Abstract
In the Western world, there are now millions of patients who undergo clinical procedures that evaluate coronary artery status each year. Methods span from direct imaging using angiography, computerized tomography, to nuclear magnetic imaging as well as to functional studies, such as positron emission tomography. These techniques have provided significant information to physicians, but there is still need for an improved accessibility. Angiographic methods are expensive and expose the patient to significant amounts of radiation, undesirable in younger patients. Among the novel technologies for coronary diagnostics, transthoracic echocardiography (TTE) of coronary arteries has provided an important alternative, particularly in everyday practice. Diagnostic arterial TTE can allow determination of the coronary wall lumen in at least three major coronary segments (left main [LM], left arterial descending [LAD] and right coronary artery [RCA]). Coronary wall thickness using the LAD has been preliminarily shown to be related to the risk of coronary events. Since it is well ascertained that coronary lesions found in any location indicate that at least 80% of the coronary tree is affected, this is very important clinical information. Evaluation of coronary status by TTE is a novel technology providing important information in ischemic syndromes, in cases of coronary malformations and other coronary diseases.
Coronary evaluation can be carried out by a variety of both invasive and non-invasive methods, many requiring radiation exposure or patient immobility.
Transthoracic echocardiography (TTE) of the coronaries can, in particular, evaluate the coronary wall thickness, and this may be directly related to the coronary disease risk.
TTE is a useful method for the monitoring of coronary flow reserve and can allow the detection of coronary malformations.
KEY MESSAGES
Introduction
Coronary artery disease (CAD) involves atherosclerosis in the coronary tree and has a long pre-clinical period in which patients are relatively asymptomatic. Imaging of the coronary arteries to detect patients at risk of a coronary event is performed as a clinical procedure on millions of individuals in the Western world each year. Methods for coronary evaluation span from the direct observation of the coronaries by angiography (CA) using contrast material under X-ray monitoring, to less direct evaluations, by computerized tomography (CT) (Citation1) or cardiovascular magnetic resonance (CMR) imaging (Citation2) for example. Functional studies, by positron emission tomography (PET), can also indicate areas of reduced flow (Citation3). Coronary artery conditions may also be evaluated indirectly by way of different risk scores (Citation4) or by the monitoring of other major arterial trees, in particular of the carotids using the intima media thickness (IMT), which appears to correlate to coronary atherosclerosis (Citation5).
All these methodologies, quite diversified, can certainly offer an excellent opportunity to physicians to evaluate or predict the coronary artery status of non-symptomatic individuals, patients with a clinical suspicion of coronary disease or patients with established disease. Non-invasive methods for the detection of coronary status have limitations as CT can expose the patients to a considerable amount of radioactivity (Citation6,Citation7). CA, with the addition of intravascular ultrasound (IVUS) (Citation8) or optical coherence tomography (OCT) (Citation9) provides the best method for the assessment of the coronary arterial status, both in terms of coronary diameters and of the arterial wall conditions (from just thickening to subocclusion). CA, however, is expensive and not without risk. Further, a recent large US study reported that approximately 60% of elective cardiac catheterizations found no obstructive coronary disease (Citation10).
It has thus become of interest to evaluate novel technologies for coronary diagnostics. Such technologies should rely on readily available and relatively inexpensive equipment. They should be non-invasive and not require contrast media, be easily repeatable and with adequate reproducibility. In the present review article, transthoracic echocardiographic (TTE) evaluation of the coronary arteries will be presented, discussing the pros and cons of this methodology and potential interactions with other presently available methods for coronary diagnostics.
Diagnostic arterial ultrasound: basic characteristics
The major problem with the uptake of TTE for coronary imaging is the requirement of high frequency imaging to improve spatial resolution for accurate detection of the small coronary arteries. The greater the depth of the structure of interest, the lower the frequency that needs to be used for optimal penetration, thus reducing image quality (Citation11). Elevated frequencies, as in the earliest experience, carried out using an epicardial echocardiography during cardiac operative procedures (Citation12) could indeed provide excellent imaging, but these high frequencies (12-MHz) may not be used for TTE. The recent development of high frequency transducers, harmonic imaging mode and the use of contrast agents have opened new paths in the TTE for coronary evaluation. By applying these latest technologies with modern, high quality US systems, visualization and analysis of the main coronary arteries by TTE are now accessible in the majority of patients (). It is possible to visualize the main coronary arteries, i.e., the left main (LM), left anterior descending (LAD), right coronary artery (RCA) and in most instances the circumflex coronary artery (Cx) using appropriate ultrasound frequencies for each coronary segment (Citation13–16).
