Author + information
- Received February 13, 2007
- Revision received August 21, 2007
- Accepted August 28, 2007
- Published online December 11, 2007.
- Wilbert Aarnoudse, MD, PhD⁎,†,1,
- Marcel van’t Veer, MSc⁎,†,1,
- Nico H.J. Pijls, MD, PhD⁎,†,⁎ (, )
- Joost ter Woorst, MD‡,
- Steven Vercauteren, MD§,
- Pim Tonino, MD⁎,
- Maartje Geven, MSc†,
- Marcel Rutten, PhD†,
- Eduard van Hagen, RN⁎,
- Bernard de Bruyne, MD, PhD§ and
- Frans van de Vosse, PhD†
- ↵⁎Reprint requests and correspondence:
Dr. Nico H. J. Pijls, Catharina Hospital, Michelangelolaan 2, P.O. Box 1350, 5602 ZA Eindhoven, the Netherlands.
Objectives This study sought to validate a new method for direct volumetric blood flow measurement in coronary arteries in animals and in conscious humans during cardiac catheterization.
Background Direct volumetric measurement of blood flow in selective coronary arteries would be useful for studying the coronary circulation.
Methods Based on the principle of thermodilution with continuous low-rate infusion of saline at room temperature, we designed an instrumental setup for direct flow measurement during cardiac catheterization. A 2.8-F infusion catheter and a standard 0.014-inch sensor-tipped pressure/temperature guidewire were used to calculate absolute flow (Qthermo) in a coronary artery from the infusion rate of saline, temperature of the saline at the tip of the infusion catheter, and distal blood temperature during infusion. The method was tested over a wide range of flow rates in 5 chronically instrumented dogs and in 35 patients referred for physiological assessment of a coronary stenosis or for percutaneous coronary intervention.
Results Thermodilution-derived flow corresponded well with true flow (Q) in all dogs (Qthermo= 0.73 Q + 42 ml/min; R2= 0.72). Reproducibility was excellent (Qthermo,1= 0.96 × Qthermo,2+ 3 ml/min; R2= 0.89). The measurements were independent of infusion rate and sensor position as predicted by theory. In the humans, a good agreement was found between increase of thermodilution-derived volumetric blood flow after percutaneous coronary intervention and increase of fractional flow reserve (R2= 0.84); reproducibility of the measurements was excellent (Qthermo,1= 1.0 Qthermo,2+ 0.9 ml/min, R2= 0.97), and the measurements were independent of infusion rate and sensor position.
Conclusions Using a suitable infusion catheter and a 0.014-inch sensor-tipped guidewire for measurement of coronary pressure and temperature, volumetric blood flow can be directly measured in selective coronary arteries during cardiac catheterization.
Direct volumetric blood flow measurement in selective coronary arteries in conscious humans has not been possible so far. Therefore, either noninvasive methods or surrogate invasive measures have been used for that purpose (1–6). For assessing the physiological significance of an epicardial stenosis, this is not a problem because epicardial coronary disease is most reliably addressed by fractional flow reserve (7,8). For the diagnosis and understanding of microvascular disease, however, absolute blood flow measurement would be a great step forward. This would especially be the case for better understanding of a number of pathophysiological conditions such as heart transplantation, stem cell therapy, and large transmural myocardial infarction. In such conditions, absolute resistance could also be quantified once absolute flow and pressure are known. In addition, from a scientific point of view, directly measuring volumetric coronary blood flow has been a major goal for decades (2–6).
Volumetric blood flow measurement by thermodilution techniques and continuous infusion of saline was proposed by Ganz et al. (2) as early as 1971 but was applied only in the coronary sinus (9,10). Theoretically, absolute blood flow (Qb) was measured from a known infusion rate of saline (Qi) at a known temperature (Ti), blood temperature before infusion (Tb), and the temperature measured downstream after complete mixing of blood and saline (T). However, aside from the fact that such coronary sinus measurement could not differentiate between blood flow from the different coronary arteries and different myocardial territories, the variability was too high to be useful for clinical application and the methodology was soon abandoned (11,12). Because of technical limitations of the equipment at that time, selective coronary artery measurements were never performed, neither in animals nor in humans. In this article, we describe the theoretical background, experimental validation, and clinical testing of a new methodology for selective measurement of coronary blood flow in individual coronary arteries, based on the theory described by Ganz et al. (2) and using a standard 0.014-inch pressure/temperature sensor-tipped guidewire. Together with distal coronary pressure, measured simultaneously by the same guidewire, also the absolute myocardial blood flow, collateral flow, and myocardial resistance can be calculated.
