- Email: [email protected]
Intravascular ultrasound criteria for the assessment of the functional significance of intermediate coronary artery stenoses and comparison with fractional flow reserve
Intravascular Ultrasound Criteria for the Assessment of the Functional Significance of Intermediate Coronary Artery Stenoses and Comparison With Fractional Flow Reserve Carlo Briguori, MD, PhD, Angelo Anzuini, MD, Flavio Airoldi, MD, Giorgio Gimelli, Takahiro Nishida, MD, Milena Adamian, MD, Nicola Corvaja, MD, Carlo Di Mario, MD, PhD, and Antonio Colombo, MD
MD,
The functional significance of coronary artery stenoses of intermediate severity is important in determining strategy in patient care. Intravascular ultrasound (IVUS) is often used to evaluate coronary stenosis severity. However, at present, few data are available about the role IVUS in the assessment of functional significance of intermediate lesions. Myocardial fractional flow reserve (FFR) <0.75 is a reliable index of a functionally severe coronary stenosis. In 53 lesions we assessed (1) by pressure wire: FFR (index of functional significance), and (2) by IVUS: minimal lumen cross-sectional area (MLA, square millimeters), minimal lumen diameter (MLD, millimeters), lesion length (millimeters), and percent area stenosis at the lesion site. By regression analysis, percent area stenosis and lesion length had a significant inverse correlation with FFR (r ⴝ ⴚ0.58, p <0.001, r ⴝ ⴚ0.41, p <0.004, respectively). MLD and MLA showed a sig-
nificant positive relation with FFR (r ⴝ 0.51, p <0.001, r ⴝ 0.41, p <0.004, respectively). By using a receiver operating characteristic (ROC) curve, we identified a percent area stenosis >70% (sensitivity 100%, specificity 68%), a MLD <1.8 mm (sensitivity 100%, specificity 66%), a MLA <4.0 mm2 (sensitivity 92%, specificity 56%), and a lesion length of >10 mm (sensitivity 41%, specificity 80%) to be the best cut-off values to fit with a FFR <0.75. The combined evaluation of both percent area stenosis and MLD made the IVUS examination more specific (sensitivity 100%, specificity 76%). In 53 intermediate coronary lesions found by angiography, IVUS area stenosis >70%, MLD <1.8 mm, MLA <4.0 mm2, and lesion length >10 mm reliably identified functionally critical intermediate coronary stenoses. 䊚2001 by Excerpta Medica, Inc. (Am J Cardiol 2001;87:136 –141)
linical decision making in patients with intermediate coronary stenoses is still challenging. IntraC vascular ultrasound (IVUS) examination and/or func-
are available on the “functional” significance of the IVUS indexes (i.e., MLD, MLA, percent area stenosis, and lesion length) of coronary lesion severity.8,9 To better clarify the relation between FFR and IVUS indexes of lesion severity, these parameters were measured in angiographically intermediate coronary lesions.
1
tional assessment of coronary stenosis (by pressure or Doppler measurements) have been used to define the severity of such lesions.1– 4 Recent data support the concept that deferring lesions of intermediate severity and a fractional flow reserve (FFR) ⱖ0.75 has good clinical follow-up.5,6 Furthermore, Abizaid et al7 found a low event rate (2% chance of death or myocardial infarction) at an average follow-up of 13 months after IVUS-guided deferred interventions (minimal lumen cross-sectional area [MLA] ⱖ4.0 mm2 and/or minimal lumen diameter [MLD] ⱖ2.0 mm) in patients with de novo intermediate native artery lesions. Therefore, these 2 methods (IVUS and FFR) seem to be complementary in the evaluation of lesions of intermediate severity. At present, little data From the EMO Centro Cuore Columbus, and San Raffaele Hospital, Milan, Italy. Dr. Briguori was supported in part by a Fellowship Grant from the Italian Society of Cardiology, Rome, Italy. Manuscript received June 13, 2000; revised manuscript received and accepted July 27, 2000. Address for reprints: Antonio Colombo, MD, EMO Centro Cuore Columbus, Via M. Buonarroti, 48, I-20145, Milan, Italy. E-mail: [email protected].
136
©2001 by Excerpta Medica, Inc. All rights reserved. The American Journal of Cardiology Vol. 87 January 15, 2001
METHODS
Study population: The study consisted on 43 consecutive patients scheduled for routine coronary angiography who had de novo coronary lesions of intermediate severity (e.g., 40% to 70% diameter stenosis). All patients signed informed consent before entry into the study. Angiographic analysis: Patients received intracoronary isosorbide dinitrate (0.1 to 0.3 mg) before initial and final angiograms to achieve maximal vasodilation. Angiographic measurements were performed with an automated computer-based system by experienced angiographers not involved in the procedure. Image calibration was performed with a contrast-filled catheter. The external diameter of the catheter was used as the calibration standard. Coronary end-diastolic frames from matched views obtained on angiograms were analyzed with an automated contour detection system 0002-9149/01/$–see front matter PII S0002-9149(00)01304-7
TABLE 1 Angiographic and Intravascular Ultrasound Characteristics of 53 Lesions Coronary artery Left anterior descending Left circumflex Right Diagonal Obtuse marginal Lesion site Ostial Proximal Midvessel Distal Lesion types* A B1 B2 C Quantitative angiography Vessel size (mm) MLD (mm) Lesion length (mm) Percent stenosis (%) IVUS measurements Reference site Vessel cross-sectional area (mm2) Lumen cross-sectional area (mm2) Plaque-media cross-sectional area (mm2) Lesion site Vessel cross-sectional area (mm2) MLA (mm2) MLD (mm) Length (mm) Plaque-media cross-sectional area (mm2) Area stenosis (%) Remodeling
32 5 14 1 1
(60.4%) (9.4%) (26.4%) (1.9%) (1.9%)
4 16 28 5
(7.5%) (30.3%) (52.8%) (9.4%)
1 24 24 4
(1.9%) (45.3%) (45.3%) (7.5%)
3.08 1.69 8.5 52
⫾ ⫾ ⫾ ⫾
0.73 0.77 6.4 11
13.0 ⫾ 6.1 7.8 ⫾ 4.4 7.2 ⫾ 3.5 12.0 3.9 1.9 9.0 8.3
⫾ ⫾ ⫾ ⫾ ⫾
4.6 2.5 1.0 7.0 4.1
65 ⫾ 18 1.07 ⫾ 0.65
*Modified American Heart Association/American College of Cardiology criteria.
