Cardiac Tests

There are an increasing number and type of cardiac tests used to help stratify patients thought to be at risk for symptomatic coronary artery disease (CAD), specifically for short-term complications such as myocardial infarction (MI) or sudden cardiac death. Increasingly, due to changes in the  clinical practice environment, emergency healthcare providers are ordering these tests and using the results for clinical decision making.

The image below depicts Wellens syndrome, a preinfarction stage of CAD that often progresses to a devastating anterior wall MI.

Classic Wellens syndrome T-wave changes. This ECG represents a patient after becoming pain free secondary to medications. Notice the deep T waves in V3-V5 and slight biphasic T wave in V6 in this chest pain free ECG. The patient had negative cardiac enzyme levels and later had a stent placed in the proximal left anterior descending (LAD) artery.

Types of tests

Cardiac testing encompasses diagnostic coronary angiography (invasive) or a variety of noninvasive tests. Noninvasive tests include the following:

• Exercise stress testing

• Pharmacologic stress testing

• Myocardial perfusion imaging

• Stress echocardiography

• Cardiac computed tomography (CT) scanning

These noninvasive tests can be performed in an outpatient setting, in a physician's office, in a hospital, or in an observation unit, as well as for admitted inpatients. The American Heart Association recommends that in nonemergency settings, patients should be informed of the risks (including those associated with radiation) and benefits involved in the use of cardiac CT scanning, radiopharmaceuticals, and fluoroscopy. ^[1]

Exercise stress test

Multiple protocols exist for exercise tolerance tests. A bicycle ergometer or treadmill is most often used. The goal is to increase workload incrementally to induce ischemia or until a predetermined workload is reached. The goal of exercise testing in the setting of acute chest pain is typically to evaluate for coronary ischemia and not for exercise capacity per se.

Pharmacologic stress test

Pharmacologic stress testing, established after exercise testing, is a diagnostic procedure in which cardiovascular stress is induced by pharmacologic agents in patients with decreased functional capacity or in patients who cannot exercise. The most widely available pharmacologic agents for stress testing are dipyridamole (Persantine), adenosine, regadenoson (Lexiscan), and dobutamine. However, the US Food and Drug Administration (FDA) warns against the use of adenosine and regadenoson in patients with signs or symptoms of unstable angina or cardiovascular instability. ^{[2, 3]}

Myocardial perfusion imaging

A myocardial perfusion SPECT (single photon emission computed tomography) test is a procedure that demonstrates the function of the myocardium. It is the test of choice for patients with active chest pain, an ECG with no ischemic changes, and an initial negative troponin result, according to the American College of Radiology guidelines. ^[4]

Stress echocardiography

Another method of indirectly detecting coronary artery disease is to perform echocardiography while the heart is undergoing exercise or pharmacologically induced stress. Exercise is performed using a treadmill or a bicycle ergometer. If a treadmill is used, images are obtained prior to exercise and then within 60-90 seconds of completing exercise. Bicycle ergometry has the advantage of being able to perform the echocardiogram at different stages of exercise. Supine ergometry provides the most information, as four cardiac views can be obtained.

Computed tomography

Calcium deposits are commonly found in atherosclerotic coronary plaques. The total amount of coronary calcium is predictive of future cardiac events. Cardiac computed tomography (CCT) can measure the density and extent of calcifications in coronary artery walls. The technique relies on ECG "gating" to compensate for cardiac motion. Coronary computed tomographic angiography (CCTA) allows direct visualization of the coronary artery lumen, similar to traditional angiography.

The goal of cardiac testing in the emergency department (ED) setting is to help stratify patients thought to be at risk for symptomatic coronary artery disease, specifically for short-term complications such as myocardial infarction (MI) or sudden cardiac death (SCD). Risk stratification of chest pain patients in the ED or other outpatient settings also includes interpretation of the history, as well as findings of the physical examination, electrocardiogram (ECG) and, when indicated, cardiac biomarkers levels. Cardiac testing encompasses diagnostic coronary angiography (invasive) or a variety of noninvasive tests.

This article focuses on the physiology, technique, interpretation, and utility of common noninvasive cardiac testing modalities and their role in risk-stratifying ED patients and other outpatients. The tests reviewed include exercise stress testing; pharmacologic stress testing; myocardial perfusion imaging; stress echocardiography; and cardiac computed tomography (CT) scanning, magnetic resonance imaging (MRI), and positron emission tomography (PET) scanning. These noninvasive tests can be performed in an outpatient setting, in a physician's office, in a hospital, or in an observation unit, as well as for admitted inpatients.

