The effect of reduced blood-flow on the coronary wall temperature

Are significant lesions suitable for intravascular thermography?

Leonidas Diamantopoulosa,*, Xiaoshun Liua, Ivan De Scheerder, Rob Kramsb, Shengiao Lia, Johan Van Cleemputa, Walter Desmeta and Patrick W Serruysb

a Cardiology Dept., University Gasthuisberg Leuven, Belgium
b Thoraxcenter, Erasmus University Rotterdam, Rotterdam, Netherlands

* Corresponding author. Leonidas Diamantopoulos MD, PhD, Department of Cardiology, University Hospital Gasthuisberg, Herestraat 49, 3000 Leuven, Belgium. Tel.: +32-497459597; fax: +32-16604009
E-mail address: leo{at}otenet.gr

Received 20 February 2003; revised 2 July 2003; accepted 23 July 2003 This paper was guest edited by Prof. Antonio Colombo, EMO Centro Cuore Columbus S.r.l., Italy

Abstract

Aims The purpose of this study was to investigate the relation between acute coronary flow reduction and arterial wall temperature.

Methods and results Five pigs with normal coronary arteries were catheterized. Arterial wall temperature was studied with a thermographic system that uses a 4-thermistor sensor tip. Flow velocity was studied at the same time and place with the temperature measurements, using a Doppler wire. In order to modify the coronary flow, a balloon was gradually inflated proximally to the thermographic sensors. Temperature differences and flow velocities were simultaneously recorded.

Flow velocities above an average peak velocity (APV) of 9cm/s were associated with unaffected temperature measurements. At flow velocities around 4cm/s, the wall temperature was increased ({Delta}T=0.015±0.005oC, P~0.05), following the heart-rate. When flow velocity dropped further below this value, the local wall temperature was logarithmically increased to a maximum value observed at total vessel occlusion ({Delta}T=0.188±0.023oC, P<0.001).

Conclusion The reduction of coronary flow has an effect on the arterial wall temperature. This effect however, appears only below a critical threshold of APV and in a logarithmic fashion. Above this threshold, temperature measurements should be unaffected from flow reductions and related to the regional temperature heterogeneity.

Key Words: Thermography • Flow • Temperature • Inflammation • Vulnerable

1. Introduction

Intracoronary thermography is a new promising method that aims to spot the presence of an inflamed atherosclerotic plaque and monitor its progress.1,2Although appealing, thermography had to face several technical problems concerning a potential application in vivo. One of the most important issues that should be investigated is the effect of blood velocity on the arterial wall temperature. Blood, being basically constituted of water has undoubtedly significant cooling capabilities; its relatively high flow in combination with the small amount of heat that is produced due to the inflammation process, may affect a potential intravascular temperature measurement in vivo. However, due to the heat-insulating lipids, the arterial wall tissue has reduced thermal conductive properties in respect to the blood; moreover, the moderate thermal emissivity of the wall surface, restrict the creation of thermal vectors with high magnitude. Therefore, a temperature gradient could be created between the plaque and the blood. These calculations were verified by the up to date thermographic experience,2,3that demonstrated the feasibility of such in-vivo measurements.

A crucial issue is the status of the wall temperature when blood-flow is reduced, i.e. after a significantlesion. The complicated nature of the thermodynamic balances inside an in vivo coronary artery makes the creation of in-vitro representation models very difficult. This study aimed to explore the relation between an acute reduction of coronary flow and the arterial wall temperature, in an in-vivo pig model with normal coronary arteries.

2. Methods

In these experiments, five non-atherosclerotic pigs were selected, weighting 25kg and being otherwise healthy. All animals were treated and cared for in accordance with the National Institute of Health Guide for the care and use of laboratory animals. For the flow-velocity study, an ultrasound Doppler wire (flow-wire) was used connected to a Flowmap device (Cardiometrics, Inc., Mountain View, California, USA).