Table 1. Success rates in visualizing the proximal coronary arteries by transthoracic echocardiography.
Contrast agents
Use of contrast agents has improved the analysis of coronary imaging by TTE (). The peripheral intravenous injection of a contrast agent enhances blood echogenicity and amplifies the duration and intensity of the ultrasonic signal. Strengthening the US signal reflected by the blood flow can be achieved by the presence of encapsulated microbubbles contained in the injected product. Several contrast agents have been developed but two in particular have been used for the analysis of the coronary arteries in TTE: Levovist®, a galactose compound of microbubbles, and the Sonovue®, consisting of sulfur hexafluoride. Contrast agents enable better visualization of the coronaries, facilitate the positioning and alignment of the pulsed Doppler sample volume, and improve the study of coronary reserve (Citation17–20). Use of contrast agents, however, is not always necessary for the achievement of high quality TTE of the coronaries, now mainly dependent upon the technological improvements of the US evaluation.
Table 2. Success rate of coronary artery visualization by transthoracic echocardiogram without and with contrast agent.
Examination of the proximal segments of the coronary arteries
Several windows allow visualization of the coronary arteries with patients in the supine or left decubitus positions. In the standard parasternal short axis view, the origins of both coronary arteries can be visualized by scanning superior to the aortic valve with careful interrogation of the aortic sinuses (). The LCA generally arises approximately at 4 o’ clock and the RCA at 12 o’ clock if you consider the aortic root as a clock face. Coronary arteries appear as linear intramyocardial color fragmental structures approximately 0.5–3.5 cm in length and 2–4 mm in diameter (). Initially, a short portion of arteries can be visualized. Then, by step-by-step movement of the transducer according to the course of the vessel, a longer segment of arteries can be assessed (). Visualization of the circumflex (Cx) coronary is less frequently reported since the position of this last artery is of more complex approach by TTE. Cx can be, in fact best visualized in the parasternal short axis view with imaging traversing the mitral annulus, sometimes just below the left atrial appendage (Citation21).
Figure 1. Standard parasternal short axis view: visualization of the origins of both coronary artery segments by scanning superior to the aortic valve with careful interrogation of the aortic sinuses. The left coronary artery generally arises at approximately at 4 o’ clock and the right coronary artery at 12 o’ clock, if we consider the aortic root as a clock face.
Figure 2. Standard parasternal short axis view: coronary arteries appear as linear intramyocardial fragmental structures. RCA: right coronary artery.
Figure 3. Standard parasternal short axis view. LAD: left anterior descending coronary artery.
After obtaining optimal quality B-mode images, the search for coronary arteries, particularly in the case of the Cx, can be helped by color Doppler mapping (). To obtain the best image quality, the sample size of color Doppler should be kept at a minimum. As the Doppler velocities of coronary blood flow are low, the velocity range should be set with a low Nyquist limit (15–20 cm/s), and filters should be reduced.
Figure 4. Standard parasternal short axis view: the search for coronary arteries is started with color Doppler mapping. Doppler velocity range should be set with a low Nyquist limit (15–20 cm/s).
Coronary evaluation can, in addition, also rely solely on the Doppler effect from basal flow and from changes following flow reduction due to coronary stenosis. The US morphological method is, however, closer to the physician’s expectations in assessing coronary status.
Applications of coronary TTE in different clinical conditions
Coronary disease
It is now well understood that atherosclerosis is not a luminal disease, but a disease of the vessel wall (Citation22). A phenomenon known as remodeling occurs in response to the atherosclerotic process (Citation23): histological and IVUS studies have shown that there are two types of arterial remodeling – positive and negative (Citation24–27). When there is an increase in the artery size to accommodate a plaque, this is known as “positive remodeling” (Citation28–32).
Positive remodeling may overcompensate for early atherosclerotic changes (Citation33,Citation34). Negative remodeling is the opposite, i.e., a decrease in the artery size. When positive remodeling occurs, this renders the plaque “invisible” to angiography as the luminal area of the artery remains the same even when associated with a large plaque burden (Citation35–37). There is thinning and focal atrophy of the media induced by atherosclerosis to accommodate the expanding plaque into the arterial wall allowing the plaque to bulge outward rather than inward (Citation38,Citation39).
