The clinical history and physical examination are cornerstones in the diagnosis of cardiovascular disease. A careful history that includes symptom characteristics, timing, and duration; factors that exacerbate or relieve symptoms; and functional capacity is critical to ensure a focused and appropriate diagnostic evaluation. Abnormal findings on the cardiovascular examination may also raise suspicion for specific cardiac conditions and guide the selection of tests.
Cardiovascular testing provides both diagnostic and prognostic information, and its use should be guided by symptoms, the pretest likelihood of heart disease, and whether testing results will alter patient management.
Diagnostic testing for coronary artery disease (CAD) can be categorized as providing functional and/or anatomic information regarding atherosclerotic disease burden. Functional studies reveal the presence of ischemia (exercise electrocardiography [ECG], single-photon emission CT [SPECT], PET), the extent and severity of ischemia (SPECT, PET), information on coronary blood flow (PET, fractional flow reserve [FFR]–CT), and development of wall motion abnormalities (echocardiography, cardiac magnetic resonance [CMR] imaging). Anatomic information is obtained from invasive angiography, coronary CT angiography (CTA), and coronary artery calcium (CAC) scoring. Cardiac diagnostic testing modalities are summarized in Table 1.
Cardiac stress testing is commonly performed to diagnose CAD. Appropriate, cost-effective stress testing is based on the history, physical examination, and pretest probability of CAD, which takes into account age, sex, symptoms, and prevalence of disease. Cardiac stress testing is most effectively used in patients with an intermediate pretest probability of CAD, in whom a positive test result significantly increases disease likelihood and a negative test result significantly decreases likelihood (see Coronary Artery Disease). Performing stress testing in persons with a low likelihood of disease (such as young patients with atypical symptoms) yields a high incidence of false-positive test results, potentially resulting in unnecessary testing, inaccurate diagnoses, and harms. In patients with a high pretest probability of disease, invasive angiography rather than stress testing is appropriate.
Assessment of the patient's functional capacity and ability to exercise is important in determining the most appropriate stress testing. Exercise ECG is recommended as the initial test of choice in patients with normal findings on baseline ECG. If there are baseline ECG abnormalities (such as ST-segment depression >1 mm, left bundle branch block, left ventricular hypertrophy, paced rhythm, or preexcitation), ST-segment changes with exercise cannot be used to evaluate for the presence of obstructive CAD; these abnormalities will result in a nondiagnostic ECG stress test. Functional testing with imaging (with exercise or pharmacologic stress) or anatomic assessment with coronary CTA is indicated in these instances.
Stress testing may also be used for risk assessment in patients known or suspected to have CAD. The ability to exercise and, more important, exercise capacity are strong predictors of cardiovascular events. ECG changes, hemodynamic response to exercise (blood pressure and heart rate recovery), and other measures (such as the Duke Treadmill Score) also provide prognostic information. Stress imaging studies provide information on the extent and severity of disease, which is helpful for risk assessment.
The decision of whether to withhold cardiac medications, such as nitrates and β-blockers, before stress testing should be individualized. In patients who are undergoing exercise stress testing to diagnose CAD, cardiac medications that impair heart rate response (β-blockers) should be withheld for at least 24 hours before testing because these agents may lead to an inadequate peak heart rate. If the stress test is being performed to evaluate symptoms or determine prognosis in a patient with known CAD, patients should continue their cardioactive medication regimen.
Stress testing should always be performed with exercise, unless exercise is contraindicated or the patient is unable to exercise. Exercise stress testing protocols use treadmill or stationary bicycle ergometry, and each protocol should increase workload in a stepwise manner over a period of 6 to 12 minutes to allow adequate time for development of maximal metabolic demand. A standard Bruce protocol increases the speed and grade of the treadmill every 3 minutes. Achieving 85% of the age-predicted maximal heart rate adequately rules out obstructive CAD; however, patients should exercise until limited by symptoms. Because heart rate and blood pressure are the major determinants of myocardial oxygen demand, achieving a rate pressure product (heart rate × systolic blood pressure) of at least 25,000 is considered an adequate workload and reflects overall left ventricular myocardial performance. Stress testing should be terminated when the patient has exerted maximal effort, requests to stop, or experiences significant angina or other physical symptoms. The test should also be stopped for exertional hypotension, significant hypertension (>200/110 mm Hg), ST-segment elevation or significant ST-segment depression, or ventricular or supraventricular arrhythmias.