An understanding of these tests is important to for two primary reasons. First, patients frequently present that have undergone prior noninvasive testing. Knowing the value and limitations of that testing can be valuable in the care of such patients. Second, with the relatively recent expansion of observation medicine, it has become the responsibility of emergency physicians to choose and utilize the results of noninvasive cardiac testing in many hospitals. Noninvasive cardiac testing is an important adjunct to the broader scheme used to risk stratify chest pain patients. Use of cardiac biomarkers alone without additional noninvasive testing has not been shown to confer a low-enough risk to safely discharge a large proportion of chest pain patients from the ED. ^{[5, 6, 7]}

Explicitly or implicitly, physicians use a Bayesian model to interpret the results of cardiac tests. They generate a pretest probability of disease for an individual patient based on history, ECG findings, laboratory results, and other clinical factors. Then, by using the sensitivity and specificity of a given test for the population of interest, a post-test probability is calculated which can guide decision making. In day-to-day practice, this is performed more qualitatively than quantitatively. In addition, this process is reflected in diagnostic protocols for chest pain.

Test physiology and technique

Physical exercise places stress on the cardiopulmonary system. The physiologic response to exercise is an increase in heart rate and blood pressure (BP). This results in increased myocardial oxygen demand. In some patients with coronary artery disease (CAD), myocardial ischemia can be induced during exercise. This may result in both chest pain and a characteristic electrocardiographic (ECG) response. The goal of exercise testing in patients with acute chest pain is to identify these responses and, thus, the implied presence of significant CAD in a controlled setting.

Multiple protocols exist for exercise tolerance testing. A bicycle ergometer or treadmill is most often used. The strategy is to increase workload incrementally until a predetermined level is reached or ischemia is induced. A typical protocol would be to reach a workload of 10 metabolic equivalents of task (METs) or achieve 85% of the maximum predicted heart rate for a given age. If these levels are reached, without induction of ischemia, the test is considered adequate and negative. If these levels are unable to be achieved, the test is considered indeterminate.

Test interpretation

The primary finding resulting in a “positive” exercise tolerance test is ST depression on the ECG monitor. A test is considered positive when one or more cardiac leads shows ST depression of 1 mm or greater. The probability and severity of CAD is related directly to the amount of depression and downslope of the ST segment. It is also correlated with the lowest workload at which the depression occurs.

An exercise test will be terminated and considered positive if significant chest pain develops during the test. It is more predictive of CAD if it is also associated with ST depression. Other symptoms such as lightheadedness, vertigo, or peripheral cyanosis may be indicative of inadequate cardiac output.

Secondary endpoints of note in exercise tolerance testing include exercise capacity and hemodynamic response. Exercise capacity is measured in METs. One MET is the equivalent of the resting oxygen uptake while sitting quietly. An exercise of capacity of 5 METs or less is associated with poor prognosis in patients younger than 65 years. An exercise capacity of 13 METs or more indicates a good prognosis even when an abnormal ECG response is noted. ^[8]

Systolic BP at peak exertion is consider a clinically useful estimation of the inotropic capacity of the heart. A drop of systolic BP below that at rest is associated with an increased risk in patients who have known CAD. Heart rate response to exercise can be affected by left ventricular dysfunction, ischemia, arrhythmias, cardioactive drugs, and autonomic dysfunction. Failure to achieve at least 80% of the age-predicted maximum exercise heart rate is associated with an 84% increase in all-cause mortality in the subsequent 2 years. ^[9]  The heart rate and BP recovery patterns after cessation of exercise also hold prognostic significance. Slower return to baseline vital signs is associated with higher long-term mortality.

Test utility

Exercise tolerance testing has the advantages of a long history of experience, widespread availability, relatively low cost compared to other forms of noninvasive cardiac testing, and no radiation exposure. Multiple studies have validated the safety and efficacy of exercise testing in low-risk chest pain patients. ^[10]  It has even been shown to be safe when performed immediately in low-risk patients with a normal ECG and a single negative cardiac biomarker measurement. ^[11]

A meta-analysis of the diagnostic accuracy of 147 published reports involving 24,045 patients who underwent both exercise tolerance testing and coronary angiography by the American College of Cardiology and American Heart Association (ACC/AHA) showed a mean sensitivity of 68% and mean specificity of 77%. ^[12] Despite the low sensitivity when compared to angiography results, the purpose of stress testing in the context of the emergency department (ED) evaluation of chest pain is not to rule out CAD but to be used as short-term prognostic tool to aid the safe disposition of patients.

