You are in: eMedicine Specialties > Cardiology > Cardiovascular Syndromes in Systemic Diseases Treadmill and Pharmacologic Stress TestingArticle Last Updated: Jan 8, 2008AUTHOR AND EDITOR INFORMATIONSection 1 of 13
 
Author: David Akinpelu, MD, Staff Physician, Department of Internal Medicine, Brooklyn Hospital Center, Weill Medical College of Cornell University David Akinpelu is a member of the following medical societies: American College of Physicians-American Society of Internal Medicine and American Medical Association Coauthor(s): Javier M Gonzalez, MD, Consulting Staff, Department of Cardiology, Citrus Memorial Hospital Editors: Justin D Pearlman, MD, PhD, ME, MA, Director of Dartmouth Advanced Imaging Center, Professor of Medicine, Professor of Radiology, Adjunct Professor, Thayer Bioengineering and Computer Science, Dartmouth-Hitchcock Medical Center; Francisco Talavera, PharmD, PhD, Senior Pharmacy Editor, eMedicine; Ronald J Oudiz, MD, Director of Pulmonary Hypertension, Associate Professor, Department of Medicine, Division of Cardiology, Harbor-UCLA Medical Center, David Geffen School of Medicine at UCLA; Amer Suleman, MD, Consultant in Electrophysiology and Cardiovascular Medicine, Department of Internal Medicine, Division of Cardiology, Medical City Dallas Hospital; W Robert Taylor, MD, PhD, Professor of Medicine, Division of Cardiology, Emory University; Professor of Biomedical Engineering, The Wallace H Coulter Department of Biomedical Engineering, Georgia Tech and Emory University; Consulting Staff, Department of Cardiology, Atlanta Veterans Affairs Medical Center and Emory University Hospital Author and Editor Disclosure Synonyms and related keywords: preoperative testing, diagnostic testing, stress test, exercise stress test, cardiovascular testing, cardiovascular disease, coronary artery disease, CAD, standardized exercise protocol, functional capacity, hemodynamic response, diagnostic exercise variables, prognostic exercise variables, ischemic heart disease, IHD, stable chest pain, adenosine, dobutamine, dipyridamole, cardiopulmonary exercise testing, CPET, pharmacologic stress testing, pharmacologic stress test, stress test post-MI, postmyocardial infarction stress test INTRODUCTION AND EXERCISE PHYSIOLOGYSection 2 of 13
 
History Cardiovascular exercise stress testing in conjunction with an ECG has been established as one of the focal points in the diagnosis and prognosis of cardiovascular disease, specifically coronary artery disease (CAD). Feil and Seigel first noticed the significance of cardiovascular exercise stress testing in 1928; they reported ST and T changes following exercise in 3 patients with chronic stable angina.1 The following year, Master and Oppenheimer introduced a standardized exercise protocol to assess functional capacity and hemodynamic response. Continued research into causal mechanisms of ST displacement, refinement of exercise protocols, and determination of diagnostic and prognostic exercise variables in clinical patient subsets have continued to evolve since 1929. After the establishment of coronary angiography as a diagnostic tool, the limitation of exercise-induced ST-segment depression as a diagnostic marker for obstructive CAD in patient populations with a low disease prevalence became apparent. Introduction Exercise testing is a cardiovascular stress test using treadmill bicycle exercise with ECG and blood pressure monitoring. Pharmacologic stress testing, established after exercise testing, is a diagnostic procedure in which cardiovascular stress induced by pharmacologic agents is demonstrated in patients with decreased functional capacity or in patients who cannot exercise. Pharmacologic stress testing is used in combination with imaging modalities such as radionuclide imaging and echocardiography. Exercise stress testing, which is now widely available at a relatively low cost, is currently used most frequently to estimate prognosis and determine functional capacity, to assess the probability and extent of coronary disease, and to assess the effects of therapy. Ancillary techniques, such as metabolic gas analysis, radionuclide imaging, and echocardiography, can provide further information that may be needed in selected patients, such as those with moderate or prior risk. Exercise physiology The initiation of dynamic exercise results in increases in the ventricular heart rate, stroke volume, and cardiac output due to vagal withdrawal and sympathetic stimulation. Also, alveolar ventilation and venous return increase as a result of sympathetic vasoconstriction. The overall hemodynamic response depends on the amount of muscle mass involved, exercise efficiency, conditioning, and exercise intensity. In the initial phases of exercise in the upright position, cardiac output is increased by an augmentation in stroke volume mediated through the use of the Frank-Starling mechanism and heart rate. The increase in cardiac output in the later phases of exercise is due primarily to an increase in ventricular rate. During strenuous exertion, sympathetic discharge is maximal and parasympathetic stimulation is withdrawn, resulting in autoregulation with generalized vasoconstriction, except in the vital organs (cerebral and coronary circulations). Venous and arterial norepinephrine release from sympathetic postganglionic nerve endings is increased, and epinephrine levels are increased at peak exertion, resulting in an increase in ventricular contractility. As exercise progresses, skeletal muscle blood flow increases; oxygen extraction increases as much as 3-fold; peripheral resistance decreases; and systolic blood pressure (SBP), mean arterial pressure, and pulse pressure usually increase. Diastolic blood pressure (DBP) remains unchanged or may increase or decrease by approximately 10 mm Hg. The pulmonary vascular bed can accommodate as much as a 6-fold increase in cardiac output, with only modest increases in pulmonary arterial pressure, pulmonary capillary wedge pressure, and right atrial pressure; this is not a limiting determinant of peak exercise capacity in healthy subjects. The maximum heart rate and cardiac output are decreased in older individuals, related in part to decreased beta-adrenergic responsiveness. Maximum heart rate can be calculated by subtracting the patient's age (y) from 220 (has a standard deviation of 10-12 beats per minute [bpm]). The age-predicted maximum heart rate is a useful measurement for safety reasons and as an estimate of the adequacy of the stress to evoke inducible ischemia. A patient who reaches 80% of the age-predicted maximum is considered to have a good test result, and an age-predicted maximum of 90% or better is considered excellent. In the postexercise phase, hemodynamics return to baseline within minutes of discontinuing exercise. The return of vagal stimulation is an important cardiac deceleration mechanism after exercise and is more pronounced in well-trained athletes but blunted in patients with chronic congestive heart failure. Intense physical work or important cardiorespiratory impairment may interfere with achievement of a steady state, and an oxygen deficit occurs during exercise. The oxygen debt is the total oxygen uptake in excess of the resting oxygen uptake during the recovery period. CLINICAL GUIDELINESSection 3 of 13
