IntraVascular UltraSound Anton FW van der Steen, Johannes A Schaar, David Goertz, Martijn Frijlink, Nico de Jong Patrick W Serruys and. Nicolaas Bom, Thoraxcentre; Erasmus Medical Center Rotterdam, The Netherlands Interuniversity Cardiology Institute of the Netherlands Introduction Currently, IVUS is, beside OCT the only clinically available technique, capable of providing real time cross-sectional images in vivo. It delivers information that is not available from X-ray angiography. Since the number of available interventional techniques for treatment of atherosclerotic luminal narrowing increases, specific diagnostic information that can aid in the selection becomes increasingly important. For this reason, IVUS is more and more routinely used for guiding interventional procedures and for studying the mechanisms for restenosis i. In the last couple of years the possibilities to access a sufficient amount of RF data at adequate speed have improved significantly. This has given the possibility to study IVUS data in a totally different way. In the traditional way the emphasis was always on imaging itself while RF-analysis also allows tissue characterization, elasticity imaging, flow estimation and enhanced boundary detection. Construction of an IVUS catheter Rotating element In Figure 1, the rotating tip system is schematically illustrated. The driving motor is connected to the proximal end of the catheter. The shaft (1) must be very flexible and contains the electric wires for the transducer. The shaft needs to be flexible; yet it must drive the tip in a predictable way. This is not always possible when the catheter must follow a tortuous path. As a result, the beam deflection on the display may not correspond with the acoustic beam deflection. This causes errors in the image. Capacitive and optical feed-back techniques have been suggested to cope with this problem. The element (3) is positioned in such a way that no transmission pulse effect appears on the display, since the echo travel time to the dome (2) is of sufficient duration. It allows imaging very close to the catheter outer wall since no 'dead zone' is present. The dome must be acoustically transparent. Results obtained in-vitro are often reported without such a dome, thus increasing image quality and avoiding the liquid filling process necessary for acoustic coupling. Figure 1. - Flex-shaft rotating element principle. This contains a rotating shaft (1); acoustically transparent dome (2); and echo element (3) in a catheter tip. The flex shaft is powered by a proximal motor outside the catheter. In some practical applications an external guide wire is added and can be inserted through an added catheter nose part. 1
Figure 2. - The rotating mirror principle. This contains the flex shaft (1); The transparent dome (2); the acoustic element (3) and the rotating mirror (4). Rotating mirror The rotating mirror technique is similar to the previously described method. Schematically this method is shown in Figure 2. The flexible shaft (1); the transparent dome (2); the echotransducer (3) are complemented with a mirror. The mirror creates an even shorter dead zone outside the catheter due to the longer acoustic pathway inside the catheter. The non-moving transducer avoids the necessity of rotating electric wires. Acoustic lenses and focussing shapes of the mirror have been described. Electronically switched phased array The catheter shown in Figure 3 contains many small acoustic elements (2) which are positioned cylindrically around the catheter tip. The number of elements may be any practical number such as 16, 32, 64 or 128. The tip may contain an electronic component to reduce the number of electric wires. Figure 3. - Electronically switched phased array catheter tip with integrated circuitry for reduction of the number of wires (1); the elements (2) and a guide wire (3). The construction allows for the introduction of a central guidewire (3). A first prototype, using the same principle but meant for intracardiac imaging was already described in 1972 ii. By introduction of time delays subgroups of elements may together form a "single larger echo transducer". This process can be repeated with any other subgroup. This allows aperture variation and electronic focussing methods. On the other hand, acoustic element geometry is not optimal and a near-field dead zone may exist. In a second principle, all elements are used individually for transmission and reception. Beam forming is created with computer algorithms using a Synthetic Aperture System (SAS). A summary of today s IVUS methods is illustrated in Figure 4. Mostly, the intravascular procedure is applied for decision-making when angiographic data are less conclusive. For obvious reasons, there is a strong urge to combine see and do in interventional procedures. This leads to catheters in which, for instance, an angioplasty balloon is combined with ultrasonic imaging in or close to the balloon. Another combination may provide guidance during stent implantation (Figure 4d). 2
