that an increase in left ventricular volume would result in an increase in the R-wave amplitude, while a decrease in left ventricular volume would result in a decrease in R-wave amplitude. The concept of the “Brody effect”x” raised the question of the ability of R-wave amplitude changes to predict left ventricular volume changes during stress testing, since it is known that patients with coronary artery disease will develop increases in left ventricular volume with exercise, while the normal ventricle will decrease its volume due to tachycardia and catecholamine release.” ‘I’

.AR$T=+4.

:

,:

I

Fig. 7. The R wave is measured from the baseline the tip of the R weve in millimeters. The index is formed adding the R-wave change to the ST segment change. depression is taken es e positive value. (Reproduced permission of Circulation 57:904-910. 1978.1

to by ST by

STRESS

TESTING:

APPLICATION

AND

PREDICTIVE

CAPACITY

Our laboratory has investigated this phenomenon, and Fig. 7 demonstrates the method devised for the measurement of R-wave amplitude. The R-wave is measured from the P-Q junction to the tip of the R-wave. Several beats are measured and an average obtained to minimize the effect of respiration for both the control and immediate period. The difference between R-wave amplitude averages for the control and immediate post exercise period is the change in the R-wave. The index is obtained by adding the R-wave amplitude change to the change in the ST segment. The ST segment depression is taken as a positive value (Fig. 7). A positive index or no change is indicative of disease since the normal response is a decrease in R-wave with exercise.

Correlation

With Normal

Coronary Anatom)~

The incidence of R-wave amplitude decrease after exercise in patients with angiographically normal coronary anatomy or insignificant coronary artery disease was 90!%, 79%) and 84% in three groups of patients analyzed.” ” In a subset of 53 healthy, young individuals who were asymptomatic and underwent treadmill stress testing as a part of a screening profile, 905% had a decrease in R-wave amplitude.gJ In patients who are stress tested for symptoms of chest pain and have no or insignificant coronary disease, increases in R-wave amplitude are frequently associated with contraction abnormalities suggesting a cardiac etiology other than coronary artery disease.

Correlalion

443

nary disease, while an R-wave amplitude decrease is associated with significant single- or double-vessel disease where ventricular compensation is possible. When the R-wave decreased, an average of 69% of the cases have no or insignificant coronary disease. When the R-wave increases, 83% have significant coronary disease.

Correlation With Segmental Contraction Abnormalities Figure 8 shows the comparison between segmental contraction abnormalities on resting left ventricular angiography and the R-wave response. In the patients with an R-wave amplitude decrease, 72% have normal wall motion or only one segment of abnormality. Sixty-two percent of those with R-wave amplitude increase have greater than two segments of abnormal

With Coronar)! ArterJs Disease

In the three studies previously mentioned, the R-wave amplitude increased in approximately 63%) of those with coronary disease.‘> 9hOf those with an R-wave increase and significant coronary artery disease in the original study.” 11%) had I-vessel disease, 31% had 2-vessel disease, and 58%’ had 3-vessel disease. In our experience, about 40% of those with coronary disease have an R-wave decrease instead of the expected increase. Their distribution is skewed in the direction of lesser disease with 2 at 3-vessel disease averaging only 24% while in those with an increasing R-wave, about 55%’ were found to have this finding. R-wave amplitude increase is associated with the presence of significant 2- or 3-vessel coro-

2-4

O-l SEOMENTS

Fig. 8. Changes in R wave correlated with segmental contraction abnormalities in angiography. R-wave increase is associated with 2 or more areas of abnormal motion, while R-wave decrease is correlated with no or only one area of abnormal contraction. (Reproduced by permission of American Journal of Cardiology41 :846-851, 1978.)

ELLESTAD,

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COOKE,

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EXERCISE:

I ivv F t C.O. & t E.F. A R-wave

1

Exercise

t L.V. meets Body Demands 1 L.V.V.

\ Regional lschemia

depressed contractility Minimal Segmental Contraction Abnormality

Compensation with t on P-V curve + Hypercontractility normal segment

minimal shift in

J

B ST1

Severe Segmental Contraction Abnormality

More kchemia

) \

tin L.V. “,‘z

C

1 ‘I R wave

tin L.V.V. L-

J

Shift in P.V. C”rw

L.V%.P. 1STL

wall motion. It should be noted that these contraction abnormalities on left ventriculography occur at rest rather than with exercise. It is well documented that the contraction abnormalities increase qualitatively and quantitatively as ischemiadevelops.8’m83

Fig. normal decrease physiology disease.

