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TRANSLATIONAL PHYSIOLOGY
1Department of Cardiology; and 2Department of Physiology, Institute for Cardiovascular Research-Vrije Universiteit; and 3Department of Clinical Epidemiology and Biostatistics, VU University Medical Center, Amsterdam, The Netherlands
Submitted 6 January 2006 ; accepted in final form 11 August 2006
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ABSTRACT |
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 TOP ABSTRACT METHODSRESULTSDISCUSSIONREFERENCES |
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coronary disease; physiology; catheterization; coronary blood flow
The combination of both flow velocity and pressure measurements and, more specifically, the diastolic flow velocity-pressure gradient (v-dp) relation gives a comprehensive description of the coronary stenosis severity as has been shown in animal experiments by Gould (7). Recently, we reported on the feasibility and reproducibility of the v-dp relation in humans and found distinct v-dp relations in normal arteries versus intermediate and severe coronary stenoses (16).
We propose a new index, the dpv50, which is derived from the v-dp relation. dpv50 is the instantaneous pressure gradient at a middiastolic coronary flow velocity of 50 cm/s.
The aim of the present study is to compare the diagnostic performance of the dpv50 with the CFVR and FFR in the assessment of the coronary stenosis severity.
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METHODS |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONREFERENCES |
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Myocardial perfusion scintigraphy. SPECT was performed according to a 2-day stress/rest protocol. Exercise or adenosine was used for the stress images. Technetium-99m-labeled sestamibi was injected at maximal exercise or after intravenous infusion of adenosine (0.14 mg·kg–1·min–1). SPECT was performed by using a two-headed gamma camera equipped with low-energy high-resolution collimators. Acquisition was performed using a 360-degree circular orbit. The scintigraphic images were analyzed using a 13-segment model (24). Stress and rest segments were semiquantitatively scored as normal (grade 0) or having a mild, moderate, or severe (grade 3) perfusion defect. Perfusion defects were allocated to the territory of a coronary artery. Defects located in the anterior and anteroseptal region were allocated to the left anterior descending coronary artery (LAD); defects in the posterolateral wall were allocated to the left circumflex coronary artery (LCx) and inferior and basal inferoseptal defects were allocated to the right coronary artery (RCA). Apical defects were considered to be located in the LAD region unless the defect extended to the posterolateral (LCx) or inferior (RCA) wall. Reversible perfusion defects were present when the rest perfusion score improved one grade or more and were considered as positive for the presence of ischemia. Segments with irreversible perfusion defects or normal perfusion were considered negative for the presence of ischemia. The technetium-99m-methoxyisobutylisonitrile (MIBI) scintigrams were scored by two experienced cardiologists; in case of disagreement, a majority decision was achieved by a third cardiologist.
Dobutamine stress echocardiography. An intravenous infusion of dobutamine was started at a rate of 10 µg·kg–1·min–1 and was increased by 10 µg·kg–1·min–1 every 3 min until either wall motion abnormalities were observed or a maximal rate of 40 µg·kg–1·min–1 was reached. In patients who did not reach 90% of their age-adjusted maximal heart rate and who had no objective signs of ischemia, 0.25 mg of atropine was given every minute up to a maximum of 1.0 mg while the dobutamine infusion was continued. End points for stopping the infusion were the same as mentioned in the guidelines (23). Two-dimensional echocardiography was performed obtaining parasternal long- and short-axis views and apical four- and two-chamber views. Imaging was performed throughout the study and during recovery until resolution of new wall motion abnormalities. On-line digital images in quadscreen format were analyzed for the presence, extent, severity, and location of segmental wall motion abnormalities. Myocardial contractile function was graded as normal, hypokinetic, akinetic, or dyskinetic in each segment. An echocardiographic stress test was considered positive when new or worsening stress-induced wall motion abnormalities were observed. The standard algorithm was used to assign ventricular segments to coronary territories: LAD (basal and midanteroseptal segments; basal, mid, and apical anterior segments; mid and apical septal and apical lateral segments); LCx (basal and midlateral segments; basal and midposterior segments); and RCA (basal, mid, and apical inferior segments and basal septal segments) (6). The dobutamine stress echocardiograms were scored by two experienced cardiologists; in case of disagreement, a majority decision was achieved by a third cardiologist.