applying a minimum cost algorithm to the brightness profile of all scan lines perpendicular to the vessel center line (QCA-CMS version 3.0, MEDIS, Leiden, The Netherlands). Interpolated reference lumen diameter, lesion MLD, and lesion length were measured. Percent diameter stenosis was calculated as the reference lumen diameter minus the MLD divided by the reference lumen diameter. Lesions were characterized according to the modified American College of Cardiology/American Heart Association classification.10 Pressure measurements and calculation of FFR: An 8Fr sheath was inserted in the femoral artery, and an 8Fr guiding catheter was used to cannulate the coronary ostium. If damping of pressure by the guiding catheter occurred, the guiding catheter was pulled back during the measurements. To measure distal coronary pressure, a 0.014-in high-fidelity pressure monitoring wire (Wave Wire, Cardiometrics, Inc. Mountain View, California) was used. The sensor (a piezo resistive pressure sensor) was located just proximal to the junction between the radiopaque distal tip and the nonradiopaque part of the wire. The proximal end of the wire was disconnectable and was plugged into a special connector, which also helped rotate the wire. The signal was transmitted to a small interface, which in turn was connected to an ordinary pressure moni-
TABLE 2 Correlation Coefficients Between FFR and Quantitative Coronary Angiography and Intravascular Ultrasound (IVUS) Parameters of the Coronary Stenosis Severity Parameter Quantitative coronary angiography indexes Percent diameter stenosis MLD Lesion length Intravascular ultrasound indexes MLD MLA Percent area stenosis Lesion length Plaque-media cross-sectional area Remodeling
Correlation Coefficient
p Value
⫺0.56 0.55 ⫺0.47
⬍0.001 ⬍0.001 0.006
0.51 0.41 ⫺0.58 ⫺0.41 ⫺0.13 ⫺0.16
⬍0.001 ⬍0.004 ⬍0.001 ⬍0.004 0.40 0.40
toring system in the cardiac catheterization laboratory. The pressure monitoring guidewire was first zeroed and advanced up to the tip of the guiding catheter, where mean and phasic pressures were recorded simultaneously to verify equality of pressure (i.e., normalization). Thereafter, the pressure monitoring guidewire was advanced through the stenotic segment. Mean aortic pressure (Pa, measured by the guiding catheter) and mean distal coronary pressure (Pd, measured by the microsensor tip manometer wire) were recorded at rest and during maximal hyperemia induced by adenosine (18 g in the left and 12 g in the right coronary arteries). Pressure tracing were visualized on the monitor and also recorded on paper (50 mm/s) for further analysis. FFR was calculated by the following equation: FFR ⫽ Pd/Pa where Pa and Pd were recorded simultaneously at maximum vasodilation.2,3 Intravascular ultrasound examination: IVUS examination was performed with 3.2Fr monorail system with a 30-MHz transducer-tipped catheter (Ultracross, Cardiovascular Imaging System, CVIS, Boston Scientific CO., Boston, Massachusetts). IVUS imaging was performed during the motorized pullback (0.5 mm/s) of the imaging catheter. The IVUS images were recorded on a 0.5-in SuperVHS videotape for subsequent review and quantitative analysis. The lesion site selected for analysis was the image slice with the smallest lumen cross-sectional area. The external elastic membrane cross-sectional area was defined as the area encompassed by the ultrasonic media and/or adventitia border, by tracing the leading edge of the adventitia. Lumen measurements were made at the inner border of the echo-dense plaque.11 Because media thickness cannot be measured accurately, plaquemedia (P&M) cross-sectional area (external elastic membrane cross-sectional area minus lumen crosssectional areas) was used as a measure of atherosclerotic plaque. The proximal and distal reference segments had the most normal-appearing cross sections within 10 mm proximal or distal to the lesion but before any side branch. The following parameters were measured at the lesion site: (1) MLD (millime-
CORONARY ARTERY DISEASE/IVUS AND FRACTIONAL FLOW RESERVE
137
FIGURE 1. Plot showing relation between FFR and the percent area stenosis assessed by IVUS. Inner lines around the fitted line, the 95% confidence limits for the fitted line; outer lines, the 95% confidence limits for a single observation. A percent area stenosis >70% had 100% sensitivity and 68% specificity in identifying abnormal (<0.75) and normal (>0.75) FFR, respectively.
determined by dividing the targetlesion external elastic membrane cross-sectional area by the average of the proximal and distal reference-segment external elastic membrane cross-sectional area to create a remodeling index. Positive remodeling was defined as a remodeling index ⬎1.0, and intermediate and/or negative remodeling as a remodeling index ⱕ1.0.13 All measurements were performed by a single individual blinded to the FFR results. Statistical analysis: Differences between groups were assessed by chi-square analysis for categorical variables and paired and unpaired Student’s t test for continuous variables. The FFR was calculated 3 times and coefficient of variability was calculated as the percentage of the ratio of the SD to mean. Univariate linear regression analysis was used to define correlation coefficients between FFR and IVUS indexes of lesion severity. Receiver operating characteristic (ROC) curve analysis was performed to establish the value of IVUS indexes (i.e., MLD, MLA, lesion length, and area percent stenosis) that were most predictive of FFR ⬍0.75. Stepwise multiple linear regression analysis was performed to identify the best IVUS parameter predictive of FFR value. Values of p ⬍0.05 were considered significant. Data were analyzed with SPSS 10 for Windows (SPSS Institute, Chicago, Illinois).