The methodology of blood flow measurement used in this study is based on thermodilution and continuous infusion of saline at room temperature through a 2.8-F infusion catheter, advanced into the coronary artery over a 0.014-inch pressure/temperature sensor-tipped guidewire (Fig. 1).According to theory, during steady-state hyperemia, Qbcan be calculated as follows:where Qirepresents the volumetric infusion rate of the saline, Tbthe temperature of the blood before the start of saline infusion, Tithe temperature of the infusate at the tip of the infusion catheter, and T the temperature at the sensor in the distal coronary artery during steady-state infusion (i.e., the temperature of the blood after complete mixing with the infused saline) (2,10). The correction factor 1.08 is necessary to compensate for the difference in specific heat between saline and blood (11).
When Tbis set to 0 and Tiand T are expressed as the deviation of the respective temperatures from Tb, the equation can be rewritten as:
Validation in Dogs
Five mongrel dogs (weight 26 to 41 kg) were used for this study. Animal handling was performed according to the European directive on laboratory animals (86/609/EEC), and the study protocol was approved by the animal ethics committee of the University of Maastricht. After premedication with Acetadon (CZE Inc., Ede, the Netherlands) 0.1 ml/kg intramuscularly and buprenorphine 0.01 mg/kg intravenously, the dogs were anesthetized with thiopental 15 mg/kg intravenously and ventilated by room air with 1% isoflurane and 0.5 l N2O/min.
A left thoracotomy was performed, and the proximal left circumflex artery was dissected free. A perivascular ring-mounted volumetric flow meter of appropriate size (PS series, Transsonic Inc., Ithaca, New York) was placed around the artery and a circular balloon occluder (IVM, Healdsburg, California) was placed just distal to the flow probe for creating stenosis of variable degree (Fig. 1).
After the equipment was checked for proper functioning, the pericardium and chest were closed and the instrumentation leads were stored in a subcutaneous pocket in the neck of the animal until the time of the study. Long-acting ampicillin was administered 1 h before the operation and repeated every 48 h.
Eight days after instrumentation, each dog was anesthetized again by nicomorphine 10 mg/h intravenously and 1% isoflurane. The subcutaneous pocket was opened, the lead of the flow probe was connected to the appropriate recording equipment (Transsonic 400 series Modular Flowmeter), and the tube of the occluder connected to a 5-ml syringe for creating different steps of coronary stenosis.
Subsequently, cardiac catheterization was performed. A 6-F arterial sheath and a 5-F venous sheath were introduced into the left femoral artery and vein, 5,000 U of heparin were administered, and a 6-F left Judkins guiding catheter was advanced into the ostium of the left coronary artery. Next, a commercially available 0.014-inch pressure/temperature sensor-tipped guidewire (PressureWire 5, Radi Medical Systems, Uppsala, Sweden) was introduced by a Y-connector, advanced through the guiding catheter into the left circumflex artery, and positioned with its sensor approximately 6 cm distal to the flow probe and occluder. This sensor-tipped guidewire measures pressure with an accuracy of 1 mm Hg at a frequency of 600 Hz and temperature with an accuracy of 0.02°C at a frequency of 600 Hz, and can be connected to an appropriate interface (Radi-Analyzer, Uppsala, Sweden) for simultaneous recording of aortic and coronary pressure and coronary temperature (Fig. 2)(4,13).
Thereafter, a specially designed infusion catheter was advanced over the sensor-tipped guidewire until its tip was just proximal to the flow probe. The details of this infusion catheter are described herein. The infusion catheter was connected to a dedicated infusion pump (Angiomat-6000, Liebel, Flasheim, Germany) by way of a second Y-connector, and a maximum of 40 ml saline/min could be infused through this infusion catheter when it was advanced across the guidewire (Fig. 1).
To ensure adequate mixing of blood and saline, a special infusion catheter was designed with an outer diameter of 2.8-F, a tapered tip, an end hole to advance it across a 0.014-inch guidewire, and 4 small side holes in the last 5 mm proximal to its tip (Occam Inc., Eindhoven, the Netherlands). The end hole of this infusion catheter precisely fits the guidewire to prevent saline from being infused through the end hole along the wire. When this infusion catheter is advanced across a guidewire, a maximum of 40 ml/min of saline at room temperature can be infused and is leaving the distal end of the catheter exclusively by the side holes. We have tested this catheter extensively under laboratory circumstances, and we validated in an in vitro model that complete mixing of saline with blood occurs within a distance of 3 cm from the tip at physiological flow rates as encountered in coronary arteries.
