A Novel Device for Immediate Measurement of Arterial Lumen Cross-Sectional Area During Percutaneous Coronary or Peripheral Inter

Why is appropriate stent sizing important? Dr. Movahed: There are many reasons why appropriate stent sizing is important. There are many studies available in the literature showing that undersizing or underdeployment predisposes the patient to a higher rate of instent restenosis and acute stent thrombosis. On the other hand, oversizing has been shown to cause vascular wall trauma, inducing inflammation and again, a higher rate of instent restenosis. Furthermore, life-threatening perforations and edge dissections are complications of oversizing balloon angioplasty or stenting. Currently, physicians use visual estimation, which is not accurate, or intravascular ultrasound, which is costly and time-consuming, and an adds additional risk of catheter manipulation to the procedure. Dr. Kassab: Maybe what I can add to Dr. Movahed's comments is that even a small error in sizing can lead to large difference in blood vessel wall stress. For example, the difference in sizing a vessel to 3.0 or 3.2 mm may be a small difference in stretch or strain, but this would produce a large difference in wall stress. The reason is that the mechanical properties of the coronary arteries are highly nonlinear; that is, a small change in stretch can lead to a large change in stress. A significant increase in wall stress can, of course, cause trauma to the vessel wall and possible dissection. Even with the advent of drug-eluting stents, are vessel and stent sizing still important issues? Dr. Movahed: The use of drug-eluting stents has markedly reduced the instent restenosis rate. However, restenosis is not entirely eliminated with an approximate rate of 8% in drug-eluting stent era.¹ Furthermore, appropriate stent sizing is very important during high-risk procedures, such as left main stenting in order to reduce acute and long-term complications and instent restenosis. The ability to optimize stenting using simple method of low cost, will most likely increase the usage of percutaneous coronary intervention in high-risk patients. Dr. Kassab: There are about one million angioplasty and stent procedures performed per year. If we assume that 70% of those patients receive drug-eluting stents, the 8% restenosis rate translates into 56,000 patients per year. That is still too many patients. If the cost for re-treatment is about $15,000, this means over 800 million dollars per year in cost. Furthermore, although drug-eluting stents can reduce restenosis as compared to plain old balloon angioplasty and bare metal stents, they cannot prevent edge dissection or vessel trauma due to over-sizing. Undersizing on the, other hand, can increase the risk of thrombosis. Hence, regardless of the use of a drug-eluting stent, sizing is still a fundamental issue. What is the LumenRECON and how does it help with these issues? Dr. Kassab: The LumenRECON is a catheter or guidewire-based device that allows us to size the lumen cross-sectional area (CSA) of a blood vessel based on the electrical impedance principle. Basically, the device involves mounting four electrodes or electrical wires onto any standard catheter (balloon or non-balloon) or guidewire (peripheral or central) (Figure 1). We mount the electrodes through the lumen of the catheter or guide wire and then exteriorize them in four different positions, along the tip of the catheter. The wires are spaced a few millimeters apart. The two outer electrodes serve to excite an electrical current, and the two inner electrodes serve to measure the voltage difference (Figure 2). If we know the current (voltage), the electrical spacing between the electrodes, and the conductivity of the fluid, we can calculate the CSA of the vessel at any point where the inner electrodes are placed, provided that we account for the current loss through the vessel wall and surrounding tissue. Currently, the most obvious application of the device is sizing basically, knowing the proximal and distal portion of the vessel that needs to be distended or stented. Hence, this device allows accurate lumen sizing similar to IVUS but overcomes many of the limitations of IVUS (Table 1). To measure stent deployment, we put electrodes inside the balloon (Figure 3). Once the cardiologist knows the proper vessel size as determined by the device, then the stent can be deployed or expanded to just the right amount because the sensors inside the balloon will provide the CSA of the balloon and hence stent in real time. Cardiologists can have immediate feedback of the quantitative dimension of the stent balloon. The interventionalist will become armed with two quantitative capabilities: 1) The ability to determine the proximal and distal vessel size and 2) The ability to determine exactly how much to expand the stent balloon. This device enables both diagnosis and therapy for vessel stenosis. Beyond the sizing issue, the electrical impedance theory allows us to measure how much of the electrical current actually leaks