RESULTS Thirty-seven of the 43 patients were men (86.1%). Thirty-one patients had systemic arterial hypertension (48.8%), 5 patients had diabetes mellitus (11.6%), 14 patients were current smokers (32.5%), and FIGURE 2. Plot showing relation between FFR and the MLD assessed by IVUS. Inner lines 25 patients had hypercholesterolaround the fitted line, the 95% confidence limits for the fitted line; outer lines, the 95% confidence limits for a single observation. A MLD <1.8 mm had 100% sensitivity and 56% emia (ⱖ200 mg/dl) (58%). Ten of specificity in identifying abnormal (<0.75) and, normal (>0.75) FFR, respectively. 43 patients had previous myocardial infarctions (18.6%), and 4 patients had previous bypass surgery ters), (2) MLA (square millimeters), (3) percent area (9.3%). The left ventricular ejection fraction was 60 ⫾ stenosis (100 ⫻ [lesion external elastic membrane 8% (range 40% to 80%). Twenty-eight patients had area ⫺ lesion lumen area]/lesion external elastic mem- atypical chest pain, whereas 14 patients had stable brane area), (4) P&M cross-sectional area (square angina. Noninvasive stress tests had been performed millimeters). Lesion length was measured from num- in only 26 patients (60.5%). Stress testing was positive ber of seconds on videotape. At a pull-back speed of in 20 patients, and negative or inconclusive in 6. 0.5 mm/s, 2 seconds of videotape playback equaled 1 Nineteen patients had single-vessel, 15 patients had mm of axial lesion length.12 Vessel remodeling was 2-vessel, and 9 patients had 3-vessel disease. 138 THE AMERICAN JOURNAL OF CARDIOLOGY姞
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JANUARY 15, 2001
FFR was 0.82 ⫾ 0.16 (range 0.30 to 1.0). Twelve lesions were functionally critical (e.g., FFR ⬍0.75). The variability for FFR was 1%. Relation between FFR and morphologic indexes of coronary lesions: The correlation coefficients
between FFR and IVUS indexes of coronary lesions are listed in Table 2. By ROC analysis, we identified the best IVUS cut-off values that fit with a FFR of ⬍0.75. A percent area stenosis ⬎70% by IVUS had 100% sensitivity and 68% specificity (positive predictive value 69%; negative predictive value 100%; accuracy 87%; Figure 1). A MLD ⱕ1.8 mm had 100% sensitivity and 66% specificity (positive predictive value 46%, negative predictive value 100%, accuracy 79%, Figure 2). A MLA ⱕ4 mm2 FIGURE 3. Plot showing relation between FFR and the MLA assessed by IVUS. Inner lines had 92% sensitivity and 56% specaround the fitted line, the 95% confidence limits for the fitted line; outer lines, the 95% ificity (positive predictive value confidence limits for a single observation. A MLA <4.0 mm had 92% sensitivity and 46%, negative predictive value 54% specificity in identifying abnormal (<0.75) and normal (>0.75) FFR, respectively. 96%, accuracy 79%, Figure 3). Lesion length ⬎10 mm had 41% sensitivity and 80% specificity (positive predictive value 42%, negative predictive value 83%, accuracy 55%, Figure 4). By multiple linear regression analysis, percent area stenosis, MLD, and lesion length were predictors of FFR (multiple r ⫽ 0.74; p ⬍0.001; F ⫽ 15.140; odds ratio per unit of measurement: 0.072, 5.6, and 0.060, respectively). According to the results of the regression and ROC analyses, we developed an algorithm for the assessment of lesion severity by IVUS (Figure 5). All lesions with IVUS percent area stenosis ⱕ70% had FFR ⬎0.75. However, only 12 of the 25 lesions (48%) with percent area stenosis ⬎70% had a critical FFR; this explains the relatively low specificity of the index (Figure 5). In lesions with percent area stenosis ⬎70%, the combined FIGURE 4. Plot showing relation between FFR and the lesion length assessed by IVUS. evaluation of the MLD did not Inner lines around the fitted line, the 95% confidence limits for the fitted line; outer lines, modify the sensitivity of the test, the 95% confidence limits for a single observation. A length >10 mm had 42% sensitivbut increased the specificity (from ity and 83% specificity in identifying abnormal (<0.75) and normal (>0.75) FFR, respec68% to 76%). Three lesions with tively. percent area stenosis ⬎70% and a MLD ⬎1.8 mm had a FFR ⬎0.75 Morphologic and functional assessment of the coro- (Figure 5). However, considering FFR values between nary lesions: Angiographic and IVUS indexes of the 0.75 and 0.80 (i.e., the “clinical relevant range”), the 53 lesions are listed in Table 1. Angiographic percent specificity of the IVUS indexes increased to 85%. diameter stenosis was 52 ⫾ 11% (range 40% to 70%). Four cases with “critical” IVUS parameters had an Positive remodeling occurred in 17 lesions (32%). FFR value between 0.75 and 0.80. CORONARY ARTERY DISEASE/IVUS AND FRACTIONAL FLOW RESERVE
139
FIGURE 5. Flowchart for the assessment of lesion severity by IVUS examination.
In lesions with percent area stenosis ⬎70% and MLD ⱕ1.8 mm, the evaluation of lesion length (ⱕ10 vs ⬎10 mm), makes the test very specific (100%), but relatively insensitive (42%). In fact, 5 of the 22 lesions with percent area stenosis ⬎70% and MLD ⱕ1.8 mm were long (⬎10 mm); all of them had a critical FFR. In contrast, only 10 of the remaining 17 lesions (59%) ⱕ10 mm length had a FFR ⬎0.75, whereas 7 had a critical FFR.
DISCUSSION Coronary lesions of uncertain severity occur in up to 30% of current angioplasty procedures.14 In these situations, assessment of the functional significance of the lesion is essential in clinical decision making. In the setting of the catheterization laboratory there are 2 fundamental ways of describing stenosis severity based on anatomic and physiologic approaches. From a physiologic basis, FFR has been developed as an invasively determined lesion-specific index of the functional severity of coronary stenosis.2,3 This index represents the fraction of the normal maximum myocardial flow that can be achieved despite the coronary stenosis. In contrast to other functional methods, such as Doppler velocimetry and videodensitometry, FFR is independent of changes in systemic blood pressure, heart rate, and contractility, and is unaffected by conditions known to increase baseline myocardial flow.2,3 The normal value of the index is 1.0, regardless of the patient or the specific vessel studied. A value of FFR ⬍0.75 identifies functionally important stenosis—that is, stenosis associated with inducible myocardial ischemia—with an accuracy of 95%.2,3 From an anatomic basis, IVUS, which provides 2-dimensional tomographic views of the coronary lumen and wall morphology in vivo, has several advantages compared with angiography, and is more accurate than quantitative coronary angiography when there is complex luminal geometry.15 Relation between FFR and IVUS indexes of lesion severity: In the present study we found that IVUS-
determined measures showed optimal sensitivity and good specificity, and could be clinically used as tools 140 THE AMERICAN JOURNAL OF CARDIOLOGY姞
VOL. 87
