Cardiac stress test



A Cardiac Stress Test is a medical test performed to evaluate arterial blood flow to (and indirectly the amount of oxygen that will reach) the myocardium (heart muscle) during physical exercise, compared to blood flow while at rest. As an exercise test, the results can also reflect overall physical fitness. These tests do not assess Emotional stress, or other connotations of the term stress.

Stress test abnormalities (i.e. if it is "positive") are an indication of marked imbalances of relative blood flow to different portions of the Left Ventricular muscle tissue of the heart. This is important because the Left Ventricle of the heart performs the greatest amount of work involved in pumping blood around the body. Blood flow imbalances within the heart muscle of the other three heart chambers are not detected this way.

Usually, only High Grade Stenoses (i.e. severe narrowing) of the larger coronary    (surface of the heart) arteries can be detected. Severe stenoses, e.g. those greater than 75% occlusion, are usually the result of advanced Atherosclerosis (i.e. hardening of the arteries, or arterial disease) and these High Grade Stenoses are the usual cause for both "stable" or reproducible exercise-related Angina (chest pain) and for "positive" stress tests. Less severe stenoses are automatically compensated for, by vasodilation (widening or relaxing) of the ventricular arterioles during exercise, and do not usually produce enough of an imbalance of relative blood flow, to be detectable by stress test methods.

What most laypersons do not realize, is that stress tests do not detect Atheromata  (plaques of Cholesterol and other fats, etc)  present throughout the heart or other body arteries, nor do they reveal the Vulnerable Plaques, which are the cause of most Heart Attacks or Myocardial Infarctions. Recent (late 1990's) clinical studies have shown, that the vulnerable plaques which produce most myocardial infarctions are commonly present within many regions of the coronary (surface of the heart) arteries, yet are typically relatively flat, i.e. not protruding into the artery lumen sufficiently to produce enough stenosis (usually less than 50%, average 20% by some IVUS studies) to be detectable by stress test methods. Thus, over the last 20 years or so, newer approaches in research, have increasingly focused on IMT to detect plaque at earlier stages of progression, before the artery lumen becomes severely stenosed, or compromised.

So the major limitation of the stress test approach, is that it needs a high grade stenosis as an indicator of heart attack risk. High grade stenosis, while being a good indicator of advanced arterial disease, is not the major cause for the majority of heart attacks. This issue is also reflected in the results of the COURAGE trial, which demonstrated that "intensive pharmacologic therapy and lifestyle intervention", which they called "Optimal Medical Therapy" (not opening stenoses with Angioplasty, per-se) produced the more effective results in survival and quality of life.

Test overview
The patient either walks on a treadmill, or is given IV medication which simulates exercise, while connected to an ECG machine, usually the standard 10 connections, used to record a 12-lead ECG. The level of exercise is increased by 3 minute stages, of progressively increased Grade (% incline) and Speed (mph, km/h, etc). The patient's symptoms, and blood pressure response are repeatedly checked. When using ECG and Blood Pressure monitoring alone, the test is variously called a Cardiac Stress test, Exercise Stress test, Exercise Treadmill test, Exercise Tolerance test, Stress Test or Exercise ECG test.

If Radioactive Isotopes are also used (commonly, Technetium Tc99m Sestamibi and rarely, Thallium-201), then it is usually called a Nuclear Stress Test. Given the ability to visualize the relative amounts of radioisotope within different regions of the heart muscle, nuclear stress tests are more accurate in detecting regional areas of decreased blood flow to myocardial (heart muscle) cells. However, diffuse global ischemia (decreased blood flow that is evenly spread out) may still not be recognized, because absolute blood flow is not quantitatively measured, only regional comparative variations.

Purpose
The American Heart Association recommends EKG treadmill testing as the first choice for patients with medium risks of coronary heart disease based on the risk factors of smoking, family history of coronary stenosis, hypertension, diabetes and high cholesterol.

Perfusion radioisotope stress testing using Tc-99m tetrofosmin, Tc-99m sestamibi, or Tl-201 is appropriate for select patients, especially those with an abnormal resting EKG. More severe stenosis (probably greater than 70% occlusion) can produce abnormalities in both EKG waveforms and cardiac wall motion at rest or under stress echocardiographic testing. Such high grade narrowings are typically the primary culprit responsible for those angina episodes which reproducibly occur at a given level of exercise. However, most heart attacks result from rupture of atheroma lesions associated with only mild narrowing (20% on average by intravascular ultrasound (IVUS) clinical studies), thus stress tests do not work well for detecting the vulnerable plaques which are responsible for most heart attacks. Like all tests, stress testing has problems with both falsely positive and falsely negative results compared with other clinical tests.