Ischemia is defined by the development of horizontal or downsloping ST-segment depression of at least 1 mm occurring 80 milliseconds after the J point on exercise ECG, although ST-segment depression cannot localize ischemia (Figure 1). The development of hypotension or lack of blood pressure augmentation during exercise can indicate the presence of significant obstructive disease. Heart rate recovery after cessation of exercise provides incremental prognostic information. A heart rate drop of less than 12/min in the first minute after exercise termination is associated with higher mortality. Functional capacity is also a powerful predictor of outcomes; individuals unable to achieve 5 metabolic equivalents, or the first stage of a Bruce protocol, have higher all-cause mortality. Information obtained from exercise stress testing can be combined with clinical information in risk prediction models. The Duke Treadmill Score incorporates duration of exercise, development of symptoms, and degree of ST-segment depression to calculate 5-year all-cause mortality in patients without CAD.
In patients with obstructive CAD, reduced blood flow and myocardial ischemia lead to a progression of myocardial abnormalities, termed the ischemic cascade. Initially, ischemia induces changes in perfusion, followed by diastolic and (at a later stage) systolic dysfunction, ECG changes, and eventually angina. The addition of imaging studies to ECG stress testing increases diagnostic sensitivity by detecting earlier signs of ischemia.
Stress testing with imaging is indicated in patients with an inability to exercise, contraindications to exercise, baseline ECG abnormalities that would preclude interpretation of the exercise ECG, or indeterminate findings on the exercise ECG. Imaging with SPECT, PET, or CMR can be used to detect reduced myocardial perfusion as early evidence of ischemia. Systolic dysfunction, indicated by wall motion abnormalities during stress, can be detected by echocardiography or CMR imaging. Overall, imaging choice should consider characteristics of the patient and modality as well as local availability and expertise (see Table 1).
Stress testing with adjunctive imaging compares wall motion, perfusion, and/or metabolism at baseline and after stress, depending on the modality used (Table 2). Exercise is the stress modality of choice. Patients should undergo pharmacologic stress if they are unable to exercise or have contraindications to exercise. Dobutamine, like exercise, increases myocardial oxygen demand and elicits ischemia because of insufficient perfusion to the affected myocardium. Vasodilators, such as dipyridamole, regadenoson, and adenosine, produce hyperemia and a flow disparity between myocardium supplied by unobstructed vessels and myocardium supplied by the stenotic vessel because of the inability of the distal vasculature to dilate. In patients with left bundle branch block undergoing nuclear stress testing, vasodilator-induced stress is preferred to exercise or dobutamine because of the potential for false-positive septal perfusion abnormalities.
Exercise stress echocardiography provides information on ischemia, hemodynamic significance of valvular abnormalities, and pulmonary pressures during exercise. Exercise is performed with supine or upright bicycle ergometry, which allows for continuous imaging, or with a treadmill protocol, which requires acquisition of post-stress images within 90 seconds. The development of new wall motion abnormalities indicates ischemia in the visualized territory. Resting wall motion abnormalities that do not change at peak exercise may indicate infarcted or hibernating myocardium (chronic but potentially reversible ischemic dysfunction).
With pharmacologic stress echocardiography, dobutamine is progressively infused (up to 40 μg/kg/min) to achieve 85% of age-predicted maximal heart rate. Atropine is administered if the target heart rate is not achieved. The development of new wall motion abnormalities indicates myocardial ischemia. Dobutamine infusion may also be used in patients with low-gradient aortic stenosis to help differentiate between severe aortic stenosis and pseudostenosis. Patients with reduced systolic function who are able to augment their stroke volume in the setting of severe aortic stenosis may benefit from aortic valve replacement.