to discriminate significant from nonsignificant coronary stenoses. An area stenosis ⬎70% (sensitivity 100%, specificity 68%), a MLD ⱕ1.8 mm (sensitivity 100%, specificity 66%), and a MLA ⱕ4.0 mm2 (sensitivity 92%, specificity 56%) were the best cut-off values fitted to a FFR of ⬍0.75. In particular, the combined assessment of the percent area stenosis and MLD made the IVUS examination very sensitive (100%) and specific (76%). In fact, the percent area stenosis was highly accurate and useful in the assessment of lesion severity. All lesions with area stenosis ⱕ70% had FFR ⬎0.75. However, about 50% of lesions with area stenosis ⬎70% had FFR ⬍0.75. In these situations (lesions with area stenosis ⬎70%), a MLD ⬎1.8 mm was always associated with a FFR of ⬎0.75. There was no correlation between FFR and plaque cross-sectional area and remodeling pattern. These findings suggest that maximum anatomic lumen compromise determines FFR, not the atherosclerotic plaque burden. FFR and lesion length: Lesion length is an important geometric characteristic that should be taken into account when defining stenosis severity.16 By multiple linear regression analysis, lesion length (besides percent area stenosis and MLD) was one of the predictors of FFR. We found a weak inverse relation between FFR and lesion length. The best cut-off value of lesion length that predicted an FFR ⬍0.75 was 10 mm; this cutoff had an optimal specificity but very low sensitivity. The combined evaluation of the length in lesions with area stenosis ⬎70% and a MLD ⱕ1.8 mm (where IVUS has a nonoptimal specificity), gave IVUS examination the best specificity (100%) but a low sensitivity (42%). Previous studies: Takagi et al8 first determined IVUS parameters for predicting FFR. IVUS thresholds identified in that study were area stenosis ⬎60% (sensitivity 92%, specificity 88.5%) and MLA ⬍3.0 mm2 (sensitivity 83%, specificity 92.3%). The combination of the MLA and area stenosis had 100% sensitivity and 90% specificity to predict FFR. These IVUS thresholds differ from our findings. In that JANUARY 15, 2001
study, however, only half of the lesions were intermediate stenoses. In contrast, in the present study, we included only lesions with intermediate angiographic severity. The results of Takagi et al’s study8 and our study are consistent with the concept that IVUS definitions of lesion severity are more sensitive than specific in predicting FFR. It is possible that inadequate hyperemia, besides previous myocardial infarction and left ventricular hypertrophy, may affect the validity of the FFR measurements, and may be responsible in some cases for this lower specificity. Nishioka et al9 found that MLA ⱕ4.0 mm2 differentiated critical from noncritical lesions, using the single-emission photon computed-tomographic result as the “gold standard” (sensitivity 88%, specificity 90%). Furthermore, an area stenosis ⱖ73% had 84% sensitivity and 81% sensitivity. Despite a difference in the methods utilized as gold standard, these cut-off values were similar to ours. Furthermore, according to our findings, taking into account coronary remodeling did not significantly improve the sensitivity and specificity of the lesion percent area stenosis. Intracoronary Doppler flow measurements have been used as an alternative tool to assess the functional significance of stenosis severity, although this method is affected by several factors, which include epicardial coronary stenosis and microvascular abnormalities, as well as loading conditions such as systemic blood pressure and heart rate.4 A recent study by Abizaid et al7 found a high diagnostic accuracy of an IVUS lumen area ⱕ4.0 mm2 and MLD ⱕ2.0 mm at the lesion site in predicting an abnormal coronary flow reserve ⱕ2.0. These IVUS cut-off values are similar to ours. 1. Abizaid A, Mintz GS, Pichard AD, Kent KM, Satler LF, Walsh CL, Popma JJ,
Leon MB. Clinical, intravascular ultrasound, and quantitative angiographic determinants of the coronary flow reserve before and after percutaneous transluminal coronary angioplasty. Am J Cardiol 1998;82:423– 428. 2. Pijls NHJ, Van Gelder B, Van der Voort P, Peels K, Bracke FALE, Bonnier HJRM, El Gamal MIH. Fractional flow reserve: a useful index to evaluate the influence of an epicardial coronary stenosis on myocardial blood flow. Circulation 1995; 92:3183–3193.
3. Pijls NHJ, De Bruyne B, Peels K, Van der Voort PH, Bonnier HJRM, Bartunek J, Koolen JJ. Measurement of fractional flow reserve to assess the functional severity of coronary-artery stenoses. N Engl J Med 1996;334:1703–1708. 4. Baumgart D, Haude M, Goerge G, Ge J, Vetter S, Dagres N, Heusch G, Erbel R. Improved assessment of coronary stenosis severity using the relative flow velocity reserve. Circulation 1998;98:40 – 46. 5. Bech GJW, De Bruyne B, Bonnier HJR, Bartunek J, Wijns W, Peels K, Heyndrickx GR, Koolen JJ, Pijls NHJ. Long-term follow-up after deferral of percutaneous transluminal coronary angioplasty of intermediate stenosis on the basis of coronary pressure measurement. J Am Coll Cardiol 1998;31:841– 847. 6. Bech GJW, Pijls NHJ, De Bruyne B, de Muninck ED, Hoorntje JCR, Escaned J, Stella PR. Deferral versus performance of PTCA based on coronary pressure derived fractional flow-reserve: the DEFER study (abstr). Eur Heart J 1999;20: 371:1957. 7. Abizaid AS, Mintz GS, Mehran R, Abizaid A, Lansky AJ, Pichard AD, Satler LF, Wu H, Pappas C, Kent KM, Leon MB. Long-term follow-up after percutaneous transluminal coronary angioplasty was not performed based on intravascular ultrasound findings. Importance of lumen dimensions. Circulation 1999; 100:256 –261. 8. Takagi A, Tsurumi Y, Ishii Y, Kazuhito S, Kawara M, Kasanuki H. Clinical potential of intravascular ultrasound for physiological assessment of coronary stenosis. Relationship between quantitative ultrasound tomography and pressurederived fractional flow reserve. Circulation 1999;100:250 –255. 9. Nishioka T, Amanullah AM, Luo H, Berglund H, Kim CJ, Nagai T, Hakamata N, Katsushika S, Uehata A, Takase B, Isojima K, Berman DS, Siegel RJ. Clinical validation of intravascular ultrasound imaging for assessment of coronary stenosis severity. J Am Coll Cardiol 1999;33:1870 –1878. 10. Ryan TJ, Faxon DP, Gunnar RM, Kennedy JM, King SB III, Loop FD, Pererson KL, Reeves TJ, Williams DO, Winters WL Jr, et al. Guidelines for percutaneous transluminal coronary angioplasty: a report of the American College of Cardiology/American Heart Association Task Force on assessment of diagnostic and therapeutic cardiovascular procedures. Circulation 1988;78:486 – 502. 11. Colombo A, Hall P, Nakamura S, Almagor Y, Maiello L, Martini G, Gaglione A, Goldberg SL, Tobis JM. Intracoronary stenting without anticoagulation accomplished with intravascular ultrasound guidance. Circulation 1995;91:1676 – 1688. 12. Fuessl RT, Mintz GS, Pichard AD, Kent KM, Satler LS, Popma JJ, Leon MB. In vivo validation of intravascular ultrasound length measurements using a monitorized transducer pullback system. Am J Cardiol 1996;77:1115–18. 13. Dangas G, Mintz GS, Mehran R, Lansky AJ, Kornowski R, Pichard AD, Satler LF, Kent KM, Stone GW, Leon MB. Preinterventional arterial remodeling as an independent predictor of target-lesion revascularization after nonstent coronary intervention. An analysis of 777 lesions with intravascular ultrasound imaging. Circulation 1999;99:3149 –3154. 14. Kern MJ, De Bruyne B, Pijls NHJ. From research to clinical practice: current role of intracoronary physiologically based decision making in the cardiac catheterization laboratory. J Am Coll Cardiol 1997;30:613– 620. 15. Bartunek J, Sys SU, Heyndrickx FR, Pijls NHJ, De Bruyne B. Quantitative coronary angiography in predicting functional significance of stenoses in an unselected patient cohort. J Am Coll Cardiol 1995;26:328 –334. 16. Goldstein RA, Kirkeeide RL, Demer LL, Merhige M, Nishikawa A, Smalling RW, Mullani NA, Gould KL. Relation between geometric dimensions of coronary artery stenoses and myocardial perfusion reserve in man. J Clin Invest 1987;79:1473–1478.