9. (A) Physiology of R-wave decrease in patients. IB) Pathophysiology of R-wave in patients with coronary disease. (Cl Pathoof R-wave increase in patients with coronary

Pathophysio1og.v

The pathophysiology of the R-wave amplitude changes is depicted in Fig. 9. As the normal individual exercises, catecholamine release resuits in enhanced contractility of the left ventri-

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TESTING:

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PREDICTIVE

445

CAPACITY

cle with improved output and ejection fraction. This, combined with the shortened time for diastole due to tachycardia, results in reduced left ventricular volume, and by the Brody effect, R-wave amplitude decreases (Fig. 9A) Exercise in the patient with one- or two-vessel disease results in ischemia of the regions supplied by the diseased vessel or vessels. As a result, the ventricle becomes less compliant, and to maintain a given output, a greater enddiastolic pressure is required. However, the remaining myocardium becomes hypercontractile, and because there is a relatively small nonfunctioning area, the remaining muscle can compensate and meet the metabolic demands during exercise. (Fig. 9B) The ejection fraction and cardiac output therefore continue to increase, and the systolic and diastolic volume continue to decrease in a normal manner, resulting in a decrease in R-wave amplitude. The patient with two- or three-vessel disease with many vessel branches involved in the atherosclerotic process is unable to compensate effectively for the ischemic contractile patterns that develop. The number and qualitative contractile abnormalities are so great that the left ventricle cannot adequately respond to the catecholamine stimulus to enhance its output as demand increases. In fact, the ejection fraction decreases, and the cardiac output fails to increase normally with a progressive increase. This results in an R-wave amplitude increase (Fig. 9C). Figure 10 shows examples of the three types of R-wave responses to exercise noted above. The first example is a normal patient. Note that the R-wave decreases. The second case is an individual with single-vessel disease. Note the decrease in ST segment with a decrease in R-wave. This patient is able to compensate for his ischemia. The third example is a patient with three-vessel disease. Note the decrease in ST segment with an increase in R-wave amplitude as the left ventricular volume increases due to ischemia. Ability to Decrease False Positive and Negative ST Responses Once it was established that R-wave amplitude changes were correlated with significant coronary artery disease and segmental contraction abnormalities, the question of whether or

B

Fig. 10. Examples of R-wave change. (A) Normal patient with R-wave decrease. (8) R-wave decrease in patient with single-vessel disease and ST depression. (Cl R-wave increase in 3-vessel disease with ST depression. (Reproduced by permission of American Journal of Cardiology41:846-851, 1978.)

not R-wave changes could reduce the number of false positive and false negative results by ST criteria arose.9” A group of 159 patients were randomly selected by computer who were false positive (52) and false negative (107) by ST segment changes.” An increase or no change in R-wave amplitude postexercise was taken as evidence of coronary artery disease, while a decrease in R-wave amplitude was evidence of no or insigni’. icant coronary disease. The R-wave amplitude changes reduced the false positive by ST criteria group by 37 or 7170, while the index, formed from the summation of the R-wave and ST changes, reduced the false positive group by 31 or 60%. The false negative group was reduced by 47 or 46% by R-wave changes and 62 or 58% by the index. This study demonstrated that R-wave amplitude changes can reduce the incidence of false positive and negative tests in treadmill stress testing. Furthermore, ST segment depression with a decrease in R-wave amplitude suggests a false positive test or single-vessel disease, while an increase in R-wave amplitude without significant ST depression suggests a false negative response.

ELLESTAD.

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Sensitivity

and Specificit?)

When a patient cohort with a more normal distribution of disease typical of the patient population refered to most cardiac centers is analyzed, the ST segment depression criteria have a sensitivity of 49% and a specificity of 74%. R-wave amplitude changeshave a sensitivity of 68% and a specificity of 84%. The index has a sensitivity of 76% with a specificity of 78% (Fig. I I). ST segment changescompared to the R-wave changes revealed that the R-wave is more sensitive, while the index is significantly more sensitive than ST segment depression. Infarcts

The sensitivity of ST segment depression increasesfrom 49%) to 55% when patients with previous infarcts are excluded, while the sensitivity of R-wave changes increases from 68% to 78% and the index increased from 75%,to 86s.‘” R-wave amplitude changes will reduce the false negative group by ST segment criteria by approximately one-half, while the index reduces it by 67%. R-wave amplitude changes as a predictor of coronary disease have decreased value in the presenceof an old infarct. However, it remains at least as sensitive and specific as ST changes ALL PATIENTS IN-1081 TST

PATIENTS WITHOUT

AND

GREENBERG

and can markedly reduce the number of false negatives by ST criteria. The index represents a combination of both ST and R-wave change criteria. The sensitivity is greater than either alone, but the specificity is slighty reduced. Conclusions

R-wave amplitude changes correlate with coronary artery atherosclerotic lesions and segmentalcontraction abnormalities on the resting left ventriculogram. An increase in R-wave amplitude correlates with 2- or 3-vesseldiseaseand with poor ventricular function, while a decreasein R-wave amplitude correlates with no diseaseor I- or 2-vessel diseasewith good ventricular function. The sensitivity and specificity of R-wave amplitude change as a predictor of coronary disease is better in our laboratory than ST segmentdepression. An increase in R-wave amplitude with no ST depressionsuggestsa false negative test by ST criteria. A decreasein R-wave amplitude with significant ST depressionsuggestsa false positive test or may be seen with I- or 2-vesseldiseasewith good ventricular function. POSTINFARCTION

MijN.:z’

COOKE,

STRESS

TESTING

Attention has recently been focused on the postinfarction exercise test. Such tests can be performed early on at about 2 wk or at the more conventional 2 or 3 mo. The early test is designed to study the patient’s responseto stress equivalent to that imposed by his daily activity upon returning home. The late test is the standard symptom-limited or heart-rate-limited test. The goal of the early test is to determine if ischemia still exists and to detect findings suggestive of increased risk of death or of future coronary events. It is also a useful tool for planning the patient’s cardiac rehabilitation program and provides important information about limitation on return to work.

