ABSTRACT: Background. Patients with acute coronary syndromes (ACS) have been shown to have a local increase in culprit lesion temperature of at least 0.5ºC using a specialized thermography catheter. However, this device is unique, not clinically available and unable to provide information other than temperature. The 0.014-inch Radi™ PressureWire^® XT (RPW) contains a high-sensitivity thermistor in the sensor that has a sensitivity of 0.1ºC. We evaluated the ability of the RPW to detect an increase in plaque temperature in patients with ACS. Methods and Results. Patients with ACS and a culprit lesion of > 70% stenosis and who were candidates for percutaneous coronary intervention (PCI) were eligible (n = 20). Fractional flow reserve (FFR) post-adenosine administration and temperature estimations were performed prior to PCI. All demographic data are presented as mean ± SD, and temperature data (using delta temperature from baseline) as mean ± SEM. Fifteen men and 5 women were enrolled (age 59.5 ± 11.6 years). The FFR pre-PCI was 0.65 ± 0.06, consistent with hemodynamically significant stenoses. The baseline delta temperature was 0.00 ± 0.01ºC. The delta temperature at the culprit lesion was -0.02 ± 0.01ºC (p = NS), a result below the resolution of the thermistor. Post-PCI, the FFR was 0.95 ± 0.01 (p < 0.0001). Conclusions. The RPW was unable to detect any temperature increase in patients with ACS.

       The underlying pathobiology in most patients with acute coronary syndromes (ACS) is culprit lesion disruption with associated thrombosis.¹ There is an increasing body of evidence showing that these culprit lesions, the so-called “vulnerable” plaques, have an increase in local temperature when compared with the temperature of a more normal region of the coronary wall. In ex vivo studies, inflammatory cells within atherosclerotic lesions have been shown to release heat, and more importantly, the actual recorded temperature correlated with the density of macrophages, a critical cellular determinant of atherosclerotic plaque vulnerability.² Recent in vivo work in the human coronary circulation has shown that patients with unstable angina pectoris and acute myocardial infarction have mean increases in the local temperature of the culprit atherosclerotic lesion of 0.7ºC and 1.5ºC, respectively.³ Furthermore, an increase in local temperature has been shown to predict worse clinical outcomes in patients undergoing percutaneous coronary intervention (PCI).⁴ However, in most of these studies, a unique custom-built polyamide thermistor catheter has been used that is not commercially available.⁵ The characteristics of this specialized catheter include a temperature accuracy of 0.05ºC, spatial resolution of 0.5 mm, a time constant of 300 msec and a linear correlation of resistance versus temperature between 33ºC and 43ºC. Furthermore, the thermistor sensor is mounted on “wings” which allow the sensor to directly contact the vessel wall.
       The Radi™ PressureWire^® XT (Radi Medical Systems, Uppsala, Sweden) is a second-generation commercially available, high-fidelity, sensor-tipped 0.014-inch diameter coronary guidewire. The pressure sensor is positioned 30 mm from the tip of the guidewire and contains a high-sensitivity thermistor. The RPW has been extensively used for the purposes of estimating coronary fractional flow reserve (FFR), an important hemodynamic parameter in assessing coronary lesion severity and results post-PCI.^6–8 The purpose of the temperature sensor is to allow coronary flow velocity estimation using thermodilution techniques. The sensitivity of the high-sensitivity thermistor is 0.1ºC, and although not as sensitive as the previously described thermography catheter, its sensitivity should be adequate to detect the temperature elevations described in ACS patients.
       We examined the utility of the Radi PressureWire XT for the purpose of detecting local temperature increases in patients with ACS undergoing PCI.

Methods
       Study population. Patients who were admitted with a diagnosis ACS without ST-segment elevation were eligible for enrollment. Criteria included the presence of angina at rest or with minimal exertion within the 72 hours prior to cardiac catheterization and new transient or persistent ST-T ischemic changes on the electrocardiogram (ST-segment elevation or depression of 0.1 mV or more, T-wave inversion of 0.3 mV or more in 3 or more limb leads, or 4 or more precordial leads excluding V1, or pseudonormalization of 0.1 mV or more), or an elevation of plasma levels of cardiac troponin I (cTnI) without elevation of the creatine kinase or of the creatine kinase-MB. Furthermore, the culprit lesion as identified at coronary angiography needed to have a stenosis of at least 70% and deemed to require PCI by the attending interventional cardiologist.
       Exclusion criteria were ST-segment elevation lasting more than 20 minutes, thrombolysis in the previous 48 hours, coronary angioplasty within the previous 6 months or bypass surgery within the previous month, or angina caused by identifiable factors. Patients who had an identifiable inflammatory or neoplastic disorder