In view of these newer concepts on coronary disease development, coronary wall imaging has become the most ambitious potential clinical application of TTE. A number of reports have indicated that the initial parts of two major coronary arteries can well be visualized by TTE, i.e., the LAD and the RCA, allowing determination of lumen diameter and, more important, of wall thickness. Evaluation of wall thickness of the Cx is of more complex approach, but the luminal diameter can be evaluated in most patients.
Just limiting evaluation at LAD and RCA, older and more recent reports have indicated that the arterial wall thickness can be reliably measured by TTE. Initially, Gradus-Pizlo et al. (Citation40) indicated that a comparison between epicardial echocardiography and TTE provided rather consistent findings: there was evidence of a reduced coronary thickness when the TTE evaluation was compared to the epicardial measurement (Citation41).
More recently, Perry et al. (Citation42) provided detailed information on the feasibility of assessing wall thickness of the LAD in 240 patients free of CAD, but suspected of subclinical disease. An average wall thickness of 1.1 ± 0.2 mm for the anterior wall of the LAD is described with an essentially identical posterior wall thickness (). The external elastic membrane (EEM) diameter, as generally used in most studies on coronary IVUS was 4.5 ± 9 mm (Citation43). This approach appears to be of satisfactory reliability, with a test–retest variability correlation for the same operator of R = .86 for LAD wall thickness. Correlation for test–retest variability for two separate operators was R = .82.
Figure 5. Modified parasternal long axis view showing LAD measurements. Dashed arrows demonstrate anterior wall thickness measurement, solid arrows demonstrate external elastic membrane measurement and double headed arrow demonstrates luminal measurement. RVIT: right ventricular inflow tract; LAD: left anterior descending coronary; IVS: interventricular septum.
Both Perry et al. (Citation44) and Gradus-Pizlo et al. (Citation41) found that the TTE measured LAD wall thickness and the EEM diameter of patients with CAD were significantly larger than those of normal volunteers, even when matched for age. The luminal diameter, instead, was maintained in both groups indicating that the CAD group had undergone positive remodeling at the site measured. This objectively visualized evidence of coronary atherosclerosis with TTE would likely go undetected during coronary angiography that images the lumen and not the vessel wall. Moreover, all of the clinical CAD patients analyzed by Perry et al. (Citation44) had an angiographically “normal” appearance of the LAD indicating that the detected wall thickening was subclinical in nature.
While conventional cardiac risk factors (RF) do not fully explain the incidence of CAD and coronary events, thus potentially excluding a population who would otherwise benefit from lifestyle and RF modifications, a TTE evaluation can demonstrate subclinical CAD, thus addressing the patient to a more appropriate prevention strategy. In a pilot study, Perry et al. used TTE visualization of the proximal LAD to determine the coronary wall thickness in 121 subjects in low, intermediate, and high risk groups, all free of clinical CAD. The average length of follow up was 39.0 ± 5.7 (SD) months. Overall there were nine (7%) documented ischemic events on follow up. Subjects who had an event were older and had a larger LAD wall thickness than those who did not have an event. Kaplan–Meier event free survival analysis demonstrated that the baseline LAD wall thickness was able to predict event rate in the whole cohort (p = .006, ). Furthermore, to account for the effects of age, only those subjects aged over 55 years (n = 58) were used to determine if the LAD wall thickness could independently predict event rate, which it was able to do (p = .02, ). There were seven events in this sub-group.
Figure 6. Kaplan–Meier survival graph using the cut-off value of the baseline LAD wall thickness as the factor for analysis.
Figure 7. Kaplan–Meier survival graph using the cut-off value of the baseline LAD wall thickness as the factor for analysis in subjects over 55 years of age.
Other than age, a known and non-reversible RF, the only predictor of an event was the baseline LAD wall thickness in this small sample. However, in order to minimize the influence of age on this analysis, only those aged >55 years were analyzed and the ability of the LAD wall thickness to predict an event was better than that provided by any other conventional RF. This association supports the premise that LAD wall thickness as determined by TTE may reflect coronary atherosclerotic burden. Standard conventional RF analysis was unable to accurately predict event rates in this subject cohort with the exception of age. In fact, other than age, only a LAD wall thickness of ≥1.5 mm was predictive of future events.
