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Original Contribution
Vulnerable Plaque Detection by Temperature Heterogeneity Measured with a Guidewire System: Clinical, Intravascular Ultrasound an
February 2007
Temperature heterogeneity due to inflammatory activity may have a pivotal role in predicting plaque composition and allow differentiation between stable and unstable atherosclerotic plaques. Plaques prone to rupture1 are associated with greater macrophage accumulation than are stable plaques, which have less intense inflammatory activity.2,3 Characterizing atherosclerotic plaque’s propensity for rupture may further our understanding of how pharmacological treatments alter clinical outcomes.4–7
Casscels et al measured the intimal surface temperatures of a freshly obtained carotid endarterectomy specimen and showed a significant correlation between macrophage density and local temperature.8 Clinical9–11 and experimental12,13 studies have subsequently shown thermal heterogeneity within diseased arteries. Heterogeneity is larger for plaques in patients with unstable angina or myocardial infarction than plaques in patients with normal coronary arteries or with stable angina.9 Finally, local temperature in atherosclerotic plaques was shown to be a strong predictor of unfavorable clinical outcome in patients with coronary artery disease.10,11
Many approaches to measuring vascular wall temperature have unavoidably impaired coronary flow and thereby altered heat transfer within the vessel. To minimize effects on flow, we investigated the safety and feasibility of guidewire-based thermography to detect temperature heterogeneity in human coronary atherosclerotic plaques and correlated temperature heterogeneity with intravascular ultrasound (IVUS) and tissue histopathology.
Methods
Clinical protocol. We studied 13 consecutive patients undergoing percutaneous coronary intervention (PCI) for a variety of clinical coronary syndromes presenting to the catheterization laboratory of the Hospital de Clinicas de Porto Alegre. The protocol was reviewed and approved by the local Institutional Review Board. All patients signed informed consent. Serum was collected prior to and the day following PCI for measurement of CPK, CK-MB, troponin I, C-reactive protein, total cholesterol, triglycerides, LDL and HDL.
After diagnostic coronary angiography and identification of culprit lesions (based on clinical data and angiographic stenosis >70% by visual estimation), a 6 Fr guiding catheter was selectively engaged in the left or right coronary artery. Intravenous heparin was administered to achieve an activated clotting time (ACT) >300 seconds. No patients were given glycoprotein IIb/IIIa receptor antagonists. A conventional 0.014 inch angioplasty guidewire was used to cross the target lesion. After administration of nitroglycerin 200 µg IC, a 2.3 Fr Endosonics Avanar IVUS catheter (Volcano, Inc., Rancho Cordova, California) was introduced distal to the stenosis and images were obtained during automated pullback at 0.5 mm/second. When the IVUS study was complete, the initial guidewire was removed and the Thermocoil guidewire (Imetrx, Inc, Mountain View, California) was advanced until its tip was distal to the target stenosis. The Thermocoil wire was attached to an automated pullback device for thermographic mapping of the entire coronary segment. Thermography was performed twice for each coronary segment beginning at the same location and with the same wire tip orientation, and the results were averaged.
Upon completion of thermography, a standard balloon was used to predilate the lesion and one or more bare-metal stents deployed. In 2 patients, directional coronary atherectomy using the Flexicut system (Guidant Corp., Indianapolis, Indiana) was performed immediately after thermography and the tissue was analyzed histopathologically.
Device description. The ThermoCoil system has been described previously.14 In brief, it consists of a 0.014 inch guidewire, pullback handle and data acquisition system. The temperature sensor is located in the tip of the wire and has a resolution of 0.08°C. The tip of the wire is pre-bent in an angled curve 10 mm proximal to the tip, which brings the tip into contact with the vessel wall. The guidewire attaches to the pullback handle, which in turn attaches to the data acquisition system via an integrated cable. The data acquisition system receives and displays data collected by the ThermoCoil guidewire. ThermoCoil guidewire sensing is initiated by depressing the activation button on the pullback handle. Once activated, the pullback handle causes the ThermoCoil guidewire to rotate at a speed of 30 revolutions per minute and move proximally at a rate of 0.5 mm per second, covering 5 cm of vessel wall length in just under 2 minutes. The rotation speed permits the mapping of a complete 360 degrees for every millimeter of the vessel wall. The sensing tip of the wire transmits a signal as it rotates by contacting the vessel wall due to the curvature in the tip. The signals are converted to temperature readings and displayed in real time as a digital readout and in graphical form.