TST

Early Stress Testing

Fig. 11. ST depression,

Comparison R-wave

of sensitivity and change, and index.

specificity

for

Several studies” ‘“’ have shown that the early stresstest is safe and has no excessivemorbidity or mortality rate. Theroux et al.‘” used 70% of the maximal age-predicted heart rate, 5 meta-

STRESS

TESTING:

APPLICATION

AND

PREDICTIVE

CAPACITY

bolic equivalents, ST depression of > 1.5 mm, angina1 pain, fatigue, or the development of severe arrhythmias as end-points for termination of the test. Most centers currently engaged in early stress testing use a 60%-70% maximal age-predicted heart rate response as the termination point. It should be noted, however, that Ibsen et al.‘“’ performed a maximal symptomlimited test using the bicycle ergometer in 209 patients at a mean of 18 days postinfarction and had no serious complications or deaths. In this study, 70% had ST-T changes and 42% had ventricular ectopic beats. They concluded that such a test could be safely performed. Many studies97.“9.‘“0 have shown the early test to be extremely helpful in detecting serious ventricular arrhythmias and in assessing drug therapy at discharge. Smith et al.“’ found that the stress test influenced management in 21% of the cases tested, while Ericsson et al.“” noted a change in therapy in 16% of cases tested. Whether or not the early test predicts early mortality or morbidity remains controversial. Smith et al.97 found the early test was not predictive of mortality in the first 21 mo postinfarction. Theroux et al.9q found a positive test predicted the development of angina, but not early death or coronary events. Ericsson et al.“‘” found PVCs during the stress test to be predictive of increased mortality. Late Stress Testing Few detailed studies have been done concerning the reliability of the late postinfarction stress test. Paine et al.“* found that a positive test had a predlctlve value of 86% for multivessel coronary artery disease postinfarct. They noted that a negative test suggested I- or 2-vessel disease. They also found that ST elevation correlated with a ventricular aneurysm. In another study, Weiner et al.‘“’ found that ST depression with or without ST elevation alone or a negative test suggested single-vessel disease. Savron et al.,“” in a study of young males postinfarction, found the stress test to be an effective method for detecting patients with additional coronary disease from those with disease limited only to the vessel supplying the infarcted area. They found that 12 of 12 patients with disease of vessels other than those to the infarcted area had positive stress tests. Miller et al.‘05 found that a

447

positive test in patients with an old stable inferior infarction was predictive of multivessel disease, but a negative test was nonspecific. Castellanet et al.‘06 reported the sensitivity was 84% for inferior infarctions and the specificity was 90%; while for anterior infarctions, the sensitivity was 52% and the specificity was 90%. Q waves in the precordial leads from VI-V4 or beyond lowered sensitivity for the anterior infarcts to 33%. They concluded that for a previous inferior infarct, the stress test was reliable. For anterior infarcts, a positive test was of value but a negative test provided little information. It can be seen that these studies are more or less in agreement and indicate the greatest usefulness is in those with previous inferior wall infarctions. Postoperative

Stress Testing

Stress testing has been used extensively to evaluate the results of coronary bypass surgery. Considerable uncertainty seems to exist regarding its value.‘07.‘0x Because of this, we should ask ourselves some critical questions about what the procedure can and cannot accomplish. In preoperative testing they are: (1) Can the severity of coronary disease be predicted? (2) Can the postoperative result be predicted? (3) Does the presence or absence of pain during testing predict the surgical result’.’ (4) Does ischemia at low workloads predict surgical result? In those with postoperative testing: ( 1) Does postoperative ST depression predict graft patency or lack of patency? (2) Does the ST depression correlate with the relief of angina? (3) Does exercise tolerance correlate with graft patency’? (4) Does comparison of pre- and postoperative testing aid in evaluation? (5) Does serial post-op testing aid in evaluation? As previously stated, stress testing in most subjects is a reliable aid in the prediction of serious disease, although there are a significant number of errors.13 In order to answer the questions about the

