Chronic Coronary Syndromes Diagnostics

Laboratory tests provide information related to the possible causes of ischemia, establish cardiovascular risk factors and determine prognosis. A fasting lipid profile is used to determine the presence of dyslipidemia, establish the patient’s risk profile and help determine the need for treatment. Fasting blood glucose and glycated hemoglobin (HbA1c) are done to identify undiagnosed diabetes mellitus and establish patient’s risk profile. An oral glucose tolerance test is recommended if both tests are inconclusive. A complete blood count (CBC) that includes hemoglobin and white cell count is done to check for underlying anemia and/or infection and provide prognostic information. Serum creatinine is used to assess renal function. Cardiac enzymes (troponins, creatine kinase) are requested to rule out myocardial injury/necrosis. Creatine kinase measurement may be decreased for patients on statin therapy with accompanying symptoms of cardiac injury. C-reactive protein (CRP) is a predictor of an individual’s risk of coronary artery disease and can predict the risk of cardiovascular event in chronic coronary syndrome patients. Liver function tests are recommended prior to initiation of statin therapy. A pulmonary function test is done if dyspnea is the main symptom. Thyroid function test is done to identify other causes of ischemia. Plasma fibrinogen platelet count is for prothrombotic assessment. Fibrinogen is a predictor of an individual’s risk of coronary artery disease and can predict the risk of cardiovascular events in chronic coronary syndrome patients. Other tests associated with risk of future cardiovascular events include brain natriuretic peptide (BNP), N-terminal pro-BNP, lipoprotein (a), apolipoprotein B, small dense LDL cholesterol, and lipoprotein-associated phospholipase A₂. 

Chest X-ray  

Chest x-ray is commonly used to evaluate patients with suspected heart disease but does not provide the exact diagnosis nor classify risk group. It is usually normal in patients with chronic ischemic heart disease and stable angina. This should be considered for patients with signs and symptoms of heart failure, suspicion of acute pulmonary disease or suspected aortic, non-coronary cardiac or other thoracic causes of pain. The presence of cardiomegaly, pulmonary congestion, atrial enlargement and cardiac calcifications has been related to poor outcome.   

If the patient has a low probability of ischemic heart disease, then appropriate diagnostic tests should focus on non-cardiac causes of chest pain. 

Non-invasive Cardiac Investigations  

Non-invasive cardiac investigations are used in the assessment of angina, in diagnosis, evaluation of treatment efficacy and risk stratification. The choice for the initial non-invasive test should be based on the pre-test likelihood of obstructive coronary artery disease, availability of the test, the test’s performance in diagnosing obstructive coronary artery disease, patient characteristics and local expertise. 

Resting Electrocardiogram (ECG) 

A resting electrocardiogram is recommended in all patients with chest pain, including patients suspected of vasospastic angina. This should be done during or immediately after an episode of chest pain to detect ST-T segment changes (eg ST segment elevation, ST segment depression and T wave inversion) in the presence of ischemia. This is also used in patients without an obvious non-cardiac cause of chest pain. A normal resting electrocardiogram is common even in patients with severe angina which does not exclude the possibility of ischemia. This assists in clarifying the differential diagnosis if taken in the presence of pain which can detect dynamic ST-T segment changes in the presence of ischemia or by identifying features of pericardial disease. An electrocardiogram during an episode of chest pain is useful if vasospasm is suspected.  







Electrocardiogram abnormalities indicating a worse prognosis are evidence of prior MI, especially Q waves in multiple leads or an R wave in V1; persistent ST-T wave inversions, particularly in leads V1 to V3; LBBB, left anterior hemiblock, bifascicular block, 2nd- or 3rd-degree atrioventricular (AV) block or ventricular tachyarrhythmia/atrial fibrillation; and left ventricular hypertrophy.  

