Key Points
- •
Exercise stress testing is a safe procedure in asymptomatic or minimally symptomatic individuals and provides both diagnostic and prognostic information.
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A growing body of literature supports the utility of nonelectrocardiographic parameters, including exercise capacity, chronotropic response, exercise blood pressure, and heart rate recovery, in determining prognosis in asymptomatic subjects beyond traditional risk factors or global risk scores.
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There are no Class I indications for exercise testing in asymptomatic individuals in the American College of Cardiology/American Heart Association guidelines because of insufficient clinical trial evidence of efficacy.
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Exercise testing may be considered in asymptomatic subjects before vigorous exercise is started if they are diabetic, older, at higher risk for CHD because of comorbid conditions, or involved in occupations potentially affecting public safety.
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Exercise testing with imaging should be used as an initial test in the following situations: preexcitation syndrome (Wolff-Parkinson-White), electrically paced ventricular rhythm, more than 1 mm of resting ST-segment depression, and complete left bundle branch block.
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Although some studies suggest additional prognostic value of imaging along with stress testing in asymptomatic individuals, this is not cost-effective in low-risk populations (low event rates and low specificity).
Data from 2006 indicate that 16,800,000 U.S. adults aged 20 years or older have coronary heart disease (CHD), with an annual incidence of myocardial infarction (MI) of 1,450,000. Among patients experiencing sudden death, it is the first presentation of CHD in about 25%. For these reasons, there has been considerable interest in risk stratification of asymptomatic individuals without a diagnosis of CHD to prevent future events. Given its noninvasive nature and the prognostic information it provides in established CHD, exercise testing has generated considerable interest.
A promising avenue for improving cardiac risk stratification has come from studies evaluating the prognostic value of exercise testing in asymptomatic populations with test variables that are not related to exercise-induced ST-segment depression. In particular, functional measures such as exercise capacity, blood pressure, and heart rate recovery have been linked to increased CHD and all-cause death in both women and men.
Additional imaging with myocardial perfusion or echocardiography may further identify another subgroup of asymptomatic individuals at higher risk for future events. However, despite the increased risk associated with certain aspects of the exercise test, the low cardiac event rate and low positive predictive value of abnormal test results in asymptomatic populations do not support a strategy of routine screening of adult asymptomatic populations. Clinical trial data are scarce and are eagerly awaited to answer the important question facing clinicians and patients alike: to screen or not to screen asymptomatic adults for CHD?
Current Guidelines and Limitations
Current guidelines do not recommend exercise testing for routine screening in asymptomatic subjects. Recent guidelines from the U.S. Preventive Services Task Force found insufficient evidence to recommend routine screening because of the low positive predictive value (estimates ranging from 6% to 48%) among asymptomatic men. Similarly, there are no Class I indications for exercise testing in asymptomatic adults in the 2002 American College of Cardiology/American Heart Association (ACC/AHA) guidelines ( Table 29-1 ). However, these guidelines have been based largely on data regarding the performance of stress electrocardiography for diagnosis of coronary disease in a low-risk population.
| Class I |
| None |
| Class IIa |
| Evaluation of asymptomatic persons with diabetes mellitus who plan to start vigorous exercise (Level of Evidence: C) |
| Class IIb |
|
| Class III |
|
There is a growing body of literature suggesting the utility of nonelectrocardiographic exercise testing parameters in determining prognosis in asymptomatic subjects, beyond current risk stratification with commonly used global risk scores. As reviewed in more detail later, these parameters include exercise capacity, chronotropic response, exercise blood pressure, heart rate recovery, and ventricular arrhythmias. All have demonstrated prognostic utility even after accounting for traditional risk factors or global risk scores (e.g., the Framingham risk score).
Use as a Screening Test
Broadly conceived, the purpose of a screening test is either earlier diagnosis of disease or risk stratification to allow effective interventions to prevent adverse outcomes. Current guidelines recommend office-based risk stratification of all individuals with multiple risk factor scores to determine global risk. This is most commonly accomplished by the Framingham risk score as modified by the National Cholesterol Education Program Adult Treatment Panel III. In this framework, patients can be stratified into low-risk (predicted 10-year absolute risk of MI or CHD death <10%), intermediate-risk (6% to 20%), and high-risk (>20%) groups.