44%

usefulness of stress testing in the prediction of the outcome of vein graft surgery, Stuart and Ellestad conducted a study on 387 operated patients, 196 of whom had completed preop and postoperative treadmill stress tests. Of this latter group, 54 were excluded because of abnormal tracings at rest, i.e., ST depression or elevation, digitalis therapy, or a conduction defect. Postoperative angiography was not performed. They found a 61% improved double product (pulse X pressure product) at the point of ST depression, and a 58% improvement in the peak double product obtained. In those 73 patients with 2 or more postoperative stress tests, 57% had continuous improvement or improved on later tests. Twenty-six patients demonstrated chronotropic incompetence (inappropriately slow heart rate response to exercise). Of these, 17 (65%) had it appear postoperatively, persist, or appear later on in subsequent tests, suggesting a deterioration of left ventricular function. It disappeared in 6 (23%) or became intermittent with successive stress tests in 3 (12%). In an attempt to identify if any of the information in the preop stress test would predict the postoperative results of saphenous vein bypass surgery, they found that the patient’s age, angina during stress testing, and the workload associated with ischemia failed to predict those who could benefit from surgery. This study, like others, demonstrated the disparity between symptomatic and functional improvement following surgery. A number of studies have been published showing the correlation between exercise stress test results and angiographically demonstrated patent grafts. Recent reports, however, have cast doubt on whether the postoperative stress test correlates with angiographically complete or incomplete revascularization.‘“9 McConahay et al.“’ showed a poor correlation between stress testing and the completeness of revascularization. They went on to conclude that an electrocardiographically abnormal treadmill exercise test was as frequently associated with residual coronary disease postoperatively as preoperatively. A normal test was of limited value. With an abnormal preoperative stress test, a normal or improved postoperative test correlated with at least one patent graft, no residual disease, or single coronary artery disease

ELLESTAD,

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successfully bypassed. Exercise-induced angina correlated with residual coronary disease or incomplete revascularization. The absence of angina on a postoperative test was of no value in estimating completeness of myocardial revascularization or saphenous vein graft patency. Block et al.“’ found an improved exercise performance following unsuccessful myocardial revascularization (Fig. 12). Their study group of 23 patients showed a statistically significant improvement in maximal heart rate and lesser improvement in functional aerobic impairment. absolute duration of exercise, and pressure--rate products, while having occlusion of all implanted grafts. There appeared to be a good correlation between disappearance of treadmill-induced angina and improvement in overall exercise capacity as measured by exercise duration or workload achieved, irrespective of mechanism. Assad-MorelI”’ from Mayo Clinic reported an excellent correlation, however, with graft patency and exercise ST depression (Table 4). Because pain is often relieved by surgery even when revascularization is not complete, the ability to exercise to higher workloads and reach greater double products cannot be interpreted as evidence of improved coronary blood flow. The only reasonable evidence of improved flow is when ST depression is manifested at a higher

Pre-op

Post - op

Fig. 12. The changes in functional class after unsuccessful revascularization surgery. (Reproduced by permission of AmeriC8n Journal of Cardiology 40:673-680. 1977.)

STRESS

TESTING:

Table

APPLICATION

4.

AND

Postoperative

PREDICTIVE

Treadmill

CAPACITY

Exercise

449

Response

by Number

No VLU

Total patients (no.1 Treadmill exercise response Negatwe Patients by vessels

diseased

Three vessels Total grafts*

(VLU)

2 VLU

33

24

3 VLU

5

2 (9%)

23 (70%)

23 (96%)

21 (91%)

10 (30%)

1 (4%)

0 (0%)

5 (100%)

10 11

2 18

0 7

0 0

2 38

13 56

17 46

5 9

38 100

42 75

23 50

0 0

patent

No. % Correlation a posittve *Total

Ungrafted

(no.)

one vessel Two vessels

Grafts

Left

1 VLU

.23

Positive

of Vessels

between

a positive

test Increases. number of grafts

Reproduced

by permission

test and the number

of ungrafted

vessels;

as the number

of ungrafted

vessels

increases,

the likelihood

of

in group. of Mayo

Clinic

Proceedings,

July

1975,

workload after surgery than on the control, or when the ST depression recorded preoperatively is absent postoperatively. McConahay”’ found that if the preoperative test was positive and became normal postoperatively, 96% had improved myocardial circulation. We have also found the stress test useful as a means of serially evaluating patients. If a patient has converted from a positive to a negative test, and then after some months or years again develops ST depression, the finding reliably indicates a decrease in myocardial perfusion. The same can be said for those patients who have ST depression at high levels of work and who later manifest ST changes at lower workloads and lower double products. Busch and colleagues”3 have also found repeated testing to be a useful indicator of graft closure and progression of disease. They report a steady decline in the percentage of patients with a normal test as they are evaluated yearly, which would be consistent with the anticipated progression of coronary narrowing. Finally, the investigation of the effect of exercise on arrhythmias and on blood pressure response must be mentioned. The persistence of “ominous” exercise-induced ventricular arrhythmias postoperatively is an important clinical finding that suggests that antiarrhythmic therapy may be indicated. In summary then, stress testing is of value postoperatively but must be interpreted cautiously: (1) The presence of persistent angina and/or

Vol 50.

ST segment depression is good evidence for continued myocardial ischemia. (2) A conversion from a positive to a negative test is usually associated with good coronary perfusion if the patient is able to reach a high level of exercise, although there are many exceptions. (3) A resolution of ST segment depression is less common than the relief of angina. (4) Exercise tolerance correlates weakly with graft patency, but the patient’s strength and conditioning must be taken into account. (5) Comparison of pre- and postoperative tests are useful. (6) Serial postoperative testing is a clinical aid in long-term management of coronary bypass patients.

