Coronary Artery Atherosclerosis Workup
- Author: F Brian Boudi, MD; Chief Editor: Yasmine Subhi Ali, MD, MSCI, FACC, FACP more...
Approach Considerations
Routine blood tests include complete blood count (CBC), chemistry panel, lipid profile, and thyroid function tests (to exclude thyroid disorders). Routine measurement of blood glucose and hemoglobin A1C is appropriate in patients with diabetes mellitus. A study by Paynter et al found that models incorporating HbA1c levels significantly improved prediction of CVD risk among patients with diabetes.[18]
Measuring any number of parameters that may reflect coagulation, fibrinolytic status, and platelet aggregability is possible. These measurements may prove to be valuable, but how these measurements affect clinical decision-making is unclear at this time, and including them in routine clinical practice is premature.
Standardization of the CRP assay is required before this test may be clinically useful, and whether CRP is a truly modifiable risk factor remains unclear.
The majority of atherosclerotic lesions responsible for the most serious CAD events (that is, the lesions that are most likely to rupture) are mild stenoses of inconsequential hemodynamic significance and are characterized by an abundance of lipid, numerous inflammatory cells, and a thin, fragile fibrous cap. This suggests that although measurements of coronary flow reserve (CFR) and fractional flow reserve (FFR), both of which are discussed below, may be useful in the assessment of the severity of stenoses and in the identification of lesions responsible for effort angina, they are not likely to identify the more dangerous plaques responsible for unstable angina, AMI, and sudden ischemic death.
Fractional Flow Reserve
Myocardial FFR has been used as an index of functional severity of coronary artery stenosis. FFR represents the fraction of the normal maximal coronary flow that can be achieved in an artery in which flow is restricted by a coronary stenosis. The concept of FFR is based on the observation that myocardial perfusion is entirely pressure dependent during maximal hyperemia.
Maximal blood flow in the presence of a stenosis is therefore determined by the driving pressure distal (Pd) to the stenosis, whereas the theoretical normal maximal blood flow is determined by the pressure proximal (Pp) to the stenosis. FFR is calculated during maximal hyperemia (obtained with adenosine or papaverine) as FFR = Pd/Pp. FFR less than 0.75 is typically associated with other objective evidence of myocardial ischemia. FFR is calculated from the ratio of the mean pressure distal to a coronary stenosis to the mean aortic pressure during maximal hyperemia. If the FFR is less than 0.75, sensitivity is at least 80% and specificity is at least 85% for the presence of ischemia on noninvasive stress testing.
Lipid Studies
Fasting lipid profile includes the following[19, 20, 21] :
- Total cholesterol level
- LDL cholesterol (LDL-C) level
- HDL cholesterol (HDL-C) level
- Triglyceride level
Specific lipid studies (if necessary) include the following:
- Small, dense LDL-C level
- Lipoprotein (a) level
- Apoprotein profile
- Direct measurement of HDL-C
C-Reactive Protein
CRP appears to provide prognostic information for CAD, although as stated above, the CRP assay must be standardized before CRP testing has a clinical benefit.
Men with CRP levels in the highest quartile had a 3-fold greater risk of MI, according to the Physicians’ Health Study. Use of aspirin resulted in a significant (55.7%) reduction in the risk of MI in men in the highest CRP quartile, suggesting that the aspirin-related reduction in the risk of first MI was clearly related to the level of CRP.[22]
One study found that patients with baseline CRP levels of more than 10 mg/L had significantly worse outcomes than did patients with lower CRP levels. This investigation, the Fragmin and/or Early Revascularization During Instability in Coronary Artery (FRISC-II) study, included 900 subjects followed for 4 years.[23]
CRP can also help to predict treatment efficacy, as demonstrated in the Cholesterol and Recurrent Events (CARE) trial of pravastatin treatment in post-MI patients. CRP levels tended to increase over time in the study’s placebo group, whereas levels remained lower in the statin-treatment group at 5 years. Additionally, the efficacy of statin therapy was greater in subjects with higher levels of CRP.[24]
Serum Markers
Serum markers in patients with suspected acute cardiac events (ACS, MI) include the following:
- Troponins (I or T)
- Creatine kinase with MB isozymes
- Lactate dehydrogenase and lactate dehydrogenase isozymes
- Serum aspartate aminotransferase
Biomarkers
In a 10-year comparison of 10 biomarkers for predicting death and first major cardiovascular events in approximately 3000 individuals, the most informative biomarkers for predicting death were the following[25] :
- B-type natriuretic peptide
- CRP
- Homocysteine
- Renin
- Urinary albumin-to-creatinine ratio
The most informative biomarkers for predicting major cardiovascular events were B-type natriuretic peptide and the urinary albumin-to-creatinine ratio. Individuals with elevated multimarker scores had a risk of death 4 times higher and a risk of major cardiovascular events almost 2 times higher than those with low multimarker scores. However, the use of multiple biomarkers added only moderately to the overall prediction of risk based on conventional cardiovascular risk factors.