For the study of the coronary arterial wall temperature the ThermoSense (Thermocore Medical Ltd, UK) system was used. The system consists of a thermography catheter, and an electronic console. The thermography catheter (Fig. 1) is a 4 French (F) over-the-wire intravascular catheter that has a body length of 140cm. The distal tip has four independent angled arms, made of a superelastic material. At the end of each arm there is an accurate thermistor temperature microsensor. Each microsensor has a certified accuracy of 0.01oC, and a time constant of 150ms. The sensor arms can be held parallel to the catheter body covered by a sliding incorporated sleeve; when the sleeve is retracted (Fig. 1), the arms are released to open to the maximum possible diameter, bringing the sensors in closecontact with the vascular wall. The catheter can be used in two configurations: open and closed. The closed configuration (lowest possible profile) is used during the catheter insertion in the coronary artery, using standard interventional techniques, while the open configuration is used for the temperature study. All thermographic data collected from the four sensors are sent to the computer-based console for analysis and storage.



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Fig. 1 The thermography catheter used in the study. Due to the independent movement of the four superelastic arms, the sensors never lose contact with the arterial wall even in the most tortuous segments.

 
2.1. Procedure
Pigs were sedated using intramuscular azaperone 3mg/kg (Stresnil, Janssen Pharmaceutics). General anaesthesia was induced with intravenous ketamine (2mg/kg, Ketalar, Parke Davis) and further intravenous bolus Diprivan (3.5mg/kg, NV AstraZeneca SA) followed by intravenous infusion of Diprivan at a rate of 3mg/kg/h. Then, pigs were intubated and ventilation (Mark 7A, Bird Cooperation) was started using a mixture of 20% volume of pure oxygen and 80% volume of room air. Ventilation was adjusted by frequent blood gas analysis in order to maintain a minimum PaO2of 100mmHg, and physiologic PaCO2and pH parameters. Continuous electro-cardiographic, pressure and core blood temperature monitoring was performed throughout the procedure.

Heparin 15 000IU and 250mg acetylsalicylic acid were administered intravenously as a bolus. Furthermore, 400IU/h heparin was given as a continuous infusion during the procedure.

The left carotid artery was surgically exposed and canalized using a 10F-introducing sheath. A 10F Judkins-R guiding catheter was then used (Fig. 2) over a 0.038'' exchange wire, to engage the ostium of the left main coronary artery (LMCA).



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Fig. 2 Fluoroscopy frames of the experiment on one of the animals: (Upper row=RAO-Caudal projections. Lower row=LAO-Cranial projections). From left to right: (a) The left coronary artery is normal, with a diameter around 3mm. (b) The thermography catheter is placed into the middle-LAD over a Flow-Wire. A balloon catheter is also placed into the LAD over a second guidewire. (c) The ballon is inflated to restrict flow.

 
A Balance MiddleWeight guide-wire (Guidant Inc. Indianapolis U.S) was introduced in the distal segment of the left anterior descending artery (LAD) or the Circumflex artery (LCX). The thermographic catheter was then placed over the wire until the sensor markers were at least 60mm from the coronary ostium. For the correct positioning of the catheter, fluoroscopy was used. Then, the guide-wire was exchanged to a Flow-Wire that was forwarded until the ultrasound sensor was 3 to 5mm out of the distal catheter-tip (Fig. 2).

The thermography sensor sleeve was retracted, leading to sensor-arm opening and contact between the four sensors and the arterial wall.

The thermography catheter was locked in place and simultaneous temperature and flow-velocity recordings were started. Recording of the signals lasted 120s or 160 heart-cycles (baseline recording).