ISOTOPE

STRESS TESTING

Since the pioneering work by Zaret,“4”” stress perfusion scanning has rapidly evolved into a widely usedand useful adjunct to the more established approach to stress testing. The first application of radioactive tracers to the investigation of physiology occurred in 1927 when Blumgart”6 used radon gas administered intravenously in a cloud chamber as a radiation detector to measurethe circulation tirne in intact man. Perfusion scanning is a measureof cardiovascular physiologic function, as are the electrophysiologic alterations seen in the ST segment analysis. Although there has been an attempt to correlate both of these findings with anatomical

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changes in the coronary arteries, they are only partly related. This method has become, however, a major adjunct to our evaluation of patients with ischemic heart disease. All tracers used for evaluation of regional perfusion are substances that are rapidly cleared from the blood and are concentrated in the organs under investigation. This allows for the distribution of the tracer to measure indirectly the blood flow to that area. The most important tracers used in cardiac stress testing are the monovalent cations potassium, rubidium, cesium, and thallium, although, none of these distributes exclusively to the heart. Significant concentrations of tracer in the liver, kidney, thyroid, and intestine as well as skeletal muscles are seen. It is believed that the distribution of the tracer represents the product of the regional distribution of blood flow and the activity of sodium potassium ATPase in each organ. The blood-brain barrier effectively excludes thallium. These cations do not all behave identically, however, and studies performed reveal that thallium concentrates in the myocardium to a greater extent than potassium, rubidium. or cesium. Over time, the myocardial concentration diminishes, with potassium and rubidium turning over most rapidly, thallium next. and cesium the slowest. Potassium half-life in the human myocardium is approximately 90 min in normal patients, whereas thallium half-life is about 5-7 hr. Control experiments in normal animals and those with partial occlusion of coronary arteries checked against radioactive microspheres reveal a linear relationship between the regional distribution of potassium-43 and microspheres. Similar experiments seem to suggest that thallium and rubidium react in the same way.“‘.“’ When intravenous thallium-201 is given in a resting state, the left ventricular myocardium is well visualized because it has a mass approximately 3 times greater than the right ventricle and a greater blood flow.“’ Although the right ventricle concentrates thallium, it is usually not seen clearly because of the underlying activity of the lung and because of the minimal blood flow. In right ventricular hypertrophy, however, it becomes well defined and in such a situation one should suspect pulmonary hypertension. Patients with transmural myocardial infarctions have resting perfusion deficits in about 80% of those

COOKE,

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tested,“’ and these must be separated from those seen with stress injections. Data have suggested that nontransmural infarctions are more difficult to define and can be seen in about 50%. of subjects in a clinical setting. Method Because perfusion of the left ventricle at rest in a patient without previous infarction is usually normal even in the face of severe coronary narrowing, a scan at rest and after isotope injection at peak exercise is necessary. It appears that with exercise the ratios of blood flow to the normally perfused myocardium and the ischemic myocardium change dramatically. Therefore, a larger dose may be delivered to the working myocardium with normal flow, and the ischemic muscle picks up a relatively smaller amount of isotope, resulting in a difference in tracer concentration. Recent data, however, suggest that the uptake in exercising heart muscle may not be increased so much as the ischemic muscle decreased? It is important to inject the intravenous isotope at peak exercise and to continue the test for at least a minute following the injection so that the tracer can be picked up by the muscle according to the distribution of blood flow. Data suggest that the tracer redistributes within about an hour so that imaging should be completed within 45 min, if at all possible. Within 4 hr the redistribution of the tracer will be almost identical to a resting scan. This makes it possible to do a second scan without a second injection of isotope.“’ During the stress test, the patient’s ECG, blood pressure, and clinical findings must be monitored exactly the same as with regular stress testing. It is of interest that when the tracer is injected at peak stress, the background activity in the pulmonary bed all but disappears. The ischemic myocardium tends to be correlated with the area of perfusion by the diseased coronary artery, particularly if there is a single vessel involved. When there are multiple vessels involved, it is difficult to anticipate which vessels will play a major role by observing the perfusion defect. The knowledge of the ischemic area, however, can at times be very useful in determining which area of narrowing seen on the angiogram is of most importance (Fig. 13).

