The primary technique for detecting the presence and monitoring the development of carotid atherosclerotic plaque is ultrasound. The development of ultrasound techniques has made it possible to precisely visualise not only blood flow, but also vessel walls, including atherosclerotic plaque. Contrast-enhanced ultrasound examination enables one to make an objective observation of atherosclerotic plaque neovascularisation, clearly indicating active inflammation, which is an inherent feature of vulnerable (unstable) plaque. Depending on the examination method used, it is possible to precisely visualise different components of the plaque and its behaviour during blood flow through the vessel lumen or through the neovessels of the plaque, and, consequently, determine the possible presence of inflammation, which is a defining feature of plaque stability. The full utilisation of physical phenomena that underlie contrast-enhanced ultrasound will bring further enormous progress of diagnostic and probably also therapeutic methods for carotid atherosclerosis. The selection of the right examination method significantly accelerates diagnosis and adequate classification of plaque, and makes it possible to monitor the progression of atherosclerosis. However, one needs to bear in mind that ultrasound remains a very subjective method. The success of contrast-enhanced ultrasound also depends on the skills and experience of the examiner. Current attempts at increasing the objectivity of contrast-enhanced ultrasound examination using artificial intelligence will make it possible in the future to make a definitive evaluation of atherosclerotic plaque stability. This will allow one to assess the risk of ischaemic stroke adequately.
Key words:
ultrasound, unstable atherosclerotic, plaque, CEUS, ischaemic stroke
In a situation where ultrasound examination of carotid arteries reveals the presence of a potentially unstable plaque, meeting instability criteria, and the patient has a history of cerebrovascular accident (CVA) with no clear aetiology, a CEUS examination is warranted to detect possible plaque neovascularisation, which is practically a definitive sign of plaque instability (Fig. ).
Open in a separate windowA contrast-enhanced ultrasound examination is not a unidirectional procedure. The type of data acquired changes depending on the contrast agent used, manner of its administration and method of observation.
Ultrasound examination using UEA has a limited spatial and temporal scope considering the manner of administration and the method of acquisition and observation. Therefore, after the patient’s eligibility for the procedure has been determined, a precise algorithm of action should be established, which includes the selection of:
UEA,
UEA manner of administration,
phase of observation of UEA propagation in the vessel and tissues,
method of UEA interaction with the ultrasound system,
mode of procedure recording,
method of assessment of examination findings.
An ultrasound system equipped with contrast-enhanced examination option is necessary. This option usually has one or two timers displaying the length of the loop recorded during the procedure. For this option, the system itself should include the possibility to record a film as raw data with a length covering at least the following phases: wash-in, arterial, venous and wash-out. The systems available on the market enable one to acquire a few loops, including their combined record. The contrast option should also include flash mode, which makes it possible to use the pulse inversion method. This method involves the emission of two ultrasound pulses with the same amplitude, shifted by 180° between one another, at a very short interval. This method utilises a non-linear response of UEA microspheres: overlapping echoes of fundamental wave harmonics. It is also necessary to have an indication of the mechanical index displayed on the desktop.
The standard options of systems supporting the use of ultrasound enhancing agents include the colour flow mode (CFM) and power Doppler (PD) or its modification: directional power Doppler (DPD). Power Doppler options (PD, DPD) are necessary for possible microsphere rupturing using the flash or replenish method. A PD pulse necessary for the flash method is released automatically by the ultrasound system at preset moments or delivered on demand by the examiner after they press an appropriate function key.
An appropriate ultrasound probe is necessary to conduct contrast-enhanced examination of atherosclerotic plaque. Carotid atherosclerotic plaques are usually examined using vascular probes with a foot print of approximately 45 mm, frequency range of 3–11 MHz and nominal frequencies of 5–8 MHz.
Studies are also conducted on the use of a linear high speed volumetric imaging probe with UEA for three-dimensional imaging of the surface of atherosclerotic plaque(37,40,41).