The 2014 AHA/ACC guidelines for the management of non-ST-elevation myocardial infarction (NSTEMI) and acute coronary syndrome (ACS) state that “Noninvasive stress testing is recommended in low- and intermediate-risk patients who have been free of ischemia at rest or with low-level activity for a minimum of 12 to 24 hours.” ^[13] Additionally, the 2010 ACC/AHA guidelines for the management of low-risk chest pain note that if follow-up ECGs and cardiac marker measurements are normal, a stress test (exercise or pharmacologic) to provoke ischemia may be performed in the ED, in a chest pain unit (CPU), or on an outpatient basis shortly before discharge. Low-risk patients with a negative stress test can be managed as outpatients. ^[14]

These recommendations are based on expert literature review and consensus. The recommendations are predicated on the concept that a negative exercise test has the ability to confer an excellent short-term (1-6 month) cardiovascular prognosis for patients having presented with chest pain.

Test limitations

Many patients should not undergo exercise tolerance testing. If a patient’s probability of coronary disease is very low, the chance of a false-positive result exceeds the chance of a true-positive test, therefore stress testing is not indicated. This is also the rationale behind the recommendation that stress testing not be used for screening in asymptomatic patients or those who have had no change in status since a prior stress test. Likewise, if the result of a stress test will not change management, it should not be performed. Stress testing is not the initial test of choice in high-risk patients, as even a negative test would not eliminate the need for angiography.

Other specific contraindications to exercise electrocardiography include patients with:

• Resting ECG abnormalities (eg, left bundle branch block, paced rhythm, pre-excitation syndromes, or ≥1-mm ST depression at rest),
• Inability to exercise (better suited to pharmacologic testing)
• Medications such as digoxin, beta-blockers, and some calcium channel blockers may blunt the ischemic response to stress. When feasible, these agents may be held and the patient monitored until the test can be performed. However, abrupt withdrawal, especially of beta blockers, may be harmful.
• Acute myocardial infarction (MI)
• Sustained ventricular arrhythmias or high-grade heart block
• Wellens syndrome (see the image below)
•  

  Classic Wellens syndrome T-wave changes. This ECG represents a patient after becoming pain free secondary to medications. Notice the deep T waves in V3-V5 and slight biphasic T wave in V6 in this chest pain free ECG. The patient had negative cardiac enzyme levels and later had a stent placed in the proximal left anterior descending (LAD) artery.
• Hemodynamically significant aortic stenosis
• Severe hypertension
• Serious coexisting illness (such as pneumonia or diabetic ketoacidosis [DKA])
• Symptomatic congestive heart failure (CHF)
• Active venous thromboembolic disease (deep venous thrombosis [DVT] or pulmonary embolism [PE])
• Pericarditis, myocarditis, or endocarditis

Test physiology and technique

Myocardial perfusion imaging offers a method of visualizing blood flow to the heart by injection of a radioactive cardiac specific tracer. This improves the diagnostic accuracy of a stress test since it gives another method of detecting perfusion defects in addition to measuring ST depression. Myocardial perfusion imaging offers the additional advantage of estimating left ventricular function. The technique can also be used independent of a stress test when given to patients with acute active chest pain.

There are two widely used agents for myocardial perfusion imaging. Thallium (Tl)-201 was the first agent widely used in clinical practice. It is a cation that acts similarly to potassium and is taken into viable cardiac myocytes. It has a half-life of 73 hours and distributes in cardiac tissue roughly in proportion to regional blood flow. In practice, Tl-201 is injected while the patient is at peak exercise or shortly after the pharmacologic stress agent is administered. Images are taken with a photon camera shortly thereafter and then again in 3-4 hours.

Defects on the initial image can represent regional ischemia or nonviable myocardium. After the cardiac stress is discontinued, the Tl-201 redistributes and fills in areas that were underperfused due to ischemia (reversible defect). Regions of the heart that have been irreversibly damaged by previous myocardial infarction (MI) do not demonstrate resolution of the defect on the delayed image (fixed defect). In this way, the test can discriminate between regions of inducible ischemia at risk for future MI and areas that have already been irreversibly damaged by prior MI.