Whereas aggressive medical interventions are clearly indicated in high-risk patients, population-based studies suggest that less than 3% of asymptomatic subjects fall into the high-risk group, particularly among women. Although all patients should control known risk factors, some have argued that given the substantial variation in risk among intermediate-risk patients and the sizable proportion of patients falling in this category, these patients would benefit from further risk stratification ( Fig. 29-1 ).
As presented in the following sections, multiple stress testing parameters have been demonstrated to add prognostic information beyond risk factor scores. However, data are still lacking that such refinements in prognostic assessment actually influence patient management and outcomes. As discussed more fully in a later section, this critical information still awaits large-scale randomized clinical trials to assess the impact of risk stratification by exercise testing on outcomes.
Exercise Stress Test Performance
Safety, Contraindications, and Indications for Test Termination
Exercise stress testing is a generally safe procedure. Recognized serious complications of exercise testing include MI, malignant ventricular arrhythmias, and sudden death ( Table 29-2 ). Large survey studies have reported acute MI in 0.9 to 3.6 per 10,000 tests, serious arrhythmias in 0.3 to 4.8 per 10,000 tests, and death in 0 to 0.5 per 10,000 tests. The risk of adverse events is higher in post-MI patients and patients undergoing evaluation for malignant ventricular arrhythmias. Given the potential for serious risks (although rare), clinical judgment is essential in selecting patients appropriate for stress testing, as is careful monitoring by appropriately trained staff before, during, and after testing.
| Cardiac |
|
| Noncardiac |
|
| Miscellaneous |
|
Absolute and relative contraindications to exercise testing are listed in Table 29-3 . In general, any patient with evidence of clinical or hemodynamic instability should not undergo exercise testing until the condition is stabilized. Absolute and relative indications for termination of exercise testing are listed in Table 29-4 .
| Absolute |
|
| Relative |
|
| Absolute |
|
| Relative |
|
Commonly Used Exercise Protocols
In general, exercise protocols are designed to assess exercise capacity. Maximum oxygen consumption ( 
), defined as the maximal amount of oxygen a subject can take in from inspired air during dynamic exercise, is considered the best measure of cardiovascular fitness and exercise capacity. When peak consumption is achieved, 
can estimate cardiac output. Oxygen uptake can be expressed in units of sitting/resting requirements or metabolic equivalents (METs); a MET is defined as a unit of sitting/resting oxygen uptake (approximately 3.5 mL O 2 /kg/min). 
varies significantly with age (declining by 8% to 10% per decade ), gender (generally lower in women), physical activity (nearly 25% reduction noted with 3 weeks of bed rest ), heredity, and degree of myocardial impairment.
Exercise protocols with progressive incremental increases in workload tend to estimate 
more accurately. The optimal protocol will vary by patient and should last for 6 to 12 minutes to reliably reflect the upper limit of the patient’s cardiorespiratory function. Exercise is most commonly performed with bicycle ergometry or treadmill. Commonly used protocols are illustrated in Figure 29-2 . Compared with the cycle ergometer, treadmill tests tend to demonstrate 10% to 15% higher 
, 5% to 20% higher peak heart rate, and more frequent ST-segment changes.
The most commonly used treadmill protocol in the United States is the Bruce protocol. Whereas a large amount of published data exist with use of the Bruce protocol, the relatively large increments in work between stages can make 
estimation less accurate and cause some patients to terminate exercise before 
is achieved. Estimation of 
appears more accurate with use of exercise duration–targeted ramp protocols, which constantly increase work by increasing incline at set brief intervals and increasing ramp speed on the basis of estimated functional capacity. The major limitation is the need to accurately predict a patient’s functional capacity.
Exercise Stress Test Interpretation
Exercise testing produces both electrocardiographic and nonelectrocardiographic data that can be used both for diagnosis of CHD and for prognosis. Interpretation of exercise testing data must incorporate the clinical context of the test and, most important, the pretest probability of disease.
Performance Characteristics of Exercise Testing and Bayes’ Theorem
Definitions of parameters used to quantify the diagnostic accuracy of a test are listed in Table 29-5 . Sensitivity defines the probability that a patient with disease will have a positive test result, and specificity defines the probability that a patient without disease will have a negative test result. However, the clinically relevant information in interpreting the results of any given test is the likelihood that a positive result is truly indicative of disease (positive predictive value) and that a negative result truly excludes disease (negative predictive value). As Table 29-5 illustrates, these parameters are dependent not only on the test but also on the prevalence of disease in the population (i.e., the pretest probability).