Resting Echocardiography  

A resting echocardiography is recommended in the initial evaluation of all patients with symptoms suggestive of stable ischemic heart disease. This helps detect alternative causes of chest pain. A resting 2-dimensional and Doppler echocardiography is recommended to measure left ventricular ejection fraction, volumes and diastolic function (eg detect regional wall motion abnormalities, detect or rule out other cardiovascular disorders [eg valvular heart disease, hypertrophic cardiomyopathy, pericardial effusion], evaluate RV function and estimate systolic pulmonary artery pressure) and to refine risk stratification and guide therapy. An estimation of systolic left ventricular function is very important in risk stratification. The use of transthoracic echocardiography in the assessment of left ventricular systolic function is suggested in the following patients with chronic coronary syndromes: Prior MI, signs or symptoms of heart failure, undiagnosed cardiac murmur or complex ventricular arrhythmias. This is not indicated for repeated use on a regular basis in patients with uncomplicated stable angina in the absence or change in clinical condition. 

Exercise Electrocardiogram or Electrocardiogram Stress Test  

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Exercise electrocardiography is a commonly used diagnostic test for ischemic heart disease. This is recommended in selected patients to evaluate exercise tolerance, symptoms, blood pressure response, arrhythmias and event risk. This may be considered in patients with low pre-test likelihood of obstructive coronary artery disease. This is used for risk stratification and prognostication. This may be considered as an alternative test to diagnose coronary artery disease when other noninvasive imaging tests are unavailable. This should be done only after clinical examination and a resting electrocardiogram under careful monitoring. Complications during exercise testing are few but severe arrhythmia and sudden death may occur. Absolute contraindications to exercise electrocardiograms are myocardial infarction within the last 2 days, cardiac arrhythmias causing symptoms or hemodynamic compromise, symptomatic and severe aortic stenosis, hypertrophic cardiomyopathy, symptomatic heart failure, pulmonary embolism, pulmonary infarction, myocarditis, pericarditis and acute aortic dissection. This is more sensitive (58%) and specific (62%) than a resting electrocardiogram for detecting myocardial ischemia. The test should be standardized using nomograms taking into account age, gender and body size. There is no diagnostic value in patients with LBBB, paced rhythm and Wolff-Parkinson-White (WPW) syndrome. A normal test in patients taking anti-ischemic drugs does not rule out significant coronary disease. Withhold beta-blockers for 48-72 hours prior to testing to prevent false-negative findings. In patients unable to perform an adequate amount of treadmill or bicycle exercise, various types of pharmacological stress tests can be useful (eg Adenosine, Dipyridamole). Selection and type of pharmacological stress will depend on individual patient factors. Treatment can be initiated without a stress test if the patient has a high probability of coronary artery disease but the test is contraindicated because of comorbidity or patient preference. This can be useful for prognostic stratification, to assess the efficacy of medical therapy or revascularization or to assist prescription of exercise after control of symptoms. The prognostic value is increased by considering heart rate variability, predicted maximum heart rate and heart rate recovery index. 

Stress Testing in Combination with Imaging  

The most well-established stress imaging modalities that may be used with either exercise tests or pharmacological stress tests are stress echocardiography, myocardial perfusion scintigraphy (SPECT, PET), stress CMR, and others (hybrid SPECT and CT, PET and CT, PET and CMR). Further studies are needed to prove the accuracy of hybrid techniques for coronary artery disease imaging. This is recommended in patients with a change in symptoms or functional capacity that persists despite guideline directed medical therapy (GDMT). Functional imaging using stress echocardiography, SPECT, PET or CMR is the preferred diagnostic modality in the following conditions: Moderate or high pre-test likelihood of obstructive coronary artery disease; and when the information on myocardial ischemia, viability or microvascular disease is desired. This may be performed after an inconclusive CCTA in intermediate- to high-risk patients ≥65 years old with stable chest pain. This helps in the diagnosis of myocardial ischemia, estimation of major adverse cardiovascular events risk and guidance of treatment decisions in patients with obstructive coronary artery disease.  