In every dog, measurements were performed in 4 series, corresponding with 4 different levels of coronary stenosis: mild stenosis (i.e., balloon occluder not inflated at all), moderate stenosis, severe stenosis, and very severe stenosis. To test reproducibility, all measurements were performed twice with an interval of 3 min. Furthermore, to test the independency of the methodology of the position of the sensor, all measurements were performed at a distance of 6 and 3 cm distal from the tip of the infusion catheter. To validate the independency of the methodology of the infusion rate, all measurements for all of the degrees of stenosis and all sensor positions were also performed using a high and a low infusion rate (8 to 15 ml/min and 15 to 25 ml/min, respectively, depending on the size of the coronary artery).
In this way, a total of 4 × 2 × 2 × 2 = 32 measurements were performed in every dog. During the complete sequence of measurements, maximum hyperemia was induced by continuous administration of adenosine 140 μg/kg/min in the femoral venous sheath, combined with administration of norepinephrine in a low dose, if necessary, to maintain mean blood pressure at a level of 60 to 100 mm Hg. The presence of steady-state maximum hyperemia was confirmed before and at the end of each series of 8 measurements by verifying that after a 20-s occlusion period, no further reactive hyperemia was present (14).
During steady-state hyperemia, the blood temperature in the distal coronary artery (Tb), measured by the pressure/temperature sensor, was set to 0. Thereafter, infusion of saline at room temperature was started at a constant rate (Qi; 8 to 25 ml/min) using the infusion pump. During steady-state continuous infusion of saline, the decrease of temperature of the blood (T) after adequate mixing with the infused saline was measured and recorded for 30 to 60 s (Fig. 2).
Next, the pressure/temperature sensor was pulled back into the infusion catheter and the temperature Tiof the infused saline at the location of the side holes was measured as deviation from Tb. Volumetric blood flow in the respective coronary artery was calculated then as described by Equation 2, and this calculated value of flow was called Qthermo. An example of such a measurement and calculation is presented in Figure 2.
Thereafter, the wire was advanced again to the original position, and after waiting for 3 min, the procedure was repeated for assessing reproducibility. During the procedure, all registrations were continuously displayed on the Radi-Analyzer, using specific software and a display, indicating T and Tias the deviation from the blood temperature as measured immediately before saline infusion and making calculations rather easy as mentioned above. During the complete procedure, aortic pressure (Pa, recorded by the guiding catheter) and distal coronary pressure (Pd, recorded by the sensor) were displayed continuously, as well as fractional flow reserve (FFR), which is defined as Pd/Paat maximum hyperemia (7,15). This sequence of in-duplo measurements was performed at the 4 different stages of stenosis as described above.
Variation of infusion rate
Theoretically, the calculations should be independent of the infusion rate of saline (2,10). Therefore, in all dogs and at every degree of stenosis and at every sensor position, all measurements were performed with 2 different infusion rates (low rate and high rate). The low rate varied between 8 and 15 ml/min, and the high rate between 15 and 25 ml/min, depending on the size of the coronary artery. No infusion rates below 8 ml/min were used to avoid unfavorable signal-to-noise ratios, and no infusion rates above 25 ml/min were used to avoid excessive cooling of the myocardium with possible adverse effects on the conduction system.
Variation of sensor position
Theoretically, the calculations should also be independent of the position of the temperature sensor in relation to the infusion site (2,10). Therefore, in all dogs at every degree of stenosis and at all infusion rates, the measurements were performed with the sensor position at a distance of 3 cm and 6 cm distal to the tip of the infusion catheter (proximal and distal sensor position, respectively). Positions <3 cm from the tip of the infusion catheter were avoided to prevent incomplete mixing, whereas a position too far distally was avoided to prevent loss of indicator by inappropriate heating of saline by the vessel wall or surrounding myocardium.
For all dogs, the relationship between calculated and measured blood flow was evaluated by linear regression. Agreement between the calculated and measured blood flow was assessed by Bland-Altman plots of the relative difference between Qthermoand Q (16).