The second widely used agent is technetium (Tc)-99m sestamibi, which acts as a calcium analog when taken up by the heart. It has a shorter (6 hour) half-life than thallium and redistribution does not occur as it does for the tl-201, although Tc-99m is taken up by the cardiac myocytes. Consequently, when performing a Tc-99m scan, a second injection is given at the time of the delayed image. Interpretation of the stress and delayed images is similar to that of Tl-201. Tc-99m tetrofosmin behaves similarly to Tc-99m sestamibi.

Images are obtained by a gamma camera that rotates around the body, obtaining a tomographic image. This is termed single-photon emission computed tomography (SPECT) scanning. Planar images are also available, but they are less accurate.  The images are interpreted qualitatively and can also be analyzed quantitatively by a variety of automated protocols.

Image quality can be improved by gating. This is a technique in which image acquisition is timed to only occur while the heart is in diastole, offering an image with greater resolution.

Test interpretation

A positive myocardial perfusion study is one that demonstrates reversible ischemia. Information on the size of the perfusion defect has additional prognostic value. A manual or automated scoring system may be used as well. These scoring systems have been validated and correlate with cardiac mortality. The results of myocardial perfusion imaging (MPI) provide prognostic value independent of the treadmill electrocardiographic (ECG) results.

Computer software with the capacity to perform regional quantitative assessment of radionuclide concentration appears to improve diagnostic accuracy over conventional perfusion imaging assessment. Use of appropriate software can also reduce the radiation dose. ^[15]

Test utility

Because myocardial perfusion imaging increases the diagnostic accuracy of stress testing, the American College of Cardiology and American Heart Association (ACC/AHA) guidelines recommend that it be used in several patient subsets. Thus, it should be used if there are any baseline ECG abnormalities that would interfere with the measurement of stress-induced ST-segment changes, such as left ventricular hypertrophy (LVH), bundle branch blocks, or digoxin use. In addition, myocardial perfusion imaging should always be used as an adjunct when pharmacologic stress testing is performed. Finally, it is useful in patients at higher risk, such as those with diabetes.

The ACC/AHA guidelines report that when both exercise and pharmacologic stress tests with SPECT imaging are compared to angiography, the test is 87% sensitive and 73% specific for significant stenosis (>50%). ^[16]

In a 6-year follow-up study of 1,137 patients with normal tl-201 perfusion studies, the annual rate of MI or cardiac death was only 0.88%. ^[17] In a meta-analysis of 14 trials with over 12,000 patients, normal Tc-99m sestamibi imaging was associated with a cardiac event rate of 0.6% per year. ^[18]

A difficulty that commonly arises is when there is disagreement between the ECG evidence and myocardial perfusion imaging on a stress test. In a study of 473 patients with chest pain, two-thirds of whom had abnormal ST-segment response on exercise, normal Tc-99m sestamibi SPECT studies were associated with an annual mortality of 0.2%. ^[19]  Thus, when interpreting stress tests, more significance is generally placed on the myocardial perfusion results than the ECG results. ^[19]

Test limitations

A Tc-99m sestamibi scan exposes a patient to approximately 8 milliseverts (mSv) of radiation. This is roughly half the radiation exposure from a chest or abdomen CT scan. The thallium test exposure is approximately equal to that of a CT scan. ^[4]  Equivocal results may result from poor image quality. Interference by the breasts and diaphragm may also impair image quality in some patients.

Test physiology and technique

Pharmacologic stress testing differs from exercise testing in that it does not rely on the patient's own ability to increase cardiac oxygen demand. Rather, the patient can remain at rest while the heart's response to a drug is measured. The most widely available pharmacologic agents for stress testing are dipyridamole (Persantine), adenosine, regadenoson (Lexiscan), and dobutamine. The adenosine analog regadenoson has a longer half-life than adenosine; this allows for a simpler bolus versus continuous administration.

Pharmacologic agents

For patients unable to exercise, pharmacologic agents are used to stress the myocardium and produce the characteristic electrocardiographic (ECG) or nuclear imaging findings. Pharmacologic stress testing is indicated for patients who would be unable to adequately perform an exercise stress test. An exercise test is considered inadequate when a patient cannot either reach 85% of the predicted maximum heart rate or achieve a workload of 5 metabolic equivalents of task (METs) for 3 minutes. A pharmacologic test is preferred over an exercise test in patients with aortic stenosis, left bundle branch block, a paced rhythm, recent myocardial infarction (MI), and severe hypertension, even if they were able to exercise adequately. ^[20]

Adenosine, regadenoson and dipyridamole are coronary vasodilators. In terms of blood flow, normal vessels are up to 400% more responsive to the vasodilatory effect than stenotic vessels. This difference in response leads to differential flow, and perfusion defects appear in cardiac nuclear imaging or as ST-segment changes on the ECG.