STRESS

TESTING:

APPLICATION

AND

PREDICTIVE

CAPACITY

451

during exercise tends to implicate arteries not already responsible for an area of infarction. (2) Patients with chest pain who have ECGs that are difficult to interpret, such as those with left bundle branch block (LBBB), left ventricular hypertrophy, or patients on digitalis. McGowan “’ and colleagues, using potassium-43 and rubidium-81, have found that resting scans in patients with LBBB may show areas of decreased radionuclide uptake in the septum, suggesting an area of regional ischemia. However, most patients who have normal coronary arteries have clearing of this finding after exercise, whereas in patients with coronary disease and LBBB, the ischemic area became more pronounced or new areas of ischemia developed when injections were made at peak exercise. (3) Suspected false positive responders on the stress test who are in population groups that suggest that they may not have coronary disease, e.g., women with atypical chest pain, young athletes, and in people who have no symptoms but positive stress tests where their occupation or life style makes it extremely important to gather more evidence about their coronary circulation. A summary of the reliability of nuclide imaging by several authors is listed in Table 5. It seems clear in most publications that the sensitivity and specificity of this method is somewhat better than the analysis of the ST segment alone, but by no means is it 100% reliable. An evaluation of the reproducibility of stress scanning by McLaughlin”3 suggests that it is of very high order. One of the factors that must be taken into consideration is the intraobserver agreement in the evaluation of the scan.

Ant

LAO

697

?K

Fig. 13. Shown are the various views obtained during thallium scanning. ANT. anterior; LAO, left anterior oblique; LL, left lateral. (Reproduced by permission of Clinical Nuclear Medicine 2:64-73. 1977.)

Reliability The test is particularly useful in a number of special situations: (1) Patients with a previous myocardial infarction suspected of having coronary disease in other areas that have not yet infarcted. The appearance of a new area of underperfusion Table

5. Sensitivity

and

Posttwe Total Pattents

Powive Thai.

N

Berman (Rubldlum)

52

49

43 (87%)

McGowen (Thallwm)

160

98

81 (91%)

Rltchle IThallwm)

101

76

58 (76%)

63 (75%)

47 (75%)

19

18 (94%)

Ewey (Abstr) Shames (Abstr) Shown those

23 ts the

sensitivity

for ST depression.

and Note

specificity that

thallium

for thallium appears

Specificity

of Thallium

Stress

Testing

Anglography Negatw Thai.

POSItWe ST

Negative ST

30 (61%)

1 stress superior

41 (65%)

for several

to ST depression.

N

Anglography

Negatwe Thai.

0

--__

Posltlvf! ST

--___

Negafwe ST

3

62

11 (17%)

51

26

2 (4%)

24

4 (15%)

21

11117%)

12 (63%) testing

Positive Thai.

3

34 (45%) 11

--__ Negative

4 studies

in the

0

4 literature.

These

0 values

4 are contrasted

to

ELLESTAD,

452

agreement in Ritchie3’ reports intraobserver 79% when using 3 observers. His group found that when the ST segment and thallium defects were combined, the sensitivity was 91%, if one took into consideration the presence or absence of Q waves in those with suspected previous myocardial infarction. We have found that one of the most important applications that is not primarily related to stress testing is in the evaluation of patients for surgery. Those patients who have reduced contractility in certain areas of their myocardium and who also have transient stress-induced perfusion deficits, often can be improved by revascularization. The presence of reduction in myocardial perfusion with stress, as indicated by thallium uptake, suggests that the circulatory changes in a given area are reversible. This has been validated by postoperative angiograms in a few cases, and should it be confirmed in a statistically significant sample, will add to our ability to make important decisions for surgical candidates. STRESS TESTING THE ASYMPTOMATIC PATIENT Although there has been considerable criticism of the reliability of treadmill stress testing in asymptomatic subjects3 we all recognize the desirability of identifying coronary disease before it appears as an acute myocardial infarction or sudden death. The issues are: What is the best way to identify patients at risk? If they are identified, what measures can be taken to alter the likelihood that a coronary event will occur’? A careful review of the available literature indicates that coronary vein and internal mammary bypass surgery not only improve symptoms in patients with angina, but also prolong life in subjects with multivessel coronary disease.‘14 13’These same subjects are those most likely to have sudden death or a significant infarction, and the attendant disability associated with the loss of a large amount of myocardium. It therefore follows that the methods of identifying these subjects should be carefully scrutinized. History of Chest Pain Although it is commonly thought that coronary insufficiency can be diagnosed by taking a

COOKE,

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careful history,‘j3 our experience suggests that only about 30% of those with severe coronary disease have chest pain recognizable as angina, even when tested to maximum capacity on a treadmill.” A positive history of classical angina is reliable evidence of coronary narrowing, but the absence of pain is no guarantee of normal coronary flow. It seems likely that more than half of those who die suddenly have death as their first symptom. It has also been well documented that at least 75% of the victims of sudden death have severe 2- or 3-vessel disease.‘3J Physical and Laboratory