American College of Cardiology (ACC)/American Heart Association (AHA) guidelines for exercise stress testing were initially formed in 1997 to create recommendations regarding the appropriate use of testing in the diagnosis, prognosis, and treatment of patients with known or probable cardiovascular disease. These guidelines were revised in 2002.2 The new recommendations that appear in this update are based on significance of the supporting data. The weight of evidence was ranked highest (A) if the data were based on multiple randomized clinical trials that involved large numbers of patients. An intermediate rank (B) indicates that the data were derived from a limited number of randomized trials that involved small numbers of patients or from careful analyses of nonrandomized studies or observational registries. If expert consensus was the primary basis for the recommendation, a lower rank (C) is given. Exercise testing is a well-established procedure that has been in widespread clinical use for decades, and, although it is generally a safe procedure, both myocardial infarction and death have been reported and can be expected to occur at a rate of 1 incident per 2500 tests. Therefore, use good clinical judgment when deciding which patients should undergo exercise testing. When considering the use of exercise testing in individual patients, factors that are important in establishing good clinical outcomes include the quality, expertise, and experience of the professional and technical staff performing and interpreting the study to reduce observer error; the sensitivity, specificity, and accuracy of the technique to establish limitations of this procedure; and the cost and accuracy of the technique as compared with more expensive imaging procedures to establish the risk-to-benefit ratio, to determine the effect of positive or negative results on clinical decision making, and, lastly, to weigh the potential psychological benefits of patient reassurance. Contraindications to exercise stress testing The following contraindications are from the AHA/ACC guidelines published in 1997.
The vast majority of treadmill exercise testing is performed on adults with symptoms of known or probable ischemic heart disease. Candidates for exercise stress testing may have stable symptoms of chest pain, may be stabilized by medical therapy following symptoms of unstable chest pain, or may have already had a myocardial infarction or a vascularization procedure. The clinical suggestion of CAD based on patient history findings, ECG tracings, and symptoms of chest pain must be established and used as a guide to determine if treadmill exercise testing may be useful according to the Bayes theorem, which states that the diagnostic power of exercise stress testing is maximal when the pretest probability of CAD is intermediate (30-70%) based on age, sex, and the nature of the chest pain. When the diagnosis of CAD is certain, based on age, sex, description of chest pain, and history of prior myocardial infarction, a clinical need may arise for risk or prognostic assessment to reach a decision regarding possible coronary angiography or revascularization to guide further medical management. Myocardial infarction is a common first presentation of ischemic heart disease. This subset of patients also may require prognostic and/or risk or assessment. In the original guidelines, the committee did not rank the available scientific evidence as A, B, or C, as described above. The level of evidence is considered in the new recommendations that appear in this update. The weight of evidence was ranked highest (A) if the data were based on multiple randomized clinical trials that involved large numbers of patients. An intermediate rank (B) indicates that the data were derived from a limited number of randomized trials that involved small numbers of patients or from careful analyses of nonrandomized studies or observational registries. If expert consensus was the primary basis for the recommendation, a lower rank (C) is given. When few or no data exist, this is noted in the text, and the recommendations are based on the expert consensus of the committee. The ACC/AHA classifications I, II, and III are used to summarize indications for exercise stress testing and are listed as follows:
Treadmill protocol Report exercise capacity in estimated metabolic equivalents (METs) of exercise. A MET refers to the resting volume oxygen consumption per minute (VO2) for a 70-kg, 40-year-old man. One MET is equivalent to 3.5 mL/min/kg of body weight. An example is the standard Bruce protocol, which starts at 1.7 mph and 10% grade (5 METs) with larger increments between stages than other protocols, such as the Naughton, Weber, and Asymptomatic Cardiac Ischemia Pilot (ACIP) study, which start at less than 2 METs at 2 mph and increase in 1- to 1.5-MET increments between stages. The Bruce protocol has 3-minute periods to allow achievement of a steady state before workload is increased. Stage 1 is 1.7 mph at 10% grade (5 METs). Stage 2 is 2.5 mph at 12% grade (7 METs). Stage 3 is 3.4 mph at 14% grade (9 METs). The modified Bruce protocol has two 3-minute warmup stages at 1.7 mph and 0% grade and 1.7 mph and 5% grade, and it is most often used in older individuals or those whose exercise capacity is limited by cardiac disease. Other exercise protocols include bicycle and arm ergometry, both of which are used less often than treadmill stress testing in North America. The bicycle ergometer has the advantage of requiring less space than a treadmill. It is quieter, permits sensitive precordial measurements without much motion artifact, and is generally safer because the risk of falling from the machine is lower. Indications for terminating exercise testing According to the ACC/AHA guidelines, the following are indications for termination of exercise testing:
Interpretation Interpretation should include exercise capacity and clinical, hemodynamic, and ECG response. The occurrence of ischemic chest pain consistent with angina is important, particularly if it forces termination of the test. The classic criteria for visual interpretation of positive stress test findings are J-point (defined as the junction of the point of onset of the ST-T wave and normally at or near the isoelectric baseline of the ECG) and ST80 (defined as the point that is 80 ms from the J point) depression of 0.1 mV (1 mm) or more and/or an ST-segment slope within the range of ±1 mV/s in 3 consecutive beats. Noncoronary causes of ST-segment depression include the following:
DIAGNOSIS OF OBSTRUCTIVE CORONARY ARTERY DISEASESection 4 of 13