An alternative to imaging by TTE of the coronaries, can be by a combined Doppler ultrasound approach. Vegsundvag et al. (Citation45) proposed an evaluation of coronary flow in different segments of the LAD and also of the RCA and of the Cx, this last not always well visualized by the direct TTE approach. The Doppler method, when carefully applied, can detect variations in flow and different flow levels can indicate a significant coronary stenosis. Very recently this research group (Citation46) indicated that the peak stenotic to restenotic velocity ratio (pSVR) measurements might be compared to quantitative coronary angiography and coronary flow velocity reserve (CFVR). The sensitivity and specificity of demonstrating significant stenoses (diameter stenosis, 50–99%) in the LM, LAD, Cx, and RCA were 75 and 98%, 74 and 95%, 40 and 87%, and 34 and 98%, respectively (Citation46). These quite exciting findings, on the other hand, do not provide any data on the coronary arterial wall conditions in the evaluated patients.
Invasive procedures such as IVUS are better able to determine stability and composition of atherosclerotic plaques, whereas TTE at the moment can only measure wall thickness. This does not provide information on the arterial wall structure or vulnerability; however, it is an ideal screening tool for the early detection of CAD. It is a relatively inexpensive technique that in experienced hands is rapid and easy to perform. Unlike coronary computed tomography (CT), scanning by TTE does not need the presence of calcium to determine wall thickness and therefore earlier and less stable plaques can be detected.
It is possible that the use of sublingual Nitroglycerin (NTG) may improve visualization of the coronary arteries by dilatation of the coronary artery tree. In a pilot study on 19 male subjects, LAD wall thickness, luminal diameter, and external diameter were evaluated after sublingual NTG (300 μg). The LAD luminal diameter was increased by 60 ± 30% from baseline (Citation47).
Coronary reserve evaluation
Coronary flow reserve (CFR) defines the maximum increase in blood flow through the coronary arteries above the normal resting flow. CFR is generally evaluated in the course of CA, by infusing a potent vasodilator, such as papaverine or adenosine (Citation48). During CA, after injection of the vasodilator, the pressure wire is pulled back and pressure recorded across the vessel length. CFR is the ratio between the maximum blood flow distal to the lesion, and the normal maximum proximal flow in the same vessel. It thus provides a functional evaluation by measuring a pressure decline along the vessel length. An increase in flow of ≥2 is considered as normal, whereas lower ratios, i.e., figures below 1, are definitely pathological.
CFR is of course of significant clinical interest in view of the consequent clinical indications to the correction of coronary stenosis. CFR values are not markedly influenced by catheter selection or vasodilator doses. Reduced sensitivity to the vasodilator, on the other hand, may indicate increased arterial thickness and the possible need for correction with drugs. The complexity and duration of CFR recording during angiography suggested the use of echocardiography as an alternative. In this case, the US unit can make use of a built in calculation package and flow velocity measured in the mid distal portion of the LAD by Doppler flow imaging. The CF velocity reserve (CFVR) is defined as the ratio between the hyperemic response, following in this case dipyridamole (0.84 mg/kg over 6 min) and the basal peak diastolic CF. CFVR ≤2.0 is considered as abnormal and this clinical finding is of additive prognostic value in patients with chest pain and normal or near-normal coronary arteries (Citation49).
Present status of coronary evaluation by TTE versus other non-invasive techniques and possible future developments
The interest in the newer non-invasive methods for the evaluation of coronary arteries has led to a number of recent studies evaluating these technologies versus invasive procedures. Most significant has been the very recent contribution by Greenwood et al. (Citation50) testing the hypothesis that CMR guided care may be superior to the NICE Guidelines directed care. In the 1202 evaluated symptomatic patients, the CMR approach led to a 50% lower number of angiographies versus the NICE approach, and a dramatic reduction of unnecessary angiographies. A similar study on the TTE approach would indeed be desirable.
The interest in coronary evaluations is not only restricted to cardiologists. A non-invasive evaluation of the coronaries can provide data of clinical value for the internists and can be a useful completion in the general assessment of the patient’s health. TTEs can, in fact, also detect malformations, be they congenital (Citation16) or acquired (Citation51). Internists who are, at present, frequently excluded from the final diagnostic conclusions in patients with arterial disease, can receive direct information on the coronary status, thus helping them develop a therapeutic strategy, involving not only coronary procedures but also drug treatments. In a very recent review article on arterial imaging, the challenges of noninvasive coronary imaging were underlined, encouraging technological advances improving image quality and reducing radiation exposure (Citation52). In view of the growing capacity of TTE to provide reliable information on the coronary arterial status, it is possible that this technique may become of routine use, also providing important data on the value of any present or future treatment for CAD.
Disclosure statement
The authors have no conflicting interests to declare.
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