Also the reproducibility (first vs. second measurement), the influence of different infusion rates of saline (low vs. high rate), and the influence of sensor position (distal vs. proximal) were evaluated by linear regression analysis and Bland-Altman plots of relative differences. All hemodynamic data are mentioned as mean ± standard deviation.
Results of the Animal Study
Baseline hemodynamic characteristics and procedural results
The instrumentation was uneventful and uncomplicated in all dogs, and the cardiac catheterization and measurements after 8 days also could be performed without difficulties in all 5 dogs.
In the first dog, at the location of the coronary occluder, an angiographic stenosis of approximately 50% was visible and fractional flow reserve was 0.55, indicating that already a hemodynamically rather severe stenosis was present at the location of the instrumentation. Therefore, in this first dog only 2 of the 4 planned series of measurements could be performed (severe and very severe stenosis). In all other dogs, the 4 complete series could be performed as planned (mild, moderate, severe, and very severe stenosis).
During all series in all dogs, steady-state maximum hyperemia could be achieved by infusion of adenosine (140 μg/kg/min) combined with a low dose of norepinephrine (0.10 to 0.30 μg/kg/min). Mean arterial pressure, heart rate, and absolute blood flow measured by the flow probe for the different dogs and the different series are presented in Table 1.
Agreement between measured and calculated blood flow
In all dogs, by different degrees of inflation of the perivascular balloon occluder, maximum blood flow could be varied over a wide range (Table 1).
The relationship between blood flow as measured by the perivascular flow probe (Q) and blood flow as calculated from the thermodilution experiments (Qthermo) is presented for all 5 individual dogs in Figure 3.In all dogs except the first, an excellent correlation was found. The agreement between calculated flow and measured flow for all dogs together, as well as the corresponding Bland-Altman diagram, is presented in Figure 4A.
All measurements in all dogs, at all sensor locations and at all infusion rates, were performed twice with an interval of 3 min. The agreement between the first and second measurement is presented in Figure 4B. As can be observed, reproducibility was excellent. For all dogs together, Qthermo,2equaled 0.96 Qthermo,1+ 3 ml/min (R2= 0.89, p <0.001). Also when studying reproducibility independently for the different degrees of stenoses, the different sensor positions, or the different infusion rates, comparably high reproducibility was obtained.
Influence of infusion rate
In all dogs and for all degrees of stenoses and all sensor positions, the in-duplo measurements were performed at a low and high infusion rate. Infusion rate was chosen in such a way that distal coronary blood temperature at steady-state infusion was in the range between 0.5°C to 2.0°C below blood temperature. Our experiments rapidly taught us that in a large, almost normal coronary artery the infusion rate should be between 15 and 25 ml/min, and in a stenotic artery it should be between 8 and 15 ml/min.
In all of our experiments we started with the lower infusion rate and increased this rate by a factor of 2, called low and high infusion rate. In all dogs, a good agreement was found between the calculated blood flow at both different infusion rates (Qthermo,high= 1.0 × Qthermo,low+ 19 ml/min, R2= 0.66, p < 0.01). These results are presented in Figure 4C.
Influence of sensor position
In all dogs, at all degrees of stenosis and all different infusion rates, the in-duplo measurements were performed at locations of 3 and 6 cm distal to the coronary occluder. In all dogs and at all degrees of stenoses and all infusion rates, an excellent agreement was found between calculated blood flow at the 2 different sensor positions (Qthermo,dist= 1.1 × Qthermo,prox− 5 ml/min, R2= 0.92, p < 0.001). These results are shown in Figure 4D.
Testing in Humans
Thirty-five patients referred for elective percutaneous coronary intervention or intracoronary physiological measurements were studied. These patients were selectively chosen from our regular population on the basis of the following criteria. In case of a stenotic artery, there should be a segment of at least 3 cm without major side branches proximal to the index stenosis. In case of contralateral normal coronary artery, a segment with a length of at least 3 cm without major side branches had to be present. The study was approved by the institutional review board, and informed consent was obtained from all patients.