When using exercise testing in patients thought to have CAD, classify these patients to properly assess the risks versus benefits. The ACC/AHA guidelines outline these as follows:
Rationale Exercise stress testing can be useful in establishing the diagnosis of significant obstructive CAD when the diagnosis is in question, and, although other clinical findings such as dyspnea upon exertion, resting ECG tracing abnormalities, or multiple risk factors for atherosclerosis may suggest the possibility of CAD, the most important clinical finding is a history of chest discomfort or pain. Myocardial ischemia is the most important cause of chest discomfort or pain and is most commonly a consequence of underlying CAD. Pretest probability The clinician's estimation of the pretest probability of CAD is primarily based on the patient's history. The most predictive parameters are the description of chest pain, sex, and age. The pretest probability of CAD based on these parameters is applied in the Bayes theorem, and, according to this theorem, the diagnostic power of exercise testing results is maximal when the pretest probability of CAD is intermediate (30-70%). The usefulness of exercise testing for the diagnosis of CAD is expressed most commonly by sensitivity and specificity. Sensitivity varies from 61-73% as reported by various analysts, and specificity varies from 59-81% depending on the study or article referenced. Results of correlative studies have been divided concerning the use exercise stress testing in patients with 50% or 70% luminal diameter occlusion. A meta-analysis of 58 consecutively published reports involving 11,691 patients without prior myocardial infarction who underwent coronary angiography and exercise testing revealed a wide variability in sensitivity and specificity. Mean sensitivity was 67%; mean specificity was 72%. In the 3 studies in which workup bias was avoided by having the patients agree to undergo both coronary angiography and exercise testing, the approximate sensitivity and specificity of 1 mm of horizontal or down-sloping ST depression for diagnosing CAD were 50% and 90%, respectively. The true diagnostic value of the exercise ECG findings apparently lies in their relatively high specificity. The wide variability in test performance apparent from this meta-analysis demonstrates the importance of using proper methods for testing and analysis. Consider up-sloping ST depression as a borderline positive test result or a result possibly warranting further diagnostic testing. The standard exercise test remains the first option in the evaluation of possible CAD in patients with an indeterminate pretest probability, although resting ST depression of less than 1 mm somewhat lowers specificity. LVH with less than 1 mm of ST depression (at the ST80 point) and the use of digoxin with less than 1 mm of depression also lower specificity, but the standard exercise test remains a reasonable option in such patients. In contrast, other baseline ECG abnormalities, such as preexcitation, ventricular pacing, greater than 1 mm of ST depression (at the ST80 point) at rest, and complete left bundle branch block, greatly affect the diagnostic performance of the exercise test results. Imaging modalities are preferred in the subset of patients with other baseline ECG abnormalities. While computer processing of the exercise ECG can be helpful, it can result in a false-positive depiction of ST depression. To avoid this problem, the physician should always be provided with ECG recordings of the raw unprocessed ECG data for comparison with any averages the exercise test monitor generates. New pretest probability considerations In the new guideline review, other clinical scores have been developed that could better predict pretest probability of CAD. These mathematical equations, or scores, developed from multivariable analysis of clinical and exercise test variables provide superior discrimination over the ST segment response alone in the diagnosis of CAD. Such scores can provide probabilities of CAD that are more accurate than ST measurements alone. Detailed nomograms are available that incorporate the effects of a history of prior infarction, electrocardiographic Q waves, electrocardiographic ST- and T-wave changes, diabetes, smoking, and hypercholesterolemia. History and electrocardiographic evidence of prior infarction dramatically affect pretest probability. The Duke treadmill prognostic score has been shown to be better than ST depression alone for diagnosing angiographic coronary disease. The variability of the reported diagnostic accuracy of the exercise ECG has been studied by meta-analysis and, despite workup bias, this analysis provides the best description of the diagnostic accuracy of the exercise stress test. Confounders of exercise stress testing Confounders of exercise stress testing include the following:
Right-sided chest leads In a new approach, Michaelides et al examined 245 patients who underwent exercise testing with standard 12 leads, right ventricular leads, and thallium-201 scintigraphy. They found sensitivities of 66%, 92%, and 93% and specificities of 88%, 88%, and 82%, respectively, for the detection of CAD based on angiography, ie, results comparable with those of perfusion scanning when right-sided leads were added. However, this study was performed in a population with an abnormally high prevalence of coronary disease, and the committee would not recommend clinical use of right-sided chest leads until these results are confirmed by others. ST–heart rate adjustment Several methods of heart rate adjustment have been proposed to increase the diagnostic accuracy of the exercise ECG. The maximal slope of the ST segment relative to heart rate is derived either manually or by computer. A second technique, termed the ST–heart rate (ST/HR) index, divides the difference between ST depression at peak exercise by the exercise-induced increase in heart rate. ST/HR adjustment has been the subject of several reviews since the last publication of these guidelines. The major articles that used this approach for diagnostic testing include Morise's3 report of 1358 individuals undergoing exercise testing (only 152 with catheterization data) and the report by Okin et al4 considering heart rate reserve (238 controls and 337 patients with coronary disease). Viik et al5 considered the maximum value of the ST/HR hysteresis over a different number of leads for the detection of CAD. The study population consisted of 127 patients with coronary disease and 220 patients with a low likelihood of the disease referred for an exercise test. Neither the Okin et al study nor the Viik et al study considered consecutive patients with chest pain, and both had limited challenge. Limited challenge favors the ST/HR index because healthy patients have relatively high heart rates and sick patients have low heart rates. Because this leads to a lower ST/HR index in those without disease and a higher index in sicker patients, the enrollment of relatively healthy patients in these studies presents