Angiogram and/or intracoronary ultrasound (preferably in a hospital capable of Percutaneous Coronary Intervention [PCI] with stenting) can provide even greater information, but at the risk of complications associated with cardiac catheterization.

Variations
Some patients with abnormal resting EKGs, or those who are unable to walk safely, can be "exercised" pharmacologically instead of walking on a treadmill. The patient will typically receive a pharmaceutical such as dipyridamole or adenosine (both vasodilators) or dobutamine (stimulates heart rate and pumping force) while a cardiologist or physician assistant reviews the electrocardiogram (EKG) tracing and checks blood pressure periodically.

A radiotracer (typically Technetium-99m sestamibi, Technetium-99m tetrofosmin, or Thallium-201) is injected at peak exertion. After a suitable waiting period, pictures are taken with a gamma camera. The pictures can then be compared with the patient's resting images in order to assess the status of the patient's coronary arteries.

Diagnostic value
The American Heart Association journal, Circulation, describes:


 * Treadmill test: sensitivity of 67%, specificity of 70%
 * Nuclear test:   sensitivity of 81%, specificity of 85-95%

However, these numbers reference detection of advanced artery luminal narrowing as assessed by stress methods compared with angiography as the "gold standard". As a predictor of future heart attack, both methods suffer in that they only detect lumen stenosis, a common symptom of some very advanced atheroma, but not the vulnerable plaques which produce most heart attacks. Because of this, most clinical cardiology experience demonstrates that the actual sensitivity and specificity values for detecting likelihood of future heart attack, as opposed to lumen narrowing, are much lower than stated above.

Whatever the actual numbers, the value of stress tests has increasingly been recognized as limited, especially for people without symptoms. Yet, according to United States data from 2004, for about 65% of men and 47% of women, the first symptom of cardiovascular disease is heart attack or sudden death (death within one hour of symptom onset).

Over the last couple of decades, other methods have been increasingly developed as ways to better detect atherosclerotic disease before it becomes symptomatic. These have included both (a) anatomic detection methods and (b) physiologic measurement methods.

Examples of anatomic methods include: (1) coronary calcium scoring by CT, (2) carotid IMT (intimal medial thickness) measurement by ultrasound, e.g. IntiMaTe, and (3) IVUS.

Examples of physiologic methods include: (1) lipoprotein subclass analysis, (2) HbA1c, (3) hs-CRP, and (4) homocysteine.

The example of the metabolic syndrome combines both anatomic (abdominal girth) and physiologic (blood pressure, elevated blood glucose) methods.

Advantages: The anatomic methods directly measure some aspect of the actual atherosclerotic disease process itself, thus offer potential for earlier detection, including before symptoms start, disease staging and tracking of disease progression. The physiologic methods are often less expensive and safer and changing them for the better may slow disease progression, in some cases with marked improvement.

Disadvantages: The anatomic methods are generally more expensive and several are invasive, such as IVUS. The physiologic methods do not quantify the current state of the disease or directly track progression. For both, clinicians and third party payers have been slow to accept the usefulness of these newer approaches.

Risks
Absolute contraindications to cardiac stress testing include acute myocardial infarction [MI] (heart attack) within 48 hrs, unstable angina not yet stabilized with medical therapy, uncontrolled arrhythmia which may have significant hemodynamic responses (for example ventricular tachycardia), symptomatic severe aortic stenosis, aortic dissection, pulmonary embolism, pericarditis.

Major side effects from cardiac stress testing can include palpitation, chest pain, shortness of breath, headache, nausea, or fatigue. Adenosine and dipyridamole can cause mild drug-induced hypotension. However, hypotension caused by exercise stress testing or dobutamine is almost always abnormal and concerning for severe coronary disease.