Stress echocardiography is recommended in patients with suspected chronic coronary syndromes with moderate or high pre-test likelihood of obstructive coronary artery disease to diagnose myocardial ischemia and estimate the risk of major adverse cardiovascular events. This is used to detect myocardial ischemia by evaluating regional systolic wall-thickening abnormalities during stress. The use of commercially available intravenous (IV) ultrasound contrast agents during stress echocardiography is recommended when ≥2 contiguous myocardial segments are not visualized to improve diagnostic accuracy. Myocardial perfusion with the use of commercially available IV ultrasound contrast agents during stress echocardiography is recommended to improve diagnostic accuracy and refine risk stratification beyond wall motion. Doppler left anterior descending coronary artery flow reserve during stress echocardiography may be considered to improve risk stratification beyond wall motion and assess microvascular function. The advantages include low cost, wide availability, can be performed and interpreted at bedside, rapid, free from ionizing radiation and can be repeated without safety concerns. Exercise imaging is preferable if possible because it allows more physiological reproduction of ischemia and assessment of symptoms. A high event risk in a patient with established chronic coronary syndromes includes a finding of ≥3 of 16 segments with stress-induced hypokinesia or akinesia on stress echocardiography and ≥10% ischemic area on the left ventricular myocardium on SPECT or PET perfusion imaging. SPECT or preferably PET myocardial perfusion imaging is recommended in patients with suspected chronic coronary syndromes with moderate or high pre-test likelihood of obstructive coronary artery disease to diagnose and quantify myocardial ischemia and/or scar, estimate the risk of major adverse cardiovascular events and quantify myocardial blood flow (PET). Measurement of CACS from unenhanced chest CT imaging is recommended in patients selected for PET or SPECT myocardial perfusion imaging to improve detection of both non-obstructive and obstructive coronary artery disease. PET should be considered in patients with heart failure with preserved EF (HFpEF) with angina or equivalent symptoms and normal or non-obstructive epicardial coronary arteries to detect or exclude coronary microvascular dysfunction.  

Pharmacological stress testing is indicated in patients who are not able to exercise adequately or may be used as an option to exercise stress tests. The two approaches that are used are infusion of short-acting sympathomimetic drugs (eg Dobutamine) in an incremental dose which increases myocardial oxygen consumption and mimics the effect of physical exercise; and infusion of coronary vasodilators (eg Adenosine and Dipyridamole) which provide a contrast between regions supplied by non-diseased coronary arteries where perfusion increases and regions supplied by significant stenotic coronary arteries where perfusion will increase less or even decrease (steal phenomenon). The advantages of stress imaging over conventional exercise electrocardiogram testing are superior diagnostic performance for detecting obstructive coronary disease; ability to quantify and localize ischemic areas; ability to provide diagnostic information if there are resting electrocardiogram abnormalities or the patients are unable to exercise; ability to establish the functional significance of lesions in patients with confirmed lesions by invasive coronary angiography; and ability to show myocardial viability. 

Computed Tomography (CT)  

Ultra-fast or electron beam computed tomography and multi-detector or multi-slice computed tomography are two modalities of CT imaging that were developed to improve spatial and temporal resolution in CT. This is effective in detecting coronary calcium and quantifying the extent of coronary calcification. Calcium is deposited in atherosclerotic plaques within the coronary arteries and coronary calcification increases with age. The extent of coronary calcification correlates more closely with the overall burden of plaque than with the location or severity of stenoses. The detection of coronary calcium may identify those at higher risk of significant coronary disease, but assessment of coronary calcification is not recommended routinely for the diagnostic evaluation of patients with stable angina.  

Carotid Artery Ultrasonography  

Carotid artery ultrasonography is used to identify plaque in patients suspected of chronic coronary syndromes with no known atherosclerotic disease. 

Cardiac Magnetic Resonance (CMR)  

Cardiac magnetic resonance is used to define structural cardiac abnormalities and evaluate ventricular function. This is an alternative diagnostic modality in patients suspected of coronary artery disease if the echocardiogram is inconclusive. Cardiac magnetic resonance perfusion imaging is recommended in patients suspected with chronic coronary syndromes with moderate or high pre-test likelihood of obstructive coronary artery disease to diagnose and quantify myocardial ischemia and/or scar and estimate the risk of major adverse cardiovascular events. This should be considered in patients with HFpEF with persistent angina or equivalent symptoms and normal or non-obstructive epicardial coronary arteries to detect or exclude coronary microvascular dysfunction. In conjunction with Dobutamine or adenosine infusion, CMR stress testing can be used to detect wall motion abnormalities or perfusion defects induced by ischemia. A high event risk in a patient with established chronic coronary syndromes includes a finding of ≥2 of 16 segments with stress perfusion defects or ≥3 Dobutamine-induced dysfunctional segments. 