Echocardiography
Transthoracic echocardiography helps to assess left ventricular function, wall-motion abnormalities in the setting of ACS or AMI, and mechanical complications of AMI.
Transesophageal echocardiography is most often used for assessing possible aortic dissection in the setting of AMI. Stress echocardiography can be used to evaluate hemodynamically significant stenoses in stable patients who are thought to have CAD. Treadmill echocardiography stress testing and dobutamine echocardiography stress testing provide equivalent predictive values. ECG findings are depicted below.
Stress test, part 1. Resting ECG showing normal baseline ST segments. (See the image below for part 2.) 
Stress test, part 2. Stress ECG showing significant ST-segment depression. (See the image above for part 1.) Nuclear Imaging Studies
These studies are useful in assessing patients for hemodynamically significant coronary artery stenoses. Stress and rest nuclear scintigraphic studies using thallium, sestamibi, or teboroxime are sometimes helpful.
Types of nuclear imaging stress tests include a treadmill nuclear stress test, a dipyridamole (Persantine) or adenosine nuclear stress test, and a dobutamine nuclear stress test. Stress nuclear imaging findings are depicted below.
Stress nuclear imaging showing anterior, apical, and septal wall perfusion defect during stress, which is reversible as observed on the rest images. This defect strongly suggests the presence of significant stenosis in the left anterior descending coronary artery. Radionuclide stress myocardial perfusion imaging can be used to quantify CFR. Thallium-201 (201 Tl) or sestamibi are widely used for this. Flow reserve is typically assessed during exercise or with pharmacologic coronary vasodilators.
MI-avid scintigraphy may be indicated for detection and localization of infarcted myocardium if evidence from other tests is inconclusive.
Computed Tomography Scanning
Multidetector computed tomography (MDCT) scanning can allow excellent visualization of the coronary arteries, but its relatively high radiation dose is one of the limitations of this approach. Newer generations of CT scanners may be able to reduce the required radiation exposure to make this technology more promising for screening asymptomatic patients. Low-dose CT attenuation correction (CTAC), which is performed for hybrid positron emission tomography (PET)/CT and single-photon emission computed tomography (SPECT)/CT myocardial perfusion imaging (MPI) can visually assess coronary artery calcium with high agreement with the Agatston score (AS).[26] These scans should routinely be assessed for visually estimated coronary artery calcium.
However, guidelines that address the use of CAD imaging tests may disagree. A study by Ferket, et al found several guidelines for risk assessment of asymptomatic CAD to have conflicting recommendations.[27] More research, especially randomized controlled trials, are needed in order to establish the actual impact imaging has on clinical outcomes.
A meta-analysis by Bamberg et al concluded that coronary CT angiography is an important tool in detecting the presence and extent of coronary artery disease and independent predictors of significant coronary stenosis and other cardiovascular events.[28] Glineur et al found that preoperative angiography predicts graft patency in the right gastroepiploic artery and right internal thoracic artery, whereas the flow pattern in saphenous vein grafts is significantly less influenced by quantitative angiographic parameters.[29]
Another study has shown that assessment with PET is a powerful, independent predictor of cardiac mortality in patients with known or suspected coronary artery disease and provides meaningful incremental risk stratification over clinical and gated myocardial perfusion imaging variables.[30]
Min et al suggest patients with CAD have an increased mortality risk that was highest among those with 3 vessel disease or left main disease. Conversely, the lack of CAD portended a good prognosis.[31]
Electron Beam Computed Tomography Scanning
Electron beam CT (EBCT) scanning is a relatively new, noninvasive method of evaluating calcium content in the coronary arteries. Healthy coronary arteries lack calcium. As atherosclerotic plaques grow, calcium accumulates because of a perpetuating inflammatory process or the healing and scarring induced by this process. EBCT is currently used as a screening test in asymptomatic patients and as a diagnostic test for obstructive CAD in symptomatic patients, although experts in the field have reached no consensus regarding indications for its use.