Contraindications to adenosine use include active asthma, high-grade heart block, and hypotension. Caffeine or theophylline should be stopped 12 hours before adenosine is given. Regadenoson and dipyridamole have similar contraindications (although studies have indicated that regadenoson is relatively safe in patients with asthma). ^[21] In addition, in November 2013, the US Food and Drug Administration (FDA) issued a warning that regadenoson and adenosine should not be used for cardiac nuclear stress tests in patients with signs or symptoms of unstable angina or cardiovascular instability, because these drugs may increase the risk for a fatal heart attack. ^{[2, 3]}

Dobutamine is a direct cardiac inotrope and chromotrope. It consequently increases myocardial oxygen demand similar to exercise and allows ischemic areas to become visible on nuclear scanning or apparent as ST depression on the ECG.

Dobutamine contraindications include hemodynamically significant left ventricular outflow tract obstruction, tachyarrhythmias (including prior history of ventricular tachycardia), uncontrolled hypertension (blood pressure > 200/110 mmHg), aortic dissection, or large aortic aneurysm. Beta-blockers should be discontinued so that the response to dobutamine will not be attenuated.

Test interpretation

The pharmacologic stress test is interpreted in a manner similar to the exercise stress test (see the Exercise Tolerance Test section). Additionally, myocardial perfusion imaging is advisable in all patients undergoing pharmacologic stress testing.

Test utility

Pharmacologic stress testing with nuclear imaging is equivalent to an exercise stress test with nuclear imaging at detecting coronary artery disease. Note, however, that because patients undergoing pharmacologic stress testing tend to have more comorbidities, the posttest probability of disease is higher in patients who have undergone a pharmacologic test. A normal pharmacologic stress test result confers a 1-2% per year cardiac event rate, whereas a normal exercise test result with nuclear imaging has a rate of less than 1% per year. ^[22]

Test limitations

Theophylline can reduce ischemic changes on the ECG with vasodilator stress testing. Caffeine has been reported to have a similar effect. However, one study demonstrated that one cup of coffee, 1 hour prior to stress testing did not attenuate the results of adenosine nuclear imaging. ^[23] Calcium channel blockers, beta-blockers, and nitrates can also alter perfusion defects on pharmacologic stress tests and therefore ideally should be withheld for 24 hours prior to pharmacologic stress testing. Dipyridamole and adenosine can lead to bronchospasm; they are generally avoided in patients with severe reactive airway disease or active wheezing. Dobutamine is safe to use in these patients.

Test physiology and technique

Another method of detecting coronary artery disease is to perform echocardiography while the heart is undergoing exercise or pharmacologically induced stress. Wall motion abnormalities can be visualized with the technique. The exercise is performed using a treadmill or a bicycle ergometer. If a treadmill is used, images are obtained prior to exercise and then within 60-90 seconds of completing exercise. Bicycle ergometry has the advantage of being able to perform the echocardiogram at different stages of exercise. Supine ergometry provides the most information since 4 cardiac views can be obtained. Dobutamine is the most common pharmacologic agent used in conjunction with echocardiography. Image quality can be enhanced by injection of echogenic microbubbles.

Test interpretation

A positive stress echocardiogram is defined by stress-induced decrease in regional wall motion, decreased wall thickening, or regional compensatory hyperkinesis. In experienced hands, this can have a diagnostic accuracy similar to that of nuclear stress testing. However, results are operator dependent. ^[24]

Test utility

Advantages to stress echocardiography are that it is a faster test to perform than a nuclear stress test because delayed images are obtained much sooner. It has no associated radiation exposure. It is less costly than nuclear stress testing, and therefore performs well on cost analysis studies. The test can be more readily performed in an office setting.

In a meta-analysis that included data from 24 studies, Fleischmann et al found that exercise echocardiography had a sensitivity of 85% and a specificity of 77% when compared with coronary angiography. The results were felt to be similar to those for single photon emission computed tomography (SPECT) imaging. ^[25]

Test limitations

As stated above, the test is dependent on the experience of the operator. Obesity, lung disease, and tachycardia can limit image quality. Up to 10% of cases have inadequate image quality.