Stress tests using radiological agents confer a definite (albeit low) long term risk of cancer, but patients undergoing such examinations often receive little or inaccurate information about these risks. For comparison, the annual background radiation per annum a person receives is approximately 3 mSv. A chest xray is approximately 0.1 mSv. A coronary angiogram (cardiac catheterization) has an effective dose of 3-20 mSv (depending on operator skill, type of intervention, etc). A routine chest helical MDCT is around 5-7 mSv. A cardiac CT (with retrospective EKG gating) is around 8-13 mSv (Morin). A sestamibi scan is approximately 12 mSv. A thallium scan is approximately 25 mSv. A thallium scan corresponds the dose of 250 chest x rays, or an extra cancer risk of about 1 in 16000 exposed patients (A. de González). The lifetime risk of fatal cancer development is 4%/Sv or 0.004%/mSv or about 0.1% for a thallium scan. Therefore, frequent usage of these tests has to balance the benefits against the risks of radiation.

Another major risk of stress testing, whether by exercise or pharmacological agents, is the possibility of inducing an MI, especially in patients with severe multi-vessel coronary artery disease. This risk, however, is substantially lower than the risk of major complications (such as inducing a heart attack, stroke, peripheral artery clot and embolism) from cardiac catheterization (about 1%).

The choice of pharmacologic stress agent to be used (dobutamine, adenosine, dipyridamole) depends on factors such as concurrent medications and diseases. Dobutamine is usually used when a patient has asthma or severe COPD, takes the medication theophylline or has ingested coffee or chocolate (anything with caffeine), or has 2nd or 3rd degree AV block (a type of heart block). Adenosine or dipyridamole is generally used when a patient has poorly controlled hypertension, glaucoma, or has left bundle branch block (LBBB, another type of heart block). It is well known that patients with LBBB can have false positive septal ischemia if dobutamine is used as a pharmacologic agent in nuclear stress test. The adverse effects associated with the use of pharmacologic stress test agents can be reversed upon completion of the test. For drugs that promote adenosine (including dipyrimadole or adenosine itself), adenosine antagonists that constrict blood vessels such as theophylline or caffeine can be given. The adverse effects of beta-agonists like dobutamine can be reversed with the administration of a beta-blocking agent such as propranolol.

Conclusion
Most physicians support the population-wide reduction of risk factors which cause heart attack. These risk factors are contained in the well-known cardiac Framingham Risk Score. Physicians typically take a history; perform a physical and then obtain baseline bloodwork and a resting EKG. Stress testing is the established method of investigating moderate-risk patients for coronary artery disease as well as obtaining prognostic information for the patient.

Further research
Magnetic resonance imaging (MRI) has expanded the choice of modalities available for cardiac stress testing. MRI has superior spatial resolution (on the order of around 1.5 mm for cine imaging and 2.5 mm for perfusion imaging), and temporal resolution (around 40 ms for cine imaging), compared with that of a nuclear or PET stress test (spatial resolution of around 9mm for nuclear and 6mm for PET). The increased spatial resolution allows for more sensitive detection of ischemia, which initially starts at the thin subendocardial layer, due to stenotic epicardial supply vessels. First-pass stress perfusion cardiac MR imaging is performed using a rapid bolus injection of gadolinium based contrast and rapidly obtaining T1 weighted images of the myocardium at every R-R interval after pharmacologic stress induced with adenosine. The stress and resting first-pass perfusion MRI data can then be analyzed using a convolution model (such as the Marquard-Levenberg least-squares algorithm) to determine the quantitative global myocardial perfusion reserve (Michael Jerosch-Herold). Delayed hyper-enhancement imaging can be done after 10-15 minutes of contrast injection to evaluate for regions of infarction or fibrosis which has increased signal due to the slower washout of contrast from these areas (Thomson LE). Stress cardiac MRI perfusion testing thus is sensitive enough to detect subtle ischemia and myocardial infarctions even if they are limited only to the subendocardial level. The major problem again is that they still do not detect the "vulnerable plaques" which is the major cause of most heart attacks.

Stress testing, even if done in time, will detect only some of these people before symptoms, debility or death. Stress testing methods, though more effective than a resting EKG, only detect medium to high grade flow limitations; this assuming the testing is fully and aggressively performed. However, most acute artery flow disrupting events leading to heart attacks are due to rupture of "vulnerable plaques". Most of the "vulnerable plaques" cause less than 40% lumen narrowing, a degree of stenosis too small for most stress testing methods to detect.