a limited challenge to the ST/HR index. Likewise, the Morise study had a small number of patients who underwent angiography. The only study with neither of these limitations was QUEXTA. This large, multicenter study followed a protocol to reduce workup bias and was analyzed by independent statisticians. The ST/HR slope or index was not found to be more accurate than simple measurement of the ST segment. Although some studies in asymptomatic (and therefore very low likelihood) individuals have demonstrated additional prognostic value with the ST/HR adjustment, these data are not directly applicable to the issue of diagnosis in symptomatic patients. Nevertheless, one could take the perspective that the ST/HR approach in symptomatic patients has at least equivalent accuracy to the standard approach. Although not yet validated, the ST/HR approach could prove useful in some situations, such as in rendering a judgment concerning certain borderline or equivocal ST responses (eg, ST-segment depression associated with a very high exercise heart rate). Although the initial reports were promising, neither meta-analysis nor a subsequent study found convincing evidence of benefit. In interpretation of exercise tests, exercise capacity is more important to consider than exercise heart rate. Computer processing Although computer processing of the exercise ECG can be helpful, it can result in a false-positive indication of ST depression. To avoid this problem, the physician should always be provided with ECG recordings of the raw, unprocessed ECG data for comparison with any averages the exercise test monitor generates.
None of the computerized scores or measurements has been validated sufficiently to recommend their widespread use. At least one study in which these shortcomings have been addressed showed that computerized measurements are comparable with visual measurements and that they can provide excellent test characteristics when combined with scores. RISK ASSESSMENT AND PROGNOSIS OF SYMPTOMATIC PATIENTS OR THOSE WITH CADSection 5 of 13
For proper evaluation, risk assessment, and prognosis in symptomatic patients or those with CAD, the ACC/AHA guidelines are as follows:
Patients with possible or known CAD and new or changing symptoms that suggest ischemia should generally undergo exercise testing (only if cardiac catheterization is not indicated) to assess their risk for future cardiac events. Documentation of exercise or stress-induced ischemia is desirable for most patients undergoing evaluation for revascularization, according to the ACC/AHA guidelines for percutaneous transluminal coronary angioplasty (PTCA) and coronary artery bypass graft (CABG). When determining the initial stress test modality, evaluate the patient's resting ECG findings, physical ability to exercise, and local expertise and technologies. For risk assessment, the exercise test should be the standard initial mode of stress testing used in patients at the provider's institution who have normal ECG tracings and who are not taking digoxin. In patients who are unable to exercise because of physical limitations (eg, arthritis, amputations, severe peripheral vascular disease, severe chronic obstructive pulmonary disease [COPD], general debility), pharmacological stress testing in combination with imaging is recommended. Exercise testing may be useful for prognostic assessment of patients taking digoxin or patients with abnormal resting ECG findings, but its usefulness is less well established in this setting. Patients with preexcitation, ventricular-paced rhythm, widespread ST depression (>1 mm), or complete left bundle branch block (an intraventricular conduction defect with a QRS duration >120 ms) should usually be tested with an imaging modality. Exercise testing may provide prognostic information (particularly exercise capacity) in patients with nondiagnostic ECG changes, but it cannot be used to identify ischemia. One of the strongest and most consistent prognostic markers identified in exercise testing is maximum exercise capacity, which is at least partly influenced by the extent of resting left ventricular dysfunction and the amount of increased left ventricular dysfunction induced by exercise. When interpreting an exercise test result, considering exercise capacity is very important. This may be achieved with one of several markers of exercise capacity, including maximal exercise duration, maximal MET level achieved, maximum workload achieved, or maximum heart rate and heart rate–blood pressure product. A second group of prognostic markers identified from the exercise test relates to exercise-induced ischemia and includes exercise-induced ST deviation (elevation and depression) and exercise-induced angina. The Duke treadmill score incorporates both groups of prognostic markers (exercise capacity and exercise-induced ischemia). This score was originally developed using data from 2842 inpatients with known or possible CAD who underwent exercise testing before diagnostic angiography and had no prior revascularization or recent myocardial infarction. The score applies equally well in males and females but has not been evaluated extensively in elderly patients. Risk assessment also may be appropriate in certain patients with unstable angina. Guidelines for the diagnosis and treatment of unstable angina endorsed by the ACC and the AHA stratify risk assessment as being low, moderate, or high based on patient history, physical examination findings, and initial resting ECG tracings. In low-risk patients with unstable angina who are evaluated in an outpatient setting, exercise or pharmacological stress testing should generally be performed within 72 hours of presentation. In low- or intermediate-risk patients with unstable angina who have been hospitalized for evaluation, exercise or pharmacological stress testing should generally be performed unless cardiac catheterization is indicated. Testing can be performed when patients have been free of active ischemic or heart failure symptoms for a minimum of 8-12 hours. Intermediate-risk patients can be tested after 2-3 days, but selected patients can be evaluated earlier as part of a carefully constructed chest pain management protocol (see Chest pain centers). In general, as with patients with stable angina, the treadmill test should be the standard stress test for patients with normal resting ECG tracings who are not taking digoxin. Most patients with unstable angina have an underlying ruptured plaque and significant CAD. Some have a ruptured plaque without significant lesions in any coronary segment as determined by angiography. Still others have no evidence of a ruptured plaque or atherosclerotic coronary lesions. Very little evidence exists with which to define the safety of early exercise testing in unstable angina. One review of this area found 3 studies covering 632 patients with stabilized unstable angina who had a 0.5% mortality or myocardial infarction rate within 24 hours of their exercise