Bayes’ theorem states that the probability of disease after a diagnostic test is equal to the pretest probability of disease multiplied by the probability of a true positive result from the test. A corollary is that the chances of a positive result truly reflecting disease (i.e., positive predictive value) will be higher in high-prevalence populations and lower in low-prevalence populations. This point is illustrated in Figure 29-3 . Bayesian analysis is critical in the appropriate interpretation of stress testing.
Test Interpretation: Diagnosis
Estimates of the diagnostic accuracy of electrocardiographic exercise stress testing for the diagnosis of hemodynamically significant coronary disease vary widely and are confounded by the fact that the majority of studies suffer from workup bias, discussed in further detail later.
Determining the Pretest Probability of CHD
Multiple predictive models have been developed to assist the clinician in assessing the pretest probability of CHD in a given patient. These models consistently show age, gender, and chest pain history to be the most powerful predictors of CHD, although additional factors such as smoking and history of diabetes are also predictors. The most commonly used assessment tool is demonstrated in Table 29-6 . Pretest probability of CHD is determined as high (>90%), intermediate (10% to 90%), low (5% to 10%), and very low (<5%). On the basis of the previous discussion of bayesian conditional probabilities, the results of exercise testing will have the greatest effect on post-test probability of CHD in subjects with intermediate pretest probabilities.
| Age (years) | Gender | Typical/Definite Angina Pectoris | Atypical/Probable Angina Pectoris | Nonanginal Chest Pain | Asymptomatic |
|---|---|---|---|---|---|
| 30-39 | Men | Intermediate | Intermediate | Low | Very low |
| Women | Intermediate | Very low | Very low | Very low | |
| 40-49 | Men | High | Intermediate | Intermediate | Low |
| Women | Intermediate | Low | Very low | Very low | |
| 50-59 | Men | High | Intermediate | Intermediate | Low |
| Women | Intermediate | Intermediate | Low | Very low | |
| 60-69 | Men | High | Intermediate | Intermediate | Low |
| Women | High | Intermediate | Intermediate | Low |
Interpretation of Electrocardiographic Response
Normally encountered electrocardiographic changes with exercise include increased P wave magnitude in the inferior leads with shortening of the PR interval, decreased R wave amplitude in the lateral leads, and depression of the J-point in the lateral leads. Assessment of electrocardiographic manifestations of exercise-induced myocardial ischemia focuses on the ST segment.
In exercise electrocardiography, the ST-segment deviation is measured relative to the P-Q junction. Generally accepted criteria for abnormal ST-segment depression are horizontal and downsloping ST-segment depression of ≥0.10 mV (1 mm) for 80 msec, with downsloping ST-segment depression being more specific than horizontal or upsloping ST-segment depression ( Fig. 29-4 ).
ST-Segment Depression
Resting ST-segment depression is a risk marker of adverse cardiac prognosis in itself. Resting ST-segment depression of <1 mm has been shown to increase the sensitivity but to decrease the specificity of exercise testing, and exercise testing is still considered a reasonable first test in these patients. Importantly, ischemic ST-segment depression occurring only during the recovery phase of an exercise test appears to have comparable diagnostic significance to ST-segment depression occurring during exercise.
Exercise-induced ST-segment depression has diagnostic properties that vary widely. Important methodologic limitations that may inflate estimates of ST-segment depression sensitivity are inclusion of subjects with high probability of having disease (e.g., prior MI) and workup bias. Workup bias refers to inclusion of subjects based on the results of the test being evaluated, that is, only subjects undergoing both stress testing and coronary angiography are included, although the decision to pursue angiography is influenced by the results of the exercise test.
A meta-analysis of 147 studies involving 24,074 patients and comparing exercise-induced ST depression with coronary angiography reported a mean sensitivity and specificity of 68% and 77%, respectively. However, both the sensitivity and specificity calculations varied widely; the range of reported sensitivity was 23% to 100%, and the range of reported specificity was 17% to 100%. Studies that avoided workup bias and did not include many patients with high pretest probability of disease suggest a sensitivity of 50% and a specificity of 90% associated with exercise-induced 1-mm ST-segment depression.
ST-Segment Elevation
The development of ST-segment elevation, measured from the baseline ST level, is not infrequent in leads with preexisting Q waves and is of unclear significance among patients with prior MI. Exercise-induced ST-segment elevation in subjects without preexisting Q waves is rare, occurring in an estimated 0.1% of patients in a clinical laboratory. It is associated with transmural ischemia and reliably localizes the area of ischemia.