Instrumentation and measurement procedure
A 6-F arterial and a 5-F venous sheath were introduced into 1 femoral artery and vein, respectively. After administration of 5,000 U heparin, a guiding catheter was advanced into the coronary ostium. Intracoronary nitroglycerin 0.2 mg was administered, and reference images were made. Next, the instrumentation was performed as depicted in Figure 1(inset). A standard sensor-tipped pressure/temperature guidewire (PressureWire-5) was advanced into the distal part of the index coronary artery, and FFR was measured during hyperemia, induced by intravenous adenosine 140 μg/kg/min, administered through the venous sheath. Thereafter, the infusion catheter was advanced over the wire into the coronary artery. In case of a stenotic artery, the infusion catheter was placed proximal to the stenosis with the side holes positioned distally from major side branches, if present. In the normal or almost normal coronary arteries, the infusion catheter was placed within a 3-cm-long segment without major side branches. The position of the pressure/temperature sensor was chosen to be 3 to 6 cm distal to the tip of the infusion catheter (Fig. 5).
After instrumentation, hyperemia was induced again, and during steady-state hyperemia, the blood temperature (Tb), measured by the pressure/temperature sensor, was set to 0. Next, saline at room temperature was infused at a constant rate (Qi,10 to 25 ml/min) using a similar infusion pump as in the animal study. During steady-state continuous infusion of saline, the temperature of the blood after adequate mixing with the infused saline (T) was measured and recorded for approximately 30 s. Thereafter, the pressure/temperature sensor was pulled back into the infusion catheter, and the temperature of the infused saline (Ti) at the location of the side holes was measured. Volumetric blood flow in the respective coronary artery was calculated as described above. Next, adenosine was stopped and restarted after 3 min, after which the complete measurement cycle was repeated for assessing reproducibility. During the procedure, all registrations were continuously displayed on the Radi-Analyzer, using specific software and indicating T and Tias a deviation from blood temperature Tbat hyperemia immediately before saline infusion, making calculations rather easy (Figs. 6 and 7).⇓⇓Aortic and coronary pressure were also continuously recorded.
In the 21 patients without significant epicardial stenosis (FFR >0.75), no intervention was performed and measurements were just performed as described. In the other 14 patients with a significant coronary artery stenosis (FFR ≤0.75), stenting was performed and the thermodilution-based flow measurements were repeated after stenting of the epicardial lesion. In these patients, coronary wedge pressure measured by the pressure wire during balloon occlusion of the coronary artery (Pw) also was recorded during a 1-min balloon inflation to enable separate measurement of coronary, myocardial, and collateral fractional flow reserve, as will be explained later. At the end of the procedure, after removing the infusion catheter, angiograms from 2 directions were repeated and also FFR measurements were always repeated. In Figures 6 and 7, examples of temperature tracings and the calculation of blood flow are shown.
In all patients, all measurements were repeated after 3 min to assess reproducibility. In 7 patients, measurements also were performed in a normal or almost normal contralateral artery. Therefore, a total of 42 coronary arteries in 35 patients were studied.
Variation of infusion rate
To determine the effect of a different infusion rate (Qi), in 11 patients the measurements were repeated using a different infusion rate varying from 10 to 25 ml/min. No infusion rates below 10 ml/min were used to avoid an unfavorable signal-to-noise ratio, and infusion rates above 25 ml/min were not used to avoid excessive cooling of the myocardium with possible adverse effects on the conduction system.
Variation of sensor position
To investigate the influence of different sensor positions within the coronary artery, in 10 other patients the measurements were repeated using a different position of the pressure/temperature sensor. Sensor position was varied between 3 and 6 cm distal to the tip of the infusion catheter.
Indirect quantitative validation
Because direct validation of this technique for measuring absolute coronary flow is not possible in a closed-chest human model, indirect validation was performed in those 14 patients undergoing stenting as follows: at first, flow was measured by the thermodilution technique before the intervention and called Qthermo. Next, a stent was placed and Pwwas measured during balloon inflation. From the hyperemic coronary pressure measurement before stenting, during occlusion, and after stenting, coronary fractional flow reserve (FFRcor) can be determined before and after stenting (15,17). In contrast to FFRmyo, which is representative of maximum myocardial flow, FFRcorrepresents maximum coronary artery flow as a percentage of normal maximum flow, and therefore the ratio between FFRcorafter and before stenting is proportional to the increase of maximum coronary blood flow achieved by stenting (15,17). Next, Qthermowas measured after stenting by the new thermodilution technique. The ratio of Qthermoafter and before stenting should also reflect the increase of maximum coronary blood flow achieved by stenting, and therefore should be equal to the ratio of FFRcorafter and before stenting. By comparing these ratios, indirect evidence of the accuracy of the new method could be obtained in patients.
