Stress Echocardiography: Comparison With Other Techniques

Aims of Noninvasive Coronary Imaging

With respect to the choice and role of noninvasive cardiac imaging, it is important to distinguish between patients based on the absence or presence of symptoms related to myocardial ischemia. In patients with suspected angina pectoris and acute coronary syndromes, the diagnostic objective is to identify or exclude the presence of obstructive plaques causing sufficient compromise to the blood flow or to identify an alternative etiology for the symptoms. In contrast, in the asymptomatic patient population, the goal is largely targeted at estimating the risk of future events through the identification of atherosclerotic burden, including nonobstructive disease and high-risk plaque.

Most studies performed thus far have compared noninvasive imaging testing with invasive angiography. Important data have shown that angiographic appearance of coronary atherosclerosis does not always correlate with its functional significance. The FAME (Fractional Flow Reserve versus Angiography for Multivessel Evaluation) trial showed that 20% of stenoses in the range of 70% to 90% were not severe enough to impede coronary flow. The FAMOUS-NSTEMI (Fractional Flow Reserve versus Angiographically Guided Management to Optimize Outcomes in Non-ST-segment Elevation in Myocardial Infraction) trial showed there was significant discordance between angiography and FFR in 32% of cases.

Given the potential discordance between the degree of a coronary stenosis and its hemodynamic significance, it may be more clinically relevant to compare noninvasive stress testing techniques that are being used to identify hemodynamically significant CAD against FFR rather than ICA as a reference standard. FFR is quantified as the ratio between the maximum achievable myocardial blood flow in the case of a stenosis and the maximum achievable myocardial blood flow in the absence of stenosis. It is measured during ICA by calculating the ratio between the distal and proximal stenotic coronary artery pressure during maximal myocardial hyperemia. FFR has an ischemic threshold value between 0.75 and 0.80. Multiple studies have shown that FFR 0.75 or less reliably identifies inducible myocardial ischemia, whereas FFR greater than 0.80 reliably excludes myocardial ischemia. The benefits of FFR over other methods quantifying hemodynamically significant CAD are that it is not affected by changes in heart rate, blood pressure, and contractility of the heart.

Numerous cardiac imaging methods exist to diagnose ischemia causing CAD, including single-photon emission computed tomography (SPECT), positron emission tomography (PET), stress echocardiography (SE), cardiac magnetic resonance imaging (CMRI), CT coronary angiography (CTCA), fractional flow reserved derived from CTCA (CT-FFR), CT perfusion (CTP), and ICA.

Several studies and meta-analyses have reported the accuracy of stress testing for the diagnosis of CAD as defined by the gold standard of cardiac catherization. Without imaging, the sensitivity and specificity of an exercise treadmill test for detecting CAD are modest at 70% to 80%. Adding myocardial imaging to standard exercise testing increases the sensitivity for detecting CAD. SPECT and exercise testing are most commonly used in the United States.

A more recent meta-analysis by Danad and coworkers showed that CMRI had the highest diagnostic performance for detecting hemodynamically significant CAD on both a per-patient and per-vessel basis compared with invasive FFR. Both CTCA and CT-FFR yielded high diagnostic sensitivity with low specificity for CTCA. Diagnostic performance of SPECT, SE, and ICA were generally poorer. Interestingly, both SE and SPECT appeared to be more accurate than ICA. Surprisingly, ICA exhibits both a low sensitivity (69%) and specificity (67%). This finding has been helpful in showing the role of noninvasive imaging to guide clinical decision making and questions the role of ICA for the initial workup of patients with suspected CAD. SPECT performed poorly on a per-vessel level (sensitivity 57% vs 70% on a per-patient basis). A significant mismatch between SPECT-defined myocardial territories and real coronary anatomy in more than half of the cases has been shown. In the presence of multivessel CAD, SPECT has the potential to miss ischemia because of the presence of balanced ischemia or underestimate the ischemic burden because only the region with the most severe ischemia is identified. Performance of SE was modest despite operator bias. CMRI and CPET have a higher diagnostic performance because of higher spatial resolution and better image quality and better endocardial definition. CTCA, on the other hand, has high diagnostic sensitivity, resulting in a high negative predictive value (NPV) to exclude hemodynamically significant CAD. The specificity of CTCA, as well as ICA, is low, which emphasizes discordance between stenosis severity and ischemia causing coronary artery lesions. CT-FFR has emerged as a new tool for the noninvasive diagnosis of ischemia causing CAD by applying computational fluid dynamics to conventional CTCA images. Higher sensitivity of CT-FFR with a modest specificity was noted compared with invasive FFR. In most studies, CT-FFR was evaluated in isolation to CTCA, and therefore the combination would be expected to improve overall specificity.

Anatomy Versus Physiology

Noninvasive imaging of the coronary arteries using CTCA allows for detailed visualization of coronary atherosclerosis and the degree of coronary stenosis. It also holds the promise of providing new insights into plaque biology and pathophysiology. Atherosclerosis is a chronic inflammatory state that is characterized by the formation of lipid-rich plaques. The hallmarks associated with high-risk plaques are characterized as either the macroscopic feature of the plaque versus the biological process within it. Histologic and imaging data have consistently demonstrated that culprit plaques responsible for myocardial infarctions (MIs) have the following characteristics: lipid-rich necrotic core, positive remodeling, microcalcification, chronic inflammation, and a thin fibrous cap. Each of these characteristics represents a potential imaging target.