Based on pharmacokinetic properties, ultrasound enhancing agents are divided into those which:
do not pass through the pulmonary vascular bed (only the right ventricle of the heart is visualised; short-term action): Echovist;
pass through the pulmonary vascular bed, have a short half-life (less than 5 minutes from intravenous administration), produce a low signal on harmonic imaging when low acoustic power is used: Albunex, Levovist;
pass through the pulmonary vascular bed, have a long half-life (over 5 minutes from intravenous administration), produce a high signal on harmonic imaging when low acoustic power is used: Echogen, Optison, SonoVue, Sonovist;
are captured in the liver and spleen, make imaging possible after the vascular phase: Levovist, Sonovist, Sonazoid.
Currently, in Poland, two ultrasound enhancing agents are approved for use. SonoVue, a Bracco product, contains sulphur hexafluoride and phospholipid stabilisers. It is a contrast agent that can be used to examine peripheral vessels. Sulphur hexafluoride (also called elegas, SF6-enflurane) is an inorganic chemical compound with very good dielectric properties. It does not have any colour, taste or odour and is approximately 6 times heavier than air. Sulphur hexafluoride is a non-flammable gas with a low chemical activity, which is non-toxic under normal conditions (comparable to noble gases such as argon or helium). It is only at very high temperatures (>200°C, e.g. at electric arc temperature) and at the presence of humidity or oxygen that small amounts of toxic substances can occur, mainly sulphur tetrafluoride (SF4) and thionyl fluoride (SOF2).
Enhancing agent microspheres are ruptured with ultrasounds; fine bubbles of gas can circulate freely in the bloodstream. Larger amounts are exhaled and the lipid “shells” are metabolised in the liver and subsequently excreted with bile.
Another UEA is Optison (General Electric), which is currently approved for the Polish market, but only for cardiac ultrasound scans.
Ultrasound enhancing agents are tolerated very well: the reported anaphylactic reactions following their administration are estimated to occur in 0.001% of cases. No kidney toxicity has been found. UEA half-life is approximately 12 minutes.
The amount of UEA administered during the procedure depends on the method and the result analysis protocol used.
The selection of the contrast agent administration technique depends on the structure of the examined object and on the aspect for which observation has been planned. Therefore, it needs to be decided whether atherosclerotic plaque itself, the boundary between the vessel lumen and plaque or plaque vascularisation will be observed. Thus, the contrast agent administration technique should be selected with a view to its most effective use.
The currently used methods allow one to make complex observations provided that the advantages and possibilities of the contrast agent are used properly. Combinations of the methods described below are used to examine carotid atherosclerotic plaques.
1.
Classic method: the contrast agent is administered as a bolus, with saline washing. A low MI value (up to 0.4) should be set in the ultrasound system.
During the procedure, the contrast agent is used as a modifier of tissue impedance: with a low mechanical index of the sound wave, the microspheres are not ruptured (the microbubbles pass through the vessels that are large enough). During the procedure, it is possible to observe echoes appearing in the atherosclerotic plaque’s topography, consistent with wash-in and wash-out phases.
This method allows one to determine the presence of vessels in the observed atherosclerotic plaque. Due to a low image resolution, relatively wide vessels and a small amount of the contrast agent entering a neovascularised plaque are visualised. In this method, it is only possible to make a subjective evaluation and observe potentially contrast-enhanced atherosclerotic plaque components (Fig. ). The amount of UEA administered is from a minimum of 4 ml (Clevert) up to 8 ml (Feinstein).
Open in a separate window2.
Modified classic method: the contrast agent is administered in fractions.
Half of a single dose should be administered in a bolus, then saline washing is performed, and subsequently the remaining portion of the contrast agent is administered. A low MI value (up to 0.5) should be set in the system. This method makes it possible for contrast agent microspheres to stay longer in the neovascularised plaque. However, the assessment of the wash-out phase is not possible (Fig. ). The total amount of UEA is 8 ml administered in fractions (as described above).
Open in a separate window3.
Transient method: the contrast agent is administered as a bolus, with saline washing.
It is necessary to set the mechanical index in the ultrasound system to high values: MI >1.2(31) (0.8 according to other authors)(45). This method makes it possible to rupture the microspheres immediately after they reach the region of interest. During the procedure, due to the distinctly increased extinction of the medium, the plaque/vessel lumen boundary can be assessed more precisely. This method partly utilises the TMIP phenomenon (Fig. ). The amount of UEA administered is a minimum of 4 ml.