Test methodology

Calcium deposits are commonly found in atherosclerotic coronary plaques. The total amount of coronary calcium is predictive of future cardiac events. Cardiac computed tomography (CCT) scanning can measure the density and extent of calcifications in coronary artery walls. The technique of CCT was established with electron beam scanners, but it has been refined and made more widely available with the introduction of multidetector scanners. The technique relies on electrocardiographic (ECG) "gating" to compensate for cardiac motion. No contrast is used. The coronary lumen itself is not visualized. A related technique is cardiac CT angiography (CCTA). CCTA uses intravenous (IV) contrast material to provide direct visualization of the coronary lumen. Gating is also used to decrease motion artifact. CCTA has been shown to have good correlation with the criterion standard of conventional coronary angiography.

CCTA techniques are under rapid development. A low and regular heart rate (typically sinus rhythm) is necessary for optimal imaging, and it is often necessary to administer beta-blockers to achieve an adequately low heart rate (approximately 60-65 bpm or less). Studies have shown that if a patient's heart rate can be brought below 60 bpm, only about 3% of coronary segments will be unevaluable by the CCTA, while at 61-65 bpm, over 21% are unevaluable. Obtaining optimal images with the least radiation exposure depends on control of the heart rate. ^[26]

Test interpretation requires special training and is usually performed by a radiologist or cardiologist.

Test outcomes and interpretation

The amount of calcium seen in coronary vessels on CT scanning is usually expressed as a calcium score ("Agatston score"), which is based on the area and the density of the calcified plaques. A typical report provides a calcium score for the major coronary arteries as well as a total score. A test result is considered to be positive if any calcification is detected within the coronary arteries. A positive test result is nearly 100% specific for atheromatous coronary plaque but not highly correlated with obstructive disease. A negative test result has a 96-100% negative predictive value (NPV) for obstructive lesions. Scores of less than 10, 11-99, 100-400, and above 400 have been proposed to categorize individuals into groups having minimal, moderate, increased, or extensive amounts of calcification, respectively.

Conversely, a study by Rosen et al found that "although there is a significant relationship between the extent of calcification and mean degree of stenosis in individual coronary vessels, 16% of the coronary arteries with significant stenosis had no calcification at baseline." ^[27]

Calcium scores greater than 1000 have been associated with significant increases in morbidity and mortality independent of other risk factors. Scores greater than 100 are consistent with a high risk (>2% annually) of a coronary event within 5 years. The amount of calcification can give, to some extent, an indication of the overall amount of atherosclerosis. In addition, a greater amount of calcification and a higher calcium score increase the likelihood that coronary angiography will detect significant coronary artery stenosis. However, there is not a 1-to-1 relationship between a high score and the presence of coronary artery stenosis. In other words, a positive scan result indicates atherosclerosis but not necessarily significant stenosis. ^[28]

Individuals with calcium scores greater than 400 have an increased occurrence of coronary procedures (bypass, stent placement, angioplasty) and events (myocardial infarction [MI] and cardiac death) within the 2-5 years after the test. Individuals with very high scores (>1000) have a 20% chance of suffering a MI or cardiac death within a year. Even among elderly patients (>70 y), who frequently have calcification, a calcium score greater than 400 was associated with a higher risk of death. In one study, patients with calcium scores greater than 1000 were found to have a relative risk of death at 5 years of 4.03 (95% confidence interval [CI], 2.52-6.40). However, calcium scores reflect overall risk and cannot be used to diagnose the presence of a specific obstructing lesion. ^[29]

Test utility

Studies have investigated the use of CCT in the emergency department (ED). These studies report a NPV of 97-100%. For example, in one study, CCT was performed in 192 patients presenting to the ED with chest pain, with an average follow-up interval of 50 months. The NPV of the test was 99%. Patients with the absence of coronary artery calcium (CAC) had a 0.6% annual cardiovascular event rate. In another study of ED chest pain patients, a negative test result (absence of coronary calcification) was associated with a very low adverse event rate over a 7-year follow-up period. Increasing score quartiles were strongly correlated with risk (P< 0.001). ^[30] Another recent study evaluated 1,031 patients admitted to an observation unit with CCT. Only two events occurred in 625 patients with a calcium score of 0 (0.3%; 95% confidence interval, 0.04-1.1%). ^[31]

The absence of detectable calcium has a very high NPV for ruling out obstructive coronary artery disease (CAD) and confers an excellent long-term prognosis for future cardiac events. Thus, use in low-risk patients is the most important application of CCT. An NPV of 98% has been reported for coronary chest pain or myocardial infarction in patients with acute symptoms and nonspecific ECG results. ^{[32, 33]}

As with other noninvasive techniques, CCT cannot be used to identify or rule out the presence of an unstable plaque. A problem with the use of CCT is that calcification is present much more often than significant stenosis. Most patients with coronary calcification who go on to conventional invasive catheter angiography will therefore not have significant obstructive disease. CCTA may be a less invasive alternative in these cases, but there are limitations of the currently available data for CCTA. These include the fact that most reports have been based on single-center experiences and have been conducted with a subset of symptomatic middle-aged white men who had a high prevalence of CAD. Multicenter trials and studies with intermediate-risk populations are warranted.