Coronary Artery Calcium Scoring

Atherosclerotic calcification is a well-known process that occurs as a healing response to pathologic inflammation within the plaque. In its earliest stages, there is calcium deposition, and the resultant microcalcifications increase the likelihood of rupture of the surface of fibroatheroma. In more advanced disease by which the calcium is detected on computed tomography (CT), these microcalcifications have coalesced into a large calcific nodules. The assessment of coronary artery calcification is one of the major applications of noninvasive coronary artery imaging. Coronary artery calcium (CAC) scoring is now commonly performed using noncontrast images and are obtained from multidetector CT scanners at submillisevert radiation doses. Arterial calcium is defined as the presence of a lesion with a density greater than 130 Hounsfield units across an area of at least 1 mm2. Most commonly, these scans are described in Agatston units (AU), a semiquantitative measure that incorporates aspects of calcium density and distribution.

Calcium score has been evaluated in patients with angina and asymptomatic patients. In symptomatic patients, a CAC score greater than 0 has a diagnostic sensitivity for identifying a coronary stenosis of 50% or greater of between 0.89 and 0.99; however, specificity is low, ranging between 0.40 and 0.59. Consequently, in a low-risk population with atypical symptoms in the outpatient clinic, the low positive predictive value (PPV) necessitates additional diagnostic imaging in many cases. Alternatively, in patients with high pretest probability of disease among those with positive troponin in the emergency department, the test will have an unacceptably high “false-negative” result. Therefore, calcium scoring is not recommended as a diagnostic test in patients with chest pain.

Understanding that not all plaques contain calcium, the total CAC score offers an approximate overall atherosclerotic burden for an individual. Multiple studies have confirmed the prognostic values of such scores. The St. Francis Heart Study showed an improvement in the c-statistic for clinical events from 0.69 to 0.79 when added to the Framingham risk score. These findings have been confirmed in larger cohort studies, including the MESA (Multi-Ethnic Study of Atherosclerosis) trial. Calcium scoring has the most clinical value in intermediate-risk patients without established cardiovascular disease when considered whether to initiate primary prevention therapy. In this context, the 2018 American College of Cardiology/American Heart Association (ACC/AHA) guidelines on the prevention of cardiovascular disease give a class IIa recommendation to calcium scoring.

Computed Tomography Coronary Angiographyβ

The clinical application of CTCA for a long time was limited because of high radiation exposure and cardiac motion artifact. These problems have now mostly resolved because of advances in scanner technology and introduction of multiple dose reduction techniques. With available technology, diagnostic image quality can be obtained in 95% of scans. Limiting factors in obtaining diagnostic image quality include motion artifacts at higher heart rates, presence of significant dense coronary calcification, and coronary stents. These limitations can be minimized by appropriate patient selection and preparation, including use of β-blocker and nitroglycerin therapy. Imaging is being performed on 64-slice or greater CT scanners using intravenous contrast and can be performed with radiation exposure range of 3 to 5 mSv. CTCA detect luminal narrowing 50% diameter or greater with high sensitivity and NPV. The diagnostic accuracy of CTCA for detection of 50% or greater stenosis using ICA as the reference standard has been shown to be high in a number of multicenter studies. A meta-analysis published in 2007 described a sensitivity of 93% and specificity of 96% on per segment basis for detection of CAD. In symptomatic patients with an intermediate pretest probability of obstructive CAD, the NPV of a negative CTCA is more than 95%. In addition to diagnosing coronary obstruction, the use of CTCA for risk stratification has been supported by a large body of literature.

The clinical utility of CTCA has been rigorously evaluated in randomized trials: PROMISE (Prospective Multicenter Imaging Study for Evaluation of Chest Pain) and SCOT-HEART (Scottish Computed Tomography of the HEART). PROMISE ( n = 10,003) randomized intermediate-risk symptomatic patients being evaluated for CAD to CTCA or noninvasive functional testing (67% nuclear stress imaging, 23% SE, 10% exercise electrocardiography [ECG]). The median follow-up duration was 25 months, and no difference in the primary composite endpoint (death, MI, hospitalization for unstable angina, or major procedural complications) was shown; however, it showed downstream reduction in the rate of unnecessary coronary angiograms and apparent reduction in death or MIs at 12 months.

The SCOT-HEART trial ( n = 4146) evaluated the utility of adding CTCA to standard of care (predominantly exercise ECG) in rapid access chest pain clinics across Scotland. The primary endpoint of diagnostic certainty as 6 weeks was increased with CTCA. The 5-year composite clinical outcome of coronary death or nonfatal MIs reported a marked 40% relative risk reduction in the CTCA arm of the trial. These trials show a strong evidence of benefit of CT first approach for the assessment of chest pain.