Cardiac catheterization procedure. All patients received 5,000 IU heparin at the beginning of the procedure. After intracoronary administration of 0.2 mg nitroglycerine, coronary angiography of the left and right coronary artery was performed according to standard procedures. At least two, preferably orthogonal, views were obtained displaying each coronary lesion with minimal foreshortening and no vessel overlap. Quantitative coronary angiography (QCA) was performed off-line using the CAAS II system (CAAS System; Pie Medical Data, Maastricht, The Netherlands). Percentage diameter stenosis and minimal lumen diameter were measured in a standard manner.
FFR, CFVR, and simultaneous flow velocity and pressure measurements. First, the sensor of the pressure wire (Wavewire, Volcano Therapeutics or Radi pressure wire, Radi Medical Systems, Uppsala, Sweden) was advanced close to the tip of the guiding catheter. If a pressure difference was found, the measurement of the pressure wire was electronically adjusted to obtain equalization of pressures. The pressure wire was then advanced distal to the coronary stenosis. The FFR was calculated as the ratio of Pd and Pprox at maximal hyperemia, induced by intracoronary administration of 40 µg adenosine. Subsequently, the Doppler guide wire (Flowire, Volcano Therapeutics) was advanced distal to the stenosis with the Doppler crystal near the sensor of the pressure wire. The Doppler wire was manipulated until an optimal and stable flow velocity signal was obtained. Hyperemia was induced again. Finally, the pressure wire was withdrawn and the CFVR was measured with the Doppler wire as the ratio of mean maximal hyperemic to baseline flow velocity, averaged over two heartbeats.
Assessment of the v-dp relation and dpv50. The pressure measured at the tip of the guiding catheter (aortic pressure), the distal coronary pressure measured by the pressure wire, the instantaneous coronary flow velocity, and the ECG were recorded on a data acquisition unit (Cardiodynamics, Zoetermeer, The Netherlands) connected to a personal computer. Data acquisition (sample frequency 100 Hz) was started before administration of adenosine to disappearance of the hyperemic response (Fig. 1).
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p = 0 + kv + Sv2, where p is the pressure gradient (mmHg), v is the coronary flow velocity (cm/s), k is (mmHg·s/cm) the coefficient of pressure loss due to viscous friction, and S (mmHg·s2/cm2) is the coefficient of pressure loss due to flow separation or localized turbulence (26). The k and S coefficients were determined by using the least squares curve-fitting algorithm in the SPSS 9.0 for Windows software package (SPSS, Arlington, VA). In the search for the single instantaneous flow velocity value yielding the highest diagnostic accuracy for all patients and all measurements, we assessed the flow velocities from 10 to 150 cm/s, with incremental steps of 10 cm/s. The highest accuracy was found at a flow velocity of 50 cm/s. Third, based on the k and S coefficients, the dpv50 was calculated. An example is given in Fig. 2.
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dpv50 and submaximal hyperemia. To investigate the influence of submaximal hyperemia on the assessment of the dpv50, the following procedure was undertaken. As described in the section on the assessment of the dpv50, all middiastolic flow velocity and corresponding pressure gradient data were plotted. We determined the range of instantaneous flow velocity values for each individual measurement, with the lowest flow velocity value representing 0% and the highest value representing 100% of the range. Then, all data with a flow velocity higher than 75% of the maximal flow velocity were disregarded. The dpv50 was again determined after regression analysis of the remaining data.