EBCT scanning has been demonstrated to have high sensitivity, with an overall predictive accuracy of 70%, according to the American College of Cardiology (ACC)/American Heart Association (AHA) Expert Consensus Document.[32]
However, EBCT has low specificity, ie, a substantial false-positive rate, which raises the index of suspicion for CAD and leads to expensive and unwarranted additional testing to exclude CAD. Consequently, the ACC/AHA report did not recommend EBCT scanning to help diagnose obstructive CAD.
Whether EBCT scanning is a worthwhile tool for screening of CAD is still unclear. Well-established clinical indicators, such as the Framingham risk score and the National Cholesterol Education Program (NCEP) risk calculator, already accurately predict the likelihood of CAD. Whether EBCT scanning adds to these indicators has yet to be shown. The Multi-Ethnic Study of Atherosclerosis (MESA), sponsored by the US National Institutes of Health, has been assessing prospective evaluation of EBCT scanning in asymptomatic subjects to answer this question.[33]
EBCT scanning may have niche uses, including (1) determination of whether individuals who appear to be at intermediate risk are really at a higher risk (eg, asymptomatic elderly patients who have high calcium scores) and (2) determination of a low likelihood of significant CAD if EBCT scanning demonstrates a low or absent calcium score.
Optical Coherence Tomography Imaging
Optical coherence tomography (OCT) imaging is a method of catheter-based, high-resolution intravascular imaging. Unlike IVUS, it measures the backreflection of infrared light rather than sound. The main advantage of OCT is its remarkable resolution, which is in the range of 10-20 µm. In addition, acquisition rates are near video speed, an advantage relative to many other technologies for assessing plaque. In contrast to IVUS scanning, the typical OCT catheters contain no transducers within their frame, which makes them small and inexpensive. Because OCT imaging uses light, a variety of spectroscopic techniques are available, including polarization spectroscopy, absorption spectroscopy, elastography, OCT Doppler, and dispersion analysis.
Magnetic Resonance Imaging
Magnetic resonance imaging (MRI) may be used to gain information noninvasively about blood vessel wall structure and to characterize plaque composition.
Coronary Angiography
Coronary angiography was the first available in vivo assessment of the coronary arteries. In this technique, an iodinated contrast agent is injected through a catheter placed at the ostium of the coronaries. The contrast agent is then visualized through radiographic fluoroscopic examination of the heart.
Coronary angiography remains the criterion standard for detecting significant flow-limiting stenoses that may be revascularized through percutaneous or surgical intervention (as seen in the image below).
Cardiac catheterization and coronary angiography in the left panel shows severe left anterior descending coronary artery stenosis. This lesion was treated with stent placement in the left anterior descending coronary artery, as observed in the right panel. Quantitative coronary angiography (QCA) is used to perform computerized quantitative analysis of the entire coronary tree and has been widely employed in many trials of atherosclerotic progression and regression.
Coronary angiography has several limitations. Severity of stenosis is generally estimated visually, but estimation is limited by the fact that interobserver variability may range from 30-60%. The presence of diffuse disease may also lead to underestimation of stenoses, because the stenosed areas are expressed as a percent of luminal diameter compared with adjacent normal coronary segments, and, in diffuse disease, no such segments are noted. This usually occurs in diabetic patients, in whom coronary arteries are traditionally described as small-caliber vessels, when that appearance is actually due to the presence of diffuse symmetrical involvement of the entire vessel, as elucidated by IVUS studies.
One of the other limitations of coronary angiography is that only the vessel space occupied by blood is visualized. The actual extent of atherosclerotic plaque volume in the wall cannot be assessed with this technique.
Angiography does not provide information about plaque burden, which may be significant due to positive remodeling of the plaque, even when the degree of luminal obstruction is mild.