After the baseline recordings, a 3.0/15mm balloon (Crossail, Guidant Inc. Indianapolis U.S) was introduced through the same guiding catheter over a Balance MiddleWeight guide-wire, into the ostium of the LAD or LCX respectively (Fig. 2). The balloon was kept at least 10mm before the sensor area to avoid temperature impairment due to the (cooler) contrast agent that was used to inflate it. Once again, temperature and flow-velocity recording was started, and the balloon was inflated in a stepwise fashion, until the vessel was totally occluded. The vessel occlusion was verified by the elimination of measurable flow velocity; contrast injections were avoided to prevent wall temperature alteration. Each flow restriction step lasted for 30s and then the balloon was deflated to allow restoration of blood-flow.

2.2. Statistical analysis
For the determination of blood flow velocity, the Average peak Velocity (APV) was used, expressed in cm/sec. Temperature differences were defined as temperature at each stage of APV minus the temperature at baseline (unrestricted flow). These differences were expressed in degrees Celsius (C). Data are presented as mean±SEM. The significance of the temperature differences was assessed with the one-way ANOVA test followed by a Bonferroni correction. Regression analysis was used to examine the correlation between temperature differences and APV changes during the balloon inflation. A P value <0.05 was considered as statistically significant. Statistical analysis was performed using the SAS statistical software (SAS version 8.2, SAS Institute).

3. Results

The results of the study are summarized in Table 1. The core blood temperature of the animals was 37.62±0.109oC and was maintained stable during the procedure. The heart rate was also not affected and remained stable (87±5 beats/min). In normal flow conditions, the blood flow velocity inside the coronary artery varies periodically during the heart cycle. However, this variation proved to have no measurable effect on the arterial wall temperature (Fig. 3). In a normal coronary artery, one would expect to see periodic wall temperature oscillation following the flow velocity; such aphenomenon was not observed.


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Table 1 Wall temperature disturbance during controlled variation of APV

 


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Fig. 3 Continuous static temperature recording at the same spot of the middle segment of the LAD under normal flow conditions. Although flow velocity periodically changes following the heart cycle, the coronary wall temperature remains stable.

 
Gradual flow restriction due to the balloon inflation revealed (Fig. 2, Fig. 4. Table 1) that flow velocities above an APV of 9cm/s were associated with unaffected temperature measurements.



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Fig. 4 Simultaneous flow velocity and static temperature recording at the same spot of the middle segment of the LAD, during flow restriction with a balloon at the proximal LAD. When APV is higher than 9cm/s the arterial temperature status is maintained. If APV is below 5cm/s, and especially in total vessel occlusion the temperature increment is obvious.

 
At flow velocities around 4cm/sec, wall temperature was increased ({Delta}T=0.015±0.005oC, P~0.05). In the APV range between 4–6cm/s, periodic temperature variation appeared, following the pressure wave (Fig. 5). The amplitude of this variation was lower than 0.03oC.



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Fig. 5 Continuous temperature recording, when APV is near the threshold values. Temperature variation is periodic and seems to follow the driving pressure (Heart rate was 84 beats/min, exactly the same as the frequency of the temperature oscillation).

 
When flow velocity dropped further below these values, the local wall temperature was logarithmically (Fig. 6) increased to a maximum value observed at total vessel occlusion ({Delta}T=0.188±0.023oC, P<0.001).



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Fig. 6 Up: The relation of APV and coronary wall temperature, as shown from our experiments. Down: The relationship of APV and tdf (temperature differences) is logarithmic. All temperature differences refer to the baseline temperature (unrestricted flow).

 
4. Discussion

During their passage through a stenosed coronary segment, the thermography catheters occupy lumen space, and could eventually worsen the already limited blood flow. In such a case, there might be a risk of false temperature measurements, due to reduced heat dissipation towards the blood. Indeed, the up to now thermographic studies1–5do not seem to agree about the exact levels of measured heat at the site of an inflamed wall area. High-profile thermographic catheters that severely obstruct coronary flow seem to measure higher temperature differences than others that are less occlusive.3–5A potential effect of flow reduction on the wall temperature threatens the accuracy of intravascular thermography, since the exact flow parameters are too many to be predicted, and are different between individual patients.