out of the vessel lumen. How much current leaks out depends on the vessel wall plaque characteristics. Some plaques may have a high lipid core, which may make them more vulnerable to rupture. Electrical current conductivity is much lower in those plaques as compared to the fibrotic and more stable plaques. This is based on the fact that electrical conductivity through fat is about 10 times lower than normal tissue, for example, or even calcified plaque. Therefore, we can potentially use this device and associated principle to say something about the plaque composition. Plaque characterization is a very hot area of research in cardiology. IVUS can image the vessel wall, but there are limitations with the spatial resolution. Due to the limited resolution, some researchers have looked to OCT, which has higher spatial resolution than IVUS. However, the trouble with OCT, similar to IVUS, is that the probes are fairly stiff and bulky. These probes also cannot be incorporated into a standard catheter or a guidewire, for that matter. Since the device size is large, it has to be mounted on its own catheter. This adds the use of an extra catheter to the procedure. One of the advantages of LumenRECON is that is can be implemented into an existing catheter. Furthermore, LumenRECON provides a digital output of the lumen size rather than an image, and hence it is immediate and objective. With OCT or IVUS, the cardiologists must be trained in the use of these instruments and the interpretation of corresponding images. The conversion of images into a digital output of a dimension requires an extra step. Also, because there is interpretation, the process maybe subjective and the results may vary from machine to machine. Furthermore, IVUS or OCT adds additional time to the procedure, because one has to use a different catheter. Finally, one often cannot push the IVUS or OCT probe through tortuous vessels, nor through vessels that have severely calcified plaque. For these reasons, OCT and IVUS do not enjoy routine usage, despite their benefits. Dr. Movahed: The main limitation of IVUS is the cost, extra time and additional risk that is added to the procedure. The IVUS machine costs over $100,000 and each catheter cost more than $500. Furthermore, IVUS could be difficult to use in tortuous vessels. LumenRECON is inexpensive and adds minimal time to the procedure. This technology can be mounted on the angioplasty or stent balloon, on small coronary catheters or on coronary wires, which make this technology inexpensive and easy to use. Is LumenRECON based on a conductance or impedance catheter? Dr. Kassab: Conductance and impedance are the inverse of each other. This is electrical engineering jargon, and people use these terms almost interchangeably. Some say impedance catheter, and some, conductance catheter. What are the issues with conductance catheters in vessel measurement, and how did you overcome those issues? Dr. Kassab: The concept of conductance catheter for measurement of chamber lumen has been around for 25 years or more. In fact, people have tried to use it to measure the chamber volume in the heart, in the ventricle itself. Researchers are interested in how the heart volume changes, both under normal as well as abnormal conditions. The major challenge has been that the current is not restricted to the lumen of the organ of interest, whether it is the heart chamber or a blood vessel that is, the current actually leaks out into the vessel wall and surrounding tissue. Researchers have attempted to correct for this leakage. The issue is, how does one quantify how much of the current stays inside the lumen of the vessel and how much leaks out? The approach in the past has been to give an injection of 9% sodium chloride, which is 10 times the NaCl in the blood. Researchers give these injections into the pulmonary artery. The transient change of blood conductivity is extrapolated to zero to determine the parallel conductance due to the surrounding tissue. Multiple injections pose a problem for patients, however, especially if they have renal failure. The two-injection method that I proposed avoids this problem because the injection is done locally so we don't need to use very high salt concentration. Blood is 0.9%, and we use 0.5% and 1.5% saline injections. Each pair of injections averages to the concentration of saline which is physiological. An additional advantage of the local injection is that it flushes the blood for a few seconds. This circumvents another major problem in lumen measurements using conductance methods. Unlike the heart, where the orientation of blood cells is random, in the blood vessel, the cells have preferential orientation which interacts with the flow of current in a complex manner. This interaction of blood rheology and electrical conductivity has been a major problem for lumen measurements in the aorta. The two-injection method completely eliminates this problem since the electrical conductivity measurements are made in the absence of blood. The recordings are made in the presence of 0.5% and 