 Hello, I'm Dr. Raymond Steinbeck, medical director of non-invasive cardiology at the Texas Heart Institute here in Houston, Texas. Today I'm speaking to you about the use of non-invasive imaging in coronary syndromes, which may be either acute or chronic. I was invited to speak on this topic in part because of a long-awaited release of an updated ACC chest pain guideline and a related EACVI-ASC guideline on multiple modality imaging in coronary syndromes. Both of which were published in the fall of 2021. Both documents provide updated basic knowledge on this subject in a way that may be helpful for cardiologists, emergency and primary care physicians as they evaluate patients with possible cardiac-related chest pain. Should non-invasive cardiac testing be performed, and if so, which test? It is a chance for our institution and others to examine their chest pain protocols, particularly in the emergency room. A guidelines review with numerous comprehensive care diagrams can be challenging, but my plan is to touch on the most high-level information so that you can review the new documents at your leisure. I have no relevant disclosures. Coronary syndromes can be divided into acute and chronic. Non-invasive stress testing plays a minor role in high-risk acute coronary syndrome patients and those diagnosed with acute myocardial infarction. As invasive testing with cardiac catheterization is the preferred strategy in those patients. But for patients with lower intermediate risk, acute coronary syndromes, and moderate to high-risk stable or ambulatory patients, non-invasive testing plays a major role. The established modalities include stress echo, nuclear myocardial profusion imaging, either SPECT or PET, stress CMR, and cardiac CT angiography. The recent guidelines will divide these tests into functional and anatomical testing. However, the additional of fractional flow reserve testing for computed tomography imaging adds a layer of functional testing which could be appropriate in a subset of patients undergoing CTA. We must distinguish between a resting transtheracic echo, which is indicated in all patients with suspected cardiac chest pain, and the stress echo cardiogram, which may be used to assess for ischemia in a subset of patients presenting with chest pain. Deciding on how to evaluate patients, apply non-invasive testing, and overall assessment is nuanced and recommendations have been under evolution for 10 to 15 years. As I mentioned, although the two new guidelines provide a focused update, I would like to show you the historical recommendations, some of which remain relevant. These are the guidelines addressing chest pain and non-invasive imaging published over the last 12 years. The older documents above the dotted line make strong recommendations for when to perform non-invasive testing, but the nuance of test selection is avoided. This is due to lack of outcomes data for imaging and the fact that numerous factors guide test selection, including patient age, other risk factors, body habitus, heart rhythm, and concomitance disease, all interacting with differing test imaging physics constraints to create somewhat of a puzzle. However, and fortunately, all of our non-invasive tests operate reasonably well and carefully selected, moderate to high risk patients. And since no test is perfect, equivocal test results can be used in a complimentary supplementary imaging fashion when needed to improve diagnostic certainty in difficult cases. The EACVAI-ASC guideline in particular at the bottom democratizes some of the thinking on test selection for non-imagers. I have not shown the many modality specific guidelines for exactly how to perform each test, but the EACVAI-ASC document at the bottom illustrates the continuing trend towards a multimodality imaging approach. The appropriate use guidelines were initially developed for non-invasive test modalities to address overuse of these emerging technologies and to complement the clinical practice guidelines. They included all common clinical scenarios where each modality may be used. But from 2006 until 2013, these appropriate use documents remained modality specific, including appropriate use statements for nuclear myocardial perfusion imaging, cardiac CT, and MR, and echocardiography. But it was difficult for physicians to cross-reference the coronary artery disease indications across different documents of different vintages and with evidence for consensus having been gleaned from a variety of related clinical guidelines document, also differing of differing vintages as shown by the evidence sources on the left. The 2013 multimodality appropriate use criteria document for the detection and risk assessment of stable ischemic heart disease was the first AUC document to start with a suspected diagnosis, a stable ischemic heart disease in this case, and then to provide consensus on whether or not any amongst a group of tests was appropriate for different related clinical scenarios. This was thought to be a much more practical approach for clinicians taking care of patients. However, the ratings for tests were explicitly not competitive in the rankings of different non-invasive tests due to limited availability of comparative evidence and other patient variables that cannot be captured in this type of exercise. From this 2013 AUC guideline, we see the first six among 80 common clinical scenarios separating symptomatic patients into low, intermediate, and