Intravascular Thermographic Assessment in Human Coronary Atherosclerotic Plaques by a Novel Flow-Occluding Sensing Catheter: A S

Previous studies support the concept that atherosclerosis is an inflammatory disease.^1,2 Inflammation plays an important role not only in the development, but also in the acute complications of atherosclerotic plaques.³ The detection of plaque temperature heterogeneity, a surrogate of inflammation, identifies a plaque as having a greater risk of acute complications.^4–7 However, plaque temperature is often underestimated due to the uninterrupted blood flow, which acts as a natural cooling system.^8,9 To avoid this limitation, we have developed a new thermographic catheter by which temperature assessment is performed during complete occlusion of the coronary blood flow. This study describes our experience with this catheter in patients with coronary obstructive artery disease. Methods Thermal sensing system catheter. The thermal sensing system (TSS) 5 French (Fr) catheter (Accumed Systems, Inc., Ann Arbor, Michigan) consists of an expandable braid at the distal portion of the catheter that is mounted on a pair of nested plastic tubes and covered by a silastic sleeve. Three thermistors are attached to the exterior surface of the sleeve (Figure 1). A controller located outside the patient enables expansion of the braid by pulling on the inner tube that is attached to the distal end of the braid. The body of the catheter has two lumens. The thermistor lead wires run through the first lumen, while the second lumen is solely for expansion purposes. Each thermistor has a variable resistance linearly correlated with temperature values (30,000 ohms at 25ºC, which translates to about 18,000 ohms resistance at 37ºC). The thermistors have a range of 33–410.4ºC, accuracy of ± 0.05ºC, with a time constant of 200 milliseconds (0.2 seconds), and a sampling rate of 5 Hertz (0.20 seconds between samples). Procedure. The lesion of interest was outlined in two well-opacified views using biplane angiography. These projections were obtained before and after the procedure. Through an 8 Fr guidingcatheter, the TSS catheter was advanced using the over-the-wire technique. When needed, predilatation of the target lesion was performed using commercially available angioplasty balloons ranging in size from 2.0–3.0 mm. The reference or baseline temperatures were taken in flowing blood inside the guiding catheter, and then the braided sensing element was placed at the lesion site. By expanding the TSS catheter, the flow was interrupted with minimal dilatation of the arterial wall. Complete occlusion of blood flow caused by the sensing element was checked by coronary contrast injections. Flow was typically occluded for 30–60 seconds. Once blood flow was occluded, the lesion wall temperatures were measured by the three thermistors on the surface of the braided sensing element. Following lesion thermographic assessment, contrast injection was performed to exclude any TSS catheter-related complication. All patients underwent successful bare metal stent implantation of the studied coronary lesions. Reproducibility of the TSS catheter. We have recently tested our device in dogs, in which external heat was applied with a heating cuff system around the carotid arteries. We observed an excellent correlation between actual heating input imposed and the temperature values obtained by the use of the TSS catheter (Figure 2, Michael Lauer, personal communication). Definition of hot lesion. “Hot lesions” were defined as a difference between the baseline and the occluded thermographic assessment at the atherosclerotic plaque 0.2ºC. Results Baseline and angiographic characteristics are shown in Table 1. Overall, the majority of the patients were men, and the mean age was 60.1 ± 9.7 years. The clinical profile showed a high percentage of patients with multivessel disease, with the expected prevalence of hypertension, diabetes, hyperlipidemia and currentsmoking. Thermographic assessments were attempted in 15 patients. In one patient, the TSS catheter was unable to reach the lesion point due to tortuosity (Figure 3). From a total of 20 successfully accessed lesions, 15 accurate temperature measurements were achieved. Five measurements were excluded because the expanded sensing element did not result in complete interruption of blood flow (n = 5). In most instances, TSS catheter occlusion was achieved with very little expansion of the braided sensing element,while on 4 occasions, no TSS catheter expansion was required in order to completely interrupt blood flow. A total of 15/20 (75%) of the accessed lesions required predilatation with a regular 3.0 mm diameter coronary balloon. Safety. Temporary occlusion during the measurement process was well tolerated by all patients. There was no angiographic evidence of dissection, coronary perforation or spasm. In addition, thrombus formation or material embolization was not observed during the study. The TSS catheter did not cause any other adverse clinical events. No visible evidence of thrombogenic activity was found on the TSS catheter upon visual inspection following removal from the patients. Temperature measurements. In the 15 measurements, temperature elevation of at least 0.3°C was recorded in 5 of them. Temperature assessments between thermistors showed a strong linear relationship (Figure 4). In 1 patient, 2 serial lesions were studied. Of interest, the distal lesion was cold, while the proximal lesion had a 1°C elevation (Figure 5). Clinical events. At 6-month follow-up, only 1 patient underwent repeat target vessel revascularization of an ostial RCA lesion that had a temperature elevation > 0.2°C. Discussion Several invasive and noninvasive methods focus on the structural assessment of the atherosclerotic plaques such as intravascular ultrasound, MRI and multi-slice CT. In contrast, intravascular thermography is a functional imaging method that provides information on the metabolic activity of the atherosclerotic plaque,^4,10,11 with great potential for detection of a vulnerable plaque, and hence, the prediction of acute coronary events. In addition, the assessment of plaque temperature is emerging as a new endpoint in therapeutic interventions.