Cardiac CT angiography (CCTA)

CCTA, coronary CT scanning using IV contrast and gating to allow visualization of the coronary artery lumen, is becoming more broadly used in the ED and for other outpatient settings. Studies have found good NPV for CCTA compared with the criterion standard of catheter angiography. A normal CCTA study (stenosis of < 50% is considered nonsignificant.) reliably rules out clinically significant stenosis and confers a low risk for these patients. ^[34] A 2-year follow-up study of CTCA patients found 25 adverse events (6.8%). There were no cardiac deaths, 12 MIs, and 23 revascularizations. ^[35]

The ROMICAT-II trial followed ED chest pain patients with negative initial troponin determinations and nonischemic ECG tracings for 28 days after being randomized to CCTA or standard treatment and found four with acute MI and two with unstable angina requiring coronary intervention from 495 patients in the standard evaluation group compared to one case each of MI and unstable angina from 501 patients in the CCTA group. Although the difference in adverse events was not statistically significant between the groups, the number of patients discharged from the ED and length of stay was significantly less in the CCTA group. ^[36]

At present, there is enough evidence to allow safe discharge from the ED of patients without acute ECG changes or elevated troponin levels, as well as with benign CCTA examinations. Of course, this assumes other serious causes of chest pain have been considered and excluded as needed. 

Magnetic resonance angiography

Cardiac magnetic resonance angiography (cMRA) allows visualization of coronary vessels without radiation or contrast dye. However, with contrast medium and the addition of vasodilators or dobutamine, cMRA can be used to assess myocardial viability as well. By synchronizing image acquisition with the patient's cardiac cycle, new protocols allow the patient to breathe during the test. Although cardiac magnetic resonance imaging (MRI)/MRA continues to evolve, it shows promise as the only imaging modality that can combine angiography with perfusion and wall-motion assessments.

A 2010 study on the use of stress MRI in an observation unit compared to routine inpatient care in a group of non–low-risk patients reported that 30-day outcomes were the same in both the admitted group and the observation/MRI patients. ^[37] However, observation/MRI patients had significantly lower costs ($336-$811; 95% CI).

Carotid intima-media thickness

Carotid artery ultrasonography and measurement of the intima-media thickness is another area of investigation. Observational studies have shown that intima-media thickness is an independent marker of cardiovascular risk, but whether it is more accurate than traditional risk factors is unclear. However, it could prove valuable as a rapid, low-cost, low-risk test easily obtainable in the emergency department (ED).

Combined CT studies for chest pain evaluation: the "triple rule out"

Conceptually, a CT scan with intravenous (IV) contrast can combine imaging of the coronary arteries, ascending aorta, and pulmonary arteries; this allows assessment of coronary artery disease (CAD), pulmonary embolism, and disease of the thoracic aorta (dissection) with a single study. This type of evaluation has been called the "triple rule out (TRO)." Technical aspects of this type of study differ from that of CCTA, owing to a wider field of view and a different protocol for the administration of IV contrast. The technique involves substantial cost and radiation exposure. 

A review of TRO suggests that this approach may have utility under relatively limited circumstances. ^[38]  In a 2013 study that evaluated 100 intermediate-risk patients with acute chest pain and an intermediate risk for acute cornary syndrome, coronary CT angiography (CCTA) and TRO-CTA both allowed the rapid and safe discharge of a majority of these patients as well as identified those wth significant coronary artery stenosis. ^[37] All patients had D-dimer testing; those with positive results were imaged with either a TRO protocol or with CCTA. Of the 60 of 100 discharged with a negative CCTA, 0 adverse events occurred at 90-day follow-up; of the 19 of 100 with a positive CCTA, 17 were determined to be true positives based on catheter angiography. Thirty-six patients underwent a TRO-CCTA protocol due to elevated D-dimer levels: 5 had pulmonary embolism, 3 had pleural effusion of unknown etiology, and 1 each had severe right-sided ventricular dysfunction with pericardial effusion or an incidentally detected bronchial carcinoma. ^[39]

In current practice, TRO-CTA exposes patients to significant radiation but shows promise in appropriately selected patients. Improved scanning hardware and imaging algorithms have the potential to reduce radiation exposure without compromising accuracy. To date, no consensus has been reached as to which patients are most appropriate for TRO imaging. 