1.5% NaCl solution. The voltage readings are shown in Figure 4, with baseline measurements followed by a 2-second injection. In this way, by only doing two injections, we can actually discern both the CSA of the vessel as well as how much current is lost to the external environment. Does the interventional cardiologist have to manually give the two saline injections and calculate the cross-sectional area? Dr. Kassab: No, the entire process is automated. Once the cardiologist places the catheter or guide wire in the desired vessel, the catheter is connected to the LumenRECON system. The system is loaded with pre-packaged, sterile solutions of 0.5% and 1.5% NaCl. A push of a button will heat the solutions to body temperature. The machine will flash a ready signal and the push of a second button will initiate the injections. The rest of the process is automatic. An internal pump delivers each of the two injections in turn through a side hole for the catheter or through a guide catheter for the wire. The impedance module will record the voltages for each injection and a processor will calculate both the CSA and parallel conductance due to the surrounding tissue. The two parameters will be displayed on the monitor. If a pullback reconstruction is desired, a longer injection can be made and the catheter can be pulled back at constant speed. The pullback can be motorized. The CSA along the length of the vessel will be displayed immediately. Does the impedance catheter or guide wire have to be positioned in the center of the vessel? What is the error if the cross-sectional area is not circular? Dr. Kassab: The catheter does not have to be in the center. In fact, the catheter is usually close to the wall as verified with B-mode ultrasound.² We have confirmed that this does not affect the measurements, provided that the electrodes are optimally positioned, as in our device. As for the geometry of the CSA, there are no assumptions about circularity. The method yields the CSA regardless of the shape. It can be circular, elliptical or any other more complex geometry. Of course, if one wants to calculate the diameter, then the circular assumption must be made. How was the success of this method correlated? Dr. Kassab: We have published two original peer-reviewed studies, plus a book chapter on this subject. The first study outlines the theory in terms of a distributive model.³ Basically, we solved the Poisson's equation that describes the potential field lines for a model of the catheter in the lumen of a blood vessel with surrounding tissue (Figure 2). We also provided validation data on coronary arteries of isolated hearts. The agreement was excellent. The second study, which is what we presented in an abstract at TCT 2004, was an experimental validation of the technique, in vivo, in pigs. The pig is a favorite model of the cardiologist because its anatomy and physiology are similar to humans. The majority of devices are tested in pigs prior to being used in patients. In our study, we validated the LumenRECON device in carotid, femoral, and coronary blood vessels against ultrasound.² To make a long story short, our measurements are within 5% of those obtained from ultrasound (Figure 5). If you want to call it an error, then the error is less than 5%. We also checked the reproducibility of the method; that is, what is the difference between duplicate measurements. The answer is about 2% (Figure 6). Hence, this device has great reproducibility, and when you compare it to ultrasound, the accuracy is within 5%. The experiments were carried out in Denmark, in collaboration with my colleague Dr. Hans Gregersen who is the Vice-President of Electro-Cat. The two studies, along with the book chapter2 can be downloaded from www.electro-cat.com. There is also an animation of how the device works both for sizing and stent deployment on this website. Does this device affect contrast usage? Dr. Movahed: This device has the potential to decrease contrast usage and cost by optimizing stent sizing and therefore reducing complications such as dissection. Dis-sections require additional stenting, which increases the contrast usage and cost of the second stenting. In the area of very expensive drug-eluting stents, the cost savings could be substantial. Furthermore, in a given coronary artery with multiple lesions, our device can selectively measure each lesion and limit the stent use to only those lesions with significant decrease in cross-sectional area. This will lead to a shorter procedural time and a decrease in stent and contrast usage. Dr. Kassab: In addition to reducing the contrast usage, it may also reduce the number of stents used. There are several studies and clinical trials that have compared the restenosis rate with carefully sizing the vessel with IVUS without using a stent and those with stent. It was found that by carefully sizing the vessel, the total number of stents used could be reduced by 50%. This would result in savings on the order of billions per year to insurance companies, patient premiums, and so on. Could