Because of the inherent limitations of coronary angiography, attention has been directed toward using physiologic approaches to determine the severity of coronary stenoses. The commonly used methods of measuring human coronary blood flow in the cardiac catheterization laboratory are Doppler velocity probes (for measuring CFR) and pressure wires (for measuring FFR). Although most current methods measure relative changes in coronary blood flow, useful information about the physiologic significance of stenosis, cardiac hypertrophy, and pharmacologic interventions can be obtained from these measurements.
Through the Prospective Multicenter Diagnosis of Ischemia-Causing Stenoses Obtained Via Noninvasive Fractional Flow Reserve (DISCOVER-FLOW) Study, Koo et al created a novel technique to noninvasively assess fractional flow reserve, using coronary CT angiograms (CTA). They analyzed 159 vessels in 103 patients. All patients underwent cardiac CTA, invasive angiography fractional flow reserve (FFR), and CT-FFR. FFR-CT and CTA were compared with invasive FFR as the criterion standard. In a per-vessel basis, the accuracy, sensitivity, specificity, positive predictive value, and negative predictive value were 84.3%, 87.9%, 82.2%, 73.9%, 92.2%, respectively, for FFRCT. For cardiac CTA stenosis, they were 58.5%, 91.4%, 39.6%, 46.5%, 88.9%, respectively. This technique, if widely available, may be immensely useful because CTA, although easily interpreted in terms of presence or absence of disease, can be difficult to interpret with regards to severity of disease.[34]
Doppler Velocity Probes
Doppler velocity probes use a Doppler flow meter, which is based on the principle of the Doppler effect. This is the most widely applied technique for measuring coronary flow in humans. High-frequency sound waves are reflected from moving red blood cells and undergo a shift in sound frequency proportional to the velocity of the blood flow.
In pulsed-wave Doppler methods, a single piezoelectric crystal can transmit and receive high-frequency sound waves. These methods have been successfully applied in humans by using miniaturized crystals fixed to the tip of catheters. Technological developments have further miniaturized steerable 12-MHz Doppler guide wires to a diameter of 0.014 inches. Flow to a stenosis can therefore be assessed distally and proximally. The Doppler guidewire measures phasic flow velocity patterns and tracks linearly with flow rates in small, straight coronary arteries.
Indications for Doppler velocity probe use include determining the severity of intermediate stenosis (40-60%) and evaluating whether normal blood flow has been restored after percutaneous transluminal coronary angioplasty (PTCA).
The use of smaller Doppler catheters allows measurement of selective coronary artery flow velocity. By noting the increase in flow velocity following administration of a strong coronary vasodilator, such as papaverine or adenosine, the CFR can be defined. CFR provides an index of the functional significance of coronary lesions that obviates some of the ambiguity of anatomical description.
The current Doppler probe method has limitations. Limitations include the following:
- Only changes in flow velocity, rather than absolute velocity or volumetric flow, are measurable
- The change in flow velocity is directly proportional to changes in volumetric flow only when vessel dimensions are constant at the site of the sample volume
- Other factors, including left ventricular hypertrophy and myocardial scarring, can also affect CFR
- Changes in luminal diameter and arterial cross-sectional area during interventions are not reflected in measurements of flow velocity, thus potentially causing underestimation of the true volume flow
Because this technique does not measure absolute coronary blood flow, several indices of flow velocity have been used for assessing the physiologic significance of coronary stenoses. Coronary flow velocity reserve is the ratio of maximum flow velocity to baseline flow velocity.
Patients with a coronary flow velocity ratio of less than 2 typically have other corroborating evidence of myocardial ischemia and improve symptomatically with revascularization. Conversely, patients with a ratio of more than 2 usually lack other objective evidence of myocardial ischemia and have a favorable outcome with conservative management; therefore, flow velocity measurements can be helpful in the treatment of patients with coronary lesions of intermediate severity.
Relative coronary flow reserve
Relative CFR is calculated as follows: ([rCFR] = CFR target/CFR reference). Relative CFR involves Doppler coronary flow measurements of target and reference vessel CFR with a Doppler-tipped guidewire. In one report, El-Shafei et al found that, compared with patients who had negative stress-imaging study findings, patients who had positive stress-study findings showed more angiographically severe stenoses (74% +/- 13% vs 44% +/- 24%) with lower target CFRs (1.68 +/- 0.55 vs 2.46 +/- 0.74) and lower rCFRs (0.72 +/- 0.22 vs 1 +/- 0.26).[35]
Based on cut points (CFR >1.9; rCFR >0.75), compared with CFR, rCFR had similar agreement (kappa 0.54 vs 0.5), sensitivity (63% vs 71%), specificity (88% vs 83%), and positive predictive value (83% vs 81%) with myocardial perfusion tomography.