Historically, through the mid-1980s, it was believed that detecting these high grade stenoses was the key to recognizing people who would have heart attacks in the future. However, there was also long-standing experience that some people could exercise all the way to maximum predicted heart rate, have no abnormal symptoms and completely normal stress test results, only to die of a massive heart attack within a few days to weeks. While anecdotal and not quantitative, these observations have long demonstrated the unreliability of the stress test approach as a means of diagnosing arterial disease before serious health problems occur. From the 1960s to 1990s, despite the success of stress testing identifying many who were at high risk for heart attack, its failure to correctly identify many others was a conundrum, discussed in medical circles but unexplained.

The high grade stenoses which are detected by stress test methods are often, though not always, responsible for recurring symptoms of angina. Cardiac stress tests do detect some individuals who already have with very advanced coronary arterial disease and stenosis, some of whom did not recognize that they had advanced disease. However, stress test results (especially stress perfusion cardiac MRI which can detected subtle diffuse subendocardial decreased perfusion due to microvascular disease) are also sometimes abnormal in some people who do not have high grade narrowings of their coronary arteries as visualized by coronary angiography, which provides more accurate information and partial visualization of the coronary artery lumens. This was long viewed as a false positive result, with some of these individuals diagnosed as having Syndrome X, i.e meaning clear recurring signs of angina, though with smooth open coronary artery lumens on coronary angiography. The actual underlying issues responsible for this apparent conundrum are now better understood, see atheroma and microvascular disease.

In the 1950s, heart attacks were commonly attributed to coronary thrombosis, a clot closure of a coronary artery, based on post mortem examination findings. In the late 1950s to early 1960s, this concept became replaced by the concept of stenosis based on the angiographic view of the lumens of the coronary arteries. In turn the angiographic view led to promotion of cardiac stress testing to detect stenoses, i.e. the severe ones more commonly present in people experiencing recurrent angina with physical exertion.

By the early to mid-1990s, it became more widely recognized that rupture of more rapidly evolving and unstable atheroma, hidden within the walls of the coronary arteries, called "vulnerable plaques", even though they often produce little or no stenosis of the coronary lumen, is the primary event which produces most heart attacks; thus back to the coronary thrombosis view, though with more sophistication of understanding some of the complexities. Two clinical trials published in the late 1990s, focusing on the relation between plaque structure, lumen stenosis and myocardial infarction, in which each individuals coronary anatomy was tracked with both angiography and IVUS found that 75% or greater stenotic areas were responsible for only about 14% of heart attacks. The typical heart attack occurred at an artery location with extensive, eccentric plaque within the wall but a luminal stenosis of only 20%. This finding added further evidence to the importance of the concept of vulnerable plaques. The detection of these vulnerable plaques using high resolution CT, MRI, IVUS, OCT (Optical Coherence Tomography), and molecular imaging is currently hotly researched. For CT, as of 2005, 64-slice multidetector machines are providing the best artery and lumen images, yet still do not clearly reveal which plaques are vulnerable. It is hope that perhaps with better resolution and ability to characterize the content of the plaques that an imaging modality may in the future be able to indicate which plaques is "vulnerable" as it is clear that detecting stenosis itself, however subtle, is not enough.

Unfortunately, cardiac stress tests are only capable of detecting medium to high grade limitations of blood flow to the left ventricular heart muscle which may produce recurring angina, not the atheroma which produce heart attacks. Stress test methods do not evaluate blood flow to non-left-ventricle heart muscle. Thus stress test results are often falsely negative for many people, in terms of predicting who is at high risk for myocardial infarction due to atheroma or ruptured "vulnerable plaques".

It has become clear that stress testing recognizes most people at risk for heart attacks too late, unfortunately only after the disease and symptoms of the disease have developed. By the time, a majority of people would already have at least medium stenosis of coronary vessels with development of atheroma or have already had heart attacks or died. It is hoped that research in higher resolution imaging techniques will allow for earlier detection and characterization of subtle atheroma and to initiate lifestyle changes and optimal medical therapy in "vulnerable patients" before they develop symptoms.

Additional Resources

 * Circulation, Fletcher et al. AHA Exercise Standards for Testing. 201:104:1694.


 * National Guideline Clearinghouse. Cardiac Stress Test Supplement. ICSI:2003Nov.26p.87.










 * Chung EK, Tighe D (1997). Pocket Guide to Stress Testing.