Intravascular ultrasound analysis. IVUS images were recorded on CD for offline analysis. Quantitative (volumetric) and qualitative assessment were performed along the entire coronary segment by two independent analysts (Cardiovascular Imaging Core Laboratories, University of Florida, Jacksonville, Florida) unaware of thermography readings or clinical data. A dedicated software program (QIVA, Pie Medical BV, The Netherlands) was utilized for 3-dimensional digital imaging reconstruction and quantification of vessel structure volumes.
Coronary plaques were defined as the presence of intima-media complex with a thickness >0.3 mm (intimal thickening). Individual plaque segments were defined as the presence of a major side branch or a segment free of disease >5 mm (reference segment). Each plaque segment was divided into 3 sub-segments (proximal, mid and distal) for qualitative assessment. Reference segments were defined as a 5 mm segment proximal and distal to the plaque segment.
Type of plaque was defined in every cross-section as soft, mixed, hard and hard/calcified defined as follows:15,16 Soft plaque: 80% of cross-sectional area (CSA) constituted by material showing less echoreflectivity than the adventitia, with an arc of calcium 90°; Mixed plaque: when the plaque did not match the 80% criteria for hard or soft plaque. In those cross-sections containing up to 90° of calcium arc, the contour of the external elastic membrane was imputed from adjacent noncalcified slices.
Histopathology. Directional atherectomy specimens were immediately placed in 10% buffered formalin, processed using a routine biopsy processing schedule and embedded in paraffin. Five µm sections were collected and stained with Mayer’s hematoxylin and eosin-Y. Immunohistochemical staining was performed to label CD68 (clone: PG-M1, Dako Co, Carpinteria, California) for monocyte/macrophages.
Results
Thirteen patients were enrolled in the study: 2 with unstable angina, 1 with non-ST-segment elevation myocardial infarction (NSTEMI), 1 with ST-segment elevation myocardial infarction (STEMI) and 9 with stable angina and/or inducible myocardial ischemia (Table 1). Fifteen arteries were evaluated. The ThermoCoil guidewire was able to cross all lesions primarily, and there were no device-related adverse effects or system failures. All patients underwent successful stenting after thermography. One patient (Patient 8) suffered stent thrombosis on the first post-PCI day.
Thermography. The thermography profiles of the 13 arteries are shown in Figure 1. In 9 arteries no temperature heterogeneity was seen (Figure 1A). In 2 arteries (Patients 7 and 8) marked intra-arterial temperature rises between 0.1 and 0.3°C were found (Figure 1B). More subtle temperature fluctuations were observed in an additional 2 patients (Figure 1C). Two-dimensional maps were calculated as well (Figures 1 D and E).
C-reactive protein in the 2 patients with temperature elevation were 44.6 and 4.0 mg/L, and in the 9 patients without elevated temperature 5.8 ± 1.5. Lipid levels were not different between patients with and without thermal heterogeneity. Preprocedure troponin levels were all normal (5 times the upper limit of normal (ULN) in only 1 patient (Patient 8).
Intravascular ultrasound analysis. IVUS identified 24 individual plaque segments (n = 72 subsegments) in 13 vessels. There were 16 soft, 12 hard, 3 hard/calcified and 41 mixed plaque subsegments. The segments with marked temperature heterogeneity (Patients 7 and 8, Figures 2 and 3) showed soft plaque with external elastic membrane (EEM) expansion compared to the reference segments.