Statistical analysis was performed with Graphpad Prism software (version 2.01, Graphpad Software Inc., San Diego, California) in an identical way as in the animal study. Agreement between the FFRcorratios and Qthermoratios was assessed by linear regression and the use of Bland-Altman plots (16) of the relative difference between both ratios. Also the reproducibility (first vs. second measurement), the influence of a different infusion rate of saline (low vs. high rate), and the influence of sensor position (distal vs. proximal) were evaluated by linear regression analysis and with Bland-Altman plots. Hemodynamic data are mentioned as mean ± standard deviation.
Results of the Study in Humans
Patients and procedural results
The baseline characteristics of the patients are presented in Table 2.As might be clear from the inclusion criteria, the right coronary artery was overrepresented. Of the 35 patients, 14 had a hemodynamic significant stenosis (FFR = 0.67 ± 0.17) in the right coronary artery (n = 10), left circumflex artery (n = 1), and left anterior descending artery (n = 3), respectively. In all of these patients, successful stenting was performed. In all other patients, measurements were performed in the vessel with the hemodynamically insignificant stenosis, and in 7 patients measurements also were performed in a normal-appearing adjacent vessel. In 2 of the patients, early in the study, transient AV conduction abnormalities occurred when distal blood temperature decreased to below 33°C. In all subsequent experiments, therefore, the infusion rate of saline was chosen in such a way that the distal temperature was between 0.5°C and 2.0°C below blood temperature. No further complications occurred in any of the patients. Once the instrumentation was achieved, which lasted approximately 10 min per patient, the time needed to perform thermodilution measurements itself was <3 min per measurement in all patients.
Absolute hyperemic blood flow in the stenotic coronary arteries was 96 ± 38 ml/min and increased to 141 ± 50 ml/min after percutaneous coronary intervention. This corresponded with FFRmyoof 0.67 ± 0.17 and 0.89 ± 0.04, respectively, and an increase of FFRcorof 0.58 ± 0.21 to 0.87 ± 0.05, respectively (Table 2). In those coronary arteries without significant stenosis and not stented on the basis of FFR, absolute blood flow was 141 ± 55 ml/min. In the patients undergoing stenting, follow-up treatment was according to local routine.
Reproducibility was tested in all 42 coronary arteries. The agreement between the first and the second measurement is presented in Figure 8.An excellent reproducibility was obtained (Qthermo,1= 1.0 Qthermo,2+ 0.9 ml/min, R2= 0.97, p < 0.001).
Variation of infusion rate
In 11 arteries, the measurement was performed at 2 different infusion rates (10 and 25 ml/min, distal coronary blood temperature at steady-state infusion between 0.5°C and 2.0°C below blood temperature). If the infusion rate selected at the initial measurement was chosen too low (resulting in a distal temperature during infusion <0.5°C below blood temperature), the infusion rate was increased. In all experiments, we started with the lower infusion rate and increased this rate by a factor of 1.5 to 2. A good agreement was obtained (Qthermo,high= 1.1 Qthermo,low+ 9.0 ml/min, R2= 0.87, p < 0.001). The results of this variation in infusion rate are presented in Figure 8.
Variation of sensor position
In 10 coronary arteries, measurements were repeated using a different position of the pressure/temperature sensor. This position was chosen between 3 and 6 cm distal to the tip from the infusion catheter. If the sensor position was chosen <3 cm from the tip, often undulations in the temperature tracing occurred, most likely caused by incomplete mixing of the saline and blood and making it difficult to interpret the correct value for T. A sensor position more than 6 cm distal to the tip of the infusion catheter was deemed to be inappropriate because previous laboratory testing showed that in such cases, loss of indicator (cold saline) into the wall is not negligible anymore and flow might be overestimated.
The results of measurements at 2 different sensor positions are shown in Figure 8. Again, an excellent agreement was present, and it is evident that the sensor position within this range is of no significant influence on the results of the measurements (Qthermo,dist= 0.99 Qthermo,prox+ 3 ml/min, R2= 0.94, p < 0.001).
Indirect quantitative validation
In 14 patients, the in-duplo measurements were performed both before and after stenting of a coronary artery stenosis, as described in the Methods section. Flow, directly measured by thermodilution before stenting (Qthermo), was compared with its value after stenting, and the ratio between both values was compared with the corresponding ratio of FFRcorbefore and after stenting. These values should be equal in theory. A good agreement was found between both ratios as shown in Figure 8, corroborating the validity of our methodology (R2= 0.84, p < 0.01).