Ambulatory Electrocardiogram (Holter) Monitoring 

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Ambulatory electrocardiogram monitoring is recommended for patients with chest pain and suspected of having arrhythmia. This should be considered in patients suspected of vasospastic angina.  

Coronary Computed Tomography Angiography (CCTA)  

Coronary computed tomography angiography is radiographic visualization of the coronary vessels after injection of radiopaque contrast material. This identifies the presence or absence of coronary lumen stenosis, stratifies the patient’s risk, provides therapeutic options (eg medical therapy or revascularization) and helps determine prognosis. This is recommended in the following: Patients suspected of chronic coronary syndromes with low or moderate pre-test likelihood of obstructive coronary artery disease to diagnose obstructive coronary artery disease and estimate the risk of major adverse cardiovascular events; patients with low or moderate pre-test likelihood of obstructive coronary artery disease if another non-invasive test is not diagnostic; preferred diagnostic tool to rule out obstructive coronary artery disease in patients with low or moderate pre-test likelihood of obstructive coronary artery disease; patients with low or moderate pre-test likelihood of obstructive coronary artery disease wherein the functional imaging for myocardial ischemia is not diagnostic; and  heart failure patients with left ventricular ejection fraction >35% and suspected chronic coronary syndromes with low or moderate pre-test likelihood of obstructive coronary artery disease. This is the preferred modality in the following conditions: Low or moderate pre-test likelihood of obstructive coronary artery disease; when the information on coronary artery disease is desired including non-obstructive coronary artery disease; and when individual characteristics suggest high-image quality.  

Coronary computed tomography angiography or a non-invasive functional imaging for myocardial ischemia may be used as an initial test to diagnose coronary artery disease in symptomatic patients in whom clinical evaluation alone cannot rule out an obstructive coronary artery disease. This is an alternative to invasive coronary angiography in patients with stable chest pain and intermediate probability of obstructive coronary artery disease. The extent and severity of angiographic coronary artery disease are the most important prognostic factors and essential for revascularization decision-making. This has a high sensitivity (97%) and specificity (78%) for detecting obstructive coronary artery disease. This is sensitive to heart rate, body weight and the presence of calcification. This has a very high negative predictive value for obstructive coronary artery disease is an advantage of coronary computed tomography angiography over standard functional testing. If the coronary computed tomography angiography demonstrated coronary artery disease of uncertain functional significance or is non-diagnostic, it is recommended to perform functional imaging for myocardial ischemia. This may be considered in patients with chronic coronary syndromes and previous coronary revascularization with a change in symptoms or functional capacity that persists despite guideline-directed medical therapy to evaluate bypass graft or stent patency. This may be used in patients <65 years old with an inconclusive prior functional study. Indications for coronary computed tomography angiography include survivors of cardiac arrest; serious ventricular arrhythmias; previous treatment by myocardial revascularization (percutaneous coronary intervention, coronary artery bypass graft) who developed early recurrence of moderate or severe angina pectoris; inconclusive diagnosis on non-invasive testing or discordant test results from different non-invasive modalities at intermediate to high risk of coronary level; and high risk of restenosis after percutaneous coronary intervention if percutaneous coronary intervention has been performed in a prognostically important site. Other indications for coronary computed tomography angiography include patients unable to exercise, those requiring assessment of aorta or pulmonary arteries or with anomalous coronary arteries. 