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141
MD,
The functional significance of coronary artery stenoses of intermediate severity is important in determining strategy in patient care. Intravascular ultrasound (IVUS) is often used to evaluate coronary stenosis severity. However, at present, few data are available about the role IVUS in the assessment of functional significance of intermediate lesions. Myocardial fractional flow reserve (FFR) <0.75 is a reliable index of a functionally severe coronary stenosis. In 53 lesions we assessed (1) by pressure wire: FFR (index of functional significance), and (2) by IVUS: minimal lumen cross-sectional area (MLA, square millimeters), minimal lumen diameter (MLD, millimeters), lesion length (millimeters), and percent area stenosis at the lesion site. By regression analysis, percent area stenosis and lesion length had a significant inverse correlation with FFR (r ⴝ ⴚ0.58, p <0.001, r ⴝ ⴚ0.41, p <0.004, respectively). MLD and MLA showed a sig-
nificant positive relation with FFR (r ⴝ 0.51, p <0.001, r ⴝ 0.41, p <0.004, respectively). By using a receiver operating characteristic (ROC) curve, we identified a percent area stenosis >70% (sensitivity 100%, specificity 68%), a MLD <1.8 mm (sensitivity 100%, specificity 66%), a MLA <4.0 mm2 (sensitivity 92%, specificity 56%), and a lesion length of >10 mm (sensitivity 41%, specificity 80%) to be the best cut-off values to fit with a FFR <0.75. The combined evaluation of both percent area stenosis and MLD made the IVUS examination more specific (sensitivity 100%, specificity 76%). In 53 intermediate coronary lesions found by angiography, IVUS area stenosis >70%, MLD <1.8 mm, MLA <4.0 mm2, and lesion length >10 mm reliably identified functionally critical intermediate coronary stenoses. 䊚2001 by Excerpta Medica, Inc. (Am J Cardiol 2001;87:136 –141)
linical decision making in patients with intermediate coronary stenoses is still challenging. IntraC vascular ultrasound (IVUS) examination and/or func-
are available on the “functional” significance of the IVUS indexes (i.e., MLD, MLA, percent area stenosis, and lesion length) of coronary lesion severity.8,9 To better clarify the relation between FFR and IVUS indexes of lesion severity, these parameters were measured in angiographically intermediate coronary lesions.
1
tional assessment of coronary stenosis (by pressure or Doppler measurements) have been used to define the severity of such lesions.1– 4 Recent data support the concept that deferring lesions of intermediate severity and a fractional flow reserve (FFR) ⱖ0.75 has good clinical follow-up.5,6 Furthermore, Abizaid et al7 found a low event rate (2% chance of death or myocardial infarction) at an average follow-up of 13 months after IVUS-guided deferred interventions (minimal lumen cross-sectional area [MLA] ⱖ4.0 mm2 and/or minimal lumen diameter [MLD] ⱖ2.0 mm) in patients with de novo intermediate native artery lesions. Therefore, these 2 methods (IVUS and FFR) seem to be complementary in the evaluation of lesions of intermediate severity. At present, little data From the EMO Centro Cuore Columbus, and San Raffaele Hospital, Milan, Italy. Dr. Briguori was supported in part by a Fellowship Grant from the Italian Society of Cardiology, Rome, Italy. Manuscript received June 13, 2000; revised manuscript received and accepted July 27, 2000. Address for reprints: Antonio Colombo, MD, EMO Centro Cuore Columbus, Via M. Buonarroti, 48, I-20145, Milan, Italy. E-mail: [email protected].
136
©2001 by Excerpta Medica, Inc. All rights reserved. The American Journal of Cardiology Vol. 87 January 15, 2001
METHODS
Study population: The study consisted on 43 consecutive patients scheduled for routine coronary angiography who had de novo coronary lesions of intermediate severity (e.g., 40% to 70% diameter stenosis). All patients signed informed consent before entry into the study. Angiographic analysis: Patients received intracoronary isosorbide dinitrate (0.1 to 0.3 mg) before initial and final angiograms to achieve maximal vasodilation. Angiographic measurements were performed with an automated computer-based system by experienced angiographers not involved in the procedure. Image calibration was performed with a contrast-filled catheter. The external diameter of the catheter was used as the calibration standard. Coronary end-diastolic frames from matched views obtained on angiograms were analyzed with an automated contour detection system 0002-9149/01/$–see front matter PII S0002-9149(00)01304-7
TABLE 1 Angiographic and Intravascular Ultrasound Characteristics of 53 Lesions Coronary artery Left anterior descending Left circumflex Right Diagonal Obtuse marginal Lesion site Ostial Proximal Midvessel Distal Lesion types* A B1 B2 C Quantitative angiography Vessel size (mm) MLD (mm) Lesion length (mm) Percent stenosis (%) IVUS measurements Reference site Vessel cross-sectional area (mm2) Lumen cross-sectional area (mm2) Plaque-media cross-sectional area (mm2) Lesion site Vessel cross-sectional area (mm2) MLA (mm2) MLD (mm) Length (mm) Plaque-media cross-sectional area (mm2) Area stenosis (%) Remodeling
32 5 14 1 1
(60.4%) (9.4%) (26.4%) (1.9%) (1.9%)
4 16 28 5
(7.5%) (30.3%) (52.8%) (9.4%)
1 24 24 4
(1.9%) (45.3%) (45.3%) (7.5%)
3.08 1.69 8.5 52
⫾ ⫾ ⫾ ⫾
0.73 0.77 6.4 11
13.0 ⫾ 6.1 7.8 ⫾ 4.4 7.2 ⫾ 3.5 12.0 3.9 1.9 9.0 8.3
⫾ ⫾ ⫾ ⫾ ⫾
4.6 2.5 1.0 7.0 4.1
65 ⫾ 18 1.07 ⫾ 0.65
*Modified American Heart Association/American College of Cardiology criteria.