Figure 4. - Overview of presently most frequently used IVUS catheters. A) flex shaft rotating element system. B) Identical to A with added guide wire capabilities. C) Phased array system with guide wire and multiplexing electronics. D) catheter combining imaging with stent delivery capabilities. Since intravascular imaging provides accurate geometrical information within the cross-section, combination with other interventional procedures is likely to expand in future. IVUS in the clinic Intravascular coronary ultrasound (IVUS) provides real-time high-resolution images of the vessel wall and lumen. iii The size of IVUS catheters is between 2.9 to 3.5 French. Depending on the distance from the catheter the axial resolution is about 150 microns, the lateral 300 microns. The images appear real time at a frequency of up to 30 frames/sec. Features of the vessel can be detected based on the echogenicity and the thickness of the material. Small structures can be visualized, however only those sized over 160 microns can be estimated accurately. The normal thickness of the media is about 125-350 μm. IVUS provides some insight into the composition of coronary plaques, among them the vulnerable plaque. Rupture of vulnerable plaques is the main cause of acute coronary syndrome and myocardial infarction. Identification of vulnerable plaque is therefore essential to enable the development of treatment modalities to stabilize such plaque. Because myocardial infarction and its consequences are so important, we must investigate options to identify those areas that will be responsible for future events. A wide variety exists in the stability of coronary atherosclerotic plaques. A plaque may be stable for years, however abrupt disruption of his structure is the main cause of acute coronary syndrome. The susceptibility of plaques to rupture is known to be related to their composition, stress distribution and degree of inflammation. Increasingly it is becoming recognized that, while not fully understood, two factors play a major role in plaque progression and vulnerability: the presence of increased plaque invasion by microvessels (vasa vasorum) and the expression of specific molecules by cells within the plaques. Both issues can be assessed with an ultrasound contrast agent (An ultrasound contrast agent contains small bubbles (~ 3µm), which are proven to be blood tracers) using special signatures of these bubbles under ultrasound insonification. The vulnerable plaque contains certain features that could be diagnosed by various specialized methods. The ideal technique would provide morphological, mechanical and chemical information, however at present, no diagnostic modality providing such all-embracing assessment is available. 3
Elastography and Palpography In 1991, a new technique was introduced to measure the mechanical properties of tissue using ultrasound: elastography. iv The underlying concept is that upon uniform loading, the local relative amount of deformation (strain) of a tissue is related to the local mechanical properties of that tissue. If we apply this concept to determine the local properties of arterial tissue, blood pressure acts as a stressor. At a given pressure difference, soft plaque components will deform more than hard components. Measurement of local plaque deformation in the radial direction can be obtained with ultrasound. For intravascular purposes, a derivate of elastography called palpography may be a suitable tool. v In this approach, one strain value per angle is determined and plotted as a colorcoded contour at the lumen vessel boundary. Since radial strain is obtained, the technique may have the potential to detect regions with elevated stress: increased circumferential stress results in an increased radial deformation of the plaque components. In vitro studies with histological confirmation have shown that there are differences of strain normalized to pressure between fibrous, fibro-fatty and fatty components of the plaque of coronary as well as femoral arteries. vi This difference was mainly evident between fibrous and fatty tissue. The plaque types could not be differentiated by echo-intensity differences on the IVUS echogram. The principal of elastography is as follows: Two IVUS images are made with a short time interval. Due to cardiac pressure there will be a small difference in intraluminal pressure. In case of little difference of pressure the pictures will be almost identical. However, thorough analysis of the ultrasound RF data tells a different story. Proper data processing will allow visualisation of the pressure caused differences. This may be called an elastogram where a colour coding is used for identification of the softness. A principle is illustrated in figure 5. Figure 5. - IVUS elastography: two IVUS images are acquired at two slightly different intraluminal pressures. A deformation image is obtained by data processing. This image displays soft regions in green. Palpography is a further development that is simulating putting your finger inside the vessel and palpating it to feel how hard it is. It is a new name for elastography in only a thin internal layer of the artery. Palpography reveals information that is not seen on IVUS. To differentiate between hard and soft tissue may be important for the detection of an instable plaque that is prone to rupture. Since palpography is based on clinically available IVUS catheters, the technique can be easily introduced into the catheterization laboratory. By acquiring data at the end of the filling phase, when catheter motion is minimal, the quality and reliability of the palpogram is increased. The clinical value of this technique is currently under investigation. 4