Invasive Cardiac Investigation  

Invasive Coronary Angiography (ICA) 

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Invasive coronary angiography is recommended as an alternative test in diagnosing coronary artery disease and for guidance during treatment decisions in patients with a high clinical likelihood and moderate to severe symptoms unresponsive to medical therapy, or typical angina with low-level exercise and clinical evaluation showing a high event risk. This is recommended for the following: Cardiovascular risk stratification of symptomatic patients with high-risk clinical profile with symptoms not responding adequately to medical therapy and revascularization is considered to improve prognosis; patients with mild or no symptoms receiving medical therapy with a non-invasive risk stratification showing a high event risk and revascularization is considered to improve prognosis; patients with chronic coronary syndromes with newly reduced left ventricular systolic function and/or clinical heart failure to assess coronary anatomy and guide potential revascularization; patients with chronic coronary syndromes and a change in symptoms or functional capacity which persists despite guideline directed medical therapy; patients with very high pre-test likelihood of obstructive coronary artery disease, especially patients with severe symptoms not responsive to guideline directed medical therapy, characteristic angina or dyspnea at a low level of exercise and/or high event risk, or left ventricular dysfunction suggesting extensive obstructive coronary artery disease; first-line diagnostic test in patients with de novo symptoms highly suggestive of obstructive coronary artery disease occurring at a low level of exercise; including invasive functional assessment is used to confirm or rule out the diagnosis of obstructive coronary artery disease or ANOCA/INOCA in patients with an uncertain diagnosis or non-invasive testing; heart failure patients with LVEF ≤35% and suspicion of obstructive coronary artery disease;  heart failure patients with LVEF >35% and suspected chronic coronary syndromes with very high pre-test likelihood of obstructive coronary artery disease; and patients with high risk of adverse events regardless of symptoms complemented with invasive coronary pressure measurement to refine risk stratification and improve symptoms and cardiovascular outcomes by revascularization. 

Measurement of fractional flow reserve or instantaneous wave-free ratio (iFR) should be considered when invasive coronary angiography is performed to assess the functional severity of intermediate left main stem stenoses before revascularization. Intravascular ultrasound should be considered when performing invasive coronary angiography to assess the severity of intermediate stenoses of the left main stem before revascularization. Selective assessment of functional severity of intermediate diameter stenoses during invasive coronary angiography is recommended to guide decisions on revascularization using the fractional flow reserve (significant ≤0.8) or instantaneous wave-free ratio (significant ≤0.89) or quantitative flow ratio (QFR) (significant ≤0.8). coronary flow reserve, hyperemic stenosis resistance (HSR) or coronary flow capacity (CFC) should be considered as complementary investigation. Resting invasive measurement of distal coronary pressure to aortic pressure ratio (Pd/Pa), diastolic pressure ratio (dPR), relative flow reserve (RFR) or angiography-derived vessel fractional flow reserve may be considered as an alternative parameter. This is considered for confirmation of coronary artery disease diagnosis (together with invasive functional evaluation) when non-invasive testing reveals an uncertain diagnosis. 

Invasive coronary functional testing is recommended in patients with refractory angina leading to poor quality of life and with documented or suspected ANOCA/INOCA to define ANOCA/INOVA endotypes and appropriate therapy. This is recommended in patients with persistent symptoms despite pharmacological therapy, with suspicion of ANOCA/INOCA and poor quality of life to identify potentially treatable endotypes and improve symptoms and quality of life. This is recommended in patients suspected of vasospastic angina and with repetitive episodes of rest angina associated with ST-segment changes relieved with nitrates and/or calcium channel blockers to confirm the diagnosis and determine the severity of underlying atherosclerotic disease. Invasive coronary functional testing should be considered in patients with HFpEF with angina or equivalent symptoms and normal or non-obstructive epicardial coronary arteries to detect or exclude coronary microvascular dysfunction. A high event risk in a patient with established chronic coronary syndromes includes a finding of 3-vessel disease with proximal stenoses, left main disease or proximal anterior descending disease (findings which may also be seen with CCTA). Invasive coronary angiography with FFR/iFR is the preferred diagnostic modality in the following conditions: Very high pre-test likelihood of obstructive coronary artery disease; low-threshold angina or equivalent; and findings suggestive of poor prognosis (eg severe left ventricular dysfunction, ventricular arrhythmia, hypotension during exercise). Radial artery access is recommended as the preferred access site and coronary artery pressure assessment is recommended when invasive coronary angiography is performed to evaluate the functional severity of intermediate non-left main stenoses before revascularization.