test. In addition, many available studies contain both patients with unstable angina and those who have experienced myocardial infarction. The limited evidence available supports the use of exercise testing in patients with acute chest syndrome (ACS) who have appropriate indications as soon as they are stabilized clinically. Larsson and colleagues compared a symptom-limited predischarge (3-7 d) exercise test with a test performed at 1 month in 189 patients with unstable angina or non–Q-wave infarction. The prognostic value of the two tests was similar, but the earlier test identified additional patients who would experience events during the period before the 1-month exercise test. In this population, these earlier events represented one half of all events that occurred during the first year. The Research on Instability in Coronary Artery Disease (RISC) study group examined the use of predischarge symptom-limited bicycle exercise testing in 740 men admitted with unstable angina (51%) or non–Q-wave myocardial infarction (49%). The major independent predictors of 1-year infarction-free survival in multivariable regression analysis were the number of leads with ischemic ST-segment depression and the peak exercise workload achieved. In 766 patients with unstable angina enrolled in the Fragmin During Instability in Coronary Artery Disease (FRISC) study between 1992 and 1994 who had both a troponin T level and a predischarge exercise test, the combination of a positive troponin T level and exercise-induced ST depression stratified patients into groups with a risk of death or myocardial infarction that ranged from 1-20%. In 395 women enrolled in FRISC I with stabilized unstable angina who underwent a symptom-limited stress test at days 5-8, risk for cardiac events in the next 6 months could be stratified from 1-19%. Important exercise variables included not only ischemic parameters such as ST depression and chest pain but also parameters that reflected cardiac workload. Over the last decade, increasing experience has been gained with the use of exercise testing in emergency department chest pain centers. The goal of a chest pain center is to provide rapid and efficient risk stratification and treatment for patients with chest pain who are believed to possibly have acute coronary disease. Various physical and administrative setups have been used for chest pain centers in medical centers across the country; review of these details is beyond the scope of these guidelines. In most of the published series, exercise testing has been reserved for the investigation of patients who are low-risk based on history and physical examination, 12-lead ECG, and serum markers. In the study by Gibler et al, 1010 patients were evaluated with clinical examination, 9 hours of continuous ST monitoring, serial 12-lead ECGs, serial measurement of creatine kinase-MB levels, and resting echocardiograms. Patients without high-risk markers based on this evaluation (78%) underwent a symptom-limited Bruce exercise ECG test. No adverse events were reported from the testing, and the authors estimated a 5% prevalence of CAD in the tested population. These results are generally representative of the results in the approximately 2100 patients with chest pain who have undergone exercise testing as part of a chest pain center protocol report. The prevalence of CAD is extremely low in such patients, and the risk of adverse events with testing is correspondingly low. Farkouh and colleagues from the Mayo Clinic examined the use of exercise testing in 424 intermediate-risk patients with unstable angina (as defined by the ACC/AHA Committee to Develop Guidelines for the Management of Patients With Unstable Angina) as part of a randomized trial of admission to a chest pain unit versus standard hospital admission. Event rates (death, myocardial infarction, congestive heart failure) did not significantly differ among the 212 patients in the hospital admission group and the 212 patients in the chest pain unit group. Of the total chest pain unit group, 60 patients met the criteria for hospitalization before stress testing, 55 had an indeterminate or high-risk test result, and 97 had negative stress test findings. No complications were directly attributable to the performance of a stress test in these patients. These results demonstrate that exercise testing is safe in low-risk patients with chest pain who present to the emergency department. In addition, testing appears safe in carefully selected intermediate-risk patients. Use of early exercise testing in emergency department chest pain centers improves the efficiency of treatment in these patients (and may lower costs) without compromising safety. However, exercise testing in this setting should be performed only as part of a carefully constructed management protocol and only after the patients have been screened for high-risk features or other indicators for hospital admission. EXERCISE TESTING AFTER MYOCARDIAL INFARCTIONSection 6 of 13
Importantly, when considering exercise stress testing after myocardial infarction, consider the appropriate time frame with regard to risks and benefits of the test before it is performed. The AHA/ACC guidelines outlining this stratification are as follows:
Current guidelines for the treatment of patients with acute myocardial infarction include medical therapy, thrombolytic agents, and coronary revascularization. These interventions have led to a marked improvement in prognosis for postinfarction patients, particularly those who have been treated with reperfusion, and mortality rates are low among patients who have received thrombolytic agents or direct angioplasty. Patients who are unable to perform an exercise test have a much higher rate of adverse events than those who are able to perform an exercise test. Symptomatic ischemic ST depression with exercise testing after thrombolytic therapy increases the risk of cardiac mortality 2-fold, but the absolute risk rate remains low (1.7% at 6 mo). Exercise testing after myocardial infarction is generally safe. Submaximal testing can be performed at 4-7 days, and a symptom-limited test can be performed 3-6 weeks later. Some experts feel that symptom-limited tests can be conducted early after discharge, at approximately 14-21 days. Exercise testing is useful in activity counseling after discharge from the hospital, and it is also an important tool in exercise training, as part of comprehensive cardiac rehabilitation for assessing the patient's response to the exercise training program. CARDIOPULMONARY EXERCISE TESTINGSection 7 of 13
Cardiopulmonary exercise testing (CPET) combines exercise testing with ventilation gas analysis, and the recommendations according to the ACC/AHA guidelines are as follows:
CPET is a useful adjunctive tool for the assessment of patients with cardiovascular and pulmonary disease and involves measurements of gas exchange, which primarily include oxygen uptake (ie, VO2), carbon dioxide output (VCO2), minute ventilation, and anaerobic (lactic acid) threshold. Patients usually wear a nose clip and breathe through a nonrebreathing valve that separates expired air from room air. VO2 at maximal exercise (peak VO2) is considered the best index of aerobic capacity and cardiorespiratory function. Estimation of maximal aerobic capacity using published formulas based on exercise time or work rate without direct measurement is limited by physiological and methodological inaccuracies. According to current data acquired from patients with heart failure undergoing cardiopulmonary stress testing using this method, subsequent analysis has been demonstrated to be reliable and important, and subsequent analysis benefits this subgroup of patients the most. Such data are only partly influenced by resting left ventricular dysfunction. Maximal exercise capacity does not necessarily reflect the daily activities of patients with heart failure. Use of this technique in stratification of patients with ambulatory heart failure has improved the clinician's ability to identify those with the poorest prognosis who should be considered for heart transplantation. Abnormal ventilatory and chronotropic responses to exercise are also predictors of outcome in patients with heart failure. In addition, evaluation of the rate of VO2 decline during exercise recovery (VO2 kinetics) may provide additional information regarding the functional state in patients with heart failure. Compared with normal oxygen kinetics, prolonged recovery time of VO2 has been correlated with poorer exercise tolerance, lower peak VO2, and a lower cardiac index. Most investigators conclude that measurement of peak VO2 yields the best prognostic information in patients with heart failure. Evaluation of submaximal and recovery ventilatory responses may be particularly useful when exercise to near-maximal levels (respiratory exchange ratio >1) is not achieved. SPECIAL GROUPS: FEMALE, ASYMPTOMATIC, AND POSTREVASCULARIZATION PATIENTSSection 8 of 13
The usefulness of exercise ECG for the diagnosis of coronary disease in women has limitations. Exercise-induced ST depression is less sensitive in women than men, reflecting a lower prevalence of severe coronary disease and the inability of many women to exercise to maximum aerobic capacity. Exercise ECG findings are also commonly viewed as less specific in women than in men, although careful review of the published data demonstrates that this finding certainly has not been uniform. Studies that demonstrated lower specificity in women have cited lower disease prevalence, non-Bayesian factors, and possible hormonal differences. Physicians must be cognizant of the decrease in sensitivity that occurs when women do not exercise to maximum aerobic capacity. Patients likely to exercise submaximally should be considered for pharmacological stress testing. Concern about false-positive ST-segment responses may be addressed by careful assessment of posttest probability and selective use of stress imaging tests before proceeding to angiography. Although the optimal strategy for circumventing false-positive test results for the diagnosis of CAD in women remains to be defined, data are insufficient to justify routine stress imaging tests as the initial test for the diagnosis of CAD in women. Diagnosis of CAD in elderly patients CAD is highly prevalent in symptomatic elderly patients (>65 y). Pharmacological stress testing is required more often in elderly patients because of their inability to exercise adequately. Interpretation of exercise test results from elderly patients differs somewhat from that in younger patients. Resting ECG abnormalities may compromise the accuracy of diagnostic data from the ECG. Nonetheless, the application of standard ST-segment response criteria to elderly subjects does not appear to be associated with a significant difference in accuracy from that of younger patients. Due to the greater prevalence of severe CAD, exercise testing in this group is reported to have a slightly higher sensitivity than in younger patients. A slightly lower specificity has also been reported, which may reflect the coexistence of LVH due to valvular disease and hypertension. Although the risk of coronary angiography may be greater in elderly patients and the justification for coronary intervention less, the results of exercise testing in elderly patients remain important because medical therapy may carry substantial risks for this group. Exercise testing in asymptomatic persons without known CAD According to the ACC/AHA classification that follows, no indications exist for routine exercise testing in asymptomatic persons without known CAD or risk factors.
The goal of screening for possible CAD in asymptomatic patients is to either prolong life or improve quality of life. This has been supported by data from the Coronary Artery Surgery Study and the ACIP study in asymptomatic patients with severe CAD, which suggests that performing revascularization may prolong life. Although current clinical guidelines suggest risk reduction factors in all people, the detection of ischemia after stress testing results indicate functional impairment may further motivate patients to be more compliant with a program of risk factor modification. Prediction of myocardial infarction and death are considered the most important end points of screening asymptomatic patients. In general, the relative risk of a subsequent event is increased in patients with a positive exercise test result, although the absolute risk of a cardiac event in an asymptomatic patient remains low. The annual rate of myocardial infarction and death in such patients is approximately 1%, even when ST-segment changes are associated with risk factors. A positive exercise test result is more predictive of later development of angina than the occurrence of a major event. Even when subsequent angina is considered an event, a minority of patients with a positive test result experience cardiac events. Unfortunately, patients with positive test results may be labeled at risk. For example, general population screening programs attempting to identify young patients with early disease are limited in that severe CAD requiring intervention in asymptomatic patients is exceedingly rare. Although the physical risks of exercise testing are negligible, false-positive test results may (1) engender inappropriate anxiety, (2) have serious adverse consequences related to work and insurance coverage, and (3) lead to complications from further diagnostic testing. For these reasons, exercise testing in healthy, asymptomatic persons is not recommended. Selected patients with multiple risk factors for CAD are at greater absolute risk for subsequent myocardial infarction and death. Screening may potentially be helpful in patients who are at moderate risk, as defined by the available prognostic data from asymptomatic persons in the Framingham study. For these purposes, define risk factors very strictly. Multiple risk factors are defined as hypercholesterolemia (cholesterol >240 mg/dL), hypertension (SBP >140 mm Hg or DBP >90 mm Hg), smoking, diabetes, and family history of heart attack or sudden cardiac death in a first-degree relative younger than 60 years. An alternative approach might be to select patients with a Framingham risk score consistent with at least a moderate risk of serious cardiac events within 5 years. Attempts to extend screening to persons with lower degrees of risk are not recommended because screening is extremely unlikely to improve patient outcome. Valvular heart disease According to the ACC/AHA guidelines, no recommendations exist for routine exercise testing of patients with valvular heart disease. The current recommendations for which patients with valvular heart disease should undergo exercise testing are as follows:
In symptomatic patients with documented valvular disease, the course of treatment is usually clear, and exercise testing is not required. Further, the expanding use of Doppler echocardiography has greatly increased the number of asymptomatic patients with well-defined valvular abnormalities, the etiology of which may be other than ischemic (ie, congenital abnormalities). The primary value of exercise testing in persons with valvular heart disease is to assess atypical symptoms, exercise capacity, and the extent of disability objectively—all of which may have implications for clinical decision making. Assessment is particularly important in elderly patients, who may not have symptoms because of limited activity. Use of the exercise ECG for diagnosis of CAD in these situations is limited by false-positive responses due to LVH and baseline ECG changes. In patients with aortic stenosis, a physician familiar with the patient's condition should supervise the test directly, and exercise should be terminated for inappropriate blood pressure augmentation, slowing of the heart rate with increasing exercise, or premature beats. Because the major indication for surgery in mitral stenosis is symptom status, exercise testing is most valuable when a patient is thought to be asymptomatic due to inactivity or when a discrepancy exists between the patient's symptoms and the valve area. Because ejection fraction is a reliable index of left ventricular function in aortic regurgitation, decisions regarding surgery are likely to be based on resting ejection fraction values, and exercise testing is not commonly required unless symptoms are ambiguous. Resting ejection fraction is a poor guide to ventricular function in patients with mitral regurgitation; thus, combinations of exercise and assessment of left ventricular function may be of value in documenting occult dysfunction. Exercise testing before and after revascularization Exercise testing in patients after revascularization constitutes an important part of treatment of these patients because the risk of undergoing major surgery—the risks versus benefits—must be considered carefully and the patients must be assessed properly. The current ACC/AHA guidelines are as follows:
PHARMACOLOGIC STRESS TESTINGSection 9 of 13
Pharmacologic stress testing is generally instituted when contraindications to routine exercise stress exist or when the patient is unable to exercise because of debilitating conditions in various forms. These include the following general indications:
Some centers prefer to use pharmacologic stress testing in conjunction with echocardiogram, MRI, or CT scanning because it avoids repositioning the patient, which may be necessary during nuclear imaging. Repositioning the patient may give a false-positive pharmacologic stress test result because of different degrees of attenuation of myocardial tissue imaging with changes in the breast positions as seen in women. Various pharmacologic agents are used for cardiovascular stress testing and are usually used in combination with radionuclide isotopes that are taken up by the myocardium during routine testing. The common ones are discussed below. AdenosineMechanism of action Adenosine is a naturally occurring substance found throughout the body in various tissues. It functions to regulate blood flow in many vascular beds, including the myocardium. The mechanisms by which adenosine is produced intracellularly are the S-adenosyl homocysteine and the adenosine triphosphate pathways; the latter plays a role during ischemia. Once transported across cell membranes, adenosine interacts and activates the A1 and A2 cell surface receptors. In the vascular smooth muscles, adenosine primarily acts by activation of the A2 receptor, which stimulates adenylate cyclase, leading to an increase in cyclic adenosine monophosphate (cAMP) production. Increased cAMP levels inhibit calcium uptake by the sarcolemma, causing smooth muscle relaxation and vasodilation. Activation of the vascular A1 receptor also occurs, which stimulates guanylate cyclase, inducing cyclic guanosine monophosphate production, leading to vasodilation. This direct coronary artery vasodilation induced by adenosine is attenuated in diseased coronary arteries, which have a reduced coronary flow reserve and cannot further dilate in response to adenosine. This is not the case in healthy or less-diseased coronary arteries in the same patient, which produces relative flow heterogeneity throughout the coronary arteries, resulting in relatively more coronary blood flow in the healthy or less-diseased coronary arteries compared with the more-diseased coronary artery. In most cases, coronary blood flow in the diseased coronary arteries does not decrease. In cases of severe vessel stenosis or total occlusions with compensatory collateral circulation, a decrease in coronary blood flow may occur in the diseased coronary artery, thus inducing ischemia via a coronary steal phenomenon. This regional flow abnormality also induces a perfusion defect during radionuclide imaging. Indications Any physical limitation that prevents a patient from exercising maximally is an indication for vasodilator stress testing. Patients taking beta-blockers or other negative chronotropic agents that would inhibit the ability to achieve an adequate heart rate response to exercise are also appropriate candidates for vasodilator stress. Patients with left bundle branch block or ventricular pacemaker (particularly those with severely diseased AV nodes or status post-AV node ablation who are unable to override their ventricular pacing rate) should undergo pharmacologic vasodilator stress because exercise stress often produces a false-positive perfusion defect in the interventricular septum. These defects are probably related to decreased septal contractility, which is accompanied by an autoregulated fall in coronary blood flow to the interventricular septum. Exercise stress or any other cause of tachycardia tends to enhance this heterogeneous perfusion by increasing the flow proportionately more in the normally contracting myocardium, resulting in a falsely underperfused interventricular septum on perfusion imaging. Vasodilator stress has been shown to overcome this coronary blood flow autoregulation, resulting in a more homogeneous perfusion pattern. Contraindications