Interpretation of stress echocardiography findings is more subjective than with other tests, and the sensitivity of stress echocardiography may be reduced in the setting of baseline wall motion abnormalities, systolic dysfunction, or single-vessel disease.
Nuclear stress testing compares blood flow in the myocardium to diagnose ischemia. In SPECT myocardial perfusion imaging, a radiotracer is injected at rest and at peak exercise/vasodilation, and the radiotracer is taken up by the myocardium relative to blood flow. Rest images are compared with those obtained after exercise or pharmacologic stress. Perfusion defects observed on images obtained after stress indicate flow-limiting CAD (Figure 2). Regions with fixed defects can indicate infarcted or hibernating myocardium, and viability assessment can help distinguish between the two. Gated images can provide an assessment of left ventricular systolic function.
SPECT imaging can also quantify the extent and severity of disease, providing additional prognostic information. High-risk features, such as several regions of hypoperfusion, a lack of augmentation or a reduction in post-stress ejection fraction, transient cavity dilatation, and wall motion abnormalities, are associated with a worse prognosis.
Technetium-based myocardial perfusion imaging has higher sensitivity and specificity than thallium-based studies and also provides better image quality. Technetium-based agents are taken up with blood flow and are bound to the mitochondria, allowing for delayed imaging. In contrast, uptake of thallium requires active metabolism, which can be useful to assess myocardial viability (Table 3).
Cardiac PET provides excellent diagnostic and prognostic information for patients known or suspected to have CAD. PET provides better temporal and spatial resolution than does SPECT imaging, which is helpful in patients with obesity or nondiagnostic SPECT results. CT may be used with PET to provide information on the presence of coronary artery calcification. PET radiotracers have a short half-life, resulting in lower radiation exposure and necessitating the use of vasodilators. Vasodilator stress allows for assessment of peak stress ejection fraction, quantification of absolute myocardial blood flow, and evaluation of myocardial metabolism. The utility of PET imaging in cardiac patients is limited by availability of the technology.
CMR imaging is used with dobutamine to assess development of wall motion abnormalities or with vasodilators to assess perfusion. Right and left systolic function can be assessed with gated imaging. CMR imaging is commonly used to evaluate inflammatory or infiltrative diseases, pericardial diseases, and the extent and severity of infarction. Viability can be determined by evaluating the extent of myocardial fibrosis (nonviable myocardium) within the left ventricular region. CMR imaging is limited by operator expertise, length of time for image acquisition, and availability.
Anatomic assessment of the coronary arteries can be performed with noninvasive coronary CTA or invasive angiography. Both tests require administration of contrast agents and expose the patient to radiation. CTA interpretation can be limited in cases of extensive calcification and with assessment of distal arteries.
In symptomatic patients with an intermediate risk for CAD, CTA may be helpful in ruling out CAD. In the PROMISE trial, 10,000 symptomatic patients suspected of having CAD were evaluated with an initial strategy of anatomic testing with CTA or functional testing. In patients with an intermediate pretest probability of CAD, the composite cardiovascular event rate was low (<1% per year) in both groups, and outcomes (death, myocardial infarction, hospitalization for unstable angina, or major procedural complication) at 2 years did not differ between groups.
Coronary CTA may also play a role in the evaluation of acute chest pain in the emergency department. CTA is appropriate in patients suspected of having an acute aortic syndrome or a coronary embolism. Coronary CTA may be helpful in patients with low or intermediate likelihood of non–ST-elevation acute coronary syndrome who have a low TIMI risk score, negative troponin level, or nonischemic ECG. It may also be useful in patients with an equivocal diagnosis of non–ST-elevation acute coronary syndrome who have an equivocal initial troponin level or single troponin elevation without further symptoms of acute coronary syndrome, or in patients who have ischemic symptoms that resolved hours before undergoing testing. Careful consideration of patient factors and selection of appropriate testing are essential to avoid additional unnecessary testing and the associated costs and potential harms.