Cardiac PET scanning for diagnosis of CAD

There are two specific clinical applications of positron emission tomography (PET) scanning that have been proposed for the evaluation of patients with known or suspected CAD. Detection of CAD and estimation of severity is performed using a PET perfusion agent at rest and during pharmacologic vasodilation. The second clinical application of PET is the assessment of myocardial viability in patients with CAD and left ventricular dysfunction. The most common approach is to determine whether metabolic activity is preserved in regions with reduced perfusion as a marker of glucose utilization and, thus, tissue viability.

The combined technique of PET/CT scanning of the coronary arteries was shown in one study to compare favorably with the criterion standard of catheter coronary angiography. One hundred seven patients with an intermediate pretest likelihood of CAD underwent PET/CT scanning, and the results were compared with invasive angiography. PET scanning and CTA alone each demonstrated 97% negative predictive value; however CTA alone provided suboptimal assessment of the severity of stenosis (positive predictive value, 81%). Perfusion imaging alone was not always able to distinguish microvascular disease from epicardial stenosis, but hybrid PET/CT scanning significantly improved this accuracy to 98%. ^[40]

Who to test

Aside from new testing modalities, there is considerable research under way to better optimize the selection of noninvasive tests for patients presenting with chest pain. In particular, there is substantial discussion regarding an acceptable risk level and defining a population of patients who are at low enough risk that they can be safely discharged without further cardiac testing. It is well known that when patients who present with chest pain have unchanged ECG’s and negative biomarkers, they are already at low risk for adverse cardiac outcomes even without the use of noninvasive testing.

One suggested approach is to use a validated risk score such as the HEART score to define a population at low short-term risk for major cardiac events. ^[41] If the score is low enough, then a shared decision-making tool may be used with a patient. ^[42] If a patient can understand and accept that their risk of adverse cardiac event is very low but more than zero, they may be discharged without further cardiac testing. Ultrasensitive troponin testing may be able to define an even lower risk population. Using these newer approaches, clinicians may be able to become far more selective in whom to choose to undergo noninvasive cardiac testing. This has the potential to both lower costs and adverse outcomes.

Cardiovascular disease is the leading cause of death for women in the United States, but a considerable body of research has demonstrated that women have different patterns of coronary artery disease and different responses to cardiac testing than their male counterparts. Women are more likely to have nonobstructive or single-vessel disease when compared with men, which decreases the diagnostic accuracy of stress testing. For example, treadmill testing in one meta-analysis was shown to have a sensitivity and specificity of 61% and 70%, respectively, for women compared with 72% and 77%, respectively, for men. ^[43]

Calcium scoring is limited because women tend to have 3- to 5-fold greater mortality rates for a given calcium score than men, suggesting that separate guidelines for interpreting scores in women should be developed.

Single photon emission computed tomography (SPECT) imaging is technically limited in women because breast tissue and relatively small left ventricle size can generate false-positive results. Technetium is less prone to attenuation artifacts than thallium and thus has higher specificity. The American Heart Association has recommended exercise tolerance testing as the initial noninvasive test of choice for symptomatic woman who are at intermediate risk for ischemic heart disease, have a normal baseline electrocardiogram, and are able to exercise. ^[44]

Noninvasive cardiac testing is used as part of a broader scheme of risk stratification for patients with possible acute coronary syndromes. Many tests exist, and each has unique advantages and disadvantages. Patient characteristics and local resources dictate which of the cardiac tests are chosen. Variability exists in how well noninvasive cardiac tests correlate with angiographic findings. Despite this variability, most of the tests are useful for determining short-term risk of myocardial infarction and cardiovascular death.

Noninvasive cardiac tests are improving as new diagnostic technologies and methods are being developed. As future studies reveal the true diagnostic characteristics and capabilities of these tests, physicians can better assess patients' risk of coronary artery disease based on their previous test results and more effectively recommend further testing and interventions.

As with all diagnostic tests, no single cardiac test is ideal. They are useful as part of a risk stratification scheme, but, with the current state of diagnostic testing, some cases of serious coronary disease will always be missed.