Figure 1. A magnified cut-away photograph of the temperature and pressure sensors within the Radi™ PressureWire®. Reproduced with permission (Dr. Jeffrey Ling, Radi Medical Systems, Uppsala, Sweden).

were receiving corticosteroids or non-steroidal anti-inflammatory agents (except for aspirin), or had serum creatinine values above 220 µmol/l were also excluded. All patients participating were required to give informed consent. The Monash University Human Ethics Committee (Melbourne, Australia) provided ethical approval. Baseline demographic and procedural information was recorded at the time of the coronary intervention.
       Radi™ PressureWire^® high-sensitivity thermistor.> The Radi PressureWire is a coronary guidewire that allows pressure measurement from a high-fidelity sensor positioned 30 mm from the tip of the wire (at the juncture of the radiopaque and radiolucent aspects of the wire) (Figure 1). The second generation of this wire is termed the XT (extra-torque), and has improved torqueability over the first prototype. Within the pressure sensor is a high-sensitivity thermistor required for the calibration of the pressure sensor. The characteristics of the thermistor include a temperature accuracy of 0.1ºC, and the ability to acquire, in real-time, the differences in temperature in multiple sites relative to a predetermined reference.
       Measurement of plaque temperature. The culprit lesion of interest was first identified with two or more orthogonal views using coronary angiography and taken as the most angiographically stenosed site. As described, only patients with a culprit lesion requiring PCI were enrolled in the study. The RPW was prepared as per FFR measurement and placed distal to the culprit lesion, such that the sensor was at least 20 mm beyond the culprit site, in the appropriate coronary artery, within a region of relatively normal coronary artery segment with no angiographic stenosis. At this point, the thermistor function was displayed in real-time and calibrated to this region. Each position within which a temperature recording made was carefully identified using coronary angiographic mapping and cine angiograms confirming the actual position of the RPW. A total of three temperature measurements were taken in each case: a distal reference temperature reading, the culprit lesion temperature and a temperature proximal to the culprit lesion (also in a more normal-looking segment of the coronary artery with no angiographic stenosis).
       The analysis of the plaque temperature data therefore would use the temperature difference (or “delta temperature”) between the temperature readings at each of the three sites (distal, culprit and proximal) versus the reference site. Since the distal temperature reading was used as the reference in this study, clearly this reading should closely approximate zero, although may not be exactly, as the mean of three measurements of each site will be used.
       Measurement of fractional flow reserve. Once the baseline temperature measurements had been performed, FFR after the administration of intracoronary adenosine was measured as previously described. In brief, after the RPW was repositioned back across the culprit lesion, 40 µg of adenosine was infused into the relevant coronary artery system and the minimum FFR was measured. This was performed

Figure 2. Graphical presentation of the individual data points showing the delta temperature relative to the distal reference site. Thus, as expected, the delta temperature at the distal reference site is essentially 0ºC, and of course has the tightest confidence intervals. Of note, there is no significant change in temperature at the culprit site, nor at the proximal reference site. However, as expected, the confidence intervals increase due to the intrinsic sensitivity limitations of the system. The error bars represent two times the standard deviation and the middle line represents the mean.

three times, and the mean of these readings was used for further analysis. This was performed pre- and post-PCI.
       Statistical analyses. All demographic data are presented as mean ± standard deviation (SD) and temperature data (using delta temperature from baseline) as mean ± the standard error of the mean (SEM). Repeated measures analysis of variance (ANOVA) techniques were used to compare the temperature data from the three sites, and post hoc testing was performed using the Bonferroni/Dunn technique as appropriate. Paired Student’s t-testing was used to analyze the results of the FFR pre- and post-PCI. All probabilities are two-sided, with statistical significance taken as p < 0.05.