Coronary angiography during a cardiac catheterization procedure is an invasive test in which nonionic contrast material is injected into the coronary arteries (or bypass grafts) by using long, thin (<2-mm) catheters. Arterial access is obtained by using the femoral or radial artery, and radiation exposure is required. This test should be considered in patients who have a high pretest probability of obstructive CAD, including symptomatic patients with abnormal findings on noninvasive functional or anatomic testing or with an acute coronary syndrome.
The addition of FFR to invasive angiography and CTA can provide additional functional information, including the hemodynamic significance of a lesion and need for intervention. FFR is the ratio of blood flow distal to the stenosis to blood flow proximal to the stenosis at maximal flow. It is typically measured during cardiac catheterization by placing a pressure wire across the stenosis and inducing conditions of maximal hyperemia, usually with adenosine. FFR-CT is an FDA-approved diagnostic test that provides both anatomic and functional data; it has higher specificity for the diagnosis of obstructive CAD than does CTA alone. Performance of FFR-CT is similar to performance of invasive FFR during angiography. The availability of this test and its delayed interpretation may limit its use in patients with acute symptoms.
Coronary artery calcification indicates atherosclerosis and may be quantified with electron-beam or multidetector CT. Although CAC scoring provides information regarding the burden of disease, it cannot determine the degree of obstruction. CAC measurement has been used for diagnosis and risk assessment in both symptomatic and asymptomatic patients; however, assessment of CAC in asymptomatic patients should be limited to those at intermediate risk (according to the Framingham score) in whom risk reclassification will influence primary prevention therapy.
CAC scores are categorized as follows: 0, no disease; 1 to 99, mild disease; 100 to 399, moderate disease; and above 400, severe disease. These scores should be interpreted in the setting of age, ethnicity, and sex. Specific nomograms and risk calculators, such as the MESA risk calculator (www.mesa-nhlbi.org/MESACHDRisk/MesaRiskScore/RiskScore.aspx), can be used for risk prediction. The absence of CAC is associated with a low risk for cardiovascular events.
Cardiac diagnostic testing carries risks related to exercise; exposure to pharmacologic stress testing agents, radiation, or contrast agents; and vascular access for invasive procedures. Additionally, inappropriate initial testing may lead to unnecessary downstream testing with added physical and financial costs.
There is a very small risk for myocardial infarction or death (1/2500 patients) in patients undergoing exercise stress testing. Absolute contraindications to exercise include unstable angina or acute myocardial infarction, uncontrolled arrhythmias, decompensated heart failure, acute pulmonary embolism or deep venous thrombosis, acute pericarditis or myocarditis, acute aortic dissection, and severe symptomatic aortic stenosis. Relative contraindications are left main coronary artery stenosis, hypertrophic cardiomyopathy with severe obstruction, electrolyte abnormalities, high-degree atrioventricular block, and significant arrhythmias.
Vasodilator stress agents (most commonly adenosine) are associated with the side effects of chest pain, headache, and flushing. Atrioventricular block and bronchospasm may also occur. Theophylline may be given after the test to reverse these effects. Vasodilator stress testing is contraindicated in patients with reactive airways disease with active wheezing, systolic blood pressure of less than 90 mm Hg, sick sinus syndrome, or high-degree atrioventricular block.
Nuclear stress testing with SPECT and PET, CAC scoring, coronary CTA, and coronary angiography all expose the patient to radiation; however, advances in techniques have resulted in reduction of overall radiation exposure. The level of radiation exposure depends on the procedure, equipment, radiopharmaceutical agent, operator technique, and patient characteristics (such as body size).