Practical considerations The use of adenosine requires an infusion pump that delivers the dose (140 mcg/kg/min) over a 6-minute period. The patient should have an intravenous line with a 3-way stopcock or should have 2 intravenous lines. If one intravenous line is used, take care to inject the radiopharmaceutical slowly because a bolus or any forceful injection will cause an abrupt increase in the infusion rate of the adenosine running through the same line. This can lead to significant AV nodal block. ECG monitoring of the vital signs is necessary as with exercise stress testing. Adenosine is infused at a rate of 140 mcg/kg/min for 6 minutes. At the 3-minute mark, the stress radiopharmaceutical is injected and the infusion is continued for 3 more minutes. Some have suggested that patients determined to be at high risk for complications (eg, questionable history of asthma, hypotension, recent ischemic event, severe bradycardia) should undergo an incremental 7-minute adenosine protocol. This protocol starts at 50 mcg/kg/min and increases to 75, 100, and 140 mcg/kg/min at 1-minute intervals followed by injection of the stress radiopharmaceutical at 1 minute after the highest tolerated dose. The test continues for 3 minutes following injection of the radiopharmaceutical. Unlike dipyridamole, the effect of adenosine dissipates promptly with discontinuation of the infusion. Thus, the infusion must continue during stress imaging until the imaging is completed, whereas for dipyridamole, imaging may follow but in a limited time window. For a stress/rest protocol, adenosine does not require reversal, whereas dipyridamole requires theophylline administration to assure prompt reversal of its stress effects. Early termination The following are indications for early termination of adenosine infusion:
Adverse effects Approximately 80% of patients experience minor adverse effects from adenosine infusion. However, an absence of these effects does not imply a lack of efficacy of the adenosine with respect to coronary vasodilation. The chest pain experienced during adenosine infusion is very nonspecific and does not indicate the presence of CAD. However, approximately a third of patients with ischemia after perfusion imaging have ST-segment depression during the infusion of adenosine. Three categories of adverse effects exist, including systemic effects (dizziness [7%], headache [21%], symptomatic hypotension [3%], dyspnea [19%], and flushing [35%]), gastrointestinal effects (nausea [5.1%]), and cardiac effects (chest pain [34%] and ST-segment changes [13%]). Adenosine-walk protocol For patients who are able, combined low-level treadmill exercise during adenosine infusion has been demonstrated in several reports to be associated with a significant decrease in the frequency of adverse effects (eg, flushing, nausea, headache). In addition, less-symptomatic hypotension and bradycardia occur. These studies have also uniformly reported improved image quality, as demonstrated by an increased target-to-background ratio. An additional advantage is that simultaneous low-level exercise allows for immediate imaging, as would be performed with exercise stress testing. This is due to the peripheral vasodilation and splanchnic vasoconstriction induced by exercise. Dipyridamole (Persantine)Mechanism of action Dipyridamole is an indirect coronary vasodilator that works by increasing intravascular adenosine levels. This occurs by the inhibition of intracellular reuptake and deamination of adenosine. However, the increase in coronary blood flow induced by dipyridamole is less predictable than that of adenosine. In one comparative study of dipyridamole and adenosine, 66% of patients (10 of 15) receiving dipyridamole versus 80% of patients (12 of 15) receiving adenosine had a maximal hyperemic response. However, this difference may not be apparent clinically. The mechanism of inducing a perfusion abnormality is similar to that of adenosine (see Adenosine) except true coronary steal occurs more frequently. Dipyridamole dosing The standard dose of dipyridamole 0.56 mg/kg infused over 4 minutes. Indications Any physical limitation that prevents a patient from exercising maximally is an indication for vasodilator stress. Patients taking beta-blockers or other negative chronotropic agents that would inhibit the ability to achieve an adequate heart rate response to exercise are also appropriate candidates for vasodilator stress. Patients with left bundle branch block or a ventricular pacemaker (particularly those with severely diseased AV nodes or status post-AV node ablation who are unable to override their ventricular pacing rate) should undergo vasodilator stress because exercise stress often produces a false-positive perfusion defect in the interventricular septum. These defects are probably related to decreased septal contractility, which is accompanied by an autoregulated decrease in coronary blood flow to the interventricular septum. Exercise stress or any other cause of tachycardia tends to enhance this heterogeneous perfusion by increasing the flow proportionately more in the normally contracting myocardium, resulting in a falsely underperfused interventricular septum with perfusion imaging. Vasodilator stress has been shown to overcome this coronary blood flow autoregulation, resulting in a more homogeneous perfusion pattern. Contraindications
Practical considerations Dipyridamole should be infused via an infusion pump over 4 minutes. However, some choose to infuse the dipyridamole by hand, which is also acceptable. The radiopharmaceutical is then injected 3-5 minutes following the completion of the dipyridamole infusion. Perform a standard ECG and monitoring of the vital signs as with exercise stress testing until the hemodynamic effects of dipyridamole have resolved. Adverse effects The adverse effects experienced are similar to those with use of adenosine. While adverse effects are less frequent with dipyridamole (47% of patients), they tend to be more serious than those associated with adenosine. The most common adverse effects of dipyridamole are chest pain (19%), headache (12%), and hypotension (4.6%). In addition, 12% of patients require aminophylline for reversal of adverse effects. Dipyridamole-walk protocol The protocol is similar to that of adenosine; however, the treadmill portion does not begin until 1 minute prior to the injection of the radiopharmaceutical (after completion of the infusion of dipyridamole) and should be continued for at least 2 minutes after the injection of the radiopharmaceutical. DobutamineMechanism of action Dobutamine is a synthetic catecholamine, which directly stimulates both beta-1 and beta-2 receptors. A dose-related increase in heart rate, blood pressure, and myocardial contractility occurs. As with physical e |