Open in a separate window4.
Replenish mode, flash mode: the contrast agent is administered in a slow infusion, with subsequent saline washing.
It is necessary to set the mechanical index to a low value (MI <0.4). Once the vessel is filled with the contrast agent, the replenish mode, a colour Doppler function is used (Fig. ). This method makes it possible to rupture the microspheres in a controlled manner to release gas in order to thoroughly fill the lumen of not only carotid arteries, but also that of atherosclerotic plaque neovessels. This method utilises the TMIP phenomenon. The examination findings can be evaluated using GSM analysis(46). GSM presents the median of the pixel tonal distribution frequency in the range of 0 (black tones) to 256 (white tones). On ultrasound, fluid corresponds to the lowest values (blood is GSM 0–5). Solid tissues, on the other hand, correspond to the highest GSM values on ultrasound (the adventitia is GSM 180–200)(47). The assessment of enhancement in the arterial phase and the wash-out phase is made using the so-called long loop: observation lasting at least 240 sec. The difference of at least 20 GSM units between plaque enhancement before and after contrast agent administration is considered significant. The amount of UEA administered is a minimum of 8 ml (Burns).
Open in a separate windowIn the studies published to date, CEUS examination of atherosclerotic plaques was analysed based on various protocols. The simplest method of atherosclerotic plaque neovessel filling assessment is the observation of loops recorded during the procedure, which was proposed by Feinstein(26). The most common protocol, which is recommended by Iezzi et al.(26,27), is that involving a dynamic examination. It consists in observing ROI enhancement during the procedure, in the wash-in and wash-out phases. This protocol includes the late phase, recorded at 6 minutes from contrast agent administration after applying flash mode and rupturing contrast agent microbubbles using a power Doppler pulse. This protocol requires continuous recording of the procedure based on the CEUS programme timer assigned to a setting in the ultrasound system.
A protocol with a late wash-out phase, with UEA wash-out curve being recorded, makes it possible to observe neovessels while avoiding blooming artefacts in microspheres washed out of the arteries.
A similar protocol was used in studies by Clevert et al. and Coli et al.(25,30), in which, apart from subjective evaluation, a full examination record consisting of a 280–360-second loop was analysed.
According to the present authors, the examination protocol proposed by Hoogi(48), among others, which includes a repeated assessment of plaque enhancement in ROI, seems to provide a precise account of the level of atherosclerotic plaque vascularisation during the procedure, slightly reducing the role of subjective evaluation for the benefit of objective assessment, with off-line enhancement analysis using GSM (Fig. ).
Open in a separate windowAnother method of increasing the assessment objectivity is the scoring system proposed by Akkus(49,50) to evaluate the enhancement of the atherosclerotic plaque in the predicted arterial, venous and interstitial phases using GSM analysis.
The ultrasound image of atherosclerotic plaque allows one to draw conclusions regarding its future fate, and, most importantly, make decisions on further patient management.
However, this is possible on condition that the findings are definitive, i.e. a comprehensive evaluation of the patient’s clinical situation has been made and the patient has been adequately assigned to a prognostic group. Considering the fact that atherosclerosis is a changeable, progressive process with atherosclerotic plaque transforming dynamically from a stable to an unstable state, one should make a very cautious evaluation of the current disease process and the potential or actual complications. This is because ultrasound examination is a highly subjective procedure whose result depends to a large extent on the experience of the examiner and the quality of the equipment used. Contrast-enhanced ultrasound allows one to determine the presence of neovascularisation in an objective manner; thus, the presence of active inflammation can be demonstrated beyond doubt, which is an inherent feature of unstable (vulnerable) plaque. Current attempts at making CEUS more objective with the help of artificial intelligence (AI) will make it possible in the future to make a definitive assessment of plaque stability, and, consequently, evaluate the risk of CVA adequately.
The authors do not report any financial or personal affiliations to persons or organisations that could adversely affect the content of or claim to have rights to this publication.
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