Contrast agents used in invasive angiography, coronary CTA, CMR imaging, and echocardiography also pose a risk to the patient. CMR imaging that requires gadolinium contrast may rarely cause nephrogenic systemic fibrosis, particularly in patients with underlying kidney disease. Iodinated contrast material used in CT may result in acute kidney injury. Microbubble contrast agents are used to enhance the endocardial borders in echocardiography and can cause hypersensitivity reactions in rare instances.
Coronary angiography can be complicated by vascular access problems; bleeding complications; coronary artery dissection; aortic dissection; and plaque disruption or thrombus leading to peripheral emboli, stroke, or myocardial infarction. Femoral artery access can be complicated by retroperitoneal hemorrhage, which should be suspected in patients with hypotension, back or flank pain, and/or a drop in hemoglobin level. Pseudoaneurysms at the arterial puncture sites occur more commonly with femoral artery access and may manifest as a large hematoma or new bruit at the access site.
Diagnostic testing for structural heart disease should be considered in patients with a suggestive history and physical examination, such as those with a systolic murmur that is grade 3/6 or higher, a late or holosystolic murmur, a diastolic or continuous murmur, or a murmur with accompanying symptoms. Routine imaging of known structural disease is unnecessary unless there is a change in the clinical presentation or examination. A change in functional status in patients with known underlying structural disease warrants evaluation. Imaging modalities to evaluate for structural heart disease are listed in Table 4.
The mainstay of noninvasive cardiovascular imaging for structural abnormalities is transthoracic echocardiography (TTE). TTE evaluates right and left ventricular size, thickness, and function, including wall motion abnormalities. It can also be used to obtain information on valvular function (including regurgitation or stenosis), diastolic function, filling pressures, and the pericardium. The presence of an intracardiac shunt can be evaluated with the use of agitated saline contrast. Initial assessment for endocarditis can also be performed with TTE.
Transesophageal echocardiography (TEE) is commonly used to evaluate for the diagnosis of infective endocarditis in patients with a high pretest probability and to assess for complications of endocarditis (such as abscess). TEE may also be used to better visualize valvular pathology, particularly when surgical repair or percutaneous intervention is planned; to evaluate specific structures that cannot be well visualized on TTE (such as prosthetic heart valves) or patients with poor transthoracic imaging; to evaluate acute aortic abnormalities; and to rule out left atrial thrombus before cardioversion (Figure 3). TEE requires moderate sedation and placement of the TEE probe in the distal esophagus and stomach. Contraindications include esophageal strictures or active esophageal varices. Esophageal injury, including perforation and bleeding, are potential complications of TEE.
The initial study in patients with a history of palpitations, presyncope, or syncope when an arrhythmia is suspected should be 12-lead resting ECG. The ECG may show evidence of preexcitation, ectopic rhythms, atrioventricular block, or intraventricular conduction delay, providing insight into the cause of the symptoms. Echocardiography should be performed in patients suspected of having structural heart disease.
The intermittent and fleeting nature of arrhythmias can make diagnosis difficult. Diagnostic studies are selected on the basis of the presence and frequency of symptoms and the duration and timing of the recording (Table 5). If symptoms occur daily, a 24- or 48-hour ambulatory ECG monitor (Holter monitor) may be used. Infrequent symptomatic events may be captured with an external patient-triggered event recorder if the event lasts long enough for the patient to trigger the device. A looping event recorder captures several seconds of the ECG signal before the device is triggered; it is useful for syncope or presyncope associated with arrhythmias. A longer-term external ECG monitor or an implanted loop recorder may be warranted in patients with very infrequent events.
Exercise stress testing is also frequently used in patients suspected of having or known to have arrhythmia. Treadmill stress testing is an important tool for evaluating chronotropic response, ischemia, and exercise-induced or adrenergically induced arrhythmia.
Most patients do not require diagnostic electrophysiology testing. Electrophysiology testing may be indicated in patients in whom the diagnosis remains indeterminate or in settings in which catheter-based interventions may be needed to treat refractory arrhythmias.