applying a minimum cost algorithm to the brightness profile of all scan lines perpendicular to the vessel center line (QCA-CMS version 3.0, MEDIS, Leiden, The Netherlands). Interpolated reference lumen diameter, lesion MLD, and lesion length were measured. Percent diameter stenosis was calculated as the reference lumen diameter minus the MLD divided by the reference lumen diameter. Lesions were characterized according to the modified American College of Cardiology/American Heart Association classification.10 Pressure measurements and calculation of FFR: An 8Fr sheath was inserted in the femoral artery, and an 8Fr guiding catheter was used to cannulate the coronary ostium. If damping of pressure by the guiding catheter occurred, the guiding catheter was pulled back during the measurements. To measure distal coronary pressure, a 0.014-in high-fidelity pressure monitoring wire (Wave Wire, Cardiometrics, Inc. Mountain View, California) was used. The sensor (a piezo resistive pressure sensor) was located just proximal to the junction between the radiopaque distal tip and the nonradiopaque part of the wire. The proximal end of the wire was disconnectable and was plugged into a special connector, which also helped rotate the wire. The signal was transmitted to a small interface, which in turn was connected to an ordinary pressure moni-
TABLE 2 Correlation Coefficients Between FFR and Quantitative Coronary Angiography and Intravascular Ultrasound (IVUS) Parameters of the Coronary Stenosis Severity Parameter Quantitative coronary angiography indexes Percent diameter stenosis MLD Lesion length Intravascular ultrasound indexes MLD MLA Percent area stenosis Lesion length Plaque-media cross-sectional area Remodeling
Correlation Coefficient
p Value
⫺0.56 0.55 ⫺0.47
⬍0.001 ⬍0.001 0.006
0.51 0.41 ⫺0.58 ⫺0.41 ⫺0.13 ⫺0.16
⬍0.001 ⬍0.004 ⬍0.001 ⬍0.004 0.40 0.40
toring system in the cardiac catheterization laboratory. The pressure monitoring guidewire was first zeroed and advanced up to the tip of the guiding catheter, where mean and phasic pressures were recorded simultaneously to verify equality of pressure (i.e., normalization). Thereafter, the pressure monitoring guidewire was advanced through the stenotic segment. Mean aortic pressure (Pa, measured by the guiding catheter) and mean distal coronary pressure (Pd, measured by the microsensor tip manometer wire) were recorded at rest and during maximal hyperemia induced by adenosine (18 g in the left and 12 g in the right coronary arteries). Pressure tracing were visualized on the monitor and also recorded on paper (50 mm/s) for further analysis. FFR was calculated by the following equation: FFR ⫽ Pd/Pa where Pa and Pd were recorded simultaneously at maximum vasodilation.2,3 Intravascular ultrasound examination: IVUS examination was performed with 3.2Fr monorail system with a 30-MHz transducer-tipped catheter (Ultracross, Cardiovascular Imaging System, CVIS, Boston Scientific CO., Boston, Massachusetts). IVUS imaging was performed during the motorized pullback (0.5 mm/s) of the imaging catheter. The IVUS images were recorded on a 0.5-in SuperVHS videotape for subsequent review and quantitative analysis. The lesion site selected for analysis was the image slice with the smallest lumen cross-sectional area. The external elastic membrane cross-sectional area was defined as the area encompassed by the ultrasonic media and/or adventitia border, by tracing the leading edge of the adventitia. Lumen measurements were made at the inner border of the echo-dense plaque.11 Because media thickness cannot be measured accurately, plaquemedia (P&M) cross-sectional area (external elastic membrane cross-sectional area minus lumen crosssectional areas) was used as a measure of atherosclerotic plaque. The proximal and distal reference segments had the most normal-appearing cross sections within 10 mm proximal or distal to the lesion but before any side branch. The following parameters were measured at the lesion site: (1) MLD (millime-
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FIGURE 1. Plot showing relation between FFR and the percent area stenosis assessed by IVUS. Inner lines around the fitted line, the 95% confidence limits for the fitted line; outer lines, the 95% confidence limits for a single observation. A percent area stenosis >70% had 100% sensitivity and 68% specificity in identifying abnormal (<0.75) and normal (>0.75) FFR, respectively.
determined by dividing the targetlesion external elastic membrane cross-sectional area by the average of the proximal and distal reference-segment external elastic membrane cross-sectional area to create a remodeling index. Positive remodeling was defined as a remodeling index ⬎1.0, and intermediate and/or negative remodeling as a remodeling index ⱕ1.0.13 All measurements were performed by a single individual blinded to the FFR results. Statistical analysis: Differences between groups were assessed by chi-square analysis for categorical variables and paired and unpaired Student’s t test for continuous variables. The FFR was calculated 3 times and coefficient of variability was calculated as the percentage of the ratio of the SD to mean. Univariate linear regression analysis was used to define correlation coefficients between FFR and IVUS indexes of lesion severity. Receiver operating characteristic (ROC) curve analysis was performed to establish the value of IVUS indexes (i.e., MLD, MLA, lesion length, and area percent stenosis) that were most predictive of FFR ⬍0.75. Stepwise multiple linear regression analysis was performed to identify the best IVUS parameter predictive of FFR value. Values of p ⬍0.05 were considered significant. Data were analyzed with SPSS 10 for Windows (SPSS Institute, Chicago, Illinois).