^12,13 Several reports showed that by dietary changes or pharmacological interventions, heat production from atherosclerotic plaques might be reduced.^12,13 This functional assessment of plaques may prove valuable in clinical investigations. Finally, the presence of metabolically active or inflamed plaques have been linked to greater neointimal proliferation following stent implantation.^14–17 Thus, the inflammatory state of the coronary plaque prior to stent implantation may be of potential interest in the decision-making process. The latter appears especially appealing in patients with multivessel coronary artery disease where the use of drug-eluting stents could be decided by lesion characteristics and even according to plaque temperature. In an attempt to avoid the cooling effect of coronary blood flow, we developed a new catheter that enables temperature assessment with concomitant complete interruption of coronary blood flow and full apposition of the sensing elements. Technical considerations. This first human experience with the TSS catheter demonstrated the safety and feasibility of this technique for thermographic evaluation of coronary atherosclerotic plaques. Catheter profile and flexibility are key elements to access the target vessels and lesions. In some instances, when the catheter did gain access to the lesion, it would immediately occlude blood flow simply by its presence in the lesion, without expanding the braid. In its current state, the sensing element portion of the catheter appeared somewhat bulky and rigid. The diameter of the braided sensing element needs to be reduced, while the flexibility of the braided sensing element needs to be increased. Clinical implications. Approximately one-third of the lesions were found to be hot, indicating that plaque inflammation was fairly prevalent. In addition, in accordance with previous reports, we also found cold lesions in patients with unstable angina and hot lesions in patients with stable angina, suggesting that clinical presentation does not necessarily predict plaque morphology and temperature values. Moreover, in 1 patient with unstable angina, lesions at the proximal and distal right coronary artery were hot and cold, respectively (Figure 5). The latter is in contrast with the current concept of diffuse “coronary arteritis”, or the presence of multiple vulnerable lesions in the unstable patient.¹⁸ The temperature elevations found in this study are consistent with recent in vitro and in vivo studies.^6,19–21 Temperature elevations between 0.3ºC and 2.2ºC were detected by at least 1 of the 3 thermistors in the 5 patients with a hot lesion. The size (diameter) of the hot spots is of interest when one considers the number of discrete temperature sensors required to avoid false negative assessments. The current TSS catheter device has 3 thermistors spaced roughly 120 degrees apart. Even though this spacing is well maintained by the construction of the sensing element, if hot spots are small, 3 sensors could miss them. It is worth noting that, in 4 of the 5 “hot” lesions found, all 3 of the thermistors recorded a temperature elevation of 0.2°C or greater. This would suggest that “hot” spots cover a significant portion of the circumference of a lesion. Interestingly, 8 lesions required predilatation, but no temperature elevation was detected, which suggests that the act of predilatation for 30–60 seconds does not stimulate a rapid heat-producing inflammatory response that might lead the clinician to a false-positive determination of “hot” plaque. Moreover, stasis of blood flow does not appear to elevate temperature. We found a stable pattern with 30–60 seconds of coronary occlusion (Figure 6). In our study, 1 patient required target vessel revascularization due to in-stent restenosis that was associated with a “hot” lesion, further suggesting that the state of coronary plaque prior to stenting may be pivotal for the choice between a bare metal or a drug-eluting stent. Study limitations. The small sample size of our study precludes us from drawing definitive conclusions regarding the safety of the device as well as the clinical relevance of its temperature measurements. A larger study may be necessary to fully delineate the role of this technology. Further improvements in catheter design, which are under way, would definitely improve the success rate, particularly in patients with tortuous and calcific vessels. Conclusions The use of the first TSS catheter prototype appears to be feasible and safe for the assessment of plaque temperature heterogeneity, while avoiding the cooling effect of coronary blood flow. Further improvements in catheter design are currently under way.