Findings

It is widely appreciated that there are no classical physical findings that identify coronary disease. Hypertension, obesity, and xanthomas identifying hypercholesterolemia are known risk factors,“5 but even in combination have a predictive capacity for the development of a future coronary event of about half that associated with ST segment depression precipitated by exercise.‘3 It has become standard practice to search for and try to correct known risk factors. The more difficult problem facing us, as more and more stress tests are done, is how to deal with ST segment depression in a subject who does not have a history of chest pain or of previous myocardial infarction. The following steps are proposed as a method of dealing with asymptomatic subjects who come in for a routine physical and as part of this evaluation undergo stress testing. We believe it is prudent at this time to do testing on those subjects at highest risk, probably males from age 40 to 65 or over, who are inclined to be sedentary in their work or recreational pursuits, especially if they have a number of the established risk factors. Allen and colleagues”h found the prevalence of exercise-induced ST depression in 709 asymptomatic men in the above age range to average about 23% while in a large series sent to a cardiac center for evaluation, the prevalence of those with abnormal ST segments was 41%,.” We might then postulate a prevalence of about 30% for those presenting for a physical examination at a doctor’s office. It has been our experience that a significant number of subjects who come for an examination will not reveal symptoms to the physician for fear of what might be found. Physicians, likewise, may not order a

STRESS

TESTING:

APPLICATION

AND

PREDICTIVE

CAPACITY

stress test for fear of having to face the decision of what to do if an abnormality is found. The Abnormal

ST Segment

When a subject has ST segment depression without symptomatology, he should be categorized as to the workload necessary to bring on the signs of ischemia. ST depression at high workloads has been shown to have a low predictive value for subsequent coronary events, whereas those with changes manifested at low workloads have a high risk.‘32 Thus, it seems prudent to usethis discriminatory information to prescribe an appropriate program. It has also been found that when a patient has ST depression occurring at high levels of exercise, he will usually have an exercise-induced reduction in R-wave amplitude, indicating good left ventricular function.‘3’ Therefore, when these changes occur, the patient should be advised of the abnormality and its possibleimplications, and an intensive program should be initiated to correct any risk factors present. Equally as important, he should be advised that follow-up is essential. If his diseaseprogresses,it may then be possible to identify the increased risk before it becomes life threatening (Fig. 14). ST Onset at High Workload Complicating Risk Factors

With Secondary

Occasionally, patients with ST segment depression manifested at high workloads have other findings, such as a reduced chronotropic

453

response, lower than normal blood pressure response to exercise, angina1 pain occurring during the test, an increasing R-wave amplitude,‘” or an ominous arrhythmia with exercise. In this case, these secondary factors would raise the question of a more severe degree of ischemia.7.62.70 In these subjects, a stress thallium scan or coronary angiogram is indicated to clarify the severity of the process. ST Onset at Medium

or Low Workloads

Reduction in R-waves suggests good left ventricular function,94 while the early onset of ST depression indicates more severe coronary disease. If the ST depression is manifested within about 4 or 5 METS,* one should probably proceed with angiography or at least with thallium studies to further confirm or rule out the presence of ischemia. A positive thallium scan may help localize the process, which is very important since ischemia of the anterior wall probably has a much more ominous prognosis than that of the inferior wa1l.‘37 If the ST segment changes are manifested at 668 METS (Bruce stage 2) and the R-wave decreases,one can be more conservative in management, possibly watching the patient carefully and repeating the stresstest at 3-6 mo intervals.

*MET: demand;

Metabolic 4 METS

equivalent would equal

= resting 4 times

uptake.

ST DEPRESSION ONSET LOW WORK LOAD i R WAVE INCREASED WITH EX & LOW ACHIEVED HEART RATE LOW ACHIEVED BLOOD PRESSURE ANGINAL PAIN DURING TEST PROGRESSIVE OMINOUS ARRHYTHMIAS EARLIER ONSET OF

Fig. 14. Recommended approach to evaluation of patients with ST depression and no symptoms of coronary disease.

ONSET MEDIUM WORK LOAD

ONSET WORK

1

HIGH LOAD

1 R WAVE DECREASED WITH EX

, -

metabolic the resting

oxygen oxygen

ELLESTAD.

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COOKE,

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GREENBERG

ST Onset at Low or Medium Workloads With No Change or Increase in R-Wave Amplitude

Those With No ST Change and No Other Findings Suggestive of lschemia

In this case an increasing R-wave indicates poor left ventricular functiony6 and ventricular dilatation with exercise. Thus, the need to proceed to angiography is more urgent. This may even be more definite if the patient terminates exercise at a heart rate less than 85% of maximum, if the blood pressure fails to rise normally, or if angina occurs with exercise. At low workloads, a marked degree of ST depression, such as 3 or 4 mm, gives even more weight to the likelihood of very severe proximal narrowing of 2 or 3 vessels or a left main lesion.36 Thus, a combination of clinical findings add weight to the impression that the disease is more or less severe and one then may proceed accordingly in dealing with the problem.

An example in this category would be a patient with a normal R-wave response. In this group one can give assurance that there is little likelihood of signilicant coronary disease and any sensible exercise program is probably safe in terms of the cardiovascular system. Follow-up tests might be advised in 2 or 3 yr, depending on the presence or absence of other risk factors. Subjects With ST Depression a Prior Negative Test

Who Had

These patients are usually recognized when they manifest ST segment depression at high workloads. and can be managed as if it were the first test. However, now the patient is identified as having an increased risk. If the ST changes should be manifested at low workloads, the implications become more serious. Men who convert from a normal to an abnormal ST segment response almost invariably have coronary narrowing.