RESULTS Thirty-seven of the 43 patients were men (86.1%). Thirty-one patients had systemic arterial hypertension (48.8%), 5 patients had diabetes mellitus (11.6%), 14 patients were current smokers (32.5%), and FIGURE 2. Plot showing relation between FFR and the MLD assessed by IVUS. Inner lines 25 patients had hypercholesterolaround the fitted line, the 95% confidence limits for the fitted line; outer lines, the 95% confidence limits for a single observation. A MLD <1.8 mm had 100% sensitivity and 56% emia (ⱖ200 mg/dl) (58%). Ten of specificity in identifying abnormal (<0.75) and, normal (>0.75) FFR, respectively. 43 patients had previous myocardial infarctions (18.6%), and 4 patients had previous bypass surgery ters), (2) MLA (square millimeters), (3) percent area (9.3%). The left ventricular ejection fraction was 60 ⫾ stenosis (100 ⫻ [lesion external elastic membrane 8% (range 40% to 80%). Twenty-eight patients had area ⫺ lesion lumen area]/lesion external elastic mem- atypical chest pain, whereas 14 patients had stable brane area), (4) P&M cross-sectional area (square angina. Noninvasive stress tests had been performed millimeters). Lesion length was measured from num- in only 26 patients (60.5%). Stress testing was positive ber of seconds on videotape. At a pull-back speed of in 20 patients, and negative or inconclusive in 6. 0.5 mm/s, 2 seconds of videotape playback equaled 1 Nineteen patients had single-vessel, 15 patients had mm of axial lesion length.12 Vessel remodeling was 2-vessel, and 9 patients had 3-vessel disease. 138 THE AMERICAN JOURNAL OF CARDIOLOGY姞
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FFR was 0.82 ⫾ 0.16 (range 0.30 to 1.0). Twelve lesions were functionally critical (e.g., FFR ⬍0.75). The variability for FFR was 1%. Relation between FFR and morphologic indexes of coronary lesions: The correlation coefficients
between FFR and IVUS indexes of coronary lesions are listed in Table 2. By ROC analysis, we identified the best IVUS cut-off values that fit with a FFR of ⬍0.75. A percent area stenosis ⬎70% by IVUS had 100% sensitivity and 68% specificity (positive predictive value 69%; negative predictive value 100%; accuracy 87%; Figure 1). A MLD ⱕ1.8 mm had 100% sensitivity and 66% specificity (positive predictive value 46%, negative predictive value 100%, accuracy 79%, Figure 2). A MLA ⱕ4 mm2 FIGURE 3. Plot showing relation between FFR and the MLA assessed by IVUS. Inner lines had 92% sensitivity and 56% specaround the fitted line, the 95% confidence limits for the fitted line; outer lines, the 95% ificity (positive predictive value confidence limits for a single observation. A MLA <4.0 mm had 92% sensitivity and 46%, negative predictive value 54% specificity in identifying abnormal (<0.75) and normal (>0.75) FFR, respectively. 96%, accuracy 79%, Figure 3). Lesion length ⬎10 mm had 41% sensitivity and 80% specificity (positive predictive value 42%, negative predictive value 83%, accuracy 55%, Figure 4). By multiple linear regression analysis, percent area stenosis, MLD, and lesion length were predictors of FFR (multiple r ⫽ 0.74; p ⬍0.001; F ⫽ 15.140; odds ratio per unit of measurement: 0.072, 5.6, and 0.060, respectively). According to the results of the regression and ROC analyses, we developed an algorithm for the assessment of lesion severity by IVUS (Figure 5). All lesions with IVUS percent area stenosis ⱕ70% had FFR ⬎0.75. However, only 12 of the 25 lesions (48%) with percent area stenosis ⬎70% had a critical FFR; this explains the relatively low specificity of the index (Figure 5). In lesions with percent area stenosis ⬎70%, the combined FIGURE 4. Plot showing relation between FFR and the lesion length assessed by IVUS. evaluation of the MLD did not Inner lines around the fitted line, the 95% confidence limits for the fitted line; outer lines, modify the sensitivity of the test, the 95% confidence limits for a single observation. A length >10 mm had 42% sensitivbut increased the specificity (from ity and 83% specificity in identifying abnormal (<0.75) and normal (>0.75) FFR, respec68% to 76%). Three lesions with tively. percent area stenosis ⬎70% and a MLD ⬎1.8 mm had a FFR ⬎0.75 Morphologic and functional assessment of the coro- (Figure 5). However, considering FFR values between nary lesions: Angiographic and IVUS indexes of the 0.75 and 0.80 (i.e., the “clinical relevant range”), the 53 lesions are listed in Table 1. Angiographic percent specificity of the IVUS indexes increased to 85%. diameter stenosis was 52 ⫾ 11% (range 40% to 70%). Four cases with “critical” IVUS parameters had an Positive remodeling occurred in 17 lesions (32%). FFR value between 0.75 and 0.80. CORONARY ARTERY DISEASE/IVUS AND FRACTIONAL FLOW RESERVE
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FIGURE 5. Flowchart for the assessment of lesion severity by IVUS examination.
In lesions with percent area stenosis ⬎70% and MLD ⱕ1.8 mm, the evaluation of lesion length (ⱕ10 vs ⬎10 mm), makes the test very specific (100%), but relatively insensitive (42%). In fact, 5 of the 22 lesions with percent area stenosis ⬎70% and MLD ⱕ1.8 mm were long (⬎10 mm); all of them had a critical FFR. In contrast, only 10 of the remaining 17 lesions (59%) ⱕ10 mm length had a FFR ⬎0.75, whereas 7 had a critical FFR.
DISCUSSION Coronary lesions of uncertain severity occur in up to 30% of current angioplasty procedures.14 In these situations, assessment of the functional significance of the lesion is essential in clinical decision making. In the setting of the catheterization laboratory there are 2 fundamental ways of describing stenosis severity based on anatomic and physiologic approaches. From a physiologic basis, FFR has been developed as an invasively determined lesion-specific index of the functional severity of coronary stenosis.2,3 This index represents the fraction of the normal maximum myocardial flow that can be achieved despite the coronary stenosis. In contrast to other functional methods, such as Doppler velocimetry and videodensitometry, FFR is independent of changes in systemic blood pressure, heart rate, and contractility, and is unaffected by conditions known to increase baseline myocardial flow.2,3 The normal value of the index is 1.0, regardless of the patient or the specific vessel studied. A value of FFR ⬍0.75 identifies functionally important stenosis—that is, stenosis associated with inducible myocardial ischemia—with an accuracy of 95%.2,3 From an anatomic basis, IVUS, which provides 2-dimensional tomographic views of the coronary lumen and wall morphology in vivo, has several advantages compared with angiography, and is more accurate than quantitative coronary angiography when there is complex luminal geometry.15 Relation between FFR and IVUS indexes of lesion severity: In the present study we found that IVUS-
determined measures showed optimal sensitivity and good specificity, and could be clinically used as tools 140 THE AMERICAN JOURNAL OF CARDIOLOGY姞