It is feasible to apply intravascular palpography during interventional catheterization procedures. In a recent study, data were acquired in patients (n=12) during PTCA procedures with echo apparatus equipped with radiofrequency output. The systemic pressure was used to strain the tissue. Significantly higher strain values were found in non-calcified plaques than in calcified plaques. vii Another in vivo validation study in atherosclerotic Yucatan pigs showed that fatty plaques have an increased mean strain value. High-strain spots were also associated with the presence of macrophages, a further feature of vulnerable plaques. viii Figure 6. - Mode vibrations for a bubble with a diameter of 4 µm. Here a mode n = 3 is observed, however a range of modes is observed for a transmit frequency of 3.5 Mhz. Contrast imaging Unfortunately, in smaller vessels and capillaries blood detection is not possible due to low signal strengths from blood, tissue motion effects, and limited resolution (~ 0.5-1 mm). Ultrasound contrast agents (UCA, consisting of small (encapsulated) gas bubbles), will increase the reflection of ultrasound by the blood pool, after intravenously administer, and by that make it possible to provide perfusion images and imaging the vascularity in plaques. When a gas bubble in liquid is subjected to pressure variations induced by an acoustic wave it acts as a forced, damped, oscillator, with a resonant frequency that is inversely related to its diameter. If the incident acoustic wave is of sufficient amplitude and of a frequency near to the resonant frequency of the bubble, the induced radial oscillations will become more pronounced and track the incident pressure wave in a nonlinear manner. As a result, re-radiated acoustic energy will be coupled into other frequency bands. The coupling of acoustic energy into the second harmonic frequency region occurs most efficiently when a bubble is insonated at or near its resonant frequency. Subharmonics (at half the insonation frequency) can be efficiently generated at twice the natural resonant frequency. Optical observation of the vibrating bubble with a fast frame camera and acoustic measurements with high frequency ultrasound reveal these nonlinear vibrations. The fast-frame camera Brandaris 128, developed at the Erasmus medical center in collaboration with Twente University, can be used to visualize microbubble agent behavior at high ultrasound frequencies. Designed to investigate microbubble dynamics at conventional ultrasound frequencies, it has a unique capablilty to image bubble dynamics at a frame rate of up to 25 Mega frames-per-second for 128 consecutive frames. For bubble sizes of 4 micrometer figure 6 shows both radial oscillations and surface modes. In this figure only 5 frames from the 128 available frames are plotted, with an interframe time of 100 ns. In vivo Experiments In ultrasound contrast imaging, these nonlinear emissions are the foundation of specific microbubble detection schemes, which are essential for detecting small vessel In vivo. Such In vivo studies were conducted in atherosclerotic rabbit abdominal aortas. Atherosclerosis was initiated using endothelial cell injury procedures followed by a high cholesterol diet ix. Experiments were performed 10 11 weeks after initiation of atherosclerosis. Example in vivo results are shown in fig. 7 for fundamental and harmonic imaging modes. In fundamental mode (top) the injected contrast can hardly be discriminated from the tissue. In the special contrast mode (harmonic imaging) results 5
are substantially different. Post-injection, agent was first visualized in the main lumen. By approximately 5 seconds post injection a ring at the boundary of the main lumen could be seen, which can be attributed to the presence of a small amount of more slowly moving agent adjacent to the aortic wall. This effect enabled the lumen boundary to be easily distinguished. There is then an eccentric circumferential region devoid of enhancement, with a thickness larger in the 2 o clock direction than in the 8 o clock direction. Outside this hypoechogenic region, numerous locations of enhancement are observed that are associated with the presence of agent. While towards 10 o clock the enhancement is associated with the vena cava, the other locations are consistent with the detection of microvessels outside the main vessel lumen x. Figure 7. - In vivo results in an atherosclerotic rabbit aorta using decanted Definity TM. Left: normal imaging. Right: 10 second post-injection harmonic mode shows significant adventitial enhancement, consistent with the detection of adventitial microvessels. Scale of images is 12 mm across. The dynamic range of the fundamental and harmonic images are 40 and 25 db respectively. References: i G. S. Mintz, J. J. Popma, K. M. Kent, L. F. Satler, S. C. Wong, M. K. Hong, J. A. Kovach, and M. B. Leon, "Arterial remodeling after coronary angioplasty. A serial intravascular ultrasound study," Circulation, vol. 94, pp. 35-43, 1996. ii Bom N, Lancée CT, Van Egmond FC (1972) An ultrasonic intracardiac scanner. Ultrasonics 10: 72- iii Bom N, Li W, van der Steen AF, Lancee CT, Cespedes EI, Slager CJ, de Korte CL. Intravascular imaging. Ultrasonics 1998; 36: 625-8. iv Ophir J, Cespedes I, Ponnekanti H, et al. Elastography: a quantitative method for imaging the elasticity of biological tissues. Ultrason Imaging 1991; 13: 111-34. v Doyley MM, Mastik F, de Korte CL, et al. Advancing intravascular ultrasonic palpation toward clinical applications. Ultrasound Med Biol 2001; 27: 1471-80. vi de Korte CL, Pasterkamp G, van der Steen AF, et al. Characterization of plaque components with intravascular ultrasound elastography in human femoral and coronary arteries in vitro. Circulation 2000; 102: 617-23. vii de Korte CL, Carlier SG, Mastik F, et al. Morphological and mechanical information of coronary arteries obtained with intravascular elastography; feasibility study in vivo. Eur Heart J 2002; 23: 405-13. viii de Korte CL, Sierevogel MJ, Mastik F, Strijder C, et al. Identification of atherosclerotic plaque components with intravascular ultrasound elastography in vivo: a Yucatan pig study. Circulation 2002; 105: 1627-30. ix J. A. Schaar, C. L. de Korte, F. Mastik, L. C. van Damme, R. Krams, P. W. Serruys, and A. F. W. van der Steen. Three-dimensional palpography of human coronary arteries. Herz, 30(2):125 133, 2005. x Goertz D. E., Frijlink M. E., Tempel D., Van Damme L. C. A., Krams R., Schaar J. A., Ten Cate F. J., Serruys P. W., De Jong N. and Van der Steen A. F. W. Contrast Harmonic Intravascular Ultrasound: a Feasibility Study for Vasa Vasorum Imaging Invest. Radiol 2006;41:631-38 6