high-risk pre-test probability of coronary artery disease, EKG and exercise status, and whether exercise, nuclear stress, stress echo, or stress, calcium scoring, or CT angio may or may not be appropriate. However, because details of such things as patient age body habits and rhythm and imaging status were not included in these grids, guidance for the last mile selection amongst the tests is problematic, but at least the multimodality imaging AUC provided some reasonable criteria for determining cases where noninvasive imaging is rarely appropriate with a major goal being the elimination of costly unnecessary testing. The appropriate use criteria documents remain relevant quality tools as the only available consensus documents for usage patterns, particularly in stable patients where imaging overuse has been documented. Appropriate use criteria in symptomatic hospitalized patients are more likely to be met based on validation studies, and overuse can be reduced particularly in the outpatient setting. The Intersociatal Accreditation Commission requires that labs performing noninvasive testing assess appropriate use as one component of the required quality improvement program. We now reach a newer guideline below the green dotted line that we saw in our prior slide, the 2019 ESC guideline for the diagnosis and management of chronic coronary syndromes. This lists as a class one indication, selection of an initial noninvasive test based on the clinical likelihood of coronary artery disease and other patient characteristics that influence test performance, local expertise, and the availability of tests locally. The ESC guidelines have used the term chronic coronary syndrome to classify patients as opposed to the American classification of stable ischemic heart disease. This guideline emphasizes the crucial role of healthy lifestyle behaviors and other preventive actions in decreasing the risk of subsequent cardiovascular events and mortality, and discusses the utility of noninvasive testing for potentially influencing patient outcomes. I think this guideline is helpful from a taxonomy standpoint. It identifies six categories of chronic coronary syndromes, two without a prior diagnosis of coronary artery disease, with either symptoms suspicious for CAD or new onset heart failure with suspicion of CAD etiology. The remaining four include patients with established coronary artery disease, either symptomatic or asymptomatic early and late after the diagnosis or revascularization. And importantly, there is a new emphasis placed on patients with angina and no epicardial coronary artery disease with suspected vasospatic or microvascular disease that can be detected only by functional imaging studies. And finally, number six, asymptomatic individuals with the diagnosis of subclinical coronary artery disease detected on screening evaluations, and this would include by anatomic testing using CTA. All of these scenarios are classified as chronic coronary syndrome, but they involve different risks for the development of future adverse events, and the risk may change over time, and non-invasive imaging is important for both disease detection and risk stratification. This illustration from the ESC guideline shows why stable ischemic heart disease could be misleading when applied to the diversity of patients with chronic coronary syndromes, as patients particularly towards the upper right may become unstable at any time, and their trajectory can be uncertain, depending upon revascularization status and the intensity of life and risk factor modification. How do we properly perform risk assessment in this diverse population of chronic coronary syndrome patients, and is the concept of stable ischemic heart disease a misdomer in many cases where conversion to an acute coronary syndrome scenario could be imminent? This illustration from the ESC chronic coronary syndrome guideline shows how we may think about risk in these patients with known disease by incorporating symptoms, comorbidities, and echocardiography findings, including ejection fraction, in the choice of appropriate imaging based on these many factors. Patients with lower risk in the left side may need no testing, although consideration of anatomic imaging with CTA can be used to guide management. CTA has a very high negative predictive value. A negative test is truly a negative result, and it offers the opportunity to discover subclinical plaque, which can potentially improve the trajectory of risk in patients as seen on the previous slide, if preventive measures are implemented. The Scott Hart trial demonstrated the significantly lower rate of combined endpoint of cardiovascular death and non-fatal MI during five-year follow-up in patients who had coronary CTA in addition to routine testing with exercise ECG. But other randomized prospective clinical trials, such as the PROMIS trial, have not shown a survival advantage of the CTA strategy over the use of traditional stress testing strategies. The intermediate risk group in the center should receive non-invasive test image testing with the test choice based on patient characteristics and test availability. In very high-risk patients, an invasive approach may be needed. Recommendations from the 2019 ESC chronic coronary syndrome guideline include the recommendations for a resting trans thoracic echocardiogram as the initial test in the management of patients with suspected coronary artery