Statistical analysis. Continuous variables are presented as mean value (SD). Sensitivity was defined as the number of true positive tests divided by the total number of myocardial territories with ischemia by noninvasive stress testing. Specificity was defined as the number of true negative tests divided by the total number of myocardial territories without ischemia by noninvasive stress testing. Accuracy was defined as the total number of true positive and true negative tests divided by the total number of myocardial territories. The McNemar test was used to compare the sensitivity, specificity, and accuracy of FFR, CFVR, and dpv50. A value of P < 0.05 was considered statistically significant.
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RESULTS |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONREFERENCES |
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The quantitative coronary angiographic and hemodynamic data are displayed in Table 2. Results are given for all measurements; furthermore, a distinction is made between stenoses with corresponding abnormal and normal noninvasive stress tests. The coronary stenoses with abnormal stress tests had a smaller minimal luminal diameter and higher percentage diameter stenosis, a lower FFR and CFVR, and a higher dpv50. All these differences were statistically significant.
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The relation between FFR or CFVR and dpv50 for all measurements is graphically represented in Fig. 3, A and B. The cutoff values for the three indexes are displayed. The data in the lower right and upper left quadrant represent concordant data. In the upper right quadrant of Fig. 3A, discordant measurements (normal FFR and abnormal dpv50) can be found; there were no measurements with an abnormal FFR and normal dpv50 (lower left quadrant). Overall, concordance between dpv50 and FFR was found in 90% of all measurements. From Fig. 3B, it can be appreciated there were more discordant results between CFVR and dpv50 (upper right and lower left quadrant). For the dpv50 and CFVR, concordant results were found in 76% of all measurements.
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DISCUSSION |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONREFERENCES |
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Diastolic v-dp and dpv50 to assess the hemodynamic effect of coronary stenoses.
Fluid dynamics of coronary artery stenoses are complex (17). The pioneering work of Gould et al. (7–9) and Young et al. (27) has demonstrated that the relation between pressure gradient and flow velocity in stenoses can be described by P = 0 + kv + Sv2. We have previously shown the feasibility to measure the diastolic coronary flow velocity-pressure gradient relation in humans in a reproducible way (16).
To compare the v-dp relation of a stenosis with the FFR or CFVR, it has to be described by a single index. For this purpose the use of the k and S coefficients, which are both required to adequately describe the nonlinear v-dp relation, is not adequate. Therefore, we defined a new index, which is directly derived from the v-dp relation. In the search for the single instantaneous flow velocity value yielding the highest diagnostic accuracy for all patients and all measurements, we assessed the flow velocities from 10 to 150 cm/s, with incremental steps of 10 cm/s. From 30 to 80 cm/s, we found an identical sensitivity of 95%. The specificity ranged from 93% to 95% for the flow velocities from 30 to 60 cm/s. This indicates that within the flow velocity range of 30–60 cm/s, the corresponding instantaneous pressure gradient most reliably characterizes the hemodynamic significance of a stenosis. Within this range, the highest accuracy was found at a flow velocity of 50 cm/s; therefore this value was chosen to use in the present study.