Gender Differences in ST-Segment Changes
It is notable that exercise-induced ST-segment depression has not been found to be associated with higher risk in asymptomatic women, in contrast to findings in asymptomatic men, in whom ischemic electrocardiographic changes have been associated with higher mortality. This sex difference in the prognostic accuracy of the ST segment is consistent with previously reported sex differences regarding its diagnostic accuracy and may be related to hormonal effects on the electrocardiogram or sex differences in endothelial function. Other measures obtained from exercise testing that add useful prognostic information in women are discussed later and include functional capacity and heart rate recovery.
Test Interpretation: Prognosis
Use of Common Prognostic Scores (Duke Treadmill Score)
Multiple parameters measured during the exercise stress test yield prognostic information. Many are discussed in greater detail later. Multiple studies have demonstrated the prognostic importance of exercise capacity, measured as treadmill stage, exercise duration, metabolic equivalents, watts, or double product. In addition, studies evaluating the most predictive independent prognostic parameters from exercise tests consistently also identify the presence of exercise-induced myocardial ischemia, generally reflected in ST-segment deviation or anginal symptoms. Whereas multiple risk scores integrating these various prognostic markers have been developed, the most widely used is the Duke treadmill score (DTS).
The DTS was initially developed in 2842 subjects referred for cardiac catheterization who had also undergone exercise testing for evaluation of symptoms of CHD. The investigators identified three prognostic variables: ST-segment depression, exercise time on Bruce protocol, and Duke angina index. In the Duke angina index, angina index 0 = no angina, 1 = typical angina occurred, and 2 = angina was reason for test termination.
The resulting DTS is calculated as
DTS = Exercise time ( in minutes ) − ( 5 × ST deviation in mm ) − ( 4 × Duke angina index )
Nonelectrocardiographic Prognostic Parameters
Exercise Capacity
Exercise (or functional) capacity refers to the maximal oxygen extraction obtainable during exercise and is commonly measured in METs. METs are multiples of basal metabolism; one MET is the basal oxygen uptake during quiet sitting and is equal to 3.5 mL/kg/min. Exercise capacity is influenced by factors outside of cardiovascular fitness, most importantly age and gender. Nomograms have been developed to estimate age-predicted exercise capacity among men [18.0 − (0.15 × age)] and women [14.7 − (0.13 × age)] ( Fig. 29-6 ). For example, with use of this nomogram, women who did not achieve 85% of their age-predicted exercise capacity had a twofold higher risk of cardiovascular death.
Exercise capacity is the most powerful prognostic parameter from an exercise test. Multiple large studies in both asymptomatic and symptomatic subjects have reported similar findings. This relationship is present in both men and women. In one landmark study of more than 14,000 healthy men and women, physical fitness measured by maximal treadmill time was significantly associated with mortality during 8-year follow-up, independent of demographics and standard risk factors.
A study of 2994 asymptomatic women observed for 20 years demonstrated that women who were below the median at baseline for exercise capacity (<7.5 METs) and heart rate recovery (<55 beats/min difference between peak exercise heart rate and heart rate at 2-minute recovery) had a 3.5-fold higher risk of cardiovascular death independent of traditional risk factors. Importantly, functional capacity provides prognostic information beyond traditional risk stratification by the Framingham risk score in both men and women, as discussed later.
Chronotropic Incompetence
Chronotropic incompetence refers to an inability to achieve the expected increase in heart rate with exercise. Multiple parameters have been used to assess chronotropic incompetence. It is most commonly evaluated by the proportion of age-predicted maximal heart rate (HR) achieved during the stress test (peak HR/220 − age). However, in addition to age, the chronotropic response to exercise is also affected by resting heart rate and physical fitness. The proportion of heart rate reserve used is defined as [(peak HR − rest HR)/(maximum age-predicted HR − rest HR)] × 100 and incorporates information about resting heart rate. The chronotropic index incorporates data for both resting heart rate and physical fitness and is defined as the ratio of the metabolic reserve to the heart rate reserve:
Chronotropic index at any stage of the exercise test = [ ( METs stage − METs rest ) / ( METs peak − METs rest ) ] / ( HR peak − HR rest ) / ( HR max predicted − HR rest )
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