disease. This is to rule in or rule out other non-coronary artery disease causes of chest pain, assess regional wall motion, and LV ejection fraction in addition to diastolic dysfunction. Non-invasive functional testing for ischemia or CTA is recommended as an initial test in whom in patients in whom obstructive coronary artery disease cannot be excluded by clinical assessment alone. Selection of the particular test is based on the likelihood of coronary disease and other patient characteristics that influence test performance and of course local expertise and the availability of the testing options. Functional testing is recommended if coronary CTA has shown coronary artery disease of unclear significance. Now let's consider patients with acute coronary syndromes with the most recent guidance also coming from the European Society of Cardiology in 2020. In patients with suspected non-ST segment elevation acute coronary syndromes, a resting echocardiogram is indicated in moderate risk patients as part of the diagnostic evaluation including observation and repeat troponin and even in high risk patients who eventually go to interventional angiography. An echocardiogram is indicated even after cath or intervention to assess LV ejection fraction, regional wall motion abnormalities and for concomitant other cardiovascular conditions and complications of myocardial ischemia. In the moderate risk group, stress testing non-invasively either anatomic or with stress imaging may be indicated after a rest echo has been performed and an acute coronary syndrome has been excluded. And with this background we now come to the newly published AHA-ACC guideline for the evaluation and diagnosis of chest pain which includes general recommendations on non-invasive imaging. The document is strongly focused on the patient's overall clinical assessment as being crucial for establishing a patient's pre-test probability of disease and other factors that dictate whether or not non-invasive cardiac testing should be performed. For clinical recommendations, patients are grouped into those with acute chest pain with and without established coronary artery disease and chronic chest pain with and without established coronary artery disease. This important illustration from the 2021 ACC chest pain guideline emphasizes that classification of chest pain is a paramount important since only less than 10% of patients at many institutions presenting with chest pain can on detailed evaluation be said to have possible cardiac chest pain that would possibly indicate the need for non-invasive imaging or stress testing. And the 2021 chest pain guideline agrees with the 2019 ESC chronic coronary guideline that arresting surface echo is needed when the clinical presentation suggests cardiac or possibly cardiac chest pain but only in those with moderate or high risk. Therefore, the nature of the presenting symptoms is critical. The new guideline recommends that the chest pain be described as cardiac, possibly cardiac and non-cardiac. If the pain is thought to be cardiac, it can be further classified as ischemic or non-eschemic. Since there are many non-eschemic causes for cardiac related pain including paracarditis, severe valve disease, complications of prior myocardial infarctions, and aortic syndrome to name a few. The new chest pain guideline recommends that we abandon terms such as typical and atypical chest pain. This illustration from the guideline reminds us that the majority of patients presenting to emergency departments are found to have non-specific chest pain with less than 10% of patients having pain arising from coronary atherosclerosis or acute myocardial infarction. The frequency of actual ischemic or cardiac chest pain in younger patients, those less than 45, is quite low. And as we will see, any attempt to risk stratify most young or low risk patients using non-invasive imaging will result in a high percentage of falsely positive tests. But even in older patients, hospital administrators and other payers will be relieved to see that most chest pain is non-cardiac. However, those with suspected cardiac chest pain are indeed a very high risk group and resources must be available for these patients by the use of a thorough clinical assessment. The guideline strongly recommends that in acute patients risk assessment algorithms be employed to routinely assess patient risk. Many such acceptable clinical tools are available and listed in the guideline. At our institution, we have used the heart score algorithm to classify patients. Using a score based on history, including symptoms, EKG, age and other risk factors and troponin results, patients can be relatively consistently placed into low, intermediate and high risk groups, with validation studies having shown that low risk patients have a less than 2% risk of major adverse clinical events at six weeks without further evaluation using non-invasive cardiac testing. Since 2017, we have used a chest pain protocol here at our center that remains in keeping with the new chest pain guideline. We do an initial clinical assessment, including all the elements needed for the heart score assessment. If the patient is low risk, they can be discharged in the absence of extenuating circumstances without further testing. It is the intermediate risk patients with possible cardiac chest pain or suspected ischemic heart disease that we consider using non-invasive testing. Please notice that the