Although rCFR, as with CFR, correlates with stress myocardial perfusion imaging results, rCFR did not have significant incremental prognostic value over CFR alone for myocardial perfusion imaging. However, rCFR does provide additional information regarding the status of the microcirculation in patients with CAD and complements the CFR for lesion assessment.
Ultrasonography
Ultrasonography aids in evaluating brachial artery reactivity and carotid artery intima media thickness, which are measures of vessel wall function and anatomy, respectively. These evaluations remain research techniques at this time but hold promise as reliable noninvasive, and therefore repeatable, measures of disease and surrogate endpoints for the evaluation of therapeutic interventions.
Brachial Artery Reactivity
The loss of endothelium-dependent vasodilation is a feature of even the early stages of atherosclerosis. The availability of high-resolution ultrasonographic systems makes the visualization and measurement of small peripheral conduit vessels, such as the human brachial artery, possible. Flow-mediated dilation of the brachial artery has been pioneered as a means of evaluating the health and integrity of the endothelium. The healthy endothelium dilates in response to an increase in blood flow, whereas vessels affected by atherosclerosis do not dilate and may paradoxically constrict.
Carotid artery intima-media thickness
B-mode ultrasonography of the common and internal carotid arteries is a noninvasive measure of arterial wall anatomy that may be performed repeatedly and reliably in asymptomatic individuals. The combined thickness of the intima and media of the carotid artery is associated with the prevalence of cardiovascular risk factors and disease and an increased risk of myocardial infarction and stroke. This association is at least as strong as the associations observed with traditional risk factors.
Intravascular Ultrasonography
IVUS demonstrates the luminal dimensions and, more importantly, the tissue composition of the vascular wall in tomographic subsegments that can be summated to create a 3-dimensional picture showing arterial remodeling and the diffuseness of atherosclerosis with clarity unobtainable by angiography.
IVUS delineates vascular remodeling—positive and negative. Positive remodeling shows adaptive outward expansion of the external elastic membrane to accommodate growing plaques (Glagov phenomenon). Negative remodeling exhibits discrete areas of vascular luminal encroachment by the ingrowing plaques.
Positive remodeling is more commonly associated with unstable angina, whereas negative remodeling is associated with stable angina, according to an IVUS study of 85 patients by Schoenhagen and colleagues.[36]
The apparently paradoxical findings of angiographic studies suggesting that AMI most often occurs in less than 50% of stenosed arterial segments, and those of autopsy studies showing AMI to be associated with large plaques, are reconciled by IVUS findings. IVUS shows the responsible lesions to be large plaques that have positively remodeled, thus causing minimal luminal encroachment and exhibiting echolucency suggesting a lipid-rich pool in the plaque center.
The ability of IVUS to identify positively remodeled plaques and the presence of diffuse disease in some ways makes it better than angiography, the less-than-perfect criterion standard. IVUS can much more clearly demonstrate the presence or absence of fibrosis, calcium, and ulceration, as well as eccentricity of the plaques.
Ostial lesions can also be better defined by IVUS.
Histology
A system devised by Stary et al classifies atherosclerotic lesions according to their histologic composition and structure.[3]
In a type I lesion, the endothelium expresses surface adhesion molecules E selectin and P selectin, attracting more polymorphonuclear cells and monocytes in the subendothelial space.
In a type II lesion, macrophages begin to take up large amounts of LDL (fatty streak).
In a type III lesion, as the process continues, macrophages become foam cells.
In a type IV lesion, lipid exudes into the extracellular space and begins to coalesce to form the lipid core.
In a type V lesion, SMCs and fibroblasts move in, forming fibroatheromas with soft inner lipid cores and outer fibrous caps.
In a type VI lesion, rupture of the fibrous cap with resultant thrombosis causes ACS.
As lesions stabilize, they become fibrocalcific (type VII lesion) and, ultimately, fibrotic with extensive collagen content (type VIII lesion).
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