1. Pasterkamp G, Schoneveld AH, van der Wal AC, et al. Inflammation of the atherosclerotic cap and shoulder of the plaque is a common and locally observed feature in unruptured plaques of femoral and coronary arteries. Arterioscler Thromb Vasc Biol 1999;19:54–58. 2. Libby P. Coronary artery injury and the biology of atherosclerosis: Inflammation, thrombosis, and stabilization. Am J Cardiol 2000;86:3J–8J(Discussion 8J–9J). 3. Moreno PR, Falk E, Palacios IF, et al. Macrophage infiltration in acute coronary syndromes. Implications for plaque rupture. Circulation 1994;90:775–778. 4. Stefanadis C, Diamantopoulos L, Dernellis J, et al. Heat production of atherosclerotic plaques and inflammation assessed by the acute phase proteins in acute coronary syndromes. J Mol Cell Cardiol 2000;32:43–52. 5. Stefanadis C, Toutouzas K, Tsiamis E, et al. Identification and stabilization of vulnerable atherosclerotic plaques: The role of coronary thermography and external heat delivery. Indian Heart J 2001;53:104–109. 6. Stefanadis C, Toutouzas K, Tsiamis E, et al. Increased local temperature in human coronary atherosclerotic plaques: An independent predictor of clinical outcome in patients undergoing a percutaneous coronary intervention. J Am Coll Cardiol 2001;37:1277–1283. 7. Casscells W, Naghavi M, Willerson JT. Vulnerable atherosclerotic plaque: A multifocal disease. Circulation 2003;107:2072–2075. 8. Diamantopoulos L, Liu X, De Scheerder I, et al. The effect of reduced blood-flow on the coronary wall temperature. Are significant lesions suitable for intravascular thermography? Eur Heart J 2003;24:1788–1795. 9. Stefanadis C, Toutouzas K, Vavuranakis M, et al. New balloon-thermography catheter for in vivo temperature measurements in human coronary atherosclerotic plaques: A novel approach for thermography? Catheter Cardiovasc Interv 2003;58:344–350. 10.Casscells W, Hathorn B, David M, et al. Thermal detection of cellular infiltrates in living atherosclerotic plaques: Possible implications for plaque rupture and thrombosis. Lancet 1996;347:1447–1451. 11. Verheye S, Diamantopoulos L, Serruys PW, Van Langenhove G. Imaging of atherosclerosis. Intravascular imaging of the vulnerable atherosclerotic plaque: Spotlight on temperature measurement. J Cardiovasc Risk 2002;9:247–254. 12. Verheye S, De Meyer GR, Van Langenhove G, et al. In vivo temperature heterogeneity of atherosclerotic plaques is determined by plaque composition. Circulation 2002;105:1596–1601. 13. Stefanadis C, Toutouzas K, Vavuranakis M, et al. Statin treatment is associated with reduced thermal heterogeneity in human atherosclerotic plaques. Eur Heart J 2002;23:1664–1669. 14. Farb A, Weber DK, Kolodgie FD, et al. Morphological predictors of restenosis after coronary stenting in humans. Circulation 2002;105:2974–2980. 15. Danenberg HD, Welt FG, Walker M 3rd, et al. Systemic inflammation induced by lipopolysaccharide increases neointimal formation after balloon and stent injury in rabbits. Circulation 2002;105:2917–2922. 16. Walter DH, Fichtlscherer S, Britten MB, et al. Statin therapy, inflammation and recurrent coronary events in patients following coronary stent implantation. J Am Coll Cardiol 2001;38:2006–2012. 17. Piek JJ, van der Wal AC, Meuwissen M, et al. Plaque inflammation in restenotic coronary lesions of patients with stable or unstable angina. J Am Coll Cardiol 2000;35:963–967. 18. Rioufol G, Finet G, Ginon I, et al. Multiple atherosclerotic plaque rupture in acute coronary syndrome: A three-vessel intravascular ultrasound study. Circulation 2002;106:804–808. 19. Stefanadis C, Toutouzas K, Tsiamis E, et al. Thermal heterogeneity in stable human coronary atherosclerotic plaques is underestimated in vivo: The “cooling effect” of blood flow. J Am Coll Cardiol 2003;41:403–408. 20. Stefanadis C, Tsiamis E, Vaina S, et al. Temperature of blood in the coronary sinus and right atrium in patients with and without coronary artery disease. Am J Cardiol 2004;93:207–210. 21. Naghavi M, Madjid M, Gul K, et al. Thermography basket catheter: In vivo measurement of the temperature of atherosclerotic plaques for detection of vulnerable plaques. Catheter Cardiovasc Interv 2003;59:52–59.