routine use of resting trans-therapeutic echocardiography for intermediate and high risk patients to further assess ischemic and potentially non-ischemic causes for suspected cardiac chest pain had not previously been included since this was always considered a routine echo indication. However, the resting trans-therapeutic echo is highlighted in the contemporary ESC and ACC guidelines. I have now added this in the bright green box. Note that the clinical assessment of risk is primary, but in the intermediate initial risk patients, it is the non-invasive test itself that then further risk stratifies the patients based on the test results. The non-invasive test results can turn an intermediate risk patient into a low risk patient with the results leading to patient discharge if there is a negative study. For intermediate risk results or for an equivocal test result, the cardiologist typically decides on further clinical management and of course the high risk result, suspicion for a large area of risk, low ejection fraction and our multi-vessel disease territory, a high risk result may indicate the need for subsequent invasive strategy. This relatively simple pretest probability tool from the guideline can be used to assess risk based on gender, age, the nature of symptoms, and the coronary artery calcium score if known. Shortness of breath can be an additive symptom of ischemic heart disease, particularly in older men. And again, non-invasive stress testing performs well in the intermediate risk patients unless well in low and high risk patients because of inherent test performance characteristics related to test sensitivity and specificity, which we'll talk more about. We are not going to go through all of the extensive recommendations, flowcharts, and tables from the guideline, but we will look at a couple. Here we see the stable chest pain patient with no known coronary artery disease. In stable patients, non-invasive testing is recommended in an intermediate to high risk group, whereas non-invasive testing in acute chest pain patients is recommended only for intermediate risk group patients, as seen in our institution's ER chest pain protocol previously. In low-risk patients, no testing is recommended except for select cases where the clinical assessment is inconclusive. In patients that are intermediate or high risk with stable chest pain and no known coronary artery disease, either anatomic testing with CTA or functional stress testing with CMR, PET, SPECT, or stress echo are given class one recommendations as indicated by the blue arrows. No test is perfect, and for inconclusive studies noted by the red arrows, layered complementary testing is sometimes needed, particularly in complex cases. In patients with stable chest pain and known coronary artery disease, the management decision tree is complex. The guideline does not pretend to provide the granularity of the nuanced mix of patient characteristics and test performance characteristics that would lead to the best test selection that would lead to an accurate assessment of ischemia and disease burden, although careful study is needed for each individual case to decide the best treatment strategy. Now, let's turn to the new EACVI-ASC Multimodality Guideline, which is in pretty good harmony with the ACC's recommendations. It provides needed focus, not just when to select non-invasive imaging in patients with suspected or established coronary disease. It provides a more detailed discussion on which tests should be considered based on a more nuanced description of patient characteristics, not just when to do, but what to do. The newer EACVI-ASC Multimodality Document also highlights the importance of patient evaluation and the establishment of patient risk before determining whether a non-invasive testing would be useful. Here's a similar useful illustration that helps us determine pre-test probability of disease. Low risk is in white, intermediate risk in shades of orange, and the highest risk populations are in the purple to blue areas. In the higher risk patients not going for cath, it is wise to select a test that is very high sensitivity to decrease the chance of false negative tests based on Bayesian theory. In patients with low pre-test probability of disease, those in white or light orange, either no test should be performed or a test with high specificity is needed in order to reduce the risk of a false positive result. This would include CTA as a possibility. For intermediate risk patients, anatomic and functional tests can be somewhat interchangeable or complementary in this situation. Let's take a minute to look at the relative accuracy of stress test imaging based on estimates of sensitivity and specificity. All of these tests have very good sensitivity and specificity when it comes to utility and intermediate risk patients. For the most commonly used nuclear medicine tests, sensitivity is very high, giving it a diagnostic advantage in patients with known disease and higher risk. There would be fewer falsely negative test results. Stress echo is sensitive but has a higher specificity than nuclear stress testing and is therefore less likely to provide a positive result and a falsely positive result in an intermediate or lower risk patient. How does this work? Let's take a look at the results when we try to perform stress imaging in a very low risk population. Patients with a pretest probability of only 10% say young adults with possible cardiac chest pain. When we run 100 patients with a pretest probability of 10% through a test with 80% sensitivity and 90% specificity, this is what might happen. 