Results
       Demographic data. The demographic characteristics of the patients enrolled (n = 20) are summarized in Table 1. Of note, all patients received coronary stents during PCI, and all were receiving aspirin and clopidogrel at the time of the procedure.
       Fractional flow reserve. The mean FFR pre-PCI was 0.65 ± 0.06, consistent with the fact that this group of patients required PCI. There were good results from the coronary intervention in this group (all of whom received intracoronary stents) as evidenced by the significant increase post-PCI in the mean FFR to 0.95 ± 0.01 (p < 0.0001).
       Plaque temperature. The delta temperature at the distal site was 0.00 ± 0.01ºC, which is what would be expected given that the distal site was used to calibrate the thermistor. The delta temperature at the culprit site was -0.02 ± 0.01ºC, and at the proximal site was -0.03 ± 0.02ºC (p> = NS) (Figure 2). Although it appears that there was a small decrease in the delta temperature at the culprit site, it should be remembered that the sensitivity of the thermistor used is 0.1ºC, and thus the differences in the values shown are below the sensitivity of this thermistor.
       Assuming the greatest variation (i.e., SD 0.03ºC, SEM 0.02ºC from the proximal site), we had greater than 95% power to detect a 0.1ºC difference in temperature at the culprit site with an alpha of 0.05 in 20 patients.

Discussion
       Despite the potential of the RPW to detect temperature with a sensitivity of 0.1ºC, we were unable to detect any increase in culprit atherosclerotic lesion temperature using the high-sensitivity thermistor function of this device.
       There is a substantial body of data showing both ex vivo and in vivo that the temperature of an atherosclerotic lesion is associated with ACS. Initial ex vivo data have shown an association between the macrophage content of atherosclerotic lesions in carotid endarterectomy samples and the local temperature of these plaques.² Furthermore, in vivo data have shown that, using a specialized thermography catheter, patients with unstable angina pectoris and acute myocardial infarction had an increase in the local temperature at the culprit site over that of a more normal coronary artery segment of 0.7ºC and 1.5ºC, respectively.³ Additional studies have not only confirmed the ability of the specialized thermography catheter to detect regional differences in the coronary artery tree of up to 1.5ºC, but also demonstrated that an unfavorable PCI clinical outcome was predicted by the local plaque temperature.⁴ In that study, the incidence of adverse cardiac events was 41% in patients with a delta plaque temperature greater than or equal to 0.5ºC versus 7% in those with < 0.5ºC. The question is how do we interpret our results in light of this body of evidence? There are two obvious responses.
       Firstly, we should address the differences between the devices used in our study versus the previously mentioned literature. The sensitivity of the two devices is different. The specialized thermography catheter has an accuracy of 0.05ºC, whereas the sensitivity of the thermistor in the RPW is 0.1ºC. This is unlikely to be the explanation for the different results, as the increases in local temperature reported in the literature is five- to ten-fold that of the sensitivity of the thermistor in the RPW. The thermistor in the specialized thermography catheter is mounted on “wings” so as to ensure adequate contact with the atherosclerotic lesion, whereas the thermistor on the RPW is within the 0.014-inch guidewire. There is no assurance that the RPW thermistor will contact the coronary artery wall, and this may explain why no increase in temperature was observed in this group of patients with unstable angina pectoris. However, we specifically targeted a group of patients in whom the RPW was more likely to provide temperature information from the atherosclerotic plaques by identifying a group with significant coronary artery stenoses and thus minimal coronary lumen at the culprit site. A simultaneous comparison of the RPW and the specialized thermography catheter utilized by Stefanadis³ could have resolved this question, but was not performed in this study.
       Secondly, it could be that there is no actual regional difference in atherosclerotic plaque temperature in this group of patients. By targeting a group of ACS patients, but in the setting of a high-grade stenosis, we know that the underlying pathobiology may be somewhat different than that of patients with low-grade lesions and a large thrombotic burden.⁹ However, it has been shown that patients with unstable coronary syndromes and high-grade lesions still have a significant burden of inflammatory cell infiltrates at the surface of the atherosclerotic plaque,⁹ and thus may not explain why no temperature increase was detected at the culprit site.
       Although for a number of technical reasons the RPW thermistor device is not as good as the specialized thermography catheter used by Stefanadis and colleagues,³ it is a device that is commercially available. A study was recently published reporting a 0.07ºC mean increase in temperature at the site of the culprit atherosclerotic plaque in patients with unstable angina pectoris using the RPW.¹⁰ This reached statistical significance and the authors concluded that the RPW was able to detect temperature increases in this population. However, there are a number of concerns with this interpretation. The mean increase in temperature in this study is ten-fold less than that published by Stefanadis³ in patients with unstable angina pectoris. Furthermore, the mean increase is below the threshold of the sensitivity of the RPW catheter.
       The RPW high-sensitivity thermistor device is unable to detect a local increase in culprit site temperature, relative to a more normal coronary reference site, in patients with unstable angina pectoris and high-grade coronary artery stenoses. Further studies are required to investigate the mechanism of this finding.