Histopathologic analysis. Directional atherectomy was performed in the proximal left anterior descending coronary artery of 2 patients (Patients 7 and 11). In Patient 7, DCA was performed at a site of temperature elevation, and in Patient 11, at a site without temperature elevation. Histopathological analysis of the tissue from Patient 7 revealed dense macrophage infiltration, areas of intraplaque hemorrhage and areas of fibrous cap disruption (Figure 4). The tissue from Patient 11 contained primarily smooth muscle cells with rare macrophages and no intraplaque hemorrhage (Figure 5).
Discussion
Temperature heterogeneity is a possible surrogate measure of atherosclerotic plaque composition and therefore of propensity for plaque rupture.8–10,13 We report that a guidewire-based system can be a safe method of measuring coronary plaque temperature heterogeneity in patients with coronary artery disease. Temperature variations as high as 0.3°C were noted in 2 of 13 subjects. One patient with temperature variability had elevated C-reactive peptide levels before PCI, elevated CK-MB and troponin after the procedure, and went on to develop stent thrombosis. Furthermore, these patients had IVUS findings suggestive of soft, lipid-rich plaque composition.17 In 1 case, histopathologic findings were consistent with proposed measures of plaque instability.1–3
It is accepted that the composition of an atherosclerotic plaque, rather than the degree of stenosis it imposes, determines its proclivity for causing acute coronary syndromes. A variety of imaging or detection techniques have been proposed for assessing plaque locally, with an eye toward predicting sites at high risk for rupture.7,11,12,14,18,19 In particular, greater temperature heterogeneity within human coronary atherosclerotic plaques has been associated with unfavorable clinical outcomes.10,11 However, previous clinical studies have not included IVUS or histopathologic correlates of specific plaque temperature readings. Several mechanistic possibilities exist linking temperature to plaque composition, including inflammatory cell content13, proximity of the inflammatory cells20, fibrous cap thickness19 and plaque vascularization. Larger clinical studies incorporating histopathologic correlation will allow deeper mechanistic insights.
Not all segments with soft composition characterized by IVUS demonstrated temperature heterogeneity. The lack of temperature heterogeneity may indicate noninflamed or low macrophage density areas, which may not be prone to rupture despite their low echogenic, soft IVUS appearance. However, a true understanding of the pathophysiology of IVUS-detected soft plaques with normal temperature would require histologic correlation. Echogenicity of vessel wall structures is not consistently associated with actual histology.21,22 A combination of imaging and physiologic measurements will likely be necessary for accurate detection of vulnerable plaque.
Finally, there are intriguing questions regarding the clinical consequences of determining plaque composition. First, it remains to be determined whether local plaque characterization adds to systemic assessment of a patient’s overall risk for acute coronary syndrome (C-reactive peptide, myeloperoxidase, etc.); second, assuming high-risk plaque sites can be identified, the optimal subsequent therapeutic intervention is not known.
Study limitations. Preclinical evaluation has demonstrated that luminal flow rate affects measurement of mural temperatures, so that segments with near-occlusive disease might yield artifactually high temperature readings. However, in our study, the wire did not cause angiographic slow-flow in any case, and in vitro validation of the system in settings of flow has been published.14 It is also possible that apposition of the wire tip to the vessel wall was not maintained during rotational pullback, reducing sensitivity. However, ex-vivo analyses in phantom models have demonstrated complete apposition in settings of curvature and variable vessel size.14 Finally, the patients studied had flow-limiting coronary lesions requiring intervention. Whether these same lesions would have had detectible temperature heterogeneity in the days, weeks, months or years before they caused clinical syndromes cannot be answered from our study.
Conclusions
Using a guidewire-based system, we achieved rapid thermographic interrogation of complex coronary arterial segments, detecting temperature heterogeneity in areas of coronary stenosis in patients presenting for PCI. Both patients with a high degree of temperature heterogeneity proved to have IVUS characteristics associated with plaque vulnerability, and furthermore, one had accepted clinical markers or plaque instability, and the other had plaque histopathology suggestive of plaque rupture. Reliable local surrogate measures of plaque composition may allow tailored therapy aimed at reducing the likelihood of plaque rupture and acute coronary syndromes.
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