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to discriminate significant from nonsignificant coronary stenoses. An area stenosis ⬎70% (sensitivity 100%, specificity 68%), a MLD ⱕ1.8 mm (sensitivity 100%, specificity 66%), and a MLA ⱕ4.0 mm2 (sensitivity 92%, specificity 56%) were the best cut-off values fitted to a FFR of ⬍0.75. In particular, the combined assessment of the percent area stenosis and MLD made the IVUS examination very sensitive (100%) and specific (76%). In fact, the percent area stenosis was highly accurate and useful in the assessment of lesion severity. All lesions with area stenosis ⱕ70% had FFR ⬎0.75. However, about 50% of lesions with area stenosis ⬎70% had FFR ⬍0.75. In these situations (lesions with area stenosis ⬎70%), a MLD ⬎1.8 mm was always associated with a FFR of ⬎0.75. There was no correlation between FFR and plaque cross-sectional area and remodeling pattern. These findings suggest that maximum anatomic lumen compromise determines FFR, not the atherosclerotic plaque burden. FFR and lesion length: Lesion length is an important geometric characteristic that should be taken into account when defining stenosis severity.16 By multiple linear regression analysis, lesion length (besides percent area stenosis and MLD) was one of the predictors of FFR. We found a weak inverse relation between FFR and lesion length. The best cut-off value of lesion length that predicted an FFR ⬍0.75 was 10 mm; this cutoff had an optimal specificity but very low sensitivity. The combined evaluation of the length in lesions with area stenosis ⬎70% and a MLD ⱕ1.8 mm (where IVUS has a nonoptimal specificity), gave IVUS examination the best specificity (100%) but a low sensitivity (42%). Previous studies: Takagi et al8 first determined IVUS parameters for predicting FFR. IVUS thresholds identified in that study were area stenosis ⬎60% (sensitivity 92%, specificity 88.5%) and MLA ⬍3.0 mm2 (sensitivity 83%, specificity 92.3%). The combination of the MLA and area stenosis had 100% sensitivity and 90% specificity to predict FFR. These IVUS thresholds differ from our findings. In that JANUARY 15, 2001
study, however, only half of the lesions were intermediate stenoses. In contrast, in the present study, we included only lesions with intermediate angiographic severity. The results of Takagi et al’s study8 and our study are consistent with the concept that IVUS definitions of lesion severity are more sensitive than specific in predicting FFR. It is possible that inadequate hyperemia, besides previous myocardial infarction and left ventricular hypertrophy, may affect the validity of the FFR measurements, and may be responsible in some cases for this lower specificity. Nishioka et al9 found that MLA ⱕ4.0 mm2 differentiated critical from noncritical lesions, using the single-emission photon computed-tomographic result as the “gold standard” (sensitivity 88%, specificity 90%). Furthermore, an area stenosis ⱖ73% had 84% sensitivity and 81% sensitivity. Despite a difference in the methods utilized as gold standard, these cut-off values were similar to ours. Furthermore, according to our findings, taking into account coronary remodeling did not significantly improve the sensitivity and specificity of the lesion percent area stenosis. Intracoronary Doppler flow measurements have been used as an alternative tool to assess the functional significance of stenosis severity, although this method is affected by several factors, which include epicardial coronary stenosis and microvascular abnormalities, as well as loading conditions such as systemic blood pressure and heart rate.4 A recent study by Abizaid et al7 found a high diagnostic accuracy of an IVUS lumen area ⱕ4.0 mm2 and MLD ⱕ2.0 mm at the lesion site in predicting an abnormal coronary flow reserve ⱕ2.0. These IVUS cut-off values are similar to ours. 1. Abizaid A, Mintz GS, Pichard AD, Kent KM, Satler LF, Walsh CL, Popma JJ,
Leon MB. Clinical, intravascular ultrasound, and quantitative angiographic determinants of the coronary flow reserve before and after percutaneous transluminal coronary angioplasty. Am J Cardiol 1998;82:423– 428. 2. Pijls NHJ, Van Gelder B, Van der Voort P, Peels K, Bracke FALE, Bonnier HJRM, El Gamal MIH. Fractional flow reserve: a useful index to evaluate the influence of an epicardial coronary stenosis on myocardial blood flow. Circulation 1995; 92:3183–3193.
3. Pijls NHJ, De Bruyne B, Peels K, Van der Voort PH, Bonnier HJRM, Bartunek J, Koolen JJ. Measurement of fractional flow reserve to assess the functional severity of coronary-artery stenoses. N Engl J Med 1996;334:1703–1708. 4. Baumgart D, Haude M, Goerge G, Ge J, Vetter S, Dagres N, Heusch G, Erbel R. Improved assessment of coronary stenosis severity using the relative flow velocity reserve. Circulation 1998;98:40 – 46. 5. Bech GJW, De Bruyne B, Bonnier HJR, Bartunek J, Wijns W, Peels K, Heyndrickx GR, Koolen JJ, Pijls NHJ. Long-term follow-up after deferral of percutaneous transluminal coronary angioplasty of intermediate stenosis on the basis of coronary pressure measurement. J Am Coll Cardiol 1998;31:841– 847. 6. Bech GJW, Pijls NHJ, De Bruyne B, de Muninck ED, Hoorntje JCR, Escaned J, Stella PR. Deferral versus performance of PTCA based on coronary pressure derived fractional flow-reserve: the DEFER study (abstr). Eur Heart J 1999;20: 371:1957. 7. Abizaid AS, Mintz GS, Mehran R, Abizaid A, Lansky AJ, Pichard AD, Satler LF, Wu H, Pappas C, Kent KM, Leon MB. Long-term follow-up after percutaneous transluminal coronary angioplasty was not performed based on intravascular ultrasound findings. Importance of lumen dimensions. Circulation 1999; 100:256 –261. 8. Takagi A, Tsurumi Y, Ishii Y, Kazuhito S, Kawara M, Kasanuki H. Clinical potential of intravascular ultrasound for physiological assessment of coronary stenosis. Relationship between quantitative ultrasound tomography and pressurederived fractional flow reserve. Circulation 1999;100:250 –255. 9. Nishioka T, Amanullah AM, Luo H, Berglund H, Kim CJ, Nagai T, Hakamata N, Katsushika S, Uehata A, Takase B, Isojima K, Berman DS, Siegel RJ. Clinical validation of intravascular ultrasound imaging for assessment of coronary stenosis severity. J Am Coll Cardiol 1999;33:1870 –1878. 10. Ryan TJ, Faxon DP, Gunnar RM, Kennedy JM, King SB III, Loop FD, Pererson KL, Reeves TJ, Williams DO, Winters WL Jr, et al. Guidelines for percutaneous transluminal coronary angioplasty: a report of the American College of Cardiology/American Heart Association Task Force on assessment of diagnostic and therapeutic cardiovascular procedures. Circulation 1988;78:486 – 502. 11. Colombo A, Hall P, Nakamura S, Almagor Y, Maiello L, Martini G, Gaglione A, Goldberg SL, Tobis JM. Intracoronary stenting without anticoagulation accomplished with intravascular ultrasound guidance. Circulation 1995;91:1676 – 1688. 12. Fuessl RT, Mintz GS, Pichard AD, Kent KM, Satler LS, Popma JJ, Leon MB. In vivo validation of intravascular ultrasound length measurements using a monitorized transducer pullback system. Am J Cardiol 1996;77:1115–18. 13. Dangas G, Mintz GS, Mehran R, Lansky AJ, Kornowski R, Pichard AD, Satler LF, Kent KM, Stone GW, Leon MB. Preinterventional arterial remodeling as an independent predictor of target-lesion revascularization after nonstent coronary intervention. An analysis of 777 lesions with intravascular ultrasound imaging. Circulation 1999;99:3149 –3154. 14. Kern MJ, De Bruyne B, Pijls NHJ. From research to clinical practice: current role of intracoronary physiologically based decision making in the cardiac catheterization laboratory. J Am Coll Cardiol 1997;30:613– 620. 15. Bartunek J, Sys SU, Heyndrickx FR, Pijls NHJ, De Bruyne B. Quantitative coronary angiography in predicting functional significance of stenoses in an unselected patient cohort. J Am Coll Cardiol 1995;26:328 –334. 16. Goldstein RA, Kirkeeide RL, Demer LL, Merhige M, Nishikawa A, Smalling RW, Mullani NA, Gould KL. Relation between geometric dimensions of coronary artery stenoses and myocardial perfusion reserve in man. J Clin Invest 1987;79:1473–1478.
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