Our in-vivo study demonstrates that blood flow has indeed a significant effect on local arterial wall temperature. Specifically, a decrease of flow velocity below an APV threshold of 5-9cm/s leads to a significant increase of local arterial wall temperature. This increment is probably due to the reduction of heat dissipation towards the flowing blood. The metabolic heat and the heat due to friction, is—under normal flow conditions—‘washed away’ in part by the flowing blood. However, when the blood flow is eliminated, this heat remains on the wall as extra energy, therefore rising its temperature. This relation of flow velocity with temperature is not proportional, but logarithmic. The temperature-APV threshold operates more like a ‘switch’: above it temperature stays unaffected, while below it a logarithmic curve is observed.

The APV value, at which the ‘switch’ turns, proved to be in the range of 5–9cm/s. Since even in significantly stenosed coronary arteries APV is usually kept above these values6,7intracoronary thermography can be reproducible in a wide range of lesions. Near the ‘switching’ point, and for a short APV range, periodic temperature variation appears, following the driving pressure (Fig. 5). This variation might be useful, during routine thermographic procedures, as an indicator of catheter wedging; when it appears, the operator should bear in mind that the flow is critically affected and actual temperature values are likely to be shifted.

From a mathematical point of view, Newton’s Law of Cooling can estimate the energy flow rate due to heat transfer between an inflammed plaque and the blood, at the level of the fibrous cap. The energy flow from a solid to a liquid in contact is generally expressed as {Delta}Q=hA (Tp–Tbl), where h is the conduction constant, A is the plaque area and Tp, Tblthe temperatures of the plaque and the blood respectively. If we consider the heat generation inside the plaque as homogenous and assume that the specific heat is constant over the temperature range, the energy leakage towards the blood at the site of a hot spot can be expressed as follows:

Where m is the mass of the heat-generating plaque,cpis the specific heat of the plaque. Dividing by the constant parameters, we have:

In normal flow conditions, the blood movement ensures that Tp>Tblat all times, since the mass of the whole blood is too big to be heated up to a higher value by such a small production of energy. If however the blood-flow is stopped (i.e. by using a balloon), then the arterial geometry collapses and possible remaining local blood-pools can be heated-up by the energy leakage. This causes a reduction of Tp–Tblthat is followed by a feedback reduction of (d/dt) Tp.Since the energy leakage is reduced, the temperature of the hot wall area is elevated to higher values. Therefore, in an inflamed coronary artery, we can assume that the flowing blood behaves similarly to a high-pass filter, allowing us during normal flow to see only the ‘top of the iceberg’ (Fig. 7). The filter’s ‘cut-off’ point is reduced logarithmically when flow-velocity is reduced below a threshold value. Again, the important issue is that, above this threshold, temperature measurements remain unaffected. This indicates that flow velocity should not be a restricting factor in correlating temperature measurements between different patients, providing of course that APV in both patients is maintained above the aforementioned threshold.



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Fig. 7 The iceberg hypothesis: In an inflammed artery under normal flow we see only the top of the iceberg that is, temperatures higher than the blood cut-off point. When flow is reduced critically, the cut-off point moves to lower values, allowing more temperature differences to be measured.

 
In the specific study, the heart rate was maintained constant. Therefore, the effect of heart rate variation on wall temperature was not studied. However, we must keep in mind that a reduction or increment of heart rate may impair temperature measurements by several different mechanisms other than flow; for example, less or more muscle work reduces or increases respectively friction-produced heat and metabolic heat. This complicates further the relation between heart rate, flow velocity and wall temperature.

One could argue that the time that flow-velocity stays low might play a key role. However, we repeatedly kept APV at the levels of 9–15cm/s for 30s without noticing any measurable effect on the wall temperature (Fig. 4). What happens to arterial wall temperature if flow stays below the threshold for a longer period of time? In this study, the maximum time below threshold was 30s, during which we noticed the reported temperature changes. Longer times might additionally affect temperature through mechanisms of ischaemia and impaired heart muscular function.