The dpv50 of a coronary stenosis is calculated after regression analysis by using the k and S coefficients. This has three advantages. First, as can be seen in Fig. 2, we found scattering of the data due to noise in the flow velocity (despite a sharply defined flow velocity contour) and pressure data. With the use of all data instead of the average data only with a flow velocity of 50 cm/s, a more reliable assessment of the dpv50 is obtained. Second, in 43 of 124 measurements, a peak instantaneous middiastolic coronary flow velocity lower than 50 cm/s was recorded; 13 of these stenoses did not cause ischemia. In these measurements, the dpv50 could only be assessed after regression analysis and extrapolation. Therefore, in most hemodynamic insignificant stenoses and in some hemodynamic significant stenoses, the dpv50 is a physiological measure. Third, it can be postulated that missing the data at the highest flow velocities will not dramatically alter the course of the regression line and that maximal hyperemia thus is not a prerequisite to reliably assess the dpv50. To test the latter, we omitted for each stenosis the data in the upper quartile of the flow velocities and then reassessed the dpv50. A difference of 3% was found between the dpv50 based on the complete and incomplete data, resulting in one measurement to be reclassified from true negative to false positive. In contrast, assessment of CFVR and FFR by definition requires achievement of maximal hyperemia. In this study, we always gave 40 µg adenosine ic; it has been shown that this dose evokes an equipotent hyperemic response as intravenous adenosine (4). In the literature it has been suggested that for technical and pharmacokinetic reasons, intracoronary administration of adenosine may induce only submaximal hyperemia, resulting in underestimation of a coronary stenosis when FFR and overestimation when CFVR is used (4, 14, 19, 21). Furthermore, it remains uncertain whether adenosine can elicit maximal hyperemia. It has been shown that the addition of 
1- and 2-adrenergic blocking agents to adenosine induces a stronger hyperemic stimulus after PCI, in patients with coronary atherosclerosis and in normal humans (10–12, 15). Coronary occlusion also can induce a stronger hyperemic response than adenosine (13).
Spatial resolution of dpv50. In this study we took care to determine the dpv50 distal to the most distal stenosis visible at angiography. However, flow velocity and coronary pressure can be measured simultaneously at any location in a coronary artery. If flow and pressure data are obtained at the same spot, the dpv50 gives information on the epicardial resistance from the coronary ostium to the location where measurements are obtained. By the virtue not to be dependent on maximal hyperemia, the dpv50 of a coronary segment thus can be assessed irrespective of any additional epicardial or microcirculatory resistance distal to the point of measurement. Therefore, in case of diffuse atherosclerosis or serial epicardial stenoses, by determining the dpv50 at different spots, the location with the largest resistance can be identified.
Study limitations. In six measurements it was not possible to obtain optimal Doppler flow velocity recordings, and in these cases no reliable v-dp relation could be computed. The cutoff value of the dpv50 in this study is derived from measurements with two wires through a coronary stenosis, probably increasing its severity. Very recently, a single 0.014" wire (ComboWire, Volcano Therapeutics, Rancho Cordova, CA) allowing combined flow velocity and pressure measurements has become available for clinical use. The diagnostic performance of the dpv50 was assessed based on the cutoff value established in the same study population; this might lead to a bias toward better test results. To properly determine the accuracy of the dpv50 in the assessment of coronary stenoses, a prospective study is needed to establish the predictive value of this cutoff value. It can be assumed on theoretical grounds that the v-dp relation and dpv50 are independent of hemodynamic conditions (heart rate, aortic pressure, and contractility) (3). This has not been thoroughly evaluated yet. However, in patients with atrial fibrillation we found that the data of each cardiac cycle fitted the same v-dp curve, despite widely varying cardiac cycle lengths and aortic pressure. To further investigate the effect of heart rate and changes of preload on the dpv50, measurements at different pacing rates should be done. Measurements in a poststenotic aneurysmatic part of a coronary artery modify the v-dp relation. Therefore, we always have measured in the distal, normally sized part of the coronary artery. Coronary arteries with a very diffuse, ectatic appearance were excluded from this study. At the present time, computation of the dpv50 has to be done off-line.
In conclusion, we found a very high sensitivity and specificity for the dpv50 in the assessment of the hemodynamic significance of coronary stenoses. In contrast to the CFVR and FFR, calculation of the dpv50 is not critically dependent on the induction of maximal hyperemia.
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ACKNOWLEDGMENTS |
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FOOTNOTES |
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The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
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REFERENCES |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONREFERENCES |
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1-adrenoceptor blockade on resting and hyperemic myocardial blood flow in normal humans. Am J Physiol Heart Circ Physiol 271: H1302–H1306, 1996.This article has been cited by other articles:
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  K. L. Gould Physiological severity of coronary artery stenosis Am J Physiol Heart Circ Physiol, December 1, 2006; 291(6): H2583 - H2585. [Full Text] [PDF]
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