The novel technique described in these studies is the first method for measuring direct volumetric blood flow in selective coronary arteries during cardiac catheterization. The methodology is feasible, accurate, and reproducible. In contrast to traditional coronary sinus thermodilution technique, this methodology makes it possible to selectively determine blood flow in different coronary arteries. Its variability is less, instrumentation is less complicated, and measurements can be performed easily and quickly with standard equipment during coronary angiography and interventions using the pressure/temperature guidewire, the corresponding interface (Radi-Analyzer), and a suitable infusion catheter.
Aside from the selectivity of this method, most likely it is the complete mixing of blood and saline that explains its superiority above traditional coronary sinus thermodilution (2,11,12). The better mixing is the result of the pulsatile motion of the coronary artery, the anterograde direction of infusion, and the design of the infusion catheter.
First, if saline is infused from the tip of a traditional infusion catheter and streams down retrogradely, as is the case in the coronary sinus, a variable amount of the indicator remains entangled in the catheter itself, resulting in incomplete mixing. In contrast, in a coronary artery, flow is directed away from the catheter and therefore that problem is less pronounced. Secondly, we used an infusion catheter with 4 small side holes, ensuring adequate mixing and designed in such a way that the end hole is obstructed by the guidewire to prevent saline from being infused through that end hole and getting entangled with the wire. The 4 symmetrically positioned side holes enhance complete mixing of blood and saline. Thirdly, the pulsatile motion of blood flow in the coronary artery is much more pronounced compared with a vein, thereby favoring adequate mixing.
Our results also showed that the exact position of the sensor within the coronary artery is not paramount, indicating that within certain limits, loss of the cold indicator through the arterial wall is negligible. The positions at 3 and 6 cm were chosen because we had learned from laboratory experiments that at a position <3 cm from the tip of the infusion catheter, mixing might be incomplete, yet at a location too far from the tip of the infusion catheter, loss of indicator might occur because of heating of the saline by the vessel wall or surrounding myocardium. Also the amount of infused indicator can be varied within certain limits without affecting the accuracy of the measurements, which is in accordance with theory (2,10). In our study, the amount of the infused indicator was kept between 10 and 25 ml/min in humans, depending on the size of the coronary artery. Too low an infusion rate affects the signal-to-noise ratio unfavorably, whereas too high an infusion rate results in excessive cooling of the myocardium, which can lead to conduction disturbances.
Being able to determine absolute blood flow in selective coronary arteries quantitatively in milliliters per minute in a fairly simple and straightforward way during cardiac catheterization has not been possible so far and has several advantages.
Not only is coronary flow in itself measured, but the guidewire also measures temperature, distal coronary pressure, and fractional flow reserve. Such values of flow can be directly related to its normal maximum value, and therefore it can better be interpreted. Moreover, by measuring pressure and flow, the resistance of the coronary artery can also be calculated quantitatively from one single measurement.
Furthermore, during percutaneous coronary intervention, Pwat balloon occlusion can be measured by the same guidewire and FFRcorcan be calculated as described in the Methods section and used for the indirect testing of this method. Because FFRmyoand FFRcorrepresent the mutual relationship between maximum myocardial and coronary flow, measurement of absolute coronary flow also enables calculation of absolute myocardial blood flow in that situation and thereby also absolute collateral flow as the difference of the previous two (15,17).
Finally, because distal coronary pressure is measured simultaneously by the same sensor, myocardial resistance of a specific myocardial territory can be calculated: myocardial resistance equals myocardial perfusion pressure (measured by the sensor) divided by myocardial blood flow (13,18,19). Quantification of myocardial resistance makes it possible to selectively study the microcirculation, whereas the fractional flow reserve, simultaneously measured by the same equipment, selectively interrogates the epicardial artery. Further studies in particular groups of patients in whom microcirculatory function is affected will be possible in this way, such as in patients after myocardial stem cell therapy, myocardial infarction, or heart transplantation. Recognizing that absolute resistance is dependant on the size of the studied perfusion area, in these patients myocardial resistance of a particular territory can be followed up over time in those conditions. Therefore, we believe that this novel methodology for direct volumetric coronary flow measurement can be a valuable tool in clinical research on the coronary circulation.
Although absolute coronary blood flow has been considered the ultimate goal of coronary physiologists for decades, volumetric flow assessment in itself has several limitations for practical purposes. First, absolute coronary blood flow cannot be interpreted without knowledge of the size of the perfused myocardial territory (3,19,20).