Subjects With No ST Depression But Who Have Secondary Complicating Factors In subjects with no ST depression, there may be secondary complicating factors such as increasing R-wave, low work tolerance, reduced heart rate or blood pressure response, or angina1 type chest pains during the stress. In this patient group there will be some so-called false negatives, and therefore they should be further evaluated, either by repeat stress tests at appropriate intervals or by stress thallium scans provided other risk factors warrant further study. If the isotope studies suggest ischcmia. one should proceed with angiography (Fig. 15).

THE

SYMPTOMATIC

PATIENT

Figures I6 and I7 summarized our recommendations for the evaluation of the symptomatic patient. If the patient has ST depression during the test, but it is late in recovery, at a high workload, or the R-wave decreases. then retesting in 6 mo with medical management is suggested. However, if the ST changes occur at a low workload.

NO ST DEPRESSION POOR EXERCISE SEVERAL RISK

TOLERANCE FACTORS

FEW

RISK

FACTORS 1

R&TEST IN TWO YEARS

t

R WAVE F EXERCISE LOW ACNIEVED HEART RATE LOW ACHIEVED BLOOD PRESSURE ANOINAL PAIN DURIND TEST PROQRESSIVE OMINOUS ARRHYTHMIAS

1 CONVERT TO ABNORHAL S-T RESPONSE L ONSET WORK

STRESSTEST POSITIVE

LOW LOAD

& ONSET WORK

a HIQN LOAD

NEOAYIVE I

ANDIODRAY

I

1 _ EDUCATION RISK FACTOR CONTROL FOLLOW FREQUENTLY

Fig. 15. Recommended approach evaluation of patients with symptoms coronary disease but no ST depression during stress testing.

to of

STRESS

Fig.

TESTING:

16.

APPLICATION

Recommended

AND

PREDICTIVE

approach

to evaluation

CAPACITY

of patients

angina1 pain develops during the test, the R-wave increases, or down-sloping ST depression develops, then catheterization should be performed since these findings suggest highgrade disease and increased mortality. An inappropriate heart rate response (failure of the rate to increase to L 120/min), an inappropriate blood pressure (BP) response (failure of the systolic BP to increase to > 140), and ominous ventricular arrhythmias are additional findings with increased mortality and severe disease. If the patient has no ST depression during the test but progressive ventricular arrhythmias develop, or a short duration or workload of 3 min is noted. or an inappropriate blood pressure or heart rate response occur, then catheterization is recommended. Chest pain during the test or an R-wave increase are suggestive findings, and a

Fig. tion disease

of

17. Recommended patients with and

ST depression.

approach symptoms

of

to evaluacoronary

455

with

symptoms

of coronary

disease

but

no ST depression.

stress thallium scan should be performed. An R-wave decrease suggests good ventricular function with only single vessel disease at worst. Consequently, the patient can be followed and retested in 6 mo. CONCLUSION This description of our approach to stress testing in patients suspected of having coronary obstruction is offered only as a guideline There are many clinical findings not discussed that have value in determining the presence and severity of disease. We have used 21 clinical variables in a computer-implemented multivariate analysis that has improved the predictive capacity of stress testing.‘jx As we gain more experience with this approach, we may be able to refine our

ELLESTAD.

456

guidelines. Other diagnostic approaches such as cardiokymography,‘39 first pass nucleotide scanning with exercise,14’ the measurement of systolic time intervals,‘4’ and possibility of the correlation of systolic pressure-time index/diastolic pressure-time index (SPTI/DPTI)‘J’ may also be helpful in fine tuning our diagnostic capabilities prior to the decision to do more invasive studies. If our noninvasive tests suggest, however, that the patient is at risk of a significant coronary event, we must then proceed with the ultimate tool to make the final determination-the angiogram. As cardiovascular revascularization becomes established as being a reliable way to minimize the danger of a sudden coronary event, we can no longer ignore the obvious methods for identifying this process. It has been said that many people with sudden death have a heart that is too good to die; death, however, is not the only end-point of importance. Many patients have a massive infarct and

COOKE,

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become severely incapacitated. There are at least 400,000 subjects hospitalized for myocardial infarction each year,‘43 and death from infarction alone exceeds 600,000, many of whom fail to arrive at the hospital. We now believe that the identification of these patients and the estimation of the severity of their coronary disease is good medical practice. In certain cases, even if they do not have angina, revascularization surgery definitely carries less risk than a conservative approach.“‘4 To continue to ignore a severe overall reduction in coronary flow appears to be a “head in the sand” attitude. The time has arrived when we should use the methods at our disposal to search for and identify those at risk of sudden disability and death. Stress testing is such a method, and although we expect our ability to identify patients with coronary disease to continue to improve. we already have an established clinical tool that should be fully utilized.

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STRESS

TESTING:

APPLICATION

AND

PREDICTIVE

CAPACITY

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457

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JO: Left myocardial

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Jr: Left

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et ‘11. Reversible

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in

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