10 of the 100 patients have actual coronary artery disease but the majority, 90 of the 100 have no disease. If we focus on the 90 patients with no disease and apply the specificity of 90%, the test process would yield 9 patients out of 100 patients with a falsely positive test result. Although the test identifies most patients as having no disease, the percentage of positive tests that are false positive tests is 53%. Therefore, in the test that is positive in this low risk group, it is simply a flip of a coin as to whether the test yielded an accurate result, not very useful. Now let's look at a very high pretest probability population, say older patients with risk factors and compelling symptoms, a pretest probability of 80%. When we run this 80% pretest probability through our 80% sensitivity and 90% specificity test, although 80% sensitivity is not bad, out of the 80 patients with real disease, the test may produce 16 out of 100 results that are falsely negative in patients with real disease and if all negative tests, 40% would then be falsely negative. So the ability to interpret a false negative result is a flip of a coin and the test may miss 16 out of 100 patients with real disease. So even a test with relatively high sensitivity and specificity can be of low clinical utility in a very high risk pretest probability group, too many false negative tests. Although we just saw how we can get into trouble applying non-invasive stress testing to very low and very high risk populations, the tests are very good for the same reasons that need immediate risk patients and the pretest probability provides the link between test sensitivity and specificity and clinical utility. And because tests are not perfect, even when appropriately used, the guidelines recognize the need for complementary testing or escalation to invasive testing when results are unexpected or inconclusive. The sensitivity and specificity of stress testing is determined by the physiology of the ischemic cascade as shown here. Notice that the last phase of the ischemic cascade is a change in ECG repolarization. This explains the limited role of plain ECG stress testing with exercise in patients with increased risk. Although this test can be very helpful in low risk patients that can exercise well and have normal baseline ECGs, ischemia is the mismatch of myocardial oxygen demand in supply and the ischemic response or supply mismatch will provoke a cascade response over time. Non-invasive tests vary with respect to which aspect of the ischemic cascade the test is measuring and this in turn reflects variability in test sensitivity. Here we've turned our ischemic cascade upside down and we're going to look at the various modalities and where they fit on the cascade. Here we see cardiac CT and geography is very sensitive for picking up atheromatous disease and also for excluding its presence. When absolutely normal this can be a very positive test, however if it picks up very significant atheroma it provides no functional data by itself unless post-processing fractional flow reserve modeling testing data can be used and this can also be very accurate in certain subsets of patients. Here is a very powerful illustration of absolutely normal coronary arteries obtained non-invasively with CT and geography. Cardiac CT and geography has the advantage of direct coronary visualization, very high sensitivity and a high negative predictive value. It has been shown to decrease length of stay in lower risk patients and it can be acquired very quickly with normal with current protocols at low radiation dose. On the other hand severe calcification presence of stents and irregular or very fast heart rates can prove problematic for gating and radiation and contrasts our issues. Therefore with CTA we have to consider heart rate in regular rhythm, body mass index because of attenuation factors, the presence of significant calcification or the presence of bypass grafts or stents and when looking at native vessels although it's imaging of bypass grafts that can be an advantage of this technique. Also with patient age and increased likelihood of disease it could be less useful. Here we see how fractional flow reserve testing can be added to CT and geography and this can be very helpful in intermediate test results where there's not enough calcium to really obscure the exam too much but there's just enough to impair our ability to determine the functional significance so intermediate disease can be adjudicated in CTA if you're able to add on CT FFR testing and we do use this at our facility. Nuclear stress emitting doesn't directly look at the coronary arteries but it does look at perfusion. It evaluates perfusion and membrane integrity with a radio tracer uptake. It can calculate ejection fraction and myocardial perfusion and metabolism are possible with PET including the use of glucose uptake. It's also useful for looking at scar and viability. The advantages of nuclear stress imaging is that exercise physiology can be determined with bicycle or treadmill exercise. It's very automated and can provide a highly reproducible ejection fraction. Disadvantages of nuclear include the use of radiation. Sometimes the studies can be long including rest and stress injections, patients inability