this device help in measuring fractional flow reserve (FFR)? Dr. Movahed: Currently there are two technologies that are available in order to assess a coronary lesion of unknown significance. IVUS is able to measure cross-sectional area and the pressure wire is able to calculate FFR. LumenRecon is very comparable to IVUS. By measuring cross-sectional area and luminal diameter, we can assess a lesion as accurately as IVUS in a very simple and inexpensive way. Furthermore, we could combine our technology with a pressure wire system on one wire and be able to measure the cross-sectional area and FFR with the same wire. This combination makes the assessment of a coronary lesion very precise. Dr. Kassab: There are pressure and velocity wires on the market. Some wires have combined pressure and velocity sensors. What we have here is a CSA wire. One of our goals is to develop a CSA/pressure/velocity wire, which is certainly feasible. Our interest in this development stems from the fact that pressure/flow relation is more relevant to vascular physiology than pressure/velocity. If you combine velocity with cross-sectional area, then you get flow. If you have the pressure/flow relationship of any organ, you will learn a great deal about the circulatory physiology and pathology of that organ. In the laboratory, when we’re studying coronary circulation, we're very interested in the pressure/flow relationship. When we know the coronary pressure/flow relationship, then we know the resistance to flow through the circulation. That is, we not only know something about the severe lesions that are in the large vessels but we can also learn other important things. Is there diffuse disease? Is there, microcirculatory disease? and so on. By combining our technology with the pressure and velocity measurements, we can take some of the same scientific tools that we use in the laboratory to the clinic. The technology for the marriage of CSA wire with pressure and flow wires is certainly available and that is one of our current efforts. Could you update us in terms of the status of the device and share your own backgrounds? Dr. Kassab: At this point, we're pursuing some pilot studies in humans. As the Medical Director of Electro-Cat, Dr. Movahed is taking the lead on that and we’re currently in the process of taking care of some of the regulatory issues. Dr. Movahed: We are planning to use LumenRECON in 10 patients with normal iliac arteries and in 10 patients with significant atherosclerotic disease. In this pilot study, we will compare the measurement of the cross-sectional area made by LumenRECON with IVUS. Furthermore, we will investigate and compare procedural times and contrast amounts using these two technologies. Dr. Kassab: The beauty of this device is that we don’t need clinical trials prior to marketing. The reason is very simple. If we can show in humans, as we’ve shown in pigs, that our method is essentially equivalent to IVUS, then these two technologies can be used interchangeably. We can then tap into all the research that has already been done with IVUS. There are advantages and benefits to using IVUS, and if we can show that our technique is equivalent to IVUS for lumen sizing, then all the benefits translate to our device. Unlike IVUS, however, LumenRECON is cheaper, easier to use, requires minimal training, etc. Hence, we expect a greater adaptability of this device in comparison to IVUS. We are currently exploring the licensing of the technology with several medical device companies and hope to have this device on the market in the very near future. My background is in engineering sciences (chemical and mechanical) but I also have training in physiology. In fact, I consider myself as much a cardiovascular physiologist as a bioengineer. Some of my current interests encompass the biomechanics of the coronary circulation in health and disease, such as hypertrophy and heart failure. Dr. Kassab discloses that he is the inventor of LumenRECON, Founder/President of Electro-Cat and shareholder. He can be reached at gkassab@uci.edu. Dr. Movahed discloses that he is one of the founders, shareholder and medical director of Electro-Cat company and can be reached at rmova@aol.com or mmovahed@uci.edu.

1. Babapulle MN, Joseph L, Belisle P, Brophy JM, Eisenberg MJ. A hierarchical Bayesian meta-analysis of randomised clinical trials of drug-eluting stents. Lancet. 2004;364(9434): 583-591.

2. Kassab, GS, Lontis ER, Gregersen H, Harlyck A. Measurement of Medium Size Arterial CSA Using an Impedance Catheter: In Vivo Validation. Am. J. Physiol, In Press.

3. Kassab, GS, Lontis ER, Gregersen H. Measurement of Coronary CSA Using an Impedance Catheter: Finite Element Model and In Vitro Validation. Ann Biomed Eng. 2004;32(12):1642-1653.

4. Kassab, GS, Lontis ER, Movahed MR, Gregersen H. Measurement of Cross-Sectional Area for Diagnosis and Treatment of Coronary Artery Stenosis Using an Impedance Catheter. In: Impedance Planimetry: Scope and Use in Biomedical Research, Hans Gregersen (ed.). Harwood Academic Publisher, London, In Press.