The maximum deviation between the four independent sensors was observed at total occlusion of the artery and it was 0.036oC (Fig. 4). However, during all the other stages of the flow impairement and at free flow, the maximum intra-sensor deviation was insignificant (<0.004oC, that is below the proven sensor sensitivity). These intra-sensor differences during the occlusion phase might be explained by a collapse of the arterial geometry at the site of measurement and the formation of regional remaining blood-pools. Such phenomena could affect the contact between the sensors and the wall, or create environmental differences between the individual sensors.

All flow-reduction experiments were performed in animals with constant blood core temperature. It is possible that in different blood core temperatures the above APV threshold lies in higher or lower levels. The study was performed in animals with normal coronary arteries, and therefore we describe the effect of temperature reduction on the normal metabolic-heat of the endothelium. A question arises whether the presence of a very warm plaque might affect the ‘swithing point’ at which a flow-reduction has a measurable effect on the area’s temperature. However, the actual temperature differences are generally small, only fractions of a degree, and therefore we should not expect significant shifting of the ‘switch’. In such a case nevertheless, a flow reduction might lead only to a slight overestimation of an existing hot spot, and should not limit the ability of thermography to signify the presence and location of a hot plaque.

What about the feasibility of measuring the temperature of the flow-restricting lesion itself? Taking in consideration the simplified law of Bernouli, the flow velocity will be the same in all the arterial segments that have the same diameter, since Velocity x Area=constant. At the site of the flow-restricting lesion however, a higher local velocity might be present. Higher flow might theoretically provide increased local cooling, since there are more blood molecules per unit of time, passing in close contact with the hot spot. Following this scenario, the local hot spot might be underestimated or ‘hidden’. Things become more complicated if we take into consideration the friction-originated local vorticity of the blood stream, that usually accompanies high-speed movements of every liquid. Other investigators8have previously demonstrated that blood flow leads to underestimation of temperature in significant lesions. However, the methodology of that study8generates critical debate: The temperature sensor was placed in close proximity with an occluding balloon. The balloon was inflated to impair flow using a mixture of contrast with normal saline at 37oC. From our experience, and according to physics, in such cases the heat of the contrast media inside the balloon seriously affects the sensor. Moreover, in most cases of that study, the preprocedural lesion MLD was less or equal to the tip-diameter of the used thermography catheter. Consequently, the thermography catheter should either fail to cross the lesions (at least without predilatation), or induce severe impairment of flow already before the use of a proximal balloon. Studies with special instrumentation might be required to drop more light into the effect of flow on the temperature of the flow-restricting lesion itself.

Finally, our study investigated only the effect of a reduction of blood flow velocity on the arterial wall temperature. We did not investigate the opposite, which is finding the minimum increment of APV that starts to affect wall-temperature due to higher flow. It is possible that faster blood flow will lower the coronary wall temperature due to an increment of heat dissipation towards the blood. However, this hypothesis remains to be tested, together with the value of APV that starts to affect temperature. Since flow increments above 20cm/s have most probably a metabolic origin, they might not appear as fast as flow reductions. Therefore, during a thermography procedure, reductions of flow are more important since they might appear acutely, i.e. due to catheter wedging while crossing a stenotic segment.

5. Conclusions

The study showed that in the total absence of coronary blood flow, coronary wall temperature is shifted to higher levels. A coronary flow reduction has a logarithmic effect on the coronary wall temperature, that appears only if it is reduced below a specific APV threshold, providing that the heart rate and core temperature are constant, and that the ischaemia does not impair the mechanical function of the heart. This threshold is clearly low enough to allow reproducible temperature measurements inside a stenosed coronary artery. Further investigation of this phenomenon taking in consideration the blood core temperature, the heart rate and the role of ischaemia, will probably drop more light into the pathophysiology of the flow effect on the arterial wall temperature.

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