to live still, irregular rhythms ingating and also attenuation artifacts can be problematic and these can lower the specificity. Stress echo evaluates wall thickening and wall motion which is a little bit further down the line. It could evaluate myocardial perfusion and scar and also assess viability with protocols. The advantages of stress echo are again that it's exercise physiology additive data. It's readily available in most facilities. No contrast is needed although echo enhancing agents can be very beneficial. There's no radiation involved and myocardial contrast imaging with perfusion is possible. Here you can see a wall motion abnormality is not present but you can see decreased myocardial perfusion in this distal LAD territory and this correlates with an occluded LAD shown there on the right on invasive imaging. This is even without stress. These are dupeenamine stress testing images in a 50 year old male with diabetes and hypertension who presented with no chest pain but worsening dyspnea exertion and an abnormally KG. He was unable to exercise due to a foot infection. He developed slight chest discomfort and augmented ST depression during dopidamine infusion and there is suspicion for subtle hypokinesis in the mid lateral wall in this four chamber view is seen on the left lower blue arrow and you can see how nice the endocardium is seen in this image even without an ultrasound enhancing agent. In the apical long axis view the infralateral wall is normal at baseline in the upper left but becomes hypokinetic rather than augmented at peak in the lower left. This is a typical ischemic response but it can be subtle. In our lab we sometimes acquire a global longitudinal strain image at baseline in the early recovery phase though this is not an official protocol. This takes just a couple of minutes and in this case the abnormal strain pattern in the left circumflex territory and both our visual assessment in the coronary angiography showed severe left circumflex stenosis. The sensitivity of a conventional stress echo are dictated in part by the fact that global systolic function and regional wall motion abnormalities occur somewhat late in the ischemic cascade but as we saw before the added assessment of strain imaging in addition to the assessment of diastolic dysfunction with stress can can move this test further up the ischemic cascade and has the potential to improve sensitivity. Detection of regional wall motion abnormalities by stress echo can lead to variability and interpretation and extensive training and experience are needed. Imaging quality has greatly improved with ultrasound enhancing agents improving the quality of stress echo in recent years and as we saw before there are increasing attempts to improve the sensitivity of the test. Cardiac MRI for ischemia testing evaluates wall thickening and wall motion in a similar fashion. It can evaluate my cardio perfusion with early contrast uptake and importantly it can detect scar. Advantages of cardiac MRI as I mentioned are the detection of scar imaging and the high special spatial resolution image quality. On the other hand no exercise can be performed there are some monitoring difficulties in the presence of calcium irregular rhythms the need for breath holding among other technical difficulties can limit this study's potential. We are learning more about a syndrome called Inoka or ischemia with no obstructive coronary artery disease. Sometimes stress imaging reveals ischemia and the cardiac catheterization shows no obstructive epicardial coronary artery disease and this is not necessarily a false negative stress test result as these patients have been shown to have a worse prognosis. Ischemia may result from coronary basispasm, coronary bridging, microvascular or other metabolic or flow limiting dysfunctions. We are learning more about patients exhibiting Inoka and the need for possibly further evaluation. Stress echo and other metabolic and perfusion based imaging can detect this condition and in some cases further evaluation can be taken at the time of invasive catheterization. In closing I'd like to point your attention to this article describing a patient-centered medicine approach when selecting pathways for treating patients with coronary artery disease. It is quite a complex with no one strategy fits all approach. Here's some take-home messages. We've discussed two new guidelines that address non-invasive coronary imaging and coronary syndromes and their guidance is consistent. The initial clinical assessment is key. Recommended descriptors for chest pain include cardiac chest pain, possible cardiac chest pain and non-cardiac chest pain which is actually the majority of patients. Assess for ischemic versus non- ischemic causes for cardiac chest pain and this highlights the role for comprehensive trans thoracic echo. Not recommended are typical chest pain and atypical chest pain descriptors. A pre-test probability assessment tool is critical. The role for initial surface echo versus cardiac focus is an area for development and collaboration. Non-invasive testing is highly useful in intermediate risk patients in the acute setting and in intermediate to high risk patients in the chronic setting. Non-invasive testing should only be applied with very great caution in the very low and very high risk patient groups. Thank you very much for your attention and here's how I can be reached if you have any further questions.