Secondly, it is dependent on hemodynamic variations in blood pressure, heart rate, and contractility (21,22). Therefore, one specific value of blood flow is not so easy to interpret. However, because fractional flow reserve can be measured simultaneously and relates a particular value of flow to its theoretical normal maximum value achievable in the respective coronary artery under similar hemodynamic conditions, interpretation of individual values of flow is made easy (14,16).
Thirdly, it is not coronary but myocardial blood flow that is most important for a patient, preferably calculated during maximum hyperemia. In normal coronary arteries, it can be hypothesized that myocardial blood flow equals coronary blood flow, but in the presence of a stenosis, the collateral component plays an increasing role with increasing stenosis severity (13,17). Fortunately, if stenting is performed in such a situation, coronary wedge pressure can be measured and myocardial blood flow (and collateral flow) are directly derived from coronary blood flow as discussed previously.
Furthermore, the instrumentation of the coronary artery is somewhat more complicated than in regular diagnostic or interventional intracoronary procedures. The pressure/temperature guidewire must be introduced first, after which the infusion catheter should be introduced over the wire using a second Y-connector connected to the infusion pump (Fig. 1). In our studies, these extra steps required only approximately 10 min. Once the instrumentation was accomplished, the measurements could be performed quickly and easily. Nevertheless, the need for a second Y-connector and the infusion pump will most likely limit the use of this method to investigational studies and specific groups of patients.
Another technical issue is the infusion catheter itself, which was specifically designed for this study to ensure complete mixing of blood and saline, which is paramount for this technique. Theoretically, if the technique is used in patients with a very severe stenosis with decreased resting coronary blood flow, blood flow can be so slow that indicator (cold) will be lost through the arterial wall, resulting in overestimation of true flow and making the methodology unreliable. In our series, however, this problem was not observed despite the presence of severe lesions with an FFR as low as 0.43. Therefore, for clinical purposes, this limitation does not seem to be relevant.
Finally, to ensure that blood flow was kept constant during the measurement itself, we only measured during maximum hyperemia. This is not a true limitation because maximum achievable blood flow is the most important clinical parameter to characterize the coronary circulation and the severity of an epicardial coronary stenosis (7,8,14,16).
We described a new technique for direct volumetric measurement of coronary blood flow in selective coronary arteries during cardiac catheterization in animals and in conscious humans, using a thermodilution technique with continuous infusion of saline at room temperature and a standard sensor-tipped pressure/temperature guidewire. This methodology is fairly simple to perform, accurate, and very reproducible. Together with distal coronary pressure, measured by the same guidewire, absolute resistance of the coronary artery and the coronary microcirculation can also be calculated. Therefore, this methodology constitutes the first direct volumetric blood flow measurement in select human coronary arteries and will facilitate pathophysiological studies of the coronary circulation.
The authors thank the technicians and staff of the Central Animal Laboratory of the University of Maastricht for their hospitality and support in performing the animal experiments, the nurses and technicians of the catheterization laboratory of the Catharina Hospital, and Ingrid Aarts for her assistance in preparing the manuscript.
↵1 Drs. Aarnoudse and van’t Veer contributed equally to this work.
Supported by grant EPG.54.54 of STW (Foundation of Applied Scientific Research) of the Dutch Ministry of Economic Affairs, by Radi Medical Systems, Uppsala, Sweden, and by the Friends of the Heart Foundation (Stichting Vrienden van het Hart), Eindhoven, the Netherlands.
- Abbreviations and Acronyms
- fractional flow reserve
- coronary fractional flow reserve
- myocardial fractional flow reserve
- aortic pressure (mm Hg) measured by the guiding catheter
- distal coronary pressure (mm Hg) measured by the pressure wire
- coronary wedge pressure (mm Hg) measured by the pressure wire during balloon occlusion of the coronary artery
- absolute coronary blood flow (ml/min) measured by the perivascular flow probe
- theoretical value of absolute coronary blood flow during saline infusion
- volumetric infusion rate of saline (ml/min)
- volumetric coronary blood flow (ml/min) calculated by thermodilution
- temperature of blood (°C) in the coronary artery at steady-state saline infusion
- temperature of blood (°C) in the coronary artery before start of saline infusion
- temperature of the infused saline (°C) when entering the coronary artery at the tip of the infusion catheter
- Received February 13, 2007.
- Revision received August 21, 2007.
- Accepted August 28, 2007.
- American College of Cardiology Foundation
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